ANNUAL REPORT 2010 Contents

I. Overviews ...... 3

Year 2010 in review, Director of FIMM ...... 3

Views from the former and current Chair of the Board ...... 5

II. FIMM Launch Event ...... 6

III. How is the Nordic EMBL Partnership build-up progressing in Oslo and Umeå? ...... 7

IV. Academician of Science, Professor Leena Peltonen-Palotie in memoriam ...... 8

V. Research ...... 10

Human Genomics ...... 10

Medical Systems Biology and Translational Research ...... 14

Research collaborations and highlights ...... 21

Personalized medicine of cancer becoming a reality...... 25

Doctoral Training ...... 26

VI. Technology Centre ...... 28

Genomics Unit ...... 28

Sequencing Unit ...... 29

Metabolomics Unit ...... 30

RNAi Unit ...... 31

Chemical Biology Unit ...... 32

Bioinformatics, Data Management and IT-support Unit ...... 33

VII. Biobank ...... 35

National and International Infrastructure Projects ...... 37

VIII. Administration Unit, Board and Scientific Advisory Board (SAB) ...... 39

IX. Selected Events in 2010 ...... 41

X. FIMM in Figures ...... 44

Financial Report ...... 44

Personnel Statistics ...... 45

XI. Publications by FIMM researchers 2010 ...... 48

Publications by FIMM Molecular Medicine Network and adjunct researchers 2010 ...... 62 I. Overviews

Year 2010 in review, Director of FIMM ramatic research progress is now being made in launched with funding from Biocenter Finland and a pi- Dhuman genomics, bioinformatics, systems biology lot project to support the build-up of international ESFRI and many other fields of biomedical research. The need infrastructure programmes. Almost half of FIMM’s activi- to bring breakthroughs in science to the everyday prac- ties (measured both in terms of funding and personnel) tice of medicine remains one of mankind’s biggest chal- are now focussed on infrastructure. FIMM is a prominent lenges. The mission of FIMM is to build a bridge from national and international infrastructure provider, help- discovery to medicine. The foundations for building ing a large community of researchers to do better sci- translational molecular medicine in Finland are excel- ence and facilitate translational medicine. lent. Finland has both a strong scientific base in biomedical research, but also excellent clinical and epidemiolog- The year 2010 started with dramatic news of the death ical research and a high-quality equal-access healthcare of the Academician of Science, Professor Leena Peltonen- infrastructure. However, unless these major advantages Palotie. Leena’s death was a deep loss to all of us at are brought together by multidisciplinary research col- FIMM as well as to the international human genomics laborations, we will not realize our full potential. This is community. Leena’s key impact in building the scientific what FIMM and the Nordic EMBL Partnership for Molec- foundation of FIMM is felt today and it will continue well ular Medicine are all about, realizing the full potential of after her death. In May 2011, we will organize a major small countries in Northern Europe to advance transla- international symposium to celebrate Leena’s lifetime tional molecular medicine by multidisciplinary collabo- achievements in genomics. rations with national and international networks. In March 2010, FIMM celebrated its official inauguration The year 2010 marked the third year in the build-up of ceremony followed by a scientific symposium. FIMM is FIMM as an international research institute. The year therefore now officially up and running and we can turn was characterized by rapid growth, exciting research the focus towards making progress in molecular med- progress, the setup of major national and international icine. Indeed, significant research progress has already research infrastructures and the launch of new biobank- been made, as demonstrated by the 90 publications by ing operations in the Meilahti Campus. By combining FIMM researchers, of which 21 were in top journals with first class molecular medicine research, state-of-the-art an impact factor >20. Many of the top publications repre- technology capabilities and access to large biobanks sent major international consortium studies on human and clinical data, we can build major translational op- genetics, largely initiated by the late Professor Leena Pel- portunities. This vision is behind the new organization tonen-Palotie, and now continued by the group leaders structure of FIMM, which is planned to take effect in at FIMM and at THL. In the area of human genomics, the 2011 (Figure 1). The primary focus of FIMM in translating role of FIMM group leaders has been leading in uncover- molecular medicine to clinical practice is via advancing ing e.g. the genetic basis of migraine and cardiovascu- personalized medicine, which is an area where we hope lar disease and the genetic origins of Finnish people. In to be able to also soon help patients and contribute to other areas, FIMM researchers published the first tran- the health of societies. scriptomic sequencing paper about breast cancer, set up a new personalized medicine profiling of cancer and car- During the year 2010, the number of employees at FIMM ried out many other key observations. In addition to the grew from 99 to 125, and the staff now represents 20 na- 90 publications by FIMM researchers, members of the tionalities. There are 13 group leaders at FIMM, all ap- FIMM National Network for Molecular Medicine and ad- pointed based on international evaluation. Half of the junct researchers published another 43 publications. group leaders are EMBL-style principal investigators and two are established Finland Distinguished Professors. In FIMM researchers have also been very successful in se- 2010, the build-up of new infrastructures at FIMM was curing external competitive research funding, such as

FIMM 3 new projects from the EU and the IMI (Innovative Medi- land (please see below) put an overwhelmingly strong cines Initiative), a joint EU – Pharma collaborative pro- emphasis on improving the international profile of Finn- gramme. External funding now amounts to >50% of the ish science. This is seen as a key aspect of helping Fin- total FIMM budget, with a further increase predicted land stay competitive in the global competition for sci- in this percentage in 2011—2012. Acquiring, reporting ence and innovation. We have seen tremendously rapid and managing a project portfolio of some 30 individual progress at FIMM, which can to a large extent be cred- grants at FIMM in 2010 is starting to be a significant ad- ited to its international profile and strong networks, the ministrative challenge. While the increased external sup- brand of the EMBL partnership as well as the strategic port is overwhelmingly positive, there are also many as- international recruitment of talent to Finland. Thus, we pects of an international EMBL-associated institute that hope that FIMM will continue to prosper by building up- cannot be run only based on short-term competitive on these strengths. funding. Recruitment of international, talented principal investigators will continue to require a strong institu- Professor Olli Kallioniemi, Director, FIMM tional funding base. In the first five years, private foundations have done a remarkable job in helping to sup- Research and innovation policy guidelines for 2011–2015; port this aspect of FIMM operations. We hope to work research and Innovation Council with the partners and supporters of FIMM to maintain a strong basic funding also in the future when the first five Research Policy: Tools and Practices – A Five-Country years of FIMM start-up funding comes to an end. Comparison; Publications of the Academy of Finland 2/10

Recent research policy statements, such as those from The state and quality of scientific research in Finland; the National Innovation Council and the Academy of Fin- Publications of the Academy of Finland 9/09

BOARD SAB

STEERING GROUP DIRECTOR ADMINISTRATION

BIOBANK T ECHNOLOGY C ENTRE RESEARCH INFRASTRUCTURE • Genomics • Genomics • Disease-oriented • Sequencing • Systems biology collections • Metabolomics - Cancer • Population-based • RNAi - Cardiovascular & metabolic collections (THL) • Chemical Biology - Neuro-psychiatric ESFRIs • Bioinformatics - Viral • IT-support

T RANSLATION • Diagnostics development, personalized medicine • National network, clinical collaborators

Figure 1. Organization structure of FIMM, planned to take effect in 2011 (as presented at the Board Meeting on 25 February 2011).

4 FIMM Views from the former and current Chair of the Board

During my term on the Council of the European Molecular Biology Labo- ratory, it was my honour and pleasure to contribute to the proposal for the establishment of institutes for molecular medicine in the Nor- dic countries that would network with each other and the EMBL. After discussions at the national level, Sweden, Norway and Finland decided to create such institutes and the Nordic EMBL Partnership in Molecular Medicine. Whilst I was serving as Vice-Rector for Research at the Uni- versity of Helsinki, the then Rector Professor Ilkka Niiniluoto, mandated me to create a concept for the Institute for Molecular Medicine Finland FIMM, to formulate its mission and vision, assemble strategic partners to support and fund it, and drive its establishment on the medical campus. As first Chair of the Board of FIMM, I also had the privilege to recruit the Director, Professor Olli Kallioniemi, and the first set of group leaders. In 2010 we recruited Dr. Jonathan Knowles from Basel and Dr. Juni Palmgren from Stockholm as Finland Distinguished Professors, funded by Tekes and the Academy of Finland, respectively.

It is with warmth and humility in front of life’s unpredictability that I wish to acknowledge the contribution of Professor Leena Peltonen- Palotie, whom we lost last year. She was a visionary and an inspiring researcher who was afraid of nothing. If it were not for her stellar work in human genetics, there would have been no foundation in Finland on which FIMM could have been built.

I would like to take this opportunity to thank the members and the deputy members of the first Board and the staff of FIMM, the Scientific Advisory Board, and all stakeholders and supporters for their brilliant collaborations in setting up an Institute, which conforms to the most up-to-date concepts and is already delivering both quality and impact. I wish the best of success to the current Board, the Director and staff, and the Nordic EMBL partners.

Professor Marja Makarow, Chief Executive, European Science Foundation Chair of the Board of FIMM (2007 — 2010)

I have had the privilege to serve as the Chairman of the Board of FIMM since 2010. We are witnessing one of the most exciting phases of biomedical research as the use of genomic data is transforming from analysis of bioprofiles to exact individual characteristics, by virtue of new sequencing technologies with rational availability and cost level. The advance in structural and functional genomics is supplemented by recent approaches of different omics techniques, and progress in bioinformatics that is enabling a meaningful understanding of the plethora of data. This enormous progress coupled with rational use of biobank infrastructures paves the way for development of personalized medicine, which should result in novel tools for the delineation of disease subtypes as well as more exact assessment of diagnosis and tailored drug treatment. When striving toward these goals, FIMM is greatly benefiting from its central position at the Meilahti Medical Campus, which ranks among the top five research-oriented medical schools in Europe and hosts the University Hospital that serves 1.5 million people. The partnership with the EMBL organization ensures close intellectual collaboration with the top European research centres.

The Board, composed of experts from the Faculty of Medicine, the Uni- versity Hospital, Public Sector Research Institutes and other important partners feels motivation and responsibility. The mission of FIMM is today even more clear and justifiable than when it was established in 2007.

Professor Kimmo Kontula, Vice Rector of the University of Helsinki Chair of the Board of FIMM (2010 — 2014)

FIMM 5 II. FIMM Launch Event

he FIMM Launch Event was arranged on 16—17 March 2010. The event gathered altogether about 250 partici- Tpants as well as international and national speakers. The Minister of Education Henna Virkkunen (Ministry of Education, as of 1 May 2010 Ministry of Education and Culture), the Minister of Health and Social Services Paula Risikko (Ministry of Social Affairs and Health) and Director General Petri Peltonen, (Ministry of Employment and the Economy) stressed the importance of collaboration among the founding organisations of FIMM. Rector Thomas Wilhelmsson (University of Helsinki), Director General Pekka Puska (THL), Research Director Lasse Viinikka (HUS), Executive Vice President, Professor Jorma Lammasniemi (VTT) Director General, Professor Iain Mattaj (EMBL) and the Directors of the other Nordic nodes, Professor Kjetil Taskén (NCMM, Norway) and Professor Bernt Eric Uhlin (MIMS, Sweden) foresaw great opportunities and synergies in the collaboration both nationally and internationally.

The Chair of the Scientific Advisory Board (SAB) of FIMM Professor Kai Simons (Dresden) gave the Marja Makarow Lecture entitled “Lipid rafts as a membrane-organizing principle”. Also Members of the SAB of FIMM Professors Carl Henrik Heldin (Uppsala), Edison Liu (Singapore) as well as Nadia Rosenthal (Monterotondo) gave presentations that highlighted the potential of molecular medicine as viewed by the international experts.

6 FIMM III. How is the Nordic EMBL Partnership build-up progressing in Oslo and Umeå?

he overall objective of the Centre for Molecular Medicine Norway (NCMM, www.ncmm.uio.no) is to Tfacilitate translation of discoveries in basic medical research into clinical practice with focus particularly on disease mechanisms. From its start in late 2008 and with the official inauguration of NCMM in the fall of 2010 NCMM is now gaining significant momentum with the four groups of NCMM/EMBL group leaders Ian G. Mills, Erlend A. Nagelhus, Preben Morth and NCMM Director Kjetil Taskén in addition to the founding partner groups of Ole Petter Ottersen/Mahmood Amiry-Moghaddam and Stefan Krauss. Two additional new NCMM/EMBL group leaders, Toni Hurtado and Judith Staerk, have been identified and are starting 2011/2012. NCMM also has a network of prominent Norwegian Associate Investigators affiliated. The NCMM groups investigate cancer, cardiovascular and CNS-related diseases and haematological and immune disorders. In my view, the Nordic EMBL Partnership has gained significant momentum in 2010 and offers great opportunities and synergies within the Nordic region as we progress towards more molecular and personalized medicine as well as access to a wealth of research and facilities at the EMBL and its outstations. We look forward to the continued collaboration with FIMM, MIMS and EMBL investigators.

Professor Kjetil Taskén, Director of the Centre for Molecular Medicine Norway (NCMM)

he Laboratory for Molecular Infection Medicine Sweden (MIMS, www.mims.umu.se) was initiated Twith main support from the Swedish Research Council and with the aim to form a national centre for research in molecular infection medicine at Umeå University. MIMS is placed within the Umeå Cen- tre for Microbial Research (UCMR), which is an interdisciplinary research consortium devoted to molecular research and novel applications in fields relevant to infectious diseases. It is promoting career opportunities for young researhers and several new group leaders have been establishing their groups during the period 2008—2010: Emmanuelle Charpentier, Constantin Urban, Jörgen Johansson, and Nelson Gekara have been recruited with support to build new groups; Niklas Arnberg and Andrei Chabes are provided support as affiliated group leaders. Starting in January 2011 two new young group leaders, Anna Överby and Rickard Lundmark, are joining MIMS. Together with the founding groups of Anders Sjöstedt, Bernt Eric Uhlin, Hans Wolf-Watz, Sven Bergström, Thomas Borén, and Åke Forsberg, the MIMS groups represent several different areas of infectious disease research and include investigations of many bacterial pathogens, viruses, and pathogenic fungi. During 2010 a new initiative with the recruitment of MIMS Clinical Research Fellows was launched. “It is clear from the successful joint efforts between FIMM, NCMM, and EMBL in the recruitment and build-up phase of the three Nordic nodes during the past cou- ple of years that the establishment of the Nordic EMBL Partnership for Molecular Medicine has provided a very good basis for expanding our collaborative efforts and synergistic scientific interactions. We are with great enthusiasm looking forward to the continued partnership activities among the research groups.”

Professor Bernt Eric Uhlin, Director of the Laboratory for Molecular Infection Medicine (MIMS)

FIMM 7 IV. Academician of Science, Professor Leena Peltonen- Palotie in memoriam

Leena earned her medical degree in 1976 and PhD in 1978 from the University of Oulu, Finland. She carried out postdoctoral research at Rutgers Medical School, New Jersey after which she returned to Finland, becoming Professor at the Na- tional Public Health Institute in 1991 at the age of 39. In 1998 she took up a new challenge, return- ing to the US to establish a major genetics research centre at the University of California Los Angeles (UCLA), which she led for four years. In 2002, Leena returned to a Professorship in the cademician of Science, Professor Leena University of Helsinki and the National Public APeltonen-Palotie was Research Director at Health Institute. She was invited to a Visiting the Institute for Molecular Medicine FIMM, Re- Professorship at the Broad Institute, one of the search Professor at the National Institute for world’s leading genetics institutions. Health and Welfare, Finland and Head of Human Genetics at the Wellcome Trust Sanger Institute. Leena’s role was instrumental when setting up She was also a visiting professor at the Broad In- and shaping up the FIMM research profile. She stitute of MIT and Harvard University, USA. Lee- was a visionary leader of the Human Genom- na passed away on 11 March 2010 in her home in ics Research Area. With a firm hand, she built Finland after a long and courageous battle with a highly competitive research group analyzing cancer. genetic and epidemiological variation in connection to a broad range of diseases and traits Leena had a distinguished career and published by fully utilizing the well-characterized Finn- more than 580 research papers as well as almost ish population samples. The work was carried 80 reviews, with many articles in the most pres- out by many of her students at FIMM. After her tigious journals. Her research has enormously death, the supervision of the current students increased our knowledge on the molecular ba- has been taken over by the rest of the FIMM fac- sis human diseases. These studies have gained a ulty members. wide national and international recognition as reflected by the numerous prizes and honors she In 2007 Leena assumed the position of Head of has received including, the Anders Jahre Prize in Human Genetics at the Wellcome Trust Sanger 1992, the Margaret Pittman lectureship award in Institute, while continuing her work in Finland 2003, the Nordic Fernström Prize and the Euro- and in the US. The three roles complemented pean van Gysel Prize, both in 2006, and the Cart- each others and opened exciting new collabo- er medal and the Hugh Sinclair Lecturer, both in rative research avenues. She also brought to- 2010. In 2009, the President of the Republic of gether numerous top researchers and research Finland Tarja Halonen awarded Leena the honor- groups by leading the Center of Excellence in ary title of Academician of Science, and she be- Disease Genetics of the Academy of Finland, the came one of only 12 Academians in post in Fin- Nordic Center of Excellence in Disease Genetics, land at one time. GenomEUtwin (FP5) and ENGAGE (FP7). She was

8 FIMM elected as the President of Human Genome Or- trainees is given below. Her legacy, though, is in- ganization HUGO in 2005 – 2007. She was also ternational: she has transformed science and sci- nominated as one of the founding members for entists all over the world. She was a prime exam- the European Research Council and elected to ple how a woman can create a career in a com- the Institute of Medicine of the National Acad- petitive field, being simultaneously dedicated to emy of USA. her family. But it is also personal: one of Leena’s special abilities was her ability to listen careful- Leena was a visionary geneticist, and a champi- ly, think fast, and make you want to go out and on of population genetics and public health. Lee- make a difference. “Aim for the best”, she used to na’s vision and charisma have been inspiration- say and she was able to make it always sound al to many, particularly the younger generation. both simple and the only natural way to work. As a teacher and scholar she has fostered the next generation of geneticists, supervising more Jaakko Kaprio than 70 PhD students. Many of her former stu- Professor of Genetic Epidemiology dents now hold prominent positions in Finland Samuli Ripatti and abroad. The complete list of her former PhD FIMM-EMBL Group Leader

