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
FIMM
launched with funding from Biocenter Finland and a pi- lot project to support the build-up of international ESFRI infrastructure programmes. Almost half of FIMM’s activi- ties (measured both in terms of funding and personnel) are now focussed on infrastructure. FIMM is a prominent national and international infrastructure provider, help- ing a large community of researchers to do better sci- ence 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 FIMM as well as to the international human genomics community. Leena’s key impact in building the scientific foundation of FIMM 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, FIMM celebrated its official inauguration ceremony followed by a scientific symposium. FIMM is therefore now officially up and running and we can turn the focus towards making progress in molecular med- icine. Indeed, significant research progress has already been made, as demonstrated by the 90 publications by FIMM researchers, of which 21 were in top journals with an impact factor >20. Many of the top publications repre- sent major international consortium studies on human genetics, largely initiated by the late Professor Leena Pel- tonen-Palotie, and now continued by the group leaders at FIMM and at THL. In the area of human genomics, the role of FIMM group leaders has been leading in uncover- ing e.g. the genetic basis of migraine and cardiovascu- lar disease and the genetic origins of Finnish people. In other areas, FIMM researchers published the first tran- scriptomic sequencing paper about breast cancer, set up a new personalized medicine profiling of cancer and car- ried out many other key observations. In addition to the 90 publications by FIMM researchers, members of the FIMM National Network for Molecular Medicine and ad- junct researchers published another 43 publications.
FIMM researchers have also been very successful in se- curing external competitive research funding, such as
Year 2010 in review, Director of FIMM
D
ramatic 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 prac- tice of medicine remains one of mankind’s biggest chal- lenges. The mission of FIMM is to build a bridge from discovery to medicine. The foundations for building translational molecular medicine in Finland are excel- lent. Finland has both a strong scientific base in biomed- ical research, but also excellent clinical and epidemiolog- ical research and a high-quality equal-access healthcare infrastructure. However, unless these major advantages are brought together by multidisciplinary research col- laborations, we will not realize our full potential. This is what FIMM and the Nordic EMBL Partnership for Molec- ular Medicine are all about, realizing the full potential of small countries in Northern Europe to advance transla- tional molecular medicine by multidisciplinary collabo- rations with national and international networks.The year 2010 marked the third year in the build-up of FIMM 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 biobank- ing 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 op- portunities. This vision is behind the new organization structure of FIMM, which is planned to take effect in 2011 (Figure 1). The primary focus of FIMM 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 FIMM grew from 99 to 125, and the staff now represents 20 na- tionalities. There are 13 group leaders at FIMM, all ap- pointed 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 FIMM was
I. Overviews
3
BOARD
STEERINGGROUP
SAB DIRECTOR
BIOBANK
INFRASTRUCTURE
•
•
TECHNOLOGY CENTRE
•Genomics
•Sequencing
•Metabolomics
•RNAi
•Chemical Biology
•Bioinformatics
•IT-support
RESEARCH
•Genomics
•Systems biology
-Cancer
-Cardiovascular & metabolic -Neuro-psychiatric -Viral
TRANSLATION
•Diagnostics development, personalized medicine
•National network, clinical collaborators
ESFRIs
ADMINISTRATION
Disease-oriented collections Population-based collections (THL)
new projects from the EU and the IMI (Innovative Medi- cines Initiative), a joint EU – Pharma collaborative pro- gramme. External funding now amounts to >50% of the total FIMM budget, with a further increase predicted in this percentage in 2011—2012. Acquiring, reporting and managing a project portfolio of some 30 individual grants at FIMM in 2010 is starting to be a significant ad- ministrative challenge. While the increased external sup- port is overwhelmingly positive, there are also many as- pects 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 institu- tional funding base. In the first five years, private foun- dations have done a remarkable job in helping to sup- port this aspect of FIMM operations. We hope to work with the partners and supporters of FIMM to maintain a strong basic funding also in the future when the first five years of FIMM start-up funding comes to an end.
