AIMMS. Amsterdam Institute for Molecules, Medicines and Systems. Annual Report 2011

Transcription

1 AIMMS Amsterdam Institute for Molecules, Medicines and Systems Annual Report 2011

2 Address Amsterdam Institute for Molecules, Medicines and Systems De Boelelaan HV Amsterdam The Netherlands phone: (31) website :

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4 1. Table of Contents 2. Preface 6 3. Description of AIMMS 3.1 Background 3.2 Mission 3.3 Aims and objectives Structure of AIMMS 4.1 Research groups 4.2 Research programmes and interactions 4.3 Key facilities and infrastructure 4.4 Management and governance 5. SWOT 6. News 7. International collaboration and funding 8. Input of AIMMS Output of AIMMS 9.1 Scientific output & quality 9.2 Indicators of esteem 9.3 Societal impact 10. Education & Training 11. Section reports Bio-Computational Chemistry (Bickelhaupt) Biomolecular Analysis (Niessen) Bio-Organic Chemistry (Orru) Genetics (Koes) Integrative Bioinformatics (Heringa) Medicinal Chemistry (Leurs) Molecular Cell Physiology (Westerhoff)

5 Molecular Microbiology (Bitter & Luirink) Molecular Neurobiology (Smit) Molecular Toxicology (Vermeulen) Structural Biology (Lill) Synthetic Chemistry (Lammertsma) Systems Bio-informatics (Teusink) Target and Systems Biochemistry (Smit) Theoretical Chemistry (Visscher) Appendices 12.1 Output AIMMS Theses Scientific papers, refereed Books Book chapters Output AIMMS Theses Scientific papers, refereed Books Book chapters 12.3 Input AIMMS Input AIMMS AIMMS Seminars and Lectures

6 It is my pleasure to present to you the first Annual Report of AIMMS, the Amsterdam Institute of Molecules, Medicines and Systems. This Annual Report provides an overview of the mission, the structure and organization of the institute as well as an overview of its research programmes and research staff. The report also summarizes the input and output data of the institute as a whole and of separate research programmes. Finally, each of the constituting Sections is presenting their research profile and research in The last decade has witnessed major breakthroughs in the fields of molecular, cellular and systems biology, but also in related enabling technologies. These innovations fuel a general excitement that a molecular up to systems understanding of health and disease is within our reach. This has lead to establishment of AIMMS, at April 1 st 2010, in which seventeen of the best research groups in pharmaceutical sciences, life sciences, computational life sciences and molecular sciences at the VU Campus joined forces. By integrating these scientific disciplines, AIMMS focuses at the elucidation of molecular 2. Preface Word from the director mechanisms of diseases and the development of novel and safer drugs, therapeutics (e.g. proteins, antibodies and other biologics) and diagnostics (e.g. molecular and translational biomarkers). Since the start of AIMMS, much effort has been invested in structuring the institute and creating a scientific environment in which interactions between research groups from the constituting faculties (Science and Earth & Life Sciences, FEW and FALW respectively) can interact and optimally exploit new opportunities for synergy. To stimulate this process, for example competitive grants for seven AIMMSbridging PhD-projects and MScstudents grants were initiated. The research carried out by AIMMS groups has been assessed as very good or excellent. This is the outcome in two recent (separate) evaluation reports by the Chemistry and Biology Review Committees, which have assessed research at universities across the Netherlands. The number of theses and publications in high impact journals has risen in Moreover, the external funding of AIMMS was 8.5 M, which is significantly higher than in Obviously, the success of a research institute is very much dependent on the quality, the ambitions and the successes of its students, postdocs, staff and other co-workers. It is thanks to them all, that we can present to you this AIMMS Annual Report. On behalve of the students, postdocs, staff and Management Team of AIMMS, Prof. dr. Nico P.E. Vermeulen (Director) 6

7 External Promotion A crucial tool to promote AIMMS and its activities consists of its website ( Moreover, a 5 minutes movie was created to introduce AIMMS, its mission, its ambitions, its research and two of her young scientists. 3. Description of AIMMS 3.1 Background Today there is still an unmet societal need, and enormous scientific challenge, for innovative development of new drugs and therapeutic and diagnostic strategies. As a matter of fact, even with relatively well known diseases, current therapies are effective in only 40% of patient populations, while other diseases still lack effective therapies. A recent report by PriceWaterhouseCoopers (PWC), Pharma 2020, predicts that by 2020, the most successful organizations in health will be those that focus on a better understanding of the molecular mechanisms and the patho-physiology of diseases. This requires basic and integrated research from molecules up to the systems level. The research process should thus tackle both the biology and chemistry of disease mechanisms, targets and metabolic pathways in an integrated fashion. The last decade has witnessed important breakthroughs in the fields of molecular and cellular biology, designer synthesis and chemical space, bio-analytical technologies and approaches, and in the understanding of the biological fate and effects of medicines. Combined with new perspectives to integrate and understand biological systems with the systems biology of molecular networks, this has led to the belief that the issues sketched above can be addressed with more comprehensive and sophisticated strategies, thus improving the molecular up to a systems understanding of health and disease. 3.2 Mission The mission of AIMMS is to conduct excellent, basic molecular life sciences aiming at fundamental breakthroughs in translational molecular medicine, drawing on the integrated study of biological processes and systems that will lead to new drugs, diagnostics and treatments. 3.3 Aims and objectives In accordance with its mission, AIMMS is contributing to the fundamental understanding of: Molecular and biochemical processes, i.e. from molecule to system; Discovery and validation of new targets, design and synthesis of new chemical entities, the disposition and safety and effects of drugs and therapeutics (e.g., biologics); Moreover, at April 1st 2011, the first external meeting has been organized to celebrate the first anniversary of AIMMS. Apart a speech from VU Chancellor prof. Lex Bouter, prof. Douwe Breimer, prof. Adriano Henney (Heidelberg), prof. Nick Turner (Manchester) and prof. Rob Leurs were presenting current and future developments and the challenges in AIMMS-related disciplines. Bioanalysis of drugs, therapeutics (e.g. biologics) and molecular diagnostics (e.g., translational biomarkers and diagnostic tools) and molecular mechanisms of diseases. 7

