Annual Report

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5 Table of contents 1. List of Contents Preface Description Research Institute Structure Research Institute SWOT Analysis News & Highlights International Collaboration Input Research Institute a) Funding b) Fte per type of funding c) Number of newly started PhD projects Output Research Institute a) Scientific Output b) Scientific Quality c) Indicators of Esteem d) Societal Impact 10. Per Research Program a) Description b) Input (per program) c) Output (per program) 11. Scientific Research Committees Education & Training Appendices

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7 2. Preface "Our mission is to study the brain and its disease mechanisms through an integrative approach running from molecule-to-bedside. We apply a systems biology approach of the brain where clinicians and clinical researchers are working side-by-side with neuroscientists, geneticists, psychologists, biophysicists and statisticians. Through this collaboration we aim at delivering proof-ofconcept for radically new approaches in the early diagnosis of brain disease, the elucidation of its underlying mechanisms, and thus providing new perspectives on therapy." This quote from last year's announced 'mission' called for a strong and concerted action of the researchers. Now one year later, we would like to present our second annual report. We have grown since the end of 2008 both in numbers of coworkers being involved, in the total number of publications and in particularly also with regard to the high impact of our collaboration. Moreover we have achieved great grant successes, including the award of the Erasmus Mundus Joint Doctorate program, a growing number of shared and high impact publications, and a collective strategy, resulting in a major wave of collaborative projects, started in Therefore, it is on behalf of all coworkers and collaborators - from master students up to senior professors - that we proudly present this years' report. Arjen Brussaard director 5

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9 3. Description Research Institute Neuroscience Campus Amsterdam Neuroscience research has become a high profile knowledge industry and aims at making seminal contributions to the understanding of the human brain and the fight against brain disease. Our current insight coming from recent studies of Neuroscience Campus investigations into the human genome and networks of genes, interacting proteins, neuron-glia interactions, and synaptic transmission embedded in neuronal networks has paved the way towards the understanding the molecular and cellular basis of higher brain functions and its pathology. In parallel, on our campus, numerous brain imaging, neurological studies and psychiatric research of large cohorts of patients have created valuable assets that are unique worldwide. We are currently transcending the boundaries of various disciplines including biomedical, biophysical, psychological and clinical neurosciences. The ongoing research strategy, and output of the collaborative research programs of the Neuroscience Campus Amsterdam, thereby focusing on the most important and pioneering areas of neuroscience, have been described in the annual report. Meanwhile the Neuroscience Campus Amsterdam houses more than 450 professionals on one campus and they all collaborate in the field of Integrative Neurosciences to an extent that is unique in the Netherlands. The partners in this network organization are the investigators, gathered in interdisciplinary research teams and executing our research programs. All our research activities are essentially interdisciplinary and incorporate the newest theoretical, methodological and application paradigms currently available. Our strongholds and international reputation build on previous work in molecular biology and biology and genetics of the brain, synapse function and neuronal networks, as well as on clinical studies of the major brain diseases. We study the brain and its disease mechanisms through an integrative approach from molecule-to-bedside. We apply a systems biology approach of the brain where clinicians and clinical researchers are working side-by-side with neuroscientists, geneticists, psychologists, biophysicists and statisticians. Through this collaboration we aim at delivering proof-of-concept for radically new approaches in the early diagnosis of brain disease, the elucidation of its underlying mechanisms, and thus providing new perspectives on therapy. 7

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11 4. Structure Research Institute Mission The mission of the Neuroscience Campus Amsterdam is to study the brain and its disease mechanisms through an integrative approach running from molecule-tobedside. We apply a systems biology approach of the brain where clinicians and clinical researchers are working side-by-side with neuroscientists, geneticists, psychologists, biophysicists and statisticians. Aims & Objectives The Neuroscience Campus Amsterdam currently the largest neuroscience research community gathered on one campus in the Netherlands. We are strongly focusing on molecular neurobiology, going all the way from biophysics, genetics, genomics and systems biology of the synapse, to heritability and genetic basis of brain function. Research Activities The Neuroscience Campus Amsterdam teams focus on three areas of research supported by Support Facilities: Advanced technology Programs, Genes & the Brain and Brain Disease Mechanisms. Advanced Technology Programs Brain Disease Mechanisms Research Support Facilities Genes & the Brain Figure 1. Main stream research areas of the Neuroscience Campus Amsterdam 9

12 Figure 2. Research Programs. As shown in Figure 2, each research activity area is further subdivided in a focused number of research programs and facilities. These have been further described in section 10 of this annual report. 10

