In 1949, cancer researcher Bert Vogelstein was born at the Johns Hopkins Hospital—just two blocks from where he works today. When asked why he became interested in science, Vogelstein replies, “How could anyone not be?” With an inherent interest in science, he was intrigued by a pamphlet he received in the mail from Johns Hopkins University at age 14 about what physicians do, what kind of education they get, and how they serve society. That inspired him to consider medicine as a career.
But before becoming a doctor, Vogelstein gained a strong quantitative background as a mathematics major at the University of Pennsylvania. For a time, he considered doing a doctoral degree in math and even applied to some graduate programs, but ultimately he decided to go to medical school, believing it was the most direct way to help people. For that endeavor, he returned to Johns Hopkins.
Vogelstein recalls one experience during his residency on the pediatrics unit that left an indelible impression on him and shaped his career. One of his patients, a girl around the age of four, had cancer—and her father, a mathematician, asked Vogelstein what caused his daughter to get such a terrible disease. “Of course I hadn’t the foggiest idea,” says Vogelstein. “I thought, if we’re ever going be able to help patients like this man’s daughter, we’re going to have to figure out what the cause of this disease is. Without knowing the cause of the disease, it’s seemed impossible to figure out a way to prevent it or cure it.”
In the late 1970s, when Vogelstein set out to study the genetics of cancer, the idea that cancer was fundamentally a genetic disease caused by combinations of inherited and acquired mutations was not universally held. At the time, many different explanations were under investigation, such as breakdowns in immunity, microbial infections, or epigenetic changes. But it seemed to Vogelstein that genetic changes were the most likely explanation and that this explanation could be solidified by finding the genes that were actually altered in cancers.
Due to Vogelstein’s experiences during his pediatrics residency and his devotion to children, his team initially set out to work on Wilms tumors, a type of kidney cancer that affects children. Their work yielded some provocative results, but it became clear to them that the key to understanding how cancer develops would be to study a cancer type in which the stages of development could be clearly identified and visualized. That’s why Vogelstein’s team decided to study colorectal cancer, with its orderly progression from very small benign tumor to full-blown malignancy.
He and Stan Hamilton, a pathologist, spent countless hours dissecting tumors excised from human patients to separate the cancer cells from the rest and comparing the cancer cells to those from other tumors. Vogelstein says this work was not always viewed favorably by others in the field—in fact, he recalls, “I was advised by some accomplished cancer researchers that if I wanted to learn anything about cancer, I should study animal models of cancer or tissue culture, not try to look at the actual cancer tissues themselves.” But this effort directly led to one of the group’s most important early observations: that tumors are clonal and even large cancers are derived from a single cell.
This finding—which was in direct contradiction to some previous reports—had profound implications. Vogelstein interpreted it to mean that in each tumor, a genetic alteration that spurred its growth must have occurred in a single cell and been passed on each time the cell divided. There was no way to know yet what genetic changes were responsible, but the results told Vogelstein that “these changes were likely to be there and could be found if one looked hard enough.”
Without modern DNA sequencing techniques, finding those genes was a challenge, but the group had uncovered clues about broad regions on the chromosomes where the genes could be located. Under Vogelstein’s supervision, graduate students Suzanne Baker (now a faculty member at St. Jude Children’s Research Hospital) and Janice Nigro discovered that one of these genes was TP53, which encodes the cell-cycle protein p53. We now know that TP53 is the most frequently mutated gene across all human cancer types.
Vogelstein and his long-time colleague Kenneth W. Kinzler went on to discover additional genes in which mutations are causally linked to cancers and, critically, to find that these mutations often occur in a specific sequence, with each mutation being associated with a higher level of tumorigenicity. This orderly progression of mutations and tumor stages was summarized diagrammatically in a model other researchers dubbed the “Vogelgram”. Nearly three decades after its formulation, the Vogelgram remains a useful model that is often taught to undergraduate biology students.
After making these major conceptual advances, Vogelstein’s group has remained at the pinnacle of cancer research, though its focus has evolved with time. Today, the Vogelstein-Kinzler lab is increasingly involved in translational research, particularly research with the goal of developing and improving diagnostics by exploiting the knowledge gained from their and others’ prior basic research. “The reason I went into this field was not primarily to learn about cancer,” Vogelstein says. “It was because I wanted to keep people from dying from it. But I thought I had to learn something about it and its pathogenesis before ever hoping to be able to do something about it.”
In the past decade, Vogelstein has become convinced we finally know enough to make the kind of translational research his group is now engaged in worthwhile. “I’m very optimistic about the future of cancer research and that cancer deaths will decrease,” Vogelstein says. They won’t decrease to zero, he quickly adds—but with better detection methods and earlier diagnoses, coupled with new therapies, more people will receive treatment before it’s too late.
Vogelstein has received dozens of awards for his research, including the 2013 Breakthrough Prize in Life Sciences. His work so far has an immense impact: with over 374,000 citations at this time, he is among the most highly cited scholars in any field of all time.