8 4. Structure of AIMMS 4.1 Research groups In 2011, seventeen research groups from the FEW-Department of Chemistry & Pharmaceutical Sciences (CPS; Faculty of Sciences), the FALW-Department of Molecular Cell Biology (MCB, Faculty of Earth & Life Sciences) and the Institute for Integrative Bio-Informatics (IBI- VU, Department of Informatics) constituted AIMMS. The AIMMS research groups represent different keyscientific disciplines, namely Pharmaceutical Sciences, Life Sciences, Computational Life Sciences and Molecular Sciences (Figure 4.1). integrates top-level chemical, biological, pharmaceutical, systems biology and related medical sciences at VU University. The projected research activities of AIMMS can be clustered around three inter-related main research programmes aiming at in-depth understanding of the molecules and biological processes relevant to life (in health and disease). Moreover, it includes more specifically disease target identification and validation by combined molecular and network-based research. b) Design and characterization of molecules and medicines Research towards the discovery, design, synthesis, analysis and characterization of novel drug and therapeutic candidates, typically being small organic molecules, peptides, proteins, antibodies and other biologics. This includes the disposition, safety and pharmacological effects of the drug and therapeutic candidates. Figure 4.1 The participating research groups within AIMMS AIMMS translational research strategy is greatly facilitated (see also Figure 4.2). Each AIMMS research by a horizontal integration of key programme comprises the required c) Biomarkers and diagnostics disciplines within the institute. disciplines to achieve critical mass. The At the same time, a conventional research programmes comprise: vertical and discipline-oriented organization may remain crucial in a) Molecular mechanisms of biological today s research landscape in The processes Netherlands and beyond. This programme comprises research Multiple and close cooperations exist between AIMMS research groups and research groups within the VUmc, c.q other Interfaculty Institutes. Most notable are NCA (Neuroscience Campus Amsterdam), CCA/V-ICI (VUmc Cancer Center Amsterdam), ICAR-VU (Institute for Cardiovascular Research) and LaserLAB (Institute for Lasers, Life and Biophotonics) This AIMMS research programme comprises the discovery of appropriate translational biomarkers and corresponding in vitro and in vivo molecular diagnostic tools to facilitate the elucidation of molecular mechanisms 4.2 Research programmes and interactions The research in AIMMS focuses on the fundamental understanding of biological processes from molecules up to systems. AIMMS 8

9 speaker of the day: Guus van Dongen (VUmc), young AIMMS talent was selected (and awarded) in a PhD-oral communication competition and a large poster session. b) Competitive AIMMS grants for Bridging PhD-projects Figure 4.2 AIMMS research groups and their respective contributions towards the three selected AIMMS programmes are illustrated of selected diseases and dedicated (novel) drug and therapeutic candidates. Since the start of AIMMS in April 2010, the management team has arranged multiple activities to create a top-scientific environment and synergy through interactions between its scientists, e.g. by a) an Annual AIMMS Meeting, b) a competition for AIMMS grants for Bridging PhD-projects, c) small AIMMS grants for common MSc-projects, and d) AIMMS seminar- and lectures series. a) The first AIMMS Annual Meeting at March 31 st Almost 150 persons attended this day: PhD students, MSc students, postdocs, professors! Apart from keynote lectures of AIMMS researchers (Martine Smit, Bas Teusink and Romano Orru) and keynote In 2010 it was decided to actively stimulate mutual interactions between AIMMS research groups. Thus six competitive bridging PhDprojects were selected in which groups from the two faculties were involved (Table 4.1). Project selection was primarily based on external peer review to ensure scientific excellence, but complemented by strategic considerations. The funding was based on a 50% matching by the research groups, thus allowing more projects and ensuring full commitment to the projects. In 2011, all projects are now fully staffed. A seventh project was complementary funded by four research groups in order to optimize interaction and synergy between experimental and systems biology approaches in the pathophysiology of tumorgenisis. Most of the AIMMS bridging PhD projects fit in the programmes a) Molecular mechanisms of biological processes and b) Design and characterization of molecules & medicines, which reflects the current strength and major focus Table 4.1 Bridging PhD projects granted PI's AIMMS Sections Title de Boer - Siderius Esch-Luirink Kool-AB.Smit Structural Biology / Target and Systems Biochemistry Medicinal Chemistry / Molecular Microbiology Bionolecular Analysis / Molecular Neurobiology GPCR-mediated oncogenic signaling, targeting as mediators of apoptotic/proliferative switching Spider in the web: multiple interactions of the essential cell division protein FtsQ as novel targets for antibiotic intervention Identification of novel bioactive substances on brain receptors Kooter-Vos Genetics / Molecular Toxicology Drug-induced genome instability: translation from yeast to human Ruijter-van Spanning Bioorganic Synthesis / Molecular Cell Physiology Acetogenins: chemo-enzymatic synthesis and molecular probing of respiratory NADH-dehydrogenases Giera-Teusink Bruggeman-MJ.Smit Biomolecular Analysis / System Bioinformatics Molecular Cell Physiology / Target and Systems Biochemistry The network pathophysiology of tumorigenesis: a systems biology approach (I) The network pathophysiology of tumorigenesis: a systems biology approach (II) 9