13 Advanced Technology Programs The Neuroscience Campus Amsterdam puts much effort in Advanced Technology Programs, thereby securing a strong translational link between those groups providing for instance tailor-made Photonics technology and laboratories where these methods can be successfully applied (i.e. human health and life sciences). In additional there is an established translational link between the experts and those involved in any of our Brain Disease Programs, including our so-called imaging genetics initiatives. Statistical geneticists, biostatisticians and bioinformatics experts provide state-of-the-art Integrated Analysis and Modeling methodology; (neuro)psychologists and clinicians apply this methodology when screening patients, their genes and their endophenotypes. Further novel insight is being generated through reconstruction of synaptic gene networks in the Systems Biology of the Synapse program. Finally, there is potentially a strong link between the Drugs screening and Therapy Design program and clinical activities of the Brain Disease Mechanisms teams Genes and the Brain The words molecules, genes, synapses, connectivity and brain function are the buzzwords of all our initiatives. This interest provides a strong translational potential between genetics, molecular neurobiology, functional genomics, neurophysiology, psycho-pharmacology and behavioral neuroscience within the area 'genes and the brain' but also between the latter and the 'brain disease mechanism' programs. There is strong collaboration between labs providing research support and investigators that largely depend on such activities including the clinicians and the statistical geneticists. Brain Disease Mechanisms All research in the Brain Disease Mechanisms programs is aimed and integrated with our in-house patient clinics, notably the Alzheimer Center, the Multiple Sclerosis Center Amsterdam and the treatment of Depression in the GGZBAclinic. In addition, given the fact that we have a growing number of Parkinson's disease patients, the research program also includes research on patientmaterial from there patients. Moreover, also nicotine- and alcohol-abuse data of our depressed patients is being analyzed in the Addictive Behavior Program. The link between attentive traits in human twins and those being observed in ADHD patients provide a further strong translational program towards the understanding of attentive behavior, impulsivity and cognition in general. Support Facilities Support Facilities are aimed at one-way research support, thereby serving as core facilities to generate data and provide tissue- or sample-analysis, or generate models (including transgenic mice and cell lines) in relation to specific research-project questions. The research project questions are generated, 11

14 prioritized and argued (in relation to the overall research program) by the program committee c.q. the program leaders. 12

15 5. SWOT Analysis Strength The Neuroscience Campus Amsterdam gathers more than 450 VU/VUmc professionals involved in Brain Research. Such campus-wide integration in the field of Integrative Neurosciences is unique in the Netherlands. The 'partners' in this network organization are the investigators, gathered in interdisciplinary research teams. All our research activities are essentially interdisciplinary and incorporate the newest theoretical, methodological and application paradigms currently available. Our strongholds and international reputation come from previous work on the molecular biology and genetics of the brain, synapse function and neuronal networks, as well as from clinical studies on the development and aging of the brain. Our current output is large in volume and of high impact. Notably in 2009 we had over 50 papers with an Impact Factor of ~ 10 or higher, of which > 20 as primary and/or senior author. Moreover the acquisition 'power' of the organization is also becoming apparent with over 22 M of external funding awarded in In addition there was the award of the Erasmus Mundus Joint Doctorate program of 6.7 M funded by the EU and currently under coordinatorship of the director of the Neuroscience Campus. Finally, the translational potential is currently becoming established as is evident by an increasing of collaborative papers and grant acquisitions. Weaknesses Our research institute has (still) two weaknesses. The first is that our investigators are spread all over the Campus, in many different laboratories, which is an extra barrier when trying to bring cohesion. The second is that endureable funding for so-called glue projects and young talent appointments remains an open issue. These are the symptoms of an organization in transition, going from a pure disciplinary organization to a so-called matrix organization where research is formalized around interdisciplinary research themes. While at the VUmc the history of working in a matrix organization has already matured resulting in a allocated yearly budget for the research strategy of interdisciplinary institutes, in the VU board rooms, there is still discussion about the nature, the putative strength and future (and in particular also the funding) of interdisciplinary research institutes. While this may affect the future of a research institute like the Neuroscience Campus Amsterdam beyond the scope of the initial funding period ( ) our challenge is to secure the strength of interdisciplinary research and a campus wide research policy with regard to Neuroscience research. Such endeavor needs further concerted action and robust measures in the way professionals are organized, in governance structure, in campus facilities (see below) and in conditional strategic funding. 13

16 Opportunities With the reconstruction of the VU/VUmc campus there are major opportunities for our research organization. The first is that research labs can be further focused around core facilities such as the new Imaging Building (including the activities of the RNC, Cyclotron and Laser Center) of the VUmc, a putative Genomics Center, a central Biobank Facility and the University Experimental Animal Center (UPC). The second is that the boundaries between the faculties can be further dissolved and that clusters of 3 to 4 departments collaborating intensively, can be housed together. The third is that partnership with Amsterdam collaborators (such as the Netherlands Institute of Neuroscience (NIN-KNAW), with major national partners (such as the Neuroscience groups of the Erasmus MC) and with international consortia and foreign partners (European Neuroscience Campus Network and an organization such as NeuroSpin, in Orly- Paris) can be further developed; the director needs to take action in this respect. Threats Currently the Neuroscience Campus Amsterdam has been well branded in the region of Amsterdam and as an research organization, applying for major funding in Brussels. Initiatives to further synchronize our research activities in the region of Amsterdam however needs a followup both in view of future grant opportunities (aiming at major EU funding) and in view of the valorization potential of our organization. The political climate of research funding in the Netherlands is leaning towards funding of socalled 'superclusters' which can function both as regional center of excellence and as European node. Competition in view of the Amsterdam-ambitions with Health & Life Science and for instance a putative participation in Joint Programming in the field of or other funding such as those coming from ERC, might come from Groningen (who may participate in Joint Programming in Healthy Aging), Nijmegen (which focus on Cognition) and Rotterdam (strong in Clinical Neurology and Genetics). Within the Amsterdam region, we need to provide the right political and collaborative climate, such that cooperation with the University of Amsterdam (Cognitive Science Center Amsterdam - CSCA) and the Netherlands Insitute of Neurosciences (NIN-KNAW) can florish. To this end, the director of the Neuroscience Campus Amsterdam should lead the opinion and in accordance is currently working on new plans towards a large scale initiative (working-title 'Amsterdam Program for Neuroscience and Cognition', in collaboration with Prof. E. de Haan, UvA and the CvB-chairs of VU and UvA). 14

