Svetlana Mojsov

On a late summer day in 1983, Svetlana Mojsov perused a double-spaced printout of the DNA code for a gene named pre-pro-glucagon. To a non-scientist, it might have resembled a word-search puzzle. Mojsov, an Assistant in Biochemistry at Massachusetts General Hospital (MGH), in Boston, was hunting for the “word” for a hypothetical hormone known as glucagon-like peptide 1. Dubbed GLP-1, it was thought to play some role in regulating glucose levels in the human body, but its exact sequence was undetermined.

Mojsov’s printout displayed the DNA bases three “letters” at a time; above them were the 180 amino acids they would generate in living cells. Hormones are often initially produced within a longer precursor protein, which enzymes then snip at specific sites to release the biologically active molecule. Researchers in California, led by Graeme Bell, had recently described GLP-1 in hamsters and humans as a chain of 37 amino acids within pre-pro-glucagon. When Mojsov had seen the California reports, however, she instantly spotted a probable cleavage site that the others had missed.

“I just looked at it, and it was obvious,” she recalls. She marked arrows on her printout at the bases where she predicted GLP-1 would start and end. It was shorter than Bell’s sequence—just 31 amino acids long. Scientists had theorized for many years about an as-yet-unidentified gut hormone—a so-called incretin, produced after a meal to robustly stimulate the pancreas to release insulin. (Insulin, in turn, lowers blood sugar levels after eating.) Mojsov suspected that GLP-1 was this missing incretin. She drew up an experimental plan for testing her hypothesis in her small laboratory.

Mojsov was uniquely positioned to solve this molecular mystery. She combined an intimate knowledge of protein biochemistry, and deep expertise in synthesizing peptides, with a desire to discover molecules of therapeutic importance. Her subsequent investigations, which included collaborations with bigger research groups at MGH and elsewhere, proved her hypothesis about GLP-1’s structure and function was right. This foundational accomplishment paved the way, decades later, to blockbuster diabetes and obesity drugs that mimic GLP-1, benefiting millions of people. However, Mojsov’s indispensable scientific contributions have only recently begun to receive public recognition.

Mojsov’s development as a biochemist who specialized in making and investigating proteins in the lab was like a potent synthesis in itself. She came to the lab bench with astute problem-solving instincts, systematic, clear-eyed thinking, and laser-focused tenacity—raw strengths honed with Nobelist-caliber mentoring. The starting reagents included an early curiosity about nature. Growing up in the 1950s in Skopje, in the former Yugoslavia, she collected butterflies and rhinoceros beetles from parks, and pinned them into wooden display boxes. When her family moved to Belgrade, she was captivated by physics and chemistry in middle-school science courses. Lab class experiments—illustrating that two or three chemicals mixed together could create something new—were magical to her.

Thanks to postwar Yugoslavia’s education system, which encouraged students to pursue their interests, regardless of gender, Mojsov earned a physical chemistry degree from Belgrade University. In 1972, she began Ph.D. studies in Manhattan at The Rockefeller University, joining the research group of biochemistry professor Bruce Merrifield. Merrifield had invented a revolutionary way to simplify and speed up protein and peptide synthesis (work that earned him the 1984 Nobel Prize in Chemistry). Using classical protocols, it would take a dozen or more scientists to laboriously create protein molecules in a chemical brew through a series of reactions. With Merrifield’s approach, known as the solid-phase method, the work could be carried out by a single biochemist.

Merrifield’s lab illustrated the impressive power of this approach by making a large enzyme, ribonuclease A. “This was before molecular biology burst into the place,” Mojsov recalls.
“I thought, this is terrific—you can use chemistry to design and make new peptides and proteins, and maybe make new discoveries.” Merrifield’s vision was that through engineering of slightly different versions, or analogs, of proteins, you could study how their structure affected their function. Analogs that mimicked or blocked the activity of key biological molecules might offer potential as new drug therapies.

While many research assistants in Merrifield’s lab were women, Mojsov was the first female graduate student. Nonetheless, she felt she was treated no differently than her male peers.
“We were just colleagues. We were all interested in doing science, learning science.” Merrifield was a “fantastic mentor” with an understated demeanor, she says. He gave lab members tremendous freedom, guiding them to become independent thinkers by learning from mistakes. Mojsov became interested in the hormone glucagon, which increases blood sugar levels in the body. While injections of insulin were the mainstay treatment for the chronic hyperglycemia of diabetes, inhibiting glucagon might offer an alternative therapy.