10 of the research groups in AIMMS. For program c) Biomarkers and diagnostics discovery stronger interactions with VUmc and other iozis are required, as many patientrelated and high throughput data is generated there. With the aid of three Taskforces, in , these interactions were initiated and still are developing further. This is for example the case with a broad Chemical Biology platform representing several key technologies in AIMMS (see paragraph 4.4, below) and a Systems Biology & Networks platform. These initiatives will be further developed in the context of the Human Health and Life Sciences (H2LS), a new initiative of VU and VUmc. Generally speaking, technologies and facilities and the data generation, management and analyses are currently still fragmented. From discussions with groups at the VUmc, but also the AMC and the NKI, it is clear that, apart from experimental data production, a core business of AIMMS, data management, data analysis and systems biology will become an important infrastructural need in the life sciences in general, notably also in AIMMS. Researchers of AIMMS are at the forefront of local (Amsterdam) initiatives, national initiatives such as the National Data Integration and Stewardship Center (DISC), and European initiatives such as Elixir (Bioinformatics) and ISBE (Systems Biology infrastructure) c) AIMMS Seminar and Lectures Research themes, progress and ideas are shared amongst AIMMS group members through bi-weekly seminars. These seminars are well visited and mostly two speakers present and discuss work of their group to the whole of AIMMS. AIMMS further supports Lectures from external guests and visitors (see Appendix 12.5) 4.3 Key-facilities and infrastructure The focus of AIMMS is on top-quality basic and application-directed molecular life sciences research. State-of-the art research facilities and technologies are indispensible for that purpose. Investments in the context of ongoing and new, externally granted projects have led to significant improvement of Figure 4.3 AIMMS key facilities 10

11 the research infrastructure in the key areas of AIMMS research. Figure 4.3 provides an overview of several of the research facilities and platforms. Examples of newly acquired grants for research facilities: - Dr. H. Irth et al: Instrumentation for specific bioanalysis of living systems (180 keuro) (SNS-Sector plan, NWO-Bazis equipment ( ). Two AIMMS sections involved. Dr. L. Visschers et al: Amsterdam Laboratory for Computational Chemistry (350 keuro), SNS-Sector plan, NWO-Bazis equipment ( ). Four AIMMS sections involved. Medicinal Chemistry and Molecular Toxicology invested in 2011 in an auto- ITC (250 k ) which is an automated highthroughput ITC-instrument to investigate energy changes upon protein-ligand binding. 4.4 Management and governance The management team consists of the scientific director (Professor Nico P.E. Vermeulen) and a managing direcetor (Jacqueline E. van Muijlwijk-Koezen) and three programme managers who are opinion leaders and heads of the departments involved (Professor Holger Lill, Professor Romano V.A. Orru, and Professor Bas Teusink). Annual Meeting 2011 The Tuinzaal was almost too small for all the posters and animated discussions around them. Overall, the quality of the posters was of a very high level! Three posters were selected as the best posters of this Annual Meeting by a jury. The chairman of the jury, professor Nicholas Turner who is the director of the Interdisciplinary Biocenter in Manchester and member of the Scientific Figure 4.4 Governance and management structure of AIMMS The scientific director and managing director are responsible for day-to-day management. The management team (MT) meets on a bi-weekly basis and takes amongst others responsibility for: Preparation of long-term and annual policy plans; Preparation of annual reports and standard protocol evaluations; Suggestion to the Supervisory Board of appointments at chair level and of membership of the Scientific Advisory Committee; Approval of research projects to be Young talent Advisory Board of AIMMS, awarded the winners: Azra Delic - Sabrina de Munnik - Meike Wortel Next to the poster competition, there was a PhD competition for oral contributions. Each of the seventeen Chairs of AIMMS has pointed one PhD student and based on the abstracts, six have been chosen to present their results. undertaken at the Institute; Deciding on further approval for projects that fail to meet the quality parameters. In 2011, the MT has prepared an AIMMS Visions document in which the current outcome of three Taskforces on Platforms and Keyfacilties, possible crystallisation themes for research, collaboration with other VU/VUmc iozis, and the new opportunities following integral housing of all AIMMS groups in the new O O Building at the VU Campus (planned for 2015) are indicated. This Vision document is the basis for strategic discussions within AIMMS and for new future directions. The audience scored the six candidates and the winner appeared to be Ewald Edink of the section of Medicinal Chemistry. 11

12 5. SWOT Analysis In order to further improve the performance of AIMMS as a research institute, a SWOT analysis has been made. It summarizes current strengths, opportunities, weaknesses and threats Strengths Vertical and horizontal integration of multiple scientific disciplines on the VU campus, i.e. Life, Pharmaceutical, Computational Life and Molecular Sciences, in one institute Coverage of scientific disciplines at molecular, cellular and translational stages of the development of novel drugs, therapeutics (incl. biolologics) and molecular diagnostics, thus adding significant value to high-impact scientific and social topics Strong position within FEW and FALW and strong links with other organizations/institutes, both at and outside the VU Campus. This is promoting a dynamic research environment Excellent research facilities and several platforms Strong and well organized PhD-programme, partly in collaboration with related Reseach institutes (e.g. LACDR, HRSMC, etc) Unique and leading position in research oriented MScprogrammes Opportunities Altering R&D strategies in Life Sciences and Pharma industry offer new opportunities for academia-industry collaborations Realization of strategic alliance (s) and collaborations with VUmc, based on outcomes of taskforces Potentially strong position in H2LS-VU can be substantiated, both in research and in education Room for improving European funding, both for research and for educational activities Relocation to the planned new O O building offers new opportunities to exploit intra- AIMMS collaborations and centralization of technology platforms Weaknesses Innovation and valorization strategies for AIMMS are still to be developed. Currently primarily based on individual groups and group leaders Scouting and stimulation of scientific talent can be improved Synergy in research within AIMMS suffers from spatial dislocation Threats Uncertainties about (reducing) internal budgets Uncertainties related to reorganization of VU governance iozis have no formal nor integral control over finances 6. News Only a selection of AIMMS news in 2011 is provided. A complete list can be found on During an Anniversary celebration on 18 November 2011 the University of Copenhagen appointed Professor Nico P.E. Vermeulen as honorary doctor associated with the Pharmaceutical Sciences. During the international igem jamboree at the VU University, the igem team Amsterdam has won a golden medal for their contribution bacteria are cool in the category lab results and human outreach. In September 2011, Dr. Maarten Honing was appointed at the special chair Drug Discovery Analytics in the Biomolecular Analysis group. Dr. Iwan de Esch (Medicinal Chemistry) won the Galenus Research prize for Biocomputational Molecular Design & Chemical Synthesis. The prize (5.500 Euros and a golden medal) was awarded on June 27th in the presence of minister Schippers. 12

