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As a young boy in China, Yigong Shi was introduced to mathematics by his father. A mechanical engineering professor, Shi's father had spent the Cultural Revolution working in the countryside, making little use of his technical and professional skills. When the Revolution ended in 1976, "all of a sudden my father found his old skills in mathematics and physics useful again," says Shi.
 | | | | |  |  | | | | | |  | Yigong Shi, Ph.D.
Photo: Christopher Barth/AP, ©HHMI
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Shi's father enthusiastically introduced his children to basic math, writing out equations on the ground in chalk. "Even in first grade, I saw those funny letters he would write—x, y, z, π, and the others—and they were fascinating," he says. "I was heavily influenced by that."
So it should come as no surprise that Shi planned to become a professor of math or physics. Then an admissions officer from Tsinghua University told Shi he was making a mistake. "He said the 21st century was going to be the century of biology," remembers Shi. "And even better, he said the newly established department of biology was headed by a professor from the United States." That professor, Mu-ming Poo, was also a neuroscientist at New York's Columbia University at that time. Shi was impressed.
"Many students like myself really longed for a Western-style education," says Shi. "We wanted to go abroad, [to] have a link with the Western world. Knowing that the biology department was headed by a U.S. professor meant a lot." So Shi entered Tsinghua University as a biology major, although he continued to study math at the same time.
During his career as a structural biologist, Shi has drawn on both math and biology to help him understand the physical structures of proteins, the large molecules that carry out most of the critical functions inside cells. "If you're a car mechanic, you need to understand what all the parts look like to understand how the engine runs," says Shi. "Likewise, you have to know the structural details of proteins to understand how they work inside a cell."
Classical structural biology relies on a technique called x-ray crystallography, a means of mapping the location of every atom in a protein by analyzing how it scatters a beam of x-rays. And to be sure, Shi has mastered this skill. But x-ray crystallography yields only the basic framework of a protein; it doesn't explain how that protein works inside a cell. So Shi has learned a suite of other biochemical techniques to probe how proteins behave. "We use just about any technique to attack the problem we're looking at," says Shi. "It's a need-based approach."
When Shi set up his lab at Princeton University in 1998, he decided to focus these tools on proteins involved with apoptosis, or programmed cell death. The process is triggered in cells that are no longer needed, or when damage has occurred that is too severe to be repaired. At the time, interest in apoptosis was soaring because researchers had begun to realize that the process goes haywire in cancer and other diseases. So Shi diligently solved the structures of dozens of key proteins involved in apoptosis and learned how some of these proteins interact with each other.
One such finding launched a whole new area of cancer drug development. The discovery, which was made in collaboration with another HHMI investigator, Xiaodong Wang at the University of Texas Southwestern Medical Center at Dallas, suggests a way to restore apoptosis in cancer cells. In normal cells, when mutations or other forms of cell stress accumulate, apoptosis destroys the cell. But in many cancer cells, apoptosis stops working, thus giving the cell the potential to proliferate. In early 2000, Australian scientists reported that a protein called Smac/DIABLO can stimulate apoptosis. Shi and Wang discovered that the front end of Smac/DIABLO, a tiny fragment only four amino acids long, will trigger apoptosis by itself. "You don't need the whole protein," says Shi. "You only need the business end, this little stretch of it."
The discovery, published in 2000, led to frantic competition among pharmaceutical companies to design drugs to mimic Smac/DIABLO. Shi cofounded a company, TetraLogic, that had the same goal. Late last year, the first of these drugs, made by Genentech, entered human trials. "If I could help save a few patients' lives, or prolong their lives, that would be much more gratifying than publishing a few Science papers," Shi says.
With much of the machinery of apoptosis now well understood—thanks in large part to Shi's efforts—he has begun studying other cellular processes. In particular, he's intrigued with integral membrane proteins that have important biological functions, especially those that might play a role in Alzheimer's disease. "This is our next major challenge," says Shi. "There are many classes of membrane proteins that are completely mysterious."
For the past three years, Shi has been spending time at his alma mater in China, building the university's biological sciences program. He's recruiting faculty from the West and teaching seminars to students.
"I've come full circle, I guess," says Shi, referring to how Mu-ming Poo first drew him to Tsinghua University. "I'm a firm believer that science is without borders. Whether a basic science discovery is made in China or the U.S. makes little difference in the end."
Yigong Shi is the Warner-Lambert Parke-Davis Professor of Molecular Biology at Princeton University. He received his B.S. in biology and mathematics at Tsinghua University in China and his Ph.D. in biophysics at the Johns Hopkins University School of Medicine. He is the recipient of an Irving Sigal Young Investigator Award from the Protein Society, a Searle Scholar Award, and a Rita Allen Scholar Award.
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Jennifer Michalowski
