I. Overviews...3. Year 2010 in review, Director of FIMM Views from the former and current Chair of the Board II. FIMM Launch Event...

Transcription

1 ANNUAL REPORT 2010

2 Contents I. Overviews...3 Year 2010 in review, Director of... 3 Views from the former and current Chair of the Board... 5 II. 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 Human Genomics...10 Medical Systems Biology and Translational Research Research collaborations and highlights Personalized medicine of cancer becoming a reality...25 Doctoral Training...26 VI. Technology Centre...28 Genomics Unit...28 Sequencing Unit...29 Metabolomics Unit RNAi Unit 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 X. in Figures...44 Financial Report Personnel Statistics...45 XI. Publications by researchers Publications by Molecular Medicine Network and adjunct researchers

3 I. Overviews Year 2010 in review, Director of Dramatic research progress is now being made in human genomics, bioinformatics, systems biology and many other fields of biomedical research. The need to bring breakthroughs in science to the everyday practice of medicine remains one of mankind s biggest challenges. The mission of is to build a bridge from discovery to medicine. The foundations for building translational molecular medicine in Finland are excellent. Finland has both a strong scientific base in biomedical research, but also excellent clinical and epidemiological research and a high-quality equal-access healthcare infrastructure. However, unless these major advantages are brought together by multidisciplinary research collaborations, we will not realize our full potential. This is what and the Nordic EMBL Partnership for Molecular Medicine are all about, realizing the full potential of small countries in Northern Europe to advance translational molecular medicine by multidisciplinary collaborations with national and international networks. The year 2010 marked the third year in the build-up of as an international research institute. The year was characterized by rapid growth, exciting research progress, the setup of major national and international research infrastructures and the launch of new biobanking operations in the Meilahti Campus. By combining first class molecular medicine research, state-of-the-art technology capabilities and access to large biobanks and clinical data, we can build major translational opportunities. This vision is behind the new organization structure of, which is planned to take effect in 2011 (Figure 1). The primary focus of in translating molecular medicine to clinical practice is via advancing personalized medicine, which is an area where we hope to be able to also soon help patients and contribute to the health of societies. During the year 2010, the number of employees at grew from 99 to 125, and the staff now represents 20 nationalities. There are 13 group leaders at, all appointed based on international evaluation. Half of the group leaders are EMBL-style principal investigators and two are established Finland Distinguished Professors. In 2010, the build-up of new infrastructures at was launched with funding from Biocenter Finland and a pilot project to support the build-up of international ESFRI infrastructure programmes. Almost half of s activities (measured both in terms of funding and personnel) are now focussed on infrastructure. is a prominent national and international infrastructure provider, helping a large community of researchers to do better science and facilitate translational medicine. The year 2010 started with dramatic news of the death of the Academician of Science, Professor Leena Peltonen- Palotie. Leena s death was a deep loss to all of us at as well as to the international human genomics community. Leena s key impact in building the scientific foundation of is felt today and it will continue well after her death. In May 2011, we will organize a major international symposium to celebrate Leena s lifetime achievements in genomics. In March 2010, celebrated its official inauguration ceremony followed by a scientific symposium. is therefore now officially up and running and we can turn the focus towards making progress in molecular medicine. Indeed, significant research progress has already been made, as demonstrated by the 90 publications by researchers, of which 21 were in top journals with an impact factor >20. Many of the top publications represent major international consortium studies on human genetics, largely initiated by the late Professor Leena Peltonen-Palotie, and now continued by the group leaders at and at THL. In the area of human genomics, the role of group leaders has been leading in uncovering e.g. the genetic basis of migraine and cardiovascular disease and the genetic origins of Finnish people. In other areas, researchers published the first transcriptomic sequencing paper about breast cancer, set up a new personalized medicine profiling of cancer and carried out many other key observations. In addition to the 90 publications by researchers, members of the National Network for Molecular Medicine and adjunct researchers published another 43 publications. researchers have also been very successful in securing external competitive research funding, such as 3

