Bioinformatics Institute

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1 Bioinformatics Institute Opening New Frontiers in Biology Dr Guna Rajagopal, Deputy Director & Professor Santosh Mishra, Executive Director Bioinformatics Institute Introduction At the dawn of the 21st Century, our perception of biomedical research has changed from a mainly qualitative hypothesis driven endeavor towards a more quantitative, high-throughput, discovery/hypothesis based approach reflecting significant advances in instrumentation and computing technology. The universe of biological data emanating from a variety of technologies continues to expand at almost alarming rates. Novel technologies addressing views of the complex biological systems in near molecular resolution have emerged with breakthroughs in the ultra-high throughput DNA sequencing, transcript (mrna) profiling as whole genome biosensors, and protein profiling strategies based in the core technologies of analytical chemistry and mass spectrometry. Emerging, molecule and tissue imaging technologies coupled with the advances being made in nanotechnologies not only provide more data but also provides even higher resolution for visualization and understanding of biological processes. We are now in a world where scientists can examine a biological system at high level of resolution that exceeds their capacity to manually understand the results in supporting or refuting the hypothesis. This welcome metamorphosis is vital if one wants to unravel the complex processes prevalent in living systems in their normal state that govern their growth and development and to understand the consequences when they break down leading to disease. Furthermore, modern biology is very much data driven, so the key challenge involves extracting information and knowledge from the deluge of data emerging from the laboratory and the clinic, so that we can make sense of them. This requires an intellectual fusion of many disciplines that is targeted to addressing problems that will have direct consequences for the well being of our citizens. Our efforts at BII are focused on developing and refining the computational biology tools and techniques in conjunction with experimental collaborations at the national and international stage to meet this challenge. 1299

2 The BII was founded in July 2001 with a goal of generating human, intellectual and industrial capital to support the efforts of ASTAR to develop Singapore as a key biomedical hub in Asia. Its early research focus encompasses a wide spectrum of problems in computational and system biology and is aimed are deploying mathematical and computational techniques to understand a range of problems ranging from efficient multiple-sequence alignment, tools for facilitating evidencebased medicine, modeling metabolic and signaling pathways to collaborative projects with its sister institutes on mass spectrum data management and analysis (GIS and BTI), ditag sequencing (GIS), assembly and annotation of the Fugu Genome (IMCB) etc. Having developed these capabilities, its current research focus is on using our quantitative modeling expertise to address questions at the fundamental and applied level in partnership with researchers within and outside the Biopolis. This includes a Cancer Biology Programme (with IMCB and GIS) initially focused on the control and regulation of the p53 tumor suppressor; a Stem Cell Biology programme (with the MIT Whitehead Institute as part of the Singapore MIT Alliance as well as members of the Singapore Stem Cell Consortium) that is focused on identifying and characterizing epithelial stem cells to understand the nature of stemness ; a Clinical Biomarkers Discovery Programme (as part of a national programme to discover biomarkers for gastric cancer and a international consortium on cancer biomarker discovery led by the Fred Hutichinson Cancer Research Institute in the United States), a Chemoinformatics Programme (in collaboration with IMCB, the National Eye Institute, NUS etc.) that is focused on using computational structural biology to address questions relating to protein-drug interactions and the Cell Interaction Programme that is focused on understanding the role of chemokines/cytokines in the innate immune response. Details of these projects will be provided below. Since its inception, it has been involved in postgraduate training programmes with the National University of Singapore in training bioinformaticians at the Masters level and with the ASTAR/ NUS Graduate Schools in PhD level training. Many of the graduates of these programmes play a significant role in the R&D efforts within and outside the BII Its IT team, in partnership with government and commercial organizations has successfully planned, deployed and managed the construction of state-of-theart Cyber-infrastructure and services to meet the evolving needs of the Biopolis user community. The BII has been a pioneer in Grid Computing in Singapore, especially in its deployment and exploitation in the biomedical context. This includes research on the technology of grid computing, the development of applications that take advantage of the aggregate compute power to attack challenging problems in biomedicine and training the pool of talent to develop and enhance this technology (through a generous grant from the InfoComm Development Authority of Singapore). RESEARCH FOCUS Research at the BII is concentrated mainly in the Center for Computational Biology (CCB). A brief overview of the goals of the five research programmes is as follows. 1300

3 Cancer Biology The research programme of the Cancer Biology group concentrates on modeling the control and regulation of signaling in cancer with an initial focus on tumor suppression by the p53 pathway. The protein p53, as the guardian of the genome, plays a key role in the process of killing cells with damaged DNA that threaten the genetic integrity of an organism. Concurrently, BII s team of Bioinformatics Specialists, in collaboration with various research groups in BII, IMCB and GIS, are creating a comprehensive online knowledgebase to integrate and analyse complex data about p53. The p53 Knowledgebase can be viewed at bii.a-star.edu.sg/. Cell Interaction The Cell Interaction group has taken-up the challenge of building the first onestop Cell Interaction Knowledgebase, an in silico computational platform on immune cell interaction for the local and international immunology community. The Cell Interaction Knowledgebase is designed to expand to manage information on Toll-like receptor (TLR) and NF-κB areas. The TLR acts as sensors of danger signals and the NF-κB acts in the capacity of mediating the innate and adaptive immune response. The Cell Interaction Knowledgebase can be viewed at cell-interaction.bii.a-star.edu.sg. 1301

