Contributions to Science

CONTRIBUTIONS to

SCIENCE Volume 8 Issue 2 December 2012

From genes to jeans: challenges on the road to personalised medicine. Annual Conference of the European Parliamentary Technology Assessment (EPTA) Network, Barcelona 2012

Barcelona • Catalonia

CONTRIBUTIONS to

SCIENCE

Free online access via www.cat-science.cat http://revistes.iec.cat/contributions/

CONTRIBUTIONS TO SCIENCE The International Journal of the Biological Sciences Section and the Science and Tech­ nology Section of the Institute for Catalan Studies (IEC). www.iec.cat Contributions to Science is also available on­line at: www.cat-science.cat http://revistes.iec.cat/contributions/

Cover: The Session Chamber of the Parlia­ ment of Catalonia. The building of the Palace of the Parliament is the former arsenal of the citadel built by order of Philip V in the begin­ ning of the eighteenth century to dominate Barcelona. The old armory was transformed into a royal palace in the late nineteenth cen­ tury. The photograph corresponds to the room where the plenary sessions of the Parliament of Catalonia are celebrated. Although it was originally designed by Pere Falqués as the Throne Room, in 1932 it was enabled as the site of the Parliament. Originally it was fur­ nished with seats in a U-shape, but the fol­ lowing year, the designer Santiago Marco modified the layout and transformed it into a hemicycle. Since the Parliament of Catalonia was restored in 1979, it has been renewed several times to incorporate new technolo­ gies and to make it accessible for people with disabilities.

ISSN print edition: 1575-6343 ISSN electronic edition: 2013-410X Legal Deposit: B. 36385-1999

Contributions to Science is an open access journal that aims to promote the international dissemination of scientific research per­ formed 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 scien­ tific 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 scien­ tists from such countries.

Preference will be given to original articles in the form of critical reviews that deal with the present state of a scientific field of current in­ terest, by one or several authors. Such arti­ cles 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 Cat­ alonia and its areas of influence.

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 back cover of each issue.

PUBLISHER AND ADVERTISEMENTS All business correspondence, reprint re­ quests, requests for missing issues, per­ mission from the Publisher to reproduce published material and information on adver­ tisements should be addressed to the Pub­ lishing De­part­ment.

SUBSCRIPTIONS Volume 8 (2 issues).

Subscription orders should be sent to the Publishing Departament.

The subscription fee for two issues (including handling charges) is 75 Euros (VAT not included).

Airmail charges are available on request.

COPYRIGHT AND RESPONSIBILITIES

This work including photographs and other illustrations, unless the contraty is indicated, is subjected to an Attribution—Non-Commercial—No Derivative Works 3.0 Creative Commons License, the full text of which can be consulted at http://creativecommons. org/licenses/by-nc-nd/3.0/. You are free to share, copy, distribute and transmit the work provided that the author is credited and reuse of the material is restricted to non-com­ mercial purposes only and that no derivative works are created from the original material.

ADDRESSES Contributions to Science Institut d’Estudis Catalans Carrer del Carme, 47 E-08001 Barcelona, Catalonia, EU Tel. +34 932701620 Fax +34 932701180 Email: contributions@iec.cat Publisher Institut d’Estudis Catalans Editorial Office Nicole Skinner, Managing Editor Wendy Ran, Copy-editing services Estudi Puche S.L., Layout

Printed in Catalonia

CONTRIBUTIONS to

SCIENCE Volume 8 Issue 2 December 2012

From genes to jeans: challenges on the road to personalised medicine. Annual Conference of the European Parliamentary Technology Assessment (EPTA) Network, Barcelona 2012

Special Issue

CAPCIT Consell Assessor del Parlament sobre Ciència i Tecnologia

CAPCIT Consell Assessor del Parlament sobre Ciència i Tecnologia

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CONTRIBUTIONS to

SCIENCE

Free online access via www.cat-science.cat http://revistes.iec.cat/contributions/

CONTRIBUTIONS TO SCIENCE The International Journal of the Biological Sciences Section and the Science and Tech­ nology Section of the Institute for Catalan Studies (IEC). www.iec.cat Contributions to Science is also available on­line at: www.cat-science.cat http://revistes.iec.cat/contributions

Cover: The Session Chamber of the Parlia­ ment of Catalonia. The building of the Palace of the Parliament is the former arsenal of the citadel built by order of Philip V in the begin­ ning of the eighteenth century to dominate Barcelona. The old armory was transformed into a royal palace in the late nineteenth cen­ tury. The photograph corresponds to the room where the plenary sessions of the Parliament of Catalonia are celebrated. Although it was originally designed by Pere Falqués as the Throne Room, in 1932 it was enabled as the site of the Parliament. Originally it was fur­ nished with seats in a U-shape, but the fol­ lowing year, the designer Santiago Marco modified the layout and transformed it into a hemicycle. Since the Parliament of Catalonia was restored in 1979, it has been renewed several times to incorporate new technolo­ gies and to make it accessible for people with disabilities.

ISSN print edition: 1575-6343 ISSN electronic edition: 2013-410X Legal Deposit: B. 36385-1999 A2

Contributions to Science is an open access journal that aims to promote the international dissemination of scientific research per­ formed 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 scien­ tific 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 scien­ tists from such countries.

Preference will be given to original articles in the form of critical reviews that deal with the present state of a scientific field of current in­ terest, by one or several authors. Such arti­ cles 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.

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 back cover of each issue.

PUBLISHER AND ADVERTISEMENTS All business correspondence, reprint re­ quests, requests for missing issues, per­ mission from the Publisher to reproduce published material and information on adver­ tisements should be addressed to the Pub­ lishing De­part­ment.

SUBSCRIPTIONS Volume 8 (2 issues).

Subscription orders should be sent to the Publishing Departament.

The subscription fee for two issues (including handling charges) is 75 Euros (VAT not included).

Airmail charges are available on request.

COPYRIGHT AND RESPONSIBILITIES

This work including photographs and other illustrations, unless the contraty is indicated, is subjected to an Attribution—Non-Commercial—No Derivative Works 3.0 Creative Commons License, the full text of which can be consulted at http://creativecommons. org/licenses/by-nc-nd/3.0/. You are free to share, copy, distribute and transmit the work provided that the author is credited and reuse of the material is restricted to non-com­ mercial purposes only and that no derivative works are created from the original material.

ADDRESS Contributions to Science Institut d’Estudis Catalans Carrer del Carme, 47 E-08001 Barcelona, Catalonia, EU Tel. +34 932701620 Fax +34 932701180 Email: contributions@iec.cat Publisher Institut d’Estudis Catalans Editorial Office Nicole Skinner, Managing Editor Wendy Ran, Copy-editing services Estudi Puche S.L., Layout

Printed in Catalonia

CONTRIBUTIONS to

SCIENCE Volume 8 Issue 2 December 2012

Editor-in-chief Ricard Guerrero Department of Microbiology University of Barcelona

Associate Editor Salvador Alegret

Founder Editor Salvador Reguant

Department of Chemistry Autonomous University of Barcelona

Department of Stratigraphy and Paleontology University of Barcelona

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. García-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 • Federico Mayor-Zaragoza, Foundation for a Culture of Peace (Madrid) • Joan Massagué, Memorial Sloan-Kettering Cancer Center, New York (USA) • 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) • Manuel Ribas-Piera, Technical University of Catalonia • 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

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CONTRIBUTIONS to SCIENCE Institut d’Estudis Catalans, Barcelona

contents Volume 8 Issue 2

December 2012

de Gispert N

119

foreword Parliamentary Technology Assessment

Cope D

121

Forty years on

Domínguez García F

131

CAPCIT: The Advisory Board of the Parliament of Catalonia for Science and Technology Annual Conference of the EPTA Network 2012

Castellà A, Aymerich M

137

Presentation Keynote Lectures

Vendrell M

139

Personalised medicine: needs, challenges, and considerations

Esteller M

145

Forecasting limits in personalised medicine

de Solà-Morales O

149

Sustainability of personalised medicine Genetic and Socio-Cultural Risk Contributions to Disease

Beato M

155

What is our level of knowledge about the genome today?

Salas E

161

Complex diseases: the relationship between genetic and sociocultural factors in the risk for disease Bioethics and Social Responsabilities

Granados A

167

Challenges for industry developers

Camí J

171

Bioethical challenges in personalised medicine Global Implications of Personalised Medicine

Plasència A

175

Global health challenges and personalised medicine

Cardona P-J

181

Will personalised medicine be the key to eradicating TB?

Guerrero R

187

Conclusions

189

Participants of the Annual Conference of the EPTA Network 2012 “From genes to jeans: challenges on the road to personalised medicine”

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CONTRIBUTIONS to SCIENCE, 8 (2): 119–120 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.142 ISSN: 1575-6343 www.cat-science.cat

Pròleg Foreword El congrés «From jeans to genes: challenges on the road to per­ sonalised medicine», celebrat en el marc de la reunió anual de la Xarxa Europea d’Assessorament Tecnològic als Parlaments (European Parliamentary Technology Assessment, EPTA) a Barcelona el 23 d’octubre de 2012, reconeix la importància del camp de la medicina personalitzada que es desenvolupa ràpi­ dament, i que ja s’ha establert a Catalunya gràcies a moltes con­ tribucions rellevants del país. Però, sobretot, la medicina perso­ nalitzada és una fita del futur que s’està construint. La medicina serà cada cop més personalitzada. A mesura que els metges adoptin cada vegada més aquest enfocament, es donarà una nova interpretació i vigència al vell aforisme mèdic: «no hi ha ma­ lalties sinó malalts». De fet, el camp de la medicina passarà de ser reactiva a ser proactiva i preventiva. La recerca en medicina personalitzada ha de permetre tractaments més eficaços i, en conseqüència, una millora de l’atenció sanitària. L’impuls i els assoliments en aquest camp són una altra mostra del paper tan rellevant que assumeix la ciència en la preservació de la dignitat humana i en la millora del nostre entorn, perquè posa les perso­ nes al centre del procés assistencial.

El Parlament de Catalunya, la seu d’aquest congrés anual de la xarxa d’EPTA, és un edifici molt singular, la història del qual explica els últims tres segles de la història de Catalunya.

Tot i que fou construït com l’arsenal d’una ciutadella militar, la seva funció no era la defensa de Catalunya, sinó la de contro­ lar-la després de la derrota en la Guerra de Successió espa­ nyola (1701–1714). Barcelona, que havia donat suport a la rei­ vindicació al tron espanyol feta per l’arxiduc Carles d’Àustria, finalment es va rendir a l’exèrcit borbònic l’11 de setembre de 1714, després d’un llarg setge que va acabar amb la presència dels aliats d’Espanya. Aquest dia és recordat com la Diada Na­ cional de Catalunya. En aquell moment, el rei Felip V va orde­ nar la construcció del parc de la Ciutadella, on està ubicat el palau, com a instrument de repressió.

Abans d’esdevenir la seu del Parlament, el 1932, durant el Govern de la Generalitat de la Segona República— en el qual totes les regions d’Espanya tenien el dret a l’autonomia— i de nou a partir de 1980, aquest edifici va ser primer un Palau Reial i més tard un museu d’art. Així, al setembre de 2012, quan es va celebrar el Dia Nacional de Catalunya, també vam celebrar el vuitantè aniversari del palau com a seu del poder legislatiu cata­ là. La conferència d’EPTA a Barcelona per tant es va dur a terme durant un moment històric i excepcional per a tots els catalans.

En programar aquestes activitats, no podíem haver previst que ens trobarien al mes d’octubre amb la legislatura acabada i amb la convocatòria anticipada d’eleccions per al 25 de novem­ bre. Aquesta novena legislatura es va iniciar al novembre i havia d’acabar quatre anys després, és a dir, el 2014. Diferents esde­ veniments importants van fer que el president de Catalunya anti­ cipés les eleccions. L’11 de setembre de 2012, més d’1,5 mili­ ons de persones van manifestar-se pels carrers de Barcelona.

Per a un país petit com Catalunya, amb una població de 7,4 mi­ lions d’habitants això va ser notable. Mai havien sortit al carrer

The conference ‘From jeans to genes: challenges on the road to personalised medicine,’ in the framework of the annual meeting of the European Parliamentary Technology Assessment (EPTA) network in Barcelona on 23 October 2012, acknowledges the importance of this rapidly developing field, which has already be­ come established in Catalonia, through the country’s many sig­ nificant contributions. But mostly, personalised medicine is a landmark of the future currently under construction. As physi­ cians increasingly adopt this approach, a new interpretation and validity will be given to the old medical aphorism, “there are no diseases, only sick people.” Indeed, the field of medicine will shift from being reactive to being proactive and preventive. Research in personalised medicine will allow for more effective treatments and, consequently, an improvement in the quality of healthcare.

The momentum and achievements in this field, in these still early stages, are a good example of the role that science assumes in preserving human dignity, by putting people at the centre of the healthcare process.

The Parliament of Catalonia, the site where this annual EPTA conference was held, is a very unique building whose own his­ tory explains the last three centuries of Catalonian history. Al­ though it was built as the arsenal of a military fortress, its function was not to defend Catalonia but to control it after its defeat in the War of the Spanish Succession (1701–1714). Barcelona, which had supported the Archduke of Austria’s claim to the Spanish throne, finally surrendered to the Bourbon army on 11 Septem­ ber 1714, following a long siege that ended with the presence of the allies in Spain. This day is remembered as the National Day of Catalonia. At that time, King Philip V ordered the construction of the Ciutadella park, the location of the palace, as an instru­ ment of repression.

Before becoming the Parliamentary headquarters, in 1932, during the Government of Catalonia of the Second Republic—in which all of Spain’s regions had the right to autonomy—and again beginning in 1980, this building was first a Royal Palace and later on an art museum. Thus, in September 2012, when we celebrated the National Day of Catalonia, we also celebrated the palace’s 80th anniversary as the headquarters of the Catalan legislature. The EPTA conference in Barcelona therefore took place during an exceptional, historic moment for all Catalans.

In scheduling these activities, we could not have foreseen that in October 2012 the Parliament would cease meeting and early elections would be held in November, since the 9th legis­ lative term began in December 2010 and was expected to fin­ ish, as always, four years later, in this case in 2014. Several important events led the Catalan President to anticipate the elections. On 11 September 2012, more than 1.5 million peo­ ple marched through the streets of Barcelona. For a small country like Catalonia, with a population of 7.4 million people, this was remarkable. Never had so many Catalans taken to the streets in such a festive, democratic, and civic manner, but nonetheless with an undeniably assertive tone. They came out to demand wider freedoms, claiming their right to decide Cata­

120 Contrib. Sci. 8 (2), 2012 

d’una manera festiva, democràtica, cívica, i amb un to innega­ blement reivindicatiu tants catalans. I van sortir per demanar més drets i llibertats, reclamant el seu dret a decidir el seu futur com a poble. Després de trenta anys d’estat autonòmic a Espa­ nya, i després de trenta anys de tenir una autonomia insuficient per a la voluntat del propi poble de Catalunya, després del col· lapse d’aquest sistema autonòmic, el que ha volgut i el que vol el poble de Catalunya és clarificar el seu estatus jurídic, polític i constitucional. I va ser per aquesta raó que el president de la Generalitat de Catalunya va dissoldre el Parlament i va convocar eleccions anticipades.

En tot cas, vull fer arribar un missatge de pau alhora que els demano que el transmetin als seus col·legues i conciutadans.

Els catalans som on sempre hem estat. Som una nació d’Euro­ pa, som un país de pau i de concòrdia, amb una llengua prò­ pia, el català, parlada per 10 milions de persones, amb una cultura i una identitat diferenciada, que ha tingut unes instituci­ ons molt antigues d’autogovern i basades en el pactisme. És important saber que el primer president de la Generalitat de Catalunya va ser escollit al segle XIV, el 1359. Catalunya té una identitat històrica diferenciada, i és per això que sempre hem defensat que Catalunya és una nació, una nació sense estat, però una nació que té el desig de poder decidir el seu futur.

Som un poble que aspira a contribuir al benestar comú i al pro­ grés d’un ideal de construcció europea que la uneixi i l’enfortei­ xi des de la seva rica diversitat. En aquest marc, no hauria de sorprendre a ningú que ens plantegem el nostre dret legítim i democràtic a decidir el nostre futur com a poble.

Vivim també moments de turbulències econòmiques. Tenim molt clar que de la crisi hem de saber fer oportunitat. Ens els àmbits de recerca, innovació, talent, etc., per progressar cal optimitzar recursos i donar suport a l’excel·lència, cal concen­ trar esforços en aquells projectes que sobresurtin i demanar la implicació del món empresarial i de l’economia productiva, i també l’activisme de la societat civil. Hi ha molts exemples a Catalunya en els quals allò que no han pogut fer les estructures públiques ho ha fet la societat civil catalana. És un projecte de país i no pas del govern de torn, no és un caprici d’alguns sinó una necessitat de tothom. La ciència i la tecnologia són motors econòmics i socials que contribueixen al prestigi de les naci­ ons, petites o grans, que han apostat per l’economia del co­ neixement, com ha estat el cas de Catalunya des de fa anys. El nostre país vol pertànyer a aquest grup selecte de nacions ben posicionades davant els reptes del segle XXI. La ciència i el seu mètode ens donen vies positives per encarar el futur. Totes dues ens ensenyen a fer-nos les preguntes pertinents i no pas a imposar respostes. I totes dues emfatitzen la importància de tenir una mentalitat oberta i un tarannà constructiu i també do­ nar protagonisme a la creativitat i a la innovació.

Desitjo que el treball i els debats han sorgit d’aquesta reunió d’EPTA serveixin per estrènyer relacions entres les entitats i les persones participants i els governs que representen i, alhora, per afirmar el valor de l’assessorament en matèria científica i tecno­ lògica per la millora de la qualitat legislativa i de l’activitat parla­ mentària, però també per a la difusió del coneixement científic.

lonia’s future as a country. After 30 years of state autonomy in Spain—30 years of insufficient autonomy, in which the will of the people of Catalonia was ignored—and after the collapse of the autonomic system, the Catalan people have always sought and continue to seek a clarification of their legal, political and constitutional status. It was for this reason that the President of the Government of Catalonia dissolved the Parliament of Cata­ lonia and called early elections.

In any case, I want to leave a message of peace that I ask you to convey to your colleagues and fellow citizens. Catalans are where they have always been. We are a European nation, a country of peace and harmony, with its own language, Catalan, spoken by 10 million people, with a distinct culture and identity, with its own, very old, self-governance institutions founded on formal pacts. It is important to know that the first President of the Government of Catalonia was elected in the 14th century, in 1359. Catalonia has a distinct historical identity, which is why its citizens have always argued that it is a nation, a nation with­ out a state, but a nation with a desire to decide its own future.

We are a nation that aspires to contribute to the welfare and progress of a common ideal of European integration, uniting and strengthening it through its own rich diversity. Accordingly, it should come as no surprise that we consider it to be our le­ gitimate and democratic right to decide and redefine our future as a people.

We also live in times of financial and economic turmoil. We are convinced that the crisis is also a moment of opportunity. In terms of research, innovation, talent, etc., progress requires that we optimise our resources and support excellence, con­ centrating our efforts on those projects that stand out and de­ manding the involvement of the private sector, the productive economy, and civil society in their success. There are many examples in Catalonia in which goals that could not be achieved by public structures were adopted as the responsibil­ ity of Catalan civil society. This is the task of a country, not of the latest government in power, it is not the whim of a few, it is a universal need. Science and technology are social and eco­ nomic engines that contribute to the prestige of nations, whether large or small, that have opted for a knowledge-based economy, as has long been the case in Catalonia. The country seeks to belong to the select group of nations that are well po­ sitioned to meet the challenges of the 21st century. Science and the scientific method have given us positive ways to face the future. Both teach us how to ask the right questions and how to avoid imposing pre-formed answers. And both empha­ sise the importance of keeping an open mind and a construc­ tive spirit as well as the need to grant creativity and innovation the recognition that they deserve.

It is my wish that the work and discussions that have arisen from this EPTA meeting strengthen the relationships between the relevant institutional entities and the governments represent­ ed by the meeting’s participants, and affirm the value of scientific and technological advice in improving not only the quality of leg­ islative and parliamentary activity, but also the dissemination of scientific knowledge.

Núria de Gispert Presidenta, Parlament de Catalunya

Núria de Gispert President, Parliament of Catalonia

CONTRIBUTIONS to SCIENCE, 8 (2): 121–130 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.143 ISSN: 1575-6343 www.cat-science.cat

Parliamentary Technology Assessment

Forty Years On David Cope Clare Hall, University of Cambridge, Cambridge, England

Resum. Amb motiu de la celebració del quarantè aniversari de la creació de l’Oficina d’Assessorament en Tecnologia del Congrés dels Estats Units, aquest article examina què és l’as­ sessorament científic i tecnològic als parlaments (PTA). Primer fa una revisió d’exemples de protoassessorament parlamenta­ ri que es remunten cent cinquanta anys enrere i, a continuació, examina alguns dels èxits de l’actual PTA, així com alguns dels desafiaments que continua afrontant. L’article conclou amb di­ verses recomanacions sobre cap a on convindria que evoluci­ onés el PTA els propers anys.

Paraules clau: assessorament tecnològic ∙ Xarxa Europea d’Assessorament Tecnològic als Parlaments (EPTA) ∙ Oficina d’Assessorament Tecnològic (OTA) ∙ Oficina Parlamentària de Ciència i Tecnologia (POST) ∙ Consell Assessor del Parlament sobre Ciència i Tecnologia (CAPCIT)

Introduction The title of this paper is that of a famous English school song, itself actually written some 140 years ago. The song has a du­ ality to its lyrics which is perhaps also appropriate to the theme of this paper—and indeed to the entire volume. It encourages the current schoolboys (and yes, it has been invariably boys) to look forward to where they might be in forty years’ time, but it also urges those who are already that far on from their school­ days to look back, and to nurture the prospects of their suc­ cessors, the current generation of schoolboys.

Technology assessment: a retrospective Just under forty years ago, in January 1974, the Office of Technology Assessment (OTA) at the US Congress began its work, having been established by the Technology Assess­ ment Act of 1972 (Public Law 92-48). This Act was the culmi­ nation of at least five years of congressional discussion on the

Correspondence: D. Cope, Clare Hall, Herschel Road, Cambridge CB3 9AL, United Kingdom. Tel. +44-2078286635. Fax +442076301326. E-mail: drc48@cam.ac.uk

Summary. Motivated by the fact that 2013–2014 sees the 40th anniversary of the creation of the Office of Technology As­ sessment at the US Congress, this paper looks at what has come to be called Parliamentary Technology Assessment (PTA). It reviews some examples of proto-technology assess­ ments with parliamentary links, going back 150 years, before examining some of the successes of contemporary PTA as well as some of the challenges that continue to face it. It con­ cludes with several personal recommendations about how PTA might evolve in the coming years.

Keywords: technology assessment ∙ European Parliamentary Technology Assessment (EPTA) ∙ Office of Technology Assessment (OTA) ∙ Parliamentary Office of Science and Technology (POST) ∙ Advisory Board of the Parliament of Catalonia for Science and Technology (CAPCIT)

desirability of establishing a technology assessment (TA) function to support congressional activity. Even after its pas­ sage, issues remained about its financing and it was only in November 1973 that funds were secured to enable actual op­ erations to begin. The OTA published its first report, on Drug Bioequivalence, in July 1974.

Of course, the output of the US OTA was by no means the first manifestation of TA. In fact, before the OTA began its work, the British weekly journal New Scientist devoted a special sup­ plement to the theme of ‘Technology Assessment: a route through the chaos?’ in May 1973. This was informed by the plans for the OTA but drew also on what at the time were re­ cent explorations of TA in Europe and made reference to the then inchoate proposals for similar services at parliaments in Europe. Forty years on, it is well worth going back to the prog­ noses, expectations and admonitions contained in this supple­ ment to appreciate what has subsequently occurred [50].

It is a matter for probably never-ending discussion as to what was the very first TA. I think strong candidates are some of the British Royal Commission studies conducted at the turn of the 19th and 20th centuries [1], or the mid 19th century pio­ neering work of Baptiste Alexis Victor Legrand, Director-Gen­ eral of the Ponts et Chaussées organisation in France, who in­ vestigated the feasibility of a national rail system and could be considered as the father of the French railways. Such studies

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have all the characteristics of what nowadays might be seen as ‘expert TA’. The British studies were conducted by a team of experts specially appointed for the purpose [2]. They assem­ bled prodigious amounts of statistical information and issued general calls for submissions from outside organisations but proceeded mainly through the examination of witnesses, simi­ lar to the main method today used by the Office Parlementaire d’Evaluation des Choix Scientifiques et Technologiques (OPECST) in its work for the French Houses of Parliament.

What is also interesting is that these early studies had parlia­ mentary links. British Royal Commissions formally report to the ‘monarch in Parliament’, while Legrand’s work was at the be­ hest of the Chambre des Députés and the Chambre des Pairs, then the two Houses of the French Parliament. He himself be­ came a member of the Chambre des Députés.

Looking at the USA, possibly not the first study that might be considered a TA, but certainly one of the most remarkable, was the 1937 report of the House of Representatives’ National Resources Committee’s Subcommittee on Technology, enti­ tled Technological Trends and National Policy, Including the Social Implications of the New Inventions. This study obviously had parliamentary origins. Not once in its 388 pages does the word ‘assessment’ occur, but that it was indeed a TA is indi­ cated by the letter that accompanied the report when it was submitted to the US President: “This document is the first major attempt to show the kinds of new inventions which may affect living and working condi­ tions in America in the next 10 to 25 years. It indicates some of the problems which the adoption and use of these inven­ tions will inevitably bring in their train. It emphasizes the im­ portance of national efforts to bring about prompt adjust­ ment to these changing situations, with the least possible social suffering and loss, and sketches some of the lines of national policy directed to this end.”

The antecedents of this gargantuan study are particularly in­ teresting. The USA (and indeed Europe) was fitfully emerging from the Great Depression. The technological transformation that would accompany WWII was some years off, and essen­ tially unanticipated [3]. At the height of the Great Depression, there was considerable Congressional discussion in the USA on the negative effects of technological developments (in par­ ticular, their impacts on employment) and even suggestions that all government investment in technological research and development be abandoned because of this [4].

I do not think that associated with the 19th or early 20th century studies or the US 1937 report there was any sense of the need for ‘permanent’ bodies to be attached to, or associ­ ated with, the parliaments to conduct assessments, justified by the singular importance of scientific and technological issues.

That would have to wait for the OTA. However, it could be ar­ gued that the OTA was closely ‘pipped’, at least in the field of environmental sciences, by the creation in the UK in 1970 of a standing (i.e. permanent) Royal Commission on Environmental Pollution (RCEP) [5]. This body was unfortunately abolished in a cost-saving move by the UK government in 2011.

Technology assessment: international to subnational One of the great strengths of European Parliamentary Technol­ ogy Assessment (EPTA) is that it has, as members, parliamentserving organisations at three levels of democratic governance: supra-national, through the European Parliament and its Sci­ ence and Technology Options Assessment (STOA), national, with various organisational forms, making up the majority of members and sub-national. This last, after the demise of the service at the Flemish Parliament, is represented solely (but for­ cibly) by the Advisory Board of the Parliament of Catalonia for Science and Technology (CAPCIT) in Catalonia. However, there are suggestions that the Wallonian Parliament in Belgium may step into the gap left by the ending of its Flemish sister in­ stitute [54].

The historical stimulus for the creation of sub-national TA offices has been that in some countries, responsibility for sci­ ence and technology policy is devolved to sub-national region­ al assemblies. Interestingly, there was some discussion a dec­ ade or so ago about the creation of a mini-OTA to serve the California State Legislature in the USA, although nothing be­ came of this. That legislature does, however, have a research office attached to its Senate (it is a bicameral legislature) that covers scientific and technological matters alongside others.

This actually predates the OTA, having been created in 1969.

Of course, with a population of 38 million, California might be seen as virtually a country in its own right, as only Germany, the UK, France, Italy and Poland (just), as EPTA member countries, have larger populations.

It is an interesting question whether sub-national democrat­ ic units, even if they do not have overarching responsibility for scrutinising science and technology policy, might create TA units. To be strictly analogous with the national, sub-national and EU units that constitute the membership of the EPTA, any such unit would need to serve the requirements of the ‘elected democratic assembly’, rather than the administration or, in common with several EPTA members, to do this at least to some extent while also serving an administrative entity (national government). Between 1965 and 1986, the then Greater Lon­ don Council (GLC) in the UK had a Research and Intelligence Unit [6]. Interestingly, this was created specifically at the rec­ ommendation of a Royal Commission that looked at London government and noted the dearth of strategic intelligence and analysis for the metropolis as a whole. This unit was an agency of the administration but enjoyed support and patronage from some enthusiastic Council members. It disappeared when the GLC was disbanded in 1986. For 14 years, there was no stra­ tegic authority for the Greater London area. Although one was recreated in 2000 and does do some analytical work, there is no contemporary unit with the full characteristics of the 1965– 1986 office. I have not been able systematically to explore whether there exist, anywhere else in the world, TA or quasi-TA units serving the ‘elected representatives of sub-national dem­ ocratic institutions’. For the moment it would seem that the California Senate unit mentioned above is the only example.

Closely linked to this matter of the geographic or compe­

Forty Years On

tence scale of parliamentary TA units is the matter of the focus of their studies. Many issues that fall within the purview of TA have international, if not global, dimensions. STOA at the Eu­ ropean Parliament naturally focuses its attention on matters over which the EU has (or aspires to have!) legislative compe­ tence. National parliamentary TA units in Europe also have to pay some attention to EU (or EEA) level considerations as the impacts of EU legislation can play out in quite distinctive ways in individual countries. Given the focus of concerns of national legislatures, the lion’s share of the work of most national TA institutes will be on matters that are on the immediate and short-term agendas of their respective parliaments. These may be quite distinctive. For example, the Greek Permanent Committee of Technology Assessment has paid attention to the subject of gold-mining in Greece, a matter that has been, and remains, far higher up the national agenda there than in any other European country. Some years ago, the UK Parlia­ ment desperately sought advice from the Parliamentary Office on Science and Technology (POST) on the latest technologies for marine oil-spill clean-up—a subject that clearly is unlikely ever to be at the top of the agenda in sister countries such as Switzerland or Austria.

However, even where competence remains firmly at a na­ tional level, given the ineluctable forces of globalisation, indi­ vidual national TA units are finding themselves focusing on similar or identical areas, including the common topics of ener­ gy security, impacts of information technology, biotechnology, and so on. The EPTA has been able, to some extent, to re­ spond to this phenomenon by conducting joint research, such as on information technologies and privacy. Beyond this, there have been joint explorations of procedures and methodolo­ gies, above all the Technology Assessment, Methods and Impacts (TAMI) study [37], which to some extent are being taken forward through the current PACITA (Parliaments and Civil So­ ciety in Technology Assessment) project [45].

Much more could be done in this respect, and more sys­ tematically, through greater coordination between individual EPTA members. Not only would this respond to (or even bet­ ter, anticipate) the manifestations of the globalisation process­ es mentioned above but it could also lead to economic efficien­ cies, which are much to be desired under the current circumstances. Thus, several EPTA members (for a host of reasons, it is unlikely that all EPTA members could ever, at any one time, universally collaborate in a project) might undertake to divide up the information-collection stages of a TA analysis, with common access to the resulting information bank for their individual use in preparing a national assessment.

One particular study that I would like to see pursued is meth­ odological or procedural rather than addressing a specific poli­ cy area. The legislatures of many (although not all) of the EPTA countries are composed of members who have been elected by specific parts of their countries, i.e. geographical constitu­ encies. Where this is the case, it is an oft-repeated truism that nothing captures the attentions of such members, if they are looking to be re-elected, more than matters that impinge spe­ cifically on those constituencies. Although involving considera­ ble data-crunching, it should be possible, given modern infor­

Contrib. Sci. 8 (2), 2012 123

mation technology techniques, to target some TA studies to specific features of particular constituencies, even across countries, at least within similar socio-geographical areas. This might most easily be done with environmentally-focussed studies. POST has already initiated some activity in this way, at the national level, within the UK. For example, a TA on invasive tree pests and diseases specifically targeted members of the House of Commons whose constituencies had above a certain proportion of their land area covered in woodland. Another study, on bio-digesters, was specifically aimed at the Members of Parliament in whose constituencies such facilities were ei­ ther under construction or planned (a fact that POST came to suspect was actually not known by some of them!)

