Bert Vogelstein, M.D.

scientific_american

By John Rennie, Science Editor & Journalist

When four-year-old Melissa’s parents brought her into the emergency room of Johns Hopkins Hospital one Friday night in 1974, it fell to young Dr. Bert Vogelstein, the new resident in charge, to tell them the diagnosis was leukemia. Her parents absorbed the news as best they could, hoping for a cure that didn’t exist, but they also desperately needed an answer: why was she sick? Had they done something wrong? Something they should have done differently to prevent the cancer?

Vogelstein tried to reassure them they were not to blame, but he knew the heartbreaking truth was that medical science had no answer. “I was just being polite,” he recalls. “I had absolutely no idea of what caused this little girl’s illness” because cancer was a “total black box.”

That nagging, crucial question—what caused this cancer?—was one Vogelstein heard over and over again from parents, children, and others during his two-year pediatrics residency. His frustration over it, Vogelstein says, is what propelled him into the laboratory. “You’ve got to try and change that,” he recalls thinking. “Whether you can or not, we don’t know, but at least you’ve got to try.” It initiated the decades of astonishing research success studded with genuine scientific breakthroughs that have defined Vogelstein’s career.

Vogelstein is credited with developing the detailed, gene-centered understanding that modern science has about how all cancers arise…” For example, Vogelstein and his collaborators were the first to explain the precise genetic process by which a common human malignancy, colorectal cancer, originates in healthy tissues. More broadly, Vogelstein is credited with developing the detailed, gene-centered understanding that modern science has about how all cancers arise: he showed that they are diseases that evolve through generations of cells and the gradual accumulation of specific mutations that make them increasingly lethal to their host. His research group is credited with identifying the genetic basis of at least 10 types of cancer, more than any other laboratory. The phenomena that Vogelstein identified have become the foundations of new anti-cancer therapies, diagnostics, and preventative strategies. Because of the importance of his work and his prolific authorship of more than 450 papers, Vogelstein is the most cited scientist in the world—not just in cancer research or even in biology, but in all of science. In recognition of this amazingly rich record of accomplishment, Vogelstein was named as the 2015 winner of the Dr. Paul Janssen Award for Biomedical Research honors.

A Baltimore native born in 1949, Vogelstein was an enthusiastic independent reader as a boy, although he frequently skipped out of classes at the private middle school he attended. He majored in mathematics as an undergraduate at the University of Pennsylvania and graduated summa cum laude in 1970. For a brief time he worked toward a master’s degree in mathematics, but he eventually decided that medicine and human health fascinated him more, so he instead pursued a medical degree from the Johns Hopkins University School of Medicine. After graduating in 1974 and serving his formative pediatric residency at Johns Hopkins Hospital, Vogelstein worked as a research associate of the National Cancer Institute between 1976 and 1978, until Johns Hopkins University appointed him as an assistant professor of oncology.

As an oncology researcher, Vogelstein could finally begin to explore how the origins of cancer might be genetic. Today, the idea that cancer results from genes gone wrong is practically common knowledge. Yet it was not always so: by the 1970s scientists had begun to implicate a variety of genes in cancer but there was still little consensus about whether the blame for triggering a tumor’s growth and spread lay primarily with mutations, failures of the immune system, or infectious agents like viruses. Vogelstein was most suspicious of mutations, but proving that theory—or even investigating it—had stymied most efforts.

He and his team began to look at the progression of human colorectal tumors at a level of genetic detail. (Colorectal tumors were their subject of choice because obtaining sequential tissue samples from patients over time was relatively easy.) A particular innovation they brought to their approach was to study how individual clones of tumor cells changed and proliferated inside the body. They accomplished this by restriction fragment length polymorphism (RFLP) analysis, a DNA profiling technique that can identify telltale differences in the base sequences of corresponding genes in different cells.

Vogelstein’s group found that in more than half the tumors they studied, the cells had mutations in one particular gene called K-ras. That discovery made sense in that K-ras had previously been classified as an oncogene, a gene that in its normal form signaled for cells to grow and that when mutated signaled them to grow uncontrollably. But a single mutation could not by itself be causing cancer. Rather, as Vogelstein proposed in 1988, cancer more likely the result of mutations in several specific classes of genes, including oncogenes, that accumulated sequentially. As clones of tumor cells replicated, they acquired more mutations over generations and became increasingly deranged and unruly, until some of them bloomed into full malignancies.

Vogelstein confirmed that hypothesis in 1989, the year in which he was named a professor of oncology at Johns Hopkins, when he and his colleagues published a seminal paper on mutations in the p53 gene on chromosome 17. They showed that p53 was mutated not just in most colon cancers but also in more than half of all cancerous tumors. (Indeed, subsequent work has confirmed that p53 is the most commonly mutated gene in cancers.) It had been known that p53 was involved in cancer for 10 years, which is why it had been classified as an oncogene. But Vogelstein’s work showed conclusively that p53 instead belonged to a different class: it was a tumor-suppressor gene, one that normally suppressed replication in abnormal cells. Thus, mutations in p53 cut the brakes on a process that should stop new tumors from expanding.

