Computation and Systems Biology (CSB)

Tissue Systems Biology (TSB) is a biology-based research programme whose goals are to study complex molecular problems at the tissue level and from a systems biology perspective. The broad biology goals are to identify key developmental processes of a tissue and the response of a tissue to infection in a living animal. A fundamental requirement of tissue-level studies is to identify, quantify, and manipulate processes at the molecular level within live tissues. TSB will employ state-of-art approaches in genomics and proteomics, and develop new technologies in computation and imaging. These studies should identify emergent properties of cells within the context of tissue systems and thus provide information about the properties and responses of cells to infectious and pharmacological agents. This expectation is destined to answer important and medically-relevant questions in biology, to develop important and long-lasting molecular, cellular, and tissue-related technologies, and to create significant intellectual property.

The TSB Flagship research programme focuses on the development and function of endoderm-derived tissues. On the one hand, the embryonic endoderm generates the epithelial lining of the lung, swim bladder, gut, pancreas, and liver. However, the function of the epithelium requires interactions with the embryonic mesenchyme to develop the underlying connective tissue, hematopoetic cells, muscle, and cartilage. Stem cells in the adult tissue regenerate the epithelium. For example, infection of the lung leads to turn-over of the epithelium. The gut is regenerated from stem cells in the crypts. The role of microRNAs in the development of mesenchyme stem cells and maintenance of mesenchymal tissue is unknown. Studies on the stem cells, mesenchyme, and microRNAs are complementary to studies on lung infection, swim bladder ontogeny, and endoderm differentiation.

A distinguishing feature of TSB is the interlocking relationships among programmes in the InterUniversity and Flagship research projects. In general, a Flagship project will collaborate with several IU projects in the application of advanced technologies to a tissue-level systems biology problem. Both efforts will be supported by technologies developed in the computing and imaging core facilities at MIT, NUS, and NTU. For example, imaging technologies developed by the IR microscope IU team and the core imaging resource facilities will be applied in the endoderm development, tissue defense, and microRNA TSB Flagship research projects. Data from these studies will be compiled, organized, processed, analyzed, and modeled by the computing IU and Flagship projects. The integration between groups and projects is designed to maximize interactions and resources across programs. Individual IU and Flagship research projects will be selected and awarded from a pool of internally submitted project proposals. These proposals will serve as the basis for budgetary decisions and resource allocations. In following years, pilot research projects will help identify new courses for the SMA/CSB PhD curriculum, potential faculty candidates among the SMA graduate students, and newly developed advanced technologies for application in the Flagship research programme.

The Flagship programme will study the systems biology of tissues for the purpose of developing systems-level genetic, proteomic, and mechanical models that predict outcomes from perturbation caused by mutations, drugs, and infectious agents. A particular focus is to describe molecular processes in live tissues on a genome-wide scale. The tissue biology of zebrafish will serve as a platform for understanding basic biological processes of vertebrate animals. Specific problems will be studied by focused projects in fish and mice. We have identified for study two interlocking system-level problems in tissue biology:

(*) Stem Cell-to-Tissue Development—the development of endoderm and mesenchyme tissues from stem cells in zebrafish and mice

(*) Tissue Defense Against Infection—infection and immunity of engineered endoderm-derived tissues by the influenza virus

In addition, technology pilot projects will investigate new statistical approaches for evaluating data, novel chemical probes for deep tissue imaging, and the mechanical properties of cell and tissues.

Other projects, possibly in collaboration with local Singapore industry, are an imaging-based high-content screening of tissues for drug discovery, new infectious disease and cancer models, and computational modeling of molecular networks in tissues. Flagship research projects will have a three-year duration. A competition for Pilot Flagship projects will identify new opportunities in this rapidly moving field.

Inter-University Programmes -- Systems biology problems require new technologies. The InterUniversity (IU) programme will fund the development of advanced technologies in key areas of computational biology, mechanics, and imaging. These technology areas apply concepts and examples taught in the SMA/CSB PhD courses. The technology areas will devote initial efforts to bring state-of-art tools to TSB researchers and then to develop new tools as TSB problems are better defined through the partnership among universities, institutes, and industry. The IU projects are organized into two broad areas, computation and engineering measurement. The computation projects are devoted to the problems associated with storing and organizing large data sets, statistically evaluating the quality of data, faster data processing algorithms, and integrating information from disparate types of data. The engineering measurement projects range from advanced biological probes capable of molecular detection in tissues to novel infrared imaging technologies for whole body imaging. The IU projects are chosen from submitted research proposals from MIT/Singapore teams. Each project will be two-three years in duration and renewable upon a competitive application.

Industry -- Systems biology is the fastest growing area in biology, bioengineering, and biotechnology with the creation of large, multi-investigator, multi-institution, and multi-disciplinary NIH-funded programs at academic institutions across the United States. We foresee that this will also be the trend in Singapore.

In addition to the academic interest, systems biology is also an area of great commercial potential. High enthusiasm from industry is reflectedin a strong endorsement of the SMA/CSB programme from our industry partners who are world-class leaders in their sectors. Through their participation they recognize the value of the MIT CSBi Programme and its preeminent status in systems biology and computation. Singapore-based companies, such as IBM, Lilly and Novartis, all cited their interest including SMA/CSB PhD students in their future workforce. In addition, there is considerable interest by these companies to host SMA/CSB PhD students as summer interns.

In addition to the students, the companies are also interested in the technological aspects of the programme, with a focus on imaging and image informatics technologies. Imaging is the basis for the next wave of innovation in drug discover and image-based technologies represent an emerging technology platform in the pharmaceutical industry. For that reason, imaging has been identified as the next technology driver in the business plans of computer companies including EMC, IBM, Hitachi, and SGI. Discussions are underway with several companies to develop substantial collaborations with the CSB/SMA research programmme and many of these companies have expressed an interest in a multi-partner industry collaboration.