Dr. Daniel Drucker: Exploring the mechanics of digestive hormones leads to a Gairdner Award

By Jana Manolakos

This is a story of the relentless pursuit of new knowledge, driven by observation, collaboration and hope. It’s almost epic in some ways, but quiet champions like Dr. Daniel Drucker probably wouldn’t classify it that way. The endocrinologist is a professor of medicine at the University of Toronto (UofT) and senior scientist at Sinai Health’s Lunenfeld-Tanenbaum Research Institute. He is also a winner of the 2021 Canada Gairdner International Award, along with two of his colleagues, Joel Habener of Harvard Medical School and Jens Holst of the University of Copenhagen.
It’s an honour bestowed on them for their work with previously unfamiliar hormones – glucagon-like peptides (GLP-1 and GLP-2) – which they found help maintain healthy sugar levels in our blood. The team’s work also led to the development of dipeptidyl peptidase-4 (DPP-4) inhibitors. The decades-long research opened the door to life-saving drugs for the treatment of Type 2 diabetes, obesity and bowel disorders that affect millions of people worldwide.

Every year, seven winners are selected for the Gairdner, each receiving $100,000. Almost a quarter of them go on to win Nobel prizes.

“The path to commercial success and the introduction of a drug to the clinic is not always a rapid, straightforward journey,” explains Drucker, who holds the Canada Research Chair in Regulatory Peptides and the Banting and Best Diabetes Centre – Novo Nordisk Chair in Incretin Biology. “There are all kinds of challenges to be met, and it can be a long and difficult process. But many things in life are like that.”

Indeed, the work for which the trio was recognized represents four decades of research, eventually leading to the development of several new classes of drugs for treating more than 100 million people worldwide. These unique peptides are released by the lining of the intestines and act to control insulin and glucagon for the management of sugar levels in the body. Smaller than proteins, peptides play key roles in regulating the activities of other molecules. Drucker, Holst and Habener identified GLP-1 and -2, observing and classifying their molecular and physiological effects in cells and animals, and applying their discovery in human studies.

“GLP-1 therapies have really advanced our treatment for diabetes and metabolic disorders, and GLP-2 can effectively address a huge unmet need in people with intestinal failure,” notes Drucker.

Based on his work, effective medications like Trulicity and Ozembic became available in Canada in the last few years. These mimic GLP-1 and GLP-2, so that when sugar levels rise after someone has eaten, the drugs trigger the secretion of insulin. Worldwide, millions of people with Type 2 diabetes have benefitted from either GLP-1 analogue or a DPP-4 inhibitor, another class of drugs that supports GLP-1 and GLP-2 functions in the body. Drugs based on GLP-2 can improve nutrient absorption in people with short-bowel syndrome, eliminating the need for intravenous feeding in some patients. GLP-1-based drugs show promise as cardio-protective agents and may help against non-alcoholic fatty liver disease and dementia.

Beyond the simple joy Drucker finds while working alongside other great minds – people like University of Toronto’s Charles Hollenberg, Gerard Burrow and Patricia Brubaker, as well as his colleagues, Habener and Holst – he is also fascinated by the human body’s ability to produce hormones in the pancreas, gastrointestinal tract and the brain. The story began in 1984, when the Montreal-born Drucker worked as a research fellow at the Massachusetts General Hospital and Harvard Medical School, studying molecular endocrinology.

“I loved the simplicity of the endocrine system – too much or not enough hormone is easy to understand – and I was excited that many endocrine disorders are not that difficult to diagnose and treat, often with excellent clinical outcomes,” he explains. In the mid-1980s, Drucker joined Habener’s team as a post-doctoral researcher, helping to detail the biological function and systemic effects of glucagon-like peptides that Habener had discovered. His discovery was based on work by Holst, who had identified a type of glucagon in blood that originated in the gut but was different from glucagon made in the pancreas.

Holst made the initial observation that patients who had undergone intestinal surgery experienced a rise in insulin, followed by a drop in blood sugar after eating – an early sign of links between the gut, sugar levels and the pancreas, which is the main site of insulin and glucagon production.

The scientists later observed that gut cells release GLP-1 into the blood in response to food – increasing insulin release in the pancreas and tempering glucagon, while also slowing digestion and decreasing appetite, a promising discovery for the treatment of obesity.

Together with Patricia Brubaker in UofT’s Department of Physiology and Department of Medicine, Drucker worked on the role GLP-2 plays in supporting the growth and health of intestinal cells that enable food absorption, which led to a new treatment for short-bowel syndrome.

Subsequent work on a chemical that inhibits gut hormones yielded another class of drug called DDP-4 inhibitors. Both classes of drugs help people with diabetes lower their blood sugar without causing weight gain or hypoglycemia, side effects of previous generations of drugs.

As both a physician and a scientist, Drucker believes much of his success lies in asking research questions with medical relevance. “I’m a clinician-scientist, and I probably know far more clinical medicine than I do science, to my embarrassment, but I’ve always kept one eye on unmet clinical needs and chosen research experiments accordingly,” he explains.

“For a physician, there’s nothing better than every day doing something that may improve the health of someone. For me, to actually see decades of work translate into medicines that actually make a difference, that the GLP-1 drugs do things that the other medicines don’t do, [that’s a great feeling].”

Commercialization isn’t a primary driver for Drucker. “We study basic mechanisms of hormone action. We do not set out initially to design our experiments with a view towards discovering an invention,” he admits. “We do the science, we hope that we ask good questions and we hope that our findings are novel and of interest. When we make observations or discoveries, we always have a little light on that says, beyond the pure joy and satisfaction of understanding how this works, might this be relevant to treatment of human disease, and might this have commercialization potential?”

On the 10th floor of Mount Sinai Hospital in downtown Toronto, Drucker often can be found glued to his computer in a nondescript office, pouring over reports and studies, or wearing a white coat in his lab among benches, a jumble of tubes, banks of refrigerators and analyzers. Over decades of seeking answers, he’s relied on highly sensitive equipment to point the way. The most stalwart has been the Mettler Toledo balance. “Our research is not very sophisticated, and we often make fascinating discoveries by weighing animals and their organs’ hormone administration, like body weight loss or intestinal growth,” Drucker explains.

As a standard bearer for the Gairdner Award, Drucker encourages young people to pursue STEM fields. “I can’t think of a better place to put yourself in, to be able to lead the health and prosperity of your nation, while having a great time, constantly learning new things, being very productive and being challenged and excited,” he says. Drucker believes the global pandemic has made the need to engage and support young researchers even more relevant than before. To young scientists, he says, “Stay focused, rigorous, persistent, committed and patient. Solid important science ultimately triumphs, but not overnight.”

So, what needs to happen to encourage future scientific discovery and build the country’s reputation as a global leader in the innovation space? Drucker explains, “Canada has wonderful scientific talent and very good infrastructure, yet as a nation, we seriously under-invest in funding scientific research, relative to our economic peers. We also have a less developed pharmaceutical biotechnology sector, for various reasons, and no philanthropic organizations to rival those operating in other countries, so it is a challenging environment right now for Canadians in science to maintain an internationally competitive program.” At a time when every nation is recognizing the importance of their scientific communities, Drucker is among the leaders we should listen to.

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