ANNUAL REPORT 2012
Editors: Olli Kallioniemi, William Hennah, Mari Kaunisto, Marja Medina, Reetta Niemelä, Gretchen Repasky, Susanna Rosas, Jouko Siro, Tiina Vesterinen Photos and graphics: Jouko Siro, Masha Anastasina, Lise Balsby, Sami Blom, Jason DeBose, Oxana Denisova, Henrik Edgren, Samuel Eldfors, Caroline Heckman, William Hennah, Wilma Hurskainen, Harri Itkonen, Mari Kaunisto, Siv Knaappila, Sergey Kuznetsov, Kari Likonen, Michel Mees, Muntasir Mamun Majumder, Ruusu-Maaria Merivirta, Timo Miettinen, John Patrick Mpindi, Katja Närhi, Tea Pemovska, Aleksi Poutanen, Maija Puhka, Gretchen Repasky, Mikko Sallinen, Veikko Somerpuro, Rauno Träskelin, Tiina Vesterinen Academy of Finland, EATRIS, European Molecular Biology Laboratory (EMBL), Finnish Red Cross Blood Service and University of Helsinki are acknowledged for the photos. Juvenes Print 2013
Contents Director s overview... 4 The first five years at FIMM... 6 Nordic EMBL Partnership for Molecular Medicine expanded to Denmark... 8 Greetings... 9 Bridge-building towards the clinic... 9 Chair of the Board of FIMM...10 Former Chair of the Board of FIMM, Vice President for Research, Academy of Finland...10 Chancellor of the University of Helsinki...11 Grand Challenges... 12 Individualized Systems Medicine (ISM) for accelerating translational oncology in AML...12 Utilizing Finnish Genomes to empower personalised and predictive health...13 Research Highlights... 14 Research Groups in Human Genomics... 18 Group Palotie...19 Group Hennah...21 Group Palmgren...22 Group Ripatti...23 Group Saarela...24 Group Widen...25 Research Groups in Systems Medicine and Translational Research... 26 Group Kallioniemi...26 Group Aittokallio...27 Group Kainov...28 Group Knowles...29 Group Kuznetsov...30 Group Lundin...31 Group Verschuren...33 Group Wennerberg...34 Finland Distinguished Professors at FIMM... 35 Doctoral Training... 36 Technology Centre... 39 Biobanking... 46 Administration... 52 Examples of On-going Projects... 55 A year at FIMM... 59 FIMM in Figures... 64 Publications 2012... 68 FIMM 3
Director s overview When starting as the Director of FIMM in December 2007, I was asked to prepare a plan for the development of the new institute as part of the Nordic EMBL Partnership for Molecular Medicine. The following is an excerpt from these plans: Molecular medicine of the future needs to focus on personalised medicine, making use of molecular data at the level of the individual patient to drive diagnostic and therapeutic decisions. FIMM represents a unique opportunity to advance molecular medicine in Finland. The focus and mission should revolve around translational research, i.e. taking advantage of the high-quality biomedical discoveries in Finland to advance personalised medicine in the decades to come. Everything above is still very true as we now venture towards the next 5-year period. However, as compared to the 2007, we now have almost 200 people, 15 group leaders, a strong Technology Centre and Biobanking Infrastructure to help realize such goals. Significant progress towards scientific breakthroughs and personalised medicine has happened and much more is now underway. Photo by Michel Mees EATRIS is credited for the photo. FIMM was awarded an excellent start-up funding to recruit EMBL-style group leaders and to launch a new institute. The support from Jane and Aatos Erkko Foundation, Sigrid Jusélius Foundation, The Finnish Medical Foundation, Orion- Farmos Research Foundation, the City of Helsinki, Ministry of Education and Culture, the University of Helsinki and the Hospital District of Helsinki and Uusimaa (HUS) is gratefully acknowledged. This annual report is a testimony to what has been achieved in the past five years. The start-up funding helped to build an institute and recruit an excellent group of young talented investigators at all levels, from PIs to PhD students. Due to everybody s dedicated work, FIMM is now established in the international arena as an expert site for human genomics and personalised medicine research, with groundbreaking translational and clinical capabilities. The FIMM start-up funding is now ending in 2013 2014. As a result of the University Reform Act in 2009, the future of FIMM will remain largely dependent on the basic funding support from its primary host, the University of Helsinki. Since the budgets for universities are not increasing, it is very difficult for the University to assume responsibility for all the work previously supported by the start-up funds at FIMM. Therefore, most likely the total support for FIMM research will go down in 2014 2015. Fortunately, FIMM has acquired significant external project funding from diverse sources, about 10 M /year in 2012 2013. The science policy in Finland is designed such that the research community is dependent on a continuous supply of competitive external grants. While FIMM researchers have been very successful in acquiring such funding, this will not serve as a replacement for basic funding. Therefore, our ability to operate an EMBL-style molecular medicine institute with rotating group leader positions is far from certain in this scenario. Like any other institute under the University of Helsinki umbrella, FIMM has to rely largely on competitive national and international project funding for its support. This is not quite like the EMBL model, where recruitment of international top talent to rotational 5+4 year PI-positions with good basic support is a key feature. Also, term-limited grant support is not optimal for running long-term highrisk and ambitious research goals of societal importance. With these challenges on the future in mind, what is the FIMM strategy for the future? We remain committed to carry out high-quality research and to translate these to the clinic. We believe that an important way to achieve this will be to focus strongly on grand challenges in the society, and make almost the entire institute to work together towards such goals. We have two established and one emerging grand challenge initiatives under development at FIMM. The first one involves the application of Finnish ge- 4 FIMM