There is no reason why such targeting should be restricted to an individual country, as the features of a bio-digester facility will be much the same, whether in the UK or Finland. Further­ more, such characterisation could go well beyond purely envi­ ronmental subjects. I think it could be hugely valuable to as­ semble information on jobs linked directly to various science- and technology-related sectors, because probably no single characteristic of a constituency engages parliamentary representatives looking to burnish their reputations more than employment. This could be done in sophisticated ways, for ex­ ample, related to employment catchment areas instead of the often rather arbitrary geographical boundaries of constituen­ cies. Furthermore, there could be all manner of other indicators related to other major themes of TA. For example, in the sociomedical area, studies on the characteristics of population age­ ing would have obviously greater specific relevance to those places within countries that are especially favoured by retirees.

Even in those democratic assemblies in which members are not elected by a geographically-based electoral system (or in­ deed, are not elected at all, as with the UK’s House of Lords) there may well be ways to link in other information that ties members’ interests to specific areas.

Normative or informative There is a rich diversity of institutional forms among the organi­ sations that collaborate within EPTA [7] but also a fairly definitive dichotomy. As a general rule, those parliamentary TA units that are closer to, or actually within, a parliament, institutionally es­ chew recommendations, while those with an external locus of­ ten seek to make recommendations. This rule breaks down significantly, however, on one side of the dichotomy, in that OPECST, which is certainly an internal institution of the Assemblée Nationale and Sénat in France, not only makes recommen­ dations but is unique among parliamentary TA institutions in be­ ing able directly to promulgate legislation in its parliament [8].

However, there is a general principle under which most TA units closely associated with their respective parliaments oper­ ate; namely, that it is for the ‘elected representatives’ and not the TA units to make and take forward recommendations. The understanding has come into being that TA institutions serve perhaps their highest purpose when they explore ‘options’ or ‘choices’. The word ‘options’ is codified in the very title of the

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European Parliament’s office. It is true, as a reading of the previ­ ous paragraph forcibly demonstrates, that the French parlia­ mentary office, although having the word ‘Choix’ in its title, most definitely does make recommendations. It has been explained to me that this is because the French word emphasises the act of choosing, whereas the word in English carries more of a con­ notation of embracing the range of entities on which the choos­ ing act is implemented. I think this helps to explain why, in Eng­ lish, the title ‘Science and Technology Options Assessment’ sounds correct, whereas the term ‘Science and Technology Choices Assessment’ sounds somewhat maladroit.

In fact, quite frequently, parliamentary TA institutions that are constrained from making recommendations—and whose mandate allows only the exploring of options—can make im­ plicit recommendations. If they present an assessment saying, in effect, (reductio ad absurdum) “there is Option A, and if it is adopted, or comes into being, the four horsemen of the apoca­ lypse will stalk our land for a century, but there is also Option B, which, if taken, will provide heavenly harmony and ambrosia for our population to dine on for the rest of their lives,” it is fairly clear what the preference of the TA institution is!

There is the strongest obligation on parliamentary TA institu­ tions to present to their parliamentary clients an exhaustive ex­ ploration of what the ‘most complete’ range of options actually is. An important point is that this applies even to those parlia­ mentary TA institutions that have the ‘luxury’ of concluding their report with recommendations. Obviously, all must exercise dis­ cretion on ruling out what options are unrealistic. For example, many TA institutions recently have been concerned with various aspects of the consequences of an ageing society. I am relieved (reductio ad absurdum) that none has (at least not yet?) present­ ed the ‘option’ of culling the national population of people over age 65! But, there is a huge range of economic, social, medical, biotechnological and other science and technology dimensions to that one issue for which they must provide an exegesis. TA institutions will always be under scrutiny from particular interests who will unfailingly argue that due recognition has not been given to an option favoured by those interests. Furthermore, any op­ tion invariably leads to second and higher order considerations [9]. TA institutions also have to explore these to their best en­ deavours, within the constraints of time and resources.

Those constraints, especially that of time, are probably the key characteristics that distinguish the products of parliamen­ tary TA institutions from more conventional academic analyses.

Parliamentarians are usually marching to a very rapid drumbeat. They want answers virtually as soon as they ask ques­ tions. To compound matters, those parliamentary TA units that conduct their own research are universally frugally provided with person-power, while those who contract-out research face the time constraints of that process.

A further consideration that impacts on the time of a TA pro­ duction process is the critical consideration of peer review.

Most [10] TA units subject their output to some form of external review. Certainly for POST, peer review at draft stage is a fun­ damental principle that is not compromised under any circum­ stance. Peer reviewers provide their services for free, and an inevitable consequence is that they must be allowed some time

to schedule their evaluations into their wider commitments.

In extremis, things can be fast-tracked as much as possible.

At POST, in the oil-spill case mentioned above, it would clearly have been of little use to parliamentarians to provide advice on best possible practices after potential coastal contamination had already occurred. Rather, the mini-TA was produced in the space of a week, with peer reviewers lined up and ready to go beforehand [51]. However, this was a frenetic pace that obvi­ ously cannot be implemented in other than exceptional circum­ stances. Looking at the opposite extreme, the lengthiest study that POST has ever produced (lengthiest in time but also in size) was on the risks of sabotage and external assaults at UK nu­ clear facilities, conducted at the specific request of the influen­ tial House of Commons Defence Committee in July 2002 [11].

This involved about 18 months of calendar time and about two years of person-input. In this case, the primary aim was to pro­ duce a fundamentally authoritative report exhaustively assess­ ing the wide-ranging dimensions of this very profound subject.

Depth of analysis was felt to trump the needs of expedition.

Clearly, fast-moving, or emergency, circumstances can pre­ sent a real challenge to systematic, comprehensive, TA. The se­ rious 2001 foot-and-mouth disease outbreak in England and Wales caught most, including POST, by surprise give that the last serious outbreak occurred in 1967. POST was not able to produce any output on the subject, so fast-moving was the spread of the epidemic and the evolution of the official attempts to eradicate it. More recently, the April 2010 air travel ash cloud incident following the eruption of the Eyjafjallajökull volcano in Iceland was also a huge challenge, given the rapidity of its devel­ opment. In the UK, the situation was compounded by the fact that it occurred exactly at the time when a general election cam­ paign began and the UK parliament was not sitting. During such periods, POST does not publish any reports and, ironically, turns its attention to a systematic analysis of issues likely to be of con­ cern to Parliament over the following five years (see below). In the end, the ‘honour’ of parliamentary TA institutions in address­ ing this amazing incident was salvaged by STOA in Brussels, which held an important workshop on the subject [12].

Of course, one way in which TA institutions can attempt to minimise the constraints of time is to attempt to identify potential subjects and circumstances that might emerge on parliamentary agendas in the future, and ideally to have a ‘bank’ of research and information collation that can be drawn on rapidly, should this become relevant. This is a major reason why parliamentary TA institutions have a profound engagement with foresight, sce­ nario-building and similar exercises. As noted above, in the case of POST, in the roughly one-month period when a general elec­ tion is called in the UK (occurring every 4–5 years), POST has, since 2001 immediately begun an intensive internal brain-storm­ ing process to identify subjects and issues to be featured in a special Science in the New Parliament publication that looks for­ ward five years. Uniquely among POST publications, this is sent to all Members of Parliament (and members of the House of Lords) as soon as the new Parliament convenes [13].

In closing this discussion on matters of time, there is a final cautionary point to be made. This is that parliamentary TA insti­ tutions have to be careful not to become, unwittingly, agents

Forty Years On

for attempts at procrastination. Interests opposed to a particu­ lar policy proposal quite frequently will call for further research on it before implementation. Such calls can be quite seductive, especially when the independence, integrity, etc. of the parlia­ mentary TA institution that may be identified as the preferred analyser is invoked. The intention of the opponents is not nec­ essarily, of course, to acclaim the outcome of any such further research, but often a hope that deferred implementation will lead to the proposal withering from neglect, or becoming inap­ propriate through changing circumstances [14].

Costs and the expansion of parliamentary TA An aspiration that has driven the parliamentary TA community, certainly in Europe, since the earliest days has been the estab­ lishment of TA functions serving an increasing number of parlia­ ments. Indeed, the period from the late 1990s to the late 2000s was remarkable for the success achieved on this front, from Norway to Catalunya. This has partly been due to the proselytis­ ing zeal of the community itself, but at least as much to a wave of realisation that swept through legislature after legislature that scientific and technological advancement, especially innovation, was critical to the well-being of all economies and societies.

Apart from the obvious exception of the recent creation of the Centre for Science, Technology and Engineering (CSTE) at the US Government [15] Accountability Office (GAO), which in some ways a reincarnation of the OTA and serves the US Congress, parliamentary TA has not been so success­ ful in expansion outside Europe. In 2011, there was some ex­ citement about the possible creation of an institution some­ what similar to the Finnish Parliament’s Committee for the Future, at the Chilean Parliament, to mark the bicentenary of its foundation, but I for one have not heard so much about its progress subsequently [16]. For some years, there have been series of delegations from, or to, countries in East Asia, such as Japan, Korea and Taiwan. In that part of the world the greatest progress in this regard has been in Japan, when in March 2011 a new science and technology committee was established at its House of Representatives, which undertook to embrace a TA function. This was, however, disrupted by the earthquake and tsunami disaster that followed, although a small support unit has been created at the National Diet [17] Library, which hopefully, in liaison with the Diet, will be able to take things forward. Canada also has made preliminary ex­ plorations, but, disappointingly for such a politically progres­ sive country, these have yet to reach fruition.

Within Europe (and indeed further afield) the economic and political climate is not currently very favourable to initiatives within other countries, especially as these tend to be countries outside of the relatively economically-favoured western Euro­ pean ‘core’ countries. This raises the immediate question of the costs of establishing a viable parliamentary TA function.

These were examined by Vig and Paschen as early as 2000, but the figures they give are not truly comparable [53] and it is remarkably difficult to produce figures that are. For example, for services by units that are integral parts of a parliamentary

Contrib. Sci. 8 (2), 2012 125

institution, many overheads may be met centrally and thus not attributed specifically to the unit’s cost.

Some figures are, however, illustrative. Its annual report re­ veals that in 2012 the research budget of STOA at the Europe­ an Parliament was € 684,806.24 [49]. If one adds the costs of administration and overheads this suggests something in the region of €1 million a year as the total cost of running STOA. The Rathenau Instituut in the Netherlands, which provides a service to the Dutch parliament and is the largest TA unit in Europe, reported a total 2011 budget of €5.8 million. However, this also includes its other function of Science Systems As­ sessment and a reasonable estimate for what it actually spent on TA is about €2.5 million [44]. A rough rule-of-thumb might be that to establish and run a basic, viable TA unit is likely to cost about €1 million a year.

Such a figure may well be beyond the means of the legisla­ tures of smaller countries, especially, as noted, when they are under pressure not just to support general adjustments to eco­ nomic austerity, but are also under public scrutiny to be seen to be tightening their own belts (something which affects es­ tablished units at other parliaments as well). One mooted re­ sponse to these circumstances is the creation of institutions that would serve more than one parliamentary institution, on a joint basis. This could have merit in situations where, as in the Baltic States, there is geographical contiguity and roughly simi­ lar circumstances (although Lithuania has the population of Es­ tonia and Latvia combined). It is more difficult to envisage, for example, Iceland and Slovenia, both countries which have ex­ pressed interest in parliamentary TA, being able to operate in this way. Another possible route to the expansion of the parlia­ mentary TA family might be for (a) charitable foundation(s), of impeccable status, to agree to support a service for a parlia­ ment or parliaments. There have been some suggestions of the Gulbenkian Foundation taking on such a role in Portugal, an­ other country that has flirted with the prospect of parliamentary TA, although nothing has come of this to date.

It is perhaps not widely known that for the first three years of its life, POST itself was a charitable foundation, receiving funding from prestigious UK charities such as the Wellcome Trust and Nuffield Foundation. It was also supported by various blue-chip companies, but that is something that would probably not be acceptable today. Even support from the national science and engineering academies or the like, which POST also received, might be regarded as undermining impartiality and independ­ ence. It was, in truth, a relief when the UK Parliament embraced POST as an internal institution, not just because of these con­ siderations of independence but also because reliance on chari­ table donations is not a very secure basis for long-term survival, something which is probably true everywhere outside the USA.

Nailing the coffin lid on ‘technology arrestment’ Looking back over the past forty years, I think one of the more interesting developments in TA has been that it has, essentially, been able to shake off an interpretation and an epithet that plagued it in the formative years before, and early after, the

126 Contrib. Sci. 8 (2), 2012 Cope

OTA came into being. This was that TA actually stood for ‘tech­ nology arrestment’ [18] and that its application, explicitly or im­ plicitly, would be a brake on entrepreneurship and innovation.

In truth, when one reads some of the early writing on TA, it was somewhat replete with an emphasis, explicit or implicit on con­ trol or regulation. For example, the New Scientist introduced the special supplement of May 1973 [36] thus: “One result of the growth of consumer and environmentalist movements in recent years has been to show that new sci­ ence and technology does not necessarily make life more comfortable or enjoyable. Technological innovation can just as easily impair “the quality of life” as promote it. As an in­ creasing number of people question the idea tht ‘science is good for you’, it is inevitable that there will be growing de­ mands for controls on science and technology.”

I would dispute that excerpt’s assertion that it was the growth of ‘consumer and environmentalist movements’ that were the first to ‘show’ anything. Rather, at that time, such organisations frequently latched onto the output of proto-TAs, and by dint of their media-savvy inclinations often took them in directions that differed from those that the original research suggested. It is perhaps not surprising that reading that excerpt, and similar statements of the time, might have caused apprehension not only among entrepreneurs but, considering in particular the last line above, also among the science and technology research community. It conjures up visions of controls on even earlystage research, and of course, there are voices still raised in that cause today, in fields such as stem cell research, geoengineer­ ing or the development of hydraulic enhancement techniques for liquid and gaseous hydrocarbon extraction.

‘Arrestment’ accusations are rarely, if ever, made today against the outputs and institutions of TA. There are several reasons for this welcome evolution, all rather complexly inter­ twined. First, the entire socio-political context of policy dis­ course has moved on from the rather ‘statist’ dominance of the 1960s and 1970s. Second, some of the national institutions created to carry out TA have also had a complementary, or even dominant, remit, namely to explore innovation [20]. Obvi­ ously linked to that, but with a life of its own, has been the en­ tire emergence of innovation as a subject of research and ex­ hortation. TA institutions have sought to justify their activities by being incorporated into the push for innovation but have also, I would assert, never lost sight of the fact that they must explore in its shadows as well as following its light. In fact, it could be said that one reason why the ‘arrestment’ accusation is rarely made today—and the enthusiasm for innovation is generally so ubiquitous—is precisely because of the successful application of TA in the early identification of things that create the shad­ ows, so that the light can penetrate there as well [21].

Engagement, participation and all that The ‘embrace of innovation’ process I consider above was a somewhat gradual process, perhaps like the fog in Sandburg’s

famous poem that “comes on little cat feet”. It came silently to embrace most, if not all, parliamentary TA units. However, if one looks at the evolution of TA in Europe over the past 40 years, something that certainly did not come as silently has been the embrace of participation, to the point that when the acronym PTA is used, there frequently has to be an explanation of whether the author is referring to ‘Parliamentary Technology Assessment’, or to ‘Participatory Technology Assessment’. In fact, in writing this section on participation or engagement, nothing comes to my mind more than G. F. Handel’s famous sinfonia from his opera Solomon, The Arrival of the Queen of Sheba, which so wonderfully captures in music a celerity in­ fused with impetuosity. Few, including POST, have been able to resist the seduction of Sheba’s fluttering eyelids. And, in truth, she was apparently a thing of beauty.

However, POST did not, for good reasons, embrace the queen from the south as fully as some [22]. POST collaborated with two ‘consensus conferences’ in the UK, in 1994 on geneti­ cally modified foods [42] and in 1998–1999 on radioactive waste management [39]. I use the word ‘collaborate’ carefully here be­ cause POST did not play a central role in the organisation, and dissemination of the results of, the citizen engagements. POST is an internal institution of a body (the UK Parliament) that is in­ tensely proud of its tradition of representative democracy. The members of the House of Commons see themselves as the two-way link to and from the citizenry through their attachment to their constituencies but not necessarily bound by any mo­ mentary capturing of what is claimed to be the will of those citi­ zens. Indeed, in the famous Speech to the Electors of Bristol the English politician/philosopher Edmund Burke forcibly set out these principles as early as 1774 [23]. He observed that while an elected representative will always strive to nurture the well-being of his [24] electorate his premier duty to them was to exercise his judgement and discretion and to be prepared, where he thought a higher, national, interest trumped local circumstanc­ es, to go against his electorate’s will. This principle has subse­ quently become extended from a purely geographical basis (Bristol being a major port, Burke’s electorate were particularly keen to preserve trade interests) to one which embraces all spe­ cial interests, even if not geographically expressed.

The implications of this long-established principle for POST were that it might have been extremely inadvisable for it, as an internal institution of the Parliament, to be seen to be opening up an alternative, direct, route to the national will that in any way might be construed as bypassing the role of the elected repre­ sentative. The outcome was that POST observed and assisted these early UK experiments in public engagement and reported back to Parliament on them [48]. In 2000, when POST was made a permanent institution of both Houses of the UK Parlia­ ment (it had until then existed on a five-yearly renewable basis), it was given a specific remit to report to Parliament on the devel­ opment of public consultation activities in the field of science and technology policy in the UK, but not specifically to conduct them itself. POST largely took this remit forward through developing already existing initiatives in the use of on-line consultation activi­ ties. The first of these had involved a survey of the career devel­ opment of female scientists [25] and was followed by some ex­

Forty Years On

tensive work on consultation on the consequences of inland flooding, following some severe incidents in the UK in 2001. This capitalised, if that is the right word, on the intense public concern on the subject. In the following years, the use of online consulta­ tions by UK parliamentary committees expanded considerably (and has extended to many other policy areas besides science and technology) such that it became unnecessary to demon­ strate further its potential applications. It is my impression that in recent years, however, this use of online consultations has reached its peak, though I have not explored this systematically.

Online consultations had a very specific attraction for POST, namely that they are relatively cheap to conduct. The same can­ not be said for consultations involving the real-life engagement of people, especially those of a deliberative nature that need to bring a sample of the public together on multiple occasions. The radioactive waste consultation in 1997–1998, discussed above, cost €185,000 at current prices [26].

There is also a fundamental ‘catch-22’ in attempting to ad­ dress a methodological criticism of real-life deliberative exer­ cises. This is that the citizen sample assembled to engage is often said to be too small to be representative [27]. To ad­ dress this claim, the pressure rises to increase the number of citizens involved; but that inevitably raises costs. This will ap­ ply a fortiori to international exercises. The King Baudouin Foundation funded EU-level consultation on brain research in 2005–2006, called The Meeting of Minds, engaged 126 citi­ zens from across the EU and is reported to have had a total budget in excess of €2.3 million [47].

I suggest that a consequence of the likely extended period of economic stringency in Europe and elsewhere will be that relatively few such exercises will be conducted in the near fu­ ture. The experimentation that has occurred over the past 20 or so years has been very valuable, but I would argue that the use of such expensive consultation approaches is not the most cost-effective means of advancing TA under current cir­ cumstances.

The restoration of expertise: ‘traditional’ technology assessment Instead, I would assert that the advancement of parliamentary TA (and TA more generally) in the future will better, and more likely, come from what I have encapsulated in the title of this sec­ tion. While expert analysis TA may in some respects be tradi­ tional, at least in the sense that it can claim a long history, some of which I have adumbrated in the earlier sections of this paper, it has in this time been through a formative process of ‘the refiner’s fire’ [28]. One could argue that a great deal of expert analysis could be assembled with €2.3 million! However, my argument is not, by any means, solely based on cost-effectiveness. Accord­ ing to the New Scientist 1973 special supplement, [29] the de­ velopment of TA “may lead to the creation of new professions, such as that of the technology assessment analyst”. I think that this has indeed occurred over the past 40 years. Furthermore, the development of expert-originating TA is likely to be given a major boost by the re-establishment of the Congressional TA

Contrib. Sci. 8 (2), 2012 127

function in the USA, which I understand to be firmly wedded to the application and further refinement of this approach.

I am not in any way arguing that a new ‘deferment to exper­ tise’ will, or should, emerge. If that ever existed, its days are long over. Instead, I foresee real challenges to the profession.

Of these, I think the most demanding will be the nurturing and extension of ‘trust’. A decade ago, Baroness Onora O’Neill, probably the UK’s leading living moral philosopher said that there was a “need to free professionals and the public service to serve the public...[and] to rethink a media culture in which spreading suspicion has become a routine activity”. She has explored the dialectic between trust and ‘trustworthiness’, something that I think would handsomely repay deeper explo­ ration by EPTA and the wider TA community [43]. This could be seen as a specific dimension of the wider issue of ‘impact’, which has much concerned the parliamentary TA community.

The extent to which we are trusted, by whom, how we can en­ hance and fortify our trustworthiness and how we can extend the field of those who place their trust in us should, I repeat, be a continual leitmotif, running through all parliamentary TA activ­ ity and questions to be perpetually asked by all its institutions in a constant critical self-examination.

I do not have space to elaborate on this idea in this paper but hope to return to it in more detail in the future. I should say that I am well aware that some point to ways in which the di­ lemmas of expertise and the concerns of the citizenry (which relate to this matter of trust, although conceptually separate) can be reconciled, or more positively, can actively interact with synergistic outcomes. The perspective, or approach, that has come to be called Constructive Technology Assessment (CTA), associated in particular with the Dutch leading social studies of science specialist Arie Rip, is perhaps the most highly devel­ oped, although CTA may have political and philosophical di­ mensions that are perhaps above the station of workaday par­ liamentary TA units. A recent Japanese study at the University of Tokyo, which has been highly influential in the progress to­ wards institutionalising parliamentary TA in that country, was, I believe, the first to use the term ‘third generation TA’, also with a sense of some form of synergistic unification of different TA methodologies, again especially those expert-based and those more consultative [41]. Although this was not made explicit, that study was perhaps infused by a sense of the ‘advantages of backwardness’ [30], or ‘late mover advantages’. It is an in­ teresting idea that those countries coming later to the parlia­ mentary TA table might, by the very virtue of that, become the vanguard in the development of its practices. I include the CSTE at the US GAO in this category; although the USA, through the OTA, was the original setter of the feast on the ta­ ble, it subsequently disappeared like the prodigal son, only re­ cently returning to join the family [31].

The garnering and nurturing of parliamentary TA champions I have been increasingly conscious as I have laboured over this paper that it is perhaps somewhat introspective. It is, in

128 Contrib. Sci. 8 (2), 2012 Cope

truth, primarily addressed to my fellow TA professionals. Liter­ ature and indeed oral tradition is replete with stories of the critical role of champions: King Arthur and his Knights of the Round Table in English mythology, the fallen heroes gathered alongside the gods in Valhalla in Norse and Germanic tradi­ tion, are examples [32].

Parliamentary TA could not have progressed to where it is now without its early-day champions within the Parliaments that have successively embraced it. In the case of the UK, I think in particular of Lords Kennet and Flowers and Dr Ashok Kumar MP [33], (now all unfortunately deceased) but there were many others. I am sure each EPTA member country can point to its champions. But I also think of people like Claude Birraux (now retired), at the Assemblée Nationale, and in the USA the indefatigable Congressman Rush Holt, who, begin­ ning in 1999 and continuing to the present has sometimes sin­ gle-handedly championed the cause of TA in the US House of Representatives, [34] and of course, the ‘second coming’ champion, Congressman Bart Gordon, who greatly assisted in the establishment of the GAO’s CSTE. Perhaps I am writing these final paragraphs drawing on a UK experience that is not widespread; if so, that would be reassur­ ing. It was a source of concern to me in my later days at POST that, with notable exceptions, such as the recruitment of the current Chairman of POST’s Board, Adam Afriyie, it seemed to be becoming more difficult to engage UK parliamentarians. In­ deed, for some periods the Board operated with unfilled plac­ es. Parliamentary TA is no longer a chubby, gurgling, heartstealing new-born, to be ‘coo-cooed’ over by an adoring crowd of admirers, above all, its parents. It has grown up, with a succession of celebrations of adulthood over the past few years at STOA, OPECST, TAB, TA-Swiss and POST itself. Per­ haps in that growing-up period, as teenagers, we have some­ times been seen as a bit spotty and tetchy!

We do, however, still need our champions and it is why I was so pleased that Leonhard Hennen and Armin Grunwald conceived of the session at the recent PACITA conference in Prague (which they gave me the honour of inviting to chair) on the relationship between TA practitioners and their parliamen­ tary (and governmental, which is also a role for some units that serve parliaments) ‘clients’ [35]. The need for champions certainly extends well beyond those who specifically request studies but certainly includes them. I very much hope that this interaction, and the wider matter of champions, will be taken up in continuing dialogues within and beyond the PACITA framework.

A Personal Coda I have plumbed the depths of my mind to find some way of ending this paper fittingly. As I have said, in no sense would I want it to have any eschatological overtones, quite the reverse.

In that vein, I will end by quoting a few words from a wonderful poem by Arthur Hugh Clough (1819–1861), Say Not the Struggle Nought Availeth.

For while the tired waves, vainly breaking Seem here no painful inch to gain, Far back through creeks and inlets making, Comes, silent, flooding in, the main [36].

Acknowledgements. I am grateful to the US Embassy, Lon­ don, which in 1979 awarded me a research scholarship that enabled me to spend a study period at the US Congressional Office of Technology Assessment and also to interact with two giants in the evolution of TA: the late Professor Harvey Brooks of Harvard University, USA and the late Professor Alvin Weinberg, of Oak Ridge Associated Universities, USA, former Director of the Oak Ridge National Laboratory, Ten­ nessee, USA. This opportunity kindled a lifelong interest in all aspects of TA. Naturally, I must also thank all colleagues from EPTA offices, or associated with EPTA, with whom I have in­ teracted over the years.

Notes & References Notes 1. Such as the 1903–1906 Royal Commission on London Traffic, which produced an eight volume report, or the 1898–1915 Royal Commission on Sewage Disposal which during this exceptionally long time for the existence of a Royal Commission published nine reports, many of which laid the foundation for the UK’s procedures for wastewater treatment until the mid-1970s.

2. I apologise that I have not been able to establish the working methods of Legrand’s inquiry and would be very grateful for any information about it.

3. Some might dispute that observation, and there were, it is true, around the time, some remarkable publications, above all H. G. Wells’ 1933 ‘future history’ novel The Shape of Things to Come.

4. As discussed in the writings of Carroll W. Pursell, espe­ cially The Machine in America: A Social History of Technology, 2007.

5. Although as a Royal Commission, the RCEP reported (through the monarch) to the UK Parliament, it was not technically an office of the Parliament.

6. See [40]. The unit gained a reputation in particular for its demographic analytical work.

7. There are several taxonomies of the different institutional forms, but I stand by the one which my colleague Diana Malpede and I put forward in [52].

8. The most significant example is probably its proposal for the subsequent “loi no 2006-739 du 28 juin 2006 de pro­ gramme relative à la gestion durable des matières et dé­ chets radioactifs”. OPECST also appoints some mem­ bers of the Board of the Commision Nationale d’Evaluation des Recherches et Etudes Relatives à la Gestion des Matières et des Déchets Radioactifs which was created by the law. Moreover, each year, the French Parliament commits to OPECST for examination the re­

Forty Years On

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

port which the National Commission submits to it.

Which was delightfully encapsulated by the English satiri­ cal poet, Jonathan Swift, in 1733, “So, naturalists ob­ serve, a flea / Has smaller fleas that on him prey; / And these have smaller still to bite ‘em, / And so proceed ad infinitum.”

I use the word ‘most’ without having had the chance to check this fact systematically with EPTA members, and will take the first opportunity to do so.

See [46]. I would like to record here my profound grati­ tude to my colleague, Dr. Chandrika Nath, who was the lead researcher on this study.

The contribution of this workshop to the development of policy in this area has not been recognised as much as it deserves. It was at the STOA event that aircraft engine manufacturers first publicly discussed agreeing on ash concentration levels below which they could guarantee the integrity of their engines.

In general, POST sends its publications only to parlia­ mentarians who have actively signed up to receive them.

This is to avoid any risk of accusations of ‘bombarding’ parliamentarians with unwanted material. These special publications also do not go through POST’s usual axio­ matic processes of external peer review, because of time constraints, although there is informal consultation with external experts.

Readers will realise that I have written this last paragraph based on some degree of actual experience of such cir­ cumstances, although confidentiality prevents me from giving specific references. For completeness, I should also add another caution, not associated with matters of time. This is that, fortunately on very few occasions in my own experience, TA institutions may receive encourage­ ment to conduct an analysis from sources which, further investigation shows, have a pecuniary interest in the mat­ ter in some way.

For those not familiar with the US situation, the title of this institution can be rather misleading. It is not a government (i.e. executive) office, but rather an office of the legislature that is concerned with government accountability.

If any reader has further information, I would be interested to receive it.

That is, Parliament, which is composed of two Houses – the House of Representatives and the House of Council­ lors I have been unable to establish authoritatively the etymol­ ogy of this epithet. The term is referred to in a 1972 Business Week article called ‘The Debate Over Assessing Technology: Congress wants to set up an office to evalu­ ate the impact of new developments’ [http://www.prince­ ton.edu/~ota/ns20/ota72_f.html]. Here it is attributed to Joe Coates of the US National Science Foundation. But, whether Coates was himself quoting, or originated the expression is unclear. There is also some discussion of the concept in: Dickson D (1988) The New Politics of Sci­ ence, University of Chicago Press.

See [9]. Excerpt taken from page 466.

Contrib. Sci. 8 (2), 2012 129

20. This applies to CAPCIT itself, of course; the Norwegian Board of Technology is perhaps another good example.

However, I would argue that all parliamentary TA units are now suffused by this perspective.

21. In writing this section, I clearly have had in mind the semi­ nal book by Collingridge D (1980) The Social Control of Technology, St. Martin’s Press. It is indicative, however, that he uses the word ‘control’ in its title, rather than ‘as­ sessment’.

22. Actually, a better analogy might be a queen from the north, but Sheba definitely came from the south (of Isra­ el).

23. See [38]. The irony is that the electors of Bristol showed what they thought of Burke’s ringing declaration by de­ clining to elect him at the subsequent general election!

24. Of course, in those days, it was only ‘hes’ in the House of Commons.

25. This had fed into the above referenced House of Lords committee report. Interestingly, in 2013, the House of Commons Science and Technology Committee has re­ turned to this theme and is conducting a similar consulta­ tion. This might reveal the progress that has been made in this area in the intervening years.

26. The costs were met by the government body that funds environmental research in the UK, the agency then re­ sponsible for low and intermediate level radioactive waste management and a charitable foundation.

27. It is, of course, very difficult to establish what is the nec­ essary minimum size to be representative. A further un­ certainty arises because, especially with exercises involv­ ing citizens convening on multiple occasions, those who volunteer to do so (and of course they cannot be com­ pelled) are hardly likely to be truly representative. The very act of volunteering shows that they are, in perhaps critical respects, atypical. I am well aware of assertions that the aim of such exercises is not to obtain a representative opinion but to explore ranges of opinion, and similar ar­ guments, but these are often a rather weak rationalisation in face of a de facto situation.

28. In the sense in which this phrase, or those similar to it, is used in various places in both the Old and New Testa­ ments, perhaps most particularly in Malachi 3:2 29. See [49]. The specific quotation in the following sentence in the main text above is on page 466 30. I hasten to say that I use the word ‘backwardness’ solely in the sense that it was first codified in: Gerschenkron A (1962) Economic Backwardness in Historical Perspective, Harvard University Press. There was nothing ‘back­ ward’ about the study!

