"Centre for Molecular Biodiscovery Annual Report 30 June 2003"
Centre for Molecular Biodiscovery Annual Report 30 June 2003 Contents Page 1.0 Centre Profile 3 2.0 Director’s Report 4 3.0 Governance 6 4.0 Research Highlights 4.1 Theme 1: Structural genomics and bioinformatics 10 4.2 Theme 2: Structure-based design of new therapeutics 12 4.3 Theme 3: Proteomics as a route to new therapeutics 13 4.4 Theme 4: Modelling cellular and sub-cellular processes 14 4.5 DNA50 Symposium 15 4.6 Bio-mirror site 15 4.7 International Academic visitors 15 4.8 Presentations 16 4.9 Publications 17 5.0 International Linkages 19 6.0 Funding awarded to CMB Principal Investigators in Year 1 21 7.0 Financial Reports 7.1 Operating Grant 22 7.2 Capital Expenditure Grant 23 Appendix A: Personnel employed by the Centre for Molecular Biodiscovery 24 Year 1. Appendix B: Contact Details for Key CMB Personnel 25 1.0 Centre Profile The genomic revolution in the biological sciences offers arguably the greatest challenges and opportunities of today: extracting new knowledge from genome sequence data, developing new therapies, and developing an understanding of whole cell behaviour. Ideas, innovation, and a merging of traditional disciplines are required to meet these challenges. The overall goal of The Centre for Molecular Biodiscovery (CMB) is to address the challenges and opportunities of this genomic revolution in the biological sciences by integrating five research groups from the University of Auckland, with extensive national and international networks and complementary skills in the following areas: • Structural biology (led by Prof. Ted Baker) • Microbial biology, molecular immunology and bioinformatics (led by Prof. John Fraser) • Chemotherapeutic drug development (led by Prof. Bill Denny) • Proteomics and drug discovery (led by Prof. Garth Cooper) • Bioengineering and advanced mathematical modeling (led by Prof. Peter Hunter) We believe that these fields of research are of vital importance to New Zealand. The “post-genomic” era offers huge wealth generating opportunities in biomedicine and biotechnology for those equipped with the right skills and knowledge to be able to extract and use the information in an intuitive way. It is “knowledge-driven” research that is highly appropriate for a small country like New Zealand; good ideas can be developed as well here as anywhere. The Centre for Molecular Biodiscovery has three broad goals: • To develop the skills and fundamental knowledge that will enable us to use genomic data in a way that extends from bioinformatics to whole cell function. This will involve a large element of training and fundamental research. • To develop new therapeutic agents for medicine, aimed at diabetes, cancer and infectious disease, and new tools for biotechnology. These will be discovered through bioinformatics, proteomics, structural biology and modelling, coupled with state-of- the-art methods in chemical array synthesis and screening. The integration of biology and chemistry, linked by molecular structure, will be critical. • To create a facility that will serve a national role in post-genomic science, and make its facilities accessible to users from outside institutions, recognising that key infrastructure, in particular major equipment and computer resources, cannot easily be duplicated. 3 2.0 Director’s Report The first year of operation of the CMB has been exciting, and at times frustrating. The excitement comes both from the opportunity to begin new research, and develop new facilities, and from the evident enthusiasm with which this initiative has been greeted from around New Zealand. We feel a keen sense of responsibility to realise these expectations. The frustrations come from the delays that come with the need to recruit new staff in a highly competitive world market for scientific skills, and from the delays that accompany the need to set up new administrative structures. In this sense the first year has been, in part, a development phase. Four aspects of this first year deserve special mention. First, the formation of the CMB has stimulated new collaborative interactions. The seeds for these were sown at the beginning, when our original proposal was being formulated, and they are already being translated into new projects that we had not previously envisaged. One that has been already realised has been the development of the CMB Bio-mirror data repository site by Professors John Fraser and Peter Hunter. This will serve as an open ftp server for the whole country and will provide users throughout NZ with high-speed access to the latest bio-database repositories. The availability of supercomputing facilities at the University of Auckland, supported in part by the CMB, has also enabled us to begin new initiatives in bioinformatics. In one of these, which includes staff from the School of Biological Sciences and the Departments of Statistics and Computer Science, Steven Huang has developed new approaches to developing functional linkages from genome sequences. New research collaborations have also been initiated, for example between Professor Baker and Professor Cooper (on potential drug targets for Type 2 diabetes), and between Professor Cooper and Professor Hunter (on the structure and function of the heart). Second, with about 70% of our professional staff now recruited, several of our keynote research projects are now in full operation. Professor Hunter’s group has made exciting progress in the development of tools that will, in time, offer a ground-breaking view of cellular processes. Already, about 150 models of cellular processes covering metabolic pathways, signal transduction, gene regulation, ion channels etc. have been developed. This is being done in the context of a major international initiative called the Physiome Project, which is led by Professor Hunter as the chairman of the Physiome Commission of the International Union of Physiological Sciences. The structural and functional genomics programme led by Professor Ted Baker, Professor John Fraser and Drs. Shaun Lott and Indira Basu has seen an acceleration of our work on defining new drug targets for TB therapy, and the initiation of new work focused on virulence factors from the significant human pathogen, Staphylococcus aureus. In the TB work, which is part of an international collaboration embracing research groups from 12 countries, we have defined the precise atomic structures of several drug targets, which are now being assessed by Professor Denny’s drug development group. The work on S. aureus has led to the discovery of several completely novel virulence proteins with previously-unrecognised activities. These and other projects, which have important implications for human health, are also stimulating considerable graduate student interest, which bodes well for the expansion of the scientific workforce in New Zealand. 