nome information for the development of personalised and predictive health care. The second one involves the development of the concept of individualized systems medicine for cancer care, starting from acute leukaemias. The third grand challenge involves digital image-based pathological diagnostics, which will be required as we move molecular pathology towards multiplexed in situ assays, quantitative assays and automatic decision support. Taken together, we believe that these three grand challenges will help to refine the institutes mission. In 2020, we hope to have contributed to a national policy that enables Finland to be a leading country in the implementation of personalised medicine in health care at the level of the citizens, primary care, secondary care, both public and private. Professor Olli Kallioniemi, Director, FIMM Orion-Farmos Research Foundation FIMM 5
The first five years at FIMM 2007 2008 2009 Janna Saarela appointed Research Director, FIMM Technology Centre 200 Personnel FIMM-EMBL Group Leaders Emmy Verschuren and Denis Kainov FIMM National Network for Molecular Medicine 150 First FIMM-EMBL Group Leader Sergey Kuznetsov EATRIS project ENGAGE project 100 50 2002: The idea to establish an international molecular medicine research centre in the Nordic countries. Academy Professor Olli Kallioniemi appointed first Director of FIMM 2007-2012 Academy Professor Leena Peltonen-Palotie appointed Research Director of FIMM Human Genomics 2002 2003 2004 2005 2006 2007 2008 2009 Initiative of the Academy of Finland to establish a research centre in Finland with EMBL Report of the Biotechnology 2005 Expert Group of the Ministry of Education Decision on the establishment of FIMM by the Senate of the University of Helsinki as a joint institute of the University, HUS and KTL Finnish Genome Centre merged to FIMM VTT joined FIMM Biomedicum Helsinki 2U building The Board and SAB of FIMM nominated Start-up funding from the Ministry of Education (2007-2009), Erkko, Jusélius, Finnish Medical and Orion-Farmos Foundations, the City of Helsinki and HUS THL established (KTL and Stakes merged) 6 FIMM Establishment of the Nordic EMBL Partnership for Molecular Medicine 2007-2012
2010 2011 2012 2013 2014 2020 FiDiPro Professor Jonathan Knowles FIMM-EMBL Group Leaders Krister Wennerberg and Samuli Ripatti FIMM Clinical Collaboration Programme FIMM-EMBL PhD International Training Initiative Biomedinfra (national ESFRI collaboration) PREDECT (Innovative Medicine Initiative) Biocenter Finland funding EU-OPENSCREEN project FiDiPro Professor Juni Palmgren FIMM-EMBL Group Leader Tero Aittokallio Johan Lundin appointed Research Director, Diagnostic Development Olli Kallioniemi appointed Director of FIMM 2012-2017 FiDiPro Professor Leif Groop BBMRI-LPC project Aarno Palotie appointed Research Director, FIMM Human Genomics Vision: 2020 FIMM is an international leading centre for molecular medicine and Finland is a leading country in personalised medicine. 2010 2011 2012 2013 2014 2020 New University Law FIMM Launch Event and SAB Visit The Board of FIMM nominated 2010-2014 International Evaluation of Research and Doctoral Training at the University of Helsinki 2005-2010 Academician of Science Leena Peltonen-Palotie Memorial Symposium Renewal and expansion of the Nordic EMBL Partnership for Molecular Medicine 2013-2023 SAB Visit and FIMM 5-year Evaluation SAB Visit FIMM 7
Nordic EMBL Partnership for Molecular Medicine expanded to Denmark The Nordic EMBL Partnership for Molecular Medicine expanded to Denmark as the agreement between EMBL, DANDRITE, Aarhus University, FIMM, University of Helsinki, MIMS, Umeå University and NCMM, University of Oslo was signed on 5 March 2013 in Aarhus, Denmark. The Agreement for Establishing the Nordic EMBL Partnership was initially signed in 2007 for a five-year period. Now the agreement was renewed for a ten-year period. Rector Thomas Wilhelmsson and Director Olli Kallioniemi signed the agreement on behalf of FIMM, University of Helsinki. When establishing the Nordic EMBL Partnership in 2007, the idea was to promote synergistic collaboration between the Nordic countries and EMBL. The Partnership has achieved its goals. stated Director General of EMBL, Professor Iain Mattaj in Aarhus. He also found it important that the collaboration is based on national strengths of the four Nordic countries and that the research focus areas in the nodes are complementary in nature. The Nordic EMBL Partnership provides an excellent platform for Nordic and European research and infrastructure collaboration. In addition, joint training initiatives and mobility of researchers can be supported in many ways within this institutional and coordinated Partnership. said Rector Thomas Wilhelmsson. DANDRITE (Danish Research Institute of Translational Neuroscience) started in January 2013 with three core groups of Professors Poul Nissen (Interim Director), Anders Nykjaer and Poul Henning Jensen. Altogether five EMBL style selected group leaders will be recruited to the Institute. In addition to Aarhus University, the Lundbeck Foundation is committed to fund DANDRITE for a ten-year period. Photos by Lise Balsby 8 FIMM
