THE LUNDBECK FOUNDATION 2009│10

LUNDBECKFONDEN

THE LUNDBECK FOUNDATION 2009│10

MELIE CAMMILLA ANDERSEN┃PROFESSOR PH.D. JENS SKORSTENGAARD ANDERSEN┃KLINISK ASSIST LDURSDOTTIR┃PROFESSOR DR.MED. PER BECH┃STUD.SCIENT. BIRGITTE BERTELSEN┃VIDENSKABE PH.D. CORD BRAKEBUSCH┃LEKTOR PH.D. SUSANNE BRIX PEDERSEN┃PROFESSOR DR.PHARM. HANS GE CHRISTINA CHRISTOFFERSEN┃PH.D.-STUDERENDE CAND.POLYT. ANETTA CLAUSSEN┃LEKTOR PH FFEL DINANT┃PROFESSOR DR.MED. HENRIK JØRN DITZEL┃LEKTOR LIC.SCIENT. MICHAEL ROHR DRE PH.D. CHRISTER STENBY EJSING┃LEKTOR PH.D. LARS ELLGAARD┃FORSKNINGSLEDER PH.D. LARS H RASMUSSEN┃ASSISTANT PROFESSOR PH.D. ROBERT ANDREW FENTON┃POST DOC. PH.D. AASA FER NDERS FUGLSANG-FREDERIKSEN┃PH.D.-STUDERENDE CAND.MED. JASNA FURTULA┃LÆGE ELISABE . CLAUS HØJBJERG GRAVHOLT┃PROFESSOR DR.MED. NIELS GREGERSEN┃LEKTOR PH.D. MICHAEL J ESSOR TEKN.DR. VIKTORIA HANCOCK┃PROFESSOR DR.SCIENT. STEEN HANNESTAD┃AFDELINGSLÆG N┃PH.D.-STUDERENDE CAND.SCIENT. SIMON HAUERSLEV┃POST DOC. PH.D. JAKOB HULL HAVGAARD SCIENT. PHILIP HOFMANN┃PH.D.-STUDERENDE CAND.SCIENT. MARLENE VIND HOFMEISTER┃POST DO COB PADE RAMSØE JACOBSEN┃LÆGE PH.D. LINDA JAKOBSEN┃VIDENSKABELIG ASSISTENT CAND.S A. JENSEN┃PH.D.-STUDERENDE CAND.SCIENT. SØREN SKOV JENSEN┃PROFESSOR DR.MED. THOMAS ENDE CAND.SCIENT. MATHIAS JUL JØRGENSEN┃LEKTOR PH.D. THOMAS J.D. JØRGENSEN┃LEKTOR P AGNETE KIRKEBY┃SCHOLARSTIPENDIAT ANNA MATHIA KLAWONN┃AFDELINGSLÆGE SENIORFORSKE EGAARD LARSEN┃POST DOC. PH.D. MAGDALENA JANINA LASKA┃POST DOC. PH.D. JENS PETER HOL DR.MED. YAWEI LIU┃ASSOCIATE PROFESSOR PH.D. ROSA LAURA LÓPEZ MARQUÉS┃POST DOC. PH.D DERENDE CAND.SCIENT. OLE AALUND MANDRUP┃LEKTOR PH.D. VLADIMIR MATCHKOV┃PROFESSOR POST DOC. PH.D. NINELL POLLAS MORTENSEN┃ADJUNKT PH.D. JENS PREBEN MORTH┃POST DOC. P NNE NIELSEN┃PH.D.-STUDERENDE CAND.SCIENT. JOACHIM NIELSEN┃PROFESSOR PH.D. JOHN NIELS PH.D.-STUDERENDE CAND.SCIENT. RIE NYGAARD┃POST DOC. PH.D. RIKKE NØRREGAARD┃DIREKTØR RESEARCHER PH.D. BOB ORANJE┃BIOKEMIKER PH.D. CARLO GUNNAR OSSUM┃POST DOC. PH.D. SY S STEEN PEDERSEN┃LEKTOR PH.D. STEEN PEDERSEN┃MOLEKYLÆRBIOLOG PH.D. TANJA XENIA PED UGDAHL┃PROJEKTLEDER CAND.SCIENT. THOMAS RASMUSSEN┃POST DOC. PH.D. MARTIN FREDENSB ARSEN┃FYSIKER PH.D. MADS T. FRANDSEN┃POST DOC. JUNIOR GROUP LEADER CAMILLA SCHEELE K FORSKNINGSLEKTOR DR.MED. LISELOTTE SKOV┃POST DOC. CAND.SCIENT. GUSTAVO STADTHAGE T. PER SVENNINGSEN┃STUD.MED. ASGER SVERRILD┃POST DOC. PH.D. RIKKE SØGAARD┃POST DOC ØRRING┃POST DOC. CAND.SCIENT. WIMAL UBHAYASEKERA┃VIDENSKABELIG MEDARBEJDER CAND. ARD┃PROFESSOR PH.D. PETER VUUST┃PROFESSOR DR.MED. GUNHILD WALDEMAR┃VIDENSKABELI DBY┃LEKTOR PH.D. DANIEL WÜSTNER┃LEKTOR CAND.SCIENT. KIRSTEN WØLDIKE┃PH.D.-STUDEREN ERENDE CAND.POLYT. MORTEN ALHEDE┃LEKTOR PH.D. TINE ALKJÆR ERIKSEN┃VIDENSKABELIG ASS USANA AZNAR KLEIJN┃LÆGE PH.D. IBEN BACHE┃LEKTOR PH.D. LASSE KRISTOFFER BAK┃ADJUNKT DERENDE MADS TVILLINGGAARD BONDE┃ADJUNKT PH.D. CHARLOTTE MENNÉ BONEFELD┃POST DOC ØREN BUUS┃LEKTOR PH.D. LI CHEN┃ADJUNKT CAND.SCIENT. MARCO CHIARANDINI┃ADJUNKT PH.D. E CAND.SCIENT. THOMAS DALSGAARD┃CAND.SCIENT. BRIAN DELLA VALLE┃PH.D.-STUDERENDE CAN TER EDUARD┃POST DOC. PH.D. KRISTOFFER LIHME EGEROD┃POST DOC. CAND.SCIENT. VERA EHRE ARSTEN FABER┃VIDENSKABELIG ASSISTENT PH.D. HELENE FAUSTRUP┃PH.D.- STUDERENDE CAND.S ERG┃POST DOC. PH.D. AGLA JAEL RUBNER FRIDRIKSDOTTIR┃PH.D. CAND.SCIENT. MADS T. FRANDSE ER CAND.SCIENT. GEORGE GEGELASHVILI┃PROFESSOR DR.MED. ULRIK GETHER┃LEKTOR DR.PHIL. M SIG FAARUP RASMUSSEN┃AFDELINGSLÆGE DR.MED. JENS PETER GØTZE┃RESEARCH SCHOLAR CA H.D. LARS HESTBJERG HANSEN┃LÆGE PH.D. TINE WILLUM HANSEN┃RESEARCH ASSISTANT PH.D. LI . PH.D. PETER FØNSS HERSKIND┃LEKTOR PH.D. ASGER HOBOLTH┃PROFESSOR PH.D. ELSE KAY HOF HVID┃PH.D.-STUDERENDE CAND.SCIENT. SARA MAJ WÄTJEN HYLDIG┃LEKTOR PH.D. ALBERTO IMPAR DR.MED. KIMMO JENSEN┃PROFESSOR DR.SCIENT. MOGENS HØGH JENSEN┃KLINISK ASSISTENT CAN RUD JORDAN┃STUD.SCIENT. FREDERIK CUNDIN JØLVING┃LEKTOR DR.MED. ARNE LUND JØRGENSEN

THE LUNDBECK FOUNDATION 2009│10

Board of Trustees

Jes Østergaard, Director, Civil Engineer Thorleif Krarup, Director, B.Sc. (econ), B.Com. Jeanette Larsen, Laboratory Specialist, employee representative

BOARD OF TRUSTEES AND MANAGEMENT

Niels Johansen, Research Director, Civil Engineer, employee representative Mikael Rørth, Professor, Chief Physician, M.D.

Steen Hemmingsen

Management

Nils Axelsen, Vice-Chairman, Chief Physician, M.D. Mogens Bundgaard-Nielsen, Chairman of the Board, Director, Civil Engineer, B. Com.

Anne-Marie Engel

Management Steen Hemmingsen, Managing Director, Ph.D. Grants Administration/secretariat Britt Wilder, Executive Secretary

Bertil From

Research Anne-Marie Engel, Director of Research, Ph.D. Ulla Jakobsen, Science Manager Kirsten Ljungdahl, Secretary

Finance and Investment Bertil From, Chief Financial Officer Portfolio investments Peter Sehested, Senior Investment Manager Susanne Bernth, Senior Controller

Peter Adler Würtzen, Research Scientist, Ph.D. employee representative Jørgen Huno Rasmussen, Group CEO, Civil Engineer

Mette Kirstine Agger

LFI Life Science Investments Mette Kirstine Agger, Executive Director, Head of LFI Life Science Investments Johan Kördel, Senior Investment Director Casper Breum, Investment Director

Accounting/Controlling Claus Køhler Carlsson, Director, Accounting & Tax Vibeke Bache, Head of Accounts Danielle Bernth, B.Sc.

THE LUNDBECK FOUNDATION The Lundbeck Foundation is a commercial foundation established in 1954. Its main objective is to maintain and expand the activities of the Lundbeck Group and to provide funding for scientific research of the highest quality.

100%

LFI a/s Investment & holding company

LISTED SUBSIDIARIES

70%

H. LUNDBECK A/S

OTHER INVESTMENTS

38%

ALK ABELLÓ A/S

(66%.OF THE VOTES)

LFI LIFE SCIENCE INVESTMENTS

50%

OBEL-LFI EJENDOMME A/S

PORTFOLIO

contents

THE LUNDBECK FOUNDATION'S ACTIVITIES IN 2009

2

GRANTS IN 2009

5

GRANT-MAKING POLICY

10

THE FIRST GENOME FROM A PREHISTORIC HUMAN

12

NANOMEDICINE – AN INTRODUCTION

17

CENTRES OF EXCELLENCE 2009 – NANOMEDICINE

20

THE LUNDBECK FOUNDATION'S RESEARCH PRIZES

26

THE LUNDBECK FOUNDATION'S JUNIOR GROUP LEADER FELLOWSHIPS

34

LFI a/s – THE LUNDBECK FOUNDATION'S COMMERCIAL ACTIVITIES

41

THE LUNDBECK FOUNDATION'S MANAGEMENT AND CORPORATE GOVERNANCE

43

RESULTS 2009

44

THE LUNDBECK FOUNDATION 2009│10

THE LUNDBECK FOUNDATION'S ACTIVITIES IN 2009

2009 in brief

The Lundbeck Foundation donated DKK 340 million to research in the biomedical and natural sciences in 2009, funding some 500 researchers at Danish universities and, increasingly, Danish researchers at universities abroad. Despite the financial crisis in 2008 and early 2009, a combination of the scale of its financial resources and its long-term outlook have enabled the Foundation to stick to its strategy of not allowing the return on investment in any particular year to have a negative impact on its funding activities. Funding will also continue in 2010 at around the level of 2009.

The Ministry of Science devised a Research Barometer in 2009.

It shows, for example, that Danish research is ranked very highly internationally in terms of the number of publications and citations from them. However, it seems to be increasingly difficult to translate basic research into new products. Ownership of the pharmaceutical companies H. Lundbeck A/S and ALK-Abelló A/S and support for university research mean that the Foundation is involved in the whole chain, from basic research through applied research and development to production and marketing. In addition to the researchers funded by the Foundation at universities and university hospitals, the two companies mentioned above employ approx. 1,800 people and spent a total of approx. DKK 3.5 billion p.a. on research and development.

The basic research conducted at universities has to be qualified by broader criteria than just new products that reach the market in a short time-scale, of course, but it is also important that opportunities are created to exploit the business potential that emerges from university research. In 2009, the Lundbeck Foundation set up a special investment entity, primarily for life-science companies, in Denmark and abroad. As part of this strategic enhancement, the Foundation's investment and holding company, LFI a/s, has assumed responsibility for a number of biotech investments previously under the auspices of H. Lundbeck A/S, concentrating the Group's resources in the life-science sector in the new investment entity LFI Life Science Investments.

The Ministry of Science's Research Barometer reveals that 2.5% of research funding at the universities is donated directly by business, a comparatively low figure in international terms. However, Danish foundations, including the Lundbeck Foundation and the Novo Nordisk Foundation, together fund almost 10% of total Danish university research, a comparatively high figure that puts

the business community's contribution to university research in a more balanced perspective. Much of the Lundbeck Foundation's revenue stems from dividends from the companies in which it is the majority shareholder. A proportion of these profits is channelled into university research, and thereby also to the education of the graduates that the business and the health sector need.

Financially, 2009 was a good year for the Foundation. It made a profit of DKK 2,639 million, of which DKK 1,505 million consists of return on investment, and DKK 1,169 million represents a share of the operating profit from Group companies.

The fair value of the Foundation's liquid funds, i.e. investments not related to H. Lundbeck A/S and ALK-Abelló A/S, increased from DKK 10,834 million at the end of 2008 to DKK 12,091 million. In other words, the investment loss suffered in 2008 has now been recouped. The return on investment was 14.3%. At the end of 2009, equity was DKK 18,324 million. Measured at market prices this corresponds to a value of DKK 26,138 million.

Most of the Foundation's grants go to what is referred to as unrestricted research, i.e. the grants are awarded solely on the basis of the quality, rather than the subject, of the research. These are known as bottom-up grants. In 2009 as in previous years, topdown or strategic grants have been allocated to research centres in areas defined by the Foundation Board. The theme in 2009 was nanomedicine. This theme was selected following consultation with the Foundation's advisors in Denmark and abroad. DKK 100 million was donated to the three successful applications to emerge from the tendering process. The nanomedicine theme and each of the three centres of excellence are described in detail elsewhere in this publication.

These three centre grants bring the total number of research centres launched by the Foundation in the last five years to 15 and the number of researchers therein to 300. As a private body, it is important that the Foundation continually evaluates where it can make a difference compared to the initiatives taken by the public research councils, the universities and other private foundations.

As a private body, the speed of the decision-making process enables the Board to adapt the Foundation’s activities to trends it considers significant. The importance of the work of the private foundations is illustrated by this quote from Professor Eske Willerslev, whose ground-breaking project was funded by the Lundbeck Foundation in 2009: "without these private donations, Denmark would never

At the award ceremony of the Lundbeck Foundation's Talent Prizes are the recipients (seated from left) Ph.D. Mads Toudal Frandsen, Ph.D. Kamilla Miskowiak, Ph.D. Emil Loldrup Fosbøl and Managing Director Steen Hemmingsen, Chairman of the Board of Trustees Mogens Bundgaard-Nielsen and Chairman of the Foundation's Research Prize Committee, Nils Axelsen.

have won the race to sequence the first genome from an extinct type of human – a breakthrough that puts Denmark on the world map”……..” Scientific breakthroughs often don't just depend upon the amount of money, but also on how quickly the cash is activated. Top international leading research groups are engaged in fierce competition, so it's only weeks or months that separate winners from losers – and there is only one winner, i.e. the team that gets there first. The Lundbeck Foundation realises this, and for this reason alone plays an absolutely crucial role in Danish basic research” (see article elsewhere in the publication).

In recent years, the Foundation has noted the establishment of a wide range of research centres that involve both public and private

funders, including newer, private stakeholders. At present, the need for the Lundbeck Foundation to make new investments in research centres is therefore considered to be less pronounced.

The Board has therefore decided that the Foundation would exert a more positive influence on Danish research by prioritising the funding of smaller new groups headed by outstanding young researchers - from Denmark or abroad - who will be responsible for their own choice of research area at a Danish institution. The Foundation's total allocations budget for 2010 (approx. DKK 340 million) is therefore allocated to bottom-up research in biomedical and natural sciences, including neuroscience in a broad sense without subject limitation. This is unrestricted research, and the crucial

THE LUNDBECK FOUNDATION 2009│10

THE LUNDBECK FOUNDATION'S ACTIVITIES IN 2009

factor is the combination of the cutting-edge nature of the project and the researchers’ qualifications. Examples from Nobel Prizewinners among others indicate that researchers in the age 35-40 are often particularly original and productive. It is also recognised that the traditional funding system fails to accord sufficient significance to providing outstanding researchers in this age group with the optimal working conditions that will enable them to compete with research institutions abroad. It is here that the Foundation expects to be able to make a difference. For 2010, it has earmarked a total of DKK 100 million for seven fellowships for outstanding young research leaders, from Denmark or abroad, who wish to start their own research group at a Danish institution. Of the seven fellowships, two worth DKK 25 million (€ 3 million) each will be advertised as Grants of Excellence within the neuroscience area for two researchers who already have a proven track record of international research and research management. Furthermore, five Junior Group Leader Fellowships of DKK 10 million each will be awarded to young researchers from Denmark or abroad, typically in their early-to-mid 30s, who also want to start their own research group at a Danish institution. Again, these fellowships will be awarded following open competition, international advertisement, and assessment by external experts.

cial activities. At the end of 2009, a property investment company was also established as a joint venture with C.W. Obel Ejendomme A/S, namely Obel-LFI Ejendomme A/S which is managed by C.W. Obel Ejendomme A/S. At the end of 2009, the Foundation and LFI a/s employed 14 people, up from 10 at the end of 2008. A new scientific advisory committee has been set up to process applications for research grants for natural science projects. The advisory committee for the biomedical sciences continues as before.

