Contributions to Science by Institut d'Estudis Catalans

ISSN 1575-6343 | E-ISSN 2013-410X | OPEN ACCESS JOURNAL | www.cat-science.cat

VOLUME 9 | ISSUE 1 | JUNE 2013

OPEN ACCESS JOURNAL www.cat-science.cat | http://revistes.iec.cat/contributions

Publication Board

GENERAL INFORMATION

Editor-in-Chief Ricard Guerrero, Biological Sciences Section, IEC

Contributions

Associate Editors Salvador Alegret, Science and Technology Section, IEC Ramon Gomis, Biological Sciences Section, IEC Editorial Office Managing Coordinator Carme Puche

cpuche@contributions.cat

Editors Mercè Piqueras, SCHCT-IEC mpiqueras@microbios.org

Mercedes Berlanga, University of Barcelona mberlanga@ub.edu

Carmen Chica, Barcelona cchica@microbios.org

Nicole Skinner, Imperial College, London, UK nico_skinner@hotmail.com

Wendy Ran, Wiesenttal, Germany ran.wendy@googlemail.com

Mary Anne Newman, New York, USA newm161@icloud.com

Javier del Campo, Univ of British Columbia Vancouver, Canada javier.delcampo@botany.ubc.ca

Digital Media Coordinator Jordi Rabascall, Estudi Puche S.L. jrabascall@contributions.cat

IT services Jordi Berenguer, Intergrid j.berenguer@intergrid.cat

Founded in 1999 by Salvador Reguant, Science and Technology Section, IEC Address

Science is the international

journal of the Biological Sciences Section and the Science and Technology Section of the Institute for Catalan Studies (IEC). It is an open access, peer-reviewed journal, published twice a year by the IEC. It publishes reviews on topics of the highest interest in all branches of sciences. It was first published in 1999. Aims and scope to Science is an open access journal that aims to promote the international dissemination of scientific research performed in Catalonia in any of its branches, both pure and applied. Contributions to Science also publishes research performed in countries with linguistic, cultural and historic links with Catalonia. It also publishes scientific articles of international standing related to all such territories, especially considered as a whole. The journal also covers studies performed in all parts of the world by scientists from such countries and articles based on lectures imparted by invited foreign scientists. Preference will be given to original articles in the form of critical reviews that deal with the state of the art of a scientific field of current interest, by one or several authors. Such articles should summarize the development, the present situation and, where possible, future perspectives of a research area in which the author or authors have participated directly. The journal will also publish articles, short communications, notes and news items of international interest on historical, economic, social or political aspects of research in Catalonia and its areas of influence.

Contributions

Contributions to Science

Publisher Institut d’Estudis Catalans, Barcelona, Catalonia www.iec.cat ISSN (print): 1575-6343 e-ISSN (electronic): 2013-410X D.L.: B. 36385-1999

This work including photographs and other illustrations, except where otherwise is indicated, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International, the full text of which can be consulted at http://creativecommons.org/licenses/by-ncnd/4.0/. You are free to share, copy, distribute and transmit the work in any medium and format provided that the author is credited and reuse of the material is restricted to non-commercial purposes only and that no derivative works are created from the original material.

Institut d’Estudis Catalans Carme, 47 08001 Barcelona, Catalonia Tel. +34 932701620 Fax +34 932701180 Email: contributions@iec.cat

Handling of manuscripts Manuscripts should be sent to the Editorial Office through the journal’s web site. Please read the Instructions to Authors on the page P3 of each issue. Subscriptions Volume 9 (2 issues). Subscription orders should be sent to the Publishing Department. The subscription fee for two issues (including handling charges) is 75 Euros (VAT not included). Airmail charges are available on request. Publisher and Advertisements All business correspondence, reprint requests, requests for missing issues, and information on advertisements should be addressed to the Publishing Department. Disclaimer While the contents of this journal are believed to be true and accurate at the date of its publication, neither the authors and editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no guarantee, expressed or implied, with regard to the material contained therein. Institute for Catalan Studies The Institute for Catalan Studies (IEC), academy of sciences and humanities, founded in 1907, is the top academic corporation of the territories of Catalan language and culture, and has been a full member of the International Academic Union since 1922. The IEC has 186 full or emeritus members from throughout the linguistic territory, and 72 corresponding members that represent our institution’s relations with the international scientific community, and has 28 filial societies of all fields of knowledge, with a total membership of around 10,000 across the whole territory. In addition, 111 local research centres also belong to it, and this shows how well grounded the research community is, throughout our cultural territory. The IEC is the central institution in the Catalan cultural world. It was set up in 1907 at the initiative of the Diputació de Barcelona to “establish here scientific study centres specialising and working not just in education, but in producing science and aiding research.” In the following years, the Institute set up its various science departments. The Philology Department, directed by Pompeu Fabra, played a key role in establishing the rules of the Catalan language.

VOLUME 9 | ISSUE 1 | JUNE 2013

Volume 9 | Issue 1 | June 2013

OPEN ACCESS JOURNAL

www.cat-science.cat http://revistes.iec.cat/contributions/

FRONT COVER

BACK COVER

The Sant Manuel Pavilion, at the Hospital de la Santa Creu i Sant Pau, in Barcelona, which houses the United Nations University Institute on Globalization, Culture and Mobility (UNUGCM; see article by Parvati Nair in this issue, pp 101-106). The Pavilion was built in 1922 under the direction of the architect Pere Domenech i Roura, who took over the construction of the Hospital following the death of his father, the architect Lluis Doménech i Montaner. Built between 1902 and 1930, the Hospital is one of the world’s major modernists sites and was declared a World Heritage Site by Unesco in 1997. In 2009 the working hospital was relocated in a new building and the historical site, which has recovered its artistic and heritage value, with a profound chage in internal managing services. The Hospital’s different pavillions are currently devoted to other uses, mostly as headquarters of international institutions. (Photo by Robert Ramos © Fundació Privada Hospital de la Santa Creu i Sant Pau).

Portrait of Rafael Guastavino (1842–1908), architect who worked in Catalonia and in different cities of the the United States as a builder. Guastavino was born in Valencia, Spain in 1842 and studied arquitecture in Barcelona, where he graduated in 1872. In Catalonia, he designed and built factories and homes reviving an ancient technique called the Catalan vault (volta catalana), which consisted of covering a wide space by laying long flat tiles over a wood form and holding them together with mortar, which allowed to make gentler and longer curves than other techniques. He went to the United States in 1881, founded his own family business (the Guastavino Fireproof Construction Company) and patented the “tile arch system” of his vaulting system of construction. More than 600 vaults built by his company have survived, including The Boston Public Library, and, in New York, the Ellis Island Registry Hall, and the Oyster Bar in Grand Central Terminal. He died in Asheville, North Carolina in 1908. (See pp 109-112 of this issue).

Volume 9 | Issue 1 | June 2013

Editorial Board

EDITOR-IN-CHIEF Ricard Guerrero Biological Sciences Section, IEC

ASSOCIATE EDITOR Salvador Alegret

ASSOCIATE EDITOR Ramon Gomis

Science and Technology Section, IEC

Biological Sciences Section, IEC

EDITORIAL BOARD Joaquim Agulló, Technical University of Catalonia • Josep Amat, Technical University of Catalonia • Francesc Asensi, University of Valencia • Damià Barceló, Spanish National Research Council (Barcelona) • Carles Bas, Institute of Marine Sciences-CSIC (Barcelona) • Pilar Bayer, University of Barcelona • Xavier Bellés, Spanish National Research Council (Barcelona) • Jaume Bertranpetit, Pompeu Fabra University (Barcelona) • Eduard Bonet, ESADE (Barcelona) • Josep Carreras, University of Barcelona • Joaquim Casal, Technical University of Catalonia • Alícia Casals, Technical University of Catalonia • Manuel Castellet, Autonomous University of Barcelona • Josep Castells, University of Barcelona • Jacint Corbella, University of Barcelona • Jordi Corominas, Technical University of Catalonia • Michel Delseny, University of Perpinyà (France) • Josep M. Domènech, Autonomous University of Barcelona • Mercè Durfort, University of Barcelona • Marta Estrada, Institute of Marine Sciences-CSIC (Barcelona) • Gabriel Ferraté, Technical University of Catalonia • Ramon Folch, Institute for Catalan Studies • Màrius Foz, Autonomous University of Barcelona • Jesús A. Garcia-Sevilla, University of the Balearic Islands • Lluís Garcia-Sevilla, Autonomous University of Barcelona • Joan Genescà, National Autonomous University of Mexico • Evarist Giné, University of Connecticut (USA) • Joan Girbau, Autonomous University of Barcelona • Pilar GonzálezDuarte, Autonomous University of Barcelona • Francesc González-Sastre, Autonomous University of Barcelona • Joaquim Gosálbez, University of Barcelona • Albert Gras, University of Alacant • Gonzalo Halffter, National Polytechnic Institute (Mexico) • Lluís Jofre, Technical University of Catalonia • Joan Jofre, University of Barcelona • David Jou, Autonomous University of Barcelona • Ramon Lapiedra, University of Valencia • Àngel Llàcer, University Clinic Hospital of Valencia • Josep Enric Llebot, Autonomous University of Barcelona • Jordi Lleonart, Spanish National Research Council (Barcelona) • Xavier Llimona, University of Barcelona • Antoni Lloret, Institute for Catalan Studies • Abel Mariné, University of Barcelona • Joan Massagué, Memorial Sloan-Kettering Cancer Center, New York, USA • Federico Mayor-Zaragoza, Foundation for a Culture of Peace (Madrid) • Adélio Machado, University of Porto (Portugal) • Gabriel Navarro, University of Valencia • Jaume Pagès, Technical University of Catalonia • Ramon Parés, University of Barcelona • Àngel Pellicer, New York University (USA) • Juli Peretó, University of Valencia • F. Xavier Pi-Sunyer, Harvard University (USA) • Norberto Piccinini, Politecnico di Torino (Italy) • Jaume Porta, University of Lleida • Pere Puigdomènech, Spanish National Research Council (Barcelona) • Jorge-Óscar Rabassa, National University of La Plata (Argentina) • Pere Roca, University of Barcelona • Joan Rodés, University of Barcelona • Joandomènec Ros, University of Barcelona • Xavier Roselló, Technical University of Catalonia • Claude Roux, University of Aix-Marseille III (France) • Pere Santanach, University of Barcelona • Francesc Serra, Autonomous University of Barcelona • David Serrat, University of Barcelona • Boris P. Sobolev, Russian Academy of Sciences, Moscow, Russia • Carles Solà, Autonomous University of Barcelona • Joan Anton Solans, Technical University of Catalonia • Rolf Tarrach, University of Luxembourg • Jaume Terradas, Autonomous University of Barcelona • Antoni Torre, Obra Cultural, L’Alguer, Sardinia • Josep Vaquer, University of Barcelona • Josep Vigo, University of Barcelona • Miquel Vilardell, Autonomous University of Barcelona • Jordi Vives, Hospital Clinic of Barcelona

Volume 9 | Issue 1 | June 2013

Contents

FOREWORD Tort L

The Catalan Society for Biology

DISTINGUISHED LECTURES Ramon Margalef Award for Ecology 2012 Pretus JL

Daniel Simberloff: Creative and devastating

Simberloff D

Biological invasions: Much progress plus several controversies

Piniella JF

Franco R, Aymerich MS

Smart cell-surface receptors: On the 2012 Nobel Prize in Chemistry, awarded to Robert J. Lefkowitz and Brian K. Kobilka

Mompart J

The Gedankenexperimente of quantum mechanics become reality: On the 2012 Nobel Prize in Physics, awarded to Serge Haroche and David J. Wineland

Clotet J

First International Conference of Biology of Catalonia (CIBICAT) , ‘Global questions on advanced biology ’ (Barcelona, July 9–12, 2012)

Casadesús J

Bacterial pathogenesis as an imperfect symbiosis

Buceta J

Multidisciplinary approaches towards compartmentalization in development: Dorsoventral boundary formation of the Drosophila wing disc as a case study

Jiménez-Valerio G, Casanovas O

Anti-angiogenic therapy for cancer and the mechanisms of tumor resistance

Escalas Llimona R

Temperament and tuning of early 19th century Hispanic keyboard instruments: A study of the monochord integrated into a fortepiano made by Francisco Fernández (1828)

Salat J, Umbert M, Ballabrera-Poy J, Fernández P, Salvador K, Martínez J

The contribution of the Barcelona World Race to improved ocean surface information. A validation of the SMOS remote sensed salinity

Nair P

101

The United Nations University Institute on Globalization, Culture and Mobility (UNU-GCM) in Barcelona: Mission and vision

Puche C

107

The Institute for Catalan Studies and the International Women’s Day, 2006–2013

Piqueras M

109

The Nobel Prizes of 2011 Crystallography and the Nobel Prizes: On the 2011 Nobel Prize in Chemistry, awarded to Dan Shechtman

The Nobel Prizes of 2012

Celebration of the Centennial of the Catalan Society for Biology, 1912–2012

RESEARCH REVIEWS

FORUM

HISTORICAL CORNER The American dream of Rafael Guastavino (1842–1908)

CONTRIBUTIONS to SCIENCE 9 (2013) 1-3 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.156 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

Pròleg

Foreword

Durant el 2012, la Societat Catalana de Biologia, una societat científica filial de l’Institut d’Estudis Catalans, va portar a terme diverses activitats per commemorar el seu centenari. El 1912, un grup de metges catalans la majoria dels quals treballaven en fisiologia humana i un veterinari dedicat a la microbiologia i a la producció de vacunes van posar-se en contacte amb la francesa Societé de Biologie (fundada a París el 1848). Els metges catalans, liderats per August Pi i Sunyer, i el veterinari, Ramon Turró, director del Laboratori Microbiològic Municipal, van decidir crear a Barcelona una organització germana que pogués intercanviar informació amb els col·legues francesos i també amb els de la Sociedad Española de Biología, que Santiago Ramón y Cajal (Premi Nobel de Fisiologia o Medicina de 1906), Gregori Marañón i altres metges havien creat a Madrid, també el 1912. Pi i Sunyer va adonar-se que el futur de la medicina s’havia de basar principalment en la recerca del coneixement bàsic que proporciona la biologia. Aquesta afirmació és vàlida cent anys després, i no solament per al camp de la medicina: l’enginyeria ambiental, la tecnologia dels aliments, la intel·ligència artifical, l’exploració marina, les aplicacions biotecnològiques i molts altres camps de la ciència es fonamenten en la recerca de les bases biològiques dels organismes vius i de les seves interaccions. La Societat Catalana de Biologia (inicialment coneguda com a Societat de Biologia de Barcelona), va celebrar la primera sessió científica al citat Laboratori Microbiològic Municipal el 14 de desembre de 1912. A llarg del primer any, des de desembre de 1912 fins a desembre de 1913, els membres de la nova Societat van presentar a les sessions científiques 31 contribucions, que més tard serien publicades en el primer volum de la revista Treballs de la Societat de Biologia de Barcelona, que va sortir a principis del 1914. Els autors, que eren els científics que més tard serien coneguts com a fundadors de l’anomenada escola biològica catalana, eren hereus de la tradició de la biologia experimental de Claude Bernard (1813–1878). En realitat, el primer article dels seus estatuts deia que «[la] Societat de Biologia de Barcelona té per objecte l’estudi de la ciència dels éssers organitzats a l’estat normal i patològic». La Societat de Biologia de Barcelona aviat va esdevenir una plataforma per a la interacció i la publicació de l’emergent escola biològica catalana. En aquell temps ja tenia uns trets que l’han caracteritzada al llarg de la seva història i que ara, cent anys després, encara vol mantenir. Un d’aquests trets era el seu enfocament internacional; va ser l’entitat catalana corresponent de la Societat Francesa de Biologia i els seus membres feien estades a l’estranger per col·laborar amb

Throughout 2012, the Societat Catalana de Biologia (Catalan Society for Biology), a learned society affiliated to the Institute for Catalan Studies (IEC), held different activities to commemorate its centennial. In 1912, a group of Catalan physicians working mostly on human physiology, and a veterinay devoted to microbiology and the production of vaccines had contacted the French Societé de Biologie (founded in Paris in 1848). The Catalan physicians, led by August Pi i Sunyer, and the veterinary, Ramon Turró, director of the Laboratori Microbiològic Municipal (Microbiology Laboratory of the city of Barcelona), decided to set up in Barcelona a sister organization that exchanged information with French colleagues, as well as with those of the Sociedad Es pañola de Biología, which Santiago Ramón y Cajal (awarded with the Nobel Prize on Physiology or Medicine in 1906), Gregorio Marañón and other physicians had set up in Madrid, also in 1912. Pi i Sunyer sensed that the future of medicine should be based on an in-depth research of the basic knowledge provided by biology. This statement remains valid a hundred years later, and not only for the field of medicine: environmental engineering, food technology, artificial intelligence, ocean exploration, biotechnological applications, and many others scientific fields are based on research of the biological bases of living organisms and their interactions. The Catalan Society for Biology (first known as the Barcelona Society for Biology) held its first scientific session at the above mentioned Laboratori Microbiològic Munici pal on December 14, 1912. Throughout its first year, from December 1912 to December 1913, members of the new Society presented 31 contributions to the sessions, and those contributions were published in the first volume of the journal Treballs (Proceedings) de la Societat de Biologia de Barcelona, released in early 1914. The authors, who were scientists later known as founders of the so-called “Catalan biology school”, were heirs of the tradition of Claude Bernard’s (1813–1878) experimental biology. In fact, the first article of the bylaws said that “[t]he Barcelona Society for Biology aims at studying the science of organized living beings in their normal and pathological states.” The Barcelona Society for Biology soon became a platform for interaction and for publication of the emerging Catalan biology school. At those times, it already had features that have characterized it throughout its history and that we, one hundred years later, wish to maintain. One of them was its international focus; it was a Catalan corresponding entity of the French Society for Biology and its

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 1-3

The Catalan Society for Biology

investigadors de primer nivell. Pi i Sunyer va impartir un curs sobre fisiologia a Buenos Aires el 1919, i Leandre Cervera, col·lega seu, que el va acompanyar en el viatge, va col· laborar amb Bernardo A. Houssay, que seria guardonat amb el Premi Nobel de Fisiologia o Medicina el 1947, i amb qui van publicar un article a la revista Comptes Rendues de la So ciété de Biologie de Paris, sobre l’acció fisiològica de les descàrregues d’adrenalina. La Societat de Biologia de Barcelona també va organitzar cursos i conferències impartides per científics entre els quals hi havia Gustavo Pittaluga, Gregorio Marañón, Pío del Río Hortega, Albert Calmette, i l’esmentat Houssay. Un altre tret va ser mantenir una interacció intensa entre la biologia i la medicina, que va proporcionar una plataforma per als primers científics de la ciència que avui coneixem com biomedicina. A la base d’aquesta nova disciplina hi ha els estudis de Ramon Turró durant l’epidèmia de febre tifoide (salmonellosi) de Barcelona de 1914, que va canviar la infraestructura sanitària de la ciutat, i els de Rossend Carrasco i Formiguera, que, després d’una estada al laboratori de Walter B. Cannon a la Universitat de Harvard, va aplicar insulina en un pacient diabètic per primera vegada en el continent europeu. Una tercera característica va ser l’alta qualitat de la recerca científica, que es pot exemplificar amb avenços d’abast internacional. Entre els diversos exemples, hi ha el de JosepTrueta (1897–1977) en traumatologia i el de Ramon Margalef (1919–2004) en ecologia. Trueta va haver d’exiliar-se després de la Guerra Civil Espanyola i va ser Catedràtic d’Ortopèdia a la Universitat d’Oxford des de 1949 i fins a la seva jubilació el 1967. Durant la segona part del segle xx, les contribucions de Margalef a l’ecologia van convertir-lo en un dels principals pensadors de l’ecologia moderna. Després de la Guerra Civil Espanyola (1936–1939), molts membres de la Societat de Biologia de Barcelona es van haver d’exiliar, i la Societat va ser oficialment clausurada, com també ho va ser l’Institut d’Estudis Catalans. Els seus socis que van romandre a Catalunya es trobaven de tant en tant a les llars d’alguns d’ells. I tot i que tractaven sobre biologia i medicina, ho havien de fer clandestinament. La primera d’aquestes trobades clandestines va ser el 1954, a Barcelona, a casa de l’arquitecte Josep Puig i Cadafalch, i Josep Trueta hi va parlar sobre la poliomielitis. Tanmateix, fins al 14 de desembre de 1962 no es va celebrar la primera sessió pública (“pública”, però no pas autoritzada) de la recuperada Societat, ara amb el nom de Societat Catalana de Biologia (SCB). Des d’aquell moment, la SCB ha crescut per convertir-se en una institució que, malgrat els seus cent anys, manté una vitalitat jovenívola. Els objectius bàsics de la SCB són ara els mateixos que quan va ser fundada. El seu abast, però, s’ha expansionat. A mesura que va anar augmentant el nombre de socis i que s’anaven organitzant més activitats, la SCB va crear diverses seccions especialitzades, començant amb les de Microbiologia, el febrer de 1977, i de Biologia del Desenvolupament, l’abril del mateix any. Les seccions www.cat-science.cat

members spent stays abroad collaborating with first-class researchers. Pi i Sunyer imparted a course on physiology in Buenos Aires in 1919, and Leandre Cervera—his colleague, who accompanied him in that trip—collaborated with Bernardo A. Houssay—who would be awarded the Nobel Prize on Physiology or Medicine in 1947—, and they both published an article in the French journal Comptes Rendues (Proceedings) de la Société de Biologie de Paris, on the physiological action of adrenaline discharges. The Barcelona Society for Biology also hosted courses and lectures imparted by scientists including Gustavo Pittaluga, Gregorio Marañón, Pío del Río Hortega, Albert Calmette, and the above mentioned Houssay. Another trait was maintaining an intimate interaction between biology and medicine, which provided a platform for the first scientists of what is now known as the emergent science of biomedicine. At its base were the studies of Ramon Turró during the typhoid fever (salmonellosis) epidemics in Barcelona in 1914, which changed the city’s health infrastructure, and those of Rossend Carrasco i Formiguera, who, after a research stay with Walter B. Cannon in Harvard University, applied for the first time insulin to a diabetic patient in continental Europe. A third feature was the high-quality scientific research exemplified by advances of international impact. We have several examples, among them those of Josep Trueta (1897–1977) in traumatology and Ramon Margalef (1919– 2004) in ecology. Trueta was forced to exile after the Spanish Civil War and he was Professor of Orthopaedics at the University of Oxford from 1949 until his retirement in 1967. During the second half of the twentieth century, the contributions of Margalef to ecology made him one of the world’s leading thinkers of modern ecology. After the Spanish Civil War (1936–1939), many members of the Barcelona Society for Biology were forced to exile, and the Society was officially suppressed, as it was the Institute for Catalan Studies. The members that remained in Catalonia gathered from time to time at the homes of some of them. Even if they discussed on biology and medicine, they had to do so clandestinely. The first of those clandestine meetings was held in 1954, in Barcelona, at the home of the architect Josep Puig i Cadafalch, where Josep Trueta talked about poliomyelitis. However, it was not until December, 14, 1962, that the first public session (“public”, but not authorized) of the recovered Society—now renamed as Societat Catalana de Biologia (SCB)—was held. Since then, the SCB has grown to become a thriving young one-hundred-year-old institution. The basic goals of the SCB are the same now than they were when it was founded. However its scope has enlarged. As the number of members grew ad more and more activities were organized, the SCB set up various specialized sections, starting with Microbiology, in February 1977, and Developmental Biology, in April of the 2

CONTRIBUTIONS to SCIENCE 9 (2013) 1-3

TORT

de la SCB també han anat canviant segons les necessitats dels seus participants. Actualment hi ha 27 seccions, entre les quals n’hi ha algunes dedicades a temes tan diversos com l’aqüicultura, la biofísica, la genòmica i la proteòmica, senyalització cel· lular i metabolisme, biologia molecular, biologia de plantes i biologia de sistemes. A més, des de 1962, la SCB convoca un premi anual per a estudiants, que reconeix el millor treball de recerca portat a terme per estudiants de llicenciatura o de postgrau. La SCB dedica també una atenció especial als professors de biologia, que disposen d’una secció que té com a objectiu posar al dia els seus coneixements sobre les ciències de la vida. Des de finals de la d’ecada de 1970, la SCB ha anat ampliant les seves activitats cap a altres territoris de llengua catalana, incloent tot Catalunya, les Illes, València, Andorra i la ciutat sarda de l’Alguer. La revista oficial, Treballs, i les altres publicacions de la SCB, s’han adaptat als nous temps i ara es troben en versió digital d’accés gratuït a través de la xarxa. Al llarg de les últimes dècades, bastants científics de renom internacional han participat en activitats organitzades per la SCB. Hi podem comptar Severo Ochoa, Christian de Duve, François Jacob, John Kendrew, Stanley Miller, Lynn Margulis, Joan Oró, Federico Mayor Zaragoza, John Ingraham i Valentí Fuster. Finalment, voldria esmentar un acte destacat de la celebració del centenari: el primer Congrès Internacional de Biologia de Catalunya (CIBICAT), ‘Global Questions on Advanced Biology’, que va celebrar-se a Barcelona, del 9 al 12 de juliol de 2012. (vegeu pp 43-73 d’aquest número). La SCB, una jove institució, malgrat els seus cent anys, desitja continuar la seva tasca de qualitat, servei a la comunitat científica i internacionalització. Té la voluntat de ser un referent i un punt de trobada de la biologia i la biomedicina dels territoris de llengua i cultura catalanes.

same year. The SCB sections have indeed changed according to the needs of its members and are currently 27, including those devoted to topics as diverse as aquaculture, biophysics, genomics and proteomics, metabolism and cell signaling, molecular biology, plant biology, and systems biology. In addition, since 1962, the SCB has called for an annual prize for students, which recognizes a work describing the research carried out as either undergraduate or graduate student. Also, the SCB pays special attention to biology teachers, who gather in a section aimed at updating their knowledge of the life sciences. Since the late 1970s the SCB has expanded its activities to other territories where Catalan is spoken, including all over Catalonia, the Balearic Islands, Valencia, Andorra and the Sardinian city of Alghero (l’Alguer). The official journal Treballs, as well as other publications of the SCB, have adapted to the new times and have now digital versions freely available online. Worldwide recognized scientists have participated in activities organized by the SCB over the last decades. They include Severo Ochoa, Christian de Duve, François Jacob, John Kendrew, Stanley Miller, Lynn Margulis, Joan Oró, Federico Mayor Zaragoza, John Ingraham, and Valentí Fuster. Finally, I wish to mention a major event in the celebration of the Centennial: the First International Conference of Biology of Catalonia (CIBICAT), ‘Global Questions on Advanced Biology,’ held in Barcelona, from the 9th to the 12th of July, 2012. (See pp 43-73 of this issue.) The SCB, a one-hundred-year-old young institution, wishes to continue its work of quality, service to the scientific community and internationalization. It aims to be a referent and a meeting point of biology and biomedicine across the territories of Catalan language and culture.

Lluís Tort

President, Societat Catalana de Biologia Filial de l’Institut d’Estudis Catalans

President, Catalan Society for Biology Affiliated to the Institute for Catalan Studies

Fundada el 1912 – Founded in 1912

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 1-3

DISTINGUISHED LECTURES CONTRIBUTIONS to SCIENCE 9 (2013) 5-6 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.157 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

Ramon Margalef Award for Ecology 2012

Daniel Simberloff: Creative and devastating Joan L. Pretus Department of Ecology, University of Barcelona, Catalonia

I would like to start by expressing the immense satisfaction I felt at the presence of Daniel Simberloff at the Faculty of Biology of the University of Barcelona on the occasion of the award of the Premi Margalef d’Ecologia 2012 (2012 Margalef Ecology Award). It was a privilege to introduce him to all those present, especially to our students, who were there in the expectation of something truly special. It is in fact as students taking our first steps into the world of ecology that communities is one of the paths we tread most often. Just as the biologist is expected to have the skill to recognise the commonest species in a specific taxonomic group, so ecologists are expected to interpret the sense of the specific make-up of samples and thus the general distribution of species, analysing what we have come to call the struc ture of the community. The work of the ecologist therefore consists of organising a data table of species sorted into samples and squeezing it numerically in a convenient way. In essence, what is being sought is the empiric verification of how competition among species has organised their distribution into different degrees of abundance and into different rates of occurrence in samples. This would finally allow us to verify the activity of competition (note the vicious circle) and thus understand the niche of each species. And I say ‘would’, as at the turning of the 1970s and into the 1980s the validity of this procedure for gaining access to what we imagined were the great issues of ecology, this quick way of ecology, was shattered to pieces, and the theory that had supported the analysis became something close to a fairytale. At that time, acclaimed authors still used

similar reasoning applied to the distribution of birds in the set of islands making up remote archipelagos, in order to list rules and more rules for the assembly of communities from the organising principle of competition, as if the patterns observed in Nature would directly reflect the processes or mechanisms involved. It was in fact Daniel Simberloff who woke us up suddenly from this dream. In a devastating article in 1979, Daniel Simberloff and Edward Connor rebutted one by one all the ecological mechanisms that the observed patterns seemed indisputably to reveal [1]. In the exposure of scientific hypotheses as false, it was made clear that it was urgent to help to mature the assumptions of ecology. Classical niche ecology, that nourished by Hutchinson and MacArthur with their charismatic style, was fatally shaken, and with it the presuppositions of an idealistic, metaphysical and deductive way of doing science. From then on, observations began to have their own personality and an intrinsic refutation value, and ceased to be considered simple degenerate deformations of unattainable ideal models, like the deformed shadows projected onto the cave of the philosopher. The ecology of communities had still not managed to free itself from them, deeply rooted as it was in the doctrine that worshipped the Logistic Equation above all contrary evidence. The Simberloff school, based at Florida State University at Tallahassee, kept developing null models for the different hypotheses gathered over the years—hypotheses that seem naive to us now—about the structure of communities. The so-called Tallahassee Mafia played a leading role in the turbulent 1980s. With the relevant null models there appeared patterns that were too similar to those observed, and this time only from independent—not interdependent— processes. In fact, null models generated patterns through the randomisation of the supposed mechanism they were meant to test. But we should say that Dan Simberloff does not like talking about chance, but rather about independence [6]. If we preserve some simulation variables resembling sufficiently the conditions observed, the null model provides us with the expected patterns under inde-

Based on the introduction to the lecture given by Daniel Simberloff, recipient of the Ramon Margalef Award for Ecology, at the Aula Magna of the Faculty of Biology of the University of Barcelona on 31 October 2012.

Correspondence: Department of Ecology Facultat de Biologia, Universitat de Barcelona Av. Diagonal, 643 08028 Barcelona, Catalonia Tel. +34-934021509. Fax +34-934111438 E-mail: jpretus@ub.edu

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 5-6

Daniel Simberloff: Creative and devastating

pendence instead of interdependence, in the absence of the mechanism, while the remaining factors imitate observed reality. The interest of Dan Simberloff in laying down alternative hypotheses and fighting against fairytales had a long background. In 1969, the insular theory having just been launched, the supposedly informative indices of the evolutionary mechanisms in islands was already questioned in an article he sent to Evolution [4]. But despite the collapse of the paradigm and the apparent anarchy in how communities began to be interpreted, Simberloff did not abandon this discipline at all. Yet many ecologists did so, clutching at the straw that the ecology of ecosystems offered them as a salvation tending towards a less problematic sphere and objectives, framed in modernity. An escape towards a discipline that has been recently enriching itself with the complexity of adaptive functional traits, but which at that time added apparently little to the understanding of how nature works. It perpetuated, using a renewed terminology, the myth of the Balance of Nature [2] that had always been so difficult to resist. The ecology of today is the offspring of those changes, traumatic in their way, in the subject. It is not by chance that ecology should have emerged into a period in which neutrality is the real ruler and in which, stochastic processes generate their own patterns. We are late in tracing the steps of evolutionary biology itself, where for a time it has been necessary for neutralism to rule, before making it possible, in an era technically much more sophisticated, to recover interest in the activities of natural selection. For all the reasons set out, Daniel Simberloff has been defined as an iconoclast, even though I would think it more appropriate to define him as a scientist committed to the improvement of scientific progress understood as a tool for the perception of the material reality that surrounds us, so stripping that reality of anachronistic idealisms. In him, as in Margalef, we detect the clear profile of the man of science—one involved, committed and independent, both creative and destructive, especially when detaching himself from concepts that, if ever they had once been useful, regular science has transformed into obstacles, or, as Slobodkin put it, has reified them, thus thwarting progress. Margalef outlined his own way of understanding ecology by removing himself from the reigning statu quo under the niche theory, about which he eventually went on to affirm that ‘it was simply a function of our dissection skills and had no positive characteristics’ and that ‘the concept of niche, just as that of trophic chain, had already

www.cat-science.cat

come to the end of its mission and was not worth keeping in an active role’ [3]. One discovers here a personal style identical in the deep conviction and determination with which both scientists express their positions, as when Simberloff writes in regard to the hypothesis of the existence of a minimum quotient of measures among competing species that this rule has outlived its own usefulness. Despite all that we have said, Dan Simberloff has greatly contributed to grasping specific situations in which competition is the dominant driving agent, as in the detection of the evolutionary displacement of characters. In addition, he has not spared creativity when suggesting new mechanisms, such as invasional meltdown, in an already classic article, a kind of invasive shock whereby at least two non-native species establish positive responses by increasing their effect on the local community [5]. Dan Simberloff’s dedication to invasive species in the last two decades bears witness to the strength of his internal agenda and to his commitment to the real problems of ecology. A coherence that leads from the freshness of his youth, where he became involved in insular theory through experimentation, and the fertile and combative period of his early maturity, to his full maturity where we see him making use of his rigorous scientific spirit to reorganise disciplines involving complex socio-environmental problems that go beyond any academic debate and necessitate taking stances in the social arena as well. Finally, I would like to stress that, over and above specific styles and preferences, it is the ‘emerging’ traits such as valour, honesty and sincerity, that best unite great scientists: individualities that, as seen in Simberloff and Margalef, we appreciate above all as they tell of exemplary human beings and extraordinary individuals.

References 1. 2.

3. 4. 5. 6.

Connor EF, Simberloff D (1979) The assembly of species communities: chance or competition? Ecology 60:1132-1140 Holling, CS, Gunderson LH, Ludwig D (2001). In quest of a theory of adaptive change. In: Gunderson LH & Holling CS (eds). Panarchy: understanding transformations in human and natural systems. Island Press, Washington DC, pp 3-24 Margalef R (1980) La biosfera: entre la termodinámica y el juego. Omega, Barcelona, Catalonia Simberloff D (1970) Taxonomic diversity of island biotas. Evolution 24:23-47 Simberloff D, Von Holle B (1999) Positive interactions of nonindigenous species: invasional meltdown? Biol Invasions 1:21-32 Vázquez D, Collins M (1999) Modelos en ecología: entrevista con Daniel Simberloff. Boletín de la Asociación Argentina de Ecología 8:34-38

CONTRIBUTIONS to SCIENCE 9 (2013) 5-6

DISTINGUISHED LECTURES CONTRIBUTIONS to SCIENCE 9 (2013) 7-16 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.158 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

Ramon Margalef Award for Ecology 2012

Biological invasions: Much progress plus several controversies Daniel Simberloff Department of Ecology and Evolutionary Biology, University of Tennessee, Knoxville, TN, USA

Based on the lecture given by the author at the Aula Magna of the Faculty of Biology of the University of Barcelona on 31 October 2012. Daniel Simberloff received the Ramon Margalef Award for Ecology 2012. Correspondence: Dept. of Ecology and Evolutionary Biology University of Tennessee Knoxville, TN 37996, USA Tel. +1-8659740849 Fax +1-8659743067 E-mail: dsimberloff@utk.edu

Summary. Invasion biology has allowed to progress in our understanding of invasions and our ability to manage them. Recent research has largely focused on invasions that impact entire ecosystems. Molecular genetics has revealed the relative commonality of hybridizations between introduced and native species and between genetically different populations introduced into the same region. Controversies surrounding the findings of invasion biology and management include: i) The claim that most invasions are inconsequential, even if they have been scarcely studied. ii) The argument that invasions can increase local biodiversity, without recognizing that they decrease global biodiversity. iii) The statement that invasion biology is a form of xenophobia, downplaying evidence that fighting invasive species is motivated by their negative impacts. iv) The belief that there is little we can do to prevent or control invasions, ignoring successful eradication and management projects and promising novel approaches. iv) Animal rights objections to the management of invasive vertebrates, particularly mammals, which reflects different philosophical stances and will not be easily resolved. Keywords:

biological control · biological invasion · ecosystem impact · eradication · hybridization · lag time · maintenance management Resum. La biologia de les invasions ha permès avançar en la comprensió de les invasions i de la capacitat per gestionar-les. La recerca recent s’ha centrat sobretot en les invasions que afecten ecosistemes sencers. La genètica molecular ha revelat la generalització relativa d’hibridacions entre espècies introduïdes i natives, i entre poblacions genèticament diferents introduïdes en una mateixa regió. Les controvèrsies sobre els resultats de la biologia de les invasions i de la seva gestió són: i) L’afirmació que la majoria d’invasions causen poc impacte, encara que hagin estat poc estudiades. ii) L’argument que les invasions poden augmentar la biodiversitat local, sense reconèixer que disminueixen la biodiversitat global. iii) L’afirmació que la biologia de les invasions és una forma de xenofòbia, restant importància al fet que la lluita contra les espècies invasores està motivada pels seus impactes negatius. iv) La creença que hi ha poc que puguem fer per prevenir o controlar les invasions, fent cas omís de l’éxit dels projectes d’eradicació i gestió i de nous enfocaments prometedors. iv) Les objeccions dels defensors dels drets dels animals a la gestió dels vertebrats, particularment mamífers, sent aquest un problema que no es resoldrà fàcilment. Paraules clau: control

biològic · invasió biològica · impacte a l’ecosistema · eradicació · hibridació · desfasament temporal · gestió del manteniment

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 7-16

Biological invasions: Much progress plus several controversies

The recognition that biological invasions constitute a global change of the first order—along with changes in climate, nutrient cycles, and land use—came slowly. As early as the 18th century, the Swedish Finn Pehr Kalm noted fifteen European plant species and several European insects during his travels in North America [13]. Early phytogeographers, such as the Augustin Pyrame de Candolle, from Switzerland, greatly expanded the records of species believed to be introduced, deliberately or inadvertently, by humans to various locations around the world [13]. Victorian naturalist-explorers continued this tradition of documentation during the 19th century. Among them, Charles Darwin lamented the replacement of native plants by two invaders from the Old World into the Patagonian pampas [19], while Alfred Russel Wallace deplored the devastation wrought by some invasive species on various islands [107]. However, except for Darwin and Wallace, the focus of all these investigators was squarely on the geography of life—which species are where—and not on the impacts of non-native species. In the early 20th century, George M. Thomson [94] wrote entirely about introduced plants and animals and their impacts in New Zealand, and James Ritchie [64] detailed the impacts of animal invaders in Scotland. Neither book led to new research efforts to study the effects of the entire gamut of biological invaders, although Thomson’s work was rediscovered almost a century later and his data were used in analyses of bird introductions in New Zealand [23,24,99]. Through the mid-20th century, scientists would occasionally point to the impacts of particular species as meriting greater consideration [e.g., 52], but still no broadbased movement arose to study invasions. In 1958, Charles Elton published his famous monograph, The ecology of inva sion by animals and plants [26], which is often cited as the founding document of modern invasion biology [62,63]. Although this book addressed the ecological impacts of invasive plants, animals, and microbes worldwide, it had little contemporary influence and did not inspire a wave of research on invasions [77]. Rather, modern invasion biology largely arose from a project of the Scientific Committee on Problems of the Environment (SCOPE) in the 1980s that engaged over 100 prominent ecologists and evolutionists in a series of workshops held in various countries and which resulted in several widely read books [77]. Thus, given the long history of the problem of invasive species, the modern field of invasion biology is remarkably young.

while others are relatively unscathed? (iii) How can the knowledge developed in response to these two questions be used to improve the management of invasive species? In fact, these questions (i) and (ii) dominated the SCOPE workshops and publications, whereas management was a lesser concern. The SCOPE project as well as much of the research it inspired over the next decade greatly expanded our understanding of how particular invaders affect native species. The majority of cases could be placed in a few well-understood categories. The phenomenon receiving the most attention was predation by an introduced predator on native prey, with the most dramatic outcome being the complete loss of the native species. Striking examples include the extinction of more than 200 native cichlid fish species in Lake Victoria in response to predation by the introduced Nile perch, Lates niloticus [57], and the extinction of 15 species and subspecies of forest birds on Guam after the introduction of the brown tree snake Bioga irregularis [45]. Herbivory by invaders, both vertebrates and invertebrates, is also common. For instance, the South American nutria (Myocastor coypus), introduced into North America and Europe, has caused both the local extirpation of several aquatic plants and important crop losses [69]. In the 19th century, an insect from North America, the phylloxera Daktulosphaira vitifoliae, devastated European vineyards [56]. Invaders can carry diseases to which they are resistant such as the crayfish plague (Aphanomyces astaci) transmitted by North American to European crayfish [46]. Similarly, squirrel pox (Parapox virus), which arrived in Europe with the North American gray squirrel (Sciurus carolin ensis), is currently devastating the native red squirrel (S. vul garis) population in Great Britain and Italy [7,68]. Invaders can also compete with native species. In Spain, the African ice plant (Carpobrotus spp.) outcompetes native plants for light and water, while a North American turtle, the red-eared slider (Trachemys scripta elegans), excludes native turtle species from their optimal habitats [69]. During and in the wake of the SCOPE project it was determined that introduced species often hybridize with closely related native species [61]. Indeed, when native populations are small relative to the size of the invasive population, as was the case for the native white-head duck Oxyura leuco cephala in Spain, which hybridized with the North American ruddy duck O. jamaicensis [51], this phenomenon can even lead to a sort of “genetic extinction,” as the original native genotypes become lost in a hybrid swarm. Moreover, hybridization can generate new species, as occurred in Great Britain when North American smooth cordgrass (Spartina alterni flora) hybridized with native small cordgrass S. maritima to produce the polyploid hybrid common cordgrass, S. anglica [93]. In this case, although the native parent S. maritima is never invasive [92], the new hybrid species is listed among a selection of 100 of the world’s worst invaders [48].

The first fifteen years The SCOPE mandate was to determine: (i) Why are certain species particularly invasive once introduced, while others either disappear or remain restricted and innocuous? (ii) What makes certain habitats particularly prone to invasions www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 7-16

SIMBERLOFF

Expanded and new research directions Not in print

The SCOPE contributions and the immediately ensuing research were largely focused on one-on-one ecological interactions—how does a single particular invader affect one native or a particular group of them? However, even in the initial SCOPE project, Peter Vitousek [104,105] called attention to the fact that certain invasive species can fundamentally alter an entire ecosystem, involving a large number of species that play various roles in the biotic community. In Vitousek’s example, the particular invader was the Atlantic shrub Morella faya (or Myrica faya), introduced to the Hawaiian Islands. As a nitrogen-fixer in mid- and upper-elevation areas characterized by nutrient-poor volcanic soils—to which native plants were adapted—and in the absence of native nitrogen-fixers, M. faya effectively fertilized the soil, making it more hospitable to other non-native plants previously excluded by the low nitrogen levels. It also entrained a number of other changes in the ecosystem [4]. Further, this ecosystem change was exacerbated by “invasional meltdown” [87], in which the combined impact of two or more invaders is greater than their summed impact. The major seed-disperser of M. faya is the Japanese white-eye, Zosterops japonicus [111]; by clustering under M. faya, introduced earthworms increase the rate at which nitrogen is added to the soil [3]. Another ecosystem-wide impact of a single invader was described by Fukami et al. [31], who found that both the above-ground and below-ground communities differ profoundly on small New Zealand islands invaded by rats (either Rattus rattus or R. norvegicus) compared to rat-free islands. This type of research is distinct from many previous studies of the impact of introduced rats on islands [5,96]. Ecosystem-level research has now become a leading edge of invasion biology and it has shown that many ecosystem impacts are caused by changes in nutrient and fire regimes and in physical structure [25,78]. The other major new thrust of invasion biology research is the role of evolution in invasions. It is puzzling that, despite the participation of several prominent evolutionists in the SCOPE program and the obvious possible relevance of invasion events to evolutionary questions (e.g., the relative importance of founder effects and natural selection in small, newly established populations), evolutionary biologists did not join the rapidly growing biological invasions research program in great numbers for over a decade after SCOPE [77]. Spurred by the rapid increase in the development and availability of molecular genetic technologies, evolution has since become an integral part of the invasion biology research program. Yet, the first monograph on evolution and biological invasions was published only in 2004 [16]. Nowadays, molecular tools, particularly the study of microsatellite and mitochondrial DNA sequences, are used www.cat-science.cat

The achievements by great scientists can be usually found in the articles and books they have published throughout their careers. Many of their ideas and thoughts, however, are not always left in print, unless they write memoirs or books of essays. Ramon Margalef used to say, in a tone half-humorous and half-sarcastic, that he felt suspicious—and had had good reasons for it—of the traditional systems of education, especially higher (i.e., university) education. On one occasion, when we were discussing an emergent and significant issue in the young science of microbial ecology, he told me: “This is so important, Ricard, that in twenty years it will already be included in textbooks”. R. Guerrero.

Professor Ramon Margalef. (Images courtesy of Gallery of Catalan Scientists, Institute for Catalan Studies).

CONTRIBUTIONS to SCIENCE 9 (2013) 7-16

Biological invasions: Much progress plus several controversies

ly evolved a cline of increased wing length with increased latitude, but a different section of the wing is responsible for the cline in South American than in either North American or Old World fruit flies. Furthermore, many traits other than morphology have evolved in introduced populations, including changes in life history, physiology, and behavior [16]. Perhaps best known to the public are the many cases in which insects have evolved resistance to insecticides, either physiological changes to tolerate or detoxify the chemical or behavioral changes to avoid it [67,108]. Native species sometimes also evolve very quickly in response to invasions [91]. For instance, after introduction of the predatory green crab (Carcinus maenas) to the Atlantic coast of North America, the dog whelk (Nucella lapillus), a native prey species, evolved thicker shells [100]. The explosion of research publications on invasions has led to a proliferation of formal meta-analyses of that literature—as the method became known outside the field of medicine [11]—particularly regarding the first two questions of the SCOPE agenda: what determines the invasiveness of species and the invasibility of sites or habitats (e.g., [43,44,102]). However, it seems unlikely that such efforts will advance our understanding of invasions substantially for two reasons. First, particular invasions are highly idiosyncratic such that a fundamental requirement of meta-analysis is violated: the different studies can by no means truly be viewed as replicate tests of the same hypothesis. Second, this same idiosyncrasy implies that an effect size in an analysis in one case will have limited predictive value for an invasion by the same species or type of species in another. This is most clearly shown by the fact that a single species can be highly invasive at one site and either fail utterly or have minor impact at another [114]. What is needed most to advance our understanding of invasions is not the study of effect sizes but of actual effects, on the ground and in a multitude of cases [74]. Unfortunately, this sort of research is largely in the tradition of detailed natural history at the community level, which has fallen from academic favor precisely because community dynamics are too variable and idiosyncratic [41]. Yet, even though community studies are highly idiographic, they are precisely what is needed if we are to understand and successfully address many environmental and conservation issues, including invasions [73].

to trace the origins of particular invasive species. An example is the demonstration that the Cuban anole (Anolis sagrei) in Florida must have undergone multiple introductions because many locations in Florida have a greater diversity of mtDNA haplotypes than does any one location in Cuba [38]. The same study was able to show that invasions by this lizard of Hawaii and Taiwan must have arrived from Florida rather than Cuba. This particular study did not demonstrate that the multiple origins had consequences for the invasion. However, for reed canary grass (Phalaris arun dinacea) in North America [40] and the multicolored lady beetle (Harmonia axyridis) in North America and Europe [47], similar genetic analyses show that, as noted above, hybridization between individuals introduced separately from different regions can produce more invasive genotypes. Hybridization between a native and an introduced oomycete is responsible for alder blight (Phytophthora alni), a new pathogen that is killing alders (Alnus spp.) throughout Europe [113]. In general, the plethora of genetic studies on invaders has detected far more multiple introductions than had been suspected as well as frequent hybridizations between populations introduced from different regions. These studies also revealed that hybridizations between introduced and related native species occur more often than previously assumed based on simple morphological analyses. The frequency of multiple introductions at least partly resolves the “paradox of invasion genetics.” That is, it has long been noted that although very small populations are frequently presumed to be endangered by genetic deterioration, engendered by genetic drift and inbreeding-induced genetic depression [2,28], many strikingly successful invasions have originated from very small propagules, which greatly reduced genetic variation by virtue of the “bottleneck effect” [75]. However, we now know that some introduced populations, such as the Florida populations of the Cuban anole, have greater genetic variation than any one native population, thereby hindering the expected genetic deterioration [66]. Many introduced populations have evolved morphologically in their new homes. A remarkable example is the Old World fruit fly Drosophila subobscura, introduced into western North and South America. Old World populations have a pronounced latitudinal cline in wing length whereas in North American populations no wing length cline was detected ten years after introduction of the species; but after 20 years a cline had evolved that largely converged with the Old World cline [35]. However, different sections of the wing are responsible for the cline in North American vs. Old World populations. Thus, the evolution of geographic variation in wing length was predictable, but expression of the genes by which the cline was achieved depended on other factors. Introduced South American populations also rapidwww.cat-science.cat

Controversies surrounding invasions and invasion biology Aspects of invasion management and policy have been controversial since well before the advent of modern invasion biology [72], but for the most part criticism arose from the humanities and social sciences. More recently, these controversies have become more visible as the field of invasion 10

CONTRIBUTIONS to SCIENCE 9 (2013) 7-16

SIMBERLOFF

biology itself expands and matures. Matters came to a head with a Comment in Nature [20] signed by 19 ecologists and an immediate rebuttal [84] signed by 141 ecologists. Popular science writers, sensing a hot topic, have also entered the fray (e.g., [49,103]). In fact, there are several distinct criticisms, with different critics focusing on different ones [80,82]. These boil down to five main areas of contention.

cies; in this light, the instances in which non-native species confer conservation benefits are highly questionable [106]. (ii) Introduced species increase biodiversity. It has been

frequently noted that introduced species increase local bio diversity in certain circumstances or even maintain local biodiversity in the face of extinctions (e.g., [70]). However, invasions cause a sharp decrease in global biodiversity. Consider the birds of the Hawaiian Islands [85]. Of 114 known bird species present at the time of human colonization of the archipelago, at least 56 are globally extinct [9]. Introduced bird species contributed to this hecatomb through disease transmission [112] and possibly through competition [29]. Remarkably, 53 non-native bird species are now established on the islands [65], approximately “balancing” the extinctions. However, almost all of the introduced birds are common in their native ranges, and many have been introduced to other sites. They can hardly be said to “compensate” for the global extinction of the native birds. Certain introduced species in specific circumstances increase biodiversity very locally by providing a resource for native species that would otherwise be more sparsely distributed in the region. For instance, in Argentina the kelp Undaria pinnatifida, native to cold temperate regions of the Pacific northwest, constitutes a new structural habitat that increases the local richness of native animal species [36]. As with the introduced species claimed to aid conservation, discussed above, it is important in each case to tally the long-term net benefits and debits to regional ecosystems.

(i) Which invasive species are harmful? It is widely ac-

knowledged that a minority of biological invaders have harmful impacts, and critics of invasion biology (e.g., [20]) take that finding as evidence that the entire invasion problem is overblown. In fact, for three reasons the statistics on known invasion impacts should be interpreted with caution. First, the great majority of introduced populations have not been studied in any detail, so that their true impact is as yet unknown. For instance, of the over 10,000 non-native plants in Europe, the ecological effects have been studied in fewer than 11 % [101]. Second, in a number of instances invasions are substantial and even affect entire ecosystems, but their impacts are nonetheless subtle and not readily apparent. A good example is the fertilization of Hawaiian Islands by the nitrogen-fixing M. faya [104,105], discussed above. The gradual change was not obvious, but since the reporting of this phenomenon many similar examples have been uncovered [25]. Third, many introduced populations remain more or less restricted and innocuous for long periods, often several decades, before abruptly exploding across the landscape with broad-ranging consequences [17]. Thus, even if we were aware of the current effects of all introduced populations, their future impacts would be severely underestimated, even if no further invasions occurred. This phenomenon—that future impacts will arise because of populations already introduced—has been called the “invasion debt” [27]. The charge that most invasions are not known to be harmful is occasionally buttressed by either or both of two observations. First, some native species have ecologically or economically harmful impacts that are analogous to those caused by invasive non-natives. This is true, but the likelihood of such impacts is far less than for non-natives [53,86]. For instance, plant species introduced to the United States are 40× more likely than native plant species to generate harmful effects. In the relatively few instances in which this indeed occurs, it is almost always in the wake of an anthropogenic environmental modification, such as changed fire regime or overgrazing by livestock [86]. A second occasional observation is that sometimes non-native species actually aid conservation in some way (e.g., [71]). Of course, this is true; any time a species, including an introduced one, becomes common, some other species will use it as a resource. However, one must always consider the full panoply of impacts on the ecosystem and all of its spewww.cat-science.cat

(iii) Are actions against introduced species xenophobic?

