Stephen Harrison’s program at Harvard revealed how HIV changes shape to enter a host cell and Tom Steitz at Yale studied the virus’s enzyme reverse transcriptase.

“The 1980s were a time when a lot of the technologies that are now the backbone of structural biology and crystallography were introduced,” says Johann Deisenhofer, an HHMI alumnus at the University of Texas Southwestern Medical Center. By the middle of the decade, three developments had pushed crystallography into its heyday. The first was the recombinant DNA revolution. Genetic research had finally made it possible to clone DNA and make ample amounts of any protein. “It was a wonderful moment because we recognized that we were going to be liberated from the constraint of working on proteins that happened to be very abundant,” says Stephen Harrison, an HHMI investigator at Harvard Medical School.

The second advance was the availability of computers that could handle the complex algorithms that turned a diffraction pattern into a molecular map. It became possible to do scientific computations that were unthinkable in Kendrew’s day.

“Right now, we are at the point where the techniques have become almost perfect.”

Johann Deisenhofer

Third, and perhaps most significant, was the availability of a powerful new source of x-rays: the synchrotron. These massive machines fling subatomic particles faster and faster around a huge ring—about the size of a football field—until they approach the speed of light. The powerful radiation emitted by these flying bits of matter can produce x-rays about a thousand times stronger than the ones created in the average laboratory, allowing scientists to speed up their data collection by as much as 100-fold. “This was very important because it turned out in the long run that a lot of our laboratory-based x-ray facilities were not good enough for the job,” says Deisenhofer.

Breaking the Barrier

By 1985, nearly 200 protein structures had been solved, almost all of them by using crystallography. Despite this incredible progress, the field was stalling. The technology was there, but it was elaborate, expensive, hard to use, and often inaccessible.

In a 1985 report to the Board of Trustees, HHMI President Donald Fredrickson wrote, “Soon the access to [the technologies] and the paucity of persons trained to use them will be the critical barrier to continued progress in cell biology.”

The situation prompted Fredrickson to assemble a committee to determine what the Institute could do to break through this barrier. Davies and seven other structural biology experts met in Boston on a Saturday in early March. They spent the day evaluating the state of structural biology and deliberating about how HHMI could support its development. The final verdict: The Institute should create several structural biology laboratories at research hospitals and medical schools around the United States, each associated with an existing HHMI “unit.” Each of the new laboratories would have 1 or 2 principal investigators and a team of 6 to 10 associates, all funded by HHMI. The cost of purchasing and maintaining all the necessary equipment—computers, microscopes, x-ray generators—would be covered. The intention was to make the resources available to HHMI investigators and other scientists at the universities as a way to bolster the field as a whole.

The Trustees supported the scientific leadership’s decision, allocating about $25 million initially and promising $60 million over the next five years. Structural biology became the fifth major area of research for HHMI, joining cell biology and regulation, genetics, immunology, and neuroscience. Despite the prevalence of x-ray crystallography, the new program also committed to supporting emerging technologies such as electron and optical microscopy, magnetic resonance imaging, and nuclear magnetic resonance (NMR).

“Crystallography wasn’t the only tool in the world, but it was the dominant tool,” says Purdue University’s Michael Rossmann, who was then a member of HHMI’s Scientific Review Board. “The labs that were funded were fairly solid crystallographic labs, but many of them have blossomed out to using other tools as they became available.”

Eight scientists at six institutions were selected for the program: David Agard and John Sedat at the University of California, San Francisco (UCSF); Stephen Harrison and the late Don Wiley at Harvard University; Wayne Hendrickson at Columbia University; Florante Quiocho at Baylor College of Medicine; Stephen Sprang at the University of Texas Southwestern Medical Center; and Thomas Steitz at Yale University.

HHMI also agreed to support the creation of a protein crystallography facility at the National Synchrotron Light Source at Brookhaven National Laboratory. More scientists would now have access to a high-intensity x-ray source (see sidebar, “Accelerating Discovery”).

		Accelerating Discovery HHMI invested in a synchrotron beamline to speed protein crystallography. Read More

A Torrent of Findings

The initiative worked and had a cumulative effect.

“Yale already had a center for structural biology that included five senior investigators studying diverse problems,” says Steitz. “HHMI provided technical support, technicians, equipment, and soon there were about a hundred postdocs and students who were using the Yale facility.”

Photos: Harrison: Paul Fetters; Steitz: Brian Ach / AP, ©HHMI

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