All grant applications are now put before an advisory committee with a majority of external members. Ad hoc committees are set up to process applications for centres and fellowships. A list of members of the two advisory committees is available on page eight and nine of this publication and at the Foundation's website, summary of all donations made up to and including 2009. The site also functions as a portal to the Foundation's online application system.

This publication contains details of the grants allocated in 2009, articles by and about the five recipients of the Junior Group Leader Fellowships, the recipients of research prizes and the new research centres, as well as an article about the Foundation's business activities carried out in the wholly owned investment and holding company LFI a/s.

Mogens Bundgaard-Nielsen Chairman of the Board of Trustees

The Board remained unchanged in 2009. The Civil Affairs Agency approved an amendment to the Board's statutes so that all chartered members now have to stand for re-election every year and the maximum term for each member is 12 years. Every effort will continue to be made to ensure that the six chartered members elected by the Board represent different areas of scientific, financial and business expertise. This serves the best interests of the Foundation's funding activities as well as its commercial activity in LFI a/s, whose board consists of the same members as the Board of the Foundation.

The Foundation and LFI a/s increased its scope of investment activities in 2009 with the addition of LFI Life Science Investments under LFI a/s. Additional resources were added to the finan-

The Lundbeck Foundation would like to thank its employees, managers of subsidiaries and partners on scientific advisory committees, universities and official bodies for their positive input in 2009.

Steen Hemmingsen Managing Director

grants 2009

In 2009, the Lundbeck Foundation allocated a total of DKK 340 million in research grants. Based on academic evaluations by assessment panels and ad hoc review committees with a majority of external assessors, the Board has approved DKK 295 million in grants to basic research, DKK 37 million to clinical/applied research and DKK 8 million to other forms of research.

The three centres are: NanoCAN – The Lundbeck Foundation Nanomedicine Research Centre for Cancer Stem Cell Targeting Therapeutics, headed by Professor Jan Mollenhauer, Department of Molecular Medicine, University of Southern Denmark. The Centre received a grant of DKK 35 million.

research centres In 2008, the Lundbeck Foundation hosted an inspiration seminar, at which Danish universities and university hospitals were invited to propose fields of study in which they believed that Danish research was of a high international standard and had the potential to further strengthen its position. Based on the proposals submitted, some of which were presented at the seminar, the Board decided, in consultation with an international panel, that the 2009 theme for the Lundbeck Foundation's research grants should be nanomedicine.

After consideration and recommendation by an international panel with expertise in both nanomedicine and nanotechnology, a total of DKK 100 million was donated to three Centres of Excellence.

The centre’s research focuses on the targeted treatment of cancer stem cells via nano-carriers.

In the same way that the body's ordinary stem cells are responsible for maintaining normal tissue, the so-called cancer stem cells seem to give rise to tumours. Cancer stem cells are suspected of being resistant to radiation and chemotherapy, and of helping to spread cancer cells. This means that new ways of treating cancer must be found. NanoCAN's goal is to develop new nano-medicines that kill cancer stem cells without causing harm to normal stem cells.

One of the key activities at NanoCAN will be to devise new drugs by studying each of the 20,000 human genes – this will be done using advanced robots that function as a miniature assembly line.

NanoCAN's strategy is to combine nano-medicines on the basis

the grants awarded in 2009 can be broken down as follows: The Foundation’s funding strategy and grants can be viewed on the Foundation’s website: www.lundbeckfonden.dk

      

  ( )

3 Centres of Exellence Prizes Fellowships Projects Total (DKK million)

100 1 50 144 295

2 35 37

Number of project grants Average per project grant

180 0.8

63 0.6





8 8

100 3 50 187 340

22 0.4

265 -

THE LUNDBECK FOUNDATION 2009│10

GRANTS IN 2009

The beneficiary of the Foundation's Prize for Young Researchers 2009, Professor Niels Mailand in conversation with the Chairman of the Foundation's Research Prize Commitee Nils Axelsen and the Chairman of the Board of Trustees Mogens Bundgaard-Nielsen (right).

of various biological building blocks made up of lipids and RNAs that either contain a medicine or which can locate and possibly kill a cancer cell.

The Lundbeck Foundation's NanoCAN Centre will initially focus on breast cancer, the leading global cause of cancer deaths in women.

CBN – The Lundbeck Foundation Centre for Biomembranes in Nanomedicine headed by Professor Ulrik Gether, Department of Neuroscience and Pharmacology and Associate Professor Dimitrios Stamou, Department of Neuroscience and Pharmacology & Nano-Science Centre, both of the University of Copenhagen. The centre received a grant of DKK 34 million.

Communication between nerve cells and signaling between bacteria.

The centre will study the basic biological processes in the cell's outer barrier, the cell membrane, which forms the basis for the cells' ability to communicate with each other via chemical signals.

Surprisingly, the membrane processes exhibit many features common to both bacteria and human cells, which underlines their fundamental importance to all living organisms. Disruption of the chemical signals between cells is a key element in the development of diseases in the brain. Chemical signaling between bacteria is presumed to play a crucial role in their ability, in some cases, to bypass the body's immune system.

The centre will use a whole range of new nanoscale technologies to study membrane processes all the way down to single-molecule level. In the long term, the results may not only lead to new treatments for brain diseases and new ways of combating bacterial infections, but may also lead to the development of new biological nanosensors for use in the diagnosis and design of nanoscale medicine capsules for targeted treatment of specific cell types.

LUNA – The Lundbeck Foundation Nanomedicine Centre for Individualized Management of Tissue Damage and Regeneration, headed by Professor Allan Flyvbjerg, Aarhus University Hospital and Faculty of Health Sciences, Aarhus University and Professor Jørgen Kjems, Interdisciplinary Nanoscience Center, Aarhus University. The centre received a grant of DKK 30 million.

The mechanisms behind the imbalance between tissue damage and tissue repair, caused by disease.

The centre's core hypothesis is that cardiovascular diseases and musculoskeletal disorders are caused by an imbalance between disease-induced tissue damage and the body's natural ability to repair or rebuild damaged tissues. The projects are designed to illustrate the key mechanisms that cause disease, and to develop techniques to restore this balance and stimulate tissue repair.

The centre will focus on a newly discovered group of recognition molecules that are expected to rectify the imbalance between tissue damage and tissue repair, as well as explain differences in the development of these diseases between different individuals.

Studies of these molecules and the way they work will be conducted using new techniques from the nano world. The project will develop nano-based techniques for developing new 'molecular' medicine, new disease-imaging methods, tissue-specific administration of medication and new technologies for tissue protection and reconstruction.

junior group leader fellowships In 2009, the Lundbeck Foundation awarded five Junior Group Leader Fellowships for young researchers who conducted outstanding research and are now qualified to set up their own research groups. Three fellowships were awarded to life-science researchers, and two to natural-science researchers.

In 2010, in accordance with the Foundation's decision to focus on research management and future managers, five Junior Group Leader Fellowships will also be awarded to researchers from Denmark and abroad who wish to establish their research with a group at a Danish university or university hospital.

The Fellowship recipients in 2009 were: Post doc. Søren Gøgsig Faarup Rasmussen, Ph.D., the University of Copenhagen, Department of Neuroscience and Pharmacology. Søren Gøgsig Faarup Rasmussen comes to the University of Copenhagen after completing his post-doctorate at Stanford University. His new group's research will focus on understanding the three-dimensional structure of different types of cellmembrane proteins (proteins that are integrated into the surface of the body's cells) and how they change shape and structure as a result of their function.

The title of the project is: Structural and functional studies of monoamine neurotransmitter activated G-protein-coupled receptors and monoamine transporters Associate Professor Steen Brøndsted Nielsen, Ph.D., Department of Physics and Astronomy, Aarhus University. Steen Brøndsted Nielsen will continue as associate professor at Aarhus University, and will lead a group that focuses on research into and description of excited molecular states, their appearance, dynamics and influence on reaction paths. One objective of this work is to understand DNA molecules' reactions to light. At the same time, work will be done to investigate DNA's properties as 'nanowires', for use in the molecular electronics of the future.

The title of the project is: Excited state physics of bare and solvated molecular ions

Neuroscience Cell & Molecular Biology Physiology + pharmacy Cancer research Microbiology + immunology Biochemistry Genetics + other basic biomedical research

Total

  

 .

39 29 16 4 18 2

47 17 9 3 10 1

17

9

125

The title of the project is: Functional characterization of depolarization-dependent signaling pathways in nerve terminals.

Assistant Professor Lene Niemann Nejsum, Ph.D., Department of Molecular Biology, Aarhus University. Lene Niemann Nejsum returns to Denmark following a post doc. stay

P    ,   ( )   

    ,   

Associate Professor Martin Røssel Larsen, Ph.D., University of Southern Denmark, Department of Biochemistry and Molecular Biology. His group will focus on examining the underlying mechanisms in the molecular signaling inside nerve cells, which serves to maintain the communication between nerve cells that is essential for a functioning nervous system. Martin Røssel Larsen previously had a prolonged research stay in Australia, where he established a fruitful collaboration with a group that will play a part in his fellowship project.

96



  .  

Neurology, neurosurgery, psychiatry and physiology Clinical pharmacology, genetics and microbiology Hepatology, endocrinology, nephrology and gastroenterology Cardiology Gynaecology, ophthalmology, obstetrics, surgery, anaesthesiology and paediatrics Oncology + haematology General medicine, infection medicine and lung diseases Internal medicine, public-health medicine, geriatrics and more

Total

14

11

8

2

6 5

6 1

7 4

3 3

4

2

13

5

61

33

THE LUNDBECK FOUNDATION 2009│10

GRANTS IN 2009

the lundbeck foundation’s international scientific advisory committees

Mikael Rørth, Chairman, Professor, Chief Physician, M.D. Member of the Foundation’s Board of Trustees

Ole Petter Ottersen, Professor, M.D. Institute of Basic Medical Sciences, Centre for Molecular Biology and Neuroscience, Oslo University, Norway

Ole William Petersen, Professor, M.D. Institute for Cellular and Molecular Medicine, Copenhagen University, Denmark.

Bertil Hamberger, Professor, M.D., Department of Surgery, Karolinska Hospital Solna, Stockholm, Sweden

Edvard Smith, Professor M.D., Clinical Research Center, Karolinska Institutet, Stockholm, Sweden

Jørgen Frøkiær, Professor, M.D Department of Clinical Physiology and Nuclear Medicine, Aarhus University Hospital, Skejby Denmark

Anders Bjørklund, Professor, M.D., Ph.D. Department of Physiological Sciences, Wallenberg Neuroscience Centre, Lund University, Sweden.

Nils Axelsen, Chief Psysician, M.D. Vice-Chairman of the Foundation's Board of Trustees

at Stanford University in the USA. Her research there led to the description of an important directional-sorting mechanism for membrane proteins in epithelial tissues. Her group in Denmark will continue work on mapping and describing this mechanism.

Research Prizes Since 1987, the Lundbeck Foundation has awarded research prizes in recognition of excellent research and/or particularly promising young researcher profiles.

The title of the project is: Regulation of post-Golgi sorting and trafficking in polarized epithelial cells

The Lundbeck Foundation Nordic Research Prize of DKK 2 million was awarded to Professor Jes Olesen, Danish Headache Centre, Glostrup Hospital. He received DKK 600,000 as a personal honorary award and DKK 1,400,000 for research of his choice.

Associate Professor Troels C. Petersen, Ph.D. the Niels Bohr Institute, University of Copenhagen. Troels C. Petersen is establishing himself with a research group at the Niels Bohr Institute. He has studied particle physics at several research institutions, most recently at the Large Hadron Collider at CERN, which remains the basis for the experimental part of his research.

His group will focus on the description of the 'dark matter' that constitutes a large proportion of our universe, and about whose properties we currently know very little.

The title of the project is: Searching for dark matter at Cern’s LHC accelerator Project funding The majority of the Foundation's project funding is allocated to biomedical research. In 2009, the Foundation received a total of 1,055 applications for project funding. Of these, 778 concerned biomedicine and 229 natural sciences. Grants were approved for a total of 265 projects, 180 of which were basic research projects.

The tables show how project funding in biomedical science is divided between basic and clinical/ applied research, and how the grants are divided between subject groups in terms of number and amounts.

In natural science, a total of DKK 35 million was awarded to 62 projects (52 basic research and 10 applied research and development).

Jes Olesen founded the Danish Headache Centre at Glostrup Hospital, a national research- and treatment centre for particularly severe cases of migraine and other headaches. For over three decades, he has led a headache-research group that has made several groundbreaking discoveries with great international impact. Jes Olesen's detailed description and classification of the different types of migraine has also led to the establishment, under his initiative, of a set of internationally accepted standards for defining and classifying over 100 different types of headache. This has helped to strengthen international collaborative research on migraines as research findings in one country can now be transferred directly to other countries. The prize was handed over at a ceremony in Glostrup Hospital in March 2010.

The Foundation's Research Prize for Young Scientists under 40 was in 2009 awarded to Professor Niels Mailand, Group Leader in the Department of Disease Biology, Novo Nordisk Foundation Centre for Protein Research, University of Copenhagen. He was awarded the prize in recognition of his outstanding contribution to the understanding of the DNA damage response – a cellular surveillance system that protects against mutations and major genetic damage, and which, for normal cells, serves as a primary defence against the development of serious diseases such as cancer. Niels Mailand describes his research in detail in an article in this publication.

Jes Østergaard, Chairman, Director, Civil Engineer. Member of the Foundation’s Board of Trustees

Björn Lindman, Professor, Ph.D., Dept. of Chemistry & Chemical Engineering, Lund University, Sweden

Knut Conradsen, Professor, Dr.Scient., The Technical University of Denmark

Torkild Andersen, Professor, Dr. Phil., Aarhus University

Talent Prizes The Lundbeck Foundation awarded prizes to three talented researchers under 30 who have conducted particularly promising research in biomedical and natural sciences. The 2009 awards, which consist of personal prizes of DKK 100,000, went to Kamilla Miskowiak, Emil Loldrup Fosbøl and Mads Toudal Frandsen.

Kamilla Miskowiak (28) is a Psychologist with degrees from the University of Copenhagen and Oxford University, and a Ph.D. from Oxford. Her current research is based on her previous projects on how EPO (erythropoietin) may help rehabilitation from brain damage in animals, and how antidepressant treatment affects the processing of emotional information.

Against this background, she is now investigating the extent to which EPO may prevent the degradation of brain tissue (as seen in depression), including examination of whether prolonged treatment reduces the symptoms and improves the learning ability of patients with depression and bipolar disorder.

Emil Loldrup Fosbøl (27) graduated as a Doctor of Medicine in summer 2009, and submitted his Ph.D. thesis at the same time. His research is conducted in the Cardiology Department at Gentofte Hospital. Based on clinical epidemiology, it focuses on risk factors in the use of over-thecounter painkillers in healthy humans. He has already published a number of articles on this subject in prominent international journals, and his research findings about the risk of cardiovascular complications from mild analgesics has received considerable publicity, both in Denmark and abroad.

Mads Toudal Frandsen (28) studied physics at the University of Copenhagen, has a Ph.D. from the Niels Bohr Institute and the University of Southern Denmark, and is now employed as a post doc. at Oxford University. His research aims to contribute to the understanding of the Universe's 'dark matter', which is known to possess mass but does not emit

or reflect light. Mads T. Frandsen's focus is on the development and testing of mathematical models that can be used to explain the existence of dark matter in the Universe. In part, this is tested on the basis of the experiments conducted in the Large Hadron Collider at CERN. Based on its strategy for donations, which was amended at the Foundation's strategy seminar in 2009, the Lundbeck Foundation will focus its 2010 awards on key support areas in the strategy, and on the research leaders of the future. New research centres will therefore not be funded in 2010, as the Board has chosen to prioritise funding for fellowships, for which a total of DKK 100 million has been earmarked in 2010.