PhD Students supervised by Professor Leena Peltonen-Palotie:

Ritva Halila Lasse Lönnqvist Jani Saarela Seppo Pakkala Kai Tenhunen Ville Holmberg Irma Järvelä Petra Pekkarinen Heidi Lilja Marc Baumann Iiris Hovatta Nabil Enattah Päivi Helminen Paulina Paavola Lisa Lanyi-Mee Elina Ikonen Tuomas Klockars Denis Bronnikov Antti Sajantila Päivi Pajukanta Tero Ylisaukko-oja Kati Kainulainen Markus Perola William Hennah Raili Kauppinen Teppo Varilo Elina Suviolahti Miikka Vikkula Minna Savukoski Jenny Ekholm Anu Suomalainen Petra Björses Niklas Pakkasjärvi Pentti Tienari Tomi Pastinen Mira Kyttälä Nina Enomaa Jyrki Kaukonen Joni Turunen Tiina Paunio Hannele Kangas Anna Kiialainen Jouni Vesa Miina Öhman Kirsi Auro Elina Hellsten Pirjo Salomäki Sampo Sammalisto Pekka Nokelainen Jesper Ekelund Nora Pöntynen Ritva Tikkanen Mari Auranen Jussi Naukkarinen Aija Riikonen-Kyttälä Ilona Visapää Kati Kristiansson Leena Karttunen Juha Isosomppi Suvi P. Kallio Johanna Aaltonen Maria Halonen Karola Rehnström Terhi Rantamäki-Häkkinen Chris Ramsey Juho Wedenoja Minna Peltola Juha Paloneva Outi M. Palo Annukka Uusitalo Daniel Chen Johannes Kettunen Satu Kuokkanen Nina Aula Liisa Tomppo Kaisu Nikali Henna Haravuori Helena Kilpinen

FIMM 9 V. Research Human Genomics

Group Palotie

Professor Aarno Palotie, MD, PhD

he overall goal of Aarno Palotie´s group is to improve our understanding of Tthe genetic mechanisms underlying neurological and neurodevelopmental traits by combining genome-wide information of both single nucleotide poly- morphism and structural variants across classical diagnostic phenotypes. Much of our work draws on the unique clinical and population-based samples collected from the Finnish founder population. These include such clinical collections as the Finnish Migraine Family sample (collected by Dr. Mikko Kallela), the Finnish Schizophrenia family samples (collected by Dr. Jouko Lönnqvist) and the Finnish Group Members: Autism Sample collection (collected by Dr. Lennart von Wendt) and such population cohorts as the Finrisk, Helsinki Birth Cohort, Northern Finnish Birth Cohort PI: Aarno Palotie and Health 2000 cohorts (www.nationalbiobanks.fi). The long lasting geographi- Senior Researchers: Kaisa Silander, cal and linguistic isolation, internal migrations, famines and rapid, recent expan- Maija Wessman sions have moulded the population structure of Finland for thousands of years. Postdoctoral Researchers: Verneri Anttila, Such population isolates provide exceptional opportunities for identification of William Hennah genome variations underlying disease traits. When the unique population struc- PhD Students: Tiia Luukkonen, Mikko Muona, ture is combined with the one payer health care system, the harmonized training Emma Nyman, Olli Pietiläinen of physicians and tradition in epidemiological research Finland has become one Technicians: Eija Hämäläinen, Elli Kempas, the most interesting places for genetic epidemiology. Anne Nyberg, Minna Suvela, Anne Vikman The Palotie group aims to identify both common and low frequency variants Research Nurses: Carita Jussila, Leena Leikas, associated to two paroxysmal neurological disorders migraine and epilepsy, and Anne Nyrhinen two neurodevelopmental disorders, schizophrenia and autism using GWA and Project Coordinator: Sari Kivikko next gene generation sequencing techniques. To combine different fields of ex- Collaborators in the Helsinki University Central pertise and to have sufficient power these studies are performed in collaboration Hospital: Ville Artto, Markus Färkkilä, with several international groups and high throughput platforms. The wealth of Mikko Kallela, Salli Vepsäläinen multiple large study samples enables the group to use different study designs for genome variant identification and verification and for the estimation of the size of the effect contributed by the variants. As an example of a successful study, we recently published results from a genome-wide association study of migraine with aura, in collaboration with six major headache research centres in Europe and Australia. This study identified a susceptibility variant on chromosome 8q that is potentially linked to glutamate neurotransmitter regulation. We are now following up this initial result in different migraine subtypes from population cohorts and individuals suffering from chronic pain. Dr. Palotie is a faculty member at the Wellcome Trust Sanger Institute in Cam- bridge UK and a visiting faculty member at the Broad Institute of MIT and Harvard.

Key publications: Anttila V, Stefansson H, Kallela M et al. Identification of a migraine-associated variant on 8q22.1, Nat Genet. Oct;42(10):869-73, 2010. Inouye M, Silander K, Hamalainen E et al. An immune response network associated with blood lipid levels. PLoS Genet. Sep 9;6(9), 2010. Yasuno K, Bilguvar K, Bijlenga P et al. Genome-wide association study of intracranial aneurysm identifies three new risk loci Nat Genet. May;42(5):420-5, 2010. The 1000 Genomes Consortium: A map of human genome variation from population scale sequencing. Nature. Oct 28;467(7319):1061-73, 2010. External research funding: Academy of Finland Center of Excellence, Helsinki Biomedical Grad- uate School (HBGS, 2011), EU-FP7: SYNSYS

10 FIMM Group Ripatti

FIMM-EMBL Group Leader (Sigrid Jusélius Foundation) Samuli Ripatti, PhD

he Ripatti research group is working on genetic epidemiology and the statis- Ttical genetics of complex diseases with special emphasis on cardiovascular disease and metabolic traits. The group studies genomic variation measured in Finnish and European large-scale epidemiological cohorts to find genes modify- ing trait levels, estimate their effects sizes and predict the risk of future cases of clinical endpoints. To gain sufficient statistical power, the work often calls for national and international collaborations. During 2010 the group described Finnish genetic variability using a special Finnish Hapmap 3 reference sample (Surakka et al 2010). The Finnish Hapmap Group Members: panel was also shown to be powerful when tagging common SNPs and copy num- PI: Samuli Ripatti ber variants and imputing Finnish GWAS datasets for dense genetic marker reso- Senior Researcher: Maria Krestyaninova lution. Postdoctoral Researcher: Johannes Kettunen Together with members of the Nordic Center of Excellence in Complex Diseas- PhD Students: Marine Largeau, es, a Nordic common GWAS control database was established and the Nordic ge- Pirkka-Pekka Laurila, Mari Rossi, netic population structure described (Leu et al 2010). The group also participated Antti-Pekka Sarin, Jarkko Soronen, in several consortia for finding further genes for lipids (Teslovich et al 2010), and, Ida Surakka, Emmi Tikkanen, for example, for glycemic traits, obesity and human height. This work is currently Taru Tukiainen being extended to a wider range of potential biomarkers for cardiovascular dis- Project Coordinator: Huei-Yi Shen eases. Together with Veikko Salomaa from THL, Sekar Kathiresan from the Broad In- stitute and others the group created a genetic risk score for coronary heart disease. The multilocus risk score was evaluated in six prospective cohorts from Fin- land and Sweden and shown to be strongly associated with incident heart disease (Ripatti et al 2010).

Key publications: Leu M, Humphreys K, Surakka I et al. NordicDB: A Nordic pool and portal for genome-wide control data, European Journal of Human Genetics, advance online publication 28 July 2010; doi: 10.1038/ejhg.2010.112, 2010. Ripatti S, Tikkanen E, Orho-Melander M et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses, The Lancet 2010; 376: 1393–400. Surakka I, Kristiansson K, Anttila V et al. Founder Population-Specific HapMap Panel Improves Im- putation Accuracy and CNV Tagging in GWA Studies, Genome Res., doi:10.1101/gr.106534.110. Pub- lished in Advance September 1, 2010. Teslovich TM, Musunuru K, Smith AV et al. Biological, Clinical, and Population Relevance of 95 Loci Mapped for Serum Lipid Concentrations, Nature, Aug 5;466(7307):707-13, 2010. External research funding: Sigrid Juselius Foundation, Academy of Finland Center of Excel- lence, Helsinki Graduate School of Biotechnology and Molecular Biology (GSBM), Helsinki Bio- medical Graduate School (HBGS, 2011), EU-FP7: ENGAGE and BioSHaRE

FIMM 11 Group Saarela

Research Director Janna Saarela, MD, PhD

oth genetic predisposition and environmental triggers are thought to contrib- Bute to the development of autoimmune diseases. Despite extensive research the detailed genetic and molecular background of most of the autoimmune diseases are still relatively unclear. Our goal is to improve understanding of biological pathways and pathogenic mechanisms behind common autoimmune diseases such as multiple sclerosis (MS) and osteoarthritis (OA). Our group is using novel genomics, statistical genetics and bioinformatics tools to investigate MS and OA. In addition to utilizing the Finnish twin and population cohorts and collaborating with large international consortia to identify Group Members: genes predisposing to autoimmune diseases by genome-wide association analy- PI: Janna Saarela ses, we have used an alternative approach to take advantage of the population Postdoctoral Researcher: Eveliina Jakkula history of Finland and the province of Southern Ostrobothnia, which is an old PhD Students: Virpi Leppä, Annu Näkki, isolate with increased prevalence and familial occurrence of MS. For example, we Anna-Maija Sulonen identified a novel MS predisposing gene, STAT3, using genome-wide association Undergraduate Students: Henrikki Almusa, analysis in only 68 distantly related individuals from two extended megapedi- Maija Lepistö grees (Jakkula et al 2010). In collaboration with the FIMM Technology centre’s sequencing and bioinformatics units we have been developing laboratory and analysis methods for next- generation sequencing: we have optimized the sample preparation protocols for next-generation sequencing (Lepistö M, Master’s thesis), evaluated the commer- cially available exome capture kits (Sulonen et al, manuscript), tested a solution based custom targeting capture method and developed a bioinformatics pipeline for NGS genome sequence analysis (Almusa H, Master’s thesis in preparation, Sulonen et al, manuscript).

Key publications: Jakkula E, Leppä V, Sulonen AM, et al. Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene. Am J Hum Genet. 2010, 86:285-91. International Multiple Sclerosis Genetics Consortium (IMSGC), Lack of support for association between the KIF1B rs10492972[C] variant and multiple sclerosis. Nat Genet. 2010, 42:469-70. Evangelou E, Valdes AM, Kerkhof HJ, et al. Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22. Ann Rheum Dis. 2010. De Jager PL, Baecher-Allan C, Maier LM, et al. The role of the CD58 locus in multiple sclerosis. Proc Natl Acad Sci U S A. 2009, 106:5264-9. External research funding: Sigrid Juselius Foundation, State funding for research to university hospitals (EVO), National Graduate School of Musculoskeletal Disoreders and Biomaterials (TBGS), Helsinki Biomedical Graduate School (HBGS, 2011)

12 FIMM Group Widén

Academy Research Fellow Elisabeth Widén, MD, PhD

he focus of the research group is to identify genes influencing puberty and to Tevaluate their impact on adult health. Complex interactions between genes and environmental factors contribute to the lifetime risk for common, non-communicable disease. Yet, most of the underlying disease genes and mechanisms remain poorly understood. Based on epidemiological studies it appears that the disease risk correlates with distinct patterns of fetal and childhood growth. Puberty is an example of such an event. It is strongly regulated by genes and its early timing is associated with increased risk for several adult health outcomes, e.g. obesity, type 2 diabetes and hormone dependent Group Members: cancers, but the underlying mechanisms linking early puberty with adult disease remain unknown. However, the ongoing global secular trend towards earlier puber- PI: Elisabeth Widén tal onset, which is paralleled by rapidly increasing rates of obesity and associated PhD Students: Diana Cousminer, disease, clearly underscores the urgency of clarifying the disease mechanisms from Jaakko Leinonen a life-course perspective. We hypothesize that the same genes and genetic pathways may regulate both pubertal timing and its associated adult health outcomes and that the identification of genes influencing pubertal timing and growth can enhance our understanding of mechanisms leading to adult disease. Therefore, our research aim is to identify genes that regulate pubertal growth and maturation, and to clarify how these genes/genetic pathways may impact adult health. During 2010, our main research activities have been targeted towards identifying genes influencing puberty using the well-established genome-wide association (GWAS). Studying unique longitudinal height growth data available in Finnish population-based cohorts we identified a significant association between the timing of the pubertal growth spurt and variants nearby the gene LIN28B (Widen et al, Am J Hum Genetic 2010;86:773-782). We further demonstrated that distinct variants in the LIN28B-region affect both prepubertal and pubertal growth in a complex and sex-specific manner. In addition to studying Finnish population cohorts, we have engaged in international collaborations aiming at large-scale meta-analysis of GWAS data. One of these collaborations, resulted in the identification of 32 loci significantly associated with age of menarche (Elks et al, Nat Genet 2010;42:1077-1085). To facilitate efficient research on the genetics underlying childhood growth and health related phenotypes, we have together with others formed the international research consortium EAGLE (The Early Genetics and Lifecourse Epidemiology Con- sortium; http://wiki.genepi.org.au/display/EAGLE/EAGLE). Our first collaborative GWAS-study within the consortium interrogated genetic variants associated with birth weight providing significant evidence for an association with variants nearby ADCY5; a gene previously implicated in Type 2 diabetes (Freathy et al, Nat Genet 2010; 42: 430-435). During 2010, we set up and coordinated a GWAS-project within EAGLE, encompassing 20,000 samples specifically targeting pubertal growth. This project is still ongoing.

Key publications: Widén E, Ripatti S, Cousminer DL, et al. Distinct variants at LIN28B influence growth in height from birth to adulthood Am J Hum Genet 2010;86:773-782 Freathy RM, Sovio U, Mook-Kanamori DO, et al. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 2010; 42: 430-435 Elks CE, Perry JR, Sulem P, et al. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat Genet. 2010;42:1077-1085 External research funding: Academy of Finland FIMM 13 Medical Systems Biology and Translational Research

Group Kallioniemi

Professor Olli Kallioniemi, MD, PhD High-throughput cancer biology and translation towards personalized medicine

e are integrating genomic profiling, high-throughput RNA interference and Wchemical biology data to investigate the molecular basis of human breast and prostate cancer. These bioinformatic and systems biological studies of cancer are coupled with translational research on the responses of cancer cells to drugs as well as the molecular features of biobanked human tumour cohorts. The aim is to combine the understanding of the molecular pathogenesis of cancer with the patterns and pathways that play a role in anti-cancer drug response. This should make it possible to develop synergistic combinatorial strategies to block the “es- Group Members as of January cape routes” of cancer. 2011: This approach is also providing an exciting ability to generate rapidly actiona- PI: Olli Kallioniemi ble personalized medicine strategies for the clinical treatment of cancer patients. Senior Researcher: Maija Wolf In order to promote translational opportunities, we have recently shifted our in- Postdoctoral Researchers: Sara Kangaspeska, terests to studies of human leukaemias as a model to advance the personalized Astrid Murumägi, Teijo Pellinen, Xiaofeng Dai medicine of cancer. In collaboration with Jonathan Knowles/Caroline Heckman PhD Students: Anna Aakula, Henrik Edgren, and Krister Wennerberg at FIMM, as well as Kimmo Porkka and the Finnish He- Sami Kilpinen, John Patrick Mpindi, Kalle Ojala, matology Association, we are using high-throughput ex-vivo drug sensitivity test- Khalid Saeed, Saana Sandström (FIMM-EMBL ing to leukemic cells, coupled with the molecular profiling of the cancer cells by Rotation PhD Student) RNAseq, exome-seq, and phosphoproteomics. We believe that the implementa- Technician: Katja Välimäki tion of these types of personalized molecular and functional profiles is possible in Research is done in collaboration with the management of human leukaemias today, while it may take several years to the Medical Biotechnology Group of the VTT achieve similar translational progress for the common solid tumours. Technical Research Centre of Finland and the University of Turku. Key publications: Edgren H, Murumagi A, Kangaspeska S, Nicorici D, Hongisto V, Kleivi K, Rye IH, Nyberg S, Wolf M, Borresen-Dale AL, Kallioniemi O. Identification of fusion genes in breast cancer by paired-end RNA-sequencing. Genome Biol. 2011 Jan 19;12(1):R6.

ImageX.dll (JPEG Image, 1500x892 pixels) - Scaled (95%) http://www2.primed.helsinki.ﬁ/ecwp/ImageX.dll?image?layer... Ostling P, Leivonen SK, Aakula A, Kohonen P, Mäkelä R, Hagman Z, Edsjö A, Kangaspeska S, Edgren H, Nicorici D, Bjartell A, Ceder Y, Perälä M, Kallioniemi O. Systematic Analysis of MicroRNAs Targeting the Androgen Receptor in Prostate Cancer Cells. Cancer Res. 2011 Mar 1;71(5):1956-1967. Kilpinen S, Ojala K, Kallioniemi O. Analysis of kinase gene expression patterns across 5681 human tissue samples reveals functional genomic taxonomy of the kinome. PLoS One. 2010 Dec 3;5(12):e15068. Iljin K, Ketola K, Vainio P, Halonen P, Kohonen P, Fey V, Grafström RC, Perälä M, Kallioniemi O. High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin Cancer Res. 2009 Oct 1;15(19):6070-8. Hanash SM, Baik CS, Kallioniemi O. Emerging molecular biomarkers-blood-based strategies to detect and monitor cancer. Nat Rev Clin Oncol. 2011 Mar;8(3):142-50. International Cancer Genome Consortium, Hudson TJ, et al. International network of cancer genome projects. Nature. 2010 Apr 15;464(7291):993-8. External research funding: Academy of Finland Center of Excellence, Biocentrum Helsin- ki (2011), Cancer Society of Finland, Helsinki Biomedical Graduate School (HBGS), Sigrid Jusélius Foundation, Tekes, EU-FP7: Marie Curie Initial Training Network PRO-NEST, EU-FP7: Systems Microscopy Network of Excellence (2011)

14 FIMM

1 of 1 3/7/11 10:27 PM Group Kainov

FIMM-EMBL Group Leader (Jane and Aatos Erkko Foundation) Denis Kainov, PhD

ur group studies the principles that govern influenza A virus-host relation- Oships, aiming to develop (1) novel anti-influenza therapeutics and (2) diagnostic tests for individuals at risk of developing severe influenza infections. On average, 10% of the population are infected with influenza viruses annu- ally, from which 0.5% are hospitalized for severe influenza infections and 0.03% die. Antiviral therapy is vital for immediate control of the spread of influenza. The current generation of the anti-influenza drugs is designed to bind viral proteins. However, viral proteins mutate rapidly and acquire resistance to the exist- Group Members as of January ing therapeutics. In contrast to viral proteins, cellular factors are not prone to 2011: rapid mutations. Cellular vacuolar ATPase represents a potential antiviral target. PI: Denis Kainov It acidifies endosomes and the acidification serves as a signal for the release of the viral cargo into the cytoplasm. Our recent study demonstrated that saliphe- Postdoctoral Researchers: Andrey Golubtsov, Laura Kakkola nylhalamide, a compound targeting vacuolar ATPase, is an effective inhibitor of influenza infection in vitro and in vivo. Another interesting anti-influenza target PhD Students: Maria Anastasina, Puwei Yuan is the cellular translation apparatus. Viral NS1 protein interacts with translation Technicians: Minttu Kaloinen, Alun machinery to promote the synthesis of influenza proteins. We have developed a Parsons cell-free translation assay for mechanistic studies of NS1-stimulated translation and for the screening of small molecules that block the synthesis of viral proteins without affecting cellular mRNA translation. The host immune system is often able to eliminate influenza A virus infections, but it sometimes fails to do so. In collaboration with researchers from THL, HUS and TTL we are studying the mechanism of host immune system fail- ure in response to influenza A virus infection. Our findings may provide insights into individual susceptibility to influenza infections and result in novel diagnostic tests for people at risk of developing severe influenza-associated diseases.

