annual report 2011

ANNUAL REPORT 2011
www.fimm.fi • PL 20, 00014 Helsingin yliopisto • Biomedicum Helsinki 2U, Tukholmankatu 8, 00290 Helsinki
Contents
Overviews and Greetings..................................................................................................... 3
Research Groups in Human Genomics................................................................................. 7
Group Palotie........................................................................................................................7
Group Palmgren................................................................................................................... 8
Group Ripatti....................................................................................................................... 9
Group Saarela.....................................................................................................................10
Group Widén....................................................................................................................... 11
Research Groups in Medical Systems Biology and Translational Research..........................12
Group Kallioniemi............................................................................................................... 12
Group Aittokallio................................................................................................................ 14
Group Kainov...................................................................................................................... 15
Group Knowles................................................................................................................... 16
Group Kuznetsov.................................................................................................................17
Group Lundin...................................................................................................................... 18
Group Verschuren.............................................................................................................. 20
Group Wennerberg............................................................................................................. 21
Research Highlights........................................................................................................... 22
Grand Challenges............................................................................................................... 26
Doctoral Training............................................................................................................... 27
Technology Centre............................................................................................................. 29
Genomics Unit................................................................................................................... 30
Sequencing Unit................................................................................................................. 31
RNAi Unit...........................................................................................................................32
Chemical Biology Unit........................................................................................................33
Metabolomics Unit............................................................................................................ 34
Bioinformatics and IT Unit..................................................................................................35
Biobank Services and Translational Projects.......................................................................37
Meilahti Integrated Biobank Infrastructure (MIBI): A leading national centre for
next-generation biobanking................................................................................................37
Integrated full-service biobanking...................................................................................... 38
Major ongoing clinical biobanking projects.........................................................................42
Integration of mibi with the European Biobanking Infrastructure BBMRI.......................... 44
Administration Unit, Board and SAB.................................................................................. 45
Examples of Ongoing Projects........................................................................................... 47
Events and Visits................................................................................................................50
FIMM in Figures................................................................................................................. 54
Publications 2011................................................................................................................ 58
Overviews and greetings
director olli kallioniemi
I
lected from a global pool of applicants in a major annual
has grown to an institute with 160 employees repre-
selection process, with 1—2 % of the applicants accepted
senting 27 nationalities, 13 research groups and an an-
each year. All activities at FIMM are reviewed by out-
nual budget of about 14 M€. Every year since its launch
side international experts. The research groups at FIMM
in 2007—2008, the institute has grown at a rate of about
closely collaborate with one another, and increasingly
20—30% a year. FIMM is a member of the Nordic EMBL
with their Nordic and EMBL colleagues. Like the par-
Partnership for Molecular Medicine, signed in 2007 be-
ent EMBL, FIMM develops and maintains cutting-edge
tween EMBL and representatives from Finland, Sweden
technologies and infrastructures, including participa-
and Norway. We are very thankful to the private founda-
tion in national (Biocenter Finland) and international
tions whose support made it possible to launch an EMBL
(ESFRI) infrastructure networks for genomics, bioinfor-
partnership institute in Finland. How is the internation-
matics, biobanking, chemical biology and translational
al EMBL model working at FIMM and how will the future
research.
n 2011, at the end of its fourth year of operation, FIMM
look like after the FIMM start-up period, which will soon
come to an end? In December 2011, the FIMM stakeholder
There are also some differences between operations
meeting discussed these issues and challenges at length.
at FIMM and those at the EMBL. In comparison with
the basic research focus at EMBL, progress at FIMM is
There are many similarities between the operations at
strongly dependent on local medical infrastructures,
FIMM and those of the parent EMBL. FIMM closely fol-
such as clinical contacts and expertise, biobanks and
lows the EMBL practices for staff turnover, such as re-
associated clinical data, which also take time to build.
cruiting young group leaders globally for rotational 5+4
Fortunately, FIMM is located on the Meilahti Campus,
year contracts. As a unique international institute in
which has been ranked among the top five in Europe
Finland, FIMM is committed to attracting global talent
in clinical medicine and provides plenty of opportunities
at all levels. For example, FIMM PhD students are se-
for networking as well as access to unique clinical and
FIMM
3
epidemiological samples and data. In contrast to EMBL,
of-the-art biobank infrastructure in Finland. Most im-
which receives most of its funding from member state
portantly, we have made breakthrough discoveries that
contributions, FIMM receives a continuously increasing
are likely to have significant practical significance, such
fraction of its funding (now 65 %) from project funding,
as the discovery of genes for migraine, pubertal growth
which is often temporary in nature. Indeed, FIMM sci-
and the risk of metabolic disorders, genetic risk factor
entists have been very successful in raising outside sup-
scores for cardiovascular disease, a new gene mutated
port for science and infrastructures from the Academy
in leukaemias, personalized medicine approaches for
of Finland, Tekes, EU and others. However, in order to
cancer, emerging cellular targets for influenza antiviral
sustain the EMBL partnership, continue pursue global
agents, mobile microscopy for diagnostics, just to men-
recruitments and attack grand challenges for research,
tion a few.
the level of basic funding at FIMM has now become critically important. International talent will not come to
Indeed, this is where molecular medicine is special. We
Finland based on the opportunity to compete for project
make discoveries which are exciting and of immediate
funding. We will need to offer internationally competi-
human interest. People increasingly also expect con-
tive recruitment packages and funding, and make use of
crete returns from investment in science, and research-
the brand name and recognition of EMBL. We will need
ers need to be engaged with the grand challenges in so-
our stakeholders’ continued support to ensure that the
ciety. In the years ahead, we will ensure that benefits of
international EMBL model will continue to prosper after
FIMM research will flow to society, in the form of better
the first five years.
health care, new diagnostics, treatments and individualized medicine. FIMM has launched grand challenge re-
Overall, as the first five-year period for FIMM will soon
search programmes in “Finnish genomes and health” and
come to an end, there has been enthusiastic support
“Individualized cancer treatments” which will pioneer
for what has been achieved so far. The EMBL partner-
new approaches for health care and medicine. These pro-
ship has been a cornerstone for the success of FIMM.
grammes are based on the unique strengths provided by
In 2011, FIMM researchers published 118 papers and the
the four host institutions of FIMM, the University of Hel-
FIMM National Network for Molecular Medicine another
sinki, HUS, THL and VTT. We are also planning to capital-
73. FIMM researchers were prominently involved in the
ize on opportunities in Finland for collaboration across
top networks in the university-wide evaluation, both in
the different sectors of the society, and propose to place
scientific quality and in society impact. We have helped
Finland in the global forefront in the adoption of indi-
dozens of research groups outside FIMM by offering cut-
vidualized medicine in health care.
ting-edge technology services and built the first state-
4
FIMM
views from the chair of the board and chair of the sab of fimm
FIMM occupies – both physically and operationally – a central position at
the “Meilahti Academic Medical Center” of Helsinki. Since the research
activities started in 2008, FIMM has grown as a research institute with
a distinct role within the academic environment of Finland. It combines
knowledge in the rapidly growing field of genomic medicine, infrastructure needed for research utilizing a wide variety of biological samples of a
varying nature, and all the prerequisites for pivotal translational research,
thus transporting ideas in both ways between the patient´s bed and the
laboratory. FIMM complements and reinforces the resources of its most
important partners, the Faculty of Medicine and the University Hospital.
FIMM also responds to one of the biggest present-day challenges high
level research and education in Finland must face, which is the urgent
need for internationalization. As the Finnish node of the EMBL partnership, FIMM has built up a network of contacts with the top-class international research institutes. The Government and Ministry of Education and Culture should carefully consider the designation of a “national
special mission” to this unique activity of the University of Helsinki, in
order to improve the country´s threatened position in its recruitment of
international scholars.
I wish to warmly thank the members of the Board of FIMM, representing
many of the stakeholders of the institute, for their altruistic availability
and activities toward the development of FIMM during 2011. In addition, I wish to express my sincerest gratitude to the
Chair and Members of the Scientific Advisory Board; their continuous and constructive assessment of FIMM is an essential
element to maintain its credibility.
Professor Kimmo Kontula, Chair of the Board of FIMM; Vice-Rector of the University of Helsinki
The Scientific Advisory Board (SAB) of FIMM had a meeting in Helsinki
on 17 May 2011. Based on the presentations and meetings with the group
leaders, postdoctoral researchers and PhD students as well as members
of the FIMM National Network for Molecular Medicine, the SAB was
impressed by the generally enthusiastic atmosphere within the different groupings of FIMM. Everyone seemed positive about their work and
the progress that had been made. The SAB also noted with satisfaction
that the research efforts are merging such that links are being formed
between the different research groups, creating synergies essential for
future success. These are still early days for FIMM but its productivity is
already impressive. The level of external funding is also impressive and
shows how capable FIMM researchers are in attracting competitive research grants.
Due to the big changes in the Finnish University system in 2010, new issues have arisen with respect to the funding of FIMM. The SAB emphasizes that FIMM indeed should have a role beyond being one research
institute within the University of Helsinki framework. The reason for
founding FIMM was to establish an international institute for molecular
medicine. It is important for the success of FIMM to ensure continuity of
the model adopted from EMBL: the young group leaders have 5+4 years
before leaving FIMM. Only if this is the case can FIMM continue to attract international staff as it successfully does now. EMBL partnership
institutes in Norway and Sweden receive direct support from their governments or the research councils. SAB recommended that discussions should be held between the government, the University of Helsinki and the other stakeholders to guarantee a future for FIMM. Rector Thomas Wilhelmsson of the University
hosted the FIMM Stakeholder Meeting in December 2011 and the discussion, which was very positive, will continue in 2012.
Professor Kai Simons, Chair of the Scientific Advisory Board (SAB) of FIMM;
Max-Planck-Institute of Molecular Cell Biology and Genetics, Germany
FIMM
5
nordic embl partnership for molecular medicine
The Nordic EMBL Partnership for Molecular Medicine with Helsinki, Oslo and Umeå was established in 2007. We expect that a
Danish node will be established and that it will join the Partnership in 2012. The requirements for EMBL Partnerships are scientific
excellence, scientific complementarity to EMBL as well as scientific interaction and common initiatives. In addition, international
recruitment, staff turnover system, regular external reviews and
training are the core principles of EMBL; these are also followed
in its partner institutes. Young group leaders are recruited internationally and they are initially offered posts for a five-year period
with a possible extension of four years based on satisfactory performance. With staff turnover comes turnover in expertise and,
therefore, renewal and the broadening of the research portfolio.
The Scientific Advisory Committee (SAC) of EMBL stated in its evaluation report in May 2011 that although still in its initial phase,
the Nordic EMBL Partnership has developed successful scientific collaborations which attract significant local, national and
European funding and has secured dissemination of the successful EMBL operational model and scientific standards. At least
ten years of sustainable funding is required to secure scientific continuity and attract top European talents in a highly competitive market.
Professor Iain Mattaj, Director General of European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
nordic embl partnership for molecular medicine: 35 group leaders and
330 people with common values and collaborative potential
The Centre for Molecular Medicine Norway (NCMM) and the Laboratory for Molecular Infection Medicine Sweden (MIMS), which
were established in 2007, are young institutes like FIMM. The overall objective of NCMM is to facilitate translation of discoveries in
basic medical research into clinical practice with a particular focus
on disease mechanisms. There are altogether five NCMM-EMBL research groups and three founding groups at NCMM. At MIMS the
molecular mechanisms of infectious diseases are in the research
focus areas. MIMS has six full funded EMBL style group leaders and
two partially funded MIMS group leaders together with six mentors/founding groups. Therefore, taken together with FIMM statistics, the Nordic EMBL Partnership for Molecular Medicine currently
consists of 35 group leaders and a staff about 330.
During the first five-year period of the Nordic EMBL Partnership the three nodes have had joint recruitments for group leaders and PhD students. In addition, all the nodes have recruited postdoctoral researchers and other research staff as well as
built up the infrastructure to be shared within the partnership. NCMM and MIMS are both funded by their host Universities
(Oslo and Umeå). In addition both NCMM and MIMS receive governmental funding from the Norwegian Research Council
and the Swedish Research Council for Infrastructure respectively.
The added value of the Nordic EMBL Partnership, to be completed with a Danish node in 2012 in the field of neurosciences,
can be summarized as i) participation in an organised structure for collaboration with EMBL and inside the Nordic member
countries; ii) organising a structure to effectively translate discoveries in molecular medicine to clinical practice; iii) capitalising on Nordic and European investments in molecular biology to extent applications to medicine; iv) attracting top
international talent and v) educating specialists in molecular medicine, translational research and personalized medicine.
Professor Kjetil Taskén, Director of the Centre for Molecular Medicine Norway (NCMM), Oslo, Norway
Professor Bernt Eric, Director of the Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå, Sweden
6
FIMM
research groups in human
genomics
Group Palotie
Genomics and Health
Professor Aarno Palotie, MD, PhD
T
he 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 will produce 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 47 000 Finns, we will have a rich resource that can be further
expanded and used to facilitate 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 Researchers: Kaisa Silander,
Maija Wessman
Postdoctoral Researchers: Verneri Anttila,
William Hennah
PhD Students: Tiia Luukkonen, Mikko Muona,
Olli Pietiläinen, Mari Rossi (together with
Iiris Hovatta and Samuli Ripatti)
Technicians: Eija Hämäläinen, Elli Kempas,
Minna Suvela
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:
Anttila V, Stefansson H, Kallela M et al. Identification of a migraine-associated variant on 8q22.1,
Nat Genet. Oct;42(10):869-73, 2010.
Inouye M, Silander K, Hamalainen E et al. An immune response network associated with blood
lipid levels. PLoS Genet. Sep 9;6(9), 2010.
Yasuno K, Bilguvar K, Bijlenga P et al. Genome-wide association study of intracranial aneurysm
identifies three new risk loci Nat Genet. May;42(5):420-5, 2010.
The 1000 Genomes Consortium: A map of human genome variation from population scale sequencing. Nature. Oct 28;467(7319):1061-73, 2010.
External research funding: Academy of Finland: Center of Excellence and Academy Project,
Helsinki Biomedical Graduate Program (HBGP), Sigrid Juselius Foundation, EU-FP7: SYNSYS
FIMM
7
group palmgren
Data Integration and Statistical Modelling
FiDiPro Professor Juni Palmgren, PhD (Finland Distinguished Professor,
Academy of Finland)
T
Group Members:
PI: Juni Palmgren
Postdoctoral Researchers: Alfredo Ortega-Alonso,
Ola Spjuth, Martin Eklund
he Palmgren group has a strong biostatistics background coupled with more
recent efforts to integrate data and the modeling process. Several of the ongoing projects are collaborations between Karolinska Institutet, where Palmgren
has her Swedish base, and the FIMM human genomics group.
In 2011, our focus has been on:
i) Characterization of genetic structure. Swedish groups together with the FIMM Human Genomics groups investigated the genetic structure of the Swedish population. Using genome-wide data from more than 5 000 Swedes a strong difference
was observed between northern counties compared to the rest of Sweden, challenging the view that the Swedish population is genetically homogenous.
ii) Mediation of genetic effects on circulating metabolites. As a part of the work in the
human genomics group on characterizing genetic effects on circulating metabolites we have contributed with aspects of how biological and environmental factors
can act as mediators. In particular Alfredo Ortega-Alonso has carried out study on
the heritability of a wide range of serum metabolites, how differences in sex and
body adiposity mediates in the genetic regulation of serum metabolites, and the
possibility to disentangle how habitual physical activity jointly with genes affects
the development of adverse metabolic profiles. The results have relevance for prevention and treatment of metabolic disorders.
iii) Data integration. As part of the SIMBioMS (System for Information Management in BioMedical Studies) project led by Dr Maria Krestyaninova we are pursuing
a project to provide integrated information on data availability, facilitating project
planning and integration of distributed data sources. This infrastructure project
involves scientists across Europe. An ongoing pilot led by Ola Spjuth is to connect
health care quality registries with biobanks in cancer research.
iv) Integrated data-infrastructure for population biobanks and registries. Triggered by the
ongoing revision of the EU Data Directive for personal data we have initiated discussions between THL, CSC and FIMM on integrating biobank data and population
and health registers. Building on the revised legislation the ambition is to open up
for closer harmonization of procedures within the Nordic countries.
Work will continue on contributing to general data infrastructures as well as
more specific modeling tasks in human genetics.
FiDiPro Professor Juni Palmgren is also Professor of Biostatistics at the Department of Mathematics, Stockholm University and Guest Professor of Biostatistics at
Karolinska Institutet, Sweden.
Key publications:
Humphreys K, Grankvist A, Leu M, Hall P, Liu J, Ripatti S, Rehnström K, Groop L, Klareskog L, Ding
B, Grönberg H, Xu J, Pedersen NL, Lichtenstein P, Mattingsdal M, Andreassen OA, O’Dushlaine C,
Purcell SM, Sklar P, Sullivan PF, Hultman CM, Palmgren J, Magnusson PK. The genetic structure of
the Swedish population. PLoS One. 2011;6(8):e22547.
Kettunen J, Tukiainen T, Sarin AP, Ortega-Alonso A, Tikkanen E, Lyytikäinen LP, 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 MR, 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. Nat Genet.
2012 Jan 29;44(3):269-76
Ortega-Alonso A, Pietiläinen KH, Silventoinen K, Saarni SE, Kaprio J. Genetic and environmental factors
influencing BMI development from adolescence to young adulthood. Behav Genet. 2012 Jan;42(1):73-85
Krestyaninova M, Spjuth O, Hastings J, Dietrich J, Rebholz-Schuhmann D. Biobank metaportal to
enhance collaborative research: sail.simbioms.org<http://sail.simbioms.org>. Journal of Systemics, Cybernetics and Informatics. 2012. Accepted for publication.
External research funding: Biocenter Finland, Swedish Research Council, Swedish
eScience Center, SeRC
8
FIMM
Group Ripatti
Statistical and Computational Genetics
FIMM-EMBL Group Leader (supported by the Sigrid Jusélius Foundation)
Samuli Ripatti, PhD, Adjunct Professor
U
nprecedented amounts of new knowledge about the genetic architecture of
common complex diseases have been accumulated over the past five years.
Cataloguing common genetic variation in large well-phenotyped and populationbased biobanks around the world has been the key factor for this success. Finnish
cohorts and case-control samples have often been instrumental in these studies.
Currently, the biobank samples are going to provide much more precise descriptions of our genomic, transcriptomic, metabolomics, proteomic and other high
throughput variations.
Our research group studies these sources of variation and their relation to
complex traits and diseases through adapting and further developing biostatistical and computational methods. With particular focus on cardiovascular diseases
and metabolism, the aim is i) to identify genes modifying trait variation in populations, ii) to estimate the effect sizes of and joint effects of genes, biomarkers
and lifestyle and iii) to predict the risk of future cases of clinical endpoints. To
gain sufficient statistical power, the work often calls for national and international collaborations.
In the past year, the group took part in Global Lipid Genetics and ENGAGE
consortiums to find genes modifying circulating lipid levels (Teslovich et al 2010;
Surakka et al 2011). We also showed that the currently known lipid genes explain
a much larger proportion of population level lipid variation in children than in
adults (Tikkanen et al 2011).
The work on lipid modifying genes was also extended to the genetic architecture of a broad spectrum of serum metabolites. More than 30 loci were identified and shown to modify metabolite levels. We also showed that many of the
previously known lipid loci associate not only with lipoproteins but also with a
much more broad range of different metabolites (Kettunen et al 2012, Tukiainen
et al 2012).
These studies are now being extended to describe genomic and metabolomic
variations in a much greater detail. We are also evaluating how the new genomic
and other high-throughput information helps to identify high-risk groups for cardiovascular diseases (Ripatti et al 2010).
Dr Ripatti is also an Honorary Faculty Member at Wellcome Trust Sanger Institute.
Group Members:
PI: Samuli Ripatti
Senior Researcher: Maria Krestyaninova
Postdoctoral Researchers: Johannes Kettunen,
Taru Tukiainen, Peter Würtz, Alfredo Ortega-Alonso,
Karola Rehnström (WT Sanger Institute,
with Richard Durbin and Aarno Palotie)
PhD and MD Students: Pirkka-Pekka Laurila,
Pietari Ripatti, Mari Rossi, Antti-Pekka Sarin,
Ida Surakka, Emmi Tikkanen
Project Coordinator: Huei-Yi Shen
Key publications:
Kettunen J, Tukiainen T, Sarin AP et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels, Nat. Genet. 2012, Jan 29. doi: 10.1038/ng.1073.
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 Imputation Accuracy and CNV Tagging in GWA Studies, Genome Res., doi:10.1101/gr.106534.110. Published 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.
Tikkanen E, Tuovinen T, Widén E, et al. Association of known loci with lipid levels among children and prediction of dyslipidemia in adults. Circ Cardiovasc Genet. 2011 Dec;4(6):673-80. Epub
2011 Oct 7.
Tukiainen T, Kettunen J, Kangas AJ et al. Detailed Metabolic and Genetic Characterization Reveals
New Associations for 30 Known Lipid Loci, Hum. Mol. Genet. first published online December 9,
2011 doi:10.1093/hmg/ddr581.
External research funding: Academy of Finland Center of Excellence and Academy Project,
Helsinki Graduate School of Biotechnology and Molecular Biology (GSBM), Helsinki Biomedical
Graduate Program (HBGP), EU-FP7: ENGAGE and BioSHaRE
FIMM
9
group saarela
Genetics of Autoimmune Diseases
Research Director Janna Saarela, MD, PhD
A
Group Members:
PI: Janna Saarela
Postdoctoral Researcher: Eveliina Jakkula
(part time)
PhD Students: Virpi Leppä, Annu Näkki,
Anna-Maija Sulonen, Himanshu Chheda
n autoimmune disease is a condition where the immune system mistakenly
attacks and destroys healthy body tissue. The cause of most autoimmune
diseases is unknown, but both genetic predisposition and environmental triggers
are thought to contribute to the development of the diseases. With a typical onset in young adulthood, autoimmune diseases have severe economical and social
impacts on the lives of the patients and their families.
Our goal is to improve understanding of the biological pathways and pathogenic mechanisms behind autoimmune diseases, especially multiple sclerosis
(MS). We are also implementing and developing novel genomics and bioinformatics methods to investigate both autoimmune diseases and rare diseases with genetic causes. Our strategy is i) to identify predisposing genes for MS by genomewide (GWA) and fine-mapping analysis of large international cohorts and by utilizing a specific high-risk MS subisolate originating from Southern Ostrobothnia
with increased prevalence and familial occurrence of the disease, ii) to characterize the impact of the identified autoimmune disease predisposing variants
in Finnish population cohorts, and iii) to implement novel genomics and bioinformatics tools for identifying causative mutations in MS and in rare, inherited
diseases.
During 2011 we identified 29 novel MS susceptibility variants in a large international collaboration effort with the IMSGC and the WTCCC2, including nearly 10 000 MS cases from 15 different populations of European descent (IMSGC &
WTCCC2, Nature 2011). All except two of the currently confirmed 50 MS loci map
within or near genes with immune functions and many of them have been implicated also in other autoimmune diseases, which confirm that the critical disease
mechanism in MS is primarily immune dysregulation. In 2011 we also conducted
an extensive comparison of commercially available exome capture kits (Sulonen
et al, Genome Biol. 2011), and developed a bioinformatics pipeline for NGS genome
sequence analysis (Sulonen et al, Genome Biol. 2011) and for CNV analysis from
the exome sequence data (EXO-CNV, Sulonen et al. manuscript in preparation) in
close collaboration with the FIMM Technology Centre sequencing and bioinformatics units.
