Bert Vogelstein

Bert Vogelstein (born 1949) is Director of the Ludwig Center, Clayton Professor of Oncology and Pathology and a Howard Hughes Medical Institute investigator at The Johns Hopkins Medical School and Sidney Kimmel Comprehensive Cancer Center. A pioneer in the field of cancer genomics, his studies on colorectal cancers revealed that they result from the sequential accumulation of mutations in oncogenes and tumor suppressor genes. These studies now form the paradigm for modern cancer research and provided the basis for the notion of the somatic evolution of cancer. Together with Martin Nowak at Harvard University, he developed many mathematical models to understand the evolutionary process of cancer which lead to various hypotheses about mechanisms and timing of progression and seeding of metastases.

In the 1980s, Vogelstein developed new experimental approaches to study human tumors. His studies of various stages of colorectal cancers led him to propose a specific model for human tumorigenesis in 1988. In particular, he suggested that "cancer is caused by sequential mutations of specific oncogenes and tumor suppressor genes".

The first tumor suppressor gene validating this hypothesis was that encoding p53. The p53 protein was discovered 10 years earlier by several groups, including that of David Lane and Lionel Crawford, Arnold Levine, and Lloyd Old. But there was no evidence that p53 played a major role in human cancers, and the gene encoding p53 (TP53) was thought to be an oncogene rather than a tumor suppressor gene. In 1989, Vogelstein and his students discovered that TP53 not only played a role in human tumorigenesis, but that it was a common denominator of human tumors, mutated in the majority of them. His group's more recent studies examining the entire compendium of human genes have shown that the TP53 gene is more frequently mutated in cancers than any other gene.

In 1991, Vogelstein and long-time colleague Kenneth W. Kinzler, working with Yusuke Nakamura in Japan, discovered another tumor suppressor gene. This gene, called APC, was responsible for Familial Adenomatous Polyposis (FAP), a syndrome associated with the development of numerous small benign tumors, some of which progress to cancer. This gene was independently discovered by Ray White's group at the University of Utah. Vogelstein and Kinzler subsequently showed that non-hereditary (somatic) mutations of APC initiate most cases of colon and rectal cancers. They also showed how APC functions - through binding to beta-catenin and stimulating its degradation.

Vogelstein and Kinzler worked with Albert de la Chapelle and Lauri Aaltonen at the U. Helsinki to identify the genes responsible for Hereditary NonPolyposis Colorectal Cancer (HNPCC), the other major form of heritable colorectal tumorigenesis. They were the first to localize one of the major causative genes to a specific chromosomal locus through linkage studies. This localization soon led them and other groups to identify repair genes such as MSH2 and MLH1 that are responsible for most cases of this syndrome.

Beginning in 2004, Vogelstein and Kinzler, working with Victor Velculescu, Nicholas Papadopoulos and others in their group, began to perform large scale experiments to identify mutations throughout the genome. They were the first to perform "exomic sequencing", meaning determination of the sequence of every protein-encoding gene in the human genome. The first analyzed tumors included those of the colon, breast, pancreas, and brain. These studies outlined the landscapes of human cancer genomes, later confirmed by massively parallel sequencing of many different tumor types by laboratories throughout the world. In the process of analyzing all the protein-encoding genes within cancers, Vogelstein and his colleagues discovered several novel genes that play important roles in cancer, such as PIK3CA, IDH1, IDH2, ARID1A, ARID2, ATRX, DAXX, MLL2, MLL3, CIC, and RNF43.

Vogelstein and Kinzler concomitantly, in collaboration with Luis Diaz, developed ways to use these mutations as biomarkers in cancer patients, either for early diagnosis or for monitoring the extent of disease in cancer patients. For this purpose, they developed "Digital PCR" in which DNA molecules are examined one-by-one to determine whether they are normal or mutated. One of the techniques they invented for Digital PCR is called "BEAMing", in which the PCR is carried out on magnetic beads in water-in-oil emulsions. BEAMing is now one of the core technologies used in some next-generation, massively parallel sequencing instruments.

In the mid 2000s, Vogelstein started collaborating with the group of Martin Nowak at Harvard University. Together with their groups, they developed mathematical models to explain the evolution of resistance against targeted therapies. They showed that the sequential administration of multiple targeted drugs precludes any chance for cure — even when there are no possible mutations that can confer cross-resistance to both drugs.