Undergraduate researcher Brian Reilly prepares liquid nitrogen at MacCHESS for an X-ray crystal diffraction experiment. Reilly, a senior biology major, is investigating the growth of the protein Concanavilin A under Dan Thiel, assistant professor of biochemistry, molecular and cell biology

Much of what is known about the way a protein folds is based on the three-dimensional arrangement of atoms as revealed by a scientific technique called X-ray diffraction crystallography. A decade ago obtaining such an image of the molecule's crystal structure took three years. Today, fast-imaging techniques produce an image in a matter of hours.

This stunning advance in technology is due largely to research at a Cornell facility whose name sounds like an instant board game: MacCHESS. In fact, the acronym stands for Macromolecular Diffraction Facility at the Cornell High Energy Synchrotron Source (CHESS). Since its founding in the early 1980s, MacCHESS has earned a global reputation for pioneering biological research into X-ray diffraction crystallography. This technique produces images of molecular structures by blasting them with intense bursts of X-rays.

"Understanding the three-dimensional structure of molecules is some of the most important science going on from many points of view," says MacCHESS Director Steven Ealick, who also is a professor of chemistry and chemical biology. Adds Associate Director Dan Thiel, assistant professor of biochemistry, molecular and cell biology: "It is such a competitive process to do research here, based strictly on the quality of the science, that the great majority of crystallographers donÔt even apply." Indeed, users liken MacCHESS to a select research club.

Select indeed. MacCHESS is one of only five such facilities in the United States and just 12 in the world. Not that the lab is particularly glamorous, in fact it is downright pokey, consisting of labyrinthine passages snaking around the CHESS accelerator and leading to three closet-like, lead-lined "hutches" where frozen crystals, the size of grains of salt, are pounded by 25 kiloelectronvolts of radiation produced by the accelerator. The scattering patterns from the diffraction are captured by highly sensitive light-gathering semiconductors called charge-coupled devices, and images emerge on the computer screen as patterns of lines and circles.

Much of the labÔs research over the years has been in the field of structural biology, aimed at understanding protein structures with the goal of creating new drugs (HIV protease inhibitors developed for anti-AIDS drugs is one example). Increasingly though, a new buzz phrase has crept into research at MacCHESS: "structural genomics," or the study of proteins encoded by an entire genome.

The proteinÔs structure tells researchers much about its function, which drug companies need to know in order to identify genes that are associated with disease. The fundamental question being asked at the lab today is "how do you inhibit the protein or produce drugs that can affect it?" Ealick explains: "The ultimate goal is to be able to take a sequence, generate the three-dimensional structure and determine its chemical function."

At the heart of much of this research lies the protein-folding problem, of which, Ealick notes, "we donÔt even fully understand the rules." Researchers estimate that about one-third of all protein folds in the human genome probably are experimentally known. "The guess is that there are about 1,000 unique folds and that all proteins are made from a combination of these," says Ealick.

Eventually, he believes, a national protein database will contain all the folds. But MacCHESS researchers are confident that the only way this is going to be achieved is experimentally. Says Thiel: "The only way you can get real atomic detail and exact, precise positioning is by X-ray crystallography. Computational methods simply can't approach this accuracy."