Our future research aims at identifying causative genetic variants for MS and
rare inherited diseases, and characterizing their function in order to uncover the
underlying disease mechanisms. This will allow improved diagnosis of the diseases and potentially offer clues on how to treat these patients.
Dr. Janna Saarela also acts as Research Director of the FIMM Technology Centre.
Key publications:
International Multiple Sclerosis Genetics Consortium & Wellcome Trust Case Control Consortium
2, Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
Nature. 2011, 476:214-9.
Sulonen AM, Ellonen P, Almusa H, et al. Comparison of solution-based exome capture methods
for next generation sequencing. Genome Biol. 2011, 12(9):R94.
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. 2011,
70:349-55
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.
External research funding: Sigrid Jusélius Foundation, State funding for research to university
hospitals (EVO), National Graduate School of Musculoskeletal Disorders and Biomaterials (TBGS),
Helsinki Biomedical Graduate Program (HBGP)
10
FIMM
group widén
Genetics of Puberty and Adult Health
Academy Research Fellow Elisabeth Widén, MD, PhD
P
uberty is the last and very important developmental phase during which a
child matures into an adult, attains fertility and the capacity to reproduce. Its
timing varies quite substantially in the population, both due to mostly unknown
genes and the environment. Accumulating epidemiological data suggests a link
between early puberty and adult health outcomes, e.g. obesity, Type 2 diabetes,
and hormone-dependent cancers, although the mediating mechanisms remain
unclear, and the majority of the data are based on studies done only on females.
The goal of our research is to discover and characterize novel critical mechanisms influencing pubertal maturation and growth. The strategy is i) to identify
the underlying genes by genome-wide association (GWA) mapping utilizing very
large population cohorts with longitudinal growth data, and ii) to characterize
their impact on adult health both in Finnish population-based cohorts and in targeted study populations manifesting puberty-associated diseases.
During 2011 we have characterized the link between puberty and adult disease
risk, and performed genetic mapping studies to identify novel puberty-associated
genes. Using a large Finnish birth cohort, with data on a wide spectrum of adult
metabolic risk factors, we carried out detailed studies of the relationship between
puberty and adult metabolic health. Our data showed that earlier pubertal timing is associated with adult metabolic syndrome-related derangements both in
males and females. We also showed that this association is independent of preceding childhood growth events, thereby emphasizing that mechanisms advancing puberty also may contribute to adult metabolic disorders. To identify pubertyassociated genes we lead a large international collaborative GWA meta-analysis
project, including as many as 24 000 study subjects of both Finnish and European
descent. The meta-analyses are still ongoing, but we have at present identified
10 loci showing significant association and 24 gene regions displaying suggestive
evidence for association with pubertal growth. The preliminary analyses also indicate overlapping genetic architecture linking height growth, pubertal timing
and childhood adiposity.
Our future research will aim at functional characterization of the genes pinpointed by our GWA study in order to uncover and elucidate the underlying causal
pathways. We anticipate that these pathways may more accurately predict puberty-associated outcomes, of which some are health related, than any specific
growth event.
Group Members:
PI: Elisabeth Widén
PhD Students: Diana Cousminer, Jaakko Leinonen
Genome-wide Association of Pubertal Growth
Chromosome
Key publications:
Widén E, Silventoinen K, Sovio U, et al. Pubertal Timing and Growth Influences Cardiometabolic
Risk Factors in Adult Males and Females. Diabetes Care. 2012 Feb 14. [Epub ahead of print ]
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
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
External research funding: Academy of Finland
FIMM
11
research groups in medical systems
biology and translational research
group kallioniemi
Individualized Systems Medicine
Professor Olli Kallioniemi, MD, PhD
M
Group Members:
PI: Olli Kallioniemi
Senior Researchers: Taija af Hällström,
Vilja Pietiäinen, Päivi Östling, Maija Wolf
(leave of absence)
Postdoctoral Researchers: Sara Kangaspeska,
Astrid Murumägi, Teijo Pellinen
PhD, MD and MSc Students: Anna Aakula,
Disha Malani, Henrik Edgren, Jenni Säilä,
John Patrick Mpindi, Kalle Ojala, Oscar Brück,
Petra Mäki-Teeri, Poojitha Kota Venkata,
Sami Blom, Khalid Saeed, Susanne Hultsch
Senior Laboratory Technicians: Mariliina Arjama,
Katja Välimäki (leave of absence)
Visiting Clinical Researcher: Akira Hirasawa
12
FIMM
aking cancer care more individualized is a central aim for cancer researchers worldwide. To a large extent, this is being pursued via DNA sequencing-based efforts. Our focus is on individualized systems medicine, where we attempt to i) integrate genomic and proteomic data, along with tissue imaging and
functional drug response data for individual cancer patients, ii) understand how
these parameters change during the cancer progression and drug resistance, iii)
develop means to guide patient treatments and study how the treatments help
or why they fail, thus iv) creating a systems medicine opportunity to build and
refine models.
In 2011, we applied drug sensitivity and resistance testing for the identification of novel efficacies of existing and emerging drugs in vitro, such as Disulfiram
and Monensin in prostate cancer. We also developed new methods for individualized diagnostics, such as the classification of unknown primary tumours with
the help of microarray reference databases (Ojala et al, 2011). We published one
of the first next-generation RNA sequencing papers in breast cancer highlighting
24 novel fusion genes (Edgren et al., 2011) and reported on the identification of
microRNAs regulating androgen receptor in prostate cancer (Östling et al., 2011).
We also published an ultra-high-throughput method for RNAi screening using cell
spot microarrays (Rantala et al., 2011).
Our current activities are strongly focusing on individualized medicine, as
part of a “grand challenge” programme at FIMM to develop technologies for individualized cancer therapy. Using adult Acute Myeloid Leukaemia (AML) as a key
model disease, we aim to: i) pioneer the combination of high-throughput ex-vivo
functional drug sensitivity and resistance testing (DSRT) as well as molecular profiling for the identification of effective emerging and targeted drugs for AML, ii)
identify molecular mechanisms of drug resistance, and iii) translate these data
towards the clinic, for individualized treatment of AML patients. We are also undertaking similar studies in breast and prostate cancer, focusing on understanding drug resistance mechanisms in solid tumors. The complexity of solid tumours
obviously provides more challenges for such applications.
The personalized medicine efforts are undertaken together with the groups of
Wennerberg, Heckman/Knowles, Aittokallio and Lundin, together with key clinical collaborators in haematology, urology, oncology and pathology at HUS as well
as bioinformatics collaboration with Professor Samuel Kaski at the Helsinki Institute for Information Technology (HIIT).
Recent key publications:
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.
Koskela HLM, 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, Heckman C, Maciejewski JP, Mustjoki S. Somatic STAT3 Mutations in
Large Granular Lymphocyte Leukemia. NEJM, in press, 2012.
Ojala KA, Kilpinen SK, Kallioniemi OP. Classification of unknown primary tumors with a datadriven method based on a large microarray reference database. Genome Med. 2011 Oct 17;3(9):63.
Rantala JK, Mäkelä R, Aaltola AR, Laasola P, Mpindi JP, Nees M, Saviranta P, Kallioniemi O. A
cell spot microarray method for production of high density siRNA transfection microarrays. BMC
Genomics. 2011 Mar 28;12:162.
Östling 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):1956-67.
Epub 2011 Feb 22.
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;12(1):R6. Epub 2011 Jan 19.
External research funding: Academy of Finland, Biocentrum Helsinki, Cancer Society of Finland, Sigrid Jusélius Foundation, Helsinki Biomedical Graduate Program (HBGP), and DIANET
graduate school, EU-FP7: Systems Microscopy Network of Excellence, Marie Curie Initial Training
Network PRO-NEST: Innovative Medicine Initiative: PREDECT, ERDF: Biomarkers
The group is also involved in infrastructure programs: Biocenter Finland: Translational research
and genome-wide networks; specifically Drug Discovery and Chemical Biology (DDCB) program,
ESFRI programs: EU Openscreen, Biomedinfra (ELIXIR, BBMRI and EATRIS collaboration), Tekes:
Next-generation biobanking
FIMM
13
group aittokallio
Computational Systems Medicine
FIMM-EMBL Group Leader (supported by the University of Helsinki)
Academy Research Fellow Tero Aittokallio, PhD
O
Group Members:
PI: Tero Aittokallio
Senior Researcher: Jing Tang
Postdoctoral Researcher: Petteri Hintsanen
PhD Students: Agnieszka Szwajda,
Bhagwan Yadav
The research is done in collaboration with the
Turku Biomathematics Research Group
(Laura Elo, Marja Heiskanen, Teemu Daniel
Laajala, Sebastian Okser, Rolf Lindén)
ne reason why the genetic basis of disease susceptibility has proven so difficult to identify is due to genetic interactions between genes: mutations that
have no discernible individual effect on disease phenotypes may have strong synergistic effects leading to disease when combined. While such epistatic genetic
interactions are prevalent and known to be involved in many disease phenotypes,
such as in the development of cancers and cardiovascular diseases, they have remained extremely difficult to identify on a global scale because of the vast number of potential interactions and non-linear genotype-phenotype relationships.
Our FIMM-EMBL group was established in August 2011, with a focus on developing network-centric modeling frameworks for predicting and analyzing genetic
interactions in the context of large-scale experiments, including i) ‘reverse-genetic’ approaches, in which the function of genes are systematically perturbed using
e.g. high-throughput RNAi screening or chemical compounds; and ii) ‘forward-genetic’ approaches, such as genome-wide association or next-generation sequencing studies, where naturally occurring mutations pinpoint the loci that are associated with the trait of interest. Such experimental-computational approaches
have the potential to identify key players and their interaction partners in disease
networks, as well as to suggest targets for personalized therapies.
During 2011, two specific application cases were initiated: i) Modelling and
prediction of synthetic lethal interactions in cancers, where we are applying a
top-down modelling approach to predict synthetic lethal partners of individual
cancer-causing mutations, the optimal targeting of which holds great promise of
being a highly specific and selective means to kill the cancer cells without severe
side-effects to normal cells; and ii) Exploring epistatic interactions among genetic
loci in cardiovascular diseases and metabolic traits, where we are developing and
exploiting computationally efficient statistical and predictive strategies for mining interactions among panels of genetic variants, environmental factors, and underlying pathways, which are most predictive of increased disease risk.
The future plan is to combine the information from the reverse and forwardgenetic approaches to provide a more comprehensive view of the molecular
mechanisms behind disease processes and system-level responses to genetic and
chemical perturbations.
Key publications:
Corander J, Aittokallio T, Ripatti S, Samuel K. The rocky road to personalized medicine – computational and statistical challenges. Commentary article, Personalized Medicine (in press).
Heiskanen MA, Aittokallio T. Mining high-throughput screens for cancer drug targets – lessons
from yeast chemical-genomic profiling and synthetic lethality. Focus article, Wiley Interdisciplinary Reviews: Data Mining and Knowledge Discovery (in press).
Elo LL, Kallio A, Laajala TD, Hawkins RD, Korpelainen E, Aittokallio T. Optimized detection of transcription factor-binding sites in ChIP-seq experiments. Nucleic Acids Research 2012 Jan; 40(1): e1.
Lindén RO, Eronen VP, Aittokallio T. Quantitative maps of genetic interactions in yeast - comparative evaluation and integrative analysis. BMC Systems Biology 2011 Mar 24; 5: 45.
Okser S, Lehtimäki T, Elo LL, Mononen N, Peltonen N, Kähönen M, Juonala M, Fan YM, Hernesniemi JA, Laitinen T, Lyytikäinen LP, Rontu R, Eklund C, Hutri-Kähönen N, Taittonen L, Hurme M,
Viikari JS, Raitakari OT, Aittokallio T. Genetic variants and their interactions in the prediction of
increased pre-clinical carotid atherosclerosis - the cardiovascular risk in young Finns study. PLoS
Genetics 2010 Sep 30; 6(9) e1001146.
External research funding: Academy of Finland, Biocenter Finland, and the Finnish Funding
Agency for Technology and Innovation (Tekes).
14
FIMM
Group Kainov
Medical Systems Virology
FIMM-EMBL Group Leader (supported by Jane and Aatos Erkko Foundation)
Denis Kainov, PhD, Adjunct Professor
I
nfluenza A viruses (IAV) cause significant morbidity and mortality. Different
prevention and treatment options (e.g. vaccinations and virus-directed drugs)
have been developed. However, these are insufficient in the face of recent IAV
epidemics and pandemics. Our mission is to improve human health using a new
concept of controlling influenza infections. This concept includes assessment
of risk of developing severe diseases in IAV-positive individuals and subsequent
treatment of individuals at risk using next-generation antiviral drugs.
Our specific aims are: i) to identify genetic/environmental factors associated with severe forms of influenza infections, utilizing integrative omics profiling and genome sequencing of flu patients and associated IAV strains; ii) to
identify and develop next-generation antiviral drugs. These drugs will create a
barrier to viral drug resistance by targeting cellular factors that are essential for
virus replication.
During 2011, we established a novel method of whole genomes sequencing
of influenza isolates from Finnish patients. This method allows routine identification of drug-resistant strains and their attenuated/virulent variants. This
method increases the resolution and accuracy of IAV investigations supporting
surveillance and outbreak investigations. Towards the second aim, we identified
two novel antiviral compounds and their cellular targets, providing an opportunity for future treatment of IAV infections and better understanding of virushost cell interaction.
Our future focus from 2012 onwards is to launch a project on “Individual susceptibility to severe IAV infections” and continue to evaluate the novel antiviral
compounds with in vivo and ex vivo assays, focusing on safety, broad-spectrum
efficacy and delivery issues.
Group Members:
PI: Denis Kainov
Postdoctoral Researcher: Laura Kakkola
PhD Students: Oxana Denisova, Maria Anastasina
Technician: Minttu Kaloinen
Key publications:
Mueller KH, Kakkola L, Nagaraj AS, Cheltsov AV, Anastasina M, Kainov DE. (2012) Emerging cellular targets for influenza antiviral agents. Trends Pharmacol Sci. 33: 89-99
Mueller KH, Kainov DE, El Bakkouri K, Saelens X, De Brabander JK, Kittel C, Samm E, Muller CP.
(2011) The proton translocation domain of cellular vacuolar ATPase provides a target for the treatment of influenza A virus infections. Br J Pharmac. 164: 344-357
Kainov DE, Mueller KH, Theisen LL, Anastasina M, Kaloinen M, Muller CP. (2011) Differential effects of NS1 proteins of human pandemic H1N1/2009, avian highly pathogenic H5N1 and low
pathogenic H5N2 influenza A viruses on cellular pre-mRNA polyadenylation and mRNA translation. J Biol Chem. 286: 7239-7247
External funding: Academy of Finland, CIMO, Helsinki Biomedical Graduate Program (HBGP)
FIMM
15
Group Knowles
Personalized Cancer Medicine
FiDiPro Professor Jonathan Knowles, PhD (Finland Distinguished Professor, Tekes)
A
Group Members:
PI: Jonathan Knowles
Senior Researcher and co-principal investigator:
Caroline Heckman
Senior Research Technician: Alun Parsons
Bioinformatician: Samuli Eldfors
PhD Students: Riikka Karjalainen,
Muntasir Mamun Majumder
Undergraduate Students: Heikki Kuusanmäki
dvanced cancer treatment may now include the use of targeted therapies that
have been developed to inhibit specific cellular pathways important for cancer
cell function. However, in recent years there have been fewer approvals for novel
agents largely due to their insufficient efficacy. While these new agents may target
previously unmet mechanisms and pathways, the lack of efficacy may not necessarily be due to insufficient effect, but due more to patient and disease heterogeneity.
In order to improve clinical trial outcome and match patients with the correct therapies, it will become essential to better understand the genomic and molecular background of the patient and the disease.
The Personalized Cancer Medicine programme at FIMM is a cooperative study
between basic and clinical investigators that uses cutting-edge technologies including next-gen whole genome and exome sequencing, transcriptome sequencing, proteomics and high-throughput drug sensitivity testing to screen clinical samples. Using these platforms, our group focuses on the discovery of biomarkers including novel genetic alterations and understanding their role in disease pathogenesis. We also
aim to understand tumour heterogeneity, characterize resistant clones and further
develop methodologies to improve our screening platforms. Our group, along with
those of Olli Kallioniemi, Krister Wennerberg, Tero Aittokallio and members of the
FIMM Technology Centre work in close collaboration with Professor Kimmo Porkka
and Dr Satu Mustjoki of the HUS Hematology Clinic and Hematology Research Unit
to screen leukaemia patient samples and analyze data from the various platforms,
ultimately determining if viable therapeutic options exist for patients who have otherwise failed to respond to conventional therapeutics.
During 2011, samples from 19 leukaemia patients were screened against a comprehensive oncology drug library with half of these analyzed by in-depth genomic and
molecular profiling. These initial datasets not only allowed us to find new treatment
ideas for these patients (Kontro et al 2010), but also identify important driving mechanisms for disease progression and drug resistance. In addition, exome and RNA sequencing studies led to the discovery of novel recurrent pathogenic mutations in rare
leukaemias with previously unknown cause (Koskela et al 2010).
In future efforts, we will expand our study to include more patients focusing on
understanding recurrent and resistance disease. Through these studies we will develop more targeted methodologies to follow the disease in the patient and eventually
identify new treatment strategies.
Key publications:
Koskela HLM, 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, Heckman C, Maciejewski JP and Mustjoki, S. NEJM, in press, 2012.
Kontro, M, Heckman, C, Kulesskiy, E, Pemovska, T, Bespalov, M, Eldfors, S, Erkki, E, Karjalainen,
R, Knowles, J, Malani, D, Majumder, MM, Mpindi, JP, Murumagi, A, Mustjoki, S, Turunen, L, Wolf,
M, Porkka, K, Wennerberg, K and Kallioniemi, O. Development of a Cancer Pharmacopeia-Wide
Ex-Vivo Drug Sensitivity and Resistance Testing (DSRT) Platform: Identification of MEK and mTOR
As Patient-Specific Molecular Drivers of Adult AML and Potent Therapeutic Combinations with
Dasatinib. Blood 2010; 118: 2487.
Koskela, H, Eldfors, S, Almusa, H, Andersson, E, Ellonen, P, Edgren, H, Koistinen, P, Kuittinen, T,
Penttinen, K, Knowles, J, Saarela, J, Kallioniemi, O, Wennerberg, K, Porkka, K, Heckman, C and
Mustjoki, S. Recurrent Missense Mutations in the STAT3 Gene in LGL Leukemia Provide Insights
to Pathogenetic Mechanisms and Suggest Potential Diagnostic and Therapeutic Applications.
Blood 2010; 118: 936.
External research funding: Tekes, Cancer Society of Finland, Sigrid Jusélius Foundation, Helsinki Biomedical Graduate Program (HBGP)
16
FIMM
Group Kuznetsov
Breast Cancer Biology
FIMM-EMBL Group Leader (supported by Finnish Medical Foundation and
Sigrid Jusélius Foundation)
Academy Research Fellow Sergey Kuznetsov, PhD
B
reast cancer is the most common malignancy in women. At least four different subtypes of breast cancer can be recognized, among which basal-like
breast cancers have the worst prognosis due to the lack of suitable molecular targets for therapeutic intervention.
The goal of our research is to identify essential pathogenic events involved in
basal-like breast cancers that could be targeted therapeutically. For this purpose
we aim to investigate molecular events associated with genetic mutations known
to predispose individuals to basal-like breast cancers and how they contribute to
cancer progression and therapy resistance.
During 2011 we evaluated existing therapeutic approaches in a panel of breast
cancer cell lines carrying a mutant BRCA1 gene, one of the best known tumour
suppressors predisposing to basal-like breast cancers. All these cell lines may be
considered as a model of advanced breast cancer as they were resistant to the
most common targeted therapeutics - cisplatin and PARP inhibitors. Interestingly,
these cells were still sensitive to a well-known drug 6-thioguanine, recently shown
to be active against BRCA2-deficient tumours. However, this sensitivity is affected
by at least three different factors, which need to be considered before this therapy
can be used on patients.
We also generated a mouse model, which showed that loss of Rad51c, another
breast cancer predisposition gene, causes a mild differentiation defect in sebaceous glands but does not lead to tumours. Tumour progression required deletion
of Rad51c together with p53. We expect that the ongoing gene expression profiling
will provide insights into the molecular events underlying cancer progression and
point towards possible therapeutic targets.
In the future we plan to identify modifiers of drug response in BRCA1-deficient
tumour cells using high throughput siRNA screens. In addition, we will extend
our analysis to novel tumour suppressors involved in basal-like breast cancers for
which we are developing an in vivo validation system.
Group Members:
PI: Sergey Kuznetsov
Postdoctoral Researcher: Pauliina Munne
PhD Students: Yuexi Gu, Manuela Tumiati,
Daria Bulanova
Master student: Sharif Iqbal
Technicians: Sonja Koopal,
Annabrita Schoonenberg
Key publications:
Biswas K, Das R, Alter BP, Kuznetsov SG, Stauffer S, North SL, Burkett S, Brody LC, Meyer S, Byrd
RA, Sharan SK. A comprehensive functional characterization of BRCA2 variants associated with
Fanconi anemia using mouse ES cell-based assay. Blood. 2011; 118(9): 2430-42.
Kuznetsov S, Haines D, Martin B, Sharan S. Loss of Rad51c leads to embryonic lethality and modulation of Trp53-dependent tumorigenesis in mice. Cancer Res. 2009; 69: 863-872
Kuznetsov S, Liu P, Sharan S. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat Med. 2008; 14: 875-881
Kuznetsov S, Pellegrini M, Shuda K, Fernandez-Capetillo O, Liu Y, Martin B, Burkett S, Southon
E, Pati D, Tessarollo L, West S, Donovan P, Nussenzweig A, Sharan S. Rad51c deficiency in mice
results in early prophase i arrest in males and sister chromatid separation at metaphase ii in females. J Cell Biol. 2007; 176: 581-592
External funding: Academy of Finland, Cancer Society of Finland, Biocenter Finland, Helsinki
Biomedical Graduate Program (HBGP), Helsinki Graduate School of Biotechnology and Molecular Biology (GSBM)
FIMM
17
Group Lundin
Clinical Informatics and Image-Based Diagnostics
Research Director Johan Lundin, MD, PhD
O
Group Members:
PI: Johan Lundin, MD, PhD
Senior Researcher: Nina Linder, MD, PhD
Postdoctoral Researchers: Ville Ojansivu, Dr. Tech.,
Margarita Walliander, Dr. Tech.
PhD Students: Juho Konsti, MD, Tiina Lehtimäki,
MD, Mikael Lundin, MD
Graduate student: Riku Turkki, Tech. stud.
18
FIMM
ur group develops methods for personalized prediction of disease outcome
and image based diagnostics. Genetic and molecular information combined
with clinical data using advanced informatics support will help identify patients
at risk for disease recurrence and tailor individualized treatment, particularly in
cancer. Our goal is to promote implementation of new decision-support technology, as well as improve the flow of information from basic research to the clinic.