17 6. News & Highlights of the year 2009 Events Opening Symposium Neuroscience Campus Amsterdam - First Annual Meeting - 1 April 2009 Appointment of Committee of Recommendation (Alexander Pechtold, Raoul Obermann, Rik van Terwisga and Herman Leisink) Start of the European Neuroscience Campus Network Major Publication Output Cell paper (Impact Factor 31.5) by the group of prof Matthijs Verhage Science paper (Impact Factor 32) by the group of prof Dorret Boomsma Twenty additional research papers in peer reviewed journals with Impact Factor of ~ or > 10 as primary and/or last/senior author Thirty additional papers in peer reviewed journals with Impact Factor of around 10 or higher as associated author(s) 45% of 424 papers in Top 10% of International Journals sorted on Relative Impact Factor (see fig. 9 in section 9) Additional 25% of > 400 papers in Top Quartile (10-25%) of International Journals sorted on Relative Impact Factor (see fig. 9 in section 9) Honorary Research Price Prof. Peter Heutink was awarded with the Prinses Beatrix Research Price of > 1 M of research support, to be applied to the field of Neurodegenerative (PD) brain disease and in particular to application of new cellomics technology (research programs & Drugs Screening & Therapy Design - see also section 10) Major external funding acquired in 2009 Donation (4.5 M ) from Innovation Zorgverzekeraars to Alzheimer Center VUmc of prof Philip Scheltens (research program ) ZON - MW TOP-subsidy to Ruud Toonen, c.s. (675 k, research program Systems Biology of the Synapse) ZON - MW TOP-subsidy to Taco de Vries c.s. (675 k, research program Addictive Behavior) BrainTrain - International Training Network Marie Curie (~ 3.5 M ) to Heidi de Wit, profs Peter Heutink, Matthijs Verhage, Huibert Mansvelder en Guus Smit and others ENC-Network - Erasmus Mundus Joint Doctorate grant (6.7 M of which ~ 3 M for NCA) to Prof. Arjen Brussaard c.s. to Neuroscience Campus Amsterdam and others EuroSpin - FP 7 grant ( 1,5 M ) to profs. Matthijs Verhage & Arjen Brussaard, in collaboration with Synaptologics (EuroSpin - research program Systems Biology of the Synapse), starting in 2010 SynSys - FP 7 grant (12 M of which 2.5 M for NCA) to profs. Guus Smit (coordinator), Huibert Mansvelder & Matthijs (SynSys - research program Systems Biology of the Synapse, website coming up), starting in

18 NeuroBsik PP - FES grant support (Bsik) (13 M of which 4.8 M for NCA) to profs Arjen Brussaard (managing director), Matthijs Verhage, Guus Smit en Huibert Mansvelder, in collaboration with Synaptologics (NeuroBsik PharmaPhenomics), starting in 2010 VIDI grant to Rhianon Meredith (research program Attention & Cognition) VENI grant to Stefan Witte (research program Photonics & Life Cell Imaging) BBMRI - Biobanking Infrastructure: Biobanking and Biomolecular Resources Research Infrastructure to profs Jan Smit & Dorret Boomsma as coapplicants (chair prof. GertJan van Ommen c.s. (total grant 22 M ; participation from Neuroscience Campus Amsterdam-part pending), starting in 2010 NIMT grant - Integration of genomics and transcriptomics in normal twins and major depression to profs Brenda Penninx, Dorret Boomsma, Eco de Geus, Jan Smit and Witte Hoogendijk (with Patrick Sullivan, 5.6 M - full NCA participation) ZON MW grant - Deep Brain Stimulation in Chronic Treatment Refractory Drug Dependence: a Translational Study - to profs Schoffelmeer, Taco de Vries, Tommy Pattij and Dick Veltman (500 k ). ZON Middelgroot - Tandem-illumination microscopy (TIM) for synchronous photo-manipulation and uninterrupted, fast life cell imaging - to prof Matthijs Verhage c.s. (500 k ). New Facilities: Profs. August Smit and Peter Heutink install Cellomics facility with automated Cell Culture and Drugs Screening robotics, financed by the NWO ZONMW 'Middelgroot'-grant acquired during the setup-phase (2008) of the Neuroscience Campus. The setup of this facility is then later-on further supported by the Prinses Beatrix Price awarded to prof Peter Heutink (c.s.). Prof. Marjo van der Knaap (c.s.) in collaboration with FALW makes a start with the setup of a Stem Cell Facility in order to design new therapy for child neurology disorders. The new facility and the recruitment of new tenure track personnel, is made primarily possible by the Spinoza Premie (2008) awarded to Van der Knaap. Prof. Cees Stam (c.s.) acquires and sets up a new MEG facility at the VUmc, with ongoing research activities embedded in three major Neuroscience Campus Amsterdam research programs (, and White Matter Disorders). Newly appointed professors: Prof Annemieke Rozemuller newly appointed as research professor at VUmc Prof Bernard Uitdehaag appointed as research professor at VUmc Prof Brenda Penninx appointed as full professor at VUmc Renewal appointment of prof Nick Fox as strategic professor at VUmc Renewal appointment of prof Pieter Roelfsema as strategic professor at VU 16