13 Chemistry VU in top 75 Academic Ranking of World Universities: Chemistry VU is ranked at position of this Academic Ranking. Only Chemistry of Utrecht University scores higher (position 43). Prof Cees Gooijer, Section Biomolecular Spectroscopy retired in June A well attended mini-symposium was organized, preceding his farewell lecture, entitled: Light on chemistry: moving borders with lasers. Bas Teusink (System Bioinformatics) received a Zenith grant in the Horizon programme of NGI: From gene to microbial communities: exploring microbial communities at genome scale using constraint-based modeling and community experimentation (postdoc and a PhD student). Henry Vischer, Rob Leurs (Medicinal Chemistry) and Martine Smit (Target and Systems Biochemistry) scored an STW grant in collaboration with Ablynx entitled Variable domains of camelid heavy chain-only antibodies (VHH) to selectively inhibit oncogenic virally-encoded G protein-coupled receptors (postdoc, technician and PhD student). Enade Istyastono (Medicinal Chemistry) obtained a prestigious Henk Timmerman Award, honoring outstanding young Indonesian researchers who are working in the area of pharmaceutical sciences. Rogier Smits and Herman Lim (Medicinal Chemistry) discovered and pharmacologically characterized VUF8430 as a selective agonist of the histamine H4 receptor. Recently VUF8430 has been included in the chemical catalogues of Ovata Chemicals and Tocris Bioscience, making this pharmacological tool generally available to the study of H4R-mediated inflammation. F. (Filipe) Branco dos Santos (Systems Bioinformatics) received a VENI grant. His resarch project entitled Life continuously evolves in a dynamic environment. has been awarded with this prestious grant of NWO. Therapeutic nanobody discovered by VU Medicinal Chemists enters clinical trials Martine Smit and Rob Leurs and the Belgian Biotech company Ablynx have discovered the first llama-derived single chain antibody (nanobody) targeting the CXCR4 chemokine receptor, a protein that plays a key regulatory role in hematopoietic stem cell trafficking. Ablynx has developed and initiated a Phase I clinical trial in healthy volunteers with the therapeutic nanobody ALX- 0651, for use in stem cell mobilisation. ALX-0651 is the first Nanobody in clinical trials targeting a GPCR, a target class that has proven to be difficult to address with conventional antibodies. AIMMS initiates seven bridging PhD projects to stimulate the collaboration between members of the institute from the different faculties. After a selection procedure including a review by external reviewers seven proposals have been granted and from this moment on, the projects can start! Nico Vermeulen (Molecular Toxicology) in Nature Reviews Drug Discovery: Adverse Drug Reactions (ADRs) are a major complication of drug therapy and an impediment to drug development and clinical use after marketing. Chemically reactive metabolites (CRMs) constitute a major cause of ADRs. With a number of other experts in the field he has evaluated the current strategies to manage the challenge of chemically reactive metabolites (CRMs) in drug development and they proposed new insights and practices to manage CRMs. Medicinal Chemistry team VU University Amsterdam World Champion GPCR modeling: Luc Roumen and Chris de Graaf (Medicinal Chemistry) recently won a prestigious international challenge in predicting the binding orientation and interactions of a small molecule inhibitor in the CXCR4 chemokine receptor. Almost 20 post-docs and PhD-students from AIMMS, Leiden University and industry, followed the final workshop of Hein Coolen (LAC- DR, StagePharma io) on Lead Finding Strategies. They were well prepared for this job, because they followed during two days several lectures on Chemical Biology, taught by AIMMS professors. They learned the basics, background and scope of Chemical Biology, and introductions into Pharmacodynamics, Target Finding and Signal Transduction, Pharmacokinetics, ADMET, Drug Discovery and Safety, Biomarkers, Organic Chemistry, Computational Modeling and Radiolabels and Imaging. They visited the RNC and tried to make their own first ligand-protein models during a modeling workshop. 13