4 Third, the infusion of new capital equipment is already beginning to transform our capabilities. The first major development has been the purchase of a state-of-the-art QStar mass spectrometer which is now the centrepiece of a purpose-built proteomics facility located in the School of Biological Sciences, University of Auckland. A user guide has been produced and we hope that researchers from round New Zealand will be encouraged to take advantage of this facility. Already, Professor Cooper’s research, making use of these capabilities, has identified one very exciting potential new therapeutic agent. Further major equipment, including a protein crystallization robotics facility, will be installed in the next few months and planning for our small animal magnetic resonance imaging (MRI) facility is at an advanced stage. The upgrading of New Zealand’s scientific infrastructure is of such vital importance to the future that we see it as critical that the CoRE initiative be part of a long- term strategy for continued renewal of major equipment. Fourth, we are excited by the quality of our advisors. We are fortunate to have an outstanding Governing Board, with diverse and relevant expertise, which is chaired by Mr. Bill Falconer. Delays in finalising the Board membership meant that it has only met once in the first year, but we hope that it will provide valuable strategic advice to the CoRE, and confirm the independence of the CMB as a research institution. We also have an international Scientific Advisory Board of remarkable quality. It was extremely pleasing that all of our chosen advisors, two from within New Zealand, and the other four from the UK, USA and Australia, accepted our invitation with alacrity. Although their international commitments are such that it will not be easy to bring all SAB members together at one time, we are confident that they will provide a continuing stimulus to our development. It is already clear that the synergies and new capabilities that come from the establishment of the CMB are a significant attractor of new research funding; Professor Baker has received a major FRST grant ($1.45 million pa for 7 years) to further extend the structural genomics programme, Professor Cooper has received HRC Programme funding for his diabetes research, and Professor Denny’s commercial contracts continue to grow. There are still unresolved issues, however, the major ones being the level of independence the CMB should have from the host institution, and the way in which it interacts with departments. We have taken the view that the CMB should not be physically relocated from the departments in which members have built their laboratories, since this retains a natural flow of graduate students into the CMB. On the hand, questions of whether new grants are routed through the CMB or through departments, how this should be done and how overheads should be handled have not yet been resolved. Financially, our Year 1 funds were underspent because of the delays in the recruitment of personnel and the purchase of equipment. We hope to use the unspent funds, and the accrued interest, for new initiatives in Year 2. As a final comment we are grateful to the Royal Society for their patient guidance during this first year, to our colleagues at the University of Auckland and throughout New Zealand for their support, and we look forward to the next year with enthusiasm. Ted Baker Director, Centre for Molecular Biodiscovery 5 3.0 Governance 3.1 Management Committee The Management Committee is comprised of all five CMB Principal Investigators; Prof. Ted Baker, Prof. John Fraser, Prof. Bill Denny, Prof. Peter Hunter, Prof. Garth Cooper and Ms. Rochelle Ramsay, the CMB Research Manager. The Management Committee meets on a monthly basis and is responsible for the overall direction of the CMB, including science (new projects etc.), infrastructure (equipment requirements), allocation of resources and personnel appointments and issues. The Research Manager is responsible for the routine management of the CMB. This includes monitoring and controlling CMB expenditure in accordance with the annual budget, co- ordinating the appointment of staff and co-ordinating the purchase of capital equipment. 3.2 Governing Board The role of the Governing Board is to guide and monitor the activities of the CMB in accordance with both the guidelines of Centres of Research Excellence, published by the Royal Society, and with University of Auckland policy governing the operation of University Units, Centres and Institutes1. Membership of the Governing Board was finalised in late May 2003. The six board members are; Mr. Bill Falconer (Chairman BIOTENZ, Co-Chair Biotechnology Taskforce) Prof. Dick Bellamy (Dean, Faculty of Science, Auckland University) Prof. Marston Conder (Mathematics Department, Auckland University) Prof. Gary Hook (CEO, Te Whare Wänaga o Awanuiärangi, Whakatane) Prof. Peter Smith (Dean, Faculty of Medical & Health Sciences, Auckland University) Dr. John Taylor (Director, External Relations, Auckland University) The first meeting of the Governing Board was held on the 6th of June 2003. Prof. Ted Baker gave a presentation to the Governing Board outlining the background to the establishment of the Centre for Molecular Biodiscovery and progress to date. Other issues were also discussed such as the future self-funding status of the CMB, use of accumulated depreciation and future research collaborations. Profiles of Governing Board Members Bill Falconer LL.B is a practicing commercial barrister and has extensive corporate experience. He has served as director of a variety of organisations and public companies during his career to date. His current positions include the chairs of the Meat Industry Association, Kiwifruit International and Hellaby Holdings. He served as co-chair of the Biotechnology Taskforce and has chaired the Environmental Risk Management Authority. 