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The Scripps Research Institute/Genomics Institute for the Novartis Research Foundation
University of California, San Diego/San Diego Supercomputer Center
Stanford University/Stanford Synchrotron Radiation Laboratory

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Robin B. Goldsmith
858-784-8134
The Scripps Research Institute
Office of Communications
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David Hart
858-534-8314
dhart@sdsc.edu

Kim McDonald
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kimmcdonald@ucsd.edu

P.A. Moore
650-926-2605
xanadu@slac.stanford.edu

New Genomic Center Funded To Advance HighThroughput Protein Structure Determination

La Jolla and Stanford, Calif., September 26, 2000 -- To deliver on the promise of the genome project for health care, scientists must understand the information implicit in the genome, specifically, the functions of the proteins encoded by the genes. The Joint Center for Structural Genomics (JCSG), a consortium of California scientific research organizations, has received a National Institutes of Health (NIH) grant of $24 million over a five-year period to expand on the body of knowledge made available by the completion of the human and other genome sequencing projects. Its goal is to determine the three-dimensional structure of up to 2000 proteins by developing state-of-the-art high-throughput technology, thereby advancing efforts to understand structure-function relationships important for diseases and their treatments.

The main organizations comprising the JCSG consortium are: The Scripps Research Institute (TSRI)/ Genomics Institute for the Novartis Research Foundation (GNF); University of California, San Diego (UCSD)/San Diego Supercomputer Center (SDSC); and Stanford University/Stanford Synchrotron Radiation Laboratory (SSRL, a Division of the Stanford Linear Accelerator Center, SLAC). Associated with the JCSG are also 29 scientific collaborators from other institutions around the world, including The Salk Institute and Syrrx Inc. in La Jolla.

Principal investigator Ian Wilson, D.Phil., Professor, Department of Molecular Biology and The Skaggs Institute for Chemical Biology at TSRI, said, "This initiative in structural genomics is the next step beyond the sequencing of the human and other genomes and an opportunity to gain a more profound understanding of how individual proteins work in the body. The consortium represents a close synergy between academic and research institutions, along with their biotechnology partners, combining their expertise in a large-scale effort with enormous potential benefits." Co-principal investigator of the Center is John Wooley, Ph.D., Associate Vice Chancellor, Research, UCSD. Dr. Wooley and other senior investigators at UCSD will direct the bioinformatics component for JCSG. Said Dr. Wooley, "Today biology is a data-driven science and bioinformatics is the sine qua non of modern biology. Data emerging from this project will provide us comprehensive knowledge in atomic detail of the molecular machines that drive cellular processes."

There are five major steps in high-throughput protein structure determination:

  • Selection of the best protein targets
  • Expression and purification of proteins
  • Crystallization of proteins
  • Collection of x-ray diffraction data
  • Structure determination at high resolution

The primary aim of the JCSG is to develop and integrate high-throughput robotic technologies for these steps, ultimately providing us with key insights about biological function. Automating each step is JCSG's goal for its contribution to the NIH target of 10,000 protein structures in ten years. "Structural genomics has the potential to impact contemporary biology in a significant way by building on the foundation of the sequencing genome projects," Wilson said. For rapid, efficient, cost- effective determination of novel protein structures through advances in experimental and computational methods, JCSG has established three collaborative teams. The bioinformatics team directs target selection, informatics, and validation; the crystallomics team is responsible for production of protein samples and crystallization; the structure determination team orchestrates x-ray data collection and analysis, structure determination, and refinement.

The initial focus of the JCSG will be on the complete worm (C. elegans) genome and its 18,000 genes to provide a suitable number of targets to optimize each component of the system. The JCSG's target selection committee is chaired by Susan Taylor, Ph.D., Professor of Chemistry and Biochemistry at UCSD and HHMI Investigator. "We will focus on proteins implicated in cell signaling information transmission within and between cells," she said, "because these provide clues to many aspects of disease. Using C. elegans signaling proteins as templates, JCSG will investigate genetically related proteins in fruitfly (Drosophila), mouse and human. Bioinformatics will be essential to identify the most promising targets and ascertain genetically related proteins among the various organisms.