A persistent claim, originally from scholars in the social sciences and humanities (references in [72]), is that antipathy towards introduced species is simply displaced xenophobia. This suggestion is rarely expressed by scientists working on invasions, but the burst of recent criticism at least hints at this charge: consider the title of Davis et al. [20]: “Don’t judge species on their origins.” A full examination of this allegation is beyond the scope of this article; I have treated it fully elsewhere [72,79]. This view of invasion biology amounts to a classic social construction of science [10], in which the development of a field is ascribed to the psychological states and power relationships among the participants rather than to increasing knowledge of the subject of study. An excellent example is the work of the American historian Philip J. Pauly [54], who saw the approximate syn chrony of the first American laws restricting human immigration and the earliest statutes attempting to prevent harmful biological invasions as proof of his thesis. The increasingly strict immigration laws are widely acknowledged to have reflected a growing nativism in early 20th century America [33,95]; so, in Pauly’s view, the anti-invasion regu11

CONTRIBUTIONS to SCIENCE 9 (2013) 7-16

Biological invasions: Much progress plus several controversies

lations could only reflect the same xenophobic sentiment: “attitudes towards foreign pests merged with ethnic prejudices: the gypsy moth and the oriental chestnut blight both took on and contributed to characteristics ascribed to their presumed human compatriots” [54]. In fact, the invasions of both the gypsy moth Lymantria dispar [90] and the chestnut blight Cryphonectria parasitica [30] were devastating and widely lamented by the contemporary public and politicians. The discussions in Congress and the federal agencies that led to early regulations of species introductions referred heavily to these impacts [72]. This is not to say that nativists of the period did not occasionally deplore non-native species, but the scientists of that era and modern invasion biologists focused, in fact, on impacts, not origins [15]. Absent from analyses such as Pauly’s is a consideration of the impacts of introduced species, much less sophisticated insights such as those of Aldo Leopold, who recognized that the absence of co-evolution with native species led to far greater risks of damage from introduced species than from native ones [42].

would otherwise have become devastating invasions [81,82]. It is often argued that eradication of a long-established, widespread invader is impossible (e.g., [18,60]), and there is little doubt that is far more difficult than eliminating a limited, narrowly distributed population. However, several very widely established invaders have nevertheless been eliminated, such as the pasture weed Kochia scoparia in Western Australia [58] and the melon fly Bactrocera cucur bitae in the entire Ryukyu Archipelago [37,39]. Recently, the viral pathogen of ungulates, rinderpest, which devastated Africa in the 20th century, was eradicated from the face of the Earth [50]. These successes are not to say that eradication is straightforward, only that it is often technologically feasible and that recent advances (see, e.g., [12,98]) have made possible many eradication efforts that would have seemed hopeless only one or two decades ago. If eradication fails, there are several technologies that can maintain invasive populations at levels that are not problematic. Traditional maintenance management approaches are physical control, mechanical control, chemical control, and biological control. Each has achieved major success, and each has failed in other circumstances [76,83]. The important point is that the technologies associated with all of these methods have evolved (e.g., [14,21,55,97,109]). In addition, novel approaches to maintenance management (and in some cases possibly eradication) of particular invaders arise occasionally. The essence of creativity is that we cannot predict exactly when it will arise and from what direction, only that new ideas will occur with some frequency. This is certainly proving true for the management of invasive species, as interest in and publicity about the problem increase. For instance, invasive sea lampreys (Petromyzon marinus) in the North American Laurentian Great Lakes—long controlled somewhat successfully with lampricides and dams but at great expense and with some non-target impacts—can now be managed in many circumstances by exploiting a pheromone emitted by larval lampreys to attract adult lampreys to particular streams to breed [88,89]. Invasive zebra mussels (Dreissena polymor pha), long intractable to chemical control because they are acutely sensitive to the presence of toxins in the water and shut their valves in response to them, can now be managed at municipal and industrial water facilities where non-target native mollusks are not a concern. This is achieved by “BioBullets,” minute beads of toxic potassium chloride that the mussels cannot sense because they are coated with a masking fatty substance that dissolves after they have been filtered out of the water by the mussels [1]. Autocidal methods that manipulate an invasive species’ genetics in such a way as to lower its population size were proposed in the 1960s and 1970s (e.g., [32]), but the necessary technologies were lacking. Today, in an era of transgenes and ge-

(iv) Whatever their impacts, is it futile to fight invaders?

Several critics of the effort to stem invasions concede that at least some of them do wreak substantial damage, but they argue that, in the face of growing trade and travel, the effort is largely hopeless and we should not waste precious resources trying to stop them. This sentiment was captured vividly by Mark Gardener (in [103]), a signatory to the Comment by Davis et al. [20], as he neared the end of his tenure as director of the Charles Darwin Research Station in the Galapagos: “It’s time to embrace the aliens. Blackberries now cover more than 30,000 ha here, and our studies show that island biodioversity is reduced by at least 50 % when it’s present. But as far as I’m concerned, it’s now a Galapagos native, and it’s time we accepted it as such.” In fact, such pessimism is not warranted, particularly in light of the relative youth of modern invasion biology and the tremendous recent strides in management technologies [76]. Of course, the best approach is to have sufficiently stringent regulations and inspection such that few invaders enter in the first place; as in medicine, an ounce of prevention is worth a pound of cure. The experience of New Zealand in the wake of its Biosecurity Act of 1993 shows that such measures are both feasible and effective [85]. The impediments to putting such measures in place are mostly political, although the expense of establishing adequate inspection has played a role [81]. If an introduced population nevertheless becomes established, the next step would be to find it quickly and try to eradicate it. Nowhere in the world are there adequate monitoring programs to find such incipient invasions, even though engaging citizen scientists is a cost-effective way to greatly improve monitoring and it has led to several remarkable eradications of populations that almost certainly www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 7-16

SIMBERLOFF

netic modification, such methods are again being researched and have reached the testing state in both fishes (e.g., [6]) and dipterans (e.g., [59]).

favor humane ways of killing invasive sentient individuals if such individuals are to be killed, but even if a completely painless management or eradication method were to be devised, certain advocates of animal rights would object to it.

(v) Animal rights objections to the management and eradication of vertebrates. Attempts to eradicate or

Discussion

even simply to manage mammals and birds often generate heated opposition from animal rights and animal welfare organizations, such as People for the Ethical Treatment of Animals and The Fund for Animals (PETA) [80,83]. Perhaps the best known example is the spread of the North American gray squirrel in Italy. As noted above, in Great Britain the gray squirrel has greatly reduced native European red squirrel populations, by spreading squirrel pox and by competition [110]. An escaped population in central Italy led to a well-planned eradication campaign, because of the feared threat to mainland European red squirrels [8]. However, a lawsuit by animal rights advocates, sustained by Italian courts, stopped the campaign in its tracks [7] and the gray squirrel has, accordingly, continued to spread; it is currently nearing France [22]. Even rats threatening seabird populations have elicited enough sympathy to inspire attempts to impede eradication campaigns [34,80]. This issue usually boils down to whether one considers collective entities, such as species or populations, to be worthy of moral consideration, if that moral consideration confers rights on such entities (say, a population of an endangered seabird), and whether such rights trump the rights to continued life of individuals of some other species, introduced by humans, that may threaten them (e.g., introduced rats) [80]. Philosophers are divided on this issue, so it is not surprising that so is the public. Animal rights advocates generally come down on the side of the rights of individual sentient animals to continued life. Clearly, all sides of this debate

Controversies over the urgency and scope of the problems posed by invasions, the real impact of invasions on biodiversity, the charge of xenophobia, and the argument that opposing invasions is largely futile are not likely to ever go away, but they will be less divisive with continued research and especially education of the public about the results of that research. As more people learn more about the impacts of invasions and the developing technologies for managing them, they will be increasingly inclined to support management activities. Policymakers, reflecting the will of the public, will follow suit. However, the controversy revolving around animal rights is of a different type. It reflects deepseated differences in worldview and an almost religious zeal in certain individuals on either side of the issue. Such profound underlying differences will not quickly yield to better education about the negative impacts and the promising management possibilities. In such cases, society as a whole will have to reach a decision, as scientists are simply citizens among many others in society. Perhaps the early engagement of social scientists in attempting to understand the differing viewpoints and to adjudicate among them would aid in generating good outcomes. The ability of a segment of the Italian population to determine the fate of a species and, consequently, various ecosystems throughout Europe suggests that better methods are needed to allow all stakeholders to have input into decisions that are urgent, irrevocable, and of great consequence.

Daniel Simberloff is the Nancy Gore Hunger Professor of Environmental Studies at the University of Tennessee at Knoxville. At Harvard University, he received his A.B in mathematics (1964) and obtained his doctoral thesis under Prof. E.O. Wilson (1969). He worked at Florida State University from 1968 to 1997, when he became the Nancy Gore Hunger Professor of Environmental Studies at the University of Tennessee, where he directs the Institute for Biological Invasions. His research focuses on ecology, evolution, conservation biology, biogeography, and statistical ecology, with specific topics including invasion biology, community composition and structure, and community morphological structure; he is considered to be a world leader in the study of invasive species. In 1971 he shared with E.O. Wilson the Mercer Award of the Ecological Society of America. Other awards include the 2006 Eminent Ecologist Award of the Ecological Society of America, and the 2012 Ramon Margalef Award for Ecology. He is a fellow of several academies including the American Academy of Arts and Sciences, and the US National Academy of Sciences. (Image courtesy of Generalitat de Catalunya).

Professor Daniel Simberloff, recipient of the Ramon Margalef Award for Ecology 2012, delivered the lecture entitled â&#x20AC;&#x153;Biological invasions: much progress, plus several controversiesâ&#x20AC;? on 31 October 2012 at the University of Barcelona.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 7-16

Biological invasions: Much progress plus several controversies

References

25. 26.

2. 3. 4. 5.

6. 7.

9. 10. 11. 12.

13.

14. 15. 16.

17.

18.

19.

20.

21.

22.

23.

24.

Aldridge DC, Elliott P, Moggridge GD (2006) Microencapsulated BioBullets for the control of biofouling zebra mussels. Environ Sci Technol 40:975-979 Allendorf FW, Lundquist LL (2003) Introduction: population biology, evolution, and control of invasive species. Conserv Biol 17:24-30 Aplet GH (1990). Alteration of earthworm community biomass by the alien Myrica faya in Hawai’i. Oecologia 82:414-416 Asner GP, Vitousek PM (2005) Remote analysis of biological invasion and biogeochemical change. Proc Natl Acad Sci USA 102:4383-4386 Atkinson IAE (1985) The spread of commensal species of Rattus to oceanic islands and their effects on island avifaunas. In: Moors PJ (ed) Conservation of island birds. International Council of Bird Conservation Technical Publication 3:35-81 Bax NJ, Thresher RE (2009) Ecological, behavioral and genetic factors influencing the recombinant control of invasive pests. Ecol Appl 19:873-888 Bertolino S, Genovesi P (2003) Spread and attempted eradication of the grey squirrel (Sciurus carolinensis) in Italy, and consequences for the red squirrel (Sciurus vulgaris) in Eurasia. Biol Conserv 109:351-358 Bertolino S, Lurz PWW, Sanderson R, Rushton SP (2008) Predicting the spread of the American grey squirrel (Sciurus carolinensis) in Europe: a call for a coordinated European approach. Biol Conserv 141:2564-2575 Boyer AG (2008) Extinction patterns in the avifauna of the Hawaiian islands. Divers Distrib 14:509-517 Brown JR (2001) Who rules in science?: an opinionated guide to the wars. Harvard University Press, Cambridge, MA Cadotte MW, Mehrkens LR, Menge DNL (2012) Gauging the impact of meta-analysis on ecology. Evol Ecol 26:1153-1167 Campbell KJ, Baxter GS, Murray PJ, Coblentz BE, Donlan CJ, Carrion GV (2005) Increasing the efficacy of Judas goats by sterilization and pregnancy termination. Wildlife Res 32:737-743 Chew MK (2006) Ending with Elton: Preludes to invasion biology (doctoral thesis). Arizona State University [http://www.academia. edu/4948103/Ending_with_Elton_Preludes_to_Invasion_Biology] Clout MN, Williams PA (2009) Invasive species management: a handbook of principles and techniques. Oxford University Press, Oxford Coates PA (2006) American perceptions of immigrant and invasive species: strangers on the land. University of California Press, Berkeley, CA Cox GW (2004) Alien species and evolution: the evolutionary ecology of exotic plants, animals, microbes, and interacting native species. Island Press, Washington DC Crooks JA (2011) Lag times and exotic species: the ecology and management of biological invasions in slow-motion. In: Simberloff D, Rejmánek M (eds) Encyclopedia of biological invasions. University of California Press, Berkeley, CA pp 404-410 Dahlsten DL (1986) Control of invaders. In: Mooney HA, Drake JA (eds) Ecology of biological invasions of North America and Hawaii. Springer, New York, pp 275-302 Darwin C (1838-1843) The zoology of the voyage of H.M.S. Beagle, under the command of captain FitzRoy, during the years 1832 to 1836. 5 vols. Smith, Elder and Co., London (reprint C Darwin [1958] The voyage of the Beagle. Bantam, New York) Davis MA, Chew MK, Hobbs RJ, Lugo AE, Ewel JJ, Vermeji GJ, Brown JH, Rosenzweig ML, et al. (2011) Don’t judge species on their origins. Nature 474:153-154 DiTomaso JM (2011) Herbicides. In: Simberloff D, Rejmánek M (eds) Encyclopedia of biological invasions. University of California Press, Berkeley, CA, pp 323-330 Dozières A (2012) Conservation de l’écureuil roux en France: de l’état des populations aux enjeux liés à l’introduction de l’écureuil à ventre rouge (doctoral thesis). Muséum National d’Histoire Naturelle [http://ecureuils. mnhn.fr/sites/default/files/documents/theseannedozieres1.pdf] Duncan RP (1997) The role of competition and introduction effort in the success of passeriform birds introduced to New Zealand. Am Nat 149:903-915 Duncan RP, Blackburn TM (2002) Morphological over-dispersion in game birds (Aves: Galliformes) successfully introduced to New Zealand was not caused by interspecific competition. Evol Ecol Res 4:551-561

www.cat-science.cat

27.

28. 29.

30. 31.

32. 33. 34.

35.

36.

37.

38.

39.

40.

41. 42. 43. 44.

45. 46.

47.

48.

Ehrenfeld JG (2010) Ecosystem consequences of biological invasions. Annu Rev Ecol Evol Syst 41:59–80 Elton CS (1958) The ecology of invasions by animals and plants. Methuen, London Essl F, Dullinger S, Rabitsch W, Hulme PE, Hülber K, Jarošík V, Kleinbauer I, Krausmann F, et al. (2011) Socioeconomic legacy yields an invasion debt. Proc Natl Acad Sci USA 108:203-207 Frankham R (2005) Invasion biology – resolving the genetic paradox in invasive species. Heredity 94:385 Freed LA, Cann RL, Bodner GR (2008) Incipient extinction of a major population of the Hawaii akepa owing to introduced species. Evol Ecol Res 10:931-965 Freinkel S (2007) American chestnut: The life, death, and rebirth of a perfect tree. University of California Press, Berkeley, CA Fukami T, Wardle DA, Bellingham PJ, Mulder CPH, Towns DR, Yeates GW, Bonner KI, Durrett MS, et al. (2006) Above- and belowground impacts of introduced predators in seabird-dominated island ecosystems. Ecol Lett 9:1299-1307 Hamilton WD (1967) Extraordinary sex ratios. Science 156:477-488 Higham J (1984) Send these to me: immigrants in urban America. Johns Hopkins University Press, Baltimore, MD Howald GR, Faulkner KR, Tershy B, Keitt B, Gellerman H, Creel EM, Grinnel M, Ortega ST, Croll DA (2005) Eradication of black rats from Anacapa Island: biological and social considerations. In: Garcelon DK, Schwemm CA (eds) Proceedings of the Sixth California Channel Islands Symposium. Institute for Wildlife Studies, Arcata, CA, pp. 299-312 Huey RB, Gilchrist GW, Carlson ML, Berrigan D, Serra L (2000) Rapid evolution of a geographic cline in size of an introduced fly. Science 287:308-309 Irigoyen AJ, Trobbiani G, Sgarlatta MP, Raffo MP (2011) Effects of the alien algae Undaria pinnatifida (Phaeophyceae, Laminariales) on the diversity and abundance of benthic macrofauna in Golfo Nuevo (Patagonia, Argentina): potential implications for local food webs. Biol Invas 13:1521-1532 Iwahashi O (1996) Problems encountered during long-term SIT program in Japan. In: McPheron BA, Steck GJ (eds) Fruit fly pests: a world assessment of their biology and management. St. Lucie Press, Delray Beach, FL, pp 391-398 Kolbe JJ, Glor RE, Schettino LR, Lara AC, Larson A, Losos JB (2004) Genetic variation increases during biological invasion by a Cuban lizard. Nature 431:177-181 Kuba H, Kohama T, Kakinohana H, Yamagishi M, Kinjo K, Sokei Y, Nakasone T, Nakamoto Y (1996) The successful eradication programs of the melon fly in Okinawa. In: McPheron BA, Steck GJ (eds) Fruit fly pests: a world assessment of their biology and management. St. Lucie Press, Delray Beach, FL, pp 534-550 Lavergne S, Molofsky J (2007). Increased genetic variation and evolutionary potential drive the success of an invasive grass. Proc Natl Acad Sci USA 104:3883-3888 Lawton JH (1999) Are there general laws in ecology? Oikos 84:177-192 Leopold A (1939) A biotic view of the land. J Forest 37:727-730 Levine JM, Adler PB, Yelenik SG (2004) A meta-analysis of biotic resistance to exotic plant invasions. Ecol Lett 7:975-989 Liao C, Peng R, Luo Y, Zhou X, Wu X, Fang C, Chen I, Li B (2008) Altered ecosystem carbon and nitrogen cycles by plant invasion: a meta-analysis. New Phytol 177:706-714 Lockwood JL, Hoopes MF, Marchetti MP (2007) Invasion ecology. Blackwell, Malden, MA Lodge DM, Deines A, Gherardi F, Yeo DC, Arcella T, Baldridge AK, Barnes MA, Chadderton WL, et al. (2012) Global introductions of crayfishes: evaluation the impact of species invasions on ecosystem services. Annul Rev Ecol Evol Syst 43:449-472 Lombaert E, Guillemaud T, Cornuet J-M, Malausa T, Facon B, Estoup A (2010) Bridgehead effect in the worldwide invasion of the biocontrol harlequin ladybird. PLoS ONE 5(3):e9743. doi:10.1371/journal. pone.0009743 Lowe S, Browne M, Boudjelas S (2000) 100 of the world’s worst invasive alien species. A selection from the global invasive species database. The Invasive Species Specialist Group, IUCN, Auckland, New Zealand

CONTRIBUTIONS to SCIENCE 9 (2013) 7-16

SIMBERLOFF

49. Marris E (2009) Ragamuffin Earth. Nature 460:450-453 50. McNeil Jr DG (2011) Rinderpest, scourge of cattle, is vanquished. New York Times, June 28: D1 51. Muñoz-Fuentes V, Vilà C, Green AJ, Negro JJ, Sorenson MD (2007) Hybridization between white-headed ducks and introduced ruddy ducks in Spain. Mol Ecol 16:629-638 52. Myers GS (1947) Foreign introductions of North American fishes: inadvisability of recommending North American fishes without careful appraisal of foreign fishes and ecology. Prog Fish Cult 9:177-180 53. Paolucci EM, MacIsaac HJ, Ricciardi A (2013) Origin matters: alien consumers inflict greater damage on prey populations than do native consumers. Divers Distrib 19:988-995 54. Pauly PJ (1996) The beauty and menace of the Japanese cherry trees. Isis 87:51-73 55. Pickart A (2011) Mechanical control. In: Simberloff D, Rejmánek M (eds) Encyclopedia of biological invasions. University of California Press, Berkeley, CA, pp 449-452 56. Pouget R (1989) Histoire de la lutte contre le phylloxéra de la vigne en France (1868-1895). Institut National de la Recherche Agronomique, Paris 57. Pringle RM (2011) Nile perch. In: Simberloff D, Rejmánek M (eds) Encyclopedia of biological invasions. University of California Press, Berkeley, CA, pp 484-488 58. Randall R (2001) Case Study 5.5. Eradication of a deliberately introduced plant found to be invasive. In: Wittenberg R, Cock MJW (eds) Invasive alien species: a toolkit of best prevention and management practices. Centre for Agricultural Bioscience International, Wallingford 59. Reeves RG, Denton JA, Santucci F, Bryk J, Reed FA (2012) Scientific standards and the regulation of genetically modified insects. PLoS Negl Trop Dis 6: e1502. doi:10.1371/journal.pntd.0001502 60. Rejmánek M, Pitcairn MJ, (2002) When is eradication of exotic pest plants a realistic goal? In: Clout MN, Veitch CR (eds) Turning the tide: the eradication of invasive species: proceedings of the International Conference on Island Invasives. The Invasive Species Specialist Group, IUCN, Auckland, New Zealand, pp 249-253 61. Rhymer JM, Simberloff D (1996) Extinction by hybridization and introgression. Annu Rev Ecol Syst 27:83-109 62. Ricciardi A, MacIsaac HJ (2008) In retrospect: the book that began invasion ecology. Nature 452:34 63. Richardson DM, Pyšek P (2008) Fifty years of invasion ecology – the legacy of Charles Elton. Divers Distrib 14:161-168 64. Ritchie J (1920) The influence of man on animal life in Scotland: a study in faunal evolution. Cambridge University Press, Cambridge 65. Rodriguez-Cabal MA, Williamson M, Simberloff D (2013) Overestimation of establishment success of non-native birds in Hawaii and Britain. Biol Invas 15:249-252 66. Roman J, Darling JA (2007) Paradox lost: genetic diversity and the success of aquatic invasions. Trends Ecol Evol 22:454-464 67. Roush RT, Tabashnik BE (1990) Pesticide resistance in arthropods. Chapman and Hall, New York 68. Rushton SP, Lurz PWW, Gurnell J, Nettleton P, Bruemmer C, Shirley MDF, Sainsbury AW (2006) Disease threats posed by alien species: the role of a poxvirus in the decline of the native red squirrel in Britain. Epidemiol Infect 134:521-533 69. Sans X, Caño L, Green AJ (2008) Las especies invasoras reducen la diversidad de especies nativas y su integridad genética. In: Vilà M, Valladares F, Traveset A, Santamaría L, Castro P (eds) Invasiones biológicas. Consejo Superior de Investigaciones Científicas, Madrid, pp.103-116 70. Sax DF, Gaines SD, Brown JH (2002) Species invasions exceed extinctions on islands worldwide: a comparative study of plants and birds. Am Nat 160:766-783 71. Schlaepfer MA, Sax DF, Olden JD (2011) The potential conservation value of non-native species. Conserv Biol 25:428-437 72. Simberloff D (2003) Confronting introduced species: a form of xenophobia? Biol Invas 5:179-192 73. Simberloff D (2004) Community ecology: Is it time to move on? Am Nat 163:787-799 74. Simberloff D (2006) Invasional meltdown 6 years later—important phenomenon, unfortunate metaphor, or both? Ecol Lett 9:912-919 75. Simberloff D (2009) The role of propagule pressure in biological invasions. Annu Rev Ecol Evol Syst 40:81-102

www.cat-science.cat

76. Simberloff D (2009) We can eliminate invasions or live with them!: successful management projects. Biol Invas 11:149-157 77. Simberloff D (2010) Charles Elton - Neither founder nor siren, but prophet. In: Richardson DM (ed) Fifty years of invasion ecology: the legacy of Charles Elton. Wiley, New York, pp 11-24 78. Simberloff D (2011) How common are invasion-induced ecosystem impacts? Biol Invas 13:1255-1268 79. Simberloff D (2011) The rise of modern invasion biology and American attitudes towards introduced species. In: Rotherham ID, Lambert RA (eds) Invasive and introduced plants and animals: human perceptions, attitudes and approaches to management. Earthscan, London, pp 121-135 80. Simberloff D (2012) Nature, natives, nativism, and management: worldviews underlying controversies in invasion biology. Environ Ethics 34:5-25 81. Simberloff D (2012) Sustainability of biodiversity under global changes, with particular reference to biological invasions. In: Weinstein M, Turner RE (eds) Sustainability science: the emerging paradigm and the urban environment. Springer, New York, pp 139-157 82. Simberloff D (2013) Invasive species: what everyone needs to know. Oxford University Press, New York 83. Simberloff D (2014) Biological invasions: What’s worth fighting and what can be won? Ecol Eng (in press). Corrected proof available online 18 September 2013 [http://www.sciencedirect.com/science/article/pii/S0925857413003431] 84. Simberloff D, Alexander J, Allendorf F, Aronson J, Antunes PM, Bacher S, Bardgett R, Bertolino S, et al. (2011) Non-natives: 141 scientists object. Nature 475:36 85. Simberloff D, Martin J-L, Genovesi P, Maris V, Wardle DA, Aronson J, Courchamp F, Galil B, et al. (2013) Impacts of biological invasions: what’s what and the way forward. Trends Ecol Evol 28:58-66 86. Simberloff D, Souza L, Nuñez MA, Barrios-Garcia MN, Bunn W (2012) The natives are restless, but not often and mostly when disturbed. Ecology 93:598-607 87. Simberloff D, Von Holle B (1999). Positive interactions of nonindigenous species: invasional meltdown? Biol Invas 1:21-32 88. Sorensen PW, Fine JM, Dvornikovs V, Jeffrey CS, Shao F, Wang J, Vrieze LA, Anderson KR, Hoye TR (2005) Mixture of new sulfated steroids functions as a migratory pheromone in the sea lamprey. Nat Chem Biol 1:324-328 89. Sorensen PW, Vrieze LA (2003) The chemical ecology and potential application of the sea lamprey migratory pheromone. J Great Lakes Res 29 (S1):66-84 90. Spear RJ (2005) The great gypsy moth war. University of Massachusetts Press, Amherst, MA 91. Strauss SY, Lau JA, Carroll SP (2006) Evolutionary responses of natives to introduced species: what do introductions tell us about natural communities? Ecol Lett 9:357-374 92. Strong DR, Ayers DA (2013) Ecological and evolutionary misadventures of Spartina. Ann Rev Ecol Evol Syst 44:389-410 93. Thompson JD (1991) The biology of an invasive plant: What makes Spartina anglica so successful? BioScience 41:393-401 94. Thomson GM (1922) The naturalisation of animals and plants in New Zealand. Cambridge University Press, Cambridge, MA 95. Tomes N (1998) The gospel of germs: men, women, and the microbe in American life. Harvard University Press, Cambridge, MA 96. Towns DR, Byrd GV, Jones HP, Rauzon MJ, Russell JC, Wilcox C (2011) Impacts of introduced predators on seabirds. In: Mulder CPH, Anderson WB, Towns DR, Bellingham PJ (eds) Seabird islands. Ecology, invasion, and restoration. Oxford University Press, New York, pp 56-90 97. Van Driesche RG, Hoddle M, Center T (2008) Control of pests and weeds by natural enemies: an introduction to biological control. Blackwell, Malden, MA 98. Veitch CR, Clout MN, Towns DR (eds.) (2011) Island invasives: eradication and management. Proceedings of the International Conference on Island Invasives. The Invasive Species Specialist Group, IUCN, Auckland 99. Veltman CJ, Nee S, Crawley MJ (1996) Correlates of introduction success in exotic New Zealand birds. Am Nat 147:542-557 100. Vermeij GJ (1982) Phenotypic evolution in a poorly dispersing snail after arrival of a predator. Nature 299:349-350

CONTRIBUTIONS to SCIENCE 9 (2013) 7-16

Biological invasions: Much progress plus several controversies

101. Vilà M, Basnou C, Pyšek P, Josefsson M, Genovesi P, Gollasch S, Nentwig W, Olenin S, et al. (2010) How well do we understand the impacts of alien species on ecosystem services? A pan-European, crosstaxa assessment. Front Ecol Environ 8:135-144 102. Vilà M, Espinar JL, Hejda M, Hulme PE, Jarošík V, Maron JL, Pergl J, Schaffner U, et al. (2011) Ecological impacts of invasive alien plants: a meta-analysis of their effects on species, communities and ecosystems. Ecol Lett 14:702-708 103. Vince G (2011) Embracing invasives. Science 331:1383-1384 104. Vitousek P (1986) Biological invasions and ecosystem properties: can species make a difference? In: Mooney HA, Drake JA (eds) Ecology of biological invasions of North America and Hawaii. Springer, New York, pp 163-176 105. Vitousek PM, Walker LR, Whiteaker LD, Mueller-Dombois D, Matson PA (1987) Biological invasion by Myrica faya alters ecosystem development in Hawaii. Science 238:802-804 106. Vitule JRS, Freire CA, Vazquez DP, Nuñez MA, Simberloff D (2012) Revisiting the potential conservation value of non-native species. Conserv Biol 26:1153-1155 107. Wallace AR (1880) Island life: or, The phenomena and causes of insular faunas and floras, including a revision and attempted solution of the problem of geological climates. Macmillan, London

108. Whalon ME, Mota-Sanchez D, Hollingworth RM (2008) Global pesticide resistance in arthropods. Centre for Agricultural Bioscience International, Wallingford 109. Whisson DA (2011) Pesticides (mammal). In: Simberloff D, Rejmánek M (eds) Encyclopedia of biological invasions. University of California Press, Berkeley, CA, pp 535-538 110. Williamson M (1996) Biological invasions. Chapman and Hall, London 111. Woodward SA, Vitousek PM, Matson K, Hughes F, Benvenuto K, Matson PA (1990) Use of the exotic tree Myrica faya by native and exotic birds in Hawai’i Volcanoes National Park. Pac Sci 44:88-93 112. Woodworth BL, Atkinson CT, LaPointe DA, Hart PJ, Spiegel CS, Tweed EJ, Henneman C, LeBrun J, et al. (2005) Host population persistence in the face of introduced vector-borne disease: Hawaii amakihi and avian malaria. Proc Natl Acad Sci USA 102:1531-1536 113. Woolhouse MEJ, Haydon DT, Antia R (2005) Emerging pathogens: the epidemiology and evolution of species jumps. Trends Ecol Evol 20:238-244 114. Zenni RD, Nuñez MA (2013) The elephant in the room: the role of failed invasions in understanding invasion biology. Oikos 122:801-815

Scientists awarded the Ramon Margalef Prize for Ecology (2005–2012) The Autonomous Government of Catalonia created the Ramon Margalef Award for Ecology to honor the memory of the Catalan scientist Ramon Margalef (1919−2004), one of the main thinkers and scholars of ecology as a holistic science. His contributions were decisive to the creation of modern ecology. This international award recognizes those people around the world who have also made outstanding contributions to the development of the science of ecology. More information can be obtained at: www.gencat.cat/premiramonmargalef.

Year

Winner

Main topic of research

2005

Paul Dayton

Population and community ecology, mostly in benthic environments.

USA

2006

John Lawton

Dynamics of populations and communities, impact of global changes in organism populations and communities.

2007

Harold A. Mooney

Plant physiological ecology and phenomena affecting global changes, such as ecological invasions, the loss of diversity and the degradation of ecosystems.

USA

2008

Daniel Pauly

Study of the decline of fish stocks and the ecosystems’ response to human pressure.

2009

Paul R. Ehrlich

Population and human over-population.

USA

2010

Simon A. Levin

Mathematical modelling and empirical studies in the understanding of macroscopic patterns of ecosystems and biological diversities.

USA

2011

Juan Carlos Castilla

Marine ecology, mostly rocky ecosystems and theur sustainability.

Chile

2012

Daniel Simberloff

Invasive species and their impact in the loss of diversity.

USA

www.cat-science.cat

Country

France

CONTRIBUTIONS to SCIENCE 9 (2013) 7-16

DISTINGUISHED LECTURES CONTRIBUTIONS to SCIENCE 9 (2013) 17-23 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.159 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

The Nobel Prizes of 2011

Crystallography and the Nobel Prizes: On the 2011 Nobel Prize in Chemistry, awarded to Dan Shechtman Joan F. Piniella Department of Geology, Autonomous University of Barcelona, Barcelona, Catalonia

Based on the lecture given by the author at the IEC, Barcelona, on 13 December 2011 for the Nobel Prizes of 2011 Sessions. Correspondence: Departament de Geologia Facultat de Ciències Universitat Autònoma de Barcelona 08193 Bellaterra, Catalonia Tel. +34-935813088 Fax +34-935811263 E-mail: Juan.Piniella@uab.cat Received: 24.10.13 Accepted: 25.11.13

Summary.

Crystallography has a considerable presence among Nobel Prize laureates. Indeed, 48 of them have close links to crystallography. The 2011 Nobel Prize in Chemistry was awarded to Dan Shechtman for his discovery of quasicrystals. In addition to the scientific merit of the work, the Prize is a personal recognition of Dan Shechtman, whose ideas were initially rejected by the international scientific community. Yet, reason prevailed in the end, supported by arguments that arrived from seemingly unrelated directions, such as the study of Arab building tiles and the mathematical concept of tessellation. Concepts of a more crystallographic nature, such as twinned crystals and modulated and incommensurate crystal structures, also played an important role. Finally, in 1992, the International Union of Crystallography modified the definition of “crystal” to include quasicrystals.

Keywords: crystal structure · electron diffraction · quasicrystals · tessellations Resum. La

cristal·lografia té una gran presència en els premis Nobel; així doncs, 48 guardonats estan estretament vinculats a la cristal·lografia. El Premi Nobel de Química 2011 va ser concedit a Dan Shechtman pel descobriment dels quasicristalls. A part del mèrit científic del descobriment, el Premi és un reconeixement al treball de Dan Shechtman, ja que les seves idees van ser rebutjades inicialment per la comunitat científica internacional. Finalment la raó es va imposar, amb el suport d’arguments que van venir per camins insospitats i aparentment sense cap relació, com ara l’estudi dels mosaics presents en edificacions àrabs i també del concepte de tessel·lació. També hi van contribuir conceptes més pròpiament cristal·logràfics com les macles i les estructures modulades. L’any 1992 la Unió Internacional de Cristal·lografia va modificar la definició de cristall per tal d’incloure-hi els quasicristalls.

Paraules clau: estructura cristal·lina · difracció d’electrons · quasicristalls · tessel·lacions

The number of scientists working in the field of crystallography whose studies have been recognized with a Nobel Prize is remarkable. Indeed, according to the website of The International Union of Crystallography (IUCR) [http:// www.iucr.org /people/nobel-prize] there are 48 such laureates: 31 in Chemistry, 14 in Physics, and three in Physiology or Medicine. Given that, thus far, 166 scientists have www.cat-science.cat

been awarded the Nobel Prize in Chemistry and 198 the Nobel Prize in Physics, Nobel laureate crystallographers account for 18.7 % and 7.1 %, respectively. In the 21st century, nine crystallographers have been awarded the Nobel Prize in Chemistry and two the Nobel Prize in Physics. As for female Nobel laureates in Chemistry, the proportion of those recognized for their work in crystallography is 17

CONTRIBUTIONS to SCIENCE 9 (2013) 17-23

Crystallography and the Nobel Prizes: On the 2011 Nobel Prize in Chemistry, awarded to Dan Shechtman

Table 1. Noble Prizes in Chemistry awarded to women Scientist

Year

Prize

Comments

Marie Curie

1911

“in recognition of her services to the advancement of

Also awarded the 1903 Nobel Prize in Physics.

chemistry by the discovery of the elements radium and polonium, by the isolation of radium and the study of the nature and compounds of this remarkable element” Irène Joliot-Curie

1935

“in recognition of their synthesis of new radioactive

Awarded jointly with her husband, Frédéric Joliot.

elements”

Daughter of Nobel Prize winners Pierre Curie and Marie Curie.

Dorothy Crowfoot

1964

Hodgkin Ada E. Yonath

“for her determinations by X-ray techniques of the

Known as a founder of protein crystallography.

structures of important biochemical substances” 2009

“for studies of the structure and function of the

Pioneer of ribosome crystallography. Awarded jointly

ribosome”

with Venkatraman Ramakrishnan and Thomas A. Steitz.

ogy. Among the milestones noted in Table 2, we should mention the 1915 Nobel Prize, awarded to the Braggs, father and son; the two crystallography Nobel Prizes awarded in 1962; and the chemist Linus Pauling, who in 1954 received the Nobel Prize in Chemistry and in 1962 the Nobel Peace Prize. Given this impressive history, it comes as no surprise that the 2011 Nobel Prize in Chemistry was once again awarded to a crystallographer, specifically to Professor Dan Shechtman, born in Tel Aviv (Israel) in 1941 (Fig. 1). In this particular case, not only was the Prize awarded to just one person, who carried out scientific work of great importance, but it also honored the perseverance of a man who confronted the international scientific community with ideas that took many years to be accepted.

particularly noteworthy: two of the four women laureates were recognized for their work in this field (Table 1). Table 2 provides a list of all the crystallography Nobel Prizes, beginning with the earliest awards of the prize, in 1901. As can be seen in Table 2, initially all Nobel Prizes awarded to crystallography were in the field of Physics, a trend that later evolved towards Chemistry. In the most recent years, crystallography awards have honored an important number of works in the field of Biology—there is no Nobel Prize in Biol-

Dan Shechtman and his experiment This story starts in 1982, when Dan Shechtman was on sabbatical at the Johns Hopkins University in Baltimore (Maryland, USA). The focus of his research, carried out in collaboration with the U.S. National Bureau of Standards (Washington DC, USA), was alloys of aluminium and transition metals, obtained through fast cooling. Such alloys are of practical interest in the aeronautical industry. One of the experiments consisted of measuring electron diffraction by means of an electron microscope, such as shown in Fig. 1. On the morning of April 8, 1982, Dan Shechtman obtained several electron diffraction images showing a 5-fold symmetry (Fig. 2). Not only was this observation unique, but scientifically this type of symmetry was considered to be impossible [20]. As can be readily imagined, Dan Shechtman’s surprise was enormous, as he noted in his laboratory logbook (Fig. 3) with the comment: “(10 fold ???).” As any good scientist would do, Shechtman repeated the experiments many times and under different conditions, but those impossible

Fig. 1. Dan Shechtman and the electron microscope—the tool that enabled him to discover quasicrystals. (Image courtesy of Technion, Haifa, Israel © Technion Spokesperson).

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 17-23

PINIELLA

Table 2. Nobel Prizes related to crystallography Year, category

Awarded to

Awarded for

1901, Physics

Wilhelm Conrad Röntgen

“the extraordinary services he has rendered by the discovery of the remarkable rays subsequently named after him”

1914, Physics

Max von Laue

“his discovery of the diffraction of X-rays by crystals”

1915, Physics

Sir William Henry Bragg, Sir William Lawrence Bragg

“their services in the analysis of crystal structure by means of X-rays”

1917, Physics

Charles Glover Barkla

“his discovery of the characteristic Röntgen radiation of the elements”

1929, Physics

Prince Louis-Victor Pierre Raymond de Broglie

“his discovery of the wave nature of electrons”

1936, Chemistry

Petrus (Peter) Josephus Wilhelmus Debye

“his contributions to our knowledge of molecular structure through his investigations on dipole moments and on the diffraction of X-rays and electrons in gases”

1937, Physics

Clinton Joseph Davisson, George Paget Thompson

“their experimental discovery of the diffraction of electrons by crystals”

1946, Chemistrya

James Batcheller Sumner

“his discovery that enzymes can be crystallized”

1954, Chemistry

Linus Carl Pauling

“his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances”

1962, Physiology or Medicine

Francis Harry Compton Crick, James Dewey Watson, Maurice Hugh Frederick Wilkins

“their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material”

1962, Chemistrya

John Cowdery Kendrew, Max Ferdinand Perutz

“their studies of the structures of globular proteins”

1964, Chemistrya

Dorothy Crowfoot Hodgkin

“her determinations by X-ray techniques of the structures of important biochemical substances”

1972, Chemistrya

Christian B. Anfinsen

“his work on ribonuclease, especially concerning the connection between the amino acid sequence and the biologically active conformation”

1976, Chemistry

William N. Lipscomb

“his studies on the structure of boranes illuminating problems of chemical bonding”

1982, Chemistry

Aaron Klug

“his development of crystallographic electron microscopy and his structural elucidation of biologically important nucleic acid-protein complexes”

1985, Chemistry

Herbert A. Hauptman and Jerome Karle

“their outstanding achievements in the development of direct methods for the determination of crystal structures”

1988, Chemistrya

Johann Deisenhofer, Robert Huber, Hartmut Michel

“the determination of the three-dimensional structure of a photosynthetic reaction centre”

1991, Physics

Pierre-Gilles de Gennes

“discovering that methods developed for studying order phenomena in simple systems can be generalized to more complex forms of matter, in particular to liquid crystals and polymers”

1992, Physics

George Charpak

“his invention and development of particle detectors, in particular the multiwire proportional chamber”

1994, Physics

Clifford G. Shull, Betram N. Brockhouse

“pioneering contributions to the development of neutron scattering techniques for studies of condensed matter”

1996, Chemistry

Robert F. Curl Jr., Sir Harold W. Kroto, Richard E. Smalley

“their discovery of fullerenes”

1997, Chemistrya

Paul D. Boyer, John E. Walker, Jens C. Skou

“their elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)”

2003, Chemistrya

Peter Agre, Roderick MacKinnon

“structural and mechanistic studies of ion channels”

2006, Chemistrya

Roger D. Kornberg

“his studies of the molecular basis of eukaryotic transcription”

2009, Chemistrya

Venkatraman Ramakrishnan, Thomas A. Steitz, Ada E. Yonath

“studies of the structure and function of the ribosome”

2010, Physics

Andre Geim, Konstantin Novoselov

“groundbreaking experiments regarding the two-dimensional material graphene”

2011, Chemistry

Dan Shechtman

“the discovery of quasicrystals”

2012, Chemistrya

Robert J. Lefkowitz, Brian K. Kobilka

“studies of G-protein-coupled receptors”

Martin Karplus, Michael Levitt, Arieh Warshel

“the development of multiscale models for complex chemical systems”

2013, Chemistry

The research awarded was related to biology

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 17-23

Crystallography and the Nobel Prizes: On the 2011 Nobel Prize in Chemistry, awarded to Dan Shechtman

Fig. 2. (A) The electron diffraction of a quasicrystal. (B) Detail. The 5-fold symmetries are highlighted in color. (Image courtesy of Prof. Sven Lidin).

The reaction of the scientific community

5-fold symmetries stubbornly kept appearing. The seeming impossibility was due to the fact that, given their periodicity, crystals can only present rotational symmetries of 2-fold, 3-fold, 4-fold, and 6-fold, as can be shown mathematically (crystallographic restriction theorem). The symmetry of periodic media, such as crystals, had been firmly established by the end of the 19th century and had culminated in the enumeration of 230 symmetry space groups. Figure 4 provides a graphic demonstration of the crystallographic restriction theorem in the case of a 4-fold rotation axis. Thus, when two parallel quaternary axes are rotated 90º, new quaternary axes are generated that place themselves periodically. Figure 5 illustrates the analogous situation for a 6-fold rotation axis (60º). With 2-fold and 3-fold axes, the same result is obtained; in other words, a periodic medium is also generated. When trying the same procedure for the 5-fold axis (Fig. 6) or any other rotation axis other than those listed above, the result is not a periodic medium, but rather many points that continue to densely fill the space. www.cat-science.cat

When Dan Shechtman tried to publicize his results, he was met with strong opposition, as has so often happened in the history of science (think of Miguel Servet, Galileo Galilei, and others). Luckily, in the 20th century being burned at the stake or sentenced to prison was no longer considered an appropriate response to controversial ideas such as Shechtman’s. Nevertheless, he ended up leaving the laboratory where he had worked and his findings continued to receive intense criticism from the scientific community. Even such an important personality as the double Nobel Prize laureate L. Pauling was of the opinion that “there is no such thing as quasicrystals, only quasi-scientists.” His results were repeatedly denied publication in the scientific journals until two long years later, when they were published in the journal Physical Review Letters, in 1984 [20]. Meanwhile, the work of other scientists furthered the doubt of the scientific community regarding the existence of quasicrystals. 20

CONTRIBUTIONS to SCIENCE 9 (2013) 17-23

PINIELLA

Fig. 3. Dan Shechtmanâ&#x20AC;&#x2122;s laboratory logbook for April 8, 1982.

Fig. 4. The action of a 4-fold rotation axis generates four new axes. If the process is repeated, a periodical medium is obtained. To illustrate this, axis A has been applied first, and axis A1 after.

Acceptance of quasicrystals and new discoveries Nonetheless, Dan Shechtman and other scientists were ultimately able to build support for the existence of quasicrystals [16,18,21,23] such that by the early 1990s this phenomenon had gained general acceptance. Most quasicrystals described to date correspond to alloys, but others of different composition were discovered as well. Thus, quasicrystals turned out to be a more general phenomenon than had originally been thought and they have been observed in, for example, chalcogenides [9], polymers [13], liquid crystals [25], and nanoparticles [22]. There is even a natural quasicrystal, a mineral called icosahedrite [5,6].

Properties and applications The first quasicrystals obtained were metastable, which made them difficult to study and seemed to limit their possible applications, as their structure would disappear rapidly. In 1987, the first stable quasicrystal, with the formula Al65Cu20Fe15, was discovered [23], followed by reports of other stable quasicrystals. These were essentially aluminum alloys and they opened the door both to detailed studies of their properties and to their possible applications [10]. Along these lines, important differences were observed regarding the thermal and electrical properties of alloys with a quasicrystalline vs. crystalline structure. For example, the thermal conductivity of AlFeCu and AlPdMn, two alloys with a quasicrystalline structure, is 100 times lower than that of either pure aluminum or zirconium dioxide (ZrO2), which is known to be a good thermal insulator [11]. The electrical conductivity of quasicrystals is also highly inferior to that of metals, but they cannot be considered as standard insulators, since their conductivity increases substantially as the temperature rises. However, their behavior differs from that of semiconductors, too [4]. Quasicrystals also have an atypical magnetic behavior, with alloys conwww.cat-science.cat

Fig. 5. Action of a 6-fold rotation axis. As with the axis in Fig. 4, a periodic medium is obtained.

Fig. 6. The action of a 5-fold rotation axis produces close points (for instance, A2 and A3), which as the process continues densely fill the plane with 5-fold axes. There is no periodicity.

CONTRIBUTIONS to SCIENCE 9 (2013) 17-23

Crystallography and the Nobel Prizes: On the 2011 Nobel Prize in Chemistry, awarded to Dan Shechtman

Fig. 7. (A) Darb-e Imam, Isfahan (Iran). (Image courtesy of Prof. Dudley / Elliff, www.kendalldudley.com, Arlington, MA). (B) The Alhambra, Granada (Spain). (Image courtesy of Roberto Veturini,“Alhambra Tiles 15” November 7, 2008 via Flickr, Creative Commons Attribution). (C) Sultan Ahmed Mosque, Istanbul (Turkey). (Image courtesy of Prof. Mehmet Erbudak, Bogaziçi University, Istanbul).

pear in massive form. At the same time, however, when used as coatings or surface treatments their inherent fragility is reduced. Chemically, quasicrystals are highly resistant to oxidation and corrosion, comparable to stainless steel [8], which has encouraged their patented application in surgical material, acupuncture needles, and razor blades [17]. In addition, quasi crystal surfaces have very small coefficients of friction and are therefore of interest as antiadhesive materials [12], e.g., in cookware and in parts of combustion engines. In the case of cooking utensils, superficial treatment with Teflon has been replaced by quasicrystal coatings, as these are much more heat resistant [1]. A disadvantage is that the antiadherence of Teflon is slightly better and that with quasicrystals spallation of the material must be avoided, as it can result in toxicity. Numerous potential applications of quasicrystals have been described, including the storage of hydrogen [15], catalysis [14], and the strengthening of composites [7]. These and other applications of quasicrystals are currently fields of active investigation that will no doubt eventually yield interesting results.

taining transition metals, such as Fe or Mn, tending to be diamagnetic rather than paramagnetic [3]. In terms of their mechanical properties, quasicrystals are exceptionally hard [24]. This is a function of their nonperiodic nature, which hinders the presence and propagation of dislocations. For this same reason, quasicrystals are also fragile, which limits their practical use when they ap-

The structure of quasicrystals Soon after the discovery of quasicrystals, efforts were made to elucidate the distribution of their atoms, i.e., to determine their crystalline structure and thus why their diffractions violate the sacred rules of crystallography. In 1986, P. Bak published an article with the title, “Icosahedral Quasicrystals: Where Are the Atoms?” [2]. A rigorous explanation of the structure of quasicrystals is beyond the scope of this report, but a basic explanation

Fig. 8. Penrose tiling. The mosaic is made up of two types of rhombuses that, once coupled, produce a 5-fold symmetry. There is no periodicity. (Image courtesy of Domesticat, June 8, 2012 via Flickr, Creative Commons Attribution-Noncommercial-ShareAlike).

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 17-23

PINIELLA

can be attempted. Quasicrystals can be described as groupings of ordered atoms that have long-distance symmetry (just like conventional crystals) but no periodicity. It is this organization of matter that was previously considered to be scientifically impossible. An excellent bidimensional model of the structure of quasicrystals can be found in some of the tiling of mosques and other Islamic buildings. Indeed, it is quite remarkable that a structure that puzzled 20th century science was in full view for centuries and been seen and admired by thousands of people for centuries [19]. Figure 7 provide representative examples of the typical symmetries of quasicrystals. In addition, in 1970, the mathematician and physicist Roger Penrose described what came to be called “Penrose tiling,” which are basically mosaics made up of two pieces of rhombic shape that can fill (tile) the whole plane while never repeating (i.e., there is no periodicity) and which present pentagonal symmetry, as do quasicrystals. Figure 8 shows one of these mosaics.

References 1.

Anonymous (2011) Sputtering technique forms versatile quasicrystalline coatings. MRS Bulletin 36:581 2. Bak P (1986) Icosahedral crystals: Where are the atoms? Phys Rev Lett 56:861-864 3. Belin-Ferré E, Klanjsek M, Jaglicic Z, Dolinsek J, Dubois JM (2005) Experimental study of the electronic density of states in aluminiumbased intermetallics J Phys: Condens Matter 17, 6911-6924 4. Bianchi AD, Bommeli F, Chernikov MA, Gubler U, Degiorgi L, Ott HR (1997) Electrical, magneto-, and optical conductivity of quasicrystals in the Al-Re-Pd system. Phys Rev B 55:5730–5735 5. Bindi L, Steinhardt PJ, Yao N, Lu PJ (2009) Natural quasicrystals. Science 234:1306-1309 6. Bindi L, Steinhardt PJ, Yao N, Lu PJ (2011) Icosahedrite, Al63Cu24Fe13, the first natural quasicrystal. Am Mineral 96:928-931 7. Bloom PD, Baikerikar KG, Otaigbe JU, Sheares VV (2000) Development of novel polymer/quasicrystal composite materials. Mat Sci Eng 294-296:156-159 8. Chang SL, Chin WB, Zhang CM, Jenks CJ, Thiel PA (1995) Oxygen adsorption on a single-grain, quasicrystalsSurface. Surf Sci 337:135-146 9. Conrad M, Krumeich F, Harbrecht B (1998) A dodecagonal quasicrystalline chalcogenide. Angew Chem Int Ed 37:1383-1386 10. Dubois JM (2005) Useful Quasicrystals. World Scientific Publishing Co, Singapore 11. Dubois JM (2012) Properties- and applications of quasicrystals and complex metallic alloys. Chem Soc Rev 41:6760-6777 12. Dubois JM, Kang SS, Massiani Y, (1993) Application of quasicrystalline alloys to surface coating of soft metals. J Non-Cryst Solids 153154: 443-445 13. Hayashida K, Dotera T, TakanoA, Matsushita Y (2007) Polymeric quasicrystal: Mesoscopic quasicrystalline tiling in ABC star polymers. Phys Rev Lett 98:195502. 14. Kameoka S, Tanabe T, Tsai AP (2004) Al–Cu–Fe quasicrystals for steam reforming of methanol: a new form of copper catalysts. Catal Today 93-95:23-26 15. Kocjan A, Kovacic S, Gradisek A, McGuiness PJ, Apih T, Dolinsek J, Kobe S (2011) Selective hydrogenation of Ti–Zr–Ni alloys. Int J Hydrogen Energ 36:3056-3061 16. Levine D, Steinhardt R (1984) Quasicrystals: A new class of ordered structures. Phys Rev Lett 53:2477-2480 17. Liu P, Stigenberg AP, Nilsson JO (1994) Isothermally formed quasicrystalline precipitates used for strengthening in a new maraging stainless steel. Scripta Metall Mater. 31:249-254 18. Lu PJ, Deffeyes K, Steinhardt PJ, Yao N (2001) Identifying and indexing icosahedral quasicrystals from powder diffraction patterns. Phys Rev Lett 87:275507 19. Makovicky E (2007) Comment on "Decagonal and Quasi-Crystalline Tilings in Medieval Islamic Architecture". Science 318:1383 20. Shechtman D, Blech I, Gratias D, Cahn JW (1984) Metallic phase with long-range orientational order and no translational symmetry. Phys Rev Lett 53:1951-1953 21. Shechtman D, Blech I (1985) The microstructure of rapidly solidified Al6Mn. Metall Trans 16A:1005-1012 22. Talapin DV, Shevchenko EV, Bodnarchuk MI, Ye X, Chen J, Murray ChB (2009) Quasicrystalline order in self-assembled binary nanoparticle superlattices. Nature 461:964-967 23. Tsai AP, Inoue A, Matsumoto T (1987) A stable quasicrystal in Al-CuFe system. Jpn J Appl Phys 26:L1505-L1507 24. Tsai AP, Aoki K, Inoue A, Masumoto T (1993) Synthesis of stable quasicrystalline particle-dispersed Al base composite alloys. J Mater Res 8:5-7 25. Zeng X, Ungar G, Liu Y, Percec V, Dulcey AE, Hobbs JK (2004) Supramolecular dendritic liquid quasicrystals. Nature 428:157-160

* * * Given the great number of cases of quasicrystals described experimentally, and the convincing theories that explain their structure and properties, in 1992 the International Union of Crystallography changed the definition of “crystal” to incorporate quasicrystals. This was, all things considered, a great triumph for Dan Shechtman… and for science in general.

