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Bert Vogelstein, M.D. "What do you think of my shoes?" asks Bert Vogelstein, as he leans forward to hike up the cuff of his jeans. Vogelstein's sneakers are covered with paint and they look like he might have worn them while slapping a second coat on his wrought-iron porch railings. "They used to be white," he says of his footwear, "but I painted them black." Why? "They're my dress shoes," he says with a smirk. But the spray-painted sneakers say more about Vogelstein than the fact that he has trouble finding dress shoes that fit. An accomplished cancer biologist at the Johns Hopkins University School of Medicine, Vogelstein is playful, unconventional, and likes to do things his own way. He reads research journals to relax. He orders tomatoes over the Internet and once went on an "all-carrot-cake" diet. He is fiercely competitive when it comes to sports—his lab holds annual basketball and tennis tournaments—yet he appears to have no ego when it comes to science. Perhaps that's because Vogelstein and his colleagues have chosen to devote their intellect and energies to finding ways to beat cancer. "It's amazing how much someone can accomplish if he doesn't care who gets the credit," says Vogelstein. And with lives at stake, he says, "who does the work and who gets the credit are such minor issues." Vogelstein's interest in cancer stretches back to his childhood. "I knew I wanted to work on cancer by the time I was 13 or 14," he says. "I don't know why. Maybe it was the challenge. Or maybe because I knew it was a horrible disease." Most likely he read about it in a book. Vogelstein skipped most of his middle school classes and instead spent three years reading his way through the local library. "I just didn't like school," he says. And because he was enrolled in a private institution, Vogelstein says, "they didn't take attendance. As long as you paid, they were happy." When he hit high school, Vogelstein says he "actually paid attention." And he found himself drawn to science and math. Indeed, math was so "challenging and exciting" that Vogelstein decided to major in the subject as an undergraduate at the University of Pennsylvania. He even considered getting a Ph.D. in mathematics, but in the end Vogelstein opted to go to medical school so that he could focus on problems in human health. He enrolled at Johns Hopkins University, where he has remained ever since. For a world-renowned researcher, Vogelstein has stuck close to his native Baltimore. "I was born across the street," he says, pointing out his office window. A bit further away are his high school and the house he grew up in. "I'm at the center of my world," he chuckles, surveying the neighborhood. Indeed, Vogelstein can almost always be found within shouting distance of his office—either in the lab, at home, or on the racquetball courts at the local gym, where he frequently runs into the mayor. Vogelstein began his career in the clinic, but two things drew him to the laboratory. First was a desire to be able to make sense of cancer. One of his earliest patients was a four-year-old girl with leukemia. Vogelstein was frustrated by how little was known about the disease. "Her father asked good questions, but no one knew the answers," he says. "And how can we hope to do any good if we don't understand anything about the disease?" That lack of understanding drove Vogelstein toward experimental research. "I realized that I needed to ask questions and to try to answer them through experiments," he says. At the same time, Vogelstein discovered that he enjoyed working at the bench. "I just couldn't wait to get to the lab," he says. "I liked the fact that you could do things that hadn't been done before. You could be as creative as you wanted to be. "I decided that if I wanted to do research, I wanted to give it my best shot," he says. "I wanted to continue to interact with patients, but I decided I couldn't be their physician." So Vogelstein established a laboratory at Hopkins and focused his attention on discovering the genes that cause cancer in humans. He chose colon cancer as a model in part because colorectal tumors can be easily removed for analysis. In particular, Vogelstein hoped to find evidence that colon cancers can be caused by the loss of a tumor suppressor, a gene that in normal cells acts as a molecular brake to control growth and division. At the time, tumor suppressors were "mythical beasts," says Vogelstein. Although several researchers had proposed that such growth-inhibiting genes exist, he says, "no one had ever seen one in the flesh." With defective molecular brakes, a cancer cell could divide without restraint, forming the tumors that are the first step on the road to full-blown cancer. Vogelstein imagined that tumor suppressors might be involved in human cancers because cancer cells frequently contain chromosomes that are broken or missing large chunks. These deleted regions, Vogelstein thought, are likely to harbor the tumor suppressor genes that normally restrict cell growth. Vogelstein started his search on chromosome 17, looking at genes that are located in a section of the chromosome that is frequently missing in cells from colorectal tumors. And he hit on p53, a gene named after the weight of its protein product. But Vogelstein thought it was the wrong gene. Other researchers were already studying p53, he says, and they all thought that p53 was an oncogene—a type of gene that gets switched on in cancers, not shut off. So Vogelstein kept looking—and kept coming up with p53. So he decided to put p53 to the test. If the gene really were a tumor suppressor, both of its copies—one inherited from mother, the other from father—would have to be turned off before a tumor would grow. Eliminating only one copy would leave cells with one functional "brake"—enough to allow them to keep their growth in check. In most cancer cells, one copy of p53 is missing—because the section of chromosome 17 on which it resides has been lost. If p53 were a true tumor suppressor, Vogelstein figured, the remaining copy in those cells would contain a mutation that inactivates it. The gene passed the test. Vogelstein collected cells from a tumor in which one copy of the p53 gene was lost. He found that the remaining copy harbored a single mutation. "Initially we thought this single mutation might not be important," he says. But the mutation was never found in people who were cancer free, and Vogelstein and his colleagues found similar mutations in every colorectal tumor they tested. Further, they subsequently found that p53 is involved not only in colon cancers but in most types of human cancer, suggesting that the gene might be a sort of common denominator for human cancers in general. After nailing p53, Vogelstein joined forces with Ken Kinzler, who started out as a graduate student in Vogelstein's lab and is now a full professor. Working together, these researchers and their colleagues have identified several other genes that are responsible for the development of colon cancer and other cancers. Today, Vogelstein and Kinzler preside over a sprawling laboratory that bustles with the activity of three young faculty members and twenty-odd trainees. Although Vogelstein still manages to squeeze in a few hours at the bench each day, he spends most of his time interacting with people in the lab, offering advice and providing them with the guidance and support they need to tackle cancer. "We've tried to craft an environment," says Vogelstein, "where people can focus on the important things—trying to help people who have cancer and trying to prevent others from getting it."
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