BIO
Joel Habener (Indianapolis, Indiana, United States, 1937) received his MD from the University of California, Los Angeles in 1965. After two years at the Johns Hopkins Hospital, he worked for the National Institutes of Health in Bethesda (1967-1969) before moving to Massachusetts General Hospital (MGH), where he remains to this day, combining his work as Physician Investigator with the leadership (since 1979) of the Laboratory of Molecular Endocrinology. He has also held a professorship of medicine at Harvard Medical School since 1989. Habener was a Howard Hughes Medical Institute investigator from 1976 and 2006. He sits on the editorial boards of several scientific journals and has served on numerous advisory committees for pharmaceutical companies and the National Institutes of Health.
CONTRIBUTION
The combined work of the four laureates elucidated the biological function of the hormone known as GLP-1, produced in the small intestine after food intake, and playing a fundamental role in both the maintenance of glucose levels and the regulation of appetite. “These findings have been exploited to develop novel therapeutics for treating type 2 diabetes and obesity,” in the words of the committee deciding the award.
“The awardees’ discoveries laid the biological foundations for what is nothing less than a pharmacological revolution. Their work has mapped the pathway to a new generation of drugs that are effective both to treat diabetes and to achieve significant weight loss in obesity sufferers while helping to combat the cardiovascular problems associated with this disease,” said committee member Dario Alessi, Director of the MRC Protein Phosphorylation and Ubiquitylation Unit at the University of Dundee (United Kingdom).
Not only that, treatments based on the GLP-1 hormone have shown exciting therapeutic potential in neurological conditions, like Parkinson’s and Alzheimer’s, and addiction disorders, with studies now underway to gauge their effectiveness.
In the exploration of the biological roots of obesity, the laureates’ findings intersect with the insights of Douglas Coleman and Jeffrey Friedman on the role of another hormone, leptin, in regulating appetite and body weight, distinguished in 2013 with the 5th Frontiers of Knowledge Award in Biomedicine.
The discovery of a fundamental hormone
In the 1980s, three scientists at Massachusetts General Hospital in Boston set out to explore the potential of the newly discovered hormones known as glucagon-like peptides. When Joel Habener succeeded in cloning the gene that coded for these hormones, Svetlana Mojsov, then working in another lab in the same hospital, began looking at their chemical properties to determine which of their forms might have biological activity in living beings. She managed to identify and synthesize one such form, the GLP-1 peptide, and to show that, in small quantities, it stimulated insulin production in the pancreas of rats.
At the same time Daniel Drucker, a postdoctoral fellow in Habener’s laboratory, was striving to get a more precise handle on the function of GLP-1. After multiple experiments, he finally deduced that insulin production only occurred in very short forms of the peptide, and only when blood sugar levels were high.
Meanwhile, in Copenhagen, Jens Juul Holst was examining how gut hormones were able to stimulate insulin secretion. He knew from his experience as a surgeon that the blood sugar levels of some patients could fall dangerously low after their time in the operating theater, causing hypoglycemia. It seemed clear that the reason for this was the gut overstimulating insulin production, but the question remained as to what was triggering the process.
Holst made this the subject of his PhD thesis, and in the early 1980s, together with his team, made the independent discovery that GLP-1 stimulated insulin release in the pancreas. Although other hormones were known to perform this function, what the team observed was that GLP-1 also inhibited production of glucagon, a hormone secreted by the pancreas that increases levels of sugar in the blood. It was this second property that drew their attention, as it was precisely the effect sought in type 2 diabetes patients, and they immediately got to work on exploring its potential as a therapeutic agent. “We did this seminal study administering GLP-1 via blood infusion to type 2 diabetes patients, and found that in four hours we could lower glucose to completely normal levels. It was a real turning point,” the awardee recalls.
Encouraged by these experimental results, they launched a large-scale clinical trial – published by The Lancet in 2002 – in which, over a six-week period, they replaced insulin with GLP-1 in the drug infusion pumps used daily by diabetes patients. “The results were remarkable,” Holst says today. “Not only did we almost cure diabetes, but in those six weeks our patients lost weight, and all of this without side effects.” In 2005 the first GLP-1 drug was approved for the treatment of type 2 diabetes, and several more have followed based on the same underlying principles.
From bench to bedside: effective drugs for diabetic and obese patients
The weight loss Holst had observed in his experiment was more than fortuitous. In 1996, Drucker had found that GLP-1 suppressed appetite in the animals to which it was administered and led them to shed weight. In parallel, Holst was able to confirm the satiating effect of GLP-1 in human subjects, paving the way for the 2014 approval of the first anti-obesity drug based on the peptide.
In the past two decades, GLP-1 has marked a game-changing advance in the treatment of both type 2 diabetes and obesity. Various diabetes treatments were already in use, but the advantage of GLP-1 was that it only stimulated insulin production when blood sugar levels were high, dramatically reducing the risk of them dropping below the safe limit. For the first time, patients were freed of the need to continually measure their blood sugar, since the drug itself would regulate its level.
In addition, being overweight can worsen outcomes with type 2 diabetes. Yet most previous treatments caused weight gain, diminishing their overall effectiveness. With GLP-1, this side effect not only disappears, but the drug actually helps patients lose weight, providing a two-way improvement in the disease prognosis. Recently, moreover, these new medications have been observed to reduce the risk of other complications of type 2 diabetes, including blindness, kidney disease and heart attacks.
On the obesity score, they have achieved first-time reductions in body mass ranging from 15% to 20%, beyond anything witnessed with existing treatments. And, as with diabetes, GLP-1 drugs also reduce obesity-related risks, among them cardiovascular disease.
Exciting potential for the treatment of neurodegenerative and addiction disorders
The committee stressed that the impact of the four scientists’ fundamental discoveries is not confined to the development of novel therapeutics for diabetes and obesity. They have also spawned a new research field exploring their treatment potential for other disorders like degenerative diseases and addictions. Indeed right now, as Mojsov states, “the pharmacological use of GLP-1 analogs for treatments of addiction and neurological disorders are being evaluated in clinical trials.”
GLP-1 based treatments have also been shown to have a powerful anti-inflammatory effect, and as such hold out considerable promise in neurodegenerative conditions. Drucker is currently exploring this avenue with his team at Mount Sinai Hospital in Toronto. “We are taking an in-depth look at the drugs’ effects against inflammation processes, a line of research that I am particularly excited about. We want to understand this mechanism to see, for example, whether it could be effective in reducing inflammation in the brain as a way to combat Alzheimer’s disease. The science here holds great promise and we have a large number of trials underway studying whether GLP-1 medicines will be potentially useful in these conditions. I’m really looking forward to the results.”
Holst believes that GLP-1 drugs may find use in treating drug addiction disorders, since “they have quite a pronounced effect on the reward center in the brain.” So “just as these treatments inhibit food reward as a means to suppress appetite and achieve weight loss, they might also serve to reduce dependence on alcohol and other addictive substances.”
Says Drucker, “what I’m most excited about going forward are new innovations in the field that will bring GLP-1 drugs to many millions of people who currently can’t access these medicines, enabling the health benefits to be extended not just to rich countries that can afford them, but to people all over the world.”
