How a mere fishing quest contributed to the discovery of GLP-1

Occasionally, a significant revelation arises from a fishing expedition. In Joel Habener’s instance, it was a real one.

More than thirty years subsequent to the identification of GLP-1, the hormone has revolutionized the management of obesity, diabetes, and cardiometabolic ailments impacting over a billion individuals globally. Habener, Svetlana Mojsov, Daniel Drucker, and Jens Juul Holst — researchers instrumental in the hormone’s discovery and characterization — have been honored with some of the highest accolades in science.

However, more than thirty years ago, when Habener, an emeritus investigator at Massachusetts General Hospital and Harvard Medical School, initiated an experiment contributing to this discovery, the result was far from assured.

“It’s been nothing but surprises,” Habener remarked. “It’s astonishing to me.”

The peculiar pancreas of an unattractive fish facilitated a transformation in contemporary medicine.

Back in the late 1970s, Habener aimed to pinpoint potential prohormones — hormone precursors — for the pancreatic hormones glucagon, which elevates blood sugar, and somatostatin, which suppresses both insulin and glucagon.

He and MGH researchers P. Kay Lund and Richard H. Goodman opted to utilize recombinant DNA gene cloning to extract these prohormones from rat pancreases, but encountered a hurdle. The National Institutes of Health, which aided in financing this basic research, had imposed a halt on recombinant DNA studies in warm-blooded animals as scientists assessed the ethical and safety implications of the emerging technology.

“The answer to the dilemma,” Habener noted, “called for a fishing expedition.”

A member of his lab was acquainted with a commercial fisherman who had supplied research specimens for other scientists. The anglerfish was considered due to its status as a “trash fish,” according to Habener. “We discard them, and they’re large and unappealing.”

Moreover, it was also cold-blooded, making it exempt from the NIH moratorium.

The anglerfish proved to be highly advantageous for Habener’s research. While endocrine and exocrine tissues are intermixed in a rat’s pancreas, the two types of tissue are distinct in anglerfish — with endocrine cells housed in a marble-sized organ called the Brockmann body. This separation simplified the isolation of mRNA, peptide hormones, and their precursors.

Upon obtaining mRNA from the Brockmann bodies, Habener and his team were astonished to discover that glucagon and somatostatin were embedded within larger proteins that later cleaved into their active forms.

“The eureka moment,” as Habener describes it, occurred when they recognized that in the larger precursor protein proglucagon, there was a signal peptide, an intervening peptide, a peptide homologous to mammalian glucagon, and then a subsequent GLP-related peptide, which was later identified as GLP-1.

Numerous more fundamental breakthroughs were necessary before this revelation could convert into therapeutic application. Mojsov, presently an associate research professor at Rockefeller University and then a member of MGH’s endocrine unit, pinpointed the biologically active form of GLP-1, known as GLP-1(7-37).

Holst, a professor at the University of Copenhagen, uncovered that GLP-1 functions as an incretin hormone, promoting insulin secretion in response to nutrition.

Drucker, a clinician scientist at Sinai Health’s Lunenfeld-Tanenbaum Research Institute — and a former participant in Habener’s MGH research group — elucidated more of GLP-1’s physiological effects and facilitated the translation of GLP-1’s therapeutic advantages into pharmaceuticals.

The influence of GLP-1 medications may seem obvious today, but Habener understands that some of the federally funded advancements leading there were anything but predetermined.

“I think the term is serendipity,” he stated. The unusual pancreas of an unattractive fish helped catalyze a transformation in modern medicine.