Key publications: Mueller KH, Kainov DE, El Bakkouri K, Saelens X, De Brabander JK, Kittel C, Samm E, Muller CP. (2011) The proton translocation domain of cellular vacuolar ATPase provides a target for the treatment of influenza A virus infections. Br. J. Pharmac. doi: 10.1111/j.1476-5381.2011.01346.x. Kainov DE, Mueller KH, Theisen LL, Anastasina M, Kaloinen M, Muller CP. (2011) Differential effects of NS1 proteins of human pandemic H1N1/2009, avian highly pathogenic H5N1 and low pathogenic H5N2 influenza A viruses on cellular pre-mRNA polyadenylation and mRNA translation. J Biol Chem. 286: 7239-7247 Kainov DE, Vitorino M, Cavarelli J, Poterszman A, Egly JM. (2008) Structural basis for group A tri- chothiodystrophy. Nat. Struct. Mol. Biol. 15: 980 - 984 Mancini EJ, Kainov DE, Grimes JM, Tuma R, Bamford DH, Stuart D.I. (2004) Atomic snapshots of an RNA packaging motor reveal conformational changes linking ATP hydrolysis to RNA translocation. Cell. 118: 743-755 External funding: Jane and Aatos Erkko Foundation, Academy of Finland (2011), CIMO, Ministry of Employment and the Economy, Helsinki Biomedical Graduate School (HBGS, 2011)

FIMM 15 Group Knowles

Personalized Cancer Medicine Group

ith the development of targeted therapies, identifying the right patient for Wthe right drug will become an essential part of clinical practice. The treatment decision, however, may not be clear and additional molecular information could provide better guidance. In 2010 FiDiPro Professor Jonathan Knowles and Senior Re- searcher Caroline Heckman were recruited to FIMM to establish the Personalized Cancer Medicine Group. The aim of this group is to utilize cutting-edge technologies for cancer patient sample analyses including next-gen genomic and transcriptomic sequencing, proteomics and high-throughput drug screening. Integrative processing of datasets generated from these analyses will not only identify patient specific bio- Group Members: markers, but also endeavor to determine new therapeutic options. Furthermore, a PI: Jonathan Knowles better understanding of disease pathogenesis offered by in-depth molecular profiling Senior Researcher and co-principal may yield new ideas for drug development. investigator: Caroline Heckman The group works closely with clinicians in order to facilitate patient sample Senior Research Technician: Alun Parsons access for basic researchers and to move information derived from molecular profiling and high throughput drug studies back to the clinic. This is exemplified by collaboration with Professor Kimmo Porkka and Dr. Satu Mustjoki of the HUS Hematology Clinic and Hematology Research Unit (see “Personalized medicine of cancer becoming a reality”). Investigations of leukaemia patient samples have already identified novel pathogenic mutations, revealed altered signaling pathways and are leading to the development of new protocols for patient treatment.

Key publications: Heckman C, Holopainen T, Wirzenius M, et al. The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis. Cancer Res 2008;68:4754-62. Heckman CA, Holopainen T, Alitalo K. Molecular targeting of lymphangiogenesis and tumor metastasis. Current Clinical Oncology 2008;Chapter 28: Cancer Metastasis: From Local Proliferation to Distant Sites Through the Lymphovascular System. Duan H, Heckman CA, Boxer LM. Histone Deacetylase Inhibitors Down-Regulate bcl-2 Expression and Induce Apoptosis in t(14;18) Lymphomas. Mol Cell Biol 2005;25:1608–19. McBride DJ, Orpana AK, Sotiriou C, et al. Use of cancer-specific genomic rearrangements to quan- tify disease burden in plasma from patients with solid tumors. Genes, Chromosomes and Cancer 2010;49:1062–9. Kallioniemi O, Pitkänen K, Knowles JKC. Molekyylitason näkökulma potilaan hoitoon. Duodecim 2010;126(19):2329-32 External research funding provided by: Tekes, Cancer Society of Finland, Sigrid Jusélius Foundation

16 FIMM Group Kuznetsov

FIMM-EMBL Group Leader (Finnish Medical Foundation and Sigrid Jusélius Foundation) Sergey Kuznetsov, PhD

reast cancer is the most common malignancy among women. One out of ten Bbreast cancers is hereditary. Half of all hereditary cases are due to mutations in homologous recombination genes such as BRCA1, BRCA2, RAD51C and others. Homologous recombination is the most accurate mechanism for repairing DNA errors occurring spontaneously or caused by toxic substances. When this repair pathway is disabled, cells rely on less accurate mechanisms to repair damaged DNA, leading to new mutations, genomic instability, and cancer. At the same time dysfunctional homologous recombination limits cell¹s ability Group Members: to repair certain types of DNA damage, which can be used to kill such cancer cells PI: Sergey Kuznetsov without much toxicity to normal tissues. This idea is the basis for the concept of Postdoctoral Researchers: Xiaofeng Dai, synthetic lethality gaining popularity among oncologists in the recent years. Pauliina Munne We use a panel of BRCA1-mutated breast cancer cell lines to search for new PhD Students: Yuexi Gu, Manuela Tumiati synthetic lethal drugs against recombination-deficient cancers. Our current data Technicians: Sonja Koopal, indicate that these cells are highly heterogeneous in their drug sensitivity pro- Annabrita Schoonenberg files. We use genome-wide RNA interference and systems biology approaches to identify biomarkers predicting sensitivity to select therapeutic agents and understand the mechanisms of acquired drug resistance. We also develop advanced animal models for preclinical testing of new breast cancer treatment strategies.

Key publications: Kuznetsov S, Chang S, Sharan S. Functional analysis of human BRCA2 variants using a mouse embryonic stem cell-based assay. Meth Mol Biol. 2010;653:259-280. Kuznetsov S, Haines D, Martin B, Sharan S. Loss of Rad51c leads to embryonic lethality and mod- ulation of Trp53-dependent tumorigenesis in mice. Cancer Res. 2009;69:863-872. Kuznetsov S, Liu P, Sharan S. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat Med. 2008;14:875-881. Kuznetsov S, Pellegrini M, Shuda K, Fernandez-Capetillo O, Liu Y, Martin B, Burkett S, Southon E, Pati D, Tessarollo L, West S, Donovan P, Nussenzweig A, Sharan S. Rad51c deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. J Cell Biol. 2007;176:581-592. External funding: Finnish Medical Foundation, Sigrid Jusélius Foundation, Cancer Society of Finland, Helsinki Biomedical Graduate School (HBGS), Helsinki Graduate School of Biotechnology and Molecular Biology (GSBM)

FIMM 17 Group Lundin

Dr. Johan Lundin, MD, PhD

he Lundin Group develops methods for personalized prediction of disease out- Tcome and image based diagnostics. Genetic and molecular information combined with clinical data by the use of advanced informatics support will help identify patients at risk for disease recurrence and tailor individualized treatment, particularly in cancer. The goal is to promote implementation of new decision- support technology, as well as improve the flow of information from basic research to the clinic. We developed an online risk calculator – “Prognomics” – for personalized prediction of cancer outcome. The calculator is an extension of our previously published “case-match” method (1) and is connected to a database with molecular, clinical and outcome data on ca. 5 million cases worldwide. Survival estimates can be retrieved for major cancers and the database allows for estimation of risk even in rare subgroups. The case-match approach is also used for explorative analysis of novel biomarkers and is linked to our image analysis system. In 2010 the case-match method was applied in studies of the biomarkers MDGI, NPM, Bmi-1, XOR and FOXA1 (2 – 4). The other major research area is image-based diagnostics. In collaboration with the Machine Vision Group, University of Oulu, we are exploring high- throughput computer assisted methods for automated analysis of digitized cancer tissue and microbiological samples. Methods for computerized quantification Group Members as of January and segmentation of digitized tumor samples are applied in analysis of TMAs 2011: from breast-, prostate- and colorectal cancers (5). PI: Johan Lundin The webmicroscopy developed (fimm.webmicroscope.net) is a method of digi- Postdoctoral Researchers: Nina Linder, tizing entire microscope specimens and viewing as well as processing the virtual Ville Ojansivu slides through a web interface. The technology is a research infrastructure within PhD Students: Juho Konsti, Tiina Lehtimäki, Biocenter Finland and via the EU funded EATRIS. Applications include analysis Mikael Lundin, Riku Turkki and management of TMAs, laboratory quality assurance, consultation and education. The webmicroscopy methods will be useful for remote diagnostics within Global health in collaboration with Kalorinska institutet.

Key publications: Lundin J, Lundin M, Isola J, Joensuu H. A web-based system for individualized survival estimation in breast cancer. BMJ 2003;326:29. Nevo J, Mai A, Tuomi S, Pellinen T, Pentikäinen OT, Heikkilä P, Lundin J, Joensuu H, Bono P, Ivaska J. Mammary-derived growth inhibitor (MDGI) interacts with integrin alpha-subunits and sup- presses integrin activity and invasion. Oncogene 2010;29:6452-63. Häyry V, Mäkinen L, Atula T, Sariola H, Mäkitie A , Leivo I, Keski-Säntti H, Lundin J, Haglund C, Hagström J. Bmi-1 expression predicts prognosis in squamous cell carcinoma of the tongue. Br J Cancer 2010;102:892-7. Karhemo P, Lundin J, Rivinoja A, Hyvönen M, Chernenko A, Lammi J, Sihto H, Lundin M, Heikkilä P, Joensuu H, Bono P, Laakkonen P. An Extensive Tumor Array Analysis Supports Tumor Suppres- sive Role for Nucleophosmin in Breast Cancer. Am J Pathol. In Press. Konsti J, Lundin M, Joensuu H, Lehtimaki T, Sihto H, Holli K, Turpeenniemi-Hujanen T, Kataja V, Sailas L, Isola J, Lundin J. Development and evaluation of a virtual microscopy application for automated assessment of Ki-67 expression in breast cancer. BMC Clin Pathol 2011;11:3. External funding: Sigrid Jusélius Foundation, Cancer Society of Finland, State funding for research to university hospitals (EVO), Helsinki Biomedical Graduate School (HBGS)

18 FIMM Group Verschuren

FIMM-EMBL Group Leader (Orion-Farmos Research Foundation and Sigrid Jusélius Foundation) Emmy Verschuren, PhD

Lung cancer is the leading cause of cancer-related mortality worldwide, with traditional chemotherapy and surgery constituting the most effective treatments currently available. Innovative, versatile methods to study the causes of lung cancer and aid the design of new treatment options are therefore of crucial importance. Research in the Verschuren lab is centred on defining cell biological and biochemical properties of putative lung cancer tumour suppressor genes, and building in vivo mouse lung cancer models to study them in complex microenviron- ments. The lab develops sophisticated methods to manipulate lung epithelial cells via intranasal delivery of engineered viral particles to newborn mice, allowing for rapid and versatile generation of mice carrying lung cancers of different molecular compositions. Advanced lung cancer models will be used for target validation and gene therapy approaches, and preclinical research angles are pursued through active participation in the European public-private IMI consortium PREDECT (coordinated by Emmy Verschuren). Key findings in animal models will be aligned with primary lung cancer patient materials, integrating biobanking and molecular profiling capacities available at FIMM and associated Biocenters. In the past year, much progress was made in studies on the EPHA3 receptor tyrosine kinase gene, a gene frequently mutated in human lung adenocarcinomas. Group Members as of January Through generation of a series of cell lines that express tagged forms of human 2011: lung cancer-associated variants, we generated the first evidence that point muta- PI: Emmy Verschuren tions lead to a decrease in receptor function, consistent with a putative tumour Postdoctoral Researcher: Merja Särkioja suppressor function. Since Eph receptor family signalling generally controls cell shape and contact-based cell repulsion, we are pursuing studies to address its PhD Students: Jenni Lahtela, Rita Matos function in architecturally sound in vivo mouse models. The lab’s general research CIMO Research Fellow: Ashwini Nagaraj strategy constitutes a powerful multi-pronged approach combining highly spe- Undergraduate Student: Nitai Peled cific dual tagging-based protein purification methods to define protein molecular Technicians: Sonja Koopal, Annabrita networks, with cell biological assessment of protein (co-) localisation and func- Schoonenberg, Danielle Bansfield tion in vitro and in vivo. This approach has been extended to reverse genetics approaches of a set of candidate lung cancer tumour suppressors.

Key publications: Peart, M.J., Pyurovsky, M.V., Ulrist M., Verschuren, E.W., Jackson, P.K. and Prives, C. (2010). APC/ CCdc20 targets E2F1 for degradation in prometaphase. Cell Cycle. 9: 3956-64. Verschuren, E.W., Ban, K.H., Masek, M.A., Lehman, N.L. and Jackson, P.K. (2007). Loss of Emi1-dependent APC/C inhibition deregulates E2F target expression and elicits DNA damage-induced senescence. Mol. Cell. Biol. 27: 7955-65. Verschuren E.W. and Jackson, P.K. (2007). Putting transcription repression and protein destruction in pRb’s pocket. Review. Dev. Cell. 12: 169-70. Marangos P., Verschuren E.W., Chen, R., Jackson P.K. and Carroll, J. (2007). Emi1-mediated regulation of the APC controls timing of progression through meiosis in mouse oocytes. J. Cell. Biol. 176: 65-75. Eldridge, A.G., Loktev, A.V., Hansen, D.V., Verschuren, E.W., Reimann, J.D. and Jackson, P.K. (2006). The evi5 oncogene regulated cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor Emi1. Cell. 124: 367-380. Christophorou, M.A., Martin-Zanca, D., Soucek, L., Lawlor, E.R., Brown-Swigart, L., Verschuren, E.W. and Evan, G.I. (2005). Temporal dissection of p53 function in vitro and in vivo. Nat. Genet. 37: 718-26. Verschuren, E.W., Hodgson, J.G., Gray, J.W., Kogan, W., Jones, N. and Evan G.I. (2004). The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis. Cancer Res., 64: 581-589. Verschuren, E.W., Klefstrom, J., Evan, G.I. and Jones, N. (2002). The oncogenic potential of Kaposi’s sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell, 2:229-241. External research funding: Orion-Farmos Research Foundation, Sigrid Jusélius Foundation,Helsinki Biomedical Graduate School (HBGS), CIMO, EU-FP7: SYSTUMS, FCT Portuguese Science Foundation. FIMM 19 Group Wennerberg

FIMM-EMBL Group Leader (Jane and Aatos Erkko Foundation) Krister Wennerberg, PhD

he research in the Wennerberg group aims to identify novel mechanisms that Tare associated with cancer malignancy with the ultimate goal of validating those as novel drug targets or as biomarkers for personalized treatment regimens. To date, we have addressed this approach in two ways: a) We have identified and began evaluating novel malignancy signals as drug targets and biomarkers and b) we are developing the tools and protocols for comprehensive in vitro drug sensitivity testing of primary cancer cells and cell lines. Among the malignancy signals, we have focused on two cellular mechanisms that stand out as significant, potential therapeutic and diagnostic targets: The MKLP1/MgcRacGAP/Ect2 protein complex and its role in driving malignancy, and the role of a set of novel cell stress and mitosis related gene products that cancer cells with high levels of DNA damage appear to become dependent on. Since a) intrinsic DNA damage is a hallmark of malignant and invasive cancer cells, and b) radiotherapy and a majority of chemotherapeutic agents induce cancer cell killing through DNA and other cellular damage, we expect that these proteins may serve as cancer specific and radio/chemosensitizing drug targets or as biomarkers. In the personalized medicine project, a large collaborative program between FIMM, the Finnish Hematology Registry and Biobank (FHRB) and HUS, our group Group Members: has together with the Chemical Biology unit developed protocols and analysis methods to screen relapsed leukemias and other primary cells as well as cell lines PI: Krister Wennerberg for connecting biomarkers to drug responses. The goal is to use the assays for Senior Researcher: Gretchen Repasky quick and accurate testing of cells for their in vitro sensitivity to drugs to allow Postdoctoral Researcher: Leena Karhinen for a prediction of clinical responses. To this end, we have assembled a compre- PhD Students: Arjan van Adrichem, hensive oncology screening collection, currently containing about 220 approved Tonge Ebai, Muntasir Mamun Majumder and investigational oncology drugs. (FIMM-EMBL Rotation PhD Student) During 2010, several new group members were recruited. Gretchen Repasky is a senior researcher working on the mitotic kinesin KifC1. Arjan van Adrichem working on MgcRacGAP. Tonge Ebai is a PhD student who is focusing her studies on MKLP1. Leena Karhinen is a postdoctoral researcher who is studying Ect2 and cell stress and hypoxia signaling. Muntasir Mamun Majumder, one of the two FIMM-EMBL PhD students that were recruited to the Institute in 2010, did a research rotation in the group working on DNA damage response genes.