For protein expression, purification and crystallization, JCSG will use breakthrough robotic technologies pioneered by Peter Schultz and Raymond Stevens at the Genomics Institute of the Novartis Research Foundation, Lawrence Berkeley National Laboratory and Syrrx, Inc. JCSG will also incorporate SSRL's novel technologies for synchrotron-based data collection and structure solution. Similarly, JCSG will develop new structural bioinformatics methods, exploiting SDSC cutting edge research in the Biology WorkBench, the Protein Data Bank, the Storage Resource Broker and other informatics activities. In addition to improving and integrating these technologies, JCSG will construct new systems resulting in a complete, highly automated "pipeline" within a knowledge-based feedback system.

A key enabling technology for the high-throughput structure determination component is the combination of synchrotron x-rays and robotic crystal mounting being developed at SSRL and the Advanced Light Source (ALS), Berkeley. According to Keith Hodgson, Ph.D., Professor and Director of SSRL, " Synchrotron-based macromolecular crystallography has revolutionized our ability to determine structures with much higher quality and at a much faster rate than before. It is a particular privilege and honor that SSRL will be one of the key partners in the JCSG. SSRL was the site of the first pioneering protein crystallography experiments in the mid-to-late seventies, and we look forward to helping the JCSG reach its goal of high-throughput structure determination as a means to remarkable discoveries in the biological and biomedical sciences."

The JCSG will build on the foundation its members and collaborators have already laid in high- throughput protein expression, purification, crystallization and crystallographic data collection and analysis. According to Wilson, "We expect to refine essential tools and develop new ones; such progress is imperative for the successful operation of a second-generation structural genomics center that can exploit the tremendous opportunities in structural biology and medicine that arise from the sequencing of the human genome."

Genes are the blueprint, whereas the proteins they encode are the workers, the molecular machinery, in all living organisms. They digest food; provide us with energy; allow the blood to carry oxygen; fight infections; enable us to think, reason and speak; and perform many other critical activities. A protein's function depends on the exquisitely fine details of its structure and shape -- the grooves, ridges, and pockets on or near its surface. By studying thousands of molecules in this project, researchers will deepen their understanding of how protein structure and function are interrelated. Scientists will better understand how each protein functions normally, and how defective proteins malfunction and cause disease. Ultimately, this knowledge will lead to new diagnostic techniques and therapeutics.

The JCSG is funded by the National Institutes of General Medical Science (NIGMS,), one of the main supporters of basic biomedical research within the National Institutes of Health (NIH). NIGMS is funding seven such projects throughout the U.S.; the Joint Center for Structural Genomics is one of three such centers in the Western U.S. NIGMS anticipates spending a total of $140 to $175 million over five years. According to NIGMS Director, Marvin Cassman, "This project can be viewed as an inventory of all the protein structure families that exist in nature. We expect that this effort will yield major biological findings that will shed light on health and disease." Preliminary results laying the foundation for the centers were supported by the NIH, the National Science Foundation (NSF), the Department of Energy Office of Biological and Environmental Research (DOE-BER), the Genomics Institute for the Novartis Research Foundation and Syrrx Inc. Hodgson noted " All seven new centers will use synchrotron radiation, an essential component of these technologies made available only because of the sustained funding provided by DOE and NSF in operating these user facilities."

URLs for further information:
Joint Center for Structural Genomics: http://www.jcsg.org
The Scripps Research Institute: http://www.scripps.edu
The University of California San Diego: http://www.ucsd.edu
San Diego Supercomputer Center: http://www.sdsc
Stanford Synchrotron Radiation Laboratory: http://www-ssrl.slac.stanford.edu
National Institutes of General Medical Sciences: http://www.nigms.nih.gov


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