Greetings Bridge-building towards the clinic Cancer diagnostics and treatments have changed substantially during the last several years. No longer are all cancers considered to behave similarly in all patients. Instead, a more precise diagnostic workup is anticipated to reveal different subcategories for different cancer types. All this aims at optimized patient outcome as treatments can be individualized. This personalised approach to cancer diagnostics and treatments is to a large extent driven by a fast development of laboratory technologies. Not only have techniques like next-generation sequencing become cheaper and faster, but also novel and exciting technologies such as high-throughput drug testing and automated image analysis are around the corner. To eventually utilize these techniques in patient care, thorough translational research needs to be conducted. In this respect, the natural collaborator for a clinician in Helsinki University Central Hospital (HUCH) is FIMM, with its impressive infrastructure and innovative research groups. A good example of successful collaboration is individualized treatment of Acute Myeloid Leukaemia (AML) patients using Drug Sensitivity and Resistance Testing (DSRT) technology in a joint program between Division of Hematology at HUCH and FIMM. This programme is backed up by an ambitious national biobanking protocol set up between the Finnish Association of Hematology and FIMM (http://www.hematology.fi/fhrb). A similar approach is used for urologic solid organ tumours, also backed up by a collaborative biobanking protocol between Department of Urology at HUCH and FIMM with impressive 600 patient consents and more that 10.000 sample aliquots collected after the first year of operation only (http://www.hubbiobank.fi/en/). Professor Kimmo Porkka and Docent Antti Rannikko, University of Helsinki and Helsinki University Central Hospital (HUCH) FIMM 9
Chair of the Board of FIMM The year 2012 concluded the five-year (2008 2012) start-up and construction phase of FIMM. During this period, FIMM has become an international high-profile research institute in molecular medicine research, with world-class infrastructure, focus towards creating tangible benefits to the society and applications linking top-class medical research with industrial collaboration. The results of the International Evaluation of Research and Doctoral Training of the University of Helsinki 2005 2010 were published in 2012. FIMM researchers were involved in three Researcher Communities: Cancer Biology (CANBIO), Complex Disease Genomics Group (CompDisGen) and Personalised Molecular Medicine (P-Molmed). All of these received top scores, with the P-Molmed receiving the highest ranking score in the category for societal impact. In 2012, based on the recommendations of the Scientific Advisory Board (SAB) and Board of FIMM, Rector Thomas Wilhelmsson appointed Professor Olli Kallioniemi the Director of FIMM for another five-year term, starting in December 2012. Olli Kallioniemi s Inauguration Lecture Personalised Medicine 2020 took place in January 2013. Together with Rector Thomas Wilhelmsson and the Board of FIMM, we have carefully discussed the FIMM funding situation in the forthcoming years. International recruitment of global experts to Finland has been implemented with internationally competitive support packages (about 1.5 M /group leader/five years) during the first five-year period, by virtue of valuable support from several private foundations and the University of Helsinki. FIMM researchers have been successful in competition of external project funding. However, maintenance of EMBL group leader salaries and attractive long-term start-up packages cannot be covered by external project funding only. Acquisition of sustainable funding to maintain the EMBL status remains a challenging, but reachable, task in the future. Professor Kimmo Kontula, Vice Rector of the University of Helsinki, Chair of the Board of FIMM 2010 2014 Former Chair of the Board of FIMM, Vice President for Research, Academy of Finland The European Molecular Biology Laboratory (EMBL) was founded in 1974 as an intergovernmental institute to initiate in Europe research in the then new field, molecular biology. Today, EMBL is one of the world s leading institutes in the life sciences, funded by 20 Member States and operating in its headquarters in Heidelberg and four outstations, embracing four partnerships. One of the latter is the Nordic EMBL Partnership for Molecular Medicine, established in 2007, between EMBL, the Institute for Molecular Medicine Finland (FIMM) in Helsinki, the Centre for Molecular Medicine Norway (NCMM) in Oslo and the Laboratory for Molecular Infection Medicine Sweden (MIMS) in Umeå. The high quality health care systems, population-based registers, and