4 new projects from the EU and the IMI (Innovative Medicines Initiative), a joint EU Pharma collaborative programme. External funding now amounts to >50% of the total budget, with a further increase predicted in this percentage in Acquiring, reporting and managing a project portfolio of some 30 individual grants at in 2010 is starting to be a significant administrative challenge. While the increased external support is overwhelmingly positive, there are also many aspects of an international EMBL-associated institute that cannot be run only based on short-term competitive funding. Recruitment of international, talented principal investigators will continue to require a strong institutional funding base. In the first five years, private foundations have done a remarkable job in helping to support this aspect of operations. We hope to work with the partners and supporters of to maintain a strong basic funding also in the future when the first five years of start-up funding comes to an end. Recent research policy statements, such as those from the National Innovation Council and the Academy of Finland (please see below) put an overwhelmingly strong emphasis on improving the international profile of Finnish science. This is seen as a key aspect of helping Finland stay competitive in the global competition for science and innovation. We have seen tremendously rapid progress at, which can to a large extent be credited to its international profile and strong networks, the brand of the EMBL partnership as well as the strategic international recruitment of talent to Finland. Thus, we hope that will continue to prosper by building upon these strengths. Professor Olli Kallioniemi, Director, Research and innovation policy guidelines for ; research and Innovation Council Research Policy: Tools and Practices A Five-Country Comparison; Publications of the Academy of Finland 2/10 The state and quality of scientific research in Finland; Publications of the Academy of Finland 9/09 BOARD SAB STEERING GROUP DIRECTOR ADMINISTRATION ESFRIs BIOBANK INFRASTRUCTURE Disease-oriented collections Population-based collections (THL) T ECHNOLOGY C ENTRE Genomics Sequencing Metabolomics RNAi Chemical Biology Bioinformatics RESEARCH Genomics Systems biology - Cancer - Cardiovascular & metabolic - Neuro-psychiatric - Viral IT-support T RANSLATION Diagnostics development, personalized medicine National network, clinical collaborators Figure 1. Organization structure of, planned to take effect in 2011 (as presented at the Board Meeting on 25 February 2011). 4

5 Views from the former and current Chair of the Board During my term on the Council of the European Molecular Biology Laboratory, it was my honour and pleasure to contribute to the proposal for the establishment of institutes for molecular medicine in the Nordic 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 University of Helsinki, the then Rector Professor Ilkka Niiniluoto, mandated me to create a concept for the Institute for Molecular Medicine Finland, 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, 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 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, 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 ( ) I have had the privilege to serve as the Chairman of the Board of since 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, 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 University Hospital, Public Sector Research Institutes and other important partners feels motivation and responsibility. The mission of is today even more clear and justifiable than when it was established in Professor Kimmo Kontula, Vice Rector of the University of Helsinki Chair of the Board of ( ) 5

6 II. Launch Event The Launch Event was arranged on March The event gathered altogether about 250 participants 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. 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 Professor Kai Simons (Dresden) gave the Marja Makarow Lecture entitled Lipid rafts as a membrane-organizing principle. Also Members of the SAB of 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

7 III. How is the Nordic EMBL Partnership build-up progressing in Oslo and Umeå? The overall objective of the Centre for Molecular Medicine Norway (NCMM, is to facilitate 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, MIMS and EMBL investigators. Professor Kjetil Taskén, Director of the Centre for Molecular Medicine Norway (NCMM) The Laboratory for Molecular Infection Medicine Sweden (MIMS, was initiated with 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 Centre 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 : 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, NCMM, and EMBL in the recruitment and build-up phase of the three Nordic nodes during the past couple 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) 7