We have developed an online risk calculator - “Prognomics” - for personalized
prediction of cancer outcome. The calculator is an extension of our previously
published “case-match” method and is connected to a database with molecular,
as well as clinical and outcome data on more than 5 million cases from 15 countries. Survival estimates can be retrieved for all major cancers and the extensive
database allows for estimation of risk even in rare subgroups. The case-match approach is also used for explorative analysis of novel biomarkers and is linked to
our image analysis system described below.
The other major research area is image-based diagnostics, with special focus
on microscopy images. In collaboration with the Machine Vision Group at the
University of Oulu, we are exploring high-throughput computer assisted methods
for automated analysis of digitized cancer tissue (breast, prostate and colorectal)
and microbiological samples (e.g. malaria).
The webmicroscopy developed by our group (fimm.webmicroscope.net) enables digitization of entire microscope specimens and viewing as well as processing the virtual slides through a web interface. The technology is implemented as a
research infrastructure on a national level within Biocenter Finland and on an international level via the EU funded EATRIS. Applications of the technology include
analysis and management of tissue microarrays, laboratory quality assurance,
consultation and education. The methods are implemented for remote diagnostics within global health in collaboration with Karolinska Institutet, Stockholm.
In 2011 a prognostic tool was developed for sarcoma patients (1) and the casematch method was applied for biomarkers XOR, PROX1 and FOXA1 (2-4). An automated computer vision method for segmenting tumour epithelium from stroma
was developed (5) and a study regarding the effect of compression and scaling on
automated IHC scorings (6) was published. A nationwide cohort study on breast
cancer biological subtypes and metastasis sites (7) and a study concerning longterm prognosis of screen-detected breast cancer were published (8).
Key publications:
1. A web-based prognostic tool for extremity and trunk wall soft tissue sarcomas and its external
validation. Sampo M, Tarkkanen M, Tukiainen E, Popov P, Gustafson P, Lundin M, Böhling T,
Blomqvist C, Lundin J. Br J Cancer. 2012 Mar 13;106(6):1076-82.
2. Decreased xanthine oxidoreductase (XOR) is associated with a worse prognosis in patients with
serous ovarian carcinoma. Linder N, Bützow R, Lassus H, Lundin M, Lundin J. Gynecol Oncol.
2012 Feb;124(2):311-8. Epub 2011 Oct 29.
3.Expression and prognostic value of transcription factor PROX1 in colorectal cancer. Skog M,
Bono P, Lundin M, Lundin J, Louhimo J, Linder N, Petrova TV, Andersson LC, Joensuu H, Alitalo
K, Haglund CH. Br J Cancer. 2011 Oct 25;105(9):1346-51. Epub 2011 Oct 4.
4. Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate
cancer. Sahu B, Laakso M, Ovaska K, Mirtti T, Lundin J, Rannikko A, Sankila A, Turunen JP, Lundin M, Konsti J, Vesterinen T, Nordling S, Kallioniemi O, Hautaniemi S, Jänne OA.
5. Identification of tumor epithelium and stroma in tissue microarrays using texture analysis.
Linder N, Konsti J, Turkki R, Rahtu E, Lundin M, Nordling S, Ahonen T, Pietikainen M, Lundin J.
Diagn Pathol. 2012 Mar 2;7(1):22. [Epub ahead of print]
6. Effect of image compression and scaling on automated scoring of immunohistochemical stainings and segmentation of tumor epithelium. Juho Konsti, Mikael Lundin, Nina Linder, Caj Haglund, Carl Blomqvist, Heli Nevanlinna, Kirsimari Aaltonen, Stig Nordling and Johan Lundin.
Diag Athol, in press, 2012
7. Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: a nationwide cohort study. Sihto H, Lundin J, Lundin M, Lehtimäki T, Ristimäki A,
Holli K, Sailas L, Kataja V, Turpeenniemi-Hujanen T, Isola J, Heikkilä P, Joensuu H. Breast Cancer
Res. 2011 Sep 13;13(5)
8. Long-term prognosis of breast cancer detected by mammography screening or other methods.
Lehtimäki T, Lundin M, Linder N, Sihto H, Holli K, Turpeenniemi-Hujanen T, Kataja V, Isola J,
Joensuu H, Lundin J. Breast Cancer Res. 2011 Dec 28;13(6):R134. [Epub ahead of print]
FIMM
19
Group Verschuren
Lung Cancer Model Systems
FIMM-EMBL Group Leader (supported by the Orion Farmos Research
Foundation and Sigrid Jusélius Foundation)
Emmy Verschuren, PhD
T
Group Members:
PI: Emmy Verschuren
Postdoctoral Researchers: Katja Närhi,
Dat Nguyen
PhD Students: Jenni Lahtela, Rita Matos,
Ashwini Nagaraj
Undergraduate Student: Nitai Peled
Technician: Annabrita Schoonenberg
he aim of our research group is the discovery of new strategies for lung cancer
intervention, the leading cause of cancer mortality. Personalised medicine approaches to lung cancer face big challenges: diagnoses are typically made when
the disease is already metastatic, and cancer cell populations are notably heterogeneous, complicating molecular profiling. New methods to study the causes of
lung cancer and inform the design of novel treatment options are therefore of
crucial importance.
Our group studies cell biological and biochemical properties of key genes or
pathways commonly altered in human lung disease, focusing on early initiation
and metastasis. Our goal is to integrate expertise in both human and functional
biology to create versatile mouse cancer models, matched with patient cohorts,
for discovery of biomarkers or therapeutically targetable events. As an example,
we identified functional inactivation of the EPHA3 receptor tyrosine kinase protein, which is mutated in six per cent of human cancers, and are creating in vivo
models to study its physiological role in cancer susceptibility. Our approach uses
pathological read-out of disease to comprehensively model complex pathway interplay and heterogeneity, with implications on drug response and drug resistance. We have successfully developed strategies for viral delivery to, and manipulation of, the mouse lung epithelium.
Increasing evidence suggests a crucial role for the cancer microenvironment
and immune system in cancer surveillance and therapeutic responses. These are
traditionally not accounted for in the drug discovery cascade, potentially explaining why many cancer drugs fail in patients. Within the EU public-private IMI-PREDECT project, coordinated by Emmy Verschuren on the academic side, complex
models of the three most common solid tumours are systematically compared, to
evaluate responses to inhibition of potential new targets. To this end, our lab has
established organotypic lung explant models, enabling measurement of stem cell
fate, viability, cell architecture and immune responses. These models also serve as
an ultimate in vitro system to systematically validate lung cancer gene and pathway functions. We envision that PREDECT will shift paradigms in the preclinical
pharmaceutical pipeline, guiding selection of optimal models representative of
patient cohorts.
Key publications:
Peart, M.J., Pyurovsky, M.V., Ulrist M., Verschuren, E.W., Jackson, P.K. and Prives, C. (2010). APC/
CCdc20 targets E2F1 for degradation in prometaphase. Cell Cycle. 9: 3956-64.
Verschuren, E.W., Ban, K.H., Masek, M.A., Lehman, N.L. and Jackson, P.K. (2007). Loss of Emi1- dependent APC/C inhibition deregulates E2F target expression and elicits DNA damage-induced senescence. Mol. Cell. Biol. 27: 7955-65.
Verschuren E.W. and Jackson, P.K. (2007). Putting transcription repression and protein destruction in
pRb’s pocket. Review. Dev. Cell. 12: 169-70.
Marangos P., Verschuren E.W., Chen, R., Jackson P.K. and Carroll, J. (2007). Emi1-mediated regulation
of the APC controls timing of progression through meiosis in mouse oocytes. J. Cell. Biol.176: 65-75.
External research funding: Helsinki Biomedical Graduate Program (HBGP), CIMO, Marie Curie EUFP7 IRG: SYSTUMS, FCT Portuguese Science Foundation, Biocenter Finland emerging technologies:
LentiGEMM, Innovative Medicines Initiative Joint Undertaking (IMI-JU): PREDECT
20
FIMM
Group Wennerberg
Chemical Biology of Cancer
FIMM-EMBL Group Leader (supported by Jane and Aatos Erkko Foundation)
Krister Wennerberg, PhD
D
espite a tremendous progress in identifying mutations and genetic aberrations associated with different cancer types and an increasing number of
targeted cancer-selective drugs in the clinic, we still lack targeted and safe and
effective therapeutic strategies for the majority of cancers.
Our research aims to address the cancer undruggability problem both by
screening for personalized and selective sensitivities to approved and investigational among primary cancer samples and cell lines as well as by the development
of proof-of-principle small molecule inhibitors of promising novel molecular targets.
In 2011, our group at developed an ex vivo Drug Sensitivity and Resistance
Testing (DSRT) platform together with the Chemical Biology Unit that measures
the sensitivity of cancer cells to all approved cancer drugs and more than 150
clinically investigated cancer drugs. The platform has been used both on relapsed
and AML patient cells and on cancer cell lines. Our clinical collaborators have already used the primary AML DSRT data in their clinical decisions with considerable success. Furthermore, we initiated the development of inhibitors against
the MKLP1/MgcRacGAP/Ect2 protein complex and we began exploring a set of
metabolic genes that are overexpressed in breast cancers where their expression
is correlated with poor clinical outcome, and that are upregulated in response to
chemotherapeutic agents.
Looking forward, we will continue to develop novel types of cancer-relevant
small molecule inhibitor as well as the DSRT platform: refining the readouts, explore drug combination testing and together with Tero Aittokallio’s group develop
analysis tools that allow for the identification of oncogenic driver signals based
on the DSRT data and the target specificities of the inhibitors used and most importantly, link DSRT data to biomarkers that will allow clinical translation.
Group Members:
PI: Krister Wennerberg
Senior Researcher: Gretchen Repasky
Postdoctoral Researcher: Leena Karhinen
PhD Students: Arjan van Adrichem, Muntasir Mamun Majumder, Tea Pemovska
Masters Student: Sawan Kumar Jha
Undergraduate Student: Amy Sessions
Key publications:
Kontro, M., Heckman, C., Kulesskiy, E., Pemovska, T., Bespalov, M., Eldfors, S., Erkki, E., Karjalainen, R., Knowles, J., Malani, D., Majumder, M. M., Mpindi, J. P., Murumagi, A., Mustjoki, S., Turunen, L., Wolf, M., Porkka, K., Wennerberg, K., and Kallioniemi, O. (2011) Development of a cancer
pharmacopeia-wide ex-vivo drug sensitivity and resistance testing (DSRT) platform: identification
of MEK and mTOR as patient-specific molecular drivers of adult AML and potent therapeutic combinations with dasatinib, ASH Annual Meeting Abstracts 118, 2487.
Manuvakhova, M. S., Johnson, G. G., White, M. C., Ananthan, S., Sosa, M., Maddox, C., McKellip, S., Rasmussen, L., Wennerberg, K., Hobrath, J. V., White, E. L., Maddry, J. A., and Grimaldi, M.
(2011) Identification of novel small molecule activators of nuclear factor-kappaB with neuroprotective action via high-throughput screening, J. Neurosci. Res. 89, 58-72.
Zhang, L., Nebane, N. M., Wennerberg, K., Li, Y., Neubauer, V., Hobrath, J. V., McKellip, S., Rasmussen, L., Shindo, N., Sosa, M., Maddry, J. A., Ananthan, S., Piazza, G. A., White, E. L., and
Harsay, E. (2010) A high-throughput screen for chemical inhibitors of exocytic transport in yeast,
ChemBioChem 11, 1291-1301.
Swenson-Fields, K. I., Sandquist, J. C., Rossol-Allison, J., Blat, I. C., Wennerberg, K., Burridge,
K., and Means, A. R. (2008) MLK3 limits activated Galphaq signaling to Rho by binding to
p63RhoGEF, Mol. Cell 32, 43-56.
External research funding: Biocenter Finland, Helsinki Biomedical Graduate Program (HBGP)
FIMM
21
research highlights
Group Ripatti: Genetic regulation of metabolomic biomarkers
– paths to cardiovascular diseases and type 2 diabetes.
In a study of the genetic variances of human metabolism, we have identified 31
regions of the genome that associate with circulating metabolites, i.e., small
molecules that take part in various chemical reactions in the human body. Many
of the metabolites studied are biomarkers for cardiovascular disease or related
disorders, thus the loci uncovered may provide valuable insight into the biological
processes leading to common complex diseases.
Kettunen J, Tukiainen T, Sarin AP, Ortega-Alonso A, Tikkanen E, Lyytikäinen LP, 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 MR, 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. Nat Genet. 2012 Jan 29;44(3):269-76. doi: 10.1038/ng.1073.
Group Widén: Molecular mechanisms triggering early puberty
may increase risk of metabolic syndrome in adults
Early puberty in females may correlate with increased risk for obesity, and type
2 diabetes, but the mediating mechanisms remain unclear. Utilizing unique longitudinal data from a large Finnish birth cohort we showed that earlier pubertal
timing is associated with adult metabolic syndrome-related derangements both
in males and females. We also showed that this association is independent of preceding childhood growth events, thereby emphasizing that mechanisms advancing puberty also may contribute to adult metabolic disorders.
Widén E, Silventoinen K, Sovio U, Ripatti S, Cousminer DL, Hartikainen A-L, Laitinen J, Pouta
A, Kaprio J, Järvelin M-L, Peltonen L, Palotie A. Pubertal Timing and Growth Influences Cardiometabolic Risk Factors in Adult Males and Females. Diabetes Care. 2012 Feb 14.
Group Ripatti: Complex genetic and metabolic architecture
underlies genetic loci affecting serum lipid levels.
We used a comprehensive metabolomic profiling and genotyping to uncover the
strikingly complex and heterogeneous basis of the known lipid loci. The results
also showed that commonly used laboratory lipid measures do not capture the
complexity of the underlying lipoprotein metabolism, showing the advantages of
the NMR metabolomics platform utilized in the study.
Tukiainen T, Kettunen J, Kangas AJ, Lyytikäinen LP, Soininen P, Sarin AP, Tikkanen E, O’Reilly PF,
Savolainen MJ, Kaski K, Pouta A, Jula A, Lehtimäki T, Kähönen M, Viikari J, Taskinen MR, Jauhiainen M, Eriksson JG, Raitakari O, Salomaa V, Järvelin MR, Perola M, Palotie A, Ala-Korpela
M, Ripatti S. Detailed metabolic and genetic characterization reveals new associations for 30
known lipid loci. Hum Mol Genet. 2012 Mar 15;21(6):1444-55. Epub 2011 Dec 9.
22
FIMM
4d-kuva
Group Palotie: A new approach for comprehensive
understanding of disease risks associated with genes
Clinical decision making will soon move from a “one fits all” towards more personalized treatment, largely driven by the paradigm change facilitated by genomic
and other omics techniques. These techniques provide an opportunity to classify
diseases from a new angle. Typically scientists have searched for specific gene
variants behind a predetermined phenotype. In contrast, we have developed new
techniques to identify all phenotypic features that are overrepresented in individuals with particular genotypes. Such studies are ideally suited for studies of large,
well characterized population cohorts, such as the national biobanks in Finland.
We can now define subjects based on their genotype and ask what phenotypes
are associated. Therefore, we can move from genes to phenotypes instead of the
traditional way of using phenotype to define risk genotypes.
The first proof of principal study investigated what phenotypes would be associated with large genomic deletion in an unselected population cohort. We identified all individuals in the Northern Finnish Birth Cohort that had a deletion larger
than 500 kb. Individuals carrying such deletions had an overrepresentation of
neurodevelopmental related traits such as cognitive- and hearing impairments
and poor school performance.
Pietiläinen OP, Rehnström K, Jakkula E, Service SK, Congdon E, Tilgmann C, Hartikainen AL,
Taanila A, Heikura U, Paunio T, Ripatti S, Jarvelin MR, Isohanni M, Sabatti C, Palotie A, Freimer
NB, Peltonen L. Phenotype mining in CNV carriers from a population cohort. Hum Mol Genet.
2011 Jul 1;20(13):2686-95.
Group Kainov: New approaches towards combating deadly
influenza epidemics
Our research is focusing on developing future personalized strategies for treatment of infection diseases. We have summarized current knowledge on influenza
virus (IAV) replication, focusing on emerging cellular drug targets. Recent advances in understanding of IAV replication have revealed a number of cellular drug targets that counteract viral drug resistance. For many of these targets, compound
safety testing in humans is available. Some of these compounds may be beneficial
for the clinical therapy, especially in the case of severe infections, drug-resistant
IAV strains and epidemics.
Mueller KH, Kakkola L, Nagaraj AS, Cheltsov AV, Anastasina M, Kainov DE. (2012) Emerging
cellular targets for influenza antiviral agents. Trends Pharmacol Sci. 33: 89-99
FIMM
23
Group Palotie: Genome-wide association study reveals three
susceptibility loci for common migraine in the general
population.
We expanded our understanding of genes associated with the most common neurological trait migraine. We identified three gene regions associated to migraine
in a population cohort, which represent a very different ascertainment than headache patients drawn from speciality clinics. These gene regions suggest both pain
and glutamate pathways to be involved in migraine susceptibility.
Chasman DI, Schürks M, Anttila V, de Vries B, Schminke U, Launer LJ, Terwindt GM, van den
Maagdenberg AM, Fendrich K, Völzke H, Ernst F, Griffiths LR, Buring JE, Kallela M, Freilinger
T, Kubisch C, Ridker PM, Palotie A, Ferrari MD, Hoffmann W, Zee RY, Kurth T. Nat Genet. 2011
Jun 12;43(7):695-8.
4f-kuva
Group Kallioniemi: miRNAs regulate the androgen receptor
(liittyy Palotien artikkeliin)
expression and provide potential therapeutic approaches to
inhibit androgen-dependent growth of prostate cancer cells.
Despite the continuously increasing detection of small early-stage prostate cancers by PSA screening, the mortality associated with the disease has remained relatively stable. Androgen receptor signaling remains the central target of therapy
for prostate cancer. Here, we show that expression of specific miRNAs provides
a means to inhibit AR function in human prostate cancer and provide evidence
of a previously unanticipated network structure regulating the AR at the posttranscriptional stage. Furthermore, the study highlights the role of UTRs in the
regulation of gene activity.
Östling 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):1956-67. Epub 2011 Feb 22.
Group Saarela: Genetic risk and a primary role for cellmediated immune mechanisms in multiple sclerosis
FIMM researchers were involved in a large collaborative genome-wide association analysis with the International MS Genetics Consortium and the Wellcome
Trust Case Control Consortium 2. This study involved almost 10,000 cases of European descent from 15 different countries. We identified 29 novel regions of the
genome that associate with MS disease. We also confirmed the previously identified 20 loci. All except two of the loci mapped closest to an immunologically relevant gene. The results implicate T-helper-cell differentiation in the pathogenesis
of multiple sclerosis.
International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011 Aug 10;476(7359):214-9.
24
FIMM
Group Lundin: Identification of tumor epithelium and stroma
in tissue microarrays using texture analysis
The aim was to assess whether texture analysis is feasible for automated identification of epithelium and stroma in digitized tumor tissue microarrays (TMAs).
The results illustrate the capability of automated segmentation of epithelial and
stromal tissue (accuracy 0.995; CI95% 0.991-0.998) in TMAs based on texture features and an SVM classifier. Applications include tissue specific assessment of
gene and protein expression, as well as computerized analysis of the tumor microenvironment.
Linder N, Konsti J, Turkki R, Rahtu E, Lundin M, Nordling S, Haglund C, Ahonen T, Pietikainen
M, Lundin J. Identification of tumor epithelium and stroma in tissue microarrays using texture
analysis. Diagnostic Patholology 2012 Mar 2;7(1):22. Epub ahead of print.
Group Lundin: Big size multitouch displays turned into
microscopes
Researchers at the Institute for Molecular Medicine Finland (FIMM) have in collaboration with the Finnish company Multitouch Ltd created a hand and finger
gesture controlled microscope. The method is a combination between two technologies: web-based virtual microscopy and giant size multitouch displays.
The result is an entirely new way of performing microscopy: by touching a tableor even wall-sized screen the user can navigate and zoom within a microscope
sample in the same way as in a conventional microscope. Using the touch control
it is possible to move from the natural size of the sample to a 1000-fold magnification.
Biological samples are digitized using a microscopy scanner and stored on an image server. Samples displayed on the screen are then continuously read from a
remote image server over the Internet and the size of a single sample can be more
than 200 gigabytes.
The developers think that the method will revolutionize the way microscopy is
being performed and the learning curve for using the multitouch microscope is
practically zero. Microscopy at the same time changes from a private, single-user
experience, to something social where groups of people can view, examine and
learn from a same sample simultaneously.
FIMM
25
grand challenges
FIMM research groups, Technology Centre and Biobank working together to solve major
questions of importance to the society
Finnish Genomes and the Future Health Care
Palotie, Ripatti, Biobank, Technology Centre together with researchers at THL
Finland has a unique opportunity to make use of the national biobanks, specifically the unique THL collection of 200,000
DNA samples from the general population, not only to discover genes for diseases (as has been successfully done in the past
20 years), but to generate an important resource to guide health care decisions, and to enable intelligent targeted monitoring of health in people according to their individualized risk of diseases. This grand challenge project is therefore planning to
genotype, and eventually sequence, all the 200,000 DNA samples and connect this massive amount of data on the complete
genetic variation with the excellent long term follow-up and health data. 8000 Finnish genomes will already be sequenced
by the end of 2012, which forms a strong starting point for the project.
Systems Medicine for Individualized Therapy of the Cancer Patients
Wennerberg, Heckman/Knowles, Kallioniemi, Aittokallio, Lundin groups, Biobank and the Technology Centre, and clinical collaborators at HUCH
This project advances the major unmet needs in the society for (i) better and more efficient treatments for cancer patients by
the individualized combination of new targeted drugs, for (ii) the health care system to better individually optimize cancer
treatments and for (ii) the global industry to derisk and clinically introduce new drugs to specific molecularly identified patient subgroups. The individualized systems medicine (ISM) project is a key clinical and translational study at the University
of Helsinki, carried out in collaboration between FIMM, HUCH, along with national and international collaborators, both
in the academia and in the industry. The unique part of the program is our Drug Sensitivity and Resistance Testing (DSRT)
technology that has been developed at the Institute for Molecular Medicine Finland (FIMM) and piloted in Acute Myeloid
Leukaemia (AML) diagnostics at the Helsinki University Central Hospital, Division of Hematology (HUCH). DSRT has already
delivered groundbreaking results, especially when combined with other novel diagnostic modalities, such as next-generation
sequencing (NGS).
5a-kuva
26
FIMM
doctoral training
Research training continued to grow at FIMM during 2011. Several new PhD students joined FIMM
research groups, bringing the total number of doctoral students at FIMM to over 40, with approximately 40 % international students and 60 % Finnish students. In the autumn, FIMM celebrated the
admission of many of these new students into Finnish doctoral programmes including the Helsinki
Biomedical Graduate Program (HBGP), the National Doctoral Programme of Advanced Diagnostic
Technologies and Applications (DIA-NET), and FinPharma Doctoral Programme (FPDP).
The year 2011 was the second year of the FIMM-EMBL International PhD Training Initiative, bringing two new outstanding doctoral students to the institute. Naga Poojitha Kota Venkata and
Himanshu Chheda, both from India, were selected from a strong and large international applicant pool. These two successful candidates represent only 1 % of the total applicant pool. Poojitha and Himanshu joined FIMM in late August and after a few days of orientation began their
first research rotation. All of the FIMM-EMBL PhD students participated in the EMBL International PhD Symposium, an annual training session at the EMBL (Heidelberg, Germany), in November 2011.