1. From the ‘Constitution of The Centre for Molecular Biodiscovery 6 Dick Bellamy MSc, PhD, FRSNZ is the Dean of Science at the University of Auckland. He is a Professor of Cellular and Molecular Biology and his research background is in human viruses, in particular rotavirus, a virus responsible for gastroenteritis in young children. He was a contributing author to the background papers used by the Royal Commission on Genetic Modification in 2000/2001. He currently serves on the Boards of Auckland UniServices Ltd and DNA Diagnostics Ltd. Marston Conder DSc FNZMS FRSNZ is a Professor of Mathematics at the University of Auckland and Co-Director of the NZ Institute of Mathematics and its Applications (NZIMA). He is a member of the Marsden Fund Council and is currently chairing a Working Group for the NZ Ministry of Education, charged with helping design a Performance Based Research Fund (PBRF) for tertiary eduction institutions in NZ. Gary Hook DSc is the Chief Executive Officer of Te Whare Wänaga o Awanuiärangi, a position that he took up on his return to New Zealand in 2002. Prior to this appointment he spent many years working for the National Institute of Environmental Health Sciences in the United States of America. He has recently been appointed a board member of the Foundation for Research Science and Technology. Peter Smith RFD MD FRACP FRCPA is currently the Dean of Medical and Health Sciences at the University of Auckland. He has an extensive research and clinical background in childhood cancer and has served as a director on the boards of many child health organisations in Australia including the Kids with Cancer Foundation, Royal Children’s Hospital Foundation and Murdoch Children’s Research Institute. He has also served on several Commonwealth and state Government Committees and Advisory Boards in Australia. John Taylor is Director of External Relations and Development at the University of Auckland. He was appointed to this position after retiring from the Headmasterships of s King' College, 1988-2002, and Rathkeale College, Masterton, 1979-1987. He is a member of the Advisory Board of the Liggins Institute, a Trustee of the NZ Education and Scholarship Trust, an Executive Committee member of the Knowledge Wave Trust, and Deputy Chairman of the Auckland Theatre Company. 3.3 Scientific Advisory Board The role of the Scientific Advisory Board is to ensure the performance and activities of the CMB remain focused on its core scientific goals. The CMB Scientific Advisory Board consists of six internationally recognised scientists; Prof. Peter Andrews (University of Queensland) Dr. Paul Atkinson (AgResearch Ltd.) Prof. Sir Tom Blundell (Professor of Biochemistry, Cambridge University) Prof. Janet Thornton (Director, European Bioinformatics Institute) Dr. Jim Watson (CEO, Genesis Research and Development Ltd.) Dr. Jilly Evans (Merck, USA) 7 No meetings have been held by the Advisory Board to date, although plans have been made in the Year 2 annual plan for a possible meeting in February or March of 2004. Profiles of Scientific Advisory Board Peter Andrews played a leading role in pioneering the discipline of drug design in Australia, establishing research laboratories at the Australian National University, Victorian College of Pharmacy, Bond University and the University of Queensland. He served as Co-director of the Institute for Molecular Bioscience at the University of Queensland 2000-2002, and CEO of its commercialisation arm IMBcom Pty Ltd, and currently chairs the Queensland State Government’s Biotechnology Advisory Council. Paul Atkinson is one of New Zealand’s foremost biological scientists. After a distinguished career at the Albert Einstein College of Medicine, New York, where he became Associate Director of the Cancer Center, he returned to New Zealand to take up a position with AgResearch where he is now General Manager Science. He has made major contributions to vaccine development and to TB research in New Zealand, and also has particular interests in genomics, bioinformatics and NMR. Sir Tom Blundell, FRS is currently Professor of Biochemistry at Cambridge University, UK, where his research speciality is in structural biology, bioinformatics and structure-based drug design. He has received many international honours for his scientific achievements in these fields. In addition he served as Director General/Chief Executive of the UK Research Councils 1991-1996, is a consultant to a number of international pharmaceutical companies, and is co-founder of Astex Technology Ltd (UK). Jilly Evans is currently director of pharmacology at Merck Research Laboratories, USA. A New Zealander, she is now one of the world’s leading researchers in the development of therapies for cancer and arthritis. Her current research focuses on the so-called “orphan” receptors that have been discovered from genome sequencing, which may offer novel drug development targets. Her knowledge of the pharmaceutical industry and her passion for the promotion of science will provide very important input into the core missions of the CMB. Janet Thornton, FRS is currently Director of the European Bioinformatics Institute, Hinxton, Cambridge, UK. Her research speciality is in structural bioinformatics, analysing protein structures to identify common features that can relate structure to function, or allow the prediction of protein structure and function. She has taken a leading role in functional genomics, and was co-founder of Inpharmatica, a company formed to develop tools for the extraction of biological information for industry from genomic data. Jim Watson, FRSNZ was co-founder of Genesis Research and Development Ltd. in 1994 and is currently its Chief Executive Officer. He is one of New Zealand’s leading molecular biologists, having previously been Professor of Molecular Medicine at the University of Auckland, following a research career that included posts at Syntex Corp., the Salk Institute, and the University of California, Irvine. He has been a Director of FRST, and is a member of the Government’s Growth and Innovation Advisory Board. 