Recent research policy statements, such as those from the National Innovation Council and the Academy of Fin-
land (please see below) put an overwhelmingly strong emphasis on improving the international profile of Finn- ish science. This is seen as a key aspect of helping Fin- land stay competitive in the global competition for sci- ence and innovation. We have seen tremendously rapid progress at FIMM, which can to a large extent be cred- ited 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 FIMM will continue to prosper by building up- on these strengths.
Professor Olli Kallioniemi, Director, FIMM
Research and innovation policy guidelines for 2011–2015;
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
Figure 1. Organization structure of FIMM, planned to take effect in 2011 (as presented at the Board Meeting on 25 February 2011).
FIMM
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 cam- pus. 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 lead- ers. 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)
Views from the former and current Chair of the Board
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 bio- medical research as the use of genomic data is transforming from analy- sis of bioprofiles to exact individual characteristics, by virtue of new sequencing technologies with rational availability and cost level. The ad- vance in structural and functional genomics is supplemented by recent approaches of different omics techniques, and progress in bioinformat- ics that is enabling a meaningful understanding of the plethora of data.
This enormous progress coupled with rational use of biobank infrastruc- tures 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 to- day 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)
5
II. FIMM Launch Event
T
he FIMM Launch Event was arranged on 16—17 March 2010. The event gathered altogether about 250 partici- pants 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.
FIMM
III. How is the Nordic EMBL
Partnership build-up
progressing in Oslo and Umeå?
T
he overall objective of the Centre for Molecular Medicine Norway (NCMM, www.ncmm.uio.no) is to facilitate translation of discoveries in basic medical research into clinical practice with focus partic- ularly 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 mo- lecular 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)
T
he Laboratory for Molecular Infection Medicine Sweden (MIMS, www.mims.umu.se) 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 Cen- tre for Microbial Research (UCMR), which is an interdisciplinary research consortium devoted to molecu- lar research and novel applications in fields relevant to infectious diseases. It is promoting career oppor- tunities 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 rep- resent several different areas of infectious disease research and include investigations of many bacteri- al 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)
7
IV. Academician of Science,
Professor Leena Peltonen-
Palotie in memoriam
A
cademician of Science, Professor Leena Peltonen-Palotie was Research Director at the Institute for Molecular Medicine FIMM, Re- search 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 In- stitute of MIT and Harvard University, USA. Lee- na 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 pres- tigious journals. Her research has enormously increased our knowledge on the molecular ba- sis 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 Euro- pean van Gysel Prize, both in 2006, and the Cart- er medal and the Hugh Sinclair Lecturer, both in 2010. In 2009, the President of the Republic of Finland Tarja Halonen awarded Leena the honor- ary title of Academician of Science, and she be- came one of only 12 Academians in post in Fin- land 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 re- turned 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 re- search 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 FIMM research profile. She was a visionary leader of the Human Genom- ics Research Area. With a firm hand, she built a highly competitive research group analyzing genetic and epidemiological variation in con- nection to a broad range of diseases and traits by fully utilizing the well-characterized Finn- ish population samples. The work was carried out by many of her students at FIMM. After her death, the supervision of the current students has been taken over by the rest of the FIMM fac- ulty 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 collabo- rative research avenues. She also brought to- gether 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
FIMM
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
elected as the President of Human Genome Or- ganization HUGO in 2005 – 2007. 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 Acad- emy of USA.
Leena was a visionary geneticist, and a champi- on of population genetics and public health. Lee- na’s vision and charisma have been inspiration- al 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 stu- dents now hold prominent positions in Finland and abroad. The complete list of her former PhD
trainees is given below. Her legacy, though, is in- ternational: she has transformed science and sci- entists all over the world. She was a prime exam- ple how a woman can create a career in a com- petitive field, being simultaneously dedicated to her family. But it is also personal: one of Leena’s special abilities was her ability to listen careful- ly, 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
FIMM-EMBL Group Leader
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
Group Palotie
Professor Aarno Palotie, MD, PhD
T
he 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 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 Autism Sample collection (collected by Dr. Lennart von Wendt) and such popula- tion cohorts as the Finrisk, Helsinki Birth Cohort, Northern Finnish Birth Cohort and Health 2000 cohorts (www.nationalbiobanks.fi). The long lasting geographi- cal and linguistic isolation, internal migrations, famines and rapid, recent expan- sions 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 struc- ture 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 ex- pertise 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 co- horts 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.