8 IV. Academician of Science, Professor Leena Peltonen- Palotie in memoriam Academician of Science, Professor Leena Peltonen-Palotie was Research Director at the Institute for Molecular Medicine, Research Professor at the National Institute for Health and Welfare, Finland and Head of Human Genetics at the Wellcome Trust Sanger Institute. She was also a visiting professor at the Broad Institute of MIT and Harvard University, USA. Leena passed away on 11 March 2010 in her home in Finland after a long and courageous battle with cancer. Leena had a distinguished career and published more than 580 research papers as well as almost 80 reviews, with many articles in the most prestigious journals. Her research has enormously increased our knowledge on the molecular basis human diseases. These studies have gained a wide national and international recognition as reflected by the numerous prizes and honors she has received including, the Anders Jahre Prize in 1992, the Margaret Pittman lectureship award in 2003, the Nordic Fernström Prize and the European van Gysel Prize, both in 2006, and the Carter medal and the Hugh Sinclair Lecturer, both in In 2009, the President of the Republic of Finland Tarja Halonen awarded Leena the honorary title of Academician of Science, and she became one of only 12 Academians in post in Finland at one time. 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 National Public Health Institute in 1991 at the age of 39. In 1998 she took up a new challenge, returning 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 University of Helsinki and the National Public Health Institute. She was invited to a Visiting Professorship at the Broad Institute, one of the world s leading genetics institutions. Leena s role was instrumental when setting up and shaping up the research profile. She was a visionary leader of the Human Genomics Research Area. With a firm hand, she built a highly competitive research group analyzing genetic and epidemiological variation in connection to a broad range of diseases and traits by fully utilizing the well-characterized Finnish population samples. The work was carried out by many of her students at. After her death, the supervision of the current students has been taken over by the rest of the faculty members. In 2007 Leena assumed the position of Head of Human Genetics at the Wellcome Trust Sanger Institute, while continuing her work in Finland and in the US. The three roles complemented each others and opened exciting new collaborative research avenues. She also brought together numerous top researchers and research groups by leading the Center of Excellence in Disease Genetics of the Academy of Finland, the Nordic Center of Excellence in Disease Genetics, GenomEUtwin (FP5) and ENGAGE (FP7). She was 8

9 elected as the President of Human Genome Organization HUGO in She was also nominated as one of the founding members for the European Research Council and elected to the Institute of Medicine of the National Academy of USA. Leena was a visionary geneticist, and a champion of population genetics and public health. Leena s vision and charisma have been inspirational to many, particularly the younger generation. As a teacher and scholar she has fostered the next generation of geneticists, supervising more than 70 PhD students. Many of her former students now hold prominent positions in Finland and abroad. The complete list of her former PhD trainees is given below. Her legacy, though, is international: she has transformed science and scientists all over the world. She was a prime example how a woman can create a career in a competitive field, being simultaneously dedicated to her family. But it is also personal: one of Leena s special abilities was her ability to listen carefully, think fast, and make you want to go out and make a difference. Aim for the best, she used to say and she was able to make it always sound both simple and the only natural way to work. Jaakko Kaprio Professor of Genetic Epidemiology Samuli Ripatti -EMBL Group Leader PhD Students supervised by Professor Leena Peltonen-Palotie: Ritva Halila Seppo Pakkala Irma Järvelä Marc Baumann Päivi Helminen Elina Ikonen Antti Sajantila Kati Kainulainen Raili Kauppinen Miikka Vikkula Anu Suomalainen Pentti Tienari Nina Enomaa Tiina Paunio Jouni Vesa Elina Hellsten Pekka Nokelainen Ritva Tikkanen Aija Riikonen-Kyttälä Leena Karttunen Johanna Aaltonen Terhi Rantamäki-Häkkinen Minna Peltola Annukka Uusitalo Satu Kuokkanen Kaisu Nikali Lasse Lönnqvist Kai Tenhunen Petra Pekkarinen Iiris Hovatta Paulina Paavola Tuomas Klockars Päivi Pajukanta Markus Perola Teppo Varilo Minna Savukoski Petra Björses Tomi Pastinen Jyrki Kaukonen Hannele Kangas Miina Öhman Pirjo Salomäki Jesper Ekelund Mari Auranen Ilona Visapää Juha Isosomppi Maria Halonen Chris Ramsey Juha Paloneva Daniel Chen Nina Aula Henna Haravuori Jani Saarela Ville Holmberg Heidi Lilja Nabil Enattah Lisa Lanyi-Mee Denis Bronnikov Tero Ylisaukko-oja William Hennah Elina Suviolahti Jenny Ekholm Niklas Pakkasjärvi Mira Kyttälä Joni Turunen Anna Kiialainen Kirsi Auro Sampo Sammalisto Nora Pöntynen Jussi Naukkarinen Kati Kristiansson Suvi P. Kallio Karola Rehnström Juho Wedenoja Outi M. Palo Johannes Kettunen Liisa Tomppo Helena Kilpinen 9