19 7. International Collaboration Implementation of newly established collaborations Prof. Philip Scheltens, representing the Alzheimer Center VUmc and the Neuroscience Campus Amsterdam, appointed as national coordinator Joint Programming (FP7 collaboration) Center for Neurogenomics and Cognitive Research (CNCR, an expertise center of the Neuroscience Campus Amsterdam) and Synaptologics (a spinoff company of the Neuroscience Campus Amsterdam) join in major FP7 collaboration called EuroSpin - prof Matthijs Verhage (senior partner, see CNCR and Synaptologics join in major FP7 collaboration called NeuroCypres (awarded in 2008) - coordinator prof Guus Smit (see CNCR and Synaptologics join in major FP7 collaboration called SynSys - coordinator prof Guus Smit ( being released shortly) CNCR and Synaptogics join in setting up and acquiring new FES consortium called NeuroBsik PharmaPhenomics - managing director prof Arjen Brussaard (see Neuroscience Campus Amsterdam sets up and coordinates the European Neuroscience Campus Network (ENC-Network), an Erasmus Mundus Joint Doctorate Programme, aimed at funding 53 new PhD project, many of which will be executed in collaboration with VUmc/VU. The estimate is that of around thirty of the newly appointed PhD students will graduate at VU/VUmc - director prof Arjen Brussaard (see Neuroscience Campus profs Peter Heutink, Matthijs Verhage, August Smit, Huibert Mansvelder and senior investigator Heidi de Wit join in setting up BrainTrain, a Marie Curie International Training Network with 12 new PhD projects, all in collaboration with VU/VUmc - Heidi de Wit, coordinator (see 17

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21 8. Input Research Institute 8a) Funding Combined financial investments in 2009 At the start of the organization, the Neuroscience Campus Amsterdam was supported with significant starting grant by the CvB, RvB and other participating faculties. This starting grant is currently being invested in Support Facilities and Research Program activities, on the principle that any investment from this starting grant is (at least) equally matched by financial support from the participating labs. Thus far towards the end of 2009, this type of financial strategy amounted to a combined funding of 3.2 M in Advanced Technology Programs (including 800 keuro for Photonics) 2.5 M in Innovation of Infrastructure of the Support Facilities (including 250 keuro for Genomics/Proteomics/Cellomics and 100 keuro for EM microscopy) 3.1 M in Research Projects (Meetfonds fase 1 and Centre Medical Systems Biology -granted in 2008 and matched by Neuroscience Campus) Combined acquisition in 2009 In addition, the collective and aggregate acquisition of external funding in 2009 amounted to major wave of awarded grants with many highlights (see section 6) and a cumulative sum of more than 22 M of external grant support. In addition, thanks to embedding in the Neuroscience Campus Amsterdam, we participate in a number of major grants with (inter)national consortia acquired in but starting in 2010 (such as the ENC-Network Erasmus Mundus grant 6.7 M, a number of FP7 grants including SynSys - 12 M, a FES-subsidy of 13 M for NeuroBsik 2 and the BBMRI grant of 22 M for Biobanking as mentioned in section 6). Also excluded in this overview is the support from Zorgverzekeraars to the Alzheimer Center VUmc. External Funding Research Institute gs 2 gs 3 gs 4 Total Total Total ,594,300 13,580,420 2,576,000 22,750,720 3,533,146 6,449, ,165 10,909,000 Table 1 Acquisition and grants started in 2009 by collaborative efforts of the Neuroscience Campus Amsterdam in 2009 and compaired with 2008; this overview excludes participation in a number of major grants acquired in 2009, but starting in 2010 such as the ENC-Network, two FP7 grants, a major FES subsidy and participation in a so-called BBMRI biobanking grant mentioned in section 6. For further information, on acquisition per research program, see section 10b. 19

22 8b) Fte per type of funding (research time) Total fte research (including PhD students) Type of funding gs 1 gs 2 gs 3 gs 4 mixed Total Total n.a Total Total fte research PhD students Type of funding gs 1 gs 2 gs 3 gs 4 mixed Total Total n.a Total Table 2 Total of the time spend on research. A total of 450 collaborators contribute to this total sum of research time. The research time per research program is split in section 10. For a full list of all coworkers see appendix 1. 20

23 8c) Newly started PhD projects 2009 In 2009, 31 new PhD projects were started. For a full list of all newly started projects and PhD students, see appendix 2. Compared to the 45 newly started PhD projects in 2008, the 2009 score may seem like a 'dip' in the acquisition of new projects, however there is growing trend compared to the 28 new project of 2007 and the 21 new projects in Moreover in 2008, a relative high number of 1st 'geldstroom' PhD students started under the former regime of ICEN funding. We are confident about the future perspectives of Neuroscience Campus Amsterdam, given the recent acquisitions of the Erasmus Mundus Joint Doctorate (with in total 50 additional PhD projects to be appointed up to 2014, of which ~ 25 projects are primarily or in collaboration with the Neuroscience Campus Amsterdam) and the International Training Network (Marie Curie) called BrainTrain (with in total 12 additional PhD projects, all in executed in Neuroscience Campus Amsterdam labs). 21

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25 9. Output Research Institute 9a) Scientific Output Theses Scientific papers Rest DissA DissC DissB DissD Wp WpREF WpNR VP Total Books Chptrs Total Total Table 3 Aggregate of the output of Neuroscience Campus Amsterdam. The numbers of refereed papers has increased compared to 2008, the number of books and book-chapters and non-sci contributions was deliberately lowered since then. A full list of publications published is outlined in appendix 3. Abbreviations: Theses A: Promotion VU/VUmc PhD-student at VU Theses B: Promotion external PhD-student at VU Theses C: Promotion VU/VUmc PhD-student at other university Theses D: Promotion external PhD-student at other university (promotor, co-promotor) Wp: Books/monographs/book chapters/proceedings WpRef: Scientific Papers refereed WpNR: Scientific Papers non-refereed WB: Books/monographs WBC: - Book chapters/proceedings VP: Professional publication 23