31. The Biblical prodigal son is not, I admit, perhaps the best analogy. Unlike him, the US OTA did not leave the house­ hold of its own free will but was forced out, in some sens­ es by its own father, the US Congress. Also, the return of the prodigal son was not, at least initially, greeted with untrammelled enthusiasm by his siblings who had stayed, the complete reverse of the response of the EPTA ‘family’ to the return of the USA. If any reader can suggest a bet­

130 Contrib. Sci. 8 (2), 2012 Cope

ter analogy, I would welcome it.

32. Again, these analogies are not, perhaps, ideal, in that they have central eschatological dimensions. I am not, in any way, suggesting that I fear that TA faces its ‘End of Days’!

33. Dr. Kumar would frequently say to me, “You know, David, I do not win any votes through my work for POST!”. He was meaning constituency votes because his seat was quite marginal at times.

34. And who is now seeking nomination for a seat in the US Senate.

35. See the conference book of Abstracts to be found at [http://www.pacitaproject.eu/?ai1ec_event=technologyassessment-and-policy-areas-of-greattransitions&instance_id] and in particular the description of II. Parallel event: Politicians and Researchers – Respective Views on Joint Projects, 14 March 2013.

36. For the benefit of my non-native English speaker col­ leagues, I should explain that the ‘main’ is the deep sea.

References 37. Decker M, Ladikas M (2004) Bridges between Science, Society and Policy, technology assessment - methods and impacts, Springer 38. Edmund Burke, Speech to the Electors of Bristol (1774) The Founders’ Constitution. Volume 1, Chapter 13, Doc­ ument 7:446-448 [http://press-pubs.uchicago.edu/ founders/documents/v1ch13s7.html] 39. European Sociologists Archive [https://www.jiscmail. ac.uk/cgi-bin/webadmin?A2=european-sociologist;c83a 95c4.9904]

40. Fry RE, Martin FM (1968) The Research and Intelligence Unit of Greater London Council. The Statistician 18:345354 [http://www.jstor.org/stable/2987137] 41. Innovation and Institutionalization of Technology Assess­ ment in Japan [http://i2ta.org/english/english.html] 42. National Centre for Biotechnology Education (1994) UK

National Consensus Conference on Plant Biotechnology [http://www.ncbe.reading.ac.uk/ncbe/gmfood/confer­ ence.html] 43. O’Neill O (2002) A Question of Trust: the BBC Reith Lec­ tures, Cambridge University Press 44. Overview of the activities of the Rathenau Institute in 2011 (Overzicht van de activiteiten van het Rathenau In­ stituut in 2011) [http://www.rathenau.nl/publicaties/pub­ licatie/jaarverslag-2011.html] 45. Parliaments and Civil Society in Technology Assessment [www.pacitaproject.eu] 46. Parliamentary Office of Science and Technology (Febru­ ary 2004) Assessing the Risks of Terrorist Attacks on Nu­ clear Facilities, Report 222 47. Rauws G (2006) Meeting of Minds: The biggest-ever con­ sultation of science in Europe [http://ec.europa.eu/re­ search/science-society/document_library/pdf_06/gerritrauws-meeting-of-minds_en.pdf] 48. Science and Technology Committtee (House of Lords) (February 2000) Science and Society [http://www.publi­ cations.parliament.uk/pa/ld199900/ldselect/ld­ sctech/38/3801.htm] 49. Science and Technology Options Assessment, Europe­ an Parliament (2013) Annual Report 2012 50. Technology assessment: a route through chaos? (24 May 1973) New Scientist 58: 847 51. The Sea Empress Oil Spill (February 1996) POSTnote 75 [http://www.parliament.uk/briefing-papers/POSTPN-75] 52. UNESCO/ISESCO (June 2006) Science, Technology and Innovation Policy: the role of parliaments, p. 12 53. Vig N, Paschen H (2000) Parliaments and Technology; the development of technology assessment in Europe, State University of New York, p. 12 54. Wallonian National Workshop: Provocative reflections to build TA in Wallonia [http://www.pacitaproject.eu/?page_ id=1222]

CONTRIBUTIONS to SCIENCE, 8 (2): 131–135 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.144 ISSN: 1575-6343 www.cat-science.cat

Parliamentary Technology Assessment

CAPCIT: The Advisory Board of the Parliament of Catalonia for Science and Technology Fernando Domínguez García CAPCIT, Parliament of Catalonia, Barcelona

Resum. A tot el món, els parlaments i altres òrgans legislatius representen societats en les quals les tecnologies de la infor­ mació i els coneixements científics avancen a un ritme frenètic.

No obstant això, la major part dels legisladors no tenen els co­ neixements o la formació necessària per a comprendre o afrontar les conseqüències de la revolució tecnològica i científi­ ca. Seguint la tendència d’assessorament científic i tecnològic als parlaments (PTA) d’Estats Units i d’Europa en les darreres dues dècades, el 2008 es va crear el Consell Assessor del Par­ lament sobre Ciència i Tecnologia (CAPCIT) al Parlament de Catalunya. Tot i la curta història d’aquesta institució, el CAPCIT representa el primer i més seriós intent a Espanya de reunir les principals fonts d’informació científica i tecnològica en un fò­ rum comú al servei de la formulació de polítiques.

Summary. Throughout the world, parliaments and other leg­ islative bodies represent societies in which information tech­ nologies and scientific knowledge are advancing at a frantic pace. Yet, most legislators lack the knowledge or training re­ quired to understand and deal with the full implications of the technological and scientific revolution. Following the trend of Parliamentary Technology Assessment (PTA) in the United States and Europe over the past two decades, the Advisory Board of the Parliament of Catalonia for Science and Tech­ nology (CAPCIT) was established in 2008. Despite the institu­ tion’s short history, CAPCIT represents the first and most se­ rious attempt in Spain of bringing together the main scientific and technological sources in a common forum at the service of policy-making.

Paraules clau: assessorament científic i tecnològic als parlaments (PTA) ∙ Oficina d’Assessorament Tecnològic (OTA) ∙ Xarxa Europea d’Assessorament Tecnològic als Parlaments (EPTA) ∙ Consell Assessor del Parlament sobre Ciència i Tecnologia (CAPCIT)

Keywords: Parliamentary Technology Assessment (PTA) ∙ Office of Technology Assessment (OTA) ∙ European Parliamentary Technology Assessment (EPTA) ∙ Advisory Board of the Parliament of Catalonia for Science and Technology (CAPCIT)

Introduction and historical notes

sions must consider the needs of future generations. Through­ out the world, parliaments and other legislative bodies represent societies in which information technologies and sci­ entific knowledge are advancing at a frantic pace. Yet, most legislators lack the knowledge or training required to under­ stand and deal with the full implications of the technological and scientific revolution. Moreover, their respective institutions continue to search for the best way to support scientific and technical innovations.

Over the past few decades, attempts have been made to tackle and anticipate such challenges. In 1972, the Congress of the United States of America created the Office of Technol­ ogy Assessment (OTA). The Congress considered that agen­ cies from the Executive Branch were not designed to provide it with adequate information on science and technology and found “essential that, to the fullest extent possible, the conse­ quences of technological applications be anticipated, under­ stood, and considered in determination of public policy on existing and emerging national problems.” Therefore, the Congress equipped itself with a new office in charge of “se­

As in many territories around Europe, the parliamentary tradi­ tion of Catalonia traces back to medieval times. The Catalan quest for democracy also has several similarities with that of the region’s European neighbours due to the coincidence of time and several ideological parallelisms. In the 20th century, during the Second Spanish Republic (1931–1939), a demo­ cratically elected Parliament of Catalonia was established in 1932. However, only its first few years were peaceful and it was abolished in 1938. After that, Franco dictatorship (1939–1975) abrogated most of the Catalan legal order. The Parliament of Catalonia was re-established in 1980 and combines modernity with tradition, youth with expertise.

Today, the Parliament of Catalonia is confronted with a mul­ titude of complex economic and social problems and its deci­ Correspondence: F. Domínguez, Parlament de Catalunya, Parc de la Ciutadella, E-08003 Barcelona, Catalonia, EU. Tel. +34-933046500.

Fax +34-932213989. E-mail: fdominguez@parlament.cat

132 Contrib. Sci. 8 (2), 2012

curing competent, unbiased information concerning the physical, biological, economic, social, and political effects of such applications” [1]. In 1995, the OTA was abolished, but the idea of a TA survived. In 2008, the Government Account­ ability Office (GAO) of the United States Congress incorpo­ rated a new function through a TA unit, taking on the former duties of OTA [2].

In subsequent decades, a few European states instituted a unit or office based on the OTA. For example, in 1986, the Netherlands created the Organization for Technology Assess­ ment (NOTA), later renamed the Rathenau Institute; in 1989, the UK Parliament’s Parliamentary Office of Science and Tech­ nology (POST) was established [3]. In 1990, the European Par­ liamentary Technology Assessment (EPTA) was founded as a network for the exchange of ideas and experiences. This inter­ nationalization has helped to define TA as a process for study­ ing and evaluating new technologies by providing information about their possible unintended negative effects, costs, and ethical and societal implications. Concretely, Parliamentary Technology Assessment (PTA) is a kind of TA oriented to in­ form members of Parliament [4].

Following that trend, in the 8th legislative term (2006–2010) of the Catalan Parliament, the Advisory Board of the Parliament of Catalonia for Science and Technology (CAPCIT, its Catalan abbreviation) was formally established, in the decision of the Parliamentary Bureau (also referred as the Board of the Parlia­ ment of Catalonia) of 15 July 2008. The first meeting of CAPCIT was held on 10 November 2008, during which it ratified its Rules of Organisation, as agreed by the Parliamentary Bureau decisions of 15 July 2008 and 7 October 2008 [5]. CAPCIT is the first scientific and technical advisory body to be set up di­ rectly by the Parliament of Catalonia.

However, it was not without precedent and its origins can be traced to an autonomous unit created by the Catalan Gov­ ernment in 1999, the Advisory Commission on Science and Technology (CACIT), which essentially functioned as unit of the Executive branch. CACIT was closed in 2004 but during its short life it established a link with the Parliament of Catalonia.

On 29 April 2003 the Parliament of Catalonia approved a mo­ tion asking the Government to change the decree concerning CACIT in order to add a new function to the unit: the provision of information and consultation to the Parliament in matters re­ lated to science and technology [6].

On 1 December 2003, a letter from the Speaker of the Par­ liament of Catalonia requested that CACIT be registered as member of the European Parliamentary Technology Assess­ ment (EPTA), taking into account the motion of 29 April 2003.

Although the request was granted, membership was not fully completed until CAPCIT was founded, which required another formal application to the EPTA in a letter dated 14 October 2009. Finally, full membership rights were granted to CAPCIT at the EPTA Council meeting of 2 November 2009, held in Lon­ don. Currently, the Parliament of Catalonia is the only parlia­ ment in Spain to have a scientific and technical advisory body.

Indeed, there is not a single TA body attached to the Spanish Parliament nor to any of the other parliaments of the autono­ mous regions of the country.

Domínguez García

CAPCIT’s mission CAPCIT aims to coordinate all science- and technology-related information and advice required by the Parliament of Catalonia.

It provides a forum in which to present members of the Parlia­ ment of Catalonia with the results and findings of the TA tasks carried out by several Catalan scientific and technical institu­ tions. Although CAPCIT has not yet undertaken any kind of public debate or participation, this is a possibility for the future.

Nonetheless, CAPIT is not a closed organization. Rather, it seeks to establish long-term relationships through a ‘pairing scheme’ with scientific enterprises and research centres that allows members of Parliament (MPs) to be kept abreast of is­ sues related to the scientific community.

CAPCIT is not a ‘watch-dog’ agency. Nor is it directly re­ sponsible for scientific policy, which is the domain of the Commission of Education and Universities. Instead, CAPCIT focuses on TA and the relationship between the Catalan Par­ liament and science conducted in Catalonia. The working fields of CAPCIT can be summarized as follows: (a) science, in the broadest sense; (b) technology, the Internet, and com­ munications; (c) bioethics and health; (d) the environment and energy; (e) the dissemination of information and the provision of education in the above spheres [7]. Thus, the goals of CAPCIT are [8]: • Contributing to the improvement of the Catalan Parlia­ ment’s scientific and technical knowledge and dissemi­ nating this knowledge throughout Catalan society.

• Channelling participation from the main scientific and technical institutions in Catalonia when it comes to shap­ ing the will of the Parliament in these spheres.

• Cooperating with institutions, scientific and technological bodies, professional associations, universities, and other organizations and institutes that operate in the fields of science and technology as well as coordinating activities with them.

• Promoting shared responsibility with regard to public sci­ ence and technology policies.

The principle for all of the actions undertaken by CAPCIT is the fostering of a diversity of opinions and encouraging awareness of scientific and technical alternatives in order to ensure that any consultation provided is neutral, objective, and independent.

Composition CAPCIT is a mixed body whose size depends on the number of parliamentary groups present in the Catalan Parliament and the scientific and technical institutions of Catalonia that are in­ vited to send representatives. In the current, 10th legislative term, CAPCIT is composed of 20 members and a secretary [9]. Ten of those members are members of the Parliament of Catalonia, including the Speaker-President of the Parliament, who also holds the presidency of CAPCIT; seven MPs were

CAPCIT: The Advisory Board of the Parliament of Catalonia for Science and Technology

appointed from each of the seven parliamentary groups repre­ sented in the Parliament of Catalonia and two MPs are from the Parliamentary Bureau.

The remaining ten members are representatives from the main scientific and technical institutions of Catalonia: three from the Institute for Catalan Studies (IEC), two from the Catalan Foundation for Research and Innovation (FCRI); one from the Catalan Council for Scientific Communication (C4); three from the Catalan Public University Association (ACUP), and one from the private universities. The IEC is both the scientific academy of Catalonia and the academy for the Catalan language. The goal of the FCRI is to support and promote research and innovation.

C4 is devoted to scientific dissemination and the ACUP serves as the principal voice of the public universities of Catalonia.

The secretary of CAPCIT is one of the lawyers of the Parlia­ ment’s Legal Service. He or she has speaking but not voting rights and must draw up the minutes of agreements and re­ ports. CAPCIT does not have its own staff. Instead, prepara­ tions for meetings as well as other administrative tasks and services are carried out by officials from the Parliament of Cata­ lonia. Once CAPCIT decides that one of the scientific and tech­ nical institutions is responsible for drafting a report, that institu­ tion draws upon its own staff and resources.

Legal nature PTA institutions are typically divided into three categories dif­ fering in their forms of institutionalization: the parliamentary committee model, in which a specific parliamentary political structure performs the duties of the PTA office; the parliamen­ tary office model, in which a unit within the parliamentary struc­ ture leads the PTA; and the independent institute model, in which an office operates distinct from and external to Parlia­ ment [10]. CAPCIT follows the parliamentary committee model, although it is not formally a committee [11]. Also, it should be noted that this model does not require the establishment of a ‘committee’ but instead allows for a political structure within Parliament. While CAPCIT does not directly provide TA it does commission other bodies, usually the scientific and technical institutions from which its members are drawn, to create re­ ports and provide advice. It is a body of the Parliament of Cata­ lonia but its nature, structure, and duties distinguish it from other bodies of the Parliament of Catalonia.

The Parliament of Catalonia meets in a plenary session and in several committees, which, as noted above, do not include CAPCIT. MPs also have other forms of institutionalized meetings.

In modern parliaments, MPs from more than one parliamentary group may collaborate within a structure other than the plenary session or the committees, either for one-off matters or for issues of a more ongoing nature. In parliamentary law, these working platforms or informal groupings are referred to as intergroups; they are also called cross-party and all-party groups. In the Par­ liament of Catalonia, intergroups were not subject to Parliamen­ tary Rules until 2005. Since then, they have been regulated through Article 62 of the Rules, which defines an intergroup as a mixed parliamentary body in that it comprises not only MPs but

Contrib. Sci. 8 (2), 2012 133

also technicians, specialists, and members of civic organizations.

In the Parliament of Catalonia, an intergroup is formally cre­ ated by the Parliamentary Presiding Board, unlike in the Euro­ pean Parliament, for example, in which an intergroup is created by the MPs by virtue of the right of association. The duties of intergroups are perhaps best characterized as those of promo­ tion, which underlines the fact that their activities are of a fos­ tering nature and as such are not result-oriented. Promotion encompasses research (studies), dissemination (raising aware­ ness), and the establishment of external contacts (solidarity and friendship). However, in the Parliament of Catalonia inter­ groups are not allowed to substantiate or process parliamen­ tary initiatives, or to present them in order for the parliamentary body competent in such matters to do so; rather, an intergroup usually reaches a consensus over texts that parliamentary groups then present to the relevant committee or to the plenary session. Therefore, intergroups are not parliamentary decisionmaking bodies and the position of the Catalan chamber cannot be derived from the agreements they reach. In the 10th legisla­ tive term, there are four intergroups: (a) to promote cycling, (b) to provide support for gypsies, (c) to support efforts for peace and freedom in the Sahara, and (d) to encourage efforts at population, development, and reproductive health.

CAPCIT is similar in nature to the intergroups. It is a mixed body since, as noted above, it consists not only of MPs but also of representatives of Catalonia’s foremost science and technology institutions. However, unlike the intergroups, CAPCIT is chaired by the President of the Parliament (Speak­ er), with two additional members from the Parliamentary Pre­ siding Board, in recognition of the importance attached by the chamber to CAPCIT’s responsibilities. CAPCIT, as happens with intergroups, is unable to process parliamentary initiatives.

CAPCIT does encompass improving the scientific and techno­ logical knowledge of the Parliament, cooperating and collabo­ rating with the foremost science and technology institutions, and promoting co-responsibility in public science and technol­ ogy policies. Thus, CAPCIT could be seen as a sort of inter­ group, albeit with greater institutional presence because of the involvement of the Presiding Board and thereby of the cham­ ber’s governing body.

Functioning CAPCIT meets at least twice a year: at the start of each session of Parliament (September and mid-January) (Table 1) and in informal meetings and working sessions as needed.

CAPCIT is charged with decision-making regarding its working plan and the issues that require the preparation of TA reports. Thus not only politicians but also members of the sci­ entific and technical institutions are involved in these delibera­ tions from the outset, choosing the issues and determining the suitability of devoting time and resources to specific topics.

One of the strengths of CAPCIT is that the various institutions can express their opinions on the topics to be addressed; how­ ever, working issues and decision-making must be conducted from a political standpoint to a certain degree. Furthermore,

134 Contrib. Sci. 8 (2), 2012

Domínguez García

Table 1. CAPCIT’s formal meetings between 2006 and 2013 Legislative term

CAPCIT session

8th (2006–2010)

10 November 2008 23 February 2009 15 June 2009 23 November 2009 21 June 2010

9th (2010–2012)

11 April 2011 20 June 2011 12 December 2011 02 July 2012

10th (2012–)

15 April 2013

Source: Own elaboration.

the Parliamentary Bureau (Board of the Parliament of Catalo­ nia) and its committees can request that CAPCIT work on a particular topic and individual MPs can formulate suggestions via their parliamentary groups. Although requests to CAPCIT for reports usually come from parliamentary groups or CAPCIT’s member scientific institutions, generally a consen­ sus, or at least the consent of different groups, is required to finally adopt a decision to ask for a TA report.

As in other parliaments, Catalan political groups sometimes use only the scientific information that is in accordance with their ideals. This applies to parties on the left (e.g., regarding the environment) and on the right (e.g., in efforts to avoid inves­ tigations of the pharmaceutical industry). Moreover, political parties are reluctant to consider scientific reports in areas in­ volving their ‘core’ political ideology. In some debates, the evi­ dence is respected and political positions seek to accommo­ date the scientific evidence (for example, in debates on certain health-related issues). But often times the objectivity of the evi­ dence, reports, and scientific information is questioned and the discussions become rather ‘fact free politics’ (for example, the debate on unconventional gas).

Finally, though, CAPCIT is aware of the different rhythms of the political and scientific worlds. There is no synchronization between the political and the scientific agenda. Thus, it is sometimes not possible to complete a scientific report on a matter that needs a political response in a short period of time. Nevertheless, there are cases in which parliamentary debates have an impact on the scientific agenda and in which scientists require that Parliament reach a decision. Indeed, in 2008 there was synchronicity with the topic of GMOs. Spe­ cifically, a popular initiative was presented in Parliament, with enough time to allow a TA report that in turn was used by the political groups in their internal debates and cited in the final debate. More often, however, TA reports are not related to a concrete parliamentary initiative.

Once CAPCIT decides that it is necessary to address a par­ ticular topic or the issue has been put forward to the body by

the Board of the Parliament of Catalonia, or any of the parlia­ mentary committees, a decision needs to be made as to who shall be responsible for drawing up the report, either (a) one of the scientific and technical institutions represented in CAPCIT or (b) another scientific and technical institution, with proceed­ ings initiated to appoint that institution. This latter option is not generally used.

Each of the scientific and technical institutions represented

by CAPCIT has its own analysts and scientific directors, who are in charge of preparing the reports, and can thereby count on the availability of in-house expertise and economic resourc­ es. The scientific and technical institution committed to writing a TA report decides the on methodology used to elaborate the report. The reports presented to CAPCIT may or may not in­ clude recommendations. The TA method currently used by CAPCIT’s scientific and technical institutions is the classical ap­ proach of expert-based policy analysis to evaluate the conse­ quences of scientific and technological advances and thus to provide the most neutral support for decision making. No quali­ ty controls have been established inside the institution; rather, each institution produces reports according to its own stand­ ards. Although in this respect harmonization may be beneficial, the reports presented to CAPCIT are not of a binding nature and thus do not demand a specific format. Since its inception, CAPCIT has worked on areas including GMOs, human papillo­ maviruses, nanotechnology, nuclear power after the Fukushima event, neuroscience and personalised medicine.

Concluding remarks The impact of CAPCIT and its role in politics are still quite limit­ ed due to the institution’s short history. However, before the creation of CAPCIT, Catalan MPs had little contact with scien­ tific reports and evidence, instead they pursued matters ac­ cording to their interests. CAPCIT’s merit lies in setting the ba­ sis for formalized TA practices. CAPCIT itself is a forum that can be seen as a way to bring together the political and scien­ tific worlds. Equally important as the information and scientific reports it provides is the opportunity for MPs and scientists to meet and thus to personally and directly present their ideas and visions. CAPCIT can foster mutual trust between scientific and technical institutions and the Parliament of Catalonia. It also offers a channel of communication for scientific and tech­ nical entities, other organizations, and society at large [12].

CAPCIT represents the first and most serious attempt in Spain of bringing together the main scientific and technological sources in a common forum at the service of policy-making.

Notes and References Notes 1. The Office of Technology Assessment Act of 1972, Pub­ lic Law 92-484, 92nd Congress, H.R. 10243, 13 October 1972. See:http://govinfo.library.unt.edu/ota/Ota_5/ DATA/1972/9604.PDF

CAPCIT: The Advisory Board of the Parliament of Catalonia for Science and Technology

2.

See: Vig NJ, Paschen H (2000) Parliaments and Technol­ ogy: The Development of Technology Assessment in Eu­ rope. State University of NY Press, New York 3. A standard definition of Technology Assessment (TA) can be found in: Vig NJ, Paschen H (2000) Parliaments and Technology: The Development of Technology Assess­ ment in Europe. State University of NY Press, New York, p. 3 4. In the US Senate report accompanying the proposed bill for the legislative branch fiscal year 2008 appropriation, the Senate Committee on Appropriations recommended the establishment of a permanent technology assess­ ment function within GAO. See: http://www.gao.gov/ technology_assessment 5. See: Official Gazette of the Parliament of Catalonia (Butl­ letí Oficial del Parlament de Catalunya) number 357 (24 November 2008), p. 57. CAPCIT Rules of Organisation and first composition can be found in that Gazette.

6. Point (f) of the Motion number 240 of the 6th Legislative terms says: The Parliament of Catalonia urges the Gov­ ernment to endow the Advisory Commission on Science and Technology (CACIT), created by the Decree of the Government 49/1999, of the 23 of February, with new functions of scientific and technological assessment of the Parliament of Catalonia, in the line of similar offices of countries of our surroundings, with the paramount func­ tion of advising the Parliament and the Government so

Contrib. Sci. 8 (2), 2012 135

they can establish the strategic lines of research, techno­ logical development and in relation with the creation of industries of the knowledge and of the learning, optimis­ ing the public resources and ensuring the participation of enterprises.

7. See Article 4 of the CAPCIT Rules of Organisation.

8. See Article 5 of the CAPCIT Rules of Organisation.

9. See: Decision of Parliamentary Bureau of 12 February 2013. Butlletí Oficial del Parlament de Catalunya 357 (24 November 2008), p. 27 10. Science and Technology Options Assessment (2011) Technopolis Report: Technology Across Borders. Ex­ ploring perspectives for a pan-European Parliamentary Technology Assessment [http://www.europarl.europa. eu/RegData/etudes/etudes/join/2011/482684/IPOLJOIN_ET(2011)482684_EN.pdf] 11. The so called ‘Technopolis Report’ places CAPCIT in the Parliamentary Office model. But the Parliament of Catalo­ nia has not its own fully equipped office for TA studies. It is necessary to insist that CAPCIT does not perform PTA di­ rectly, but commissions other bodies, usually scientific and technical institutions present in its composition, to make reports and advice. See: page 13 of TECHNOLOGY ACROSS BORDERS - Exploring perspectives for pan-Eu­ ropean Parliamentary Technology Assessment [10] 12. See Article 3 of the CAPCIT Rules of Organisation.

CONTRIBUTIONS to SCIENCE, 8 (2): 137–138 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.145 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Presentation Antoni Castellà i Clavé Secretary for University and Research, Ministry of Economy and Knowledge, Government of Catalonia In 2002, a debate took place in Catalonia as to whether we

seek new hiring formulas competitive with those of other re­

should change our research system. I participated in the Euro­

search systems and to recruit to the Catalan R&D system top

pean Parliamentary Technology Assessment (EPTA) confer­

scientists capable of leading new research groups, strengthen­

ence held in Switzerland, where the Catalan branch was invited

ing existing ones and establishing new lines of research. Sec­

to become a member. At the time, we did not have a parlia­

ond, the country profits from a large-scale infrastructure for or­

mentary assessment commission. It was only then that we

ganizing science, consisting of a system of public, autonomous

learned about its importance in advising members of Parlia­

research centres. Third, this large-scale system must be at the

ment on all research-related laws discussed on a regular basis.

disposal of our research community.

Thus, the Advisory Board of the Parliament of Catalonia for

We think that the results over the past 15 years have been

Science and Technology (CAPCIT), the Catalan branch of EPTA,

very good for a small country, such as ours: Catalonia con­

was founded in 2008. CAPCIT is an example of the differences

tributes 1.5 % of the population of Europe and produces 3 %

in the Catalan model for technology transfer. We strongly believe

of Europe’s total scientific production. We also attract 2 % of

that we will only be able to emerge from the economic crisis in

the 7th Framework Programme funds, and in terms of ERC

our country if we invest in a knowledge-based economy—one of

grants per million inhabitants, Catalonia is third in the Euro­

the cornerstones of which is high-quality research. Of course,

pean Union (if Israel and Switzerland are included in an ex­

this is not the only criterion, but it is an absolutely necessary one.

panded list, Catalonia is 5th in the ranking). But having at­

That is why, about 15 years ago, we implemented a new re­

tained a high level of research, the Catalan system faces the

search policy in Catalonia. Its three basic guidelines are as fol­

enormous challenge of converting this knowledge to eco­

lows: First of all, strong instruments must be put in place to at­

nomic gain. In this debate, of course, the Government plays a

tract and retain both talent and an open system of research. The

role, but so does Parliament. Thus, working with CAPCIT, the

best example of this is the Catalan Institution for Research and

Parliament needs to define the path to be taken by Catalonian

Advanced Studies (ICREA), created in response to the need to

research in a knowledge-based economy.

Marta Aymerich Head of Health, Research and Innovation, Ministry of Health, Government of Catalonia Genomic technologies have the potential to transform the

lated information. Until recently, it was assumed that we could

delivery of healthcare in Europe: (i) by providing vital insights

identify prognostic factors for ‘subgroups’ of patients that

that support the more accurate diagnosis of diseases and (ii) by

would explain their different prognoses, while also recognizing

informing therapeutic decisions, so that more patients receive

common characteristics. Today, our expectations have been

the right treatment at the right time [1]. These two aims go

raised, and accurate prognostic judgments are expected on an

hand in hand with preventive care, by extending our under­

‘individual patient’ basis [2].

standing of the risk of disease and helping us to quickly control new outbreaks of infectious diseases.

Personalized medicine is the term used to herald this incipi­ ent prognostic transformation of biomedicine. It refers to

Preventive care is implicitly linked to prognosis and predic­

healthcare guided by detailed prognostic and predictive infor­

tion. But, as a matter of fact, the challenge of improving out­

mation that is formulated for each patient. Nonetheless, some

comes through prognostic and predictive information is not

scientists would argue that the era of personalized medicine

new one in medicine. Indeed, it can be traced back to, at least,

has not yet arrived; instead we are only in an era of stratified

Hippocratic times. What has changed in the last few years,

medicine, because mainly what we are able to predict is the

however, is the strength of our expectations from this accumu­

risk for a patient subgroup.

138 Contrib. Sci. 8 (2), 2012

Of greater concern is that the benefits of biomedical sci­

ized medicine were the topics discussed at the 2012 Annual

ence and clinical and public health research have not been

EPTA Meeting in Barcelona, “From Genes to Jeans: Chal­

made available to everyone. Personalized or stratified, if you

lenges on the Road to Personalised Medicine.”

will, medicine will essentially allow those in rich countries to create individually tailored drug regimens and behavioural modifications for overcoming predicted individual diseases

References

risks, thus creating a new field of ‘boutique medicine,’ as Bar­ ry Bloom wrote in Nature more than a decade ago [3]. Yet,

1.

2012

the resources to obtain boutique treatment and prevention to overcome these risks will simply not be available to 85 % of

Human Genomics Strategy Group. Building on our inher­ itance. Genomic technology in healthcare. UK:London,

much of the knowledge derived from biomedical science and 2

Ioannidis, JPA. Limits to forecasting in personalized

the world’s population, i.e. the developing world. The benefits

medicine:An overview. International Journal of Forecast­

conferred by personalized medicine, together with considera­

ing 2009;25:773–783

tions regarding sustainability, bioethics, social responsibili­ ties, and the challenges or limits to forecasting in personal­

3. Bloom BR. The future of public health. Nature 1999;402(6761 Suppl):C63-4

CONTRIBUTIONS to SCIENCE, 8 (2): 139–143 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.146 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Keynote Lectures

Personalised medicine: needs, challenges, and considerations * Montserrat Vendrell Biocat, Barcelona Council of European Bioregions (CEBR), Brussels

Resum. La proporció de població mundial més gran de seixan­ ta anys doblarà l’actual l’any 2050. Això implicarà un augment de la prevalença de les malalties cròniques, que són de les més costoses, i que constitueixen una creixent pressió sobre els sis­ temes de salut. En aquests temps de restriccions pressupostàri­ es, l’envelliment de la població condueix a la necessitat d’un canvi en l’assistència sanitària. Cal un enfocament triple basat en el disseny de programes que millorin l’experiència del paci­ ent, així com la salut de la població, alhora que en redueixin els costos. El desenvolupament de la biologia molecular ha revelat els mecanismes subjacents de moltes malalties, i ens ha condu­ ït cap a la medicina personalitzada. A mesura que la porta a l’atenció predictiva i preventiva s’obre, els problemes d’accés, lliurament i assequibilitat a l’atenció sanitària també s’alteraran: del tractament de les malalties a la preservació del benestar; d’un sistema reactiu, orientat a la malaltia, a un sistema de salut predictiu, personalitzat i preventiu.

