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Topping what is already the best and brightest is hard, but that’s just what researchers at St. Jude Children’s Research Hospital have done. For several years, St. Jude investigators have been tapping into X-ray crystallography—the process of using high-powered X-ray beams to probe protein crystals and reveal their secrets—but the process was hampered by limited technology. Until recently, St. Jude scientists only had two moderately powerful X-ray crystallography machines they could use. Collecting the data was laborious and time consuming, and the resulting image quality was limited.
More than 100,000 kinds of proteins exist in the human body, from those in the hair and skin and muscles to ones that aid in digestion. Some proteins fight infection, while others speed up important chemical reactions. “Most diseases occur when things go wrong with proteins,” says Stephen White, DPhil, Structural Biology chair. Consequently, understanding what these proteins do is crucial to advancing medical research.
That is where high-powered X-ray technology comes into play. The Advanced Photon Source (APS), located at the Argonne National Laboratory in Chicago, Illinois, is a place where St. Jude structural biologists can collect data on proteins in minutes instead of days. APS is the only such center in the United States, and only the third center of its caliber in the world. The facility is so large that a professional sports arena could fit inside it. And size does matter. While the complex is huge, the crystals the scientists are concerned with are unbelievably small and fragile.
“It’s difficult to appreciate just how many atoms there are in a crystal,” White says. “A crystal is less than a millimeter in size. One way to think about it is that if the typical distance between atoms were a centimeter, then one crystal would fit on top of Memphis.”
However, while the crystal itself is miniscule, the macromolecular structure that holds the key information is extremely large at the atomic level. Only a super-powerful radiation beam can determine that structure with clarity. And it is the atomic structure of the macromolecules of protein or DNA complexes that scientists really want to see.
Scientists have solved part of that problem by forcing the macromolecules to crystallize—a time-consuming process—so that the structures can more easily be handled. However, unlike the strong crystals school children create with sugar or salt, protein crystals are delicate, “like cubes of jelly—very small and just as fragile,” White explains.
The sheer size of the task is why advances at APS are such a big deal. Freed from limitations of time, space and quality, scientists can get nearly instant results that are much richer in data quality and magnitude. But it gets even better. For the past few years, St. Jude researchers have had to take the crystals to Chicago, load them and personally run the equipment to yield the desired results. Now, permanent staff in place at APS can process crystals that have been shipped overnight from St. Jude. In the past few weeks, St. Jude scientists have even acquired the ability to sit at their computers in Memphis and manipulate the crystal remotely by computer.
The Argonne laboratory, which was created and is maintained by the Department of Energy through the efforts of the University of Chicago, is a fantastic resource for St. Jude. The hospital is a founding member of the Southeast Regional Collaborative Access Team, otherwise known as SER-CAT, and White is the board’s Tennessee representative.
SER-CAT includes 24 other members from such prestigious organizations as the National Institutes of Health, the National Aeronautics and Space Administration, Wyeth Pharmaceuticals, Georgia Tech Research Corp. and a host of top-notch universities and medical centers. The new facility offers one of the world’s most sophisticated X-ray capabilities to macromolecular crystallographers and structural biologists. Instead of having access to one beamline, or super-X-ray tract, St. Jude now has access to two such beamlines. This is significant because the second beamline only recently became operational, and the amount of X-ray time available to St. Jude scientists has doubled. With the hospital’s participation in the SER-CAT consortium, beamline access is guaranteed, which allows time-sensitive St. Jude research to proceed without delay.
The hospital’s new department of Chemical Biology and Therapeutics will have an increasing need for structural information, so the enhanced access will be beneficial to them as well. “Rapid access to crystal structures of inhibitors bound to their target proteins is crucial for drug discovery,” says Kip Guy, PhD, the department’s chair. “Without access to a facility like the APS though SER-CAT, we would be severely hampered in optimizing inhibitors.”
APS has become one of the most productive facilities in the world, with government, industry and medicine sharing its resources. St. Jude continues to stand on the threshold of tomorrow, looking for ways to understand the diseases of children and prevent the suffering of other kids. SER-CAT and the Advanced Photon Source at the Argonne National Laboratory are making that hope a reality.
Reprinted from Promise magazine, autumn 2006.
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