10 V. Research Human Genomics Group Palotie Professor Aarno Palotie, MD, PhD Group Members: PI: Aarno Palotie Senior Researchers: Kaisa Silander, Maija Wessman Postdoctoral Researchers: Verneri Anttila, William Hennah PhD Students: Tiia Luukkonen, Mikko Muona, Emma Nyman, Olli Pietiläinen Technicians: Eija Hämäläinen, Elli Kempas, Anne Nyberg, Minna Suvela, Anne Vikman Research Nurses: Carita Jussila, Leena Leikas, Anne Nyrhinen Project Coordinator: Sari Kivikko Collaborators in the Helsinki University Central Hospital: Ville Artto, Markus Färkkilä, Mikko Kallela, Salli Vepsäläinen The overall goal of Aarno Palotie s group is to improve our understanding of the genetic mechanisms underlying neurological and neurodevelopmental traits by combining genome-wide information of both single nucleotide polymorphism 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 Autism Sample collection (collected by Dr. Lennart von Wendt) and such population cohorts as the Finrisk, Helsinki Birth Cohort, Northern Finnish Birth Cohort and Health 2000 cohorts ( The long lasting geographical and linguistic isolation, internal migrations, famines and rapid, recent expansions have moulded the population structure of Finland for thousands of years. Such population isolates provide exceptional opportunities for identification of genome variations underlying disease traits. When the unique population structure is combined with the one payer health care system, the harmonized training of physicians and tradition in epidemiological research Finland has become one the most interesting places for genetic epidemiology. The Palotie group aims to identify both common and low frequency variants associated to two paroxysmal neurological disorders migraine and epilepsy, and two neurodevelopmental disorders, schizophrenia and autism using GWA and next gene generation sequencing techniques. To combine different fields of expertise and to have sufficient power these studies are performed in collaboration with several international groups and high throughput platforms. The wealth of 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 Cambridge 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, Inouye M, Silander K, Hamalainen E et al. An immune response network associated with blood lipid levels. PLoS Genet. Sep 9;6(9), 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, The 1000 Genomes Consortium: A map of human genome variation from population scale sequencing. Nature. Oct 28;467(7319): , External research funding: Academy of Finland Center of Excellence, Helsinki Biomedical Graduate School (HBGS, 2011), EU-FP7: SYNSYS 10

11 Group Ripatti -EMBL Group Leader (Sigrid Jusélius Foundation) Samuli Ripatti, PhD The Ripatti research group is working on genetic epidemiology and the statistical 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 modifying 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 panel was also shown to be powerful when tagging common SNPs and copy number variants and imputing Finnish GWAS datasets for dense genetic marker resolution. Together with members of the Nordic Center of Excellence in Complex Diseases, a Nordic common GWAS control database was established and the Nordic genetic population structure described (Leu et al 2010). The group also participated in several consortia for finding further genes for lipids (Teslovich et al 2010), and, for example, for glycemic traits, obesity and human height. This work is currently being extended to a wider range of potential biomarkers for cardiovascular diseases. Together with Veikko Salomaa from THL, Sekar Kathiresan from the Broad Institute and others the group created a genetic risk score for coronary heart disease. The multilocus risk score was evaluated in six prospective cohorts from Finland and Sweden and shown to be strongly associated with incident heart disease (Ripatti et al 2010). Group Members: PI: Samuli Ripatti Senior Researcher: Maria Krestyaninova Postdoctoral Researcher: Johannes Kettunen PhD Students: Marine Largeau, Pirkka-Pekka Laurila, Mari Rossi, Antti-Pekka Sarin, Jarkko Soronen, Ida Surakka, Emmi Tikkanen, Taru Tukiainen Project Coordinator: Huei-Yi Shen 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: /ejhg , 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: Surakka I, Kristiansson K, Anttila V et al. Founder Population-Specific HapMap Panel Improves Imputation Accuracy and CNV Tagging in GWA Studies, Genome Res., doi: /gr Published in Advance September 1, 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, External research funding: Sigrid Juselius Foundation, Academy of Finland Center of Excellence, Helsinki Graduate School of Biotechnology and Molecular Biology (GSBM), Helsinki Biomedical Graduate School (HBGS, 2011), EU-FP7: ENGAGE and BioSHaRE 11