8 3.4 Organisational Structure The organisational structure of The Centre for Molecular Biodiscovery is detailed in the following diagram: The Centre for Molecular Biodiscovery Organisational Chart Scientific Advisory Board Governing Board Prof. S ir Tom Blundell, Prof. Janet Thornton, Mr. Bill Falconer, Prof. Dick Bellamy, Dr. Jilly Evans, Dr. Jim Watson, Prof. Marston Conder, Prof. Gary Hook, Prof. Peter Andrews, Dr. Paul Atkinson Prof. Peter S mith, Dr. John Taylor Management committee Pro fs. Ted Baker, Garth Cooper, Bill Denny, Uniservices John Fraser, Peter Hunter Ms Rochelle Ramsay Pharma Research Team Students General staff Research Fellows Visiting Fellows 9 4.0 Research Highlights 4.1 Theme 1: Structural genomics and bioinformatics In this theme we focus on two pathogenic organisms, Mycobacterium tuberculosis, the causative agent of TB, and Staphylococcus aureus, which causes a number of serious human diseases. By using bioinformatics, genetics, molecular and structural biology, we aim to define new targets for the development of therapeutic drugs. • Dr. Indira Basu arrived in March from Tufts University, Boston, to take up a postdoctoral position in the CMB. Indira has been working on the identification of novel Staphylococcal genes as potential anti-microbial targets and has cloned a number of interesting candidates identified in a preliminary search. Indira will also develop gene deletion methods, based on anti-sense knockdown technology, to test the essentiality of genes. • Mr. Steven Huang has been developing a bioinformatic method for assigning function to unknown proteins, based on their patterns of inheritance across fully sequenced genomes. This ‘phylogenetic profiling’ method should cluster proteins that have similar functions, or are involved in a common pathway, or form a macromolecular complex, independent of their sequence similarity. He has assessed the robustness of the method using randomisation testing, and is now planning to use the database to perform functional predictions for proteins of interest to other members of the CMB. • Progress has been made on a project focusing on the structure and biology of microbial virulence factors, a collaboration between the microbial genomics and structural biology groups (Fraser and Baker). Three students, Matthew Chung (PhD student), John Steemson (MSc student) and Aurelie Laugraud (MSc student), have been working on virulence proteins from S. aureus. Matthew is working on the isolation of recombinant molecules to test as targets for newly identified staphylococcal virulence factors (SETs). He is currently working on the SET3 and SET15 proteins. John is working on the crystal structure of one of the SETs (we have already determined the structures of two others) and Aurelie is working on the structure of an enzyme whose function we suspect is to degrade host proteins. • We have developed an excellent collaboration with Dr. Mark Hogarth and Dr. Bruce Wines at the Austin Institute in Melbourne to provide us with reagents to examine the function of a number of staphylococcal virulence factors and these have been used to assist Mathew Chung and Ries Langley to identify the function of a set of staphylococcal virulence factors. Dr. Wines conducted a number of biophysical measurements for us on the binding of the SETs to various recombinant receptors to determine specificity and affinities. 10 • The function of SET1 has been determined. It binds IgA and complement C5 with nanomolar affinity. A talented student Ms. Natasha Willoughby has joined the project as a prospective PhD student. Natasha has identified SET1 as a powerful binder and deactivator of the complement component C5 and has started a mutagenesis approach to identify the active domains of the SET1 molecule that bind IgA and C5 separately. • Dr. Erika De Moliner has arrived from the University of Padua (Italy) to work on the TB programme. She is working on the structures of proteins that are essential for the survival of the TB organism or are important for persistence. These are potential drug targets. To date she has cloned three proteins of interest, proB (Rv2439c), proC (Rv0500) and Rv1290. • Seven students, Nayden Koon (PhD), Clare Scott (PhD), Jodie Johnston (PhD), Miriam Sharpe (PhD), Anthony Harrison (MSc), Edward Walker (MSc) and Jessica Chaston (BSc Hons) are also involved in the TB project. Dr Indira Basu 11 4.2 Theme 2: Structure-based design of new therapeutics This theme will use the protein structures determined in Theme 1 and by others as a knowledge base for the design and development of new chemotherapeutic agents. • In collaboration with Prof. Stephen Neidle’s group in the London School of Pharmacy, University of London, we have completed the first part of a project on the structural biology of the E. coli nitroreductase NTR (the nfsB gene product) as an enzyme for activating prodrugs. • We are evaluating the bacterial enzymes MurC and MurF (peptidoglycan biosynthesis), MenB (menaquinone biosynthesis) and LeuA (leucine biosynthesis), for which crystal structures are being completed in Prof Baker’s laboratory, as possible targets for new antibacterial agents. • We have made progress towards high-throughput synthesis technology by the purchase and installation of autosamplers for our NMR and analytical facilities, to accelerate compound identification and quality control. This upgrade was completed in June 2003 with the installation a mass spectrometer detector on the HPLC. • Dr Michael Hay was appointed to the CMB as a Senior Research Fellow in February 2003. Dr Hay’s main focus is in the design and synthesis of compounds that are selectively toxic to cells that over-express the transcription factor HIF-1α. This work is an ongoing collaboration with Dr Amato Giaccia of Stanford University. • A collaboration with Epigenx (Santa Barbara, US) has resulting in the screening of about 250 compounds for their ability to selectively inhibit the enzyme cytosine DNA methyltransferase (Dmnt1). From this, two new classes of small-molecule inhibitors with sub-micromolar potency have been discovered, and preliminary structure-activity relationships for each class have been established. This has allowed the planning of new synthesis and evaluation projects in each series. 