Genomics Research Center: Current Status & Future Development

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1 Genomics Research Center: Current Status & Future Development Introduction Research in the life sciences has entered a new era after completion of the human genome project and the sequencing of the genomes of other species. The challenge that now lies ahead is to understand the functions of genes and apply that knowledge to the development of new technologies and medicines. Academia Sinica is making great efforts to integrate domestic and international resources to foster innovative scientific research in areas related to genomics and proteomics. The Genomics Research Center (GRC) is expected to become a center of excellence for genomic research and education. Through the process of using breakthrough discoveries and inventions in the commercial realm, the Center has established a biotechnology incubator to advance the development of biotechnology and pharmaceutical industry in Taiwan. The GRC research programs consist of five major areas: Functional Genomics, Chemical Biology, Cellular and Molecular Medicine, Bioinformatics, and Key Technology Development. There is also one additional unit, the Incubation Center for pursuing technology transfer and collaboration with peer institutions. To support these research programs, Academia Sinica has established several national genomic core facilities including mouse mutagenesis and disease models, genotyping, microarrays, mass spectrometry and proteomics, X-ray and NMR for structural genomics, MRI, and bioinformatics. Current Research Programs In addition to conducting their own research programs, our fellows and specialists also participate in the International Graduate Programs at Academia Sinica and engage in the research and teaching activities in universities through joint appointment or collaboration. A major mission of the GRC is to transfer new discoveries to commercial opportunities to help create a strong biotechnology and pharmaceutical industry in Taiwan. The following briefly describes current research programs at the GRC. Functional Genomics This Division is coordinated by Dr. Ming-Daw Tsai. Major efforts are directed toward identification and validation of important targets associated with cancer and infectious diseases and development of new methods and strategies to study the 75

2 function of these targets at the molecular level. Using state-of-the-art mass spectrometry, NMR, and X-ray crystallography as well as other genomic and proteomic tools, the structures and functions of targeted proteins, especially membrane proteins, glycoproteins and intracellular proteins involved in cell cycle and signaling will be studied. A major program on proteomics and structural biology has been established under the leadership of Dr. Andrew Wang. It is hoped that novel therapeutic strategies will be developed through this research. Chemical Biology This Division is currently coordinated by Dr. Chi-Huey Wong with major emphasis on the development of chemical and biological approaches to solve problems in living systems. Current research interests include mechanism-based and structure-based drug discoveries and development of high-throughput systems to facilitate the process, design of new molecular probes for imaging and proteomic analysis, nano- and microfabrication for high-throughput analysis, and development of new reactions and methods of interest to functional study and drug discoveries. A high-throughput laboratory and a P3 laboratory have been established to facilitate the drug discovery research. Dr. Edmond Cheng is responsible for these two core facilities. Cellular and Molecular Medicine This Division, led by Dr. Alice Yu, aims to bridge the gap between laboratory research and clinical medicine, with an ultimate goal of developing new therapeutics based on small molecules, biologics, and cell-based approaches. Current research interests include cell cycle regulation and receptor-mediated signaling in cancer and stem cells, and in the immune system, development of disease models in vitro and in 76

3 vivo, identification of molecular signature of cancer, and implementation of protocols for preclinical and clinical investigations. The stem-cell research program, directed by Dr. John Yu, is currently focused on the mechanistic study of differentiation and plasticity and development of embryonic stem cells and therapeutic cloning. Bioinformatics This Division is currently led by Dr. Wen-Hsiung Li. The aim is to pursue functional and evolutionary genomics as well as structural informatics, using a combination of tools and resources from bioinformatics, computer sciences, statistics, molecular biology, biochemistry, genetics and evolution. It focuses on development of methods for alignment of genomic sequences, identification of gene regulation pathways, study of yeast protein interaction net work, structure-based molecular modeling and design, and prediction of pharmacology. A long-term goal is to develop computational models for use in understanding cellular functions and other biomedical applications. Key Technology Development This Division is currently led by Dr. Chung-Hsuan Chen and aims to develop new tools with improved sensitivity and resolution for use in studying the dynamics of complex biological systems. Current interests include development of biomolecular mass spectrometry, microarray and nanotechnology for genomic and proteomic research, development of optical device and single cell research, fabrication of biological and biomimetic materials and development of functional supramolecular structures. 77