Summary. The proportion of the world’s population over the age of 60 will more than double by 2050. By extension, this means an increase in the prevalence of chronic diseases, which are among the costliest and constitute a growing pres­ sure on healthcare systems. In this time of budget constraints, aging populations drive the need for change in healthcare. A triple-pronged approach is needed consisting of the design of programs that improve the patient experience as well as the health of the population while lowering the costs. The develop­ ment of molecular biology has revealed the mechanisms un­ derlying many diseases, in turn leading us towards personal­ ised medicine. As the door to predictive and preventive care opens, the problems of access, delivery and affordability of healthcare will be correspondingly altered: from treating sick­ ness to preserving wellness; from a reactive, disease-oriented healthcare system to a personalised, predictive, and preventive one.

Paraules clau: medicina personalitzada ∙ envelliment de la població ∙ sistemes de salut ∙ innovacions disruptives ∙ centres d’innovació terapèutica (CTI)

Keywords: personalised medicine ∙ aging population ∙ healthcare systems ∙ disruptive innovations ∙ centres for therapeutic innovation (CTI)

Around the world, life spans are increasing and populations are aging. The proportion of the world’s population over the age of 60 will more than double by 2050, to more than 1 bil­ lion people—or 37% of the active population (Fig. 1). By ex­ tension, this means an increase in the prevalence of chronic diseases, such as cardiac and pulmonary diseases, stroke, cancer, diabetes, and dementia, which are among the costli­ est and constitute a growing pressure on healthcare systems.

We are heading towards a situation in which 10 % of the pop­ ulation accounts for > 70 % of the healthcare costs (Fig. 2).

How are we going to maintain the quality and type of health­

care systems that in the past effectively met the demands of the respective populations, when healthcare costs have regu­ larly outpaced the gross domestic product (GDP) for around the last 30 years in a row? Healthcare currently accounts for approximately 10 % of GDP spending in most member coun­ tries of the OECD. In the United States, it is about 17 %.

There is a definite and imperative need for change. Since the global financial crisis hit in late 2008, the situation has become particularly dramatic. The crisis has taken a severe toll on the system’s input (funding from the government, companies, and taxpayers) and placed output (innovation in business, quality of healthcare delivery) under intense strain, raising questions as to how we shall pay healthcare costs in the future. In this time of budget constraints, aging populations drive the need for change in healthcare. This is a challenge that also opens up a wealth of opportunities for innovative approaches to the shift in healthcare delivery. For the elderly, for example, we must move from reactive care, which is typically hospital-based, to proac­ tive care, at home and integrated with social care.

* Based on the lecture given by the author at the Parliament of Catalo­ nia, Barcelona, on 23 October 2012 for the annual conference of the EPTA network, ‘From genes to jeans: challenges on the road to per­ sonalised medicine.’

Correspondence: M. Vendrell, Biocat, Passeig de Gràcia 103, 3ª planta, E-08008, Barcelona, Catalonia, EU. Tel. +34-933103330.

Fax +34-933103360. E-mail: info@biocat.cat

140 Contrib. Sci. 8 (2), 2012 Vendrell

To do so requires the following: • Innovative ways to achieve compliance • Early diagnosis • Integrated care models for chronic diseases (remote monitoring) • Increase uptake of technology-based solutions for inde­ pendent living • Corresponding integration of these concepts in the plan­ ning of buildings, cities, and environments Active and healthy aging is a priority in Europe, as addressed by the program ‘European Innovation Partnership (EIP) in Ac­ tive and Healthy Aging,’ which seeks to integrate projects ad­ dressing this issue from social, clinical, technological, and eco­ nomic points of view.

There are many different perspectives regarding how health­ care can become more sustainable. According to Harvard Business School professor Clayton Christensen, in his book

The Innovator’s Prescription, healthcare management is an is­ sue in which ‘disruptive innovation’ is needed to change the way healthcare is accessed, delivered, and paid for; to provide treatment for unmet clinical needs; and to bend the cost curve for healthcare. Innovation should provide not only improve­ ments in care but also value, defined according to patient out­ comes and the impact on healthcare system resources. ‘Dis­ ruptive innovations’ could come in the form of new technological enablers that simplify processes, or as new business models, or in the form of economically coherent value networks, all of which redesign the way we treat patients.

Wireless sensors and devices, genomics, social networking, mobile connectivity and bandwidth, imaging, health informa­ tion systems, the Internet, and big data are the top technologi­ cal trends in the digital revolution that are transforming health­ care (Fig. 2). There is a convergence of the potential of all these technologies and over time their level of development will make them more affordable. For example, in the space of 10 years, the cost of sequencing a genome has gone from more than 10 million USD to less than 1000 USD. Billions of data points per individual are being generated with these new technologies. The great challenge of medicine in the 21st century is complexity: How do we extract useful information from these data? How do we make correlations?

How do we interpret the data? Medicine is increasingly be­ coming an informational science: through systems and holistic approaches we will be able to understand wellness and dis­ ease, by attacking complexity efficiently; emerging technolo­ gies will allow us to explore new dimensions of the patient ‘data space’; and with the aid of transforming analytic tools we will be able to decipher the billions of data points for the indi­ vidual, by acquiring, storing, transmitting, integrating, mining, and creating predictive models.

Personalised medicine

Fig. 1. Population aged 60 and over: world and development re­ gions, 1950–2050. Source: Department of Economic and Social Af­ fairs, United Nations.

The development of molecular biology has revealed the mecha­ nisms underlying many diseases, in turn leading us towards per­ sonalised medicine. As the door to predictive and preventive care opens, the problems of access, delivery and affordability Fig. 2. Imperative for change: the few cost the most.

Personalised medicine: needs, challenges, and considerations

will be correspondingly altered: from treating sickness to pre­ serving wellness; from a reactive, disease-oriented healthcare system to a personalised, predictive, and preventive one.

The digitalization of biology and medicine is transforming the way we treat patients in what is now called P4 Medicine: predictive, because from the available information we can predict the phenotype or the pathology of a patient’s disease; personalised, because we can treat patients individually, according to their specific condition; preventive, because the emphasis will ex­ pand to include disease prevention; and participatory, because it enables patients to be an active part of their own healthcare.

Since 2003, coinciding with the Human Genome Project, we have progressed from understanding the structure of ge­ nomes to understanding the biology of genomes and subse­ quently the biology of disease. This new knowledge is the key to advancing the science of medicine and to improving the ef­ fectiveness of healthcare. The goal of personalised medicine is to be able to distinguish between patients who, while they may have the same symptoms, differ in the pathways underlying their disease. Moreover, we know that patients react very dif­ ferently to therapeutics, reflected in differences in the percent­ age response to therapy. With personalised medicine, non-re­ sponders can be identified prior to treatment, thus sparing these patients unnecessary discomfort and the healthcare sys­ tem unnecessary costs.

Let us take lymphoma as an example. Only 100 years ago, lymphoma was described as a disease of the blood. But thanks to molecular biology we have been able to discriminate be­ tween lymphoma and leukaemia (80 years ago) and between different types of lymphomas and leukaemia according to the dysfunctional mechanisms—from a total of five types 60 years ago to the 38 types of leukaemia and 51 types of lymphoma recognised today. But of course, all these studies take time and need to be conducted through huge consortiums based on col­ laborations between researchers from different fields. Here in Catalonia, these research groups include that of Professor Elías Campo. Dr. Campo’s laboratory is financed by the NIH and is leading a huge effort in the study of chronic lymphatic leukaemia (CLL). This group recently published a report on the types of cells that give rise to CLL and the elements that cause certain cells to develop this pathology. Another group is that of Profes­ sor Roderic Guigó, co-head researcher of the ENCODE project and a leader in bioinformatics who works at the Centre for Ge­ nomic Regulation. An example of the new business models is Inbiomotion, a spin-off of the Institute of Biomedical Research (IRB) and the Catalan Institution for Research and Advanced Studies (ICREA). Headed by Professor Roger Gomis, the com­ pany has just obtained venture capital to fund the development of an assay for use in validating the capacity of a biomarker to predict bone metastases in cancer patients.

Redefining business models The rules under which the healthcare industry has operated since its inception have changed completely because of glo­ bal economic trends, policy revisions, marketplace demands,

Contrib. Sci. 8 (2), 2012 141

and technological breakthroughs. Consequently, companies have been compelled to devise new strategies to ensure their continued success.

Biopharmaceutical companies are under pressure to reduce expenditures, as drug development costs increase, patents ex­ pire, competition from generics increases, regulations become stiffer, and pipelines dry up. The pressure is causing these com­ panies to redefine completely their approach to innovation, in turn realigning the roles of the different stakeholders, such as academia, venture capitalists, and biotech. Faster and cheaper ways to bring new drugs to the market are needed. The era of blockbusters such as Pfizer’s Lipitor is over. As the annual sales trends of traditional pharmaceuticals decrease and the sales of bio-therapeutics increase, the pharmaceutical industry is shift­ ing from medium efficiency/overall-patient medicines to an in­ creasing focus on high efficiency/patient-targeted and person­ alised therapies. As such there is a move away from internal R&D to approaching external resources for new ideas, e.g., through greater reliance on partnerships with biotech and academia as sources of innovation. Pharmaceutical companies are no longer able to generate and access all the information underlying the different pathologies they consider to be of inter­ est. Instead, they are financing collaborations with different re­ search groups and universities but also with smaller companies to be able to more efficiently access innovation. For example, Pfizer has established a CTI (Center for Therapeutic Innovation) at the University of California-San Francisco and another at New York University. The company has invested US$50M over 5 years to finance an open network of researchers from universi­ ties, hospitals, and Pfizer itself to identify and advance promis­ ing experimental drugs to proof-of-concept stage. This strategy is expected to accelerate pre-clinical development.

Similar approaches have been initiated by the other major pharmaceutical companies to achieve the same goal: bringing new technologies to the patient. Johnson and Johnson, for in­ stance, has launched a new incubator, Janssen Labs, in San Diego, California, which finances research that comes out of public laboratories, typically in the form of small biotech com­ panies. This is more efficient in terms of access to basic re­ search, in particular the elucidation molecular pathways. In ad­ dition, the industry is increasingly turning to other strategies, including the use of virtual models, the variabilization of fixed costs, and outsourcing non-critical steps in drug development.

Strong project management, research and clinical oversight, and the taxpayers’ involvement are critical in the new ecosys­ tem. Pharmaceutical companies must also work on a more eq­ uitable level with diagnostic companies, e.g., by involving them at earlier stages of drug development, as companion diagnos­ tics become more common. Diagnostics accounted for less than 2 % of healthcare spending but affected more than 60 % of critical decision-making. Interest in these measures is also being shown by large research institutes. Francis Collins, the director of the NIH, has launched the National Center for Ad­ vancing Translational Sciences (NCATS) to develop innovative ways to reduce, remove, or bypass the many time-consuming, costly bottlenecks in the translational pipeline. Again, the goal is to shorten the path to clinical phases.

142 Contrib. Sci. 8 (2), 2012 Vendrell

Genomic medicine, education, and society The imperatives for genomic medicine are: • Making genomics-based diagnostic routine • Defining the genetic components of disease • Comprehensive characterization of cancer genomes • Implementing practical systems for clinical genomics in­ formatics • Understanding the role of the human microbiome in health and disease Certainly we have to move from healthcare based on data collection to a system that is more proactive, in which the data are integrated. Bioinformatics and computational biology are the tools that allow us to analyse, integrate, and visualize the data. Moreover, training and education are essential. Clini­ cians are not trained to deal with all the genomic information that is available, nor do they possess the skills needed to cope with the possible social, communication, legal, and ethical im­ pacts of this information. In the coming years, primary and secondary education must incorporate this type of training, equipping students with general information about the ge­ nome, its ethical use, and the concepts of risk and probability.

Public outreach is crucial to truly sensitise the population about the opportunities but also the risks involved with the ad­ vancement of these new technologies. It is also important to train and build the genomic competences of genomic provid­ ers, clinicians, nurses, etc. And of course, the next generation of genomic researchers must be trained in statistics, compu­ ter science, and other, related fields that are currently not part of the biological and medical science curricula.

Similarly, with regard to genomics and society there are many ethical, psychosocial, legal, and public policy issues that need to be dealt with. The ability to identify an individual’s ge­ netic background and the possible outcomes of it could signifi­ cantly influence the behaviour of that person, the many implica­ tions of which must be taken into account.

Drivers. There are many drivers in the healthcare system. The main ones are: (i) patients, who want safer and more effective drugs but also a more active role in the own healthcare; (ii) pay­ ers, who need to be certain that the money spent generates significant medical benefit for the patient; (iii) regulators, whose approval of a drug is based on its safety and efficacy; and (iv) industry, which by reducing development time and costs can increase its success and thus their success rate.

Barriers. Of course, there are also barriers that hinder the full integration of personalised medicine into medical practice.

These include: (i) scientific and technical barriers, such as data management, storage and analysis; (ii) regulators, whose knowledge does not evolve at the same pace as scientific and technical progress demand; (iii) reimbursement processes, as clear guidelines specifying reimbursement for services provided are lacking, including the assurance to molecular diagnostic companies that they will be paid for the value they contribute;

(iv) physicians, who are challenged by structural barriers in which incentives are not aligned to prioritize prevention versus treatment and who are thus not trained accordingly; and (v) pharmaceutical and diagnostic companies, who must recog­ nize the need to work together to provide value to the system.

A more holistic strategy is needed, such as the top down approaches used in some countries to implement genomics in healthcare. In the United Kingdom, for example, a joint strategy for the National Health Service (NHS) was recently commissioned with the aim of incorporating genomics into the healthcare system. Thus, the Human Genomics Strategy Group (HGSG) is responsible for monitoring advances in ge­ netics and genomics research, both basic and translational, to evaluate their benefit to the healthcare services within the NHS: translating research into quality-assured care path­ ways; developing a service delivery infrastructure (from com­ missioning initial tests to counselling patients and their fami­ lies); providing a bioinformatics platform to store and manage data; training the NHS workforce; addressing the legal and ethical issues; and raising public awareness.

Challenges ahead A triple-pronged approach is needed consisting of the design of programs that improve the patient experience as well as the health of the population while lowering the costs. This is likely to best be accomplished by moving from a data-collecting healthcare system to one that is data-driven. We must devel­ op both medium- and long-term strategies (at the policy and clinical levels). Performance must be monitored by linking technology to health outcomes. There needs to be a realign­ ment of incentives such that waste is punished and quality and results rewarded. Other issues to be addressed include those dealing with reimbursement and the need to better promote the role of health technology assessment in verifying that in­ novations introduced into the system bring value to it and jus­ tify the additional cost. The technological revolution is limited by economic, organisational, and technological disparities among countries, and the capacity of these countries to over­ come them must be taken into account. But there will also be a new range of competences, in the form of systematic think­ ing, project management, communication, clinical genomics and IT. These will involve everyone who participates in the healthcare system, from clinicians to patients.

If we really want to have a continuously adapting health­ care system, one that is able to incorporate innovation and assessment, we must begin by being efficient, specifically at the level that connects care, research, and evidence, and in building networks between clinicians, patients, researchers, and society at large.

References 1. Biotech 2012: Innovating in the New Austerity (2012) Burrill & Company

Personalised medicine: needs, challenges, and considerations

2. Biotech 2011 – Life Sciences: Looking Back to See Ahead (2011) Burrill & Company 3. Chanock S (2012) Towards mapping the biology of the genome. Genome Research 22:1616-1625 4. Christensen CM, Hwang J (2009) The Innovator’s Pre­ scription: A Disruptive Solution for Health Care. McGrawHill, 496 pp 5. Ministry of Health (2012) Genomic Technology in Health­ care: Building on Our Inheritance, 83 pp

Contrib. Sci. 8 (2), 2012 143

6.

7.

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Institute for Systems Biology [www.systemsbiology.org] MedTech Europe [www.medtecheurope.org] Misfit [www.misfitwearables.com/references] Green ED,Guyer MS (2011) Charting a course for genomic medicine from base pairs to bedside. Nature 470:204–213 10. Smith M, Suanders R, Stuckhardt J, McGinnis M (2012) Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. The National Academic Press, 416pp

CONTRIBUTIONS to SCIENCE, 8 (2): 145–148 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.147 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Keynote Lectures

Forecasting limits in personalised medicine * Manuel Esteller ICREA Research Professor, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Health Institute (IDIBELL), Barcelona Department of Genetics, Faculty of Medicine, University of Barcelona, Barcelona

Resum. La medicina personalitzada significa trobar el tracta­ ment adequat per al pacient adequat en el moment adequat.

Per bé que aquesta és una idea molt global i molt simple, és molt difícil d’aconseguir. Fer-ho requereix un esforç conjunt dels professionals de tots els àmbits: científics, polítics, advo­ cats, economistes, etcètera, així com de sinergies entre investi­ gadors, companyies farmacèutiques i biotecnològiques, i entre el sector públic i el privat. En la medicina personalitzada del càncer, un tumor s’analitza segons la genòmica, genètica, epi­ genòmica, característiques cel·lulars i bioquímiques que té, i se cerca la baula més feble per a millorar la probabilitat que el paci­ ent respongui bé a la teràpia escollida. Els nombrosos avantat­ ges d’aquest enfocament fan que sigui crucial per a donar su­ port a la investigació que conduirà al descobriment de nous biomarcadors, capaços de predir la sensibilitat d’un pacient als medicaments, per al seu ús en la medicina personalitzada.

Summary. Personalised medicine means finding the right treatment for the right patient at the right time. Although this is a very global, very simple idea, it is nonetheless very difficult to achieve. To do so requires a concerted effort from profession­ als in all fields: scientists, politicians, lawyers, economists, etc., as well as synergies between researchers, pharmaceutical and biotech companies, and between the public and private sec­ tors. In personalised cancer medicine, a tumour is analysed ac­ cording to its genomics, genetics, epigenetics, epigenomics, cellular features, and biochemistry, and searches for its weak­ est link in order to improve the likelihood that the patient will respond to the therapy chosen accordingly. The numerous ad­ vantages of this approach make it crucial to support the re­ search that will lead to the discovery of new biomarkers ,capa­ ble of predicting a patient’s sensitivity to drugs, for their use in personalised medicine.

Paraules clau: medicina personalitzada ∙ epigenètica ∙ epigenòmica ∙ càncer ∙ metilació del DNA ∙ biomarcadors ∙ MGMT ∙ BRCA1

Keywords: personalised medicine ∙ epigenetics ∙ epigenomics ∙ cancer ∙ DNA methylation ∙ biomarkers ∙ MGMT ∙ BRCA1

Every year, 33,700 new cases of cancer are diagnosed in Catalonia; and one in two men and one in three women will develop cancer in their lifetime. Consequently, cancer is a very important health issue with serious financial implica­ tions. In the period 2001–2007, the number of cancer-asso­ ciated deaths decreased by only 1.3–1.4 % and the 5-year survival rates have not been optimistic either: 51 % for men and 63 % for women. The slightly higher rate for women mainly reflects the fact that survival rates for breast cancer patients are around 83 % because of good management of this type of cancer, which is often detected at very early

stages. But there are also tumours for which the outcome of affected patients is dismal, such as small-cell lung cancer (5year survival rate of 14 %).

Why has there been much less progress in treating lung and pancreatic cancers than breast cancer? Are there differences in the biology of these tumours? Is it only because of the earlier detection of breast cancer? We are not going to be able to get answers to these questions by random chance, nor is a single discovery in a small lab likely to cure cancer. Instead, a sus­ tained effort is needed over many years, aided by the European Union in bringing together the best scientists around the world to tackle the problem.

If we look at different types of cancer in Catalonia (2003– 2007, Fig. 1), we observe that the incidence of cancer is very similar to that in the rest of Europe: in men, prostate, lung and colon cancers are the most common malignancies. In wom­ en, breast cancer is the most frequent, but lung cancer is in­ creasing, as women started smoking later such that only now is the peak of what is expected to be a massive incidence of lung cancer occurring.

* Based on the lecture given by the author at the Parliament of Catalo­ nia, Barcelona, on 23 October 2012 for the annual conference of the EPTA network, ‘From genes to jeans: challenges on the road to per­ sonalised medicine.’

Correspondence: M. Esteller, Institut Català d’Oncologia – Programa d’Epigenètica i Biologia del Càncer, Av. Gran Vía 199-203, E-08908, L’Hospitalet de Llobregat, Catalonia, EU. Tel. +34-932607140 / +34-932607733. E-mail: mesteller@idibell.cat

146 Contrib. Sci. 8 (2), 2012 Esteller

Fig. 1. Cancer incidence in Catalonia (2003–2007): The ten most common tumour types.

Personalised medicine in the treatment of cancer What is the role of personalised medicine in the treatment of cancer? It is finding the right treatment for the right patient at the right time. Although this is a very global, very simple idea, it is nonetheless very difficult to achieve. To do so requires a con­ certed effort from professionals in all fields: scientists, politi­ cians, lawyers, economists, etc. Personalised medicine is like finding the Achilles heel, the weakest point, in the disease process. In conventional therapy, if a person has a tumour, the oncologist or the pathologist will analyze a biopsy under the optical microscope.

But if the patient’s tumour exhibits all the features of another patient’s tumour, the same treatment will be administered for the same clinical stage, although the two patients may com­ pletely differ in their therapeutic responses. This is because the cellular and molecular repertoires of the tumours may be com­ pletely distinct, reflecting different genetic alterations. Person­ alised medicine, by contrast, considers a tumour according to its genomics, genetics, epigenetics, epigenomics, cellular fea­ tures, and biochemistry, and searches for its weakest link in any one in order to improve the likelihood that the patient will respond to the therapy chosen accordingly.

There are many advantages to this approach, but first and foremost is the fact that patients receive the right treatment for the right tumour; second, the use of ineffectual therapies is avoided, which reduces healthcare costs and spares non-re­ sponding patients unnecessary toxicity while improving his or her quality of life.

of biomarkers that predict which drug the patient’s tumour should be more sensitive to. Moreover, there may be five/six genetic mutations targeted by five/six approved drugs to which patients are likely to respond. But this is just the tip of the ice­ berg and much more research is needed before a complete therapeutic picture is obtained for each and every patient.

Our lab, like many labs around the world, is studying an­ other aspect of cancer: epigenetics. Epigenetics considers DNA as a part of the story, but not the whole story. For exam­ ple, all our cells contain the same DNA, but neurons look very different from muscle cells. This is because different chemical markers regulate the expression of genes, including those re­ sponsible for switching-on and switching-off other genes.

These markers may consist of DNA-methylation, histomodifi­ cations, etc. and they are responsible for producing different cellular phenotypes. Thus, in monozygotic (identical) twins, even though their DNA is the same, one twin may develop breast cancer at age 25 and the other at age 65, because of epigenetic differences. In one twin the gene in question may be methylated, and in the other unmethylated [7].

Since the difference in control of the gene is chemical and does not involve sequences, it will not be detected by se­ quencing. In the words of Francis Collins, director of the US National Institutes of Health (NIH), “here is something where Mendel, Watson and Crick all seem to have missed some cru­ cial goodies.” Methylation can be imagined like a traffic signal, blocking the expression of some genes and enhancing the ex­ pression of others. At the moment we are studying these changes in DNA methylation and the genes that are altered in cancer only by DNA methylation. Some of this knowledge has reached clinical stages.

“One dumb tumour is smarter than 100 oncologists” This anonymous sentence appeared on the web a few years ago, but unfortunately it remains true today. The combined ef­ forts of 100 oncologists cannot cure 80–90 % of lung tumours.

Cancer is a complex disease that requires intense research ef­ forts and investment. But there is light at the end of the tunnel.

If we look at the genetics of cancer, what we have is a handful

From single epigenetic biomarkers to epigenomics As an example of therapy prediction in personalised cancer medicine, take the example of a particular marker, MGMT. Im­ agine that a patient goes to the doctor, who finds a tumour that is already metastatic. The doctor is unable to say what type of

Forecasting limits in personalised medicine

tumour it is, where it came from, and therefore what the appro­ priate therapy is. But what if we could take a picture or obtain a fingerprint and compare it to a collection of pictures/finger­ prints of known tumours? This would allow us to determine whether the patient’s tumour resembles breast cancer, colon cancer, a brain tumour, etc. (Fig. 2) [8,9] The tumour marker MGMT provides us exactly with this infor­ mation, in the form of a DNA methylation profile of a tumour sam­ ple analyzed for this tumour marker—and this offers a strategy for many of the markers we know. Accordingly, further research, diagnostic development, and clinical trials will require synergies between academics, researchers, pharmaceutical and biotech companies, and between the public and private sectors.

MGMT is a gene that codes for a DNA repair enzyme, and we discovered that the respective gene is silenced—methylat­ ed—in cancer. We made this discovery in 1999, before the ‘-omics’ revolution, by looking at candidate genes one by one and realizing that the MGMT gene is methylated in gliomas, which are tumours that start in the brain or spine. In its methyl­ ated state, MGMT cannot repair damaged DNA, such that tu­ mours with methylated MGMT have more mutations and are more aggressive [3] We showed that gliomas with MGMT methylation are more sensitive to the family of drugs that in­ cludes procarbazine, dacarbazine, BCNU, and ACNU, be­ cause they target the same site in the DNA [4].

Ten years later, in 2009, in the ‘–omics’ era, we were able to address this same issue using a micro-array, which identi­ fied MGMT, the same gene that we had found 10 years be­ fore. In parallel, scientists collaborating in the Cancer Genome Atlas Research Network arrived at the same conclusions [1].

This research was particularly satisfying because it yielded consistent results, with the effect of the MGMT gene validated using the new technology. Consequently, genomics seems to be a profitable route to finding new biomarkers for use in a

Contrib. Sci. 8 (2), 2012 147

personalised medicine approach to cancer.

Another example is BRCA1, a breast cancer susceptibility gene mapped to chromosome 17q21 by linkage studies. De­ fects in this gene are predicted to be responsible for 45 % of inherited breast cancers and >80 % of inherited breast and ovarian cancers. However, despite the high incidence of a loss of heterozygosity of the BRCA1 region in sporadic breast and ovarian cancers, BRCA1 somatic mutations have been found only in a few cases of sporadic ovarian and breast cancers.

This suggests that an alternative mechanism for the inactiva­ tion of BRCA1, or other genes in its vicinity, plays an important role in the development of sporadic breast and ovarian can­ cers. Importantly, several labs found that a genetic alteration in BRCA1predicts that the tumour cells will be very sensitive to a family of drugs called PARP inhibitors [2].

While this is great news, the disadvantage is that out of a hundred patients with breast or ovarian tumours, only one or two will have this mutation, which in turn reveals one of the typical problems of personalised medicine: drug approval. The problem is actually two-fold, because if the drug is of interest for only a few patients, the economic benefits for the company that produces it will be too low to justify its production. How can we treat small populations of patients such that pharma­ ceutical companies can recover their costs?

In this particular case, we determined that it is not only the mutation but also the methylation state of the gene that pre­ dicts DNA damage and therefore the response to the drug. If 25 out of 100 breast cancer patients can be identified as re­ sponders, in this case to PARP inhibitors, the production of this drug may be justified, by introducing the right biomarker [5,6].

Thus, in clinical trials, the inclusion of biomarkers is critical be­ cause they will encourage the approval of effective drugs.

Moreover, there are also many effective drugs from the past that can be rescued, if they are administered to patients tested Fig. 2. Methylation Specific PCR (MSP) of MGMT. ‘U’ in­ dicates the presence of un­ methylated genes of MGMT; ‘M’ indicated the presence of methylated genes. (A) Normal Tissue. IVD: in vitro methylat­ ed DNA as positive control for methylation; H20: water con­ trol for PCR. (B) Cancer cell lines. (C) Primary gliomas. (D) Colorectal carcinoma. (E) Lung carcinoma. (F) Primary lymphomas. Source: [3]].

148 Contrib. Sci. 8 (2), 2012 Esteller

for the appropriate biomarkers.

Nowadays, we can use micro-arrays to obtain a complete DNA methylation fingerprint of any tumour. Over 20 methylated genes predict the responses to different chemotherapy drugs [12]. At the moment, however, only one such gene, MGMT, has been approved in Europe, to stratify patients with glioma.

Other marker genes await approval for different reasons, e.g., they are very new, discovered in the last month, the last year, or the last 2 years. But in other cases there is insufficient inter­ est on the part of pharmaceutical companies in their diagnostic development and other sources of investment are lacking. In the latter case, investment must come from the public arena, especially the European Union.

Thus, research leading to the discovery of new biomarkers for use in a personalised medicine approach to cancer must be supported. For example, the project called ‘Curelung,’ [www.curelung.eu] coordinated from our lab in Barcelona, has been funded in its totality by the FP7 program of the Eu­ ropean Union. Its aim is to find biomarkers that predict the response to chemotherapy in lung cancer, which is still the most lethal type of cancer worldwide and specifically in Eu­ rope, where it accounts for 12.3 % of all new cancer cases every year. As noted in the first paragraphs of this article, lung cancer patients have a very poor prognosis, with a 5-year survival of only 14 %. One of the objectives of the project is to define the epigenetic markers that could determine the effi­ cacy of or resistance to targeted therapies. Preliminary results indicate the stratification of lung tumours according to their genetic background, which translates into improved patient selection. We now have the technology not only to sequence complete genomes, but also to obtain complete epigenomes, complete methilomes. In 5 years we will probably be able to understand much of the data generated in these types of analyses.

longer under patent protection or its continued manufacture is not financially profitable for the drug company. Third, we must stop using inefficient drugs. For example, some recent­ ly approved drugs increase survival by only 3 weeks—can this truly be claimed as a statistically significant effect? As a scientist, I do not see the benefit from their continued use.

And yet these drugs have been approved. Fourth, it is crucial to avoid toxicity to respect the quality of life of cancer pa­ tients. Some of the drugs used in cancer treatment are not only of extremely limited efficacy, they are highly toxic. Some patients prefer a shorter survival but one that offers a higher quality of life, allowing them to spend time with friends and family and to avoid unnecessary financial burdens. This deci­ sion must be honoured.

Personalised cancer medicine also translates into cost sav­ ings for the healthcare industry as it can avoid useless treat­ ment while freeing up resources for those patients likely to re­ spond. Pathologists, for example, often ask me, “How can I convince my hospital director to implement personalised can­ cer medicine in my hospital?” The use of IT and cost-benefit analyses are powerful tools for convincing hospitals that per­ sonalised medicine is not the way of the future; it should be implemented now.

References 1.

2.

3.

Final considerations on personalised cancer medicine 4.

To end this discussion on personalised medicine in the treat­ ment of cancer, I would like to offer five considerations. First, is the need to keep in mind that tumours are heterogeneous.

This means that even within a tumour there are small popula­ tions of cells that differ from the majority. Thus, even if we have a good biomarker for, say, 90 % of the cells, the remain­ ing 10 % will be different and are likely to be the source of a relapse, with reappearance of the tumour. The answer is likely to be personalised cancer therapy that differs accord­ ing to disease stage: primary tumour, metastasis, relapse, etc. Second, it is important that good drugs, both new and recycled, receive timely approval and that all clinical trials in­ clude the use of a biomarker, if at all possible. Very good drugs are already available. But if they are given to all patients at the same disease stage, their true benefit may not be ap­ preciated. However, if biomarkers predict the efficacy of the drug for the cancer stage of a particular patient, even if the drug is an older one he or she should receive it, even if it is no

5.

6.

7.

8.

9.

Cancer Genome Atlas Research Network (2008) Compre­ hensive genomic characterization defines human glioblas­ toma genes and core pathways. Nature 455:1061-1068 Cancer Genome Atlas Research Network (2011) Inte­ grated genomic analyses of ovarian carcinoma. Nature 474:609-615 Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA Repair Gene O6-Meth­ ylguanine-DNA Methyltransferase by Promoter Hyper­ methylation is a Common Event in Primary Human Neo­ plasia. Cancer Res 59:793-797 Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Bayling SB, Herman JG (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Eng J Med 343:1350-1354 Farmer H, et al. (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917-921 Fong PC, et al. (2009) Inhibition of Poly(ADP-Ribose) Pol­ ymerase in Tumors from BRCA Mutation Carriers. N Eng J Med 361:123-134 Fraga MF, et al. (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci 102:10604-10609 Heyn H, Esteller M (2012) DNA profiling in the clinic: applica­ tions and challenges. Nature Reviews Genetics 13:679-692 Rodríguez-Paredes M, Esteller M (2011) Cancer epige­ netics reaches mainstream oncology. Nature Medicine 17:330-339

CONTRIBUTIONS to SCIENCE, 8 (2): 149–154 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.148 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Keynote Lectures

Sustainability of personalised medicine * Oriol de Solà-Morales Pere Virgili Institute for Health Research (IISPV), Tarragona

Resum. Per aconseguir l’equilibri econòmic, hi ha una equació molt bàsica que diu que els ingressos han de superar les des­ peses. Tot i que la crisi financera ha fet que la despesa en sani­ tat hagi caigut dràsticament des de l’any 2010, el consum pú­ blic dels recursos d’assistència sanitària continua creixent.