12 4.3 Theme 3: Proteomics as a route to new therapeutics This theme focuses on the identification of new therapeutics particularly for diabetes and heart disease. Proteomics is used to identify proteins implicated in disease. These proteins may themselves be potential therapeutics or may serve as targets for the design of new drugs. • Dr. Yu Wang started as a CMB Research Fellow in February. Her research focuses on adiponectin, a fat cell-derived hormone that has therapeutic potentials in obesity, Type 2 diabetes, atherosclerosis and fatty liver diseases. Since February she has been using different proteomic strategies to characterize the posttranslational modifications occurring on endogenous adiponectin purified from fetal bovine serum. She is also currently involved in identifying potential adiponectin-binding proteins within human plasma. • A purpose-built proteomics facility has been constructed in the School of Biological Sciences. Dr. Wang has been appointed as the Research Fellow in charge of this facility and has commissioned a series of new items of equipment, and produced a guide to the proteomics facility. The centrepiece of this facility is the AB QStar mass spectrometer which has been purchased by the CMB. This state-of-the-art acquisition supplements the existing AB Voyager MADLI-TOF mass spectrometer which identifies proteins through mass fingerprinting. The QStar enables us to perform de novo sequencing of peptides and to identify individual proteins from mixtures with higher sensitivity and accuracy, which is fundamental to a number of the CMB’s objectives. For more information on this facility see http://www.sbs.auckland.ac.nz/services/proteomics/index.htm • A PhD student, Peter Brown, is working on a joint project between the proteomics and structural biology groups (Cooper and Baker), the expression and structural analysis of two enzymes implicated in diabetic complications. Peter has cloned and expressed these two proteins and aims to solve their crystal structures, as a basis for structure- based drug design. He already has small crystals of one of these enzymes. Peter has also developed a polyclonal antibody to one of the two proteins and is using this in protein expression experiments. • A summer student in the proteomics group, Ms. Dina Jezdic, carried out preliminary s work for proteomic analysis of the human brain in Huntington' disease. She performed different sample preparation and two-dimensional gel electrophoresis s techniques on cingulate gyrus samples from Huntington' cases and controls, successfully determining the best methods to use for the proposed analysis. 13 4.4 Theme 4: Modelling cellular and sub-cellular processes The CellML project, aimed at modelling cellular pathways, is a major one within the CMB and is stimulating wide international interest and many collaborative links. Ontologies of cell structure and function are being developed to facilitate the modelling of cellular processes such as transport, metabolism, signalling, motility, cyto-skeletal organisation and the cell cycle. The markup language ' CellML' is being developed to encapsulate the mathematical descriptions of cell functions. • We are making good progress on the development of CellML models (see www.cellml.org) and tools for rendering protein pathways and simulation tools for running the models. We have now assembled about 150 models of cellular processes covering metabolic pathways, signal transduction, gene regulation, membrane ion channels, etc. • The CellML 1.0 standard has now been published as an international standard and we are working towards 2.0. We have recently established a sourceforge site for opensource software related to our CellML developments (see cellml.sourceforge.net). • In particular we have completed the development of a C++ API (Application Programming Interface) to enable software developers to read and write CellML files. Dr. Matt Halstead 14 4.5 DNA50 Symposium The CMB, along with the School of Biological Sciences, hosted a DNA50 Symposium that was held at the School of Biological Sciences on 10th June 2003, as part of the 50th anniversary of the discovery of the structure of DNA. The attendance of two international speakers, Prof. Neil Hall (Sanger Institute, UK) and Dr Owen White (TIGR, USA) was sponsored by the Royal Society of New Zealand, British Council New Zealand, Fulbright New Zealand, and Montana Wines under the theme ‘Masterclass! Science – Deciphering the Genome’. A further 4 local speakers also gave presentations at the symposium; Prof. Ted Baker, Prof. John Fraser, Prof Allen Roderigo (University of Auckland) and Dr. Doug Williams (Genesis R&D). 4.6 Bio-mirror site Genuine progress has been made towards the establishment of the New Zealand’s first bio- mirror ftp site provided by the Centre of Molecular Biodiscovery. The site is located at ftp://cmb1.auckland.ac.nz/pub/biomiror and is accessible to all users within New Zealand. The IBM Linux server purchased by the CMB and is up and running and we have negotiated with Australian National University to provide us with monthly “dumps” of the entire bio- mirror databases which current run to 150 GB of information. In the first instance, because of the limited bandwidth across the Tasman, the transfers will be by removable disk. CMB will provide this site as a “free access” ftp site for New Zealand. There will also be a number of tools provided to researchers who wish to perform searches and other functions that will be built over the database. 