patient and sample databases in the Nordic countries provide the unique niche for this collaboration. In March 2013, the Nordic EMBL Partnership was extended by a most welcome new member, the Danish Research Institute of Translational Neuroscience (DANDRITE) in Aarhus. The strengthening of the Nordic EMBL Partnership could not be timelier, as the Nordic Council of Ministers is in the process of considering opening up of research and funding opportunities and access to infrastructure across the borders of Denmark, Finland, Iceland, Norway and Sweden. The Nordic EMBL Partnership is optimally placed to further and take advantage of collaboration not only in the Nordic countries, but also to bridge it with research activities, funding opportunities and infrastructure at the European level. Professor Marja Makarow, Vice President for Research, Academy of Finland (Vice Rector of the University of Helsinki 2003 2007; Chief Executive of the European Science Foundation 2008 2011; Chair of the Board of FIMM 2007 2010) 10 FIMM
Chancellor of the University of Helsinki In spring 2006, the Ministry of Education and Culture (then, the Ministry of Education) commissioned the University of Helsinki to begin preparatory work to establish a research institute for molecular medicine as a joint undertaking with other biocentre universities, as well as with other institutions in the field. Background for the assignment was the initiative of an expert group of the Academy of Finland and the Biotechnology 2005 committee report of the Ministry of Education. After some negotiations, the other biocentre universities decided not to join to the institute. As the Rector of the University of Helsinki, I chaired the University Senate meeting in autumn 2006 which decided to establish the Institute for Molecular Medicine Finland (FIMM) as a joint effort of the University, the Hospital District of Helsinki and Uusimaa (HUS), and the National Institute for Health and Welfare (THL, then the National Public Health Institute, KTL). VTT Technical Research Centre of Finland joined FIMM in 2008. The Agreement for Establishing the Nordic EMBL Partnership for Molecular Medicine was signed in Heidelberg in 2007. Today, I am happy to see that only five years after its establishment, FIMM is a highly successful international institute with a clearly defined profile in basic and translational research, with highly qualified doctoral students, researchers, group leaders and Finland Distinguished Professors, and with a world-class research infrastructure and nation-wide and international technology services. FIMM has fully accomplished the objectives set in the reports initiating the establishment of the institute. Professor Ilkka Niiniluoto, Chancellor of the University of Helsinki (Rector of the University of Helsinki 2003 2008) EMBL signing ceremony in 2007. EMBL is credited for the photo. FIMM 11
Grand Challenges Individualized Systems Medicine (ISM) for accelerating translational oncology in AML We have established a close collaboration with hematologists at the Helsinki University Central Hospital (HUCH) to develop a novel Individualized Systems Medicine (ISM) strategy for translational cancer research. We combine biobanking, state-of-the-art genomic technology, high-throughput drug testing, and rapid clinical translation in a programme that has grown into a major effort at FIMM and HUCH. We selected adult Acute Myeloid Leukaemia (AML) as the primary target of our studies due to its lower complexity as compared to solid tumours. Millions of cells can be readily obtained for both molecular and ex vivo drug response studies. Sampling at the time of diagnosis, remission and relapse and drug resistance is easily accomplished. Indeed, analysis of temporal evolution patterns in individual patients represents the unique opportunity. AML patients, particularly those with treatment-refractory disease with less than 10% long-term survival expectation, desperately need new therapeutic options to replace the 30 50 year-old chemotherapeutic regimens. Refractory AML therefore represents an ideal indication to introduce individualized treatments to improve cancer care. ISM combines multiple levels of medical, technological, scientific, and strategic aspects to practice translational cancer medicine as follows: Focus on individual patients: We will seek to understand and interpret the unique genomic and molecular profile of the disease in each individual patient. Direct prediction of response to all drugs: Functional, large-scale drug response data are acquired from ex vivo primary culture of cancer cells from patients. Real-time science: Biobanking, profiling, analysis, and interpretation of each case in 1 4 weeks, with feedback to the clinician. Scientists work in parallel with clinical developments one case at-a-time. Consecutive sampling from different stages of cancer evolution: Understanding of mechanisms of drug resistance and cancer evolution for each patient. Integration of in vivo, ex vivo and in vitro data: Model systems will be designed to understand mechanisms and causalities, such as drug combinations, based on ex vivo data from patient samples. Thus patient samples and models are compared to one another. Implementation: Patient consent and ethical permission allow implementation of actionable results in the clinic at a time when no other therapy options exist. Drug combinations: We will identify synergistic drug regimens blocking multiple cancer subclones and escape routes for cancer cells. Systems medicine strategy: Continuous circle of (re)analysis of data and improving models and understanding: learning from each patient and each consecutive sample. De-risking clinical trials: ISM is likely to help choose the right patients and new drugs for clinical trials. 12 FIMM