14 fte were funded by EC and IMI (see Table 8.1). Formal collaboration agreements 7. International collaboration and funding Several AIMMS-groups participate already a long time in unique international consortia, such as the International HRSMC-IRTG Graduierten Kolleg (Münster, supported by NWO and DFG) and the ULLA consortium (LACDR and 6 other European Schools of Pharmaceutical Sciences). EU - Marie Curie In 2011 AIMMS promoted initiatives to prepare and submit proposals for ECfunded projects by EU-proposal training for senior scientists and by hiring professional support for the preparation of proposals. This has led to significant funding, notably from IMI. The Molecular Toxicology group thus got in total three IMI-projects funded, namely The development of a European Modular Education and Training Program in Safety Sciences for Medicines (SafeSciMET), a second project Integrating bioinformatics and chemoinformatics approaches for the development of expert systems allowing the in silico prediction of toxicities (etox; and a 3rd project in 2011, Mechanism-based Integrated Systems for the Prediction of Drug-Induced Liver Injury (MIP-DILI). Apart from in-kind contributions (50%) from private partners, the total in-cash contribution amounts upto 3 M for the group. Currently, the various research groups from AIMMS participate in multiple ECfunded projects. In 2011, 14.5 research In collaboration with the Leuven University, the University of Copenhagen and the University of Uppsala, AIMMS started an EMJD grant application which has been submitted in the spring of The application consists of a training programme for joint PhD students on the design and development of anti-bacterial compounds. Furthermore, two grant applications for an international PhD training programme with AIMMS as leading instute has been submitted to the EU-ITN calll Finally, AIMMS is working on setting up several Joint Degree Programmes with foreign institutes. In 2012 the first Joint PhD students will start with their research projects in AIMMS groups. To further encourage international collaboration and to support the PhD-student exchanges and visiting scientists, AIMMS aimed to sign formal inter-institute collaborations and exchange agreements with related key centres abroad. For example, in 2011, formal agreement for 6 double degree PhD-students was signed with the University of Copenhagen. Previously, an agreement for a double degree MSc-programme on Drug Discovery and Safety was signed already with this University. Erasmus Mundus AtoSiM prolongated The international master AtoSiM (Bio-Computational Chemistry and Theoretical Chemistry) will get a follow up with AtoSim 2.0. In 2011 it was granted by the EU. Read more in Chapter 10.Education&Training A reliable computer replica of a complete biochemical pathway? In 2011 an initiative was started by the Systems Bioinformatics and Molecular Cell Physiology groups to bring together all international experts on the best-studied pathway in the life sciences: the conversion of glucose into ethanol by the yeast Saccharomyces cerevisiae. Almost 40 scientist from all over Europe attended a Lorentz workshop in Leiden where a work plan was developed to achieve this goal. Main issues were data sharing, standardization and protocol development: how to collect and combine all the data from the literature and from the labs? Some external funding from the Netherlands Consortium for Systems Biology has been attracted and two postdocs will start in 2012, one at AIMMS and one in Groningen, to execute the plan. 14

15 fte, calculated according to VSNU standards for the different categories of research personnel. Table 8b) indicates the breakdown per type of funding and the VSNU standards used. Detailed information on the total staff of AIMMS, per category and per type of funding, is given in Appendices 12.3 and 12.4). 8. Input of AIMMS At the start of AIMMS, in April 2010, for a period of 5 years a significant starting grant was received from the CvB and from the participating faculties, namely the faculties of Science and Earth & Life Sciences. These university-based starting funds (in total 2.4 M ) were primarily used to initiate and stimulate synergy between research groups within AIMMS (e.g. grants for AIMMS bridging projects for PhD-students and collaborative MSc-projects) and for the initiation and structuring of AIMMS as an Interfaculty Research Institutes (iozi), for promotion and for its governance. Remaining university-based funds are being used for infrastructure and key-facilities (see paragraph 4), innovation in MSc-education and for developing other new activities, such as new valorization initiatives. The university-based funding is complemented by external support from nonprofit (2GS), industry (3GS) and EU (4GS) funds. The aggregated external funding (2GS + 3GS + 4GS) has grown significantly from 2010 to 2011 (i.e. from 6.3 to 8.4 M, Table 8.1). Here and elsewhere in this Annual Report, bench mark figures either from 2008 or 2009 are provided. This is depending on which figures have been reported in the Business/Institute plan of AIMMS The total research staff of AIMMS at the end of 2011 added up to 112 research Compared to 2009 (Institute plan), in 2010 and 2011 the total number of fte s has somewhat reduced, amongst others due to the fact that research personnel of other research institutes (e.g. LaserLab) has not been included anymore. In 2011, the department of Chemistry & Pharmaceutical Sciences became part of a reorganization, also resulting in some reduction in fte s. In 2011, 16 new PhD-students started their programme. The total number of PhD-students in 2011 (i.e. 65) was comparable with New initiatives have been taken to increase the number of PhD-students. Thus, a collaborative agreement was signed with the University of Copenhagen, Faculty of Pharmaceutical Sciences for 6 new double degree PhD-projects. Moreover, two ITN- and one EMJD-application were submitted in Details on the current and newly started PhD-students are given in Appendices 12.3 and 12.4 external funding AIMMS ( ) Table 8.1 Acquisition of AIMMS per type of funding 2008 bench mark (business plan) non profit support (2GS) 2,909,894 2,823,694 support from industry (3GS) 1,894,279 3,522,538 EU projects (4GS) 1,540,604 2,134,401 TOTAL 5,500,000 6,344,778 8,480,632 15

16 Table 8.2 Research fte per type of funding fte per type of funding for research AIMMS juli 2009 bench mark (business plan) direct funding (1GS) non profit support (2GS) support from industry (3GS) EU projects (4GS) TOTAL research effort according to VSNU Prof., Assoc. Prof, Assist. Prof 0.5 Postdocs 0.9 Technicians 0 PhD students 0.75 Table 8.3 Number of PhDs of AIMMS PhDs real fte bench mark (business plan) Total Started Output of AIMMS 9.1 Scientific output & quality AIMMS publishes all its research results, including those from collaborative EUand industry projects, in the international scientific literature. It is the ambition of AIMMS to increase both the quality and the quantity of the scientific publications by setting a standard of two publications per investigator per year in an international journal with an impact factor in the top 20% of his/her scientific domain. Furthermore, the number of PhD-theses should increase up to an average of two per Principle Investigator. For the national Chemistry and Biology Reviews, CWTS Leiden conducted citation analyses for respectively the Department of CPS/FEW and the Department of MCB/FALW, the two major departments of AIMMS. During the past 10-year periods the section chairs and scientific staff published in high-profile journals like Nature (and affiliated journals), Science, Angewandte, PRL, PNAS, JACS, J of Clinical Investigation, Nucleic Acids Research etc. The overall CWTS crown-index (CPP/FCSm) FEW/CPS ( ) was 1.62, and for MCB/FALW ( /2010) the crown-index was 1.5. In both cases, 20% of the scientific publications resided in the top-10% of scitations. As to the nature and the total of the scientific output of the AIMMS research groups, a significant increase 16