The rigorous FIMM-EMBL recruitment began with an international call announced jointly with
NCMM and MIMS in early 2011. Students selected through the institute level evaluation process
spend the first 6—9 months engaged in research rotations with the aims of diversifying individual
research training and building connections within FIMM. At the end of the rotational period, students then select a research group, in mutual agreement with the group leader, in which to complete their PhD studies. Based on the continued success of this training plan, a third joint call was
initiated at the end of 2011.
In addition to the FIMM-EMBL PhD training initiative, FIMM was engaged in several other aspects
of doctoral training. For example, the EU FP7 Marie Curie Initial Training Network (ITN) PRO-NEST
continued and a new ITN proposal was filed in late 2011. In addition, through the Biocenter Finland
International Visitor Program, FIMM recruited several doctoral students and postdoctoral researchers from abroad to drive research activities in eight different groups at FIMM.
FIMM
27
FIMM researchers offered several courses and lectures for doctoral and masters students, including courses in chemical biology,
functional genomics, disease genomics, next generation sequencing, and cancer. There are future plans for multiple courses on
topics such as molecular and personalized medicine, DNA repair,
molecular pathology and imaging, biostatistics, and biobanking
to be developed and offered in the upcoming year.
FIMM joined the EU-, Finnish-, and City of Helsinki-funded PhDs
to Business Life project coordinated by Culminatum Innovation,
Ltd. This project aims to train PhD students and postdoctoral
researchers in business principles, career coaching, and project
management with the ultimate goals of enhancing collaborations between doctoral programmes
and business as well as readying doctoral students for careers in industry.
FIMM Scientific Coffee Breaks are arranged twice a month. Students, postdoctoral researchers, as
well as senior researchers and group leaders present their work for FIMM staff.
Finally, FIMM celebrated the completion of the two doctoral dissertations in 2011 at the University
of Helsinki:
Anu Kemppinen:
“Studies on Causes of Multiple Sclerosis : From Genes to Transcriptome” Supervisors: Leena PeltonenPalotie and Janna Saarela
Sami Kilpinen:
“Studies of the Human Transcriptome” Supervisor: Olli Kallioniemi
In addition, the following dissertations were completed at the University of Turku and VTT Technical Research Centre of Finland:
Santosh K. Gupta:
“Functional Study of Oncogenic Transcription Factor ERG and its Signaling in Prostate Cancer” (supervised by Olli Kallioniemi)
Juha K. Rantala:
“A cell spot microarray method for high-throughput biology” (supervised by Olli Kallioniemi and Johanna Ivaska)
Paula Vainio:
”High-Throughput Screening for Novel Prostate Cancer Drug Targets –Getting Personal” (supervised
by Kristiina Iljin and Olli Kallioniemi)
Kirsi Ketola:
”Chemical Biology Screen for Prostate Cancer Therapeutics” (supervised by Kristiina Iljin and Olli
Kallioniemi)
28
FIMM
technology centre
research director janna saarela
Overview
T
he FIMM Technology Centre is a national and international research core unit providing an extensive
spectrum of biomedical research services. FIMM Technology Centre operates seven core units with
a total of 41 technology experts from diverse educational backgrounds being involved in the operations.
Technology Centre develops methods and offers services in the areas of genomics (sequencing, genotyping,
expression, methylation and CNV profiling), high throughput screening (chemical compounds, approved
drugs, and siRNA), bioinformatics and IT services using state-of-the-art technologies. During 2011 we also
started setting up metabolomics and translational research (serum and oligonucleotide arrays) technologies. FIMM Technology Centre operates in close collaboration with the Biocenter Finland infrastructure
networks and is strongly involved in the European Research Infrastructure (ESFRI) networks.
In 2011 we completed altogether over 150 projects serving or collaborating with tens of research groups from
over 10 national and international universities and research institutes, including all Biocenter Finland universities, as well as from a few companies. Technology Centre played a key role in the development of personalized
medicine activities at FIMM by setting up fast-track services for exome, transcriptome and drug sensitivity and
resistance profiling of leukemia samples. Further development of clinical profiling services and efficient integration of the comprehensive profiling data will be our next major challenges.
Services
Samples/Cell lines
User Groups
35
6
Exome sequencing
286
21
Custom targeted sequencing
325
12
81
2
992
17
20 093
22
Metagenomics
64
1
RNA sequencing
116
10
Gene expression microarrays
174
5
Cell line identification
2
1
Immunoprecipitates (ChIP-seq etc.)
7
1
15
7
7
6
84
9
497
29
79
8
18 000
1
Genomics
Genome sequencing
Amplicon sequencing
Genome-wide SNP genotyping
Targeted SNP genotyping
High through-put screening
siRNA screens
Chemical screens
Drug sensitivity and resistance screens
Bioinformatics
Genome seq analyses
RNA seq analyses
Translational research
Serum printing
FIMM
29
genomics unit
T
Personnel:
Contact Person, Senior Researcher: Päivi Lahermo
Postdoctoral Researcher: Mari Kaunisto
Senior Laboratory Technicians: Sirkka Ekström,
Annika Korvenpää, Anu Yliperttula
Research Assistant: Mikko Siurala
(until December 2011)
he Genomics Unit of the FIMM Technology Centre is the only nationwide centre that offers high-throughput genotyping, gene expression, and DNA methylation analysis services in Finland. These services were provided on several platforms in year 2011: Illumina’s iScan and BeadStation, Sequenom MassArray, Roche
Light Cycler 480, Affymetrix GeneChip, and ABI 3730XL. The Unit produced approximately 572 million genotypes or gene expression and methylation analysis
results this year for over 21 000 DNA or RNA samples. This included whole genome
SNP genotyping with nine different microarray types, fine mapping genotyping
with three platforms, and gene expression analysis of three different organisms.
Our first custom DNA methylation project was also performed. As a new service
for year 2011 we provided genotyping for cell line authentication. The genotyping
unit was involved in nearly 70 service and/or collaborative projects from eight
national and three international universities or other research institutes, as well
as one commercial customer. In addition to high quality and high-throughput
laboratory services, the Genomics Unit offered expertise in project planning, data
handling, and analysis. The focus in our internal development was placed on further strengthening our database tools and management of laboratory processes.
Besides research collaborations, the staff of the Genomics Unit is also active in
their own research projects, especially on genetics of complex traits, including
e.g. migraine and genetic structure of populations.
Statistics on 2011 services
No of genotypes or expression/methylation data points produced: 572 million
No of samples genotyped with Genome-wide SNP arrays : 992
No of samples genotyped with targeted SNP assay: 20 093
No of samples profiled with genome wide expression arrays: 174
No of cell line genotyped for identification: 2
Services provided by the Genomics Unit
- targeted and genome-wide SNP genotyping
- targeted and genome-wide microsatellite genotyping
- expression profiling on microarrays
- targeted and genome-wide methylation profiling
- cell line authentication
Publications utilizing genomics services in 2011:
Nieminen TT, Abdel-Rahman WM, Ristimäki A, Lappalainen M, Lahermo P, Mecklin JP, Järvinen HJ, Peltomäki P. BMPR1A mutations in hereditary
nonpolyposis colorectal cancer without mismatch repair deficiency. Gastroenterology. 2011 Jul;141(1):e23-6
Salmela E, Lappalainen T, Liu J, Sistonen P, Andersen PM, Schreiber S, Savontaus ML, Czene K, Lahermo P, Hall P, Kere J. Swedish population substructure revealed by genome-wide single nucleotide polymorphism data. PLoS One. 2011 Feb 9;6(2)
Niittymäki I, Tuupanen S, Li Y, Järvinen H, Mecklin JP, Tomlinson IP, Houlston RS, Karhu A, Aaltonen LA. Systematic search for enhancer elements
and somatic allelic imbalance at seven low-penetrance colorectal cancer predisposition loci. BMC Med Genet. 2011 Feb 14;12:23.
Heikkinen T, Greco D, Pelttari LM, Tommiska J, Vahteristo P, Heikkilä P, Blomqvist C, Aittomäki K, Nevanlinna H. Variants on the promoter region of
PTEN affect breast cancer progression and patient survival. Breast Cancer Res. 2011 Dec 15;13(6):R130
Haataja R, Karjalainen MK, Luukkonen A, Teramo K, Puttonen H, Ojaniemi M, Varilo T, Chaudhari BP, Plunkett J, Murray JC, McCarroll SA, Peltonen
L, Muglia LJ, Palotie A, Hallman M. Mapping a new spontaneous preterm birth susceptibility gene, IGF1R, using linkage, haplotype sharing, and association analysis. PLoS Genet. 2011 Feb 3;7(2):e1001293.
Wessman M, Forsblom C, Kaunisto MA, Söderlund J, Ilonen J, Sallinen R, Hiekkalinna T, Parkkonen M, Maxwell AP, Tarnow L, Parving HH, Hadjadj
S, Marre M, Peltonen L, Groop PH; FinnDiane Study Group. Novel susceptibility locus at 22q11 for diabetic nephropathy in type 1 diabetes. PLoS One.
2011;6(9):e24053.
Sandbacka M, Bruce S, Halttunen M, Puhakka M, Lahermo P, Hannula-Jouppi K, Lipsanen-Nyman M, Kere J, Aittomäki K, Laivuori H. Methylation
of H19 and its imprinted control region (H19 ICR1) in Müllerian aplasia. Fertil Steril. 2011 Jun 30;95(8):2703-6
Uimari P, Sironen A, Sevon-Aimonen ML. Whole-genome SNP association analysis of reproduction traits in the Finnish Landrace pig breed. Genet
Sel Evol. 2011 Dec 1;43(1):42.
Uimari P, Tapio M. Extent of linkage disequilibrium and effective population size in Finnish Landrace and Finnish Yorkshire pig breeds. J Anim Sci.
2011 Mar;89(3):609-14.
30
FIMM
Sequencing Unit
T
he Sequencing Unit is a national and international service provider for next
generation sequencing (NGS) and capillary sequencing services. The Sequencing Unit has been operating in the NGS field with Illumina sequencing-by-synthesis technology since early 2008. The Unit receives support from Biocenter Finland
as a part of the Genome-Wide Methods network and participates in EATRIS, The
European Advanced Translational Research Infrastructure in Medicine, activities.
Year 2011 was once again an era of rapid growth and development in terms of personnel, technology, capacity and number of scientific projects. Sequencing unit
succesfully recruited three professionals to better respond to the demands of the
scientific community.
During March 2011 the Sequencing Unit moved to new lab facilities. As a part
of the move sequencing capacity was upgraded through installation of Illumina HiSeq2000 platform. Platform was rapidly adapted to laboratory’s workflow.
HiSeq2000 platform is capable of producing sequence data in genome scale volumes. Since March 2011 over 4.4 Terabases of sequence, equivalent to amount of sequence of about 1 460 human genomes, was produced for scientific projects with
NGS platforms. In addition, we operate a capillary sequencing service, where request increased by 24 % exceeding 200 000 capillary sequencing reactions per year.
Altogether 51 new service projects were initiated (+45 %) and a total of 914 libraries were processed (+228 %) for various applications. The most used services were
exome analysis (n=286) and custom targeted genome sequencing (n=325). Transcriptome sequencing services were set up at first quarter of the year and gained immediate interest (n=116). Bioinformatics analysis pipelines were further developed
in collaboration with the Bioinformatics Unit and research groups towards more
in-depth analysis of structural and copy number variation of the genome and Sequencing unit’s research collaboration with its clientele led to a highly accessed
publication comparing available exome sequencing methods. Scientists of the sequencing unit were co-authors in four peer reviewed articles during 2011.
The Sequencing Unit played also an important role in the development of
personalized medicine activities in FIMM by setting up fast-track services for PM
projects and processing 48 exomes and 27 transcriptomes for molecular profiling
of leukaemia patients. Additionally a new development was launched towards ultra-deep amplicon sequencing where the goal is to validate low quantity somatic
mutations, provide disease marker follow up tool and enable the study of clonal
evolution in cancers. Growing interest towards clinical sequencing has led to initiation of several studies where exome sequencing will be used to identify causative mutation in cases where the genetic basis of the disease in unclear.
Personnel:
Contact Person, Head of Laboratory: Pekka Ellonen
Senior Researcher: Pirkko Mattila
Senior Laboratory Technicians: Maija Lepistö,
Sari Hannula, Sonja Lagström
Laboratory Analysts: Tiina Hannunen,
Anna Kossila, Aino Palva.
Statistics on 2011 services
Amount of sequence produced: >4.4 Terabases
No of genome sequenced samples: 35
No of exome sequenced samples: 286
No of custom targeted samples sequenced: 325
No of sequenced transcriptomes: 116
No of amplicon sequenced samples: 81
Services provided by the Sequencing unit
- Targeted re-sequencing (exomes, custom
targets)
- Transcriptome sequencing (RNA-seq,
small RNA-seq)
- Genomic sequencing
- Ultra-deep amplicon sequencing
- Metagenomics
- Capillary sequencing, fragment analysis
Publications, where the sequencing unit contributed:
Mäkinen N, Mehine M, Tolvanen J, Kaasinen E, Li Y, Lehtonen HJ, Gentile M, Yan J, Enge M, Taipale M, Aavikko M, Katainen R, Virolainen E, Böhling
T, Koski TA, Launonen V, Sjöberg J, Taipale J, Vahteristo P, Aaltonen LA. MED12, the mediator complex subunit 12 gene, is mutated at high frequency
in uterine leiomyomas. Science. 2011 Oct 14;334(6053):252-5. Epub 2011 Aug 25.
Saarinen S, Aavikko M, Aittomäki K, Launonen V, Lehtonen R, Franssila K, Lehtonen HJ, Kaasinen E, Broderick P, Tarkkanen J, Bain BJ, Bauduer F,
Ünal A, Swerdlow AJ, Cooke R, Mäkinen MJ, Houlston R, Vahteristo P, Aaltonen LA. Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma. Blood. 2011 Jul 21;118(3):493-8. Epub 2011 May 11.
Juhila J, Sipilä T, Icay K, Nicorici D, Ellonen P, Kallio A, Korpelainen E, Greco D, Hovatta I. MicroRNA expression profiling reveals miRNA families
regulating specific biological pathways in mouse frontal cortex and hippocampus. PLoS One. 2011;6(6):e21495
Götz A, Tyynismaa H, Euro L, Ellonen P, Hyötyläinen T, Ojala T, Hämäläinen RH, Tommiska J, Raivio T, Oresic M, Karikoski R, Tammela O, Simola
KO, Paetau A, Tyni T, Suomalainen A. Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet. 2011 May 13;88(5):635-42
Sulonen AM, Ellonen P, Almusa H, Lepistö M, Eldfors S, Hannula S, Miettinen T, Tyynismaa H, Salo P, Heckman C, Joensuu H, Raivio T, Suomalainen A, Saarela J. Comparison of solution-based exome capture methods for next generation sequencing. Genome Biol. 2011 Sep 28;12(9):R94.
Tyynismaa H, Sun R, Ahola-Erkkilä S, Almusa H, Pöyhönen R, Korpela M, Honkaniemi J, Isohanni P, Paetau A, Wang L, Suomalainen A. Thymidine
kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions. Hum Mol Genet. 2012
Jan 1;21(1):66-75. Epub 2011 Sep 21.
Klockars T, Kyttänen S, Ellonen P. TBX22 and Tongue-tie. Cleft Palate Craniofac J. 2011 Sep 9.
Alinikula J, Nera KP, Junttila S, Lassila O. Alternate pathways for Bcl6-mediated regulation of B cell to plasma cell differentiation. Eur J Immunol. 2011
Aug;41(8):2404-13. doi: 10.1002/eji.201141553. Epub 2011 Jul 6.
FIMM
31
RNAi Unit
T
Personnel:
Contact Person, Postdoctoral Researcher: Carina von Schantz-Fant
Senior Researchers: Vilja Pietiäinen, Päivi Östling
Senior Laboratory Technician: Ruusu-Maaria Merivirta
Statistics on 2011 services
No of data points produced: 3 840
No of targeted siRNA screen initiated or completed: 10
No of serum samples printed: 18000
Services provided by the RNAi unit
- plate based screens of targeted siRNA libraries
- printing of serum samples
- printing oligonucleotides
32
FIMM
he main goal of the FIMM Technology Centre RNAi Unit is to facilitate the application of high-throughput screening approaches,
primarily small interfering RNA (siRNA) screening, to basic biomedical research by providing up-to-date instrumentation and adequate
expertise to the research community. The RNAi Unit receives support
from Biocenter Finland as a part of the “Genome-Wide Methods” network.
The RNAi Unit maintains a genome-wide collection of siRNAs and
houses instruments needed to process a large amount of samples in
high-throughput fashion. Our platforms include both plate-based and
cell-spot microarray-based screening, currently enabling screens of
targeted libraries. We are constantly developing our platforms to enable genome-wide siRNA screening. We support both plate reader assays and high-content microscopy. We also provide expertise in assay
development and optimization, and are further developing our image
and data analysis capabilities.
Besides siRNA screening, we also offer array printing services,
such as serum and oligonucleotide array printing. A pilot project to
set up serum microarrays was initiated in 2011.
During the year 2011, the Unit became fully operational. Altogether six projects were initiated and transfection conditions of 10 cell
lines were optimized. Our first screening project with 2 688 siRNAs on
the 384 well- platform was completed. Most of the initiated screens
were solely siRNA screens whereas a few were combining siRNAs and
drugs in a screen. Three serum printing projects were completed during the past year including over 18 000 serum samples in total.
Two new senior researchers were recruited to the RNAi Unit in
2011, bringing with them expertise on cell biology, imaging, miRNA
and protein lysate array screening. We also continued developing new
technologies for the unit. The first microRNA screens were initiated
already during year 2011 whereas development of the protein lysate
microarray platform has just begun.
Chemical Biology Unit
T
Chemical Biology Unit of the Technology Centre is focused on assay development and high throughput screening in plate-based
formats. It is designed to operate as a local, national and eventually
as an international research infrastructure. The Chemical Biology unit
receives support from Biocenter Finland for and coordinates the “Drug
Discovery and Chemical Biology” platform of the national Translational Technologies research infrastructure platform and participates as
the Finnish partner in the preparatory phase of EU-OPENSCREEN,
a European strategic research infrastructure initiative that aims at
building up a pan-European open access chemical biology research
infrastructure.
The Unit provides screening services of many types, including molecular probe discovery, screening of large chemically diverse libraries, biological profiling screening using libraries of known bioactives,
drug repositioning and personalized medicine screening using approved and investigational drugs, and combining compound screening with genetic screens using siRNA libraries. The Unit manages
two screening laboratories, one self-service facility that contains the
equipment to perform small chemical and genetic screens on a largely
manual basis and one fully automated state-of-the-art HTS system
that can process more than 100 000 data points per day. Both facilities are set up to handle cell-based and biochemical screens. To support the use of the screening facilities, the Unit maintains a chemical
collection of 120 000 compounds and together with the RNAi Unit, a
genome-wide collection of siRNAs.
In 2011, the Unit handled a wide array of projects all the way
from small-scale cherry-picking of a handful compounds for directed
screens, up to screening of tens of thousands compounds in a day. A
total of 93 screens in 16 different user-driven projects were handled.
An important direction the Unit took was to work very actively within the personalized medicine program and run more than 80 oncology compound screens on both patient samples and cancer cell lines.
Several combined chemical and siRNA-based screens were initiated
together with the RNAi Unit and the establishment of a system for
distributing small-scale amounts of bioactive compounds to researchers in Finland was begun.
Personnel:
Contact Person, PI: Krister Wennerberg
Senior Researcher: Jani Saarela
Coordinator: Laura Turunen
Assay Developer: Evgeny Kulesskiy
Senior Laboratory Technician: Anna Lehto
Statistics on 2011 services
No of data points produced: XXXXXX
No of chemical screens completed: 7
No of drug sensitivity and resistance screens completed: 84
Services provided by the Chemical biology unit:
- Maintenance, support and user training for High Throughput Centre 1 in BMH 1
- HTS assay development and optimization
- High throughput screening in 96-, 384 and 1536-well formats
- DSRT and other small molecule bioprofiling screens
- Virtual screening and follow-up confirmatory screening together with collaborators in national DDCB network
- Batch as well as custom compound and siRNA delivery in assay plates
- Development and running of nanoliter scale bioassays with the Labcyte Echo
- Distribution of proof of concept scale bioactive compound aliquots
- Providing assay plates and HTS reagents in small scales at big batch prices as well as batch-controlled FBS for researchers at FIMM
FIMM
33
Metabolomics Unit
T
Personnel:
Contact person, Research Coordinator: Vidya Velagapudi
Analytical Chemist: Jean-Christophe Yorke
Master’s Thesis Student: Vasudev Kantae, B.Tech
34
FIMM
he Metabolomics Unit of the Technology Centre focuses on targeted quantitative analyses of endogenous metabolites in high
throughput manner. A list of different classes of metabolites that will
be targeted by the analysis include sugars, nucleotides, nucleosides,
nucleobases, organic compounds, bile acids, amino acids, central carbon metabolites, TCA cycle, urea cycle and neurotransmitter metabolic intermediates, enzyme cofactors, etc. During 2011 all the available
information about these metabolites was retrieved from the Human
Metabolome DataBase (HMDB, www.hmdb.ca) and collected into
an in-house developed database covering the details of HMDB ID,
chemical formula, molecular weight, structure, CAS, KEGG, METLIN &
pubchem IDs, water solubility, concentration ranges etc for about 150
polar metabolites.
A Waters Xevo TQ-S triple quadrupole mass spectrometer (UPLCMS/MS system) used in the analysis was installed in 2011. Further,
an analytical method for the extraction of most of the endogenous
polar metabolites was developed. It includes fast and simple preparation techniques (protein precipitation), separation of a mixture of
basic, neutral and acidic molecules within a single chromatographic
run (Hydrophilic interaction liquid chromatography, Hilic separation)
and short run times (15 minutes/run, i.e., 96 samples in 24 h). A pilot study with human plasma samples was run in December 2011 to
assess the performance of the developed method. Sample extraction
method for the rest (1/3rd ) of the compounds is still being developed
and optimized.
We also acquired a liquid handling platform, MicroLab Star, from
Hamilton in 2011.The currently developed sample extraction protocol
has been programmed into the software and already successfully implemented. The liquid handling system is also used to make serial dilutions of pure compounds for calibration curves.
Bioinformatics and IT Unit
I
nformation and communication systems are as vital an infrastructure as heating, plumbing, ventilation and electrical systems for a
biomedical research institute - hardly appreciated when working as
intended but causing misery and suffering when not. FIMM has continued investing in both equipment as well as the people to implement solutions to make modern science happen.
FIMM’s computing infrastructure has been designed for scalability
and flexibility utilizing the latest virtualization and scale-out storage
technologies, to enable us to meet the rapidly increasing capacity and
performance demands of data-intensive research. In 2011, we expanded the capacity of the EMC CX4-480 storage system by 60TB. That and
the additional 20TB storage pool hosted at CSC-IT Center for Science
Ltd. increased the total storage capacity by roughly 35 % in 2011 (30 %
growth in 2010 and 2009).