Utilizing Finnish genomes to empower personalised and predictive health The Human Genomics Programme at FIMM builds on a long Finnish tradition of high-impact genetic research. Finland was one of the first countries to embrace advances of molecular genetics already in the 1990s, leading to the identification of mutations causing the Finnish disease heritage. More recently, during the past three years, FIMM researchers have with 44 publications in top medical journals, e.g. Science, Nature, Nature Genetics, Lancet, importantly contributed to the recent discoveries of novel genes and gene loci that underlie common disease. Right now, the rapidly increasing capacity to describe the complete genetic and molecular makeup of an individual is changing the way we understand and treat disease. We foresee that Finland has a unique opportunity to be at the forefront of this developing field. To meet this upcoming grand challenge and opening, our strategy is to work towards building a platform that integrates genomic and health outcome data from Finnish national population biobanks into a globally unique and valuable big data repository. This plan relies on a close collaboration between FIMM and THL, but also on extensive multidisciplinary collaborations with other national stakeholders, e.g. VTT, the University of Eastern Finland, the Health & Technology Center in Oulu, the Finnish Medical Society Duodecim, the City of Helsinki and Kymenlaakso Social and Health Services and international cutting edge scientists and institutions, such as the Wellcome Trust Sanger Institute, Broad Institute and UCLA. We envision that data mining of such a massive health data resource will facilitate predictive and preventive approaches, catalyze innovations in health care, as well as empower individuals to reach out towards better health. In our vision, patients and people are seen as active participants and drivers of a health care system 2.0. FIMM 13
Research Highlights Mutation in the STAT3 gene identified as the cause for LGL leukaemia Large granular lymphocytic (LGL) leukaemia is a relatively rare, malignant blood disease of the mature T-cells and, in many cases, it is related to autoimmune diseases such as rheumatoid arthritis. The pathogenetic mechanism of the disease has been unknown. Utilizing the latest DNA sequencing methods that can examine the entire genome, the research groups investigated if the LGL leukaemia cells carry mutations that would explain the onset of the disease. It was discovered that patients suffering from LGL leukaemia have a mutation in the STAT3 gene in a very restricted SH2 area, which has a key effect on the function of the gene. In the future, this result can be utilized in diagnosing the disease and possibly also in treatment, since the first STAT3 inhibitors are already undergoing early clinical trials. The cooperation project of the Meilahti campus research groups was led by Satu Mustjoki, Adjunct Professor (University of Helsinki/HUCH), together with FIMM s researchers Caroline Heckman, Ph.D., and Olli Kallioniemi, Professor, in addition to Kimmo Porkka, Professor, Chief Physician at the Division of Hematology (HUCH). Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, Lagström S, Clemente MJ, Olson T, Jalkanen SE, Majumder MM, Almusa H, Edgren H, Lepistö M, Mattila P, Guinta K, Koistinen P, Kuittinen T, Penttinen K, Parsons A, Knowles J, Saarela J, Wennerberg K, Kallioniemi O, Porkka K, Loughran TP Jr, Heckman CA, Maciejewski JP, Mustjoki S. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 2012 May 17;366(20):1905-13. A Multi-Omic Study Highlights the Link between Inflammation and Low HDL-C We have performed the first genome-wide association analysis on low HDL-C. By combining genomic data with adipose tissue transcriptome and HDL particle lipidome analyses, we provide important insights into HDL biology. We show that genetic variants within inflammatory pathways are associated with low HDL-C. These variants also regulate both adipose tissue and vascular inflammation, suggesting a genetic link between inflammation and low HDL-C. We also demonstrate that not only the quantity but also the quality differs in HDL particles between subjects with low and high HDL-C; antioxidative lipid species are less abundant in HDL particles of subjects with low HDL-C highlighting the importance of distinguishing HDL particles from HDL-cholesterol when relating HDL with cardiovascular risk and atherosclerosis. Importantly, we show the value of using extreme phenotypes in genetic analysis: there are genes, especially in the HLA region, which are not associated with HDL-C in general, but only with extreme HDL-C phenotypes. This observation suggests the presence of low/high HDL-C genes in addition to the HDL-C genes that have been reported in population-based GWA studies. This paper was selected the publication of the week by the Faculty of Medicine, University of Helsinki. Laurila PP, Surakka I, Sarin AP, Yetukuri L, Hyötyläinen T, Söderlund S, Naukkarinen J, Tang J, Kettunen J, Mirel DB, Soronen J, Lehtimäki T, Ruokonen A, Ehnholm C, Eriksson JG, Salomaa V, Jula A, Raitakari OT, Järvelin MR, Palotie A, Peltonen L, Oresic M, Jauhiainen M, Taskinen MR, Ripatti S. Genomic, Transcriptomic, and Lipidomic Profiling Highlights the Role of Inflammation in Individuals With Low High-density Lipoprotein Cholesterol. Arterioscler Thromb Vasc Biol. 2013 Feb 14. [Epub ahead of print] PubMed PMID: 23413431. 14 FIMM
