Lab Meeting: Daniel Drucker

“You only get better by being challenged, and listening to really important ideas.”

When I reached out to Dr. Daniel Drucker for an interview, I got a somewhat muted reply: “OK, we can try…I am generally a low-key guy, so I might disappoint.” I soon learned that Drucker has a self-deprecating bent— on full display during our interview.

He describes a childhood admiration for the laws and rules that govern science—ones that lead to definitive answers. Plus, the humanities were off the table: “Maybe I was also insecure and just unable to extend myself into the humanities…but I gravitated to science in high school.” Yet as Drucker moved through undergraduate science coursework and entered medical school in Toronto (1976), there was no evidence to suggest he would become a scientist: “I did not do any research…I see today that many students are doing phenomenal research—I went to Europe with a backpack, slept on the beach, drank cheap wine and had a good time.”

The young medical student did, however, possess two traits in spades: the desire to help people, and the need to challenge himself: “You only get better by being challenged, and listening to really important ideas.” This led Drucker to a medical internship at Johns Hopkins (1981) and later, after finishing endocrinology training, to a research fellowship with Joel Habener at the MGH. The plan was to study thyroid hormone synthesis in Boston, and eventually land a job back in Toronto—but things did not go smoothly: “When I arrived [1984], I was told that the thyroid work was being taken over by another lab…[Habener] told me that I could work on the glucagon gene instead. This was a hard moment…but I had no choice.” Working long hours, Drucker toiled on the proglucagon gene with little initial success: “I was completely incompetent, and I really struggled at first. The hours were very long, there were a lot of financial pressures, and we had a kid to look after. I was desperate to succeed.”

Despite these pressures, Drucker started to make progress. He found that endocrine [and later intestinal] cells transfected with the proglucagon gene (cDNA) produced several smaller protein products—among these were several forms of the incretin hormone, GLP-1: “We noticed that for GLP-1 there were multiple immunoreactive forms of different sizes…in our second paper we used these smaller peptides to show that GLP-1 stimulates insulin gene expression and secretion from pancreatic islets.” It was a finding that would change not only his life, but the entire field of endocrinology.

Drucker knew he was on to something: “my boss [Habener] was really excited: he took all my notebooks away and filed patents. So, I got the sense that this work could lead somewhere.” After landing a faculty job back in Toronto, he had room to breathe: “At this point, there was a huge sigh of relief.” Now a PI in his own lab, Drucker discovered that by inhibiting a protease called DPP-4 (which degrades GLP-1) he could increase GLP-1 levels and lower blood glucose in animals: “In medicine there is a principle: ‘see one, do one, teach one.’ Well, I saw one in the Habener lab…we filed our own patents for DPP-4 inhibitors for diabetes treatment.”

After developing an immortalized enteroendocrine cell line (GLUTag) in his lab that stably expresses high levels of proglucagon, Drucker also found that the GLP-2 hormone [produced in mice with transplanted GLUTag cells] stimulated intestinal cell growth: “another high point was discovering that this peptide [GLP-2] caused massive small bowel growth—we also filed patents for this peptide as a treatment for treatment of gut injury and short bowel syndrome.”

Over the next several decades, Drucker’s basic and translational work led to the clinical development of GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes, and GLP-2 receptor agonists for short bowel syndrome: “Getting close to having some science being of any translational benefit to patients is very difficult. To be associated with a drug approval is, in many ways, like winning the lottery.” With GLP-1 drugs in ongoing trials for obesity, cardiovascular outcomes, kidney disease and neurodegeneration, the impact of Drucker’s work may not yet be fully realized. He sums it up: “As a clinician scientist, this is just really exciting.”

Daniel Drucker is currently a Professor of Medicine at the Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital in Toronto. He is considered one of the world’s leading physician-scientists; he holds a Canada Research Chair in Regulatory Peptides and the Banting and Best Diabetes Centre-Novo Nordisk Chair in Incretin Biology. Drucker was also named an Officer of the Order of Canada and elected a Fellow of the Royal Society (FRS) in 2015.  In 2021 he was awarded the Canada Gairdner International Award, and in 2023 the Wolf Prize in Medicine (considered a predictor of the Nobel).

In 1984, when Drucker ran his first experiments on the proglucagon gene, he could not have imagined that this piece of DNA would yield multiple medications: “there was never a sense of accomplishment or a victory lap…just relief that I survived my fellowship and didn’t fail,” he admits. In the ensuing decades, Drucker has consistently pursued solid, reproducible science with patients in mind. There are few alive today, who have taken a scientific story from cDNA to several clinical approvals—literally from bench to bedside. This is certainly worthy of a victory lap.

In our interview, Drucker shares the ups and downs of a physician-scientist path, describes his lab’s past discoveries and current work regarding GLP-1, gives an overview of the ongoing clinical trials, and offers advice to trainees. Despite Drucker’s own reservations, I assure the reader that this interview will not “disappoint.”

Below is an interview with Dr. Daniel Drucker from April 2023:

Dr. Daniel Drucker: source

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1. What was your first taste of science and medicine? Briefly, what about this initial experience drew you in?