Future expectations In 2007, the Foundation decided that grants for the three-year period 2008-2010 would amount to a total of approx. DKK 1 billion. This strategy has been maintained despite fluctuations in the Foundation's annual results in the wake of the 2008 financial crisis. In 2008 and 2009, DKK 328 million and DKK 340 million were awarded, respectively. A similar level is envisaged for 2010.

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GRANT-MAKING POLICY

grant strategy

The Lundbeck Foundation, through the awarding of grants, aims to strengthen Danish research of the highest quality in biomedicine and natural sciences.

Neuroscience is a core area for the Foundation, but projects within other areas are also supported. However, the Foundation has reservations in areas where other Danish foundations and institutions have special interests and obligations.

Projects outside the fields of biomedicine and natural sciences are only funded to a very limited degree, and it is normally a precondition that they are scientific in nature.

Re.: Biomedical Sciences The Lundbeck Foundation divides biomedical research into three levels: basic research, applied (translational / clinical) research and research within epidemiology and prevention of disease.

Basic research is generally perceived as research into disease mechanisms, and consequently focus on a particular topic is not required for applications within this area.

Applied research and prevention research Within these areas, there will be more emphasis on projects with immediate or expected future relevance for or impact on neuroscience.

The Lundbeck Fundation is committed to maintain and exploit the opportunities and freedom of a private foundation as being independent of special interests and public institutions.

Instruments: The Lundbeck Foundation supports high-quality research in biomedicine and natural sciences carried out in Denmark or by Danish researchers abroad through a number of instruments: Applications can be submitted for: • Research projects • Visiting researchers and travel stipends • Junior Group Leader Fellowships • Grants of Excellence in Neuroscience Research prizes: The prizes cannot be applied for but nominations are accepted from leading scientists at Danish universities.

• Talent Prizes • Research Prizes for Young Scientists

Research in epidemiology and disease prevention

Translational and clinical biomedical research

Assessment of applications and nominations All project applications are assessed by one of the Foundation’s two International Scientific Advisory Committees, i.e. biomedical sciences or natural sciences.

Assessment of other applications to the Foundation takes place in collaboration with independent external experts according to generally accepted standards of impartiality and competence.

Basic research including physics and chemistry.

Research into disease mechanisms

Re.: Natural Sciences Within the natural sciences the Foundation supports non-biological research in chemistry and physics.

The Fundation also supports research in subjects that border on the biomedical sciences. Such research is assessed by the Foundation’s International Scientific Advisory Committee for biomedicine.

Research funding The Lundbeck Foundation’s overriding criterion for granting research funds is solely based on the quality of the research.

This relates to the quality of the project’s scientific content, the applicant's qualifications and to the host institution's academic focus on high quality.

As a general aim, grants must make a difference. Thus, the Foundation devotes relatively large financial resources to a small number of projects, rather than small amounts to a large number of projects.

The effects of the grants are monitored and evaluated.

General guidelines / conditions The recruitment of scientists is supported through the granting of scholarships and Ph.D. stipends, in addition to projects that stimulate interest in biomedicine and natural sciences in general.

Scholarships are awarded only for research, though not when the research is an integral part of an education.

Project funding is provided in the form of salaries for academic staff (e.g. post docs.) technical personnel and to a lesser degree to project relevant equipment.

As a general rule, the Foundation places no restrictions upon the patenting or commercialisation of research results from project grants.

Research projects conducted by private businesses and trials of commercial drug candidates are not eligible for funding.

THE lundbeck FOUNDATION PROFESSORSHIPS AND THE junior group leader fellowships Junior Group Leader, Post doc., Ph.D. Søren Gøgsig Faarup Rasmussen, University of Copenhagen, Institute of Neuroscience and Pharmacology.

Established 2009 Junior Group Leader, Assoc. Professor, Ph.D. Steen Brøndsted Nielsen, University of Aarhus, Institute for Physics and Astronomy.

Established 2009 Junior Group Leader, Assoc. Professor, Ph.D. Martin Røssel Larsen, University of Southern Denmark, Institute for Biochemistry and Molecular Biology. Established 2009 Junior Group Leader, Ass. Professor, Ph.D. Lene Niemann Nejsum, University of Aarhus, Institute for Molecular Biology.

Established 2009 Junior Group Leader, Assoc. Professor, Ph.D. Troels C. Petersen, University of Copenhagen, Niels Bohr Institute.

Established 2009 Junior Group Leader, Professor, Ph.D. Jakob Balslev Sørensen, Institute of Neuroscience and Pharmacology, Copenhagen University, Established 2008 Junior Group Leader, Assoc. Professor, Ph.D. Jakob Nilsson, Biotech Research and Innovation Centre (BRIC), Copenhagen University, Established 2008 Junior Group Leader, Assoc. Professor, Ph.D. Sune Toft, Niels Bohr Institute, DARK, Copenhagen University, Established 2008 Junior Group Leader, Assoc. Professor, Ph.D. Anja Groth Biotech Research and Innovation Centre (BRIC), Copenhagen University, Established 2007 Junior Group Leader, Assoc. Professor, Ph.D. Henrik B. Pedersen Institute for Physics & Astronomy, Aarhus University, Established 2007 Professor, M.D., M.Sc., Ph.D. Shohreh Issazadeh-Navikas Biotech Research and Innovation Centre (BRIC), Copenhagen University, Established 2007 Professor, M.D. Jens Bukh Subject: ‘Experimental studies of human viruses and infections’, Institute of Medical Biology and Immunology, Copenhagen University, Established 2006 Professor, Director of Research, Ph.D. Lis Adamsen Subject: ’Clinical nursing’, Institute of Public Health, Copenhagen University, Established 2006 Professor, M.Sc., Ph.D. Ole Nørregaard Jensen Subject: ’Protein mass spectrometry’, Institute of Biochemistry and Molecular Biology, University of Southern Denmark, Established 2004

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THE FIRST GENOME FROM A PREHISTORIC HUMAN

the first genome from a prehistoric human

By Professor Eske Willerslev Basic Research Centre for GeoGenetics, University of Copenhagen

"We can do it!" I shout, and sit up in bed. I'm still not quite awake. "Go upstairs and work," snaps Ulrikke, sleepily. She turns around and goes back to sleep. I've got a new idea and, as is often the case, it came to me in the middle of the night. I rub my eyes and jump out of bed. It's just past five in the morning. "Should I e-mail Rasmus and Tom?" I wonder. Experience tells me that not all of my night-time ideas are equally constructive. But I believe in this one. I write an e-mail. "I think we should consider sequencing the whole core genome from the hair sample of the 4,000-year-old Greenlander," I write, and return to Ulrikke in bed. It's a pretty wild idea. Until now it has only been possible to sequence mitochondria genome from old material. This small genome, inherited through the maternal line, is only 16,000 base pairs long. By comparison, the core genome that I have in mind, 50% of which stems from the father, 50% from the mother, is approximately 3 billion base-pairs long. The decision to sequence the core genome of a living person for the first time was taken two decades ago. In the end, it took 14 years and cost more than DKK 15 billion. Now I'm thinking about doing the same, but for a person who died 4,000 years ago, and whose DNA is about as intact as Berlin at the end of World War II. "Maybe it's one of my less realistic ideas," I ponder as I fall back asleep.

took place about 5,500 years ago. Multiple traces of early hunter settlements have been found all the way from Alaska in the east to Greenland in the west. But who these early Arctic explorers were, and whence they came, no one seems to know for sure. Some surmise that the first humans in the Arctic were ancestors of today's Inuit who now populate the easternmost corner of Siberia, Alaska, Arctic Canada and Greenland. Some argue that these palaeo-Eskimos, as they are called, were related to Native Americans. Others believe they were close kin of the Siberian peoples.

Close, but no cigar It all started when I read about the first humans in the Arctic. This inhospitable and treeless landscape, which stretches along the coast of the ice sea in the northern hemisphere, was the last of Earth's land areas to be permanently inhabited by humans. This probably

The hunt for the first people in the Arctic "The helicopter has crashed! The helicopter has crashed!" shouts Claus. It's summer 2006, three years after my visit to the National Museum. We're at Station North in North-east Greenland - the last outpost before the wilderness that is Peary Land, the northern-

I try to find answers to my questions by visiting the Arctic archaeologists at the National Museum, but am told that, despite countless archaeological finds, only one single site has contained human remains - four bone fragments, found on the ice fjord in West Greenland. "Perhaps they buried their dead on the sea ice," suggests Bjarne Grønnow, the person in charge of Greenland archaeology, by way of explanation for the scarcity of human material. I am determined to test the human bones for DNA, but Niels Lynnerup, from the Anthropology Laboratory that houses the four pieces, refuses my request. The bones are too valuable it would seem. They are also in an incredibly poor state, so it's doubtful whether any DNA has been preserved.

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most land area on Earth, just 740 km from the North Pole. We're heading out into this wilderness to spend a month and a half searching for human remains. But the helicopter has crashed in a snowstorm somewhere out there. A rescue team has been sent to find the pilot. "We need to change our plans," says Claus Andreasen, from the Greenland National Museum in Nuuk. "We need to use a small aeroplane instead."

Despite trekking over the ice thin in the wilderness of Peary Land, Claus and I find no remains from the earliest human inhabitants of Greenland. We find several settlements but all we excavate, with great difficulty, are stone tools and animal bones. It's possible that the bones retain traces of ancient human DNA from the last time they were touched. Although DNA is a highly unstable molecule and degrades over time, the rate of degradation slows significantly at temperatures as low as those in Peary Land. Every time he digs, Claus therefore dutifully pulls on the "space suit" as well as a face mask and disposable gloves – in order to minimise the possibility of him contaminating a sample with his own DNA. It's a cold task.

By day, the temperature hovers around the freezing point – even though it's mid-July. We return home with more than 100 objects.

Unfortunately, not a single one of them proves to contain human DNA. All we find is animal DNA from the bones themselves.

The forgotten tuft of hair I have almost given up hope of discovering where the first humans in the Arctic came from – and then in autumn 2008, I meet with Morten Meldgaard, Director of the Natural History Museum. The meeting is principally about reindeer, but our conversation soon turns to Greenland and the earliest humans. Morten's father, Jørgen, was one of the archaeologists who established the presence of a Stone Age in the Arctic, and Morten himself has participated in several excavations as a zoo archaeologist. "I'm pretty sure the National Museum has a tuft of human hair from the earliest Greenlanders from a dig in 1986," he says. I refuse to believe it.

"No, that can't be right." I'd talked to Bjarne Grønnow in person in 2003 after all, and was told that only four fragments of human bone had been found. But Morten insists, and doubts set in. He's known for his remarkably good memory.

Soon after, we are in Bjarne Grønnow's office at the National Museum – and in front of us lies a huge clump of long, black hair.

I don't know whether to laugh or cry. I froze my butt off in Peary Land to find something even remotely similar to this, and here it is,

THE FIRST GENOME FROM A PREHISTORIC HUMAN

just 10 minutes by bike from where I live. My irritation is quickly replaced with enthusiasm for the rediscovery of this valuable material. Since the hair is officially owned by Greenland, we have to ask the permission of my old expedition friend, Claus Andreasen, before we can run any tests – we get it right away. Claus wasn't aware the hair existed either. Nevertheless, he reminds me that the Greenland trip was certainly not in vain, since we did bring back many valuable specimens. In my mind, I thank Morten Meldgaard for his good memory and Claus for his benevolent attitude towards new scientific projects. Without them, this would never have been a success story. The hair is dated. It's 4,000 years old.

The mitochondria genome A couple of years earlier, a new type of technology had revolutionised molecular biology. It consists of different sequencing platforms – 454, Solexa, Solid, etc. – collectively referred to as "Second Generation High Throughput Sequencing". Without getting too technical, there are two particularly amazing things about these technologies: i) They liberate us from our dependency on classic, primer-based PCR technology, which set clear limits for how short DNA pieces could be for testing purposes (i.e. they had to include both primer binding sites and an informative sequence in between). This has enormous importance for the study of DNA from ancient material, in which the molecules are heavily fragmented. ii) In just a few days, it is possible to sequence in parallel millions and billions of nucleotides, which means that whole genomes can be sequenced within a manageable time scale.

Naturally, we in Copenhagen are not the only ones to see the potential in these new technologies. While we are struggling to raise money for just one of these highly coveted machines, people from Max Planck and the USA have already bought four machines each and started to sequence the genomes of extinct species. Luckily for us, both the Germans and the Americans think too traditionally.

They extract DNA from old bones, as studies of ancient materials have indeed shown that bones contain the most endogenous DNA. The result is that most of their sequences are from microbes. Unlike traditional, primer-based PCR technology, this is not "target sequencing". You get sequences from the most prevalent DNA in the extraction – and in the case of bones, that means bacteria.

Tom Gilbert, a post doc. in my group, has an ingenious idea: "What's important isn't the absolute quantity of DNA, but the relative proportions of endogenous and polluting DNA," he

exclaims. "Bones and teeth are full of microscopic holes that are penetrated by micro-organisms over thousands of years – but what about hair?" Hair is made of a different material, keratin, which doesn't have the porosity of bones and teeth. This means that most of the pollution would sit on the surface. The idea is good, and worth testing. Tom buys some toilet cleaner from the local supermarket, and a piece of mammoth hair is placed in it. The DNA is extracted from the cleaned hair and run on a 454 machine in the USA. Bingo! 90% of all the sequences stem from the mammoth.

Without the grant from the Lundbeck

Foundation, all would have been lost, but

now we have at least a chance of beating the Germans and Americans in the race to sequence the first 'old' genome.

In autumn 2008, we sequence the first complete mitochondria DNA from the 4,000-year-old Greenlandic hair samples. The article is published at express speed in Science. We are the first to sequence the entire mitochondria genome from a prehistoric human – beating the Germans from Max Planck by only a few months. The result isn't just a technological breakthrough. It also shows that the maternal line to the old Greenlanders is closer to the people of the Aleutian Islands - the islands lying between Siberia and Alaska - than it is to modern Greenlanders. This suggests that the first people in Greenland are not direct ancestors of the modern Inuit people. However, all genes in the mitochondria are linked, and can therefore, in an evolutionary context, only be perceived as a single gene. In other words, we have to be very cautious before drawing conclusions.

The core genome The next day, we discuss my middle-of-the-night idea to sequence the whole core genome from the 4,000-year-old Greenlander.

Rasmus (Morten Rasmussen, my Ph.D.-student) and Tom don't think the idea is stupid at all. It should be possible. However, both the Germans and the Americans have a very big head start, and we lack both machines and money. I apply for more funding, but in vain. The responses are always the same. Would it work? What would the ordinary Dane in the street use it for? Each time, I reply that I don't know the commercial significance and that there's no guarantee it'll work, but the project has the potential to revolutionise science and generate massive international interest in Danish science. My arguments seem to fall on deaf ears.

Then two amazing things happen almost simultaneously. Frederik Paulsen, Director of the Ferring Group hears about the project, recognises its potential and decides to donate DKK 250,000 of his own money. It's nowhere near enough, but a fantastic gesture, and means we can get the ball rolling. Shortly after that, I receive a reply to an urgent application to the Lundbeck Foundation. The Foundation also sees great potential in the project, and understands that time is running out. They've decided to donate DKK 1.5 million. Financially, we are up and running. Without the grant from the Lundbeck Foundation, all would have been lost, but now we have at least a chance of beating the Germans and Americans in the race to sequence the first ’old’ genome.

I put everything I have into it. There can be only one winner in this race - the one that comes first. The Germans and Americans have budgets of DKK 50 million, and have everything they need ’in-house’ – machines, molecular biologists, bioinformaticians, etc.

I may only have DKK 1.75 million, but I've also got an ace up my sleeve. Morten Rasmussen is one of my Ph.D.- students and undoubtedly one of the most gifted people I’ve ever met. Some might argue that one man doesn’t count for much – but they’d be wrong. Morten and I have the perfect working relationship, and we’ve pipped other more well-heeled researchers at the post on several occasions.

Morten and I divide the work between us. He takes care of the laboratory details while I concentrate on the big picture. I get Jun Wang, head of BGI in China, the world's largest sequencing unit, interested in the project, so that's the machinery in place. At the same time, I secure assistance from some of the world's best bioinformaticians and population genetics researchers, including our own Anders Krogh and Søren Brunak. I procure DNA extractions from Greenlanders, Native Americans and Siberian peoples, so we

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can simultaneously generate comparative population-genetic data.

All of the participants understand the importance of the project and give it their all – day and night. To solve the problem of contamination of DNA samples after they leave the special clean laboratories in Copenhagen, we mark every single sequence with a unique code, so we can tell which DNA sequences are subsequently introduced in China. We also solve the problem of deamination damage in the DNA, which causes sequence errors, by multiplying the genomic DNA with a polymerase enzyme that cannot read over the damaged bases. Everything is running like clockwork – until we run out of DNA samples. We need more hair. Everything grinds to a halt. The delay lasts for what seems like an eternity. I shuffle about impatiently. Fortuntely we're finally allowed to take another bit of hair.