A quantitative tool for strand-specific mrna expression analysis Primer-independent cdna synthesis during reverse transcription hinders quantitative analysis of bidirectional mrna in eukaryotes as well as in cells infected with RNA viruses. We have developed a simple RT-PCR-based assay for strand-specific geneexpression analysis. By modifying the cdna sequence during reverse transcription, using specially designed primers, the opposite strands of target sequences can be simultaneously detected by postamplification melting curve analysis and primerinitiated transcripts are readily distinguished from nonspecifically primed cdna. We have demonstrated the utility of this technique for analysis of (+) and (-) RNA synthesis of influenza A virus in infected cells. This technique represents a powerful tool for analysis of bidirectional RNA synthesis and it can also be utilized for monitoring primer-independent cdna synthesis during reverse transcription. The technique was highlighted in Biotechniques 2012 year in review as number one of the best PCR methods published in the journal during the year. Feng L, Lintula S, Ho TH, Anastasina M, Paju A, Haglund C, Stenman UH, Hotakainen K, Orpana A, Kainov D, Stenman J. Technique for strand-specific gene-expression analysis and monitoring of primer-independent cdna synthesis in reverse transcription. Biotechniques. 2012 Apr;52(4):263-70. Genome-wide association study reveals genetic loci predisposing to the most common form of migraine By analysing close to 5,000 migraneurs and 7,200 controls by genome-wide association, we identified four gene loci predisposing to the most common form of migraine, migraine without aura. The pathophysiology of migraine is poorly understood. Identification of genes that contribute to the disease susceptibility should improve our understanding of basic disease mechanisms. Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, Terwindt GM, Pozo-Rosich P, Winsvold B, Nyholt DR, van Oosterhout WP, Artto V, Todt U, Hämäläinen E, Fernández-Morales J, Louter MA, Kaunisto MA, Schoenen J, Raitakari O, Lehtimäki T, Vila-Pueyo M, Göbel H, Wichmann E, Sintas C, Uitterlinden AG, Hofman A, Rivadeneira F, Heinze A, Tronvik E, van Duijn CM, Kaprio J, Cormand B, Wessman M, Frants RR, Meitinger T, Müller-Myhsok B, Zwart JA, Färkkilä M, Macaya A, Ferrari MD, Kubisch C, Palotie A, Dichgans M, van den Maagdenberg AM: International Headache Genetics Consortium. Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet. 2012 Jun 10;44(7):777-82. The genetics of pubertal growth Growth patterns during puberty correlate with pubertal timing, and variability in pubertal timing associates with health risks later in life, for example for hormonedependent cancers and adverse cardiovascular health. Although there is mounting evidence for these links, few studies have addressed the genetics of distinct phases of childhood growth. With access to over 18,000 study subjects with multiple height measurements from childhood and adolescence within the Early Growth Genetics Consortium, we identified ten loci associated with height growth during the pubertal growth spurt. Among these loci, LIN28B exemplifies a gene which may mediate the link between pubertal development and health risks later in life, as it is a gene known to influence childhood growth, pubertal timing, and cancer progression and prognosis. We also identified a novel growth and pubertal timing locus that influenced expression of the gene MAPK3, also involved in several forms of cancer. Finally, while epidemiological studies suggest that early puberty marks a pathway FIMM 15
from rapid prepubertal growth to reduced final height and adult obesity, we show that this is not always the case for individual genetic variants. Our study shows that tracking the genetic effects of individual genes across multiple growth periods may help uncover specific pathways linking childhood events to adult outcomes. Cousminer DL, Berry DJ, Timpson NJ, Ang W, Thiering E, Byrne E, Taal HR,Huikari V, Bradfield JP, Kerkhof M, Groen-Blokhuis MM, Kreiner-Møller E,Marinelli M, Holst C, Leinonen JT, Perry JR, Surakka I, Pietiläinen O, Kettunen J, Anttila V, Kaakinen M, Sovio U, Pouta A, Das S, Lagou V, Power C, Prokopenko I, Evans DM, Kemp JP, St Pourcain B, Ring S, Palotie A, Kajantie E, Osmond C, Lehtimäki T, Viikari JS, Kähönen M, Warrington NM, Lye SJ, Palmer LJ, Tiesler CM, Flexeder C, Montgomery GW, Medland SE, Hofman A, Hakonarson H, Guxens M, Bartels M, Salomaa V; The ReproGen Consortium, Murabito J, Kaprio J, Sørensen TI, Ballester F, Bisgaard H, Boomsma DI, Koppelman GH, Grant SF, Jaddoe VW, Martin NG, Heinrich J, Pennell CE, Raitakari O, Eriksson JG, Smith GD, Hyppönen E, Järvelin MR, McCarthy MI, Ripatti S, Widén E; for the Early Growth Genetics (EGG) Consortium. Genome-wide Association and Longitudinal Analyses Reveal Genetic Loci Linking Pubertal Height Growth, Pubertal Timing, and Childhood Adiposity. Hum Mol Genet. 