L’única manera d’aconseguir l’equilibri és que la despesa en nous recursos quedi compensada per guanys futurs. Pot satis­ fer la medicina personalitzada aquesta necessitat? De mo­ ment, hi ha poques evidències que facin pensar que la medici­ na personalitzada reduirà els costos sanitaris pel fet de reduir els costos dels medicaments. En un escenari de medicina per­ sonalitzada per als propers anys, els ingressos seran, en el mi­ llor dels casos, neutres, mentre que les despeses per al diag­ nòstic i la prevenció augmentaran i el tractament tindrà, com a molt, un efecte neutral.

Summary. To achieve sustainability, there is a very basic equation that says that income has to be equal to or greater than expenditure. Despite the financial crisis, that lead ex­ penditure in healthcare to fall sharply since 2010, consump­ tion of healthcare resources continues to grow. The only way to achieve equilibrium is for expenditure on new resources to be balanced by future gains. But can personalised medicine meet this need? At the moment, there is little reason to think that personalised medicine will reduce healthcare costs by re­ ducing drug costs. In a personalised medicine scenario, in­ come will, at best, most likely be neutral in the coming years whereas expenditures for diagnostics and prevention will in­ crease and treatment will, at best, have a neutral effect.

Keywords: personalised medicine ∙ sustainability ∙ pharmacogenetics ∙ orphan drugs ∙ drug pricing mechanisms

Paraules clau: medicina personalitzada ∙ sostenibilitat ∙ farmacogenètica ∙ medicaments orfes ∙ mecanismes de fixació dels preus dels medicaments

The current environment The following are some thoughts that I would like to share on the sustainability of personalised medicine. I present my per­ sonal view because unfortunately there have been very few studies on this topic.

To achieve sustainability, there is a very basic equation that says that income has to be equal to or greater than expenditure.

The same applies for a good or commodity in question, so that, Income ≥ Expenditure (eq. 1) Income ≥ Price × Quantity (eq. 2)

* Based on the lecture given by the author at the Parliament of Catalo­ nia, Barcelona, on 23 October 2012 for the annual conference of the EPTA network, ‘From genes to jeans: challenges on the road to per­ sonalised medicine.’

Correspondence: O. de Solà-Morales, Institut d’Investigació Sanitària Pere Virgili (IISPV), Centre d’R+D+I en Nutrició i Salut, Avda. de la Uni­ versitat 1, 2a planta, E-43204 Reus (Tarragona), Catalonia, EU. Tel. +34-977759394. Fax +34-977759393. E-mail: direccio@iispv.cat

If we look at the cost of sequencing a complete genome, we see that it is steadily decreasing. According to Moore’s Law, which describes the trend of a computer processor doubling in complexity, generally translating into greater practical comput­ ing performance every two years accompanied by a decrease in cost, then sequencing costs (which depend to a great extent on computer hardware, computational tools, and other tech­ nological developments) should likewise progressively become much lower (Fig.1) [4]. The Google-launched initiative 23andMe, Inc., for example, has reduced the cost of sequenc­ ing an entire human genome from US$299 in 2012, to just US$99 in 2013. Thus, with regard to equation 2, price is no longer the limiting factor; instead, it will soon be quantity.

According to the OECD, while health spending grew, on aver­ age, close to 5 % from 2000 to 2009, expenditures in healthcare fell sharply in 2010 and remained flat in OECD countries in 2011 as the economic crisis continued to have a particularly strong impact in those European counties hardest hit by it (Fig. 2). But if we look at the standardised units of parity purchasing power, standardised to US$ to facilitate international comparisons, we

150 Contrib. Sci. 8 (2), 2012 Solà-Morales

Fig. 1. Cost of sequencing a human-sized genome and hypothetical data reflecting Moore’s Law. The costs include: labour, sequencing equipment, IT ac­ tivities related to sequence production, shotgun library construction, and indirect costs. There is a profound outpace of Moore’s Law in 2008 when sequencing centres transitioned to ‘second-/next-generation’ DNA sequencing technologies. Source: National Hu­ man Genome Research Institute [4].

Fig. 2. Average OECD health expenditure growth rates in real terms, 2000–2011, public and total. Source: OECD Health Data 2013 [5].

Fig. 3. Average annual growth in health spending across OECD countries in real terms, 2000–2011. Source: OECD Health Data 2013, [5].

see that healthcare expenditures have actually increased in re­ cent years (Fig. 3). In other words, despite the financial crisis, consumption of healthcare resources is growing. If this has a real impact on resource availability, then the only way to achieve equilibrium is for expenditures on new resources to be balanced by future gains. But can personalised medicine meet this need?

Income ≥ Price × (increased cost of new technology – future savings) (eq. 3)

Market size forecast: the supply side If we look at the supply side and try to assess the size of the mar­ ket, it becomes immediately clear that the numbers for the core of P4 medicine (personalised, preventive, predictive, and partici­ patory medicine), i.e., personalised medical care, nutrition and wellness, are very, very large. Moreover, the 2015 predictions for this market are even larger (Fig. 4). The figure for the market size in 2012 is approximately U$208 billion [7]. But we have to con­

Sustainability of personalised medicine

Contrib. Sci. 8 (2), 2012 151

Fig. 4. Personalised medicine market size, 2009 and 2015. Source: Pricewa­ terhouseCoopers analysis [7].

sider that much of this sum includes mergers and acquisitions, infrastructure construction for personalised medicine (new labs, and the hiring of skilled staff), with a far smaller amount devoted to drug costs and direct healthcare provision.

Table 1. Average percentage of the patient population for which a particular drug is ineffective Disease

Patient population for which a particular drug is ineffective (%)

Pharmacogenetics and public expenditure on drugs

Anti-depressants (SSRIs)

38

Asthma

40

A look at the phamacogenetics aspect of personalised medi­ cine, the equivalent of its Holy Grail, quickly shows that: (i) there are many diseases for which a particular drug is ineffective (Ta­ ble 1) and (ii) there are many diseases that have a genetic com­ ponent, reflecting genetic mutations that may be targetable by specific drugs. These observations provide the scientific ration­ ale underlying the claim that personalised medicine can lower drug costs. But we should also consider how drug prices are set: the smaller the target population, the higher the price.

Imagine a newly developed drug that will cure twice as many people or will cure the same number of people but only half of the population must be treated. There is no doubt that the price of that drug will be twice the current standard. Ac­ cordingly, there is little reason to think that personalised med­ icine will reduce healthcare costs by reducing drug costs. In this sense, we can learn a lot from the market for orphan drugs, i.e., drugs developed specifically to treat rare medical conditions (orphan diseases). The orphan drug market shares several features with personalised medicine. Moreover, sub­ stitution is not possible. In some diseases, treating a subpop­ ulation responsive to the drug does not mean that other pop­ ulations will not be treated, nor does it mean that whenever this drug fails—because it will still fail—other drugs will not be used, such that, ultimately, the drug armamentarium for cer­ tain diseases will expand. Finally, there is the J-curve effect on drug substitution, in which relatively efficient drugs are withdrawn to incorporate more effective (though less efficient)

Diabetes

43

Arthritis

50

Alzheimer’s

70

Cancer

75

Source of data: [4].

ones, but since price is supposed to be proportional to vol­ ume, the overall drug costs increase.

In Spain, the healthcare drug bill has decreased since 2003, reflecting the targeting of drug prices. However, the prescription trend has remained unchanged or is even slightly higher than before. Thus, by replacing cheaper drugs for more expensive ones, the impact will be even greater. A good example of this is Trastuzumab, a drug that targets breast cancer with a particular genetic biomarker. But while the incidence of breast cancer has decreased over the last decade, the use of Trastuzumab has increased. Why this is so merits investigation.

As the European Science Foundation has stated, “[a] realistic expectation could thus be cost containment rather than reduc­ tion, along with improved public health and quality of life. In other words, personalised medicine might be reasonably expected to generate a more efficient, rational use of resources. A more real­ istic promise is thus an improved return on investment.” [2] Another important consideration on the supply side is mar­ ket segmentation. Again, comparison with the orphan dis­

152 Contrib. Sci. 8 (2), 2012 Solà-Morales

ease market is appropriate [6]. In the view of some pharma­ ceutical companies, the identification of a gene that determines some features of a disease defines a separate disease with very low incidence, which accordingly should benefit from the privileges granted orphan drugs. This strate­ gy has been around for a few years, but its practice should be scrutinised. For example, atrial fibrillation is the most common cardiac arrhythmia. If, based on genetic findings, it were to qualify as an orphan disease, the impact on healthcare costs would be enormous. The same is true for chronic pulmonary disease, and the combined impact of these two diseases on healthcare costs would be insurmountable.

Market expectations and value From the business side, the pharmaceutical industry has a huge stake in genetic diseases, but its business model is not affected by supply and demand. Take the example of Roche, which a few years ago sought to buy the genetic diagnostics firm Illumina. In 2010, the share price of Illumina had fallen significantly, but as rumours of the purchase circulated, the share value increased steeply and then continued to fluctu­ ate. Meanwhile, the value of Roche’s shares remained stable.

While the investment was likely to be quite profitable, the gene diagnostics industry is very unstable. Indeed, in 2012, the value of genetics or genetics-based companies was ei­ ther stable or decreased slightly. For the major players in the pharmaceutical industry, the value of the genetics market is not clear, but it is innovation-based and therefore potentially highly profitable down the road.

It is highly likely that most biotechnology companies will fail in the very short run, so their business model is largely based on rapid growth followed by the sale of the company. This de­ mands that the company generates high short-term profits to guarantee its eventual sale. The figures for failure in the bio­ technology business are illustrative: if failure is defined as liqui­ dating all assets, with investors losing most or all of the money they invested in the company, then the failure rate for start-ups is 30–40 %; if failure is defined as the failure to see a return on investment, then the failure rate is 70–80 %; if failure is defined as the failure to meet projections, then the failure rate is a spectacular 90–95 %. The biotechnology bubble is expanding very fast, supported by enormous sums of money, but its burst seems inevitable.

the knowledge to recognise the value of the object of interest.

In the case of genetics-based and personalised medicine, the buyer has to be trained in its evaluation, despite the many uncertainties regarding the therapeutic impact on disease.

Because basically buyers do not purchase genes, they pur­ chase diseases and their treatment.

However, the major issue is that personalised medicine is, as defined by Pricewaterhouse Coopers, “a holistic, individual model of care that examines each individual’s unique makeup and designs appropriate strategies for maintaining wellness and treating illness. ” In most developed countries, we have been successful at building health systems that are not individual, but rather that are based on risk sharing. Individualised medicine goes against that idea, moving from the fundamental goal of population-based, public benefit to non-risk-sharing among in­ dividuals. This is an important consideration because there will be obvious consequences in the attempts to bridge this gap.

The main concerns of regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medi­ cines Agency (EMA), are efficacy, quality, and safety, whereas those of purchasers, on the demand side, are related to a drug’s efficacy, e.g., whether an appropriate adjustment on the supply side is needed to meet the health needs of citi­ zens, or whether a comprehensive or reasonable range of

Creating value: the demand side On the demand side are the buyers, which basically means the various countries, as purchasers of healthcare products.

As they say, beauty is in the eye of the beholder, and this is true for value as well. Value is subjective and related to indi­ vidual willingness to pay a price that is more than the cost of production. Value is related to several factors: novelty, appro­ priateness, competitive advantage, dynamic capabilities, or­ ganizational knowledge, etc. Furthermore, buyers must have

Fig. 5. Danseuse espagnole I (Spanish dancer I, 1928), by Joan Miró (Barcelona, Spain, 1893–Palma de Mallorca, Spain, 1983). Source: Reina Sofía National Art Museum, Madrid [http://www.museoreinaso­ fia.es/en/collection/artwork/danseuse-espagnole-i-spanish-dancer-i].

Sustainability of personalised medicine

services should be offered. Consider the painting by Joan Miró shown in Fig. 5. It is the minimal expression of a dancer, and a good reminder of the aim of public health: the minimum amount of healthcare provision that will achieve the appropri­ ate level of care while taking into account opportunity cost, equity, and combinations thereof.

Contrib. Sci. 8 (2), 2012 153

Table 2. Comparative cost of different procedures related to colorectal cancer diagnostic and treatment in Spain.

The health policy implications Understanding the macroscopic (ethical, legal, and social) im­ plications of genomic medicine requires an analysis of the ways in which genetic information and genetic approaches to dis­ ease affect people individually, both within their families and communities and in their social and working lives. Genomic medicine presents particular challenges to clinicians regarding their ethical and professional responsibilities [1]. At the micro­ scopic level there are pharmacogenetics and pharmacoge­ nomics implications, since patients vary in their drug respon­ siveness. Within a tumour, for example, some drug-targetable genes might be expressed and others not.

It is too soon to evaluate the link between personalised medicine and its impact on the population. In the word of Io­ annidis, “[…] the ambitious enterprise of personalised medi­ cine has to meet many challenges: a torrent of information with poor research and reporting standards, and a poor repli­ cation record; intrinsic difficulties in the predictive modelling; a lack of systematization; subtle effects of small magnitude; a disconnect between the science and its understanding by health practitioners and the general public; uncertainty even in the types of outcomes that we want to employ this informa­ tion for, if at all; and even risks of causing more harm than good in some circumstances.” [3] So we return to the basic equation, income ≥ price * ( ∑ diagnostic + prevention + treatment use) (eq. 4) Should diagnosis, prevention, and treatment compensate for the expected increased costs? Whenever new diagnostic tools and treatments enter the market, there is an increase in the target population as new cases are detected, which im­ plies higher diagnostic costs. Furthermore, in this newly dis­ criminated population, we can ask: What is the cost of the new treatment? What is the cost of the side effects? What is the cost of the use of healthcare resources? The new diagnos­ tic tools must also be incorporated into the payment system, as specified by the Diagnostic Related Group. Table 2 shows the comparative costs of different procedures related to colo­ rectal cancer for Spain. The cost KRAS determination is a fifth of that of total colectomy. How can we incorporate the cost of that genetic test into our current system? In terms of diagnosis and prediction, if the genetic risk of every 20-year old in Spain (455,824 people as of October 2012) is determined, at US$99 per test [9], this comes to a total of approximately 40 million Euros per year. This is an unsustainable figure by itself, and

Procedure

Cost (€)

Total colonoscopy or ileoscopy, biopsy

210.89

Rectosigmoidoscopy, biopsy

84.36

Hemicolectomies by laparotomy

940.80

Total colectomy

1282.91

Complicated biopsy

86.38

Intraoperative biopsy

172.76

Simple biopsy, macro- and microscopic study

69.11

Detection of KRAS

a

200.00

a

A biomarker for colon cancer. Source of data: Nomenclator, Medical Association of Barcelona (COMB) [www.comb.cat].

does not even take into account the consequences of a posi­ tive test. Moreover, there are issues related to insurance, reim­ bursement, and population segmentation.

How to adapt?

Current European Health Policy is based on redistribution. Per­ sonalised medicine may impose future difficulties in ensuring equity. For individuals at high risk, moral hazard tells us that they will overuse the system, whereas individuals at low risk will choose to opt out of the system, to avoid paying for the risk of others. This is a real threat to Bismarckian models (used in Ger­ many, France, Belgium, and the Netherlands), in which the health insurance system is financed jointly by employers and employees through payroll deductions such that everyone is covered and profit-making is forbidden, and doctors and hos­ pitals tend to be private. In this case, there would be a need to further redistribute risks. There would also be profound finan­ cial, legal, and ethical implications in: the use of genetics infor­ mation, insurance de-linked to genetic testing, controlling the shift from private to public because of high risks/costs, profitmaking, higher transaction costs incurred by private insurance to check risks, etc.

How can prices be controlled? Mostly through risk-sharing schemes, although the tools needed to assess outcomes are highly complex. The Velcade experience in the UK is an exam­ ple of the very high transaction costs. Also, risk-sharing is not efficient without budget limits. It is much cheaper to incorpo­ rate uncertainty in the selling price: paying for performance within a disease group, for procedures, for capitation systems (should they include some form of redistribution), etc.? With the currently available technology, IT systems could be used to carry out observational studies and analyse potential phe­ notypic correlations. By gathering information on age, sex, place of residence, places visited, and other information that is already available, complex IT solutions can be applied to ob­ tain a similar risk profile as that promised by genetic testing.

154 Contrib. Sci. 8 (2), 2012 Solà-Morales

This is something that insurance companies are well aware of.

So rather than engage in something for which there is no link between cost and consequence, there may be other sources of relevant information.

can only be achieved when there has been a recognition of value, the enactment of policy or legislation, and pilot studies and sufficient precedent in all these sectors.

References Conclusions 1.

There is a divide between populations and individuals, there is a high level of uncertainty, and there are macroeconomic consequences. Does that mean we should not invest in per­ sonalised medicine? No, just that it may be too early to reap its benefits. So why invest in uncertainty? First, to reduce un­ certainty. Second, because it means investing in research and thus in the technology that comes with it, and that means creating wealth while educating society. I believe that we should invest even if we do not really know what the result will be. But, by investing in a cluster of businesses, not only in genetics or personalised medicine, we are investing in an ecosystem that may ultimately deliver benefits, and perhaps not only to the healthcare system.

As to whether personalised medicine will be sustainable, income will, at best, most likely be neutral in the coming years whereas expenditures for diagnostics and prevention will in­ crease and treatment will, at best, have a neutral effect. The implementation of personalised medicine requires the conflu­ ence of several sectors: insurance coverage and reimburse­ ment, genetic privacy and legal protection, medical education, healthcare information technology, and regulation. The full im­ plementation and standardization of personalised medicine

2.

3.

4.

5.

6.

7.

8.

9.

Clayton EW (2003) Ethical, Legal, and Social Implications of Genomic Medicine. N Engl J Med 349:562-569 European Science Foundation (2012) Personalised Medi­ cine for the European Citizen. Towards a more precise medicine for the diagnosis, treatment and prevention of disease Ioannidis JPA (2009) Limits to forecasting in personalized medicine: an overview. International Journal of Forecast­ ing 25:773-783 National Human Genome Research Institute [http://ge­ nome.gov/sequencingcosts] OECD Health Data 2013 [http://www.oecd.org/health/ healthdata] Orphanet. The portal for rare diseases and orphan drugs [www.orpha.net] PricewaterhouseCoopers (2009) The New Science of Personalised Medicine: Translating the promise into practice [http://www.pwc.com/us/en/healthcare/publi­ cations/personalized-medicine.jhtml].

Spear BB, Heath-Chiozzi Margo, Huff J (2001) Clinical application of pharmacogenetics. Trends in Molecular Medicine 7:201-204 23andMe [www.23andme.com]

CONTRIBUTIONS to SCIENCE, 8 (2): 155–159 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.149 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Genetic and Socio-Cultural Risk Contributions to Disease

What is our level of knowledge about the genome today? * Miguel Beato Centre for Genomic Regulation, Barcelona

Resum. L’elucidació de la seqüència del genoma humà va marcar el començament d’una nova fase de la comprensió de la biologia humana. El pas del genotip al fenotip, per mitjà de la qual la informació continguda en el DNA es transcriu en forma de RNA missatger (mRNA) i després es tradueix en proteïnes, és complicada i no s’esdevé de forma directa. A més, la major part dels mecanismes que guien aquest com­ plex procés encara no s’han resolt. Des del concepte de gen fins als diferents tipus d’informació que estan codificats en el DNA genòmic del nostre nucli i l’epigenètica, aquest article resumeix l’estat dels nostres coneixements, però també pren nota del que encara no sabem, així com de les perspectives de futur en els estudis del genoma.

Summary. Elucidating the sequence of the human genome marked the beginning of a new phase of understanding of hu­ man biology. The pathway from genotype to phenotype, through which the information contained in the DNA is tran­ scribed in the form of messenger RNA (mRNA), and then trans­ lated into proteins, is a complicated one, and does not happen in a straight line. Furthermore, most of the mechanisms guiding this complexity have yet to be unravelled. From the concept of ‘gene,’ to the different types of information that are encoded in the genomic DNA in our nucleus, to epigenetics, this article summarises our current level of knowledge, but also takes note of what we do not yet know as well as the future perspectives in genome studies.

Paraules clau: flux d’informació genètica ∙ expressió gènica ∙ regulació del DNA ∙ dominis d’associació topològica ∙ xarxes genètiques ∙ epigenètica

Keywords: flow of genetic information ∙ gene expression ∙ DNA regulation ∙ topological association domains ∙ genetic networks ∙ epigenetics

Carved into the Temple of Apollo, there is an inscription that reads one of the Delphic maxims, “Know thyself.” Humans have never followed this advice as literally as when they de­ cided to elucidate the sequence of their own genome. How­ ever, despite all the talk about the human genome in the past decade, we still know very little about it and there are many things that are still completely unknown. Here I summarise our current level of knowledge, but also take notes of what we do not yet know as well as the future perspectives in ge­ nome studies.

Elucidating the sequence of the human genome marked the beginning of a new phase of understanding of human bi­ ology. But the genome is more or less the same in every or­ ganism, with the same combination of nucleobases (A, G, T,

C) producing thousands of different life forms, and we still do not know how this happens. The challenge of modern re­ search in genomics is to understand the relationship between genotype and phenotype, how the former establishes the lat­ ter. Genotype is the genetic makeup of a cell, or organism.

While it has been traditionally ascribed to the DNA, the cur­ rent view is that RNA also plays an important role, in that there may be a pool of RNA associated with sperm and oocytes that is transmitted from generation to generation. Phenotype refers to form, structure, and function. It is the composite of an organism’s observable characteristics or traits, which we refer to when we speak of morphology, development, bio­ chemical and physiological properties, phenology, and be­ haviour. It is the result of proteins, RNA and other macromol­ ecules and it is established de novo in each generation.

An organism’s genotype comprises a set of inherited in­ structions that are carried within its genetic code. The pheno­ type is the result of genotype expression but it is also influ­ enced by environmental factors and interactions between the two. Francis Crick provided an explanation for the flow of ge­ netic information within a biological system in 1958, and restated it in paper published 1970,

* Based on the lecture given by the author at the Parliament of Catalo­ nia, Barcelona, on 23 October 2012 for the annual conference of the EPTA network, ‘From genes to jeans: challenges on the road to per­ sonalised medicine.’

Correspondence: M. Beato, Centre de Regulació Genòmica, Edifici PRBB, C/ Dr. Aiguader 88, E-08003, Barcelona, Catalonia, EU. Tel. +34-933160100. Fax +34-933160099. E-mail: miguel.beato@crg.es

156 Contrib. Sci. 8 (2), 2012 Beato

“The central dogma of molecular biology deals with the de­ tailed residue-by-residue transfer of sequential information.

It states that such information cannot be transferred back to protein to either protein or to nucleic acid.” [2]

Or as 1968 Nobel Prize Winner Marshall Nirenberg said, “DNA makes RNA makes protein.”

But how does this work? In the very complicated pathway from genotype to phenotype, the information contained in the DNA is transcribed in the form of messenger RNA (mRNA), which is then translated into proteins. But this pathway is not a direct one; there are many intermediaries. During the syn­ thesis of proteins from DNA via mRNA, proteins interact with mRNA, with DNA, with other proteins, etc. Development is certainly not a straight line, nor are we merely a homunculus that simply grows in size. Rather, in virtually all species the embryo is completely different from the adult. A further mys­ tery is how, after the complicated but similar processes of gene expression and the many other transformative process­ es that constitute development, we can end up with organ­ isms ranging from a fly to a human.

The DNA code is commonly described as a succession of ‘letters’ (representing the four nucleobases) whose sequence confers meaning on the code, analogous to the way in which the sequence of alphabet letters forms a word. But, in fact, this is a very misleading analogy, because DNA is not a binary code. It is a complicated three-dimensional chemical structure with its own dynamics. It has no defined structure derived from its sequence, but can change shape and conformation. Thus, although the genotype is encoded in the DNA, DNA is also part of the phenotype, it actively interacts with proteins and RNA to convert its own information into the final phenotype.

How this comes about is one of the main questions so far left unanswered.

Types of genomic information 1. Information encoding mRNA and proteins If take a step by step look at the types of information that are encoded in the genomic DNA in the nucleus of our cells, it is very clear that it all begins with our genetic code. There are spe­ cific genes that are transcribed to yield mRNA, which together with tRNA guides the translation of proteins. The code itself is very clear: three nucleotides define an amino acid, with the se­ quence of amino acids progressively producing a protein. But while this process seems quite straightforward, it is actually very complex. Previously, it was accepted that one gene gives rise to one mRNA, which in turn gives rise to one protein. But we now know that one gene can generate twenty, thirty, or even a thou­ sand different mRNAs, through the re-combination of the differ­ ent exons of a gene, and thus to hundreds of different proteins.

Again, the mechanisms guiding this complexity have yet to be unravelled. Furthermore, the coding part of the genome repre­ sents < 2 % of our genome. In other words, the part of our ge­

nome that is translated into proteins is merely a tiny fraction of all the information that we inherit from our parents.

Likewise, the classic concept of a gene as the molecular unit of heredity in a living organism is obsolete. The more we learn about the genome, the more difficult it becomes to define what a gene is. I recently attended a lecture by a scientist from The ENCODE Project: the Encyclopedia of DNA Elements (http:// www.genome.gov/10005107), an international collaboration of research groups that aims to build a comprehensive list of functional elements in the human genome. Even this scientist could not come up with a definition of what a gene is. There are areas of the genome that encode proteins that carry out certain functions, but overlapping with this information may be infor­ mation that affects genes located in another region of the ge­ nome. The nature of the communication between genes, the genome, and the chromosome is another mystery.

2. Information regulating gene expression and DNA replication Although only 2 % of our DNA codes for proteins, most of the human genome is still transcribed into RNA. This RNA carries information; it is not junk as was thought until just a few years ago. Nonetheless what this information is has yet to be deter­ mined. I think we have to expand our view of the genome as not only a source of information that we can exploit but also as a source of other types of information. For example, it clearly contains regulatory sequences to control the expression of protein-encoding genes. These sequences make use of a dif­ ferent alphabetic system: rather than three nucleotides per one amino acid, it is the base pairs themselves that are important, with short sequences of base pairs recognised by DNA binding proteins. However, these regulatory sequences also constitute just a tiny fraction of the whole genome, approximately 1 %.

How do proteins read information? Figure 1 shows the double helix of DNA. As the strands are not symmetrically lo­ cated with respect to each other, there are unequally sized spaces, or grooves, between them. Proteins read regulatory information from the DNA by contacting base pairs through the major groove. By the interactions between the amino acids of regulatory proteins and reactive chemical groups of the DNA, the DNA sequence is read. Depending on that sequence and on the nature of the factors that read it, a gene is kept silent, activated, expressed in coordination with several other genes, etc., because the process is controlled by the same regulatory protein(s). This process underlies, for example, embryogene­ sis. Yet, even in this case, we are still talking about only a tiny fraction of the DNA contained in a genome.

3. Topological information Other information that can be considered important in our ge­ nome is that which is conserved through evolution and involved in processes such as mRNA stability. This information is poorly

What is our level of knowledge about the genome today?

Contrib. Sci. 8 (2), 2012 157

Fig. 1. Left: The struc­ ture of DNA showing with detail the structure of the four bases (ade­ nine, cytosine, guanine, and thymine) and the lo­ cation of the major and minor grooves. Right: Major and minor grooves of DNA. Source: Rich­ ard Wheeler (Wikimedia Commons).

understood whereas there is much that we know about the top­ ological information provided by DNA: conformational properties of the sequence, organisation in nucleosomes and organisation in chromosomes. A cell nucleus contains 2 m of DNA that is roughly 10 µm in diameter. The efficient packaging of this DNA is quite dramatic, and the way it is folded depends on the DNA se­ quence itself. Specifically, the way DNA is wrapped around the histone cylinder and how the chromatin fibre is compacted de­

pends on the tendency of its sequence to bend in particular di­ rections, and this property is encoded in the sequence of dinu­ cleotides, i.e., the sequence of consecutive nucleotides. In other words, there are three nucleotides for each amino acid, there are base pairs containing regulatory information, and there are dinu­ cleotides that guide DNA topology. In nature, DNA is found in at least three conformations: A-DNA, B-DNA, and Z-DNA, with BDNA as the predominant form and the one described by James Watson and Francis Crick (Fig. 2).

A free double helix of DNA is packed around a cylinder of eight histone proteins to form a nucleosome, the basic unit of DNA packing in the cell (Fig. 3). Thus, in our cells, DNA never comes alone, it is always wrapped in proteins. As noted above, the ability of DNA to bend is a function of the ways in which the dinucleotides can be deformed—information that is encoded in their sequence. Bending, in turn, determines which part of the sequence can or cannot be read, depending on whether it is on the inside or the outside of the helix. However, there are also other types of information that are less well understood, such as genetic networks, chromatin domains, etc.

4. Other types of information Fig. 2. DNA conformations. From left to right, A-, B-, and Z-DNA. The structure of a DNA molecule depends on its environment. In aqueous environments, including the majority of DNA in a cell, B-DNA is the most common structure. The A-DNA structure dominates in dehydrat­ ed samples and is similar to the double stranded RNA and DNA/RNA hybrids. Z-DNA is a rarer structure found in DNA bound to certain pro­ teins. Source: Richard Wheeler (Wikimedia Commons).

Other types of genomic information include genetic networks, chromatin domains and morphogenetic and metabolic pro­ grams. Figure 4 provides an example of a genetic network that determines the first 24 h of sea urchin development, during for­ mation of the mesoderm and endoderm, two embryonic lay­

Fig. 3. The current chromatin compaction model. Source: Richard Wheeler (Wikimedia Commons).

158 Contrib. Sci. 8 (2), 2012 Beato

Fig. 4. Regulatory gene network for endomesoderm specification in the purple sea urchin (Stronglycentrotus purpuratus): the view from the genome [3].

Fig. 5. Simple vs. complex gene organisation.

Fig. 6. Colour-coded chromosomes in the cell nucleus.

ers. Sea urchins have long provided developmental biologists with a model organism to study the processes of embryogen­ esis, gastrulation, and tissue differentiation. The network of genes involved in endomesoderm formation, as depicted in

Fig. 4, resembles a computer circuit, including backwards and forwards loops with numerous interactions. Yet, although the various steps in this very complex system have been well eluci­ dated, we still do not understand the nature of genetic pro­ grams and how they are organised.

An important consideration is that the number of genes in the genome does not account for the complexity of an organism. If we compare yeast (S. cerevisiae, S. tombe), a very simple plant (Arabidopsis), a fruit fly (Drosophila), a mouse, and a human, we find that there is little difference in the size of the coding propor­ tion of the genome (Fig. 5). The plant has 25,000 genes, just like humans, although we are much more complex. What is differ­ ent is the non-coding part of the DNA. And again, genes are not just fixed units, with a beginning and an end, but may have sev­ eral possible starts and overlap with non-coding DNA, etc.

The topology of DNA in the nucleus is one key component of the genetic information contained in the nucleus. Figure 6 shows a cell nucleus with its chromosomes, with the chromo­ somal DNA shown in different colours. We see that the chro­ mosomes are not intermingled: they occupy specific posi­ tions in the nucleus and have specific neighbours with which they interact. Space is therefore an important aspect of the genome, and not merely 3-dimensional space, but 4-dimen­ sional space at that.

In our laboratory, we study the interaction of chromosomes in breast-cancer cells. Figure 7 shows how different regions

What is our level of knowledge about the genome today?