Main publications underpinning the award • Bak P (1986) Icosahedral crystals: Where are the atoms? Phys Rev Lett 56:861-864 • Mackay A (1982) Crystallography and the Penrose pattern. Physica A114:609-613 • Shechtman D, Blech I, Gratias D, Cahn JW (1984) Metallic phase with long-range orientational order and no translational symmetry. Phys Rev Let 53:1951-1953 • Shechtman D, Blech I (1985) The microstructure of rapidly solidified Al6Mn. Metallurgical Transactions 16A:1005-1012

To learn more • Abe E (2012) Electron microscopy of quasicrystals—where are the atoms? Chem Soc Rev 41:6787-6798 • Dubois JM (2005) Useful quasicrystals. World Scientific Pub., Singapore • Dubois JM (2012) Properties- and applications of quasicrystals and complex metallic alloys. Chem Soc Rev 41:6760-6777 • Dubois JM, Belin-Ferré E (2011) Complex metallic alloys: Fundamentals and Applications. Wiley-VCH, Weinheim, Germany • Giacovazzo C (ed) (2002) Fundamentals of crystallography. 2nd ed. Oxford University Press, New York, USA • Steurer W, Deloudi S (2008) Fascinating quasicrystals. Acta Crystallographica A64:1-11 • Steurer W, Deloudi S (2009) Crystallography of quasicrystals: Concepts, methods and structures. Springer, Berlin, Germany • Suck JB, Schreiber M, Häussler P (eds) (2010) Quasicrystals: An introduction to structure, physical properties and applications. Springer, Berlin, Germany

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 17-23

DISTINGUISHED LECTURES CONTRIBUTIONS to SCIENCE 9 (2013) 25-32 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.160 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

The Nobel Prizes of 2012

Smart cell-surface receptors: On the 2012 Nobel Prize in Chemistry, awarded to Robert J. Lefkowitz and Brian K. Kobilka Rafael Franco1,2,3, María S. Aymerich2,3 1. Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Catalonia 2. Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra 3. Department of Biochemistry and Genetics, University of Navarra, Pamplona, Navarra

Based on the lecture given by R. Franco at the IEC, Barcelona, on December 14, 2012, and at the October Centre of Contemporary Culture, València, on January 30, 2013. Correspondence: Rafael Franco Dept. de Bioquímica i Biologia Molec. Universitat de Barcelona Av. Diagonal, 643 08028 Barcelona, Catalonia Tel. +34-610306123 E-mail: rfranco@ub.edu Received: 01.02.13 Accepted: 31.10.13

Summary.

The 2012 Nobel Prize in Chemistry recognized Professors Robert J. Lefkowtiz and Brian K. Kobilka for their work on β-adrenergic receptors, which have been the paradigm for understanding the mechanism of action of receptors coupled to heterotrimeric G proteins (GPCRs). In fact, the discovery of hundreds of members of this family of cell-surface receptors has provided a detailed understanding of how cells sense their environment. This brief article draws from the summary used by the Royal Swedish Academy of Sciences to support its choice of Lefkowitz and Kobilka for the 2012 award. It also considers some of the diverse applications of GPCRs. Keywords:

G-protein-coupled receptors · adenosine receptors · adrenergic receptors · receptor heteromers

Resum. El

Premi Nobel de Química 2012 va reconèixer el treball dels professors Robert J. Lefkowitz i Brian K. Kobilka sobre els receptors β-adrenèrgics, que han estat el paradigma per a la comprensió del mecanisme d’acció dels receptors acoblats a proteïnes G heterotrimèriques (GPCRs). De fet, el descobriment de centenars de membres d’aquesta família de receptors de la superfície cel·lular ha permès entendre detalladament com detecten les cèl· lules el seu entorn. Aquest breu article està basat en el resum utilitzat per la Reial Acadèmia Sueca de Ciències per donar suport a la concessió del premi de 2012, i considera també les diverses aplicacions dels GPCRs. Paraules clau: receptor acoblat a proteïnes G

· receptors d’adenosina · receptors adrenèrgics ·

heteròmers de receptors

The beginnings and previous breakthroughs

nervous transmission, entitled “A study of the adreno tropic receptors,” in the American Journal of Physiology [1]. But the molecular nature of adrenotropic receptors, i.e., receptors for adrenaline (known today as adrenergic receptors), would remain unknown until the work of Robert J. Lefkowitz, one of the 2012 Nobel laureates, in the late 1960s. In fact, Ahlquist’s penultimate scientific publi-

The 2012 Nobel Prize in Chemistry cannot be appreciated without reference to previous work by Ahlquist and Black. In 1948, Raymond Ahlquist (Missoula, Montana, USA, 1914–1983), Professor of Pharmacology at the Medical College of Georgia, USA, published a paper on adrenergic www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 25-32

Smart cell-surface receptors: On the 2012 Nobel Prize in Chemistry, awarded to Robert J. Lefkowitz and Brian K. Kobilka

cation [2] was a review on “Adrenergic β-blocking agents,” which had been developed before β-adrenergic receptors were precisely understood. Indeed, β-blockers can be considered among the most successful drugs in the history of medicine and they remain therapeutically important in a variety of diseases, especially cardiac arrhythmias and hypertension. Due to the reduction in the heart beat rate and other calming effects, they may be used offl abel in stressful situations (for instance before a PhD defense). In the early 1960s, Sir James W. Black (Uddingston, Scotland, UK, 1924–2010) developed the first β-blockers: propranolol and pronethalol. Although pronethalol never reached the market because of carcinogenicity in mice, propranolol revolutionized the medical management of cardiovascular diseases. According to contrasted information available in the Swedish Academy and on Wikipedia, Sir James Whyte Black developed his research in both the academia and the pharmaceutical industry. One of this main achievements was the developing of the first marketed beta-blocker, propranolol. He also participated in the development of an effective anti-ulcer treatment that consisted of another drug (cimetidine) targeting a GPCR (H2 histamine receptors). Black’s contribution to developing effective therapies for two common diseases was noteworthy, and recognized by the 1988 Nobel Prize in Physiology or Medicine. Furthermore, it should be taken into account that the development was possible despite little being known about their targets: β-adrenergic receptors for propranolol, and histamine receptors for cimetidine. Both receptors belong to a superfamily known today as “G-protein-coupled receptors” (GPCRs). It was the β-adrenergic receptor that received the attention of the Nobel Prize Committee in 2012.

sisted of and how they worked remained obscured for most of the 20th Century.” We live through our senses, whose receptors are located on our anatomical surface. Certainly, one of Lefkowitz’s key insights was to consider that cells “sense their environment” via sensors/receptors and these are, necessarily, located on the cell surface. In his approach to unraveling the molecular nature of sensors/receptors he selected the adrenaline receptor, which can be easily detected. (Reasons at the origins of other scientific discoveries have been similar. Myoglobin and hemoglobin structures were first determined because these proteins could be easily followed throughout their purification due to their color.) Moreover, adrenaline receptors are abundantly expressed by cardiac muscle cells and can be studied pharmacologically in isolated beating hearts. Lefkowitz’s method to detect adrenaline receptors took advantage of the one used to detect receptors in the thyroid, by radiolabeling the ligand, which in the latter case includes the hormone thyroxine. Accordingly, soon in his career Lefkowitz used radioactivity to trace cardiac receptors for adrenaline. As noted by the Swedish Academy: “He attached an iodine isotope to various hormones, and thanks to the radiation, he managed to unveil several receptors, among those a receptor for adrenaline: β-adrenergic receptor. His team of researchers extracted the receptor from its hiding place in the cell wall and gained an initial understanding of how it works.” Later on it was demonstrated that adrenaline had quite a number of different targets depending on the cell; thus far, two alpha and three β subtypes of adrenergic receptors have been identified. While the radioactive detection of β-adrenergic receptors was an important contribution to the field of pharmacology, the obvious next step was to determine their structure. The usual techniques to resolve proteins structure are not readily applicable to proteins such as adrenergic receptors that are embedded in the plasma membrane, i.e., that are surrounded by lipids. Thus, instead, Lefkowitz and his group obtained the mRNA sequence encoding the receptor protein, from which they could easily decipher the amino acid sequence. It was at this moment, as noted by the Academy, that Brian Kobilka entered in scene: “The team achieved its next big step during the 1980s. The newly recruited Kobilka accepted the challenge to isolate the gene that codes for the β-adrenergic receptor from the gigantic human genome. His creative approach allowed him to attain his goal. When the researchers analyzed the gene, they discovered that the receptor was similar to one in the eye that captures light. They realized that there is a whole family of receptors that look alike and function in the same manner.” Interestingly, the βadrenergic receptor was similar to rhodopsin, which is the receptor for light. Solid work from many laboratories in the field showed that all GPCRs had

Molecular nature of β-adrenergic receptors Robert J. Lefkowitz (New York City, USA, 1943) heads the Howard Hughes Medical Institute at Duke University Medical Center (Durham, North Carolina, USA) and Brian K. Kobilka (Little Falls, Minnesota, USA, 1955) is a professor at the Department of Molecular and Cellular Physiology, Stanford University School of Medicine (California, USA). The two researchers received the 2012 Nobel Prize in Chemistry for: “…groundbreaking discoveries that reveal the inner workings of an important family of receptors that enable cells to sense its environment: G-protein– coupled receptors.” The Swedish Academy also noted that: “For a long time, it remained a mystery how cells could sense their environment. Scientists knew that hormones such as adrenaline had powerful effects: increasing blood pressure and making the heart beat faster. They suspected that cell surfaces contained some kind of recipient for hormones. But what these receptors actually conwww.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 25-32

FRANCO, AYMERICH

10 years, however, some of these orphan receptors, such as GPR55, now known to be the lysophosphatidylinositol receptor [29], have found their origins. In recognizing the biomedical importance of the role played by GPCRs in a variety of diseases, the Swedish Academy pointed out that “about half of all medications achieve their effect through G-protein–coupled receptors.” Although this percentage was overestimated—the real number lies around 35–40 %—it is clear that the number of “GPCR drugs” far exceeds that targeting any other family of proteins. Some of these drugs are life-saving while others improve the quality of life, for instance in cases of depression or anxiety.

the same basic structure, i.e. seven transmembrane domains. This observation suggested that these receptors originated from an ancestral gene encoding a cell surface sensor. GPCRs act as sensors for an enormous number of hormones and neurotransmitters active in our cells at every instant. Their importance is reflected in the fact that some 10 % of the genes in the human genome encode GPCRs (Fig. 1)—a percentage higher than that of any other protein family in the human genome; and there are probably even more than the currently estimated 802 GPCR genes in the human genome [3b]. As the Academy put it: “Today this family is referred to as G-protein–coupled receptors. About a thousand genes code for such receptors, for example, for light, flavor, odor, adrenaline, histamine, dopamine and serotonin.” GPCRs are subdivided into different classes: class A (Rhodopsin-like), class B (Secretin-like), class C (Glutamate Receptor-like), and other (Adhesion, Frizzled, Taste type-2, etc.) [3b]. Some 70 % of all GPCRs are of the class A type. The receptors in this class include those for odorants/ pheromones, underlining the importance of smell in evolution. There are also “orphan” receptors, whose endogenous hormones/neurotransmitters are still unknown. In the last

GPCR-mediated signaling In the last 30 years of the 20th century, hundreds of scientists participated in deciphering the mechanism by which GPCRs communicate the presence of extracellular signals to the cell interior. Because of their work, GPCR-mediated signaling is better understood than that of any other receptor family. Among the key proteins in this process are the G proteins, whose discovery and characterization merited a Nobel Prize in Physiology or Medicine in 1994, awarded to

GPRC SUPERFAMILY (802 GENES)

Class A (701 genes)

Class B (15 genes)

Class C (24 genes)

Other 62 genes

Olfactory (359 genes)

Fig. 1. Classification of the human GPCR family. The main subfamilies are: class A (rhodopsin-like), class B (secretin-like), and class C (glutamate-like); other includes Frizzled, taste type-2, and unclassified receptors. Modified from Bjarnadóttir et al., 2006 [3b]. The number of GPCR receptors in the human genome is not yet known; therefore, the numbers in the figure are estimates from data in Pubmed and Wikipedia.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 25-32

Smart cell-surface receptors: On the 2012 Nobel Prize in Chemistry, awarded to Robert J. Lefkowitz and Brian K. Kobilka

Alfred G. Gilman and Martin Rodbell for “their discovery of G-proteins and the role of these proteins in signal transduction in cells.” Further information on these G proteins and their action as mediators between GPCRs and intracellular components can also be found at the Nobel Prize web site. The first G proteins to be identified and characterized were those that regulate, either positively (Gs) or negatively (Gi), the activity of adenylate cyclase, the enzyme that produces cAMP, an important intracellular messenger. Indeed, the title of Gilman’s Nobel lecture was: “G Proteins and Regulation of Adenylyl Cyclase.” In the meantime, a number of other G proteins and cAMP-independent signaling pathways have been discovered. The history of GPCRs took an unusual turn with the discovery that they can bind to a variety of proteins other than G proteins. Consequently, GPCRs are now more accurately referred to as heptaspanning membrane receptors. It was Lefkowitz who, in 1987, reported that adrenergic receptors interact with a protein he named β-arrestin, because of its apparent involvement in receptor deactivation [3]. Lefkowitz and colleagues later observed that β-arrestin also participated in G-protein-independent signaling. They reported that β2-adrenergic receptors signal the relevant mitogen-activated protein kinase signal transduction pathway via an arrestindependent pathway that is independent of G protein coupling [41]. Adenosine receptors are likewise able to bind to a number of proteins, some of them extracellular, such as adenosine deaminase, and others intracellular, such as caveolin, the heat shock cognate protein hsc73, and alpha-actinin [4,5,12,15,20,22,35–38]. The full diversity of GPCR-related signaling options stems from the ability of these receptors to form homodimers and even heteromers. Recognition of these features provides many new opportunities to exploit the structural and functional diversity of these receptors, e.g., in drug discovery (see below).

the puzzle was greatly aided by Kobilka’s contribution, in which he helped to solve the structure of G-protein-coupled β2-adrenergic receptors (Fig. 2) [33]. In contrast to soluble proteins such as myoglobin or hemoglobin, which are easily isolated and crystallized and their 3D structure readily resolved using X-ray diffraction, membrane proteins pose a challenge, as their purification and crystallization are difficult. Rhodopsin, which is very abundant in the retina, was extracted by Palczewski and collaborators [30,31], facilitated by their use of mixed micelles of nonyl β-d-glucoside and heptanetriol. Thus, a highly purified protein preparation could be crystallized from solutions containing varying amounts of detergent and amphiphile; these crystals provided the first structure of a seven transmembrane protein [31]. The laboratory of Palczewski also carried out

Transmembrane domains of β2AR

GPCR structure The final paragraph of the statement of the Royal Swedish Academy of Sciences in support of its choice for the 2012 Nobel Prize in Chemistry is: “The studies by Lefkowitz and Kobilka are crucial for understanding how G-protein–coupled receptors function. Furthermore, in 2011, Kobilka achieved another breakthrough; he and his research team captured an image of the β-adrenergic receptor at the exact moment that it is activated by a hormone and sends a signal into the cell. This image is a molecular masterpiece—the result of decades of research.” There has been a general consensus in the GPCR field, which year after year seemed ripe for a Nobel prize, that the award would have not been possible without the resolution of the 3D structure of these proteins. This piece of www.cat-science.cat

Fig. 2. Structure of the β2-adrenergic receptor-Gs complex. The overall structure shows the β2-adrenergic receptor (β2AR) bound to an agonist and engaged in extensive interactions with a heterotrimeric Gs, which is composed of Gsa, Gb, and Gg subunits. A specific nanobody (Nb35) binds to the Gs protein between the a and b subunits. Crystallization, for purposes of structure resolution, is facilitated by NB35 and by the lysozyme of T4 bacteriophage (T4L) fused to the N-terminus of the β2-adrenergic receptor. Data taken from the protein data bank cited in the report by Rasmussen (2011) [33]. (Reprinted by permission from Macmillan Publishers Ltd.).

CONTRIBUTIONS to SCIENCE 9 (2013) 25-32

FRANCO, AYMERICH

(5 nm)-1

50 nm

15 nm

Fig. 3. Atomic force microscopy images of dimer arrays of rhodopsin in native retinal disc membranes. (From [17]; reprinted by permission from Macmillan Publishers).

pioneering work using infrared-laser atomic-force microscopy to reveal the native arrangement of rhodopsin, which forms paracrystalline arrays of dimers in mouse retinal disc membranes [17] (Fig. 3). The methodology for other GPCRs that are less abundant in natural sources is far more complex and involves the design of fusion proteins containing part of the receptor and motifs that facilitate crystallization. For example, a common strategy to promote crystallization is to fuse the protein with the lysozyme from T4 bacteriophage and to delete the carboxy-terminal tail, which has high conformational flexibility [42] (Fig. 2). These pseudo-receptors are over-expressed in heterologous systems and then further purified and crystallized using specific approaches. The first receptor structures resolved accordingly were those of the β2-adrenergic [10,34] and the A2A adenosine [23] receptors. The contribution of the laboratory of Raymond Stevens, at the Scripps Research Institute in California, to obtaining these structures was fundamental.

them. GCPRs are not the only cell-surface receptors, as these also include ionotropic and enzyme-linked receptors, which are not coupled to G proteins (Fig. 4). However, as noted above, GPCRs are the most abundant membrane receptors in mammals and they have led to the recognition of “partial agonists,” “full agonists,” “inverse agonists,” “neutral antagonists,” “biased agonism,” and “selectivity.” The signal given by a partial agonist is lesser than that achieved by the full agonist, which is usually the natural hormone/neurotransmitter. Classical antagonists are known today as neutral antagonists although many compounds initially considered as neutral are indeed inverse agonists, that is, they bind to the receptor but counteract the response of agonists and reduce the constitutive activity of GPCRs. This definition makes sense only if the GPCR is active even in the absence of agonists. Such constitutive activity was indeed shown by Lefkowitz and his group, using mutant or over-expressed receptors in heterologous cells [13,25]. There are also several diseases, such as congenital night blindness and male precocious puberty, that are caused by mutations in GPCR genes such that the encoded receptors have high constitutive activity [40]. Furthermore, many (non-mutated) GPCRs display natural constitutive activity, which has raised interest in inverse agonist development in drug discovery programs. Biased agonism describes the activation of different signaling pathways by different molecules acting on a given receptor [39]. It is an important consideration in the design of mole-

GPCRs in pharmacology An appreciation of the terms agonist (a compound that activates the receptor), antagonist (one that triggers the inactive conformation of the receptor), and allosteric modulator (a compound that modulates the effect of the agonist) is essential to understanding receptors for hormones or neurotransmitters and the activities of the drugs that bind to www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 25-32

Smart cell-surface receptors: On the 2012 Nobel Prize in Chemistry, awarded to Robert J. Lefkowitz and Brian K. Kobilka

ION CHANNELS (acetylcholine nicotinic receptor)

GPCRs (serotonin receptor)

RECEPTOR TYROSINE KINASES (insulin receptor)

Fig. 4. The three main types of cell-surface receptors. Examples are given in parentheses.

cules with therapeutic potential. Selectivity is another important concept in receptor pharmacology and drug discovery. A selective compound that binds, e.g., to β2 adrenergic receptors, would have at least 100-fold more potency for this subtype than for any other subtype of adrenergic receptor.

may occur, i.e. there are receptors that may be found as monomers in the cell surface. Homodimers have led to a dimer-based pharmacology that is very robust in defining useful parameters for drug development [9,18,19]. Yet, from a functional point of view, the monomeric or dimeric structure of a given receptor is largely irrelevant. This is not the case for heteromer formation. Indeed, if GPCRs deserve another Nobel Prize it will likely be for novel insights into their heteromeric forms. A GPCR heteromer is defined as a macromolecular complex composed of at least two different receptor units, both functional, with biochemical properties that demonstrably differ from those of the individual components [16]. In fact, heteromer-specific signaling relies on a precise quaternary structure of the whole complex [28]. The first reported heteromer for a given neurotransmitter was that formed by the kappa and delta opioid receptors [24]. The first identified heteromer formed by two receptors for two different neurotransmitters/neuromodulators was that containing the adenosine A1 and dopamine D1 receptors [21]. Several other heteromers were subsequently reported, proof that the GPCR heteromer receptor field is gaining momentum in the 21st century. There are two open questions concerning the molecular aspects of heteromerization: the size(s) of the heteromer(s) and the receptor: G protein stoichiometry. Finding answers to them will require imaginative approaches and powerful techniques, in-

The future: structure and function of GPCR heteromers The impressive research leading to the 2012 Nobel Prize in Chemistry was centered on “monomeric” receptors, including a seminal work co-authored by Leftowitz, in which the mechanism of action of a single GPCR molecule coupled to one G protein was described [14]. Unlike membrane receptors of other families, e.g., T-cell receptors and insulin receptors, the expression of class A rhodopsin-like GPCRs as monomers on the cell surface was a common assumption. But this view is progressively changing based on findings, such as those from our laboratory, in which we determined that A2A receptors are present on the cell surface as homodimers [6]. Atomic force microscopy images of retinal rhodopsin also show GPCRs as arrays of homodimers (Fig. 3). Recently, Kobilka’s laboratory reported that the µ-opioid receptor crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6 [26]. It is therefore likely that many cell-surface receptors are in the form of homodimers. Exceptions www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 25-32

FRANCO, AYMERICH

References

cluding resolution of the 3D structure of macromolecular complexes formed by heteromers and multiple G proteins. At present, complexes consisting of three different receptors (heterotrimers) and dimers of heterodimers (heterotetramers) have already been reported [7,27]. From an evolutionary point of view, heteromers seem to provide diversity in hormone- or neurotransmitter-mediated responses. The dopamine receptors subtypes 1 (D1) and 2 (D2) offer an appropriate example of functional diversity. Whereas D1 is coupled to a Gs protein and D2 to a Gi protein, the D1-D2 receptor heteromer couples to a Gq protein. G proteins are the mediators that control the concentration of second messengers, with Gs and Gi controlling cAMP and Gq controlling Ca2+ levels. Thus, while individual receptors signal via cAMP, the heteromer signals via a totally different cascade, one that is triggered by calcium ions [32]. Another example of the differential role of heteromers is provided by the adenosine A1-A2A receptor heteromer. Adenosine regulates glutamate release from cortical neurons; the regulation of neurotransmitter release via A1 receptors is negative but it is positive when A2A receptors become activated. The mystery of why nerve terminals express both A1 and A2A receptors to regulate glutamate release was solved when heteromers of A1-A2A receptors were identified and their functions elucidated [8,11]. Specifically, these heteromers constitute a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. By intra-heteromer crosstalk, the neuron senses the extracellular concentration of adenosine and responds accordingly [8,11]. In summary, the heteromer may both increase and decrease neurotransmitter release, something that would be impossible to achieve with just one adenosine receptor subtype. Promising applications can be expected as novel heteromers are identified and novel heteromer-specific functions are discovered. Drug development based on GPCR monomers, such as screening drugs in heterologous systems expressing a single receptor, was successful in the 20th century but, at least thus far, progress in the 21st century has been slow. Perhaps one way to accelerate GPCR drug discovery is to focus on GPCRs and heteromers. A two-state dimer receptor model is now available to understand the mechanism of action of GPCRs and to interpret data obtained from drugs interacting with dimers, and even from mixtures of monomers and dimers [9,19]. By contrast, heteromers are distinct entities such that a given drug will have different affinities and different efficacies depending on the heteromer. Cell models expressing receptor heteromers would allow the identification of novel pharmacological profiles [9] and would broaden the therapeutic potential of drugs targeting GPCRs while lowering the incidence of side effects. www.cat-science.cat

Ahlquist RP (1948) A study of the adrenotropic receptors. Am J Physiol 153:586-600 2. Ahlquist RP (1976) Adrenergic beta-blocking agents. Prog Drug Res 20:27-42 3. Benovic JL, Kühn H, Weyand I, Codina J, Caron MG, Lefkowitz RJ (1987) Functional desensitization of the isolated β-adrenergic receptor by the β-adrenergic receptor kinase: Potential role of an analog of the retinal protein arrestin (48-kDa protein). Proc Natl Acad Sci USA 84:8879-8882 3b. Bjarnadóttir TK, Gloriam DE, Hellstrand SH, Kristiansson H, Fredriksson R, Schiöth HB (2006) Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse. Genomics 88:263-73 4. Burgueño J, Blake DJ, Benson MA, Tinsley CL, Esapa CT, Canela EI, Penela P, Mallol J, Mayor FJr, Lluis C, Franco R, Ciruela F (2003) The adenosine A2A receptor interacts with the actin-binding protein a-actinin. J Biol Chem 278:37545-37552 5. Cabello N, Remelli R, Canela L, Soriguera A, Mallol J, Canela EI, Robbins MJ, Lluis C, Franco R, Mclihinney RA, Ciruela F (2007) Actinbinding protein a-actinin-1 interacts with the metabotropic glutamate receptor type 5b and modulates the cell surface expression and function of the receptor. J Biol Chem 282:12143-12153 6. Canals M, Burgueño J, Marcellino D, Cabello N, Canela EI, Mallol J, Agnati L, Ferré S, Bouvier M, Fuxe K, Ciruela F, Lluis C, Franco R (2004) Homodimerization of adenosine A2A receptors: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Neurochem 88:726-734 7. Carriba P, Navarro G, Ciruela F, Ferré S, Casadó V, Agnati L, Cortés A, Mallol J, Fuxe K, Canela EI, Lluís C, Franco R (2008) Detection of heteromerization of more than two proteins by sequential BRETFRET. Nat Methods 5:727-733 8. Casadó V, Barrondo S, Spasic M, Callado LF, Mallol J, Canela E, Lluís C, Meana J, Cortés A, Sallés J, Franco R (2010) Gi protein coupling to adenosine A1-A2A receptor heteromers in human brain caudate nucleus. J Neurochem 114:972-980 9. Casadó V, Cortés A, Mallol J, Pérez-Capote K, Ferré S, Lluis C, Franco R, Canela EI (2009) GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers? Pharmacol Ther 124:248-257 10. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF et al. (2007) High-resolution crystal structure of an engineered human β2adrenergic G protein-coupled receptor. Science 318:1258-1265 11. Ciruela F, Casadó V, Rodrigues RJ, Luján R, Burgueño J, Canals M, Borycz J, Rebola N, Goldberg SR, Mallol J, Cortés A, Canela EI, López-Giménez JF, Milligan G, Lluis C, Cunha RA, Ferré S, Franco R (2006) Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1–A2A receptor heteromers. J Neurosci 26:2080-2087 12. Ciruela F, Saura C, Canela EI, Mallol J, Lluis C, Franco R (1996) Adenosine deaminase affects ligand-induced signalling by interacting with cell surface adenosine receptors. FEBS Lett 380:219-223 13. Cotecchia S, Exum S, Caron MG, Lefkowitz RJ (1990) Regions of the a1-adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function. Proc Natl Acad Sci USA 87:2896-2900 14. De Lean A, Stadel JM, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled β-adrenergic receptor. J Biol Chem 255:7108-7117 15. Escriche M, Burgueño J, Ciruela F, Canela EI, Mallol J, Enrich C, Lluís C, Franco R (2003) Ligand-induced caveolae-mediated internalization of A1 adenosine receptors: morphological evidence of endosomal sorting and receptor recycling. Exp Cell Res 285:72-90

CONTRIBUTIONS to SCIENCE 9 (2013) 25-32

Smart cell-surface receptors: On the 2012 Nobel Prize in Chemistry, awarded to Robert J. Lefkowitz and Brian K. Kobilka

16.

Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, Fuxe K, George SR, Javitch JA, Lohse MJ, Mackie K, Milligan G, Pfleger KDG, Pin JP, Volkow ND, Waldhoer M, Woods AS, Franco R (2009) Building a new conceptual framework for receptor heteromers. Nat Chem Biol 5:131-134 17. Fotiadis D, Liang Y, Filipek S, Saperstein DA, Engel A, Palczewski K (2003) Atomic-force microscopy: Rhodopsin dimers in native disc membranes. Nature 421:127-128 18. Franco R, Canals M, Marcellino D, Ferré S, Agnati L, Mallol J, Casadó V, Ciruela F, Fuxe K, Lluis C, Canela EI (2003) Regulation of heptaspanning-membrane-receptor function by dimerization and clustering. Trends Biochem Sci 28:238-243 19. Franco R, Casadó V, Mallol J, Ferré S, Fuxe K, Cortés A, Ciruela F, Lluis C, Canela EI (2005) Dimer-based model for heptaspanning membrane receptors. Trends Biochem Sci 30:360-366 20. Ginés S, Ciruela F, Burgueño J, Casadó V, Canela EI, Mallol J, Lluís C, Franco R (2001) Involvement of caveolin in ligand-induced recruitment and internalization of A1 adenosine receptor and adenosine deaminase in an epithelial cell line. Mol Pharmacol 59:1314-1323 21. Ginés S, Hillion J, Torvinen M, Le Crom S, Casadó V, Canela EI, Rondin S, Lew JY, Watson S, Zoli M, Agnati LF, Vernier P, Lluis C, Ferré S, Fuxe K, Franco R (2000) Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci USA 97:8606-8611 22. Gracia E, Pérez-Capote K, Moreno E, Barkešová J, Mallol J, Lluis C, Franco R, Cortés A, Casadó V, Canela EI (2011) A2A adenosine receptor ligand binding and signalling is allosterically modulated by adenosine deaminase. Biochem J 435:701-709 23. Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC (2008) The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322: 1211-1217 24. Jordan BA, Devi LA (1999) G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399:697-700 25. Kjelsberg MA, Cotecchia S, Ostrowski J, Caron MG, Lefkowitz RJ (1992) Constitutive activation of the a1B-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation. J Biol Chem 267:1430-1433 26. Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S (2012) Crystal structure of the m-opioid receptor bound to a morphinan antagonist. Nature 485:321-326 27. Maurel D, Comps-Agrar L, Brock C, Rives ML, Bourrier E, Ayoub MA, Bazin H, Tinel N, Durroux T, Prézeau L, Trinquet E, Pin JP (2008) Cell-surface protein-protein interaction analysis with time-resolved FRET and snap-tag technologies: application to GPCR oligomerization. Nat Methods 5:561-567 28. Navarro G, Ferré S, Cordomi A, Moreno E, Mallol J, Casadó V, Cortés A, Hoffmann H, Ortiz J, Canela EI, Lluís C, Pardo L, Franco R, Woods AS (2010) Interactions between intracellular domains as key determinants of the quaternary structure and function of receptor heteromers. J Biol Chem 285:27346-27359

www.cat-science.cat

29.

Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T (2007) Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun 362:928-934 30. Okada T, Le Trong I, Fox BA, Behnke CA, Stenkamp RE, Palczewski K (2000) X-Ray diffraction analysis of three-dimensional crystals of bovine rhodopsin obtained from mixed micelles. J Struct Biol 130:73-80 31. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739-745 32. Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, O’Dowd BF, George SR (2007) D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci USA 104:654-659 33. Rasmussen SGF, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah STA, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK (2011) Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477:549-555 34. Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007) GPCR engineering yields high-resolution structural insights into β2adrenergic receptor function. Science 318:1266-1273 35 Ruiz MA, Escriche M, Lluis C, Franco R, Martin M, Andrés A, Ros M (2000) Adenosine A1 receptor in cultured neurons from rat cerebral cortex: colocalization with adenosine deaminase. J Neurochem 75: 656-664 36 Sarrió S, Casadó V, Escriche M, Ciruela F, Mallol J, Canela EI, Lluis C, Franco R (2000) The heat shock cognate protein hsc73 assembles with A1 adenosine receptors to form functional modules in the cell membrane. Mol Cell Biol 20:5164-5174 37. Saura C, Ciruela F, Casadó V, Canela EI, Mallol J, Lluis C, Franco R (1996) Adenosine deaminase interacts with A1 adenosine receptors in pig brain cortical membranes. J Neurochem 66:1675-1682 38. Saura CA, Mallol J, Canela EI, Lluis C, Franco R (1998) Adenosine deaminase and A1 adenosine receptors internalize together following agonist-induced receptor desensitization. J Biol Chem 273:17610-17617 39. Schonbrunn A (2008) Selective agonism in somatostatin receptor signaling and regulation. Mol Cell Endocrinol 286:35-39 40. Seifert R, Wenzel-Seifert K (2002) Constitutive activity of G-proteincoupled receptors: cause of disease and common property of wildtype receptors. Naunyn Schmiedeberg’s Arch Pharmacol 366:381-416 41. Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT, Lictarge O, Leftkowitz RJ (2006) β-Arrestindependent, G protein-independent ERK1/2 activation by the β2 adrenergic receptor. J Biol Chem 281:1261-1273 42. Zou Y, Weis WI, Kobilka BK (2012) N-terminal T4 lysozyme fusion facilitates crystallization of a G protein coupled receptor. PLoS ONE 7(10):e46039. doi: 10.1371/journal.pone.0046039

CONTRIBUTIONS to SCIENCE 9 (2013) 25-32

DISTINGUISHED LECTURES CONTRIBUTIONS to SCIENCE 9 (2013) 33-41 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.161 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

The Nobel Prizes of 2012

The Gedankenexperimente of quantum mechanics become reality: On the 2012 Nobel Prize in Physics, awarded to Serge Haroche and David J. Wineland Jordi Mompart Optics Group, Department of Physics, Autonomous University of Barcelona, Bellaterra, Catalonia

Based on the lecture given by the author at the IEC, Barcelona, on December 18, 2012, and at the October Centre of Contemporary Culture, València, on January 28, 2013. Correspondence: Departament de Física Facultat de Ciències Universitat Autònoma de Barcelona 08193 Bellaterra, Catalonia Tel. +34-935811652 Fax +34-935812155 E-mail: jordi.mompart@uab.cat Received: 08.03.13 Accepted: 31.10.13

Summary. The

development of quantum mechanics at the beginning of the 20th century constituted one of the greatest revolutions in the theoretical and experimental sciences as well as in philosophy, completely transforming the way we understand the world at both micro- and macroscales. In fact, as its founders pointed out, quantum mechanics is strongly counterintuitive to our classical way of thinking. To overcome this limitation, Erwin Schrödinger and Albert Einstein, among others, proposed a series of idealized experiments to illustrate the paradoxical behavior of quantum mechanics, with the best known being “Schrödinger’s cat” and the “EPR paradox” (Einstein-Podolsky-Rosen paradox). These thought experiments, referred to by the German Gedankenexperimente, made use of the superposition principle and the entanglement of quantum systems to show the strange properties of quantum mechanics. However, they were somehow ridiculous proposals since, as indicated by Schrödinger himself, we would never be able to manipulate individual particles. The 2012 Nobel Prize in Physics was awarded to Serge Haroche and David J. Wineland, who, with extremely sophisticated experimental devices, are able to trap and manipulate individual photons and ions, respectively, thus allowing the Gedan kenexperimente proposed at the beginning of quantum mechanics to become reality. In addition, these experiments set the foundations for a new field of research, quantum information science, and for the development of new applications, such as atomic clocks with unprecedented accuracy. These developments have signaled the beginning of a second quantum revolution.

Keywords: quantum

optics · quantum mechanics · cavity quantum electrodynamics · trapping and cooling of ions Resum. El

desenvolupament de la mecànica quàntica a principis del segle xx va constituir una de les més grans revolucions tant en les ciències experimentals i en les ciències exactes com en la filosofia, i va modificar completament la manera d’entendre el món tant a nivell microscòpic com macroscòpic. De fet, tal com varen fer notar els seus fundadors, la mecànica quàntica és força contradictòria respecte a la nostra forma clàssica de pensar. Per superar aquesta limitació, Erwin Schrödinger i Albert Einstein, entre d’altres, van proposar una sèrie d’experiments ideals que mostraven el comportament paradoxal de la mecànica quàntica, entre els quals l’anomenat «gat de Schrödinger» i la «paradoxa EPR» (o paradoxa Einstein-Podolsky-Rosen) són els més coneguts. Aquestes propostes experimentals, que es coneixen amb el nom alemany de Gedankenexperimente (experiments mentals), feien ús del principi de superposició i de l’entrellaçament dels sistemes quàntics www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 33-41

The Gedankenexperimente of quantum mechanics become reality: On the 2012 Nobel Prize in Physics, awarded to Serge Haroche and David J. Wineland

per mostrar les estranyes propietats de la mecànica quàntica. Tanmateix, com va indicar el mateix Schrödinger, es tractava de propostes ridícules perquè mai aconseguiríem manipular partícules individuals. El Premi Nobel de Física 2012 ha estat atorgat a Serge Haroche i David J. Wineland, que van ser capaços, mitjançant sofisticats dispositius experimentals, d’atrapar i manipular fotons i ions individuals, respectivament, tot fent realitat els Gedankenexperimente proposats als inicis de la mecànica quàntica. A més, aquells experiments van establir les bases per a un nou camp de recerca, la ciència de la informació quàntica, i per al desenvolupament de noves aplicacions com ara la construcció de rellotges atòmics de precisió anteriorment mai assolida. Aquests desenvolupaments han marcat l’inici de l’anomenada segona revolució quàntica. Paraules clau: òptica

quàntica · mecànica quàntica · electrodinàmica quàntica en cavitats · captura i refredament d’ions

been awarded to quantum optics, a field of research in physics that deals with the interaction of light with matter, in which either one, or both, can be described by the laws of quantum mechanics. Quantum optics has developed in parallel with quantum mechanics and includes phenomena such as black-body radiation and the photoelectric effect, both of which are part of the foundations of quantum mechanics. Laser cooling and trapping techniques and the generation of squeezed states of light are two modern ap-

The Royal Swedish Academy of Sciences awarded the 2012 Nobel Prize in Physics to Serge Haroche and David J. Wineland, “for ground-breaking experimental methods that enable measuring and manipulation of individual quantum systems” (Fig. 1). Haroche, born in France in 1944, works at the Collège de France in Paris, and Wineland, a US citizen also born in 1944, at the National Institute of Standards and Technology in Boulder, Colorado. The 2012 Nobel Prize in Physics adds to a series of Nobel Prizes that have

Fig. 1. Serge Haroche (left) and David J. Wineland (right). (Photos by Ulla Montan © The Nobel Foundation).

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 33-41

MOMPART

plications of quantum optics. Figure 2 shows the most recent previous Nobel Prize laureates whose research activities were in the field of quantum optics. These include in 2005, Roy Glauber, “for his contribution to the quantum theory of optical coherence”, and John L. Hall and Theodor W. Hänsch “for their contributions to the development of laser-based precision spectroscopy, including the optical frequency comb technique;” the 2001 Nobel Prize to Eric A. Cornell, Wolfgang Ketterle, and Carl E. Wieman “for the achievement of Bose-Einstein condensation in dilute gases of alkali atoms, and for early fundamental studies of the properties of the condensates;” and the 1997 Nobel Prize to Steven Chu, Claude Cohen-Tannoudji, and William D. Phillips “for development of methods to cool and trap atoms with laser light.” Science is a human activity that develops as a result of the strong and continuous efforts of many researchers around the world, whose endeavors benefit from the preceding research of their colleagues. It is non-stop, step by step collective work. In those countries that permanently

support science, outstanding research groups and laboratories are created that are conducive to success and whose efforts are recognized by the scientific community. Quantum optics is a good example of excellent collective work extending over time. Haroche’s PhD supervisor was CohenTannoudji, who received the Nobel Prize in Physics in 1997 for the development of novel techniques for trapping and cooling neutral atoms with laser light. Cohen-Tannoudji’s PhD supervisor was Alfred Kastler, who was awarded the 1966 Nobel Prize in Physics for the development of the optical pumping technique. On the other side of the Atlantic, Wineland’s PhD supervisor was Norman F. Ramsey, the 1989 Nobel laureate in Physics for the discovery of what is now called Ramsey spectroscopy. Ramsey’s PhD supervisor was Isidor Rabi, who received the Nobel Prize in Physics in 1944 for his contribution to the development of nuclear magnetic resonance. Standard experiments in quantum optics require highly sophisticated techniques that push technological frontiers, as exemplified by the creation of an extremely high quality vacuum to manipulate electrical, magnetic, and light fields with exceptional control, or to trap charged and neutral particles and cool them to temperatures nearly reaching absolute zero. Through their training at some of the best quantum optics laboratories in the world, Haroche and Wineland learned and developed these and other techniques that, later on, would allow them to follow their own careers and to become two of the most distinguished researchers in the quantum optics community. Some of their own PhD students might be future recipients of the Nobel Prize in Physics. At the beginning of the 20th century, it was widely believed that quantum theory, at the time only recently introduced, was only applicable to systems formed by a large collection of particles, such that its predictions were of statistical nature. Indeed, experiments with single particles were simply not possible. Today, however, as explicitly shown by Haroche and Wineland, technology allows for the isolation, manipulation, and measurement of single particles. Thus, it is possible to investigate individual quantum systems, whose behavior is counterintuitive compared to classical ones, and to study the transition from quantum to classical regimes when dealing with mesoscopic systems. Indeed, Haroche and Wineland were awarded the 2012 Nobel Prize in Physics for their experiments with single (or few) photons and single (or few) ions, respectively. The experimental techniques and devices involving the manipulation of photons in cavity quantum electrodynamics have nothing to do with those being used for trapping and cooling individual ions; rather, they represent two different yet complementary approaches—Haroche traps single photons, manipulating and measuring them with Rydberg atoms, while Wineland traps single ions or a chain of ions

Fig. 2. Recent Nobel Prizes in Physics related to quantum optics. Top row: the 2005 laureates. Middle row: the 2001 laureates. Bottom row: the 1997 laureates. (Photos by Ulla Montan © The Nobel Foundation).

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 33-41

The Gedankenexperimente of quantum mechanics become reality: On the 2012 Nobel Prize in Physics, awarded to Serge Haroche and David J. Wineland

(and their motional state), manipulating and measuring them with laser light. However, from a fundamental point of view the two quantum systems are quite similar since both can be modeled through the Jaynes-Cummings Hamiltonian [14], first proposed in 1963, which accounts for the dynamics of a two-level system interacting with a quantized harmonic oscillator (Fig. 3). In Haroche’s experiments the quantized harmonic oscillator accounts for one single mode of the quantum electromagnetic field while in Wineland’s experiments it describes the motional (vibrational) states of the trapped ion. g and e are the ground and excited states of the two-level atom, respectively, and n with n = 0,1,2,... are the energy eigenstates of the quantum harmonic oscillator. Ω is the so-called Rabi frequency, which accounts for the interaction strength of a laser field with the electric dipole moment of the two-level transition, and γ is the spontaneous decay rate from e to g . Both systems have allowed investigation into some of the most fundamental issues emerging from quantum mechanics, including entanglement, non-locality, wave function collapse, and the transition from quantum to classical regimes through decoherence. In addition, these technologies have been used for quantum information science implementing single and two-qubit gates as well as quantum algorithms and, in the case of the cooling and trapping of ions, to design atomic clocks of the highest accuracy. In the following, we review some of the outstanding scientific contributions that have come out of Haroche’s and Wineland’s experiments with individual quantum systems. Nevertheless, to understand the significance of their work, we first review some of the oldest and most fundamental problems in quantum mechanics, illustrated by the Gedan kenexperimente, as well as several elementary issues in

quantum optics, such as the (quantum) Rabi oscillations. We then describe the experiments of Haroche, Wineland, and coworkers, discussing the main results obtained with single photons and single ions and then pointing out some of the conclusions that can be drawn from them.

Gedankenexperimente in quantum mechanics The term Gedankenexperiment was first introduced by the German physicist Ernst Mach and refers to the conceptual counterpart of a real experiment such that if the real experiment is not possible, then an idealized, purely imaginary one is conceived of in its place. Gedankenexperimente, in English, thought experiments, were proposed in the early years of quantum theory to make apparent some of its counterintuitive aspects. Two of these Gedankenexperimente became very famous: “Schrödinger’s cat” [25] and the “EPR paradox,” the latter referring to Einstein, Podolsky, and Rosen [10]. These two thought experiments exploit the quantum superposition principle, first identified by Dirac. In quantum mechanics, the quantum state of a system can evolve in a superposition of two or more orthogonal states, e.g., the wave function of a particle can be a superposition of two non-overlapping distant wave functions such that the particle is described as being in two different positions at the same time. In Paul Dirac’s words referring to quantum states: “The original state must be regarded as the result of a kind of superposition of the two or more new states, in a way that cannot be conceived on classical ideas.” [9]. In terms of the standard (Copenhagen) interpretation of quantum mechanics, the superposition principle states that, before the measurement, a quantum system is undetermined, collapsing (randomly) to a particular possibility

|e >

|2 > |1 > |0 >

|g >

Fig. 3. Sketch of the Jaymes-Cummings model: two-level atom (in red) coupled to a quantized harmonic oscillator (in blue).

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 33-41

MOMPART

cles’ position and momentum were well-defined before the measurement, which would imply realism, or whether the measurement collapses the position and momentum of the particles, implying a “spooky” action at a distance between the two correlated (entangled) particles. The latter would mean that quantum mechanics is non-local. Today’s most advanced tests of so-called Bell’s inequalities [1] have indeed demonstrated the non-locality of quantum mechanics while leaving open the question of realism. In this short review of the Gedankenexperimente, it is important to add that, as late as 1952, Schrödinger affirmed: “We never experiment with just one electron or atom or (small) molecule. In thought-experiments we sometimes assume that we do; this invariably entails ridiculous consequences...” [26]. However, rapid advancements in the technologies to isolate, manipulate, and measure individual quantum systems, developed by Haroche and Wineland among others, have shown that Schrödinger’s statement is no longer valid. Gedankenexperimente are now real experiments being implemented in some of the world’s most sophisticated quantum optics laboratories. To explain how Haroche and Wineland have pushed technology to its present status and made real the most significant thought experiments, we need first to recall some of the basic principles of quantum optics. In the following, we describe the so-called Rabi oscillations (see [27] for a detailed review).

upon being measured. Einstein was extremely skeptical about the notion of a collapse, as in a conversation with William Hermanns he had stated: “God doesn’t play dice with the world.” [21]. “Schrödinger’s cat” [25] was proposed in 1935 by the Austrian physicist Erwin Schrödinger. This thought experiment illustrates apparently contradictory aspects of the standard interpretation of quantum mechanics as applied to classical (macroscopic) objects. Let us place a living cat into a closed chamber together with a device that contains a radioactive substance such that, if a single atom of the radioactive substance decays, a relay mechanism will activate a hammer that, in turn, will break a vial containing a poison lethal to the cat. If at a given time the radioactive atom is in a superposition state of non-decaying and decaying states, then from the standard interpretation of quantum mechanics we conclude that the cat is in an alive-dead superposition. Obviously, if we open the door and check the actual state of the cat we will only obtain one of the two possible answers: alive or dead. However, before the measurement, quantum mechanics describes the full quantum system formed by the radioactive atom and the cat as a quantum superposition in which the cat, according to its wave function, is simultaneously alive and dead. This strange and counterintuitive conclusion from the standard interpretation of quantum mechanics was criticized by Einstein who, in conversations with Abraham Pais, asked: “Do you really think the moon is not there if you are not looking at it?” [21]. The “EPR paradox” [10] was, as it name implies, proposed by Albert Einstein, Boris Podolsky, and Nathan Rosen, in 1935. It was aimed at showing the incompleteness of quantum theory. In quantum mechanics, particles satisfy Heisenberg’s uncertainty principle [12], which fixes a fundamental limit to the precision with which certain pairs of conjugate variables of a particle, such as its position and momentum, can be known simultaneously. In mathematical terms, the uncertainty principle applied to the particle’s position and momentum reads ∆x∆p ≥  2 , where ∆x and ∆p are the uncertainty in the position and the momentum and  is the reduced Planck’s constant. Contrary to classical systems, quantum particles cannot have a simultaneously well-defined position and momentum, which from Einstein’s point of view was far-removed from reality. In a modern formulation of the “EPR paradox,” two particles originating from the decay of a parental one are emitted towards two detectors such that the total energy, linear momentum, and angular momentum are conserved. Measuring the position of one of the particles and the momentum of the other, and bearing in mind the laws of conservation, the position and momentum of both particles can be deduced with accuracy, therefore violating Heisenberg’s principle. The question raised by Einstein and coworkers is whether the partiwww.cat-science.cat

Rabi oscillations Let us consider a two-level atom with ground state g and excited state e (Fig. 3 left) interacting with a monochromatic laser field that can be described in classical terms,  whose amplitude and frequency are E 0 and ω , respectively. We consider first the resonant case for which the laser frequency ω coincides with the transition frequency ω 0. Within the standard quantum optics approximations, the state vector for a two-level atom initially prepared in the ground state g is, as given in Dirac’s notation:  Ωt   Ωt   g − sin   e  2   2 

ψ (t ) = a g (t ) g + a e (t ) e = cos

(1)

where a g (t ) and ae (t ) are the complex probability amplitudes of the ground and excited states, respectively, and    Ω = µ o ·E 0 /  is the Rabi frequency, where µ o is the electric dipole moment of the two-level transition. The atomic populations of ground and excited states can be determined through p g (t ) = a g a g∗ and p e (t ) = a e a e* , respectively, and oscillate at the Rabi frequency Ω. For a two-level atom resonantly interacting with a single mode of the quantized electromagnetic field, as in Haroche’s experiments, the quantum Rabi flopping of an atom 37

CONTRIBUTIONS to SCIENCE 9 (2013) 33-41

The Gedankenexperimente of quantum mechanics become reality: On the 2012 Nobel Prize in Physics, awarded to Serge Haroche and David J. Wineland

initially prepared either in state ψ (0) g ,n +1 = g ⊗ n + 1 or state ψ (0) e,n = e ⊗ n is given, respectively, by: ψ (t )

 Ω n + 1t   Ω n + 1t   g ⊗ n + 1 − sin  0 e ⊗ n = cos 0     2 2    

(2a)

 Ω n + 1t   Ω n + 1t   e ⊗ n + sin  0  g ⊗ n +1 = cos 0     2 2    

(2b)

g , n +1

ciently strong coupling, Haroche’s experiments require the use of two-level atoms whose electric dipole moment is huge, e.g., circular Rydberg atoms. A Rydberg atom is usually an alkaline atom whose active electron has been excited, by means of subsequent light pulses, to a bound state close to the continuum, i.e., it possesses a very high principal quantum number. The core electrons shield the active electron from the attractive Coulomb field of the nucleus such that it is effectively a hydrogen-like atom. Successive microwave photons are usually sent to the Rydberg atom to reach maximum orbital and magnetic quantum numbers for the state of the active electron such that its wave function becomes an almost classical one with a toroidal shape. If so, this atom is called a circular Rydberg atom. In Haroche’s experiments, performed at the Laboratoire Kastler Brossel in Paris, circular Rydberg atoms are prepared whose principal quantum numbers are typically of 50 or 51. In this case, the electron describes a quasi-classical trajectory around the nucleus, whose radius is about 100 µm, resulting in an electric dipole moment about 1000 times larger than that of electric dipole transitions involving the ground and first excited states of the active electron. Note also that standard transition frequencies between circular Rydberg states are in the microwave range. In Haroche’s experiments, circular Rydberg atoms are sent one by one towards a microwave cavity, of a few centimeters length, whose longitudinal cavity mode frequency matches the transition frequency between two consecutive Rydberg states. Since this frequency is in the microwave domain, the cavity has to be cryogenically cooled down to temperatures as low as T = 1 mK, to reduce the presence of unwanted thermal photons. In addition, for either the Fock state or the coherent state introduced in the cavity to survive for the entire duration of the experiment, Haroche em-

and ψ (t )

e,n

where n is the number of photons of the quantized field and Ω0 is the vacuum Rabi frequency. States with well-defined photon number are called Fock states, with n = 0 as the vacuum state. Note that if the system is initially prepared in state e ⊗ 0 there will be Rabi oscillations at the vacuum Rabi frequency Ω0, i.e., vacuum induces Rabi oscillations, while for an initial state g ⊗ 0 there will be no Rabi oscillations. For the off-resonance case, the interaction between the two-level atom and the electromagnetic field yields level shifts that depend on the detuning, the number of photons in the cavity, and the state of the atom which, during the interaction, produces a state-dependent phase shift for both the atom and the electromagnetic field.

Haroche’s experiments with single photons In Haroche’s experiments (Fig. 4), a two-level atom interacts with a quantized electromagnetic field that is typically prepared in a Fock state, e.g., the vacuum state 0 , or in a coherent state, i.e., a particular superposition of Fock states that presents quasi-classical properties [27]. Since the quantized electromagnetic field in the cavity has a very small mean photon number, and in order to obtain suffi-

Circular Rydberg atom

Microwave cavity

Ionizing detector

Fig. 4. Scheme of the experimental setup for Haroche’s experiments. A two-level circular Rydberg atom is sent through a microwave cavity containing a quantized electromagnetic field. The output state of the atom is measured with an ionizing field detector.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 33-41

MOMPART

where the subscript i = 1,2 refers to the first and second atom, respectively. Therefore, the output state of the system shows a non-local correlation between the atomic states of two circular Rydberg atoms, which indeed correspond to an EPR pair consisting of two massive particles [11]. Note that the two atoms become entangled through (successive) interactions with the cavity field but without directly interacting with each other. Haroche and coworkers also have been able to trap coherent states of the electromagnetic field in a far detuned microwave interacting with a two-level atom in a superposition of two circular Rydberg states. In this case, the cavity field splits into a superposition of two coherent states with different phases, i.e., a Schrödinger’s cat for the electromagnetic field is created [5]. Additionally, with his setup, Haroche is able to physically implement quantum non-demolition measurements [3], a quantum phase gate for quantum information tasks [22], entanglement between three atoms [23], teleportation of atomic states between two cavities [20], and the observation of a single-photon without destroying it [7].

ploys the highest grade mirrors, made of niobium, such that the photons’ lifetime in the cavity is about 130 ms, i.e., the photons undergo 1.5 billion reflections before they are finally absorbed or transmitted through the mirrors; this corresponds to a total path length of 40,000 km, about the distance of the Earth’s circumference. Note also that the lifetimes of circular Rydberg states are a few tens of ms, much longer than the typical time of flight of atoms between their excitation and detection, tens of µs in Haroche’s experiments. Finally, once the circular Rydberg atoms have crossed the microwave cavity, their state can be selectively detected with high efficiency by means of the ionizing field technique, since the amplitude of the ionization electric field varies substantially with the principal quantum number. Let us consider now that an individual atom initially prepared in the excited state e of the two-level Rydberg transition is sent through the microwave cavity containing a resonant vacuum mode. Following Eq. (2b), the full system formed by the atom and the cavity mode will experience vacuum Rabi oscillations. If the atomic velocity is initially chosen such that the total duration of the interaction with the cavity mode is Ω 0 t = π / 2 , then the output state of the full system will be: 1

ψ (t output ) =

⊗ 0 + g ⊗1)

Wineland’s experiments with single ions After finishing his PhD with Ramsey in 1970, Wineland held a postdoctoral position with the group of Hans Dehmelt, at the University of Washington, where he started working on electron and ion traps. Dehmelt and Wolfgang Paul, together with Ramsey, were awarded the 1989 Nobel Prize in Physics “for the development of the ion trap technique.” In Wineland’s experiments (Fig. 5A), an ion trap is created by a combination of static and oscillatory electric fields. Ions can be individually addressed with laser beams and their fluorescence registered with a CCD camera. The experiments are performed in ultrahigh vacuum and at extremely low temperatures, to isolate the ions from heat and unwanted surrounding radiation. With this approach, in 1981, Wineland and Itano were able to trap a single 24Mg+ ion in a Penning trap [30]. Figure 5A shows the energy eigenstates of the system formed by the two internal levels of a single ion, g and e , and the ion’s motional state n . In the Lamb-Dicke regime [27], a laser field can be appropriately tuned to a transition involving ∆n = −1,0,+1 (corresponding, respectively, to the red, black, and blue double arrows in Fig. 5B), while spontaneous emission takes place predominantly into the channel ∆n = 0 . Therefore, assuming an initial state g, n , it is possible to cool down the ion’s motional degrees of freedom by the subsequent application of red- sideband laser pulses to reach state g ,0 . The sideband cooling technique was first implemented by Wineland and coworkers using 198Hg+ ions [8]. In addition, they reported the preparation of Fock, coherent, squeezed, and thermal states of motion for an isolated 9Be+ ion [17].