2013 Feb 27. [Epub ahead of print] Large population cohort studies reveal that saccular intracranial aneurysms and systolic blood pressure share genetic components Some 3% of the general population develop saccular intracranial aneurysms, the rupture of which is a major cause of life threatening subarachnoid haemorrhage. The basic mechanisms of aneurysm formation and their rupturing are poorly understood, but blood pressure is a well-known risk factor. Using well characterized Finnish population cohorts we demonstrate that one aneurysm susceptibility gene locus is associated with systolic blood pressure suggesting that these two traits have shared genetic components, possibly eluting to a shared disease mechanism. Gaál EI, Salo P, Kristiansson K, Rehnström K, Kettunen J, Sarin AP, Niemelä M, Jula A, Raitakari OT, Lehtimäki T, Eriksson JG, Widen E, Günel M, Kurki M, von Und Zu Fraunberg M, Jääskeläinen JE, Hernesniemi J, Järvelin MR, Pouta A; The International Consortium for Blood Pressure Genome-Wide Association Studies (ICBP-GWAS), Newton-Cheh C, Salomaa V, Palotie A, Perola M: Intracranial Aneurysm Risk Locus 5q23.2 Is Associated with Elevated Systolic Blood Pressure. PLoS Genet. 2012 Mar;8(3):e1002563. Harnessing anticancer drugs for the future fight against influenza Influenza viruses cause significant human morbidity and mortality. To treat the infections, different virus-directed drugs have been developed. However, the currently available drugs are targeting viral proteins and due to a high mutation rate the influenza viruses quickly develop resistance to them. For that reason, nextgeneration antiviral drugs should be directed towards the host functions. In this work, we developed a new cell screening method that can be used to identify potential antiinfluenza drugs and identified two novel compounds with anti-influenza activity. The results of this study provide a foundation for development of next-generation antiviral drugs. Furthermore, these identified compounds can be used as chemical tools when studying the molecular mechanisms of virus-host interactions. Denisova OV, Kakkola L, Feng L, Stenman J, Nagaraj A, Lampe J, Yadav B, Aittokallio T, Kaukinen P, Ahola T, Kuivanen S, Vapalahti O, Kantele A, Tynell J, Julkunen I, Kallio-Kokko H, Paavilainen H, Hukkanen V, Elliott RM, De Brabander JK, Saelens X, Kainov DE. Obatoclax, saliphenylhalamide, and gemcitabine inhibit influenza a virus infection. J Biol Chem. 2012 Oct 12;287(42):35324-32. 16 FIMM
Metabolic signatures of insulin resistance in young adults Insulin resistance is a core defect in the development of type 2 diabetes. Already in young adults, insulin resistance is associated with an adverse lipid profile and increased risk for future diabetes. To elucidate metabolic pathways underlying the pathogenesis of insulin resistance, we comprehensively characterized systemic metabolite profiles in over 7,000 apparently healthy young adults. We identified a diverse metabolic signature with insulin resistance beyond the conventional characteristics of obesity and dyslipidemia. A combination of amino acids, lipids, and intermediates of glycolysis formed sex-specific imprints of insulin resistance on the metabolite profile already in early adulthood. Although genetic evidence did not provide suggest a causal role of the metabolites in the development of insulin resistance, these metabolites may still help to identify individuals at high risk for progression towards future diabetes. Understanding the relation between insulin resistance and the systemic metabolite profile in young, healthy adults may help to promote lifestyle habits for prevention of insulin resistance prior to overt diabetes. Würtz P, Mäkinen VP, Soininen P, Kangas AJ, Tukiainen T, Kettunen J, Savolainen MJ, Tammelin T, Viikari JS, Rönnemaa T, Kähönen M, Lehtimäki T, Ripatti S, Raitakari OT, Järvelin MR, Ala-Korpela M. Metabolic signatures of insulin resistance in 7,098 young adults. Diabetes. 2012 Jun;61(6):1372-80. New computational strategies combine different omics data and identify susceptibility genes for common traits and help to construct disease networks New methods to analyse large, omics datasets provide opportunities to improve our understanding of disease mechanisms and construct disease networks. We have combined GWAs and expression data in a multivariant model and demonstrate the power of this strategy to improve the analysis of large genome datasets. Inouye M, Ripatti S, Kettunen J, Lyytikäinen LP, Oksala N, Laurila PP, Kangas AJ, Soininen P, Savolainen MJ, Viikari J, Kähönen M, Perola M, Salomaa V, Raitakari O, Lehtimäki T, Taskinen MR, Järvelin MR, Ala-Korpela M, Palotie A, de Bakker PI: Novel Loci for metabolic networks and multi-tissue expression studies reveal genes for atherosclerosis. PLoS Genet. 2012 Aug;8(8):e1002907. FIMM 17
