Investigative Instincts Guided Vogelstein's Journey of Discovery

Published: Friday, Sep 12, 2014

Bert Vogelstein, MD

Bert Vogelstein had no idea that a young girl would start him on a journey that would forever change humanity’s understanding of cancer. He was an intern fresh out of medical school when the girl’s parents brought their daughter to Johns Hopkins to find out why she’d grown so pale and started bruising so easily. The tests revealed cancer. When Vogelstein delivered the news to the stunned parents, they asked how and why a preteen could develop cancer.

Decades later, Vogelstein can still remember how terrible it was to be unable to provide an answer. “I just threw up my hands and said, ‘I don’t know. Nobody knows. It’s just this total black box, this thing that just strikes people randomly, when they shouldn’t be struck.’ And, right then and there, it became clear to me that if I wanted to spend my life on a puzzle, on a problem that I could apply my skills toward, that was going to be a good one,” he recalled.

Vogelstein’s epiphany launched a lifelong hunt for the root causes of cancer, a hunt that unveiled in 1989 the most important cancer suppressor gene, and went on to unearth much of what we know about the mutations found in many tumor types.

Vogelstein has published more than 450 papers since 1976, and those papers have been cited more than 200,000 times—a tally that illustrates their incredible impact. Vogelstein’s work not only launched a wave of genetic research around the globe, but also helped lay the groundwork for today’s era of targeted assays and therapeutics.

Choosing a Path

Vogelstein was born in Baltimore, Maryland, in 1949 and raised in the city, which then, as now, saw much of its scholarly life dominated by the various arms of Johns Hopkins University.

He came from a long line of rabbis, starting with his grandfather and going back 13 generations. His father, however, was a lawyer, as were many other men in his family, and, law—not medicine—was what appealed to Vogelstein in grade school. It wasn’t until high school that he developed a love of science and mathematics that determined the course of his life.

He left Baltimore after high school for the University of Pennsylvania in Philadelphia, majoring in math and graduating summa cum laude. (He also, perhaps to appease his rabbinical ancestors, won the school’s Rosenbaum Award for undergraduate work in Semitic languages and literature.)

After briefly pursuing graduate studies in mathematics, Vogelstein felt called upon to pursue a career path that would help others more directly. Vogelstein returned to Baltimore to study medicine at Johns Hopkins, receiving his medical degree in 1974 and remaining at Johns Hopkins for his internship and pediatrics residency. He was serving that residency, wondering what he wanted to do with his professional life, when he diagnosed that little girl’s cancer and struggled to explain it to her parents.

He soon undertook a postdoctoral fellowship at the National Cancer Institute, where he learned the basic principles of molecular biology, and then returned to Johns Hopkins, where he has remained ever since.

“I still had to decide whether I should continue to see patients and practice medicine, or devote all of my energies to research, so I tried doing both,” he said. “I found myself during the days seeing patients and during the nights going to the lab and trying to do a little bit of research. And I found at night I was really happy. I felt stimulated. I couldn’t wait to get to the lab at night so I could start experiments.”

The Tumor Suppressor Gene Theory

Vogelstein’s is one of the great careers in medical research—and it nearly ended before it began. The first two grant proposals he ever submitted to the National Institutes of Health (NIH) were rejected.

“I was getting really worried, because there’s only a limited time you can go in science without getting funded, or else you’re going to be driving a cab or something,” he said. But once money began flowing into his lab, Vogelstein focused his attention on colon cancer. He amassed a large collection of tissue samples at each step in the progression from fully healthy to malignant carcinoma, and found that colon cancer, rather than developing uniquely in each patient, went through similar genetic steps in many patients.

In a 1988 article published in The New England Journal of Medicine (NEJM), Vogelstein posited that the progression required two different types of genetic mutations: (1) the activation of oncogenes (such as the Ras gene that had already been identified); and (2) the inactivation of tumor suppressors.

The existence of tumor suppressors— genes that prevent cells from multiplying too quickly—had always struck Vogelstein as logical, particularly in light of the observation that tumor cells were almost always missing specific chunks of DNA that were present in normal cells.

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