Andrew F. Stewart, MD
A rare benign tumor may hold the key to regenerating insulin-producing beta cells and lead to novel drugs for patients with diabetes, according to a study led by Andrew F. Stewart, MD, Director of the Diabetes, Obesity and Metabolism Institute and the Irene and Dr. Arthur M. Fishberg Professor of Medicine at the Icahn School of Medicine at Mount Sinai.
Dr. Stewart’s team conducted the largest genomic study of insulinomas—benign pancreatic tumors that secrete insulin—and uncovered multiple pathways to human beta cell proliferation, long seen as a holy grail in treating, and possibly curing, diabetes.
“We’ve sequenced 38 human insulinomas with 30,000 genes each, and now know all the genes that are mutated and misregulated,” says Dr. Stewart. “For the first time, we have a genomic recipe—an actual wiring diagram in molecular terms—that demonstrates how beta cells replicate.” The results of that research were reported in the journal Nature Communications in October 2017.
Dr. Stewart says that one of the reasons he joined Mount Sinai five years ago was that its strong Genomics and Bioinformatics programs offered him the potential to assess the insulinomas he had been collecting. “I wanted to do genome sequencing and RNA expression as part of comprehensive studies to figure out which genes were turned on and which weren’t in insulinomas,” he says.
Eric Schadt, PhD, Dean for Precision Medicine, and the Jean C. and James W. Crystal Professor of Genomics, Icahn School of Medicine at Mount Sinai, assigned a team of bioinformatics specialists to work closely with Dr. Stewart, led by Carmen Argmann, PhD, Associate Professor of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai. “We are now further expanding our sequencing to 100 insulinomas. We already have found many pathways that lend themselves to new drugs,” Dr. Stewart observes.
Dr. Stewart has repeatedly undercut the argument that human beta cells were impossible to reproduce. In the March 2015 issue of Nature Medicine, his team reported the discovery of the first drug that can trigger human beta cell regeneration: harmine. In that study, Dr. Stewart’s team robotically screened 100,000 chemical compounds in search of a drug to make beta cells grow. They identified 86 potential candidates, and eventually winnowed the field to harmine, which is derived from the flowering plant harmal, or ayahuasca.
Harmine, however, has psychoactive properties that act not only on beta cells but on the brain and other tissues throughout the body. That complication has touched off a search within the research community to find other small molecules that target only beta cells. “We’re making considerable progress in making the next-generation versions of harmine in combination with other drugs that will afford us much higher proliferation of human beta cells,” Dr. Stewart says. “With the insulinoma project, we have acquired a road map to even more effective beta cell regenerative drugs.”