(3)

That is, the output state corresponds to a correlated (entangled) state between the atomic and cavity states. Measurement of the atomic state with the ionizing field detector will cause its collapse (randomly) in either the ground or the excited Rydberg state, which, in turn, will collapse the cavity into the vacuum or the one-photon state, through a non-local influence. Hence, if the outgoing Rydberg atom is in the excited Rydberg state, the cavity will collapse to the vacuum state; if the atom is in the ground Rydberg state, the cavity will collapse to a Fock state containing one photon. The observation of non-local entangled states between atomic and photon number states was reported by Haroche and coworkers in [4,11]. Let us consider now that after the generation of the entangled state, as described by Eq. (3), and before any measurement takes place, a second identical atom initially prepared in its ground Rydberg state g is sent through the cavity at a velocity such that Ω 0 t = π . Then, according to Eq. (2), the output state will be: ψ (t output ) = =

1 2

www.cat-science.cat

1 2

⊗ g

⊗ 0 − g 1⊗ e

− g 1⊗ e

)⊗ 0

⊗ 0

) (4)

CONTRIBUTIONS to SCIENCE 9 (2013) 33-41

The Gedankenexperimente of quantum mechanics become reality: On the 2012 Nobel Prize in Physics, awarded to Serge Haroche and David J. Wineland

B rap ar t ine l r la upo adr u Q

|e,n−1>

|e,n>

|e,n+1>

. . .

Energy

. . . Ions

CCD

. . . . . .

|g,n−1>

|g,n>

|g,n+1>

Lasers

Fig. 5. (A) Scheme of the experimental setup for trapping single ions. Ions are placed in a row by means of a quadrupolar linear trap and its mutual Coulomb repulsion. The ions are individually addressed by laser fields and their fluorescence is registered with a CCD camera. (B) Relevant energy levels of the coupled system formed by the g ↔ e two-level internal transition of the ion and its quantized motional states n .

The result was inhibition of the dynamic evolution to the excited state. Every time a fluorescence photon was emitted from the adjacent transition, the quantum state of the ion underwent a quantum jump that collapsed it into the ground state, i.e., frequent measurement of the fluorescence resulted in the inhibition of the excitation. Indeed, the first observation of quantum jumps from a single atom was that of Wineland and coworkers, using a trapped 198Hg+ ion [2]. Although the experiments performed by Wineland (and by Haroche) and coworkers have been used to test some of the most fundamental issues of quantum mechanics and to implement the basic elements for quantum computation, it is important to note that the experimental techniques developed by these researchers have already had real applications. In particular, Wineland and coworkers have been able to construct the world’s most accurate clock, by determining with a precision of 17 digits the ratio of Al+ and Hg+ single-ion optical clock frequencies [24]. The precision of this atomic clock is so high that the tiny effects of special and general relativity have to be taken into account to properly describe its dynamic behavior.

Following up on previous work from Cirac and Zoller [6], Wineland and coworkers also reported [18] the transfer of a quantum superposition between two electronic states of an ion to a quantum superposition between two of its motional states. Consider a single ion that is initially prepared in both the electronic and the motional ground states, i.e., ψ 0 = g ⊗ 0 , that is coupled to state e ⊗ 0 with a laser pulse, as described in Eq. (1). After the laser pulse, the ion state will be in the general superposition ψ 1 = (α g + β e ) ⊗ 0 . If a red-sideband pulse fulfilling Ωt = π is applied to the ion, then only state e ⊗ 0 will evolve, performing half a Rabi oscillation with state g ⊗ 1 such that the final state will read ψ 2 = g ⊗ (α 0 + β 1 ) , i.e., the superposition in the internal degrees of freedom is transferred to the motional degrees of freedom. In a series of articles, Wineland and coworkers extended previous work to implement quantum gates [18,15], entangle two ions [29], and generate Schrödinger cat states with the individual [19] and collective [16] motional coherent states of the ions. In 1977, George Sudarshan and Baidyanath Misra introduced the so-called quantum Zeno effect [28], which enables the dynamic evolution of a quantum system to be inhibited by applying frequent measurements. Wineland and coworkers were the first to report the observation of the quantum Zeno effect [13]. To do so, they considered 9Be+ ions confined in a Penning trap with three internal levels in a V-type configuration. Starting with the ions in their internal ground state, a laser pulse was applied to one of the transitions of the V-type system such that, as expected, the excited population followed the dynamics described in Eq. (1), i.e., p e (t ) = sin 2 (Ωt / 2 ) . During this dynamic evolution, a series of light pulses were applied to the adjacent transition and the fluorescence associated with this transition was registered. www.cat-science.cat

Concluding remarks Haroche and Wineland, benefitting from their education and training in some of the best quantum optics laboratories in the world, have been able to conceive and put into practice novel techniques to isolate, manipulate, and measure individual quantum systems with the highest precision. Their work with single photons and single ions has enabled the study of many of the most fundamental issues in quantum mechanics, such as superposition, entanglement, non-locality, Schrödinger’s cats, EPR pairs, wave function collapse, and decoherence, making real the Gedankenexperimente proposed 40

CONTRIBUTIONS to SCIENCE 9 (2013) 33-41

MOMPART

at the beginning of the quantum mechanics era. Additionally, they have used their setups for applications related to high precision measurements, to the development of quantum computation implementing quantum gates and quantum algorithms, and to engineer the most accurate atomic clock in the world. The outstanding contributions of Haroche, Wineland, and their coworkers have come to define what some scientists justifiably call the second quantum revolution.

6. 7.

8. 9. 10.

Acknowledgements. I thank my colleagues at the Quan-

11.

tum and Atom Optics Group of the Physics Department, Universitat Autònoma de Barcelona, and Dr. Luis Plaja, from the Universidad de Salamanca, for their careful reading of this manuscript and their constructive comments, which were indeed very useful to improve the quality of the final version. Finally, I especially thank Prof. Ramón Corbalán and Prof. Albert Bramon, from the Universitat Autònoma de Barcelona, for their continuous motivation in teaching quantum optics and quantum mechanics, respectively, to an entire generation of physicists.

12.

13. 14.

15.

16.

For further information: On the Nobel Prize in Physics 2012: • Cirac I (2012) Premios Nobel de Física 2012. Revista Española de Física 26:8-9 • “The Nobel Prize in Physics 2012 - Advanced Information.” Nobelprize.org. 22 Feb 2013 http://www.nobelprize.org/nobel_prizes/ physics/laureates/2012/advanced.html On Haroche’s experiments with single photons: • Raimond JM, Brune M, Haroche S (2001) Colloquium: Manipulating quantum entanglement with atoms and photons in a cavity. Reviews of Modern Physics 73:565-582 • “Serge Haroche - Nobel Lecture: Controlling photons in a box and exploring the quantum to classical boundary.” Nobelprize.org. 17 Feb 2013 http://www.nobelprize.org/nobel_prizes/physics/laureates/2012/haroche-lecture.html On Wineland’s experiments with single ions: • Leibfried D, Blatt R, Monroe C, Wineland D (2003) Quantum dynamics of single trapped ions. Reviews of Modern Physics 75:281-324 • David J. Wineland - Nobel Lecture: Superposition, entanglement, and raising Schroedinger’s cat”. Nobelprize.org. 18 Feb 2013 http://www. nobelprize.org/nobel_prizes/physics/laureates/2012/wineland-lec-

17.

18.

19. 20.

21. 22.

23.

ture.html

24.

References 1. 2. 3.

25.

Bell J (1964) On the Einstein Podolsky Rosen Paradox. Physics 1:195-200 Bergquist JC, Hulet RG, Itano WM, Wineland DJ (1986) Observation of quantum jumps in a single atom. Phys Rev Lett 57:1699-1702 Brune M, Haroche S, Raimond JM, Davidovich L, Zagury N (1992) Manipulation of photons in a cavity by dispersive atom-field coupling: Quantum-nondemolition measurements and generation of “Schrodinger cat” states. Phys Rev A45:5193-5214 Brune M, Schmidt-Kaler F, Maali A, Dreyer J, Hagley E, Raimond JM, Haroche S (1996) Quantum Rabi oscillation: A direct test of field quantization in a cavity. Phys Rev Lett 76:1800-1803 Brune M, Hagley E., Dreyer J, Maître X, Maali A, Wunderlich C, Raimond JM, Haroche S (1996) Observing the progressive decoherence of the “meter” in a quantum measurement. Phys Rev Lett 77:4887-4890

www.cat-science.cat

26. 27. 28. 29.

30.

Cirac JI, Zoller P (1995) Quantum Computations with cold trapped ins. Phys Rev Lett 74:4091-4094 Davidovich L, Zagury N, Brune M, Raimond JM, Haroche S (1994) Teleportation of an atomic state between two cavities using nonlocal microwave fields. Phys Rev A50:R895-R898 Diedrich F, Bergqvist JC, Itano WM, Wineland DJ (1989) Laser cooling to the zero-point energy of motion. Phys Rev Lett 62:403-406 Dirac PM (1930) The principles of quantum mechanics. ClarendonPress Oxford Einstein A, Podolsky B, Rosen N (1935) Can quantum-mechanical description of physical reality be considered complete? Phys Rev 47:777-780 Hagley E, Maître X, Nogues G, Wunderlich C, Brune M, Raimond JM, Haroche S (1997) Generation of Einstein-Podolsky-Rosen pairs of atoms. Phys Rev Lett 79:1-5 Heisenberg W (1927) Über den anschaulichen Inhalt der quantentheoretischen Kinematik und Mechanik. Zeitschrift für Physik 43: 172–198 Itano WM, Heinzen DJ, Bollinger JJ, Wineland DJ (1990) Quantum Zeno effect. Phys Rev A41:2295-2300 Jaynes ET, Cummings FW (1963) Comparison of quantum and semiclassical radiation theories with application to the beam maser. Proc. IEEE 51:89–109 Leibfried D, DeMarco B, Meyer V, Lucas D, Barrett M, Britton J, Itano WM, Jelenković B, Langer C, Rosenband T, Wineland DJ (2003) Experimental demonstration of a robust, high-fidelity geometric two ion-qubit phase gate. Nature 422:412-415 Leibfried D, Knill E, Seidelin S, Britton J, Blakestad RB, Chiaverini J, Hume DB, Itano WM, Jost JD, Langer C, Ozeri R, Reichle R, Wineland DJ (2005) Creation of a six-atom “Schrödinger cat” state. Nature 438:639-642 Meekhof DM, Monroe C, King BE, Itano WM, Wineland DJ (1996) Generation of Nonclassical Motional States of a Trapped Atom. Phys Rev Lett 76:1796-1799 Monroe C, Meekhof DM, King BE, Itano WM, Wineland DJ (1995) Demonstration of a fundamental quantum logic gate. Phys Rev Lett 75:4714-4717 Monroe C, Meekhof DM, King BE, Wineland DJ (1996) A “Schrödinger Cat” superposition state of an atom. Science 272:1131-1136 Nogues G, Rauschenbeutel A, Osnaghi S, Brune M, Raimond JM, Haroche S (1999) Seeing a single photon without destroying it. Nature 400:239-242 Pais A (1979) Einstein and the quantum theory. Rev Mod Phys 51:863-914 Rauschenbeutel A, Nogues G, Osnaghi S, Bertet P, Brune M, Raimond JM, Haroche S (1999) Coherent operation of a tunable quantum phase gate in cavity QED. Phys Rev Lett 83:5166-5169 Rauschenbeutel A, Nogues G, Osnaghi S, Bertet P, Brune M, Raimond JM, Haroche S (2000) Step-by-step engineered multiparticle entanglement. Science 288:2024-2028 Rosenband T, Hume DB, Schmidt PO, Chou CW, Brusch A, Lorini L, Oskay WH, Drullinger RE, Fortier TM, Stalnaker JE, Diddams SA, Swann WC, Newbury NR, Itano WM, Wineland DJ, Bergquist JC (2008) Frequency ratio of Al+ and Hg+ single-ion optical clocks; etrology at the 17th decimal place. Science 28:1808-1812 Schrödinger E (1935) Die gegenwärtige Situation in der Quantenmechanik. Naturwissenschaften 23:807-812 Schrödinger E (1952) Are there quantum jumps? Part II, Brit J Phil Sci 3:233-247 Scully MO, Zubairy MS (1997) Quantum optics. Cambridge University Press, UK Sudarshan ECG, Misra B (1977) The Zeno’s paradox in quantum theory. J Math Phys 18:756-763 Turchette QA, Wood CS, King BE, Myatt CJ, Leibfried D, Itano WM, Monroe C, Wineland DJ (1998) Deterministic entanglement of two trapped ions. Phys Rev Lett 81:3631-3634 Wineland DJ, Itano WM (1981) Spectroscopy of a single Mg+ ion. Phys Lett A82:75-78

CONTRIBUTIONS to SCIENCE 9 (2013) 33-41

DISTINGUISHED LECTURES CONTRIBUTIONS to SCIENCE 9 (2013) 43-49 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.162 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

Celebration of the Centennial of the Catalan Society for Biology, 1912–2012

First International Conference of Biology of Catalonia (CIBICAT), ‘Global questions on advanced biology’ (Barcelona, 9–12 July, 2012) Josep Clotet President of the Organizing Committee Secretary General, Catalan Society for Biology

On the occasion of the centennial of the Catalan Society for Biology (SCB, 1912-2012), the First International Conference of Biology of Catalonia (CIBICAT) was held in Barcelona from July 9 to 12, 2012. Under the motto ‘Global questions on advanced biology’, the Conference was an excellent opportunity to discuss the current frontiers—if any—in the biological sciences, and the new challenges in this domain following the conceptual and technological revolution of the last few decades. Since the different disciplines in the life sciences have definitely crossed their boundaries, specialization is no longer a hallmark of researchers involved in them. All biological disciplines have benefited from the multidisciplinary character of new techniques, and new research fields have emerged. The CIBICAT aimed at promoting interactions among the many disciplines in the life sciences and providing new insights into the most relevant emergent issues through different and sometimes opposite or contrasting points of view. At the CIBICAT, current advances in biology and biomedicine achieved in our country were presented. It was also a meeting place for scientists working on the life sciences around the world, who presented us the big questions that lie ahead in the field of biological. There we could reflect on the society’s challenges to which biologists dedicate their efforts as researchers. We asked

renowned scientists to think about these issues and make a practice of critical thinking about the present and the future of biology from the boldest possible perspective. With that Conference, the SCB celebrated hundred years of efforts of many colleagues that have worked for the advancement of our understanding of life and living organisms, of ecosystems, of health, and that have also contributed to the training and disseminating of biology. The CIBICAT aimed to be an exercise of reflection on the current frontiers of biology and the new challenges of the field. The Conference especially encouraged the participation of young researchers by offering them a framework where they could show the results of their research and discuss them with internationally renowned scientists. In addition, the conference aimed at discussing the most challenging topics in biology at present. In the following pages, the structure and development of the meeting, plus three of the main lectures, are presented. The Conference was one of the many activities of the commemoration of the SCB’s centennial and an excellent opportunity to disseminate around the world two major objectives of our Society: working to enhance biological sciences and promoting among young scientists their dedication and love for that exciting, fascinating field of science and human culture which is BIOLOGY.

The CIBICAT was held in several venues of Barcelona, mainly at the Ceremmonial Hall of the University of Barcelona (left), and at the Institute for Catalan Studies (right), from 9 until12 July, 2012.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 43-49

First International Conference of Biology of Catalonia

CIBICAT

First International Conference of Biology of Catalonia 9TH – 12TH OF JULY 2012, BARCELONA Global Questions on Advanced Biology Conference. An international conference on interdisciplinary frontiers in biology as part of the first Centenary of the Catalan Society for Biology (1912–2012)

Programme ORGANIZING COMMITTEE • • • • • • • •

Chromatin and epigenetics, genomics and proteomics, molecular biology, molecular biology of cancer, and reproductive biology

Lluís Tort, Autonomous University of Barcelona; President, Catalan Society for Biology Albert Sorribas, Vicerector for Scientific and Technology Policies, University of Lleida Albert Jordan, Molecular Biology Institute of Barcelona (IBMBCSIC) Josep Saura, University of Barcelona Josep M. Canals, University of Barcelona Pepi Sabrià, Autonomous University of Barcelona Nuria Casals, International University of Catalonia Josep Maria Espelta, Centre for Ecological research and Forestry Applications (CREAF), Autonomous University of Barcelona

Inaugural plenary lecture

Epigenetics: from biology to disease Manel Esteller, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona

Parallel sessions

EPIGENETIC MECHANISMS IN HEALTH AND DISEASE Coordinator: Albert Jordan, Molecular Biology Institute of Barcelona (IBMB-CSIC) Moderator: Marian Martínez-Balbas, Molecular Biology Institute of Barcelona (IBMB-CSIC)

Diabetes and the genomic dark matter of pancreatic beta cells Jorge Ferrer, University of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS) Overcoming the epigenetic barrier during reprogramming to pluripotency María José Barrero Núñez, Center of Regenerative Medicine in Barcelona (CMRB) Linking ZRF1 with retinoic acid pathway in the regulation of transcription and differentiation of leukemic cells Santiago Demajo Meseguer, Centre for Genomic Regulation (CRG) MacroH2A1 in myogenic differentiation and muscle regeneration – an interplay of metabolism and epigenetics Melanija Posavec, Institute of Predictive and Personalized Medicine of Cancer (IMPPC) The histone demethylase PHF8 is essential for cytoskeleton dynamics Elena Asensio Juan, Molecular Biology Institute of Barcelona (IBMB-CSIC) Snail1 regulates heterochromatin transcription Alba Millanes Romero, Hospital del Mar Medical Research Institute (IMIM) Proteomic distribution in the human sperm chromatin Judit Castillo Corullón, University of Barcelona

SCIENTIFIC COMMITTEE • • • • • • • • • • • • • • • • •

Mercè Berlanga, University of Barcelona Mario Cáceres, Catalan Institution for Research and Advanced Studies (ICREA) and Autonomous University of Barcelona Josep M. Canals, University of Barcelona Gabriel Capellà, Bellvitge Biomedical Research Institute (IDIBELL) Josep M. Espelta, Autonomous University of Barcelona Jordi Garcia, University of Barcelona Pere Garriga, UPC - BarcelonaTech Albert Jordan, Molecular Biology Institute of Barcelona (IBMBCSIC) Miguel Angel Martínez, Fundació IrsiCaixa Ramon Massana, Institute of Marine Science (ICM-CSIC) Montserrat Papaceit, University of Barcelona Josep Planas, University of Barcelona Enric Ribes, University of Barcelona Pepi Sabrià, Autonomous University of Barcelona Josep Saura, University of Barcelona Albert Sorribas, University of Lleida Francesc Viñals, Catalan Institute of Oncology and University of Barcelona

BIOMEDICAL PROTEOMICS AND TRANSCRIPTOMICS Coordinator: Mario Cáceres, Catalan Institution for Research and Advanced Studies (ICREA) and Autonomous University of Barcelona Moderator: Francesc Xavier Avilés, Autonomous University of Barcelona

High-throughput biomedical transcriptomics and proteomics: their relevance in the health system Jaume Reventós, Vall d'Hebron Research Institute and Hospital (IRVH), Barcelona The proteome of isolated human sperm tail suggests new metabolic pathways Alexandra Amaral, University of Barcelona Urine proteomic analysis for the identification of prostate cancer biomarkers Marina Rigau, Vall d'Hebron Research Institute and Hospital (IRVH), Barcelona Differential RNAs in the sperm cells of asthenozoospermic patients. Meritxell Jodar Bifet, University of Barcelona miRNA profile in “elite controllers”: a pilot study Mireia Arnedo, August Pi i Sunyer Biomedical Research Institute (IDIBAPS) Mitochondrial DNA expression and content in postmortem brain tissue of schizophrenia patients and control subjects Helena Torrell Galceran, University Rovira i Virgili, Tarragona Molecular diagnosis of glioblastoma based on discriminant equations: objective recognition of primary and secondary cases Xavier Castells, Autonomous University of Barcelona

COMMITTEE COORDINATOR Josep Clotet, International University of Catalonia; General Secretary, Catalan Society for Biology

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 43-49

CLOTET

GAMETES, STEM CELLS AND DIFFERENTIATION

GENES AND GENOMES

Coordinator: Enric Ribes, University of Barcelona Moderators: Mercè Durfort, University of Barcelona; Francesca Vidal, Autonomous University of Barcelona

Coordinator: Mario Cáceres, Catalan Institution for Research and Advanced Studies (ICREA) and Autonomous University of Barcelona Moderator: Xavier Estivill, Centre for Genomic Regulation (CRG), Barcelona

Reprogramming the potency of somatic cells: how and what for? Angel Raya, Institute for Bioengineering of Catalonia (IBEC) Chromosome size and morphology determine bivalent positioning in human spermatocytes Laia Vergés, Autonomous University of Barcelona Aneuploid and diploid spermatozoa from reciprocal translocation carriers exhibit an altered segregation pattern Anna Godo, Autonomous University of Barcelona Treatment of mouse somatic cell nuclear transfer embryos with psammaplin A improves in vitro development and quality. Anna Mallol, Autonomous University of Barcelona Complete meiosis from human induced pluripotent stem cells Cristina Eguizabal, Center of Regenerative Medicine in Barcelona (CMRB) The influence of E-cadherin on embryonic stem cell derivation from mammalian isolated blastomeres Josep Santaló, Autonomous University of Barcelona

The mutational landscape of chronic lymphocytic leukemia Elias Campo, University Hospital Clínic, Barcelona When nature decides: one gene, two DNA repair pathways and three human diseases Jordi Surralles, Autonomous University of Barcelona Molecular diagnosis of rare Mendelian diseases using whole exome sequencing Benjamín Rodríguez-Santiago, Quantitative Genomic Medicine Laboratories S.L The PLAU P141L single nucleotide polymorphism is a potential genetic predictor of the arteriogenic response in coronary artery disease Joan Duran, University of Barcelona Study of genetic association in 1q21-23 locus, a candidate region for psychosis Marta De Castro i Català, University of Barcelona Large-scale validation and genotyping of inversions in the human genome by inverse PCR Cristina Aguado Esteban, Autonomous University of Barcelona

COMPUTATIONAL AND STRUCTURAL BIOLOGY

BIOLOGY OF REPRODUCTION

Coordinator: Mario Cáceres, Catalan Institution for Research and Advanced Studies (ICREA) and Autonomous University of Barcelona Moderator: Roderic Guigó, Centre for Genomic Regulation (CRG), Barcelona

Coordinator: Enric Ribes, University of Barcelona Moderators: Joaquima Navarro, Autonomous University of Barcelona; Rafael Oliva, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona

In silico biology Modesto Orozco, University of Barcelona, Instiute for Research in Biomedicine (IRB) The role of structural disorder in the rewiring of protein interactions through evolution Roberto Mosca, University of Barcelona, Institute for Research in Biomedicine (IRB) IntOGen: Large scale analysis and integration of cancer genomics data David Tamborero, Pompeu Fabra University Alternative splicing and stochastic gene expression Xavier De La Cruz, Molecular Biology Institute of Barcelona (IBMB-CSIC) Mapping the dark side of the human genome: long non-coding RNAs Rory Johnson, Centre for Genomic Regulation (CRG), Barcelona Somatic structural mosaicism as an early genetic marker of lateonset diseases Juan R González, Centre for Research in Environmental Epidemiology (CREAL) Accurate prediction of inversions in the human genome from pairedend mapping data with the GRIAL algorithm Alexander Martinez Fundichely, Autonomous University of Barcelona

Current knowledge of the proteomics of human spermatozoa Rafael Oliva, University of Barcelona Gonadal transcriptome analysis of the effects of temperature on European seabass (Dicentrarchus labrax) sex ratios Noelia Díaz, Spanish National Research Council (CSIC) Sperm nucleoprotein structure is more resistant to sustain cryopreservation procedures in good than in poor freezeability boar ejaculates Efren Estrada, Autonomous University of Barcelona An assessment of telomeric repeat-containing RNA (TERRA) and telomerase in human fetal oocytes Rita Reig-Viader, Autonomous University of Barcelona Comprehensive analysis of sperm DNA fragmentation through alkaline and neutral Comet assay in clinical groups of infertile patients Jordi Ribas-Maynou, Autonomous University of Barcelona Evidences that ATR is involved in DSB repair during meiotic prophase Sarai Pacheco, Autonomous University of Barcelona

PROLIFERATION, ANGIOGENESIS AND METASTASIS

REGULATION OF CHROMATIN FUNCTIONS

Coordinator and moderator: Gabriel Capellà, Catalan Institute of Oncology (ICO)

Mechanism of resistance to anti-angiogenic therapies Oriol Casanovas, Bellvitge Biomedical Research Institute (IDIBELL) Identification of Sp1 targets involved in proliferation and cancer Veronica Noé, University of Barcelona Characterization of prostate cancer bone metastasis process by a highly bone metastatic cell line generated in vivo Marta Garcia, Vall d'Hebron Research Institute and Hospital (IRVH), Barcelona Cancer and arsenic: dedifferentiation and effects on CSCs Anna Pastoret, Autonomous University of Barcelona Role of MSK1 in steroid hormone-induced breast cancer cell proliferation Diana Reyes Garau, Centre for Genomic Regulation (CRG), Barcelona PFKFB3 regulation by p38 MAPK pathway Laura Novellasdemunt Vilaseca, University of Barcelona

Coordinator: Albert Jordan, Molecular Biology Institute of Barcelona (IBMB-CSIC) Moderator: Marcus Buschbeck, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona

Dealing with chromatin constrains in gene regulation Miguel Beato, Centre for Genomic Regulation (CRG), Barcelona Epigenetic regulation of centromere function Olga Moreno, Molecular Biology Institute of Barcelona (IBMB-CSIC) The MyoD-BAF60c complex poises chromatin for rapid transcription Sònia Forcales, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona SIRT2 regulates genomic stability and cell cycle progression through the control of H4K16Ac and H4K20me1 levels Paloma Martínez, Bellvitge Biomedical Research Institute (IDIBELL) Human histone H1 variants: knock-down and occupancy in the genome Lluís Millán Ariño, Molecular Biology Institute of Barcelona (IBMB-CSIC) Contribution of hydrophobic interactions to the folding and fibrillation of the C-terminal domain of histone H1 Alicia Roque, Autonomous University of Barcelona

www.cat-science.cat

Round table

Frontiers of biology: 10 years after the human genome sequencing Xavier Estivill, Centre for Genomic Regulation (CRG), Barcelona; Manel Esteller, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona; Manuel Perucho, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona; Ivo Gut, National Center for Genome Analysis (CNAG), Barcelona

CONTRIBUTIONS to SCIENCE 9 (2013) 43-49

First International Conference of Biology of Catalonia

August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Centre for Biomedical Network Research on Rare Diseases (CIBERER) Gene therapy for diabetes: moving to clinic? David Callejas Castiñeiras, Autonomous University of Barcelona Mitochondrial implication in sepsis Ester Tobias, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, University Hospital Clínic, Centre for Biomedical Network Research on Rare Diseases (CIBERER) El rol del gen CNR1 (receptor cannabinoide tipus I) en la resposta clínica i la remissió al tractament amb citalopram (ISRS) en depressió major: estudi de seguiment a 12 setmanes Marina Mitjans, University of Barcelona

Biophysics, molecular biology and systems biology, and neurobiology Plenary lecture

The evolution of language Tekumseh Fitch, University of Viena, Viena

Parallel sessions

CELL DAMAGE AND CELL DEATH Coordinator: Josep Saura, University of Barcelona Moderator: Josefa Sabrià, Autonomous University of Barcelona

Age-dependent decline of motor cortex but not hippocampal performance in heterozygous BDNF mice correlates with a decrease of cortical PSD-95 but an increase of hippocampal TrkB levels Albert Giralt, University of Barcelona Decreased PKC-delta protein levels as a neuroprotective mechanism in cells expressing mutant huntingtin Laura Rué, University of Barcelona Phenotypic and functional characterization of antigen-specific myeloid-derived suppressor cells generated during retroviral transduction of murine bone marrow Sílvia Casacuberta Serra, Vall d’Hebron Research Institute and Hospital (IRVH) Unique role of Bcl-xL regulating the antiapoptotic role of NF-kB Elisenda Casanelles Abella, Autonomous University of Barcelona Role of CDK11 in the β cell mass apoptosis in type I diabetes Ester Sala Soler, University of Lleida Failure of caspase-dependent cell death to reach the classical apoptotic phenotype in SH-SY5Y human neuroblastoma derived cells Mercè Garcia i Belinchón, Autonomous University of Barcelona Development of a network to provide fresh human tissue for research Estephan Arredondo, Barcelona Science Park (PCB) Mitochondrial toxicity of carbon monoxide from tobacco in smoking pregnant women: reduced intrauterine growth Marc Catalán, University of Barcelona, University Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Centre for Biomedical Network Research on Rare Diseases (CIBERER)

RECEPTORS, CHANNELS AND TRANSPORTERS Coordinator: Pere Garriga, Technical University of Catalonia (UPC) BarcelonaTech Moderator: Francesc Sepulcre Sánchez, UPC - BarcelonaTech

New paradigms in GPCR signaling: G proteins at the mitochondria Anna Aragay, Molecular Biology Institute of Barcelona (IBMB-CSIC) Molecular details of the apolipoprotein E and the amyloid beta peptide interaction: Analysis of a potential binding site responsible for ApoE4 misfolding Alex Perálvarez-Marín, Autonomous University of Barcelona In Silico analysis of neurokynin-1 at the sequence level: a preface to structural studies Danial Afsharzadeh, UPC - BarcelonaTech The voltage-dependent K+ channel Kv1.3 in adipocytes Mireia Pérez Verdaguer, University of Barcelona Assessment of the conformation profile of bombesin, neuromedin B and neuromedin C by computational methods Juan Jesús Pérez González, UPC - BarcelonaTech Visual phototransduction: from rhodopsin and cone opsin mutations to visual disease Eva Ramon Portés, UPC - BarcelonaTech The voltage-dependent K+ channel Kv1.5 in B lymphocytes Albert Vallejo, University of Barcelona

CELLULAR AND MOLECULAR NEUROBIOLOGY Coordinator: Josep Saura, University of Barcelona Moderator: Teresa Vilaró, Institute of Biomedical Research of Barcelona (IIBB), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Centers for Networked Biomedical Research (CIBERNED)

FROM GENOTYPE TO PHENOTYPE: WHERE ARE WE NOW? Coordinator and moderator: Albert Sorribas, University of Lleida

Scientific challenges in systems biology Luis Serrano, Centre for Genomic Regulation (CRG), Barcelona Debate: From genotype to phenotype RNA as a first phenotype (molecular) of a cell Roderic Guigó, Centre for Genomic Regulation (CRG), Barcelona Complex biological networks: challenges and opportunities Ricard Solé, Pompeu Fabra University, Barcelona; Roger Guimerà, University Rovira i Virgili, Tarragona Metabolic networks and the evolution of metabolisme Juli Peretó, University of Valencia

Normalization of P75 levels prevents cognitive decline in a knock-in mouse model of Huntington disease Veronica Brito, University of Barcelona Oxygen tension modulates glial cell lineage commitment through modifications on bmp7 expression Juan Alberto Ortega Cano, University of Barcelona Activity-dependent gene transcription and memory in Alzheimer´s disease Carlos Saura, Autonomous University of Barcelona Disrupció de les oscil·lacions corticals de baixa freqüència per fenciclidina: un model vàlid per al cribatge de nous fàrmacs antipsicòtics Eva Troyano Rodríuez, Institute of Biomedical Research of Barcelona (IIBB) Neurophysiological alterations in a mouse model of proliferative retinopathy Pilar Villacampa Alcubierre, Autonomous University of Barcelona SC-51089 chronic treatment decreases motor and cognitive deficits in mouse model of huntington’s disease Marta Anglada Huguet, University of Barcelona Parkin loss of function leads to RTP801 accumulation and neurodegeneration in parkinson's disease Joan Romaní Aumedes, University of Barcelona Effect of acute exposure to cocaine in a dopaminergic neuronal model: a gene expression study Noèlia Fernàndez Castillo, University of Barcelona

TRAFFIC AND SIGNALING IN HEALTH ANS DISEASE Coordinator: Francesc Viñals, Catalan Institute of Oncology and University of Barcelona Moderator: Víctor J. Yuste, Autonomous University of Barcelona

Biogenesis of carriers for secreting bulky cargoes and proteins that cannot enter the endoplasmic reticulum Vivek Malhotra, Centre for Genomic Regulation (CRG), Barcelona Apoptosis, immunogenicity and stability properties of PPRHs directed against survivin in mammalian cancer cell lines Laura Rodriguez, University of Barcelona Contribution of rare and common variants of PTCHD1 gene in autism Bàrbara Torrico Avilés, University of Barcelona Mitochondrial implication in adverse outcomes of HIV pregnancies Glòria Garrabou Tornos, University of Barcelona, University Hospital Clínic,

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 43-49

CLOTET

SYSTEMS BIOLOGY

Structural and biochemical insights into the human mitochondrial transcription factor A with the light strand promoter Anna Rubio Cosials, Molecular Biology Institute of Barcelona (IBMB-CSIC)

Coordinator and moderator: Albert Sorribas, University of Lleida

Organization Principles in Biology Rui Alves, University of Lleida Boundary formation in cell populations: From gene regulation to tissue mechanics Javier Buceta, Barcelona Scientific Park (PCB), University of Barcelona Integration of proteomic and genome-wide data to understand Polycomb function on mouse embryonic stem cells differentiation Luciano di Croce, Centre for Genomic Regulation (CRG), Barcelona Ligand expression ahead of neurogenic wavefronts: a new design principle? Marta Ibañes, University of Barcelona Defining the DNA interactome in a minimal bacteria Eva Yus, Centre for Genomic Regulation (CRG), Barcelona Precision of the quorum sensing switch: Stochastic and nonequilibrium effects Marc Weber, Barcelona Scientific Park (PCB) Using systems biology to learn about the synapse role in neurologic and psychiatric disorders Àlex Bayés, Sant Pau Biomedical Research Institute (IIB Sant Pau)

Round table

Following the track of DNA: from crime to evolution Jose A. Lorente, University of Granada; Assumpció Malgosa, Autonomous University of Barcelona; Tomàs Marqués, Institute of Evolutionary Biology (IBE, CSIC-UPF), Barcelona; Alicia Bofarull, National Institute of Toxicology and Forensic Sciences, Barcelona; Andrés Moya, University of Valencia

Cell signaling, developmental biology, evolutive biology, and neurobiology Plenary Lecture

Huntingtin from evolution to pathology via the embryonic stem cells Elena Cattaneo, University of Milan, Italy

Parallel Sessions

CELL SIGNALLING IN THE NERVOUS SYSTEM

MOLECULAR BIOLOGY IN MODEL ORGANISMS

Coordinator and moderator: Francesc Viñals, Catalan Institute of Oncology and University of Barcelona

Coordinator: Albert Jordan, Molecular Biology Institute of Barcelona (IBMB-CSIC) Moderator: Carles Ciudad, University of Barcelona

BIOPHYSICS

Role of hippocampal nNOS/cGMP pathway in cognitive impairment in Huntington’s disease Ana Saavedra, University of Barcelona Cox-2 regulation by IL-1β through MAPKs: A comparison of nasal mucosa and nasal polyps fibroblasts from AIA patients Francesc Josep Garcia i Garcia, August Pi i Sunyer Biomedical Research Institute (IDIBAPS) The role of PDK1 beyond PKB/AKT in regulating neuronal survival analysed by knock-in mutation Jose R. Bayascas, Autonomous University of Barcelona A circadian controlled G-protein coupled receptor heterodimer modulates melatonin production Peter Mccormick, University of Barcelona A functional A2RE sequence is responsible for transport of the DDR1 mRNA to oligodendrocyte processes Nerea Abasolo Zabalo, University Rovira i Virgili, Tarragona Hypothalamic ceramide levels regulated by cpt1c are involved in orexigenic effects of ghrelin Sara Ramírez Flores, International University of Catalonia (UIC) A potential role of Kalirin-7 in cortico-striatal learning deficits in HD Mar Puigdellívol Cañadell, University of Barcelona The persistence of memory: Two-photon imaging reveals how synapses learn and remember in real time Miquel Bosch, Massachusetts Institute of Technology (MIT)

Coordinator: Pere Garriga, Technical University of Catalonia (UPC) - BarcelonaTech Moderator: Esteve Padrós Morell, Autonomous University of Barcelona

EVOLUTION

Models diversos en genètica molecular de plantes: Arabidopsis thaliana, blat de moro, meló. Pere Puigdomènech, Center of Research in Agricultural Genomics (CRAG, CSIC-IRTA-UAB-UB), Bellaterra Dma1: E3 ligase cell cycle regulated? Natalia Ricco Pacheco, International University of Catalonia (UIC) Protection of diet-induced obesity and insulin resistance in transgenic mice overexpressing HMGA1 in adipose tissue Efrén Riu, Center of Animal Biotechnology and Gene Therapy (CBATEG), Bellaterra Deficiency of cyclin D3 contributes to the apoptosis of beta cell and development of type 1 diabetes in nod mice Alejandra Saavedra Avila, Univeristy of Lleida Hematopoietic stem cell gene therapy corrects biochemical imbalances in a murine model of MNGIE Javier Torres-Torronteras, Vall d'Hebron Research Institute and Hospital (IRVH), Barcelona AAV9-sulfamidase vector delivery to the cerebrospinal fluid corrects BRAIN and somatic pathology in MPSIIIA mice and results in detectable enzyme levels in dogs Virginia Haurigot, Center of Animal Biotechnology and Gene Therapy (CBATEG), Bellaterra

Coordinator and moderator: Montserat Papaceit, University of Barcelona

Mechanobiology of lung cells Daniel Navajas, University of Barcelona Direct observation of stalled fork restart and lesion bypass via fork regression in T4 replication system Maria Manosas, University of Barcelona Probing G-protein-coupled receptor dimerization and its role in depression Mercè Tena Campos, UPC - BarcelonaTech Unraveling nucleic acids and proteins using single molecule methods Felix Ritort, University of Barcelona UB behaviour in biomimetic membranes of DPPC and MGDG Javier Hoyo, UPC - BarcelonaTech Biochemical changes in a rat model of stroke assessed by in vivo magnetic resonance spectroscopy (MRS) and ex vivo high resolution magic-angle spinning (HRMAS) Myriam Davila, Autonomous University of Barcelona

www.cat-science.cat

Genomic shuffling affects recombination rates during mammalian diversification Aurora Ruiz-Herrera, Autonomous University of Barcelona Evolution of recent rodent gene duplicates Cinta Pegueroles, Hospital del Mar Medical Research Institute (IMIM) Biosphere‘s phylogenetic structure Cristian R. Altaba, University of the Balearic Islands Origen i evolució del sistema quimiosensorial i desenvolupament de nous marcadors moleculars en aràcnids Cristina Frias, University of Barcelona EBV strain variation in different lymphoblastoid cell lines derived from 1000 Genomes Project individuals Gabriel Santpere, Institute of Evolutionary Biology (IBE, CSIC-UPF), Barcelona Identification of selective sweeps in the genome of the Boxer breed Javier Quilez Oliete, Center of Research in Agricultural Genomics (CRAG, CSICIRTA-UAB-UB), Bellaterra

CONTRIBUTIONS to SCIENCE 9 (2013) 43-49

First International Conference of Biology of Catalonia

Molecular analysis of the mechanisms involved in THBS4 differential gene-expression in the human brain Raquel Rubio Acero, Autonomous University of Barcelona Two new plant cytogenetic online resources: the GSAD and Plant rDNA databases Sònia Garcia, University of Barcelona

Marco Vignuzzi, Institut Pasteur, Paris Archaeology of RNA applied to the study of hepatitis C virus Jordi Gomez, Institute of Parasitology and Biomedicine “López-Neyra” (IPBLN), Granada Hepatitis A virus, a very special picornavirus Albert Bosch, University of Barcelona Norovirus diversity in relation to population impact Marion Koopmans, National Institute for Public Health and the Environment (RIVM), Bilthoven; Erasmus Medical Center, Rotterdam Evolution of HIV-1 protease over 14 years: fitness loss or robustness gain Elena Capel, Glòria Martrus, Mariona Parera, Bonaventura Clotet, Miguel Angel Martínez Antiretroviral agents effectively block HIV replication after cell to cell transfer Marc Permanyer, Ester Ballana, Alba Ruiz, Roger Badia, Eva Riveira, Bonaventura Clotet, José A. Esté HIV maturation: a new RNA-supported paradigm of spatiotemporal nucleoprotein remodeling catalysed by a protease Sebastien Lyonnais, Robert J. Gorelick, Carine Tisné, Jean Christophe Paillart, Laure Dufau, Michele Reboud, Sara Nieto, Tuixent Escriba, Jose Maria Gatell, Gilles Mirambeau Transmissibility of two ipomoviruses by whitefly vectors under experimental conditions Lluisa Vilaplana, M. Urizarna, A. Mingot, J. J. López-Moya The Movement Protein of Cucumber mosaic virus (CMV) determines the virulence in the melon accession PI161375 Cèlia Guiu, Juan A. Díaz-Pendón, Ana Montserrat Martín-Hernández Changes in the evolution of sexually transmitted pathogens. From direct examination to molecular biology Martí Vall Mayans Study of hepatitis C virus infection by using a Gaussia luciferase cellbased system George Koutsoudakis, Sofía Pérez del Pulgar, Patricia González, Gonzalo Crespo, Miguel Navasa, Xavier Forns Characterization of UL8, a new member of the human cytomegalovirus RL11 multigene family Natàlia Pérez-Carmona, Domènec Farré, Pablo Engel, Ana Angulo

DEVELOPMENT Coordinator and moderator: Jordi Garcia, University of Barcelona

Gene loss impact on evo–devo: Dismantling the retinoic acid Pathway in the chordate Oikopleura dioica Cristian Cañestro, University of Barcelona Helios, a new transcription factor involved in the determination of striatal medium spiny neurons Mònica Pardo Muñoz, University of Barcelona Evolutionary conserved role of the beta-catenin/Wnt signalling throughout planarian life cycle Teresa Adell, University of Barcelona Functional characterization of neoblast specific transcription factors during planarian regeneration Alejandro González-Sastre, Institute of Biomedicine (IBUB-UB), Barcelona The role of the microRNA trio let-7, miR-100 and miR-125 in insect hemimetabolous metamorphosis Mercedes Rubio, Institute of Evolutionary Biology (IBE, CSIC-UPF), Barcelona Ovarian follicle development in primitive insects Paula Irles, Institute of Evolutionary Biology (IBE, CSIC-UPF), Barcelona Regeneration in Isodiametra pulchra (Acoela, Acoelomorpha) Elena Perea Atienza, University of Barcelona How often does natural selection targets multiple, interacting genes? The prevalence of epistasis in recent human evolution Natalia Petit, Institute of Evolutionary Biology (IBE, CSIC-UPF), Barcelona

EVOLUTION AND DEVELOPMENT IN THE NERVOUS SYSTEM Coordinator: Josep M. Canals, University of Barcelona

20 years of ephithelial to mesenchymal transition Angela Nieto, Institute of Neuroscience (IN, CSIC-UMH), Alacant No place like home: stem cells and the neurovascular niche Isabel Fariñas, Univerity of Valencia The regulation of neural stem and progenitor cell fate by the activity of transcription factors Carlos Vicario-Abejon, Cajal Institute (CSIC), Madrid An evo-devo approach for understanding the amygdala, a key forebrain center for control of emotions and social behavior Loreta Medina, Instiute for Research in Biomedicine (IRB), Barcelona

Microbiology Coordinator: Mercè Berlanga, University of Barcelona

The origins of AIDS virus Miguel A. Martínez, IrsiCaixa Symbiotic planet Ricard Guerrero, Institute for Catalan Studies (IEC) and University of Barcelona Epigenetics in ecological research and animal production Francesc Piferrer, Institute of Marine Science (ICM-CSIC), Barcelona

Presentation Teresa Vinuesa, University of Barcelona and Montserrat Agut, Chemical Institute of Sarrià (IQS) Epigenetics and evolution in bacteria Miquel Viñas, University of Barcelona Bacterial athogenesis as an imperfect symbiosis Josep Casadesús, University of Seville Endosymbiosis and evolution Juli Peretó, University of Valencia Bioremediation and cooperation Balbina Nogales, University of the Balearic Islands Extremophile microorganisms and life beyond Ricard Amils, Autónoma University of Madrid The rare biosphere: the oldest cooperative in the world Carles Pedrós-Alió, Institute of Marine Science (ICM-CSIC), Barcelona Round-table The 21st century microbiologies: prospects for the future Coordinated by Isabel Esteve, Autonomous University of Barcelona

Virology

Ecology

Coordinator: Miguel Angel Martínez, Fundació IrsiCaixa

Coordinators: Josep M. Espelta, Autonomous University of Barcelona; Ramon Massana, Institute of Marine Science (ICM-CSIC)

Aquaculture, ecology, microbiology, and virology Plenary lectures (co-organized with the SCB Sections of Ecology, Microbiology and Virology)

Presentation Miguel Angel Martinez, coordinator of the SCB Virology section Quasispecies dynamics and the control of viral infections Esteban Domingo, Severo Ochoa Molecular Biology Centre (CBMSO), Madrid Deep sequencing of naturally evolving arbovirus populations in the mosquito vector identifies new variants with epidemic potential

www.cat-science.cat

Stoichiometry and global metabolism Josep Peñuelas, Centre for Ecological research and Forestry Applications (CREAF-CSIC), Bellaterra Phylogenetics, genomics and global change: understanding the past to enlighten the future

CONTRIBUTIONS to SCIENCE 9 (2013) 43-49

CLOTET

Vincent Savolainen, Imperial College, UK Biodiversity: portfolio of responses to global change Fernando Valladares, Centre of Environmental Sciences (CCMA-CSIC), Madrid Phytoplankton as victims and players in the global change Adriana Zingone, Anton Dohrn Zoological Station, Italy The threat of Earth’s oceans becoming more acidic Carles Pelejero, Institute of Marine Science (ICM-CSIC), Barcelona Marine invasions: a future nuisance that is already present Enric Ballesteros, Centre for Advanced Studies of Blanes (CEAB-CSIC)

Round-table

Could global change finally merge terrestrial and aquatic ecologists?

Aquaculture

Coordinator: Josep Planas, University of Barcelona

CHALLENGES OF AQUACULTURE IN THE TWENTY-FIRST CENTURY

Aquaculture today, a look at challenges ahead: health management Dolors Furones, Institute of Agrifood Research and Technology (IRTA), Barcelona Molecular basis of the making of eggs in marine fish: the role of oocyte aquaporin Joan Cerdá, Institute of Agrifood Research and Technology (IRTA–CSIC), Barcelona Present and future of nutrition in fish. Applied use of biomarkers and interactive mathematical models with a high predictive value Jaime Pérez-Sánchez, Institute of Aquaculture “Torre de la Sal” (IATS–CSIC), Castelló Regulation of markers of lipid metabolism in fish Isabel Navarro, University of Barcelona Diseases in fish: what do we have to know and what can we learn? Francesc Padrós, Autonomous University of Barcelona The stress response in fish and the interaction between regulatory systems Lluis Tort, Autonomous University of Barcelona

Closing plenary lecture (co-organized with the SCB Sections of Ecology, Microbiology and Virology)

Mutualistic netwoks: the architecture of biodiversity Jordi Bascompte, Doñana Biological Station, CSIC

General Round tables

Workshop on conference presentation skills Elinor Thompson, Barcelona Biomedical Research Park (PRBB) “So now you got your PhD, what’s next …?” A first-hand review on unexpected professional Organized by Luis Ruiz, Janus Developments SL. Joan Roig Amorós, Instiute for Research in Biomedicine (IRB); Raúl Martín Ruíz, Ysios Capital; Ramon Bosser, Janus Developments SL; Cristina Malagelada, University of Barcelona; Clara Campàs, Adavancell; Ana Kosoy, Janus Developments SL; Meritxell Genesca, Germans Trias i Pujol Health Sciences Research Institute, Badalona; Albert Pol, University of Barcelona; Montse Vendrell, Biocat; Ana Kosoy, Janus Developments SL Research in Catalonia: University or research institutes? Marta Aymerich, Head of Research and Innovation, Dept. of Health, Generalitat de Catalunya; Jordi Alberch, Vicerector of Resercah, University of Barcelona; Joan Comella, Director, Vall d’Hebron Research Institute and Hospital (IRVH), Barcelona; Ramon Gomis, Director, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Albert Sorribas, Vicerector of Research, University of Lleida

www.cat-science.cat

From top to bottom: (A) Left to right: Lluís Tort, President, SCB; Antoni Castellà, Secretary for Universities and Research of the Autonomous Governement of Catalonia; Salvador Giner, president, IEC, Maria Serrat, Director General of the Liceu Conservatory Foundation. (B) Hall of the Liceu Conservatory, Barcelona. (C) Manuel Esteller, invited lecturer.

CONTRIBUTIONS to SCIENCE 9 (2013) 43-49

DISTINGUISHED LECTURES CONTRIBUTIONS to SCIENCE 9 (2013) 51-56 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.163 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

Celebration of the Centennial of the Catalan Society for Biology, 1912–2012

Bacterial pathogenesis as an imperfect symbiosis Josep Casadesús Department of Genetics, University of Sevilla, Sevilla, Spain

Based on the lecture given by the author at the Institute for Catalan Studies, Barcelona, on 12 July 2012 at the CIBICAT, ‘Global Questions on Advanced Biology’ as part of the Centennial of the SCB. Correspondence: Departamento de Genética Facultad de Biología Universidad de Sevilla 41080 Sevilla, Spain Tel. +34-955420881 E-mail: casadesus@us.es Received: 19.11.13 Accepted: 20.12.13

Summary.

Human-adapted bacterial pathogens such as Salmonella enterica serovar Typhi, Helicobacter pylori, and Mycobacterium tuberculosis cause acute infections and also latent, asymptomatic infections. During latent infection the pathogen undergoes self-attenuation of virulence, a lifestyle that reduces the impact of infection on host fitness. Evolutionary strategies of this kind may drive certain bacterial pathogens towards commensalism.

Keywords: evolution · human pathogens

· host susceptibility · symbiosis

Resum.

Els patogens bacterians adaptats als humans com ara Salmonella enterica serovar Typhi, Helicobacter pylori o Mycobacterium tuberculosis causen infeccions agudes i també infeccions latents i asimptomàtiques. Durant una infecció latent, el patogen atenua la seva virulència i adopta un estil de vida que redueix l’impacte de la infecció sobre el benestar de l’hoste. Estratègies evolutives d’aquest tipus poden dirigir alguns patògens bacterians vers el comensalisme. Paraules clau: evolució · patògens humans · susceptibilitat de l’hoste · simbiosi

1013 [44]. Large bacterial communities are present in a variety of organs (Table 1). These bacteria are part of the socalled normal microbiota, and establish commensal or mutualistic relationships with us. Bacterial contributions to human health include synthesis of vitamins, detoxification of dangerous compounds, adjustment of the immune system, and protection against pathogenic microorganisms by direct competition [44]. Compared with the thousands of bacterial species that are either innocuous or beneficial for us, pathogenic bacteria are rare. Furthermore, their involvement in disease is complex, and the view of infectious disease as the attack of one organism by another organism is often naive. Bacteria that cause disease can be classified in two types. A few species are primary (“true”) pathogens. Many others, however, are opportunistic pathogens that cause disease in specific circumstances only [42]. Environmental, usually harmless species can cause disease when a physiological alteration occurs

Popular culture views bacteria as enemies of humans, and an example is found in a monosyllabic, euphonic poem by Catalan writer Joan Oliver (aka Pere Quart): “BACIL Ni bri bo: microbi.” (“BACILLUS: Not good at all: microbe”) [36]. Popular aversion for bacteria is radically opposite to scientific knowledge. Biogeochemical cycles are made possible by bacterial metabolism, which recycles molecules and chemical elements to make life sustainable. Our body is also the home for thousands of bacterial species, and the total number of bacterial cells in a healthy human may be similar (or even exceed) the number of “human” cells: between 1012 and www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 51-56

Bacterial pathogenesis as an imperfect symbiosis

infection of new hosts and the time of host survival after infection [27]. Theoretical analysis of reproductive rates predicts that evolutionary success can be achieved in many manners, and that co-evolution of hosts and parasites can follow different paths. If new hosts are efficiently infected, host survival will matter little. However, because the number of hosts cannot be infinite, high infection rates do not warrant long-term success. In fact, lowered levels of host fitness can compromise survival of the pathogen if the number of hosts decreases below a critical level. Pathogens that do not attain high rates of infection can benefit if the fitness of their hosts is not severely impaired upon infection. The longer the host lifespan, the higher the reproductive rate. While many viruses (not all) behave as “rogue” parasites that increase their reproductive rate at the expense of host fitness, many bacterial pathogens seem to increase their reproductive rates by reducing their virulence. Self-attenuation of virulence is not only observed in opportunistic pathogens, which cause disease by accident. The evolutionary strategies of primary pathogens also show signs of self-attenuation, especially in bacterial species that colonize one or a few eukaryotic hosts. In fact, host adaptation and attenuation of virulence seem to be related evolutionary processes. This kind of evolution converts infectious disease into a sort of imperfect symbiosis. This article is mainly centered on one primary pathogen, Salmonella enterica, which presents unequivocal signs of self-restraint during infection of animals. Other primary pathogens such as Brucella, Chlamydia, Helicobacter, Staphylococcus, and Mycobacterium are also known to undergo self-restraint upon infection [38].