Research Groups in Human Genomics Based on the recommendations of the Scientific Advisory Board (SAB) and Board of FIMM Dr. Aarno Palotie was appointed Research Director in the field of Human Genomics in November 2012 (part-time position). Aarno Palotie is a former Director of the Finnish Genome Center. He has been one of the leaders of Human Genomics at FIMM during the last two years, while his main affiliation has been at the Wellcome Trust Sanger Institute in UK. FIMM will increasingly focus on the bioinformatic integration of genomics and other omics data with health care information, as well as on the implementation of genomics in health care. Dr. Palotie is committed to lead these Finnish grand challenge initiatives on genomes and health. In collaboration with our national and international partners, we aim to capitalize on Finland s unique population structure and decades of investments in epidemiological and clinical cohorts. Our goal is to make Finland the poster child of genomic medicine. he said. Dr. Palotie is also hosting FiDiPro Professor Leif Groop s project Using the unique knowledge of the genetics architecture of Finland to identify the genetic variants which explain the inherited risk of diabetes. 18 FIMM
Group Palotie Genomics and Health Research Director, Professor Aarno Palotie, MD, PhD The overall aim of our group is to build towards a more comprehensive understanding of the genomic landscape of common diseases utilizing the special opportunities provided by the Finnish population, the Finnish health care infrastructure and large national sample collections. This improved knowledge should provide us with new tools to develop more individualized health care. The recent development of high throughput genotyping and sequencing techniques has made this a realistic goal. The unique setting provided by the Finnish infrastructure has stimulated several large whole exome and whole genome sequencing projects, which have organized themselves in a collaborative initiative called SISu (Sequencing Initiative Suomi). This collaboration includes researchers from FIMM, THL, Lund University, the Broad Institute of MIT and Harvard, Michigan University, UCLA, NIH, Oxford University and the Wellcome Trust Sanger Institute. During 2012, the SISu project has produced the complete genome or exome (coding areas of the genome) sequence of thousands of Finns. When this is combined with the existing genome-wide genotyping (GWA) data from more than 50,000 Finns, we have a rich resource that can be further expanded and used to facilitate a more comprehensive understanding of the genome landscape associated with diseases that are major health burdens to the population. Our group has a special interest in the genetics of neurological and neurodevelopmental traits. Also much of this 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 (www.nationalbiobanks.fi). 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. These studies include the UK10K study (www.uk10k.org) and GWAs studies of the International Headache Genetics Consortium chaired by Dr. Palotie 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. Group Members: PI: Aarno Palotie Senior Researcher: Maija Wessman PhD Students: Tiia Luukkonen, Mikko Muona, Olli Pietiläinen Technicians: Eija Hämäläinen, Elli Kempas (until August 2012) 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 Key publications: Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, Terwindt GM, Pozo-Rosich P, Winsvold B, Nyholt DR, van Oosterhout WP, Artto V, Todt U, Hämäläinen E, Fernández-Morales J, Louter MA, Kaunisto MA, Schoenen J, Raitakari O, Lehtimäki T, Vila-Pueyo M, Göbel H, Wichmann E, Sintas C, Uitterlinden AG, Hofman A, Rivadeneira F, Heinze A, Tronvik E, van Duijn CM, Kaprio J, Cormand B, Wessman M, Frants RR, Meitinger T, Müller-Myhsok B, Zwart JA, Färkkilä M, Macaya A, Ferrari MD, Kubisch C, Palotie A, Dichgans M, van den Maagdenberg AM: International Headache Genetics Consortium. Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet. 2012 Jun 10;44(7):777-82. Gaál EI, Salo P, Kristiansson K, Rehnström K, Kettunen J, Sarin AP, Niemelä M, Jula A, Raitakari OT, Lehtimäki T, Eriksson JG, Widen E, Günel M, Kurki M, von Und Zu Fraunberg M, Jääskeläinen JE, Hernesniemi J, Järvelin MR, Pouta A; The International Consortium for Blood Pressure Genome- Wide Association Studies (ICBP-GWAS), Newton-Cheh C, Salomaa V, Palotie A, Perola M: Intracranial Aneurysm Risk Locus 5q23.2 Is Associated with Elevated Systolic Blood Pressure. PLoS Genet. 2012 Mar;8(3):e1002563. FIMM 19
Inouye M, Ripatti S, Kettunen J, Lyytikäinen LP, Oksala N, Laurila PP, Kangas AJ, Soininen P, Savolainen MJ, Viikari J, Kähönen M, Perola M, Salomaa V, Raitakari O, Lehtimäki T, Taskinen MR, Järvelin MR, Ala-Korpela M, Palotie A, de Bakker PI: Novel Loci for metabolic networks and multitissue expression studies reveal genes for atherosclerosis. PLoS Genet. 2012 Aug;8(8):e1002907 Kettunen J, Tukiainen T, Sarin A-P, Ortega-Alonso A, Tikkanen E, Lyytikäinen L-P, Kangas AJ, Soininen P, Würtz P, Silander K, Dick DM, Rose RJ, Savolainen MJ, Viikari J, Kähönen M, Lehtimäki T, Pietiläinen KH, Inouye M, McCarthy MI, Jula A, Eriksson J, Raitakari OT, Salomaa V, Kaprio J, Järvelin M-R, Peltonen L, Perola M, Freimer NB, Ala-Korpela M, Palotie A, Ripatti S: Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nature Genetics, Jan 29;44(3):269-76, 2012. External research funding: Academy of Finland and Finland Distinguished Professor programme, host for Professor Leif Groop, Helsinki Biomedical Graduate Program (HBGP), Sohlberg Foundation, Sigrid Jusélius Foundation, EU-FP7: SYNSYS, NIH/RFA-HL-12-007, Genomic and Metabolomic Profiling of Finnish Familial Dyslipidemia Families 20 FIMM