4 Chemoinformatics The Chemoinformatics group is involved in research related to drug design and discovery. The programme is currently focused on three therapeutically important systems: identification of factors that govern the intricate network of the p53 protein (the guardian of the genome), protein kinases (signalling systems of biology) and design of novel defensins (one class of nature s own antibiotics). The current work lends itself naturally to systemic developments in the future for designed inhibitor effects on different proteins. The objective is to help the group to design inhibitors that specifically target only specific proteins so as to alleviate abnormality but leave normal physiology unperturbed. Clinical Biomarkers Discovery The primary focus of the Clinical Biomarkers Discovery group is to collaborate with the international community in the International Cancer Biomarker Consortium (ICBC). This consortium led by the Fred Hutchinson Cancer Research Institute in Seattle, USA involves teams from Singapore, Korea, Taiwan, China, USA, France, Mexico among others. The goal is to discover biomarkers (validated by clinical collaborators) that are invaluable for their potential discriminatory power in the molecular classification of diseases (diagnosis), in predicting clinical outcomes (prognosis) and response to drugs (therapy). BII will take the lead to build an informatics platform that will integrate data generated by the different institutions involved. 1302

5 Stem Cell Biology The research programme of the Stem Cell Biology group touches on two major areas of focus in Singapore: Stem Cell Biology and Molecular Imaging (and Imaging Informatics). The group is involved in a number of national and international initiatives to address fundamental biological questions such as the nature of stemness, the mechanisms regulating self-renewal, asymmetric division and differentiation, in embryonic and adult stem cells. Concurrently, as part of a national effort, BII s team of Bioinformatics Specialists and Software Engineers, in collaboration with various stem cell biologists from A*STAR research institutes, is creating a comprehensive Stem Cell Knowledgebase, that will serve as a central repository for information on all aspects of embryonic and adult stem cells (i.e. structural, functional, mutation, clinical, imaging data etc). Technology Focus Effective, efficient and timely deployment of Cyber-infrastructure encompassing hardware, software and the bioinformatics expertise to address biomedical challenges is vital to the success of the research projects outlined above as well helping push the frontiers of biomedical research in a number of national and international collaborative projects where the BII is a key player. The concentration 1303

6 of expertise located within the Biocomputing Center (BCC), whose mission is to apply, innovate and provide information technology to enable advances and new discovery in the biomedical sciences for the user community within and beyond the Biopolis. Details of the roles and responsibilities of the various teams within BCC can be found at BII s website. A brief overview of the two key teams, who by working in partnership within and outside the BII help meet the evolving needs of the Biopolis user community, is as follows: Singapore Biomedical Computing Resource The Singapore Biomedical Computing Resource (SBCR) comprises of a team of bioinformatics specialists, with background in both biology and computing, to provide the research and academic communities with bioinformatics consultation, training and resources (data and tools). Working closely with the research and technical groups in BII, the SBCR focuses on project collaboration with research institutes within and beyond the Biopolis. Software Engineering Team The Software Engineering Team is responsible for the development of software infrastructure that leverages on BII s compute, storage and network infrastructure. The group works in collaboration with Scientists from A*STAR research institutes to address their BioIT needs, therefore serving as a bridge between scientists and information technology professionals. The group currently focuses on software needs in Genomics, Proteomics and Bioimaging space. 1304

7 HUMAN CAPITAL DEVELOPMENT The PhD programme is targeted towards providing multi-disciplinary training in areas that fall within the research focus of BII. BII scientists in collaboration with colleagues from its sister research institutes and academics in National University of Singapore or Nanyang Technological University are involved in the joint supervision of the students. All students admitted into the PhD programme must be supported by scholarships through the A*STAR Graduate Academy or schemes supported by the Biomedical Research Council (BMRC). ONGOING COLLABORATIONS & PARTNERSHIPS The Bioinformatics Institute (BII) strongly emphasises joint collaboration with local and international partners to develop strategic scientific projects leveraging on high-end computational technology that will put Singapore at the forefront of biomedical research. Over the past few years, BII has formed extensive networks and partnerships with its sister research institutes within A*STAR, universities, hospitals and research institutions in Singapore, as well as international collaborators such as Whitehead Institute of the Massachusetts Institute of Technology (MIT), Hammersmith Hospital in the Imperial College School of Medicine, the San Diego Supercomputing Center and the Fred Hutchinson Cancer research Insititute. SUMMARY The BII is about five years old and in this short period a lot has been achieved especially in the building up of human and intellectual capital. With its current focus on applying quantitative techniques to real biology problems ranging from Cancer, Stem Cells to understanding the immune system, and with its strong partnership with key national and international players in biomedical research, it is in an exciting position to open new frontiers in biomedicine. We at the BII would like to take this opportunity to express our gratitude to all our collaborators within and outside the Biopolis. Contact Details: Bioinformatics Institute (BII) Address: 30 Biopolis Street, #07-01 Matrix, Singapore hr@bii.a-star.edu.sg 1305