Contrib. Sci. 8 (2), 2012 159

Fig. 7. Chromosome correlation ma­ trixes for human ductal breast epitheli­ al tumour cell line, T47D.

of the chromosome interact with each other. In this matrix of interactions, we can identify neighbouring structures in the genome. This information allows us to construct a map and a model of the chromosomes that can be confirmed by highresolution microscopy. We have found that chromosomal structure is such that certain regions are closer to each other than others, which may have functional implications.

This spatial view of the genome dramatically changes our way of thinking about it. Among other things, it means that the genome’s 3D configuration must be taken into account in mechanistic considerations. Spatial relationships add another level of complexity to the genome because elements that are close to each other do not necessarily interact equally or more efficiently. Instead, the genome contains topological associa­ tion domains, regions that may include five or ten genes behav­ ing as a unit. This is an interesting approach to understanding how the genome works: it emphasises the importance not of the gene but of the topological domain. In fact, if we look at a genomic region in greater detail, we see that the way that it folds correlates with the properties of that particular genomic compartment. These compartments can be modelled in order to predict what happens when certain genes are activated. For example, when just 10 nmol of a steroid hormone is added to a breast cancer cell for 60 min, organizational changes occur: some regions unfold and others compress [1]. This means that the genome is interpreting the signal, not only in terms of the local interaction of genes or regulatory sequence, but also in terms of the global compaction of the sequence.

To summarise, the genome can be viewed as an information cycle in which different types of information are encoded in the DNA, but with different coded sequences giving rise to different consequences. The coding information produces proteins, some of which have a regulatory function and thus recognise regulatory information, such as when this coding information should be expressed. Other proteins, such as histones, wrap the DNA in a specific manner to topologically control access to regulatory information. And finally, there are genetic networks,

chromatin domains, etc., all of which are as yet poorly under­ stood but which are known to be higher-level hierarchies that regulate complex biological processes.

Further complicating our understanding of the genome is epigenetics, i.e., the changes in gene expression or cellular phenotype cause by mechanisms other than changes in the underlying DNA sequences. Epigenetic phenomena include DNA methylation; chemical modification by histones that change the way DNA is packaged and determine its accessibil­ ity, etc. The epigenome is driveable; it can be dynamically al­ tered by environmental conditions. Changes in the epigenome can cause changes in both the chromatin and the structure of the genome. Furthermore, these changes can be passed down to an organism’s offspring. For these reasons, epigenetics is currently of great interest to the pharmaceutical industry, espe­ cially in cancer therapeutics.

Many questions about the genome remain to be answered, some have implications for normal growth and development, others are related to disease. Clearly there is much research to be done in this field. Elucidating the sequence of the hu­ man genome was an enormous collaborative undertaking, but to fully understand the structure and function of the ge­ nome will require even greater efforts.

References 1.

Baù C, Marti-Renom M (2011) Structure determination of genomic domains by satisfaction of spatial restraints.

Chromosome Res 19:25-35 2. Crick F (1970) Central dogma of molecular Biology. Nature 227:561-563 3. Davidson et al. (2002) A Genomic Regulatory Network for Development. In: Livi CB. Spblimp1/krox: A transcriptional regulator with a central role in endomesoderm specification in sea urchin embryos. Dissertation (Ph.D.), California Insti­ tute of Technology [http://thesis.library.caltech.edu/2458/]

CONTRIBUTIONS to SCIENCE, 8 (2): 161–165 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.150 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Genetic and Socio-Cultural Risk Contributions to Disease

Complex diseases: the relationship between genetic and sociocultural factors in the risk of disease * Eduardo Salas Gendiag, Barcelona

Resum. Les malalties complexes són causades per una com­ binació de factors genètics, ambientals i socioculturals, que interacciones entre si i amb el factor temps. Són molt comunes en la població i bona part també són cròniques, una combina­ ció que comporta alts costos d’atenció sanitària. Però també són malalties que es poden prevenir, fet que també té moltes implicacions importants per als sistemes sanitaris. Els biomar­ cadors ens permeten integrar les dades clíniques, bioquími­ ques i genètiques per a calcular millor el risc d’una malaltia. A més, en molts casos, també sabem com controlar els factors socioculturals que contribueixen a la malaltia, com ara l’adop­ ció d’una dieta i un estil de vida diferents. En aquest sentit, la medicina personalitzada convida els pacients a prendre acci­ ons clares per a millorar llur estat de salut, prevenir el desenvo­ lupament d’una malaltia o reduir-ne la gravetat.

Paraules clau: medicina personalitzada ∙ malalties complexes ∙ factors de risc genètics ∙ factors de risc socioculturals ∙ biomarcadors ∙ malaltia cardiovascular ∙ Cardio inCode

Complex diseases If we talk about the relationship between genetics and socio­ cultural factors in determining the risk of developing a particu­ lar disease, what we are in fact talking about is complex dis­ eases, in which the relationship between genetics and sociocultural factor is well established. Thus, in complex dis­ eases, general socio-economic, cultural, and environmental conditions, such as agriculture, food production, education, work environment, unemployment, water and sanitation, healthcare services, and housing, interact with social and community networks, individual lifestyle factors, and a per­

* Based on the lecture given by the author at the Parliament of Catalo­ nia, Barcelona, on 23 October 2012 for the annual conference of the EPTA network, ‘From genes to jeans: challenges on the road to per­ sonalised medicine.’

Correspondence: E. Salas, Gendiag, Joan XXIII 10, E-08950, Esplugues de Llobregat, Catalonia, EU. Tel. +34-935093233. Fax +34-935093295.

E-mail: eduardo.salas@gendiag.com

Summary. Complex diseases are caused by a combination of genetic, environmental and sociocultural factors, interacting with one another and with the factor of time. They are very common among the population and most of them are also chronic, a combination that implies high healthcare costs. But they are also preventable, which likewise has many important implications for healthcare systems. Biomarkers allow us to in­ tegrate clinical, biochemical and genetic data to better calcu­ late the risk of disease. Furthermore, in many cases we also know how to control the sociocultural factors contributing to the disease, such as adopting different diet and lifestyle choic­ es. In this sense, personalised medicine allows and invites pa­ tients to take clear actions to improve their health status, pre­ vent the development or reduce the severity of a disease.

Keywords: personalised medicine ∙ complex diseases ∙ genetic risk factors ∙ sociocultural risk factors ∙ biomarkers ∙ cardiovascular disease ∙ Cardio inCode

son’s sex and age. According to several studies, the weight of both genetics and sociocultural factors in the risk of devel­ oping a complex disease is 40–60 % [X].

What are the characteristics of complex diseases? First of all, as their name states, they are complex, as several factors interact to promote these diseases in a particular person. An­ other characteristic of complex diseases is that they are very common among the population, and most of them are chronic diseases. The combination of common and chronic implies high healthcare costs. But, these complex diseases are also often preventable, which likewise has many important implica­ tions for healthcare systems.

In complex diseases, genes and/or our sociocultural or en­ vironmental factors may predispose a person, or not, to a particular disease. Furthermore, these factors interact not only with each other but also with another important aspect, which is time. A clear and classic example of the time-related development of a complex disease is atherosclerosis. If we look at the timeline of atherosclerosis development, we see that endothelial dysfunction progresses, sometimes as long

162 Contrib. Sci. 8 (2), 2012 Salas

Fig 1. Stages of endothelial dysfunction in atherosclerosis. Source: Wikimedia Commons.

as four decades from the initial lesion until the atherosclerotic lesion. During this period, lipid accumulation in the arteries (foam cells, fatty streaks, intermediate lesions, atheroma) is eventually followed by the formation of fibrous plaques and complicated lesions (Fig. 1).

Accordingly, time is also a very important factor in the thera­ peutic equation, because it means that we have time to inter­ vene, in this case, to prevent the development of atherosclero­ sis. Another important point is that because of the combination of genetic and sociocultural factors, the disease process can be very fast or very slow. For example, some people with an adverse combination of genes and sociocultural factors devel­ op atherosclerosis and myocardial infarction by the age of for­ ty-five whereas those with a protective combination develop atherosclerosis very late in life or not at all.

Although there might not be much we can do about the ge­ netic contribution, in many cases we do know how to control the sociocultural factors, which is thus where our efforts should be concentrated. Sociocultural factors affect our exposure and vulnerability to disease because they include risk-taking behav­ iours. They are also important in gauging the effectiveness of health promotion efforts, including the access to, availability of, and quality of healthcare, and in the perceptions of and re­ sponses to health problems.

But, has acting on sociocultural factors ever proved to be efficacious? The answer is yes. Studies of the percentage de­ crease in deaths from coronary heart disease (CHD) attributed to treatment and to risk factor changes in different countries [1] have shown that, in most cases, altering sociocultural factors is highly relevant as it is associated with a two-fold higher reduc­

tion in CHD than obtained by treatment. The goal is to integrate sociocultural, biochemical, clinical and genetic factors in an al­ gorithm that could quickly provide an estimate of the risk to develop a disease, and therefore identify preventative meas­ ures or therapeutic objectives for a particular person.

Throughout the 2012 EPTA meeting, it was often stated that we still know very little about our genes and the genome.

While this is true, the following practical example shows that, despite these gaps in our knowledge, we can learn much from the information currently available to us. During a visit to Japan, I carried out a small experiment that, since I do not know how to read Japanese, would at least allow me to iden­ tify the Japanese characters for ‘exit’ and for ‘toilet.’ Rela­ tively quickly, I was able to clearly establish a relationship be­ tween some particular characters and the exit and other particular characters and the toilet, without any problem and with a success rate of 100%.

The same type of experiment can be carried out with bi­ omarkers. Thus, even though we do not understand the rela­ tionship between certain biomarkers and either disease or sociocultural factors, it does not prevent us from establishing a clear association between a particular marker and a particu­ lar disease/sociocultural factor and then validate it. Having done so, we will find that the knowledge, like the distinction between the toilet and the exit, is highly useful. And, analo­ gous to gradually acquiring competence in a foreign lan­ guage, as our understanding of the genome expands, we will eventually understand the reasons why those particular bi­ omarkers are associated with a particular disease. But for the time being, in order to identify risk, we do not need to under­ stand the whole story. Rather, we can use the aforemen­ tioned algorithms that combine different biomarker measure­ ments to determine the risk that the individual in question will develop the disease under study.

Several speakers at this conference also mentioned the Per­ sonalized Medicine Coalition (PMC), which represents innova­ tors, academics, industry, and patient and provider communi­ ties in the advancement and adoption of the concepts and products of personalised medicine. In the view of this organiza­ tion, the future might be as follows: An email alerts the physician about a new study demon­ strating a connection between multiple rare mutations and the likelihood of developing type 2 diabetes. The physician then conducts a quick search of her patient database and finds some patients who are at risk in that according to their medical records they have pre-diabetic symptoms. The physician then sets up appointments with these patients to consider proactive treatment with drugs that can prevent disease onset. Those patients at risk but without pre-diabetic symptoms are sent a strong reminder and advice on diet and lifestyle choices they can adopt to avoid disease occurrence.

While for the PMC this is a view of the future, there are sev­ eral current examples showing that this future is now. One thing that we should keep in mind, and which is illustrated by the PMC’s vision, is that genetic and other personalised med­ icine tests should be channelled through physicians, and not offered openly to the general population. This can be regulat­

Complex diseases: the relationship between genetic and sociocultural factors in the risk of disease

ed in the same way that the acquisition of antibiotics is regu­ lated, by the requirement for a doctor’s prescription. It is im­ portant to remember that genetic tests provide information that can be very useful, but it must be used specifically and the results evaluated by those with the skills to do so.

The case of Cardio inCode To illustrate this point, I offer as an example one of the services that Gendiag (www.gendiag.com), the biotechnology compa­ ny I work for, has developed. Cardio inCode® is a personalised medicine product that is already available to physicians. It is a cardiovascular risk assessment DNA-chip that has been de­ signed to predict low-intermediate cardiovascular risk. By iden­ tifying gene polymorphisms related to cardiovascular disease phenotypes and their markers in 111 gene polymorphisms, it assesses an individual’s risk of suffering from a cardiovascular event (angina, myocardial infarction, stroke, or peripheral arte­ riopathy) in the next 10 years. To calculate this risk, Cardio in­ Code incorporates clinical, biochemical, and genetic data into a validated risk algorithm. It also assesses the genetic predis­ position to develop the classical cardiovascular risk factors. Fi­ nally, for the physician to provide advice to his or her patient, Cardio inCode’s report also considers the sociocultural factors affecting that particular patient.

For all platforms in personalised medicine, it is important to obtain both clinical validation and analytical validation. Cardio inCode has been validated clinically in several studies. Specifi­ cally, clinical validation was aimed at establishing the associa­ tion of disease biomarkers with the risk of the disease, and whether the approach used by Cardio inCode to calculate car­ diovascular risk improves the predictive capability of the risk equations currently in use. The linear relationship between as­ sociated risk and the number of risk alleles was confirmed in two different large cohorts during clinical trials carried out by the Cardiovascular Group of the Municipal Institute for Medical Research of the Hospital del Mar and Gendiag [3,4].

To validate the biomarkers, the criteria of the American Heart Association for the evaluation of novel markers of cardio­ vascular risk were followed [2]: 1. Proof of concept: Do novel marker levels differ between subjects with and without outcome?

2. Prospective validation: Does the novel marker predict the development of future outcomes in a prospective cohort or nested case-cohort/case cohort study?

3. Incremental value: Does the novel marker add predictive information to established, standard risk markers?

4. Clinical utility: Does the novel risk marker change predict­ ed risk sufficiently to change recommended therapy?

5. Clinical outcome: Does the use of the novel risk marker improve clinical outcomes, especially when tested in a randomised clinical trial?

6. Cost-effectiveness: Does use of the marker improve clin­ ical outcomes sufficiently to justify the additional costs of testing and treatment?

Contrib. Sci. 8 (2), 2012 163

The association of genetic markers with the disease is in the same range as that of currently used risk factors, such as cholesterol and high blood pressure, whose association with cardiovascular disease is well studied. From the results of Gendiag’s studies, it was concluded that Cardio inCode pro­ vides more accurate information than obtained from the clas­ sical risk equations [3,4]. This allows for more effective pre­ ventive actions, a better definition of therapeutic objectives, and their improved achievement.

Personalised medicine allows and invites patients to take clear actions to improve their health status. Figure 2 shows an example of some of the sections of the report we provide to patients. It allows us to inform a patient about the risk of de­ veloping coronary heart disease (CHD) based on his or her genetic profile genes and relevant sociocultural factors, but also to teach the patient how, by following certain actions, the risk of cardiovascular disease can be very significantly re­ duced. Thus, personalised medicine allows the physician to invite the patient to collaborate in reducing disease risk.

A few decades ago, when we talked about cholesterol as a risk factor, we meant total cholesterol. But we now know that cholesterol is made up of different fractions, and that higher serum concentrations of LDL particles (low-density lipopro­ teins) and lower serum concentrations of functional HDL parti­ cles (high-density lipoproteins) are strongly associated with cardiovascular disease, because they promote atherosclero­ sis. By measuring cholesterol in blood and identifying the differ­ ences between LDL and HDL and their relationship to CHD, we have been able to develop more appropriate drugs for the pre­ vention and treatment of atherosclerosis and CHD. In personalised medicine, a commonly voiced concern is how insurance companies will use the information provided by a person’s sequenced genome. But we forget that risk factors can be used in the same way. Should we be as con­ cerned about our cholesterol measurements as we are about our genes? Cholesterol is a marker of risk: high serum choles­ terol implies a higher risk of developing CHD. But most of us do not object to providing insurance companies with our cho­ lesterol data. Yet the ethical concerns are essentially the same for cholesterol levels as for genetic markers. Further­ more, today, we do not have any problem in analyzing a per­ son’s cholesterol level, but in the early 1950s, when the Framingham Heart Study (www.framinghamheartstudy. org)—a long-term ongoing cardiovascular study on the resi­ dents of Framingham, Massachusetts—began to evaluate these cohorts, they too were measuring several factors whose full implications they could not yet understand. This is currently the case for genetic information, which we can rela­ tively easily collect but only scarcely interpret.

Insights gained from experience I would like to share some thoughts based on our experience in the development of personalised medicine products. First, with the aid of biomarkers—although we still do not under­ stand how they work—we can integrate clinical, biochemical,

164 Contrib. Sci. 8 (2), 2012 Salas

Fig. 2. (A) Results from genetic factors associated with cardiovascular risk. Probability of coronary event in the next 10 years based on REGIOR function. (B) Results from genetic markers associated with pathophysiologi­ cal pathways.

Fig. 3. Pioneering services in personalised medicine.

genetic, and lifestyle data to better calculate disease risk.

With improved estimates, more efficacious therapeutic and preventative objectives can be established and achieved. We will thus be better able to prevent disease development and to reduce disease severity.

Second, other uses of personalised medicine are also possi­ ble, such as early diagnosis, prognosis, selection of best treat­ ment, and patient follow-up. The field of personalised medicine is just beginning, so our capabilities in terms of prediction, diag­ nosis, and prognosis are limited. But as knowledge, technologi­ cal development, and experience accumulate, so will our aware­ ness of the potential of personalised medicine. Figure 3 shows schematically how the individualised detection of genetic vari­ ants can help us predict disease predisposition as well as its use in early diagnosis and prognosis. Ultimately, we will become more efficient in prevention and treatment, thus increasing pa­ tients’ quality of life and reducing health costs.

Third, it is interesting to consider that the technology re­ quired for personalised medicine is in continuous develop­ ment. Nowadays, there is intense competition between com­ panies but also difficulties in developing and bringing to

market in vitro diagnostics (IVD) products. Well developed laboratory developed tests (LDTs) should be admissible. In the end, there will most likely be two main, complementary products: point of care (POC) and next generation sequenc­ ing (NGS). But in my opinion, from a legislative point of view, NGS should become the gold standard.

Fourth, genetic tests should be used in clinical practice and they should be reimbursed, provided that the test has clinical and analytical validation and has been subject to rigorous costefficiency studies. Educational programs on personalised med­ icine should be initiated at all levels: aimed at the public, physi­ cians, and politicians. In addition, cohort studies should be established and promoted in different countries. We have to be able to include samples and clinical data from different popula­ tions in order to better validate personalised medicine prod­ ucts, and to do so faster.

Finally, there is the need for the proper allocation of resourc­ es. In Europe, we have been very good at providing funding for basic research, conscious that it generates knowledge, wealth in the form of patents, and the overall development of society.

But we have also started funding translational medicine, as it

Complex diseases: the relationship between genetic and sociocultural factors in the risk of disease

facilitates the applicability of knowledge, increases the value of knowledge, and rewards public investments in R&D, in terms of small, medium, and large enterprises, employment, and a better public health system. The latter depends on adequate funding for the application to society of the products we have developed. It does not make sense to fund basic research and translational medicine if in the end we do not benefit, economi­ cally or in terms of improved health, from our investments. Re­ sources set aside for personalised medicine applications will increase the overall efficiency of the system, provide patients with better treatment, improve the quality of life of the popula­ tion, reduce the wasteful exposure of patients to ineffective treatments, reduce treatment side effects, delay the develop­ ment of chronic diseases, emphasise prevention over treat­ ment, and provide resources to stakeholders in the value chain.

To achieve these goals requires fairly distributed resources, both from funding agencies, proving funds for clinical analysis of the new personalised medicine tools, and from governmen­ tal bodies, to finance the purchase of these technologies so that they become adopted by the health system.

Contrib. Sci. 8 (2), 2012 165

References 1. Ford ES, Ajani UA, Croft JB, Critchly JA, Labarthe DR, Kottke TE, Giles WH, Capewell S (2007) Explaining the decrease in U.S. deaths from coronary disease (1980– 2000). N Eng J Med 356:2388-2398 4. Hlatky MA, et al. (2009) Criteria for Evaluation of Novel Markers of Cardiovascular Disease. A Scientific State­ ment From the American Heart Association. Circulation 119:2408-2416 2. Lluís-Ganella C, Lucas G, Subirana I, Sentí M, JimenezConde J, Marrugat J, Tomás M, Elosua R (2010) Efecto aditivo de diferentes variantes genéticas en el riesgo de cardiopatía isquémica. Rev Esp Cardiol 63:925-933 3. Lluis-Ganella C, Subirana I, Lucas G, Tomás M, Muñoz D, Sentí M, Salas E, Sala J, Ramos R, Ordovas JM, Mar­ rugat J, Elosua R (2012) Assessment of the value of a genetic risk score in improving the estimation of coronary risk. Atherosclerosis 222:456-463

CONTRIBUTIONS to SCIENCE, 8 (2): 167–169 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.151 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Bioethics and Social Responsabilities

Challenges for industry developers * Alicia Granados Genzyme, Barcelona

Resum. Cada vegada és més evident que el model actual de recursos i desenvolupament no és sostenible. En aquest con­ text, l’assessorament en tecnologia sanitària (HTA), un camp multidisciplinari d’anàlisi de polítiques que examina les impli­ cacions mèdiques, econòmiques, socials i ètiques de la tec­ nologia mèdica en l’assistència sanitària, està guanyant im­ portància. Com que proporciona eines que permeten esbrinar el valor de la innovació, pot assessorar en la presa de decisi­ ons en el sistema de salut, en l’àmbit clínic, de recerca i de desenvolupament. La sostenibilitat del sistema sanitari està fortament relacionada amb la responsabilitat social i hem de treballar perquè hi hagi aliances entre el sector públic i privat, i tornar-nos més eficaços a l’hora d’integrar innovacions soci­ als, organitzatives i polítiques per tal d’oferir la millor qualitat d’assistència sanitària que el sistema es pugui permetre.

Paraules clau: medicina personalitzada ∙ assessorament de tecnologia sanitària (HTA) ∙ pressions de la indústria sanitària ∙ malalties rares ∙ responsabilitat social

The context: pressures and drivers of the health system Healthcare policymakers and providers are under pressure from various sources. Public expectations, changes socio-de­ mographics, disease patterns, risk factors and scientific knowl­ edge, the globalization of information on healthcare systems, increased patient participation, pressures to achieve financial sustainability and transparency, and the growing awareness of the need for evidence-based decision-making in healthcare are just a few of the most important issues that contribute to in­ creasing pressure on the health system.

But what are the pressures on health industries? There are legitimate pressures, such as increased scientific scrutiny of

* Based on the lecture given by the author at the Parliament of Catalo­ nia, Barcelona, on 23 October 2012 for the annual conference of the EPTA network, ‘From genes to jeans: challenges on the road to per­ sonalised medicine.’

Correspondence: A. Granados, Genzyme, Aribau 127, E-08036, Bar­ celona, Catalonia, EU. Tel. +34-933632150. Fax +34-933632151.

E-mail: alicia.granados@genzyme.com

Summary. It is becoming increasingly clear that the current resource and development model is an unsustainable one.

Health technology assessment (HTA), a multi-disciplinary field of policy analysis that examines the medical, economic, social, and ethical implications of medical technology in healthcare, is gaining importance in this context. By providing tools with which to scrutinise the value of innovation, it can inform deci­ sion-making in the healthcare system, at the clinical, research and development levels. Sustainability of the healthcare sys­ tem is strongly related to social responsibility, and we have to work towards more effective public-private partnerships, and become more adept at integrating social, organisational and policy innovations in order to deliver the highest quality of healthcare that the system can afford.

Keywords: personalised medicine ∙ health technology assessment (HTA) ∙ health industry pressures ∙ rare diseases ∙ social responsability

innovations, but there are also pricing pressures, the threat of biogenerics and biosimilars, the consequences of the loss of patents, obsolete commercial models, and inflexible costs structures. It is becomingly increasingly clear that the current resource and development model is an unsustainable one. It is also clear that society’s trust of the pharmaceutical indus­ try has eroded.

In this context, there is a sense of change in health sys­ tems as they are once again evolving. What are the drivers of these changes? First, of course, there is innovation in bio­ medical science. Thanks to complex systems biology and molecular biology, to cell, gene, and enzyme therapy, and to tissue engineering, for example, we have begun to under­ stand health and disease in a new way, one that is certainly very different from how we defined medicine just a few years ago. Moreover, personalised, or stratified, medicine, through genetic research and molecular diagnostics, is changing the paradigms of biomedical and health science research.

But there are also drivers in the healthcare system; these are related to the coverage and provision of healthcare. Currently, there is a debate as to whether we should push for governance or managerialism, in other words, for more strategic or more

168 Contrib. Sci. 8 (2), 2012 Granados

tactical approaches. I think we have to do both. But the deci­ sion strongly influences the direction in which health systems evolve. Whether doctors can reasonably be expected to be­ come leaders, not just healthcare workers, is another matter of important debate, raising questions about quality and efficien­ cy, but also about professional solidarity and ethical impera­ tives. Then we have the adversarial relationship between the public and private sectors. I believe that in response to the need for cooperation in matters involving social and institution­ al responsibility, new public-private partnerships will develop.

There is also the driving pressure for healthcare accountability and last but not least, health technology assessment.

Personalised medicine and health technology assessment Health technology assessment (HTA) is a growing movement all over the world. Although it started just a few years ago, it is now a new paradigm in healthcare. But, depending on who you ask, there are different interpretations about what HTA is.

For healthcare policy makers and providers, HTA is a tool with which to scrutinise the value of innovation. How? By looking at the scientific evidence in a systematic and exhaus­ tive way and then trying to understand the quality of the evi­ dence, whether published or not, in relation to the projected costs. This information can inform decision-making in the healthcare system, at the clinical, research and development levels. However, the health industry has different perceptions of HTA, as an instrument that either poses barriers to innova­ tions or advocates cost-saving measures.

The current reality, not only for personalised medicine but for every innovation of interest to healthcare systems and in­ dustry developers, is that it is important to recognise that an innovation must be more than a scientific novelty; rather, it must, for example, be able to provide therapeutic added value superior to that of already available alternatives or standards of care. Otherwise, it will enter or be maintained in the health­ care market only with difficulty. Growing scientific knowledge often results in our confusion, as the ‘yes’ or ‘no’ responses of governments or HTA agencies no longer suffice. Nowadays, the answer is more typically something like, ‘yes, but…’ Or more specifically, ‘I allow you to enter the market but with a policy of coverage with evidence development.’ This is a type of conditional coverage in which payers agree to cover new medical technologies, provided that patients receiving care that makes use of those technologies are enrolled in a clinical study to generate the additional benefit and safety information needed to make informed coverage decisions. In fact, cover­ age with evidence development is a managed-entry scheme designed to address key health policy issues pertaining to the increasing cost pressures, uncertain effectiveness, and great­ er patient benefit per unit of currency spent. Knowledge is pressuring the system to be more creative, and policies such as coverage with evidence development ensure the preserva­ tion of public health safety issues without impeding techno­ logical evolution and innovation.

The rules on how these policies should be implemented, who pays for what, etc. are still not clear, but the outcome is of great interest to industry because it offers a path for future investments in research and development. Both the healthcare system and the healthcare industry are being forced to adapt, which requires that they work together. For now, at least, conditional coverage linked to evidence development is a way to do so.

Impacts and difficulties of personalised medicine Among the impacts of personalised medicine are: 1. Higher probability of desired outcome with a drug 2. Low probability of untoward side effects 3. Preventive strategies 4. Focused therapies 5. Potentially better health outcomes 6. Recognition of the need to change research and health­ care provision paradigms and relationships 7. Recognition of the need for holistic HTA: clinical, eco­ nomic, social and ethical assessments that include the views of patients 8. Genomics technology that generate massive amounts of information 9. Recognition of the need for alignment between pharma­ ceutical and diagnostics companies 10. New business models 11. The discovery of genes associated with specific diseas­ es, which for patients with rare diseases and subpopula­ tions of those with common diseases offers novel diag­ nostic and treatment strategies Among the main difficulties are: 1. Scientific challenges posed by the lack of validated mo­ lecular markers and consensus regarding the kind of evi­ dence needed to prove their value to HTAs 2. How do we get this evidence? Who should pay for it?

3. Operational issues 4. Economic challenges due to poorly aligned incentives 5. Ethical dilemmas not systematically addressed 6. Lack of clarity on how to evaluate clinical validity and util­ ity for decision-making 7. Lack of a revised regulatory framework 8. Opposition by healthcare and industry ‘silos’ 9. The global recession, which has forced governments to reconcile budgetary challenges. Is there a trade-off be­ tween efficiency and solidarity?

Current challenges for industry developers Below are examples from the field of rare disease, in which I work, but they show that even if we are able to identify a rare disease component, it does not mean that there are few barri­ ers to entering the market. Figure 1 shows the number of or­

Challenges for industry developers

Contrib. Sci. 8 (2), 2012 169

Table 1. Percentage of HTA decisions Agency / Institution

Yes

Yes/Restricted

No

National Institute for Health and Care Excellence (NICE)

67 %

–

33 %

Pharmaceutical Benefits Advisory Committee (PBAC)

4%

56 %

40 %

All Wales Medicine Strategy Group (AWMSG)

29 %

29 %

43 %

Scottish Medicines Consortium (SMC)

22 %

32 %

46 %

National Centre for Pharmacoeconomics (NCPE)

40 %

–

60 %

CDAC

27 %

–

73 %

Final reflections Here are just three final reflections. The first one is how can we keep healthcare systems sustainable in a changing scien­ tific and social context? In my opinion, sustainability is strong­ ly related to social responsibility. We need to avoid the ‘silo’ approach and aim towards more collaborative tools and pro­

Designated products Designated products that received market approval Number of products

phan drug designation applications, designations and ap­ proved orphan products per year. Table 1 shows the percentage of HTA decisions by different agencies. ‘No’ indi­ cates the percentage of components for which market entry was sought but not approved because evidentiary require­ ments were not met.

As industry developers, we need to receive consistent mes­ sages from the healthcare system regarding evidentiary re­ quirements and what is valued by health systems, because this will impact drug development plans. We can be very inefficient in our development processes and very ineffective. If we do not have consistency with respect to the evidence necessary to demonstrate the value of a component, then we are lost.

I would like to transmit the importance of harmonising the method and the criteria for evidentiary requirements for health­ care systems. In the therapy of rare diseases, and similarly in personalised medicine, the challenges for treatment developers are in measuring outcomes. In both cases, we are talking about small, geographically dispersed populations that present recruit­ ment challenges for clinical trials, in that low prevalence limits the ability to perform multiple studies. Also, the heterogeneity of rare diseases poses challenges to uniform treatment paradigms and to study design. The slow progression of the disease means that measurable effects may take years; surrogate endpoints (renal, cardiac, neurological disfunctions, among others) are often more apparent than final outcomes such as mortality. Furthermore, the regulatory agency requirements are not always aligned, nei­ ther are the HTAs. Finally, post-approval commitments to per­ form more real life studies to further understand the clinical out­ comes of therapies require continuous significant investments.

This means that the standards of evidence-based medicine can­ not be easily achieved, and methodological and health technol­ ogy assessment interpretation and innovation are crucial.

Designation applications submitted

Year

Fig. 1. Number of orphan drug designation applications, designations, and approved orphan products by the FDA Office of Orphan Product Development (OOPD) per year.

cesses. We have to be more inclusive, working from more ef­ fective public-private partnerships, with clear rules. Also, we have to deliver the highest quality of healthcare that the sys­ tem can afford. We need to have a better vision of integrated care and we must become more adept at integrating social, organisational and policy innovations, not only technological innovations. Technological innovation without the organisa­ tional frameworks that allow its effective and efficient imple­ mentation is a recipe for disaster.

The second reflection is that we need to keep putting ideas into practice. We need to provide the facilities that promote creativity and cross-fertilization from the public and private sectors. HTA can help us disinvest in what is not effective, what is not efficient. Thus, we have to take greater advantage of the HTA tools we currently have at our disposal, to make informed decisions about investment and disinvestment. And we should always keep in mind that compassion and solidar­ ity should be the principal elements in healthcare systems, not just in Europe but all over the world.

My final reflection is that in this era of networks that we live in today, health system sustainability means, more than ever, so­ cial responsibility. Moreover, it will mostly depend on the de­ gree of co-responsibility assumed by healthcare stake-holders.

