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One man’s war on cancer

Yigong Shi received his undergraduate degrees in biology and mathematics from Tsingha University, Beijing. He received his Ph.D. in molecular biophysics from the Johns Hopkins University School of Medicine, Baltimore. Awards he has received include the Paul Ehrlich Research Award in Basic Science (Johns Hopkins School of Medicine), the Rita Allen Scholar Award (Rita Allen Foundation, New York), the Searle Scholar Award (Chicago Community Trust), and the Wilson S. Stone Memorial Award (University of Texas M. D. Anderson Cancer Center).

Ambition has been defined as the immemorial weakness of the strong (1). For many who possess this quality, once a target is in sight, the ensuing pursuit is conducted with a zeal that is unswerving in the quest for success. They overcome daunting obstacles, frequently with spectacular results.

Yigong Shi is an ambitious man. His passion? The search for cancer cures. He got off to an ambitious start, graduating with a double major in biology and mathematics and highest honors in 1989 from Tsingha University in Beijing. He moved to the United States and completed his Ph.D. studies in the Intercampus Program in Molecular Biophysics and the Department of Biophysics and Biophysical Chemistry at the Johns Hopkins University School of Medicine, Baltimore.

His thesis adviser at Hopkins, Jeremy Berg, remembers when the young man first arrived in his lab in 1990. “His English was not great, but typical of Yigong, he set a goal to build up his vocabulary. He learned 25 new words a day. He just did it.”

Berg adds, “He’s a very strange combination of being incredibly driven and being very modest and insecure in a nice sort of way.” For example, Berg describes an update he received from Shi. Shi had had a year that would have been a source of pride to many scientists, but he fretted about not getting enough done that year. Perhaps this was because he published “only” four papers instead of six. “He sets very ambitious goals for himself, but it’s not ambition in a personal way. He doesn’t want to become famous—he sees there are things to be done, and he wants to get them done.”

Berg comments about Shi’s time in his lab: “It’s not an exaggeration to say that both the [amount of] work done—and the actual results—were 50% Yigong and 50% the other [11] people in the lab. It wasn’t that these weren’t good people, but he’d always have four to five projects going on at the same time.” Frequently, when Berg made a suggestion to Shi, rather than ponder it for a while, he would simply show up in a couple of weeks with what would be several months of work for someone else. Chuckling, Berg adds, “The only scary part about that, is that he could burn through an entire year’s worth of funding in about a month!”

After Shi completed his Ph.D. in 1995, he spent 2 years as a postdoctoral fellow in the Structural Biology Laboratory of Tumor Suppressors and Oncogenes at the Memorial Sloan-Kettering Cancer Center in New York. In February 1998, he became an assistant professor in the Department of Molecular Biology at Princeton University. In just under 4 years, Shi has been unanimously voted to the rank of associate professor—a tenured position—and published an astonishing 16 papers.

Work in progress
Shi explains that cancer is really a disease of cell immortality. Cancer cells continue to grow regardless of their environment and are “resistant” to death. In contrast, most normal cells are regulated by a process called apoptosis, or programmed cell death. When there is something wrong with normal cells, they will die “peacefully”.

“Why don’t cancer cells die of apoptosis?” asks Shi. “Part of the answer may be that cancer cells express a family of proteins called inhibitor of apoptosis-proteins or IAPs. As the name suggests, IAPs suppress apoptosis by inhibiting the ‘executioners’ of cell death: a family of special proteases called caspases. So one potential strategy in treating cancer is to find a drug that can antagonize IAP.”

Shi’s team has found such a prototypical drug. In May 2000, the team discovered that a natural human protein called Smac or DIABLO contains a seven-amino-acid sequence that can remove the inhibition of apoptosis (Smac, second mitochondria-derived activator of caspases; DIABLO, direct IAP-binding protein with low pI—the pH value at zero net protein charge). Then, in August 2000, they discovered that the effective peptide can be reduced from seven amino acids to four. This four-residue peptide sequence has since been discovered in several other natural proteins. In each case, its role is to promote cell death.