Vogelstein’s lab followed the p53 paper with studies that identified more tumor-suppressor genes, including one they called APC in 1991. (The APC gene was also discovered independently at the same time by Ray White and his laboratory at the University of Utah.) APC is mutated in the inherited condition called familial adenomatous polyposis, in which patients develop huge numbers of benign tumors. Vogelstein and Kenneth W. Kinzler, who was then a graduate student but has since become Vogelstein’s longtime laboratory colleague and a full professor at Johns Hopkins, showed that APC is also the gene that first spontaneously mutates in most cases of colorectal cancer. If a cell lining the colon gets an APC mutation, it spawns abundant benign tumors, or adenomas, in which further mutations and malignancy can emerge.

Further work by Vogelstein and his colleagues showed that mutations in the genes that enable the DNA repair mechanism called mismatch repair (or MMR) also help to enable tumorigenesis and cancer. When strands of DNA are replicating, MMR proofreads the new strands to ensure that inappropriate nucleotide bases are cut out and replaced with the right ones. Defects in MMR lead directly to more mutations and faster progression toward cancer.

Thanks to Vogelstein and his team, oncologists now know that cancers arise through mutations acquired in three classes of genes—oncogenes, tumor-suppressor genes, and DNA repair genes—which betters understanding both of how tumors progress and of why cancers can be so diverse and persistent. The challenge for modern oncology is in putting those insights to work in new diagnostics, treatments, and preventatives. It has already born fruit, and Vogelstein has continued to contribute powerfully to those efforts.

For example, back in 1999, Vogelstein and Kinzler described digital PCR, a technique that improved on the more traditional quantitative polymerase chain reaction-based method for finding specific mutations in complex DNA samples. They upgraded it dramatically in 2003 with a further procedure called BEAMing (for beads, emulsion, amplification, and magnetics) that used individual magnetic beads as anchors for thousands of identical DNA fragments to make digital PCR much easier and faster.

Digital PCR and BEAMing are now routinely used for genome analysis by laboratories everywhere. And Vogelstein and Kinzler put them to use, starting in 2004, in a massive project aimed at studying the more than 150 protein-making genes in human DNA involved in the development of tumors. The tumor-linked sequences they found are useful as biomarkers for monitoring the progression of tumors in patients.

Vogelstein has also worked on novel treatments for cancer, such as the use of bacteria to fight tumors. As solid tumors grow, their cores often become oxygen-starved because of their poor blood supply. To take advantage of that weakness, his group experimented with injecting modified versions of soil bacteria (Clostridium novyi) into tumorous laboratory animals. The bacteria, which thrive under low oxygen conditions, colonized the tumors and multiplied but stayed out of healthy tissues. Toxins released by the bacteria directly killed the surrounding tumor cells. The bacterial treatment, which is being co-developed by Johns Hopkins and BioMed Valley Discoveries, is now undergoing further animal and clinical study.

Encouraging as such treatment possibilities might be, Vogelstein nevertheless believes that the best and most realistic opportunities for fighting cancer are in prevention, early diagnosis, and early treatment rather than in cures for advanced forms of the disease. For him, that view follows logically from the recognition that cancers arise through a process of gradual transformation: it takes on average almost 30 years for cells nudged into becoming tumors by an APC mutation to acquire all the other mutations essential to colon cancers. That’s three decades in which cells drifting toward malignancy could potentially be found and stopped.

“Of course, we have to continue to cure advanced disease because no prevention net will capture all of them,” Vogelstein remarked on-stage during the Dr. Paul Janssen Award celebrations in his honor. “But unless we use all of the weapons at our disposal including early detection and prevention, my fear is that 50 years from now we’ll still be trying to mainly cure advanced cancers, which is unacceptable.”

Indeed, although Vogelstein staunchly supports trying to curb people’s exposures to carcinogenic influences in the environment, he also recognizes that prevention has its limits. Early in 2015, Vogelstein and Cristian Tomasetti published a paper that became controversial for seeming to say that “bad luck” causes two thirds of all cancers. That flip summary does not do justice to their finding, however: Vogelstein and Tomasetti’s analysis concluded that most of the mutations causing cancers result from the random errors inherent in the mechanisms responsible for normal cell replication—not from any inherited or environmental factors. As such, a certain level of risk is inevitable over time, no matter how carefully one tries to prevent it.

In recent years, therefore, Vogelstein interest in chasing new cancer genes has faded in favor of identifying telltale signs of cancers earlier. He and his colleagues have been pioneers in the development of a noninvasive “liquid biopsy” approach to cancer diagnosis. Tumor cells shed their DNA into the bloodstream, often in surprising abundance. Sensitive DNA assays of a patient’s blood sample should in theory not only be able to spot the signature of a growing tumor but even identify the tissue in which it resides. The technique is in clinical development by several groups, including Vogelstein’s, and has shown great promise in animal tests. Skeptics have raised concerns, however, about whether the ability to diagnose cancers without always being able to do anything about them will put patients and physicians in a difficult bind.

Think like a science fiction writer and then use your scientific skills to realize that future.” During his Dr. Paul Janssen Award celebrations, Vogelstein advised young investigators choosing directions for their career to think more like science fiction writers than like scientists. Scientists, he warned, can be “too tethered to reality” to recognize future possibilities. “Think like a science fiction writer and then use your scientific skills to realize that future.” He also suggested that young scientists imagine having succeeded in their goals and then writing to their mother about what they had done. “Would she be excited?” he asked. “Mothers are pretty discerning.”

© Scientific American 2016

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