(e.g., a burn or an impairment of innate immunity). Other opportunistic pathogens are commensals of the human body, and live in an equilibrium sustained by multiple factors. When the equilibrium is disrupted, the bacterial population proliferates and causes disease, sometimes colonizing organs where the microorganism is not normally found [42]. The distinction between primary and opportunistic pathogens is not absolute: upon infection by a primary pathogen, certain individuals can be spared from disease by genetic or physiological factors. A risky experiment showing that an encounter with a primary pathogen does not necessarily lead to disease was performed by German microbiologist Max von Pettenkoffer in the 19th century. As part of his polemics with Robert Koch on the ethiology of cholera, Max von Pettenkoffer drank a Vibrio cholerae preparation without suffering contagion [30]. It is also well known that epidemics affect certain members of a population while others, sometimes in the same family, do not suffer the disease. Genetic polymorphism may be a major cause of individual differences in susceptibility to infection, as predicted by the Red Queen hypothesis: because pathogens prey on the most common host genotypes, a selective advantage for rare host genotypes is generated [20]. However, nutritional and physiological factors have also a major impact on host susceptibility to infection. Table 1. Mass of bacterial communities in human organs* Organ/

Weight of

Number of

system

bacterial mass

bacterial cells

(grams, net weight) Eyes

109–1010

Nose

1010

Mouth

109–1011

Lungs

1010

Vagina

An example of primary pathogen: Salmonella Salmonella enterica is a pathogenic relative of the human commensal Escherichia coli. Although the evolutionary divergence between the genera Escherichia and Salmonella may have occurred 150 million years ago, their chromosomes remain similar [18]. A relevant difference, however, is the presence of several pathogenicity islands in the Sal monella genome [18]. Genes contained in pathogenicity islands encode type III secretion systems and effector proteins involved in host colonization. The currenty accepted taxonomy divides the genus Sal monella in species, subspecies and serovars. S. enterica subspecies enterica includes most of the serovars that cause disease in humans and livestock animals. Serovars Typhimurium, Enteriditis, and Typhi are frequently isolated from humans, and they are associated with an estimated 115 million clinical cases per year worldwide [11,37]. Depending on the serovar and the host, Salmonella infections of healthy (immunocompetent) humans can be classified into several types. One is gastroenteritis, leading to diar-

1010 10

Skin

200

10 –1011

Intestine

1000

1012

*Adapted from [44].

Evolutionary strategies of pathogens Despite the multiplicity of factors involved in host-microbe interactions, reductionist modeling of host-pathogen interactions is possible. While the Red Queen hypothesis addresses the impact of infection on host evolution, classical studies by Robert M. May have modeled the evolution of virulence in pathogens. A major question, for instance, is whether pathogens that evolve to be harmless to their hosts do better than those that do not attenuate their virulence. A useful measure of pathogen fitness is the reproductive rate, which can be defined as the product of two independent factors: the rate of www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 51-56

CASADESUS

rhea and inflammation [37]. Gastroenteritis is a mild infection, extremely common in developed countries, and involves self-limited infection of the terminal ileum and colon. In contrast, typhoid fever is a life-threatening infection in which Salmonella disseminates through the lymphatic system and is transported within phagocytes [11]. Dissemination permits colonization of the liver, the spleen, the bone marrow, and the gall bladder. Death may occur as the consequence of the phenomenon known as septic shock, an overeaction of the host immune system triggered by Salmonella lipopolysaccharide [43]. In the twentieth century, typhoid fever was virtually eradicated in developed countries by the development of drinking water treatment, water sewage control, pasteurization of milk and dairy products, and other food technology practices. However, typhoid fever remains a major problem for public health in developing countries: around 25-30 million cases are estimated to occur per year worldwide [11]. A fraction of individuals recovering from typhoid fever become asymptomatic, life-long carriers of Salmonella en足 terica ser. Typhi [11]. Non-typhoidal Salmonella serovars can also cause persistent infections, either associated with cholecystitis or asymptomatic, although the duration of carriage is usually limited to several months [37]. Persistent and chronic infections, especially if asymptomatic, may be viewed as evolutionary strategies that increase the Salmonella reproductive rate by favoring host survival. Like humans, livestock and wild animals can be asymptomatic carriers of non-typhoidal Salmonella serovars able to infect humans, thus acting as reservoirs for human infection (Fig. 1).

Fig. 1. A Salmonella enterica cell dividing in the presence of 5 % sodium deoxycholate. Survival and division in the presence of bile salts is made possible by activation of bile resistance responses [22]. (Electron microscopy image obtained by Miguel A. de Pedro, Severo Ochoa Molecular Biology Centre (CBMSO), Cantoblanco, Spain).

cidal action of bile salts. Current evidence suggests that Sal足 monella resistance to bile does not involve a single response but a variety of responses. It seems also likely that Salmonel足 la subpopulations are formed upon gall bladder colonization, and that these subpopulations respond to bile in different ways [3]. A fraction of the Salmonella population invades the epithelium, where it may be protected, at least partially, from bile salts [28]. Another subpopulation multiplies in the gall bladder lumen, either forming biofilms on gallstones or activating bile defense responses [10,19]. Biofilm formation not only contributes to bile resistance but also to antibiotic resistance, thereby explaining why patients carrying S. Typhi in the gall bladder usually fail to respond to antibiotic treatment [17]. In turn, planktonic Salmonella cells survive in the gall bladder by activating bile defense responses. In vitro studies suggest that bile defense may combine activation of efflux pumps, remodeling of the bacterial envelope, and activation of stress responses and DNA repair functions [22,33-35]. Adoption of multiple lifestyles in the gall bladder may help to understand the difficulty to eradicate Salmonella chronic carriage, which often makes cholecystectomy the only effective treatment.

Chronic carriage of Salmonella Human carriage of Salmonella Typhi is often asymptomatic, and therefore difficult to diagnose. At the beginning of the twentieth century, a famous case was protagonized by Mary Mallon, the first chronic carrier identified in the United States. Mallon, an Irish immigrant, is presumed to have infected at least 51 people, three of whom died, over the course of her career as a cook in New York [5]. Antibiotics are usually ineffective on Salmonella carriage (even if Salmonellae are susceptible to them) because Salmonella resides in the gall bladder [17]. Bacterial proliferation in the gall bladder of chronic carriers permits Sal足 monella shedding to the environment, potentially transmitting the infection. The ability of Salmonella to thrive in the human gall bladder is one of most surprising aspects of Salmonella biology because the high concentration of bile present in the gall bladder makes it a harsh environment for bacteria: bile salts disrupt the bacterial envelope, denature proteins, and damage DNA [4,8,29]. However, Salmonella escapes the bacteriwww.cat-science.cat

Stealthy Salmonella persistence inside fibroblasts The possibility that the gall bladder is not the only reservoir for Salmonella Typhi during persistent and chronic infections has been considered for decades, and has been re-ex53

CONTRIBUTIONS to SCIENCE 9 (2013) 51-56

Bacterial pathogenesis as an imperfect symbiosis

populations, one of which replicates while the other enters a dormant-like state [21]. Like other bacterial species, Salmo nella also presents phenotypic heterogeneity generated by phase variation, the reversible switch of gene expression at high frequency (e.g., >10–5 per cell and generation) [39,40]. Switching turns gene expression from OFF to ON, or from low expression to high expression, and vice versa. An example is the opvAB locus of Salmonella which controls O-antigen chain length in the lipopolysaccharide [9]. Phase variation of opvAB generates two subpopulations, one with long O-antigen chains, another with shorter O-antigen chains.

amined recently [31]. It seems possible, for instance, that Salmonella Typhi may invade cell types other than its classical cell targets (epithelial cells, dendritic cells and macrophages), perhaps adopting a latent intracellular lifestyle. In the mouse model of typhoid fever, Salmonella Typhimurium can invade fibroblasts, a ubiquitous cell type with long lifespan in connective tissues [38]. Interestingly, colonization of fibroblasts by S. Typhimurium is not followed by bacterial proliferation. This restrained lifestyle resembles the persistent state which in other microorganisms is known as dormancy [16]. Persistence of Salmonella inside fibroblasts is an example of bacterial self-restraint, as indicated by the isolation of S. Typhimurium mutants able to proliferate inside fibroblasts [6]. The bacterial functions that restrain growth inside fibroblasts are also required for virulence, and overgrowth inside fibroblasts does not cause hypervirulence but loss of virulence [15]. Hence, a tentative link can be established between successful infection and bacterial self-restraint. The peculiar nature of the Salmonella-fibroblast interaction is further illustrated by the fact that invasion of fibroblast cell lines differs from entry into epithelial cells, especially in the way the bacterium induces rearragement of the eukaryotic cytoskeleton [1]. Collectively, these findings support the possibility that Salmonella, like other intracellular pathogens, may have evolved strategies to avoid host damage and to favor stealthy bacterial persistence in host tissues. On the other hand, slow-growing S. Typhimurium variants have been isolated upon long-term passage through fibroblasts [7], and these mutants resemble the Staphylococcus aureus small colony variants that cause chronic infections [41] (Fig. 2).

Attenuation of Salmonella virulence by subpopulation formation Single cell analysis technologies (e.g., flow cytometry and microfluidics) reveal that phenotypic heterogeneity is common in bacterial populations made of genetically identical cells [12]. In some cases, formation of bacterial subpopulations is programmed by genetic or epigenetic mechanisms; in other cases, phenotypic heterogeneity is the consequence of noisy gene expression. Noise can be used also as a signal to trigger an epigenetic feedback loop when gene expression reaches a threshold [26]. Because this threshold is only reached in certain cells, the bacterial population splits into two cell types with distinct properties. Subpopulation formation is observed at several stages of Salmonella infection, and may contribute to virulence attenuation. For instance, synthesis and secretion of the Salmonella effectors necessary for epithelial cell invasion is restricted to a fraction of the bacterial population [2]. Salmonella entry into macrophages is also accompanied by formation of two subwww.cat-science.cat

Fig. 2. Overgrowth of Salmonella enterica phoPQ mutants within eukaryotic cells. A. Intracellular growth rates (Ipro values) of wild type S. enterica (SL1344), a phoP mutant (SV4056), and a phoQ mutant (SV4365) in NRK fibroblasts and HeLa epithelial cells. Overgrowth is observed in fibroblasts and to a lesser extent in epithelial cells. B. Massive overgrowth of Salmonella phoP and phoQ mutants in NRK fibroblasts as observed by immunofluorescence microscopy. Monoclonal mouse IgG anti-LPS antibody and goat anti-mouse IgG conjugated to Texas Red were used for bacterial staining (red). DAPI (4,6-diamidino-2-phenyl-indole) was used to stain eukaryotic nuclei (blue). Arrows indicate wild type bacteria that do not exhibit massive intracellular proliferation. Bar: 10 µm. (Reproduced from [6], © American Society for Microbiology, Infect. Immun. October 2001; doi:10.1128/IAI.69.10.6463-6474.2001).

CONTRIBUTIONS to SCIENCE 9 (2013) 51-56

CASADESUS

fection by Helicobacter resembles Salmonella chronic carriage in that both infections occur in hostile environments: the bile-laden gall bladder for Salmonella, the acid environment of the stomach for Helicobacter. An additional analogy is that in both cases latent infection permits shedding of bacteria and propagation to new hosts. Although the presence of Helicobacter in the stomach can cause ulcers and gastric cancer in certain individuals, epidemiologic studies suggest that latent infection with Helicobacter can protect against esophageal cancer [14]. Mycobacterium tuberculosis, the causal agent of tuberculosis, is able to persist within humans for long periods without causing clinical symptoms of disease [25]. In Europe and the U.S., carriage affects at least 1% of the population, with enormous regional differences. Chronic persistence of Mycobacte rium within the human host involves a state known as dormancy: bacterial metabolism is slowed down and cell division is arrested [16]. Dormancy occurs in the vacuole of infected macrophages. Intracellular location of the pathogen, metabolic slowdown and cell division arrest make pharmacological treatment of dormancy useless. Unlike chronic infection by Salmonella or Helicobacter, latent carriers of M. tu berculosis do not shed bacterial cells into the environment. The view that primary pathogens and commensals are separated by a blurred line is further supported by epidemiological evidence suggesting that reduction of human exposure to infectious agents may have increased allergies and autoimmune diseases [14]. In fact, a widely accepted notion is that interaction with infectious agents, especially during infancy and childhood, may play a key role in development and tuning of the human immune system. If latent infections by human-adapted pathogens play beneficial protective roles, acute disease may be considered an accident triggered by factors that disrupt the host-pathogen equilibrium. As pointed out by Stanley Falkow, organisms like Helicobacter pylori, the typhoid bacillus, and Mycobacterium tuberculosis have been our constant companions through human evolution, and might be considered part of the normal human flora along with the accepted commensals [14].

These subpopulations differ in their capacity to invade macrophages and in their resistance to serum; as a consequence, one subpopulation is more virulent than the other [9]. Other Salmonella loci that show phase variation are the pef and std operons, which encode fimbriae for attachment to specific host tissues [23,32]. Attenuation of virulence by subpopulation formation may benefit the pathogen by escaping the immune system and other host defense mechanisms. However, it can also benefit the host by reducing the burden of bacterial infection (Fig. 3).

Chronic infection as an imperfect symbiosis The ability of Salmonella Typhi to cause chronic infection may be viewed as a rudimentary symbiosis: the presence of Salmonella in the gall bladder does not cause clinical symptoms in most human carriers. The symbiosis is however imperfect because colonization of the gall bladder is not completely harmless to the host: gallstone formation is a risk factor for the development of hepatobiliary cancer, probably in combination with genetic predisposition and other risk factors [13]. Besides Salmonella Typhi, other primary pathogens establish latent infections that may be viewed as imperfect symbioses. Helicobacter pylori, for instance, causes asymptomatic infection in over 80 % of humans [24]. Latent in-

Acknowledgements. I thank Francisco García-del Portillo

(CNB, CSIC, Cantoblanco, Spain) for our long and fruitful collaboration in the study of bacterial self-restraint mechanisms, and Laura Serrano for critical reading of the manuscript.

References 1.

Fig. 3. Phase variation of the Salmonella enterica opvAB operon as observed in bacterial colonies. The Salmonella strain carries a lacZ fusion in the opvAB operon. Expression of opvAB::lac gives rise to blue colonies on LB agar containing X-gal (5-bromo-4-chloro-3-indolyl-β-d-galac topyranoside). Cells that do not express opvAB form white colonies on LB containing X-gal. (Reproduced from [9], Creative Commons License).

www.cat-science.cat

Aiastui A, Pucciarelli MG, Garcia-del Portillo F (2010) Salmonella en terica serovar typhimurium invades fibroblasts by multiple routes differing from the entry into epithelial cells. Infect Immun 78:2700-2713 Bailly-Bechet M, Benecke A, Hardt WD, Lanza V, Sturm A, Zecchina R (2011) An externally modulated, noise-driven switch for the regulation of SPI1 in Salmonella enterica serovar Typhimurium. J Math Biol 63:637-662

CONTRIBUTIONS to SCIENCE 9 (2013) 51-56

Bacterial pathogenesis as an imperfect symbiosis

4. 5. 6.

10.

11. 12. 13.

14. 15.

16. 17.

18. 19. 20.

21.

22.

Baumler A, Winter SE, Thiennimitr P, Casadesus J (2011) Intestinal and chronic infections: Salmonella lifestyles in hostile environments. Environ Microbiol Rep 3:508-517 Begley M, Gahan CG, Hill C (2005) The interaction between bacteria and bile. FEMS Microbiol Rev 29:625-651 Bourdain A (2005) Typhoid Mary. Bloomsbury, New York, NY Cano DA, Martínez-Moya M, Pucciarelli MG, Groisman EA, Casadesús J, García-del Portillo F (2001) Salmonella enterica serovar Typhimurium response involved in attenuation of pathogen intracellular proliferation. Infect Immun 69:6463-6474 Cano DA, Pucciarelli MG, Martínez-Moya M, Casadesús J, García-del Portillo F (2003) Selection of small-colony variants of Salmonella en terica serovar Typhimurium in nonphagocytic eucaryotic cells. Infect Immun 71:3690-3698 Casadesús J, Hernández SB, Cota I, Ramos-Morales F (2011) Of bacteria and bile. In: Maloy SR, Hughes K, Casadesus J (eds) The Lure of Bacterial Genetics: A Tribute to John Roth, ASM Press, Washington, pp 153-162 Cota I, Blanc-Potard AB, Casadesús J (2012) STM2209-STM2208 (opv AB): a phase variation locus of Salmonella enterica involved in control of O-antigen chain length. PLoS ONE 7:e36863 Crawford RW, Rosales-Reyes R, Ramírez-Aguilar ML, Chapa-Azuela O, Alpuche-Aranda C, Gunn JS (2010) Gallstones play a significant role in Salmonella spp. gallbladder colonization and carriage. Proc Natl Acad Sci USA 107:4353-4358 Crump JA, Luby SP, Mintz ED (2004) The global burden of typhoid fever. Bull World Health Organ 82:346-353 Davidson CJ, Surette MG (2008) Individuality in bacteria. Annu Rev Genet 42:253-268 Dutta U, Garg PK, Kumar R, Tandon RK (2000) Typhoid carriers among patients with gallstones are at increased risk for carcinoma of the gall bladder. Am J Gastroenterol 95:784-787 Falkow S (2006) Is persistent bacterial infection good for your health? Cell 124:699-702 García-del Portillo F, Núñez-Hernandez C, Eisman B, Ramos-Vivas J (2008) Growth control in the Salmonella-containing vacuole. Curr Opin Microbiol 11:46-52 Gengenbacher M, Kaufmann SH (2012) Mycobacterium tuberculosis: success through dormancy. FEMS Microbiol Rev 36:514-532 Gonzalez-Escobedo G, Marshall JM, Gunn JS (2011) Chronic and acute infection of the gall bladder by Salmonella Typhi: understanding the carrier state. Nat Rev Microbiol 9:9-14 Groisman EA, Ochman H (1997) How Salmonella became a pathogen. Trends Microbiol 5:343-349 Gunn JS (2000) Mechanisms of bacterial resistance and response to bile. Microbes Infect 2:907-913 Hamilton WD (1982) Pathogens as causes of genetic diversity in their host populations. In: Anderson RM, May RM (eds) Population biology of infectious diseases. Springer, Berlin, pp 169-296 Helaine S, Thompson JA, Watson KG, Liu M, Boyle C, Holden DW (2010) Dynamics of intracellular bacterial replication at the single cell level. Proc Natl Acad Sci USA 107:3746-3751 Hernández SB, Cota I, Ducret A, Aussel L, Casadesús J (2012) Adaptation and preadaptation of Salmonella enterica to bile. PLoS Genet 8:e1002459

www.cat-science.cat

23.

24. 25. 26.

27. 28.

29.

30.

31.

32.

33.

34. 35. 36. 37. 38.

39. 40. 41.

42. 43.

44.

Jakomin M, Chessa D, Baumler AJ, Casadesús J (2008) Regulation of the Salmonella enterica std fimbrial operon by DNA adenine methylation, SeqA and HdfR. J Bacteriol 190:7406-7413 Kusters JG, van Vliet AH, Kuipers EJ (2006) Pathogenesis of Helico bacter pylori infection. Clin Microbiol Rev 19:449-490 Lawn SD, Zumla AI (2012) Tuberculosis. Lancet 378:57-72 López-Garrido J, Cota I, Casadesús J (2012) Epigenetic gene regulation in bacteria. In: Meyers RA (ed) Epigenetic regulation and epigenomics. Wiley VCH, Weinheim, pp 1107-1138 May RM, Anderson RM (1983) Epidemiology and genetics in the coevolution of parasites and hosts. Proc R Soc Lond B Biol Sci 219:281-313 Menendez A, Arena ET, Guttman JA, Thorson L, Vallance BA, Vogl W, Finlay BB (2009) Salmonella infection of gallbladder epithelial cells drives local inflammation and injury in a model of acute typhoid fever. J Infect Dis 200:1703-1713 Merritt ME, Donaldson JR (2009) Effect of bile salts on the DNA and membrane integrity of enteric bacteria. J Med Microbiol 58:15331541 Morabia A (2007) Epidemiologic interactions, complexity, and the lonesome death of Max von Pettenkofer. Am J Epidemiol 166:12331238 Nath G, Singh YK, Maurya P, Gulati AK, Srivastava RC, Tripathi SK (2010) Does Salmonella Typhi primarily reside in the liver of chronic typhoid carriers? J Infect Dev Ctries 4:259-261 Nicholson B, Low D (2000) DNA methylation-dependent regulation of pef expression in Salmonella typhimurium. Mol Microbiol 35:728742 Prieto AI, Hernández SB, Cota I, Pucciarelli MG, Orlov Y, Ramos-Morales F, García-del Portillo F, Casadesús J (2009) Roles of the outer membrane protein AsmA of Salmonella enterica in the control of marRAB expression and invasion of epithelial cells. J Bacteriol 191:3615-3622 Prieto AI, Ramos-Morales F, Casadesús J (2004) Bile-induced DNA damage in Salmonella enterica. Genetics 168:1787-1794 Prieto AI, Ramos-Morales F, Casadesús J (2006) Repair of DNA damage induced by bile salts in Salmonella enterica. Genetics 174:575-584 Quart P (1937) Bestiari. Proa, Barcelona, Catalonia [2006 edition] Rabsch W, Tschape H, Baumler AJ (2001) Non-typhoidal salmonellosis: emerging problems. Microbes Infect 3:237-247 Tierrez A, García-del Portillo F (2005) New concepts in Salmonella virulence: the importance of reducing the intracellular growth rate in the host. Cell Microbiol 7:901-909 van der Woude MW (2011) Phase variation: how to create and coordinate population diversity. Curr Opin Microbiol 14:205-211 van der Woude MW, Baumler AJ (2004) Phase and antigenic variation in bacteria. Clin Microbiol Rev 17:581-611 von Eiff C (2008) Staphylococcus aureus small colony variants: a challenge to microbiologists and clinicians. Int J Antimicrob Agents 31:507-510 von Graevenitz A (1977) The role of opportunistic bacteria in human disease. Annu Rev Microbiol 31:447-471 Wichterman KA, Baue AE, Chaudry IH (1980) Sepsis and septic shock – a review of laboratory models and a proposal. J Surg Res 29:189-201 Wilson M (2005) Microbial inhabitants of humans: their ecology and role in health and disease. Cambridge University Press, Cambridge, UK

CONTRIBUTIONS to SCIENCE 9 (2013) 51-56

DISTINGUISHED LECTURES CONTRIBUTIONS to SCIENCE 9 (2013) 57-66 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.164 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

Celebration of the Centennial of the Catalan Society for Biology, 1912–2012

Multidisciplinary approaches towards compartmentalization in development: Dorsoventral boundary formation of the Drosophila wing disc as a case study Javier Buceta Department of Chemical Engineering, Lehigh University, Bethlehem, PA, USA

Based on the lecture given by the author at the Institute for Catalan Studies, Barcelona, on 10 July 2012 at the CIBICAT, ‘Global Questions on Advanced Biology’ as part of the Centennial of the SCB. Correspondence: Program in Bioengineering Department of Chemical Engineering Lehigh University B320 Iacocca Hall, 111 Research Drive Bethlehem, PA 18015, USA E-mail: jbuceta@gmail.com Received: 28.09.13 Accepted: 11.11.13

Summary. Lineage

restriction boundaries set stable barriers during tissue growth that compartmentalize the primordia and promote their patterning. This discovery was a major breakthrough in modern biology because of its powerful conceptual implications regarding the developmental plan in both vertebrates and invertebrates, the subject of this short review. As a leitmotif, we focus on our own recent contributions to the problem of dorsoventral boundary formation in the wing disc of Drosophila, paying special attention to recent multidisciplinary approaches that have shed light on the gene regulatory interactions and biomechanics underlying the compartmentalization process.

Keywords: compartmentalization · developmental biology · systems biology · biomechanics · gene regulatory networks Resum. Els límits de restricció dels llinatges estableixen barreres durant el creixement tissular que compartimentalitzen els primordis i promouen el seu patró. Aquest descobriment va suposar un gran avenç en la biologia moderna, gràcies a les seves poderoses implicacions conceptuals sobre el pla de desenvolupament dels vertebrats i dels invertebrats, que és el tema d’aquesta breu revisió. Com a leitmotiv, utilitzem les nostres contribucions més recents al problema de la formació del límit dorsiventral del disc imaginal de l’ala de Drosophila, tot posant especial atenció en enfocaments multidisciplinaris recents que han aclarit la biomecànica i les interaccions gèniques reguladores subjacents al procés de compartimentalització. Paraules clau: compartimentació · biologia

del desenvolupament · biologia de sistemes ·

biomecànica · xarxes de regulació gèniques

Compartments, boundaries, and the developmental plan

mapping their positions in the adult organism and thus dynamically tracing the developmental plan. Drosophila is a perfect model organism in these kinds of experiments because of the peculiarities in the development of its imaginal discs [27,48]. All cuticular structures, e.g., wings, antennas, and legs, of the adult organism (imago) distinctly derive from these groups of cells. Thus, for example, all cells of the wing

In the late 1960s and early 1970s, induced recombination techniques enabled the marking of single cells and their progeny (clones, mosaics). This, in turn, made it possible to follow the locations of cell populations in the primordium, www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 57-66

Drosophila wing disc

of an adult fly (~104) originate from the cells of its corresponding wing imaginal disc (~101). Using clonal analysis, García Bellido and colleagues showed that the wing imaginal disc is compartmentalized [20]. Clones of cells in the tissue grow and extend up to certain cellular boundaries that do not overlap, thereby preventing the intermingling of different cellular populations (Fig. 1A). The first of those boundaries to be recognized was the dorsoventral (DV) one, which segregates the prospective dorsal and ventral cellular domains of the wing (Fig. 1B). In that case, the boundary population itself becomes the wing margin. However, as demonstrated by García bellido and colleagues, boundaries are not necessarily associated with morphological hallmarks: the

wing primordium is further subdivided into anterior and posterior (AP) domains that do not correlate with particular structures of the adult wing [21] (Fig. 1B). These seminal studies fostered further work on the compartmentalization process in other imaginal discs (e.g., legs, head), revealing similar features [27,48]. Moreover, Nature has widely followed this developmental strategy, as this mechanism is evolutionarily conserved in a number of tissues and organisms. Thus, now we know that lineage restriction boundaries also exist in vertebrates at the hindbrain, in the limb buds, and in the gut [15,30]. Compartments are established by the expression and activity of “selector genes” that encode homeodomain tran-

Fig. 1. (A) A growing tissue with two identified cellular clones. Lineage restriction boundaries are evident when the positions of cells and their progeny are followed over time: the established boundaries set a barrier that cannot be crossed. (B) Schematic representation of wing imaginal disc compartmentalization in Drosophila and the prospective positions of cellular populations within the adult wing. The dorsoventral (DV) boundary population becomes the wing margin whereas the anteroposterior (AP) one is not associated with any specific morphological hallmark. The expression and activity of selector genes establish a binary combinatorial mechanism that provides cells with coarse-grained positional information: dorso-anterior (DA), dorsoposterior (DP), ventral anterior (VA), and ventral posterior (VP). (C) The French flag model. Morphogens are synthesized at, and diffuse from, localized sources determined by the boundaries, the so-called organizers. Cells at the primordium obtain positional information by “reading” the morphogen concentration, resulting in further patterning. (D, E) Basic regulatory interactions shaping AP (D) and DV (E) compartmentalization. In the former, directional signaling because of the activity of Engrailed establishes the AP organizer at the posterior side of the anterior compartment, from which the morphogen Dpp diffuses. The action of Apterous modifies Notch ligands such that Notch becomes activated symmetrically in the cells at the DV interface (see text). Notch activity identifies the DV organizer and induces expression of the morphogen Wg.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 57-66

BUCETA

scription factors and confer location identities at the single cell level. In the case of the wing imaginal disc of Drosophi la, the transcription factors Engrailed and Apterous endow cells with posterior and dorsal characters, respectively [15,27,30,48]. These properties are heritable and prevent cells from mixing with those of “anteriorness” (lack of Engrailed activity) and “ventralness” (lack of Apterous activity) characters as proliferation progresses. This differential regulation of cell “affinities” due to the activity of selector genes has remained the fundamental hypothesis explaining the correct sorting of cells at the boundaries. It derives from the theoretical work of Steinberg, who proposed that tissues differing in their adhesiveness could rearrange and segregate just as immiscible fluids do, because of polar/ non-polar interactions [53]. Accordingly, Capricious and Tartan are transmembrane proteins expressed in the dorsal compartment of the wing disc that promote cell adhesiveness [9,44]. Experiments have shown that in Apterous mutant backgrounds, in which the functionality of the DV boundary is compromised, the driven expression of these proteins can restore a functional boundary [9,44]. Likewise, cadherin expression downstream of Engrailed occurs along the anteroposterior (AP) boundary [51]. Other studies have shown that cadherins play a similar role during vertebrate development [29]. Still, as discussed below, the underlying biomechanics of cell sorting and segregation are complex and do not simply rely on adhesion properties. The consequences of compartmentalization go far beyond keeping cellular populations separated; they also reveal an organized developmental plan for shaping organisms [15,30]. First, the gene patterning of the primordium, reflecting the activity of selector genes (or the lack of them), determines a coarse-grained cell fate by means of combinatorial overlap (Fig. 1B). Second, cellular interactions at compartment boundaries induce further patterning that provides detailed positional information to cells. Specifically, short-range signaling between cells at the compartment interface triggers new gene expression/regulation and establishes a cellular population at the boundary, the organizer, from which diffusive molecules, called morphogens, are secreted. This localized source of morphogen production sets up a morphogen concentration gradient that is “read” by cells at the compartments and elicits a long-range signaling mechanism. Examples of morphogen molecules are Decapentaplegic (Dpp), produced/secreted by the AP organizer, and Wingless (Wg), the DV organizer counterpart [15,30]. The positional information of cells within the bulk compartment is then achieved in a concentration-dependent manner following the so-called French flag model [11,57] (Fig. 1C), in which the organizers provide the axes of a coordinate reference system. Nonetheless, an organizer must display several key features to guarantee its reliability www.cat-science.cat

as a source of positional information: thus, the width of the cell population is constricted to a few (two, three) cells that must develop while the correct shape is maintained. Taken together, these findings were a major breakthrough in modern developmental biology because of their powerful conceptual implications in terms of the modular design of multicellular organisms, which is conserved in both vertebrates and invertebrates, and its genetic foundation. Since the discovery of compartments, much progress has been made regarding the processes that lead to their formation and function. Yet, many aspects remain puzzling, including the gene regulatory networks responsible for the robust establishment and maintenance of gene patterning, and the biomechanical features of tissues that ensure precise and regular boundaries/organizers as cells proliferate and/or the tissue deforms. Systems-like approaches, including mathematical modeling, computational biology, and biophysics, have contributed to shedding light on these topics. Within this framework, in the following we review recent advances in the field, using the DV boundary of the wing imaginal disc as a case study.

Patterning the primordium: the establishment of boundaries and organizers How do a given cell and its progeny “know” which genes should and should not be expressed in order to perform a particular task? As mentioned above, patterning of the primordium imparts positional information to cells and establishes a “map,” by means of which the fate of a cell is determined depending on its position relative to other cells that form the tissue. Consequently, the question underlying the positional information problem is: how does genetic regulation establish such a map? In the wing imaginal disc, Engrailed induces the expression of Hedgehog, a short-range signaling molecule, in posterior cells. Anterior cells at the compartment interface transduce the Hedgehog signal via the transmembrane protein Smoothened (and the Patched receptor), which in turn induces the expression of the morphogen Dpp. As a result of this directional signaling, from posterior to anterior, the AP organizer is established at the posterior side of the anterior compartment [15,30] (Fig. 1D). While the DV case shares the basics with the AP one, there are some relevant differences. Given the morphological implications of DV compartmentalization in the adult organism, formation of the DV organizer implies more complex and bidirectional signaling between adjacent compartments. The latter might reflect the need for symmetrical positioning of the organizer since the dorsal and ventral compartments are to give rise to the apposed, specular-like surfaces of the adult wing [15,27,30,48]. Thus, Apterous in 59

CONTRIBUTIONS to SCIENCE 9 (2013) 57-66

Drosophila wing disc

ceptor activity and leading to the establishment of the DV organizer [10]. Yet, experimental studies aimed at elucidating the details of the genetic interactions that sustain both Notch and Wg activities revealed a few inconsistencies. Specifically, Dishevelled, a cytoplasmic mediator of the Wg signaling pathway, binds the intracellular domain of Notch, which blocks Notch signaling and reduces receptor activity [5]. This finding necessitated that a new property be ascribed to boundary cells that allowed them to stably maintain the organizing center: they must be refractory to the Wg signal. Indeed, refractoriness to a morphogenetic signal also develops in the AP case: Engrailed not only induces Hedgehog expression but also causes posterior cells to become refractory to it [54,59]. These observations pointed out the need to redefine the aforementioned regulatory interactions patterning DV compartmentalizationâ&#x20AC;&#x201D;a need that was met using a multidisciplinary approach.

the D cells of the early wing primordium activates the expression of the transmembrane ligand Serrate and the glycosyltransferase Fringe and restricts the expression of Delta, another transmembrane ligand, to V cells. Fringe modifies the Notch receptor and makes D cells more sensitive to Delta and less sensitive to Serrate. Conversely, unmodified Notch in V cells responds better to Serrate than to Delta. The preferential response of the Notch receptor to the ligands expressed in the opposite compartments ensures the activation of the Notch pathway only at the DV interface, i.e., symmetrically and bidirectionally (see [10] and references therein) (Fig. 1E). Other compartmentalization problems, such as separation of the animal cap cells in zebrafish, also involve bidirectional signaling [43]. Notch receptor activity causes expression of the signaling molecule Wg at the DV boundary population, which in turn drives the expression of Notch ligands, thus sustaining re-

Concentration (a.u.)

Notch (activated) Cut Wingless

Time (a.u.)

Fig. 2. (A) As shown by in silico experiments, putative regulatory interactions between Notch and Wg pathways (top) cannot sustain Notch activity at the DV boundary population; as time progresses Notch and Wg expression fades in those cells (bottom). (B) When the correct regulatory interactions are included (see Fig. 3A) in silico experiments are able to reproduce their in vivo counterparts with respect to boundary formation patterning. Top: Induced expression of Notch in a strip perpendicular to the DV boundary generates a pattern of Notch and Wg activities resembling that of the boundary, indicating that refractoriness to the morphogen signal is downstream of Notch (red: Wg expression; blue: Senseless expression). Middle: The same experiment in a Cut mutant background cannot induce refractoriness to the Wg signal. Bottom: Ectopic expression of Cut in a strip perpendicular to the DV boundary (green) drives refractoriness to the Wg signal in that region.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 57-66

BUCETA

Modeling approaches to the genetic regulation of compartmentalization

latory networks have been proposed. Both types of studies have contributed to a better understanding of the temporal modularity of the developmental plan and they have shed light on the respective genetic interactions. Thus, in silico studies helped to clarify the dynamics of patterning along developmental instars [23] and provided evidence that the putative regulatory interactions in the DV boundary could not provide a plausible explanation for its establishment [10] (Fig. 2A). The combination of experiments, mathematical modeling, and computer simulations further showed that the expression and activity of Cut are both necessary and sufficient to inhibit Wg target gene expression in boundary cells [10] (Fig. 2B) and helped to reverse-engineer a consistent DV axis regulatory network (Fig. 3A). Thus, refractoriness to Wg via Cut in the DV boundary population blocks Wg signaling pathway in these cells: the Notch ligands Serrate and Delta as well as other genes transcriptionally regulated by Wg activity

In parallel with the experimental efforts aimed at identifying gene regulatory interactions, mathematical modeling approaches have become an increasingly powerful tool based on their predictive capabilities [18]. At the root of the concept of boundaries and their functions lies the theoretical work of Meinhardt, who proposed that boundaries serve as reference points for positional information as sites of morphogen synthesis [41,42]. As reviewed here, his predictions have been experimentally confirmed to a large extent. AP patterning and boundary formation have been addressed through modeling, which has unveiled the regulatory interactions that confer robustness in terms of parameter variations [16]. In the context of DV boundary formation in the Drosophila wing, continuous [10,23] and Boolean [35] regu-

Concentration (a.u.)

Notch (activated) Cut Wingless

Time (a.u.) Fig. 3. (A) A reverse-engineering approach reveals the gene regulatory network underlying DV boundary formation (top). The role played by Cut is complex and includes the repression of Notch ligands. Cut also induces total refractoriness to the Wg signal (cf. Fig. 2A). The model takes into account cellautonomous and intercellular processes, including Wg diffusion and intracellular (cis) and intercellular (trans) interactions between the Notch receptor and its ligands Delta and Serrate. This network â&#x20AC;&#x153;circuitryâ&#x20AC;? gradually generates the robust and sustained expression of Notch and Wingless in boundary cells (bottom). (B) Depiction of Notch and Wg expression and activity profiles at the DV boundary and neighboring regions (top). Wg expression is maximal at the DV boundary but its activity is null at that domain. The interplay between Notch and Wg pathways generates mutually exclusive spatial domains in terms of their activities. In silico experiments have reproduced the evolution of the pattern that shapes the DV boundary and neighboring regions (bottom). Note the spatial refinement of Notch activity, the symmetrization of Delta and Serrate expression (Wg activity reporter), and the formation of a Wg gradient as the DV organizer becomes established.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 57-66

Drosophila wing disc

namely, network motifs [4]. Crosstalk between motifs has been shown to be useful for characterizing the spatial and temporal patterning that arises in developmental processes [14,31]. Accordingly, a motif-like formalism also has been applied to the DV boundary formation problem [12], thus confirming the robustness of DV patterning as well as the basics of the mechanism underlying the formation of mutually exclusive domains of activities. In addition, this approach has allowed the output of different mutant backgrounds to be easily analyzed (Fig. 4). All in all, the modeling of gene regulatory networks in combination with experiments has been a valuable tool for comprehending the genetic interactions that lead to a stable and robust pattern for boundary formation. Nonetheless, in spite of all the knowledge gained about the genetic regulation underlying boundary formation, the biomechanics of cell segregation long remained a conundrum. Note that during development the number of cells in the wing imaginal disc increases by approximately 1000-fold. This poses several intriguing questions: How do organizer cells deal with division events while maintaining straightness, width, and stability? How does patterning become scaled as proliferation progresses? What are the roles played by cytoskeletal remodeling, adhesiveness, and cortical tension in ensuring reliable compartmentalization?

(e.g., Senseless) are not expressed in boundary cells. Refractoriness mediates the regulatory interplay between Notch and Wg and promotes the formation of mutually exclusive spatial domains in terms of their activities in patterning the DV organizer (Fig. 3B). This systems biology approach also led to the recognition of: (a) the role of Cut in terms of the functionality of the DV boundary (Cut is not required for the formation but for the robust maintenance of patterning) and (b) so-called boundary refinement dynamics (Wg activity restricts the width of the organizer and forces polarized signaling by Notch receptor and its ligands). As the complexity of the developmental model increases in terms of the details of the interactions in gene regulation (e.g., cis versus trans interactions between ligands and receptors) and/or in terms of the number of â&#x20AC;&#x153;playersâ&#x20AC;? involved in a signaling pathway, so does the dimensionality of the parameter space. Thus, depending on the amount and quality of the experimental data, fitting or estimating parameters can set a limitation for the predictive capabilities of modeling. Moreover, conceptual abstractions about the fundamental mechanisms driving a particular process become more difficult as the modeling process becomes less and less reductive. In this regard, a powerful approach for understanding the properties and functionalities of genetic regulation is the analysis of reduced functional blocks,

Wild type

Fig. 4. (A) Network motifs capture the central functionality of interacting pathways, or species, using a minimal number of elements. Intertwined negative and positive feedback loops between two species, X (Notch) and Y (Wg), reproduce the formation of mutually exclusive activity domains and all the basic phenomenology of DV boundary formation. (B) The reduced dimensionality of the motifs enables representation of network potentiality in terms of expression and activity profiles. Here, the differences between Notch and Wg activities are shown by means of a density plot as a function of their expression levels. The triangles indicate the expression thresholds controlling network functioning. The sharp transition between full Notch (blue circle) and Wg pathway (red square) activation is marked by small variations in Notch levels (hypersensitivity). In addition, the signature of mutant backgrounds can be easily analyzed and compared with that of the wild-type (see [12] for details).

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 57-66

BUCETA

Biomechanics of compartmentalization

shown that, in addition to differences in cell affinity, some of the contributions of the cytoskeleton, e.g., increased cell tension, underlie the functioning of AP/DV boundaries [3,37]. In laser ablation experiments, mechanical tension was greater (by approximately three-fold) on cell bonds along compartment boundaries than within the remaining tissue (Fig. 5A) [3,37]. These findings were in line with theoretical work challenging Steinberg’s “differential adhesion hypothesis” and they led to the “differential surface contraction hypothesis,” in which contractility plays a crucial role in cell sorting. More recently, the “differential interfacial tension hypothesis,” combining elements of both theories, was proposed. Clearly, the biomechanics underlying cell sorting are more complex than first thought (see [34] and references therein). At the same time, other studies have indicated that dynamic and morphologic factors related to the cell cycle must be taken into account to understand the stability and

Recent research has pointed out that mechanical effects play a central role in the function of organizers/boundaries [15,30,36,47,48,56]. Thus, it has been shown that both Factin and myosin II accumulate by the zonula adherens at the junctions of the DV border [39,40]. Running along the boundary, these components putatively promote cell adhesion and increase the cortical tension of cells. In agreement with these studies, it was reported that actomyosin-based barriers (cables) are effective inhibitors of cell mixing in other developmental stages of Drosophila (parasegmental boundaries of the embryonic epidermis) and that the reduction of myosin activity causes boundary disturbance [46]. These results provided support for the crucial and active role of the cytoskeleton, and consequently of its mechanical effects, in keeping the regularity and fence-like features of boundary/organizers. Note that it was recently

Fig. 5. (A) Laser ablation experiments shed light on, and allow quantification of, cellular tension in tissues. The distance between the vertices of ablated edges changes with time because of the energy dissipated in the tissue. The initial velocity of the expansion is related to the accumulated tension: the higher the velocity, the greater the tension. The curve indicates that the tension is greater at the edges of the DV boundary (green circles) than in the bulk compartment (red circles). (B) Cleavage orientation determines the shape of organs and challenges the stability of boundaries. At the DV boundary, cleavage orientation is clearly favored over the bulk compartment, with the cells preferentially dividing perpendicular to the DV axis. (C) In the vertex model, each cell is represented by a reduced number of points (the vertices). Associated with each vertex is an energetic contribution that takes into account the different elements, such as the elastic energy of cells, their adhesion, and the cortical tension.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 57-66

Drosophila wing disc

vertex model exploits the polygonal-like morphology, monolayer character, and apicobasal mechanical polarization of epithelial cells to characterize them by a reduced set of points (the apical vertices) and to compute the dynamics of each cell vertex depending on the applied forces, which derive from mechanical considerations, e.g., cytoskeleton activity [49] (Fig. 5C). In the literature different examples show that the vertex model successfully describes the biomechanics of the wing imaginal disc. These examples include its packing [19], AP compartmentalization [37], the effects of mechanical feedback on tissue topology [1], the alignment of planar cell polarity domains with the proximal-distal axis of the wing [2] and, more recently, the DV compartmentalization biomechanics [3,13]. For example, it has been shown that cellular mechanical properties are coupled to cleavage orientation by means of the Hertwig rule [45,55] (cells divide perpendicular to their longest axis) and that this is key to the organizer stability (Fig. 6) [13]. However, some contradictions persist in terms of the influence of the cell cycle duration on the maintenance of the DV organizer. On the one

robustness of organizers. Thus, it has been demonstrated in different contexts that the orientation of cell divisions determines the shape of developing tissues and organs [2,6]. In particular, it is now clear, from measurements of the orientation of the mitotic spindle and from post-mitotic cellular allocation, that cells of the DV organizer follow a division pattern that is different from that of cells within the bulk of the compartments: in the former the division plane is perpendicular to the DV interface (Fig. 5B) [6,39,40]. In addition, the rate of proliferation decreases in the vicinity of some boundaries. In the DV case, Notch activity eventually controls cell proliferation at the organizer by arresting the G1-S cell cycle progression; also, by late third instar the DV organizer and neighboring cells clearly define the â&#x20AC;&#x153;zone of non-proliferating cellsâ&#x20AC;? (ZNC) [28,32]. In vertebrates it has been also shown that during segmentation of the chick embryo hindbrain, the duration of the cell cycle is longer at the rhombomeres interface [25]. In silico experiments are also a powerful and effective tool for studying the biomechanics of tissues. The so-called

Fig. 6. (A) The Hertwig rule establishes a phenomenological relation between the angle that defines the longest axis of a cell (l) and the division angle (da). (B) In silico experiments, in agreement with experimental data, indicate that the stability of the boundary is challenged by the cleavage orientation and the duration of the cell cycle. A randomized cleavage orientation (top) breaks the DV boundary. In the absence of distinct regulation of the cell cycle duration at boundary vs. bulk compartment (bottom) cells, the DV organizer becomes wider such that some cells cannot maintain Notch activity and DV organizer stability is therefore compromised.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 57-66

BUCETA

hand, the actomyosin cable at the DV interface is not present when the ZNC is evident [39,40]. A similar phenomenon is observed at the parasegmental boundaries of the Drosophila embryo [46]. This suggests that the challenge posed to the stability of boundaries by cell proliferation necessitates the involvement of additional, stabilizing mechanisms. Moreover, there is ample evidence (analytical, computational, and experimental) that a distinctive regulation of cell cycle duration is needed at the DV organizer in order to maintain its features [7,13] (Fig. 6B). On the other hand, a recent study showed that a decreased cell proliferation rate is not important to the maintenance of a straight and sharp DV boundary and that tissue elongation is a major factor [3]. In any case, these studies together have confirmed that an understanding of how the physical properties and cytokinetic processes of cells are regulated is crucial to understanding compartmentalization.

quired to understand how genetic regulation determines biomechanical features and vice versa [24]. Moreover, multiscale aspects are far from being understood. Also, while we have reviewed some of the techniques and studies that connect single cell behavior with that of the tissue, how molecular effectors determine collective cellular behavior and the interplay between tissues remain to be determined [17,33]. Quantitative approaches through imaging and modeling, in which the underlying biophysics are connected with the biological realm, will definitively help to answer this and other questions in the coming years [8,52]. Acknowledgements. The author thanks Carla Prat for critical reading of the manuscript. In addition, the author apologizes to those researchers whose primary research was not cited, due to space limitations. Financial support was provided by MICINN under grant BFU2010-21847-C02-01/ BMC, and by DURSI through project 2009-SGR/01055. The author also acknowledges support from the European Science Foundation, ESF, through the Quantissue programme.

Conclusions and perspectives Herein we have reviewed the dynamics of the formation and maintenance of boundaries and organizers, using DV compartmentalization as a leitmotif. In a discussion that ranged from its genetic foundations to its biomechanical properties, we showed how signaling events establish the onset of organizer formation, which further patterns the primordium and delivers positional information to cells. In this context, systems biology approaches have helped researchers to unravel some of the genetic interactions that underlie boundary formation. In addition, we pointed out that the identification and characterization of biomechanical elements are fundamental for understanding the robust maintenance of the compartmentalization process. In this regard, modeling techniques have provided both quantitative and predictive insights into the morphogenetic mechanisms driving boundary dynamics. However, interesting questions remain regarding the relative importance of signaling versus mechanical and dynamic effects in the maintenance of boundaries/organizers during development. At every developmental stage, signaling is indeed fundamental but, at the same time, once the onset of segregation has been established, mechanical and dynamic contributions become fundamental for the organizer to appropriately guide tissue growth. Systemic approaches have also been useful in revealing many aspects of the compartmentalization process, a common theme in developmental biology. Still, the big picture requires further progress. For example, the link between biomechanics and signaling and the feedback between these processes remains unclear [58]. Recently there have been advances in force-sensing, the homeostasis of cell–cell junctions [22], and the interplay between mechanical signals and gene regulation [26,50]. However, additional work is rewww.cat-science.cat

References 1.