We run the project. The volume of data is so enormous that we have to use the computer clusters at both the University of Copenhagen and The Technical University of Denmark. We sequence the possible 80% of the damaged genome, the average sequence length of which is at a paltry 55 base pairs with a depth of 20x – in other words, on average 80% of the genome is sequenced 20 times, making it possible for us to recognise both the mother’s and father's contribution. We manage to assemble an enormous jigsaw puzzle of 3.5 billion small pieces into a total genome. In other words, we now have a genome from a 4,000-year-old man, the quality of which is almost as good as if it was from a living person. This is not only the first sequenced genome from a prehistoric human, but the first in depth-sequenced genome from anything dead of any species. It's wonderful!

The unidentified migration The information we are able to derive from the genome is incredible too. We can see that the hair stems from a man, that he probably had brown eyes and brown skin, was of compact build, had a tendency towards baldness, had dry earwax and shovel-shaped incisors. Even though his ancestors had only been in the Arctic for approx. 1,500 years, he had already genetically adapted to life in a cold climate in several ways. He was inbred, which corresponds to cousins marrying and suggests that his people lived in small groups isolated from each other. His closest relatives aren't in the New World – i.e. they're neither Inuit nor Native American – but three Siberian peoples, one of which now lives more than 2,000 km from the Bering Sea that separates the New and Old World. In other words, this man has no living descendants in the

THE FIRST GENOME FROM A PREHISTORIC HUMAN

New World, where he ended his days. His genome is proof that 5,500 years ago, migration took place from Siberia to America and on to Greenland, a migration of which previous research has been blissfully unaware, a migration completely different from and independent of the ones that gave rise to today's Native Americans and Inuit. This, for me, is the true joy of working with fossil DNA. Not only can we reconstruct important components of the people from a culture of which no biological traces remain other than four bones and some tufts of hair, but we can also shed light on parts of human history and evolutionary development that modern genetic studies would not have been able to reveal because those people left behind no descendants that survive to this day. We had discovered a previously unknown migration to the New World. The study throws up the inevitable question of how many other previously unknown migrations have taken place. The 4,000-year-old Greenlander is dubbed "Inuk", meaning "man" in Greenlandic. For many years to come, we'll obtain further information about Inuk as we continue to decode our own DNA. Each time, we'll return to the genome to see what this new information tells us about Inuk.

Inuk becomes world famous The story of the prehistoric human Inuk and his genome makes the front cover of the journal Nature. The same volume carries a "News and Views" article on the discovery, as well as article profiling my Danish research group and myself. What more could you want? We won the race to be first to sequence the genome of an extinct organism. The story of Inuk received the most international press coverage in the University of Copenhagen's long history, with more than 200 million potential readers from newspapers alone.

Inuk's longer term legacy is hard to predict. The possibility now exists of exploring our molecular past and pinpointing the advent of various phenomena, e.g. genetic predisposition to given diseases or the selection of genes during the domestication of horses, cows, etc. The potential is vast. In the short term, the story has given Danish research huge international attention and advertising, the value of which is difficult to quantify. The story of Inuk exemplifies the essence of what basic research is all about – international attention and unpredictable scientific potential. Yet it is far removed from the government's battle cry: "From research to invoice", which has made it difficult in Denmark to find money for projects like this. Fortunately, funders like the Lundbeck Foundation still recognise the need for basic research and understand the importance of being first to make a breakthrough.

In this article, Dr. Lajos Balogh, who is the editor-in-chief of the scientific journal Nanomedicine NBM, gives an introduction to the world of nanomedicine, the subject for the Lundbeck Foundation's Centres of Excellence 2009

nanomedicine ‒ an introduction In the next decade, Nanomedicine will reform our understanding of biology and transform clinical medicine – it will forever change how we diagnose and treat patients.

Imagine that you cut yourself accidentally. You pull out a vial; pour some liquid over the wound. The bleeding stops in 5 seconds, the wound heals quickly and without complications. Or, you hurt your eyes in an accident and now your vision is blurred. Your doctor borrows a few cells from you, constructs a new layer of transparent skin and repairs your vision by replacing the scarred corneal epithelium with a synthetic material, actually made of you. Running a personal DNA profile allows for prescribing a treatment just for you; your personal medicine, which is effective only for you, is prepared in a day by the nearby nanopharmacist. These are not sci-fi scenarios, but existing experimental procedures in nanomedicine.

nanoscience, nanotechnology, nanomedicine The original meaning of ’nano’ is 10-9 (or 0.000000001) without a dimension. Consequently, ‘nano-scale` could be measured using any dimension, but always very small. For length, measured in meters, it usually means 1-1000 nanometer, whereas 1000 nm is equal to 1 micrometer, 1000 micrometer equals 1 millimeter and so on, (for comparison, the diameter of a red blood cell is 7.5 micrometer, or 7500 nm). Still, the relations between science, technology, medicine and business are always the same, regardless whether it is “nano” or not “nano”. Nanoscience is a multidisciplinary science studying nanoscale objects and structures to understand and control matter at the nanoscale. Nanomaterials are

NOT new magical materials, but “old” ones on a different scale (“nano-scale”) with properties that do not exist outside of the nano-range. Accordingly, nanotechnology is the application of nanoscience to study, develop, create, and use materials, devices, machines, and techniques for manufacturing nanomaterials, nanostructures and integrated systems. It works by applying engineering principles and developing processes and technology, tools and methods or methodology for nanoscale R&D and the manufacturing of nanomaterials, devices, machines and techniques.

Nanomedicine exploits and builds upon novel research findings in nanoscience, nanotechnology, biology and medicine; it unifies the efforts of scientists, engineers and physicians determined to apply their latest research results to translational and clinical medicine to develop novel and better approaches and solutions to health-related issues. Nanomedicine is not a separate discipline, rather a realm that nanoscience and nanotechnology share with life sciences (biology and medicine), a region where they overlap and interact with each other. This area includes not only various applications of nanotechnology in life sciences. Biology and medicine also breed new research in nanoscience. In other words, the world of nanoscience and nanotechnology is not vertical; it is horizontal and joins together a number of disciplines, which include life sciences.

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the nanoscopic range Many of the “nano” properties are based on the collective behavior of primary objects (atoms, molecules, macromolecules, particles, proteins, etc). Just like individuals behave differently when they are alone, from when they are part of certain groups and share an experience, atoms and molecules behave differently when they are held together in small groups by physical and physicochemical forces and share electrons. What is on the surface of nanoparticles and what is around them is also very important. Here is a simple explanation: the surface of a sphere with 1 cm diameter is 3.14 x 10—4 m2, but if we calculate the total surface of d = 3.9 nm solid spheres made of the same material and of the same total mass, the result is around 826 m2.

Consequently, what is on the much larger surface of the latter will have more impact than what is on the surface of the 1 cm. diameter sphere.

As nanoparticles grow in size, their relative differences become smaller and smaller with the addition of the next object until they reach the “bulk” state. Simultaneously, nanoscale properties also gradually disappear. In the bulk state, properties of a certain macro-scale object will not change by adding one more molecule or atom to it, while on the nanoscale they do change. As an example, gold nanoparticles are red, fluorescent, chemically reactive, and soluble in water, but bulk gold, as we all know, is a yellow inert metal, which is insoluble in water. The new nano-scale properties of well known materials can be utilized in many areas of nanomedicine.

major directions in nanomedicine The last few years have seen unprecedented advances in the field of biology. The decoding of the human genome, coupled with improving gene transfection technologies offer great opportunities for treating disease. In biologic analysis, lab-on-a-chip methods (e.g. ultra small scale diagnostic devices, large, multiple arrays that can detect thousands of signatures simultaneously) have surpassed earlier ex-vivo and in-vivo detection methods by magnitudes, and provided greatly improved diagnosis, while also aiding important toxicology efforts, such as detection of anthrax spores at the nanogram scale, identification of ten-to-twenty cancer cells in 100 microliters of blood, etc. In medicine, improvements in targeted drug delivery, imaging and therapy have led to so successful interventions in cancer therapies, that cancer is no longer the number one cause of mortality in the US.

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NANOMEDICINE – AN INTRODUCTION

Despite these achievements there is still a serious need to improve healthcare, and a lot to do. In 2007, in the United States alone, the direct medical cost for cancer was about $90B, and the direct medical cost for diabetes was about $116B. The annual medical care cost for spinal cord injury was about $1.5B; the total costs are estimated to about $10B/yr. In order to remain physically active, approximately 200,000 people received hip implants and 300,000 people received knee implants. The average lifetime of current orthopedic implants is only 10 – 15 years; and the cost of an implant varies but in 2010 it is roughly $20,000.

Let me give you three exciting (and subjective) examples of ongoing revolutionary nanomedicine research.

(1) Engineered cell sheets are prepared by culturing cells at 37o C on temperature-responsive surfaces (Masayuki Yamato). Then the cultured cell sheets are harvested by simple temperature changes from 37o C to 20o C, when the cell sheet floats to the surface of the Petri-dish, then placed by the eye-surgeon on the appropriate living surface to recover function. Various cell sheets such as corneal epithelium, corneal endothelium, skin, periodontal ligaments, oral mucosal epithelium, urothelium, and cardiomyocyte tissues have already been fabricated. Clinical treatments have already been initiated using both corneal and oral mucosal epithelial cell sheets for the treatment of patients with corneal surface diseases.

(2) Wherever cancer cells are active, metalloprotease enzymes (MMP-2 and MMP-9) are also very active, so mapping MMP2 and MMP-9 activities allows the visualization of cancer cells (Roger Tsien). When labeled activable peptides penetrate cells in the presence of MMP enzymes, they are cut by these active metalloproteases and thus become activated and fluorescent. This approach has the potential to revolutionize cancer surgery because the surgeon removing the primary tumor will be able to see what additional tissue has to be removed, instead of making assumptions based on experience.

(3) Short and water-soluble peptide sequences were designed and synthesized (Rutledge Ellis-Behnke). These peptides self-assemble into layers and, when exposed to a wound, form a strong gel within seconds thereby physically blocking the bleeding. The material then gradually deteriorates as new tissue is forming. The completely transparent gel can also be used to carry out bloodless surgeries.

”One of the major impacts of nanotechnology will be the development of ultrasensitive methods that will help us learn more about biologic mechanisms and will enrich our knowledge of biology.”

Other current R&D efforts focus on early diagnosis, early detection and treatment of disease (especially cancer), bone and tissue regeneration, development of intelligent nanobiomaterials for cell therapy to improve organ function, safe and affordable therapeutic strategies to regenerate neural tissues, hollow fiber membranes to perform kidney functions, cochlear and retinal implants, new miniature power sources, repair of articular cartilage, new anti-microbial materials, skin, tissue and nerve regeneration, targeted drug delivery, functional imaging agents, novel anticancer therapies, and so on.

nanomedicine as business Nanomedicine is beginning to have an enormous impact on the pharmaceutical market. It is estimated that life sciences and healthcare products, enabled by nanoscience and technology, currently represent a $1 billion plus market in 2009, primarily in the fields of medical devices, implants, imaging and diagnostics, with annual markets of billions of dollars predicted within ten years. Major nanomedicine development directions reflect the health needs listed earlier and the opportunities in nanoscience and nanotechnology. First generation products on the market include nanoparticulate pharmaceuticals, biocompatible (long lifetime) implants, and anti-bacterial coatings for medical supplies, and healing wound dressings. Nanomedicine will change the way pharmacologic business is done. Personalized medicine, based on the individual biomedical profile of a particular patient, will require manufacturing of small quantities of nanomedicines by experts. A DNA profiling today costs about $5000, and is presently too expensive for routine hospitalizations, but it is projected that in the not too distant future the cost of sequencing a person’s genome will drop below $1000, less than the present price of colonoscopy.

We have just started to witness this cutting edge technology appearing in medicine. One of the major impacts of nanotechnology will be the development of ultrasensitive methods that will help us learn more about biologic mechanisms and will enrich our knowledge of biology. Support from foundations like the Lundbeck Foundation is crucial to move the field forward, as inventions cannot be scheduled, only observed. In the following articles, the three Nanomedicine Centres of Excellence, granted by the Lundbeck Foundation will introduce their projects and how they plan to exploit the vast possibilities found in research and development on a very small scale.

Biomembranes which will be studied and manipulated at nanoscale in CBN (The Lundbeck Foundation Centre for Biomembranes in Nanomedicine) play a critical role in our life. Proteinmembrane and membrane-membrane interactions control signal transmissions through biological membranes and learning much more about these is crucial for successful drug delivery.

Cancer stem cells are thought to be responsible for the recurrence of cancers and may be one reason for metastasis and eventually cancer-related mortality. As cancer stem cells are usually resistant to therapies aimed at cancer cells, the ability to address cancer stem cells will be a fundamental step forward in cancer therapies that will be addressed by NANOCAN – The Lundbeck Foundation Nanomedicine Research Centre for Cancer Stem Cell Targeting Therapeutics.

Individualized management (prevention, diagnosis and treatment) of cardiovascular and musculoskeletal diseases as well as tissue damage and regeneration will be addressed by LUNA – The Lundbeck Foundation Nanomedicine Centre for Individualized Management of Tissue Damage and Regeneration. This direction is very significant, because cardiovascular diseases are now more prevalent than cancer.

The publication rate of nanomedicine related papers is exploding – it is growing faster than exponential since 2000. As Editor-inChief of Nanomedicine: Nanotechnology, Biology and Medicine (Nanomedicine: NBM) I would like to share my excitement and optimism about the future of these centres. I hope that within a short time we could welcome publications about true medical breakthroughs from all three of them in this international, peerreviewed journal, which follows the latest advances in the field of nanomedicine.

We at Nanomedicine: NBM believe that nanomedicine will have a profound impact on future medical practice. However, we strive to promote the view that nanomedicine as a solution is neither better nor worse – it is DIFFERENT.

23

THE LUNDBECK FOUNDATION 2009│10

CENTRES OF EXCELLENCE 2009 – NANOMEDICINE

big opportunities in a small world individualized prevention, diagnostics and treatment

imbalance between tissue damage and tissue regeneration in disease The aim of the new nanomedicine research centre is to develop novel clinically relevant nanobased technologies within drug design, drug delivery, bio imaging and tissue engineering and to support individualized prevention, diagnosis and treatment of cardiovascular and musculoskeletal diseases. The dramatic population ageing in Western societies poses a major burden to their healthcare systems and health economics due to an increased number of patients suffering from chronic diseases. Cardiovascular- (CVDs) and musculoskeletal diseases (MSDs) are two of the most significant contributors to this burden. Present limited success in the management of CVD and MSD is most likely a consequence of their multifactorial pathogenesis, where disease development is determined by environmental factors as well as individual susceptibility. Consequently, there is a huge need for development of new

A human stem cell cultured in a nanoporous biomaterial. (J.V. Nygaard, iNANO)

and novel approaches to individualized and targeted treatment of these important diseases. This goal can only be achieved through combining cutting-edge international competences within the areas of nanoscience and translational medicine.

a strong basis LUNA is part of a broader nanomedicine initiative established in Aarhus and builds on a number of technological platforms developed through existing cross-disciplinary projects established at the Faculty of Health Sciences and the Interdisciplinary Nanoscience Centre, iNANO. The LUNA project will benefit from these strong collaborations that have set the stage for future nanomedicine research in Aarhus. The project will be headed by leading scientists covering the areas of translational biomedical research, state-ofthe-art nanoscience, biomedical imaging, structural and molecular biology.

luna – the lundbeck

Professor Allan Flyvbjerg,

The mechanism behind the

for individualized management

the Faculty of Health Sciences

and tissue regeneration in disease

regeneration

Interdisciplinary Nanoscience

foundation nanomedicine centre of tissue damage and

Aarhus University Hospital and

and professor Jørgen Kjems,

Centre (iNANO) Aarhus University

imbalance between tissue damage

DKK 30 million in the period 2010-2105 26 senior researchers and 10 Ph.D.-students

www.nanomedicine.dk

”Clearly, nanomedicine holds an enormous potential, also for development of new treatments.

Research in the field is greatly needed, and therefore, it is a visionary and timely strategy of the Lundbeck Foundation to support the nanomedicine research area.”

Model of C5 pattern recognition molecule in complex with an inhibitor (N.S. Laursen)

“Clearly, nanomedicine holds an enormous potential, also for development of new treatments. Research in the field is greatly needed, and therefore, it is a visionary and timely strategy of the Lundbeck Foundation to support the nanomedicine research area.

Nanomedicine is a cornerstone of the research strategy of Aarhus University, which has now been replenished with vital resources,” says Professor Allan Flyvbjerg.