26 9b) Scientific Output Program leaders and Support Coordinators An historical overview of the published number of articles per year and the total number of citations each year to the aggregate of these papers published by the current program leaders of the Neuroscience Campus Amsterdam shows a solid growth in output and relevance of their output (see Fig 3 and 4). At the onset of the new era in which the Neuroscience Campus Amsterdam became operational (i.e. during 2008) all program leaders of the Neuroscience Campus together had a yearly output of research papers per year. In 2008 > 9600 citations were collected to the accumulation of these research papers. Currently, this the aggregate output of program leaders has increased to 270 research papers, with over citations in The sum of all citations to publications published by our program leaders accumulates to > to a total of 2,393 papers, being published as corresponding author and an average of ~ 30 citations per published article. If also 'coauthor' papers are included, the program leaders together have published 3838 peer reviewed publications and have collected > citations thus far. The average total number of papers published thus is > 170 papers per group leader. Shown below are two graphs indicating the historical progress - prior to and - during the last two years of Neuroscience Campus Amsterdam. Total number of published papers Figure 3. Shown is an historical perspective on the cumulative production of SCI articles (i.e. excluding reviews) per year, authored by program leaders and support coordinators (and those alike) of the Neuroscience Campus Amsterdam workforce and produced at the VU/VUmc Campus. If all program members are analyzed this way, currently the cumulative yearly output is 429 papers per year (see section 9a). 24

27 Total number of citations per year Figure 4. Historical perspective on the number of citations to scientific articles (SCI journals excluding reviews) authored by program leaders and support coordinators (and those alike) and produced at the VU/VUmc Campus. If all program members are analyzed, this way currently the yearly total number of citations is > per year. Citation analysis of program committee members To further analyze the scientific output we have also collected the aggregate data of all (61) tenure (track) staff currently collaborating in - or contributing to - the main stream activities of the Neuroscience Campus Amsterdam. Citation analysis reveals that of all staff of the Neuroscience Campus Amsterdam, on average a cumulative number of ~ 100 research articles has been produced per author, with ~ 2700 citations in total per author, an average h-value of 24 and a CPP of > 23. If we analyze program leaders only, these numbers increase to ~ 170 research articles per author, with ~ 5000 citations per author, an h-value of 29 and a CPP > 33. Figure 5: Number of published papers (research papers only) per author. Analysis of tenured staff (i.e. program committee members, and those alike, including affiliated research but only) primarily affiliated with the Neuroscience Campus Amsterdam) on the basis of ISI Web of knowledge (version 4.8) cross-checked with Publish or Perish (Google Scholar). On average a staff member in our institute had published ~ 100 items towards the end of

28 Figure 6: Total number of citations per author. Analysis of tenured staff in same databases as in figure 5. On average each staff member currently has collected > 2700 citations in total. Figure 7: The 'h-value' analysis of tenured staff. Similar database search as for figures 5 and 6. Figure 8: Average number of citations per published paper for all tenured staff. Same type of database search as for figures

29 Figure 9: Relative distribution of 2009 SCI publications (429 in total) categorized according to Relative Impact Factor. Almost half of the current output belongs to the category of highest impact papers (i.e. top 10%). And 3 out of 4 papers belongs to the top quarter of SCI journal publications and thus have a journal Impact Factor of 4 or higher. See also table 4 for comparison with the 2008 scores. To be able to make a comparison to previous years' output we have also included data and percentile scores from previous year (see Table 4). Percentage (%) of papers distributed to the quality of the research field Relative Impact Factor Quartile Category % of 2009 papers upper quartile % score in top 10 % % % % % 1 5 % of 2008 papers 52 upper quartile % score in 2008 Table 4 Comparison of Relative Impact Factors scores between 2008 and

30 9c) Indicators of esteem A shortlist of awards, more details on grants awarded, and listing of other indicators of esteem are outlined in appendix 4. 9d) Societal Impact We focus on the biological mechanisms underlying common mental health and neurological brain diseases, applying the latest technology and thereby providing new perspectives on therapy. Finding the 'cause' of brain diseases, design its 'cure' and implement this to the level of 'patient care' are all at the core of our research ambition. Many of our research projects and plans are directly (or indirectly) related to 'brain diseases' programs. This includes the activities of the VUmc Alzheimer Center, the MS Center Amsterdam, the Center for Children with White Matter Disorders and the GGZBA-clinic affiliated patient research-programs for Anxiety and Depression disorders (NESDA) of the GGZBAclinic. In doing so, we also provide community services in relation to patient care (advise and information to care takers). Notably are two initiatives, one being the so-called planned MS-supportal (a virtual reception and internet-portal for MS patients) and one the planned Memory Clinic of the Alzheimer Center to be launched coming fall. Moreover many of our senior investigators publish in national professional journals, give layman-lectures by invitation and/or participate in education projects (see appendix 5). 28

31 10. Per Research Program 10a) Description Advanced Technology Programs Research Programs in short: Figure 10 Advanced Technology Research Programs. Innovation and development of the latest techniques are embedded in independent research programs that provide 'translational potential' (as indicated by the arrows) for newly developed project in 'adjacent' research programs where this new technology is being applied in a (pre)clinical settling. 29