17 Table 9.1 Scientific output of AIMMS Scientific output AIMMS * Theses 15 ** 22 Scientific papers, refereed Books 2 5 Book chapters Total * Scientific papers, non refereed, and conference proceedings are not included ** 15 Theses, 14 thesis defenses at VU University, 1 promotion external was realized in all categories (incl. scientific publications, theses, book chapters and books), both compared to 2010 and compared to 2009 (Institute plan) (See Table 9.1) and Figure 9.2). In 2011, a significant increase of the number of finished AIMMS PhDtheseses was realized when compared to 2010 and 2009 (22 vs 14 and 13.5) see for more information and details and Indicators of esteem Several AIMMS-researchers and groups received grants and awards in 2011, among which (selection only): Figure 9.1 Nature scientific output of AIMMS per year, compared to business plan Grants Bio-Computational Chemistry, Matthias Bickelhaupt, Bio- Organic Chemistry, Romano Orru and Synthetic Chemistry, Koop Lammertsma, NRSC-C research grant Bio-Solar Cells. Bio-Molecular Analysis, NWO- STW Open Technology Program Innovative Analytical Methodologies for Biopharmaceuticals (11056, February 2011). Bio-Molecular Analysis, NWO-ACTS_ TA-COAST Enhanced bioresolution and miniaturization of Surface Plasmon Resonance optical sensing (SPRing) ( , December 2011). Genetics, Ronald Koes, ALW-TOP, Genetic control and evolution of inflorescence architecture. Integrative Bio-informatics, Sanne Abeln, NWO-VENI, Zipping proteins cause initial problems in Parkinson s disease october Medicinal Chemistry, Iwan de Esch, EU- KP7, FluCure, to continue and expand the highly innovative research to develop novel drugs against influenza. Molecular Microbiology, Joen Luirink, NWO-STW The E. coli Hbp autotransporter: a novel platform for live vaccine development and heterologous protein secretion Molecular Toxicology, Nico Vermeulen, EU-IMI-JU The development of a European Modular Education and Training Program in Safety Sciences for Medicines (SafeSciMET, Systems Bio-informatics, Filipe Branco dos Santos, NWO-VENI Life continuously evolves in a dynamic environment Target and Systems Biochemistry, Martine Smit, Henry Vischer, and Rob Leurs (Medicinal Chemistry) together with industrial partner Ablynx obtained a grant from the Technology Foundation STW to develop inhibitory Nanobodies 17

18 targeting the oncogenic activity of the viral G protein coupled receptors (GPCRs). Awards Herwig Bachmann (Systems Bioinformatics) received a prestigious Price at the 10th International Conference on Lactic Acid Bacteria (LAB10) for his work on the development of a cultivation method that allows for the selection of unicellular organisms with a high yield (patented method). Iwan de Esch, (Medicinal Chemistry), obtained a prestigious Galenus Research Prize, honoring his innovative scientific research and valorization efforts in the area of pharmaceutical sciences. Enade Istyastono, (Medicinal Chemistry) obtained a prestigious Henk Timmerman Award 2011, honoring outstanding young Indonesian researchers who are working in the area of pharmaceutical sciences. Albert Kooistra, (Medicinal Chemistry) has won the international Design a Molecule 2012 competition organized by the software company Cresset. Luc Roumen and Chris de Graaf (Medicinal Chemistry) won GPCR DOCK, a prestigious international challenge in predicting the binding orientation and interactions of a small molecule inhibitor to a protein target. Rogier Smits (Medicinal Chemistry) received the Mercachem Farmacochemieprijs 2011 for the best PhD thesis in Medicinal Chemistry in for his work on the Design and Synthesis of New Histamine H4 Receptor Ligands. Nico Vermeulen (Molecular Toxicology) of was provided with an Honorary Doctorate associated with the Pharmaceutical Sciences by the University of Copenhagen at November 18, Societal impact In this paragraph, as an illustration only a few examples are given of societal impact: Consultancy and research contract Matthias Bickelhaupt (Bio-computational chemistry) - Consultancy and contract research for Wacker Chemie AG, München, Duitsland Thesis of Jolanda van Leeuwen The thesis of Jolanda van Leeuwen on the use of yeast as an alternative tool for the testing of toxicity of drugs, defended at December 9, 2011, received much attention in the lay press, such as daily and weekly journals as well as on the national radio. Interview with Nico Vermeulen In the context of the International Year of Chemistry 2011, the VNCI and NWO- CW published jointly a booklet with extensive interviews with eight Dutch scientists in Chemistry. In this context, Nico Vermeulen was interviewed about Exciting challenges of Adverse Drug Reactions (ADRs). AIMMS reseachers on television The AIMMS researchers Fred Boogerd, Willem Reijnders and John van der Oost (Molecular Microbiology and Molecular Cell Physiology) have been interviewed for the VPRO-broadcast Labyrint. The reason was the 100th anniversary of the Dutch Society for Microbiology. This has been celebrated with a threeday symposium (18-20 April 2011) in Papendal. including five Nobel Prize winners as speakers. Prince Willem- 18