“The centre will set the very best research team by recruiting post docs and Ph.D.- students on an international basis. Furthermore, the research groups forming part of the centre all have broad international collaborations, which will contribute to the establishment of a strong research environment within LUNA”, adds Professor Jørgen Kjems.

restoring balance Central for the centre’s work is the hypothesis that cardiovascular and musculoskeletal diseases are caused by an imbalance in tissue damage and the body’s natural ability to repair or rebuild damaged tissues. Thus, an important part of the centre’s work is focused on determining the central mechanisms causing these imbalances.

Furthermore, development of nanobased techniques to stimulate tissue regeneration and to restore balance. The central hypothesis is that a group of newly discovered molecules ('pattern recognition

molecules’) play a central role in the imbalance between tissue damage and the capacity for regeneration and in part hold the explanation for individual differences in susceptibility to disease development.

The goal is, through cross-disciplinary research, to create new knowledge and translate it into novel technologies that are expected to reduce the disease burden from cardiovascular disease and musculoskeletal disorders through individualized prevention, diagnosis and treatment. The planned projects will take advantage of newly developed techniques from the nano-world to explore the role of these molecules in the disease development in two significant diseases.

Furthermore, the collaboration between health- and nanosciences will lead to the training of talented scientists with deep insight into both fields, a competence which will be in heavy demand in the future.

THE LUNDBECK FOUNDATION 2009│10

CENTRES OF EXCELLENCE 2009 – NANOMEDICINE

targeted treatment of cancer stem cells using nano carriers

smart missiles against cancer In the recent past, a rare population of tumor cells has been discovered that shares the molecular coat and properties of stem cells.

These so-called cancer stem cells are resistant to most existing therapies and highly metastatic. It is therefore thought that the next generation of anti-cancer drugs has to aim at an elimination of the cancer stem cells to decrease the number of cancer deaths.

The high degree of similarity between cancer stem cells and normal stem cells, however, poses extraordinary challenges: it has to be avoided that the anti-cancer drugs are harmful to the related normal stem cells, which are of critical importance for the regeneration of tissues and organs in the human organism.

The research at NanoCAN aims at constructing smart nano-missiles that selectively kill cancer stem cells without exerting severe side effects on normal stem cells.

“Now is the ideal time to start tackling this ambitious goal,” explains Professor Jan Mollenhauer “Techniques and know-how in the areas of nanotechnology and molecular biomedicine have reached a point of convergence that for the time allows us to systematically assemble smart drugs in academic laboratories. This is a fascinating new option to achieve rapid progress in this field.”

NanoCAN will concentrate its activities on breast cancer, which is still causing the death of every fourth patient and is the leading cause of cancer mortality among women. “The general strategies of NanoCAN, however, can also be projected to other cancer types or to direct drugs to normal stem cells for regenerative medicine,” explains Jan Mollenhauer.

a kit for smart nano-missiles “We will dissect the drugs into three parts, which includes a targeting device, a killing device, and a delivery device. The three

”We hope that NanoCAN will provide substantial and exciting progress for developing new future anti-cancer therapies and are looking forward to making use of the research opportunities opened to us by the Lundbeck Foundation donation.”

The basic principle of the smart nano-drugs that are developed in the NanoCAN centre is that the nano-drugs are guided to the stem cells via nano-scaled “radar”-structures. A selective drug, serving as the “missile” consecutively kills only the cancer stem cells (red), which cuts off supply for the cancer cells (orange). Normal cells (blue) and normal stem cells (green) remain unaffected, avoiding severe side effects.

nanocan – the lundbeck

Professor Jan Mollenhauer,

research centre for cancer

University of Southern Denmark

foundation nanomedicine

stem cell targeting therapeutics

Institute of Molecular Medicine,

Targeted treatment of cancer

stem cells using nano carriers DKK 35 million in the period 2010-2014 4 senior researchers and 7 Ph.D.-students

www.nanocan.dk

To find selective drugs, the NanoCAN centre will use cells with specific molecular fingerprints of cancer stem cells and normal stem cells. Via a highcapacity robotic workstation, each of the 20,000 human genes will be inactivated in the cells followed by a systematic scan for the effects. Frontline high-complexity biochips are developed and used for gathering data with high molecular resolution.

parts are developed in parallel and will then be assembled into the active drug. This will not only save time, but also allow us to combine the different components with each other similar to the LEGO system to find the most optimal configuration. It moreover has the advantage that we can more easily exchange one of the components in order to address another cancer type or normal stem cells for regenerative purposes,” says Jan Mollenhauer.

The various elements of the nano-drugs will be encapsulated in nanospheres. They will find their way to cancer stem cells by use of structures on their surface that recognise structures on the surface of cancer stem cells. The actual attack on the cancer stem cell is performed by small pieces of RNA, so called silencing RNA (siRNA) which is known to be able to turn off activated genes.

Thereby, specific genes in cancer stem cells can be inactivated.

finding the needle in the haystack “With regard to drug delivery devices and RNA-nanotechnology, we can profit from the groundworks that has been carried out in the two Centers of Excellence MEMPHYS and NAC, which were funded by the Danish National Research Foundation at the University of Southern Denmark. This is a good example of how an investment into basic research provides new avenues for translation,” concludes Professor Mollenhauer.

One of the major remaining challenges is that all known surface structures that allow for guiding drugs to the cancer stem cells are also present on normal stem cells, which must not be harmed by the drugs. The NanoCAN centre aims at recovering siRNAs that selectively kill cancer stem cells.

The centre's strategy comprises the construction of cells with molecular fingerprints discerning cancer stem cells from normal stem cells and consecutively testing the possible killing effect of the inactivation of each of the 20,000 human genes in these cells via siRNAs. To carry out this search strategy, the centre will use high-throughput robotics in conjunction with advanced biochip formats.

“This theoretically allows us to recover drugs for personalized cancer treatment, because the drugs are aimed at specific molecular fingerprints. The tumor of an individual patient can then be tested for the presence of such a fingerprint, making it possible to determine in advance if the patient will profit from the treatment.” says Jan Mollenhauer. “We hope that NanoCAN will provide substantial and exciting progress for developing new future anti-cancer therapies and are looking forward to making use of the research opportunities opened to us by the Lundbeck Foundation donation.

THE LUNDBECK FOUNDATION 2009│10

CENTRES OF EXCELLENCE 2009 – NANOMEDICINE

communication between nerve cells and signaling between bacteria

new insights into cell communication for the benefit of patients The Lundbeck Foundation Centre for Biomembranes in Nanomedicine (CBN) will in the next five years answer fundamental questions about how basic biological processes of cell communication take place on the nanoscale. Disturbances in cellular communication is a key element in the development of a myriad of diseases – from bacterial infections to diseases in the human brain such as schizophrenia and Parkinson's disease. The centre’s research findings may eventually lead to entirely new principles for how we diagnose diseases and develop drugs.

“We expect to get much closer to a fundamental understanding of a range of diseases by studying the biological processes taking place in the cell's outer barrier, the cell membrane. While classically recognized mostly as an inert barrier, it is now established that in both bacteria and human cells, the cell membrane plays a dynamic key role in multiple basal cellular processes”, explains Ulrik Gether.

Through complex and yet poorly understood interactions, the lipids of the membrane mediate, together with multiple embedded membrane proteins, vital processes such as transport of nutrients and ions in and out of the cell, cell-to-cell contacts and transmission of chemical signals between cells. Interestingly, these processes exhibit surprisingly many similarities between bacteria and human cells, which underline their fundamental importance to all living organisms.

"In CBN, we will focus on our key areas of expertise, neuronal and bacterial cell-to-cell signaling. We will examine two types of interactions that control the signal transfer across biological membranes - protein-membrane interactions and membranemembrane interactions right down to the single molecule level", says Dimitrios Stamou.

from nerve cells to nano containers Nerve cells communicate via use of chemical signaling molecules (neurotransmitters) that are contained within vesicles – small containers of nanoscale dimensions inside the cells. The vesicles

Biological membranes are the nanoscale boundaries that separate the cytoplasm of the cell from the extracellular environment and define intracellular compartments. The figure illustrates signal transmission across biological membranes, which represents the scientific focus of CBN. Signals are typically transmitted across biological membranes via transmembrane proteins such as transporters, ion channels and receptors. A second major mechanism of signal transmission is endo/exocytosis of vesicles that may transport signaling molecules such as neurotransmitters or virulence factors.

cbn – the lundbeck foundation

Professor Ulrik Gether,

Communication between nerve

nanomedicine

and Pharmacology and Assoc.

bacteria

centre for biomembranes in

Institute for Neuroscience

Professor Dimitrios Stamou, Institute for Neuroscience and Pharmacology and Nano-Science Center,

University of Copenhagen

cells and signaling between

DKK 34 million in the period 2010-2015 10 senior researchers and 15 Ph.D.-students

www. nanomedicine.ku.dk

”Taken together, we are convinced that our efforts over the next 5 years will lead not only to enhanced understanding of signal transmission across biological membranes but also provide new strategies for diagnostics and treatment of brain disorders and infectious diseases.”

Visualization by confocal fluorescence microscopy of the dopamine transporter in live rat dopaminergic neurons using the fluorescent cocaine analogue, JHC 1-64. The chemical structure of JHC 1-64 is seen in the background (Eriksen et al, J. Neurosci. 2009)

fuse with the nerve cell membrane in a process called exocytosis, thereby releasing the neurotransmitters to the surroundings. The transmitters exert their action by activating receptors in the cell membrane of the adjacent nerve cell. The action of the transmitter is terminated by rapid re-uptake of the transmitter via specific transport proteins in the cell membrane of the nerve cells. CBN has a particular interest in the neurotransmitter dopamine that is essential for our brain’s ability to regulate motivation, reward, learning and voluntary movements. Aberrations in dopamine function play a key role in several psychiatric and neurological disorders including schizophrenia, drug addiction, ADHD (Attention Deficit Hyperactivity Disorder) and Parkinson’s disease.

"It is our goal to develop ultra-sensitive assays for detection of individual molecules of receptors and transporters in the cell membrane as well as novel nano-biosensors for dopamine and related transmitters. This will dramatically increase our ability to investigate nanoscale events at the cellular level and hence to obtain deeper insight into the mechanisms governing communication between nerve cells and thereby improve our possibilities for treating diseases where this communication is disturbed”, says Ulrik Gether.

similarities between bacterial and nerve cell communication A second part of CBN’s project focuses on membrane functions when cells take up material from their surroundings (endocytosis), resulting in the formation of new intracellular vesicles, and when cells liberate material to their surroundings (exocytosis), resulting in the fusion of intracellular vesicles with the cell membrane. These processes are involved both in the release of neurotransmitters by nerve cells as well as in cell-to-cell signaling in bacteria. By use of advanced nanoscale methods, including new superresolution microscopic techniques, it is the aim both to study and to regulate membrane fusion- and fission- processes with the goal of generating new principles for medical intervention. Moreover, based on the insights obtained, it is the goal to investigate the basic properties and toxic effects of native and artificial vesicles with the purpose of designing novel membrane nanocontainers for drug delivery.

"Taken together, we are convinced that our efforts over the next five years will lead not only to enhanced understanding of signal transmission across biological membranes but also provide new strategies for diagnostics and treatment of brain disorders and infectious diseases”, concludes Dimitrios Stamou.

THE LUNDBECK FOUNDATION 2009│10

THE LUNDBECK FOUNDATION'S RESEARCH PRIZES

the lundbeck foundation’s research prizes

Since 1987, the Lundbeck Foundation has awarded research prizes to honor and encourage outstanding researchers in biomedicine and natural sciences and thus draw attention to the significance of research for society.

Candidates are proposed by senior researchers at the Danish research institutions following calls for nomination and the Research Prize Committee selects the recipient in conjunction with external evaluators.

The largest and oldest prize is the Lundbeck Foundation’s Nordic Research Prize, which today is DKK 2 million of which DKK 600,000 is a personal prize, and DKK 1.4 million to research of the prize recipient’s choosing.

Several of the talent prize recipients are young Danish researchers who – as part of their education – have worked at a foreign research institution. The award has also been granted to young foreign researchers who at the time of the award conducted their research at a Danish research institution.

This prize was founded in 1987 under the name the P.V. Petersen Prize and was established in respect of H. Lundbeck's former Research Director Poul Viggo Petersen, who became the first recipient of the prize.

Since 1987, the prize has been awarded to 24 researchers including 15 from the Danish research institutions, 4 from Swedish research institutions, 3 from Norwegian and 2 from Finnish research institutes. The prize is an honorary prize, for which nominations cannot be submitted. In selecting candidates for the prize the Lundbeck Foundation’s Research Prize Committee consults with leading scientists, including previous recipients, and seeks international assessment of the candidates proposed as the basis for awarding the prize.

the lundbeck foundation research prize for young scientists In 2001, the Lundbeck Foundation established a research prize for young researchers under the age of 40. The Foundation calls for nominations for the prize and candidates are suggested by senior researchers at Danish research institutions. The recipient is selected by the Lundbeck Foundation Research Prize Committee in conjunction with external evaluators. The prize is a personal prize of DKK 300,000 and the recipient must be conducting research at a Danish research institution at the time of the award.

the lundbeck foundation talent prizes Upon the establishment of the prize for Young Scientists, The Foundation’s Research Prize Committee noted a large number of nominated young researchers under the age of 30 who had already made a remarkable research contribution. In 2001, the Board of Trustees decided to award three prizes for particularly talented young scientists. The prize is a personal prize of DKK 100,000 and the recipient must be conducting research at a Danish research institution at the time of the award.

Each year the Lundbeck Foundation receives many qualified suggestions for candidates to the Lundbeck Foundation prizes for young researchers and talents, and the Foundation is pleased to note that there is a good growth layer in Danish research.

major new prize in 2011 The Lundbeck Foundation's Board of Trustees has decided to establish a major European prize within brain research to be called Grete Lundbeck European Brain Research Prize – The Brain Prize. This prize is dedicated to honor outstanding European brain researchers and to enhance the interaction between Danish and European brain research e.g. by prize recipients participating in research exchange programs with Danish research institutions, chairing symposiums and the like. The prize will be awarded for the first time in 2011.

To strengthen the new prize’s outreach activities to promote interaction between Danish and other European brain research, the Lundbeck Foundation has decided to seek to establish a separate prize foundation: "Grete Lundbeck European Brain Research Foundation" with an independent board and administration, and an internationally composed review committee. The board members will include the rectors of the universities of Copenhagen, Aarhus and Southern Denmark. The foundation and the price are named after Grete Lundbeck, who in 1954 had the foresight to establish the Lundbeck Foundation, and thereby made it possible to provide substantial support for Danish research.

Following the establishment of the new European prize the Lundbeck Foundation's Board of Trustees has decided to cease the awarding of the Nordic Research Prize. The recipient for 2010, Professor Jes Olesen from Glostrup Hospital, thus becomes the last recipient of this award.

the 24 recipients of the lundbeck foundation’s nordic prize for outstanding research Professor, M.D. Jes Olesen

2010

Professor, M.D. Lars Farde

1999

Professor, Ph.D. Mart Saarma

2009

Professor, M.D. Thue W. Schwartz

1998

Professor, M.D. Niels E. Skakkebæk

2008

Professor, Dr. Phil. Peter E. Nielsen

1997

Professor, M.D. Dr. h.c. Anders Björklund

2007

Professor, M.D. Per Andersen

1996

Professor, M.D. D.M.Sc. Jens F. Rehfeld

2006

Professor, M.D., D.M.Sc., Dr. h.c. Arvid Carlsson

1995

Professor, Ph.D. Ole Petter Ottersen

2005

Professor, Chief Physician, M.D., Dr. h.c. Niels A. Lassen

1994

Professor, Ph.D. Jon Storm-Mathisen

2005

Professor, M.D. Carl-Gerhard Gottfries

1993

Professor, Ph.D. Matthias Mann

2004

Professor, M.D. Lars-Inge Larsson

1991

Professor, M.D. Olaf Paulson

2003

Professor, M.D., D.M.Sc., Dr. h.c. Erik Strömgren

1990

Professor, M.D., Ph.D. Kari Alitalo

2002

Professor, D.Pharm. Povl Krogsgaard-Larsen

1989

Professor, M.D. Keld Danø

2001

Professor, M.D., Dr. h.c. Mogens Schou

1988

Professor, Dr. Phil. Karl Anker Jørgensen

2000

Director, Civil Eng. P.V. Petersen

1987

2010

2003

2009

2004

2008

2005

2007

1997

1991

2006

1996

1990

2005

1995

2002

2001

1994

1993

1989

1988

2000

1999

1998

1987

31

THE LUNDBECK FOUNDATION 2009│10

THE LUNDBECK FOUNDATION’S NORDIC RESEARCH PRIZE 2010

the classification, epidemiology and cost of migraine jes olesen, professor of neurology

32

THE LUNDBECK FOUNDATION'S RESEARCH PRIZES

The Lundbeck Foundation’s Nordic Research Prize is an honorary prize that is given for outstanding research in scientific areas that the Foundation supports. In 2010 the prize was awarded Professor, M.D. Jes Olesen in recognition of his seminal and comprehensive contributions to clinical headache research.

