Cancer Biology, Genetics
Dana-Farber Cancer Institute
Dr. Golub is also Charles A. Dana Investigator of Human Cancer Genetics at the Dana-Farber Cancer Institute, a professor of pediatrics at Harvard Medical School, founding core member, chief scientific officer, of the Broad Institute, and the director of the Cancer Program.
In the late 1990s, Todd Golub developed a technique that has revolutionized cancer diagnosis and treatment. He showed that DNA chips, which measure the activity or expression of thousands of genes simultaneously, could discriminate between two similar leukemias because each cancer has a unique genetic fingerprint. This work helped create the field that is now known as cancer genomics.
Golub, now the director of the Cancer Program at the Broad Institute of Harvard and MIT, which he helped to establish in 2004, continues to advance genomic methods to improve the understanding, diagnosis, and treatment of cancer and other diseases. He also is actively involved in moving genomic technology from the research laboratory into the clinic.
Genomic approaches, Golub says, can probe human disease in ways never before possible in medicine's history. "You can only be so smart in generating a hypothesis based on understanding a biological process and using experimental model systems," Golub explains. "It can be equally or perhaps more powerful to read from the human genome what the abnormalities are in a given tumor or disease state."
The ability to tailor therapies to individuals based on their unique genetic endowments should also result from the cancer genome, he says. "We need to move toward precision medicine," Golub says. "In cancer, that means giving the right drug for a given cancer rather than a generic chemotherapy." Golub and his collaborators are pursuing this goal across a broad range of human cancers.
Golub, who graduated in 1989 from the University of Chicago Pritzker School of Medicine, first identified a genetic cause for a cancer, acute lymphoblastic leukemia (ALL), as a Dana-Farber Cancer Institute research fellow in the early 1990s.
During the then pregenomic era, when technology limited analysis to one gene at a time, Golub identified the ETV6 gene, an aberrant fusion of two genes from a chromosomal abnormality, as causing ALL in one of his patients. ETV6 abnormalities now inform the routine treatment of ALL worldwide: the 25 percent of patients with the mutation need limited chemotherapy compared to other ALL patients.
Besides working on improving cancer diagnoses, Golub employs genomic approaches to identify new therapeutic strategies. For example, the same gene expression signatures that are used for cancer diagnosis can be used to screen large chemical libraries. By finding chemical compounds that can reverse a disease signature, Golub hopes to come up with new starting points for drug discovery. Golub’s first attempt to do this was in acute myeloid leukemia. He screened for compounds capable of converting the leukemia signature to a signature for normal blood cells. Findings from that study paved the way to new drugs that are now being tested in clinical trials.
Golub’s lab has also pioneered the concept of screening not one signature at a time, but rather creating a map of thousands of signatures: an effort he terms the “Connectivity Map.” The map has grown from about 500 signatures in the pilot study, to well over 2 million, serving as a resource for the entire research community. Using the Connectivity Map, a scientist can now treat cells with a drug with an unknown mechanism of action, obtain the drug's gene expression profile, and then compare its profile with those in the database, Golub says. "The software ranks results based on similarities to the profile given to it," he explains. The subset of genes found could reveal information about the potential therapeutic application of the drug.
Similarly, a disease state has a gene expression profile, Golub adds. "You can then ask the Connectivity Map to show you a drug with a profile that, perhaps, is the reverse of the diseased profile," he says. That drug might reveal a possible treatment target for that disease.
Golub credits a willingness to embrace creativity as the foundation of his science. Although many people, he says, think science requires rote learning of facts and proscribed methodologies, Golub says he tries not to let convention hamper him too much. He even created an artist-in-residence program at Broad to help scientists and artists question assumptions about their work.
Golub believes the process of creating art and science is similar. Both try to describe reality and are limited in their ability to do so: "In the visual arts, say, by canvas size," he says. "In science, by technology or resources." Golub, however, keeps pushing to find ways to overcome constraints in science's ability to render the complexities of the human genomic landscape.