V. Research
Human Genomics
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 se- quencing. 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
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
FIMM
Group Ripatti
FIMM-EMBL Group Leader (Sigrid Jusélius Foundation) Samuli Ripatti, PhD
T
he Ripatti research group is working on genetic epidemiology and the statis- tical 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 na- tional 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 num- ber variants and imputing Finnish GWAS datasets for dense genetic marker reso- lution.
Together with members of the Nordic Center of Excellence in Complex Diseas- es, a Nordic common GWAS control database was established and the Nordic ge- netic 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 dis- 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 dis- ease. 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 con- trol 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
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
11
Group Saarela
Research Director Janna Saarela, MD, PhD
B
oth genetic predisposition and environmental triggers are thought to contrib- ute 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 multi- ple 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 pop- ulation cohorts and collaborating with large international consortia to identify genes predisposing to autoimmune diseases by genome-wide association analy- ses, 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 megapedi- grees (Jakkula et al 2010).
In collaboration with the FIMM Technology centre’s sequencing and bioinfor- matics 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 univer- sity hospitals (EVO), National Graduate School of Musculoskeletal Disoreders and Biomaterials (TBGS), Helsinki Biomedical Graduate School (HBGS, 2011)
Group Members:
PI: Janna Saarela
Postdoctoral Researcher: Eveliina Jakkula PhD Students: Virpi Leppä, Annu Näkki, Anna-Maija Sulonen
Undergraduate Students: Henrikki Almusa, Maija Lepistö
FIMM
Group Widén
Academy Research Fellow Elisabeth Widén, MD, PhD
T
he 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 underly- ing disease genes and mechanisms remain poorly understood. Based on epidemio- logical 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 sev- eral 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 puber- tal 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 identifica- tion of genes influencing pubertal timing and growth can enhance our understand- ing of mechanisms leading to adult disease. Therefore, our research aim is to iden- tify 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 identify- ing genes influencing puberty using the well-established genome-wide associa- tion (GWAS). Studying unique longitudinal height growth data available in Finnish population-based cohorts we identified a significant association between the tim- ing 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 vari- ants 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 sig- nificantly 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
Group Members:
PI: Elisabeth Widén
PhD Students: Diana Cousminer, Jaakko Leinonen
13
FIMM
Group Kallioniemi
Professor Olli Kallioniemi, MD, PhD
High-throughput cancer biology and translation towards personalized medicine
W
e 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 “es- cape routes” of cancer.This approach is also providing an exciting ability to generate rapidly actiona- ble personalized medicine strategies for the clinical treatment of cancer patients.
In order to promote translational opportunities, we have recently shifted our in- terests 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 FIMM, as well as Kimmo Porkka and the Finnish He- matology Association, we are using high-throughput ex-vivo drug sensitivity test- ing to leukemic cells, coupled with the molecular profiling of the cancer cells by RNAseq, exome-seq, and phosphoproteomics. We believe that the implementa- tion 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.
Medical Systems Biology and Translational Research
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.
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 hu- man 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)
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 (FIMM-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.
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14
FIMM
Group Kainov
FIMM-EMBL Group Leader (Jane and Aatos Erkko Foundation) Denis Kainov, PhD
O
ur group studies the principles that govern influenza A virus-host relation- ships, aiming to develop (1) novel anti-influenza therapeutics and (2) di- agnostic 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 pro- teins. However, viral proteins mutate rapidly and acquire resistance to the exist- ing 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 saliphe- nylhalamide, 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 pro- teins without affecting cellular mRNA translation.