Migraine is a disease characterized by attacks of severe headache, and increased sensitivity to light and sound. When no preceding symptoms are present it is called migraine without aura and when the headache is preceded by visual or other neurological symptoms it is called migraine with aura. Patients are often debilitated and must stay in bed. It is very important to identify the mechanisms underlying the disease in order to be able to develop better treatments. This has been the most important part of the research of Jes Olesen and his group. This article focuses on the impacts on public health expenditure of migraine.

classification and diagnosis In order to know how frequent a disorder is, it must be possible to diagnose it accurately throughout the world. That became possible in 1988 when the International Classification of Headache Disorders was prepared with Jes Olesen as anchorman. It placed all headache disorders in a logical hierarchy and provided precise criteria for all the different diagnoses. Subsequently, this classification has been updated and adopted by the World Health Organization (WHO). The classification of the different types of migraine is shown in table 1 and the diagnostic criteria for migraine without aura in table 2.

how frequent is migraine?

Within the last year, 10 per cent of the Danish population have had one or more migraine attacks and 16 per cent have had migraine at least once in their life. Overall, there seems to be only small differences in these numbers between countries, between highly and less highly developed societies and between rural and urban environments. Asians may suffer less from migraine than Africans and Caucasians, but it cannot be ruled out that the reporting of frequencies has been influenced by cultural issues.

Most patients relatively rarely have attacks, but two per cent of the population has two or more monthly attacks that may last up to three days. Furthermore, those affected by migraine are also more often disposed for other ailments (so called co-morbidity) such as depressions, anxiety, allergies and metabolic disorders. An increased frequency of strokes has been seen in younger women with migraine, particularly if they suffer from migraine with aura. New Danish and international population studies indicate that migraine becomes more and more frequent, but the reason for this has not yet been determined. Increasing our knowledge of the reason for this change is of the utmost importance if we are to avoid a “migraine epidemic”.

the costs of headache disorders The Global Burden of Disease study by the WHO measured the disability caused by all diseases throughout the world using DALYs (Disability Adjusted Life Years), a time-based measure that combines years of life lost due to premature mortality and years of life lost due to time lived in states of less than full health. Migraine was in the top 20 list and for women it was number 12, reflecting increased frequency and severity in females. A Danish study showed that one out of six days of sickness absence per year or 17 per cent of all absenteeism was caused by migraine or other headaches. The advent of better medicine for the actual migraine-attacks has not yet reduced this figure, and development of better prophylactic treatments are crucial to reduce the impact of migraine on general health.

In the extensive study “Cost of Disorders of the Brain in Europe”, the financial cost of 12 major brain disorders was measured in 27 countries. The total cost of migraine in the EU (450 million inhabitants) was 27.000 million Euros per annum. One of the highest costs was absenteeism from work (figure 1). In comparison to other brain disorders, migraine came after dementia but was more costly than epilepsy, movement disorders or multiple sclerosis (figure 2).

The latter disorders, however, had a higher proportion of direct cost. According to Danish studies, non-migraine headaches are at least as costly as migraine. In an ongoing European study, the previous cost analysis is updated and extended to comprise six more disorders. Thereby the inclusion of non-migraine headache types is likely to bring the cost of headache disorders above 50.000 million Euros per annum, which equals the costs to society of dementia.

conclusions We now have clear definitions of migraine and other types of headaches, including detailed descriptions of their epidemiology and their costs to society. For 35 years, Danish migraine research has been characterized by a translational approach to understanding the molecular and cellular mechanisms underlying the disease, at the same time shedding light on the frequency, burden and cost of the disease to patients as well as to society. This has helped bring Danish migraine research to the international forefront, where scientists and clinicians are increasingly focused on neurobiological research aimed at an improved understanding of disease mechanisms, enabling the development of better drugs.

THE LUNDBECK FOUNDATION 2009│10

THE LUNDBECK FOUNDATION'S RESEARCH PRIZES

Table 1 / Classification of migraine

Table 2. / Diagnostic criteria for migraine without aura:

• Migraine without aura

A. At least 5 attacks fulfilling criteria B-D

• Migraine with aura

B. Headache attacks lasting 4-72 hours

• Typical aura with migraine headache • Typical aura with non-migraine headache • Typical aura without headache • Familial hemiplegic migraine (FHM) • Sporadic hemiplegic migraine • Basilar-type migraine • Childhood periodic syndromes that are commonly precursors of migraine • Cyclical vomiting • Abdominal migraine

(untreated or unsuccessfully treated) C. Headache has at least two of the following characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs) D. During headache at least one of the following: 1. Nausea and/or vomiting

• Benign paroxysmal childhood vertigo

2. Photophobia and phonophobia

• Retinal migraine

E. Not attributed to another disorder

• Complications of migraine • Chronic migraine • Status migrainosus • Persistent aura without infarction • Migrainous infarction • Migraine-triggered seizures • Probable migraine • Probable migraine without aura • Probable migraine with aura • Probable chronic migraine

Figure 1

         

Figure 2

      Million Euros 60000

Indirect costs Direct non-medical costs Direct healthcare costs

50000 40000 30000 20000 10000

S M

so n in rk Pa

y ps ile Ep

ke ro St

in e ra ig M

em

en t

ia

0

D

Premature death 0.5% Hospitalization 12% Drugs 5% Outpatient care 7% Social services 31% Informal care 9% Other direct costs 5% Sick leave 28% Early retirement 3%

THE LUNDBECK FOUNDATION’S RESEARCH PRIZE FOR YOUNG SCIENTISTS

dna damage response – the cell’s built-in defence against cancer professor niels mailand

The human body consists of just under one million billion cells.

For such a complex organism to function, every cell must be part of a social network that dictates how they behave. An important principle in any fully developed organism is homoeostasis, i.e. balance between how many cells die and the number of new ones

formed. As a result, strict control is exercised over cell growth, both stemming from within the cells themselves and from their environment. Cancer occurs when a single cell eludes these control mechanisms and starts to divide in an uncontrolled manner that may lead to the formation of a cluster of cells – a malignant tumour.

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THE LUNDBECK FOUNDATION 2009│10

THE LUNDBECK FOUNDATION'S RESEARCH PRIZES

”Ever since the emergence of the simplest life forms billions of years ago, cells have had to cope with the problem of DNA damage. Evolution has developed and refined methods to protect cells against the potentially lethal effects.”

The reason that cancer cells do not behave like normal cells is that their DNA is different. Random changes in the cell’s DNA, called mutations, can lead to the production of too much or too little of certain proteins, or cause them to function in a damaging manner.

As the cell’s proteins are responsible for all of its processes, these mutations can impact upon the normal process of cell division.

The vast majority of mutations are the result of DNA damage that has not been properly repaired. In reality, cells are constantly exposed to DNA damage, both by natural processes and by unhealthy lifestyles. Among the natural sources of DNA damage are free radicals, formed by the cell’s natural metabolism, as well as radiation from the Sun and from outer space. In terms of lifestyle, people expose themselves to DNA damage by, for example, smoking, excessive sunbathing or contact with toxic chemicals.

Ever since the emergence of the simplest life forms billions of years ago, cells have had to cope with the problem of DNA damage.

Evolution has developed and refined methods to protect cells against the potentially lethal effects. As a result, all cells contain a variety of proteins, the primary purpose of which is to repair DNA damage efficiently and properly. A complex network of signaling

Figure 1 Binding of proteins to DNA damage. By firing a laser beam through the cell nuclei, the DNA in the laser’s path is damaged. Many of the proteins in the DNA-damage response react to the formation of these lesions by accumulating at the points in the cell nucleus where the damage has occurred.

Here are two nuclei that contain the protein 53BP1 coupled to the

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paths, collectively referred to as ‘the DNA-damage response’, govern these proteins. In the event of DNA damage, the response affects many aspects of cell regulation, including cell growth, cell death and – of course – DNA repair. Cells that are in the process of growing and dividing are particularly sensitive to DNA damage and its consequences. Therefore, in colloquial terms, the pause button is pressed when these cells are exposed to DNA damage, temporarily halting their growth until the damage is repaired.

One of the main goals of Niels Mailand's research at the Danish Cancer Society has been to understand how the DNA-damage response functions in human cells, and therefore how it protects us against cancer. The researchers in his group have focused on identifying the proteins that help maintain and repair human DNA, in order to better understand how they interact. One important characteristic of many of these proteins is that they accumulate in the event of DNA damage (figure 1). This causes a higher local concentration of the factors that facilitate efficient DNA repair. The proteins arrive extremely rapidly, and in a specific sequence, to the DNA damages. In recent years, intensive research into the DNA-damage response has shown that the repair proteins

green fluorescent protein (GFP), which has been hit by the laser. The two photographs were taken before (left) and 10 minutes after the laser irradiation (right). The green line through the cell nucleus shows an accumulation of GFP-53BP1, evidence that DNA repair is taking place.

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A focused audience learning about the details of the DNA-damage response.

Detailed insight into the molecular aspects of the DNA-damage response is an important precondition both for understanding how cancer arises and for improving treatment. DNA damage may lie behind cancer, but paradoxically enough we treat most cancers with chemo- and radiotherapy, the aim of which is to inflict so

much damage on the cancer cells’ DNA that they die. Cancer cells are usually more sensitive to DNA damage than healthy cells because their DNA-damage response is destroyed at an early stage of their transformation from normal cell to cancer cell. This is why chemo- and radiotherapy are so effective in many cases. However, the effect of these treatments on healthy cells limits how aggressively the cancer can be treated, and the well-known side effects of chemotherapy are caused by unintentionally killing the body’s most sensitive healthy cells. As a result, intensive research is now being conducted into more precisely targeting the treatment of cancer cells, e.g. by inhibiting specific enzymes in the DNA-damage response. RNF8, RNF168 and HERC2 are all obvious inhibitory proteins that drugs should be developed to counteract. The rationale is that the cancer cells are already the result of a compromised DNA-damage response, so additional interference in their already weakened ability to repair DNA can “push them over the edge”, while normal cells will typically have alternative defence mechanisms upon which to fall back. Future research will hopefully show whether targeted inhibition of these and other enzymes in the DNA-damage response is capable of forming the basis for new, improved and less harmful cancer therapy.

Figure 2 Simplified model of how RNF8, RNF168 and HERC2 signal the presence of DNA damage and stimulate repair of DNA. When damage occurs to DNA, RNF8 is rapidly attracted to the spot on the DNA where the damage has occurred (Step I). The presence of DNA damage also stimulates the binding of RNF8 to HERC2, and together these two proteins attach a chain of ubiquitin molecules to the chromatin in the immediate vicinity of the damage (Step II). The ubiquitin chain serves as a binding platform for the

protein RNF168, which is also able to add ubiquitin chains to chromatin in the event of DNA damage, and which therefore increases the amount of ubiquitin in the vicinity of the damage. The high concentration of ubiquitin chains in the event of DNA damage now acts as an effective binding platform for a number of DNA repair factors (depicted in grey) that are brought into contact with the areas of DNA damage and efficiently repair them, restoring the DNA to an intact state.

help each other to locate damage by chemically modifying one another as well as chromatin (DNA and DNA-storage proteins in cell nuclei). These modifications act like a glue that enables the proteins to bind with each other in new ways and to “stick” to the DNA damages. Amongst other things, Niels Mailand’s research has identified three enzymes (RNF8, RNF168 and HERC2) that chemically modify chromatin in the event of DNA damage, using the molecule ubiquitin. This alters the chromatin structure and forms a binding platform for a series of DNA repair proteins (figure 2). If just one of these three enzymes is removed, the DNA repair is compromised and the cell’s ability to survive DNA damage is significantly reduced. The RNF8, RNF168 and HERC2 proteins are key components of our cells’ defence against DNA damage, and consequently potentially also against the diseases associated with defects in the response.

DNAdamage Chromatin Step 1

Step 2

Step 3

THE LUNDBECK FOUNDATION 2009│10

THE LUNDBECK FOUNDATION'S JUNIOR GROUP LEADER FELLOWSHIPS

THE LUNDBECK FOUNDATION’S junior group leader fellowships 2009

”THE GOLGI NETWORK WORKS AS A RAILWAY STATION INSIDE THE CELL. TRAINS CONSTANTLY DEPART FROM A RAILWAY STATION WITH DIFFERENT DESTINATIONS. IN THE GOLGI NETWORK, PLASMA MEMBRANE PROTEINS ARE SORTED INTO DIFFERNT TRANSPORT VESICLES AND THEN TRANSPORTED TO SPECIFIC AREAS OF THE CELL’S SURFACE.” Lene Niemann Nejsum

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Name: Steen Brøndsted Nielsen Title and age: Associate Professor, Ph.D. from University of Copenhagen, 37 years Field of research: Molecular physics and photobiophysics Research goal: To discover the electronic properties of molecular ions and study the importance of their surrounding environment.

What is the topic of your research?

My research seeks to describe excited molecular states – their appearance, dynamics and influence on reaction paths. A molecule is in an excited state when one of its electrons has been elevated to a higher energy state. Such excited states play a major role everywhere in nature, e.g. in photosynthesis. I am, for example, interested in understanding DNA’s photophysics, i.e. the molecule’s response to light, and why DNA is, in fact, so photostable. DNA works almost like a sun screen – it effectively converts electronic energy into heat. My group examines in detail the electronic communication between the bases in DNA, both in its liquid and gas phase. One goal of our research is to design a DNA strand that can be used in the future as a nanowire in molecular electronics. Peptides (short simple protein strands) are another interesting class of biomolecules. We are trying to steer the splitting of peptides in certain directions by influencing their electronic states.

We are also studying the molecule that makes fireflies emit light and metalloporphyrins, e.g. heme, which gives blood its red colour. Our research requires detailed descriptions of the molecules’ different electronically charged states. The environment surrounding the photoactive molecules is gradually built up experimentally in order to identify the importance of individual water molecules or amino acids for the photoactivity of the molecules we are investigating.

How important is co-operation with international colleagues for your work and your field of research?

I collaborate with more partners abroad than in Denmark, as it is inspiring and exciting to work with researchers from around the world and learn new ways of doing things. Bringing together the best of many research environments is ideal, and I deliberately seek to have researchers of different nationalities in my group.

What do you expect to achieve with the grant from the Lundbeck Foundation?

The grant makes it possible for me to stay at the forefront of my field. One thing is to build up a group, but quite another to keep it going. I have been able to retain very talented post docs and recruit new, committed and promising Ph.D.-students.

With advanced equipment at our disposal, such as the storage rings ELISA (gas-phase experiments) and ASTRID (synchrotron radiation beam lines for dissolution experiments – see figure), my group has unique working opportunities. Our ambition is also to develop new equipment for new types of experiments.

Electrostatic Ion Storage ring in Aarhus (ELISA). Ions are stored in the ring, and their interactions with laser light is examined.

The research is interdiciplinary. By the use of the instruments of physics, we address chemical and biological problems.

PHYSICS

CHEMISTRY

ELISA

Aarhus Storage Ring in Denmark (ASTRID) is a highly intensive lightsource. Light with wawelengths of 170-300 nm is used to study DNA.

BIOLOGY

ASTRID

THE LUNDBECK FOUNDATION 2009│10

THE LUNDBECK FOUNDATION'S JUNIOR GROUP LEADER FELLOWSHIPS

Name: Troels C. Petersen Title and age: Associate Professor, Master of Science in physics, Ph.D. from Universite de Paris XI, 34 years Field of research: Particle Physics at CERN’s LHC Accelerator Research goal: To search for new particles and new phenomena in the data from the LHC, especially dark matter.

What is the topic of your research?

The physics research of recent years has revealed that matter as we know it (in the form of atoms) constitutes only a tiny fraction of the Universe – less than 5%. The remainder is largely “invisible” to us and consists of what we call dark matter and dark energy.

Dark matter appears to consist of a yet unknown types of particles. There are also theoretical reasons to believe that other types of fundamental particles exist in addition to those we know already (e.g. electrons).

As a result, the hunt for dark matter is potentially the biggest challenge facing basic research in the natural sciences in the 21st century.

Using CERN’s new LHC accelerator, we may be able to generate these new particles in a laboratory setting by means of energy-rich proton collisions, and study them with advanced detectors such as ATLAS. The first of these collisions is shown in the figure.

