Life After the Human Genome Project: TSRI Researchers Spearhead Protein Structure Initiative
By Mika Ono
The human genome has been sequenced. Now what? According to The Scripps Research Institute (TSRI) Molecular Biology Professor Ian Wilson, one of the next steps is to focus on the proteins the genes code forto find what these proteins look like and what they do.
Right now there is no way to look at most amino acid sequences [determined by a gene] and tell what the protein looks like, comments Wilson. "To be able to do this would represent an important advance in our understanding."
The National Institutes of Health (NIH) seems to agree. Under the auspices of The National Institute of General Medical Sciences, the NIH recently launched a nationwide initiative on protein structure determination, with an emphasis on developing high-throughput technology that could one day support efforts to find and catalog the structures of all proteins active in the human body. In 2000, the NIH awarded roughly $30 million for the first year to seven centersone of which is headed by Wilson.
One of the first tasks of the centers will be to organize all known proteins into structural ("fold") families based on their genetic sequences. The centers will then determine the structure of one or more proteins from each family. The stated goal of the NIH is to determine 10,000 new protein structures in 10 years, forming the backbone of a public resource linking information on sequence, structure, and function.
A New Way of Doing Science
According to Wilson, the NIH Protein Structure Initiative is a dramatic departure from science as usual.
"The ambitious goals of the project have led us into new territory," he says. "To my knowledge, this is the first time the NIH has funded technology centers instead of hypothesis-driven research, like RO1s. But the logic goes that over the long term, the new high-throughput technologies will help drive discoveries."
The large scope of the project also has implications for the way research is organized. "This kind of project encourages multi-institutional collaborations," Wilson comments. "This is a different way of doing scienceand a different way of competingbut one I believe we'll be seeing increasingly in the future."
Wilson's group, dubbed the Joint Center for Structural Genomics, draws on talent from several top-notch California institutions, both public and private. The main players are: TSRI, The Genomics Institute of the Novartis Research Foundation (GNF), University of California at San Diego (UCSD), and the Stanford Synchrontron Radiation Laboratory (SSRL, a Division of the Stanford Linear Accelerator Center, SLAC) at Stanford University.
More than 60 researchers are involved in the consortium, which also includes collaborators from around the world and from other local institutions, such as the Salk Institute. Other TSRI scientists affiliated with the project include: Ruben Abagyan, Geoffrey Chang, Jack Johnson, Peter Schultz, and Ray Stevens.
The group will receive $24 million over five years (funds that are in addition to, not instead of, those supporting more traditional NIH projects).
"Spread among multiple institutions over five years, the amount isn't as significant as it first seems," comments Wilson. "But we're still in the pilot stage of the NIH initiative. To me, the important thing is to be involved from the beginning."
Division of Labor
The initial focus of Wilson's consortium will be on the nematode, C. elegans. The group has divided the responsibilities for developing technology and determining protein structure into three areas, reflected organizationally in three core groups.
The bioinformatics core is headed by Adam Godzik of UCSD. UCSD and Howard Hughes Medical Institute Professor Susan Taylor will be responsible for target selection. The focus will be on the large group of proteins implicated in cell signaling (information transmission within and between cells), which may provide clues to many aspects of disease. Bioinformatics, the study of the inherent structure of biological information and biological systems, will help identify the most promising targets and ascertain related proteins in the fruit fly, mouse, human, and yeast. The handling, manipulation, analysis, and storage of the vast amounts of data will be carried out by the Bioinformatics Core.
The crystallomics core, led by Stevens, will focus on sequences specified by the target selection committee, expressing, purifying, and crystallizing these proteins. Using technology initially developed by Schultz and Stevens at the Lawrence Berkeley National Laboratory and more recently at GNF, the crystallomics group will utilize a high-throughput robotic production line that can produce thousands of samples of purified proteins per year and perform over a hundred thousand crystallization screens a day. This group will then deliver crystals to the structure determination core.
The structure determination core, led by Peter Kuhn, assistant professor and Macromolecular Crystallography Group co-leader at the SSRL, will handle high-throughput structure determination and refinement. The SSRL, which provides synchrotron radiation (x-rays or light produced by electrons circulating in a storage ring at nearly the speed of light) to bombard the crystals and obtain diffraction data, will provide the group with a powerful resource for structure determination.
Wilson comments, "As we progress through the project, we will be generating enormous amounts of information. We plan to record all our results, negative as well as positive. Scientists who come later will know what didn't work for us as well as what did."
Five years hence, those involved in the Joint Center for Structural Genomics hope to have solved 2,000 protein structures, be prepared for the design and implementation of the nextgeneration of high-throughput technology, andperhaps most importantlyhave created the infrastructure to significantly advance our understanding of some fundamental principals of biology.
"Administering a multi-institutional collaboration has its challenges," comments Wilson, "But in this case it also offers a unique opportunity: to integrate biophysics in La Jolla Mesa."
Administering a multi-institutional collaboration has its challenges. But in this case it also offers a unique opportunity: to integrate biophysics in La Jolla Mesa.