I did not come from a family of scientists or doctors—I don't think I even knew any scientists while growing up.

But I noticed in high school that science was interesting and could provide concrete “yes or no” outcomes. In contrast, I found in the humanities that I would write an essay and one teacher would like it. Then a few weeks later, I would write another essay, and a different teacher thought I was incompetent. Science appealed to me in part because there are laws, rules and principles--whether it's chemistry, biology or physics.

As I made my way through high school and university-level science courses, I wondered: “what am I going to do with this?” I didn't know any scientists at all growing up. In contrast, I was more familiar with physicians, and knew that [medicine] was a science-based profession. So that is very simply how I entered medical school. I did not do any research as an undergraduate or medical student. I see today that many undergrad and medical students are doing phenomenal research—I went to Europe with a backpack, slept on the beach, drank cheap wine and had a good time. But it was a very different era, when the bar was much lower for being accepted into medical school.

When did you get involved in research?  

The first time I did research was when I was an internal medicine resident. I always loved endocrinology, and my mentor at the time—a thyroid specialist named Gerard Burrow—gave me an opportunity in his lab to study thyroid hormone synthesis. He was an important mentor who really did change the course of my career.

So [in his lab] off I went to collect sheep thyroids [from the abattoir] and bring them back to the lab to study how hormone biosynthesis occurred. As a result of this work, I had my first scientific paper published in the Canadian Journal of Physiology and Biochemistry: the topic was on post translational modification of thyroid hormone, and thyroglobulin. I thought that was cool: it's always fun to do some experiments and be a co-author on a paper. Then I started doing a little clinical research as a resident, because it was much easier to do.

But in the 1980s I looked around at my mentors, and their jobs [running labs], which seemed like fun. So, I asked them: “how do you get to be an assistant professor?” They said: “the easiest way is to go learn how to do science somewhere else and bring something new back to our division.” My mentor [Gerard Burrow] sent me to interview with three thyroid labs: Bruce Weintraub at the NIH who cloned TSH, Seymour Reichlin at Tufts who was the major leader of hypothalamic releasing factors, and Joel Habener at the Mass General who worked on glycoprotein hormones [LSH FSH and TSH]. I chose the Habener lab, and I arrived in Boston in 1984.

When I arrived, I was told that the thyroid work was being taken over by another lab at the Brigham [Bill Chin]. Joel [Habener] told me that I could work on the glucagon gene instead. This was a hard moment. I literally was sent away to learn how to do thyroid research—but I had no choice: this was the ‘80s, when we just did what we were told. So, I said: “I guess I'll work on the glucagon gene.” That is how I started trying to figure out which peptides were produced by the proglucagon cDNA, which had just been cloned. I wish I could claim to have had the foresight to have selected that [proglucagon] project myself. But honestly at the time [1984], I was very naïve, young, and ignorant about science.

What was working in the Habener lab like?

The person who really taught me science and provided me with the environment was Joel Habener at the Mass General. He just loved science.

He would get really excited about research results, and then construct exciting scenarios and stories about where this could lead. I marveled at that. But at the time, in my position as a research fellow, I had a couple of years to learn how to do science and then land a faculty job. My currency was getting these stories wrapped up into publications. But [Habener’s] world was much broader. He considered, to a much greater extent, the potential impact of our work and how it could change the field.

As a research fellow my brain was going: “So I need five figures to finish this paper…how do I get one more?” I was just very pragmatic because I had a young child, and my wife and I were paid almost nothing. In many ways, it was a difficult time. Our individual salaries were about $18,000 a year each, and daycare and rent took most of that in Brookline.

On our anniversary, my wife and I had cheese pizza—without mushrooms or pepperoni because the extra toppings cost too much. The hours were very long, there were a lot of financial pressures, and we had a kid to look after. I was desperate to succeed in science, but I didn't have the luxury of sitting back and contemplating how grand this work could become. I was just focused on the day to day.

2. What were your big findings in Joel Habener’s lab when you were studying GLP-1 and GLP-2?

There were two fundamental GLP papers from my time in the lab. The first was when we put the proglucagon cDNA into a bunch of cells just to see: which peptides are even made from this sequence?

Are smaller proteins chopped up and liberated [from this larger proglucagon form]? The answer was that in endocrine cells they are. We noticed that for GLP-1 there were multiple immunoreactive forms of different sizes. That was interesting: what was the biological significance of these forms? In the next chapter [of the work] we took full length GLP-1 [1-37] along with the smaller forms like 7-37, which turned out to be the biologically active peptides. So, our second paper we used these smaller peptides to show that the smaller form of GLP-1 stimulates insulin gene expression and secretion from pancreatic islets.

But at this time, I was really in the weeds. As I mentioned, I didn't have a promised job back in Canada. I was doing this research fellowship [at MGH] and spending three or four years working for a very low salary under difficult conditions, without any guarantees. This scenario [in 1984] is not that different from how it is today [in research]. When I finally went back to Toronto, I was very fortunate to be offered a job and a small amount of lab space.  At this point, there was a huge sigh of relief—now I could have mushrooms and pepperoni on my pizza, when it was our anniversary.

