Cancer Biology, Medicine and Translational Research
St. Jude Children's Research Hospital
Dr. Sherr is also Herrick Foundation Chair in the Department of Genetics and Tumor Cell Biology at St. Jude Children's Research Hospital.
Charles Sherr studies tumor-suppressor genes that counter uncontrolled cell proliferation in response to mutagenic oncogenic insults. A tumor-suppressor network dominated by the retinoblastoma protein (Rb), p53, and the Ink4-Arf locus may have evolved to limit stem cell self-renewal and maintain tissue homeostasis. This concept explains why three chromosomally linked and coregulated tumor-suppressor genes (Ink4a, Ink4b, and Arf) are conserved in mammals, despite their frequent codeletion in cancers.
When Charles Sherr was a postdoctoral fellow in the 1970s at the National Cancer Institute, scientists didn’t know why some viruses can make cells grow uncontrollably and form tumors. Sherr and others hypothesized that these cancer-causing viruses contained oncogenes—or cancer genes—that, after infecting cells, caused them to proliferate wildly.
But in 1975, Sherr received an auspicious invitation. Cancer researcher Harold Varmus, then at the University of California, San Francisco, invited Sherr to talk about his research. While visiting, Sherr had an opportunity to look at the laboratory notebooks in the Varmus laboratory. “It was clear to me when I looked at the data that their work revealed the future of cancer research,” Sherr says.
Varmus and his colleague J. Michael Bishop, who would later share the Nobel Prize in Physiology or Medicine in 1989 for their oncogene research, had found that oncogenes are not viral genes. Instead, they are mutated genes that viruses had picked up from a host cell’s DNA upon infection. The protein products of the normal counterparts of oncogenes, Bishop and Varmus revealed, control healthy growth and division of cells. But when these genes are mutated by chemicals or other environmental insults and inappropriately expressed, they become oncogenes and cause cancer.
Sherr took what he learned from Varmus and Bishop and changed his research strategy. He focused on oncogenes and how their normal counterparts control growth. Since then, he and others have found dozens of growth regulatory genes, which today clinicians widely use in the diagnosis and targeted treatments of different cancers.
The application of research findings to medicine is gratifying to Sherr, who was one of the first M.D./Ph.D.s to graduate from the New York University School of Medicine’s combined degree program. “I was trained by great people at N.Y.U.” Sherr says. “The program was inspired by Lewis Thomas, who was a philosopher-scientist. I was surrounded by brilliant faculty and was being constantly stimulated. They treated us [the M.D./Ph.D. students] like the crème de la crème. We were being groomed to do medical science, although at the time we (and probably they) didn't know what that meant precisely.”
Clearly, Sherr figured it out. Among his many contributions during his more than 30 years as a scientist has been identifying key proteins that regulate how cells grow and divide. His studies of oncogenes led him to identify additional novel enzymes—so called cyclin-dependent kinases or CDKs, for short—that drive cell division. In turn, further investigation of these enzymes led to the discovery of CDK inhibitors that antagonize cell proliferation and can suppress tumor development. The major targets of this regulatory network are the retinoblastoma protein (RB) and p53, which are very important, because mutations in their signaling pathways are essential in provoking cancer, Sherr says.
When cell division pathways fail, proteins that normally spur proliferation make the cell divide even more, and those that normally put the brakes on division lose their potency. RB and p53 are called tumor suppressors, meaning they normally prevent growth of damaged cells. But if the genes that code for RB or p53 become altered, suppression stops, injured cells grow, and a tumor results.
Sherr has found that three genes that regulate p53 and RB are also vitally important for governing normal cellular growth. The genes—Ink4a, Ink4b, and Arf—sit near each other on the same chromosome. Cancer cells often eliminate all three of them at once as a tumor progresses, making the cancer more virulent.
Why nature has placed these genes, which are easily lost during cancer, so close together is a major research question for Sherr. ”I think the genes’ location provides an evolutionary advantage to multicellular animals by regulating stem cell activity,” Sherr says. During development and throughout adult life, rare stem cells divide and replenish normal tissues that would otherwise wear out as we age. But to maintain this capacity throughout our lifetime, stem cells must also regenerate themselves. Sherr suggests that the proximity of the three tumor suppressor genes allows them to be switched on and off together. The three genes can be shut off when stem cells self-renew, but the genes can be turned on when stem cells give rise to more specialized cells, thereby preventing these from continuously dividing.
Besides studying the RB and p53 pathways, Sherr actively investigates new treatments for blood-borne cancers, such as leukemias, in his laboratory at St. Jude Children’s Research Hospital. Understanding how the Rb and p53 genes act in these cancers has helped clarify the need for new drugs for these diseases, he says, Up until the late 1990s, Sherr collaborated in all his research with his wife, Martine Roussel. They still work together, but she focuses on cancer neurobiology and medulloblastoma, the most common malignant brain tumor in children.
Sherr says he maintains his enthusiasm for research by collaborating with young scientists, engaging with them at scientific meetings, and keeping his mind open for new ideas, just as he did as a postdoctoral fellow. “You need to talk to people constantly and hear the latest in the field to keep being a creative and productive scientist,” Sherr says. “The new ideas don’t simply arise from your own brain de novo. You synthesize what you hear from many others and then hopefully come up with a new twist and maybe a great experiment. You need to connect the dots.”