Key publications:

Swenson-Fields KI, Sandquist JC, Rossol-Allison J, Blat IC, Wennerberg K, Burridge K, Means AR. 2008. MLK3 limits activated Gαq signaling to Rho by binding to p63RhoGEF. Mol. Cell. 32:43-56.

Dubash AD, Wennerberg K, García-Mata R, Menold MM, Arthur WT, Burridge K. 2007. A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin. J. Cell Sci. 120:3989-3998.

Wennerberg K, Forget MA, Ellerbroek SM, Arthur WT, Burridge K, Settleman J, Der CJ, Hansen SH. 2003. Rnd proteins function as RhoA antagonists by activating p190 RhoGAP. Curr. Biol. 2003 13:1106-1115.

Arthur WT, Ellerbroek SM, Der CJ, Burridge K, Wennerberg K. 2002. XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC. J. Biol. Chem. 277:42964-42972.

External research funding: Jane and Aatos Erkko Foundation, Helsinki Biomedical Graduate School (HBGS, 2011)

20 FIMM Research collaborations and highlights

FIMM National Network for Molecular Medicine

The FIMM National Network for Molecular Medicine is composed of 15 top quality molecular medicine experts. 11 joint translational research projects are funded by FIMM to foster collaborations between the National Network, the FIMM principal investigators and the FIMM technology services. The Network had two meetings in 2010, in February and November. “In Finland, there are very few instruments available for starting groups and here FIMM could make a difference”, states Dr Iiris Hovatta, University of Helsinki, a member of the Network. Professor Sirpa Jalkanen from the University of Turku states that she has had very good experiences regarding the ongoing projects. “The knowledge and infrastructure of FIMM has been synergistically combined with our knowledge and expertise and this has been very important.”

The concept of the Network will be evaluated by the SAB of FIMM in May 2011 and the future activities will be decided based on the recommendations.

FiDiPro Professor Juni Palmgren The Academy of Finland awarded Professor Juni Palmgren from Stockholm University and the Karolinska Institutet (KI) FiDiPro position at FIMM. During 2010 collaborative work has been discussed between FIMM Human Genomic research groups and the groups at the Department of Medical Epidemiology and Biostatistics at KI in the areas of high throughput genomics and metabolomics, data integration and statistical modelling.

Professor Juni Palmgren’s appointment will further reinforce the cooperation between KI and FIMM. “The data and competence of FIMM and KI supplement each other in a brilliant way, and I hope that we also can somehow involve the Department of Mathematics and Statistics of the University of Helsinki in the cooperation,” says Palmgren. According to Palmgren, the FiDiPro Professorship is very well timed due to the fact that the build-up of a comprehensive European research infrastructure is being launched at the moment: the goal is to harmonise the local, national and Europe-wide research infrastructures to get optimal advantage from them. “Researchers also understand that everyone cannot have all the equipment they need in their own basement, but cooperation is needed. It is important to be involved in the build-up of this system, and the Nordic countries should cooperate in some matters,” says Palmgren, who also is the Head Secretary of the research infrastructure area at the Swedish Research Council.

FiDiPro Professor Joseph D. Terwilliger FiDiPro Professor Joseph D. Terwilliger’s four-year project (2007—2010) involved development of statistical genetics methods to study multifactorial disease traits. Since national diseases, such as diabetes, migraine and obesity, are multifactorial diseases, computational modelling is very difficult. As genetic research methods have developed, it has become possible to use collected data to identify genes and understand their effects on the population. The first Finnish project leader was Professor Leena Peltonen-Palotie, she was succeeded by Professor Aarno Palotie in 2010.

FIMM 21 FIMM Clinical Collaboration Programme

IMM launched a Clinical Collaboration Programme in 2010 to fund joint ap- Fpointments and collaborative research opportunities for clinical investigators. FIMM aims to increase its activities in translational research, bringing discoveries from the bench to the bedside and back.

This two-year pilot programme started in late 2010 and three early and mid- career clinical investigators were selected through an international peer review process. FIMM hopes that the clinical collaborators would contribute medically important questions, insights, access to patient materials and data for FIMM investigators, while benefiting from the access to the scientific expertise and strong technology base available at FIMM.

Tuomas Mirtti, MD, PhD pathologist at the Department of Pathology in HUS and Postdoctoral Researcher at the University of Helsinki (Haartman Institute), participates in research projects on cancer biomarkers, including the developing of new webmicroscope based analysis tools and multispectral imaging applications. His expertise in histopathology and immunohistochemistry is also valuable in tissue micro array (TMA) construction and in research projects utilizing TMA sections of solid tumours. In the FIMM biobank infrastructure he is responsible for the assurance of tissue integrity and the diagnostic quality of the samples and he participates in the collection of clinico-pathological variables into the biobank database. His research is focusing on the molecular mechanisms of cancer progression and metastasis formation, the main focus being on urologi- cal cancers.

Kirsi Pietiläinen’s, MD, PhD, research group focuses on the genetic and environmental causes and metabolic consequences of obesity. They aim at a global metabolic profiling of obesity (“obesomics”) by using transcriptomics, metabolomics, genomics and epigenomics techniques in samples obtained from highly informative study materials, such as monozygotic, obesity-discordant twin pairs and clinical weight loss interventions.

Jakob Stenman’s, MD, PhD, research collaboration at FIMM, Minerva Institute for Medical Research and at the Department of Clinical Chemistry at University of Helsinki aims to develop multigene predictor assays for personalized cancer diagnostics. A novel technology for quantitative analysis of mRNA expression in formalin-fixed paraffin-embedded samples is utilized for large-scale analysis of archival tissue samples. The main focus of the research project is on colon, prostate and breast cancer.

22 FIMM Key publications: Mirtti T, Laine VJO, Hiekkanen H, Hurme S, Rowe O, Nevalainen TJ, Kallajoki M, Alanen K: Group IIA Phospholipase A2 as a Prognostic Marker in Prostate Cancer: Relevance to Clinicopathological Variables and Disease-specific Mortality. APMIS 2009; 117(3): 151-61. Gupta S , Iljin K, Sara H, Mpindi J-P, Mirtti T, Vainio P, Rantala J, Alanen K, Nees M, Kallioniemi O: FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to- mesenchymal transition in human prostate cancer cells. Cancer Res. 2010 Sep 1;70(17):6735-45 Paula Vainio, Santosh Gupta, Kirsi Ketola, Tuomas Mirtti, John-Patrick Mpindi, Pekka Kohonen, Vidal Fey, Merja Perälä, Frank Smit, Gerald Verhaegh, Jack Schalken, Kalle Alanen, Olli Kallioniemi and Kristiina Iljin: Arachidonic acid pathway members PLA2G7, HPGD, EPHX2 and CYP4F8 identified as putative novel therapeutic targets in prostate cancer. Am J Pathol. 2011 Feb;178(2):525-36

Pietiläinen KH, Róg T, Seppänen-Laakso T, Virtue S, Gopalacharyulu P, Tang J, Rodriguez-Cuenca S, Maciejewski A, Naukkarinen J, Rissanen A, Ruskeepää A, Niemelä PS, Velagapudi V, Castillo S, Sysi-Aho M, Hyötyläinen T, Kaprio J, Yki-Järvinen H, Vattulainen I, Vidal-Puig A, Oresic M. As- sociation of lipidome remodeling in the adipocyte membrane with acquired obesity in humans. PloS Biol 2011, accepted. Tyynismaa H, Raivio T, Hakkarainen A, Ortega-Alonso A, Lundbom N, Kaprio J, Rissanen A, Suomalainen A, Pietiläinen KH. Liver fat but not other adiposity measures influence circulating FGF21 levels in healthy young adult twins. J Clin Endocrinol Metab 2011 Feb;96(2):E351-5. Naukkarinen J, Surakka I, Pietiläinen KH, Rissanen A, Salomaa V, Ripatti S, Yki-Järvinen H, van Duijn CM, Wichmann HE, Kaprio J, Taskinen MR, Peltonen on behalf of the ENGAGE Consortium. Use of genome-wide expression data to mine the “gray zone” of GWA studies leads to novel candidate obesity genes. PLoS Genet 2010 Jun 3;6(6):e1000976.

Stenman J*, Paju A*, Rissanen O, Tenkanen T, Haglund C, Stenman U-H, and Orpana A. Tar- geted gene-expression analysis by genome-controlled RT-PCR. *Equal contribution. Clin Chem. 2006;52(11):1988-96.

Patents and patent applications: Stenman J, Orpana A. Method, instrument and computer program product for quantification of PCR products. FI 20095514. In PCT phase. Stenman J, Paju A, Rissanen O and Orpana A. Method for quantitative and/or comparative measurement of mRNA expression levels in small biological samples. WO2005116248. Granted in EPO, US and Australia, pending in CA and JP.

FIMM 23 Innovative Medicines Initiative (IMI): Oncology Target Validation (PREDECT) The Innovative Medicines Initiative (IMI) is a two billion Euro partnership between the European Com- mission and the European Federation of Pharmaceutical Industries and Associations (EFPIA). The aim of IMI is to support the faster discovery and development of better medicines for patients and to enhance Europe’s competitiveness by ensuring that its biopharmaceutical sector remains a dynamic high-technology sector.

FIMM/University of Helsinki is coordinating a new IMI project on cancer Target Validation consortium PREDECT (www.predect.eu). PREDECT consists of 26 principal investigators, managed by Servier, As- traZeneca and the University of Helsinki. FIMM-EMBL group leader Dr. Emmy Verschuren serves as the academic coordinator and representative of the IMI funding Managing Entity, and leads the Lung Cancer team. Professor Olli Kallioniemi, supported by Dr. Johan Lundin, leads the Systems Biology team.

PREDECT aims to address a major challenge in the cancer drug discovery process, which is the lack of efficacy of most newly developed drugs when they are first tried on patients. One reason for this may reflect the wide-spread use of over-simplified laboratory models of cancer that fail to represent the complexity and heterogeneity of human diseases. Working in teams investigating breast, prostate and lung cancers, PREDECT will generate advanced mouse models of cancer, some of which will be genetically engineered and matched to particular patient subgroups, to progressively “deconstruct” tumours for use on the laboratory bench. Examples are thin slices of tumour tissue and tumour cells growing in 3D together with supporting cells. At each deconstruction stage, cells will be profiled by applying systems pathology of key signalling proteins to establish how closely they represent the tumour of origin. Novel complex models can eventually be used to validate that a new, potential target for cancer treatment is worth pursuing. It is expected that PREDECT’s efforts will significantly shape the cancer drug discovery process in Europe.

24 FIMM

Personalized medicine of cancer becoming a reality

he personalized medicine project was inspired by our early efforts to help to manage and diag- Tnose the rare form of aggressive bone cancer that Professor Leena Peltonen-Palotie was diag- nosed with in 2008. FIMM researchers were involved in a large national and international effort to fully sequence the cancer genome and carry out transcriptomics and phosphoproteomics profiling as well as cancer drug sensitivity testing on her cancer, with the intent to provide the clinicians information to guide decisions on how cancer should be treated. Even though we were at that point unable to help Leena, this experience gave us hope that cancer can be better understood and per- haps treated in a comprehensive and individualized way in the future.

Advances in molecular profiling have led to a better classification of tumour subtypes, revealing novel biomarkers, elucidating mechanisms of drug action and identifying new drug targets. In particular, recent developments in sequencing technology have enabled in depth cancer genomic studies, which are now beginning to show that each individual tumour has a unique genetic signature that could be reflective of the pathogenesis of the disease as well as the response to treatment. As a result, cancer patients will soon benefit from more individualized care that could include perti- nent molecular and genomic data. There are, however, many significant obstacles to translating the research benefits to the clinic.

One is obviously the significant cost of the profiling. Furthermore, the traditional evidence-based medicine approach is too slow and will never form treatment paradigms for many forms of rare or recurrent cancers. Many cancers are enormously complicated eco-systems involving many cell types and the immune system, thus complicating our efforts to achieve a comprehensive molecular profile of the disease.

In the beginning of 2010, FiDiPro Professor Jonathan Knowles joined FIMM, and we formed a major Tekes-supported program to build capabilities for individualized medicine. These collaborations involve a co-principal investigator Caroline Heckman, Kimmo Pitkänen, Janna Saarela, Krister Wen- neberg, and many others, including a group of bioinformaticians. Due to the challenges with many solid tumors, we chose to initiate the profiling from human leukaemia samples, and launched a major collaborative project with Professor Kimmo Porkka and the Finnish Hematology Association. The project utilizes patient samples collected through the Finnish Hematology Clinical Registry and Biobank (FHRB), which aims to collect bone marrow, blood, plasma and serum samples along with clinical information from all acute leukaemia patients in Finland at diagnosis, remission and

FIMM 25 relapse. Using FIMM technologies researchers are conducting next-gen sequencing and in-depth molecular profiling as well as high throughput drug sensitivity testing of the FHRB samples. Com- prehensive analyses and integration of the different datasets are helping to identify new treatment options for these patients, design patient specific biomarkers and obtain a better understanding of their disease. In addition, FIMM researchers, working together with the haematologists, are able to test new therapeutic options with the patient’s own leukaemia cells in the lab before these therapies are given to the patient, thereby potentially avoiding unnecessary or toxic treatment and lim- iting the treatments to those that would be most beneficial.

The FIMM-FHRB project not only illustrates how information obtained from basic research studies can be used in the clinic, but how genomic and high-throughput technologies may in the future be readily applied for advanced personalized medical care.

Doctoral Training

Driven by the growth of the Institute, doctoral training expanded in new directions in 2010. Dr Gretchen Repasky was appointed as Coordinator of Research Training at the Institute and serves as the contact person for doctoral training. Several new PhD students joined FIMM research groups, bringing the total number of doctoral students at FIMM to over 35. FIMM celebrated the admission of many of these new students into the Helsinki Biomedical Graduate School (HBGS; Helsinki Bio- medical Graduate Programme HBGP as of 1 January 2012).

2010 was the inaugural year of the FIMM-EMBL PhD training initiative. PhD students recruited under this initiative spend the first 6—9 months engaged in research rotations with the aims of diver- sifying individual research training and building connections and collaborations within FIMM. At the end of this rotational period, students then select a research group, in mutual agreement with the group leader, in which to complete their PhD studies. To begin this training mechanism, a joint international call was placed with NCMM and MIMS in late 2009. In 2010, two exceptional students were recruited from a highly diverse international applicant pool. Saana Sandström, from Finland, and Muntasir Mamun Majumder, from Bangladesh, joined FIMM in August and after a week of ori- entation began their first rotation. Based on the initial success of this training plan, a second joint call was initiated at the end of 2010.

In addition to the FIMM-EMBL PhD training initiative, FIMM was engaged in several other aspects of doctoral training. For example, the three nodes of the Nordic EMBL Partnership joined forces in the preparation of an application, BIFROST, for a Marie Curie Initial Training Network. In addition, FIMM was involved in a joint application with HBGS to the Academy of Finland for doctoral programme funding: altogether 16 positions were granted for years 2012—2015 for HBGP-FIMM. Also, FIMM researchers offered several courses and lectures for doctoral and masters students, including courses on genomics, sequencing and cancer. There are plans for multiple courses to be developed and offered in the upcoming year.

26 FIMM FIMM celebrated the completion of six doctoral dissertations in 2010:

Juho Wedenoja “Molecular Genetics of Schizophrenia and Related Intermediate Phenotypes in a Founder Population”; supervisors: Leena Peltonen-Palotie, MD, PhD Professor, Research Director, FIMM and Anu Loukola, PhD, THL

Outi M. Palo “Genetic Background of Bipolar Disorder and Related Cognitive Impairments”; supervisors: Leena Peltonen-Palotie, MD, PhD Professor, Research Director, FIMM and Tiina Paunio, PhD, Adjunct Professor, THL

Timo Verneri Anttila “Identification Of Genetic Susceptibility Loci For Migraine”; supervisors: Aarno Palotie, M.D., Ph.D. Professor, FIMM and Maija Wessman, Ph.D. Docent, FIMM

Johannes Kettunen “Examination of Genetic Components Affecting Human Obesity-Related Quantitative Traits”; supervisors: Leena Peltonen-Palotie, MD, PhD Professor, Research Director, FIMM and Markus Pe rola, PhD, Research Professor, THL

Liisa Tomppo “The DISC1 Pathway in the Genetic Etiology of Schizophrenia”; supervisors: Leena Peltonen-Palotie, MD, PhD Professor, Research Director, FIMM, Jesper Ekelund, PhD, Associate Professor, THL and William Hennah, PhD, FIMM

Helena Kilpinen “Genetic Mechanisms Underlying Autism Spectrum Disorders”; supervisors: Leena Peltonen-Palotie, MD, PhD Professor, Research Director, FIMM and Iiris Hovatta, PhD, Docent, University of Helsinki

FIMM 27 VI. Technology Centre

Research Director Janna Saarela

he FIMM Technology Centre is a national and international research core unit Tproviding an extensive spectrum of biomedical research services. The FIMM Technology Centre currently operates seven core units with a total of 38 technology experts with diverse educational backgrounds being involved in the operations. The Technology Centre develops methods and offers services in the areas of high throughput genotyping, sequencing, chemical biology, bioinformatics and IT services using state-of-the-art technologies. During 2010 we also started setting up RNAi screening, metabolomics and translational research (serum and oligo- nucleotide arrays) technologies. The FIMM Technology Centre operates in close collaboration with several Biocenter Finland infrastructure networks and is a key national core unit involved in European ESFRI Infrastructures. In 2010 we completed over 100 projects serving or collaborating with tens of research groups from over 10 national and international universities and research institutes, as well as from two companies.

