It All Started With a Bite from the Gila Monster
I’ve spent the last 8 years thinking about diabetes as a disease of the kidney - diabetic kidney disease or diabetic nephropathy - but I’ve been reminding myself recently that diabetes is a disease of the whole body.
Sugar levels - in their simplest form, glucose - in the blood need to be kept under control. This is achieved by the concerted efforts of two hormones - insulin, which works to reduce the amount of glucose in the blood, and glucagon, which increases blood glucose by releasing it from internal stores.
Type 2 diabetes develops when either your body isn’t producing enough insulin to temper glucose levels, or somehow your body becomes insensitive to insulin and is unable to respond to its presence. The build-up of glucose over time can damage nerves and blood vessels, cause health problems like heart attacks and strokes, and problems for eyes, feet - and kidneys.
Earlier this month I found myself at ELRIG Drug Discovery conference in London. Conferences are always a great opportunity to speak to lots of different people from different backgrounds, to be challenged with different ways of thinking about a familiar problem, be that through alternate ideas or being made aware of new technologies.
Diabetes and obesity were hot topics, with several speakers talking about a class of drugs known as GLP-1 agonists - glucagon-like peptide-1 receptor agonists. The GLP-1 hormone influences the amount of both insulin and glucagon in the blood. It promotes the release of insulin from the pancreas to increase glucose uptake, and it also stops the release of glucagon so that glucose does not flood the bloodstream from internal stores. Fine-tuning the availability of both of these hormones, GLP-1 reduces the amount of glucose in the blood.
The GLP-1 story is an interesting one. GLP-1 agonists are prescribed to millions of patients worldwide for the treatment of diabetes and obesity - this group of medications are expected to be worth over $100 bn by 2030 [1]. But what is striking is the involvement of lots of different research groups, each with different motivations and curiosities to get the story to where it is today. GLP-1 agonists have needed a diversity of players to speak about and publish their work and speak to people in their institutions and at conferences. They have needed the exchange of ideas and new ways of thinking to help solve stagnant problems. And, finally, the movement of researchers between labs and groups and departments in order for them to learn new techniques.
Joel Habener was investigating how hormones are produced at Massachusetts General Hospital in the early 1980s. His group were trying to understand the processing of preprohormones - longer peptides that we now know are trimmed to their shorter, active form as a means of regulating their action. Beginning with the sequence of the precursor of glucagon from anglerfish, they went on to find a number of sequences that looked like glucagon, including GLP-1.
Svetlana Mojsov was trying to synthesise glucagon in the lab of Nobel Laureate Bruce Merrifield using a method known as solid phase synthesis. Mojsov moved to Massachusetts General Hospital as an instructor in the Endocrine Division, and subsequently began collaborating with Habener on GLP-1. With Daniel Drucker, Habener and Mojsov discovered that GLP-1 is produced in the gut and enhances insulin secretion from the pancreas. However, the first effort to develop diabetes medications that mimicked the activity of GLP-1 came from somewhere else.
A gastroenterologist named Jean-Pierre Raufman at the National Institutes for Health was trying to understand how the Gila monster (Heloderma suspectum) could survive whilst only feeding twice a year. This venomous lizard climbs trees and even rough walls to feed on all manner of small mammals, mice, young rabbits, hares, squirrels, and also snakes, frogs, insects - and eggs of birds, lizards and tortoises. It eats a lot in one meal, but then doesn’t need to feed again for a considerable amount of time.
It turns out that when the Gila monster eats, its bloodstream is flooded by a hormone called Exendin-4. Having heard about Raufman’s work, John Eng at the Veterans Administration Medical Center in New York isolated the Exendin-4 peptide from Gila monster venom in 1992. What’s more, Eng found that the sequence of Exendin-4 is very similar to GLP-1. However, it has a slightly different sequence which actually means Exendin-4 isn’t broken down as quickly as GLP-1.
Eng recognised the potential that Exendin-4 could bring to the treatment of type 2 diabetes. He moved the story from one of scientific exploration - a sense of curiosity - to seeing the potential for making a product - a therapeutic. Eng filed a patent but it was three years before he could convince a pharmaceutical company to licence the discovery from him and put in the work to make it into a therapeutic. Exenatide, a synthetic version of Exendin-4, was approved by the FDA in 2005 for the treatment of type 2 diabetes.
In Copenhagen, Jens Holst was trying to understand why blood glucose levels dropped after gastric surgery. At around the same time as Eng was isolating Exendin-4, Holst’s team were finding that GLP-1 slows the passage of food through the gut. The gut stays full for longer, meaning that you don’t feel hungry and don’t eat as much. This no doubt explained why the Gila monster eats so few meals and also meant the GLP-1 agonist group of drugs are now used not only to treat diabetes but also in the treatment of obesity.
Lotte Knudsen, a Chemical Engineer, joined Novo Nordisk in the early 1990s and was given the task of creating a form of the human GLP-1 that would last longer in the circulation. The longer the therapeutic remains in the blood, the fewer doses the patient will need to keep their condition under control. She developed Liraglutide, and later oversaw the development of Semaglutide.
So what’s next? Semaglutide is similar in sequence to human GLP-1, only with two substitutions to the sequence. One of these swaps a common amino acid with one not normally incorporated into proteins. This alteration means Semaglutide is not easily broken down, but it also makes it expensive to make.
Constructive Bio is a new company that has the vision to programme cells to become the sustainable biofactories of the future. They want to identify problems with existing protein therapeutics and - simply - fix them. In her talk at ELRIG Drug Discovery, Ola Wlodek, CEO of Constructive Bio, talked about how synthetic organisms, such as their patented Syn61 stain of E. coli, can be engineered to incorporate non-standard amino acids to make drug synthesis cheaper. These microorganisms can be grown at scale in huge bioreactors, with less detriment to the environment than current manufacturing methods.
Exploring the scales and patterning of the Gila monster (Heloderma suspectum).
Reference
J. P. Morgan: Global Research (2023). The increase in appetite for obesity drugs J. P. Morgan. Accessed October 26, 2024.
Further Reading
I’m a scientist with a PhD, not a medical doctor, and the information on this blog should not be misconstrued as medical advice. If you’re looking for medical advice, please speak to your GP or consult an organisation like Diabetes UK, whose resources are written in collaboration with qualified clinicians.
GLP-1 Agonists on the Diabetes UK website. Accessed: October 24, 2024.
Friedman, J. M. (2024) The discovery and development of GLP-1 based drugs that have revolutionized the treatment of obesity Proc. Natl. Acad. Sci. U. S. A. 121 (39) e2415550121.
Zürcher, J. F., Kleefeldt, A. A., Funke, L. F. H. et al. (2023) Continuous synthesis of E. coli genome sections and Mb-scale human DNA assembly Nature 619: 555–562.