CONTRIBUTIONS to SCIENCE, 8 (2): 171–173 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.152 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Bioethics and Social Responsabilities

Bioethical challenges in personalised medicine * Jordi Camí Barcelona Biomedical Research Park, Barcelona Pasqual Maragall Foundation, Barcelona

Resum. Gran part de les qüestions ètiques, legals i morals que es deriven del concepte de medicina personalitzada estan pro­ fundament relacionades amb les proves genètiques. En primer lloc, hi ha una creixent preocupació sobre la normalització, l’exactitud, la utilitat i la interpretació dels resultats que les pro­ ves genètiques directes proporcionen al consumidor. En segon lloc, les proves genètiques haurien d’estar restringides per pres­ cripció mèdica i, per tant, hi ha una necessitat urgent de capaci­ tar professionals de salut perquè siguin capaços de proporcio­ nar assessorament genètic específic. En tercer lloc, les proves genètiques impliquen una nova dimensió de l’ètica de la privaci­ tat, ja que els resultats obtinguts poden afectar els familiars i, en particular, la descendència del pacient. D’altra banda, també poden donar lloc a noves formes de discriminació genètica o econòmica. Tots aquests factors s’han de tenir en compte per tal que les expectatives del públic general respecte a la medicina personalitzada siguin més realistes.

Paraules clau: medicina personalitzada ∙ proves genètiques ∙ factors de risc ∙ assessorament genètic ∙ discriminació genètica

Most of the ethical, legal and moral questions that result from the concept of personalised medicine are deeply related to ge­ netic testing. On the other hands the greatest potential for medical advancements in personalised medicine is the devel­ opment of new pharmaceutical drugs for people with a particu­ lar genetic makeup. When addressing the bioethical challenges in personalised medicine, we can draw a parallel and learn from the ethical debate on direct-to-consumer genetic testing.

Over the past ten years, since the completion of the se­ quencing of the human genome, there has been an explosion of websites offering direct-to-consumer genetic testing. As a result, there is an increasing concern about the usefulness of

* Based on the lecture given by the author at the Parliament of Catalo­ nia, Barcelona, on 23 October 2012 for the annual conference of the EPTA network, ‘From genes to jeans: challenges on the road to per­ sonalised medicine.’

Correspondence: J. Camí, Parc de Recerca Biomèdica de Barcelona, C/ Doctor Aiguader 88, E-08003, Barcelona, Catalonia, EU. Tel. +933160000. Fax +34-933160019. E-mail: jcami@prbb.org

Summary. Most of the ethical, legal and moral questions that result from the concept of personalised medicine are deeply related to genetic testing. Firstly, there is an increasing con­ cern about the standardisation, accuracy, usefulness, and in­ terpretation of the results provided by direct-to-consumer genetic testing. Secondly, genetic testing should be restrict­ ed by medical prescription and as such, there is an urgent need to train healthcare professionals so that they are also able to provide specific genetic counselling. Thirdly, genetic testing involves a new dimension of ethics of privacy, be­ cause the results obtained can affect your relatives and in particular your offspring. Furthermore, it can also lead to new forms of genetic or economic discrimination. All these factors should be taken into consideration so that the expectations created within the general public with regard to personalised medicine are more realistic.

Keywords: personalised medicine ∙ genetic testing ∙ risk factors ∙ genetic counselling ∙ genetic discrimination

such tests in providing relevant clinical information for the gen­ eral public. What about the accuracy of genetic testing? What standards do we have for their evaluation? Academic scientific research laboratories and professional healthcare providers only conduct a few, 30 to 35, standardised well-established genetic tests. However, we can find at least 2700 genetic tests available for purchase online [4]. Moreover, there is a huge var­ iability between results from tests purchased online. Direct-toconsumer genetic testing has created unrealistic expectations that may induce to confusion and anxiety, because in addition to this huge variability between the websites or labs offering these services, there is a bigger problem related to the inter­ pretation of the results of these tests based on the knowledge we have at the moment, and the absence of genetic counsel­ ling, which is not provided by the testing companies.

Most genetic risks claimed in direct-to-consumer genetic testing are very uncommon. So, there are genetic risk factors that are not relevant in the clinical setting. The products of even the most reputable companies (Navigenics, 23andMe, deCODE) can show marked differences in the calculated rela­

172 Contrib. Sci. 8 (2), 2012 Camí

tive risk for individuals. Moreover, a genetic risk factor might not be the determinant for the development of a particular dis­ ease. We know that there are people with a particular genetic risk factor that will never develop the disease while others, without this genetic risk factor, may develop the disease due to other risk factors, such as environmental factors, occupa­ tional exposures, cholesterol, obesity, etc. If we wish to offer patient-tailored treatment planning, we should recognise that there is ‘intelligent life’ beyond the genetic tests.

Genetic testing should be restricted by medical prescription and as such, there is an urgent need to train healthcare profes­ sionals in genetics, so that they are able to provide specific ge­ netic counselling. This is already the case in many European countries. For instance, in France, Germany, Portugal, and Switzerland, direct-to-consumer genetic tests are illegal and only physicians can carry out genetic tests for medical purpos­ es after providing adequate information to the patients about the implications of the finding and their limitations. France, in particular, foresees fines of up to €3000 or €4000. Still, the re­ ality is another, because little can be done to stop European consumers from purchasing direct-to-consumer genetic test­ ing through websites in the United States, for example, and then receiving the results at their own homes.

The third issue that comes out from direct-to-consumer genetic testing, particularly relevant in the case of personal­ ised medicine, is related to the privacy and safeguarding of our personal and private information. When sending your bio­ logical samples to different online repositories, you run the risk of being identified. Genetic testing involves a new dimen­ sion of ethics of privacy, because the results of genetic test­ ing can affect your relatives and in particular your offspring.

And this is one of the biggest challenges to overcome in per­ sonalised medicine.

Personalised medicine can also lead to new forms of dis­ crimination. For example, certain genotypes are much more prevalent in some ethnic groups. Imagine that to recover the development costs of a particular drug, pharmaceutical com­ panies targeted the development of new drugs for the most prevalent genotypes, and the ones that best respond to treat­ ment. Thus, a large fraction of the world’s population might be left out in the development of new treatments, since com­ panies will naturally favour those groups with genotypes that hold the potential for more profit. This is a very theoretical scenario, but it is something that we should consider. Simi­ larly, insurers or employers could also use ethnic categories to lower healthcare costs by discriminating against patient groups who are labelled as difficult to treat, based on their pharmacogenomic profile. Again, this is a very theoretical scenario, but I think it is important to consider these possible new forms of genetic discrimination.

In addition, there is a real risk of economic discrimination.

The potential profits resulting from genetically tailored drugs will probably be reduced because the market is much small­ er, however, pharmaceutical companies will still need to make large investments to develop these drugs. Thus, we can pre­ dict that personalised drugs will be more, at least as expen­ sive, if not more, as the standard ones. So who will be able to

pay for them? Perhaps we should think of the consequences of a scenario where only the rich people or the rich countries, have the access and can afford the new personalised drugs.

In my opinion the expectations regarding the clinical rele­ vance of personalised medicine are excessive, have been greatly exaggerated and are highly unlikely to be accom­ plished in the short term.

There are several lobbies behind the topic of personalised medicine, scientists, pharmaceutical companies and genetic testing labs, which sometimes results in contradictory opin­ ions about the future of personalised medicine. For example, some authors think that in contrast to the profusion of genetic testing companies, we should expect that the large pharma­ ceutical companies step up their development of personal­ ised drugs very quickly. There are pharmaceutical companies that are reluctant to move to this other world where it would be more complicated to sell the pharmaceutical drugs to dif­ ferent national health services, compared to when they have a ‘blockbuster,’ a one-size-fits-all drug, where you can get a lot of revenues, independently of whether this drug works ex­ actly the same in the different populations. This is why some authors think that the pharmaceutical industry will be reluc­ tant to adapt immediately to this new world, because that would reduce the market size and the associated profits to the aforementioned one-size-fits-all drugs.

To finish, I would like to give you a brief review of state of personalised medicine in clinical practice. According to the Personalized Medicine Coalition website [2], there were “72 prominent examples of personalised medicine drugs, treat­ ments and diagnostics products available in 2011.” This is simply not true. The US Food and Drug Administration (FDA) lists 78 different pharmacogenomic associations that are in­ cluded in drug labels [1], however, more than 60 of these drug labels do not provide action-oriented information for physicians and patients, and these pharmacogenomic asso­ ciations are for the most part research-based and with no clinical use at present.

As you know, we do not know how to appropriately interpret the results from genetic testing, and as such, many genetic tests are not relevant for the course of treatment. At present we have only a few very good examples in the field of oncology where, for instance, particular genetic tests can indicate the best course of treatment.

If we take all this into consideration, the expectations creat­ ed within the general public will be more moderated, and we would also reduce the absurd consumption of genetic testing in websites that do nothing but can lead to confusion and anxi­ ety. We should help people to better understand and better in­ terpret what really is happening with the new developments and breakthroughs in science and how they really work.

In conclusion, I think we should follow the conclusions of a 2005 report from the British Royal Society entitled Personal­ ised medicines: hopes and realities [3]: “the clinical use of personalised medicines where patients are prescribed treat­ ments based on their genetic make-up will not occur for at least another 15–20 years.” Or even ten more! In any case, I think that personalised medicine is a very good endeavour

Bioethical challenges in personalised medicine

and that will help us to understand our lives. However, in practical terms, we should be very cautious regarding the ex­ pectations and promises of this new mantra.

References 1. Hudson K (2011) Genomics, Health Care, and Society.

New Eng J Med 365:1033-1041

Contrib. Sci. 8 (2), 2012 173

2. Personalized Medicine Coalition [http://www.personal­ izedmedicinecoalition.org/] 3. The Royal Society (2005) Personalised medicines: hopes and realities 4. Vogenberg FR, Barash CI, Pursel M (2010) Personalized Medicine. Part 2: Ethical, Legal, and Regulatory Issues.

Pharmacy and Therapeutics 35:624-642

CONTRIBUTIONS to SCIENCE, 8 (2): 175–180 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.153 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Global Implications of Personalised Medicine

Global health challenges and personalised medicine * Antoni Plasència Barcelona Centre for International Health Research, Hospital Clínic-Universitat de Barcelona, Barcelona

Resum. El 2001, el Banc Mundial va assenyalar que el proble­ ma més gran que la humanitat afrontaria en el segle XXI seria la pobresa. Avui dia sabem que 1.200 milions de persones, aproxi­ madament una cinquena part de la població mundial, viuen amb menys d’un dòlar al dia i que les malalties transmissibles conti­ nuen representant la meitat de les morts i gairebé dos terços dels anys de vida ajustats per discapacitat (AVADs) entre el 20 % més pobre de la població mundial. Des d’una perspectiva de salut global, es tracta d’una bretxa d’equitat en salut inaccepta­ ble. Si els medicaments i les mesures preventives existents fos­ sin més accessibles, ara mateix podrien salvar milions de vides.

Alhora, la investigació de nous medicaments i vacunes, i llur desenvolupament clínic posterior, són essencials per a obtenir munició eficaç contra les malalties que mantenen les persones en situació de pobresa. A la vista d’aquests reptes per la salut global, cal que els potencials beneficis de la medicina personalit­ zada compleixin avaluacions basades en la investigació, incloent la utilitat clínica, el baix cost i la factibilitat tècnica, en el marc de sistemes de salut prou sòlids, i amb personal degudament ca­ pacitat. Cal potenciar els partenariats amb països de baixos i mitjans ingressos, amb el suport del Programa Marc Horitzó 2020 de Recerca de la UE. Paraules clau: medicina personalitzada ∙ salut global∙ malalties relacionades amb la pobresa ∙ equitat en salut

First, I would like to briefly describe the Barcelona Centre for In­ ternational Health Research (CRESIB). CRESIB’s mission is to find solutions to current and future global health challenges. It was established in 2006 by a group of first-rate academic and biomedical research institutions (the Hospital Clínic de Barcelo­ na, the University of Barcelona, and the August Pi i Sunyer Bio­ medical Research Institute) and by the Government of Catalo­

* Based on the lecture given by the author at the Parliament of Catalo­ nia, Barcelona, on 23 October 2012 for the annual conference of the EPTA network, ‘From genes to jeans: challenges on the road to per­ sonalised medicine.’

Correspondence: A. Plasència, Centre d’Investigació en Salut Inter­ nacional de Barcelona (CRESIB), C/ Rosselló 132, 4a planta, E-08036, Barcelona, Catalonia, EU. Tel. +34-932275706. Fax +34-932279853.

E-mail: antoni.plasencia@cresib.cat

Summary. In 2001, the World Bank stated that the biggest problem facing humanity in the 21st century would be pover­ ty. Today, we know that 1200 million people, about a fifth of the world’s population, lives on less than a dollar a day and that communicable diseases continue to account for half of the deaths and almost two thirds of the disability-adjusted life years (DALYs) among the poorest 20 % of the world’s popu­ lation. From a global health perspective, this is an unaccepta­ ble health equity gap. If the existing medicines and preventa­ tive measures were made more widely available, they could already save millions of lives. At the same time, research into new drugs, vaccines, etc., and their subsequent clinical de­ velopment are crucial to obtaining effective ammunition against diseases that keep people in poverty. In the view of such global health challenges, the potential benefits of per­ sonalised medicine need to meet research-based evalua­ tions, including clinical utility, low-cost and technical feasibili­ ty, within responsive healthcare systems with adequately trained personnel. Partnerships with low and middle-income countries, with the support of the incoming EU Horizon 2020 Research Framework Programme, need to be promoted.

Keywords: personalised medicine ∙ global health ∙ povertyrelated diseases ∙ health equity

nia. More recently, in 2009, with the support of the ”La Caixa” Foundation, CRESIB became the research arm of the Barcelo­ na Institute for Global Health (ISGlobal). This institution is the fruit of an innovative alliance between academic, government, and philanthropic organizations. It seeks to provide a hub of ex­ cellence in research and healthcare that will help close the gaps in health disparities between and within different regions of the world. It includes a think tank, aimed at the management of knowledge and designed to influence policy; a training centre, aimed at the transmission of knowledge, and a technical assis­ tance centre, aimed at the application of knowledge. In 2013, ISGlobal and CRESIB signed an agreement with the Centre for Research in Environmental Epidemiology (CREAL) to become a world-leading alliance in the field of global health.

CRESIB carries out multidisciplinary and translational re­ search in molecular biology, physiopathology, immunology,

176 Contrib. Sci. 8 (2), 2012 Plasència

clinical characterization, and epidemiology, as well as in the clinical development of treatment and prevention tools, such as vaccines. Gradually, we have pursued downstream ap­ proaches with the monitoring and evaluation of public health.

Broadly stated, our goal is to improve global health through re­ search and training, with our main areas of work focused on malaria, imported diseases, HIV/AIDS and STDs, viral and bac­ terial infections, and other emerging disease-related activities.

We use a cross-sectional approach, including public health, social sciences and medical anthropology, maternal, child and reproductive health, and host-pathogen interactions.

Finally, one of the main features of our efforts is that we col­ laborate with more than 100 institutions from 40 countries across the five continents, including stable partnerships with

Fig. 1. Correlation between life expectancy (years) and income per person (GDP per capita, PPPs inflation-adjusted) in 1900, 1950, 1990 and 2011. Source: Gapminder [www.gapminder.org]

Under-five mortality rate 175 or more

125 - 174

75 - 124

50 - 74

25 - 49

Less than 25

Fig. 2. Child mortality by country, 1960 and 1990. Child mortality has fallen sharply in the past 30 years, with particularly rapid declines in parts of Asia and Latin America. Source: World Bank [5].

high quality research capacities in low-income countries such as Mozambique, Morocco, and Bolivia. As such, ISGlobal is a centre committed to translating research into action.

The global health vision One way to define Global health is ‘public health without bor­ ders.’ More specifically, this means: • Better health for all, taking into account current disparities and inequalities, with particular attention to the needs of the most vulnerable; in other words, health as a human right.

• A global perspective on both scientific inquiry and the translation of knowledge into practice.

• A scientific approach to health promotion and disease prevention, examining broad determinants of health, in­ cluding but not limited to, medical care.

• An interdisciplinary approach and collaborative team work that includes population problems analysis.

• Multilevel systems-based interventions: society, govern­ ance, corporate responsibility, environmental, behaviour­ al, and biological risk factors.

• Comprehensive frameworks for financing and structuring health policies and services that support communitybased and clinical prevention integrated with healthcare delivery. [2] Within this approach, I would like to emphasise the issue of equity, because if we talk about a global health point of view, the major challenge facing humanity is the unacceptable health equity gap. Indeed, today, in the 21st century, our life expec­ tancy is still largely determined by where we are born.

Figure 1 shows the distribution of income as well as life ex­ pectancy in different countries over time. At the beginning of the last century, in the 1900s, life expectancy varied worldwide, from about 25 to approximately 50 years, but with relatively lit­ tle difference either in life expectancy among countries or in terms of per capita income. In the 1950s, the spread became quite substantial. For some countries, those shown in blue, and specifically many African countries but also some East Asian countries, there was very little change during those 50 years. In the 1990s, the spread continued to increase, with some of these countries starting to move up, not so much in terms of income but rather in life expectancy. Finally, there is currently good and bad news. The good news is that in African and East Asian countries, as in most countries, life expectancy has steadily improved; but the bad news is that, overall, dis­ crepancies among countries have increased, ranging from less than 50 years for in some low-income countries to more than 80 years in high-income countries.

For example, in the mid-20th century, a very large part of the world had infant mortality rates that were quite high, between 15 and 20 ‰ (per thousand). Fifty years later, at century’s end, the picture had for the most part changed completely, with a reduction of more than 100 % (Fig. 2). So this is the good news.

Global health challenges and personalised medicine

Contrib. Sci. 8 (2), 2012 177

Table 1. Distribution of child deaths for selected causes by selected WHO region, 2004* Africa

South-East Asia

Rest of the World

All causes

45 %

30 %

25 %

Diarrhoeal diseases

45 %

35 %

20 %

Pneumonia

50 %

25 %

25 %

Malaria

90 %

5%

5%

HIV/AIDS

90 %

5%

5%

Measles

45 %

45 %

10 %

*Percentages rounded to the nearest 5 %. Source: World Health Organisation [7].

But if we look at the data on a regional basis, we see that al­ though infant mortality has improved in all regions, there are large differences among them. For children under the age of five years, mortality has decreased overall, but the worst rates are still those of the African continent.

The 20th century Smallpox was eradicated, while we are not far from the eradication of polio and measles. There has been a decrease in overall mortality and life expectancy at birth has in­ creased substantially, by 25 years on average. Mean individual wealth has also increased at an unprecedented rate, accom­ panied by a very strong technological revolution. These achievements are proof that with effective strategies and the proper involvement of governments, industries, scientists, etc., we can achieve success on a scale never seen before in the history of humankind.

But, is all the news genuinely good? Not really. Today, we know that 1200 million people, about a fifth of the world’s pop­ ulation, lives on less than a dollar a day and that communicable diseases continue to account for half of the deaths and almost two thirds of the disability-adjusted life years (DALYs) among the poorest 20 % of the world’s population. And for children around the globe, infectious diseases, such as diarrhoea, pneumonia, malaria, HIV/AIDS and measles, account for a substantial share of these figures (Table 1). Again, Africa and Southeast Asia suffer the highest share of this burden, largely because of the impact of infectious diseases.

In 2001, the World Bank stated that the biggest problem facing humanity in the 21st century would be poverty. Disease

Fig. 3. Percentage of the population living on less than 1.25 US$ a day at 2005 international prices. Source: World Bank [6].

generates poverty, and poverty generates disease. Nonethe­ less, the positive view of the situation, is that the percentage of people living on less than 1.25 US$ a day—that is, in extreme poverty—has decreased by half (from 43 % to 22.4 %). In fact, while in 1990, 1.9 billion people lived in extreme poverty, by 2008 the number had decreased to 1.29 billion. But it is impor­ tant to remember that this improvement has been very une­ qually distributed throughout large parts of the world. Both in Africa and in some Asian countries, a majority of the population still lives in extreme poverty, which means an especially high risk of many diseases, and not just infectious diseases (Fig. 3).

Former US Secretary of State General George C. Marshall, responsible for the Marshall Plan, the American program of aid to Europe after WWII, said over half a century ago, in 1948, that, “Little imagination is required to visualise the great increase in the production of foods and raw materials, the stimulus to world trade and above all the improvement in living condi­ tions, with consequent social and cultural advances that would result from the conquest of tropical diseases.” [4] As shown in Fig. 4, which lists the leading causes of death by income group, in low income countries, infections of the lower respiratory tract are the first cause of death, whereas is­ chemic heart disease is the most frequent cause worldwide and in high income countries. Nonetheless, cerebrovascular diseases (stroke ischemic heart disease) already rank among the ten major causes of death at all ages in low income coun­ tries, curiously mimicking the situation in the world as a whole and in some high-income countries. The same is true for some infectious diseases. But, in general, diseases of poverty con­ tinue to account for a large share of deaths. Furthermore, most countries are experiencing an epidemiological and behavioural transition, i.e., in addition to the burden already posed by mal­ nutrition and communicative diseases, there is the growing burden of non-communicable, so-called chronic diseases.

At the same time, the major disease determinants or risk factors are increasingly similar in low income as in high income countries. Many of these risk factors are largely amenable to environmental interventions. Thus, we already have the knowl­ edge that can help us to confront globally many of these risks.

It is also important to keep in mind, from this global perspec­

178 Contrib. Sci. 8 (2), 2012 Plasència

Fig. 4. Top ten causes of death in (A) low income countries vs. (B) high income countries, 2011. Source: World Health Organisation.

tive, that there is a lack of equity in the provision of health care services. One of the classical examples is maternal mortality, a good indicator of the access to primary or obstetrical care or the lack thereof with more than ten-fold differences among countries. Again, the issues of poverty and the inequitable dis­ tribution of different diseases are highly relevant.

The role of research in global health The role of research in global health is a longstanding one. Fig­ ure 5 is a very interesting British cartoon from the 1920s that depicts malaria draining the life out of tropically based indus­ tries, including tea, coffee, vegetable oil, and copper; that is, several of the main sources of revenue for the British Empire.

The work of Sir Ronald Ross, who received the 1902 Nobel Prize for his work on malaria, and the Ross Institute and Hospi­ tal for Tropical diseases were already seen as means to avoid or at least to minimise the devastating impact of malaria—and by extension of other infectious diseases—on business and the economy. The concerns depicted in the cartoon are still very familiar ones today, i.e., high costs and low efficiency, and im­ plicitly emphasise the important role of research in global health to contribute to a productive economy.

If they were made more widely available, the existing med­ icines and preventative measures for the above-mentioned diseases could already save millions of lives, although none of them can completely eliminate HIV/AIDS, TB, or malaria.

At the same time, research into new drugs, vaccines, etc., and their subsequent clinical development are crucial to ob­ taining effective ammunition against diseases that keep peo­ ple in poverty. Yet, of the 1233 new drugs that reached the market between 1975 and 1997, only 13 were for tropical diseases primarily affecting the poorest populations. This is known as the “10/90 gap” and, while not a real quantitative measure, it has become a symbol of the continuing mis­ match between global health needs and the investments to meet them. Indeed, investment studies by the Global Forum for Health Research (www.globalforumhealth.org) continue to demonstrate that “health research applied to the needs of

low- and middle-income countries (LMICs) remains grossly under-resourced in many areas”.

Potential for personalised medicine in global health So how can personalised medicine contribute to global health?

On the one hand, overall, we humans throughout the world are probably much more genetically similar than different. While this is a very broad statement, it is meant to point out that many of the findings obtained by research in wealthy countries can be generalised to the whole world. But to what extent do these one-size-fits-all strategies meet our needs? We are at the early development stages of both personalised medicine and the dif­ ferent ‘-omics.’ Thus, we need evidence-based medicine and research into the comparative effectiveness of newly developed therapies if we are to make informed decisions in this area.

So what are the real benefits of personalised medicine and what are the prospects for LMICs? The answers to these ques­ tions are closely linked to the need for research aimed at meet­ ing those challenges through, for example: • Better or targeted interventions, vaccines, or drugs; here, vaccinomics is an area of potential interest.

• Diagnostic, screening, or predictive tests.

• The need for firmly established research and care capaci­ ties (laboratory genomics, biobanks, epidemiologic co­ hort studies, clinical studies, randomised control trials, gene-based technologies, etc.)

• Collaborative research involving investigators from low and middle income countries and high income countries, including multidisciplinary and public-private partner­ ships.

• Need for training and education of the workforce.

• Ethical and legal frameworks.

• Equity of access. [3] Accordingly, is personalised medicine, from a global health standpoint, a priority? Most of the targets for public health in­

Global health challenges and personalised medicine

Contrib. Sci. 8 (2), 2012 179

health challenges we are also talking about the ability to en­ large the scope of research to include partnerships among low, middle-, and high-income countries. Only through such partnerships will we succeed in introducing whatever benefits or effective innovations come of them in order to improve global health. As an example, for over twenty years, the Clínic Foundation, Barcelona, and the Spanish Agency of Interna­ tional Cooperation have partnered with the Health Research Center in Manhiça, Mozambique. The initial focus was malar­ ia, but the partnership has expanded to other areas and is now part of a research network of African centres.

Fig. 5. Appeal in 1926 for subscriptions to funds for research on tropical diseases (From ‘Tropical Life’, London).

terventions, as described, are on the environmental side, with different strategies and stakeholders, including economic, so­ cial, and political ones. There is also a predominance of risk factors that are amenable to environmental modification. At the same time, we cannot forget that these strategies are likely to be effective for most of the previously discussed risk factors, such that the aim is to promote a more equitable provision of health services. Many of LMICs have very limited resources for health services and their distribution tends to be inequitable, which raises issues of global justice and human rights. It has been pointed out that: “A major challenge is to generate an evidence base that can demonstrate that a genomics approach is at least as safe, effective and cost effective in these settings as other, more traditional approaches, such as modifying environmental or social determinants.” [1] In this context, are there precedents of potential interest?

Here we need to consider: 1. Areas with clearly established evidence of clinical utility, for example, the prenatal or neonatal detection of certain inherited diseases.

2. Areas with currently available low-cost solutions, for ex­ ample, the more systematic use of family history informa­ tion.

3. Areas with the scope for targeted innovative technical solutions, especially regarding prevalent infectious dis­ eases.

In general, there is a need for a public health genomics ap­ proach that is applicable to all countries but at the same time relevant on a smaller scale. Here, efforts should include select­ ing evidence-based applications, maximizing heath benefits and reducing inequities, reducing harm and unnecessary healthcare expenditures (premature or inappropriate use), eval­ uating public health interventions, and fostering capacity build­ ing in research and clinical care.

When we talk about personalised medicine and global

Global health R&D on the near horizon?

As a final point, let me underline that efforts have been made to include the topics of global-poverty-related and neglected diseases in the next EU Research Framework Programme, Horizon 2020, and in the relevant discussions of the Europe­ an Parliament and the European Commission. Market forces alone will not lead to the development of sufficient, affordable, and appropriate new technologies and goods for these dis­ eases. Public support and public financing are required when public goods are under-supplied by the market, as is the case for drugs used in the treatment of malaria, TB, and HIV/AIDS, several of which were effectively introduced over the last dec­ ade in many developing countries. Horizon 2020 presents an opportunity for the European Union to step in as a leader in addressing market failure and in stimulating innovation.

It is crucial to raise awareness and to mobilise members of the European Parliament and EU policy-makers in sup­ porting stronger EU investment and commitment—both po­ litical and financial—in the fight against poverty-related and neglected diseases. This also means raising the issue of the cost-effectiveness of investing in R&D for global health and the potential of innovations in this field to for strengthen Eu­ rope’s research leadership.

Why? Basically because we can also strengthen the EU economy through support for an essential but challenged area of European innovation, by providing a competitive advantage for European industry and research. Improving the health not just of Europeans but globally will have positive effects on health systems, employment, and global health security. It can also contribute to sustaining the credibility of the EU in its com­ mitments, made through a wide range of EU policies including those on health, economic growth, social inclusion, and devel­ opment. Global health efforts can facilitate progress in other areas, such as science diplomacy, knowledge sharing, and common solutions to problems.

I end this contribution with a quote appropriate to this global approach to science, from India’s first Prime Minister, Jawaha­ rlal Nehru (1889–1964), considered the architect of this devel­ oping country’s modern nation-state, “Who indeed could afford to ignore science today? At every turn we have to seek its aid... The future belongs to science and to those who make friends with science.”

180 Contrib. Sci. 8 (2), 2012 Plasència

References 1. Burke W, et al. (2010) Extending the reach of public health genomics: What should be the agenda for public health in an era of genome-based and “personalized” medicine? Genetics in Medicine 12:785-791 2. Fried LP, Bentley ME, Buekens P, Burke DS, Frenk JL, Klag MJ, Spencer HC (2010) Global health is public health. Lancet 375:535-537 3. Khoury MJ (2009) Interview: Dr. Muin J. Khoury dis­ cusses the future of public health genomics and why it matters for personalized medicine and global health.

Current Pharmacogenomics and Personalised Medicine 7:158-163 4. Marshall GC (1948) Address of welcome by the Honora­

ble George C. Marshall, Secretary of State. Proceedings of the Fourth International Congresses on Tropical Medi­ cine and Malaria. Washington, Department of State, pp 1-4 5. World Bank (1993) World Development Report 1993: In­ vesting in Health. World Bank and Oxford University Press [http://wdronline.worldbank.org//worldbank/a/c. html/world_development_report_1993/] 6. World Bank World Development Indicators. Poverty headcount ration at $1.25 a day (PPP) (% of population) [http://data.worldbank.org/indicator/SI.POV.DDAY/ countries?display=graph] 7. World Health Organisation (2004) Global Burden of Dis­ ease: 2004 Update [http://www.who.int/healthinfo/glob­ al_burden_disease/2004_report_update/en/index.html]

CONTRIBUTIONS to SCIENCE, 8 (2): 181–186 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.154 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Global Implications of Personalised Medicine

Will personalised medicine be the key to eradicating TB? * Pere-Joan Cardona Experimental Tuberculosis Unit, Germans Trias i Pujol Health Sciences Research Institute, Barcelona Archivel Farma, Barcelona

Resum. Cada any dos milions de persones moren de tubercu­ losi. Gairebé un terç de la població mundial està infectada, i un 10 % d’aquest grup desenvoluparà la malaltia. Els dos objec­ tius principals del tractament de la tuberculosi són la prevenció de la resistència i el tractament de totes les poblacions de ba­ cils. Però l’aparició de soques de tuberculosi multiresistent i tuberculosi extremament resistent s’està convertint en un pro­ blema cada vegada més preocupant, i, perquè els tractaments s’han de perllongar, en una enorme càrrega per als sistemes sanitaris. Des d’aquesta perspectiva, la medicina personalitza­ da pot millorar el tractament dels pacients amb tuberculosi.

Mitjançant l’ús de proves genètiques que detecten polimorfis­ mes específics podem identificar els pacients que responen més bé als fàrmacs disponibles, i considerar teràpies alternati­ ves per als que no hi responen tan bé. La investigació continu­ ada en biomarcadors donarà suport a la medicina personalit­ zada en el tractament de malalties infeccioses, especialment de la tuberculosi, una malaltia per la qual els tractaments dis­ ponibles actualment tenen moltes limitacions.

Paraules clau: medicina personalitzada ∙ tuberculosi multiresistent (MDR-TB) ∙ tuberculosi extremament resistent (XDR-TB) ∙ teràpia d’observació directa de breu duració (DOTS) ∙ polimorfisme gen SLCO1B1 ∙ polimorfisme gen LTA4H

Introduction At first glance, you may ask what do personalised medicine and tuberculosis (TB) have to do with each other? When I was first invited to give a talk at the 2012 EPTA annual meeting, I asked myself the same question. As a scientist, I have two jobs: carrying out research at the Experimental Tuberculosis

* Based on the lecture given by the author at the Parliament of Catalo­ nia, Barcelona, on 23 October 2012 for the annual conference of the EPTA network, ‘From genes to jeans: challenges on the road to per­ sonalised medicine.’