Genomics Unit

he Genomics Unit of FIMM Technology Centre offers high-throughput geno- Ttyping, gene expression, and DNA methylation analysis services for national and international researchers. The available platforms included Illumina’s iScan and BeadStation for all of the above mentioned applications, as well as Sequenom MassArray, Roche Light Cycler 480, Affymetrix GeneChip, and ABI 3730XL platforms for genotyping projects. During 2010 we introduced several new chip formats for the Illumina platform. In addition, our most important internal development projects aimed at further enhancing our quality assurance steps, including implementation of an electronic laboratory notebook for monitoring our laboratory workflow. Emphasis was also placed on strengthening our database tools for data handling and analysis. In 2011 our most important point of additional focus shall be on implementing new methodologies for epigenetic and gene regulation analysis. In 2010, the Genomics Unit produced approximately 839 million genotypes or gene expression data points on a total of 33926 samples, and carried out 37 collaborative projects with 24 group leaders from eight Finnish universities and research institutes. In addition to providing research groups with high quality and high-throughput laboratory services, the Genomics Unit offers expertise in project planning, data handling, and analysis. Besides research collaborations, the staff of the Unit is also active in its own research projects, especially in the genetics of complex traits, including e.g. IBD, migraine and diabetes, as well as the genetic structure of populations. Personnel:

Contact Person, Senior Researcher: Päivi Lahermo

Postdoctoral Researchers: Mari Kaunisto, Maarit Lappalainen (until 30 September 2010)

Senior Laboratory Technicians: Sirkka Ekström, Annika Korvenpää, Anu Yliperttula

Research Assistant: Mikko Siurala

Laboratory Engineer: Jouko Siro

28 FIMM VI. Technology Centre Sequencing Unit

he Sequencing Unit is a national and international service provider for next Tgeneration sequencing (NGS) and capillary sequencing services. The Sequenc- ing Unit has been operating in the NGS field with Illumina sequencing-by-synthesis technology since early 2008. The Unit receives support from Biocenter Finland as a part of the “Genome-wide methods” network. This year 2010 was one of rapid growth for the Sequencing Unit. Growing interest towards high throughput sequencing applications was apparent: 35 new projects involving 400 samples were launched in 2010 - a new project every second week. Two new NGS instruments were ordered in the beginning of 2010 to speed up the satu- rated sequencing capacity: a second Illumina GAIIx was installed in April 2010 and a Hiseq 2000 arrived just before the end of the year. Altogether over 919 GB of sequence was produced. The rapid evolvement of the technology was apparent in the laboratory; three Sequencing chemistry updates, three cluster amplification chemistry updates and three major software updates were introduced during the year. A year-long effort on optimization of the sample preparation methods was finalized in October also producing Maija Järvinen’s Master’s thesis: Optimization of sample preparation for next-generation sequencing with an Illumina Genome analyzer II. The most commonly requested services in 2010 were exome sequencing, custom targeted sequencing and bacterial genome sequencing. Transcriptome analysis re- quests were rapidly growing and Docent Pirkko Mattila was recruited as a Senior Researcher to set up RNA and microRNA sequencing methodologies. The first steps in the personalized medicine field were also taken. As a part of FIMM’s efforts in the personalized medicine field, the Sequencing Unit performed molecular profiling of Personnel: transcriptomes and exomes of the first leukaemia patient samples. The Unit has also been actively involved in developing commercial NGS reagent kits with international Contact Person, Head of Laboratory: vendors. In 2010 we participated in developing several transcriptome profiling kits Pekka Ellonen with leading vendors of the field. Senior Researcher: Pirkko Mattila

For targeted DNA sequencing applications a bioinformatics pipeline was devel- Senior Laboratory Technicians: Maija Lepistö, oped in collaboration with the Bioinformatics Unit. The FIMM Variant Calling Pipe- Sari Hannula

line (VCP) is a SAMtools compatible pipeline for analyzing SNPs, indels and larger Laboratory Analysts: Tiina Hannunen, structural variants from any re-sequencing experiment. The pipeline was used for Anna Kossila, Suvi Kyttänen analyzing more than 400 targeted or genomic libraries. The capillary sequencing laboratory had yet another successful year. More than >200 00 sequences were produced for over 200 researchers all across Finland.

FIMM 29 Metabolomics Unit

etabolomics, systematic identification and quantification of the metabo- Mlome, is a rapidly emerging area in the biomedical field, which aims to characterize the chemical fingerprint left by metabolomics processes. The FIMM Technology Centre in collaboration with Professor Matej Orešič’s group at VTT is setting up a Metabolomics Unit that will provide metabolomics services for national and international research groups. The Unit will perform quantitative targeted metabolomics analyses in a high throughput manner. During 2010 the key activity was the evaluation process to select an instrument and robot suitable for the planned targeted metabolite profiling for medical applications. The new Waters Xevo TQ-S triple quadrupole mass spectrometer (UPLC-MS/ MS system) was selected as the most suitable instrument for that purpose, together with a metabolomics robot system from Hamilton Robotics. The Waters mass spec- Personnel: trometer, which was purchased with financial support from Biocenter Finland, arrived just before the end of the year and is currently being installed. Contact Person, Coordinator: Jean-Christophe Yorke (as of January 2011) The robot was ordered in January 2011 and the system is expected to have been set up by summer 2011. A list of interesting metabolites has been compiled and the set- Senior Researcher: Vidya Velagapudi up of the methods will continue during 2011. The unit will develop analytical methods that will cover over 100 metabolites across multiple functional classes.

30 FIMM RNAi Unit

he FIMM Technology Centre RNAi Unit has a state-of-the-art infrastructure Tfor microarray based screening. This platform is based on an Aushon high- throughput microarrayer and an Olympus ScanR high-content imaging system. The applications include cell spot microarray siRNA screening, high content screening including image analysis and microarray printing. The cell microarray technology is an exciting new high throughput, high content, genome-scale RNAi screening analysis system on a cell spot array platform, and FIMM is developing this technology together with Professor Olli Kallioniemi’s group and the VTT Technical Research Centre of Finland. The goals of the unit include developing siRNA screening on this platform as well as development and services for oligo, serum, and protein microarray printing. The set up of the RNAi Unit was started in January 2010 when Dr. Gretchen Re- pasky joined the Unit. The staff expanded when Senior Laboratory Technician, Ruu- Personnel: su-Maaria Merivirta joined the Unit in June and when Dr. Carina von Schantz-Fant Contact Person, Postdoctoral Researcher: Carina joined the Unit in August. The RNAi Unit receives support from Biocenter Finland as von Schantz-Fant a part of the “Genome-wide methods” network. Senior Researcher: Gretchen Repasky The first project of the Unit was initiated in March 2010. Since that time the unit Senior Laboratory Technician: has acquired more than 10 projects. Ruusu-Maaria Merivirta

FIMM 31 Chemical Biology Unit

he Chemical Biology Unit of the Technology Centre is focused on assay devel- Topment and high throughput screening in plate-based formats. It is designed to operate as a local, national and with time an international research infrastructure. The Chemical Biology Unit receives support from Biocenter Finland as a part of the “Drug Discovery and Chemical Biology” network and participates as the Finnish partner in the recently initiated EU-OPENSCREEN ESFRI preparatory phase project. The Unit provides screening services of many types, including molecular probe discovery, screening of large chemically diverse libraries, biological profiling screening using libraries of known bioactive substances, drug repositioning and personalized medicine screening using approved and investigational drugs, and genetic screens using siRNA libraries. The Unit manages two screening laboratories, one Personnel: self-service facility that contains the equipment to perform small chemical and genetic screens on a largely manual basis and one fully automated state-of-the-art HTS Contact Person, PI: Krister Wennerberg system that can process more than 100 000 data points per day. Both facilities are set Postdoctoral Researcher: Jani Saarela up to handle cell-based and biochemical screens. To support the use of the screen- Coordinators: Maxim Bespalov, ing facilities, the unit maintains a chemical collection of 120 000 compounds and a Laura Turunen genome-wide collection of siRNAs. Assay Developer: Evgeny Kulesskiy In 2010, the automated screening system was made fully operational and the first Bioinformatician: Samuli Eldfors complete screens were performed. Acknowledging that a major bottleneck for suc- Senior Laboratory Technician: Anna Lehto cessful high throughput screening and molecular probe discovery is assay development, we established an assay development laboratory within the unit where we can assist users in their development and optimization of assays towards high density formats such as 384- or 1536-well plates. Two PhD level assay development experts were recruited to support the operations. A high end plate reader was purchased for use as a screening backup, assay development and common equipment reader within the institute. We also acquired a controlled chemical storage system and a chemical and screening database management software solution to allow better recording, storing and analysis of our chemical collections and screening results.

32 FIMM Bioinformatics, Data Management and IT-support Unit

he explosion in scale and the need for computational analysis of biomedical Tresearch data has been axiomatic for some years. Next-generation sequencing technologies are now exacerbating the exponential growth of raw data in the biomedical sciences. Sequencing technology vendors initially concentrated on developing the sequencing technology itself, leaving it largely up to the end users to engineer solutions for extracting information, and ultimately meaning, from the masses of data generated.

Bioinformatics

Much of our recent bioinformatics work has gone into managing the increasingly voluminous amounts of data produced by next generation sequencing. The most typical use case of NGS during 2010 is aimed at identifying genetic variants in exons, or another area of interest in the genome. The underlying research Personnel: questions ranged from fine mapping regions identified by genome-wide asso- Contact Person, Bioinformatics: Dr Imre Västrik ciation analyses, to finding causative disease mutations. As such, the tasks at Contact Person, Data Management: hand entailed not only identifying the variants, but providing a plethora of addi- Senior Researcher Juha Muilu tional information, such as: the homo/heterozygous status of the variant; its lo- Contact Person, IT-support and High performance cation in relation to the protein coding sequence; its effect on protein sequence; computing: IT Designer Timo Miettinen and occurrence of the variant in other populations. To this end, our bioinforma- Postdoctoral Researcher: Daniel Nicorici ticians have developed a Variant Calling Pipeline in collaboration with the NGS Bioinformaticians: Henrikki Almusa, team and researchers. In addition to identifying and providing information on Samuli Eldfors, Päivi Rosenström single nucleotide variants, the pipeline reports small insertions and deletions Information System Specialist: and large homozygous deletions, as well as other large structural anomalies. Kyösti Sutinen We have also set up a database of new genetic variants identified in the se- IT Designers: Jani Heikkinen, Anne Leinonen, quencing projects. This enables cross-checking a variant for prior identification Teemu Perheentupa, Tomi Simonen, and, depending on the circumstances, possibly excluding it from the list of sus- Kari Tuomainen picious variants. The sample and project related information is kept confidential IT Specialist: Myles Byrne and will not be released to other research groups. While contributing to this da- System Analyst: Hannu Turunen tabase is voluntary for NGS clients, the benefits provided by the database should motivate broad participation.

Data Management

Production of genome wide association (GWA) data is expensive and time con- suming - for this reason there is high demand for data reuse. To address this need, we have developed a GWA database as part of the Nordic Center of Excellence in Disease Genetics programme activities (http://www.nordicdb.org). This database contains harmonized allele frequencies and high, dense genome wide SNP data for 6000 control samples from Denmark, Estonia, Finland and Sweden. This data is made available after a board review process, and access is granted via the Euro- pean Genome-phenome Archive (http://www.ebi.ac.uk/ega), a high security delivery channel. The Database group has been involved in developing database infrastructures in three EU programmes. Data integration strategies are developed by the BBMRI for European biobanking (http://www.bbmri.eu), in conjunction with local biobanking developments. This year saw the start of a pilot study, where 14,000 samples from THL were harmonized using standard vocabularies. The dataset was made available using the SAIL application developed as a part of the ENGAGE data coordination activity (http://www.euengage.org), led by Dr. Maria Krestyaninova. Another infrastructure development activity in 2010 was the development of the VarioML data exchange standard and semantic framework for locus-specific variation databases (http://www.varioml.org). This work was done in the Gen- 2Phen consortium (http://www.gen2phen.org), with the goal of unifying human- and model-organism genetic variation databases, and developing a holistic service infrastructure for data integration.

FIMM 33 IT-support and High performance computing

FIMM’s computing infrastructure has been designed for scalability and flexibility utilizing the latest virtualization and scale-out storage technologies, to enable us to meet the rapidly increasing capacity and performance demands of data- intensive research. FIMM’s data center facilities in Meilahti include two separate server rooms with a 100kW electricity and cooling capacity. In addition to a Linux cluster the IT infrastructure of FIMM consists of more than hundred virtual and physical servers hosting various bioinformatics applications and databases. In 2010, FIMM and the CSC-IT Center for Science Ltd. successfully piloted a hybrid cloud computing environment for biomedical research, as part of the Bio- medinfra project. The local computing environment, consisting of a small Linux cluster of 250 processors and an IBM GPFS scale-out file system, was expanded using the CSC cloud platform, quadrupling the FIMM computational capacity available for researchers to ~1000 processors. The connection between CSC and FIMM data centers was implemented using a dedicated high-speed (10 Gigabit) optical link, which can be upgraded in future if necessary. Also in 2010, FIMM’s storage infrastructure was upgraded to meet the massive growth in demand. Existing file systems and storage were migrated to the new EMC CX4-480 Storage Area Network system. The total storage capacity was increased by roughly 30% and will need to expand even more in 2011.

34 FIMM VII. Biobank

Biobank — A resource to facilitate research, diagnostic development and personalized medicine

rofessionally collected, comprehensive collections of biological samples from Phealthy individuals and patients as well as clinical and life-style follow-up data are enormously valuable resource for the development and implementation of personalized medicine. Readily accessible, high-quality biobanks with transpar- ent access policies will pave the way towards translational research and benefits to researchers, patients and health care providers and society at large. The potential is enormous and the opportunity to realize this exists on the Meilahti Campus if the key players can be brought together to collaborate. The long tradition of biobanking of the National Institute for Health and Welfare (THL), diagnostic patient samples and excellent clinical data from the Hospital District of Helsinki and Uusimaa (HUS), world-class medical science of the University of Hel- sinki, combined with the genomics, systems biology and bioinformatics expertise of FIMM, could make the Meilahti Campus into a major global biobanking center. Developing the biobanking operations on the Meilahti Campus was started in 2009—2010 and has been led by FIMM, with the support from the Steering Group chaired by the Vice Rectors of the University of Helsinki, first by Professor Matti J. Tik- kanen and subsequently by Professor Kimmo Kontula. The goal is to build and maintain, in collaboration with THL, centralized biobanking operations with national and Personnel: international links that both offer biobanking services to researchers, but also active- Coordinator: Kimmo Pitkänen ly promote the collection of new sample and data resources for high impact research Information System Specialist: Kyösti Sutinen and personalized medicine. Senior Laboratory Technician: Siv Knaappila Towards a state-of-the-art biobanking facility on the Meilahti Project Coordinator: Tiina Vesterinen Campus

In 2010, the build-up of the Meiahti Campus biobanking facility got a major boost from the funding of the Biomedinfra.fi consortium and the formation of the national BBMRI.fi network. Construction of new biobanking activities will be done together with other major centres in Finland and will benefit the Finnish biobanking community. We aim to build services, best practices, standardized procedures and national databases that help both domestic and international networks. At the end of 2010, the FIMM biobanking facility included a liquid nitrogen based sample storage system for 415 000 samples with a laboratory information system, standardized work flow and dedicated personnel. In 2010, the first collaborations on sample storage were initiated, including a collection of 215 000 cancer patients’ serum samples. Tissue microarray (TMA) and molecular pathology services, including preparation of TMA blocks and design of new study set-ups, are also up and running, coupled with a digital microscopy and image analysis facility. In 2011, we will see a major step towards campus level biobanking as the biobanking activities of the THL Public Health Genomics unit and FIMM will be brought together under one roof. The services will experience a major upgrade as fully automated sample storage and processing infrastructures will be installed on the FIMM premises.

FIMM 35 BBMRI.FI: National biobanking collaboration

BBMRI.FI is a Finnish collaborative network of scientists, clinicians, institutions and hospitals interested in the biobanking of samples from the healthy population and patients. It is being led by Dr. Anu Jalanko from THL (with steering from Professor Eero Vuorio) and will engage in a major effort to harmonize biobanking practices in Finland and to bring the large number of existing cohorts increasingly available for research purposes. The biomedinfra funding recently acquired together with FIMM,THL and CSC serves this purpose well.

Personalized medicine research and clinical biobanking

Another major effort in 2010 was the design and launch of the Finnish Hematology Registry and Biobank project (the FHRB, http://hematology.fi/fhrb) which is a joint project between the Finnish Hematology Association (Professor Kimmo Porkka and a nation-wide clinical collaborator network), the Finnish Red Cross Blood Service, and FIMM. The principal aim of the project is to establish a systematic nation-wide collection of biological samples and related clinical data from leukaemias in a format that is readily accessible for both the clinicians and researchers. The project received ethical approval in October 2010, and bone marrow, peripheral blood, plasma, serum, and cell samples will now be collected from all acute myeloid leukaemia (AML) patients, coupled with comprehensive clinical and follow-up data. The project will eventually involve all Finnish hospitals active in the diagnostics and care of patients with AML. A biobanking fee will be established and paid for as part of the routine health care costs for leukaemia. Increasingly, there is not only a research need to build biobanks, but also a clinical need to store samples from cancer patients for possible future use if the cancer recurs and treatment decisions need to be made based on availability of new diagnostic data and new drugs. At the same time, we will make use of the biobank to advance personalized medicine, as explained earlier in this report (V Research) During 2011, FIMM aims to initiate similar research and clinical biobanking collaborations in other indication areas.

36 FIMM National and International Infrastructure Projects

Biocenter Finland Infrastructure Networks Biocenter Finland infrastructure networks were set up to coordinate, integrate and restructure the significant infrastructure and expertise in biomedical research existing in Finland and make the newest technologies and know-how available to the scientific community to enable world class research and to facilitate the transfer of academic discoveries to clinical application. FIMM research groups and the Technology Centre were involved in six Biocenter Finland infrastructure networks: Bio- informatics (Imre Västrik); Genome-Wide Methods (Janna Saarela); Translational technologies: Drug Discovery and Chemical Biology (Olli Kallioniemi and Krister Wennerberg) and Biobank (Johan Lundin); Metabolomics (Vidya Vegalapudi); Emerg- ing technologies: LentiGEMM (Emmy Verschuren and Sergey Kuznetsov). Internationally peer reviewed funding channelled through the Biocenter Finland infrastructure networks has significantly improved capabilities to update existing infrastructure platforms and to set up novel platforms.