Aegerter-Wilmsen T, Smith AC, Christen AJ, Aegerter CM, Hafen E, Basler K (2010) Exploring the effects of mechanical feedback on epithelial topology. Development 137:499-506 2. Aigouy B, Farhadifar R, Staple DB, Sagner A, Röper, J-C, Jülicher F, Eaton S (2010) Cell flow reorients the axis of planar polarity in the wing epithelium of Drosophila. Cell 142:773-786 3. Aliee M, Röper J-C, Landsberg KP, Pentzold C, Widmann TJ, Jülicher F, Dahmann C (2012) Physical mechanisms shaping the Drosophila dorsoventral compartment boundary. Curr Biol 22:967-976 4. Alon U (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8:450-461 5. Axelrod JD, Matsuno K, Artavanis-Tsakonas S, Perrimon N (1996) Interaction between Wingless and Notch signaling Pathways mediated by Dishevelled. Science 271:1826-1832 6. Baena-López LA, Baonza A, García-Bellido A (2005) The orientation of oell divisions determines the shape of Drosophila Organs. Curr Biol 15:1640-1644 7. Becam I, Rafel N, Hong X, Cohen SM, Milán M (2011) Notch-mediated repression of bantam miRNA contributes to boundary formation in the Drosophila wing. Development 138:3781-3789 8. Blanchard GB, Kabla AJ, Schultz NL, Butler LC, Sanson B, Gorfinkiel N, Mahadevan L, Adams RJ (2009) Tissue tectonics: morphogenetic strain rates, cell shape change and intercalation. Nature Methods 6:458-464 9. Blair SS (2001) Cell lineage: Compartments and Capricious. Curr Biol 11:R1017-R1021 10. Buceta J, Herranz H, Canela-Xandri O, Reigada R, Sagués F, Milán M (2007) Robustness and stability of the gene regulatory network involved in DV boundary formation in the Drosophila wing. PLoS ONE 2:e602 11. Buceta J, Ibañes M, Jaeger J (2011) Modeling approaches in embryo development. In: UNESCO Encyclopedia of Life Sciences, Mathematical Physiology in Encyclopedia of Life Support Systems, Eolss Publishers, Oxford 12. Canela-Xandri O, Sagués F, Reigada R, Buceta J (2008) A spatial toggle switch drives boundary formation in development. Biophysical J 95:5111-5120

CONTRIBUTIONS to SCIENCE 9 (2013) 57-66

Drosophila wing disc

13. Canela-Xandri O, Sagués F, Casademunt J, Buceta J (2011) Dynamics and mechanical stability of the developing dorsoventral organizer of the wing imaginal disc. PLoS Computl Biol 7:e1002153 14. Cotterell J, Sharpe J (2010) An atlas of gene regulatory networks reveals multiple three-gene mechanisms for interpreting morphogen gradients. Mol Syst Biol, 6:425 15. Dahmann C, Oates AC, Brand M (2011) Boundary formation and maintenance in tissue development. Nat Rev Genet 12:43-55 16. Dassow G von, Meir E, Munro EM, Odell G M (2000) The segment polarity network is a robust developmental module. Nature 406:188-192 17. Davidson LA, Joshi SD, Kim HY, Dassow M von, Zhang L, Zhou J (2010) Emergent morphogenesis: Elastic mechanics of a self-deforming tissue. J Biomech 43:63-70 18. Di Ventura B, Lemerle C, Michalodimitrakis K, Serrano L (2006) From in vivo to in silico biology and back. Nature 443:527-533 19. Farhadifar R, Röper J-C, Aigouy B, Eaton S, Jülicher F (2007) The influence of cell mechanics, cell-cell interactions, and proliferation on epithelial packing. Curr Biol 17:2095-2104 20. Garcia-Bellido A (1968) Cell lineage in the wing disc of Drosophila melanogaster, Genetics 60:181 21. García-Bellido A, Ripoll P, Morata G (1973) Developmental compartmentalisation of the wing disc of Drosophila. Nat New Biol 245:251253 22. Gomez GA, McLachlan RW, Yap AS (2011) Productive tension: forcesensing and homeostasis of cell–cell junctions. Trends Cell Biol 21:499-505 23. Gonzàlez A, Chaouiya C, Thieffry D (2006) Dynamical analysis of the regulatory network deﬁning the dorsal–ventral boundary of the Dro sophila wing imaginal disc. Genetics 174:1625-1634 24. Gregersen H, Jiang W, Liao D, Grundy D (2012) Evidence for stressdependent mechanoreceptors linking intestinal biomechanics and sensory signal transduction. Exp Physiol 98:123-133 25. Guthrie S, Butcher M, Lumsden A (1991) Patterns of cell division and interkinetic nuclear migration in the chick embryo hindbrain. J Neurobiol 22:742-754 26. Haswell ES, Phillips R, Rees DC (2011) Mechanosensitive channels: What can they do and how do they do it? Structure 19:1356-1369 27. Held LI, Jr. (2005) Imaginal Discs: The genetic and cellular logic of pattern Formation (Developmental and Cell Biology Series). Cambridge Univ Press, Cambridge, UK 28. Herranz H, Pérez L, Martín FA, Milán M (2008) A wingless and Notch double-repression mechanism regulates G1-S transition in the Dro sophila wing. EMBO J 27:1633-1645 29. Inoue T, Tanaka T, Takeichi M, Chisaka O, Nakamura S, Osumi N (2001) Role of cadherins in maintaining the compartment boundary between the cortex and striatum during evelopment. Development 128:561-569 30. Irvine KD, Rauskolb C (2001) Boundaries in development: Formation and function. Annu Rev Cell Dev Biol 17:189-214 31. Ishihara S, Fujimoto K, Shibata T (2005) Cross talking of network motifs in gene regulation that generates temporal pulses and spatial stripes. Genes Cells: 10:1025-1038 32. Johnston LA, Edgar BA (1998) Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing. Nature 394:82-84 33. Keller R, Shook D (2011) The bending of cell sheets -from folding to rolling. BMC Biol 9:90 doi:10.1186/1741-7007-9-90 34. Krens SFG, Heisenberg C-P (2011) Cell Sorting in Development. Curr Top Dev Biol 95:189-213 35. Kyoda K, Kitano H (1999) A model of axis determination for the Dro sophila wing disc. In: Floreano D (ed) Proceedings of the 5th European Conference on Advances in Artiﬁcial Life, Springer-Verlag, London, pp 472-476

www.cat-science.cat

36. Labouesse M (2011) Forces and tension in development, Academic Press, Oxford 37. Landsberg KP, Farhadifar R, Ranft J, Umetsu D, Widmann TJ, Bittig T, Said A, Jülicher F, Dahmann C (2009) Increased cell bond tension governs cell sorting at the Drosophila anteroposterior compartment boundary. Curr Biol 19:1950-1955 38. Lye CM, Sanson B (2011) Tension and epithelial morphogenesis in Drosophila early embryos. Curr Top Dev Biol 95:145-187 39. Major RJ, Irvine KD (2005) Influence of Notch on dorsoventral compartmentalization and actin organization in the Drosophila wing. Development 132:3823-3833 40. Major RJ, Irvine KD (2006) Localization and requirement for myosin II at the dorsal-ventral compartment boundary of the Drosophila wing. Dev Dynam 235:3051-3058 41. Meinhardt H (1983) A boundary model for pattern formation in vertebrate limbs. J EmbryolExp Morph 76:115-137 42. Meinhardt H (1983) Cell determination boundaries as organizing regions for secondary embryonic fields. Developmental Biology 96:375-385 43. Mellitzer G, Xu Q, Wilkinson DG (1999) Eph receptors and ephrins restrict cell intermingling and communication. Nature 400:77-81 44. Milán M, Weihe U, Pérez L, Cohen SM (2001) The LRR proteins Capricious and Tartan mediate cell interactions during DV boundary formation in the Drosophila wing. Cell 106:785-794 45. Minc N, Burgess D, Chang F (2011) Influence of cell geometry on division-plane positioning. Cell 144:414-426 46. Monier B, Pélissier-Monier A, Brand AH, Sanson B (2010) An actomyosin-based barrier inhibits cell mixing at compartmental boundaries in Drosophila embryos. Nat Cell Biol 12:60-65 47. Monier B, Pélissier-Monier A, Sanson B (2011) Establishment and maintenance of compartmental boundaries: role of contractile actomyosin barriers. Cell Mol Life Sci 68:1897-1910 48. Morata G (2001) How Drosophila appendages develop. Nature Rev Mol Cell Biol 2:89-97 49. Nagai T, Honda H (2001) A dynamic cll model for the formation of epithelial tissues. Philos Mag B 81:699-719 50. Pouille P-A, Ahmadi P, Brunet AC, Farge E (2009) Mechanical signals trigger Myosin II redistribution and mesoderm invagination in Dro sophila embryos. Science Signal 14,2:RA16 51. Schlichting K, Demontis F, Dahmann C (2005) Cadherin Cad99C is regulated by Hedgehog signaling in Drosophila. Dev Biol 279:142-154 52. Schwarz US, Dunlop CM (2012) Developmental biology: a growing role for computer simulations. Curr Biol 22:R441-R443 53. Steinberg MS (2007) DifferentialaAdhesion in morphogenesis: a modern view. Curr Opin Genet Dev 17:281-286 54. Tabata T, Eaton S, Kornberg TB (1992) The Drosophila Hedgehog gene is expressed specifically in posteriocCompartment cells and is a target of engrailed regulation. Gene Dev 6:2635-2645 55. Théry M, Bornens M (2006) Cell shape and cell division. Curr Opin Cell Biol 18:648-657 56. Umetsu D, Dahmann C (2010) Compartment boundaries: Sorting cells with Tension. Fly 4:241-245 57. Wolpert L (1969) Positional Information and the spatial pattern of cellular differentiation J Theor Biol 25:1-47 58. Yonemura S, Wada Y, Watanabe T, Nagafuchi A, Shibata M (2010) aCatenin as a tension transducer that induces adherens junction development. Nat Cell Biol 12:533-542 59. Zecca M, Basler K, Struhl G (1995) Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing. Development 121:2265-2278

CONTRIBUTIONS to SCIENCE 9 (2013) 57-66

DISTINGUISHED LECTURES CONTRIBUTIONS to SCIENCE 9 (2013) 67-73 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.165 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

Celebration of the Centennial of the Catalan Society for Biology, 1912–2012

Anti-angiogenic therapy for cancer and the mechanisms of tumor resistance Gabriela Jiménez-Valerio, Oriol Casanovas Tumor Angiogenesis Group, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute, Barcelona, Catalonia

Based on the lecture given by the authors at the Institute for Catalan Studies, Barcelona, on 9 July 2012 at the CIBICAT. Correspondence: Oriol Casanovas Tumor Angiogenesis Group Catalan Institute of Oncology-IDIBELL Av. Gran Via de l’Hospitalet 199-203 08908 L’Hospitalet de L., Catalonia Tel. +34-932607344 E-mail: ocasanovas@iconcologia.net Received: 25.10.13 Accepted: 20.11.13

Summary. Tumor progression requires the activation of neovascularization, or angiogenesis,

a process orchestrated by tumor and by stromal cells within the tumor mass. In the therapeutic targeting of angiogenesis, the aim is to inhibit tumor growth and progression. Indeed, anti-angiogenic therapy is currently used in several types of cancer. Nevertheless, both the tumor cells and the stromal components may be variably resistant to anti-angiogenic therapy, demonstrating refractoriness, or intrinsic resistance, on the one hand, and acquired resistance, gained progressively during treatment, on the other. Several strategies have been proposed to overcome both types of resistance but they remain to be tested in preclinical studies and clinical trials. Keywords: anti-angiogenic therapy · tumor cells · stromal cells · intrinsic resistance · acquired resistance Resum. La progressió dels tumors requereix l’activació d’una neovascularització, o angiogè-

nesi, un procés orquestrat per les cèl·lules tumorals i per l’estroma dins la massa tumoral. La inhibició terapèutica d’aquest procés té per objectiu impedir el creixement i la progressió del tumor. Actualment la terapèutica antiangiogènica s’aplica en determinats tipus de càncer. No obstant això, hi ha cèl·lules tumorals i components estromals que poden presentar una resistència variable a la terapèutica antiangiogènica, que pot ser refractarietat o resistència intrínseca, per una banda, o resistència adquirida progressivament al llarg del tractament, per una altra. S’han proposat diverses estratègies per lluitar contra aquests dos tipus de resistència, però encara han de provar-se en estudis preclínics i en assajos clínics. Paraules clau: teràpia antiangiogènica · cèl·lules tumorals · cèl·lules de l’estroma · resistència

intrínseca · resistència adquirida

Angiogenesis in tumor development

essential nutrients. To meet this demand, tumors induce the growth of blood vessels, a process referred to as angiogenesis, by up-regulating the expression and secretion of growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), angiopoietins (Ang), placental growth factor (PlGF), and some integrins, and concomitantly down-regulating several anti-angiogenic factors [22]. In addition, angiogenesis coincides with increased circulating tumor cells, facilitating metastatic

Cancer cells are cells that have lost their capacity to divide in a controlled manner. They give rise to a neoplastic lesion that is supported by stromal cells. Both tumor cells and stromal cells contribute structurally and functionally to tumor development. Nevertheless, the tumor mass is typically limited to a size of 1–2 mm³, because further growth requires the diffusion of adequate amounts of oxygen and www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 67-73

Anti-angiogenic therapy for cancer and the mechanisms of tumor resistance

spread. There is also evidence that angiogenesis precedes tumor formation, which implies that it is the rate-limiting step not only for tumor growth but also much earlier, for tumor development [5]. Tumor cells cooperate with other cell types in the tumor microenvironment, such as immune cells, inflammatory cells, hematopoietic cells, and stromal fibroblasts. These cells then secrete various types of inducers, which activate endothelial cells and therefore angiogenesis [6]. In 1986, Dvorak described the inflammatory phenotype of tumors as “wounds that never heal.” In the tumor mass, the balance is tipped in favor of angiogenesis, with the newly formed vasculature able to oxygenate and nourish the growing neoplasm. The imbalance resulting in the sustained production of pro-angiogenic factors, together with the persistent lack of vascular stabilizing factors, leads to the formation of an immature and dysfunctional vascular system that cannot keep pace with the rapid growth of the tumor mass. Therefore, the vascular tree in a tumor is typically chaotic, with deadend vessel branches and areas of inverted and intermittent blow flow, which may impair vascular function and lead to regions of lowered perfusion and hypoxia. The latter in turn causes up-regulation of the transcription factor hypoxia-inducible factor (HIF) and therefore of hypoxia-dependent genes (e.g., carbonic anhydrase and glucose transporters) [42]. For example, HIF-1 modulates the transcription of genes involved in glycolytic metabolism, oxygen consumption, survival, angiogenesis, migration and invasion. Accordingly, its stabilization has dramatic repercussions for the gene expression profile and eventually the behavior of the tumor cells [2,25]. Moreover, hypoxia actively participates in the activation of angiogenesis, by regulating the inducers and inhibitors that contribute to it. Specifically, tumor hypoxia induces the expression of molecules that disrupt endothelial and pericyte coverage, such as Ang2, which further contributes to the initiation of vascular sprouting. In addition, hypoxia results in the mobilization of multiple types of stem cells from the bone marrow and the recruitment of immune cells to the tumor microenvironment [7]. Recent advances in molecular biology and the study of families with hereditary renal cancer (in the setting of von Hippel-Lindau, hereditary papillary, Birt-Hogg-Dubé, and hereditary leiomyomatosis) have led to the recognition of genes and proteins involved in the pathogenesis of several tumor entities, and thus of the potential for patient-tailored targeted therapy [35,51]. In particular, inactivation of the von Hippel-Lindau tumor suppressor gene in patients with renal cell carcinoma (RCC) involves the failed degradation of HIF1α signaling, even under normoxia, and therefore the accumulation of this transcription factor, which results www.cat-science.cat

in hyperactivation of the HIF signaling pathway and transcription of the genes encoding its downstream effectors [30,36]. Therefore, the therapeutic use of molecules that inhibit binding to, e.g., VEGF, glucose transporter GLUT1, transforming growth factor-α, and platelet-derived growth factor (PDGF) receptors, has been investigated in many types of tumors [43,44].

Anti-angiogenic strategies Discovery of the dependence of tumor growth on angiogenesis and the stromal contribution to new vessel formation suggested new therapeutic targets. Targeting of the cells that support tumor growth rather than the cancer cells themselves is a relatively recent approach in cancer therapy, one that is particularly promising because these cells are genetically stable and therefore less likely to accumulate mutations that allow them to rapidly develop drug resistance. In 1971, Judah Folkman proposed the inhibition of angiogenesis as a therapeutic strategy for cancer. Subsequently, several antiangiogenic drugs aimed at inhibiting endothelial cell growth were developed. More recently, other cell types in the tumor microenvironment, either instead of or together with endothelial cells, have been targeted. These cells include pericytes, which contribute to vascular maturation by releasing signals that maintain endothelial cell survival and structurally support the vessel wall [12] (Fig. 1). Based on their mechanism of action, anti-angiogenic drugs can be classified in two groups. (1) Direct-acting drugs that prevent vascular endothelial cells from proliferating, migrating, or avoiding cell death in response to a spectrum of pro-angiogenic proteins, including VEGF, bFGF, interleukin-8, and PDGF. In addition to the VEGF-blocking antibody bevacizumab, for use in combination with chemotherapy in patients with metastatic colorectal cancer, metastatic breast cancer, and other cancers, the U.S. FDA has approved chemical inhibitors of VEGF receptor 2 (VEGFR2), such as sunitinib and sorafenib, as first-line monotherapy for metastatic kidney cancer. (2) Indirect-acting drugs that secondarily either prevent the expression or block the activity of tumor proteins that activate angiogenesis. The targets of the latter group are the tumor-cell signaling pathways responsible for the synthesis or secretion of pro-angiogenic molecules. A typical example is mTOR inhibitors, which act on tumor-cell survival pathways and secondarily decrease VEGF expression, thereby indirectly exerting an anti-angiogenic effect. In this review we discuss direct-acting anti-angiogenic drugs, which for the most part inhibit pro-angiogenic signaling pathways. Consistent with its role as the main promoter of angiogenesis, VEGF is the primary target of the currently approved anti-angiogenic drugs, which include monoclonal antibodies and selective inhibitors of kinase activity [22]. 68

CONTRIBUTIONS to SCIENCE 9 (2013) 67-73

JIMĂ&#x2030;NEZ-VALERIO, CASANOVAS

VEGF's soluble receptors

Anti VEGF-trap Aflibercept

Sunitinib Sorafenib Axitinib Pazopanib, ...

Bevacizumab P

VEGFR inhibitors TK P

Tumor cell

VEGF

P P P P

VEGF VEGFR-2

FGF inhibitors

VESSEL

VEGF

Anti VEGF

Plexins

Anti VEGFR-2 IMC-1121B

FGFRs

FGFs

SEMAs

Endotelial cell

Fig. 1. Therapeutic targets and their angiogenic inhibitors currently used in preclinical and clinical studies. (See text for details). VEGF, vascular endotelial growth factor; anti VEFG-Trap, antiangiogenic VEGF-Trap; VEGFR-2, VEGF receptor-2; FGF, fibroblast growth factor; FGFRs, FGFreceptors; SEMAs, semaphorins. (See text for details).

VEGF as a prototypical anti-angiogenesis target

Other recently proposed novel targets

Monoclonal antibodies may be direct or indirect acting. Their direct action is to block VEGF signaling by blocking the ligand or its receptors (VEGFRs) whereas their indirect action is mediated by the immune system (complement system activation, cytotoxic lymphocytes, and macrophages), resulting in tumor-cell destruction. Monoclonal antibodies were the first anti-angiogenic drug to demonstrate a clear clinical effect, increasing the survival of patients with metastatic colorectal cancer. The most well known example of these drugs is bevacizumab, an antibody against human VEGF ligand [28] (Fig. 1). Selective inhibitors of kinase activity compete with ATP for binding to the catalytic domain of the protein, thereby blocking kinase activity including that of VEGFRs. Initial tests of these drugs as anti-proliferative agents for tumor endothelial cells resulted in the development of a large number of inhibitors acting on different pathways and different cell types apart from those expressing VEGFRs (promiscuous tyrosinekinase inhibition profile). Currently, sunitinib and sorafenib are the most widely used drugs of this class since they demonstrate the best anti-angiogenic activity [1] (Fig. 1).

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling axis plays an important role in normal organ, vascular, and skeletal development. The deregulation of FGF/FGFR signaling through the genetic modification or Ĺ&#x201C;verexpression of either component has been observed in numerous tumors, consistent with the key role of FGF/FGFR axis in driving tumor angiogenesis. Preclinical data showed that the inhibition of FGFR signaling causes antiproliferative and/or pro-apoptotic effects, both in vitro and in vivo, thus confirming the validity of the FGF/FGFR axis as a potential therapeutic target [10]. Accordingly, several drugs against different pro-angiogenic targets have been developed for testing [22]. Semaphorins (SEMAs) are a superfamily of secreted or membrane-associated glycoproteins that have been implicated in the control of axonal wiring. They are also known to be involved in angiogenesis and cancer progression. SEMAs positively or negatively modulate many intrinsic properties of tumor cells, such as proliferation, cell survival, cell adhesion, and tumor invasiveness, but they also act on stromal properties, including endothelial cell migration

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 67-73

Anti-angiogenic therapy for cancer and the mechanisms of tumor resistance

stimulates tumor angiogenesis, invasion, and metastasis through Tie2-independent pathways involving integrinmediated signaling. Therefore, Ang2 is also an attractive therapeutic target, as corroborated in recent studies using a neutralizing anti-Ang2 antibody [27].

and survival [11,48]. Thus, the overexpression of Sema3E reduces tumor burden by counteracting angiogenesis, but it also increases metastatic spread of the tumor. Casazza et al explored the pleiotropic therapeutic activities associated with an uncleavable Sema3E isoform (Uncl-Sema3E) [16], which retains the anti-angiogenic activity of endogenous p61-Sema3Ebut also has anti-invasive and anti-metastatic effects on the tumor. Similar to p61-Sema3E, Uncl-Sema3E binds to PlxnD1 in endothelial cells and induces the expected SEMA-driven anti-angiogenic collapse of the tumor. Furthermore, in tumor cells, the Uncl-Sema3E-PlxnD1complex fails to elicit the ErbB2-mediated pro-invasive and pro-metastatic pathway. With these results the authors proposed Uncl-Sema3E as a novel anti-angiogenic and antimetastatic therapeutic approach. Angiopoietins are growth factors that promote angiogenesis and help stabilize the formation of blood vessels from pre-existing ones. Ang1 and Ang2 are required for vessel maturation, as demonstrated by knock-out studies in mice [52]. Moreover, Ang2 is critically associated with tumor angiogenesis and progression, cooperating with VEGF and Ang1 through Tie2-dependent pathways. In addition, Ang2

Clinical results and remaining challenges Preclinical studies often report positive results regarding the efficacy of anti-VEGF therapy, but the results of clinical trials vary depending on the cancer type and anti-angiogenic therapy used. Phase III studies have indeed shown the benefits of bevacizumab, sunitinib, and other VEGFtargeted therapies, either as single agents or in combination with chemotherapy. Blocking the formation of new blood vessels with anti-angiogenic therapy is currently used to treat certain types of cancers, including metastatic RCC [43,44]. Several clinical trials have confirmed the positive impact of anti-angiogenic therapies in controlling the growth of this typically highly-VEGF secreting tumor [19,39,45,46]. Nevertheless, many authors have found that anti-angiogenic treatments are more effective in in-

INTRINSIC RESISTANCE

Vascular cooption

Overexpression of FGF1, FGF2, Efna1, Efna2 and Angpt1

NO EFFECT

ACQUIRED RESISTANCE

B Recruitment vascular progenitor cells (BMD Cs) Pericytes coating

Overexpression of FGF1, FGF2, Efna1, Efna2 and Angpt1

RESPONSE PHASE

RESISTANCE PHASE

Fig. 2. Mechanisms of resistance to anti-angiogenic therapy: (A) intrinsic resistance (or refractoriness); (B) acquired resistance. Mechanisms of intrinsic resistance include the multiplicity of pro-angiogenic factors produced by tumor or stromal cells within the tumor mass and vascular co-option. Mechanisms of acquired resistance include the overexpression of pro-angiogenic factors, the recruitment of vascular progenitor cells (BMDCs), and an increase in pericyte coverage. Together, they allow for revascularization despite therapeutic inhibition, and thus tumor regrowth and disease progression.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 67-73

JIMĂ&#x2030;NEZ-VALERIO, CASANOVAS

creasing progression-free survival (PFS) than in prolonging overall survival (OS). However, based on the clear clinical benefits, with a remarkable increase in PFS, despite the absence of a robust, statistically significant increase in OS, VEGF pathway inhibitors are the mainstay of therapy in RCC and have been approved by the US Food and Drug Administration (FDA) [20,26]. The discrepancy between PFS and OS has fueled the controversy of how to best measure the clinical benefits of treatment, because the effects of anti-angiogenic therapies typically include increased tumor necrosis, as observed in imaging studies. Thus, cavitation and the loss of viable tumor mass ascribed to anti-VEGF agents may indeed translate into an impact on tumor growth but without significant alteration of the tumor dimensions, as required by RECIST (Response Evaluation Criteria in Solid Tumors) guidelines [18,47]. The pattern of growth and the modifications induced at the site of tumor development are strongly dependent on the tumor type and, in particular, its angiogenic features and the pro-angiogenic capacity arising from tumor-stroma interactions. This is a crucial consideration, because in certain cancers, such as RCC and hepatocellular carcinoma (HCC), single-agent VEGF-targeted therapy has demonstrated significant activity whereas in other tumors, such as colorectal cancer (CRC), considerably fewer clinical benefits have been obtained and VEGF-targeted therapy is therefore administered in combination with chemotherapy. In RCC, angiogenesis is presumably highly VEGF-dependent, in part because of its high frequency of inactivation of the von Hippel-Landau tumor suppressor gene [53]. The same dependence on angiogenesis is presumably the key to the efficacy of anti-angiogenic therapy in HCC. These tumors are highly angiogenic in the liver and their growth displaces the normal parenchyma. This pattern is in contrast to metastatic foci of CRC in the liver, in which case the tumors often replace rather than displace the liver parenchyma, by the FAS-ligand-induced death of hepatocytes. This leads to the co-option of existing blood vessels rather than a dependence on sprouting angiogenesis [9,18].

Intrinsic resistance to anti-angiogenic therapy is defined as a total lack of response to the therapy; it is characterized by tumor indifference, as there is no response to treatment (Fig. 2A). IR has been described in patients treated with bevacizumab, sorafenib, and sunitinib, as determined by the continued growth of their tumors [3,34]. Acquired resistance refers to the adaptive capacity of tumors that allows them to evade continued therapeutic inhibition of their growth after an initial phase of effectiveness. In fact, anti-angiogenic drugs achieve clinical efficacy in many patients, but these clinical benefits are overshadowed by an apparent acquired resistance. Moreover, some patients do not respond at all to antiangiogenic therapy, indicative of intrinsic resistance. It has been shown that, from the beginning of their progression, tumors are capable of expressing multiple proangiogenic factors, which limits the efficacy of anti-VEGF therapy since in these cases angiogenesis is only partially blocked [23]. Another molecular mechanism that may be involved in IR is the de-regulation of the HIF pathway. HIF-activated tumors, such as renal tumors, express high levels of genes encoding pro-angiogenic molecules controlled by this pathway, thereby reducing the effect of antiangiogenic therapy [43,44]. Other potential mechanisms supporting tumor growth include an independence from angiogenesis, including the co-option of pre-existing vessels, vasculogenic mimicry, mosaic vessels, and the mobilization of latent vessels [50]. Could the specific angiogenic features of each tumor determine their upfront sensitivity or resistance to anti-angiogenic therapy? Interestingly, in astrocytomas, a group of highly oxygen-dependent brain tumors, there is a change in the mechanism by which they acquire their blood supply. Thus, low-grade astrocytomas grow by co-opting pre-existing, normal brain vessels whereas in the progression from grade III to grade IV, in so-called glioblastoma multiforme (GBM), the enhanced demand for oxygen and nutrients activates an angiogenic program [40]. Recently, the FDA approved bevacizumab for the treatment of recurrent GBM based on several studies demonstrating efficacy in terms of increased PFS and OS when the drug is combined with conventional chemotherapy. Unfortunately, tumor resistance occurs with new distant foci of progression or diffuse in situ infiltration associated or not with local tumor recurrence, as shown by fluid-attenuated inversion recovery and magnetic resonance imaging analyses [38,54]. In addition to the traditional forms of resistance to some drugs, which are acquired by mutations that affect the drug target of drugs or entry mechanisms [24], acquired resistance (AR) to anti-angiogenic therapies is both indirect and evasive. Typically, alternative mechanisms are created that lead to the activation of angiogenesis even when the drug target remains inhibited [33]. Tumors have remarkable plasticity

Resistance to anti-angiogenic therapy It was initially assumed that anti-angiogenic therapy does not induce resistance, because of its specific targeting of endothelial cells, which do not exhibit genetic instability [8]. However, experimental and clinical evidence has shown that the benefits of anti-angiogenic therapy are mild and transient [44] and that, as in classical chemotherapy and radiation, tumor adaptability is also a challenge [14,15]. Among tumor responses to therapy, it is essential to distinguish between refractoriness, sometimes called intrinsic reÂ sistance (IR), and acquired resistance (AR) [18]. www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 67-73

Anti-angiogenic therapy for cancer and the mechanisms of tumor resistance

and adaptability to classical chemotherapy and radiation, which contribute to their resistance to anti-angiogenic therapy [6,13,32]. However, the specific mechanisms of AR to anti-angiogenic therapies are unique, and many of them are reversible after anti-angiogenic therapy has been stopped (Paez-Ribes and Casanovas, unpublished observations). This suggests that these forms of resistance reflect adaptations to therapy instead of the accumulation of gene mutations or amplifications that characterizes the AR seen in other therapeutic strategies. Clinical evidence of AR reversibility has been described in metastatic RCC treated repeatedly with VEGFR inhibitors [44]. Several different mechanisms of AR to anti-angiogenic therapy have been described, among which are (Fig. 2):

ment of the neoplastic lesion but also for the response of the tumor to therapeutic inhibition of the VEGF pathway. Together with the characteristics of the tumor cells, the stroma contributes to both IR and AR. Indeed, many of the tumor-celldependent mechanisms of resistance are implemented through stromal modification, e.g., the recruitment of infiltrating cells, such as cancer-associated fibroblasts and tumor-associated macrophages, or the production of alternative pro-angiogenic factors. One of the main modifications induced by anti-angiogenic therapy in tumors is the abovedescribed increase in hypoxia and HIF-1 stabilization. However, neoplastic cells can become tolerant of hypoxia, and thus acquire therapeutic resistance, by modifying their metabolic characteristics. Alternatively, they can escape the hypoxic conditions, either alone or sustained by their stromal neighbors.

(i) Overexpression of alternative pro-angiogenic factors.

Perspectives

These were initially described in a transgenic mouse model of neuroendocrine tumors (RIP-Tag2). After the mice received anti-VEGFR2 therapy, there was a reduction of angiogenesis followed by initial tumor regrowth and the reinduction of induced angiogenesis. The latter was promoted by the overexpression of VEGF-independent pro-angiogenic factors, such as FGF1, FGF2, ephrin A1 and A2, and Ang1 [15,21].

Overcoming resistance is a crucial step in the development of anti-angiogenic therapies. Among the strategies proposed thus far is the use of multi-pathway inhibitors. Moreover, given the plasticity of the response to treatment, observed in preclinical studies, a sequential approach in which an anti-angiogenic drug is followed by a non-antiangiogenic drug (whether another targeted therapy or chemotherapy) may resensitize patients to a third-line antiangiogenic agent. Obviously, many studies will be needed to identify the therapeutic approach that results in maximum clinical benefit for patients. Furthermore, the role of the stroma, in addition to that of the tumor cells, in the emergence of resistance to anti-angiogenic therapies has important clinical implications and suggests innovative treatment perspectives.

(ii) Recruitment of stromal pro-angiogenic cells. The hy-

poxic conditions induced by anti-angiogenic treatment promote the recruitment at the tumor boundaries of large numbers of bone-marrow-derived cells and thus tumor revascularization [49]. (iii) Vessel coverage by pericytes. Pre-existing tumor ves-

sels with a large number of surface coverage by pericytes remain functional and do not regress [5, 29,31,37]. This suggests that endothelial cells are able to recruit pericytes, which then secrete VEGF and other factors promoting their survival [4,5,17].

Acknowledgement. The authors thank Lidia Moserle for

critical reading of the manuscript and helpful suggestions. The authorsâ&#x20AC;&#x2122; work is supported by research grants from EU-FP7 (ERC-StG-281830), and MinEco-Spain (SAF2009- 08375, RTICC RD2006-0092) and AGAUR-Generalitat (SGR681). The authors declare that there are no conflicts of interest.

(iv) Vascular mimicry. Microvascular channels that allow

the transport of oxygen and nutrients are formed by the aggressive tumor cells themselves [50].

References

Although there are some similarities between the mechanisms that lead to IR and AR, there are also several differences. In AR, the molecular changes that lead to tumor resistance develop progressively whereas in IR the tumors are immune to therapy from the beginning, as they overexpress the factors that confer resistance. In anti-angiogenic therapies, resistance involves both the tumor cells and the stromal components, but their relative contributions differ according to each cancer subtype. Thus, the interplay between tumor cells and the tumor microenvironment is crucial not only for the developwww.cat-science.cat

2. 3.

Abrams TJ, Murray LJ, Pesenti E, Holway VW, Colombo T, Lee LB, Cherrington JM, Pryer NK (2003) Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with â&#x20AC;&#x2DC;standard of careâ&#x20AC;&#x2122; therapeutic agents for the treatment of breast cancer. Mol Cancer Ther 2:1011-1021 Azam F, Mehta S, Harris AL (2010) Mechanisms of resistance to antiangiogenesis therapy. Eur J Cancer 46:1323-1332 Batchelor TT, et al. (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83-95 Benjamin I,Rubin SC (1998) Modern treatment options in epithelial ovarian carcinoma. Curr Opin Obstet Gynecol 10:29-32

CONTRIBUTIONS to SCIENCE 9 (2013) 67-73

JIMÉNEZ-VALERIO, CASANOVAS

5. 6. 7.

10.

11.

12. 13. 14. 15.

16.

17.

18. 19.

20.

21.

22. 23.

24. 25. 26. 27. 28.

29.

Bergers G, Benjam in LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401-410 Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592-603 Blouw B, Song H, Tihan T, Bosze J, Ferrara N, Gerber HP, Johnson RS, Bergers G (2003) The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4:133-146 Boehm T, Folkman J, Browder T, O’Reilly MS (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390:404-407 Brat DJ, Kaur B, Van Meir EG (2003) Genetic modulation of hypoxia induced gene expression and angiogenesis: relevance to brain tumors. Front Biosci 8:d100-116 Brooks AN, Kilgour E, Smith PD (2012) Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res 18:1855-1862 Capparuccia L, Tamagnone L (2009) Semaphorin signaling in cancer cells and in cells of the tumor microenvironment – two sides of a coin. J Cell Sci 122:1723-1736 Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653-660 Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932-936 Casanovas O (2011) The adaptive stroma joining the antiangiogenic resistance front. J Clin Invest 121:1244-1247 Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in latestage pancreatic islet tumors. Cancer Cell 8:299-309 Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O, Giraud E, Mazzone M, Neufeld G, Tamagnone L(2012) Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant semaphorin 3E isoform. EMBO Mol Med 4:234-250 Darlan DC, Massingham LJ, Smith SR, Piek E, Saint-Geniez M, D’Amore PA (2003) Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev Biol 264:275-288 Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8:579-591 Escudier B, et al. (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103-2111 Faivre S, Demetri G, Sargent W, Raymond E (2007) Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6:734-745 Fernando NT, Koch M, Rothroc C, Gollogly LK, D’Amore PA, Ryeom S, Yoon SS (2008) Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 14:1529-1539 Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273-286 Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK (2011) Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91:1071-1121 Gorre ME, Sawyers CL (2002) Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia. Curr Opin Hematol 9:303-307 Heath VL, Bicknell R (2009) Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 6:395-404 Hotte SJ, et al. (2011) Progression-free survival as a clinical trial endpoint in advanced renal cell carcinoma. Curr Oncol 18 Suppl 2:S11-19 Hu B, Cheng SY (2009) Angiopoietin-2: development of inhibitors for cancer therapy. Curr Oncol Rep 11:111-116 Hurwitz, H. (2004) Integrating the anti-VEGF-A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer. Clin Colorectal Cancer 4 Suppl 2:S62-68 Jain RK, Booth MF (2003) What brings pericytes to tumor vessels? J Clin Invest 112:1134-1136

www.cat-science.cat

30. Kaelin WG Jr. (2004) The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res 10:6290S-6295S 31. Kamba T, McDonald DM (2007) Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 96:1788-1795 32. Kerbel RS (2001) Molecular and physiologic mechanisms of drug resistance in cancer: an overview. Cancer Metastasis Rev 20:1-2 33. Kerbel RS (2005) Therapeutic implications of intrinsic or induced angiogenic growth factor redundancy in tumors revealed. Cancer Cell 8:269-271 34. Kindler HL (2007) Pancreatic cancer: an update. Curr Oncol Rep 9:170-176 35. Linehan WM, et al. (2007) Identification of the genes for kidney cancer: opportunity for disease-specific targeted therapeutics. Clin Cancer Res 13:671s-679s 36. Linehan WM, et al. (2004) Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res 10:6282S-6289S 37. Mancuso MR, et al. (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116:2610-2621 38. Motzer RJ, et al. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. New Engl J Med 356:115-124 39. Motzer RJ, et al. (2007) Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol 25:247-256 40. Norden AD, Drappatz J, Wen PY (2009) Antiangiogenic therapies for high-grade glioma. Nat Rev Neurol 5:610-620 41. O’Connor R (2007) The pharmacology of cancer resistance. Anticancer Res 27:1267-1272 42. Rapisarda A, Melillo G (2009) Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist Updat 12:74-80 43. Rini BI (2010) New strategies in kidney cancer: therapeutic advances through understanding the molecular basis of response and resistance. Clin Cancer Res 16:1348-1354 44. Rini BI, Atkins MB (2009) Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol 10:992-1000 45. Rini BI, et al. (2008a) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422-5428 46. Rini BI, et al. (2008b) Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 26:3743-3748 47. Rosner I, Bratslavsky G, Pinto PA, Linehan WM (2009) The clinical implications of the genetics of renal cell carcinoma. Urol Oncol 27:131-136 48. Serini G, Maione F, Giraudo E, Bussolino F(2009) Semaphorins and tumor angiogenesis. Angiogenesis 12:187-193 49. Shaked Y, et al. (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313:1785-1787 50. Spannuth WA, Sood AK, Coleman RL (2008) Angiogenesis as a strategic target for ovarian cancer therapy. Nat Clin Pract Oncol, 5:194-204 51. Sudarshan S, Linehan WM (2006) Genetic basis of cancer of the kidney. Semin Oncol 33:544-551 52. Thurston G (2003) Role of Angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis. Cell Tissue Res 314:61-68 53. Yoong KF, Afford SC, Randhawa S, Hubscher SG, Adams DH (1999) Fas/Fas ligand interaction in human colorectal hepatic metastases: A mechanism of hepatocyte destruction to facilitate local tumor invasion. American J Pathol 154:693-703 54. Zuniga RM, Torcuator R, Jain R, Anderson J, Doyle T, Ellika S, Schultz L, Mikkelsen T (2009) Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol 91:329-336

CONTRIBUTIONS to SCIENCE 9 (2013) 67-73

RESEARCH REVIEWS CONTRIBUTIONS to SCIENCE 9 (2013) 75-88 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.166 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

Temperament and tuning of early 19th century Hispanic keyboard instruments: A study of the monochord integrated into a fortepiano made by Francisco Fernández (1828) Romà Escalas Llimona Institute for Catalan Studies, Barcelona and Barcelona Music Museum, Barcelona, Catalonia

Correspondence: Institute for Catalan Studies Carme, 47 08001 Barcelona, Catalonia E-mail: rescalas@bcn.cat Received: 06.09.12 Accepted: 25.01.13

Summary.

The recovery of previously used tuning systems of musical instruments, led by the interpreters of historical repertoires, has widened our knowledge and our aesthetic perception of the sounds, harmonies, and repertoires of works from those times. For only a very few instruments have we been able to determine the original tones, whereas the mechanisms designed to tune keyboard instruments are of a remarkable reliability. Among the latter is the monochord integrated into the fortepiano made by Francisco Fernández in 1828. In this article, we evaluate the measurements, both physical and acoustic, of the tones of this device, and offer comparisons. Based on the conclusions of this analysis, we define a tuning system closely linked to another, contemporary one but with unique features that result in a number of sonorities perfectly adapted to the performance and aesthetics of the musical repertoires of Romanticism. Moreover, this system, which was probably used until the early 20th century, offers us a new harmonic coloring, one especially suited to the Iberian repertoire of the same time.

Keywords: Francisco Fernández (1766–1852) · Barcelona Music Museum · fortepiano · monochord · tuning · musical temperament · Romanticism Resum. La recuperació dels sistemes d’afinació dels instruments musicals anteriors al sistema

actual, liderada pels intèrprets dels repertoris històrics, ha eixamplat el nostre coneixement i la nostra percepció estètica dels sons, les harmonies i els repertoris procedents de les obres d’altres èpoques. Només hem estat capaços de determinar els sons originals de molt pocs instruments, mentre que els mecanismes ideats per afinar instruments de teclat són d’una fiabilitat considerable. Entre aquests últims hi ha el monocordi integrat al fortepiano de Francisco Fernández del 1828. En aquest article analitzem les mesures, físiques i acústiques, dels sons d’aquest aparell i oferim comparacions. Basant-nos en les conclusions d’aquesta anàlisi, hem definit un sistema d’afinació que té molta relació amb d’altres de contemporanis seus, però amb característiques pròpies que fan que gaudeixi d’unes sonoritats perfectament adaptades a la interpretació i l’estètica dels repertoris musicals del Romanticisme. Alhora aquest sistema, probablement emprat fins a principis del segle xx, ofereix un nou colorit harmònic, especialment adequat al repertori ibèric de la mateixa època. Paraules clau: Francisco

Fernández (1766–1852) · Museu de la Música de Barcelona · fortepiano · monocordi · afinació · temperament musical · Romanticisme

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

Francisco Fernández fortepiano

The tuning system of the 1828 table fortepiano kept at Barcelona’s Museu de la Música (catalogue no. MDMB 504) works by comparing the tones previously programmed on a monochord to those generated by the strings of the instrument. The monochord is a sonorous element that, although independent, has been integrated into the furniture and structure of the modern piano. It is an acoustic instrument designed to fix musical intervals based on geometric proportions, determined according to the different lengths of the strings in vibration. The name mono (one), chordium (string) comes from the fact that one works on a single string fixed on a resonance table, in which a number of positions and vibration lengths are chosen by sliding a moveable bridge, stopping it on the marked positions, which correspond to the piano notes. From the theoretical analysis of the tones produced at each position of the cursor, we can determine and compare the fifth and third intervals, which constituted the fundamental basis of the tuning of the period. Thus, a first analysis arises from the physical measurements of the vibrating string at each segment fixed by the monochord. A parallel procedure is obtained by recording the tones produced by the string at each segment fixed by the position of the cursor. To catalogue the tones, in the winter of 2002 the monochord was tuned with the A of the first octave at 103.8 Hz, corresponding to the same note A of 415 Hz of two earlier registers. Next, a tone sample was recorded for each position of the cursor using three procedures of acoustic measurement. The set of these samples was used to establish the comparisons and valuations of the initial theoretical measurements. From the analysis and the comparison of the results obtained from our study of the monochord, we were able to deduce the properties of a tuning system that was valid for the aesthetics of the musical repertoires of the end of the 18th century and beginning of the 19th century. This is especially interesting given the sonority of the works composed and interpreted at that time on the Iberian Peninsula.

in length, a linear series of inscriptions and marks drawn with the help of a compass were used to determine the positions of the cursor for each musical interval. In the 12th century, the table was replaced by a resonance case, which improved the monochord’s sonority. During the Renaissance, from 1500 onwards, a new model was introduced in which the central cursor was no longer a feature; instead, one of the fixed bridges at the ends was mobile and assumed this function. This model was less precise, as the linear nature of the string was variable, resulting in a geometry that affected the regularity of the tension. In the monochord attributed to Pythagoras, the tones were determined by the arithmetic proportions among the vibrant lengths of the string. These tones are considered the main intervals of the Pythagorean range or tuning system. In the geometric calculation of the musical intervals, the different tones could be obtained through two methods of dividing the string, which provided the higher and the lower ranges with respect to the initial one. For instance, a tone two octaves higher than D or E, or two octaves lower than C could be produced by dividing, by means of a compass, the whole string or only one section of it into nine equal parts (Fig. 1). The positioning of more complicated intervals, such as the Pythagorean semitone, was made possible with the monochord described by Odo of Saint Maurus around the year 1000, at the time of Pope Sylvester II, who authorized its scientific use. This model established the operational basis of Renaissance instruments, which rely on the ascending division, as it proved more practical for the musical language of the time. Even so, the monochord would continue to provide a meeting point between scientific reasoning, in the demonstrative field of proportions, and musical practice, in its need to define the ranges and proportions among harmonic sounds. In studying and describing the fortepiano monochord of Francisco Fernández (1828), we incorporated physical and musical measurements. Our first measurements of the marks and inscriptions on the wooden support of the string were carried out in December 2002, with the collaboration

History The first descriptions of the monochord date back to the 5th century BC. The device was attributed to Pythagoras and it continued to be in use until the 19th century. In a number of medieval treatises it is referred to by its Latin name, as the canon harmonicus. In addition, it has been linked to the study of the historical ranges and tuning systems of that time. Among the medieval descriptions, the one that occurs most frequently is that of a table with a string supported by two fixed bridges and with a mobile bridge in the middle that, when slid in the manner of a cursor, cuts the string at the selected points to yield the tones of the different musical intervals. On the surface of the table, which measures 90–120 cm www.cat-science.cat

Ascending division 2nd higher 9

Descending division 2nd lower 9

Fig. 1. Methods for the division of the monochord string.

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

ESCALAS

of Joan Pellisa. These measurements were later checked against those taken in August 2010 by Manel Barcons. The reference to the octaves, by means of the subindices –1, 1, 2, 3 and 4, were placed from the A3 corresponding to the 440 Hz A sound.

Thomson of 1787, with a patent commercialized by Longman & Broderip [7]. The latter device had a mechanism to drag the cursor, another one for its fixation, and a lever to activate the hammer. Discovery and description of the monochord. The first

The fortepiano and its maker. The fortepiano preserved at

reference to the discovery of the tuning mechanism of this fortepiano is an entry in the catalogue of Barcelona’s Museu de la Música [8, p. 225], in the description of the instrument. It is a special characteristic that has always been stressed in the other publications of the museum as well. On a later occasion, Cristina Bordas mentioned it in one of her texts as an “artilugio para afinar” (a tuning mechanism) [5,6]. There have been only a few descriptions of the use of the monochord in the process of piano tuning since the 19th century. In Spain, Felip Pedrell, in his Diccionario Téc nico de la Música, offered the following description of one of these devices, attributing its invention to a certain Baller (sic): “Cronómetro-monocordio. Aparato destinado á afinar los pianos, que resonaba por medio de un teclado. Fué inventado en 1827 por Baller, fabricante de pianos.” (Chronometer-monochord. A device used to tune pianos that resounded by means of a keyboard. It was invented by Baller, piano maker, in 1827). [9] The date of the invention is surprising, as it is a year before the construction of our fortepiano. It would be interesting to investigate the probable relationship between the two devices. This monochord was precisely integrated into the inside of the fortepiano’s case, and although it is in fact inde-

Barcelona’s Museu de la Música (Fig. 2A) was built by Francisco Fernández, a relative of Diego José Fernández, an instrument maker born in Vera (Almería, Spain), as detailed in an inscription on a frontal plaque (Fig. 2B). The instrument is of the small-case type intended for domestic use, with an area of 132.7 × 49.3 cm and a height of 22.4 cm. It is supported by four fixed legs of lathed wood. Its keyboard has 73 keys, from F –1 to F 6, spanning a width of 91.8 cm. From the keyboard, a simple English-type device is operated and acts on the 73 individual metal strings. The strings are laid out in an oblique shape on the soundboard, made of fir, and show cross-wise streaking. They are made of different materials: steel and copper for the central strings, steel for those that are high-pitched, and torched brass for those of low-pitch. The monochord is integrated inside the cabinet, mounted on a long and resistant piece of wood that is fixed on the front part of the soundboard. On the front central part of the keyboard, under the lower panels of the pinewood case, the traction of two pedals is fixed, mounted on a lyreshaped support. The pedal on the right activates the monochord and that on the left frees the dampers. The frontispiece of the piano, over the keyboard, which is curved on its ends, is decorated with latticed wood, matching the two triangular lids of the top side drawers located on both sides of the keyboard (Fig. 2C). This instrument, from the Folch i Torres-Baget collection, entered the Museum in 1947. Francisco Fernández (1766–1852) was born in Asturias, Spain, and moved to Madrid between 1792 and 1799. In 1827, he was granted the title of Honorario constructor as purveyor of musical instruments to the Spanish Royal Household. His Madrid workshop had several locations: Corredera de San Pablo, 20 in 1799; Calle del Barquillo, in 1804; Calle de San Fernando, 9 in 1827; Calle de San Fernando, 5 in 1828. In 1817 he founded a piano-making school, where students would also learn languages. The construction of the piano in the museum’s collection reflects Fernández’s many years of experience. He was 62 and his workshop was located in Calle de San Fernando 5. We therefore think that this instrument incoporates all of Fernández’s professional abilities. We do not have sufficient documentation to ascertain whether the incorporation of the monochord came through the influence and knowledge of similar devices, such as the “tuning machine for harpsichords, piano-fortes, organs, guitars” of W. www.cat-science.cat

C Fig. 2. (A) Fortepiano made by Francisco Fernández. Museu de la Música, Barcelona. (B) Plaque on the F. Fernández fortepiano’s front with the inscription “FERNÁNDEZ Constructor de Pianos / DE LA RL. CAMARA DE SS. MM. / Calle de Sn. Fernando N.º 5 / año de 1828 / Madrid”. (C) Monochord. Frontpiece of the keyboard with the top part decorated with latticed wood.

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

Francisco FernĂĄndez fortepiano

pendent of the piano, it makes use of the latterâ&#x20AC;&#x2122;s resonance to strengthen the volume of the sounds it produces. It is fixed over the keyboard, just behind the front part and perpendicular to the direction of the keys. When the lid is down, it remains hidden and it is held by means of metal bolts over the soundboard, with which it couples its vibrations. It is made of a rectangular compact piece of finegrained wood, possibly pear wood, that is 118.8 cm long and has a rectangular section of 27 Ă&#x2014; 37 mm. The narrower surface corresponds to the upper side whereas on the rear side, which looks onto the strings, there is a groove, 13 mm wide and 9 mm deep, that holds a brass string. On the left side, the string is secured with a tack and on the right, over a metal tuning pin. The string begins to vibrate by means of the movement of a brass plectrum mounted over a jujube hammer that stands perpendicular to the string, resembling that of a harpsichord, but without the damper. This hammer, which is 15 mm wide, runs inside a perforated slit located 83 mm from the extreme of the wood strip (Fig. 3A). The vibrating length of each note of the string remains set between the position of a fixed metal capo, placed between the tuning pin and the plectrum at 25 mm from the right end, and the position of the metal capo nailed to the right of the base of a moveable cursor. This cursor, resting

on the surface of the upper plane of the monochord, is made of the same wood and stands under the tension of the string by means of two metal hooks nailed to the base; one of them, as noted before, acts as a capo (Fig. 3A). Its movement along the string, eased by treating the wood with talcum powder, allows it to be placed in fixed positions, marked on the upper face with lines that are perpendicular to the string and with successive numbers. This placement determines the intonation of the different notes, which become the intonation references for the corresponding fortepiano strings. These positions also correspond to those of the lines and small holes marked next to the groove. It is very probable that the holes were used to insert blocks to fix the cursor at each position (Fig. 3B,3C). The geometric diagram of the position of the string corresponds to the one described in Fig. 3D. The first position of the cursor is marked with a square box with two diagonal lines, where the cursor has to be placed in order to produce the first note. The marks and inscriptions indicating the successive positions of the cursor consist of perpendicular engraved lines numbered from 17 to 41 and coinciding with the right end of the cursor (Fig. 4). Under the numbering at each position of the cursor, there are other numbers and symbols, not always easy

C 17.9 cm

70.15 cm 9mm

4mm

41 118.8 cm 110.8 cm 93 cm

Diameter of the string: 0.5 mm

Fig. 3. (A) Brass plectrum that, when displaced, sets the string in movement. (B) Cursor that works as a capo. (C) Mobile cursor. The lines and holes made close to the groove. (D) Geometry of the string.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

ESCALAS

Table 1. Symbols and notes corresponding to the positions of the cursor

to identify, indicating the musical notes at each point. On the front face of the monochord, the one that remains hidden by the front of the keyboard, we find other symbols indicating the musical notation of each position of the cursor, marked with letters, and an inscription written in pencil that reads “Fernando Baranda” (Fig. 4D and Table 1). Movement of the hammer and the plectrum is activated from the right pedal, from which a system of transmission levers originates. A spring guarantees the return of the hammer to the at-rest position (Fig. 5).

Use of the monochord to tune the piano The tones of the monochord, once the reference note A has been tuned, are produced by using the pedal on the right, and are selected through the different positions of the cursor. The strings of the piano are tuned with a special key that turns the wrest pins, and are made to sound from the keyboard until exact unisons are obtained, with no interfering beats, taking the monochord as a reference. For each position number of the cursor there is a corresponding string with the same number indicated on a wooden plaque attached next to the wrest plank (Fig. 6). Even so, it is not possible to tune all the strings through comparison with the monochord, as the piano has 73 strings and keys, from F–1 to F6, and the cursor only determines 24 positions. Therefore, 49 notes have to be tuned either through a comparison with their monochord octaves or with the notes of other octave of the piano.

Position of

Symbols on

the cursor

the upper

the rear face

(number)

face

illegible

True notes

A#/Bb

C#/Db

D#/Eb

F#/Gb

illegible

G#/Ab

illegible

A#/Bb

illegible

C#/Db

≠

D#/Eb

≠

illegible

F#/Gb

G#/Ab

blank space

Fig. 4. Upper side of the monochord. (A) Left. (B) Middle. (C) Right. (D) Front face with the inscription “Fernando Barana”.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

Francisco FernĂĄndez fortepiano

The notes and intervals of the monochord

Measuring the length of vibration of each note. The sequence of positions of the monochord cursor, which are marked, ruler-like, on the upper surface, determines several acoustic lengths of the string, which, once launched into vibration by means of the plectrum, yields different reference sounds. The theoretical acoustic length (L) is therefore delimited by the distance between the tuning pin of the string, on the right, and the moveable capo, which holds the string from the cursor itself, placed in such a way that its right end coincides with the numbered lines on the upper surface of the monochord. For each theoretical length, measured over the numbered position markings, a small shortening of 1.5 mm has to be taken into account, owing to the fact that the metal hook fixed to the cursor works as a capo and stands out from the edge of this piece. At each position of the cursor, a block would have been inserted in a small hole on the inner face of the monochord, the same face over which the cursor runs. That a block was used is certain, given the considerable wear along the rims of the holes. The blockâ&#x20AC;&#x2122;s thickness could have offset the sliding of the vibrating length due to the position of the capo. Thus, there is no need to correct the reading of the theoretical L if it is measured directly from the finer lines and small holes of the inner face of the monochord. In view of all these factors, the measurement of each acoustic length (L) is fixed through the measurements taken over the marks of the ruler, applying to it a correction of 1.5 mm (L1 ). These marks determine 24 positions. The first position, number 17, corresponds to the second A of the keyboard, and the last position, number 41, to the fourth A. Each stopping point of the cursor is placed at a distance of one semitone from the following one, and the whole itinerary corresponds to the complete series of semitones that comprise the division of two octaves. If the theoretical length for each position is measured in accordance with the procedure detailed above, the measurements of all the semitones that make up the three octaves can be obtained. As a first measurement unit, we have chosen the cent, because among the logarithmic units used in the measurement of intervals it is the one used on a standard basis by analysts of historical tuning systems and by practicing musicians using temperaments of the period. The number of cents in an interval is given by the formula

Fig. 5. View of the elements of the piano. (A) Pedals. (B) Transmission. (C) Puller of the plectrum.

n (cents) = log (L1/L2) Ă&#x2014; 1200/log2 where L1 and L2 are the two acoustic lengths, L2 being the minor length and L1 the major one, corresponding to that of the previous mark, placed at the distance of one semitone. Applying this calculation to all L1 corresponding to the different positions on the cursor yields all the measure-

Fig. 6. Numbering of the strings.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

ESCALAS

Table 2. Measurement of the semitones

ments of the semitones on the ruler. Table 2 shows the theoretical length of the string for each position on the cursor. From this length, the measurements of the semitone intervals and their corresponding deviations with respect to the temperate semitone of 100 cents can be deduced. We ignore the precision of these tenths-of-a-millimeter measurements of the lengths of the vibrant string segment. As we will see later, the effect on the acoustic quality of the differences does not substantially alter the analysis of the tuning system nor the tuning of the piano. We must also consider the deformations of the ruler with respect to the original construction measurements. We compared the results of a 1-mm variation in the precision of the measurement of the lengths of the string segments. The differences in positive and negative deviations were between 3 and 5 cents (data not shown), i.e., an almost imperceptible effect on the acoustic quality of the different intervals that we compared in our analysis of the tuning system. We also measured—individually and successively—the series of semitones, adding them to calculate the intervals that they determine. The results are modulated by the accumulation of partial errors arising from the individual measurements (data not shown). We therefore discarded this method.

Position of the cursor

Key and string

Acoustic L (mm)

L2 = L-d (mm)

Cent semitones

Deviation with respect to the temperate semitone

943.0

941.5

A#/Bb

876.0

874.5

127.8

27.8

822.0

820.5

110.3

10.3

775.0

773.5

102.1

2.1

C#/Db

734.0

732.5

94.2

–5.7

697.0

695.5

89.7

–10.2 10.4

D#/Eb

654.0

652.5

110.4

616.0

614.5

103.8

3.8

586.0

584.5

86.6

–13.3

F#/Gb

554.0

552.5

97.4

–2.5

526.0

524.5

90.0

–9.9

G#/Ab

493.0

491.5

112.5

12.5

467.0

465.5

94.0

–5.9

A#/Bb

442.0

440.5

95.5

–4.4

416.0

414.5

105.3

5.3

393.0

391.5

98.8

–1.1

C#/Db

372.0

370.5

95.4

–4.5

Irregularities in the octaves. To determine the general re-

354.0

352.5

86.2

–13.7

liability of the measurements, we checked the octaves generated by the positions of the cursor with respect to those that would be obtain using the theoretical length of the string. The “A” mark that would form the first octave is located 4.5 mm further to the left of its theoretical position, which can be calculated by dividing by two the L of the first A. In other words, there has been a small contraction in this segment. This can be explained by a longitudinal deformation of the monochord, owing to the loss of mass during aging of the wood and the elastic expansion of the opposite end. We tested the exactitude of other octaves in order to find the point at which these errors might affect the reliability of the measurements. In Table 3, for each position L, a of the cursor and L,b of its octave, we calculated the theoretical length of the string (theoretical b). The difference, in mm, is the error in each position, which we also took into account as a correction per semitone and per fifths, considering it applicable to the different measurement zones of the monochord. In conclusion, the distribution of these systematic errors among the 12 semitones of the octave, on the order of tenths, did not noticeably affect measurements of the semitone intervals. For calculation of the fifths, especially in measuring the notes of the central area, from F2 downward, a correction factor from –10 to 15 cents was introduced, which was offset by corrections of some +10 cents at the ends of the scale of the wood strip.