In the spring, LHC commenced 18 months of colliding protons at extreme speeds. The first step in the hunt for dark matter will be based on these collisions. The daily running of the LHC accelerator is therefore the very “pulse” of our research, and expectations of what might be found in the subsequent data analyses are sky-high.

However, there are huge challenges to face before the results are published. For example, processing the enormous volume of data (10,000,000 GB p.a.) will require entirely new ways of using computers and networks. Fortunately, the LHC accelerator and the ATLAS experiment are working better than most had dared hope, and are already generating provisional results.

How have you created a career as a researcher – did you follow a “master plan”?

I thought about it when I started a higher education. I wanted to be a scientist, but I also knew that it was not something you just choose to be. My plan has always been to pursue a research career as far as possible, safe in the knowledge that a science degree would leave me with plenty of other options.

What do you expect to achieve with your grant from the Lundbeck Foundation?

Just being part of the ATLAS experiment and making a contribution to research in particle physics and the mysteries of the Universe is for me a great motivation and an honour. If we also make a major discovery, e.g. find candidates for dark matter and/or the Higgs particle (the last hypothetical particle according to the standard model in particle physics), I will not just be extremely proud, I will also know that I added to our knowledge of the Universe.

First collision in the ATLAS detector.

On 23 November 2009 at 14:22, two protons from the LHC collided for the first time in the ATLAS detector. The result of the collision is shown here. Coloured lines and rows of white dots indicate the passage of charged particles through the detector.

Name: Lene Niemann Nejsum Title and age: Assistant Professor, Master of Science in Biology, Ph.D. from University of Aarhus, 35 years Field of research: Cell polarisation and protein sorting Research goal: To map how cells sort membrane proteins.

What is the topic of your research?

My research focuses on the specialised functions of epithelia, the tissues that form the body’s inner and outer surfaces. For an epithelium to function properly, it is important that the various parts of the cells’ surfaces (so-called plasma membrane domains) have the right mix of ion channels and transport molecules. This requires that newly synthesised proteins are transported to the correct plasma membrane domain, and that they are then correctly regulated in terms of their number, location and activity.

During my post doc. study visit to Professor W. James Nelson at Stanford University, we could prove that newly synthesised proteins designed to function in the area of the epithelium cell’s membrane, which faces away from the epithelium’s surface are sorted in the cell’s so-called Golgi network (see figure) before being transported to the plasma membrane. My new research group at Aarhus University will study the underlying molecular mechanism, i.e. identify the molecules responsible for this sorting, and study, with the aid of animal models, the physiological consequences of the sorting mechanism.

The team will also study how plasma membrane channels and transport molecules are embedded and regulated in, respectively, the lateral (contact to neighbouring cell) and basal (contact to underlying tissue) plasma membrane by using nanomaterials and specialised microscopy (total internal reflection fluorescence (TIRF)).

This research will map out completely new regulatory mechanisms for channel and transport proteins, which will contribute to increased knowledge about diseases caused by an imbalance in the cells’ salt and water levels.

How have you built up your research career?

To be considered for a post as group leader at the University and for a grant from the Lundbeck Foundation Junior Group Leader Fellowship, you must have a unique research profile, a strong publication list and a research plan. You also have to have the ability and ambition to be a supervisor and administrator. I deliberately applied for a post doc. position that was outside of my Ph.D. supervisor Professor Søren Nielsen’s (Aarhus University) network because I wanted to improve my skills in a new field. Through my existing network, Professor W. James Nelson’s laboratory at Stanford University was recommended as a world leader in epithelium cell polarisation research. I sent him an uninvited application, explaining why I had chosen his laboratory, and outlined how a prolonged stay in his research group would provide me with the background, I needed to establish an independent research career.

I had funding from Denmark which is important as it ensures a very high degree of freedom to pursue your own research interests. After nearly five years at W. James Nelson’s laboratory, I looked into the possibilities of joining a research environment in Denmark. I applied for the Lundbeck Foundation’s Junior Group Fellowship to join the Department of Molecular Biology at Aarhus University and now have the opportunity to start an independent research group. I look very much forward to training and mentoring new talent.

Schematic drawing of a polarized epithelial cell. Adherens junctions (AJ) are localized between the apical and basolateral plasmamembrane. The apical plasmamembrane is the surface of the epithelium. The lateral plasmamembrane is in contact with neighbouring cells and the basic plasmamembrane is facing the extracellular matrix. Newly synthesized plasmamembrane proteins are sorted in the Golgi network which lies as a stack of plates over the cell's nucleus, and are transported in small spheres called vesicles to the plasmamembrane.

(Figure from L.N. Nejsum and W.J. Nelson, Front. Biosci., 2009)

Apical PM

Apical PM

MT -

MT -

MT -

ARE

ARE

MT

MT

Golgi

Nucleus

Golgi

Nucleus

Nucleus

BRE Basal PM

ARE

MT

Golgi

+

Apical PM

BRE + ECM

Basal PM

BRE + ECM

Basal PM

THE LUNDBECK FOUNDATION 2009│10

THE LUNDBECK FOUNDATION'S JUNIOR GROUP LEADER FELLOWSHIPS

Name; Søren Gøgsig Faarup Rasmussen Title and age: Master of Science in Human Biology, Ph.D. from University of Copenhagen, 40 years Field of research: Structural biology and molecular pharmacology Research goal: To achieve insight into the activation mechanism for G-protein-coupled receptors and the substrate translocation mechanism for neurotransmitter transporters.

What is the topic of your research?

It is about mapping out the links between the molecular structure of G-protein-coupled receptors and neurotransmitter transporters, and the changes in the structure that form the basis for their respective functions.

G-protein-coupled receptors act a bit like switches on the surface of the cell – they can be turned on or off depending on the external stimuli acting upon the receptor, e.g. hormones, neurotransmitters or medicine.

When a hormone binds to its receptor, the receptor is activated (i.e. turned on) by changing from an inactive to an active state. Via its G-proteins on the inside of the cell membrane, the cell can register activated receptors on the cell surface, triggering an internal response to external stimuli.

While I worked as a post doc. at Professor Brian Kobilka’s laboratory at Stanford University, I helped to map out the molecular structure of a particular G-protein-coupled receptor, the beta2 adrenergic receptor, in its inactive state using X-ray crystallography. I have subsequently worked on crystallising the same receptor in an active state. However, the way in which the receptor changes its structure between inactive and active states by binding medicines or natural binding partners cannot be comprehensively illustrated by crystal structures alone.

Funding from the Lundbeck Foundation will allow my research team to map out hormone- and medicineinduced structural changes in G-protein-coupled receptors using fluorescence-spectroscopic and electronparamagnetic-resonance (EPR) techniques.

How important is collaboration with international colleagues for your work and your field of research?

It has been of great significance to my research and many advantages can be derived from establishing international research partnerships. In some cases, collaboration has been crucial to the feasibility of a research project. In others, it has enhanced a manuscript’s scientific value by including the results of experiments by one or more partners. New discoveries are frequently made during partnerships, and new ideas and opportunities emerge to develop existing projects or start new ones.

In the research fields of structural-function studies of G-protein-coupled receptors and neurotransmitter transporters, you will often encounter international partnerships between experimentalists and theoreticians with expertise in molecular-dynamic simulations. Sometimes, the experimentalists’ results are difficult to publish alone, and benefit from interpretation and being underpinned by simulations. Conversely, the theorist may need the experimentalists to test the validity of a prediction obtained by simulation.

The molecular structure of the beta2 adrenergic receptor (blue), a G—protein— coupled receptor, in its inactive conformation bound to the beta blocker carazolol (orange).

”The physics research of recent years has revealed that matter as we know it (in the form of atoms) constitutes only a tiny fraction of the Universe – less than 5%. The remainder is largely ’invisible’ to us and consists of what we call dark matter and dark energy.”

TROELS C. PETERSEN

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THE LUNDBECK FOUNDATION 2009│10

THE LUNDBECK FOUNDATION'S JUNIOR GROUP LEADER FELLOWSHIPS

Name: Martin Røssel Larsen Title an age: Associate professor, Master of Science, Ph.D. from University of Southern Denmark, 40 years Field of research: Biochemistry and Molecular Biology Research goal: Functional characterization of depolarization-dependent signaling pathways in nerve terminals

What is the topic of your research?

A synapse is a specialised contact where signals can be exchanged between two nerve cells. Chemical synapses use small signaling molecules, neurotransmitters for this cell-to-cell communication between nerve cells. They are stored in small packages termed synaptic vesicles (SVs) that are bound to the cell’s skeleton at the nerve terminals when nerve cells are not active. Upon depolarization (i.e. when the nerve cell has been triggered), neurotransmitters are released by the presynaptic nerve terminal into the synaptic cleft which is the narrow space between the pre- and postsynaptic cells (i.e. the nerve cell sending the signal and the cell receiving the signal), where they bind and activate specific receptors at the post-synaptic membrane which then pass on the signal in the cell-to-cell communication (see figure for overview). This overall process is called synaptic transmission. The release of neurotransmitters is triggered by the influx of calcium ions through ion-channels in the presynaptic membrane. An increase of calcium ions in the presynaptic nerve terminal leads to a multitude of molecular events including neurotransmitter biosynthesis, filling of the SVs with neurotransmitter, transportation of the SVs to the plasma membrane and eventually release of neurotransmitters. Most of these events are controlled by addition or removal of phosphate molecules at synaptic proteins (phosphorylation and dephosphorylation) by specialized enzymes, activated when a nerve cell is triggered. The ultimate aim of the project is to obtain a comprehensive knowledge of the phosphorylation mediated mechanisms involved in synaptic transmission, which automatically will lead to an understanding of several neurological diseases, such as epilepsy. This knowledge could lead to the development of new pharmacological targets and drugs for a number of severe neurological diseases.

In my group we have previously developed a number of specific and sensitive strategies for the identification and characterization of phosphorylated proteins from biological samples, strategies that are now widely used by researchers in the field of phosphoproteomics. We will use these strategies in combination with standard molecular cell biological methods to characterize phosphorylation sites in synaptic proteins which are important for the different molecular mechanisms underlying synaptic transmission.

How important is collaboration with international colleagues for your work?

Simplified overview of calcium signaling in nerve terminals.

One important aspect in research that I have experienced myself is the international perspective, the interaction and collaboration with internationally recognized scientists and exposure to other cultures. I started my research career in a large Danish research group in which 1/3 of the researchers were from other countries.

This meant that I became aware of a large number of new techniques and new ideas derived from challenging discussions with senior scientists who had a broad and in many cases more diverse knowledge. The present project will be performed in close collaboration with Prof. Phillip J. Robinson at the Children’s Medical Research Institute in Sydney, Australia, with whom I have had a long and fruitful collaboration. Using the synergistic interaction between our two groups, we have characterized various proteins in synapses after nerve cell triggering. Via meetings and visiting student internships, our two groups will act as training facilities for each other. This opportunity to perform international research is a very big inspiration for our young scientists and students.

lfi a s - the lundbeck foundation’s commercial activities The funding activities are carried out by the Foundation itself but are financed to a significant degree by the dividends the Foundation receives from its wholly owned investment and holding company, LFI a/s, which manages the commercial activities. LFI a/s owns controlling interests in the two listed companies H. Lundbeck A/S and ALK-Abelló A/S. In addition to this, the majority of the portfolio investments, which amount to approx. DKK 12 billion, are held by LFI a/s. In 2009, the activities of LFI a/s were expanded. At the beginning of the year, LFI a/s acquired a 28% ownership interest in the listed biotech company LifeCycle Pharma A/S as well as a number of unlisted biotech funds from H. Lundbeck A/S. Based on these assets, the establishment of a life science investment function was initiated in LFI a/s.

At the end of 2009, LFI a/s established a real estate investment company jointly with C.W. Obel Ejendomme A/S with a view to investing in commercial property located centrally in both Copenhagen and Aarhus. This company, Obel-LFI Ejendomme A/S, is managed by C.W. Obel Ejendomme A/S. H. Lundbeck A/S, of which the Lundbeck Foundation owns 70% of the share capital through LFI a/s, is a leading global pharmaceutical company which focuses on the development and marketing of medicines for the treatment of diseases of the central nervous system. The company employs a staff of approx. 5900, 1500 of whom are involved in research and development.

2009 was a good year for H. Lundbeck A/S from a financial point of view. Turnover increased by 19% to DKK 13,747 million and the financial result increased by 21% to DKK 2,007 million. The increase was driven by growth in all regions, growth in the main products Cipralex/Lexapro, Ebixa and Azilect, and the acquisition of American Ovation Pharmaceuticals Inc, which today is called Lundbeck Inc. The company, which was acquired in March 2009, has provided H. Lundbeck A/S with, among other things, a platform in the USA and access to two newly launched products, Xenazine and Sabril, both for the treatment of severely crippling diseases of the central nervous system.

H. Lundbeck A/S also invested considerable funds in research and development in 2009, and the company has several new product candidates in the pipeline which potentially can be ready to be launched within the next five years and help the replacement of the turnover from the products whose patents will expire in the

coming years. Unfortunately, Lundbeck also experienced in 2009 a delay in the development of Lu AA21004, which is currently in phase III, for the treatment of depression. This contributed to the fall in the company’s share price in 2009 by 13.9% in spite of a generally positive development on the equity market.

ALK-Abelló A/S is a global market leader in the development and marketing of drugs for allergy vaccination. Through LFI a/s, the Lundbeck Foundation owns 38% of the company’s capital and has 66% of the votes. ALK-Abelló A/S has 1500 employees and, in 2009, invested DKK 349 million in research and development.

The profit for the year increased from DKK 95 million in 2008 to DKK 118 million in 2009. The increase in operating profit (EBIT) amounted to 47%. Continued investments in research and development reduced the increase in the net result. ALK-Abelló A/S’ American partner, Merck, successfully completed two clinical studies on the company’s new, tablet-based product Grazax. As a result, registration will be applied for and it is expected that this tablet will be subsequently launched in North America. Grazax is now approved in 13 European countries as eligibile for subsidy, partly based on long-term studies which have shown a significant sustained effect after the end of treatment.

other investments In 2009, the portfolio investments, which constitute the available funds of the Foundation and LFI a/s, provided a return of 14.3%, amounting to DKK 1.5 billion. Subsequently, the available funds amount to DKK 12,091 million compared to DKK 10,834 million at the end of 2008 and DKK 12,177 million at the end of 2007. Thus, the losses in 2008, a financially unusual year, were regained in 2009. All investment classes gave a positive return in 2009. Returns of 32% on equity holdings, 6.7% on Danish bonds and 31% on corporate bonds were recorded. The return on property amounted to 22%. At the end of 2009, the portfolio activities were distributed as follows: 31% in equity holdings, 66% in bonds and the money market and 3% in real estate.

life science investments LFI a/s’ new investment entity, LFI Life Science Investments, made its first investment at the end of 2009. The investment was in EpiTherapeutics, which is a relatively new Danish company with world-leading skills in epigenetics and the use thereof for, in particular, the development of new drugs for the treatment of cancer.

THE LUNDBECK FOUNDATION 2009│10

LFI A/S – THE LUNDBECK FOUNDATION'S COMMERCIAL ACTIVITIES

Epigenetics entails chemical changes in the molecules that regulate gene expression, thus determining whether a gene is expressed or not.

LifeCycle Pharma A/S also expects a negative result in 2010.

Initiatives have been launched to ensure that the use of the company’s resources is prioritised more effectively.

Since its foundation, LFI Life Scince Investments has received many requests for investsments and, during the course of 2010, the entity is expected to make further investments. The strategy of LFI Life Science Investment is primarily to invest in European projects and companies with projects ready for actual product development.

However, individual investments will be made in newly started companies if the conditions are right. This also enables interaction between the Foundation’s grantmaking activities and the investment opportunities generated by the universities based on their research.

outlook for 2010

LFI a/s’ associate, LifeCycle Pharma A/S, is based on a patented formulation technology, MeltDose, which has proven able to improve absorption and bioaccessibility of both approved and new medicines. Based on this technology, the company has set up a pipeline of clinical projects and, in 2009, covered considerable cost of clinical trials, in particular for a product for immunosuppression in connection with organ transplants. This is the background for the negative annual result of DKK 270 million. LFI a/s’ share of this loss, amounting to DKK 76 million, was charged to the profit and loss account under the result for participating interest.

   

H. Lundbeck A/S 49% ALK-Abelló A/S 6% Portfolio investments 45%

The Lundbeck Foundation expects to distribute grants of approx.

DKK 340 million in 2010, of which DKK 100 million will be used to 7 fellowships for Research Leaders who wish to start up a research group of high international calibre at a Danish research institution. The Foundation does not anticipate establishing of new Centres of Excellence in 2010.

The Foundation’s financial result will depend on the commercial activities in H. Lundbeck A/S and ALK-Abelló A/S and the return on the portfolio investments. Further information about the outlook for the two listed subsidiaries’ expectations is available at www.lundbeck.com and www.alk-abello.com.