32 ADVANCED TECHNOLOGY PROGRAMS The aims of the methodology program are twofold. The first aim is to make optimal use of the extensive imaging facilities at the VU/VUmc campus, and to integrate these techniques with each other, wherever possible the program instigates and performs methodological imaging research, in particular with regard to functional and structural connectivity, and molecular imaging. Second, the program aims to function as a center of expertise, providing advice and if necessary assistance to scientists from other programs. Expertise in the field of imaging and imaging-analysis are two strongholds of the VUmc, and as such provide clinicians and neuroscientists in other research programs with a unique set of tools for non-invasive, in vivo investigations of the brain, both in humans and in animal models of disease. Neuroimaging is likely to be employed not only for characterizing the neural substrate of various neuropsychiatric disorders, but also for assessment of psychopathological traits cutting across diagnostic categories, and identification of endophenotypes which may aid in understanding the genetic basis of these disorders. Key Publications - Douw, L., Klein, M., Fagel, S.S.A.A., Heuvel, J. van den, Taphoorn, M.J.B., Aaronson, N.K., Postma, T.J., Vandertop, W.P., Mooij, J.J., Boerman, R.H., Beute, G.N., Sluimer, J.D., Slotman, B.J., Reijneveld, J.C. & Heimans, J.J. (2009). Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurology, 8(9), (IF 14.3) Heuvel, O.A. van den, Remijnse, P.L., Mataix-Cols, D., Vrenken, H., Groenewegen, H.J., Uylings, H.B.M., Balkom, A.J.L.M. van & Veltman, D.J. (2009). The major symptom dimensions of obsessive-compulsive disorder are mediated by partially distinct neural systems. Brain, 132, (IF = 9.6) Werf, Y.D. van der, Helm, E. Van der, Schoonheim, M.M., Ridderikhoff, A. & Someren, E.J.W. van (2009). Learning by observation requires an early sleep window. Proceedings of the National Academy of Sciences of the United States of America, 106(45), (IF = 9.6) 30

33 ADVANCED TECHNOLOGY PROGRAMS Drugs Screening and Therapy Design The aims of this advanced technology program are two fold: The first aim is to make optimal use of our growing potential in cellomics facilities, which currently include cell culture robots and automated fluorescence time lapse microscopy tools that allow for medium throughput screening of genetically modified celllines. The unique asset of this technology is that the Neuroscience Campus can offer new bioassays by taking gene polymorphisms or haplotypes selected in for instance Genome Wide Analyses (GWA) and model these directly at the cellular level to test the effect of genetic variation or mutations on for instance neuroregeneration. Since this technology is automated and executed in mutliwell plates, it allows for the focused testing of (small molecule) compound libraries (in collaboration with for instance partners from TiPharma. The second aim is to set up a so-called stem-cell facility, and to implement and further investigate to potential of stem-cell therapy (first in mutant mouse models of Childhood White Matter Disorders and in the long run in human patients). The program s collaborative research projects concern screening of potential therapeutic compounds in view of neurodegenerative disease (grey matter) as well as while matter disorders. In particular through bundling of the newest insights into the genetic vulnerability toward grey or white matter disorders in cellular assays and combining these with drug (design) screening, will help us to achieve a number of truly translated objectives. Second, in particular for the devastating (and Mendelian genetic) child neurology disorders (but potentially in the long run also for more common diseases including MS) stem-cell therapy may be a serious option when it comes to curing the diseases. Hence the group of prof Marjo van der Knaap has decided to set up a Stem Cell Lab, to a large extent being supported with the funding from her 2008 Spinoza Price. Finally, most recently there was the Prinses Beatrix price for one of the program leaders of this research, prof Peter Heutink. The group of Heutink supported by this price will use a multidisciplinary approach to confirm and characterize the biological relevance of risk factors and to identify all functionally interacting genes in the affected pathway by using a high throughput cellomics approach. The characterization of gene networks instead of single genes will help to identify those genes in the affected gene network that can best serve as lead targets for development of new therapeutic approaches. As Heutink claimed at this time of the award: "This price is a fantastic boost for the Drugs Screening and Therapy research program of the Neuroscience Campus Amsterdam. I am very happy with this award and with the funding for our cellomics research activities". Highlights - Drugs Screening & Therapy Design: Spinoza Premie 2008 to Marjo van der Knaap will in part be invested in a Stem Cell Lab in Faculty of Earth & Life Sciences. Matching for reconstruction is provided by FALW. Equipment is funded by the Neuroscience Campus Amsterdam, experts come from the lab of Van der Knaap. Prinses Beatrix Price 2009 to Peter Heutink and ZON-MW Middelgroot to Heutink & Smit is used to start a Cellomics Facility at FALW. Matching and expert come from the lab of Heutink. 31