4.7 International Academic Visitors During April the CMB hosted our first short-term visitor, Dr. Nick Dixon, a Senior Research Fellow in the Research School of Chemistry at the Australian National University (ANU). His research is focused on the structural biology of DNA replication. Dr. Dixon gave the first seminar in the CMB seminar series entitled ‘Insights into DNA replication: the structure and function of DnaB, the E.coli replicative DNA helicase’. During his four week visit, based in the Structural Biology group, Dr. Dixon shared expertise and ideas with staff and students. A continuing collaboration has been set up with ANU as a result of Dr. Dixon’s visit. Dr. Joel Gottesfeld (The Scripps Research Institute, La Jolla, USA) visited the CMB briefly in May and was hosted by Prof. Denny at the Auckland Cancer Society Research Centre. During his visit Dr. Gottesfeld gave the second seminar in the CMB Seminar Series, entitled ‘Chemical Regulation of Gene Expression’. 15 4.8 Presentations Numerous public and scientific presentations have been given by CMB principal investigators, highlighting research in the CMB at national and international forums. These included (among others) presentations to: • MoRST “Chat Shop” (Baker, Fraser) • Ministry of Health forum on “New technologies for infectious disease” (Fraser, Baker) • British Cancer Research conference (Denny) • RACI Conference (Australia) (Denny) • 8th International Pacific Rim Biotechnology Conference (Cooper, Baker, Fraser) • First New Zealand Bioinformatics Conference (Baker) • Presentations to Dr. Rita Colwell (Director, NSF) (Hunter, Baker) • First Accelrys World Conference on cell modelling (Hunter). • The Wellcome Trust (UK) on cell modelling (Hunter). • U.S. National Institutes of Health (NINDS) (Cooper). • DNA50 Symposium (Auckland) (Fraser, Baker) Posters of research associated with the CMB have been presented at conferences; • Ms. Miriam Sharpe and Ms. Rochelle Ramsay presented posters based on structural studies of Mycobacterium tuberculosis at the 28th Annual Lorne Conference on Protein Structure and Function in Victoria, Australia. • Mr. Steven Huang presented a poster on his work entitled ‘Generation and Clustering of Phylogenetic Profiles for automatic Functional Annotation of Proteins’ at the ISMB 2003 conference in Brisbane, Australia. 16 4.9 Publications Papers relating to CMB projects – recently published, submitted or in progress Johansson E, Parkinson G, Denny WA, Neidle S. (2003) Studies on the nitroreductase prodrug-activating system. Crystal structures of the enzyme active form and complexes with the inhibitor dicoumarol and dinitrobenzamide prodrugs. J. Med. Chem. submitted. Hay MP, Atwell GJ, Wilson WR, Pullen SM, Denny, WA. (2003) Structure-activity relationships for 4-nitrobenzyl carbamates of 5-aminobenz[e]indoline minor groove alkylating agents as prodrugs for gene therapy in conjunction with E. coli nitroreductase. J. Med. Chem. 46(12): 2456-2466. Gniazdowski M, Czyz M, Denny WA, Nelson SM. (2003) Transcription factors as targets of DNA-interacting drugs. Curr. Med. Chem. 10(11):909-924. Denny WA. (2003) Prodrugs for gene-directed enzyme-prodrug therapy (suicide gene therapy). J. Biomed. Biotech. (1): 48-70. Denny WA. (2003) Tumor-activated prodrugs – a new approach to cancer chemotherapy. Cancer Inv. in press. P.J. Hunter and T.K. Borg. (2003) Integration from Proteins to Organs: The Physiome Project. Nat. Rev. Mol. Cell Biol. 4(3): 237-243. see http://www.nature.com/cgitaf/DynaPage.taf?file=/nrm/journal/v4/n3/full/nrm1054_fs.html Goulding, C.W., Apostol, M., Anderson, D.H., Gill, H.S., Smith, C.A., Kuo, M.R., Yang, J.K., Waldo, G.S., Suh, S.W., Chauhan, R., Kale, A., Bachhawat, N., Mande, S.C., Johnston, J.M., Lott, J.S., Baker, E.N., Arcus, V.L., Leys, D., McLean, K.J., Munro, A.W., Berendzen, J., Sharma, V., Park, M.S., Eisenberg, D., Sacchettini, J., Alber, T., Rupp, B., Jacobs, W.Jr. and Terwilliger, T.C. (2002) The TB Structural Genomics Consortium: Providing a structural foundation for drug discovery. Curr. Drug Targets Infect. Disord.2: 121-141. Smith, C.A. and Baker, E.N. (2002) Aminoglycoside antibiotic resistance by enzymatic inactivation. Curr. Drug Targets Infect. Disord. 2: 143-160. Arcus, V.L., Langley, R., Proft, T., Fraser, J.D. and Baker, E.N. (2002) The three- dimensional structure of a superantigen-like protein, SET3, from a pathogenicity island of the Staphylococcus aureus genome. J. Biol. Chem. 277: 32274-3228. Peterson, N.A., Arcus, V.L., Anderson, B.F., Tweedie, J.W., Jameson, G.B. and Baker, E.N. (2002) The “dilysine trigger” in transferrins probed by mutagenesis of lactoferrin: the crystal structures of the R210G, R210E and R210L mutants of human lactoferrin. Biochemistry. 41: 14167-14175. Baker, E.N. and Wittinghofer, A. (2002) Proteins – from little acorns mighty oak trees grow. Curr. Opin. Struct. Biol. 12, 743-745. Nurizzo, D., Shewry, S.C., Perlin, M.H., Brown, S.A., Dholakia, J.N., Fuchs, R.L., Deva, T., Baker, E.N. and Smith, C.A. (2003) The crystal structure of aminoglycoside-3’- phosphotransferase-IIa, an enzyme responsible for antibiotic resistance. J. Mol. Biol. 327, 491-506. 17 Baker, H.M., He, Q-Y., Briggs, S.K., Mason, A.B. and Baker, E.N. (2003) Structural and functional consequences of binding site mutations in transferrin: Crystal structures of the Asp63Glu and Arg124Ala mutants of the N-lobe of human transferrin. Biochemistry. 42: 7084-7089. Baker, H.M., Anderson, B.F. and Baker, E.N. (2003) Dealing with iron: Common structural principles in proteins that transport iron and heme. Proc. Natl. Acad. Sci. USA. 100: 3579- 3583. Hendrixson, D.R., Qiu, J., Shewry, S.C., Fink, D.L., Petty, S., Baker, E.N., Plaut, A.G. and St. Geme III, J.W. (2003) Human milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites. Mol. Microbiol. 