19 Alexander received the first copy of the Micro Canon, in which more than 50 subjects from microbiology accessible are presented. The initiative for the Micro Canon is taken by the members of the Microbes Club, a group of microbiologists have worked ever all at the VU University in Amsterdam and are now employed in various universities, institutes, educational institutions and businesses in the Netherlands. Patent applications: Genetics, Provisional patent application: Plants with increased tolerance to metal ions; application number P1156NL00 (2 Nov 2011) Genetics, Nucleic acid Molecule and Uses therefor (PCT/AU2010/000504, WO2010/124344) Molecular Toxicology. and DSM, P450 BM3 mutants and regio- and stereoselective applications (EP ). Systems Bioinformatics, A method for the adaptive evolution of a cell and selection for a desired phenotype by serial propagation in an emulsion based system and uses thereof, (EP ). ICT for the Future of Medicine: truly individualized medicine after all? In the perspectives for its Horizon 2020 funding program the European Commission with Neelie Kroes as one exponent, has expressed ambition. It intends to promote a number of largescale, science-driven research initiatives in areas of Future and Emerging Information and Communication Technologies. Upon an initial 2011 call, six preproposals have been selected for the preparation of their roadmap by April 2012 and for the submission of a first funding proposal by October Because of the required man-on-themoon vision and intended magnitude of funding (1 G over 10 years) these research programmes are called FETflagships. By February 2013, two of the six proposals will be selected for funding. Hans Westerhoff (AIMMS, NISB, MC- ISB; Amsterdam/Manchester), Hans Lehrach (Max Planck Institute for Molecular Genetics Berlin; coordinator), and Kurt Zatloukal (Medical University Graz and BBMRI/Biobanking Europe) submitted one of the pre-proposals that were selected as one of the six Flagship candidates. This flagship initiative has since become an organization with 7 workpackages, i.e. on Medical aspects (coordinated by Zatloukal), Analytical aspects (Lehrach), Hardware/Software (Benhabiles, CEA, Gif-sur-Yvette and Mencer, Maxeler, London), Data pipelines (Birney, EBI), Machine learning (Girolami, UCL), and Integration (Westerhoff) and more than hundred associated research groups, centres and industries [see itfom.eu/]. This particular flagship is called Information, Communication and Computing Technologies for the Future of Medicine because it aims to engage much more modern and future ICT in health. After immediate utilization for a single patient or study, almost all results of the about 1 trillion annually that is spent on biomedical research worldwide, remain in folders in offices of individual MDs of Life Scientists, or at best in ill-connected journals. IT- FoM will use ICT to enable medicine to make much better use of that informa- tion. It will address the gigantic problem of extreme heterogeneity of the data types, by integrating the data in the predictive setting of computational models of the biology that occurs in the human, with explicit linkage to both molecules and whole-body health. Genome sequence, results of -omics analysis, but also nutrition and life-style information will be fed into the models, which will thereby become individual models, one for each human individual, 7 billion such models for the planet; here s just one of the man-on-the-moon aspects. Because human individuals are highly (99.9%) similar in terms of components and organization, the models with their data will be made to learn from each other. Because human individuals are different enough for them to contract different diseases and for therapies to differ widely in terms of success, the models will predict different disease risks and therapies for different human individuals. This will make medicine truly individual: one man one drug. Curing of most multifactorial diseases meets with very limited success. The majority of proposed drugs are thrown out in phase-1-3 trials because of lack of effect in most, or toxicity to some, individuals. The flagship will focus on ICT, but will tie the ICT close to its object, the individual, molecular human. Mathematical and other ICT modelling of drug-disease interactions will be close to the modelling activities in AIMMS and NISB; this is true for the watchmaker /siliconcell type of models as well as for more statistical and physiological models (up to PKPD). It is these models that will serve to integrate the data, much of which has been practised already in the Amsterdam-Manchester axis. Not accidentally, the biomedical focus of the first phase is on the interface between cancer and metabolic syndrome, where it should be easy to associate the various Warburg projects of AIMMS. But also the very issue of integration is one that is close to what AIMMS is aiming for: integration of the pharmaceutical, biochemical, cell biological and computational sciences. 19

20 Post-doc training and opportunities 10. Education & Training To increase the quality of its research programs and also to offer ambitious post-docs career opportunities in AIMMS-related fields, the AIMMS promotes itself extensively as an attractive host-institute for post-docs. Moreover, it actively stimulates and coaches talented post-docs to compete for personal grant programs at the national (e.g. Veni-, Vidi- and Vici-programs) and international (e.g. Marie-Curie fellowships, ERC-grants) level. Successful competition in these prestigious grant programs will be an important instrument in personal career developments and in tenured tracks. In 2011, 2 Veni s for AIMMS researchers have been granted (see 9.3) The ambition of AIMMS is to link and contribute to existing as well as future (inter-) faculty graduate programs, offering research MScprograms to prepare MSc-students for PhD-positions and other career opportunities. A strong integration of top research and top education activities will ensure an output of highly qualified graduates both at MSc- and PhD-level. AIMMS research groups play a major role in a range of established and accredited MSc- and PhD-education programs within FEW and FALW. Moreover, AIMMS participates in several graduate and top research schools such as LACDR, HRSMC and NRSCC. International PhD-courses are already offered within the frameworks of LACDR, HRSMC, NRSCC, and TI- Pharma. The same holds true for high quality Summer Schools for PhD-students from national and international organisations (e.g. HRSMC-IRTG, IMI- SafeSciMET and ULLA). About 65 PhDstudents are currently being trained (see Table 8.3). At present, AIMMS research groups are also key-players in multiple MScprogrammes. In Table 10.1 the increasing number of Master Students in these programmes are depicted. AtoSiM Erasmus Mundus international Master Out of hundreds of Study programmes, AtoSiM (Atomic Scale Modelling of Physical, Chemical and Biomolecular Systems ) has been once again considered one of the best European Master programmes and the EU will grant Erasmus Mundus scholarships for another round of 5 years. They will be available for 2012 intake. Atosim2.0 is a highly integrated TWO-year Erasmus Mundus master jointly operated by Ecole normale supérieure in Lyon, University la Sapienza in Rome, UvA and VU University Amsterdam. ( Table 10.1 Total number of AIMMS Master students AIMMS groups are currently already coordinator of several of these programs (e.g. Mariwill. IRTG, SafeSci- MET). Within the research groups participating in AIMMS, about 40 postdocs are contributing to current research projects (see 12.3 and 12.4). AIMMS post-graduate school / courses In 2011 AIMMS has started with the so-called post-graduate courses as a part of an AIMMS post-graduate school. The AIMMS PhD students Master students Bio-Informatics Bio Molecular Sciences Chemistry Drug Discovery & Safety Medical Natural Sciences TOTAL