12 Group Saarela Research Director Janna Saarela, MD, PhD Group Members: PI: Janna Saarela Postdoctoral Researcher: Eveliina Jakkula PhD Students: Virpi Leppä, Annu Näkki, Anna-Maija Sulonen Undergraduate Students: Henrikki Almusa, Maija Lepistö Both genetic predisposition and environmental triggers are thought to contribute 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 genes predisposing to autoimmune diseases by genome-wide association analyses, we have used an alternative approach to take advantage of the population history of Finland and the province of Southern Ostrobothnia, which is an old isolate with increased prevalence and familial occurrence of MS. For example, we identified a novel MS predisposing gene, STAT3, using genome-wide association analysis in only 68 distantly related individuals from two extended megapedigrees (Jakkula et al 2010). In collaboration with the Technology centre s sequencing and bioinformatics units we have been developing laboratory and analysis methods for nextgeneration sequencing: we have optimized the sample preparation protocols for next-generation sequencing (Lepistö M, Master s thesis), evaluated the commercially 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: International Multiple Sclerosis Genetics Consortium (IMSGC), Lack of support for association between the KIF1B rs [c] variant and multiple sclerosis. Nat Genet. 2010, 42: 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 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: 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

13 Group Widén Academy Research Fellow Elisabeth Widén, MD, PhD The focus of the research group is to identify genes influencing puberty and to evaluate 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 cancers, but the underlying mechanisms linking early puberty with adult disease remain unknown. However, the ongoing global secular trend towards earlier pubertal onset, which is paralleled by rapidly increasing rates of obesity and associated disease, clearly underscores the urgency of clarifying the disease mechanisms from 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: ). 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: ). 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 Consortium; 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: ). 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. Group Members: PI: Elisabeth Widén PhD Students: Diana Cousminer, Jaakko Leinonen 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: 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: 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: External research funding: Academy of Finland 13

14 Medical Systems Biology and Translational Research Group Kallioniemi Professor Olli Kallioniemi, MD, PhD High-throughput cancer biology and translation towards personalized medicine Group Members as of January 2011: PI: Olli Kallioniemi Senior Researcher: Maija Wolf Postdoctoral Researchers: Sara Kangaspeska, Astrid Murumägi, Teijo Pellinen, Xiaofeng Dai PhD Students: Anna Aakula, Henrik Edgren, Sami Kilpinen, John Patrick Mpindi, Kalle Ojala, Khalid Saeed, Saana Sandström (-EMBL Rotation PhD Student) Technician: Katja Välimäki Research is done in collaboration with the Medical Biotechnology Group of the VTT Technical Research Centre of Finland and the University of Turku. Image, 1500x892 pixels) - Scaled (95%) We are integrating genomic profiling, high-throughput RNA interference and chemical 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 escape routes of cancer. This approach is also providing an exciting ability to generate rapidly actionable personalized medicine strategies for the clinical treatment of cancer patients. In order to promote translational opportunities, we have recently shifted our interests to studies of human leukaemias as a model to advance the personalized medicine of cancer. In collaboration with Jonathan Knowles/Caroline Heckman and Krister Wennerberg at, as well as Kimmo Porkka and the Finnish Hematology Association, we are using high-throughput ex-vivo drug sensitivity testing to leukemic cells, coupled with the molecular profiling of the cancer cells by RNAseq, exome-seq, and phosphoproteomics. We believe that the implementation of these types of personalized molecular and functional profiles is possible in the management of human leukaemias today, while it may take several years to achieve similar translational progress for the common solid tumours. 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 Jan 19;12(1):R6. 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 Mar 1;71(5): 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 Dec 3;5(12):e 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 Oct 1;15(19): Hanash SM, Baik CS, Kallioniemi O. Emerging molecular biomarkers-blood-based strategies to detect and monitor cancer. Nat Rev Clin Oncol Mar;8(3): International Cancer Genome Consortium, Hudson TJ, et al. International network of cancer genome projects. Nature Apr 15;464(7291): External research funding: Academy of Finland Center of Excellence, Biocentrum Helsinki (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