During 2011 FIMM’s computing cluster, partly hosted at CSC, was
also expanded by 20 % to 1 200 processors and the total amount of
computation done in the cluster was 570 cpu years (5 million cpu
hours). In addition to the cluster the IT infrastructure of FIMM consists of more than hundred virtual and physical servers hosting various bioinformatics applications and databases. In December we further installed an experimental fast 1.2TB flash memory file system to
facilitate reading and writing of large amounts of data.
Bioinformatics and data management activities served mainly the
needs of the users of FIMM’s largest data producers next generation
sequencing (NGS) and genotyping units. The most often used analysis in 2011 was sequence variant identification and annotation in the
context of the universal reference sequence. This was performed on
497 samples from 29 research groups. We also have tools for identifying possible disease causing mutations by comparing the genome
sequences of affected individuals and healthy relatives as well as for
comparing sequences from tumor tissue and normal tissue from the
same individual. This analysis was performed on 217 samples from 9
research groups. All of these tools have also been used to analyse NGS
data from patients with the aim to understand, and help clinicians to
treat, their disease better.
In the next year, we will streamline and further automate our NGS
pipelines so that they can be applied with minimal human intervention and be executed fast. We will also refine the output. On one hand
we will have to add more in-depth information to the variants identified for the researcher or physician to be able to better and more easily evaluate the significance of the findings and how to use them. On
the other hand we need to remove (or hide) the information that just
clutters the reports and causes more confusion than helps. We can
only achieve these improvements by working closely with our clients,
listening their feedback and understanding their needs.
During 2011 the unit received support from Biocenter Finland as
part of the nationwide bioinformatics network as well as from the
Academy of Finland to the build-up phase of the EATRIS translational
research infrastructure in Finland.
Personnel:
Contact Person Bioinformatics: Imre Västrik
Contact Person IT services, Head of the IT systems unit: Timo
Miettinen
Senior Researcher Juha Muilu,
Bioinformaticians: Henrikki Almusa, Henrik Edgren, Samuli Eldfors, Jesús María López Martí (started 2012), Daniel Nicorici (left
in early 2011)
Information system specialist: Kyösti Sutinen
IT Designers: Jani Heikkinen, Anne Leinonen, Teemu Perheentupa, Tomi Simonen, Kari Tuomainen, Hannu Turunen
IT Specialist Myles Byrne
FIMM
35
Statistics on 2011 services
No of genome sequence analyses completed: 497
No of transcriptome analyses completed: 79
Services provided by the Bioinformatics and IT units
- Variant calling and annotation
- Comparative variant identification from cases and controls,
e.g. affected and healthy relatives or tumor and normal tissue
- Gene expression quantification from RNA sequence data
- Identification of fusion transcripts from RNA sequence data
- Server and application hosting
- High performance computing and bioinformatics environment
- End-user support for the computing cluster and bioinformatics
applications
- Custom software development
Publications utilizing bioinformatics services:
Juhila J, Sipilä T, Icay K, Nicorici D, Ellonen P, Kallio A, Korpelainen E, Greco D, Hovatta I. MicroRNA expression profiling reveals miRNA families regulating
specific biological pathways in mouse frontal cortex and hippocampus. PLoS One. 2011;6(6):e21495.
Sulonen AM, Ellonen P, Almusa H, Lepistö M, Eldfors S, Hannula S, Miettinen T, Tyynismaa H, Salo P, Heckman C, Joensuu H, Raivio T, Suomalainen A,
Saarela J. Comparison of solution-based exome capture methods for next generation sequencing. Genome Biol. 2011 Sep 28;12(9):R94
Tyynismaa H, Sun R, Ahola-Erkkilä S, Almusa H, Pöyhönen R, Korpela M, Honkaniemi J, Isohanni P, Paetau A, Wang L, Suomalainen A. Thymidine kinase 2
mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions. Hum Mol Genet. 2012 Jan 1;21(1):66-75.
Epub 2011 Sep 21.
36
FIMM
Biobank Services and
Translational Projects
B
iobanks of human biological samples with associated medical data represent a vital resource in unraveling the etiology of diseases, identification and validation of new diagnostic methods as well as advancing personalized medicine.
Biobanking can bridge basic, translational and clinical research, life-science industry, and help in the assessment of health
care outcomes and efficiency. Today, biobanking is not only about collecting and storing samples. It is all about building a
comprehensive and systematic approach to managing samples, patient data and data generated by deep molecular profiling.
Finnish researchers have been in the global front-line in the application of biobanks for decades. Especially the Meilahti
campus is in the position to benefit from the largest patient pool in Finland, as well as decades long tradition and experience
in collecting both clinical and population sample cohorts. For example, the DNA sample archives of the National Institute
for Health and Welfare (THL), FIMM partner institution on the Meilahti campus, cover samples from >200,000 individuals, all
linked with detailed demographic and comprehensive long-term follow-up information (www.nationalbiobanks.fi).
Meilahti Integrated Biobank Infrastructure (MIBI): A leading national centre for
next-generation biobanking
I n 2009—2011, FIMM and THL joined forces with other stakeholders (HUCH, HUSLAB) on the campus to create a state-of-theart biobanking facility, the Meilahti Integrated Biobanking Infrastructure (MIBI). FIMM and THL also serve as the coordinating node for the national BBMRI biobanking infrastructure in Finland.
Already, MIBI can currently provide access to samples from nearly 200 000 subjects (see tables below), and has a capacity
to store over a million more. As described below, new prospective clinical biobanking projects were launched in 2011. The MIBI
infrastructure also provides several capabilities for sample processing and analysis by state-of-the-art technologies, such as
exosome isolation, iPS cell preparation, sample microarrays, multi-spectral imaging for molecular pathology, web microscopy, clinical informatics and databases.
Contact at FIMM:
THL personnel:
Head of Development Kimmo Pitkänen:
Head of Laboratory: Päivi Laiho
Research Director: Johan Lundin
Senior Scientist: Aija Kyttälä
Research Director: Janna Saarela
Systems architect: Markku Laukkanen
Contact at THL:
Head of Public Health Genomics Unit
(THL), Senior Scientist
(FIMM): Anu Jalanko
FIMM personnel:
Research Technicians: Sini Lähteenmäki, Elina Mäkinen, Anne Nyberg,
Seija Puomilahti
Laboratory Coordinator: Minttu Sauramo, Tuuli Sistonen
Research Technician: Arja Terola,
Regis Wong, Anne Vikman
Project Coordinator: Tiina Vesterinen
Laboratory Engineer: Niina Eklund
IT specialist: Askar Ibragimov
Senior Laboratory Technicians:
Siv Knaappila, Minna Suvela
IT Designer: Timo Miettinen
Senior Researchers: Juha Muilu,
Kaisa Silander
Bioinformatician: Teemu Perheentupa
Information Systems Specialist:
Kyösti Sutinen
Systems Analyst: Hannu Turunen
FIMM
37
integrated full-service biobanking
A wide range of biobanking related capabilities has been set up in close collaboration with FIMM Technology Centre and the
Translational unit of FIMM.
MIBI experts can offer consultation help on how to build a biobank (ethical, consent, legal, technological, informatics,
funding and scientific advice) as well as give an overview of the wide technological capabilities that can make use of the
sample collection projects.
Sample storage services
MIBI has a liquid nitrogen based sample storage facility which provides secure and controlled storage of samples in liquid
nitrogen vapor phase. In 2011, the system was expanded with one additional freezer tank and currently has the capacity to
store 480 000 samples with a capacity upgrade available to 1,7 million.
The LN2 based sample storage is available to all research groups on the campus and elsewhere. Over 180 000 samples
were stored in the facility during 2011.
Automated DNA, RNA and protein extraction and
aliquoting
MIBI offers automated DNA extraction service from whole blood,
buffy coats, cell and tissue samples, saliva and buccal swabs, as
well as automated DNA aliquoting including normalization and
quality control. During 2012, we will also implement automatic
RNA extraction and set up protein extraction methods for tissue
samples. High-quality sample logistics is guaranteed by SamWise
database/LIMS system specifically developed in-house for biobanking.
Towards full automated next-gen sample management
In 2011 MIBI performed a tendering process for a fully automated
sample storage and retrieval system for “cherry picking” and processing of samples. The sample automation line will be completed
with -20C and -80C storage modules with a capacity to store 200,000 samples (in 0.5 ml vials). The system will be fully operational in 2012 and will facilitate sample logistics of large biobanking projects.
Contact for automated sample storage and management services:
Head of Laboratory: Päivi Laiho
DNA processing activities in 2011:
Number of active DNA biobanking projects: 29
Number of nucleic acid samples isolated: 7000
Number of nucleic acid aliquots processed: 40 000
Biobank informatics
Biobanking informatics provides a range of critical services to facilitate biobank activities, from standardized annotation
ontologies, to methods for handling large, multidimensional datasets. Biobank integration brings along the deep challenge
of managing the sensitive nature of the data at the individual level. The IT group at FIMM is building a national biobanking
IT infrastructure as part of the BBMRI.FI network, with THL, hospital districts and CSC. This infrastructure will pool national
sample data and facilitate information on their availability for research. The data management group has also been working
on harmonizing THL’s population cohorts like Finrisk studies, containing hundreds of variables.
Services:
- Development of in-house software for biobanks, research programs and consortia.
- Database services for hosting, management and curation of clinical and research data associated with biobanks.
- Data collection and federation services for research programs across multiple institutions.
Contact:
Senior Researcher: Juha Muilu
38
FIMM
Tissue biobanking, molecular pathology and imaging services
Tissue processing, histology and immunohistochemistry:
FIMM molecular pathology laboratory provides routine services for tissue embedding, sectioning, immunohistochemical
staining, quantification and analysis.
Complete Tissue Microarray (TMA) workflow
Tissue microarray technology (TMA) allows simultaneous analysis of large number of cases under standardized laboratory and
evaluation conditions without significant damage to the original tissue block. The TMA and molecular pathology services can
be coupled with digital microscopy and image analysis.
The image analysis facility provides brightfield scanning of slides and the WebMicroscope platform to researchers, as well as
the new multi-spectral microscopy imaging platform. Multi-spectral microscopy is used for imaging several different markers in
the same tissue slide. Images of formalin-fixed paraffin-embedded tissue stained with multiple antibodies can be acquired to provide substantially more information on the heterogenous nature of the cancer tissue. Both conventional chromogenic and fluorescent staining approaches are being used for multicolor tissue staining.
Services:
– Designing and preparation of TMA blocks from paraffin embedded tissues
– Sectioning of TMA and other paraffin embedded tissue blocks
– Staining of the sectioned slides histochemically and/or by using immunohistochemical techniques
Microscopy sample digitization:
Whole slide tissue samples and TMAs can be digitized with an automated high capacity microscopy scanner. The scanner captures images at high magnification (resolution approx. 0.25
micrometer) and generates a gigapixel-sized digital copy of the microscopy sample.
Webmicroscopy:
Scanned whole-slide images are automatically transferred to a digital whole-slide management
platform (fimm.webmicroscope.net). The scanned images are accessible for web-based viewing,
annotation and processing with image analysis algorithms using a standard web browser interface. The webmicroscope platform allows research groups to have password protected accounts
with project specific digital slide series. Digitized slides can be shared with other users or become part of a common tissue image repository according to agreement with the researchers.
Visual and automated microscopy image analysis:
The webmicroscope platform allows tissue and cell samples to be assessed visually and results can be entered by the use of a
graphical user interface into a database. Tissue spots in a TMA can be linked to corresponding clinical data and displayed one at
a time for visual scoring. Results of both visual and automated analysis are stored on a web server or downloaded by the user in
a spreadsheet format.
Custom image analysis development: Custom image analysis algorithms can be developed to perform automated tissue
and cell segmentation, staining quantification (IHC, FISH) and quantitative microscopy in general.
Clinical informatics and online statistical tools:
Clinical and phenotypic data related to tissue and cell samples can be linked to the image analysis results and stored in the
webmicroscope database. An online tool that uses novel adaptive informatics allows statistical analysis, correlation of image
analysis results with clinical data and generates graphical reports of results.
A prototype information management system that allows large-scale data pooling of results from tissue biomarker studies is
under development. Prognostic and predictive models (i.e. for personalized outcome estimation) can be constructed and shared
with other researchers or clinicians online. The system also allows researchers to match and compare biomarker and tissue analysis results with results stored in a pooled reference database. According to agreement with FIMM, researchers can decide to add
their study specific data to the common reference database.
Services in 2011:
Number of TMA spots processed: 11500
Number of slides digitized: 2570
Amount of server space needed for storing images: 27 terabytes
Contact:
Research Director: Johan Lundin
Project Coordinator: Tiina Vesterinen
FIMM
39
population cohorts available for researchers
Through the collaboration between FIMM and THL, MIBI can offer access to the DNA sample sets available
as part of the THL national biobanking cohorts. The ability to combine the DNA sample sets with the services offered by MIBI and the FIMM Technology Center creates a unique and powerful research infrastructure for translational research. The available DNA sample sets are listed below
Name of cohort
Participants
with blood/
DNA
Plasma
or serum
available
Participants
with GWA
data
Participants
with cardiometabochip
data
Participants
with Exome
or Genome
Sequencing in
progress
ATBC study
28 000
Yes
5000
1911
100
Finrisk 1992, 1997,
2002, 2007, 2012
37600
Yes
4923
6771
1323
Health 2000
(&2011)
8087
Yes
2603
Helsinki Birth
Cohort Study
2500
Yes
1676
Helsinki Sudden
Death Study
693
No
693
Northern Finland
Birth Cohort
1966. NFBC66
5987
Yes
5253
Northern Finland
Birth Cohort
1986. NFBC86
7342
Yes
1000 genomes
200
No
110
Twins study
15535
Yes
2661
Corogene
5367
Yes
2400
Eufam study
3046
Yes
184
Intracerebral
aneurysm
3862
No
Migraine family
study
8500
No
1123
Multiple sclerosis
family study
2586
Yes
525
Mental health
family studies
6508
Yes
625
560
Smaller misc.
projects
52319
Yes (partial)
6743
1850
Total
188132
Population
cohorts
1300
600
6500
180
Disease cohorts
40
FIMM
34519
1000
15182
6913
Access principles:
The cohorts, samples and data are accessible through applications to the cohorts’ steering committees
(see www.nationalbiobanks.fi for contact details). A short study plan (1-2 pages) is reviewed by cohorts’ key
individuals and if the plan is agreeable with the original ethical statements and consents and also seen as
scientifically valid, aliquots of samples and data can be transferred to identified scientists. A material and
data transfer agreement will be signed before the transfer by all sides.
Contact:
Research Professor, THL, and Senior Scientist, FIMM: Markus Perola
Senior Scientist: Kaisa Silander
Examples of major biobanking projects involving population cohorts
During the year 2011 we have utilized the large prospective Finnish cohorts for >10 large international collaboration projects, as part of consortia such as ENGAGE, CHARGE, GIANT, MAGIC, and SUMMIT. The cohorts most often utilized include Finrisk, Health 2000, Northern Finland Birth Cohorts and the Schizophrenia Family Collection. These international collaborations included
–a genome wide association study (GWAS) of adiponectin (ADIPOGen);
–a gene-smoking interaction analysis in coronary artery disease (CARDIoGRAMPlus);
–GWAS of leukocyte telomere length, an ENGAGE flagship project;
–genetic prediction of type 2 diabetes, an ENGAGE study;
–a CHARGE study, which used a multi-stage design in 200,000 individuals of European descent, that identified sixteen novel loci for systolic and diastolic blood pressure, including 10 novel genes that provide
new clues to blood pressure physiology; various GIANT GWAS for traits such as BMI, waist circumference,
height, weight and extreme obesity;
–MAGIC GWAS for gender specific effects on fasting insulin and glucose, and gene-BMI interaction affecting fasting insulin, glucose and HOMA-indexes;
–a SUMMIT GWAS of complications of type 1 and type 2 diabetes;
–early repolarization pattern (ERP) GWAS meta-analysis and replication in Health 2000 cohort.
Genome-wide SNP data is currently available for >30 000 Finnish individuals with rich phenotype data and
with linkage to national registers, forming the basis of a second generation biobank where the samples
are being transformed into data. These data are complemented by several other large Finnish cohorts managed elsewhere.
During 2011 we have also been involved in a new international collaborative effort to sequence the
whole genome or exome of 8000 Finnish individuals, which is being carried out in large scale sequencing
centers including the Broad Institute, the Sanger Institute and the Genome Institute at Washington University. These studies aim at constructing a Finnish haplotype catalogue, and providing a minimal set of
informative SNPs that would allow sampling nearly all the genomic variation in Finnish individuals. This
new resource is expected to have a major impact in future disease prediction studies by forming the basis
for the Finnish Genomes and the Future Health Care initiative, described on page 25.
MIBI has also been actively involved in the collection of a new cohort of newborns and their parents
from the Tampere area, to study the relationship between sleep, family environment, and genetic factors
(the Child-Sleep project). The collection is continuing in 2012, and will include approximately 2000 families
with DNA samples, and >1000 variables from each participant. A venous blood sample is collected from
both parents, and an umbilical cord blood sample is collected from the newborns.
Together with Folkhälsan, MIBI has performed a saliva DNA isolation pilot for the project Finnish
Health in Teens (Fin-HIT). The aim of Fin-HIT is to recruit a new cohort including 40,000 Finnish preadolescents. This will enable a study of a series of etiological hypotheses regarding the role of exposures and
mediating factors, including genetic susceptibility, on the development of overweight, obesity and disordered eating.
Contact:
Research Professor, THL and Senior Researcher, FIMM: Markus Perola
Senior Scientist: Kaisa Silander
FIMM
41
major ongoing clinical biobanking projects
In order to serve the future needs of personalized medicine and translational research in cancer, FIMM
has been active in promoting the establishment of modern biobanks with samples and long-term clinical follow-up data. Utilizing the integrated biobanking services of MIBI, two comprehensive new clinical
biobanking projects were launched in 2011.
Finnish Hematology Registry and Biobank (FHRB)
FHRB is a national collaborative project for collecting samples from patients with hematological disorders
(e.g. acute and chronic leukaemias, myelomas). It is operated by The Finnish Association of Hematology
(FAH), Finnish Red Cross Blood Service (FRCBS) and FIMM. The consortium offers the sample processing,
storage and management service for all the hospitals/clinics treating hematological patients. Hospital
District of Helsinki and Uusimaa (HUS) is the first hospital district to utilize the service (prof. Kimmo Porkka), and new hospital districts are expected to join during 2012.
Based on informed consent and after insuring the needs of routine diagnosis and treatment, FHRB collects bone marrow and blood samples coupled with skin biopsies and a broad range of clinical information
at the time of diagnosis and/or at follow-up visits.
FHRB is an open biorepository and the access rights will be granted by the FHRB Steering Group, based
on prepublished criteria and scientific evaluation of the proposals. Approximately 500 newly diagnosed patients with a hematological disorder are expected to be enrolled yearly.
Contact:
Head of Development: Kimmo Pitkän
Helsinki Urological Biobank (HUB)
In 2011, we designed and launched a Tekes funded Helsinki Urological Biobank (HUB) which is a joint project undertaking of FIMM and HUS. HUB is a regional development project of diagnostics and treatment of
urological cancers in the area of HUS. Peijas and Meilahti Hospitals are the main clinical centers, whereas
FIMM and HUSLAB are responsible for sample logistics, processing and storing. The FIMM data management group has been responsible for the IT connections between the data management systems at FIMM
and the Peijas hospital, as well as Finnish Red Cross Blood Service and FIMM for FHRB. The main clinical
collaborator is Docent Antti Rannikko, Department of Urology, HUCH.
HUB collects a comprehensive set of sample material from each patient: fresh frozen and formalin fixed
paraffin embedded tissue samples combined with blood and urine samples and wide clinical information.
Every year, there are about 900 urological operations performed in the Peijas Hospital. HUB aims to
enroll at least 80 % of these patients. The HUB biorepository will be open for research and R&D studies fulfilling predefined criteria.
Contact:
Senior Researcher, Pathologist, FIMM/HUSLAB: Tuomas Mirtti
Project Coordinator: Tiina Vesterinen
Personnel:
Postdoctoral Researcher: Andrey Golubtsov
Senior Researcher: Taija af Hällström
Senior Laboratory Technician: Reija Randen-Brady
42
FIMM
prostatectomy cohorts with long-term follow-up on tmas
Formalin-fixed paraffin-embedded (FFPE) samples from 452 prostate cancer patients treated with total
prostatectomy between 1982 and 1998 at the Helsinki University Central Hospital were organized as tissue
microarray blocks (TMA). The information on treatment, follow-up and survival, has been retrieved from
the medical records. All the immunohistochemical stainings done on the TMAs thus far have been digitized
and made available through the WebMicroscope platform. The project is coordinated by the Prostate Cancer Research Group Helsinki whose principal investigator is Docent Antti Rannikko, Department of Urology, HUCH. The TMAs are available for research upon request and approval.
Built in close collaboration with FIMM, FinnProstata IX is a retrospective clinical study with a collection of TMAs and detailed preoperative and follow-up information with survival data on 1,870 prostatectomies in four university hospital districts in Finland, including HUS. As a reference cohort, the study also
consists of the survival information on all prostate cancer patients treated with radical prostatectomy in
Finland during the years 1969 to 2010 (n>11.400). In these patient series, a systems pathology approach is
developed, combining clinical, pathological, biomarker and imaging data to achieve a personalized assessment of the disease. With this clinical data collection and TMA repository, FIMM participates in international collaborative prostate cancer research, such as Movember prostate biomarker global action plan.
Contact:
Research Director: Johan Lundin
Senior Researcher, Pathologist FIMM/HUSLAB: Tuomas Mirtti
technology development and emerging mibi services
Development of biobanking services at MIBI is progressing towards integrated, comprehensive service
packages addressing the state-of-the-art and future needs of translational research. Some biobaking technology development projects are highlighted below.
iPS cell technologies
Production of induced pluripotent stem (iPS) cells from somatic cell samples is a novel technique under
development at MIBI. The aim is to establish iPS techniques for utilization of previously stored samples as
well as to collect novel cell samples that are optimized for the iPS-technology. The iPS cell technique has
enormous potential for utilization of cells stored in the biobanks, as the samples can be differentiated into
various lineages. Last year, iPS optimized mononuclear blood cells were collected from 260 individuals from
Kuusamo as a pilot study for the large Finrisk 2012 cohort study.
Contact:
Senior Scientist: Aija Kyttälä
Tissue slice culture technologies
MIBI has established tissue slice cultures (TSCs) to facilitate short-term functional studies of both benign
and malignant prostate tissues ex-vivo. TSCS are thin sections of tissues that are maintained alive in culture for several days.. TSCs are perhaps the most representative model of the human prostate cancer and
tissues available, containing almost all of the cells typically present in the body, and maintaining essential
epithelial-stromal interactions as well as the differentiated cells, which are typically lost in long-term primary cultures or cell-line models .TSCs can be used for functional genomic studies, cellular and tumor biology as well as for drug response testing.