Biomedinfra Biomedinfra is the consortium three Finnish organiza- and attractive as a site for the best researchers and thriv- tions active inplanning and development of pan-Europe- ing companies. ESFRI planning was initiated in 2008, and an research infrastructures for biomedical sciences as part progressed to the development of the first European and of the European Strategy Forum on Infrastructure (ESFRI) national roadmaps, legal structures and host country selec- initiative. ESFRI initiative aims to improve research infra- tions. structures to make the EU more competitive, collaborative

Steering group

Biobanks Clinical & lifestyle data THL Molecular profiling results

FIMM Biomedinfra.fi IT-solutions Bioinformatics Knowledge mining CSC

Risk models & estimates National research Diagnostics development infrastructure Personalised medicine

Figure 2. Biomedinfra consortium of three Finnish organizations, FIMM/University of Helsinki, CSC and THL, active in planning and development of pan-European research infrastructures BBMRI, EATRIS and ELIXIR. FIMM joined Biocenter Finland (BF) in 2010.

FIMM 37 FIMM has directly or via partners been involved in three • Translational infrastructures for diagnostics and person- biological and medical sciences ESFRIs: alised medicine in cancer (EATRIS) • Biobanks and Biomolecular Resource Infrastructure (BBMRI, with THL as the national partner) As a result of Biomedinfra consortium’s coordinated ef- • European Life Science Infrastructure for Biological infor- forts Finland now has a broad-based BBMRI.FI national net- mation (ELIXIR, with CSC - IT Center for Science Ltd as work encompassing representatives from THL, most univer- the national contact point), and sity hospital districts as well as FIMM that has created a • European Advanced Translational Research InfraStructure plan for nationwide biobanking operations. A cloud com- in Medicine (EATRIS, with FIMM as a coordinator). puting interface to CSC’s computational resources was implemented as an exciting pilot project and has doubled the At the beginning of 2010 CSC, THL and FIMM/University capacity of FIMM’s compute cluster to deal with massive of Helsinki signed a Memorandum of Understanding (MoU) genomic datasets. Personalised medicine operational proce- and formed the Biomedinfra consortium. Biomedinfra de- dures were created and are refined in pilot projects for can- cided to build on existing strengths and concentrate on are- cer patient samples. as where the infrastructure initiatives can support each oth- Biomedinfra consortium members also continued to er. Biobank samples with associated clinical/lifestyle data play an active and visible role in each respective ESFRI at the and bioinformatics capabilities to analyse the genome-wide European level. Collaboration plans across the ESFRI efforts data form an excellent base to develop diagnostic biomark- were initiated in the EU level recently, and hence the exist- ers and personalised medicine, thus making actual the cen- ing collaborative approach is now implemented elsewhere. tral idea to integrate these three infrastructures in a logical way. This is also an area where discoveries in basic research are expected to be rather quickly translated into concrete benefits for patients. The Biomedinfra consortium initiated the pilot phase of the infrastructure planning and development of pilot capabilities. Specifically the goals were to: • Initiate national planning for coherent biobanking operations (BBMRI) • Develop systems for harmonising data from different collections and a database aggregating such data (BBMRI) • Run a cloud computing pilot and establish fast network access to enable researchers to match their computational capacity with the exponentially growing datasets (ELIXIR)

EU-OPENSCREEN

In November 2010, EU-OPENSCREEN, the European Infra- velopment of novel screening technologies and mechanisms structure of Open Screening Platforms for Chemical Biology, for acquisition to build the platform of screening facilities. an ESFRI Roadmap 2008 project, began the three-year pre- In the current preparatory phase, the network contains 13 paratory phase to integrate European resources for chemical partner institutes/institutions representing 12 European biology. The project ultimately aims to provide world-class countries. FIMM is the partner representing Finland in the platforms for high throughput screening, shared chemical network. More information about the project can be found libraries, resources for hit discovery and optimization, bio- at www.eu-openscreen.eu. Contact people at FIMM are Kris- and cheminformatics support, and open access to screen- ter Wennerberg and Gretchen Repasky. ing results, protocols, and chemical information, for use by European academic and SME researchers in various fields. FIMM leads the Technology Resources work package which aims to establish a map of open screening facilities in Eu- rope, develop an agreement on the design of a distributed structure for screening activities, plan for the physical con- EU-OPENSCREEN struction of screening infrastructure, and monitor the de- ESFRI ROADMAP 2008

38 FIMM VIII. Administration Unit, Board and Scientific Advisory Board (SAB)

he FIMM Administration Unit is currently composed of seven people, who Administration Unit: Tsupport the Director in the management and development of the Institute. Olli Kallioniemi, Director, Professor The Administrative Manager of FIMM is Reetta Niemelä, who is also secretary of the Board of FIMM. The Unit also includes staff responsible for financial and per- Reetta Niemelä, Administrative Manager sonnel issues. Other administrative functions, such as legal, innovation and project funding services, are provided by the University of Helsinki. Riitta Alatalo, Department Secretary The rapid growth of the Institute, both in terms of the number of new people Riitta Koskinen, Financial Planning as well as new projects and other initiatives, as well as the first year of the new Officer University system led to a very challenging and intensive year for the administra- Marja Medina, Financial Manager tion in 2010. The Administration Unit was closely involved in the planning and (as of 1 December 2010) implementation of the events mentioned in this report. Drs Kimmo Pitkänen and Sirpa Nummila, Planning Officer Imre Västrik, Project Coordinators Sari Kivikko and Huei-Yi Shen, Laboratory En- (until 21 October 2010) gineer Jouko Siro and Office Assistant Outi Wagner contributed in many ways to Susanna Rosas, Personal Assistant the work of the Unit. to Director Kallioniemi The new Board of FIMM chaired by Vice Rector, Professor Kimmo Kontula start- Virve Tiusanen, Senior Laboratory ed its term on 1 July 2010. The Board of FIMM steers and supervises the Institute’s Technician activities by approving the finances, strategic plans and objectives (Figure 1). The Scientific Advisory Board (SAB) comprised of six internationally recognised experts assesses the Institute’s activities and quality of research and provides the Board with recommendations on these matters. The Chair of the SAB is Professor Kai Simons. The Steering Group of the Institute meets every month and is composed of all the principal investigators and the people responsible for the Technology Cen- tre’s Units and the Biobank, as well as key administrative personnel. The Steering Group discusses important issues that need opinions such as equipment, joint initiatives, training and recruitments.

Scientific Advisory Board (SAB) 1 May 2007–30 April 2012 Professor Kai Simons (Chair) Max-Planck-Institute of Molecular Cell Biology and Genetics (DE) Professor Cornelia van Duijn, Erasmus University Medical Center (NL) Professor Carl-Henrik Heldin, Ludwig Institute for Cancer Research, Uppsala Uni- versity (SE) Professor Eric S. Lander, The Broad Institute of MIT and Harvard (USA) Professor Edison Liu, Genome Institute of Singapore (SG) Professor Nadia Rosenthal, EMBL, Monterotondo (IT)

FIMM 39 Board 1 July 2010 – 31 March 2014

Members (Deputy Members) Dean, Professor Risto Renkonen, Faculty of Medicine, University of Helsinki

(Professor Kalle Saksela, Haartman Institute, Faculty of Medicine, University of Helsinki)

Research Director, Professor Anna-Elina Lehesjoki, Neuroscience Center, University of Helsinki

(Research Director, Professor Irma Thesleff, Institute of Biotechnology, University of Helsinki)

Professor Kimmo Porkka, Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki

(Professor Annamari Ranki, Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki)

IT Designer Anne Leinonen, FIMM Technology Centre (personnel)

(Research Director Janna Saarela, FIMM Technology Centre (personnel))

Act. Medical Director, Chief Research Officer, Professor Lasse Viinikka, HUS

(Chief Administrative Physician, M.D., Ph.D, LL.D., MFPM, Assistant Professor Lasse Lehtonen, HUS)

Deputy Director General, Professor Juhani Eskola, National Institute for Health and Welfare (THL)

(Senior Researcher, Head of Public Health Genomics Unit, Anu Jalanko, THL)

Vice President, Professor, R&D Biotechnology, Anu Kaukovirta-Norja, VTT

(Technology Manager Kirsi-Marja Oksman-Caldentey, VTT)

Member of the Board Pekka Mattila, Strategic Centre for Health and Well-being, SalWe Oy (industry)

(CEO Saara Hassinen, Strategic Centre for Health and Well-being, SalWe Oy (industry))

Director, Professor Eero Vuorio, Biocenter Finland (BF)*

(Academy Professor Seppo Ylä-Herttuala, Biocenter Finland (BF))*

* FIMM joinded BF in November 2010 and Rector Thomas Wilhelmsson of the University of Helsinki appointed representatives of BF to the Board of FIMM in February 2011.

Permanent Expert Director, Professor Olli A. Jänne, Biomedicum Helsinki, University of Helsinki

40 FIMM IX. Selected Events in 2010

Group Leader meeting at EMBL in Heidelberg The EMBL arranged the first joint meeting for group lead- ties was offered to the Nordic group leaders. “This meeting ers and senior researchers on 14–15 January 2010 at the EMBL demonstrated the very high standards expected from our Main Laboratory in Heidelberg, Germany. Group leaders of science and gave a true meaning to our FIMM-EMBL title”, the three Nordic nodes – FIMM, MIMS and NCMM – present says Dr. Sergey Kuznetsov from FIMM. “Apart from the sci- ed their current research projects and future visions. A se- entific presentations, and the opportunity to talk to peers lection of top EMBL researchers presented their research to and establish collaborations, the meeting generated a lively the guests from the North. A tour through EMBL core facili- debate on topics as diverse as science,” say Dr. Denis Kainov.

FIMM Retreat The first FIMM Retreat was held from 9–10 June 2010 at Ki- sakallio Sports Institute. About 50 FIMM people, including PIs, senior researchers, postdoctoral researchers, PhD students as well other personnel attended the event. In an en- thusiastic succession of three minute-long presentations, meeting participants had a chance to get to know each other a little better and paint an essential social and scientific portrait of each of their colleagues. The official part of the retreat culminated with an inspiring lecture by FiDiPro Pro- fessor Jonathan Knowles followed by recreational activities and an evening dinner with karaoke at the restaurant near a picturesque lake. On the morning of the second day the FIMM Technology Centre activities were represented to research groups and the rest of this day was reserved for the TC experts to plan the future TC operations.

FIMM 41 Nordic Molecular Medicine Network (NMMN) FIMM Seminars Meeting in Lycksele FIMM seminars were launched at the fall 2009 with the in- NordForsk supports the Nordic EMBL Partnership for Mo- itial intention to introduce FIMM group leaders and their lecular Medicine to promote sustainable long term col- projects. Also the members of the FIMM National Network laboration and exchange between the three Nordic nodes for Molecular Medicine were invited to give a seminar. From FIMM, NCMM, MIMS and EMBL. The first network meeting 2010 the FIMM seminars scope was broadened and FIMM was held in Umeå/Lycksele, Sweden, from 29 August to 1 postdocs and students, as well Technology Centre research- September 2010. There were altogether 88 participants and ers have been presenting their on-going work. FIMM semi- the meeting was an opportunity for all the research groups nars have provided a fruitful environment for the institute within the Nordic nodes to get an overview of the on-going people to get together and exchange ideas. research, available infrastructure and core facilities within the Nordic EMBL Partnership for Molecular Medicine. Post- ers were presented by group leaders, postdoctoral research- Jonathan Knowles’ Inauguration Lecture ers, and PhD students representing each research group. In FiDiPro Professor Jonathan Knowles’ Inauguration Lecture addition, postdoctoral researchers and PhD student present- entitled “Personalised therapy for all patients: future vi- ed their specific research projects in short talks. According sion or immediate necessity?” on 4 October was given to a to Dr. Gretchen Repasky this meeting provided an excellent full audience in the Biomedicum Helsinki 1 lecture hall. The opportunity to make research and technology connections Chancellor of the University of Helsinki, Professor Ilkka Ni- among the nodes as well as a forum for students and post- iniluoto appointed Jonathan Knowles FiDiPro Professor in doctoral researchers to present their projects at an interna- Personalised Medicine. tional venue.

42 FIMM A spring day at Nuuksio National Park The FIMM Entertainment committee arranged a recreation day at Nuuksio National Park on May 27. Almost 70 people from FIMM went to the beautiful Nuuksio forests to hear a small presentation about the park, to hike and to grill sau- sages on a campfire.

FIMM Christmas party This year the Christmas party was arranged in Party Hall Pohjanhovi at restaurant Domus on November 26. About 80 people attended the Christmas dinner where DJs played mu- sic and there were oriental dancing performances.

FIMM Entertainment Committee 2010: Anna Lehto, Riitta Alatalo, Minna Suvela, Laura Turunen, Outi Wagner, Anu Yli- perttula.

FIMM 43 X. FIMM in Figures

Financial Report

7 %

7 % Basic funding (including University of Helsinki fund)

33 % Basic funding (including University of HelsinkiStrategic fund) funding Strategic funding

CompetitiveCompetitive external funding external funding

Service revenue (external)

ServiceService revenue (internal)revenue (external) 3 % 50 % Service revenue (internal)

Figure 3. Total funding of FIMM in 2010 (11,0 M€), divided based on the source of income. The basic and strategic funding refer to the support from the University of Helsinki. External funding refers to competitive research and infrastructure funding.

13 % 23 % Biocenter Finland 1 % Biocenter Finland Academy of Finland (including ESFRI) 7 % TEKES Academy of Finland (including ESFRI) EU funding

Other public funding (including THL, HUS, City of Helsinki) FoundationsTEKES Other international funding

EU funding 19 % Other internationalOther funding public funding (including THL, Service revenue (external) HUS, City of Helsinki) Service revenue (external) 23 % Foundations

9 % 5 %

Figure 4. Distribution of FIMM external funding 2010 (6,3 M€) according to source.

15 %

Personnel costs 44 % Personnel costs Facilities 13 % Facilities Consumables Consumables

EquipmentEquipment

ServicesServices andand other other costs costs 18 %

10 %

Figure 5. FIMM expenditure 2010.

44 FIMM 175 150 125 100 75 50 25 0 2007 2008 2009 2010 2011

Figure 6 X. FIMM in Figures

4th level (professors and research directors)

Personnel Statistics 3rd level (research coordinators, senior researchers)

2nd level (post-doctoral researchers)

175 1st level (project researchers, doctoral 150 students,research assistants) Support personnel for teaching and 125 research

100 Administrative personnel 75 Others (IT personnel) 50 25 0 2007 Figure 8 2008 2009 2010 2011

FigureFigure 6. 6Total number of FIMM employees 2007—2010, estimate 2011.

Figure 4

11 Research personnel 5 4th level (professors and research Researchdirectors) personnel

3rd levelSupport (research personnel coordinators, for research Supportsenior personnel researchers) for research EU funding

32 175 2nd level (post-doctoral researchers) Administrative personnel 150 Administrative personnel Other international funding 125 77 1st level (project researchers, doctoral 100 Othersstudents,research (IT personnel) assistants) 75 Service revenue (external) 50 SupportOthers personnel (IT for personnel) teaching and Figure 5 25 research 0 2007 2008 2009 2010 2011 Figure 7 Administrative personnel Figure 7. Number of FIMM personnel according to the type of employment Figure 6 Others (IT personnel)

4th level (Professor and Research Directors) Figure 8 3rd level (research coordinators, 4 % 4th level (professorssenior and researchers) research 9 % directors) 4 % 3rd level (research2nd coordinators,levvel (post-doctoral researchers) 19 % senior researchers)

2nd level (post-doctoral researchers) 1st level (project researchers, doctoral 1st level (projectstudents, researchers, researchdoctoral assistansts) Figure 4 students,research assistants)

26 % Support personnel for teaching and research Support personnel for teaching and 9 % research Administrative personnel

Others (IT personnel)Administrative personnel

29 % Others (IT perrsonnel)

Figure 8 Figure 8. Distribution of FIMM personnel by category of employment

Research personnel FIMM 45 Figure 4

Support personnel for research

Administrative personnel

Others (IT personnel)

Research personnel Figure 5

Support personnel for research

Figure 7 Administrative personnel

Others (IT personnel)

Figure 5

Figure 7 Nationalities represented among FIMM personnel:

Bangladesh Pakistan

Cameroon Portugal

China Romania

Estonia Russia

Finland Slovenia

France Sweden

Germany Taiwan

Great Britain Trinidad & Tobago

Italy Uganda

The Netherlands USA

46 FIMM Personnel including researchers and students with grants and Members of the FIMM National Network for Molecular Medicine

