The grant, from the National Institutes of Health, provides funds for the Midwest Center for Structural Genomics, a large-scale center of the Protein Structure Initiative headed by Argonne's Andrezej Joachimiak, principal investigator on the project. With this funding, Argonne researchers, in collaboration with biologists from around the world, will expand the information available to researchers for biomedically important proteins from humans and pathogens.
The key to understanding a protein is being able to see it. Proteins, because they are so small, can only be seen using intense X-ray sources, such as the Advanced Photon Source at Argonne. Using X-rays to produce an image of protein is often called "determining the structure" of the protein. The researchers are refining existing methods for structure determination, making a process that used to take years into an automated pipeline that can be completed in weeks. The automated process allows structure determination that used to cost more than $500,000 per structure to now be accomplished for less than $50,000. The process is now producing more than 250 protein structures each year. Ultimately, the project seeks to determine the structures of enough proteins that the structures of any new ones could be computed on the basis of structures already known.
"The project in structural genomics is a complex one, combining the fields of biology, computer science and physics to do that work," said Bob Rosner, Argonne director. "Biologists are finding new ways to quickly copy proteins for analysis; computer scientists are developing faster computers and computer programs to deal with the massive amounts of data and provide computer models of the information; and physicists have developed what is called a third generation synchrotron which provides the world's most brilliant X-rays to aid in research." That third generation synchrotron at Argonne, the Advanced Photon Source, is one of only three such machines in the world, and the only one in the Western Hemisphere.
Researchers using the Advanced Photon Source have so far determined nearly 300 different three-dimensional protein structures and contributed the images and information to the International Protein Data Bank, which provides them to researchers worldwide, who use the structures both to identify diseases and to create formulas for medicines to prevent or cure the diseases. The structures have ranged from anthrax to SARS.
The new effort will involve cloning and expressing genes and gene fragments of from microbes, plants, animals and humans; purifying and crystallizing the proteins; collecting the data; and analyzing the structures.
"The near-term goal is to provide the technological basis for rapid determination of the remaining fundamental protein structures – a concept made possible by the emerging comprehensive genomic data and the data generation capacity of third-generation synchrotrons and advances in computer science and technology," explained Lee Makowski, director of Argonne's Biosciences Division. "Achieving this goal requires enhancement of all the methods involved in protein production, crystal growth, structure determination, and structural model generation and refinement. This approach will have broad and long-lasting importance to much biomedical research as well as for its immediate goal of facilitating the development of the new discipline known as structural genomics. We plan to solve quickly large number of 'easy" targets, and in the process we will develop new, more advanced tools, methods and approaches that can be applied to unsolved and more difficult projects."
The grant, for $52,720,000 over five years, is one of ten announced today by the NIH. With the announcement, the Protein Structure Initiative launches the second phase of its national effort to find the three-dimensional shapes of a wide range of proteins. This structural information will help reveal the roles that proteins play in health and disease and will help point the way to designing new medicines.
"Illinois is at the center of a vibrant Midwest life sciences region because of the state's unparalleled research institutions, including the nation's first national laboratory, Argonne," said Gov. Rod R. Blagojevich. "This grant from the NIH will help pave the way for future discoveries and innovations in bioscience and continue to showcase Illinois as a leader in cutting edge scientific research."
The State of Illinois' long term support of Argonne National Laboratory has proven to help leverage critical federal dollars over the last 20 years. The Advanced Photon Source (APS), which the state supported with a $20 million investment, has provided groundbreaking research in structural genomics and was an instrumental component in landing this NIH grant for the Protein Structure Initiative. This partnership continues to advance the State of Illinois as a leader in biotechnology and nanotechnology in a variety of other critical research projects at Argonne. The state has invested more than $60 million for the Center for Nanoscale Materials, Advanced Protein Crystallization Facility, Ricketts Regional Biocontainment Laboratory and helping to land the $1 billion Rare Isotope Accelerator, one of the nation's premier science and technology projects.
Selection of the NIH centers, slated to receive about $300 million over the next five years, marks the second half of the decade-long initiative funded largely by the National Institute of General Medical Sciences, part of the National Institutes of Health.
When the PSI established its pilot centers beginning in 2000, its goal was twofold: to develop innovative approaches and tools, such as robotic instruments, that streamline and speed many steps of generating protein structures, and to incorporate those new methods into pipelines that turn DNA sequence information into protein structures.
Now, the focus shifts to a production phase during which the new centers will use methods developed during the pilot period to rapidly determine thousands of protein structures found in organisms ranging from bacteria to humans. These efforts will facilitate structure determination on a much larger number of proteins through computer modeling.
"The PSI has transformed protein structure determination into a highly automated process, making it possible to go from a selected target to a completed structure much more rapidly than before," said Jeremy M. Berg, Ph.D., director of NIGMS. "Building on these achievements, the new centers will take the PSI to the next level, yielding large numbers of structures and tackling significant new challenges. Importantly, the technology developed as part of the PSI will continue to impact structural studies beyond the PSI."
The PSI production phase includes two types of centers. Four large-scale centers, established during the pilot phase, expect to generate between 3,000 and 4,000 structures. Six specialized centers will develop novel methods for quickly determining the structures of proteins that traditionally have been difficult to study. These include small protein complexes; proteins that attach to a cell's outer envelope, or membrane; and many proteins from higher organisms, including humans.
"We've already made great technological strides that have enabled us to determine more than 1,300 protein structures during the first half of the PSI, and we expect the large-scale centers to extend this progress," said John Norvell, Ph.D., PSI director. "But the fact remains that some proteins are not amenable to high-throughput approaches."
The project will involve four key elements:
Gene Cloning and Expression: The researchers will implement proven methodologies, and develop new ones, for automated and rapid parallel gene cloning, gene alteration and expression using a liquid handling robot system, and develop refinements to increase robotic capabilities.
Protein Production: The researchers will develop automated systems for protein purification, planning one single process stream from cell growth to protein concentration and characterization.
Crystal Production and Delivery: The researchers will use robotic instrumentation for large-scale multi-sample screening crystallization; introduce new methods to efficiently monitor crystal growth; and develop new cryofreezing procedures for protein crystals.
Structure Determination and Refinement: The researchers will improve quality control in the data collection and analysis and increase the speed of structure determination using parallel approaches and a multiprocessor computer environment.
Other members of the Midwest Center for Structural Genomics, in addition to Argonne, are the European Bioinformatics Institute, Northwestern University, University College London, University of Texas, University of Virginia and Washington University.