The Nobel Prize in Physiology or Medicine, awarded by the Karolinska Institutet in Stockholm, often alternates between recognizing fundamental molecular biology and clinical inventions. The development of GLP-1 based drugs for diabetes and weight loss has garnered significant attention. These drugs, based on the GLP-1 hormone, are increasingly prevalent, aiding in diabetes management and weight loss, while also showing promise in reducing cardiovascular disease risk and potentially treating addiction.
GLP-1 Based Therapies: A Nobel Worthy Advance?
Randy Seeley, director of the Michigan Nutrition Obesity Research Center, suggests that the impact and potential of GLP-1 drugs are substantial enough for Nobel consideration. Other awards have already recognized scientists who made early contributions to understanding the GLP-1 hormone. The Nobel Prize Assembly often favors basic research, which poses a challenge when evaluating GLP-1 drugs, given the extensive work required to transform the hormone into effective medications.
Seeley emphasizes that all steps, from hormone discovery to translational work and drug development, were crucial. He also notes the role of serendipity, such as the unexpected finding that GLP-1 receptor targeting could lead to significant weight loss.
Each advancement in understanding GLP-1 may not be individually prize-worthy, but collectively, they have broadened the potential benefits of GLP-1 and other gut-hormone-based treatments. Compiling a comprehensive list of contributors to the 40-year history of these drugs is a daunting task.
Early Insights into GLP-1: The Foundation for Modern Therapies
In the summer of 1979, Richard Goodman sought anglerfish to study somatostatin, a hormone produced in the brain and pancreas. Goodman's work involved isolating genes and understanding their function using recombinant DNA technology. This new technology allowed mRNA to be converted into DNA, which could then be sequenced and spliced into bacteria to create biomolecular factories.
Read also: The Nobel Trick: GLP-1 drugs and weight loss.
Goodman's research focused on islet cells in the pancreas, which produce insulin and glucagon. Soon, he was growing colonies of bacteria spliced with bits and pieces of fish DNA and screening them with radioactive probes to identify the one carrying the gene for somatostatin. Later, P. Kay Lund, a postdoc, used Goodman’s anglerfish DNA-containing bacterial library to identify the genetic sequence for the precursor to glucagon, revealing that it contained the code for glucagon and two novel hormones expressed in the gut. Goodman considers his contributions to the GLP-1 story as "trivial," but during that early era of molecular biology, people were identifying new genes and peptides all the time.
In 1983, Svetlana Mojsov, a chemist, joined Mass General’s endocrine unit. Mojsov hypothesized that the active structure of GLP-1 was actually a smaller fragment of the full molecule, a truncated version she called GLP-1(7-37). Starting in 1964 with Neil McIntyre’s seminal study at Hammersmith Hospital in London, researchers had observed that when people eat sugar, they experience higher insulin levels than when they get sugar injected into their bloodstream. This suggested that the gut must secrete an insulin-stimulating substance in response to meals. As she was writing up a paper on these findings, a postdoc in Habener’s lab, Gerhard Heinrich, reached out to her. Meanwhile, Mojsov had also begun supplying peptides and other reagents to another Habener postdoc assigned to unraveling the GLP-1 mystery, an endocrinologist named Dan Drucker. He had also found GLP-1 (7-37) in experiments in cell lines. In February of 1987, Mojsov, Weir, and Habener published another paper showing GLP-1(7-37) stimulated insulin secretion in rat pancreases. Drucker’s data were published a few months later, in May.
The Search for the Missing Incretin: Holst's Contribution
Jens Juul Holst, a gastrointestinal surgeon, had been searching for the missing incretin for over a decade. He observed that bariatric surgery patients experienced surges in insulin and crashing blood sugar, indicating that alterations to their gut impacted their metabolism.
The Danish team initially struggled, but they eventually found success with the help of Thue Schwartz, who had learned peptide-synthesis techniques from Donald Steiner. From all the data the two groups had gathered, GLP-1, specifically the 7-37 version, was starting to look like a big deal. If it was really and truly a hormone that could increase glucose-dependent insulin secretion, then it had potential to treat diabetes. The big test would be to put it into people. According to Holst, in the summer of 1987, he attended a party with Stephen Bloom, an endocrinologist then at Hammersmith. And whether it was the drinks or the belief that his team had a big enough lead that someone like Bloom, who’d never worked with GLP-1 before, couldn’t catch up, Holst spoke freely about the molecule’s therapeutic potential. They had found seven healthy volunteers to hook up to IV bags containing a solution of GLP-1. “Immediately, we had proof-of-concept that this would work,” Drucker said.
Overcoming GLP-1's Short Half-Life: The Development of Long-Acting Analogs
GLP-1 has a very short lifespan in the body, lasting only minutes before being broken down by enzymes in the bloodstream. This presented a significant challenge for developing it as a therapeutic agent.