Research groups Emma Nyman Maxim Bespalov Sirpa Nummila Anne Nyrhinen Myles Byrne (until 21.10.2010) Leena Peltonen-Palotie Olli Pietiläinen Niina Eklund Susanna Rosas (Members of Group Kaisa Silander Sirkka Ekström Virve Tiusanen Peltonen-Palotie continue Minna Suvela Samuli Eldfors in other FIMM groups) Maija Wessman Pekka Ellonen FIMM Clinical Anne Vikman Sari Hannula Collaborators Denis Kainov Tiina Hannunen Tuomas Mirtti Maria Anastasina Samuli Ripatti Sampsa Hautaniemi Kirsi Pietiläinen Andrey Golubtsov Johannes Kettunen Jani Heikkinen Jakob Stenman Minttu Kaloinen Maria Krestyaninova Mari Kaunisto Alun Parsons Marine Largeau Annika Korvenpää Members of the FIMM Puwei Yuan Pirkka-Pekka Laurila Anna Kossila National Network for Mari Rossi Evgeny Kulesskiy Molecular Medicine Olli Kallioniemi Antti-Pekka Sarin Suvi Kyttänen Lauri A. Aaltonen Henrik Edgren Huei-Yi Shen Päivi Lahermo Kari Alitalo Sara Kangaspeska Jarkko Soronen Maarit Lappalainen Akseli Hemminki Sami Kilpinen Ida Surakka (until 30.9.2010) Iiris Hovatta John Patrick Mpindi Emmi Tikkanen Anna Lehto Elina Ikonen Astrid Murumägi Taru Tukiainen Anne Leinonen Sirpa Jalkanen Kalle Ojala Maija Lepistö Heikki Joensuu Teijo Pellinen Janna Saarela Pirkko Mattila Jaakko Kaprio Khalid Saeed Eveliina Jakkula Ruusu-Maaria Merivirta Heli Nevanlinna Saana Sandström Virpi Leppä Timo Miettinen Matej Orešicˇ Katja Välimäki Annu Näkki Juha Muilu Taina Pihlajaniemi Maija Wolf Anna-Maija Sulonen Daniel Nicorici Jussi Taipale Teemu Perheentupa Willem de Vos Jonathan K. C. Knowles Joseph D. Terwilliger Gretchen Repasky Anu Wartiovaara Caroline Heckman Tero Hiekkalinna Päivi Rosenström Jukka Westermarck Alun Parsons Jani Saarela Emmy Verschuren Tomi Simonen Adjunct Personnel Sergey Kuznetsov Danielle Bansfield Jouko Siro Taru Muranen Xiaofeng Dai Sonja Koopal Mikko Siurala Juba Raj Pokhanel Yuexi Gu Jenni Lahtela Kyösti Sutinen Antti Poso Sonja Koopal Ashwini Nagaraj Kari Tuomainen Päivi Tuomaala Pauliina Munne Rita Matos Hannu Turunen Annabrita Schoonenberg Nitai Peled Laura Turunen Summer Students Manuela Tumiati (until 31.8.2010) Vidya Velagapudi and Trainees Annabrita Schoonenberg Carina von Schantz-Fant Anni Honkimaa Johan Lundin Merja Särkioja Imre Västrik Susanne Hultsch Juho Konsti Krister Wennerberg Katariina Lassila Tiina Lehtimäki Krister Wennerberg Anu Yliperttula Rickard Rosas Nina Linder Arjan van Adrichem Jean-Christophe Yorke Ulla Tienhaara Mikael Lundin Tonge Ebai Brian Zhao Helene Rotkirch (until Leena Karhinen Biobank Infrastructure 30.6.2010) Gretchen Repasky Kimmo Pitkänen Riku Turkki Muntasir Mamun Elisa Moilanen (until Majumder 29.10.2010) Aarno Palotie Siv Knaappila Verneri Anttila Elisabeth Widén Kyösti Sutinen William Hennah Diana Cousminer Tiina Vesterinen Eija Hämäläinen Jaakko Leinonen Juha-Pekka Turunen Carita Jussila Elli Kempas FIMM Technology FIMM Administration Sari Kivikko Centre, including Olli Kallioniemi Leena Leikas infrastructure projects Riitta Alatalo Tiia Luukkonen Janna Saarela Riitta Koskinen Mikko Muona Henrik Alfthan Marja Medina Anne Nyberg Henrikki Almusa Reetta Niemelä

FIMM 47 XI. Publications by FIMM researchers 2010

A Comprehensive Panel of Three-Dimensional Models for A large replication study and meta-analysis in Europe- Studies of Prostate Cancer Growth, Invasion and Drug Re- an samples provides further support for association of sponses. / Harma, Ville ; Virtanen, Johannes ; Mäkelä, Rami AHI1 markers with schizophrenia. / Ingason, Andres ; Gieg- ; Happonen, Antti ; Mpindi, John-Patrick ; Knuuttila, Matias ling, Ina ; Cichon, Sven ; Hansen, Thomas ; Rasmussen, Hen- ; Kohonen, Pekka ; Lötjönen, Jyrki ; Kallioniemi, Olli ; Nees, rik B. ; Nielsen, Jimmi ; Juergens, Gesche ; Muglia, Pierandrea Matthias. In: PLoS One. 2010 ; Vol. 5, No. 5, ; Hartmann, Annette M. ; Strengman, Eric ; Vasilescu, Cat- alina ; Muehleisen, Thomas W. ; Djurovic, Srdjan ; Melle, In- A High-Throughput Screen for Chemical Inhibitors of Exo- grid ; Lerer, Bernard ; Moeller, Hans-Juergen ; Francks, Clyde cytic Transport in Yeast. / Zhang, Lisha ; Nebane, N. Mi- ; Pietiläinen, Olli P. H. ; Lonnqvist, Jouko ; Suvisaari, Jaana ; randa ; Wennerberg, Krister ; Li, Yujie ; Neubauer, Valerie ; Tuulio-Henriksson, Annamari ; Walshe, Muriel ; Vassos, Evan- Hobrath, Judith V. ; McKellip, Sara ; Rasmussen, Lynn ; Shindo, gelos ; Di Forti, Marta ; Murray, Robin ; Bonetto, Chiara ; To- Nice ; Sosa, Melinda ; Maddry, Joseph A. ; Ananthan, Subra- sato, Sarah ; Cantor, Rita M. ; Rietschel, Marcella ; Craddock, maniam ; Piazza, Gary A. ; White, E. Lucile ; Harsay, Edina. In: Nick ; Owen, Michael J. ; Peltonen, Leena ; Andreassen, Ole ChemBioChem. 2010 ; Vol. 11, . p. 1291-1301 A. ; Noethen, Markus M. ; St Clair, David ; Ophoff, Roel A. ; O’Donovan, Michael C. ; Collier, David A. ; Werge, Thomas ; A population-specific HTR2B stop codon predisposes to Rujescu, Dan ; Grp Investigators. In: Human Molecular Genet- severe impulsivity. / Bevilacqua, Laura ; Doly, Stephane ; Ka- ics. 2010 ; Vol. 19, . p. 1379-1386 prio, Jaakko ; Yuan, Qiaoping ; Tikkanen, Roope ; Paunio, Tii- na ; Zhou, Zhifeng ; Wedenoja, Juho ; Maroteaux, Luc ; Diaz, A map of human genome variation from population-scale Silvina ; Belmer, Arnaud ; Hodgkinson, Colin A. ; Dell’Osso, Lili- sequencing. / Altshuler, David L. ; Durbin, Richard M. ; Abeca- ana ; Suvisaari, Jaana ; Coccaro, Emil ; Rose, Richard J. ; Pel- sis, Goncalo R. ; Bentley, David R. ; Chakravarti, Aravinda ; tonen, Leena ; Virkkunen, Matti ; Goldman, David. In: Na- Clark, Andrew G. ; Collins, Francis S. ; De la Vega, Francisco M. ture. 2010 ; Vol. 468, No. 7327 , 01.01.2010. p. 1061-U460 ; Donnelly, Peter ; Egholm, Michael ; Flicek, Paul ; Gabriel, Sta- cey B. ; Gibbs, Richard A. ; Knoppers, Bartha M. ; Lander, Eric A Variant in LIN288 Is Associated with 2D : 4D Finger- S. ; Lehrach, Hans ; Mardis, Elaine R. ; McVean, Gil A. ; Nicker- Length Ratio, a Putative Retrospective Biomarker of Pre- son, DebbieA. ; Schafer, Alan J. ; Sherry, Stephen T. ; Wang, Jun natal Testosterone Exposure. / Medland, Sarah E. ; Zayats, ; Wilson, Richard K. ; Gibbs, Richard A. ; Deiros, David ; Metz- Tetyana ; Glaser, Beate ; Nyholt, Dale R. ; Gordon, Scott D. ; ker, Mike ; Muzny, Donna ; Reid, Jeff ; Wheeler, David ; Wang, Wright, Margaret J. ; Montgomery, Grant W. ; Campbell, Meg- Jun ; Li, Jingxiang ; Jian, Min ; Li, Guoqing ; Li, Ruiqiang ; Li- an J. ; Henders, Anjali K. ; Timpson, Nicholas J. ; Peltonen, ang, Huiqing ; Tian, Geng ; Wang, Bo ; Wang, Jian ; Wang, Leena ; Wolke, Dieter ; Ring, Susan M. ; Deloukas, Panos ; Wei ; Yang, Huanming ; Zhang, Xiuqing ; Zheng, Huisong ; Martin, Nicholas G. ; Smith, George Davey ; Evans, David M.. Lander, Eric S. ; Altshuler, David L. ; Ambrogio, Lauren ; In: American Journal of Human Genetics. 2010 ; Vol. 86, . p. Bloom, Toby ; Cibulskis, Kristian ; Fennell, Tim J. ; Gabriel, 519-525 Stacey B. ; Jaffe, David B. ; Shefler, Erica ; Sougnez, Carrie L. ; Bentley, David R. ; Gormley, Niall ; Humphray, Sean ; Kings- A combined analysis of genome-wide association studies bury, Zoya ; Koko-Gonzales, Paula ; Stone, Jennifer ; McKer- in breast cancer. / Li, Jingmei ; Humphreys, Keith ; Heikki- nan, Kevin J. ; Costa, Gina L. ; Ichikawa, Jeffry K. ; Lee, Clarence nen, Tuomas ; Aittomäki, Kristiina ; Blomqvist, Carl ; Pharoah, C. ; Sudbrak, Ralf ; Lehrach, Hans ; Borodina, Tatiana A. ; Paul D.P. ; Dunning, Alison M. ; Ahmed, Shahana ; Hooning, Dahl, Andreas ; Davydov, Alexey N. ; Marquardt, Peter ; Maartje J. ; Martens, John W.M. ; van den Ouweland, Ans M.W. Mertes, Florian ; Nietfeld, Wilfiried ; Rosenstiel, Philip ; ; Alfredsson, Lars ; Palotie, Aarno ; Peltonen-Palotie, Leena ; Schreiber, Stefan ; Soldatov, Aleksey V. ; Timmermann, Bernd Irwanto, Astrid ; Low, Hui Qi ; Teoh, Garrett H.K. ; Thalamuthu, ; Tolzmann, Marius ; Egholm, Michael ; Affourtit, Jason ; Ash- Anbupalam ; Easton, Douglas F. ; Nevanlinna, Heli ; Liu, Jian- worth, Dana ; Attiya, Said ; Bachorski, Melissa ; Buglione, Eli jun ; Czene, Kamila ; Hall, Per. In: Breast Cancer Research and ; Burke, Adam ; Caprio, Amanda ; Celone, Christopher ; Clark, Treatment. Epub 2010 Sep 26 Shauna ; Conners, David ; Desany, Brian ; Gu, Lisa ; Guccione, Lorri ; Kao, Kalvin ; Kebbel, Andrew ; Knowlton, Jennifer ; La- A bivariate survival model with compound Poisson frailty. brecque, Matthew ; McDade, Louise ; Mealmaker, Craig ; / Wienke, A. ; Ripatti, S. ; Palmgren, J. ; Yashin, A. In: Statis- Minderman, Melissa ; Nawrocki, Anne ; Niazi, Faheem ; Pare- tics in Medicine. 2010 ; Vol. 29, . p. 275-283 ja, Kristen ; Ramenani, Ravi ; Riches, David ; Song, Wanmin ; Turcotte, Cynthia ; Wang, Shally ; Mardis, Elaine R. ; Dooling, A genome-wide association scan on estrogen receptor- David ; Fulton, Lucinda ; Fulton, Robert ; Weinstock, George negative breast cancer. / Li, J ; Humphreys, K ; Darabi, H ; ; Durbin, Richard M. ; Burton, John ; Carter, David M. ; Rosin, G ; Hannelius, U ; Heikkinen, Tuomas ; Aittomäki, Kris- Churcher, Carol ; Coffey, Alison ; Cox, Anthony ; Quail, Mi- tiina ; Blomqvist, Carl ; Pharoah, PD ; Dunning, AM ; Ahmed, S chael ; Skelly, Tom ; Stalker, James ; Swerdlow, Harold P. ; ; Hooning, MJ ; Hollestelle, A ; Oldenburg, RA ; Alfredsson, L ; Turner, Daniel ; De Witte, Anniek ; Giles, Shane ; Gibbs, Rich- Palotie, Aarno ; Palotie, Leena ; Irwanto, A ; Low, HQ ; Teoh, ard A. ; Wheeler, David ; Bainbridge, Matthew ; Challis, Dan- GH ; Thalamuthu, A ; Kere, Juha ; D’Amato, M ; Easton, DF ; ny ; Sabo, Aniko ; Yu, Fuli ; Yu, Jin ; Wang, Jun ; Fang, Xiao- Nevanlinna, Heli ; Liu, J ; Czene, K ; Hall, P. In: Breast cancer dong ; Guo, Xiaosen ; Li, Ruiqiang ; Li, Yingrui ; Luo, Ruibang research. 2010 ; Vol. 12, No. 6 p. R93 ; Tai, Shuaishuai ; Wu, Honglong ; Zheng, Hancheng ; Zheng, Xiaole ; Zhou, Yan ; Yang, Huanming ; Marth, Gabor T. ; Gar- rison, Erik P. ; Huang, Weichun ; Indap, Amit ; Kural, Deniz ;

48 FIMM Lee, Wan-Ping ; Leong, Wen Fung ; Huang, Weichun ; Indap, Alexej ; Balasubramanian, Suganthi ; Bjornson, Robert ; Du, Amit ; Kural, Deniz ; Lee, Wan-Ping ; Leong, Wen Fung ; Quin- Jiang ; Grubert, Fabian ; Habegger, Lukas ; Haraksingh, Rajini lan, Aaron R. ; Stewart, Chip ; Stromberg, Michael P. ; Ward, ; Jee, Justin ; Khurana, Ekta ; Lam, Hugo Y. K. ; Leng, Jing ; Mu, Alistair N. ; Wu, Jiantao ; Lee, Charles ; Mills, Ryan E. ; Shi, Xinmeng Jasmine ; Urban, Alexander E. ; Zhang, Zhengdong ; Xinghua ; Daly, Mark J. ; DePristo, Mark A. ; Altshuler, David Li, Yingrui ; Luo, Ruibang ; Marth, Gabor T. ; Garrison, Erik P. L. ; Ball, Aaron D. ; Banks, Eric ; Bloom, Toby ; Browning, Bri- ; Kural, Deniz ; Quinlan, Aaron R. ; Stewart, Chip ; Stromberg, an L. ; Cibulskis, Kristian ; Fennell, Tim J. ; Garimella, Kiran V. Michael P. ; Ward, Alistair N. ; Wu, Jiantao ; Lee, Charles ; ; Grossman, Sharon R. ; Handsaker, Robert E. ; Hanna, Matt ; Mills, Ryan E. ; Shi, Xinghua ; McCarroll, Steven A. ; Banks, Hartl, Chris ; Jaffe, David B. ; Kernytsky, Andrew M. ; Korn, Eric ; DePristo, Mark A. ; Handsaker, Robert E. ; Hartl, Chris ; Joshua M. ; Li, Heng ; Maguire, Jared R. ; McCarroll, Steven A. Korn, Joshua M. ; Li, Heng ; Nemesh, James C. ; Sebat, Jona- ; McKenna, Aaron ; Nemesh, James C. ; Philippakis, Anthony than ; Makarov, Vladimir ; Ye, Kenny ; Yoon, Seungtai C. ; De- A. ; Poplin, Ryan E. ; Price, Alkes ; Rivas, Manuel A. ; Sabeti, genhardt, Jeremiah ; Kaganovich, Mark ; Clarke, Laura ; Pardis C. ; Schaffner, Stephen F. ; Shefler, Erica ; Shlyakhter, Smith, Richard E. ; Zheng-Bradley, Xiangqun ; Korbel, Jan O. ; Ilya A. ; Cooper, David N. ; Ball, Edward V. ; Mort, Matthew ; Humphray, Sean ; Cheetham, R. 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FIMM 59 Wareham, Nicholas J. ; Sladek, Robert ; Froguel, Philippe ; Wa- Sequence variants at CHRNB3-CHRNA6 and CYP2A6 af- tanabe, Richard M. ; Meigs, James B. ; Groop, Leif ; Boehnke, fect smoking behavior. / Thorgeirsson, Thorgeir E. ; Gudb- Michael ; McCarthy, Mark I. ; Florez, Jose C. ; Ines Barroso jartsson, Daniel F. ; Surakka, Ida Liisa ; Vink, Jacqueline M. MAGIC Investigators, Global BPgen Consortium, Procardis ; Amin, Najaf ; Geller, Frank ; Sulem, Patrick ; Rafnar, Tho- Consortium, GIANT Consortium, DIAGRAM Consortium. 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60 FIMM ; Chen, Wei ; Cornelis, Marilyn C. ; Couper, David ; Coviello, en, Kirsi H. ; Rissanen, Aila ; Salomaa, Veikko ; Ripatti, Sa Andrea D. ; d’Adamo, Pio ; de Faire, Ulf ; de Geus, Eco J. C. muli ; Yki-Järvinen, Hannele ; van Duijn, Cornelia M. ; Wich- ; Deloukas, Panos ; Doering, Angela ; Smith, George Davey mann, H. -Erich ; Kaprio, Jaakko ; Taskinen, Marja-Riitta ; ; Easton, Douglas F. ; Eiriksdottir, Gudny ; Emilsson, Valur ; Peltonen, Leena ; ENGAGE Consortium. In: PLoS Genetics. Eriksson, Johan ; Ferrucci, Luigi ; Folsom, Aaron R. ; Foroud, 2010 ; Vol. 6, No. 6:e100097. Tatiana ; Garcia, Melissa ; Gasparini, Paolo ; Geller, Frank ; Gieger, Christian ; Gudnason, Vilmundur ; Hall, Per ; Hankin- Variation in DISC1 is associated with anxiety, depression son, Susan E. ; Ferreli, Liana ; Heath, Andrew C. ; Hernan- and emotional stability in elderly women. / Harris, S. E. ; dez, Dena G. ; Hofman, Albert ; Hu, Frank B. ; Illig, Thomas ; Hennah, W. ; Thomson, P. 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Use of Cancer-Specific Genomic Rearrangements to Quan- tify Disease Burden in Plasma from Patients with Solid Tumors. / McBride, David J. ; Orpana, Arto ; Sotiriou, Chris- tos ; Joensuu, Heikki ; Stephens, Philip J. ; Mudie, Laura J. ; Hämäläinen, Eija ; Stebbings, Lucy A. ; Andersson, Leif C. ; Flanagan, Adrienne M. ; Durbecq, Virginie ; Ignatiadis, Mi- chail ; Kallioniemi, Olli ; Heckman, Caroline A. ; Alitalo, Kari ; Edgren, Sten Henrik Torstensson ; Futreal, P. Andrew ; Stratton, Michael R. ; Campbell, Peter J. In: Genes, Chro- mosomes & Cancer. 2010 ; Vol. 49, No. 11, . p. 1062-1069

Use of Genome-Wide Expression Data to Mine the “Gray Zone” of GWA Studies Leads to Novel Candidate Obesi- ty Genes. / Naukkarinen, Jussi ; Surakka, Ida ; Pietiläin-