D#/Eb

336.0

334.5

90.7

–9.2

317.0

315.5

101.2

1.2

www.cat-science.cat

297.0

295.5

113.3

13.3

F#/Gb

280.0

278.5

102.5

2.5

264.0

262.5

102.4

2.4

250.0

248.5

94.8

–5.1

237.0

235.5

93.0

–6.9

Sound imprecision: geometry and inharmonicity of the string. There are other sources of imprecision of each note’s

resulting tone with respect to the theoretical positions marked on the monochord. They are due to variation in the tension of the string, depending on the closer or more distant position of the cursor to the ends where the string is fixed, and to the actual inharmonicity of the string, which arises from irregularities in both the material and the parts of the different sections, as shown in Figure 8. General sound effect. Finally, note that the second A of the

monochord (Table 3), corresponding to note 29 of the keyboard, has a length of 467 mm, closer to the lengths of the string of the piano’s A3, which is 300 mm, and to that of other instruments of the same period, which tend to be around 400 mm. This measurement places us in a sphere of timbric perception in which the monochord seems to be tuned an octave 81

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

Francisco Fernández fortepiano

Table 3. Irregularities in the octaves (a–b)

L, a (mm)

L, b (mm)

Theoretical

Difference

b (mm)

(mm)

(cents)

Excess

Correctionby

Correction

semitone

by fifth 11.1

A1–A2

943.0

467.0

471.5

4.5

16.60

short

1.4

A2–A3

467.0

232.0

233.5

1.5

11.16

short

0.93

7.4

G2–G3

526.0

264.0

263.0

–1.0

–6.57

long

–0.5

–4.4

F2–F3

586.0

297.0

293.0

–4.0

–23.47

long

–2.0

–15.6

D2–D3

697.0

354.0

348.5

–5.5

–27.11

long

–2.3

–18.1

C2–C3

775.0

393.0

387.5

–5.5

–24.40

long

–2.0

–16.3

Table 4. Comparison between real and theoretical measurements L2 fifths

Cents

Deviation with

Correction

respect to the

+10 cents

cents of the same temperate semitone. These deviations range from +10.0 to –13.7 cents, and exceptionally, 27.8 cents in the case of the first semitone. To identify the tuning system of the monochord, we compared the true fifths, obtained through the different positions of the cursor, with the perfect fifths of 702 cents— which would be obtained as perfect fifths calculated from the same initial positions—by using the previously stated formula. The comparison between the true fifths and the theoretical ones is shown in Table 4. The cyclical order used in the table resembles the one that tuners use. In Table 4, the deviations were calculated with respect to the perfect fifth of 702 cents, and the final column shows the deviations through the correction factor suggested above, which would correct both the deformation of the scale and the change in tension of the string through sliding of the cursor. Nonetheless, we calculated that this correction only affects the real tuning by 1 Hz. The comparison between real and theoretical measurements (Table 4) led us to deduce that the set of fifths that would be obtained with the monochord can be divided into three groups: eight similar ones (A), which are close to perfect fifths (< 10 cents), specifically those formed over C, C#, D, F, F#, G, A#, B; three corresponding to A, E, G# and D# are shorter, from 10 to 20 cents (B); and one that is formed over G#, which is even shorter, with a difference of more than 25 cents.

perfect fifth C2–G2

688.8

–13.2

–3.2

G2–D3

685.6

–16.4

–6.4

D2–A2

693.3

–8.7

1.3

A2–E3

670.7

–31.3

–21.3 –12.4

E2–B2

679.6

–22.4

B1–F#2

683.1

–18.9

–8.9

F#2–C#3

689.5

–12.5

–2.5

C#2–G#2

689.0

–13.0

–3.0

G#2–D#3

663.8

–38.2

–28.2

D#2–A#2

678.3

–23.7

–13.7

A#1–F2

696.0

–6.0

4.0

F2–C3

691.6

–10.4

–0.4

Table 5. Measurements of the major third intervals Major

Cents

thirds

Deviation

Correction

Type of

with

-10 cents

thirda

respect to a perfect third C–E

398.4

12.4

2.4

D–F#

398.5

12.5

2.5

E–G#

386.7

0.7

–9.3

F–A

394.1

8.1

–1.9

G–B

407.5

21.5

11.5

A–C#

395.2

9.2

–0.8

Bb–D

385.8

–0.2

–10.2

The thirds Using a procedure similar to the one used to compare the fifth intervals, we analyzed the major third intervals of the main chords of the time, thereby obtaining greater insight into the tuning system. Table 5 shows the measurements of these intervals formed over the diatonic notes, from C to Bb, with the corresponding measurement in cents. The third column shows the deviations with respect to the perfect major third of 386 cents and to the fourth, with their values amended using the same factor applied to the fifths. The final column shows the valuations with respect to the deviations, grouped into three categories.

A, between –2 and 5; B, <–5; and C, >5

lower than the piano. But this difference in octaves does not affect or hinder the final result of the tuning process. Calculations with the lineal measurements of the cursor.

Referring again to the semitone intervals listed in Table 2, we can see that the tuning system consists of fairly different semitones, with notable deviations, with respect to the 100 www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

ESCALAS

Table 6. Measurements of the essentials in Hz with two types of software: Spectrum Analyzer and Sonic Visualizer

As seen in the table, among the measured major thirds, four from group A come close to perfect major thirds. They are those formed over C, D, F and A. There are also two shorter ones(<5 cents), over E and Bb, and a longer one (> 10 cents) that forms over the G.

Note

Acoustic analysis of the sounds of the monochord. In win-

ter 2002, we tuned the monochord with the A of the first octave at 103.8 Hz, corresponding to the same A note of 415 Hz of two registers higher. Next, we determined a tone sample for each position on the cursor, using three acoustic measurement procedures. This set of samples was used to establish the comparisons and valuations of the initial theoretical measurements. The first spectral analysis was carried out using the Spectrum Analyzer application from the software of the professional Samplitude 7.12 (VIP file, Fernández At02, and in a WAV file, named Fernández At02). The spectral graph of the first sound of the monochord, corresponding to position 17 on the cursor and to note A1 on the keyboard, is shown in Fig. 7. The graph has a first dominant frequency at 107.0 Hz, with a first partial at 301.0 Hz, a note that would correspond to the keyboard’s A1. This second peak gives us the essentials of the tones that we hear at each position of the cursor. To obtain greater precision, these measurements were checked against those made with another analyzer, the Sonic Visualizer 1.7.2 (Fig. 8). The measurements of the essentials, given in Hz, for each position on the cursor, obtained with both types of software, are shown in Table 6. The differences in the results of the two analyses are remarkable, with deviations ranging from –13.3 to +11.1 Hz. Negative deviations were more frequent. Moreover, it should be noted that the same deviations were not maintained between identical notes on different octaves. The acoustic and electronic elements used probably introduced mechanical, acoustic, and sensitivity type errors. Considering these analytical measurements as not being very precise and given the margin of error that they presented, we used yet another method to measure the frequency, comparing those results with the others. In this new method, we analyzed the sounds registered with an electronic tuner, measuring them with the deviation quadrant with respect to the note tuned in identical temperament.

Spectrum

Sonic

Differences

Analyzer

Visualizer

between spectra

107.5

107.7

0.2

A#/Bb

109.5

110.0

0.5

128.0

116.0

–12.0

129.5

128.0

–1.5

C#/Db

131.0

132.0

1.0

139.5

137.0

–2.5

D#/Eb

148.6

149.0

0.4

149.1

153.0

3.9

151.3

162.4

11.1

F#/Gb

171.9

171.0

–0.9

173.0

179.0

6.0

G#/Ab

194.0

0.0

215.3

202.0

–13.3

A#/Bb

215.4

220.0

4.6

237.1

230.0

–7.1

258.0

246.0

–12.0

C#/Db

258.1

257.0

–1.1

280.2

274.0

–6.2

D#/Eb

302.0

287.0

–15.0

322.0

310.0

–12.0

344.0

331.0

–13 0

F#/Gb

343.0

349.0

6.0

G G#/Ab

365.2 388.2

369.0 394.0

3.8 5.8

428.5

421.0

–7.5

Fig. 7. Spectral graph of the monochord.

Measurements with an electronic tuner By using the electronic Zen-On Quartz Chromatina tuner, we registered readings with reference to the fixed notes of the temperate tuning of the A at 415 Hz. Table 7 shows the results of the two methods and the deviations in cents with respect to the closer temperate note (column 3). From the www.cat-science.cat

Fig. 8. Measurements of the spectral graph as analyzed using Sonic Visualizer 1.7.2.

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

Francisco Fernández fortepiano

Table 7. Comprison of the deviations in cents with respect to the nearest note, obtained by using two measuring instruments Position on

Key

cursor

F1 temperate

Deviation from

Log F2

at 415 Hz

reading (cents)

at 415 Hz

F2 Zen-On (Hz)

Sonic

Difference

Visualizer

between the two (Hz)

98.0

103.8

2.0163

103.8

107.7

3.9

A#/Bb

110.0

2.0376

109.1

110.0

0.9

116.5

2.0590

114.5

116.0

1.5

123.5

2.0840

121.3

128.0

6.7

C#/Db

130.8

2.1104

128.9

132.0

3.1

138.6

2.1405

138.2

137.0

–1.2

D#/Eb

146.8

2.1605

144.7

149.0

4.3

155.6

2.1881

154.2

153.0

–1.2

164.8

2.2145

163.9

162.4

–1.5

F#/Gb

174.6

2.2413

174.3

171.0

–3.3

185.0

–7

2.2689

185.7

179.0

–6.7

G#/Ab

196.0

2.2897

194.9

194.0

–0.9

207.7

2.3168

207.4

202.0

–5.4

A#/Bb

220.0

2.3399

218.7

220.0

1.3

233.1

2.3650

231.7

230.0

–1.7

246.9

2.3901

245.5

246.0

0.5

C#/Db

261.6

2.4169

261.2

257.0

–4.2

277.2

–5

2.4440

278.0

274.0

–4.0

D#/Eb

293.7

–12

2.4709

295.7

287.0

–8.7

311.1

–5

2.4942

312.0

310.0

–2.0

329.6

2.5180

329.6

331.0

1.4

F#/Gb

349.2

–10

2.5456

351.3

349.0

–2.3

370.0

2.5644

366.8

369.0

2.2

G#/Ab

392.0

2.5903

389.3

394.0

4.7

415.3

2.6171

414.1

421.0

6.9

ratio of this measurement and the frequency of the temperate tuning of the lower semitone (F1), we calculated the true frequency of the note measured (F2), since the number of cents (c) in the interval between two notes with frequencies F1 and F2 is:

[4] 100–d = k × (log F2 – log F1) [5] log F2 = (100–d) / k + log 392 = 2.6171 [6] F2 = antilog (log F2) = 414.1 A comparison of the values of the frequencies measured with the Zen-On and the results of the spectral analysis of the Sonic Visualizer showed deviations of ±7, which is more acceptable than the deviations obtained when the Spectrum Analyzer from Samplitude was used. The differences between the theoretical frequencies derived from the marks of the monochord and the results measured with the Zen-On were minimal, with deviations from –4.7 to 2.2 Hz. Moreover, they were not excessively different from the variations between the results from the Zen-On and the Sonic Visualizer, of ∀ 7 Hz, as seen in Table 7, which compares the frequencies obtained with the three measuring methods. Therefore, in the following, to calculate the intervals of fifths and in the subsequent comparisons, we use the data obtained with the linear and acoustic measurements of the Zen-On. Table 8 shows the measurements of the semitones formed with the note immediately higher (F2), from the linear measurements of the monochord, obtained from the

c = 3986.3 × log (F2/F1) where F1 is the lower note. If we set F1 as a frequency, in equal temperate scale, of the note placed a semitone lower than F2, measured with the Zen-On tuner, over an A of 415 and define ‘d’ as the deviation of F2 with respect to the corresponding temperate frequency, the frequency of each note from the reading of the electronic tuner can be obtained. Below, we detail the six steps of the process following that of the A; these would repeat themselves in parallel form for each of the 40 remaining notes. For example: [1]The F2 of the A (approx. 415 Hz) has a deviation of 10 cents over the exactly tempered tuning, therefore, d = 10. [2] F1 of the temperate G# = 392 Hz [3] If k = 3986.3 www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

ESCALAS

Table 8. Measurements of the semitones estimated from the readings of the electronic tuner Cursor

Acoustic

Key

L 2 mm

Cents of the

F1 ZenOn

F2 in Hz

F2 at 415 Hz

semitone

Difference between the two F2 values

943

103.8

876

A#/Bb

127.6

109.1

111.7

110.0

1.7

822

110.2

114.5

116.2

116.5

–0.3

775

101.9

121.3

121.5

123.5

–2.0

734

C#/Db

94.1

128.9

128.1

130.8

–2.7

697

89.5

138.2

135.8

138.6

–2.8

654

D#/Eb

110.2

144.7

147.3

146.8

0.4

616

103.6

154.2

153.7

155.6

–1.9

586

86.4

163.9

162.1

164.8

–2.7

554

F#/Gb

97.2

174.3

173.3

174.6

–1.3

526

89.8

185.7

183.6

185.0

–1.4

493

G#/Ab

112.2

194.9

198.2

196.0

2.2

467

93.8

207.4

205.7

207.7

–1.9

442

A#/Bb

95.3

218.7

219.1

220.0

–0.9

416

105.0

231.7

232.4

233.1

–0.7

393

98.5

245.5

245.3

246.9

–1.6

372

C#/Db

95.1

261.2

259.4

261.6

–2.3

354

85.9

278.0

274.5

277.2

–2.7

336

D#/Eb

90.3

295.7

292.9

293.7

–0.8

317

100.8

312.0

313.4

311.1

2.3

297

112.8

329.6

333.0

329.6

3.4

280

F#/Gb

102.0

351.3

349.6

349.2

0.4

264

101.9

366.8

372.5

370.0

2.6

250

G#/Ab

94.3

389.3

387.3

392.0

–4.7

237

92.4

414.1

410.6

415.3

–4.7

reading of the Zen-On electronic tuner. F1 is the frequency of the lower note, measured with the Zen-On tuner. As stated above, c = 3986.3 × log (F2/F1). Thus, the frequency of the sound at a semitone higher is F2 = antilog (R), where R = c/3986.3 + log (F1).

in Table 9. The fifths were compared on the basis of the values obtained through the values of the vibrating length (L2) of the string and those from the Zen-On tuner. As seen in Table 9, almost all the fifths were similar, with the exception of those formed over notes A1 and A2, which differed by 66.5 cents, a little more than a quarter of a tone, while the fifth formed over A2 was wider than the fifth formed over A1. The positions of both As were very similar to the distance of an octave: 943.0 cents from A1 to A2 (see Table 3). Theoretically, A2 should be at 471.5 but it occurred at 476.0, a difference of 4.5 cents. If we compare the octave of the E, from E2 to E3, there are 616.0 cents; theoretically, E3 should be at 308.0 rather than at 317.0. The difference, therefore, is only 9 cents, which is not sufficiently larger than the different results in the fifths. We therefore re-calculated the fifths, adding the seven semitones that make them up, which yielded: (a) for the A1–E2 fifth, 737.1 cents, and (b) for the A2–E3 fifth, 670.7 cents. The difference of 66.4 cents that separates them does not differ significantly from 63.8 cents. Consequently, if we were to choose between the longest and the shortest differences, we would choose that of 670.7 cents, because the

Comparison of the different measurement methods Comparison of the intervals of fifths. The next step was to compare the fifths generated from the measurement of the samples of real sound registered, measured with the Sonic Visualizer, with those calculated from the readings by the Zen-On electronic tuner. Table 4 showed the deviation of each fifth, calculated from the vibrating length of the string (L2), with respect to perfect tuning (702.0 cents), and the values more approximate to the corrections we established earlier. Given the differences among some of the fifths based on diatonic notes, we decided to compare them with the measurements of the same intervals in other registers. In the cases in which such measurements were possible, we obtained the results shown www.cat-science.cat

0.0

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

Francisco Fernández fortepiano

Table 9. Comparison between L2 and Zen-On Fifths I

Cents I

Fifths II

Cents II

Zen-On

Deviation I

Deviation II

Difference

(exact tuning)

(exact cents)

between I and II (cents)

C2–G2

688.8

C3–G3

688.8

–13.2

0.0

D2–A2

693.3

D3–A3

694.6

–8.7

–7.4

1.4 66.5

A2–E3

670.7

A1–E2

737.2

–31.3

35.2

B1–F#2

683.1

B2–F#3

683.1

–18.9

0.0

C#2–G#2

689.0

C#3–G#3

688.0

–13.0

–14.0

–1.0

A#1–F2

696.0

A#2–F3

688.3

–6.0

–13.7

–7.7

Table 10. Quality of the fifths (L) Fifths L2

Cent

(vibrating

Table 11. Deviations of the fifths determined by Zen-On (ZO)

Exact

Correction

deviation

+10 cents

Assessment

Fifths

ZO – exact

Assessment

702 cents

length) C2–G2

688.8

–13.2

–3.2

C–G

695.0

–7.0

G2–D3

685.6

–16.4

–6.4

G–D

698.1

–3.9

D2–A2

693.3

–8.7

1.3

D–A

703.1

1.1

A2–E3

670.7

–31.3

–21.3

A–E

706.9

4.9

E2–B2

679.6

–22.4

–12.4

E–B

705.0

3.0

B1–F#2

683.1

–18.9

–8.9

B–F#

720.0

18.0

F#2–C#3

689.5

–12.5

–2.5

F#–C#

700.0

–2.0

C#2–G#2

689.0

–13.0

–3.0

C#–G#

691.0

–11.0

G#2–D#3

663.8

–38.2

–28.2

G#–D#

722.0

20.0

D#2–A#2

678.3

–23.7

–13.7

D#–A#

715.0

13.0

A#1–F2

696.0

–6.0

4.0

A#–F

710.0

8.0

F2–C3

691.6

–10.4

–0.4

F–C

700.0

-2.0

Table 12. Assessment of the deviations of the fifths (in cents) Fifths

Deviation from

the actual (linear)

the actual (ZO)

C–G

–3.2

–7.0

G–D

–6.4

–3.9

D–A

1.3

1.1

–0.2

A–E

–21.3

4.9

26.2

E–B

–12.4

3.0

15.4

B–F#

–8.9

18.0

26.9

F#–C#

–2.5

–2.0

0.5

C#–G#

–3

–11.0

–8.0

G#–D#

–28.2

20.0

48.2

D#–A#

–13.7

13.0

26.7

8.0

4.0

–0.4

–2.0

–1.6

A#–F F–C

Difference (cents)

Assessment

of linear data

of ZO data

–3.8

2.5

fifth formed over A1, captured by the tuner, would be more affected by the change in the tension of the string, since it is located closest to the cursor at the fixation key. Applying the deviation criteria with respect to the perfect fifth of the fifths calculated from the vibrating length of the string (A between –10 and 10; B < –10, and C < 20), we www.cat-science.cat

shorter

longer little longer

obtained the results shown in Table 10. If we value the deviation (in cents) of the fifths obtained by measuring the frequencies with the Zen-On tuner with respect to the perfect fifth (Table 11), using the same criteria as those in the previous table, we obtain the results shown in Table 12. 86

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

ESCALAS

The tuning system of Francisco Fernández’s fortepiano

Table 13. The monochord’s deviations with respect to the perfect fifth Fifths

With the values that we obtained from the monochord, it can be deduced that the tuning system used in this instrument was a cyclical one based on unequal fifths. All fifths were practically shorter than the perfect fifth and the system was not a closed one, since the sum of the 12 fifths is not a multiple of the 1200 of an octave, but instead gives an interval of 8235.1 cents, with a deviation of –23.6 cents with respect to the multiple of the octave, practically equivalent to that of a comma (22 cents). This interval represents less than a quarter of a tone and was distributed among the 12 fifths, at –1.9 cents per fifth. This is a nearly negligible amount for musical purposes; in fact, if while tuning, we distributed this difference among all the fifths, we would have a closed system, in which the last note of the cycle is an exact enharmonic of the first. Among the tuning systems based on the irregular temperament of the fifths, those resembling ours most closely were the ones that derived from the mesotonics, in which some fifths were modified in order to close the circle. From the measurements of the theoretical L2 of the monochord, we obtaind a tuning system based on eight fifths slightly different from perfect fifths, with three shorter ones and a longer one. But if we compare this system with the data from the tuner, we find six perfect fifths: four shorter and two considerably longer ones, as shown in Table 4. All fifths that were formed with diatonic notes were similar in the two methods, except for A#–E#, which had already shown irregularities. The fifths formed with chromatic notes also followed a similar pattern, except for G#– D#, which differed by nearly a quarter of a tone, as in A–E. From these irregularities, two important questions arose: (a) Which of the two approaches is more reliable? (b) How reliable are the marks on the tuner, if the acoustic results differed from the theoretical ones, by up to 48.2 cents in some fifths, and could the differences be attributed to the inharmonicity of the strings? In any case, two important factors should be taken into account, as already stated: the inharmonicity of the string and the variation in tension at the left end of the monochord. Finally, we decided to consider the measurements of the string as determined by the position of the cursor as the most precise, since we are studying the construction of the tuner. The tuning system that comes closest to the distribution of the theoretical fifths of the monochord is that of the 18th century French temperaments. These systems are derived from the mesotonic of one fourth of a comma, and in them some fifths are modified in order to close the circle. They are very similar to the tuning model suggested by Jean Philipe Rameau [10] in 1726, which gave way to that of www.cat-science.cat

Deviation (cents)

C–G

–10.0

G–D

–14.0

D–A

–6.9

A–E

–28.6

E–B

–20.4

B–F#

–17.4

F#–C#

–10.2

C#–G#

–11.2

G#–D#

–35.8

D#–A#

–21.8

A#–F

–4.5

F–C

–8.2

Jean Jacques Rousseau [11] in 1767. In both, the first fifths, from Bb to B, are slightly shortened so that C–E and E–G# give a perfect major third. We applied a correction factor of +15 cents to the fifths of the monochord, deduced from the vibrating lengths, and compared the results to those of the French tuning of Rousseau. The intervals of the Francisco Fernández’s monochord were notably closer to those of the method of Rousseau. Even so, two fifths, both of the wolf-tones type, more irregular than A–E and G#–D# were obtained (data not shown). The results were so coherent with the tuning systems of the period when the fortepiano was made that they could be considered a true living model of the musical temperament of the Spanish keyboard instruments of the first half of the 19th century. However, it would be advisable to compare these systems with those of other organs and fretted string instruments that have been preserved, which would provide a wider and more diverse view of the harmonic and timbric sensitivity of musicians and music, one that is definitively immersed in the world of tonal chromatism and modulation. The general diapason of the instrument might have been deeper, circa 423 Hz, according to the unpublished studies by Òscar Laguna of the Avila organ tubes made by Garcimartín in 1828. In conclusion, we suggest, for the keyboard instruments of the period that are still in use today, a tuning system based on the measurements and calculations obtained from the study of Francisco Fernández’s monochord. If a procedure of successive fifths were followed, it would be necessary to start from the deviations with respect to the perfect fifths indicated in as follows (fifth/deviation/in cents): C–G/-10.0;G–D/-14.0;D–A/-6.9;A–E/-28.6;E–B/-20.4;etc. From these values, proceeding with the necessary leaps of an octave for tuning, and adding the correction factor— approximately 5–10 cents per fifth (Table 3)—in accor87

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

Francisco Fernández fortepiano

Table 14. Monochord’s deviations from the perfect fifth after applying the correction factors Order

Fifths

Deviation from the

Deviation of the final

perfect fifth (cents)

application from the

Category

Practical deviation (cents)

perfect fifth 1

A3–D3

–6.9

–1.9

D3–G2

–14.0

–4

0 0

G2–C2

–10.0

–10

C4–F3

–8.2

–3.2

F3–Bb2

–4.5

Bb2–Eb2

–21.8

–11.1

–10

Eb4–Ab3

–35.8

–25.8

–20

G#3–C#3

–11.2

–10.2

–10

A3–E4

–28.6

–18.6

–15

E4–B4

–20.4

–10.4

–10

Up 2 octaves

Down 2 octaves 11

B2–F#3

–17.4

–15

F#3–C#3

–10.2

–10

References

dance with the proximity of the measurement taken at the lower end of the monochord, the resulting values are those in Table 14. Column 5 of the table is the result of a practical approximation to the deviations that must be measured with the tuning device, rounding them off with respect to the common values A, B, and C. In this proposal for a tuning system, two things are important: the order of operation in the tuning process from the keyboard, and the values of the deviations, in cents, to be applied to each fifth (column 5). Accordingly, a system is obtained in which four fifths can be considered perfect (A); five fifths will be tuned shorter, by some 10 cents (B), and two other fifths by some 15 cents (C); and one fifth will exceed this deviation, by 20 cents. This approach yields a tuning system based on the study of the monochord, valid for the aesthetics of the musical repertoires of the early 19th century, and especially for the pieces composed and interpreted on the Iberian Peninsula.

www.cat-science.cat

1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11.

Adkins C (1963) The Theory and Practice of the Monochord. State University of Iowa Adkins C (1967) The Technique of the Monochord. Acta Musicologica 39:34-43 Andrés R (1995) Diccionario de instrumentos musicales. Vox, Barcelona, Catalonia Barbour JM (1951) Tuning and Temperament. A Historical Survey. Michigan State College Press, East Lansing Bordas C (1988) Dos constructoras de piano en Madrid: F. Flórez y F. Fernández. Revista de musicología 11:807-851 Bordas C (1990) Otros pianos de F. Flórez y F. Fernández. Revista de musicología 13:227-230 Mackenzie of Ord A, Mobbs K (2004) The Musical Enigma of Longman and Broderip’s Monochord, c. 1790. The Galpin Soc Journal 57:46-52 Museu de la Música de Barcelona (1991) Catàleg d’Instruments. Ajuntament de Barcelona, Barcelona, Catalonia Pedrell F (1892) Diccionario técnico de la música. Isidro Torres Oriol, Barcelona, Catalonia Rameau JP (1726) Nouveau Systéme de la Musique Théorique. Paris Rousseau JJ (1767) Dictionaire de Musique Chez la veuve Duchesne, Paris

CONTRIBUTIONS to SCIENCE 9 (2013) 75-88

RESEARCH REVIEWS CONTRIBUTIONS to SCIENCE 9 (2013) 89-100 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.167 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

The contribution of the Barcelona World Race to improved ocean surface information. A validation of the SMOS remotely sensed salinity Jordi Salat, Marta Umbert, Joaquim Ballabrera-Poy, Pedro Fernández, Kintxo Salvador, Justino Martínez Institute of Marine Sciences (ICM-CSIC), Barcelona, Catalonia

Correspondence: Jordi Salat Institut de Ciències del Mar (ICM-CSIC) Pg. Marítim de la Barceloneta, 37-49 08003 Barcelona, Catalonia Tel. +34-932309511 Fax +34-932309555 Received: 25.09.12 Accepted: 19.11.12

Summary.

The oceans not only cover about three quarters of the Earth’s surface but they also constitute the most relevant climate driver. However, our present knowledge about the oceans is by no means comparable to that of terrestrial or atmospheric systems. Salinity and temperature are key parameters to understand the dynamics of the oceans; but a global network of observations is lacking in spite of valuable data on the oceans that are being accumulated through oceanographic campaigns and by using automated devices, fixed moorings, drifting instrumented buoys, and ships of opportunity. In addition, during the last 40 years, remotely sensed data from satellites have offered almost synoptic information describing the Earth’s surface. This information includes sea surface temperature, which has been routinely monitored; by contrast, ocean surface salinity was not remotely measured until very recently. The Soil Moisture and Ocean Salinity (SMOS) satellite, launched in November 2009, has been the first attempt to obtain remotely sensed surface salinity data. In this context, the Barcelona World Race has provided new opportunities not only to obtain a worldwide sequence of sea surface temperature and salinity data, through one of the participating ships, but also to validate the first salinity data obtained by the SMOS.

Keywords:

sea surface temperature and salinity · ocean circumnavigation · ocean races · ships of opportunity · SMOS

Resum. Els oceans no solament cobreixen aproximadament tres quartes parts de la superfície de la Terra, sinó que constitueixen el controlador més rellevant del clima. Així i tot, el coneixement que es té actualment dels oceans no es pot comparar amb el que es té dels sistemes terrestres o atmosfèrics. La salinitat i la temperatura són factors clau per entendre la dinàmica dels oceans, però encara no existeix una xarxa global d’observacions. Així i tot, s’estan obtenint dades molt valuoses dels oceans mitjançant campanyes oceanogràfiques i l’ús de dispositius automatitzats, ancoratges o boies a la deriva instrumentades i vaixells d’oportunitat. A més, durant els darrers quaranta anys, les dades obtingudes per teledetecció per satèl·lits han ofert informació gairebé sinòptica sobre la superfície de la Terra, que inclou la temperatura de la superfície del mar, monitoritzada de manera rutinària. En canvi, la salinitat superficial de l’oceà no s'ha pogut obtenir remotament fins fa molt poc. El satèl·lit SMOS (per les sigles en anglès de «humitat del sòl i salinitat oceànica»), llançat el novembre del 2009, n’ha estat el primer intent satisfactori. En aquest context, la Barcelona World Race ha ofert noves oportunitats per obtenir una seqüència de temperatura i salinitat superficials a escala global, a través d’un dels vaixells participants, així com per validar les primeres dades sobre salinitat obtingudes amb l’SMOS. Paraules clau: temperatura

i salinitat de la superfície marina · circumnavegació oceànica · regates oceàniques · vaixells d’observació d’oportunitat · SMOS

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

The contribution of the BWR to improved ocean surface information

The Earth, a planet of (salty) water

Atlantic Ocean because of ice melting may disrupt the process of deep water formation [11]. Because of salinity, the water column in the ocean can and actually does present temperature inversions. If the surface waters receive fresh waters, they can be cooled without sinking, as is the case in freshwater bodies. Strong surface evaporation can force relatively warm surface waters to sink, with their replacement by colder and fresher waters from the sides. Both situations produce “hidden” heat storage in deep oceans, with the best examples being the two intermediate layers found in the Atlantic between 1000 and 1500 m, the Antarctic Intermediate and Mediterranean water masses. Despite the advances achieved in physical oceanography since the end of World War II, the dynamics of the ocean are far from being completely understood or even monitored. There are two main reasons for the deficiency in our knowledge: (1) the ocean is not a linear system, so it is not possible to separate thermohaline from wind-driven circulation [10]. (2) Ocean observations are lacking, particularly before the onset of the satellite era (1980s). Furthermore, analytical, exact solutions were found for simplified (and linear) versions of the equations describing ocean dynamics. While these solutions provided qualitative descriptions of large-scale ocean circulation, they failed to reproduce the measured transports of heat and mass. With the use of numerical simulations, which provide approximations of the non-linear ocean circulation equations, our understanding of the physical processes, and of the role played by ocean transports, has improved [4,5]. However, further improvements in our ability to describe ocean dynamics require a better ocean observation system, either with a larger number of monitored variables or with increased spatial or temporal sampling rates. As emphasized below, one of the key ocean variables that still lacks a synoptic, global observational system, is salinity.

More than two-thirds of the Earth’s surface is covered by salt water. The thin layer (compared to the radius of the Earth) of water that we call oceans is in continuous movement because of the action of tides, mechanical forcing provided by winds, and the potential energy created by the density contrasts between different water masses. The density of a water parcel is function of its temperature, its content of dissolved substances (summarized by a single quantity called salinity), and pressure. Accordingly, ocean density is affected by air—sea heat and mass exchange fluxes, river outflows, the freezing and melting of sea ice, mixing, and diffusion. Together, this set of processes, which are not easily observable or quantifiable, are collectively known as thermohaline forcings. At oceanic scale, water density increases with depth so that the water column appears to be stably stratified, because the oceans are heated from above and water is almost incompressible. Because of their stratification, oceans move almost horizontally, with different spatial and temporal scales at different layers. The oceanic circulation in the upper 1000 m is well known and has a characteristic time scale of months to years. Deep oceans, by contrast, were previously considered as being almost at rest. Their dynamics remained unobserved for a long time because their characteristic time scales ranged from decades to hundreds of years. Surface ocean circulation is mainly wind-driven. Wind causes movement directly by tangential stresses that transfer momentum and indirectly by building pressure gradients. The resulting movements are predominantly horizontal but since they are constrained by the contours of land masses (bottom topography and coasts), vertical displacements occur at local and regional scales (e.g., sills, straits, coastal upwelling). Heat and mass exchanges taking place at the surface are the primary drivers of deep circulation. While the heat gain by the ocean reinforces stratification, heat losses induce water sinking and convective motions. Deep convection at regions such as the Gulf of Lions, the Labrador Sea, and the Weddell Sea play a role at basin or global scales [22]. Density changes, however, do not necessarily follow only temperature changes as ocean density also depends on salinity. At the surface, salinity changes are caused by evaporation and precipitation. Evaporation is associated with latent heat losses that decrease surface temperature in addition to the salinity increase, enhancing convection. Precipitation (as well as ice melting and riverine runoff) decreases surface salinity, thus reinforcing stratification. An example of the impact of salinity is the fact that deep water forms in the North Atlantic but not in the North Pacific, because the waters of the latter are fresher. On the other hand, negative sea surface salinity (SSS) anomalies in the North www.cat-science.cat

Salinity and climate The importance of the ocean on climate is a function of a variety of processes, ranging from its large heat storage capacity to its ability to transport heat from low to high latitudes, and from there to intermediate or deep ocean layers. For example, the top few meters of the seas store more heat energy than the entire atmosphere, and the heat absorbed by the oceans in the tropics is transported towards the poles via warm ocean currents, such as the Gulf Stream, whose heat transport is estimated to be about 1.3 petawatts (1015 W) [16]. Salinity impacts the Earth’s climate in several ways. One of them, related to its role in large-scale ocean circulation, is the above-mentioned contribution to “hidden” heat storage. Another important aspect is related to the hydrological cycle (i.e., the idealized description of the continuous movement 90

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

SALAT, UMBERT, BALLABRERA-POY, FERNÁNDEZ, SALVADOR, MARTÍNEZ

of water through its different phases of ice, atmospheric vapor, surface freshwaters, and the oceans). Yet, although it is one of the key climatic drivers, it remains poorly observed. For instance, evaporation (E) and precipitation and river runoff (P) are for the most part not being measured anywhere in the ocean. Salinity observations, in this context, could be used as an indicator of E-P. Moreover, salinity changes by themselves may modulate the intensity of the hydrological cycle, through the above-mentioned impacts on ocean density, the modulation of ocean convection, and the shielding provided by the barrier layer, as described below. One of the major sources of interannual climate variability is the El Niño/Southern Oscillation (ENSO). Since pioneering, intermediate coupled ocean-atmosphere models used to predict ENSO did not account for salinity. The situation changed by the end of the 1990s, when the role of salinity in ocean dynamics was investigated [1,12,17,19] and the importance of SSS information in the prediction of ENSO was highlighted [6]. Specifically, it was shown that although SSS observations played only a small part in the statistical nowcasts of ENSO, they provided significant information in 6- to 12-month predictions. With these lag times, positive anomalies of SSS off the equator have the potential to modify the subsurface stratification of the western Pacific as they are subducted westward. In this region, the most prominent feature related to salinity is the existence of a barrier layer [15] that isolates the surface mixed layer from the entrainment of cold water from below. Thus, salinity stratification helps to preserve a warm anomaly at the surface and increases the fetch of westerly winds, facilitating the ocean-atmosphere-coupled instabilities associated with El Niño events [18]. At the eastern Pacific, the other edge of the warm pool is distinguished by a sharp SSS gradient but by a weak sea surface temperature (SST) gradient. Remote sensing of SSS is thus expected to result in an improved characterization of the state of the equatorial Pacific prior to and during the initial phases of ENSO events. Finally, in addition to aspects related to heat storage and transport, long-term climate trends also assume a significant uptake by the ocean of atmospheric carbon dioxide (CO2). Beginning with the speculations of Arrhenius, that changes in the atmospheric CO2 concentration significantly modified SST [3], to the unfortunate evidence nowadays, oceans have been recognized as playing a key role in the evolution of anthropogenic CO2 [20]. According to recent estimates, over the last 250 years the oceans have removed about 45 % of anthropogenic CO2 [21]. In 2003, the Second Adequacy Report [9], compiled by the Global Climate Observing System (GCOS), formalized scientific requests for systematic climate observations to meet the needs of, among others, the Intergovernmental Panel on Climate Change (IPCC). Climate observations are www.cat-science.cat

needed to: (a) characterize the state of the global climate system and its variability; (b) monitor its forcings, both natural and anthropogenic; (c) help to identify the causes of climate change; (d) support climate prediction efforts; (e) infer regional and national impacts of global climate change; and (f) assess the impact of climate change on extreme events. The report defined an ensemble of essential climate variables (ECV) of the global climate system whose observation is feasible. The information provided by the ECV significantly contributes to the needs of the United Nations Framework Convention on Climate Change (UNFCCC) and the IPCC. Among the oceanic variables, temperature and salinity vertical distribution, together with their surface values were included in the ECV ensemble.

In situ measurements of temperature and salinity Temperature and salinity measurements have been recorded for more than a century. However, since the 1970s, improvements in battery capacity, microprocessors, and electronic recording devices, together with the advent of satellites, have led to quantitative and qualitative changes in the overall observations of the oceans. Today, satellites provide the bulk of ocean-surface information while in situ automatic sensor networks (moored or drifting) contribute the necessary complementary information (for calibration, validation, and detection of sub-surface long-term trends) on the ocean ground state. The SST was one of the first oceanic variables to be measured, and it continues to be one of the most widely observed. Before the satellite era, most of the SST measures were obtained by thermometers (from buckets or suspended from a ship). The first automated observations of SST were obtained, in the 1960s, by placing a sensor at the intake port of a ship. Today, automatic in situ measurements are generated by buoys, floats, research ships, and ships of opportunity. In their attempts to measure temperature below the surface (by simply sinking and retrieving mercury thermometers), scientists rapidly realized: (1) that the housings had to be carefully designed if they were to survive the high pressures of the ocean waters and (2) that the deep temperature values were modified by the water masses crossed by the thermometer on its way to being retrieved. The min-max thermometer used in the Challenger expedition (1873–1876) was able to record the minimum and maximum temperatures encountered during descent and ascent. The reversing thermometer, introduced in 1874, was widely used until the 1970s. This thermometer had a mechanism that once it was inverted, it fixed the temperature reading until it was inverted again. Such measures were taken at discrete depths but beginning in 1930 a mechanical device, the bathythermograph (BT), was used to obtain a continuous profile of temperature 91

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

The contribution of the BWR to improved ocean surface information

probes have been routinely launched in all the oceans since 1997, within the framework of the international Argo program [http://www.argo.ucsd.edu], which maintains ~3000 active profilers to provide worldwide coverage. The longterm stability and accuracy of the conductivity measurements are still an issue when the CTD probes are continuously deployed (e.g., Argo profilers and moorings).

as a function of depth. The BT was based on a stylus forced in the y direction by the pressure acting on a membrane and in the x direction by the thermal expansion of a gas in a coil. Advances in electronics led to a new method to measure temperature, by exploiting the fact that the electrical resistance of metals, and of other materials, changes with temperature. Today, all electronic thermometers are based on this principle. One of the first oceanographic instruments to exploit this property was the expendable bathythermograph (XBT), which included a thermistor (i.e., a semiconductor used as the resistive material). In the late 1960s, XBTs provided the majority of the sub-surface continuous temperature measurements in the ocean. They replaced the earlier BTs until the generalized use of the CTD (see below), beginning in the early 1980s. The theoretical accuracy of the XBT is 0.1 °C. However, its sampling depth was not measured but was instead calculated from the estimated fall rate. The various sources of uncertainty led to XBT values that were usually biased. Consequently, early estimates of global ocean climate change were distorted. Ocean salinity has been measured since the first oceanographic campaigns, through the analysis of water samples, taken either at the surface or at any depth. The chemical composition of seawater was first reported in 1877, from data collected throughout the Challenger expedition. Since then, there have been no apparent changes in the composition of seawater. In addition, there have been no significant salt losses in the ocean, with salinity only changing by mixing or by the addition or removal of freshwater via precipitation or evaporation. Thus, it can be assumed that for the time scales pertinent to climate change, i.e., decadal to centennial, salinity behaves as a conservative tracer. As the salt composition is almost constant and chloride is its most important component, until the 1950s, salinity was obtained by a chemical analysis of chlorinity. Later on, since electrical conductivity of the water depends on both salinity and temperature, salinity was measured based on the conductivity of the sampled water at a fixed temperature. The development of electronic instruments to measure conductivity and temperature evolved to yield thermosalinographs, which since the 1970s have provided continuous surface temperature and salinity data along a ship’s track. A subsequent development included a pressure sensor and resulted in the conductivity-temperature-depth (CTD) probe, which is able to provide continuous vertical profiles of temperature and salinity as deep as 10,000 m and is routinely used in all oceanographic cruises. In fact, since the 1980s the CTD has been the standard tool to determine essential physical properties of the oceans. Based on CTD technology, autonomous probes have been developed during the last 20 years that can be installed in fixed moorings, in drifting buoys, and in automatic drifting profilers, called Argo profilers. These www.cat-science.cat

Satellite measurements of temperature and salinity In general, satellite measurements have the advantage of being synoptic over large areas and the disadvantage of providing information only for a thin layer of the sea surface in contact with the atmosphere. Since the SST provides the boundary condition for estimating air-sea heat fluxes, having this information on a global scale offers insights into the heat balance in the climate system, general circulation patterns, and thermal anomalies. At smaller scales, it can provide information about the presence of fronts between different water masses and the intensity of coastal and equatorial upwelling. Satellite estimates of SST rely on thermal emissions from the surface through the atmosphere. The use of infrared (~3.7 µm and/or ~10 µm) radiometers dates back to the end of the 1960s. The main drawback of infrared observations is that they are obscured by clouds. More recently, passive microwave (4–10 GHz) measurements have resolved this problem, although their precision is lower than infrared estimates because microwave emission is not as strongly tied to the temperature of an object as infrared. Since the two methods have different strengths and weaknesses, their combination provides the most accurate SST data. As was the case for SST measurements before they were obtained by satellites, historical SSS knowledge mostly came from single water samples, followed by thermosalinograph measurements onboard research vessels and ships of opportunity, and from moored buoys. However, the success of obtaining satellite-based SST measurements contrasts with the fact that no remotely sensed data of density or salinity were acquired until very recently, i.e., more than 40 years later. The ability to estimate SSS from space relies on the fact that at low frequencies, including microwave, the thermal emissions of the ocean are proportional to its physical temperature. The proportionality coefficient, the emissivity, is a function of the dielectric constant, which depends on conductivity, i.e., salinity. The launch of the Soil Moisture and Ocean Salinity (SMOS) satellite by the European Space Agency in November 2009, followed some months later by the launch of Aquarius by the National Aeronautics and Space Administration (NASA), finally opened the door to the remote monitoring of SSS. Both instruments exploit the 92

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

SALAT, UMBERT, BALLABRERA-POY, FERNÁNDEZ, SALVADOR, MARTÍNEZ

fact that significant information on sea surface dielectric properties (related to salinity) can be retrieved from ocean microwave emissions, particularly L-band (1.40–1.43 GHz), at which the sensitivity of surface emissivity to salinity is the largest. The SMOS and the Aquarius-SAC/D mission are the first two space missions designed to provide global, synoptic estimates of the SSS, with an accuracy of about 0.1 psu (practical salinity units) every 30 days and a spatial resolution of 200 km. The weak sensitivity of brightness temperatures to salinity hinders the retrieval of the latter, with averaging over 10–30 days required to reduce random errors. In fact, after processing of the first 18 months of SMOS data, it has become clear [8] that the narrow range in brightness temperatures of ocean emissions, the unexpectedly large amplitude of the errors associated with the image reconstruction process, and the complex forward geophysical modeling (relating the physical parameters of the sea surface with the microwave emissions detected by satellite) make the retrieval of salinity from SMOS data very challenging. It is therefore critical to use in situ data to calibrate and validate remotely sensed SSS.

New opportunities. The Barcelona World Race survey Fig. 1. The Fòrum Marítim Català (FMC), an Open 60 sailing boat that participated in the second edition of the Barcelona World Race. The FMC was equipped with an ocean temperature and salinity sensor and a transmitter able to provide real-time data along its around-the-world ocean trip from December 2010 to April 2011. (Image courtesy of FMC).

Gathering temperature, salinity, and as other relevant measures needed to understand the behavior of the ocean requires immense efforts: equipping ships, deploying instruments and satellites, transmitting information, etc. A limited number of oceanographic campaigns, fixed moorings, drifting buoys, automatic profilers, etc. cover a wide area of the ocean but the spatial and time distribution of this coverage is very irregular. Indeed, at any given time, several large regions are completely uncovered while others are heavily sampled. Moreover, the actual distribution of sampling changes continuously, according to the interests of the various oceanographic studies. Most of them are local or regional in scope while others cover large regions. Further complications are that similar oceanic sections are scarce, some sections are unique, and large regions of the oceans have never been sampled. There is also no worldwide network that collects oceanographic data, as is the case for meteorological stations, although climatic and even meteorological models would benefit immensely from oceanic information. In addition to automated methods such as drifting buoys and Argo profilers, ships of opportunity can provide complementary oceanographic information. During the last 20 years, an increasing number of ferries and carriers have been equipped with thermosalinographs that report surface data along the vessels’ tracks. Although the data obtained are very useful at large scale, they are restricted to commercial routes and, again, most of the oceans, especially the www.cat-science.cat

Fig. 2. Detail of the Sea-Bird SeaCat temperature and salinity sensor and the transmitter that were installed onboard the FMC.

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

The contribution of the BWR to improved ocean surface information

Argos satellites, using a data protocol developed at the ICM. The measuring instrument was located on the bottom of the boat, in the box housing the articulation of the swing keel (Fig. 3). Although this box was open and below the waterline, ensuring good renewal of the water, it was exposed to bubbles in rough weather and even dry in case of high inclination, especially when the boat sailed against the wind. The data were stored in an internal memory at a rate of 8 scans per hour and transmitted via Argos satellites every 90 s. This gave a redundancy of six repeated measurements, in order to minimize error transmission. Instantaneous positions were estimated by the Argos constellation with low precision but were adjusted later according to the official race tracking. After a first estimation of errors, preliminary data were available with a delay of 2–3 days. At the end of the race, the instrument was recovered and the data stored in the internal memory were used in a second correction and to cover gaps in transmission. A final sequence of almost 10,000 samples of SST and SSS was obtained, with a mean spatial resolution of 5 km along the track, a maximum gap of 450 km, and 16 gaps of more than 80 km without any reliable data (Fig. 4).

southern ones, remain uncovered. Progress in this regard started in 2010, when the organizers of the Barcelona World Race (BWR) together with scientists from the Institute of Marine Sciences (ICM-CSIC), and members of the Maritime Catalan Forum (FMC) agreed to equip the FMC boat (Fig. 1) participating in the BWR with a MicroCAT temperature and conductivity sensor and an XCAT transmitter (Fig. 2). The idea was to find out whether oceanic races could be exploited to monitor surface temperature and salinity in the world’s oceans in real time but without interfering with navigation or penalizing the boats competitiveness in the race. The BWR is a non-stop regatta around the world, starting and ending in Barcelona every three years. Its second edition began in December 2010. The FMC boat completed the round trip (more than 51,000 km) in 112 days, sending 12–30 real-time temperature and salinity measures/day via

Examples of direct results transmitter and antenna

The current BWR survey of SST and SSS is the longest record of this nature ever obtained. For the first time, continuous surface monitoring has been performed during a round trip around the world’s oceans and in less than 4 months. The survey includes two passages over the Atlantic ocean, around two months apart (Fig. 5) and a complete circumnavigation of the Southern Ocean at latitudes between 30° and 56° S in less than 2 months (Fig. 6), covering wide regions rarely sampled. As shown in figures 5 and 6, the relatively high sampling frequency allowed for mesoscale resolution, revealing the position of the main oceanic fronts and thus a comparison of zones of high and low mesoscale activity, identification of the surface signature of the main oceanic water masses, and even an estimate of the impact of seasonal continental ice melting near Cape Horn. The temperature-salinity (TS) diagram in Figure 7 shows the two mode waters of the Atlantic Ocean. The North Atlantic central water (NACW) and the South Atlantic central water (SACW) are clearly separated and each has very stable properties, as shown by the overlapping of the two transits, from N to S in January 2011 and from S to N two months later. Of particular interest is the good overlap between the eastern and western SACW, separated by more than 5000 km at 40°S. Two transition zones are also clearly depicted in the TS diagram. In the northern hemisphere, there is a diapycnal transition, along the track between the Cape Verde islands and Brazil, between western equatorial

MicroCAT sensor

The swing keel is operated by very powerful hydraulic rams which press of the head of the keel. The fulcrum or keel hinge is at hull level with just a short stub on which the rams press.

Fig. 3. Sketch of the installation of the sensor and transmitter onboard the FMC.

Salinity

Barcelona–Wellington

Salinity

Wellington–Barcelona

Fig. 4. Time series of surface salinity data obtained by the FMC along its track: (a) Barcelona–Wellington through the Atlantic (N to S) and Indian Oceans, and (b) Wellington–Barcelona, through the Pacific and Atlantic (S to N) oceans. Raw data in blue, transmitted data in green, and finally accepted data in red.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

SALAT, UMBERT, BALLABRERA-POY, FERNÁNDEZ, SALVADOR, MARTÍNEZ

Sal [ppt] @ Depth [m]=Top

Fig. 6. Sea surface salinity obtained by the FMC during its participation in the Barcelona World Race along a transit through the Southern Indian and Pacific Oceans. Data are extrapolated into a band ~100 km wide across the track.

Fig. 5. Sea surface salinity obtained by the FMC during the Barcelona World Race along two transits through the Atlantic Ocean. Data are extrapolated into a band ~100 km wide across the track.

Sal [ppt]

Temp [deg.C]

Latitude [degrees_North]

Tpot-0 [ºC]

Latitude [degrees_North]

Sal [ppt]

Fig. 7. FMC data obtained during its participation in the Barcelona World Race along two transits through the Atlantic Ocean, shown below on the left side of the map. Upper panel: salinity and temperature (color scale) vs. latitude. Lower panel, right: temperature-salinity (TS) diagram, with latitude presented in color scale.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

The contribution of the BWR to improved ocean surface information

waters, under the influence of riverine inputs and heavy precipitation, and the eastern NACW, which is saltier and slightly colder. In the southern hemisphere, the transition between the SACW and the equatorial waters occurs along the Brazilian coast at almost constant temperature. This difference in temperature among the equatorial transitions in the northern and southern hemispheres can be ascribed to the respective season, winter and summer, at the time of the survey. Finally, the diagrams of Figure 7 also show the Mediterranean water masses and the transition to the NACW. In this case there are slight but significant differences between the outgoing and ongoing tracks, because of the time lapse of almost 4 months between January and April 2011, that is, early winter and early spring. The water masses along the circumnavigation from the Cape of Good Hope to Cape Horn, covering the Southern Indian and Pacific Oceans, are less definite, especially along the Indian Ocean (Fig. 8), where mesoscale activity is high because of the weather conditions and the fact that the track roughly followed the sub-tropical front, with several crossing points. The situation is clearer in the Pacific Ocean (Fig. 9), where the SASW dominates the water mass structure at the surface between the two main fronts, the sub-

tropical and the sub-Antarctic. The TS diagram also clearly depicts the coastal influence across the Cook Straits under the coastal waters of the western South Pacific, and along Cape Horn, under the effect of Patagonian ice melting. Figure 10 shows the passage along Cape Horn in detail. Temperature, salinity, and density were spatially interpolated using the DIVA method [23] over a 100 km wide band. This interpolation allows the impact of ice melting on these variables, and especially on salinity, to be visualized, although there is not enough information to estimate freshwater flow. Only a very rough estimate is possible, since the only observed data are the mean salinities and the wideness of the patch can be reasonably estimated, whereas direct information on current velocity and patch thickness are lacking. Based on an estimated patch width of ~50 km, a mean salinity of ~32.5, and an incoming salinity of ~34, and assuming a mean thickness of 10â&#x20AC;&#x201C;20 m and a mean incoming current of ~0.2 m/s, the resulting freshwater flow would be between 5000 and 10,000 m3/s. But since this result is only based on the observed salinity and horizontal dimensions of the patch, its use is limited to an indicator of the order of magnitude of the melting process at the end of the austral summer.

Fig. 8. Data obtained along the Southern Indian Ocean by the FMC during its participation in the Barcelona World Race, shown below on the left side of the map. Upper left panels: salinity and temperature vs. time (days from the race start). Right panel: TS diagram, with time shown in a color scale. The TS characteristics of the sub-tropical front are also shown.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

SALAT, UMBERT, BALLABRERA-POY, FERNÁNDEZ, SALVADOR, MARTÍNEZ

Fig. 9. Data obtained along the Southern Pacific Ocean by the FMC during its participation in the BWR, shown below on the left side of the map. Upper left panels: salinity and temperature vs. time (days from the raced start). Right panel: TS diagram, with time shown in a color scale. The TS characteristics of the sub-tropical and sub-Antarctic fronts are also shown.

Fig. 10. FMC data obtained across Cape Horn. Left upper panel, temperature. Left lower panel, density (σt ). Right panel, salinity. Data are extrapolated into a band ~ 100 km wide across the track.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

The contribution of the BWR to improved ocean surface information

Fig. 11. Sea surface salinity (SSS) on January 11, 2011. The map was generated with the optimal interpolation algorithm and using 48 h of level 2 SSS data gridded onto a 1° cell.

Data Min = 19,75, Max = 37,64

SMOS L3 BIN - BWR

Number of events

SMOS L2 - BWR

Adjustment and validation of the SMOS data

SMOS L3 OI - BWF

Number of events

Besides the importance of the direct results, the BWR survey has been successfully used to adjust the salinity data retrieved from the SMOS satellite covering the race period, from January to April 2011. In the SMOS satellite mission processing chain, level 2 (L2) SSS estimates are obtained from the measured brightness temperature at each pixel. The so-called level 3 binned (L3 BIN) product is generated by a binning process at 1° × 1° boxes and a 10-day temporal resolution of the L2 data. The L3 optimal interpolation (OI) (Fig. 11) is produced applying the OI [7] to the L3 BIN data, using Levitus climatology [2,14] as background and the following background error covariance:

Fig. 12. Histograms of the differences between the sea surface salinity estimated by SMOS at different levels: (A) L2, (B) L3 BIN, and (C) L3 optimal interpolation, and data provided by the FMC.