21 and postdocs have diverse backgrounds and come to work in the multidisciplinary environment of AIMMS. This causes a need for relatively broad courses into different. Learning about the other disciplines and more understanding of each other s work will open eyes for possible linkages with own research and will give new opportunities for cooperation. Other perspectives, new approaches will sometimes just give that special break-through! To fill this need, we started the AIMMS post-graduate school with different courses. The aim is to organize 2 courses a year within a 3-year cycle, giving 6 different courses in total. We started in September 2011 with the two-day course on Chemical Biology (see Ch 6.News). The first target group is formed by PhD students and postdocs, but the course level will be MSc-level: we assume a thinking level of graduates in science or life sciences, but without detailed knowledge of the particular subject. The courses in the AIMMS postgraduate school are open for industry and external students, notably also from other iozis. AIMMS grants The management team of AIMMS decided to actively stimulate mutual collaborations between AIMMS research groups from the two participating faculties. Amongst this was materialized by AIMMS grants for: six competitive bridging PhDprojects consumables for a collaborative PhD-project three joint writings of grant proposals four joint MSc-student projects 11. Section Reports In Section 11, each of the research groups (Sections) of AIMMS is presenting their mission, their research lines, as well as the most important results and key-publications. Moreover, one or more highlights are presented. The order of the Sections is alphabetically. 21

22 Bio-computational Chemistry Research Profile Life sciences and sustainability are the context in which research programs are developed in the AIMMS division of Bio-Computational Chemistry. Our staff consists of Matthias Bickelhaupt (professor of theoretical organic chemistry and biocatalysis) and Célia Fonseca Guerra (assistant professor of biocomputational chemistry) and MSc, PhD, PD and visiting scientists. Theories and methods We are interested in developing chemical theories and methods for rationally designing molecules, nano-structures and materials as well as chemical processes toward these compounds, based on quantum mechanics and advanced computer simulations. An essential part of these efforts is the application of our theories and models in cooperation with experimental groups. The project comprises four main directions of research that are intimately connected and reinforce each other: (1) Structure and Chemical Bonding in Kohn-Sham Density Functional Theory (DFT), (2) Molecular Recognition and Theoretical Biochemistry, in particular DNA structure, stability and replication (see Figure 1), (3) Elementary Chemical Reactions, and (4) Fragment-oriented Design of (Bio-) Catalysts. At present, the division of Bio- Computational Chemistry is undertaking much effort into making the step from Schematic representation of the minimal model system used for quantum chemically analyzing the origin of the intrinsic preference of a template-primer complex for the correct (i.e., leading to Watson-Crick pairing) incoming nucleotide in DNA replication. In he was invited for 28 lectures among which Vaste Commissie voor Onderwijs, Cultuur en Wetenschap van de Tweede Kamer der Staten-Generaal (as Chairman of the HRSMC) NASA workshop Astrochemistry (as member of NWO delegation) Matthias Bickelhaupt Matthias Bickelhaupt popular speaker International Conference on Computational Science (keynote lecture) Stanford University Cornell University WATOC 2011 (trianual conference of World Association of Theoretical and Computational chemists) understanding to rationally designing chemical reactions and catalysts as well as into understanding cooperativity effects in DNA structure and elucidating the key steps in the DNA replication mechanism that are responsible for the enormous fidelity of this complex reaction of life. Anticancer drugs An important new research line in connection with the latter project is the development of anticancer drugs that are based on the stabilization of G-DNA domains. But many more research lines are under preparation or lifting off, ranging from astrochemistry, via solar cells to the detoxification of agents for chemical warfare. Key Publications S. C. A. H. Pierrefixe, S. J. M. van Stralen, J. N. P. van Stralen, C. Fonseca Guerra, F. M. Bickelhaupt, Hypervalent Carbon. Freezing the SN2 Transition State, Angew. Chem. 2009, 121, ; Angew. Chem. Int. Ed. 2009, 48, T. van der Wijst, C. Fonseca Guerra, M. Swart, F. M. Bickelhaupt, B. Lippert, A Ditopic Ion-Pair Receptor Based on Stacked Nucleobase Quartets, Angew. Chem. 2009, 121, ; Angew. Chem. Int. Ed. 2009, 48, J. Wassenaar, E. Jansen, W.-J. van Zeist, F. M. Bickelhaupt, M. A. Siegler, A. L. Spek, J. N. H. Reek, Catalyst Selection based on Intermediate Stability measured by Mass Spectrometry, Nature Chem. 2010, 2, C. Fonseca Guerra, H. Zijlstra, G. Paragi, F. M. Bickelhaupt, Telomere Structure and Stability: Covalency in Hydrogen Bonds, Not Resonance Assistance, Causes Cooperativity in Guanine Quartets, Chem. Eur. J. 2011, 17, J. Poater, M. Swart, C. Fonseca Guerra, F. M. Bickelhaupt, Selectivity in DNA Replication. Interplay of Steric Shape, Hydrogen Bonds, π-stacking and Solvent Effects, Chem. Commun. 2011, 47,