Correspondence: P-J Cardona, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Ctra. De Can Ruti, Camí de les Escoles s/n, E-08916, Badalona, Catalonia, EU. Tel. +34-934978653.

Fax +34-934978654. E-mail: pjcardona@igtp.com

Summary. Every year, 2 million people die from tuberculosis.

Nearly one third of the world’s population is already infected, and 10 % of this group will go on to develop TB. The two basic goals of TB treatment are the avoidance of resistance and the treatment of all bacilli populations. But the appearance of multi­ ple drug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB) strains is becoming an increasingly troublesome issue, and because treatments have to be prolonged, and enormous burden for health systems. From this perspective, personalised medicine can improve the treatment of patients with TB. By using genetic testing to detect specific polymor­ phisms and identify patients that best respond to the available drugs, and to consider therapeutic alternatives for those who are not. Further research for biomarkers will support personal­ ised medicine in the treatment of infectious diseases, especial­ ly TB, where we are already confronted with the many limita­ tions of the currently available treatments.

Keywords: personalised medicine ∙ multiple drug resistant TB (MDR-TB) ∙ extensively drug resistant TB (XDR-TB) ∙ directly observed therapy- short course (DOTS) ∙ SLCO1B1 gene polymorphism ∙ LTA4H gene polymorphisms

Unit at the Germans Trias i Pujol Hospital, a public institution, but also working for the pharmaceutical industry in the devel­ opment of a TB vaccine. Thus, in the common view of aca­ demia, I have ‘crossed to the dark side,’ meaning that I have come under the spell of the power of money and am under the control of private hands, a less ‘pure’ state than that of a true academic. But I think that the private sector is the way of the future. Indeed, I have gone so far as to try and convince my colleagues that it is only through the private route that one’s scientific ideas and results can be transformed into di­ rect benefits to society.

From this perspective, personalised medicine can strongly influence the prognosis of patients with TB, a disease of global incidence with a high mortality, mostly in Africa and Asia but also in first world countries. Every year, 2 million people die from TB; there are 10 million new cases of the disease and

182 Contrib. Sci. 8 (2), 2012 Cardona

Fig 1. Estimated TB incidence rates, 2011. Source: World Health Organization [10].

Fig 2. Estimated HIV prevalence in new TB cases, 2011.

Source: World Health Organization [10].

Fig. 3. Percentage of new TB cases with MDR-TB. Fig­ ures are based on the most recent year for which data have been reported, which varies among countries.

Source: World Health Organization [10].

100 million cases of latent TB infection. In the documented history of TB, it accounts for 1000 million deaths. The problem with TB is that most infections are asymptomatic and latent.

Thus, nearly one third of the world’s population is already in­ fected, and 10 % of this group will go on to develop TB. More worrying still is that none of these infected individuals are aware that they have the infection.

Figure 1 shows the data for the estimated TB incidence rates for 2011. The highest rates are in Asia and Africa and are very much related to HIV prevalence [10]. Even more alarming is the rate in South Africa, where HIV prevalence is as high as 30% in a population with an incidence of TB infection of more

than 300 per 100,000 inhabitants (Fig. 2). That translates to approximately 1 % of the population of South Africa becoming infected with TB every year: half a million people in a population of 50 million is a massive incidence.

The situation is further complicated by the efforts of the World Health Organisation’s (WHO) to treat as many cases of active TB as possible. But the treatment of active TB favours the selection of Mycobacterium tuberculosis strains with multi­ drug resistance. Thus, while every year approximately 80 % of the 10 million cases of TB are treated, at the same time half a million people will develop multi-drug resistant TB (MDR-TB) (Fig. 3, Table 1). This is a frightening situation because TB

Will personalised medicine be the key to eradicating TB?

Table 1. Definitions of TB resistance (WHO/CDC 2006) Multidrug-resistant TB (MDR-TB)

Resistance to isoniazid and rifampicin, the two most powerful first-line treatment drugs

Extensively drugresistant TB (XDR-TB)

MDR with resistance to isoniazid and rifampin and at least three of the six main classes of secondline drugs (aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine, and para-aminosalicyclic acid)

Table 2. Anti-TB drug classes

should have been eradicated by the year 2000. This was the prediction made in the 1970s and 1980s, when short term chemotherapy of TB consisted of a six-month course of treat­ ment. But TB has become more complicated because of the presence of MDR-TB, which cannot be treated easily.

The areas of the world where MDR-TB is most problematic are the Baltic countries and Russia [9]. Despite adequate health­ care systems, treatment of these patients often fails because of logistical problems. Moreover, in cases in which the drug combi­ nation has not been efficacious, there has been a huge increase in MDR-TB, which now threatens to spread to other countries.

Worse still are the extremely drug resistant strains, which are re­ sistant to the main TB drugs available, isoniazid and rifampicin, and to other first-line drugs such as aminoglycosides. In India, for example, totally drug resistant strains or extensively drug re­ sistant TB (XDR-TB) strains have been detected. For these pa­ tients, there is no available treatment other than surgery, in which diseased portions of the lungs are removed; but these patients will suffer from chronic TB for the rest of their lives.

Around the world, the number of countries that have re­ ported at least one case of XDR-TB is growing. Resistance too, and thus mortality, is an increasingly troublesome issue, one that is not far from Europe (Fig. 4). Of particular concern are the countries of the former Soviet Union, where mortality is as high as 10 per 100,000 inhabitants [3]. But there are places in Western Europe where there is also cause for con­

Contrib. Sci. 8 (2), 2012 183

cern. For example in different quarters of London, there are areas with an alarming incidence of TB. In Spain, immigration from African countries such as Alge­ ria and Morocco plays a role in the overall incidence. In Bar­ celona, in the Raval quarter, located in the centre of the city, the incidence of TB is of 120 per 100,000 inhabitants. In other words, the risk of infection is 50 times higher than in any other quarter of the city. Fortunately, there are health programs that are especially vigilant in this and other vulnerable urban areas.

The Catalan Government and the City Council have invested enormous sums of money to create an effective program to combat TB in Barcelona. Thanks to these efforts, we can monitor the evolution of TB in this populous city, where during the 1980s the high incidence mostly involved HIV-positive in­ jection-drug users (HIV-IDU) and especially prison inmates.

Since 1990, there has been an approximate annual decline of 10 %, reflecting lower rates of HIV-IDU among prison in­ mates, and the treatment of HIV with highly active retroviral therapy (HAART); thus, today, the incidence of TB is more closely related to immigration [1].

Not surprisingly, TB is also very much related to poverty. Fig­ ure 5 shows the relationship between the incidence of TB and individual income. According to predictions for the year 2030, this trend will continue to increase [4]. However, as noted above, the paradox is that the only strategy against TB, which is to treat the disease, leads to an even worse problem, the pro­ motion of MDR-TB. To address this problem, the WHO has set up a TB control strategy, referred to as directly observed thera­ py – short course (DOTS), that combines five components: 1. Government commitment, including political will at all lev­ els, and the establishment of a centralised and prioritised system of TB monitoring, recording, and training.

2. Case detection by sputum smear microscopy.

3. A standardised treatment regimen, with adherence di­ rectly observed by a healthcare worker or community health worker for at least the first two months.

4. A stable drug supply.

5. A standardised recording and reporting system that al­ lows the assessment of treatment results. [11] Fig. 4. TB mortality rates, Europe, 2001–2005. Source: European Centre for Disease Prevention and Control/ WHO Regional Office for Europe [3]

184 Contrib. Sci. 8 (2), 2012 Cardona

Table 2. Anti-TB drug classes First-line anti-TB drug

Second-line anti-TB drugs

Third-line anti-TB drugs

Group 1 Oral isoniazid (H/Inh) rifampicin/rifampin (R/Rif) pyrazinamide (Z/Pza) ethambutol (E/Emb) rifapentine (P/Rpt) rifabutin (Rfb)

Group 2 Injectable aminoglycosides streptomycin (S/Stm) kanamycin (Km) amikacin (Amk)

Group 5 clofazimine (Cfz) linezolid (Lzd) amoxicillin plus clavulanate (Amx/Clv) imipenem plus cilastatin (Ipm/Cln) clarithromycin (Clr)

Injectable polypeptides capreomycin (Cm) viomycin (Vim) Group 3 Oral and injectable fluoroquinolones ciprofloxacin (Cfx) levofloxacin (Lfx) moxifloxacin (Mfx) ofloxacin (Ofx) gatifloxacin (Gfx)

Group 4 Oral para-aminosalicylic acid (Pas) cycloserine (Dcs) terizidone (Trd) ethionamide (Eto) prothionamide (Pto) thioacetazone (Thz) linezolid (Lzd)

However, this implies that, for the six months of chemo­ therapy, a healthcare worker must go to the residence of each patient in order to administer the medication. Obviously, this has huge logistical costs, but it is the only way to avoid MDR-TB. The two basic goals of TB treatment are the avoid­ ance of resistance and the treatment of all bacilli populations.

Table 2 shows the basis of TB treatment with the available first-line, second-line and third-line drugs [12]. Each TB lesion contains up to 109 bacilli, so a combination of these drugs is needed to avoid the development of spontaneous bacterial mutation. The administered drugs must have bactericidal ac­ tivity, with the most effective agents being rifampicin and iso­ niazid. But, for instance, imagine an infection with 109 bacilli in which 102 bacilli are already resistant to isoniazid (INH). If the patient is treated with INH, the main bulk of the bacilli load will be eradicated but at the same time the resistant strain is spared and goes on to reproduce and to perpetuate the dis­ ease. The main problem is not the continuous growth of the TB bacilli, which are in fact susceptible to INH, but their low rate of INH metabolism. This means that long term treatment is required to kill these bacilli. Thus, in order to treat TB, four drugs, INH, rifampicin, pyrazinamide, and ethambutol, are ini­ tially administered for 6 months to massively reduce the

amount of replicating bacilli, followed by another four months of INH and rifampicin to complete treatment [5].

What happens if the patient is infected with a MDR-TB strain? If INH is no longer effective, then neither is rifampicin and treatment with the other drugs must be prolonged, up to 21 months. This is an enormous burden for health systems.

Worse still, is that the main antibiotic available in such cases is an aminoglycoside, which is mostly delivered intramuscularly.

So patients must be treated intramuscularly for three months every day, in order to control the bacillary load, followed by ap­ proximately 18 more months of non-injectable anti-TB drugs, to make treatment more affordable [2]. In other words, there is a problem with the six-month treatment that can only be solved by 21 months of treatment. Furthermore, the number of highly drug-resistant (HDR) strains of TB is expected to increase.

Personalised medicine and TB Regarding personalised medicine and TB, there is good and bad news. The bad news is that it is no longer clear whether treatment adherence is the key to the effective eradication of active TB. Data from experiments in which different treatments

Will personalised medicine be the key to eradicating TB?

Fig. 5. Relationship between the number of new cases of TB and indi­ vidual income. Source: Gapminder [www.gapminder.com].

in different types of patients were simulated showed that even if adherence was moderate, there was still an adequate reduc­ tion of the bacillary load [7]. Thus, DOTS, may not be the only option. The clue actually lies in the pharmacokinetics of the various drugs, i.e., the fate of these drugs in the body. Even with the best DOTS, there are differences between patients in the degree of destruction of the bacillary load, which can only be explained by pharmacokinetics. Again, this is a frightening consideration because it includes the two aforementioned criti­ cal drugs, INH and rifampicin.

People can be grouped as slow or rapid INH acetylators, depending on the rate at which the drug is inactivated. This is crucial to achieve peaks of INH concentration. Low acetylators have larger peaks of the drugs than rapid acetylators [6]. This difference translates into a difference in drug response. In a pa­ tient who is a rapid acetylator, a higher dose would probably be needed. Slow vs. rapid INH acetylators can be determined ge­ netically. Yet, although the existence of this gene has long been known and the benefits of genetic testing in the treatment of TB are clear, it is rarely performed. Similarly, certain common variants (polymorphisms) in the SLCO1B1 gene mean that some patients have higher peaks of rifampicin and that the drug will be more effective in some patients than in others.

Both of these examples demonstrate how personalised medi­ cine can improve the treatment of patients with TB, by using genetic testing to identify drug responders and to consider the therapeutic alternatives for those who are not.

The good news is related to the natural history of TB. Ap­ proximately 90 % of the individuals who are infected with M. tuberculosis have latent, asymptomatic infections and only 10 % have active TB. Among the latter, 5 % of the cases occur because the patient is a child or in the setting of AIDS or other risk factors such as diabetes, tobacco smoking, alcohol con­ sumption or air pollution, all of which increase the likelihood of developing TB. And then there is the remaining 5 % of cases, in which the reasons for the development of active TB are un­ clear. These patients typically develop the disease 10–20 years after being infected, but why the delay occurs is not under­ stood. Immunosuppressed individuals have higher chances of contracting TB, pneumonia and other diseases but this does

Contrib. Sci. 8 (2), 2012 185

not completely explain these cases, nor does malnutrition of poverty; instead, a genetic factor is suspected.

A latent infection requires a constant reinfection process, in which the mycobacteria invade and replicate within en­ dosomes of the pulmonary alveolar macrophages, with the subsequent formation of encapsulated granulomas that pre­ vent mycobacterial dissemination. Many of the granulomas persist in a balanced state. Thus, granulomas typically drain into the alveolar fluid and then into the gastrointestinal tract, but in progressive disease bacilli are released into the airways after cavitation of the granulomas and are able to re-infect the lungs.

However, there are also local mechanisms that prevent con­ stant re-infection. Thus, in addition to encapsulation the devel­ opment of new lesions is controlled over time such that their formation occurs at a low rate. Latent infections are usually not treated at all, because this would imply treating some 2000 mil­ lion people, which is simply not practical.

The risk of having active TB is higher soon after infection. In the active stage, new lesions form constantly, which increases the likelihood that they involve the upper lobes, where cavities are generated. In fact, in adults active disease tends to focus on the upper lobes, probably because of the high oxygen pres­ sure, which favours bacterial growth, and the less dense capil­ lary network, which delays the immune response. This is less frequent in the chronic phase. How the tiny lesions in a latent infection become the huge lesions that lead to cavitation in ac­ tive TB, with lesions ranging in size from 0.5 mm to 20 mm in diameter, is unknown. Studies in mice models have shown that the lesions coalesce, a process that may be promoted by the less dense capillary network in the upper lobes rather than the reduced oxygen pressure.

There is also a genetic background that favours less capil­ lary density in the upper lobe, thereby reducing drainage and increasing the coalescence of TB lesions. Furthermore, stud­ ies in mice have shown that in some cases there is an abun­ dance of neutrophils in the lesions. The excessive inflamma­ tion results in the greater induction of active TB. Thus, host hyperactivity may be the clue to the 5 % of previously unex­ plained cases of TB. Genetically, these individuals have a poly­ morphism in the gene LTA4H, encoding leukotriene-A4 hydro­ lase. This bifunctional enzyme converts leukotriene A4 to leukotriene B4, causing higher levels of tumour necrosis factor and subsequently excessive inflammation and tissue damage.

In people who are homozygous for this polymorphism, TB meningitis is more likely to be fatal [12].

If we were able to identify patients who are high acetylators or who are homozygous for LTA4H gene polymorphisms, we could then offer them more specific treatments. Additionally, we now have a biomarker that indicates the risk of conversion from a latent infection to active TB. Further research for biomarkers will support personalised medicine in the treatment of infectious diseases, especially TB, where we are already confronted with the many limitations of the currently available treatments. In a personalised medicine approach, patients could be stratified before they start chemotherapy, in order to avoid ineffective treatments and prevent adverse drug reactions, resulting in more efficient therapy and the reduction of resistance.

186 Contrib. Sci. 8 (2), 2012 Cardona

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Cayla JA, Orcau A (2011) Control of tuberculosis in large cities in developed countries: an organizational problem.

BMC Medicine 9:127 2. Espinal M (2004) What is the “fall and rise” phenomenon and the “sequential regimen” mechanism? In: Friedan TR (ed) Toman’s tuberculosis: case detection, treatment, and monitoring: questions and answers. 2nd ed. World Health Organization, Geneva, Switzerland, pp 200-202 3. European Centre for Disease Prevention and Control/ WHO Regional Office for Europe (2009) Tuberculosis sur­ veillance in Europe 2007. European Centre for Disease Prevention, Stockholm 4. Gapminder [www.gapminder.org] 5. National Institute of Allergy and Infectious Diseases (2012) Drug-Resistant TB Visual Tour [http://www.niaid. nih.gov/topics/tuberculosis/Understanding/WhatIsTB/ VisualTour/Pages/firstLine.aspx] 6. Ramachandran G, Swaminathan S (2012) Role of phar­

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Pharmacogenomics and Personalized Medicine 5:89-98 Srivastava S, Pasipanodya JG, Meek C, Leff R, Gumbo T (2011) Multidrug-resistant tuberculosis not due to com­ pliance but to between-patient pharmacokinetic variabili­ ty. J Infect Dis 204:1951-1959 Tobin DM, Vary JC Jr, Ray JP, Walsh GS, Dunstan SJ, Bang ND, Hagge DA, Khadge S, King MC, Hawn TR, Moens CB, Ramakrishnan L (2010) The Ita4h locus mod­ ulates susceptibility to mycobacterial infection in ze­ brafish and humans. Cell 140:717-730 World Health Organization (2011) WHO Report World Health Organization (2012) Global tuberculosis re­ port 2012 [http://www.who.int/tb/publications/global_re­ port/en/] World Health Organization – The five elements of DOTS [http://www.who.int/tb/dots/whatisdots/en/index.html] Zumla A, Nahid P, Cole ST (2013) Advances in the devel­ opment of new tuberculosis drugs and treatment regi­ mens. Nature Reviews Drug Discovery 12:388-404

CONTRIBUTIONS to SCIENCE, 8 (2): 187–190 (2012) Institut d’Estudis Catalans, Barcelona DOI: 10.2436/20.7010.01.155 ISSN: 1575-6343 www.cat-science.cat

Annual Conference of the EPTA Network 2012

Conclusions Ricard Guerrero Member of CAPCIT Scientific Secretary, Institute for Catalan Studies, Barcelona Whenever there is a European Parliamentary Technology As­ sessment (EPTA) meeting, such as this one, held at the Parlia­ ment of Catalonia on 23 October 2012 (‘From Genes to Jeans: Challenges on the Road to Personalised Medicine’), the audi­ ence is a complex mixture. These meetings are attended by scientists, members of parliaments, and representatives of the advisory boards of the various EPTA organizations, who may or may not be scientists. Consequently, EPTA meetings bring together a diversity of approaches, views, and outlooks.

As a member of the Institute for Catalan Studies, the catalan academy of sciences and humanities, I am well aware that the strength of a culture, of a language, of a country, does not de­ pend on the number of square kilometers that it spans or on the size of its population. Rather, it is based mainly on the strength of the fruits of that culture and its language. As Cata­ lans we are another culture in west Mediterranean Europe of the 21st century. Núria de Gispert, president of the Parliament of Catalonia voiced these sentiments in her introduction to this meeting. Ours is an old country and merits the same rights as Germany, Italy, or Spain. We have our own language, and our roots in the Mediterranean can be traced back over centuries.

As a crosswalk of civilizations throughout our history, we are an open people. We are also Europeans and we will go together with all of you, the peoples of Europe.

After the wealth of information presented during this 2012 EPTA meeting focusing on personalised medicine, it is a difficult task to briefly summarize the conclusions of the many expert speakers. The term personalised medicine refers to the applica­ tion of genomic and molecular data to patients in order to es­ tablish the correct diagnosis and the most suitable treatment for each person. The main challenge to implementing personalised medicine is its complexity. Healthcare systems are already overwhelmed; but their sustainability is possible only if they are able to make the transition from data collection to data integra­ tion. In the common clinical practice, the skilled physician al­ ready applies personalised medicine to each patient, treating him or her as a unique individual. Indeed, despite the many technological advancements that facilitate the generation of a plethora of biochemical and physiological data, in daily clinical practice medical treatment has always been personalised.

While considering recent technological advances, it is a good idea to remember Lewis Thomas (1913–1993), author of The Lives of a Cell, and The Medusa and the Snail, among other books. He held appointments at several medical schools and hospitals and ended his professional career serving as the chancellor of the Memorial Sloan-Kettering Cancer Center, in New York City. In The Youngest Science (1983), he recalls how he became acquainted with the medical daily work by accom­

panying his father, a general practitioner in Long Island, in the 1920s. The senior Dr. Thomas made unending house calls and wrote his prescriptions in Latin. By the time his son Lewis at­ tended medical school, in the 1930s, medicine had changed and was no longer a practice but was rapidly becoming a hard science. And by the 1990s, when Lewis Thomas died, the sci­ ence of medicine had changed beyond recognition, with the diagnosis, treatment, and cure of many diseases that were previously deemed intractable. He remembers his father say­ ing: “Medicine always tries to cure by attending to the particular biological characteristics. No patient is the same as another.”

This way of thinking, of seeing the patient as an individual, has a long tradition in medicine and it must be maintained, regard­ less of technological advances.

The main objective of personalised medicine in the modern genomics era is the study of the individual genetic variability, the predisposition of a patient to a particular disease, and his or her response to the pharmacological agents used in the treat­ ment. The ideal drug, one that is effective in every patient, does not exist. For a physician, it can be difficult to assume the effi­ cacy of a drug or a given dose in one patient because the pa­ tient has the ‘same’ health disorder or ‘similar’ symptoms as another patient; forgetting this fact may be not only inadequate but even harmful. In many cases, the lack of efficiency of a par­ ticular drug is caused by the patient’s genetic characteristics, which determine the drug’s absorption, metabolism, and ex­ cretion. In the next few decades, clinical medicine, with its growing focus on patient-tailored treatments, will increasingly need to take these factors into account.

The development of methodologies that allow the rapid and inexpensive sequencing of individual genomes allows us to think that personalised medicine will soon become a reali­ ty. Two of the many anticipated benefits are sparing patients ineffective treatments and avoiding adverse side effects.

Consequently, we will avoid unnecessary suffering as well as higher healthcare costs. This aspect was commonly pointed out by many of the speakers at this meeting. Also frequently noted was that the successful implementation of personal­ ised medicine would only be possible with continuous re­ search efforts in all the new ‘-omics’ sciences.

Pharmacogenetics and, more widely, pharmacogenomics are the sciences upon which personalised medicine will be based. The most important changes in the development of new drugs will be linked to the necessity of simultaneously de­ veloping a diagnostic assay and a targeted treatment. Fulfil­ ment of the promises of pharmacogenomics has implications far beyond purely the scientific ones; it will require a radical change in the way medicine is currently practiced.

The synergy of pharmacogenomics, biotechnology, and regulatory approaches should be considered an asset if per­ sonalised medicine is to succeed. Furthermore, the ethical, le­ gal, and social consequences must be fully recognized, and

188 Contrib. Sci. 8 (2), 2012 Guerrero

fulfilled. There is also an urgent necessity for both public and private investment, and collaboration between the two. We live in a complex networking society in which the functioning of each node depends on that of the others.

I would like to end these brief comments with a quote by André Gide’s (1869–1951) that was mentioned in one of the lectures: “Toutes choses sont dites déjà, mais comme personne n’écoute, il faut toujours recommencer.” (Everything is already said, but since no one was listening, everything must be said again.) There are many challenges both in the introduction of

innovations into the healthcare system and in their long-term adoption. But, as the confused married woman in Woody Al­ len’s To Rome with Love (2012), who, when faced with temp­ tation, says: “If I try, perhaps I will be sorry for some time, but if I don’t try, I will be sorry forever,” personalised medicine is definitely an enterprise worth trying. And it is also a challenge for all EPTA members who attended this meeting. Let us go forward, spread the news, and, when we meet again in Fin­ land next year, discuss the insights and experience we have gained here and now.

List of participants

Contrib. Sci. 8 (2), 2012 189

List of participants From genes to jeans: challenges on the road to personalised medicine Annual Conference of the EPTA Network Barcelona, 23 October 2012 Participants

Institution

Marta Aymerich

Ministry of Health, Government of Catalonia

Nabajyoti Barkakati

U.S. Government Accountability Office

Dolors Batalla

MP, CAPCIT

Antoni Bayés de Luna

Autonomous University of Barcelona

Miguel Beato

Centre for Genomic Regulation

Sergio Bellucci

TA-SWISS

Robby Berloznik

IST-Flemish Parliament

Josep Maria Borràs

Catalan Cancer Strategy

Frans Brom

Rathenau Institute

Fulvio Caccia

TA-SWISS

Jordi Camí

Barcelona Biomedical Research Park, Pasqual Maragall Foundation

Mireia Canals Botines

CAPCIT, Parliament of Catalonia

Pere-Joan Cardona

Germans Trias i Pujol Health Sciences Research Institute, Archivel Farma

Antoni Castellà

Ministry of Economy and knowledge, Government of Catalonia

Enric Claverol

CAPCIT, Catalan Foundation for Research and Innovation

Montserrat Daban

CAPCIT, General Directorate for Research, Government of Catalonia

Núria de Gispert

Parliament of Catalonia

Oriol de Solà-Morales

Pere Virgili Institute for Health Research

Fernando Domínguez García

CAPCIT, Parliament of Catalonia

Manuel Esteller

ICREA Research Professor, Bellvitge Biomedical Health Institute

Yang Fang

National Center for Science and Technology Evaluation, MOST

Roberto Fasino

Parliamentary Assembly of the Council of Europe

Adela Farré

Biocat

Anna García-Altés

Catalan Agency of Information, Evaluation and Quality in Health

Margarida Garrido

Gendiag

Ingrid Geesink

Rathenau Institute

Alicia Granados

Genzyme

Francesc Xavier Grau Vidal

CAPCIT, Rovira i Virgili University

Armin Grünwald

Office of Technology Assessment at the German Bundestag (TAB)

Reinhard Grünwald

Office of Technology Assessment at the German Bundestag (TAB)

Ricard Guerrero

CAPCIT, Institute for Catalan Studies

Miroslaw Gwiazdowicz

Bureau of Research of the Chancellery of the Sejm of the Republic of Poland

Peter Ide-Kostic

European Parliament

Daniel Jositsch

National Council - Switzerland

Jan Kazmierczak

Parliamentary Assembly of the Council of Europe (PACE), Sejm of the Republic of Poland

190 Contrib. Sci. 8 (2), 2012

List of participants (continued) Tanja Kleinsorge

Parliamentary Assembly of the Council of Europe

Lars Klüver

Danish Board of Technology Foundation, Teknologiraadet

Manolis Kogevinas

Centre for Research in Environmental Epidemiology

Helene Limén

Parliament of Sweden

Päivi Lipponen

Parliament of Finland

Belén López

CAPCIT, Catalan Foundation for Research and Innovation

Hilde Lovett

Norwegian Board of Technology

Jordi Mas Castellà

General Directorate for Research, Government of Catalonia

Michael Nentwich

Institute of Technology Assessment of the Austrian Academy of Sciences

Costas Papadimitriou

Parliament of Greece

Walter Peissl

Institute of Technology Assessment of the Austrian Academy of Sciences

Antoni Plasència

Barcelona Centre for International Health Research

Josep Manuel Ricard

CAPCIT, Rovira i Virgili University

Joan Rodés

August Pi i Sunyer Biomedical Research Institute

Laura Rubio

Catalan Foundation for Research and Innovation

Eduardo Salas

Gendiag

Joan Salgado

Gendiag

Nicole Skinner

Institute for Catalan Studies

Paula Tiihonen

Parliament of Finland

Chris Tyler

Parliamentary Office of Science and Technology, London, UK

Montserrat Vendrell

Biocat, Council of European Bioregions

Barbro Westerhoml

Parliament of Sweden

Instructions to authors General Contributions to Science publishes two kinds of articles, specialized reviews and general articles on scientifical and technological research (see front cover).

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).

Submission of manuscripts Authors are requested to register and submit manuscripts to the journal’s web site. The author is asked to upload the item and provide associated metadata or indexing information to facilitate online searching and for the journal’s own use.

The author may also accompany the manuscript with supplementary files in the form of data sets, research instruments, or source texts that will enrich it while contributing to more open and robust forms of research and scholarship.

The author can track the article through the editorial process – and participate in the copy-editing and prrofreading of articles accepted for publication – by logging in with the username and password provided.

Format of manuscript All contributions should be typed, double-spaced (including references, tables,...) on paper not exceeding 30 cm in height (standard A4 paper is appropriate), with wide margins and one side of the page only. 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 warmy appreciate co-operation of authors in preparing papers in a manner that will facilitate the work of editing and publication. For research papers an abstract self-explanatory without reference to the text –in Catalan language, too– not exceeding 200 words should be provided. Authors must provide keywords.

It is essential that the author responsible for post publication correspondence (the Corresponding author) should be identified on the manuscript.

The first page of the manuscript should contain only the following: 1. ­­ Title of the paper containing keywords pertaining to the subject matter. No abbreviations should be used in the title.

2. Names (including forenames or initials) of the authors and name of the institute. 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. An abstract (in English and Catalan languages) not exceeding 200 words.

4. Full name and postal address of the author to whom all correspondence (including gallery proofs) is to be sent. Telephone and fax numbers as well as e-mail code should be included to speed up communication.

5. A list of abbreviations or acronyms used in the paper if they are not explained in the text.

6. Keywords (maximally 5), which will be used for compiling the subject index.

Tables Tables should be compiled on separate sheets (one per page table) with a descriptive title and numbered independently of the figures using Arabic numerals in the sequence in which they occur. Every table must be refereed to in the text.

References References should be indicated in the text in square brackets and listed at the end of the paper or book chapter. The list should give name(s) and initial(s) of author(s), year of publication and the exact title of the paper. For journals there should follow the title of the journal, volume number, and initial and final page numbers of article. For books there should follow the name(s) of the editor(s) (if ap­propriate), title of the book, the name of the publisher, the town of publication, and initial and final page numbers (if appropiate). References are to be numbered and arranged in alphabetical order.

Papers that are unpublished but have been submitted to 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 gallery proofs of the paper. In all other cases, reference must be made to «unpublished work» or «personal communication».

Acknowledgements Acknowledgements as well as information regarding funding sources should be provided on a separate page and will appear at the end of the text (before References).

Figures, including photographs Diagrams and photographs should also be submitted on separate pages at the end of the article (new page for each figure). Three copies of each figure are required. Figures should be numbered consecutively with Arabic numbers in the order of their appearance. Photographs should be fine quality, large glossy prints suitable for reproduction.

Figures should not be larger than the manuscript paper. Numbers and symbols inscribed must be large enough to be legible after reduction in size.

Nomenclature and units Only SI units are to be used (SI = Système International d’Unités). If a data with non-SI units are to be reported, they should be put in parenthesis behind the corresponding data with SI units.

Biographical details Each author should provide a short biography, and this should include details of affiliation, and research activities and how the research group became interested in the subject being reviewed.

CONTRIBUTIONS to SCIENCE Institut d’Estudis Catalans, Barcelona

contents Volume 8 Issue 2

December 2012

de Gispert N

119

foreword Parliamentary Technology Assessment

Cope D

121

Forty years on

Domínguez García F

131

CAPCIT: The Advisory Board of the Parliament of Catalonia for Science and Technology Annual Conference of the EPTA Network 2012

Castellà A, Aymerich M

137

Presentation Keynote Lectures

Vendrell M

139

Personalised medicine: needs, challenges, and considerations

Esteller M

145

Forecasting limits in personalised medicine

de Solà-Morales O

149

Sustainability of personalised medicine Genetic and Socio-Cultural Risk Contributions to Disease

Beato M

155

What is our level of knowledge about the genome today?

Salas E

161

Complex diseases: the relationship between genetic and sociocultural factors in the risk for disease Bioethics and Social Responsabilities

Granados A

167

Challenges for industry developers

Camí J

171

Bioethical challenges in personalised medicine Global Implications of Personalised Medicine

Plasència A

175

Global health challenges and personalised medicine

Cardona P-J

181

Will personalised medicine be the key to eradicating TB?

Guerrero R

187

Conclusions

189

Participants of the Annual Conference of the EPTA Network 2012 “From genes to jeans: challenges on the road to personalised medicine”