Contact:
Senior Researcher: Taija af Hällström
FIMM
43
Exosome technologies
Extracellular circulating microvesicles represent an emerging and rapidly growing field of biomedical research, which strongly promises diagnostic and therapeutic possibilities. Exosomes represent a particular
type of microvesicle with about 100 nm in size originating from early endocytic compartment of cells. Exosomes serve as vehicles for regulatory signaling molecules, such as miRNA, mRNA and proteins, and are
generally regarded as an important mechanism of intercellular communication. Exosomal cargo is believed
to reflect the biological status and wellbeing of specific tissues and this can be helpful for diagnostics and
monitoring of disease. We are developing the exosome-related technologies for reliable analysis, fractionation and preservation of microvesicles from human blood and urine. Importantly, exosomes require special
sample processing (plasma) and will not torelate repeated freeze-thaw cycles, providing a challenge that
underlies the importance of biobaking infras.
Contact:
Postdoctoral Researcher: Andrey Golubtsov
integration of mibi with the european biobanking infrastructure
bbmri
MIBI is the national core site of the BBMRI.fi infrastructure and FIMM and THL act as the national coordinators of the BBMRI activities in Finland. The activities are organized as part of the Biomedinfra consortium, with support from the Ministry of Education and Culture and links to biobanking activities in
all medical campuses and University Hospital sites in Finland. In September 2011, representatives of 13 EU
countries approved the principles of operation, access, funding and governance of BBMRI (Biobanking and
Biomolecular Resources Researc Infrastructure).
Contact:
BBMRI-ERIC preparation and BBMRI.fi National Coordination: Anu Jalanko, Head of Public Health Genomics Unit, THL and Senior Scientist, FIMM
BBMRI.fi National IT-infrastructure: Juha Muilu, Senior Scientist, FIMM
Personnel:
Laboratory Engineer: Niina Eklund
Systems Architect: Askar Ibragimov
Senior Scientist: Kaisa Silander
44
FIMM
administration unit, board
and sab
T
he FIMM Administration Unit is composed of eight people, who support the
Director in the management and development of the Institute. The Administrative Manager of FIMM is Reetta Niemelä, who is the Secretary of the Board of
FIMM. The Unit includes staff responsible for financial and personnel issues as
well as other institutional functions, such as the research infrastructure build up.
The Unit is also involved in the planning and implementation of the many events
mentioned in this report. A new initiative was launched in 2011 together with the
Research Sector of the University of Helsinki: joint appointment of Senior Advisor Mika Frederiksen brought project funding services closer to FIMM researchers.
When applying for external funding, researchers have support services in planning
and preparation of the applications, contract negotiations and reporting of the
projects. Senior Researcher Gretchen Repasky, Project Coordinators Sari Kivikko
and Huei-Yi Shen, Coordinator Imre Västrik and Laboratory Engineer Jouko Siro
contributed to the work of the Unit.
The Steering Group of the Institute meets every month and is composed of
all the principal investigators and the people responsible for the Technology Centre’s Units and the Biobank, as well as key administrative personnel. The Steering
Group discusses important issues that need opinions such as equipment, joint initiatives, training and recruitments.
The current Board of FIMM chaired by Vice Rector, Professor Kimmo Kontula
started its term on 1 July 2010. The Board of FIMM steers and supervises the Institute’s activities by approving the finances, strategic plans and objectives.
The Scientific Advisory Board (SAB) comprised of six internationally recognised
experts assesses the Institute’s activities and quality of research and provides the
Board with recommendations on these matters. The Chair of the SAB is Professor
Kai Simons.
Administration Unit:
Director, Professor Olli Kallioniemi
Administrative Manager Reetta Niemelä
Human Resources Coordinator Riitta Alatalo
Senior Advisor Mika Frederiksen
Department Secretary Sanni Hyppönen
Financial Planning Officer Riitta Koskinen
Financial Manager Marja Medina
Personal Assistant to Director Kallioniemi Susanna Rosas
Laboratory Coordinator Virve Tiusanen
FIMM
45
Board 1 July 2010—31 March 2014:
Chair of the Board:
Vice Rector, Professor Kimmo Kontula, University of Helsinki
Members (Deputy Members of the Board):
Dean, Professor Risto Renkonen, Faculty of Medicine, University of Helsinki
(Professor Kalle Saksela, Haartman Institute, Faculty of Medicine, University of Helsinki)
Research Director, Professor Anna-Elina Lehesjoki, Neuroscience Center, University of Helsinki
(Research Director, Professor Irma Thesleff, Institute of Biotechnology, University of Helsinki)
Professor Kimmo Porkka, Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki
(Professor Annamari Ranki, Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki)
Chief Research Officer, Professor Lasse Viinikka, HUS
(Chief Administrative Physician, M.D., Ph.D, LL.D., MFPM, Assistant Professor Lasse Lehtonen, HUS)
Deputy Director General, Professor Juhani Eskola, National Institute for Health and Welfare, THL
(Senior Researcher, Head of Public Health Genomics Unit, Anu Jalanko, THL)
Vice President, Professor, R&D Biotechnology, Anu Kaukovirta-Norja, VTT
(Technology Manager Kirsi-Marja Oksman-Caldentey, VTT, until 31 December 2011; Technology Manager
Richard Fagerström, VTT, as of 1 January 2012)
Chief Executive Officer Pekka Mattila, Desentum Oy, industry
(CEO Saara Hassinen, Strategic Centre for Health and Well-being, SalWe Oy, industry)
Director, Professor Eero Vuorio, Biocenter Finland , BF
(Chair of the Board, Academy Professor Seppo Ylä-Herttuala, Biocenter Finland, BF)
IT Designer Anne Leinonen, FIMM Technology Centre, personnel)
(Laboratory Manager Pekka Ellonen, FIMM Technology Centre, personnel)
Permanent Experts of the Board:
Director, Professor Olli A. Jänne, Biomedicum Helsinki, University of Helsinki
Scientific Advisory Board (SAB) 1 May 2007–30 April 2012:
Professor Kai Simons (Chair) Max-Planck-Institute of Molecular Cell Biology and Genetics (Germany)
Professor Cornelia van Duijn, Erasmus University Medical Center (the Netherlands)
Professor Carl-Henrik Heldin, Ludwig Institute for Cancer Research, Uppsala University (Sweden)
Professor Eric S. Lander, The Broad Institute of MIT and Harvard (USA)
Professor Edison Liu, Genome Institute of Singapore (Singapore)
Professor Nadia Rosenthal, EMBL Monterotondo (Italy) and EMBL Australia Partnership Laboratory (Australia)
46
FIMM
examples of ongoing projects
eu’s 7th framework programme, research projects
bioshare-eu (2010—2015)
BioSHaRE-EU (Biobank Standardisation and Harmonisation for Research Excellence in the European Union) is a consortium of leading biobanks and international researchers from all domains of biobanking
science. The overall aim of the project is to build upon tools and methods available to achieve solutions
for researchers to use pooled data from different cohort and biobank studies. This, in order to obtain the
very large sample sizes needed to investigate current questions in multifactorial diseases, notably on
gene-environment interactions. This aim will be achieved through the development of harmonization and
standardization tools, implementation of these tools and demonstration of their applicability. The project
involves 16 participating organizations, three of them from Canada. FIMM has played a key role and led
two work packages in this project. Contact Persons at FIMM: Group Leader Samuli Ripatti, Professor Aarno
Palotie and Senior Researcher Markus Perola, Research Professor at THL. http://www.bioshare.eu/
Engage (2008—2012)
ENGAGE (European Network for Genetic and Genomic Epidemiology) aims to translate the wealth of data
emerging from large-scale research in genetic and genomic epidemiology from European (and other) population cohorts into information relevant to future clinical applications. The concept of ENGAGE is to enable
European researchers to identify large numbers of novel susceptibility genes that influence metabolic, behavioural and cardiovascular traits, and to study the interactions between genes and life style factors. The
ENGAGE Consortium has brought together 24 leading research organizations and two biotechnology and
pharmaceutical companies across Europe and in Canada and Australia. The project was led by the worldleading human geneticist Academician of Science, Professor Leena Peltonen from FIMM, University of Helsinki for its first 26 months, until March 2010. The project co-coordinator, Professor Mark McCarthy from
the University of Oxford has assumed the leadership as Scientific Coordinator since March 2010. FIMM,
University of Helsinki continues as EC contractual Coordinator. In addition to its active involvement in
ENGAGE scientific activities, FIMM also hosts the Coordination Office in charge of day-to-day consortium
management and coordination tasks. Contact Persons at FIMM: Professor Jaakko Kaprio, Professor Aarno
Palotie and Group Leader Samuli Ripatti. http://www.euengage.org/
GEN2PHEN (2008—2012)
GEN2PHEN (Genotype-To-Phenotype Databases: A Holistic Solution). The project aims to unify human and
model organism genetic variation databases towards increasingly holistic views into Genotype-To-Phenotype (G2P) data, and to link this system into other biomedical knowledge sources via genome browser
functionality. The five-year project (2008-2012) is funded with 12 million euros and has 20 participating institutions from Europe as well as India and South Africa. Contact Person at FIMM: Dr Juha Muilu. http://
www.gen2phen.org/
SYNSYS (2010—2014)
SynSys (Synaptic Systems: dissecting brain function in health and disease) aims at molecular analysis of
synapse function and dynamic modeling. The perspective is to generate a blueprint for the discovery of
novel pathways and targets that enable rational strategies to design therapies for human brain disease.
There are altogether 16 participating institutions and the funding is for four years (2010—2014). Contact
Person at FIMM: Professor Aarno Palotie. http://www.synsys.eu/
SYSTEMS MICROSCOPY NETWORK OF EXCELLENCE (2011—2015)
The research network SYSMIC NoE (Systems Microscopy Network of Excellence) unites 15 multidisciplinary
laboratories located throughout Europe. The joint research plan spans over five years (2011—2015) and is
supported with 12 million euros. The aim is to develop next-generation systems biology tools and strategies on live cell imaging and to make them available to the wider research community. The advances in
automated fluorescence microscopy, cell microarray platforms, highly specific probes, quantitative image
analysis and data mining provide a powerful emerging technology platform to enable “Systems Microscopy” of the living cell. The core cellular processes analyzed within this NoE, cell division and cell migra-
FIMM
47
tion, are highly relevant to human cancer. Through close collaboration between biologists, physicians and
mathematicians, this NoE will create mathematical models of biological processes in time and space and
test them experimentally. This NoE will develop a powerful enabling platform for next-generation systems
biology and will apply these tools to understand cellular systems underlying human cancer. Contact Person
at FIMM: Professor Olli Kallioniemi. http://www.systemsmicroscopy.eu/network-excellence
PREDECT (2010—2015)
PREDECT is an IMI-funded partnership between nine academic, three SME (Small and Medium Enterprise) and eight EU pharmaceutical partners, aiming to develop novel, advanced, complex in vitro and in
vivo models for breast, prostate and lung cancers. Three-dimensional complex cell cultures, attempting to
closely mimic in vivo tumours, will be investigated for their improved potential to validate therapeutic
targets, applying molecular pathology and systems biology methods to compare the circuitry of resting
and perturbed states. The project is expected to shift paradigms in cell biology as well as preclinical target
validation, permitting greater predictivity of drug efficacy in patient cohorts. FIMM/University of Helsinki
is the academic coordinator of the project, which consists of 26 principal investigators. Contact persons at
FIMM: Group Leader Emmy Verschuren (academic coordinator of PREDECT), Professor Olli Kallioniemi and
Research Director Johan Lundin. http://www.predect.eu/
esfri projects (european strategy forum on research infrastructures)
BIOMEDBRIDGES (2012—2015)
BioMedBridges is a four-year project (2012—2015) addressing a call to implement common solutions for
a cluster of ESFRI infrastructures in the field of life sciences. It brings together partners from 21 institutions from 9 countries and is lead by Professor Janet Thornton from EMBL-EBI (European Bioinformatics
Institute). It will provide the computational ‘data and service’ bridges between the individual biological
and medical sciences research infrastructures, clustering them together and linking the basic biological
research and data to the clinical research and associated data. FIMM is leading the use of case work packages on personalised medicine and participating in another use case work package on large scale image
datasets. These use case work packages provide input and test-beds for designing and testing the ‘data and
service’ bridges. Contact persons at FIMM: Professor Olli Kallioniemi and Dr Imre Västrik.
EU-OPENSCREEN
ESFRI ROADMAP 2008
EU-OPENSCREEN PREPARATORY PHASE (2010—2013)
EU-OPENSCREEN (European Infrastructure of Open Screening Platforms for Chemical Biology) integrates highthroughput screening platforms, chemical libraries, chemical resources for hit discovery and optimisation, bio- and cheminformatics support, and a database containing screening results, assay protocols, and
chemical information. In the current preparatory phase (2010—2013), the network contains 13 partner institutes/institutions representing 12 European countries. FIMM is the partner representing Finland in the
network. Contact persons at FIMM: Group Leader Krister Wennerberg, Senior Researcher Heidi Virtanen
and Professor Olli Kallioniemi. www.eu-openscreen.eu
BIOMEDINFRA (2010—2013)
Biomedinfra is a Finnish collaborative endeavour to participate in the implementation of European
biobanking (BBMRI), bioinformatics (ELIXIR) and translational research (EATRIS) infrastructures. These infrastructures have been deemed strategic in Europe and are also on the national infrastructure roadmap
published in 2009. Following the completion of extensive planning stage these infrastructures are now entering the construction phase.
The Finnish collaborative approach is based on realisation that translational research - translation
of basic research discoveries and technologies into medical practice - increasingly benefits from both
biobanks and bioinformatics. Furthermore, all of these represent existing Finnish strengths.
The Biomedinfra consortium brings together the National Institute for Health and Welfare (THL), CSC
- IT Center for Science Ltd and FIMM/University of Helsinki.
The Ministry of Education and Culture via the Academy of Finland has funded the build-up of the respective national infrastructures. At FIMM the funding has been used to establish the Meilahti Integrated
Biobanking Infrastructure, to develop new imaging technologies as well as to strengthen FIMM Technology
center’s molecular profiling and bioinformatics capacities relevant to translational research.
48
FIMM
marie curie actions
PRO-NEST(2009—2013)
PRO-NEST (Prostate Research Organizations-Network of Early Stage Training) is a Marie Curie Initial
Training Network that offers training on all aspects of prostate cancer research, ranging from the molecular basis of this disease to the translation of biomarkers into the clinic, to 24 PhD students and starting
post-docs. The ultimate scientific aim of PRO-NEST is to understand the molecular basis of prostate cancer
to address prevention, and to provide novel biomarkers and therapeutic targets for monitoring and treatment of this major European health problem. PRO-NEST has started in 2009 for a period of 4 years until
2013. http://www.pro-nest.org/
SYSTUMS (2010—2014)
SYSTUMS (Systems Biology Approaches to Novel Tumour Suppressors) is a project funded by a Marie Curie
International Reintegration Grant aiming to study protein networks and molecular functions regulated by
the candidate tumour suppressor protein EphA3. This action funds individual projects presented by experienced researchers returning to Europe after having worked in a non-associated third country for at least
three years, to assist in reintegration and promote transfer of knowledge into EU Member States or Associated Countries. Grantee at FIMM: Group Leader Emmy Verschuren, for reintegration period 2010—2014.
european regional development fund
LEUKAEMIA BIOMARKERS (2011—2013)
The Leukaemia Biomarkers project (“Elämän merkit” in Finnish) aims at developing diagnostic services
based on biomarkers. The project is funded for three years (2011—2013) by the Regional Council of PäijätHäme from the Southern Finland ERDF programme. The project is coordinated by Turku Science Park and
also includes the VTT Technical Research Centre of Finland, the Hospital District of Varsinais-Suomi, the
University of Turku as well as Culminatum Innovation Oy. FIMM is developing a service which would enable the use of personalized biomarkers for measuring treatment efficacy and early detection of relapse in
leukaemia patients. Contact persons at FIMM: Professor Olli Kallioniemi and Dr Imre Västrik.
FIMM
49
events and visits
juni palmgren’s inauguration lecture
FiDiPro Professor Juni Palmgren’s (Stockholm University and
Karolinska Institute, Sweden) Inauguration Lecture entitled
“The Nordic Lead in e-Science and Health” on 21 March 2011
was given in Biomedicum Helsinki 1 lecture hall. The Chancellor of the University of Helsinki, Professor Ilkka Niiniluoto appointed Juni Palmgren to the post of Finland Distinguished Professor in Biostatistics. Professor Jaakko Kaprio is
the Finnish host.
“The data and competence of tFIMM and Karolinska Institute 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 Juni Palmgren. She also states that “Most
people do not appreciate that molecular medicine processes
amounts of data comparable in size to particle physics, but
with a more complex structure. Therefore, immense data
storage and processing capacity is required, as well as new
algorithms and models able to extract meaningful information from this avalanche of data.”
SAB visit
The SAB visited FIMM on 17 May 2011. Present were Professors Cornelia van Duijn, Carl-Henrik Heldin, Edison Liu, Nadia Rosenthal and Kai Simons (Chair of the SAB). The SAB
concluded in its report that they noted with satisfaction
that the FIMM build-up is proceeding in an outstanding
way. The SAB also recommended that the funding FIMM had
received in the start-up phase should be extended.
leena peltonen-palotie symposium
Together with the Academy of Finland, University of Helsinki and THL, FIMM arranged in May 2011 in Helsinki the symposium entitled: “A Global View of Disease Genomics” as a
tribute to Academician of Science, Professor Leena PeltonenPalotie. There were altogether over 30 distinguished speakers, including Members of the Scientific Advisory Board of
50
FIMM
FIMM, and almost 500 registered participants from all over
the world. In addition, about 300 participants attended the
public lectures.
Leena Peltonen-Palotie’s legacy is immense: “She was a
visionary in the field of science, creating an infrastructure
for research needs that weren’t even on the horizon yet,”
said Richard Durbin of the Wellcome Trust Sanger Institute
in England.
“Right now we’re in a situation where genetics research
has progressed faster than the methods it requires. We must
find a way to bridge this gap. Leena was the one who said,
‘don’t just rely on one method—use all the tools available’,”
remembered David Altshuler of the Broad Institute of MIT
and Harvard and Massachusetts General Hospital.
Leena Peltonen-Palotie, who passed away in March 2010,
built an international research network to which many of
the symposium’s 35 speakers belong. They discussed their
own research projects and shared memories of Leena: “Exceptionally intelligent, warm, supportive and demanding.
She inspired her colleagues to strive for better results and
helped fellow scientists see beyond the challenges they
faced. She believed that researchers should work together
instead of competing with each other.”
2nd annual fimm retreat
The second annual FIMM Scientific Retreat was held on 7—8
June 2011 at Hotel Rantasipi Sveitsi in Hyvinkää. The FIMM
staff was almost completely present with 133 persons attending the event. The first day programme started with a very
interesting scientific highlight from translational research
and personalized medicine. The scientific highlight was directed by Professor Olli Kallioniemi and FiDiPro Professor
Jonathan Knowles and it included a case study presented by
Professor Kimmo Porkka. It was also largely appreciated that
a patient was present speaking about his personal case. It
brought the topic to a concrete level. In the afternoon FIMM
research and technology highlights were presented by several persons from different areas and a poster session was
held which included 49 posters. The official programme was
brought to an end on the first day by the keynote speaker
Proferssor Juha Siltala, who gave a lecture about changing
working life and work motivation. The second day consisted
of group discussions.
second meeting of the nordic molecular
medicine network
Nordic Molecular Medicine Network (NMMN) promotes
collaboration between EMBL (European Molecular Biology
Laboratory) and its Nordic nodes FIMM, NCMM and MIMS,
as well as among the three Nordic nodes themselves. The
second joint meeting of the NMMN, bringing together almost 140 participants from the three nodes and the EMBL,
was hosted by FIMM in Helsinki, Finland from 29 to 30 of
September 2011. The meeting provided a highly stimulating
environment for the researchers of all three institutes and
the parent organization EMBL to share their research and
explore facilities and infrastructure within the partner institutes. Group leaders, postdoctoral researchers and PhD
students presented their research in short talks and posters
providing an overview of ongoing projects. An interactive
‘Meet the Experts’ -session, organized by FIMM technology
platforms, provided an opportunity to address technological
challenges and practical suggestions to all levels of researchers. A common initiative was forged to encourage exchange
of knowledge, technologies and personnel. In addition to
scientific interest, PhD students and postdoctoral researchers agreed to make a common platform for communication
and a Facebook group named ‘Nordic Molecular Medicine
Network (NMMN)’ was created thereof. The success of the
meeting in respect to collaboration and networking was
clearly apparent even in informal meetings during coffee
breaks, dinner and social events organized by the FIMM students. The next meeting of the NMMN will be held in conjunction with the Centre for Genomic Regulation (CRG), an
EMBL Partnership institute located in Barcelona, Spain, in
September 2012.
FIMM
51
predect consortium meeting
In September 2011 FIMM and the University of Helsinki hosted the annual IMI-PREDECT consortium meeting, which
included a scientific meeting at the Biomedicum Helsinki
premises. The meeting gathered over 50 participants from
its 20 European partner institutions, including representatives of seven major pharma industries, to discuss early partnering strategies on novel cancer target validation models.
FIMM Stakeholder meeting
A FIMM Stakeholder Meeting was arranged on 8 December
2011. The purpose of the meeting, chaired by Rector Thomas
Wilhelmsson, was to discuss the funding of FIMM and to
secure sustainable and sufficient basic funding for it in the
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FIMM
coming years as part of the Nordic EMBL Partnership, since
the university system in Finland has changed dramatically
after the establishment of FIMM in 2006.
The meeting gathered altogether 42 participants e.g.
from the Nordic EMBL Partnership, Ministries, founding organisations and supporters of FIMM as well as from national research funding agencies. The discussion at the meeting was very positive. All supporters of FIMM stated that
FIMM has fulfilled the expectations set out at its establishment and that FIMM’s role in the Nordic EMBL Partnership
for Molecular Medicine has to be secured. Follow-up actions
and further discussions with the ministries as well as other
founding organisations and current supporters of FIMM will
take place in 2012.
FIMM Scientific coffee breaks and seminars
The FIMM research community was strengthened in the
FIMM Scientific Coffee Breaks. In short talks arranged twice
a month students, postdoctoral researchers, as well as senior researchers presented their work for FIMM staff. In addition, group leaders and invited guest speakers have given
presentations in seminars open to wider researcher community on Meilahti Campus.
christmas party
The annual get together for all FIMM personnel, was arranged on 18 November 2011. For the second time, Poliisien
kesäkoti in Lauttasaari was chosen to be the venue for this
yearly event. Approximately 95 people attended the event
where dinner was served and a band, “Steppin Peanuts”, entertained the partygoers.
Entertainment Committee 2011:
Diana Cousminer
Yuexi Gu
Jani Heikkinen
Siv Knaappila
Anna Lehto
Muntasir Mamun Majumder
Minna Suvela
Laura Turunen
Anu Yliperttula
visits
In addition to the events mentioned above, FIMM was also
involved in the Meilahti Campus Day by providing lectures
and guided tours at FIMM for the general public. FIMM also
hosted amongst other things:
•Visits of representatives of the Japan Science and Technology Agency (JST) in March and December 2011, latter in connection to a symposium arranged by the Academy of Finland, Tekes and JST.
•Visit of representatives of the Joint Committee of the Nordic Medical Research Councils (NOS-M) in October 2011.
NOS-M works to promote Nordic cooperation among research councils, discusses research policy and disseminates information on national and international science
policy actions and initiatives of topical interest.