The host immune system is often able to eliminate influenza A virus infec- tions, 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 diagnos- tic 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 treat- ment 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 ef- fects 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 transla- tion. 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 translo- cation. 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)
15
Group Knowles
Personalized Cancer Medicine Group
W
ith 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 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- markers, 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 pro- filing 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 path- ways 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 me- tastasis. 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
Group Members:
PI: Jonathan Knowles
Senior Researcher and co-principal investigator: Caroline Heckman Senior Research Technician: Alun Parsons
FIMM
Group Kuznetsov
FIMM-EMBL Group Leader (Finnish Medical Foundation and Sigrid Jusélius Foundation)
Sergey Kuznetsov, PhD
B
reast 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 pro- files. We use genome-wide RNA interference and systems biology approaches to identify biomarkers predicting sensitivity to select therapeutic agents and un- derstand 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;653:259-280.
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 mu- tations 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)
17
Group Lundin
Dr. Johan Lundin, MD, PhD
T
he Lundin Group develops methods for personalized prediction of disease out- come and image based diagnostics. Genetic and molecular information com- bined with clinical data by the use of advanced informatics support will help iden- tify 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 re- search 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 esti- mation 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 sys- tem. 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 collabora- tion with the Machine Vision Group, University of Oulu, we are exploring high- throughput computer assisted methods for automated analysis of digitized can- cer 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 digi- tizing 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 edu- cation. 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 au- tomated 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 re- search to university hospitals (EVO), Helsinki Biomedical Graduate School (HBGS)
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
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 tra- ditional chemotherapy and surgery constituting the most effective treatments currently available. Innovative, versatile methods to study the causes of lung can- cer and aid the design of new treatment options are therefore of crucial impor- tance. Research in the Verschuren lab is centred on defining cell biological and bi- ochemical properties of putative lung cancer tumour suppressor genes, and build- ing 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 ac- tive participation in the European public-private IMI consortium PREDECT (coor- dinated by Emmy Verschuren). Key findings in animal models will be aligned with primary lung cancer patient materials, integrating biobanking and molecular pro- filing capacities available at FIMM and associated Biocenters.
In the past year, much progress was made in studies on the EPHA3 receptor ty- rosine 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 muta- tions 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 spe- cific dual tagging-based protein purification methods to define protein molecular networks, with cell biological assessment of protein (co-) localisation and func- tion in vitro and in vivo. This approach has been extended to reverse genetics ap- proaches 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: 3956-64.
Verschuren, E.W., Ban, K.H., Masek, M.A., Lehman, N.L. and Jackson, P.K. (2007). Loss of Emi1-depend- ent 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.
19
Group Wennerberg
FIMM-EMBL Group Leader (Jane and Aatos Erkko Foundation) Krister Wennerberg, PhD
T
he 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 sensi- tivity 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 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 compre- hensive 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 stud- ies 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 re- search rotation in the group working on DNA damage response genes.
Group Members:
PI: Krister Wennerberg
Senior Researcher: Gretchen Repasky Postdoctoral Researcher: Leena Karhinen PhD Students: Arjan van Adrichem, Tonge Ebai, Muntasir Mamun Majumder (FIMM-EMBL Rotation PhD Student)
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)
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 experi- ences 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 meth- ods 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
Research collaborations and highlights
21
FIMM Clinical Collaboration Programme
F
IMM launched a Clinical Collaboration Programme in 2010 to fund joint ap- pointments and collaborative research opportunities for clinical investiga- tors. FIMM aims to increase its activities in translational research, bringing dis- coveries 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 applica- tions. His expertise in histopathology and immunohistochemistry is also valu- able in tissue micro array (TMA) construction and in research projects utilizing TMA sections of solid tumours. In the FIMM biobank infrastructure he is respon- sible for the assurance of tissue integrity and the diagnostic quality of the sam- ples 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 envi- ronmental causes and metabolic consequences of obesity. They aim at a global metabolic profiling of obesity (“obesomics”) by using transcriptomics, metabo- lomics, 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, pros- tate and breast cancer.