4 Incubation Center This Incubation Center is led by Dr. Chi-Ming Liang. The objective is to utilize the scientific strength, international connections, and resources of Academia Sinica to help start-up companies in the Center to develop new medicines and new tools and by their combining efforts facilitating the flourishment of biotechnology industry in Taiwan. The goal of the Incubation Center is to assist the growth of start-up companies engaging in business development to commercialize biotechnology and pharmaceutical products. Highlights of Significant Achievements In the past two years, the GRC has focused its efforts on recruiting and infrastructure development. More than 20 research faculty members have been on board to work on various aspects of genome-related problems, using state-of-the-art core facilities. The Incubation Center has recruited three companies to develop new tools and new medicines. The following are highlights of GRC s recent achievements. Research on the emerging SARS epidemic The GRC has made important contributions in the SARS epidemic which has brought a great deal of global concern since A proteomic study was conducted using plasma samples from patients with SARS to explore the possible pathogenesis of this disease. The work, directed by Dr. Jenn-Han Chen of National Defense Medical Center, and Drs. Yu-Ju Chen and Chi-Huey Wong of Institute of Chemistry and the Genomics Research Center at Academia Sinica, was published in Proceedings of the National Academy of Sciences, U.S.A. (Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 17039). The study was started first by separating plasma proteins from 40 patients and some normal individuals, respectively, using two-dimensional gel electrophoresis 78

5 followed by mass spectrometry identification of differential expressed proteins. The results showed that 38 proteins were altered more than 2-fold compared to those of normal controls, and the functions of these proteins were found to be associated with acute phase response, antioxidation, transportation, and protease-related reactions. Several proteins were identified for the first time, among which an antioxidant, peroxiredoxin II (also called Natural Killer Enhancing Factor-B), was secreted by T cells and found to correlate with hemolysis. This work demonstrates that active innate immune response along with oxidation-associated injuries may play a major role in the pathogenesis of SARS. It provides a new direction for the development of diagnosis and therapy for the disease. A cell-based assay was also developed to screen existing drugs, natural products, and synthetic compounds to identify effective anti-sars agents. Of >10,000 agents tested, approximately 50 compounds were found active at 10 microm; among these compounds, two are existing drugs and several are in clinical development. Additional studies were carried out to further understand the mode of action of some active compounds, including ELISA, Western blot analysis, immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are two anti-hiv agents, one as an entry blocker and the other as a 3CL protease inhibitor (Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 10012). The protease inhibitor is also an effective inhibitor of HIV and FIV(Feline Immuno-deficiency Virus) proteases and having passed animal trials, is now ready for IND filing. 79

6 New technology development for drug discovery Researchers headed by Drs. Chun-Hung Lin and Chi-Huey Wong at the Institute of Biological Chemistry and Genomics Research Center developed a novel way of finding extremely potent enzyme inhibitors. The picomolar inhibitors discovered in this study against fucosidase represents the most powerful glycosidase inhibitor known to date. The method paves the way for drug discovery in a rapid and high-throughput manner. The rapid diversity-oriented synthesis was carried out in microtiter plates followed by enzyme activity assay in situ without any protecting group manipulation and purification. Therefore, the screening was conducted at a minimized cost. The resulting inhibitors were highly specific and showed limited or no inhibition against similar enzymes. The research team at Academia Sinica has developed at least five reactions to screen potential inhibitors for drug discovery (Angew. Chew. Int. Ed. 2003, 42, 4661; Chem. Biol. 2004, 11, 1301; J. Med. Chem. 2005, 48, 4469). Novel natural product discovery Researchers headed by Dr. Hsien-Yeh Hsu (at the Institute of Biotechnology in Medicine, National Yang-Ming University) and Drs. Shui-Tien Chen, Chun-Hung Lin and Chi-Huey Wong (at the Institute of Biological Chemistry and Genomics Research Center, Academia Sinica) unraveled the mode of action of Reishi (Ganoderma lucidium, Ling-Zhi) polysaccharides. They isolated the active component of Reishi polysaccharides that stimulate cytokine expression, and identified toll- 80

7 like receptor 4 (TLR4) as one of the receptors. Various immune cells (including macrophages, B-cells, dendritic cells and stem cells) were also found to be activated by the active component of Reishi polysaccharides. This study may lead to the development of new therapeutic agents from Reishi (J. lmmunol. 2004, 173, 5989; Bioorg. Med. Chem. 2004, 12, 5595 and 5603). New development in bioinformatics A group of researchers led by Dr. Trees-Juen Chuang from Genomics Research Center of Academia Sinica have developed a new algorithm, PSEP (Progressive Signal Extracting and Patching), which utilizes cross-species approach to identify gene structures and alternatively spliced (AS) variants. It has a much higher accuracy in genome annotation than most other well-known cross-species gene prediction programs, including the ROSETTA program, TWINSCAN, SGP-1/-2, and SLAM. In addition, with PSEP s dual functions in cross-species conserved sequence analysis and AS analysis, PSEP is highly suitable for studying the evolution of AS patterns and for finding unidentified gene expression features (Bioinformatics 2004, 20, 3064). Chi-Huey Wong Genomics Research Center, Academia Sinica 81