15 Group Kainov -EMBL Group Leader (Jane and Aatos Erkko Foundation) Denis Kainov, PhD Our group studies the principles that govern influenza A virus-host relationships, 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 annually, 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 existing therapeutics. In contrast to viral proteins, cellular factors are not prone to rapid mutations. Cellular vacuolar ATPase represents a potential antiviral target. 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 saliphenylhalamide, a compound targeting vacuolar ATPase, is an effective inhibitor of influenza infection in vitro and in vivo. Another interesting anti-influenza target is the cellular translation apparatus. Viral NS1 protein interacts with translation machinery to promote the synthesis of influenza proteins. We have developed a 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 failure 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. Group Members as of January 2011: PI: Denis Kainov Postdoctoral Researchers: Andrey Golubtsov, Laura Kakkola PhD Students: Maria Anastasina, Puwei Yuan Technicians: Minttu Kaloinen, Alun Parsons 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: /j 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: Kainov DE, Vitorino M, Cavarelli J, Poterszman A, Egly JM. (2008) Structural basis for group A trichothiodystrophy. Nat. Struct. Mol. Biol. 15: 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: External funding: Jane and Aatos Erkko Foundation, Academy of Finland (2011), CIMO, Ministry of Employment and the Economy, Helsinki Biomedical Graduate School (HBGS, 2011) 15

16 Group Knowles Personalized Cancer Medicine Group Group Members: PI: Jonathan Knowles Senior Researcher and co-principal investigator: Caroline Heckman Senior Research Technician: Alun Parsons With the development of targeted therapies, identifying the right patient for the 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 Researcher Caroline Heckman were recruited to 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 biomarkers, but also endeavor to determine new therapeutic options. Furthermore, a better understanding of disease pathogenesis offered by in-depth molecular profiling may yield new ideas for drug development. The group works closely with clinicians in order to facilitate patient sample 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: 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: McBride DJ, Orpana AK, Sotiriou C, et al. Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors. Genes, Chromosomes and Cancer 2010;49: Kallioniemi O, Pitkänen K, Knowles JKC. Molekyylitason näkökulma potilaan hoitoon. Duodecim 2010;126(19): External research funding provided by: Tekes, Cancer Society of Finland, Sigrid Jusélius Foundation 16

17 Group Kuznetsov -EMBL Group Leader (Finnish Medical Foundation and Sigrid Jusélius Foundation) Sergey Kuznetsov, PhD Breast cancer is the most common malignancy among women. One out of ten breast 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 to repair certain types of DNA damage, which can be used to kill such cancer cells without much toxicity to normal tissues. This idea is the basis for the concept of synthetic lethality gaining popularity among oncologists in the recent years. We use a panel of BRCA1-mutated breast cancer cell lines to search for new synthetic lethal drugs against recombination-deficient cancers. Our current data indicate that these cells are highly heterogeneous in their drug sensitivity profiles. 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. Group Members: PI: Sergey Kuznetsov Postdoctoral Researchers: Xiaofeng Dai, Pauliina Munne PhD Students: Yuexi Gu, Manuela Tumiati Technicians: Sonja Koopal, Annabrita Schoonenberg 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: Kuznetsov S, Haines D, Martin B, Sharan S. Loss of Rad51c leads to embryonic lethality and modulation of Trp53-dependent tumorigenesis in mice. Cancer Res. 2009;69: Kuznetsov S, Liu P, Sharan S. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat Med. 2008;14: 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: 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) 17