FIMM 61 Publications by FIMM Molecular Medicine Network and adjunct researchers 2010

A longitudinal study on genetic and environmental influ- Bruxism is associated with nicotine dependence: a na- ences on leisure time physical activity in the Finnish Twin tionwide Finnish twin cohort study. Rintakoski K, Ahlberg Cohort Aaltonen S, Ortega-Alonso A, Kujala UM, Kaprio J.. J, Hublin C, Broms U, Madden PA, Könönen M, Koskenvuo M, Twin Res Hum Genet. 2010 Oct;13(5):475-81. Lobbezoo F, Kaprio J.. Nicotine Tob Res. 2010 Dec;12(12):1254- 60. A phase I/II trial of gefitinib given concurrently with radiotherapy in patients with nonmetastatic prostate cancer/ Calcium Gluconate in Phosphate Buffered Saline Increases Joensuu, Greetta ; Joensuu, Timo ; Nokisalmi, Petri ; Reddy, Gene Delivery with Adenovirus Type 5. / Ahonen, Marko T. Chandana ; Isola, Jorma ; Ruutu, Mirja ; Kouri, Mauri ; Kupe- ; Diaconu, Iulia ; Pesonen, Sari ; Kanerva, Anna ; Baumann, lian, Patrick A. ; Collan, Juhani ; Pesonen, Sari ; Hemminki, Marc ; Parviainen, Suvi T. ; Spiller, Brad ; Cerullo, Vincenzo Akseli. In: International Journal of Radiation: Oncology - Bi- ; Hemminki, Akseli. In: PLoS One. 2010 ; Vol. 5, No. 9, . p. ology - Physics. 2010 ; Vol. 78, No. 1,. p. 42-49 e13103

Adenoviral E4ORF3 and E4ORF6 proteins, but not E1B55K, Challenging the cumulative injury model: positive effects increase killing of cancer cells by radiotherapy in vivo. / of greater body mass on disc degeneration. / Videman, T ; Liikanen, Ilkka ; Dias, Joao D. ; Nokisalmi, Petri ; Sloniecka, Gibbons, Laura E. ; Kaprio, Jaakko ; Battie, Michele C. In: The Marta ; Kangasniemi, Lotta ; Rajecki, Maria ; Dobner, Thom- spine journal 2010 ; Vol. 10, . p. 26-31 as ; Tenhunen, Mikko ; Kanerva, Anna ; Pesonen, Sari ; Ah- tiainen, Laura ; Hemminki, Akseli. In: International Journal Claudin-like protein 24 interacts with the VEGFR-2 and of Radiation: 2010 ; Vol. 78, No. 4, . p. 1201-1209 VEGFR-3 pathways and regulates lymphatic vessel development. / Saharinen, Pipsa Ilona ; Heloterä, Hanna ; Miet- Adenoviruses with an alpha(v)beta integrin targeting tinen, Juho ; Norrmen, Camilla ; D Amico Lago, Gabriela Ve- moiety in the fiber shaft or the HI-loop increase tumor ronica ; Jeltsch, Michael ; Langenberg, Tobias ; Vandevelde, specificity without compromising antitumor efficacy in Wouter ; Ny, Annelii ; Dewerchin, Mieke ; Carmeliet, Peter ; magnetic resonance imaging of colorectal cancer metas- Alitalo, Kari. In: Genes Development. 2010 ; Vol. 24, No. 9, . tases. / Lavilla-Alonso, Sergio ; Bauerschmitz, Gerd ; Abo- p. 875-88 Ramadan, Usama ; Halavaara, Juha ; Escutenaire, Sophie ; Diaconu, Iulia ; Tatlisumak, Turgut ; Kanerva, Anna ; Hem- Common Breast Cancer Susceptibility Alleles and the minki, Akseli ; Pesonen, Sari. In: Journal of Translational Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Medicine. 2010 ; Vol. 8, . p. 80- Carriers: Implications for Risk Prediction. / Antoniou, An- tonis C. ; Beesley, Jonathan ; McGuffog, Lesley ; Sinilnikova, Adolescent risk factors for excessive alcohol use at age Olga M. ; Healey, Sue ; Neuhausen, Susan L. ; Ding, Yuan 32 years. A 16-year prospective follow-up study. Huurre T, Chun ; Rebbeck, Timothy R. ; Weitzel, Jeffrey N. ; Lynch, Hen- Lintonen T, Kaprio J, Pelkonen M, Marttunen M, Aro H.. Soc ry T. ; Isaacs, Claudine ; Ganz, Patricia A. ; Tomlinson, Gail ; Psychiatry Psychiatr Epidemiol. 2010 Jan;45(1):125-34. Olopade, Olufunmilayo I. ; Couch, Fergus J. ; Wang, Xianshu ; Lindor, Noralane M. ; Pankratz, Vernon S. ; Radice, Paolo ; Are Therea Sex Differences in the Genetic and Environ- Manoukian, Siranoush ; Peissel, Bernard ; Zaffaroni, Daniela mental Effects on Mental Rotation Ability?. / Vuoksimaa, ; Barile, Monica ; Viel, Alessandra ; Allavena, Anna ; Dall’Olio, Eero ; Viken, Richard J. ; Hokkanen, Laura ; Tuulio-Henriks- Valentina ; Peterlongo, Paolo ; Szabo, Csilla I. ; Zikan, Michal son, Annamari ; Rose, Richard J. ; Kaprio, Jaakko. In: Twin ; Claes, Kathleen ; Poppe, Bruce ; Foretova, Lenka ; Mai, Research and Human Genetics. 2010 ; Vol. 13, No. 5, . p. 437- Phuong L. ; Greene, Mark H. ; Rennert, Gad ; Lejbkowicz, 441 Flavio ; Glendon, Gord ; Ozcelik, Hilmi ; Andrulis, Irene L. ; Thomassen, Mads ; Gerdes, Anne-Marie ; Sunde, Lone ; Cru- Associations between IQ and cigarette smoking among ger, Dorthe ; Jensen, Uffe Birk ; Caligo, Maria ; Friedman, Swedish male twins Wennerstad KM, Silventoinen K, Eitan ; Kaufman, Bella ; Laitman, Yael ; Milgrom, Roni ; Du- Tynelius P, Bergman L, Kaprio J, Rasmussen F. Soc Sci Med. brovsky, Maya ; Cohen, Shimrit ; Borg, Ake ; Jernstroem, He- 2010 Feb;70(4):575-81. Epub 2009 Nov 20. lena ; Lindblom, Annika ; Rantala, Johanna ; Stenmark-Ask- malm, Marie ; Melin, Beatrice ; Nathanson, Kate ; Domchek, Breaking barriers in the genomics and pharmacogenet- Susan ; Jakubowska, Ania ; Lubinski, Jan ; Huzarski, Tomasz ics of drug addiction. Ho MK, Goldman D, Heinz A, Kaprio ; Osorio, Ana ; Lasa, Adriana ; Duran, Mercedes ; Tejada, Ma- J, Kreek MJ, Li MD, Munafò MR, Tyndale RF. Clin Pharmacol ria-Isabel ; Godino, Javier ; Benitez, Javier ; Hamann, Ute ; Ther. 2010 Dec;88(6):779-91. Epub 2010 Oct 27. Review. Kriege, Mieke ; Hoogerbrugge, Nicoline ; van der Luijt, Rob B. ; van Asperen, Christi J. ; Devilee, Peter ; Meijers-Heijboer,

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Comparison of Lipid and Fatty Acid Composition of the Evening types are more often current smokers and nic- Liver, Subcutaneous and Intra-abdominal Adipose Tissue, otine-dependent-a study of Finnish adult twins. Broms and Serum. / Kotronen, Anna ; Seppänen-Laakso, Tuulikki ; U, Kaprio J, Hublin C, Partinen M, Madden PA, Kosken- Westerbacka, Jukka ; Kiviluoto, Tuula ; Arola, Johanna ; Rus- vuo M. Addiction. 2011 Jan;106(1):170-7. doi: 10.1111/j.1360- keepää, Anna-Liisa ; Yki-Järvinen, Hannele ; Oresic, Matej. 0443.2010.03112.x. Epub 2010 Sep 30. In: Obesity. 2010 ; Vol. 18, No. 5, . p. 937-944 Evidence that BMI and type 2 diabetes share only a minor Composition and lipid spatial distribution of HDL parti- fraction of genetic variance: a follow-up study of 23,585 cles in subjects with low and high HDL-cholesterol. / Yet- monozygotic and dizygotic twins from the Finnish Twin ukuri, Laxman ; Soderlund, Sanni ; Koivuniemi, Artturi ; Sep- Cohort Study Lehtovirta M, Pietiläinen KH, Levälahti E, panen-Laakso, Tuulikki ; Niemela, Perttu S. ; Hyvonen, Marja Heikkilä K, Groop L, Silventoinen K, Koskenvuo M, Kaprio J.. ; Taskinen, Marja-Riitta ; Vattulainen, Ilpo ; Jauhiainen, Mat- Diabetologia. 2010 Jul;53(7):1314-21 ti ; Oresic, Matej. In: Journal of Lipid Research. 2010 ; Vol. 51, . p. 2341-2351 Examining the etiology of associations between perceived parenting and adolescents’ alcohol use: common genet- Decreased prevalence of left-handedness among females ic and/or environmental liabilities? Latendresse SJ, Rose with male co-twins: evidence suggesting prenatal testos- RJ, Viken RJ, Pulkkinen L, Kaprio J, Dick DM. J Stud Alcohol terone transfer in humans? Vuoksimaa E, Eriksson CJ, Pulk- Drugs. 2010 May;71(3):313-25. kinen L, Rose RJ, Kaprio J. Psychoneuroendocrinology. 2010 Nov;35(10):1462-72.

FIMM 63 Externalizing Behaviors and Cigarette Smoking as Predic- Global gene expression profiles in skeletal muscle of mo- tors for Use of Illicit Drugs: A Longitudinal Study Among nozygotic female twins discordant for hormone replace- Finnish Adolescent Twins. / Korhonen, Tellervo ; Levälahti, ment therapy. Ronkainen PH, Pöllänen E, Alén M, Pit- Esko ; Dick, Danielle M. ; Pulkkinen, Lea ; Rose, Richard J. ; känen R, Puolakka J, Kujala UM, Kaprio J, Sipilä S, Ko- Kaprio, Jaakko ; Huizink, Anja C.. In: Twin Research and Hu- vanen V.. Aging Cell. 2010 Dec;9(6):1098-110. doi: 10.1111/j.1474- man Genetics. 2010 ; Vol. 13, No. 6, . p. 550-558 9726.2010.00636.x. Epub 2010 Oct 29.

Fish consumption and polyunsaturated fatty acids in re- Having a Male Co-Twin Masculinizes Mental Rota- lation to psychological distress.Suominen-Taipale AL, Tu- tion Performance in Females. / Vuoksimaa, Eero ; runen AW, Partonen T, Kaprio J, Männistö S, Montonen Kaprio, Jaakko ; Kremen, William S. ; Hokkanen, Laura ; Vik- J, Jula A, Tiittanen P, Verkasalo PK. Int J Epidemiol. 2010 en, Richard J. ; Tuulio-Henriksson, Annamari ; Rose, Richard Apr;39(2):494-503. J. In: Psychological Science. 2010 ; Vol. 21, No. 8, . p. 1069-1071

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Oncolytic Adenovirus ICOVIR-7 in Patients with Ad- vanced and Refractory Solid Tumors. / Nokisalmi, Petri Self-reported preclinical mobility limitation and fall histo- ; Pesonen, Sari ; Escutenaire, Sophie ; Sarkioja, Merja ; Ra- ry as predictors of future falls in older women: prospec- ki, Mari ; Cerullo, Vincenzo ; Laasonen, Leena ; Alemany, tive cohort study. / Mänty, M. ; Heinonen, A. ; Viljanen, A. ; Ramon ; Rojas, Juan ; Cascallo, Manel ; Guse, Kilian ; Ra- Pajala, S. ; Koskenvuo, Markku ; Kaprio, J. ; Rantanen, T. In: jecki, Maria ; Kangasniemi, Lotta ; Haavisto, Elina ; Karioja- Osteoporosis International. 2010 ; Vol. 21, No. 4, . p. 689-693 Kallio, Aila ; Hannuksela, Paivi ; Oksanen, Minna Kristina ; Kanerva, Anna ; Joensuu, Timo ; Ahtiainen, Laura ; Hem- minki, Akseli. In: Clinical Cancer Research. 2010 ; Vol. 16, . p. 3035-3043

FIMM 65 Serotype Chimeric Human Adenoviruses for Cancer Gene Petri ; Raki, Mari ; Rajecki, Maria ; Guse, Kilian ; Ranki, Tu- Therapy. / Ranki, Tuuli ; Hemminki, Akseli. In: Viruses. 2010 uli ; Oksanen, Minna Kristina ; Holm, Sirkka-Liisa ; Haavis- ; Vol. 2, . p. 2196-2212 to, Elina ; Karioja-Kallio, Aila ; Laasonen, Leena ; Partanen, Kaarina ; Ugolini, Matteo ; Helminen, Andreas ; Karli, Eerika Sex Differences in Left-Handedness Are Also Evident in ; Hannuksela, Paivi ; Pesonen, Saila ; Joensuu, Timo ; Kan- Scandinavia and in Twins: Comment on Papadatou-Pas- erva, Anna ; Hemminki, Akseli. In: Molecular therapy. 2010 ; tou, Martin, Munafo, and Jones (2008). / Vuoksimaa, Eero Vol. 18, No. 10, . p. 1874-1884 ; Kaprio, Jaakko. In: Psychological Bulletin. 2010 ; Vol. 136, Twin study of heritability of eating bread in Danish and No. 3, . p. 344-347 Finnish men and women.Hasselbalch AL, Silventoinen K, Keskitalo K, Pietiläinen KH, Rissanen A, Heitmann BL, Ky- Shift-work and cardiovascular disease: a population- vik KO, Sørensen TI, Kaprio J. Twin Res Hum Genet. 2010 based 22-year follow-up study. / Hublin, Christer ; Partin- Apr;13(2):163-7. en, Markku ; Harkonmäki, Karoliina ; Silventoinen, Karri ; Vascular Endothelial Growth Factor-B Acts as a Coronary Koskenvuo, Markku ; Kaprio, Jaakko. In: European Journal Growth Factor in Transgenic Rats Without Inducing An- of Epidemiology. 2010 ; Vol. 25, No. 5, p. 315-323 giogenesis, Vascular Leak, or Inflammation. / Bry, Maija ; Kivelä, Riikka ; Holopainen, Tanja ; Anisimov, Andrey ; Tam- Smoking strongly predicts disability retirement due to mela, Tuomas ; Soronen, Jarkko ; Silvola, Johanna ; Saraste, COPD: the Finnish Twin Cohort Study Koskenvuo K, Broms Antti ; Jeltsch, Michael ; Korpisalo, Petra ; Carmeliet, Peter ; U, Korhonen T, Laitinen LA, Huunan-Seppälä A, Keistinen Lemström, Karl Birger ; Shibuya, Masabumi ; Yla-Herttuala, T, Autti-Rämö I, Kaprio J, Koskenvuo M.. Eur Respir J. 2011 Seppo ; Alhonen, Leena ; Mervaala, Eero ; Andersson, Leif C. Jan;37(1):26-31. ; Knuuti, Juhani ; Alitalo, Kari. In: Circulation (Baltimore). 2010 ; Vol. 122, No. 17, . p. 1725-1733 Targeted Chemotherapy for Head and Neck Cancer with a Chimeric Oncolytic Adenovirus Coding for Bifunctional Suicide Protein FCU1. / Dias, Joao D. ; Liikanen, Ilkka ; Guse, Kilian ; Foloppe, Johann ; Sloniecka, Marta ; Diaconu, Iulia ; Rantanen, Ville ; Eriksson, Katja Minna-Maria ; Hakkarain- en, Tanja ; Lusky, Monika ; Erbs, Philippe ; Escutenaire, So- phie ; Kanerva, Anna ; Pesonen, Sari ; Cerullo, Vincenzo ; Hemminki, Akseli. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 9, . p. 2540-2549

The Effect of Alcohol Consumption on Later Obesity in Early Adulthood - A Population-based Longitudinal Study. / Pajari, Matti ; Pietiläinen, Kirsi H. ; Kaprio, Jaakko ; Rose, Richard J. ; Saarni, Suoma Eeva Matilda. In: Alcohol and Al- coholism. 2010 ; Vol. 45, No. 2, . p. 173-179

The genetic and environmental influences on childhood obesity: a systematic review of twin and adoption studies. / Silventoinen, Karri ; Rokholm, B. ; Kaprio, J. ; Sorens- en, T. I. A.. In: International Journal of Obesity. 2010 ; Vol. 34, No. 1, . p. 29-40 Tobacco, cannabis, and other illicit drug use among Finnish adolescent twins: causal relationship or correlated liabilities? Huizink AC, Levälahti E, Korhonen T, Dick DM, Pulkkinen L, Rose RJ, Kaprio J. J Stud Alcohol Drugs. 2010 Jan;71(1):5-14.

Tobacco use and reported bruxism in young adults: a nationwide Finnish Twin Cohort Study.Rintakoski K, Ahl- berg J, Hublin C, Lobbezoo F, Rose RJ, Murtomaa H, Kaprio J. Nicotine Tob Res. 2010 Jun;12(6):679-83.

Treatment of Cancer Patients With a Serotype 5/3 Chi- meric Oncolytic Adenovirus Expressing GMCSF. / Koski, Anniina ; Kangasniemi, Lotta ; Escutenaire, Sophie ; Pe- sonen, Sari ; Cerullo, Vincenzo ; Diaconu, Iulia ; Nokisalmi,

66 FIMM Editors: Photos: Olli Kallioniemi Ari Aalto Sanni Hyppönen Jason DeBose Sari Kivikko Eva-Maria Diehl Anne Leinonen Tero Pajukallio Marja Medina Jukka Rapo Reetta Niemelä Jouko Siro Susanna Rosas Veikko Somerpuro Imre Västrik Gary Wornell ªªªĭŻ ĭŻř ǊǈĬǈǈǈǉǌ ¦¡¡¬¢£¦§¢ř¢ ¨ ¦¡ǊĬ¨¢ ¡§¨ǐĬǈǈǊǑǈ ¦¡