47: 607-617. Johnston, J.M., Arcus, V.L., Morton, C.J., Parker, M.W. and Baker, E.N. (2003) The crystal structure of a putative methyltransferase from Mycobacterium tuberculosis: misannotation of a genome suggested by protein structural analysis. J. Bacteriol. 185: 4057-4065. Baker, E.N., Arcus, V.L. and Lott, J.S. (2003) Protein structure prediction and analysis as a tool for functional genomics. Applied Bioinf., in press. Lott, J.S. and Baker, E.N. (2003). Functional genomics of Mycobacterium tuberculosis: new insights into mankind’s deadliest pathogen. NZ Science Rev. 60: 43-47. Baker, T. (2003) Expanding dimensions in structural biology. NZ Bioscience. 12: 29-33. Aimin Xu, Yu Wang, Hussila Keshaw, Lance Yi Xu, Karen S.L. Lam, and Garth J.S. Cooper. (2003) The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J. Clin. Invest. 112: 91-100. Proft T, Webb P, Handley V, Fraser JD. (2002) Two novel superantigens found in both group A Stereptococcus and group C Streptococcus. Infect. Immun. 71(3): 1361-1369. Loh MS, Fraser J. Metal derivatised MHC zeroing in on contact hypersensitivity. J. Exp. Med. 2003.197(5): 549-552. Proft T, Sriskandan S, Yang L, Fraser JD. (2003) New Evidence for Involvement of Superantigens in Streptococcal Toxic Shock Syndrome. Emerging Infect. Dis. in press. Proft T, Fraser JD. (2003) Bacterial Superantigens. Clin. Exp. Immunol. 133(3): 299-307. Langley R, Wines B, Willoughby N, Hogarth M, Proft T, Fraser J. (2003) The staphylococcal superantigen homologue SET1 binds to IgA and complement C5 and inhibits IgA-FcgR interaction and complement mediated lysis. Submitted to J. Exp. Med.. Papers with CMB byline J Shaun Lott and Edward N Baker. (2003) Functional genomics of Mycobacterium tuberculosis: new insights into mankind’s deadliest pathogen. NZ Science Review. 60, 43 – 47. 18 5.0 International Linkages The five research groups involved with the CMB have a number of established linkages with international organisations and companies. Some of these linkages are detailed below. The Structural Biology group is part of the international Mycobacterium tuberculosis Structural Genomics Consortium which currently involves 70 research groups from 12 countries. The consortium was formed in 2000 and the overall goal is to provide a structural basis for the development of therapeutics for tuberculosis. Once determined, the 3- dimensional structures of M. tuberculosis proteins are placed in the public domain where any researcher can then access the structural information. (See http://www.doe-mbi.ucla.edu/TB/ for more information). The ACSRC and the Structural Biology group are both involved in commercial collaborations with Pfizer Global Research and Development (Ann Arbor, USA) for the structure-based design of new drugs. The ACSRC has had a long standing research collaboration with Pfizer working on the design of new anti-cancer drugs. Recently Prof. Denny and Prof. Baker negotiated (through Uniservices) a major contract (more than $2 million pa) with Pfizer Global Research for the structure-based design of antibacterial drugs. In addition the ACSRC has collaborations with the Wellcome Trust, the US National Cancer Institute and Stanford University (NCI Programme) and other commercial linkages to companies including Seattle Genetics, Xenova, Antisoma (UK) and Cancer Research Campaign Technology (UK). The BioEngineering Institute has a major involvement in the International Union of Physiological Sciences (IUPS) Physiome Project, which aims to provide a framework for modelling the human body using computational methods. The CellML project, a collaboration with Physiome Sciences (USA), is part of the Physiome Project and its purpose is to allow scientists to store and exchange computer-based biological models. Prof. Hunter is currently the chairman of the Physiome commission of the International Union of Physiological Sciences. (see http://www.bioeng.auckland.ac.nz/physiome/physiome.php for more information) The BioEngineering Institute also has collaborations with research groups at many other institutions including the University of Oxford (UK), the University of Sydney, University of Nevada (USA) and Vanderbilt University (USA). The Molecular Immunology group (Prof. John Fraser) has collaborations with other research groups at Harvard University (USA), Cornell University (USA), University of Melbourne and the ESR, Centre for Disease Control (USA), along with a commercial contract with Toxin Technology (Sarasota, USA). Prof. John Fraser is also an expert adviser to the SwissProt and Prosite databases. The Proteomics group has established linkages with many groups around the world, including s the Diabetes Division, Garvan Institute of Medical Research, St Vincent' Hospital, University of New South Wales, Sydney, Australia, the Maurice Muëller Institute for Structural Biology, University of Basel, Switzerland, the National Institute of Neurological Diseases and Stroke (NINDS, USA) and the National Institute of Diabetes, Digestive & 19 Kidney Diseases (NIDDK, USA); the Universities of Oxford, Cambridge, Tulane, Hong Kong, Tokushima, the Department of Cell & Developmental Biology & Anatomy, University of South Carolina, USA; and the Research Institute of Scripps Clinic. In early 2003, Professor Cooper was asked to act as a consultant for the NINDS, in the area of Neuroproteomics. Recent cover of the Journal of Clinical Investigation featuring a photo of adipocytes that secrete adiponectin. This work was done by members of the Proteomics Group. 