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Then, luck intervened. At a meeting in Greece in 2003, Eisenberg learned that the European Synchrotron Radiation Facility in Grenoble, France, had just launched a new “microfocus” machine that fired a beam of x-rays only 4 micrometers wide—the size of the largest amyloid crystals. By teaming with European scientists, Eisenberg and graduate student Rebecca Nelson got permission to use the new beam line, and in a matter of weeks they had captured the elusive atomic structure.
Published in 2005, the research confirmed in fine detail that amyloid fibrils contain a cross-beta “spine” made of short amino acid chains along which beta sheets assemble, forming a lengthening fiber as more units are added. The surprise was that side chains emanating from the sheets interact closely with each other like the teeth of a zipper, locking the sheets tightly in place.
“That was the ‘aha!' moment,” Eisenberg recalls. “That's what causes molecules to form the fibers.” Moreover, this so-called “steric zipper” seals the interface between sheets so that water is excluded, explaining why amyloid is so persistent and insoluble in tissues.
This landmark finding was a jumping-off point for Eisenberg. In a 2007 Nature paper, he reported the discovery of similar cross-beta spines in amyloid-forming segments of 30 disease-related proteins, including the amyloid beta and tau proteins that make up the characteristic plaques and tangles in the brains of people with Alzheimer's disease. Toxic fibrils formed by human islet amyloid polypeptide are found in the pancreas of most patients with type 2 diabetes, but their atomic structure wasn't known until Eisenberg reported it in September 2008 in Protein Science.
While much remains to be learned about the role of amyloid fibers in disease, the information gained from their atomic structure has already led to work in Eisenberg's lab on potential clinical applications. His group is designing molecular caps, for example, to attach to the ends of amyloid fibers. “It is conceivable that capping the end of a fiber might stop it from lengthening and help to break it down,” he explains.
The pursuit of amyloid and potential human therapies marks a departure for a scientist at age 69 whose body of work has leaned away from medicine (in 1969 he published the definitive book on the properties of ice and water). It's a career move he thinks would have pleased his father.
“He was a doctor and always wanted me to go into medicine,” Eisenberg says. “I thought it was about time I did something that had medical applications.”