Read also: The Victoria's Secret Diet
For the generation of biotech executives who presided over the burgeoning industry’s first few decades, GLP-1 was the multibillion dollar idea that got away.
Exendin-4: A Serendipitous Discovery from Gila Monster Venom
In the summer of 1980, Jean-Pierre Raufman, a young gastroenterologist, began researching substances that could alter human physiology. After seeing the gila monster venom spur a huge spike in amylase, Raufman began to focus on better understanding exactly what was in it. In 1983 he moved to Brooklyn and started a small lab at SUNY Downstate Medical Center. Without NIH funding, progress was slow until his boss introduced him to Rosalyn Yalow at the Bronx VA Hospital. A few years prior, Yalow had won a Nobel for her work developing the radioimmunoassay - a transformative method for measuring peptides in the blood. In her lab she had a talented research fellow, John Eng, with expertise in newer techniques for isolating peptides and determining their structures. Soon, Raufman was making the hour-long drive from his lab to the Bronx multiple times a week, transporting test tube racks filled with samples in the passenger seat of his Toyota Camry.
John Eng and Jean-Pierre Raufman discovered exendin-4 in Gila monster venom. Exendin-4 was totally new to science and yet curiously familiar. It was shaped almost exactly like GLP-1. But unlike GLP-1, which lasts less than a minute in the bloodstream before degrading, exendin-4 remains active for more than two hours. It was, they thought, a recipe for a potential blockbuster of a diabetes drug. “We presented it at meetings and people who were in the field would sort of look at it, scratch their heads,” Raufman said. Even the Veteran Affairs Department, for whom Eng worked, wouldn’t use department resources to file a patent for exendin-4. Eng wound up doing the paperwork himself. After it was issued, he tried to drum up interest with the big name diabetes drugmakers at the time, including Eli Lilly, Bristol Myers Squibb, Sanofi, and Novo Nordisk. Each turned him down. “It would take a leap of faith for a drug company to think there was something actually in this,” Raufman said.
Amylin Pharmaceuticals licensed Eng’s lizard peptide in 1996 and developed a synthetic version, exenatide, which received FDA approval in 2005 as Byetta. Users of Byetta reported not only improved blood glucose control but also weight loss.
Liraglutide and Semaglutide: Novo Nordisk's Breakthroughs
By then, Danish pharmaceutical company Novo Nordisk had already begun a clinical trial of its own GLP-1 receptor agonist, which went by the name liraglutide. At the Hagedorn Research Institute, an academic center embedded within Novo Nordisk, a cell biologist named Ole Dragsbæk Madsen had been giving rats tumors made from islet cells to study how the cells matured and turned on insulin gene expression. But then something disturbing happened. It was as though the tumors were emitting an appetite suppressant powerful enough to kill.
Read also: French Diet of 1924
Lotte Bjerre Knudsen, a Novo Nordisk researcher, saw that data and thought that GLP-1 looked like it turned off appetite just as well as it could crank up insulin secretion. It was 1995 and Knudsen had recently been tasked with figuring out what to do with the company’s GLP-1 program, which had been stagnating amid scientific dead-ends and organizational shake-ups.
Novo Nordisk’s technology for making insulin long-acting had failed when applied to GLP-1 and Knudsen had to start over. The trick was in adding long fatty acid chains that grabbed onto albumin - the most abundant protein found in the blood - allowing the GLP-1 lookalike to hide from enzymes that would chop it up. The winning molecule, called liraglutide, entered clinical testing in 2000 as an injectable drug to treat diabetes, and would eventually be approved by the FDA, as Victoza in 2010.
In the mid-1990s, there was a lot of debate about what was behind this effect. Researchers had been finding GLP-1 receptors in places outside the pancreas - including the vagal nerve, which connects the gut to the brain. Bloom’s team at Hammersmith had a hunch the action was happening in the brain itself. When they injected GLP-1 into the brains of hungry rats, the animals lost interest in their food.
In addition to helping participants control their blood sugar, liraglutide caused people to lose weight.
While Novo Nordisk began clinical testing of liraglutide for obesity, Knudsen’s team embarked on a series of studies using radioactivity to trace the drug’s path through the bodies of mice. They found that while the blood brain barrier kept liraglutide from dispersing throughout the brain, the drug was able to slip into the circumventricular organs. Since then, researchers have shown more and more convincingly that the weight loss effects of GLP-1 agonists are mediated through the brain - a separate mechanism from its impact on blood glucose.
Some of the most compelling evidence for this came when Novo Nordisk began testing a once-weekly version developed by Knudsen’s team, called semaglutide.