34 ADVANCED TECHNOLOGY PROGRAMS Integrative Analysis & Modeling The Integrative Analysis and Modeling program provides the essential expertise on modeling and data analysis for the Neuroscience Campus systems biology approach of the brain. It develops and assesses statistical methods and computational tools for the analysis of large, complex data sets. It also builds biology-based mathematical and computational models and designs modelbased statistical tools for model systems with a limited number of components that are used to unravel generic principles of the involved biological networks. The program has three aims: to develop novel research methodology for integrative research concerning large and complex data sets (Methods for Large Data Sets); to perform research aimed at developing innovative tools for dedicated mathematical and computational modeling and statistical analysis (Biologybased Modeling and Methods); to perform integrative analysis of data obtained from different disciplines and levels of data (Integrative Data Analysis) The program s collaborative research projects concern modeling and analysis of data in the areas of genetic epidemiology, gene expression analysis and gene network modeling, phenomics, and neuronal networks. The research will result in mathematical and computational models, statistical methods and data analysis tools for biological networks, as well as high-level bioinformatics algorithms, including the integration and collaborative annotation of -omic data, and optimization of statistical analyses in a cluster environment. It will also be instrumental in the transfer of technology and skills into -omic bioinformatics, and in design of experiments and predictive biology. Highlight - Integrative Analysis & Modeling: Researchers within the program developed a methodological framework to test for the role of functional gene networks and human complex traits. In doing so they combined knowledge form bioninformatics, functional genomics and molecular genetics in user friendly statistical scripts available within NCA. The first application of this novel method revealed that the functional group of G-proteins is significantly associated with human intelligence. This result was published in one of the top genetics journals (American Journal of Human Genetics (IF = 10.15): Ruano D, Abecasis GR, Glaser B, Lips ES, Cornelisse LN, de Jong AP, Evans DM, Davey Smith G, Timpson NJ, Smit AB, Heutink P, Verhage M, Posthuma D.Am J Hum Genet Feb 12;86(2): Epub 2010 Jan 7.) 32

35 ADVANCED TECHNOLOGY PROGRAMS Photonics and Life Cell Imaging In this research, the investigators develop integrated non-linear optical imaging systems consisting of an in vitro imaging platform and in vivo, whole animal, imaging platforms that make optimal use of shared versatile laser systems. Dedicated researchers will develop the setups and perform in vitro experiments aimed at photo-detection of the neurotransmitters involved in neurological disorders such as depression, Alzheimer s (AD) and Parkinson s (PD) disease: serotonin, dopamine and acetylcholine. Novel 2- and 3-photon excitation schemes will be explored that optimize detection and minimize phototoxicity. In addition the investigators identify the optimal conditions for deep-tissue imaging of endogenous fluorophores and tissue/cell morphology using pulse shaping, second- and third harmonic generation as well as Spectral Domain Optical Coherence Tomography (SDOCT). The in vitro imaging will be complemented and extended towards ongoing research at the CNCR using transgenic models available at this center. In doing so we will translate optimal biophysical detection schemes obtained on the in vitro platform to the in vivo situation; further the investigators apply SDOCT in cortical networks to detect early morphological markers of degenerative brain disorders, such as AD and PD. In addition, the investigators are able to measure dendritic calcium dynamics in developing neurons in Fragile X syndrome, detect molecular mechanisms of synaptic vesicle and large-dense core vesicle exocytosis, and investigate axon guidance and target finding in secretion-deficient transgenic mouse models. In parallel to this a second in vivo imaging platform was set up to study among others issues of inflammation and autoimmunity in relation to Multiple Sclerosis. Advancement in neuroscience research requires the development of techniques that enable in vivo visualization of individual neurons, neuronal networks, and synaptic contacts, with high spatial and temporal resolution and penetration depth, while these circuits are processing information. The development of new optical in vivo imaging modalities that have sub-cellular resolution will allow identification of novel biomarkers for early detection of brain disease. New optical tools can, in addition to identification of new biomarkers, also be developed to perturb and interfere with the progression of disease at very early (pre-clinical) stages. Hence the research programs' aim is to develop a state of the art microscope technology that combines the newest developments in the field to advance neuroscience research performed at the VU and VUmc. Highlight - Photonics & Life Cell Imaging The groups of Marloes Groot, Ruud Toonen & Huibert Mansvelder have setup two major high end Laser Scanning Microscopy setups with funding in part provided by the Neuroscience Campus Amsterdam. Key Publications - Photonics & Life Cell Imaging Witte, S.M., Baclayon, M., Peterman, E.J.G., Toonen, R.F.G., Mansvelder, H.D. & Groot, M.L. (2009). Single-shot two-dimensional full-range optical coherence tomography achieved by dispersion control. Optics Express, 17(14),

36 Genes & the Brain Research Programs in short: Figure 11 Genes & the Brain Research Programs. We have three main stream research programs in this area where mechanistic models based on the genetic makeup of the brain is the common denominator theme. The arrows indicate that the three research programs have strong translational links and in part shared expertise. 34

37 GENES & THE BRAIN Attention & Cognition Attention and cognition research is one of the main stream research topics in neuroscience research on the VU campus. A total of eight departments of three faculties have joined in the Attention & Cognition program. Researchers with different backgrounds, ranging from molecular genetics and biology to genetic epidemiology, psychology and clinical applications, contribute to this multidisciplinary program. This intense collaboration and the availability of unique resources, such as a large collection of twin families, well phenotyped longitudinal cohorts recruited from clinics throughout the Netherlands, novel animal models for attention and mental retardation and state of the art research facilities concentrated at one city campus, generates unique potential. The Attention & Cognition program covers three major aspects: Fundamental aspects of cognitive ability and mental retardation in humans and rodent models Clinical aspects of cognition problems, with a primary focus on ADHD Co-morbidity with other disorders, such as major depression and migraine Topics range from: Genetic epidemiology of cognitive ability and ADHD Identification of genes and genetic networks in attention traits and ADHD Endophenotypes of ADHD Brain mechanisms of executive control and working memory The role of synaptic plasticity in attention and cognitive ability The cellular mechanisms of Fragile-X mental retardation This program provides novel insights into the comorbidity of cognitive problems with other neurological and psychiatric disorders and identify novel common genetic pathways and networks that contribute to the genetic risk. Key Publications - Attention & Cognition Koten, J.W., Wood, G., Hagoort, P., Goebel, R., Propping, P., Wilmes, K. & Boomsma, D.I. (2009). Genetic Contribution to Variation in Cognitive Function: An fmri Study in Twins. Science 323, (IF = 32) 35