•Visits to the FIMM Biobank Infrastructure by experts from
the University of Jyväskylä, Lisbon Institute of Molecular
Medicine, Portugal as well as Facultad de Medicina, Universidad de Chile, Chile. The purposes of these visits were
to get a better knowledge of the FIMM Biobank system,
including administrative, scientific and technical aspects.
•Visits of representatives of the Embassy of Chile and Embassy of France.
•Visits of several groups of students from high schools from
Southern Finland.
FIMM
53
fimm in figures
Personnel Statistics
Figure 1. Total number of FIMM employees 2007-2011, estimate 2012
Figure 2. Number of FIMM personnel 2008-2011 according to the type of employment
13
7
Research personnel
Support personnel for research
43
Administrative personnel
96
Others (IT personnel)
Figure 3. Number of FIMM personnel in 2011 according to the type of employment
4th level (Professor and Research
directors)
8%
4%
4%
3rd level (research coordinators,
senior researchers)
21%
2nd level (post-doctoral researchers)
1st level (project researchers, doctoral
students, research assistants)
27%
9%
Support personnel for teaching and
research
Administrative personnel
27%
Others (IT perrsonnel)
Figure 4. Distribution of FIMM personnel by category of employment
54
FIMM
Nationalities represented among FIMM personnel:
(December 2011)
Bangladesh
Italy
Russia
Belgium
Japan
Slovenia
Denmark
Macedonia
Sweden
Estonia
Mexico
Spain
Finland
Nepal
Taiwan
France
Pakistan
Trinidad & Tobago
Germany
Poland
Uganda
Great Britain
Portugal
USA
India
Romania
Vietnam
FIMM
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Financial Report
3%
7%
Basic funding
(including University of
Helsinki fund) 23 %
23 %
Strategic funding 2 %
2%
Competitive external
funding 65 %
Service revenue (external) 3 %
Service revenue (internal) 7 %
65 %
Figure 5. Total funding of FIMM in 2011 (13,1 M€)divided based on the source of income. The basic funding refer to the support from the University of
Helsinki. External funding refers to competitive research and infrastructure funding.
Biocenter Finland
Academy of Finland (including ESFRI)
EU funding
TEKES
Other international funding
Other public funding (including THL, HUS,
City of Helsinki)
Service revenue (external)
Foundations
Figure 6. Distribution of FIMM external funding 2011 (8,8 M€) according to source.
21 %
47 %
Personnel cost
Facilities
1%
Consumables
10 %
Equipment
Depreciation
Services and other costs
13 %
8%
Figure 7. FIMM expenditure 2011
56
FIMM
personnel including researchers and students with grants and members of the
fimm national network for molecular medicine
Research groups
Maria Anastasina
Oxana Denisova
Laura Kakkola
Minttu Kaloinen
Eija Hämäläinen
Carita Jussila
Elli Kempas
Sari Kivikko
Leena Leikas
Tiia Luukkonen
Mikko Muona
Anne Nyrhinen
Mari Rossi
Olli Pietiläinen
Kaisa Silander
Minna Suvela
Maija Wessman
Olli Kallioniemi
Juni Palmgren
Tero Aittokallio
Petteri Hintsanen
Agnieszka Szwajda
Jing Tang
Bhagwan Yadav
Denis Kainov
Anna Aakula
Mariliina Arjama
Sami Blom
Oscar Brück
Henrik Edgren
Akira Hirasawa
Susanne Hultsch
Taija af Hällström
Sara Kangaspeska
Sami Kilpinen
Disha Malani
John Patrick Mpindi
Astrid Murumägi
Petra Mäki-Teeri
Kalle Ojala
Teijo Pellinen
Vilja Pietiäinen
Khalid Saeed
Jenni Säilä
Poojitha Kota Venkata
Katja Välimäki
Maija Wolf
Päivi Östling
Jonathan Knowles
Samuli Eldfors
Caroline Heckman
Riikka Karjalainen
Heikki Kuusanmäki
Muntasir Mamun Majumder
Alun Parsons
Sergey Kuznetsov
Daria Bulanova
Yuexi Gu
Sharif Iqbal
Sonja Koopal
Pauliina Munne
Annabrita Schoonenberg
Manuela Tumiati
Johan Lundin
Juho Konsti
Tiina Lehtimäki
Nina Linder
Mikael Lundin
Ville Ojansivu
Riku Turkki
Margarita Walliander
Aarno Palotie
Verneri Anttila
William Hennah
Martin Eklund
Alfredo Ortega-Alonso
Ola Spjuth
Samuli Ripatti
Johannes Kettunen
Maria Krestyaninova
Marine Largeau1
Pirkka-Pekka Laurila
Alfredo Ortega-Alonso
Karola Rehnström
Pietari Ripatti
Mari Rossi
Antti-Pekka Sarin
Huei-Yi Shen
Jarkko Soronen1
Ida Surakka
Emmi Tikkanen
Taru Tukiainen
Peter Würtz
Janna Saarela
Himanshu Chheda
Eveliina Jakkula
Virpi Leppä
Annu Näkki
Anna-Maija Sulonen
Emmy Verschuren
Danielle Bansfield1
Sonja Koopal
Jenni Lahtela
Rita Matos
Ashwini Nagaraj
Dat Nguyen
Katja Närhi2
Nitai Peled
Annabrita Schoonenberg
Merja Särkioja1
Krister Wennerberg
Arjan van Adrichem
Tonge Ebai1
Leena Karhinen
Sawan Kumar
Muntasir Mamun Majumder
Tea Pemovska
Gretchen Repasky
Amy Sessions1
Elisabeth Widén
Diana Cousminer
Jaakko Leinonen
FIMM Technology
Centre, including
infrastructure projects
Henrikki Almusa
Maxim Bespalov1
Myles Byrne
Henrik Edgren
Sirkka Ekström
Samuli Eldfors
Pekka Ellonen
Sari Hannula
Tiina Hannunen
Jani Heikkinen
Vasudev Kantae
Mari Kaunisto
Annika Korvenpää
Anna Kossila
Evgeny Kulesskiy
Suvi Kyttänen
Sonja Lagström
Paivi Lahermo
Anna Lehto
Anne Leinonen
Maija Lepistö
Jesús María López Martí2
Pirkko Mattila
Ruusu-Maaria Merivirta
Timo Miettinen
Juha Muilu
Daniel Nicorici1
Aino Palva
Teemu Perheentupa
Vilja Pietiäinen
Päivi Rosenström1
Jani Saarela
Janna Saarela
Tomi Simonen
Jouko Siro
Mikko Siurala1
Kyösti Sutinen
Kari Tuomainen
Hannu Turunen
Laura Turunen
Carina von Schantz-Fant
Imre Västrik
Vidya Velagapudi
Krister Wennerberg
Anu Yliperttula
Jean-Christophe Yorke
Päivi Östling
Biobank Infrastructure
Niina Eklund
Andrey Golubtsov
Taija af Hällström
Askar Ibragimov
Siv Knaappila
Aija Kyttälä
Päivi Laiho
Tuomas Mirtti
Juha Muilu
Kimmo Pitkänen
Reija Randen-Brady
Kaisa Silander
Kyösti Sutinen
Tiina Vesterinen
Biobank Infrastructure/THL personnel:
Anu Jalanko (THL/FIMM)
Aija Kyttälä
Päivi Laiho2
Sini Lähteenmäki
Elina Mäkinen
Anne Nyberg
Seija Puomilahti
Minttu Sauramo
(leave of absence)
Tuuli Sistonen
Minna Suvela
Arja Terola
Regis Wong
FIMM Administration
Olli Kallioniemi
Riitta Alatalo
Mika Frederiksen
Sanni Hyppönen
Riitta Koskinen
Marja Medina
Reetta Niemela
Susanna Rosas
Virve Tiusanen
Kari Pitkänen
FIMM Clinical
Collaborators
Tuomas Mirtti
Kirsi Pietiläinen
Jakob Stenman
Members of the FIMM
National Network for
Molecular Medicine
Lauri A. Aaltonen
Kari Alitalo
Akseli Hemminki
Iiris Hovatta
Elina Ikonen
Sirpa Jalkanen
Heikki Joensuu
Jaakko Kaprio
Heli Nevanlinna
Matej Orešič
Taina Pihlajaniemi
Jussi Taipale
Willem de Vos
Anu Wartiovaara
Jukka Westermarck
Adjunct Personnel
Tero Hiekkalinna
Taru Muranen
Markus Perola
Juba Raj Pokharel
Antti Poso
Päivi Tuomaala
1
2
until 2011
started in 2012
FIMM
57
publications 2011
publications by fimm researchers
1. High CIP2A immunoreactivity is an independent prognostic indicator in early-stage tongue cancer. / Böckelman, Camilla ; Hagström, Jaana Kristiina ; Makinen, L. K. ;
Keski-Santti, H. ; Häyry, Jaan Heikki Valtteri ; Lundin, J. ; Atula,
Timo Sakari ; Ristimäki, Ari ; Haglund, C.. In: British Journal of
Cancer, Vol. 104, No. 12, 2011, p. 1890-1895.
2. Meta-Analysis of Genome-Wide Association Studies in
&gt; 80 000 Subjects Identifies Multiple Loci for C-Reactive
Protein Levels. / Dehghan, Abbas ; Dupuis, Josee ; Barbalic,
Maja ; Bis, Joshua C. ; Eiriksdottir, Gudny ; Lu, Chen ; Pellikka,
Niina ; Wallaschofski, Henri ; Kettunen, Johannes ; Henneman,
Peter ; Baumert, Jens ; Strachan, David P. ; Fuchsberger, Christian ; Vitart, Veronique ; Wilson, James F. ; Pare, Guillaume ;
Naitza, Silvia ; Rudock, Megan E. ; Surakka, Ida ; de Geus, Eco
J. C. ; Alizadeh, Behrooz Z. ; Guralnik, Jack ; Shuldiner, Alan ;
Tanaka, Toshiko ; Zee, Robert Y. L. ; Schnabel, Renate B. ; Nambi, Vijay ; Kavousi, Maryam ; Ripatti, Samuli ; Nauck, Matthias ; Smith, Nicholas L. ; Smith, Albert V. ; Sundvall, Jouko ;
Scheet, Paul ; Liu, Yongmei ; Ruokonen, Aimo ; Rose, Lynda M.
; Larson, Martin G. ; Hoogeveen, Ron C. ; Freimer, Nelson B. ;
Teumer, Alexander ; Tracy, Russell P. ; Launer, Lenore J. ; Buring,
Julie E. ; Yamamoto, Jennifer F. ; Folsom, Aaron R. ; Sijbrands,
Eric J. G. ; Pankow, James ; Elliott, Paul ; Keaney, John F. ; Sun,
Wei ; Sarin, Antti-Pekka ; Fontes, Joao D. ; Badola, Sunita ; Astor, Brad C. ; Hofman, Albert ; Pouta, Anneli ; Werdan, Karl ;
Greiser, Karin H. ; Kuss, Oliver ; Schwabedissen, Henriette E.
Meyer Zu ; Thiery, Joachim ; Jamshidi, Yalda ; Nolte, Ilja M. ;
Soranzo, Nicole ; Spector, Timothy D. ; Voelzke, Henry ; Parker,
Alexander N. ; Aspelund, Thor ; Bates, David ; Young, Lauren ;
Tsui, Kim ; Siscovick, David S. ; Guo, Xiuqing ; Rotter, Jerome
I. ; Uda, Manuela ; Schlessinger, David ; Rudan, Igor ; Hicks,
Andrew A. ; Penninx, Brenda W. ; Thorand, Barbara ; Gieger,
Christian ; Coresh, Joe ; Willemsen, Gonneke ; Harris, Tamara
B. ; Uitterlinden, Andre G. ; Jaervelin, Marjo-Riitta ; Rice, Kenneth ; Radke, Doerte ; Salomaa, Veikko ; van Dijk, Ko Willems
; Boerwinkle, Eric ; Vasan, Ramachandran S. ; Ferrucci, Luigi
; Gibson, Quince D. ; Bandinelli, Stefania ; Snieder, Harold ;
Boomsma, Dorret I. ; Xiao, Xiangjun ; Campbell, Harry ; Hayward, Caroline ; Pramstaller, Peter P. ; van Duijn, Cornelia M. ;
Peltonen, Leena ; Psaty, Bruce M. ; Gudnason, Vilmundur ; Ridker, Paul M. ; Homuth, Georg ; Koenig, Wolfgang ; Ballantyne,
Christie M. ; Witteman, Jacqueline C. M. ; Benjamin, Emelia
J. ; Perola, Markus ; Chasman, Daniel I.. In: Circulation (Baltimore), Vol. 123, No. 7, 2011, p. 731-U151.
3. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. / Strawbridge, Rona J. ; Dupuis, Josee ; Prokopenko,
Inga ; Barker, Adam ; Ahlqvist, Emma ; Rybin, Denis ; Petrie,
John R. ; Travers, Mary E. ; Bouatia-Naji, Nabila ; Dimas, Antigone S. ; Nica, Alexandra ; Wheeler, Eleanor ; Chen, Han ;
Voight, Benjamin F. ; Taneera, Jalal ; Kanoni, Stavroula ; Peden,
John F. ; Turrini, Fabiola ; Gustafsson, Stefan ; Zabena, Carina ;
Almgren, Peter ; Barker, David J. P. ; Barnes, Daniel ; Dennison,
Elaine M. ; Eriksson, Johan G. ; Eriksson, Per ; Eury, Elodie ;
Folkersen, Lasse ; Fox, Caroline S. ; Frayling, Timothy M. ; Goel,
Anuj ; Gu, Harvest F. ; Horikoshi, Momoko ; Isomaa, Bo ; Jackson, Anne U. ; Jameson, Karen A. ; Kajantie, Eero ; Kerr-Conte,
Julie ; Kuulasmaa, Teemu ; Kuusisto, Johanna ; Loos, Ruth J.
F. ; Luan, Jian’an ; Makrilakis, Konstantinos ; Manning, Alisa
58
FIMM
K. ; Teresa Martinez-Larrad, Maria ; Narisu, Narisu ; Mannila,
Maria Nastase ; Ohrvik, John ; Osmond, Clive ; Pascoe, Laura
; Payne, Felicity ; Sayer, Avan A. ; Sennblad, Bengt ; Silveira,
Angela ; Stancakova, Alena ; Stirrups, Kathy ; Swift, Amy J. ;
Syvanen, Ann-Christine ; Tuomi, Tiinamaija ; van ‘t Hooft, Ferdinand M. ; Walker, Mark ; Weedon, Michael N. ; Xie, Weijia ;
Zethelius, Bjorn ; Ongen, Halit ; Malarstig, Anders ; Hopewell,
Jemma C. ; Saleheen, Danish ; Chambers, John ; Parish, Sarah
; Danesh, John ; Kooner, Jaspal ; Ostenson, Claes-Goran ; Lind,
Lars ; Cooper, Cyrus C. ; Serrano-Rios, Manuel ; Ferrannini,
Ele ; Forsen, Tom J. ; Clarke, Robert ; Franzosi, Maria Grazia
; Seedorf, Udo ; Watkins, Hugh ; Froguel, Philippe ; Johnson,
Paul ; Deloukas, Panos ; Collins, Francis S. ; Laakso, Markku
; Dermitzakis, Emmanouil T. ; Boehnke, Michael ; McCarthy,
Mark I. ; Wareham, Nicholas J. ; Groop, Leif ; Pattou, Francois
; Gloyn, Anna L. ; Dedoussis, George V. ; Lyssenko, Valeriya ;
Meigs, James B. ; Barroso, Ines ; Watanabe, Richard M. ; Ingelsson, Erik ; Langenberg, Claudia ; Hamsten, Anders ; Florez,
Jose C. ; Kaprio, Jaakko ; CARDIoGRAM Consortium, GIANT
Consortium, DIAGRAM Consortium, C4D Consortium, MuTHER Consortium. In: Diabetes, Vol. 60, No. 10, 2011, p. 2624-2634.
4. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. / Kilpelainen,
Tuomas O. ; Zillikens, M. Carola ; Stancakova, Alena ; Finucane,
Francis M. ; Ried, Janina S. ; Langenberg, Claudia ; Zhang, Weihua ; Beckmann, Jacques S. ; Luan, Jian’an ; Vandenput, Liesbeth ; Styrkarsdottir, Unnur ; Zhou, Yanhua ; Smith, Albert Vernon ; Zhao, Jing-Hua ; Amin, Najaf ; Vedantam, Sailaja ; Shin,
So-Youn ; Haritunians, Talin ; Fu, Mao ; Feitosa, Mary F. ; Kumari, Meena ; Halldorsson, Bjarni V. ; Tikkanen, Emmi ; Mangino, Massimo ; Hayward, Caroline ; Song, Ci ; Arnold, Alice M.
; Aulchenko, Yurii S. ; Oostra, Ben A. ; Campbell, Harry ; Cupples, L. Adrienne ; Davis, Kathryn E. ; Doering, Angela ; Eiriksdottir, Gudny ; Estrada, Karol ; Manuel Fernandez-Real, Jose ;
Garcia, Melissa ; Gieger, Christian ; Glazer, Nicole L. ; Guiducci, Candace ; Hofman, Albert ; Humphries, Steve E. ; Isomaa,
Bo ; Jacobs, Leonie C. ; Jula, Antti ; Karasik, David ; Karlsson,
Magnus K. ; Khaw, Kay-Tee ; Kim, Lauren J. ; Kivimaeki, Mika
; Klopp, Norman ; Kuehnel, Brigitte ; Kuusisto, Johanna ; Liu,
Yongmei ; Ljunggren, Osten ; Lorentzon, Mattias ; Luben, Robert N. ; McKnight, Barbara ; Mellstrom, Dan ; Mitchell, Braxton
D. ; Mooser, Vincent ; Maria Moreno, Jose ; Mannisto, Satu ;
O’Connell, Jeffery R. ; Pascoe, Laura ; Palotie, Leena ; Peral,
Belen ; Perola, Markus ; Psaty, Bruce M. ; Salomaa, Veikko ;
Savage, David B. ; Semple, Robert K. ; Skaric-Juric, Tatjana ;
Sigurdsson, Gunnar ; Song, Kijoung S. ; Spector, Timothy D.
; Syvanen, Ann-Christine ; Talmud, Philippa J. ; Thorleifsson,
Gudmar ; Thorsteinsdottir, Unnur ; Uitterlinden, Andre G. ;
van Duijn, Cornelia M. ; Vidal-Puig, Antonio ; Wild, Sarah H. ;
Wright, Alan F. ; Clegg, Deborah J. ; Schadt, Eric ; Wilson, James
F. ; Rudan, Igor ; Ripatti, Samuli ; Borecki, Ingrid B. ; Shuldiner,
Alan R. ; Ingelsson, Erik ; Jansson, John-Olov ; Kaplan, Robert
C. ; Gudnason, Vilmundur ; Harris, Tamara B. ; Groop, Leif ;
Kiel, Douglas P. ; Rivadeneira, Fernando ; Walker, Mark ; Barroso, Ines ; Vollenweider, Peter ; Waeber, Gerard ; Chambers,
John C. ; Kooner, Jaspal S. ; Soranzo, Nicole ; Hirschhorn, Joel
N. ; Stefansson, Kari ; Wichmann, H-Erich ; Ohlsson, Claes ;
O’Rahilly, Stephen ; Wareham, Nicholas J. ; Speliotes, Elizabeth
K. ; Fox, Caroline S. ; Laakso, Markku ; Loos, Ruth J. F.. In: Nature Genetics, Vol. 43, No. 8, 2011, p. 753-U58.
5. Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes. / Wessman, Maija ; Forsblom,
Carol ; Kaunisto, Mari A. ; Soderlund, Jenny ; Ilonen, Jorma ;
Sallinen, Riitta ; Hiekkalinna, Tero ; Parkkonen, Maija ; Maxwell, Alexander P. ; Tarnow, Lise ; Parving, Hans-Henrik ; Hadjadj, Samy ; Marre, Michel ; Peltonen, Leena ; Groop, Per-Henrik. In: PLoS One, Vol. 6, No. 9, 2011, p. Article Number: e24053 .
6. Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental
factors in type 1 diabetes. / Forbes, J. M. ; Soderlund, J. ; Yap,
F. Y. T. ; Knip, M. ; Andrikopoulos, S. ; Ilonen, J. ; Simell, O. ;
Veijola, R. ; Sourris, K. C. ; Coughlan, M. T. ; Forsblom, C. ; Slattery, R. ; Grey, S. T. ; Wessman, M. ; Yamamoto, H. ; Bierhaus,
A. ; Cooper, M. E. ; Groop, Per Henrik. In: Diabetologia, Vol. 54,
2011, p. 1032-1042.
7. Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy. / Lahtinen, Annukka M. ; Lehtonen, Eero ; Marjamaa, Annukka ; Kaartinen, Maija ; Heliö, Tiina Maria ; Porthan, Kimmo ; Oikarinen, Lasse ; Toivonen, Lauri ; Swan, Heikki ; Jula,
Antti ; Palotie, Leena ; Palotie, Aarno ; Salomaa, Veikko ; Kontula, Kimmo. In: Heart rhythm., Vol. 8, No. 8, 2011, p. 1214-1221.
8. Androgen Regulation of micro-RNAs in Prostate Cancer. / Waltering, Kati K. ; Porkka, Kati P. ; Jalava, Sanni E. ; Urbanucci, Alfonso ; Kohonen, Pekka J. ; Latonen, Leena M. ; Kallioniemi, Olli P. ; Jenster, Guido ; Visakorpi, Tapio. In: Prostate,
Vol. 71, No. 6, 2011, p. 604-614.
9. Conventional and Mendelian randomization analyses
suggest no association between lipoprotein(a) and early
atherosclerosis: the Young Finns Study. / Kivimaeki, Mika
; Magnussen, Costan G. ; Juonala, Markus ; Kahonen, Mika ;
Kettunen, Johannes ; Loo, Britt-Marie ; Lehtimaki, Terho ; Viikari, Jorma ; Raitakari, Olli T.. In: International Journal of Epidemiology, Vol. 40, No. 2, 2011, p. 470-478.
10. Glucocorticoid receptor (NR3C1) gene polymorphisms
and onset of alcohol abuse in adolescents. / Desrivières, S ;
Lourdusamy, A ; Müller , C ; Ducci, F ; Wong, CP ; Kaakinen, M ;
Pouta, A ; Hartikainen, AL ; Isohanni, M ; Charoen, P ; Palotie,
Leena ; Freimer, N ; Elliott, P ; Jarvelin, MR ; Schumann, G. In:
Addiction Biology, Vol. 16, No. 3, 2011, p. 510-513.
11. Long-term prognosis of breast cancer detected by
mammography screening or other methods. / Lehtimäki,
Tiina Elina ; Lundin, Mikael Edvard ; Linder, Nina ; Sihto, Harri ; Holli, Kaija ; Turpeenniemi-Hujanen, Taina ; Kataja, Vesa
; Isola, Jorma ; Joensuu, Heikki ; Lundin, Johan Edvard. In:
Breast cancer research, Vol. 13, No. 6, 28.12.2011, p. R134.
12. Swedish population substructure revealed by genomewide single nucleotide polymorphism data. / Salmela, Elina
; Lappalainen, Tuuli ; Liu, Jianjun ; Sistonen, Pertti ; Andersen,
Peter M. ; Schreiber, Stefan ; Savontaus, Marja-Liisa ; Czene,
Kamila ; Lahermo, Päivi ; Hall, Per ; Kere, Juha. In: PLoS One,
Vol. 6, No. 2, 2011, p. e16747.