Semaglutide gained FDA approval for treating diabetes (Ozempic®) in 2017 and obesity (Wegovy®) in 2021. The agent fosters almost twice as much average weight loss as liraglutide does: 28 pounds over 16 months. Semaglutide’s side effects are mostly minor, but serious gastrointestinal problems cause some individuals to discontinue the drug.
Eli Lilly’s tirzepatide, which contains not only GLP-1, but also another incretin called GIP, promotes even more dramatic effects than semaglutide does.
Unlike GLP-1’s impact on diabetes, which maps primarily to the pancreas, its appetite-suppression activities lie mainly in the brain, and numerous investigators, including Knudsen, are detailing its behavior there. Researchers are probing its use in a tremendous range of illnesses, including chronic kidney disorders, fatty liver disease, neurodegenerative conditions such as Alzheimer and Parkinson’s diseases, and addiction.
The 2024 Lasker~DeBakey Clinical Medical Research Award
The 2024 Lasker~DeBakey Clinical Medical Research Award honors three scientists for their discovery and development of GLP-1-based drugs that have revolutionized the treatment of obesity. Globally, almost 900 million adults are living with obesity. In the United States, it afflicts as many as 40% of adults; in Europe the prevalence approaches 25%. The excess pounds underlie multiple life-threatening conditions. Obesity is commonly viewed as a failure of willpower, yet for many, diet and exercise don’t cure the problem. Historically, attempts to make safe and effective drugs that help people slim down have fallen short.
Through their ambitious and committed endeavors, Habener, Mojsov, and Knudsen have transformed the health prospects for the tremendous number of people whose surplus weight compromises their wellbeing.
Autophagy: A Cellular Process with Implications for Longevity and Weight Management
The word autophagy originates from the Greek words auto-, meaning “self”, and phagein, meaning “to eat”. Thus,autophagy denotes “self eating”. This concept emerged during the 1960’s, when researchers first observed that the cell could destroy its own contents by enclosing it in membranes, forming sack-like vesicles that were transported to a recycling compartment, called the lysosome, for degradation.
Yoshinori Ohsumi used baker’s yeast to identify genes essential for autophagy. Ohsumi’s discoveries led to a new paradigm in our understanding of how the cell recycles its content. His discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes, such as in the adaptation to starvation or response to infection.
During autophagy, cells destroy viruses and bacteria and get rid of damaged structures. Ohsumi created a whole new field of science with his work studying autophagy in yeast. He discovered that the autophagy genes are used by higher organisms including humans, and that mutations in these genes can cause disease.
Scientists have found that fasting for 12+ to 24+ hours triggers autophagy, and is thought to be one of the reasons that fasting is associated with longevity. There is a large body of research that connects fasting with improved blood sugar control, reduced inflammation, weight loss, and improved brain function; Oshumi’s research provides some of the “how” to this research.
“As research into autophagy has expanded, it has become clear that it is not simply a response to starvation. It also contributes to a range of physiological functions, such as inhibiting cancer cells and aging, eliminating pathogens and cleaning the insides of cells.
Sensory Perception: Unlocking the Mechanisms of Heat, Cold, and Touch
David Julius utilized capsaicin, a pungent compound from chili peppers that induces a burning sensation, to identify a sensor in the nerve endings of the skin that responds to heat. Ardem Patapoutian used pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs.
Joseph Erlanger and Herbert Gasser received the Nobel Prize in Physiology or Medicine in 1944 for their discovery of different types of sensory nerve fibers that react to distinct stimuli, for example, in the responses to painful and non-painful touch.
Julius and his co-workers created a library of millions of DNA fragments corresponding to genes that are expressed in the sensory neurons which can react to pain, heat, and touch. After a laborious search, a single gene was identified that was able to make cells capsaicin sensitive. The gene for capsaicin sensing had been found! Further experiments revealed that the identified gene encoded a novel ion channel protein and this newly discovered capsaicin receptor was later named TRPV1.
Independently of one another, both David Julius and Ardem Patapoutian used the chemical substance menthol to identify TRPM8, a receptor that was shown to be activated by cold.
Patapoutian and his collaborators first identified a cell line that gave off a measurable electric signal when individual cells were poked with a micropipette. After an arduous search, Patapoutian and his co-workers succeeded in identifying a single gene whose silencing rendered the cells insensitive to poking with the micropipette. A new and entirely unknown mechanosensitive ion channel had been discovered and was given the name Piezo1, after the Greek word for pressure (í; píesi). Through its similarity to Piezo1, a second gene was discovered and named Piezo2. channel activated by mechanical force. identified.
The groundbreaking discoveries of the TRPV1, TRPM8 and Piezo channels by this year’s Nobel Prize laureates have allowed us to understand how heat, cold and mechanical force can initiate the nerve impulses that allow us to perceive and adapt to the world around us.