20 6.0 Funding awarded to CMB Principal Investigators in Year 1 The research programmes and collaborations being developed in the CMB are a major factor in a number of new commercial contracts and grant applications that will help to underwrite the future viability of the CMB. Still to be resolved within the University is the question of whether these grants should be routed through the CMB or through departments, and how overheads should be handled. • Professor Baker and colleagues in the Structural Biology group have been granted funding of $1,4 million per annum for 7 years from the New Economy Research Fund, to develop new programmes and technologies in structural biology for potential applications in biotechnology. This programme also involves collaborations with AgResearch, HortResearch and Otago University. • Prof. Cooper, Prof. Hunter and colleagues have been awarded an HRC programme grant covering 3 projects, all of which contain subcellular level modelling (such as pathways involved in calcium homeostasis and tissue growth pathways). • Prof. Cooper was awarded an HRC Programme for $3.1 Million for 3 years, for targeted therapy of type 2 diabetes. • Prof. Baker has been awarded a Project grant by the HRC, with funding of $234,460 per annum for 3 years, for TB structural genomics. • Prof. Denny and Prof. Baker have negotiated (through Uniservices) a major contract (more than $1 million pa) with Pfizer Global Research for the structure-based design of antibacterial drugs. • Discussions are in progress between Epigenx and UniServices, on behalf of ACSRC, on setting up a joint research programme, funded by Epigenx, to jointly develop small-molecule inhibitors of DNA methyltransferase1. This is likely to involve 2 chemistry positions in Auckland in the first instance. • Grant applications that relate to CMB research projects include: o In late May Prof. Denny and colleagues submitted a project grant (partly on HIF-1α compounds) as part of a joint application between Auckland and Stanford for an NCI Programme/Project grant. o Prof. Hunter and colleagues have submitted a European Framework 6 project on diabetes (the consortium is led by Prof Fran Ashcroft from Oxford Univ and Prof Patrik Rorseman from Lund Univ). We will be modelling ion channels, signal transduction pathways and metabolic processes in alpha and beta cells of the endocrine pancreas. o Prof. Hunter and colleagues have submitted an application to the Wellcome Trust on integrative cardiac modelling with several people at Oxford, involving molecular structure (with Mark Sansom), ion channels (Denis Noble), proton transport (Richard Vaughan-Jones) and neural control (David Paterson), as well as us (doing the modelling). 21 7.0 Financial Reports 7.1 Operating Grant Centre for Molecular Biodiscovery Financial Report 30 June 2003 Total budget Year 1 Actuals and committed Income June 30 2003 CoRE grant $ 2,542,222.00 $ 2,542,222.22 User charges $ 286,000.00 $ - Total Income $ 2,828,222.00 $ 2,542,222.22 Expenditure Salaries FTE contributions $ 70,000.00 $ 74,105.00 Postdoctoral Fellows $ 600,000.00 $ 113,775.00 Technicians/Other $ 90,000.00 $ 38,318.00 Total $ 760,000.00 $ 226,198.00 Overheads Total $ 760,000.00 $ 349,717.00 Direct costs Expendables $ 520,722.00 $ 186,306.00 Student support (PhD and other) $ 135,000.00 $ 30,527.00 Travel $ 120,000.00 $ 31,332.00 Total $ 775,722.00 $ 248,165.00 Depreciation/rental Supercomputer lease $ 100,000.00 $ 100,000.00 Annual depreciationa $ 432,500.00 $ 22,163.00 Total $ 532,500.00 $ 122,163.00 Total Expenses $ 2,828,222.00 $ 946,243.00 Balance $ - $ 1,595,979.00 Notes a Depreciation expense has been significantly lower than budgeted in Year 1due to delays in installing capital equipment items. 22 7.2 Capital Expenditure Grant Centre for Molecular Biodiscovery Capital Expenditure Financial Report 30 June 2003 Budget Actual Income Capital Expenditure grant $ 4,314,043.00 $ 4,314,043.00 Expenditure Actual $ 487,436.00 Committed $ 1,360,188.00 Total Expenditure $ 4,314,043.00 $ 1,847,624.00 Balance $ 2,466,419.00 23 Appendix A. Personnel employed by the Centre for Molecular Biodiscovery Year 1. Staff/Student Name Position Research Area Appointment Date Ms. Rochelle Ramsay Research Manager N/A 18 November 2002 Ms. Aurelie Laugraud Research Assistant Microbial Genomics/ 20 September 2002 Structural Biology Mr. Steven Huang Research Assistant Bioinformatics 2 December 2002 Mr. Peter Brown* PhD Student Structural Biology/ March 2002 Proteomics Ms. Dina Jezdic Summer student Proteomics December 2002 Dr. Yu Wang Research Fellow Proteomics February 2003 Dr. Matt Halstead Research Fellow Cellular Modelling February 2003 Mr. Matthew Chung PhD Student Microbial Genomics/ February 2003 Structural Biology Dr. Michael Hay Senior Research Structure Based Drug February 2003 Fellow Design Dr. Erika de Moliner Research Fellow Structural Biology March 2003 Dr. Indira Basu Research Fellow Microbial Genomics March 2003 and Bioinformatics Mr. Ries Langley Research Fellow Microbial Genomics March 2003 and Bioinformatics Ms. Sandra Kamphuis Short term Student Cell Modelling March 2003 Mr. David Nickerson PhD Student Cell Modelling March 2003 Mr. Chris Research Assistant Cell Modelling 23 June 2003 Brookbanks Mr. Gang Lu Casual Technician Proteomics May 2003 * only partially financially supported by the CMB. 24 Appendix B. Contact Details for Key CMB Personnel Director/Principal Investigator Professor Ted Baker School of Biological Sciences Faculty of Science University of Auckland Private Bag 92019 Auckland Ph 09 3737599 extn 84415 email: email@example.com Deputy Director/Principal Professor John Fraser Investigator School of Medical Sciences Faculty of Medical and Health Sciences University of Auckland Private Bag 92019 Auckland Ph 09 3737599 extn 86036 Email: firstname.lastname@example.org Principal Investigator Professor Bill Denny Auckland Cancer Society Research Centre Faculty of Medical and Health Sciences University of Auckland Private Bag 92019 Auckland Ph 09 3737599 extn 86144 Email: email@example.com Principal Investigator Professor Peter Hunter BioEngineering Institute University of Auckland Private Bag 92019 Auckland Ph 09 3737599 extn 88395 Email: firstname.lastname@example.org 25 Principal Investigator Professor Garth Cooper School of Biological Sciences Faculty of Science University of Auckland Private Bag 92019 Auckland Ph 09 3737599 extn 87239 email: email@example.com Research Manager Ms Rochelle Ramsay Centre for Molecular Biodiscovery c/o School of Biological Sciences Faculty of Science University of Auckland Private Bag 92019 Auckland Ph 09 3737599 extn 85533 email: firstname.lastname@example.org 26