For her thesis, with Merrifield’s enthusiastic support, Mojsov decided to synthesize glucagon using the then-standard solid-phase method. However, she had not fully grasped how arduous a task this would be. It was widely considered impossible; other labs had already tried, and failed miserably. The synthesis process, conducted in a glass reaction vessel, was like assembling a pearl necklace tethered at one end. “You can think of each amino acid as a pearl, and you put one on at a time,” she explains. Progress was halting.

But after a year and a half of painstaking efforts to employ an alternate solid-phase protocol, she succeeded. “The most difficult part was spending months thinking, Well, is this going to work or not?” she says. The final obstacle was isolating her glucagon in crystalline form. One morning, after many failures, she checked her sample under a microscope. There it was: pure, translucent, hexagonal crystals of glucagon. When she quietly showed them to Merrifield, “we just looked at each other with such a sense of gratification,” she remembers.

She received her Ph.D. in 1978, and then worked another five years in Merrifield’s lab as a postdoc and research associate, further streamlining her glucagon synthesis method. She married physician-scientist Michel Nussenzweig, who had earned a Ph.D. in immunology at Rockefeller. In May 1983, they moved to Boston, where Nussenzweig started medical residency training at MGH. Mojsov joined the MGH Endocrine Unit. That fall, she was appointed director of the unit’s core facility for peptide synthesis, which was funded by the Howard Hughes Medical Institute to produce proteins for investigators’ projects.

She also pursued her own research interests. The two papers from Bell’s California group caught her eye. Embedded within pre-pro-glucagon was her old friend glucagon, along with GLP-1 and another putative peptide, called GLP-2. Either molecule could be involved in glucose metabolism, but Mojsov found GLP-1 more promising. Starting in September 1983, working with a technician, she manually synthesized short pieces of the GLP-1 sequence with the solid-phase approach. She used those to create essential tools—antibodies, a radioimmunoassay, and chromatographic methods—for detecting the peptide’s presence in tissues and cells. Next, she synthesized large quantities of both Bell’s full sequence of GLP-1 and her truncated, 31-amino-acid version. She ran experiments looking for the molecules in rat intestinal tissue.

By summer 1985, she was writing up her results when a research fellow from a large MGH lab suggested joining forces. Their group, led by molecular endocrinologist Joel Habener, was applying powerful new molecular biology techniques to study the pre-pro-glucagon gene. They proposed combining their data with Mojsov’s findings, in which she had shown that the truncated GLP-1 peptide—technically known as GLP-1 (7-37)—naturally existed in rat gut tissue. The resulting joint publication in 1986 was the first paper to establish that.

Other collaborative projects followed, using Mojsov’s synthesized GLP-1. For a landmark 1987 paper with Gordon Weir of the Joslin Diabetes Center, she helped conduct rat experiments showing that only the truncated GLP-1 potently spurred insulin release—evidence clinching that the peptide was the long-sought incretin. In 1992, a clinical study at MGH with David Nathan demonstrated that the incretin lowered blood sugar in diabetes patients.

By that point, Mojsov had relocated to New York City with her husband, their young son, and a baby daughter. Nussenzweig had landed a job back at Rockefeller and was a rising star. Mojsov joined the Rockefeller lab of immunology pioneer Ralph Steinman, a future Nobel Laureate, and eventually found her niche there as a research associate professor. With her own funding, she investigated GLP-1 and glucagon biology in mammals and fish from an evolutionary biology perspective—work that continues to this day.

In 1996, Mojsov was stunned to learn that MGH had secured patents for the early GLP-1 work listing Habener as the sole inventor. She hired a law firm to fight MGH to add her as co-inventor. It took ten years before the U.S. Patent and Trademark Office issued the corrections to four MGH patents. Based on licensing those patents, Norvo Nordisk developed and marketed drugs including Ozempic and Wegovy for diabetes and obesity. Other GLP-1 analogs from other companies followed.

More recently, prestigious scientific prizes for GLP-1’s discovery were awarded to Habener and others without acknowledging Mojsov’s seminal insights. Mojsov is a humble, reserved, and extremely private person, yet she felt compelled to publicly correct the historical record. In 2023, journalists at Science and STAT covered the story. Her motivations weren’t about getting a prize, she says. “I just wanted my papers to be known.” The best reward, she adds, was when colleagues with diabetes told her how much their health and lifestyle have improved on GLP-1–based medications. “That was the most gratifying experience I could have.”