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

SALAT, UMBERT, BALLABRERA-POY, FERNÁNDEZ, SALVADOR, MARTÍNEZ

where A, B, and C are the reciprocals of the squared correlation lengths as described in [13]. The map (Fig. 11) reproduces the main features of the SSS distribution, although the filtering properties of the OI algorithm have reduced most of the mesoscale signatures of salinity. A comparison of the results shown in Figure 11 with the SSS data recorded by the FMC boat along its race trajectory (Figs. 5 and 6) clearly shows that the boat’s high-frequency sampling provides information on the mesoscale variability

of the ocean that is not resolved by the SMOS binned maps with the decorrelation lengths used in the above equation. One of the interesting features emerging from this plot is the high degree of variability in the Southern Ocean, mostly linked to the frontal regions, especially the sub-tropical front (see above). The histogram of the difference between the SSS estimated by SMOS at the L2 level and the data provided by the BWR, corresponding to the entire race period, is shown in Figure 12a. The standard deviation of the differences is larger than 0.94 and the average difference is about 0.01. Figures 12b, and 12c show, respectively, the histograms of the differences between the BWR and the L3BIN and the L3OI, respectively. The most interesting feature of these results is the progressive noise reduction in the SSS data as higher level salinity products are introduced: the standard deviation shifts from the above mentioned 0.94 for L2 to 0.52 for L3BIN and 0.39 for L3OI. The continuous presence of ~3000 Argo profilers scattered worldwide are being routinely used to validate the SMOS data (http://tarod.cmima.csic.es/). In this case, the information on SSS has to be extrapolated since the upper salinity value obtained by any profiler is at 7.5 m. Figure 13 provides a comparison between the information provided by an Argo profiler on 15 January 2011 at 1°N 26°W and the FMC surface value at the same time and place. The SSS value is lower than the extrapolated values obtained by the profiler at 3 and 7.5 m. On a global scale, there are also differences between the optimally interpolated maps obtained from Argo profilers at 7.5 m depth and the BWR data (Fig. 14). The mean difference of 0.2, with the BWR data being more recent, could

Depth (meters)

15 January 2011 (1ºN-26ºW)

Salinity (PSU)

Fig. 13. A vertical profile of salinity, at 1°N 26°W for January 15, 2011, as determined by an Argo profiler (red), the interpolated salinity at 7.5 m (blue) and 3 m (green), and the surface salinity value recorded by the FMC during the Barcelona World Race (black).

Fig. 14. Differences between the optimally interpolated salinity from the Argo profilers and the data recorded by FMC along the trajectory of the Barcelona World Race.

Argo OI - BWR

Data Min = -0,63, Max = 1,23

www.cat-science.cat

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

The contribution of the BWR to improved ocean surface information

reflect the existence of uppermost salinity gradients not detected by the Argo profilers. Again, larger anomalies can be found in the Southern Ocean, where there are remarkable SSS fronts, because BWR data resolve mesoscale features and Argo OI fields do not.

New perspectives and conclusions The information on SST and salinity obtained through the participation of the FMC in the BWR has contributed to the study of the ocean’s properties on a global scale, especially because the vessel’s route covered rarely sampled regions in the Southern Ocean. In particular, SSS data from the BWR has been successfully used to validate SMOS products, at least as well as the Argo profilers, providing a high-resolution view of the SSS along the path of the boat. The success of the present experience recommends incorporating similar temperature and salinity sensors on all the participating boats in the new editions of the BWR. This perspective will substantially increase the utility and performance of the information. On the one hand, redundancies will help to improve the data quality and, on the other, comparisons between data that are close in time and space will make available more information about the characteristics of mesoscale activities. This is especially relevant for large areas of the Southern Ocean, where until now there have been few mesoscale studies based on in situ data.

10. 11. 12.

13. 14.

15.

Acknowledgements. This experience would not have been

16.

possible without the enthusiastic support of Andor Serra, Txema Benavides and all the BWR organizers, and the technical team of the FMC, especially the skippers, Ludovic Aglaor and Gerard Marín, who piloted the FMC along its around-the-world trip. We are very grateful to all of them. This work was performed with the support of the MIDAS-6 project of the Spanish R+D+I National Plan (AYA201022062-C05) and is a contribution of the SMOS Barcelona Expert Centre (SMOS-BEC, CSIC/UPC).

17. 18.

19. 20.

21.

References 1.

22.

Acero-Schertzer CE, Hansen DV (1997) Evaluation and diagnosis of surface currents in the National Centers for Environmental Prediction’s ocean analyses. J Geophys Res 102:21037-21048 Antonov JI, Seidov D, Boyer TP, Locarnini RA, Mishonov AV, Garcia HE, Baranova OK, Zweng MM, Johnson DR (2010) World Ocean Atlas 2009, Vol. 2. In: Levitus S (ed) Salinity. Ed NOAA Atlas NESDIS 69, U.S. Government Printing Office, Washington DC

www.cat-science.cat

23.

100

Arrhenius S (1896) On the influence of carbonic acid in the air upon the temperature of the ground, Phil Mag 41:237-76 Anderson DLT, Stockdale T, Balmaseda M, Ferranti L, Vitart F, Molteni F, Doblas-Reyes F, Mogensen K, Vidard A (2006) Development of the ECMWF seasonal forecast system 3. ECMWF Technical Memorandum 503 Bahurel P, Mercator Project Team (1999) Mercator, developing an integrated system for operational oceanography. In: OceanObs99 Proceedings, The Ocean Observations Conference, Saint Raphael 17th to 22 October 1999 [http://www.oceanobs09.net/work/oo99/docs/Bahurel.pdf] Ballabrera-Poy J, Murtugudde R, Busalacchi AJ (2002) On the potential impact of sea surface salinity observations on ENSO predictions. J Geophys Res 107:C12, 8007. doi:10.1029/2001JC000834 Bretherton FP, Davis RE, Fandry CB (1976) A technique for objective analysis and design of oceanographic experiments applied to MODE73. Deep-Sea Res 23:559-582 Font J, Camps A, Borges A, Martín-Neira M, Boutin J, Reul N, Kerr Y, Hahne A, Mecklenburg S (2010) SMOS: The challenging measurement of sea surface salinity from space. Proc IEEE, 98:649-665 GCOS (2003) The second report on the adequacy of the global observing systems for climate in support of the UNFCCC. GCOS-82 (WMO/TD No. 1143), World Meteorological Organization, Geneva Gill AE (1982) Atmosphere-ocean dynamics. Academic Press, New York Häkkinen S (1999) A simulation of thermohaline effects of a Great Salinity Anomaly. J Clim 12:1781-1795 Ji M, Reynolds RW, Behringer DW (2000) Use of TOPEX/Poseidon sea level data for ocean analyses and ENSO prediction: some early results. J Clim 13:216- 231 Jordà G, Gomis D, Talone M (2011) The SMOS L3 mapping algorithm for sea surface salinity. IEEE Trans Geosci Remote Sens 49:1032-1051 Levitus S, Boyer TP, Conkright ME, O’Brien T, Antonov J, Stephens C, Stathoplos L, Johnson D, Gelfeld R (1998) NOAA Atlas NESDIS 18, World Ocean Database 1998, Vol 1, Introduction. U.S. Gov. Printing Office, Washington DC Lukas R, Lindstrom E (1991) The mixed layer of the western equatorial Pacific. J Geophys Res 96:3343-3357 Lund DC, Lynch-Stieglitz J, Curry WB (2006) Gulf Stream density structure and transport during the past millennium. Nature 444:601-604 Maes C (2000) Salinity variability in the equatorial Pacific Ocean during the 1993–98 period. Geophys Res Lett 27:1659-1662 Maes C, Picaut J, Belamari S (2002) Salinity barrier layer and onset of El Niño in a Pacific coupled model. Geophys Res Lett 29:2206. doi:10.1029/2002GL016029 Murtugudde R, Busalacchi AJ (1998) Salinity effects in a tropical ocean model, J Geophys Res 103:3283-3300 Revelle R, Suess H (1957) Carbon dioxide exchange between atmosphere and ocean and the question of an increase of atmospheric CO2 during the past decades. Tellus 9:18-27 Sabine CL, Feely RA, Gruber N, Key RM, Lee K, Bullister JL, Wanninkhof R, Wong CS, Wallace DWR, Tilbrook B, Millero FJ, Peng T-H, Kozyr A, Ono T, Rios AF (2004) The oceanic sink for anthropogenic CO2. Science 305:367-371 Straneo F (2006) On the connection between dense water formation, overturning, and poleward heat transport in a convective basin. J Phys Oce 36:1822-1840 Troupin C, et al. (2012) Generation of analysis and consistent error ﬁelds using the Data Interpolating Variational Analysis (Diva). Ocean Modelling 52-53:90-101

CONTRIBUTIONS to SCIENCE 9 (2013) 89-100

FORUM CONTRIBUTIONS to SCIENCE 9 (2013) 101-106 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.168 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

The United Nations University Institute on Globalization, Culture and Mobility (UNU-GCM) in Barcelona: Mission and vision Parvati Nair United Nations University Institute on Globalization, Culture and Mobility, Barcelona, Catalonia

Correspondence: United Nations University Institute on Globalization, Culture and Mobility Sant Manuel Pavilion Sant Pau Art Nouveau Site Av. Sant Antoni Maria Claret, 167 08025 Barcelona, Catalonia Email: pnair@unu.edu

Summary. Based in Barcelona, in the Sant Manuel Pavilion of the Sant Pau Art Nouveau Site,

the United Nations University Institute on Globalization, Culture and Mobility (UNU-GCM) is the newest institute to date of the United Nations University (UNU) and the only one in southern Europe. The UNU, which consists of a globally dispersed set of research and training institutes, is a global think tank and postgraduate teaching organisation headquartered in Japan. The mission of the UNU-GCM is to contribute to good governance, cultural diversity, democracy and human rights through a better understanding of cultural mobility and diversity in the context of globalisation. Its focus is thus on the major cultural and social phenomena of migration and media, as hallmarks of the era of globalisation. The institute aims to foster cutting-edge research in these areas at global and local levels through the lens of key cultural concepts, such as borders, gender and transnational connections. The UNU-GCM thereby also aims to support the achievement of the Millennium Development Goals, in particular those of gender equality and the notion of development as a global partnership. Keywords: culture · mobility · migration · diversity · globalisation Resum. L’Institut de Globalització, Cultura i Mobilitat de la Universitat de les Nacions Unides (UNU-GCM), amb seu al pavelló de Sant Manuel del complex modernista de l’Hospital de la Santa Creu i Sant Pau de Barcelona, és l’institut més recent, fins ara, de la Universitat de les Nacions Unides (UNU) i l’únic al sud d’Europa. La UNU consisteix en un conjunt d’instituts de recerca i formació escampats per tot el món que actuen a la vegada com a laboratoris d’idees (think tank) i centres de formació de postgrau, amb la central al Japó. La missió de la UNU-GCM és contribuir a la bona governança, a la diversitat cultural, a la democràcia i als drets humans a través d’una millor comprensió de la mobilitat i la diversitat culturals en el context de la globalització. Així, se centra en els principals fenòmens culturals i socials de la migració i els mitjans de comunicació com a segells distintius de l’era de la globalització. L’Institut té com a objectiu fomentar la investigació d’avantguarda en aquestes àrees, tant a escala global com local, tenint en compte conceptes culturals com ara les fronteres, el gènere o les connexions transnacionals. La UNU-GCM pretén amb això donar suport a l’assoliment dels Objectius de Desenvolupament del Mil·leni, en particular els d’igualtat de gènere i la noció d’una aliança global per al desenvolupament. Paraules clau: cultura · mobilitat · migració · diversitat · globalització

www.cat-science.cat

101

CONTRIBUTIONS to SCIENCE 9 (2013) 101-106

The United Nations University Institute on Globalization, Culture and Mobility (UNU-GCM) in Barcelona: Mission and vision

media. This is as relevant to developing and transitional countries as to more developed countries.

In an increasingly globalised world, mobility and cultural contacts are both commonplace and complicating factors with regard to national, regional and communal identities. At the same time, mobility is also the means through which globalisation propels itself. Within this context, two phenomena come to the fore as key social processes: migration, understood as the movement of peoples and cultures; and media, understood as increased and diverse modes of communication across space via technological and other means. The aim of the United Nations University Institute on Globalization, Culture and Mobility (UNU-GCM) [gcm.unu. edu], as the academic arm of the United Nations, is to contribute towards an improved understanding of migration and the media, as key aspects of culture, in terms of globalisation, that are vital for the promotion of good governance, cultural diversity, democracy and human rights. It goes without saying that the media plays a crucial role in many aspects of the migration process. Whether by influencing popular perceptions of migrants, or by spurring migration by relaying images from destination countries, or by allowing diasporic communities to remain connected with homelands, understandings and perceptions of migration are always closely determined by its representation by the

The UNU-GCM concept The United Nations University (UNU) bridges the academic world and the UN system. Its goal is to develop sustainable solutions for current and future problems of humankind in all aspects of life. Through a problem-oriented and interdisciplinary approach it seeks to carry out applied research and education on a global scale. The UNU was founded in 1973 and is an autonomous organ of the UN General Assembly. Headquartered in Tokyo, Japan, it encompasses 15 research and training institutes and programmes located in 13 countries around the world. The global UNU system is coordinated by the UNU Centre. The UNU-GCM became operational in 2012 and was officially approved by the Council of the UNU in April 2013. In its adherence to the UNU’s focus on pressing questions of development, human rights and the fostering of tolerance and diversity, the UNU-GCM considers issues of culture and mobility, with the rationale that globalisation is a key socio-cultural and economic facet of the mod-

Fig. 1. Sant Manuel Pavilion of the Sant Pau Art Nouveau Site, designed by Lluís Domènech i Montaner and build under the direction of his son, Pere Domènech i Roure, in 1923. (Photo by Robert Ramos © Fundació Privada Hospital de la Santa Creu i Sant Pau).

www.cat-science.cat

102

CONTRIBUTIONS to SCIENCE 9 (2013) 101-106

NAIR

Table 1. United Nations University (UNU) Associated Institutions. In many of its activities, the UNU is assisted by a network of designated Associated Institutions. These typically are organisations that implement large, multiyear joint programmes with the UNU. Currently, 20 institutions have been designated as UNU Associated Institutions by the UNU Council. UNU Associated Institutions Asian Institute of Technology; Bangkok, Thailand Centre for Development Research, University of Bonn; Bonn, Germany Cornell University; Ithaca, NY, USA Department of Food Science, Nutrition and Technology, University of Nairobi; Nairobi, Kenya Department of Nutrition and Food Science, University of Ghana; Legon, Ghana

Fig. 2. On Tuesday, 17 September 2013, the United Nations University Institute on Globalization, Culture and Mobility (UNU-GCM) in Barcelona hosted an inaugural lecture and reception to celebrate its official opening in the Administration Pavilion of the Sant Pau Art Nouveau Site. The event was attended by a number of dignitaires, including UNU Rector David Malone; the President of the Generalitat of Catalunya, Artur Mas; the Mayor of Barcelona, Xavier Trias; and the Secretary General of Universities, Federico Morán-Abad. (© Photo by Pere Virgili).

Gansu Natural Energy Research Institute; Gansu, China Global Fire Monitoring Centre, Max Planck Institute for Chemistry; Freiburg, Germany Griffith University; Queensland, Australia Gwangju Institute of Science and Technology; Gwangju, Republic of Korea Institute of Nutrition and Food Technology, University of Chile;

ern world, one that functions principally through the expansion of markets, leading in turn to movements, flows and fluxes of capital, goods and peoples. Globalisation and its effects also rely on technology and complex, mediatised modes of communication across space. An initial line of research at the UNU-GCM will focus on the Mediterranean Basin, as the confluence of three continents: Europe, Africa and Asia. Research plans also include projects that offer comparative and global perspectives.

Santiago, Chile Institute of Nutrition, Mahidol University; Nakhon Pathom, Thailand Institution for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences; Shanghai, China International Conflict Research Institute, University of Ulster; Northern Ireland, UK International Institute for Geo-Information Science and Earth Observation; Enschede, Netherlands National Energy Authority of the Republic of Iceland; Reykjavík,

The UNU-GCM in Barcelona

Iceland National Food Research Institute; Ibaraki, Japan

The UNU-GCM is located in the Sant Manuel Pavilion of the Sant Pau Art Nouveau Site, in Barcelona (Fig. 1). The official opening of the institute was celebrated on September 17, 2013, and was attended by Artur Mas, President of the Autonomous Government of Catalonia, and by other officials. The Sant Manuel Pavilion was built in 1923 under the direction of the Catalan architect Pere Domènech i Roura, who took over the construction of the Hospital de la Santa Creu i Sant Pau, following the death of his father, the architect Lluis Domènech i Montaner. As one of the world’s major modernist sites, the hospital was declared a World Heritage Site by UNESCO in 1997. Built between 1902 and 1930, the 12 pavilions housed the Santa Creu i Sant Pau Hospital, one of the most modern hospitals of its time, for nearly a century. In 2009, the working hospital was relocated in order to facilitate rehabilitation of the historic site, as part of Europe’s major efforts at heritage restoration. www.cat-science.cat

National Institute of Public Health, Nutrition and Health Research Centre; Cuernavaca, Mexico National Nutrition Institute, Egyptian Ministry of Health and Population; Cairo, Egypt Scottish Association for Marine Science; Oban, Scotland, UK Tufts University; Boston, MA, USA

The Sant Manuel Pavilion, where general and gastric surgery were previously carried out, has been restored to enable new uses but also to recover its artistic and heritage value. Víctor Argentí, the architect in charge of the restoration, has emphasised the recovery of the original dimensions of this building, with its surface area of 2300 m2. With financial support from the European Fund for Regional De103

CONTRIBUTIONS to SCIENCE 9 (2013) 101-106

The United Nations University Institute on Globalization, Culture and Mobility (UNU-GCM) in Barcelona: Mission and vision

essential aspect of globalisation, has led to the proliferation of the media, especially digital media, which allows for representation and communication whilst also offering outreach to specific ideological and other agendas. Migration and media are twin facets of globalisation that directly influence questions of culture, by imposing change, mobility and the crossing of traditional or established borders. This is the nexus that forms the research focus of the UNU-GCM. In fact, the UNU-GCM was founded on the premise that a better understanding of these key phenomena of migration and media is imperative to resolving the cultural dilemmas that have proliferated in the contemporary world within the framework of globalisation. In particular, there is a need to overcome divisions between the south and north, and to understand the ways in which developed and developing nations and regions are fundamentally connected and mutually implicated. It is our hope that the this awareness will pave the way for tolerance, understanding and good governance to overcome historical inequalities and injus tices. Research efforts at the UNU-GCM are therefore devoted to the issues of global migration, gender, culture and migrancy, developments in media in the digital age and the proliferation of borders, routes and networks at local and global levels in a variety of contexts and geo-cultural spaces. Since its inception, the UNU-GCM has adopted a staged plan to develop an analysis of the strategic research categories of migration and media within the overarching umbrella of globalisation, culture and mobility. It does so through a series of focused research projects with multiple outcomes aimed at disseminating knowledge, informing policy, enhancing the promotion of cultural dialogue and furthering the understanding of cultural mobility and cultural diversity. The UNU-GCM extends its work to collaborate with and meet the needs of a wide range of recipients, such as educational institutions, policy makers, cultural institutions and non-governmental organisations. Accordingly, the UNU-GCM functions primarily as a think tank, bridging the worlds of academic scholarship and policy formation. It is therefore strategically positioned to intervene positively in questions of governance, legislation and perceptions of diverse forms of mobility, such as migration, migrancy, statelessness and diasporas. Research activities and outputs reflect this aim to make scholarship relevant to diverse forums. In 2013, events under the UNU-GCM’s aegis included workshops, a training seminar, a two-day international conference, film screenings and open forums for debate. UNU-GCM publications thus far range from the production of ten policy reports to scholarly articles in refereed journals and in the UN Chronicle. Many more are underway. UNU-GCM also contributed to the High Level Dialogues on Migration and Development at the United Nations, which can be read online on the UNU-GCM’s website. [http://gcm.unu.edu/index.php/publications/un-interventions]

velopment (FEDER), the Sant Manuel Pavilion is now a functional building, reflecting its heritage value while also equipped with the utmost consideration for energy efficiency and sustainability.

The UNU-GCM’s mission and vision The mission of the UNU is to contribute, through collaborative research and education, to efforts to resolve the pressing global problems of human survival, development and welfare, which are the concern of the UN, its peoples and its member states. In carrying out this mission, the UNU works with leading universities and research institutes in UN member states (Table 1), functioning as a bridge between the international academic community and the UN system. At the UNU-GCM, we believe that there is an urgent need for better understandings of culture and mobility in ways that view cultures as mobile and mobility as a feature of everyday life. As such, the prime concerns at the UNU-GCM revolve around questions of migration and media, as inroads to better understandings of culture, understood as lived realities. For reasons that are economic, political and environmental, among others, migration and media are important intertwined aspects of today’s globalised world and they work together to mobilise cultures in diverse ways. The study of culture cannot be confined to the abstraction of theory: instead, it takes place on multiple levels, linked inevitably to questions of power and representation, not least as the politics of the margins, wrought from the rough grain of everyday life and from specific contexts. Cultural migrancy and cultural change arise from the struggle for self-definition and self-representation amongst those who are faced with discrimination and prejudice. These are also processes that emerge spontaneously from the many dislocations, migrations and relocations that accompany modernity and its attendant socio-economic processes. Indeed, migration looms large on any mapping of socio-economic development on global and most local scales. It is a vital part of contemporary social and cultural realities. To quote the Secretary General of the UN as he opened the latest High Level Dialogues on Migration and Development, which took place in New York in October 2013, “the face of migration is changing. Today, migrants are coming from, and going to, more places than ever before. Almost half of migrants are women. One of every 10 migrants is under the age of 15. And 4 of every 10 migrants are living in developing countries.”[http://www.un. org/News/Press/docs/2013/sgsm15367.doc.htm] Migration has become a key feature of the contemporary global scenario. It affects the ties of humankind to land, to place, to nation and to identity. It has led to major social changes, which, in turn, impact heavily on questions of culture and identity for nation states and communities, collectives and individuals alike. The rise of technology, an www.cat-science.cat

104

CONTRIBUTIONS to SCIENCE 9 (2013) 101-106

NAIR

Within the UNU, the UNU-GCM also plays the very important role of serving as a focal point for the UNU Migration Network, which brings together six UNU institutes through a shared interest in migration that ranges across disciplinary areas. Thus, aspects of migration such as forced migration, climate refugees, the displacement of indigenous peoples, questions of economic remittances by migrants, migration and the use of social media, etc. come under research scrutiny. The first workshop of this network was held in Barcelona in June 2013.

A forum for dialogue: the journal of the UNU-GCM The Crossings: Journal of Migration and Culture, published by Intellect, reflects the research areas that are the focus of the UNU-GCM. Indeed, the foundation of the journal acted as a useful precursor to the UNUGCMâ&#x20AC;&#x2122;s conception and birth. By eschewing the more traditional sociological approaches to the study of migration, and focusing instead on theorising the paired notions of culture and migration in terms of a mobility that is mutually applicable, the journal provides a space for examining the inevitable and ever present overlap of migration and culture from myriad perspectives and through myriad contexts. Cultural texts and lived experiences form the core of its analyses; interdisciplinary theoretical approaches offer conceptual routes that lead beyond the issue at hand. As such, this journal seeks to establish a forum for a much needed dialogue between academia and the practitioners of culture, especially those working specifically within migrant contexts, to explore both the cultural aesthetics of migration and the ethical importance of interpreting culture in terms of migrancy.

The UNU-GCMâ&#x20AC;&#x2122;s research programmes Research programmes currently planned and underway at the UNU-GCM include: migration, media and intercultural dialogue; statelessness and transcontinental migration; female agency, mobility and socio-cultural change in developing countries; the impact of the global economic crisis on migration; diasporas and changes to cultures, peoples and places. Migration, media and intercultural dialogue. This research

programme focuses on a range of issues, both theoretical and practical, related to cultural diversity and difference. Migration and media are twin facets of globalisation, the one demographic, with crucial spatio-temporal consequences, and the other cultural and technological. While migration often poses the question of cultural difference, diverse forms of media play a key role in enabling its representation, thus forging modes of communication. Through a focus on the media, this research programme will explore the extent to which it is able to bridge cultural differences with respect to migration and to facilitate intercultural dialogue. Of interest too will be the ways in which the media can mobilise societies and cultures, and its role in triggering migration and in connecting migrants to their homelands. Statelessness and transcontinental migration. This re-

search programme examines a range of issues related to the well-being and recognition of people who traverse continents, devoid of citizenship. Issues related to refugees remain crucially unanswered in debates and policies surrounding migration. In the wake of the acknowledgement that it is not always possible to isolate refugees from migrants, this programme analyses a range of contexts in which dignity and human rights are compromised through the absence of legal and political recognition. By focusing on situations of extreme vulnerability and on lives lived on the borderline, this research programme seeks to articulate and address the urgent needs of the stateless migrants who have entered Europe. Fig. 2. Cover of the latest issue of Crossings: Journal of Migration and

Female agency, mobility and socio-cultural change. The

Culture also available on-line [ http://www.intellectbooks.co.uk ]

feminisation of migration is one of the most significant sowww.cat-science.cat

105

CONTRIBUTIONS to SCIENCE 9 (2013) 101-106

The United Nations University Institute on Globalization, Culture and Mobility (UNU-GCM) in Barcelona: Mission and vision

cial patterns to have emerged in the course of the last century. Too often, female migrants occupy vulnerable positions in their host societies, engaging in domestic work, sex work and other unregulated sectors. Despite their vulnerability and the established patterns of exploitation, the number of women who choose to migrate is rising. This research programme looks closely at this phenomenon in order to better understand why and how migration may offer routes to female empowerment. A specific focus will be the extent to which migration allows women from the global south to encounter new sociocultural horizons as they cross over and settle in the global north.

the publication of a series of ten Policy Reports on Migration, Media and Intercultural Dialogue, available via the website. The Director of the UNU-GCM is also the founder and Principal Editor of Crossings: Journal of Migration and Cul ture (Fig. 2).

UNU-GCM’s future plans The UNU-GCM actively seeks collaborations with research entities in Catalonia and elsewhere so as to explore synergies and share knowledge. These collaborations may range from joint activities, such as workshops or training seminars, to teaching contributions at the postgraduate level or shared supervision, to working on joint research projects. The UNU-GCM runs a Visiting Researcher programme in conjunction with each of its research lines. The programme is advertised periodically via its website and its goal is to facilitate the exchange of research interests, methodologies and expertise. In addition, the many research activities organised at the UNU-GCM are designed to open spaces for contact, collaboration and debate. The UNU-GCM is as yet in a fledgling state but its emerging research profile ambitiously seeks to explore many dimensions related to questions of culture and mobility in the contemporary world. Its aim is to combine research excellence with an ethics of commitment in order to further the ways in which questions of culture and migration are perceived, experienced and imagined in our contemporary world. It invites collaboration from interested colleagues in Catalonia and elsewhere in carrying out its mission.

Sociocultural impacts of the global economic crisis on migration. The impact of the global economic crisis on

migration has been the subject of numerous recent studies, most of which have focused specifically on economic and labor issues. This research programme analyses the sociocultural issues that arise in the wake of the ongoing crisis on migration. In particular, it examines the geo-cultural spaces of the northern shores of the Mediterranean, where the crisis is most acute, and the ramifications of this both in these areas and further south, in Africa. As countries of recent immigration, such as Spain, return to becoming countries of emigration and as migrants from the global south turn elsewhere to seek their fortunes or else find themselves trapped in the throes of the crisis, a shifting landscape of (dis)empowerment has emerged within and without Europe. Interestingly, as migrancy and displacement become commonplace, the long-standing demands of migrants for citizenship, recognition and belonging become mainstream concerns.

The UNU-GCM’s staff

Useful links

At the UNU-GCM, the very international character of the UN and the interdisciplinary nature of the research undertaken are reflected in the institute’s staff. While the team is still small, dynamic work is already underway, as evidenced by

• Website of UNU-GCM [gcm.unu.edu] • Website of UNU [www.unu.edu] • Crossings: Journal of Migration and Culture [http://www.intellectbooks.co.uk/journals/view-Journal,id=173/]

Parvati Nair is the Founding Director of the United Nations University Institute (UNU-GCM) in Barcelona. She is Professor of Hispanic, Cultural and Migration Studies at Queen Mary, University of London. Her research focuses on migration, ethnicity and gender through the study of photography, music and film, as well as with ethnography. Her concern is primarily with the displacements and mobilities of globalization. She is the author of Configuring Community: Theories, Narratives and Practices of Community Identities in Contemporary Spain (2004), Rumbo al norte: inmigración y movimientos culturales entre el Magreb y España (2006) and A Different Light: The Photography of Sebastião Salgado (2012). She is the Principal Editor of Crossings: Journal of Migration and Culture and co-editor of Gender and Spanish Cinema (2004) and of Hispanic and Lusophone Women Filmmakers: Critical Discourses and Cinematic Practices (2013). Currently, she is writing a monograph entitled Flamenco Rhythms: People, Place, Performance, as well as working on several other migration-related projects. She also writes a blog on flamenco music [www.flamencorhythms.com].

www.cat-science.cat

106

CONTRIBUTIONS to SCIENCE 9 (2013) 101-106

FORUM CONTRIBUTIONS to SCIENCE 9 (2013) 107-108 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.169 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

The Institute for Catalan Studies and the International Women’s Day, 2006–2013 Carme Puche Contributions to Science, Barcelona, Catalonia

Many countries around the world celebrate the International Women’s Day (IWD), which commemorates women’s past struggles to reivindicate their rights, recognizes their social achievements in those struggles and looks ahead to what remains still to do to gain full and equal participation in society. The United Nations (UN) started celebrating the IWD on 8 March in 1975, on the occasion of the International Women’s Year. In December 1977, a resolution of the UN General Assembly proclaimed a UN Day for Women’s Rights and International Peace, which would be observed on any day of the year by Member States, according to their traditions. In fact, a Women’s Day had been observed since the early 20th century, when the Socialist Party of America designated the last Sunday of February as the National Woman’s Day. According to Temma Kaplan, in Europe, it was first celebrated on March 18, 1911, coinciding with the 40th anniversary of the Paris Commune [On the origins of International Women’s Day. Feminist Studies (1985) 11:163-171]. Nowadays, the IWD is observed in more than 100 countries and in some of them it is even an official public holiday.

As the UN Secretary-General Ban Ki-moon wrote: «Co untries with more gender equality have better economic growth. Companies with more women leaders perform better. Peace agreements that include women are more durable. Parliaments with more women enact more legislation on key social issues such as health, education, anti-discrimination and child support. The evidence is clear: equality for women means progress for all.» International Women’s Day is celebrated in many countries around the world. It is a day when women are recognized for their achievements without regard to divisions, whether national, ethnic, linguistic, cultural, economic or political. It is an occasion for looking back on past struggles and accomplishments, and more importantly, for looking ahead to the untapped potential and opportunities that await future generations of women. International Women’s Day first emerged from the activities of labour movements at the turn of the twentieth century in North America and across Europe: 1909 The first National Woman’s Day was observed in the United States on 28 February. The Socialist Party of America designated this day in honor of the 1908 garment workers’ strike in New York, where women protested against working conditions.

Fig. 1. Fragment of The School of Athens, one of the most famous frescoes by Raphael, painted for the Apostolic Palace in the Vatican between 1509 and 1510. The interpretation of this figure as Hypathia (square) seems to have originated from the Internet. With some exceptions, serious sources do not accept it.

www.cat-science.cat

107

CONTRIBUTIONS to SCIENCE 9 (2013) 107-108

The Institute for Catalan Studies and the International Women’s Day, 2006–2013

1917 Against the backdrop of the war, women in Russia again chose to protest and strike for “Bread and Peace” on the last Sunday in February (which fell on 8 March on the Gregorian calendar). Four days later, the Czar abdicated and the provisional Government granted women the right to vote.

1910 The Socialist International, meeting in Copenhagen, established a Women’s Day to honor the movement for women’s rights and to build support for achieving universal suffrage for women. The proposal was greeted with unanimous approval by the conference of over 100 women from 17 countries, which included the first three women elected to the Finnish Parliament. No fixed date was selected for the observance. 1911 As a result of the Copenhagen initiative, IWD was marked for the first time (19 March) in Austria, Denmark, Germany and Switzerland, where more than one million women and men attended rallies. In addition to the right to vote and to hold public office, they demanded women’s rights to work, to vocational training and to an end to discrimination on the job. 1913–1914 International Women’s Day also became a mechanism for protesting World War I. As part of the peace movement, Russian women observed their first IWD on the last Sunday in February. Elsewhere in Europe, on or around 8 March of the following year, women held rallies either to protest the war or to express solidarity with other activists.

*** Since those early years, the growing international women’s movement, which has been strengthened by four global UN women’s conferences, has helped make the commemoration a rallying point to build support for women’s rights and participation in the political and economic arenas. Increasingly, IWD is a time to reflect on progress made, to call for change and to celebrate acts of courage and determination by ordinary women who have played an extraordinary role in the history of their countries and communities. Accordingly, the Institute for Catalan Studies, always eager to follow international trends and multi-national cooperation, is celebrating the IWD since 2006 with a special session held during the week of March 8. Female researchers and scholars have talked on a great variety of topics, as shown in the box below.

DIA INTERNACIONAL

INTERNATIONAL

DE LES DONES A L’IEC

WOMEN’S DAY AT THE IEC

International Women‘s Day at the Institute for Catalan Studies 2006 2007 2008 2009

“The challenges of subalternity: Women's movements” Mary Nash, University of Barcelona “The eloquent silence of Rachel Carson” Mercè Piqueras, Catalan Association for Science Communication (ACCC) “Laura Bassi and Giuseppe Cerati: an ’electric‛ couple” Marta Cavazza, University of Bologna “Sex and family throughout evolution” Anna Omedes, Barcelona Natural History Museum

2010

“European Spatial Agency (ESA) Gaia Mission”

2011

“Women, reproduction, and in vitro fertilization”

2012 2013

Carme Jordi, University of Barcelona

Francesca Vidal, Autonomous University of Barcelona “Lynn Margulis: The will to be, the impetus to do” Carmen Chica, International Microbiology; Olga Guerrero Miracle, soprano; et al. “Two cultures, three cultures, or one only culture?” Dacha Atienza, Barcelona Natural Science Museum; Mercè Berlanga, University of Barcelona; and Genoveva Martí, Catalan Institution for Research and Advanced Studies (ICREA)

www.cat-science.cat

108

CONTRIBUTIONS to SCIENCE 9 (2013) 107-108

HISTORICAL CORNER CONTRIBUTIONS to SCIENCE 9 (2013) 109-112 Institut d’Estudis Catalans, Barcelona, Catalonia doi: 10.2436/20.7010.01.170 ISSN: 1575-6343 www.cat-science.cat

OPENAACCESS

The American dream of Rafael Guastavino (1842–1908) Mercè Piqueras Catalan Society for the History of Science and Technology, Barcelona, Catalonia

Many millions of immigrants to the United States passed through Ellis Island, in Upper New York Bay, from 1892 to 1954, and millions of visitors have seen it since it was made part of the Statue of the Liberty National Monument in 1965. When in 1916, an explosion caused serious structural damages to the great Registry Hall, it was restored and a new vault was built in a style that had been taken to America in the late 19th century (Fig. 1). The owners of the company that built it—Guastavino Brothers—were the children of Rafael Guastavino (1842–1908), Valencian architect and builder that, after having had a great success in Catalonia, moved to the United States in 1881. There he founded his own family business and patented the “tile arch system” of his vaulting sys-

tem of construction, which was based on a centuries-old Catalan building technique. The Guastavinos where the builders of many public spaces in the United States between 1881 and 1962, and revolutionized architectural design and construction in the country. Differently from most immigrants arriving in the United States due to the poor conditions in which they lived in their home countries, in 1881 Guastavino was already well known both as architect and builder in Barcelona, and his work had been present at first-rank exhibitions and competitions, including the World Exposition of Vienna (1873) and the Philadelphia Exhibition (1876) that commemorated the Centennial of the United States and was the first major World’s Fair held in that country, attracting around nine million visitors. Rafael Guastavino was born in Valencia, Spain on March 1, 1842, the fourth of fourteen children of Pascuala Moreno and Rafael Guastavino, the son of an Italian immigrant that

Fig. 1. Current view of Ellis Island Registry Room, where immigrants went through medical and legal inspections. It was restored to host the Ellis Island Immigration Museum. (Image courtesy of Flodigrip's world, “The Registry Room” March 29, 2011 via Flickr, Creative Commons Attribution).

www.cat-science.cat

109

CONTRIBUTIONS to SCIENCE 9 (2013) 109-112

The American dream of Rafael Guastavino (1842–1908)

had settled in Barcelona in the late 18th century. Young Guastavino moved to Barcelona to study at the Escola Especial de Mestres d’Obres (Master Builder’s School), the only institution that offered degree studies in architecture and art building at that time in Spain, along with that in Madrid. He started working on his own as a builder in Barcelona and soon received commissions from wealthy owners to build both industrial buildings and private residences. Among his major

works of that period is the factory for the Batlló brothers (Fig. 2). The factory included a 60-m octagonal brick chimney and a loom room containing several spherical vaults that rested on metallic supports, and was built using what Guastavino himself called “cohesive construction”, based on a Catalan technique that had been used for centuries and that allowed to span wide spaces and produce fireproof vaults strong enough to support a floor above them. The so-called

Fig. 2. Overview of Fàbrica de Batlló & Batlló (Batlló Brothers), a textile factory built by Rafael Guastavino between 1868 and 1870 in Les Corts de Sarrià, at the time an independent village and nowadays a quarter in the Eixample of Barcelona, occupying ca. six hectares. Top: An advertising card from 1870. Bottom: Current view of a part of the premises, now a teaching and services complex of the Technical University of Catalonia. At the bottom left, a soccer field (green) for young students covers a large underground rainwater storage tank, aimed at retaining runoff water from sudden storms, typical of the Mediterranean region, during the rainy seasons (spring and autumn). The water collected is used for watering trees and green areas. (Photo by Mercedes Berlanga).

www.cat-science.cat

110

CONTRIBUTIONS to SCIENCE 9 (2013) 109-112

PIQUERAS

Catalan vault (volta catalana) or timbrel vault had been traditionally constructed interlocking thin terracotta tiles over a wood pattern and holding them together with mortar, which allowed gentler and longer curves than other techniques. Guastavino replaced mortar by materials that were common at his time such as Portland cement. The Australian chronicler and historian Robert Hugue, author of a monumental guide of Barcelona and its history [Barcelona, Vintage Books, NY, 1992], describes the chimney in the Batlló Factory as “a high octagonal pipe that rises from a flaring base, tapering slightly toward the top, and finished with a small cornice. It has a breathtaking simplicity and the beauty of ancient Persian prayer towers.” The Batlló factory was a landmark in industrial architecture, and Guastavino was soon commissioned other projects including other factories (Vidal i fills, Martí i Rius, Carreras i fills, Modest Casademunt); a monument to “La Gloriosa” (the revolution that took place in Spain in 1868 and resulted in the deposition of Queen Isabella II) in plaça Nacional (currently plaça Reial); private houses in the Eixample (a city quarter whose main features are its grid pattern and square blocks; it was constructed during the second half of the 19th century between the old city and what were once surrounding small towns); and a theatre (Teatre La Massa) in Vilassar de Mar (a seaside village 25-km north from Barcelona), with a ca. 17-m-diameter flattened dome. In 1876, Guastavino presented the project “Improving Public Health in Industrial Towns” at the Exposition held in Philadelphia to commemorate the Centennial of the United States. His work was awarded a prize due to the advantages of the proposed technique, which was unexpensive and fire resistant. That recognition of his work encouraged him to migrate to the United States when his marriage broke down and his wife decided to leave for Argentina with three of their fourth children. Guastavino could see many opportunities in the United States, and in February 1881 he sailed from Marseille to New York with his nineyear-old Rafael Jr. (1872-1950) and the nanny, with whom it seems he had an affair, and her two children. Years later, he established a relationship with a Mexican woman, Francisca Ramírez, whom he described as his housekeeper. He married her when he learnt his first wife had died. Guastavino settled in the United States at the right moment, when the mark left by the Great Chicago Fire in 1871 stirred the use of fireproof building materials such as Portland cement, laminated steel and concrete to replace traditional wooden structures. Guastavino took advantage of that trend and patented fire-resistant building techniques and materials; by 1885 he had even registered the name “Construction of Fireproof Buildings”. In 1889 he founded the Guastavino Fireproof Construction Company, which soon had offices also in Boston and Chicago and collaborated with the major teams of architects in the Boston and New York www.cat-science.cat

areas. Since then, the term Guastavino vaults have identified a complex building process that oulived its founder, who was replaced by his son Rafael Guastavino Jr to take charge of the company. In addition, in the 1870s, neo-Romanesque and neo-Gothic architecture, based on large vaults, had become popular in the United States thanks to the work by architect Henry Hobson Richardson. However, there was not any tradition in using stone or bricks and most of the vaults in the buildings designed in those styles were made of plasterboard or plaster. Guastavino’s cohesive construction was thus a competitive alternative, but American architects were first reluctant to accept that construction system, even if it was guaranteed by the many works that Guastavino had carried out in the Barcelona area, and by letters of support he took with him from Barcelona. Guastavino was a tenacious man and publicized himself through his monthly contributions to a magazine on architecture and decoration (Decorator and Furnisher, 1881–1883) and by wining the competitions to construct several buildings in New York.

Fig. 3. Guastavino standing up on a newly built arch during the construction of the Boston Public Library, 1889. (Image courtesy of Boston Public Library, "Boylston Street" August 31, 2006 via Flickr, Creative Commons Attribution).

Fig. 4. View of a vault in the Basilica of St. Lawrence in Asheville, NC (Image courtesy of Jacqueline Poggi, “Basilica of St Lawrence” October 16, 2011 via Flickr, Creative Commons Attribution).

111

CONTRIBUTIONS to SCIENCE 9 (2013) 109-112

The American dream of Rafael Guastavino (1842–1908)

lished. In his seminal book Essay on the theory and history of cohesive construction, applied especially to the timbrel vault (Ticknor, Boston, 1892), he described this technique, its history and the theory in which it was based, its advantages and its potential applications to all kinds of buildings. Immigrants that entered the United States from 1916 to 1954 through Ellis Island surely did not know that the Registry Hall of that immigrant inspection station had been constructed by a company funded by a man that, like themselves, arrived once to the United States with a dream. Guastavino’s dream was of another kind, however. Whereas they wanted to find in America a way of life, sometimes even just surviving, Guastavino dreamt of introducing in the United States a construction style that had been in use for centuries in the Mediterranean region. He succeeded indeed in his dream, and his name and work are now part of the history of the United States architecture.

Guastavino’s first major project in the United States was the Boston Public Library (1889, Fig. 3), which he carried out in collaboration with the architectural firm McKim, Mead and White and brought him great prestige. When he died in 1908—in his home in Asheville, North Carolina, where he had bought a estate—the company, which had already become “Guastavino and Company”, was about to start building the great 40-m-diameter dome of Saint John the Divine Cathedral in New York. Guastavino and Company was a thriving firm until the 1930s, when it started a gradual decline due to several factors including the growing use of reinforced concrete, architectural trends that favoured an angular style, and the fact that the tile arched system was labour intensive and expensive. The company eventually closed in 1962, and its archive was transferred to the Avery Library, in Columbia University. More than 600 vaults built in the United States by the company funded by Guastavino have survived, including those of the two above mentioned Boston Public Library and the Ellis Island Registry Hall, and those of the New York University, Bronx, New York; Institute of Art and Sciences, Brooklin, New York; Bank of Montreal, Canada; Madison Square Presbiterian Church, New York; City Hall Subway Station, New York; St. Paul’s Chapel, Columbia University, New York; Rodef Sholem Synagogue, Pittsburgh, Pennsylvania; McKinley National Memorial, Canton, Ohio Oyster Bar in Grand Central Terminal, New York; Basilica of St. Lawrence, in Asheville, North Caroline (Fig. 4); Elephant House, Bronx Park, New York; the Smithsonian Museum, Washington D.C.; Girard Trust and Company, Philadelphia, Pennsylvania; and Cathedral of St. John the Divine, New York. When, in 1967, the American Institute of Architects listed the most important buildings in Manhattan built over the previous thirty years, more than half of the 22 that had been built before War World II were works by Guastavino and Company. Rafael Guastavino was not only a builder, he was a man of science. He did theoretical an empirical studies, which he made public mostly through lectures, which were later pub-

www.cat-science.cat

Bibliography García-Gutiérrez Mosteiro J (2003) The adventure of Guastavino vaults. In: Huerta S (ed) Proceedings of the First International Congress on Construction History, Madrid 20-24 January 2003, pp. 957-964 Huerta S, López G, Redondo E (2001) Selected, annotated bibliography on Guastavino and the timbrel vaulting (In Spanish) In: Huerta S (ed) Las bóvedas de Guastavino en América, Instituto Juan Herrera, Madrid, pp 373-393 Rosell i Colomina J (1995) Rafael Guastavino i Moreno: enginy en l’arquitectura del segle xix. In: Camarasa JM, Roca A (eds) Ciència i Tècnica als Països Catalans: una aproximació biogràfica. Fundació Catalana per a la Recerca, Barcelona, pp 494-522. (In Catalan; English translation available at: http://tinyurl.com/o5sd92b)

Websites on Guastavino’s work Guastavino.net, web of the Guastavino Project at the Massachusetts Institute of Technology, dedicated to documenting and preserving the tile vaulted works of the Guastavino Company. http://architecture.mit.edu/class/ guastavino “The reinvention of public space in New York City”, website of the exhibition held in Valencia, Guastavino’s hometown, in 2009, promoted by the Autonomous Government of Valencia. http://www.rafaelguastavino. com/en/

112

CONTRIBUTIONS to SCIENCE 9 (2013) 109-112

Institute for Catalan Studies

The Institute for Catalan Studies (IEC), academy of sciences and humanities, founded in 1907, is the top academic corporation of the territories of Catalan language and culture, and has been a full member of the International Academic Union since 1922. The IEC has 186 full or emeritus members from throughout the linguistic territory, and 72 corresponding members that represent our institution’s relations with the international scientific community, and has 28 filial societies of all fields of knowledge, with a total membership of around 10,000 across the whole territory. In addition, 111 local research centres also belong to it, and this shows how well grounded the research community is, throughout our cultural territory. The IEC is the central institution in the Catalan cultural world. It was set up in 1907 at the initiative of the Diputació de Barcelona to “establish here scientific study centres specialising and working not just in education, but in producing science and aiding research.” In the following years, the Institute set up its various science departments. The Philology Department, directed by Pompeu Fabra, played a key role in establishing the rules of the Catalan language.

Instructions to authors General Contributions to Science publishes two kinds of articles, specialized reviews and general articles on scientific and technological research (see front cover). Submission of manuscripts Manuscripts submissions are preferably made online, at the journal’s website. Authors are asked to upload the items and provide associated metadata or indexing information to facilitate online searching and for the journal’s own use. Articles can be tracked at any time through the editorial process, and authors can participate in the copy-editing and proofreading of articles accepted for publication by logging in with the username and password provided. Contributions to Science does not charge publication fees. However, processing fees may be requested if the manuscript needs substantial languageediting and copyediting. The amount requested will not depend on the length of the manuscripts but on the time devoted to their editing. In special cases, processing fees can be waived. In no case will the acceptance of manuscripts depend on the authors possibility to pay processing fees. Format of manuscripts All contributions should be typed double-spaced (including references and figure legends) on pages not exceeding 30 cm in height (standard A4 is appropriate), with wide margins, and font (preferable Times New Roman) size not smaller than 12 points. If Greek letters (α, β, χ , et cetera) are required, use the “insert symbol” function to write them. It is the policy of the Journal to publish in English only (authors are recommended to have the manuscript thoroughly checked and corrected before submission). The Editors will warmly appreciate co-operation of authors in preparing papers in a manner that will facilitate the work of editing and publication. For research papers a self-explanatory abstract without reference to the text—in Catalan language, too—not exceeding 200 words should be provided. It is essential that the author responsible for post publication correspondence (the Corresponding author) should be identified on the manuscript. Manuscript organization The manuscript should begin with the following: 1. Title of the paper containing keywords pertaining to the subject matter. No abbreviations should be used in the title. 2. Author full names (including forenames and initials, if used) and their affiliations. If the publication originates from several institutes the affiliations of all authors should be clearly stated by using superscript numbers after the name and before the institute. 3. Postal address of the author to whom all correspondence (including preprints) is to be sent. Telephone and fax numbers as well as e-mail address should be included to speed up communication. 4. A summary (in English and Catalan languages) not exceeding 200 words. 5. A maximum of 5 keywords, which will be used for compiling the subject index. References References should be cited in the text in square brackets and listed at the end of the paper in alphabetical order. Papers not yet published but accepted by a journal may be cited with the journal’s name followed by “in press”. However, this practice is acceptable only if that author has at least received preprints of the paper. In all other cases, reference must be made to “unpublished data” or “personal communication”.

Accepted unpublished papers Same as above, but “in press” must appear instead of the volume and page numbers Books Miller JH (1972) Experiments in molecular genetics. 2nd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York Book chapters Lo N, Eggleton P (2011) Termite phylogenetics and co-cladogenesis with symbionts. In: Bignell DE, Yves R, Nathan L (eds) Biology of termites: a modern synthesis, 2nd ed. Springer, Heidelberg, Germany, pp 27-50 Electronic journal articles Citation of articles published in electronic-only journals must provide a DOI (preferable) or URL if they do not have traditional page numbers or electronic article identifiers. For all references, list the first eight authors and then add “et al.” if there are additional authors. Since references that are downloaded from online databases do not always show accents, italics, or special characters, the authors should refer to the PDF files or printed versions of the articles and correct accordingly the submitted manuscript. The journal titles should be abbreviated. Tables Tables should be compiled on separate sheets (one per page table) with a concise, descriptive title and numbered independently of the figures using Arabic numerals in the sequence in which they occur. Every table must be referred to in the text. In the text, the position for a table is to be marked by “Table...” in the middle of an extra line. The caption must explain in detail the contents of the table. As for the table itself, it must be written so that it can be read and understood without reference to the text. References to a table are to be handled in the same way as references to the text (see References). Figures Figures, including photographs should also be submitted on separate pages at the end of the article (new page for each figure). In addition, they must be submitted also in JPG separate files with a resolution of 300 dpi. Figures should be numbered consecutively with Arabic numbers in the order of their appearance. A separate file of fine quality suitable for reproduction is required. Figures should not be larger than the manuscript page. Numbers and symbols inscribed must be large enough to be legible after reduction. If a figure comprises several separate parts, a single composite illustration containing all parts of the figure must be submitted. It is the responsibility of the author(s) to obtain the required permissions to reproduce figures and other material that has been published previously, and the source should be always indicated in a reference. The permission must be obtained from the publishers or where they credited to third parties, from those third parties.

References should be in the following style:

Nomenclature, abbreviations and units Internationally standardized nomenclature should be used. Abbreviations and acronyms should be kept to a minimum and spelled out in full at first mention in both the summary and main text. Non-standard abbreviations should be avoided if they appear not more than three times in the text. Only SI units are to be used (SI = Système International d’Unités). If data with non-SI units are to be reported, they should be put in parenthesis behind the corresponding data in SI units.

Published papers Venugopalan VP, Kuehn A, Hausner M, Springael D, Wilderer PA, Wuertz S (2005) Architecture of a nascent Sphingomonas sp. biofilm under varied hydrodynamic conditions. Appl Environ Microbiol 71:2677-2686

Acknowledgements Acknowledgements to individuals that have contributed to the study and are not named as authors as well as information regarding funding sources should be included in this sections after the main text (before References).

CONTRIBUTIONS to SCIENCE | VOLUME 9 | ISSUE 1 | JUNE 2013 Institut d’Estudis Catalans, Barcelona, Catalonia

FOREWORD

57 Multidisciplinary approaches towards compartmentalization in development: Dorsoventral boundary formation of the Drosophila wing disc as a case study

DISTINGUISHED LECTURES

Jiménez-Valerio G, Casanovas O 67 Anti-angiogenic therapy for cancer and the mechanisms of tumor resistance

1 Tort L The Catalan Society for Biology

Ramon Margalef Award for Ecology 2012

5 Pretus JL Daniel Simberloff: Creative and devastating

RESEARCH REVIEWS

7 Simberloff D Biological invasions: Much progress plus several controversies

The Nobel Prizes of 2011

17 Piniella JF Crystallography and the Nobel Prizes: On the 2011 Nobel Prize in Chemistry, awarded to Dan Shechtman

The Nobel Prizes of 2012

25 Franco R, Aymerich MS Smart cell-surface receptors: On the 2012 Nobel Prize in Chemistry, awarded to Robert J. Lefkowitz and Brian K. Kobilka Mompart J 33 The Gedankenexperimente of quantum mechanics become reality: On the 2012 Nobel Prize in Physics, awarded to Serge Haroche and David J. Wineland

Celebration of the Centennial of the Catalan Society for Biology, 1912–2012

Clotet J 43 First International Conference of Biology of Catalonia (CIBICAT) , ‘Global questions on advanced biology’ (Barcelona, July 9–12, 2012)

Escalas Llimona R 75 Temperament and tuning of early 19th century Hispanic keyboard instruments: A study of the monochord integrated into a fortepiano made by Francisco Fernández (1828) Salat J, Umbert M, Ballabrera-Poy J, Fernández P, Salvador 89 K, Martínez J The contribution of the Barcelona World Race to improved ocean surface information. A validation of the SMOS remote sensed salinity

FORUM

Nair P 101 The United Nations University Institute on Globalization, Culture and Mobility (UNU-GCM) in Barcelona: Mission and vision Puche C 107 The Institute for Catalan Studies and the International Women’s Day, 2006–2013

HISTORICAL CORNER

Piqueras M 109 The American dream of Rafael Guastavino (1842–1908)

Casadesús J 51 Bacterial pathogenesis as an imperfect symbiosis Buceta J

Rafael Guastavino (Valencia 1842–Asheville, NC, 1908)

OPEN ACCESS JOURNAL www.cat-science.cat http://revistes.iec.cat/contributions