38 GENES & THE BRAIN Addictive Behavior This program addresses the development of drug and alcohol addiction as well as relapse to compulsive drug- and alcohol-seeking behavior during abstinence in both laboratory animals (rodents) and humans. The availability of operant animal models to study the motivational and cognitive aspects of addiction, the availability of advanced in vitro and in vivo neurophysiological techniques and that of state-of-the-art genomics/proteomics expertise in this program is unique. Moreover, the availability of genome-wide data in NESDA as well as the Dutch Twin Register allows us to identify genetic risk factors, whereas the application of brain imaging enables us to examine the motivational and cognitive aspects and pharmacotherapy of relapse behavior in humans. The investigators examine how individual differences in cognition (such as attention and impulsivity) and emotion (anxiety), primarily addressed in other research programs of the institute, determine the individual susceptibility to develop addictive behavior and the individual s risk to relapse to drug- and alcohol-seeking behavior during abstinence. In this respect, animal and human studies aimed to identify the genetic basis of addiction proneness (identification of vulnerability genes, including studies in twins), will be initiated. Animal studies address the psychopharmacology and neurobiology of cue-induced relapse to drug- and food-seeking behavior as well as that of reconsolidation of drug/food-related memories during abstinence. Clinical studies are being performed in drug addicts, employing brain imaging (fmri) and pharmacotherapy, in order to examine the functional anatomy and pharmacotherapy of relapse behavior (predicted by animal studies). Major deliverables of this research are: Identification of genetic risk factors (polymorphisms) for the acquisition of nicotine and alcohol addiction. Identification of novel targets (e.g. synaptic proteins) for pharmacotherapeutical intervention of relapse to drug and/or alcohol consumption during abstinence. Identification of distinct impulsivity traits as treatable risk factors for the development of compulsive nicotine- and alcohol-seeking behavior. Synthesis and in vivo application of compounds targeting nicotine and glutamate receptors as putative future medicines. Key Publications - Addictive Behavior Vink, J.M., Smit, A.B., Geus, E.J.C. de, Sullivan, P.F., Willemsen, G., Hottenga, J.J., Smit, J.H., Hoogendijk, W.J.G., Zitman, F. G., Peltonen, L., Kaprio, J., Pedersen, N.L., Magnusson, P.K.E., Spector, T.D., Kyvik, K.O., Morley, K.I., Heath, A.C., Martin, N.G., Westendorp, R.G.J., Slagboom, P.E., Tiemeier, H., Hofman, A., Uitterlinden, A.G., Aulchenko, Y.S., Amin, N., Duijn, C. van, Penninx, B.W.J.H. & Boomsma, D.I. (2009). Genome-wide Association Study of Smoking Initiation and Current Smoking. American Journal of Human Genetics, 84(3), (IF = 10.2) 36

39 GENES & THE BRAIN Systems Biology of the Synapse The overall aim of this program is to understand molecular function and plasticity of the synapse in health and disease. In order to do so, the collaborating investigators aim at constructing protein interaction models (interactome) of the synapse that will be based on different conditions of synaptic function and on mouse knockouts of synaptic proteins. The synaptic interactome models are based on quantitative experimental data, which ultimately explain how a complex protein network drives synaptic functions in the brain and predicts its adaptive capacities in response to environmental cues, such as behavioral challenges and pharmacological interventions. Finally, knowledge about synaptic function is being integrated to study synaptic networks in vitro and in vivo. Specific objectives are to provide targets for synaptic modulation and to dissect disease phenotypes by identifying crucial nodes and connectivity of the network. In order to generate quantitative experimental data on proteins and protein states and to reveal crucial nodes of the complete synaptic system, the research apply genetic, behavioral and pharmacological intervention and analyze the perturbation outcome using synapse-wide proteomics, synapse physiology, life cell imaging techniques and electron microscopy. Currently, > 20 projects have been defined in which various technical approaches are applied, ranging from whole synapse screens (itraq (quantitative) high-throughput MALDI-TOF) and subsynaptic protein complex analysis (immunoprecipitations and pull-down of tagged proteins) to biocore interaction analysis to derive kinetic parameters for proteins of interest, synaptic localization of proteins using confocal and electron microscopy. The loop between computational science and experimental neuroscience is being 'closed' by using several perturbation approaches, involving gene knockdown, over-expression, pharmacological agents, and the use of peptide mimetics to test model robustness and refine parameters. Modeling the synapse will allow us to predict and test synapse function and the physiology of neuronal circuitry. This information is crucially needed to design future therapeutic strategies addressing the many brain disorders for which synaptic dysfunction is a central aspect. Hence a truly integrated experimental and theoretical systems approach is applied to reach the objectives. Key Publications - Systems Biology of the Synapse Wit, H. de, Walter, A.M., Milosevic, I., Gulyas-Kovacs, A., Riedel, D., Sorensen, J.B. & Verhage, M. (2009). Synaptotagmin-1 docks secretory vesicles to syntaxin-1/snap-25 acceptor complexes. Cell, 138(5), (IF 31.3) 37