“Serendipitous” Discoveries Related to Two “Odd-Looking” Animals Was Source of Weight-Loss Drugs

(p. A1) The blockbuster diabetes drugs that have revolutionized obesity treatment seem to have come out of nowhere, turning the diet industry upside down in just the past year. But they didn’t arrive suddenly. They are the unlikely result of two separate bodies of science that date back decades and began with the study of (p. A2) two unsightly creatures: a carnivorous fish and a poisonous lizard.

In 1980, researchers at Massachusetts General Hospital wanted to use new technology to find the gene that encodes a hormone called glucagon. The team decided to study Anglerfish, which have special organs that make the hormone, simplifying the task of gathering samples of pure tissue.

. . .

After plucking out organs the size of Lima beans with scalpels, they dropped them into liquid nitrogen and drove back to Boston. Then they determined the genetic sequence of glucagon, which is how they learned that the same gene encodes related hormones known as peptides. One of them was a key discovery that would soon be found in humans, too.

It was called glucagon-like peptide-1 and its nickname was GLP-1.

After they found GLP-1, others would determine its significance. Scientists in Massachusetts and Europe learned that it encourages insulin release and lowers blood sugar. That held out hope that it could help treat diabetes. Later they discovered that GLP-1 makes people feel fuller faster and slows down emptying of food from the stomach.

. . .

The key to the first drug would come from a serendipitous discovery inside another odd-looking animal.

Around the time Goodman was cutting open fish, Jean-Pierre Raufman was studying insect and animal venoms to see if they stimulated digestive enzymes in mammals.

“We got a tremendous response from Gila monster venom,” he recalled.

It was a small discovery that could have been forgotten, but for a lucky break nearly a decade later when Raufman gave a lecture on that work at the Bronx Veterans Administration. John Eng, an expert in identifying peptides, was intrigued. The pair had collaborated on unrelated work a few years before. Eng proposed they study Gila monsters.

. . .

Eng isolated a small peptide that he called Exendin-4, which they found was similar to human GLP-1.

Eng then tested his new peptide on diabetic mice and found something intriguing: It not only reduced blood glucose, it did so for hours. If the same effect were to be observed in humans, it could be the key to turning GLP-1 into a meaningful advance in diabetes treatment, not just a seasickness simulator in an IV bag.

Jens Juul Holst, a pioneering GLP-1 researcher, remembers standing in an exhibit hall at a European conference next to Eng. The two had put up posters that displayed their work, hoping top researchers would stop by to discuss it. But other scientists were skeptical that anything derived from a lizard would work in humans.

“He was extremely frustrated,” recalled Holst. “Nobody was interested in his work. None of the important people. It was too strange for people to accept.”

After three years, tens of thousands of dollars in patent-related fees and thousands of miles traveled, Eng found himself standing with his poster in San Francisco. This time, he caught the attention of Andrew Young, an executive from a small pharmaceutical company named Amylin.

“I saw the results in the mice and realized this could be druggable,” Young said.

When an Eli Lilly executive leaned over his shoulder to look at Eng’s work, Young worried he might miss his chance. Not long after, Amylin licensed the patent.

They worked to develop Exendin-4 into a drug by synthesizing the Gila monster peptide. They weren’t sure what would happen in humans. “We couldn’t predict weight loss or weight gain with these drugs,” recalled Young. “They enhance insulin secretion. Usually that increases body weight.” But the effect on slowing the stomach’s processing of food was more pronounced and Young’s team found as they tested their new drug that it caused weight loss.

To get a better understanding of Exendin-4, Young consulted with Mark Seward, a dentist raising more than 100 Gila monsters in his Colorado Springs, Colo., basement. The lizard enthusiast’s task was to feed them and draw blood. One took exception to the needle in its tail, slipped its restraint and snapped its teeth on Seward’s palm—the only time he’s been bitten in the decades he’s raised the animals. “It’s like a wasp sting,” he said, “but much worse.”

Nine years after the chance San Francisco meeting between Eng and Young, the Food and Drug Administration approved the first GLP-1-based treatment in 2005.

The twice-daily injection remained in the bloodstream for hours, helping patients manage Type 2 diabetes. Eng would be paid royalties as high as $6.7 million per year for the drug, . . .

For the full story, see:

Rolfe Winkler and Ben Cohen. “Two Monsters Spawned Huge Drugs.” The Wall Street Journal (Friday, June 24, 2023): A1-A2.

(Note: ellipsis added.)

(Note: the online version of the story has the date June 23, 2023, and has the title “Monster Diet Drugs Like Ozempic Started With Actual Monsters.” The sentence about “a serendipitous discovery” appears in the online, but not the print, version of the article. The passages quoted above also include several other sentences that appear in the more extensive online version, but not in the print version.)

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