18 Group Lundin Dr. Johan Lundin, MD, PhD Group Members as of January 2011: PI: Johan Lundin Postdoctoral Researchers: Nina Linder, Ville Ojansivu PhD Students: Juho Konsti, Tiina Lehtimäki, Mikael Lundin, Riku Turkki The Lundin Group develops methods for personalized prediction of disease outcome 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 decisionsupport 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 biomark- ers 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 highthroughput computer assisted methods for automated analysis of digitized cancer tissue and microbiological samples. Methods for computerized quantification and segmentation of digitized tumor samples are applied in analysis of TMAs from breast-, prostate- and colorectal cancers (5). The webmicroscopy developed (fimm.webmicroscope.net) is a method of digitizing entire microscope specimens and viewing as well as processing the virtual slides through a web interface. The technology is a research infrastructure within Biocenter Finland and via the EU funded EATRIS. Applications include analysis 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 suppresses integrin activity and invasion. Oncogene 2010;29: 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: 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 Suppressive 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

19 Group Verschuren -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 microenvironments. 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 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. Through generation of a series of cell lines that express tagged forms of human lung cancer-associated variants, we generated the first evidence that point mutations lead to a decrease in receptor function, consistent with a putative tumour suppressor function. Since Eph receptor family signalling generally controls cell shape and contact-based cell repulsion, we are pursuing studies to address its function in architecturally sound in vivo mouse models. The lab s general research strategy constitutes a powerful multi-pronged approach combining highly specific dual tagging-based protein purification methods to define protein molecular networks, with cell biological assessment of protein (co-) localisation and function in vitro and in vivo. This approach has been extended to reverse genetics approaches of a set of candidate lung cancer tumour suppressors. Group Members as of January 2011: PI: Emmy Verschuren Postdoctoral Researcher: Merja Särkioja PhD Students: Jenni Lahtela, Rita Matos CIMO Research Fellow: Ashwini Nagaraj Undergraduate Student: Nitai Peled Technicians: Sonja Koopal, Annabrita Schoonenberg, Danielle Bansfield 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: 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: Verschuren E.W. and Jackson, P.K. (2007). Putting transcription repression and protein destruction in prb s pocket. Review. Dev. Cell. 12: 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: 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: 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: 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: 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: External research funding: Orion-Farmos Research Foundation, Sigrid Jusélius Foundation,Helsinki Biomedical Graduate School (HBGS), CIMO, EU-FP7: SYSTUMS, FCT Portuguese Science Foundation. 19

20 Group Wennerberg -EMBL Group Leader (Jane and Aatos Erkko Foundation) Krister Wennerberg, PhD Group Members: PI: Krister Wennerberg Senior Researcher: Gretchen Repasky Postdoctoral Researcher: Leena Karhinen PhD Students: Arjan van Adrichem, Tonge Ebai, Muntasir Mamun Majumder (-EMBL Rotation PhD Student) The research in the Wennerberg group aims to identify novel mechanisms that are 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, the Finnish Hematology Registry and Biobank (FHRB) and HUS, our group 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 for connecting biomarkers to drug responses. The goal is to use the assays for quick and accurate testing of cells for their in vitro sensitivity to drugs to allow for a prediction of clinical responses. To this end, we have assembled a comprehensive oncology screening collection, currently containing about 220 approved and investigational oncology drugs. 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 -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 MLK3 limits activated Gαq signaling to Rho by binding to p63rhogef. Mol. Cell. 32: Dubash AD, Wennerberg K, García-Mata R, Menold MM, Arthur WT, Burridge K A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin. J. Cell Sci. 120: Wennerberg K, Forget MA, Ellerbroek SM, Arthur WT, Burridge K, Settleman J, Der CJ, Hansen SH Rnd proteins function as RhoA antagonists by activating p190 RhoGAP. Curr. Biol : Arthur WT, Ellerbroek SM, Der CJ, Burridge K, Wennerberg K XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC. J. Biol. Chem. 277: External research funding: Jane and Aatos Erkko Foundation, Helsinki Biomedical Graduate School (HBGS, 2011) 20