“If this four-acid sequence (Ala-Val-Pro-Ile) can promote cell death, then it should be able to facilitate the killing of cancer cells. Indeed, in collaboration with Xiaodong Wang at the University of Texas Southwestern Medical Center, Dallas, we showed that this peptide can facilitate the killing of cancer cells in the laboratory,” says Shi.

Peptides are generally not good drugs because they are degraded rapidly by proteases. How can the degradation be slowed or stopped? “The reason that this tetrapeptide can help kill cells is because it occupies a binding pocket on IAPs,” explains Shi. “Thus the best idea is to find something else to occupy this pocket—something that is resistant to protease and binds this pocket even more strongly.”

Shi summarizes his major research contributions in the box “Apoptosis and TGFβ signaling”.

Multidisciplinary teamwork
Shi finds that the study of cancer poses a huge intellectual challenge. At the same time, he is quite irritated that society has not been able to conquer this disease. “I just cannot tolerate that, after many decades of cancer research, we are still unable to make a bigger impact in terms of treating it. This is very frustrating. It’s almost as if the more we learn, the more we realize what we don’t know,” he says. However, by inching closer to the goal with some exciting discoveries, he remains hopeful and optimistic.

He attributes his success in part to a multidisciplinary approach. “Each cancer is complex and different. We really need to combine many approaches, and this is one of the hallmarks of my laboratory.” He explains that although a genetic strategy can identify genes that are responsible for causing cancer, once the gene is identified, the genetic approach has only a limited benefit in the subsequent steps. Cellular and molecular biology methods, which characterize how the gene works in cancer cells, are similarly limited. He uses structural biology, which allows researchers to understand how the protein product of a gene works and how it is regulated in atomic detail. “But this approach also has its own limitation because we are merely visualizing the 3-D image. We can interpret this image, but to take advantage of this image and to design drugs, we actually need a chemical approach that allows for drug screening and design.”

Shi points out that he has an equal number of chemistry and biology students in his lab. He calls this a layered approach. “They complement each other with their expertise. It also enriches the environment of the lab. And we are close to the next practical target, which is to uncover a drug. The chemical approach will determine what kind of drug we should be looking for.” This may be good news for millions of people around the world who suffer from any of the more than 100 forms of cancer.

George McLendon, chair of the chemistry department at Princeton, says “Yigong is a world leader—despite his tender age—in the exploding field of apoptosis.” McLendon points out that the controlled cell death is critical to normal development. For example, the webs between embryonic human fingers are destroyed selectively during the development process. He adds that it is equally critical that “rogue” cells such as cancer cells be eliminated for the good of the whole [organism], and that at a deep level, all cancers can be considered as failures of the apoptosis pathway.

“Given his passionate interest in the chemistry and biology of cancer, Yigong set out to provide a fundamental structural understanding, at the atomic level afforded by X-ray crystallography, of the protein interactions which control this pathway,” says McLendon. Step by step, in a masterful series of papers published in journals such as Nature, Cell, and Science, Shi has defined the way in which the “executioner” proteases are activated; and most recently, he has defined the atomic basis for the interaction of IAPs with these proteases, which appear central to the survival of some drug-resistant tumors (see the box, “Yigong Shi’s significant publications”).

McLendon concludes, “His structure of the Smac–IAP complex has profound implications for drug design. In short, he is brilliant, creative, and possibly the single most energetic human I have encountered. Cancer research is entering a period of great ferment as the genome project merges with structural understanding and rational drug design. Yigong is one of the world leaders in this effort.”

Reference

1. Sackville-West, V. No Signposts in the Sea; Doubleday: New York, 1961; quoted in Maggio, R. The New Beacon Book of Quotations by Women; Beacon Press: Boston, 1996, p 25.

Sandra Phinney (s.phinney@ns.sympatico.ca) is a freelance writer based in Yarmouth, Nova Scotia, Canada.