13. At-Risk Variant in TCF7L2 for Type II Diabetes Increases
Risk of Schizophrenia. / Hansen, Thomas ; Ingason, Andres ;
Djurovic, Srdjan ; Melle, Ingrid ; Fenger, Mogens ; Gustafsson,
Omar ; Jakobsen, Klaus D. ; Rasmussen, Henrik B. ; Tosato, Sarah ; Rietschel, Marcella ; Frank, Josef ; Owen, Mike ; Bonetto,
Chiara ; Suvisaari, Jaana ; Thygesen, Johan Hilge ; Petursson,
Hannes ; Lönnqvist, Jouko ; Sigurdsson, Engilbert ; Giegling,
Ina ; Craddock, Nick ; O’Donovan, Michael C. ; Ruggeri, Mirella ; Cichon, Sven ; Ophoff, Roel A. ; Pietiläinen, Olli ; Palotie,
Leena ; Noethen, Markus M. ; Rujescu, Dan ; St Clair, David ;
Collier, David A. ; Andreassen, Ole A. ; Werge, Thomas. In: Bio-
logical Psychiatry, Vol. 70, No. 1, 2011, p. 59-63.
14. Hostility in adolescents and adults: A Genome-wide
association study of The Young Finns. / Merjonen, Päivi ;
Keltikangas-Järvinen, Liisa ; Jokela, Markus ; Seppälä, Ilkka ;
Lyytikäinen, Leo-Pekka ; Pulkki-Råback, Laura ; Kivimäki, Mika
; Elovainio, Marko ; Kettunen, Johannes ; Ripatti, Samuli Olli ;
Kähönen, Mika ; Viikari, Jorma ; Palotie, Aarno ; Palotie, Leena
; Raitakari, Olli T. ; Lehtimäki, Terho. In: Translational Psychiatry, Vol. 1, No. e11, June 2011, 21.06.2011.
15. Genome-wide association study identifies five new
schizophrenia loci. / Ripke, Stephan ; Sanders, Alan R. ; Kendler, Kenneth S. ; Levinson, Douglas F. ; Sklar, Pamela ; Holmans,
Peter A. ; Lin, Dan-Yu ; Duan, Jubao ; Ophoff, Roel A. ; Andreassen, Ole A. ; Scolnick, Edward ; Cichon, Sven ; Clair, David St.
; Corvin, Aiden ; Gurling, Hugh ; Werge, Thomas ; Rujescu,
Dan ; Blackwood, Douglas H. R. ; Pato, Carlos N. ; Malhotra,
Anil K. ; Purcell, Shaun ; Dudbridge, Frank ; Neale, Benjamin
M. ; Rossin, Lizzy ; Visscher, Peter M. ; Posthuma, Danielle ;
Ruderfer, Douglas M. ; Fanous, Ayman ; Stefansson, Hreinn ;
Steinberg, Stacy ; Mowry, Bryan J. ; Golimbet, Vera ; De Hert,
Marc ; Jonsson, Erik G. ; Bitter, Istvan ; Pietiläinen, Olli ; Collier, David A. ; Tosato, Sarah ; Agartz, Ingrid ; Albus, Margot ;
Alexander, Madeline ; Amdur, Richard L. ; Amin, Farooq ; Bass,
Nicholas ; Bergen, Sarah E. ; Black, Donald W. ; Borglum, Anders D. ; Brown, Matthew A. ; Bruggeman, Richard ; Buccola,
Nancy G. ; Byerley, William F. ; Cahn, Wiepke ; Cantor, Rita
M. ; Carr, Vaughan J. ; Catts, Stanley V. ; Choudhury, Khalid ;
Cloninger, C. Robert ; Cormican, Paul ; Craddock, Nicholas ;
Danoy, Patrick A. ; Datta, Susmita ; De Haan, Lieuwe ; Demontis, Ditte ; Dikeos, Dimitris ; Djurovic, Srdjan ; Donnelly, Peter
; Donohoe, Gary ; Duong, Linh ; Dwyer, Sarah ; Fink-Jensen,
Anders ; Freedman, Robert ; Freimer, Nelson B. ; Friedl, Marion
; Georgieva, Lyudmila ; Giegling, Ina ; Gill, Michael ; Glenthoj,
Birte ; Godard, Stephanie ; Hamshere, Marian ; Hansen, Mark
; Hansen, Thomas ; Hartmann, Annette M. ; Henskens, Frans
A. ; Hougaard, David M. ; Hultman, Christina M. ; Ingason,
Andres ; Jablensky, Assen V. ; Jakobsen, Klaus D. ; Jay, Maurice
; Juergens, Gesche ; Kahn, Renes ; Keller, Matthew C. ; Kenis,
Gunter ; Kenny, Elaine ; Kim, Yunjung ; Kirov, George K. ; Konnerth, Heike ; Konte, Bettina ; Krabbendam, Lydia ; Krasucki,
Robert ; Lasseter, Virginia K. ; Laurent, Claudine ; Lawrence,
Jacob ; Lencz, Todd ; Lerer, F. Bernard ; Liang, Kung-Yee ; Lichtenstein, Paul ; Lieberman, Jeffrey A. ; Linszen, Don H. ; Lönnqvist, Jouko ; Loughland, Carmel M. ; Maclean, Alan W. ; Maher, Brion S. ; Maier, Wolfgang ; Mallet, Jacques ; Malloy, Pat ;
Mattheisen, Manuel ; Mattingsdal, Morten ; McGhee, Kevin A.
; McGrath, John J. ; McIntosh, Andrew ; McLean, Duncan E. ;
McQuillin, Andrew ; Melle, Ingrid ; Michie, Patricia T. ; Milanova, Vihra ; Morris, Derek W. ; Mors, Ole ; Mortensen, Preben
B. ; Moskvina, Valentina ; Muglia, Pierandrea ; Myin-Germeys,
Inez ; Nertney, Deborah A. ; Nestadt, Gerald ; Nielsen, Jimmi
; Nikolov, Ivan ; Nordentoft, Merete ; Norton, Nadine ; Noethen, Markus M. ; O’Dushlaine, Colm T. ; Olincy, Ann ; Olsen,
Line ; O’Neill, F. Anthony ; Orntoft, Torben F. ; Owen, Michael
J. ; Pantelis, Christos ; Papadimitriou, George ; Pato, Michele
T. ; Palotie, Leena ; Petursson, Hannes ; Pickard, Ben ; Pimm,
Jonathan ; Pulver, Ann E. ; Puri, Vinay ; Quested, Digby ; Quinn,
Emma M. ; Rasmussen, Henrik B. ; Rethelyi, Janos M. ; Ribble,
Robert ; Rietschel, Marcella ; Riley, Brien P. ; Ruggeri, Mirella ;
Schall, Ulrich ; Schulze, Thomas G. ; Schwab, Sibylle G. ; Scott,
Rodney J. ; Shi, Jianxin ; Sigurdsson, Engilbert ; Silverman, Jeremy M. ; Spencer, Chris C. A. ; Stefansson, Kari ; Strange, Amy
; Strengman, Eric ; Stroup, T. Scott ; Suvisaari, Jaana ; Terenius,
Lars ; Thirumalai, Srinivasa ; Thygesen, Johan H. ; Timm, Sally
; Toncheva, Draga ; van den Oord, Edwin ; van Os, Jim ; van
Winkel, Ruud ; Veldink, Jan ; Walsh, Dermot ; Wang, August G.
FIMM
59
; Wiersma, Durk ; Wildenauer, Dieter B. ; Williams, Hywel J. ;
Williams, Nigel M. ; Wormley, Brandon ; Zammit, Stan ; Sullivan, Patrick F. ; O’Donovan, Michael C. ; Daly, Mark J. ; Gejman,
Pablo V. ; Schizophrenia Psychiat Genome-Wide. In: Nature
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publications by fimm national
network for molecular medicine
1. Breast tumors from CHEK2 1100delC-mutation carriers:
genomic landscape and clinical implications. / Muranen,
Taru A. ; Greco, Dario ; Fagerholm, Rainer ; Kilpivaara, Outi ;
Kämpjärvi, Kati ; Aittomaki, Kristiina ; Blomqvist, Carl ; Heikkila, Paivi ; Borg, Ake ; Nevanlinna, Heli. In: Breast cancer
research, Vol. 13, 2011, p. R90.
2. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis.. / Takeda,
Yukiji ; Costa, Sandra ; Delamarre, Estelle ; Roncal, Carmen ;
Oliveira, Rodrigo Leite de ; Squadrito, Mario Leonardo ; Finisguerra, Veronica ; Deschoemaeker, Sofie ; Bruyere, Françoise ; Wenes, Mathias ; Hamm, Alexander ; Serneels, Jens
; Magat, Julie ; Bhattacharyya, Tapan ; Anisimov, Andrey ;
Jordan, Benedicte ; Alitalo, Kari ; Maxwell, Patrick ; Gallez,
Bernard ; Zhuang, Zhen ; Saito, Yoshihiko ; Simons, Michael ;
Palma, Michele De ; Mazzone, Massimiliano. In: Nature, Vol.
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4. Growth factor therapy and autologous lymph node
transfer in lymphedema. / Lähteenvuo, Markku ; Honkonen,
Krista ; Tervala, Tomi ; Tammela, Tuomas ; Suominen, Erkki
; Lähteenvuo, Johanna ; Kholova, Ivana ; Alitalo, Kari ; YläHerttuala, Seppo ; Saaristo, Anne. In: Circulation Research,
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5. Shorter Adult Stature Increases the Impact of Risk
Factors for Cognitive Impairment: A Comparison of Two
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; Koskenvuo, Markku ; Raiha, Ismo ; Rinne, Juha O. ; Christensen, Kaare ; Kaprio, Jaakko ; Silventoinen, Karri. In: Twin
Research and Human Genetics, Vol. 14, No. 6, 2011, p. 544552.
6. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. /
Chambers, John C. ; Zhang, Weihua ; Sehmi, Joban ; Li, Xinzhong ; Wass, Mark N. ; Van der Harst, Pim ; Holm, Hilma
; Sanna, Serena ; Kavousi, Maryam ; Baumeister, Sebastian
E. ; Coin, Lachlan J. ; Deng, Guohong ; Gieger, Christian ;
Heard-Costa, Nancy L. ; Hottenga, Jouke-Jan ; Kuehnel, Brigitte ; Kumar, Vinod ; Lagou, Vasiliki ; Liang, Liming ; Luan,
Jian’an ; Vidal, Pedro Marques ; Leach, Irene Mateo ; O’Reilly,
Paul F. ; Peden, John F. ; Rahmioglu, Nilufer ; Soininen, Pasi
; Speliotes, Elizabeth K. ; Yuan, Xin ; Thorleifsson, Gudmar ;
Alizadeh, Behrooz Z. ; Atwood, Larry D. ; Borecki, Ingrid B.
; Brown, Morris J. ; Charoen, Pimphen ; Cucca, Francesco ;
Das, Debashish ; de Geus, Eco J. C. ; Dixon, Anna L. ; Doering, Angela ; Ehret, Georg ; Eyjolfsson, Gudmundur I. ; Farrall, Martin ; Forouhi, Nita G. ; Friedrich, Nele ; Goessling,
Wolfram ; Gudbjartsson, Daniel F. ; Harris, Tamara B. ; Hartikainen, Anna-Liisa ; Heath, Simon ; Hirschfield, Gideon M.
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Isleifur ; Penninx, Brenda W. ; Pouta, Anneli ; Prins, Bram P. ;
Prokopenko, Inga ; Puls, Ralf ; Ruokonen, Aimo ; Savolainen,
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41. Heritability of spherical equivalent : A populationbased twin study among 63- to 76-year-old female twins.
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Journal of Psychiatry, Vol. 168, No. 8, 2011, p. 848-852.
67. Associations of Nicotine Intake Measures With CHRN
Genes in Finnish Smokers. / Keskitalo-Vuokko, Kaisu ; Pitkaniemi, Janne ; Broms, Ulla ; Heliovaara, Markku ; Aromaa,
Arpo ; Perola, Markus ; Ripatti, Samuli ; Salminen, Outi ; Salomaa, Veikko ; Loukola, Anu ; Kaprio, Jaakko. In: Nicotine &
Tobacco Research, Vol. 13, No. 8, 2011, p. 686-690.
68. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic
study. / Suomalainen, Anu ; Elo, Jenni M. ; Pietiläinen, Kirsi
H. ; Hakonen, Anna H. ; Sevastianova, Ksenia ; Korpela, Mari
; Isohanni, Pirjo ; Marjavaara, Sanna K. ; Tyni, Tiina ; KiuruEnari, Sari ; Pihko, Helena ; Darin, Niklas ; Ounap, Katrin ;
Kluijtmans, Leo A. J. ; Paetau, Anders ; Buzkova, Jana ; Bindoff, Laurence A. ; Annunen-Rasila, Johanna ; Uusimaa, Johanna ; Rissanen, Aila ; Yki-Järvinen, Hannele ; Hirano, Michio ;
Tulinius, Mar ; Smeitink, Jan ; Tyynismaa, Henna. In: Lancet
Neurology, Vol. 10, No. 9, 2011, p. 806-818.
69. VEGF Mediates Commissural Axon Chemoattraction
through Its Receptor Flk1. / de Almodovar, Carmen Ruiz ;
Fabre, Pierre J. ; Knevels, Ellen ; Coulon, Cathy ; Segura, Inmaculada ; Haddick, Patrick C. G. ; Aerts, Liesbeth ; Delattin,
Nicolas ; Strasser, Geraldine ; Oh, Won-Jong ; Lange, Chris-
tian ; Vinckier, Stefan ; Haigh, Jody ; Fouquet, Coralie ; Gu,
Chengua ; Alitalo, Kari ; Castellani, Valerie ; Tessier-Lavigne,
Marc ; Chedotal, Alain ; Charron, Frederic ; Carmeliet, Peter.
In: Neuron, Vol. 70, No. 5, 2011, p. 966-978.
70. CKIα ablation highlights a critical role for p53 in invasiveness control. / Elyada, E. ; Pribluda, A. ; Goldstein, R.
E. ; Morgenstern, Y. ; Brachya, G. ; Cojocaru, G. ; Snir-Alkalay,
I. ; Burstain, I. ; Haffner-Krausz, R. ; Jung, S. ; Wiener, Zoltan
; Alitalo, Kari ; Oren, M. ; Pikarsky, E. ; Ben-Neriah, Y. In: Nature, Vol. 470, No. 7334, 2011, p. 409-413.
71. Association of Lipidome Remodeling in the Adipocyte
Membrane with Acquired Obesity in Humans. / Pietiläinen, Kirsi Hannele ; Rog, Tomasz ; Seppanen-Laakso, Tuulikki
; Virtue, Sam ; Gopalacharyulu, Peddinti ; Tang, Jing ; Rodriguez-Cuenca, Sergio ; Maciejewski, Arkadiusz ; Naukkarinen,
Jussi ; Ruskeepaa, Anna-Liisa ; Niemela, Perttu S. ; Yetukuri,
Laxman ; Tan, Chong Yew ; Velagapudi, Vidya ; Castillo, Sandra ; Nygren, Heli ; Hyotylainen, Tuulia ; Rissanen, Aila ; Kaprio, Jaakko ; Yki-Järvinen, Hannele ; Vattulainen, Ilpo ; VidalPuig, Antonio ; Oresic, Matej. In: PLoS Biology, Vol. 9, No. 6,
2011, p. -.
72. Lihavuuden hoidossa on terästäydyttävä. / Pietiläinen, Kirsi ; Sane, Timo ; Nieminen, Markku S.. In: Suomen
lääkärilehti, Vol. 66, No. 10, 2011, p. 804-805.
73. Genetic Liability to Disability Pension in Women
and Men: A Prospective Population-Based Twin Study.
/ Narusyte, Jurgita ; Ropponen, Annina ; Silventoinen, Karri
; Alexanderson, Kristina ; Kaprio, Jaakko ; Samuelsson, Asa ;
Svedberg, Pia. In: PLoS One, Vol. 6, No. 8, 2011, p. -.
FIMM
75
publications by fimm / thl 2012
1. Family history of psychiatric disorders and the outcome
of psychiatric patients with DSM-IV major depressive disorder. / Holma, K. Mikael ; Melartin, Tarja K. ; Holma, Irina A.
K. ; Paunio, Tiina ; Isometsä, Erkki T.. In: Journal of Affective
Disorders, Vol. 131, No. 1-3, 2011, p. 251-259.
2. Dehydroepiandrosterone fatty acyl esters in high density lipoprotein: Interaction with human vascular endothelial cells and vascular responses ex vivo. / Paatela, Hanna
; Vihma, Veera ; Jauhiainen, Matti ; Mervaala, Eero ; Tikkanen,
Matti J.. In: Steroids, Vol. 76, 2011, p. 376-380
3. P2RX7 Gene Is Associated Consistently with Mood
Disorders and Predicts Clinical Outcome in Three Clinical Cohorts. / Soronen, Pia ; Mantere, Outi ; Melartin, Tarja
; Suominen, Kirsi ; Vuorilehto, Maria ; Rytsala, Heikki ; Arvilommi, Petri ; Holma, Irina ; Holma, Mikael ; Jylha, Pekka
; Valtonen, Hanna M. ; Haukka, Jari ; Isometsä, Erkki Tapio ;
Paunio, Tiina. In: American journal of medical genetics. Part
B, Neuropsychiatric genetics, Vol. 156B, No. 4, 2011, p. 435-447.
4. Apolipoprotein A-I Exerts Bactericidal Activity against
Yersinia enterocolitica Serotype O:3. / Biedzka-Sarek, Marta ; Metso, Jari ; Kateifides, Andreas ; Meri, Taru ; Jokiranta, T.
Sakari ; Muszynski, Artur ; Radziejewska-Lebrecht, Joanna ;
Zannis, Vassilis ; Skurnik, Mikael ; Jauhiainen, Matti. In: Journal of Biological Chemistry, Vol. 286, No. 44, 2011, p. 38211-38219.
5. Dry Eye Symptoms Are Increased in Mice Deficient in
Phospholipid Transfer Protein (PLTP). / Setälä, Niko ; Metso, Jari ; Jauhiainen, Matti ; Sajantila, Antti ; Holopainen, Juha
Marko. In: American Journal of Pathology, Vol. 178, No. 5, 2011,
p. 2058-2065.
6. Impact of temperament on depression and anxiety
symptoms and depressive disorder in a population-based
birth cohort. / Nyman, Emma ; Miettunen, Jouko ; Freimer,
Nelson ; Joukamaa, Matti ; Maki, Pirjo ; Ekelund, Jesper ; Peltonen, Leena ; Jarvelin, Marjo-Riitta ; Veijola, Juha ; Paunio,
Tiina. In: Journal of Affective Disorders, Vol. 131, No. 1-3, 2011,
p. 393-397.
7. Common Genetic Variants, QT Interval, and Sudden
Cardiac Death in a Finnish Population-Based Study. /
Noseworthy, Peter A. ; Havulinna, Aki S. ; Porthan, Kimmo ;
Lahtinen, Annukka M. ; Jula, Antti ; Karhunen, Pekka J. ; Perola, Markus ; Oikarinen, Lasse ; Kontula, Kimmo K. ; Salomaa,
Veikko ; Newton-Cheh, Christopher. In: Circulation, Cardiovascular genetics, Vol. 4, No. 3, 2011, p. 305-311.
8. Associations between interleukin-1 (IL-1) gene variations or IL-1 receptor antagonist levels and the development of type 2 diabetes. / Luotola, K. ; Pietila, A. ; Zeller, T. ;
Moilanen, L. ; Kahonen, M. ; Nieminen, M. S. ; Kesaniemi, Y. A.
; Blankenberg, S. ; Jula, A. ; Perola, M. ; Salomaa, V. ; Hlth 2000
& FINRISK97 Studies. In: Journal of internal medicine, Vol. 269,
No. 3, 2011, p. 322-332.
9. The effect of proatherogenic microbes on macrophage
cholesterol homeostasis in apoE-deficient mice. / Tuomainen, Anita M. ; Hyvärinen, Kati ; Ehlers, Pauliina I. ; Mervaala, Eero ; Leinonen, Maija ; Saikku, Pekka ; Kovanen, Petri T. ;
Jauhiainen, Matti ; Pussinen, Pirkko J.. In: Microbial Pathogenesis, Vol. 51, 2011, p. 217-224.
76
FIMM
10. Shared Genetic Background for Regulation of Mood
and Sleep: Association of GRIA3 with Sleep Duration in
Healthy Finnish Women. / Utge, Siddheshwar ; Kronholm,
Erkki ; Partonen, Timo ; Soronen, Pia ; Ollila, Hanna M. ; Loukola, Anu-Maria ; Perola, Markus ; Salomaa, Veikko ; PorkkaHeiskanen, Tarja ; Paunio, Tiina. In: Sleep., Vol. 34, No. 10,
2011, p. 1309-1316.
11. Macrophage cholesterol efflux to plasma and HDL in
subjects with low and high homocysteine levels: A FIELD
substudy. / Maranghi, Marianna ; Hiukka, Anne ; Badeau,
Robert ; Sundvall, Jouko ; Jauhiainen, Matti ; Taskinen, MarjaRiitta. In: Atherosclerosis, Vol. 219, No. 1, 2011, p. 259-265.
Contents
Overviews and Greetings..................................................................................................... 3
Research Groups in Human Genomics................................................................................. 7
Group Palotie........................................................................................................................7
Group Palmgren................................................................................................................... 8
Group Ripatti....................................................................................................................... 9
Group Saarela.....................................................................................................................10
Group Widén....................................................................................................................... 11
Research Groups in Medical Systems Biology and Translational Research..........................12
Group Kallioniemi............................................................................................................... 12
Group Aittokallio................................................................................................................ 14
Group Kainov...................................................................................................................... 15
Group Knowles................................................................................................................... 16
Group Kuznetsov.................................................................................................................17
Group Lundin...................................................................................................................... 18
Group Verschuren.............................................................................................................. 20
Group Wennerberg............................................................................................................. 21
Research Highlights........................................................................................................... 22
Grand Challenges............................................................................................................... 26
Doctoral Training............................................................................................................... 27
Technology Centre............................................................................................................. 29
Genomics Unit................................................................................................................... 30
Sequencing Unit................................................................................................................. 31
RNAi Unit...........................................................................................................................32
Chemical Biology Unit........................................................................................................33
Metabolomics Unit............................................................................................................ 34
Bioinformatics and IT Unit..................................................................................................35
Biobank Services and Translational Projects.......................................................................37
Meilahti Integrated Biobank Infrastructure (MIBI): A leading national centre for
next-generation biobanking................................................................................................37
Integrated full-service biobanking...................................................................................... 38
Major ongoing clinical biobanking projects.........................................................................42
Integration of mibi with the European Biobanking Infrastructure BBMRI.......................... 44
Administration Unit, Board and SAB.................................................................................. 45
Examples of Ongoing Projects........................................................................................... 47
Events and Visits................................................................................................................50
FIMM in Figures................................................................................................................. 54
Publications 2011................................................................................................................ 58
ANNUAL REPORT 2011
www.fimm.fi • PL 20, 00014 Helsingin yliopisto • Biomedicum Helsinki 2U, Tukholmankatu 8, 00290 Helsinki