base at Brookhaven National Laboratory, and sequences are stored at Georgetown University and the National Institutes of Health. There are about 1200 three-dimensional structures in the Brookhaven data base, and Georgetown and NIH have a combined total of about 60,000 different sequences. "We used those data bases in our research," says Eisenberg. "We started with the structure of lysozyme, and computed a three-dimensional profile, and we were able to find all the sequences in the sequence data base which are compatible with the lysozyme structure."

But so far this method has had its own limitations and failures. A coiled coil that Eisenberg had predicted should be a dimer turned out to be a trimer. And Alber says, "Our finding that the shape of an amino acid makes a difference to the structure suggests that something is missing from his calculations, because he doesn't consider shape at all."

"It's not that his method is wrong," Alber hastens to add. "It's just not fully developed." Will the two methods eventually merge somehow in a way that will generate general principles, much as theoretical physicists hope to combine the four forces into a grand unifying theory?

The best answer that either researcher could give was Alber's response that on occasion his predictions agree with Eisenberg's. For example, in the case of one coiled coil sequence, both methods correctly predicted a trimer. This weak response suggests that both methodologies remain embryonic.

APPLICATIONS: A CANCER DIAGNOSTIC

While a grand unified theory of protein folding is probably years in the future, the basic research is already yielding useful developments. So far, most of them involve research methods, but Alber and Ray White, of the University of Utah, are working on a diagnostic system for colon cancer.

White and Bert Vogelstein, of Johns Hopkins University, had discovered mutations in the so-called APC gene. That gene is present in many people who have colon cancer. The mutations truncate the APC protein but leave a coiled coil intact. One of White's first-year graduate student advisees at Utah who had been working with him brought Alber and White together. Now Alber is designing a coiled coil to be used in the diagnostic system.

The diagnostic would work as follows. Doctors would take cells from patients' colons, use laboratory techniques to separate the proteins by size, and label APC proteins using Alber's coiled coil—radioactively tagged—as a hook. These would then be analyzed to see if truncated APC proteins were present.



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