    

Danish bonds 47% Corporate bonds 7% Cash and cash eqvivalents 12% Equity holdings 26% Private equity 3% Life Science 2% Real estate 3%

management and corporate governance

The Lundbeck Foundation is managed by a Board of Trustees consisting of six members elected among themselves and three members elected by employees of the two companies, H. Lundbeck A/S and ALK-Abell贸 A/S. The board appoints the Foundation's managing director.

The Board members are elected among themselves and are self-supplementing. Election takes place at the annual meeting. The members of the board, who are elected by the employees of the two companies, cannot participate in the election.

Members of the Board are elected for one year, i.e. for the period until the end of the next annual meeting. Re-election can take place.

However, election or re-election of someone who has been a member of the board for more than a total of 12 years or has turned 75 years cannot take place. The rule in the previous sentence can be dispensed of under special circumstances.

The Board of Trustees reconstitutes itself after each annual meeting through the election of its chairman and vice-chairman.

LFI a/s has the same board and managing director as the Foundation. The chairman of the Foundation's Board of Trustees is also chairman of LFI a/s' board but, if it is deemed practical, there may be different vice-chairmen on the two boards.

The Lundbeck Foundation (and LFI a/s) holds a minimum of four board meetings a year, plus a two-day seminar to discuss strategy, etc.

The board also visits the Foundation's research centres and attends contact meetings with Danish universities where the Foundation has interests.

There are written rules addressing potential conflicts of interest in relation to grant-making, as well as rules governing Trustees' and others' use of these allocations.

The Board of Trustees subjects itself to continuous evaluation in dialogue with the chairman and individual board members, followed by discussions among the board as a whole. The Foundation aims to hold an "arm's length" relationship to the board of directors of H. Lundbeck A/S and ALK-Abell贸 A/S. These two boards, at any given time, must comprise a majority of members, normally including the chairman, who are independent of the Foundation. The Foundation's policy regarding its relationship to these companies remains unchanged: that two board members from each company also serve on Foundation's Board of Trustees, that the Foundation's board chairman is not a member of either of the companies' board of directors, and that the Foundation's board members who also serve on the companies' boards normally do not serve as a chairmen, but can serve as vice-chairmen.

The Foundation's Board of Trustees does not interfere with the companies' daily operations, but considers it important that the companies have qualified and effective boards of directors that can support the development of the companies to the benefit of shareholders.

The Lundbeck Foundation (and LFI a/s), its Board of Trustees and members of management only trade stock in H. Lundbeck A/S and ALK-Abell贸 A/S in special periods designated by the companies' boards of directors in connection with announcements to the stock market.

47

THE LUNDBECK FOUNDATION 2009│10

RESULTS 2009

summary of financial statement for the foundation 2009 DKK mio.

Share of results of H. Lundbeck A/S, ALK-Abelló A/S and LCP Investment income from LFI a/s Operating costs in LFI a/s

1,169

1,334

-15

commercial profit

2,488

Investment income in the Lundbeck Foundation Operating in the Lundbeck Foundation

non-commercial profit

155

Income before tax Tax

2,643 -4

Result for the year before grants

2,639

6,837 9,522

16,359

2,224 27 359 2,610

18,969 645

18,324

income statement for the year ended 31 december 2009

171 -16

net assets at 31 december 2009 Commercial investments:

Shares in H. Lundbeck A/S, ALK-Abelló A/S and LCP

Portfolio investments, etc.

Non-commercial investments: Financial assets in the Lundbeck Foundation Property and buildings Receivables and cash

Total assets Amounts granted and payables, etc.

The Lundbeck Foundation is subject to the Danish Commercial Foundations Act and the Danish Financial Statements Act, and the Foundation’s financial statements will be submitted to the authorities together with the consolidated financial statements of the LFI Group, comprising the wholly-owned subsidiary LFI a/s, as well as the Lundbeck Group and ALK-Abelló Group.

The above financial statements differ from the provisions of the mentioned Act as regards specifications and presentation.

The commercial shareholdings in H. Lundbeck A/S and ALK-Abelló A/S are measured at equity value, a total of DKK 6,748 mio. The total market value of LFI a/s’ shareholding in H. Lundbeck A/S and of B shares in ALK-Abelló A/S, measured at market prices at 31 December 2009, was DKK 14,193 mio.

THE LUNDBECK FOUNDATION 2009│10

CENTRES OF EXCELLENCES 2005-2009

       











   -

  

 

CBN – The Lundbeck Foundation Centre for Biomembranes in Nanomedicine

Professor, M.D. Ulrik Gether and Assoc. Professor, Ph.D. Dimitrios Stamou

LUNA – The Lundbeck Foundation Nanomedicine Centre for Individualized Management of Tissue Damage and Regeneration

Professor, M.D. Allan Flyvbjerg and Professor, Ph.D. Jørgen Kjems

NanoCAN – The Lundbeck Foundation Nanomedicine Research Centre for Cancer Stem Cell Targeting Therapeutics

Professor, M.D. Jan Mollenhauer

CINS – The Lundbeck Foundation Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research

Professor, M.D. Birte Glenthøj

Fast-Track – The Lundbeck Foundation Centre for Fast-Track Pain and Risk Free Hip and Knee Arthroplasty

Professor, M.D. Henrik Kehlet and Professor, M.D. Kjeld Søballe

CIRRO – The Lundbeck Foundation Centre for Interventional Research in Radiation Oncology

Professor, M.D. Jens Overgaard and Professor, M.D. Cai Grau

LUCAMP – The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction

Professor, M.D. Oluf Borbye Pedersen

COPSAC – The Lundbeck Foundation Centre for Copenhagen Studies on Asthma in Childhood

Professor, M.D. Hans Bisgaard

CETAME – The Lundbeck Foundation Centre for Translational Medicine

Professor, M.D. Torben F. Ørntoft

LCTC – The Lundbeck Foundation Centre for Theoretical Chemistry

Professor, Dr.Phil.

Poul Jørgensen

LTC – The Lundbeck Foundation Theoretical Centre for Quantum System Research

Professor, Ph.D. Klaus Mølmer

CAMD – The Lundbeck Foundation Centre for Atomic-scale Materials Design

Professor, Ph.D. Jens K. Nørskov

MIND – The Lundbeck Foundation Centre for Membrane-receptors in Neuronal Disease

Professor, Ph.D. Anders Nykjær and Professor, M.D. Claus Munck Petersen

CIMBI – The Lundbeck Foundation Centre for Integrated Molecular Brain Imaging

Professor, M.D. Gitte Moos Knudsen

LUCENS – The Lundbeck Foundation Centre for Neurovascular Signaling

Professor, M.D. Jes Olesen

The Foundation’s support of scientific activities comprises specific scientific projects, Junior Group Leader Fellowships and centres of excellence within biomedical and natural sciences.

The list below shows the Foundation’s centres of excellence 2005-2009. You can read more about the centres established in 2009 in this publication.  

    

.  

Communication between nerve cells and signaling between bacteria

DKK 34 million in the period 2010-2015

10 senior researchers and 15 Ph.D. students

The mechanisms behind the imbalance between tissue damage and tissue regeneration in disease

DKK 30 million in the period 2010 – 2015

26 senior researchers and 10 Ph.D. students

Targeted treatment of cancer stem cells using nano carriers

DKK 35 million in the period 2010 - 2015

4 senior researchers and 7 Ph.D. students

Research into tools for use in individualised schizophrenia treatment

DKK 30 million in the period 2009-2014

7 senior researchers and 9 Ph.D. students

Quicker recovery through optimised surgical intervention

DKK 35 million in the period 2009-2014

2 senior researchers and 10 Ph.D. students

Research into better radiotherapy for the benefit of cancer patients

DKK 30 million in the period 2009-2014

47 senior researchers and 30 Ph.D. students

The influence of genes on arteriosclerosis – possible methods for preventing lifestyle diseases

DKK 60 million in the period 2008-2013

60 senior researchers and Ph.D. students

The centre studies the impact of the interaction between heredity, lifestyle and environment on development of asthma

DKK 20 million in the period 2008-2013

5 senior researchers and 4 Ph.D. students

Molecular diagnostic and bioinformatic risk calculation of common cancers

DKK 20 million in the period 2008-2013

5 senior researchers and 2 Ph.D. students

Interpretation of macroscopic measurements on a molecular basis

DKK 20 million in the period 2007-2012

9 senior researchers and 10 Ph.D. students

Studies of atoms and their interaction with light

DKK 20 million in the period 2007-2012

17 senior researchers and 16 Ph.D. students

Developing theories of how a material can be structured atom by atom to achieve certain properties

DKK 25 million in the period 2007-2012

26 senior researchers and 19 Ph.D. students

Multidisciplinary basic research into molecular cell functions

DKK 50 million in the period 2006-2011

24 senior researchers and 15 Ph.D. students

Studies of factors in the brain that increase the risk of developing brain disorders, including depression and memory disturbance

DKK 40 million in the period 2006-2011

35 senior researchers and 15 Ph.D. students

Research into the role of blood vessels in brain disorders

DKK 30 million in the period 2006-2011

12 senior researchers and 18 Ph.D. students

   -   +      +     @. ..

MORTEN ALHEDE┃LEKTOR PH.D. TINE ALKJÆR ERIKSEN┃VIDENSKABELIG ASSISTENT CAND.SCIENT. GE PH.D. IBEN BACHE┃LEKTOR PH.D. LASSE KRISTOFFER BAK┃ADJUNKT CAND.SCIENT. STEFANIA G ONDE┃ADJUNKT PH.D. CHARLOTTE MENNÉ BONEFELD┃POST DOC. PH.D. JONAS BORCH┃PROFESSO ADJUNKT CAND.SCIENT. MARCO CHIARANDINI┃ADJUNKT PH.D. BIRGITTE MØNSTER CHRISTENSEN┃L SCIENT. BRIAN DELLA VALLE┃PH.D.-STUDERENDE CAND.SCIENT. THI AI DIEP┃POST DOC. PH.D. CHRIST GEROD┃POST DOC. CAND.SCIENT. VERA EHRENSTEIN┃LEKTOR LIC.SCIENT. HANS EIBERG┃ADJUNK ENE FAUSTRUP┃PH.D.- STUDERENDE CAND.SCIENT. MUSTAFA FAZLI┃KLINIKCHEF DR.MED. ULLA FELD TIR┃PH.D. CAND.SCIENT. MADS T. FRANDSEN┃LEKTOR PH.D. BENTE FRØLUND┃PROFESSOR DR.MED DR.MED. ULRIK GETHER┃LEKTOR DR.PHIL. MARCUS THOMAS PIUS GILBERT┃AFDELINGSLÆGE DR.ME D. JENS PETER GØTZE┃RESEARCH SCHOLAR CAND.POLYT. JANUS A. J. HAAGENSEN┃ASSOCIATE PRO ANSEN┃RESEARCH ASSISTANT PH.D. LINDA HARKNESS┃LEKTOR PH.D. RASMUS HARTMANN-PETERS LTH┃PROFESSOR PH.D. ELSE KAY HOFFMANN┃LEKTOR PH.D. HANS JÜRGEN HOFFMANN┃LEKTOR D YLDIG┃LEKTOR PH.D. ALBERTO IMPARATO┃POST DOC. CAND.SCIENT. ADIBA ISA┃POST DOC. PH.D. J ØGH JENSEN┃KLINISK ASSISTENT CAND.MED. MORTEN KVISTHOLM JENSEN┃PROFESSOR PH.D. NIEL DR.MED. ARNE LUND JØRGENSEN┃POST DOC. PH.D. CHARLOTTE GRUBE JØRGENSEN┃PH.D.-STUDE AN KELLY┃PROFESSOR DR.MED. LARS VEDEL KESSING┃DR.MED. JØRGEN KIELER┃POST DOC. PH.D DR.MED. KLAUS KROGH┃SENIOR RESEARCHER PH.D. RON KUPERS┃AFDELINGSLÆGE PH.D. OLE HYL CHE┃ADJUNKT CAND.SCIENT. JACEK LICHOTA┃POST DOC. PH.D. HANNA SOFIA LINDGREN┃POST DO NANNA MACAULAY┃LÆGE PH.D. KIRSTEN MADSEN┃GROUP LEADER PH.D. NIELS MAILAND┃PH.D.-S KAMILLA MISKOWIAK┃POST DOC. PH.D. BRIAN MOLDT┃PROFESSOR DR.SCIENT. JAN MOLLENHAUER N┃PH.D.-STUDERENDE CAND.SCIENT. JAKOB VENNIKE NIELSEN┃PH.D.-STUDERENDE CAND.SCIENT. J SSOR DR.MED. BØRGE GRØNNE NORDESTGAARD┃PROFESSOR DR.MED. JENS RANDEL NYENGAARD .D. RIKKE KATRINE JENTOFT OLSEN┃ADJUNKT PROFESSOR DR.MED. SJURDUR FRODI OLSEN┃SENIO ARIA PAULSSON┃PH.D.-STUDERENDE CAND.SCIENT. NIS BORBYE PEDERSEN┃POST DOC. PH.D. RASM CÉSAR DA SILVA PINHEIRO┃LEKTOR PH.D. JEPPE PRÆTORIUS┃MOLEKYLÆRBIOLOG PH.D. KIRSTEN PH.D. ADAM ANDERS EDVIN ROTH┃LÆGE PH.D. MORTEN RUHWALD┃LEKTOR PH.D. MARTIN RØSSEL TSLEV┃PROFESSOR DR.MED. ULF SIMONSEN┃PH.D.-STUDERENDE STUD.MED. TORJUS SKAJAA┃KLIN R PH.D. CHARLOTTE SUETTA┃PROFESSOR PH.D. INGE MARIE SVANE┃PH.D.-STUDERENDE CAND.SCIE OMMERUP┃PH.D.-STUDERENDE CAND.MED. FRANCESCO TREPICCIONE┃KLINISK LEKTOR PH.D. NIELS D. LARS LINDHARDT VINDELØV┃PROFESSOR DR.MED. JOHN VISSING┃LEKTOR PH.D. THOMAS VOSEG CHAEL WINTERDAHL┃PROFESSOR PH.D. JØRGEN F.P. WOJTASZEWSKI┃LEKTOR PH.D. DAVID P.D. WO ED. NIELS FEENTVED ØDUM┃POST DOC. PH.D. AMANDA RODRIGUES AMORIM ADEGBOYE┃PH.D.-STU E ARLETH┃SYGEPLEJEDIREKTØR MARGIT ASSER┃SENIORFORSKER OG LABORATORIELEDER PH.D. OR DR.MED. HANS BISGAARD┃DIREKTØR MIKKEL BOHM┃PROFESSOR DR.SCIENT. MIKAEL BOLS┃ST LEKTOR PH.D. STEEN BRØNDSTED NIELSEN┃LEKTOR PH.D. LENNART BUNCH┃PROFESSOR DR.MED. JOHN COUCHMAN┃PH.D.-STUDERENDE CAND.SCIENT. JACOB FLYVHOLM CRAMER┃PH.D.-STUDEREN NT. LINE DRUBE┃PH.D.-STUDERENDE CAND.SCIENT. KRISTINA B. V. DØSSING┃LEKTOR CAND.SCIENT. RENDE CAND.SCIENT. TILDE ESKILDSEN┃STUD.SCIENT. KELECHI EZEKWE┃LÆGE PH.D.-STUDERENDE .MED. ANE BÆRENT FISKER┃STUD.MED. EMIL LOLDRUP FOSBØL┃PROFESSOR DR.MED. ALLAN FLYV LIC.SCIENT. MICHAEL GAJHEDE┃LEDENDE OVERLÆGE DR.MED. STEEN GAMMELTOFT┃SENIORFORS ØNTVED┃ASSOCIATE PROFESSOR PH.D. THOMAS GÜNTHER POMORSKI┃POST DOC. PH.D. SØREN GØ D.-STUDERENDE CAND.SCIENT. JONAS TIND HANSEN┃GRUPPELEDER PH.D. KLAUS HANSEN┃LEKTOR HAY-SCHMIDT┃LEKTOR PH.D. YLVA HELLSTEN┃UDVIKLINGSCHEF KIM GLADSTONE HERLEV┃POST DO POST DOC. PH.D. CHRISTIAN ANSGAR HUNDAHL┃PH.D.-STUDERENDE CAND.SCIENT. LARS GRØNDAH N┃PROFESSOR DR.MED. BOYE LAGERBON JENSEN┃POST DOC. PH.D. JAN KRISTIAN JENSEN┃LEKTO PH.D. TERRY LYNNE JERNIGAN┃PROFESSOR DR.MED. BENTE JESPERSEN┃PRODUCER PH.D. ANDERS