[On the difficulties of research]

I probably spent five or six months in the Habener lab before I had any data. I was completely incompetent, initially. I remember I had a meeting in December of 1984 where I finally was able to show my supervisor [Habener] some cool data. He looked at it, and he got excited. He said: “you know, this means you actually might be able to spend some time here and be successful.”

It became apparent that from his perspective, it wasn't at all clear that things would work out well for me. But I was shocked by this mentality because I had gone from doing well in high school, to doing well in university, to getting through medical school and residency with reasonable success. But research was just so hard, and I really struggled at first. It was interesting to hear Joel [Habener] conceptualize the fact that yesterday he thought I was going to be a total failure. But today, I showed him some cool and exciting data. Now I had a chance [of succeeding].

3. What have been some scientific high points? — What do you consider to be the most exhilarating set of discoveries you have been involved in throughout your career?  

There are two levels of high points. One involves the experiments in the lab. For example, showing how GLP-1 can stimulate insulin secretion. That was cool. I knew my boss was really excited about it: he took all my notebooks away and filed patents. So, I got the sense that this work could really lead somewhere.

Back in [my lab in] Toronto we also did experiments with DPP-4, which demonstrated that DPP-4 inhibitors could increase GLP-1 levels and thereby lower blood glucose. In medicine there is a principle: “see one, do one, teach one.” Well, I saw one in the Habener lab [GLP-1 patents]. So, we filed our own patents for DPP-4 inhibitors for diabetes treatment. Another [experimental] high point was discovering what the GLP-2 peptide did. We found that this peptide caused massive, small bowel growth in animals—we also filed patents for this peptide as a treatment for short bowel syndrome. There are many other highlights from my trainees over the years who have done lots of cool experiments. I’m still very excited by experimental science today. 

The second level of high points are experiencing drug approvals—I am very fortunate in this respect. I remember April 28, 2005 we were waiting for the fax machine at Amylin Pharmaceuticals in La Jolla to receive the official notification from the FDA that exenatide twice daily was going to be approved as the first GLP-1 agonist for type 2 diabetes. Then on October 16, 2006 the FDA approved the first DPP-4 inhibitor [sitagliptin for T2D]. I later [October 2012] went to the FDA Advisory Committee to discuss the data and mechanisms of action for the GLP-2 agonist teduglutide, which was also discovered in my lab. When I watched the FDA panel vote unanimously to recommend teduglutide, part of my brain is going: “you must be kidding me.” Getting close to having some science being of any translational benefit to patients is very difficult. To be associated with a drug approval is, in many ways, like winning the lottery. So, I do feel that in my career I've won the lottery several times over. It continues to this day—there are multiple phase three trials going on for GLP-1 in multiple indications beyond type 2 diabetes. As a clinician scientist this is exciting.

[On remaining concerns regarding GLP-1 agonists]

I don't believe that there are many important issues to resolve in terms of safety, regarding these medications. 

From 2009 to 2011, there was a great deal of public concern about whether these GLP-1 drugs were safe. Were they going to cause pancreatitis? Were they going to cause pancreatic or thyroid cancer? You see some of these concerns come back around today with the Ozempic discussions. People say: “GLP-1 drugs are new medications. How do you know it's going to be safe?” The truth is that these drugs have been evaluated in animals and patients for over 18 years—we know a lot about them. So, I don't see any remaining critical issues in terms of the safety.  A more interesting point is that we don't yet understand how [GLP-1 receptor agonists] truly work.

4. What set of research questions or projects has you most excited about coming into lab today? 

I could talk to you for a couple hours on this question. As someone who spends my whole life trying to understand endocrinology, it is a great academic exercise to try to understand how GLP-1 agonism works in diabetes, obesity and other indications. We do this so that we can make these drugs better in the future.

The combination [of mechanisms] that we're seeing now is cool. Are these combinations going to be safe? How do these combination drugs work? There are tremendous controversies in this field. I'll give you one example: Eli Lilly has a fantastic drug [tirzepatide] that was just approved for type 2 diabetes. It's the best drug we've ever seen for type 2 diabetes and obesity. Tirzepatide’s alleged mechanism of action is that it activates both the GLP-1 and GIP receptors with same molecule: it's a co-agonist. But Amgen has a molecule in phase 2 trials, that activates the GLP-1 receptor but blocks GIP [unlike tirzepatide]

So it [Amgen drug] has completely reversed 50% of the intended mechanism of tirzepatide [Eli Lily]. The Amgen data looks amazing: in humans three injections produces 14.5% weight loss. I look at that and ask: how does that happen?

These are the questions we like to tackle in our lab. Because if you really want to make these drugs better in the next generation, you need to understand mechanism. What's the mechanism for the benefits of GLP-1 in the heart, liver or brain? I would say to you humbly, that nobody fully knows all the details. We have all these successes in the clinic. But mechanistically, there is quite a bit to do understand how they are working, so that we can make the next generation better.

5. What do you see as the biggest remaining scientific question in GLP1 or 2 biology? What are any historical technical limitations in studying these systems, and are new technologies helping circumvent these issues?

I think this is a really relevant question. Often there are very few GLP-1 receptors located in tissues that GLP-1 seems to have profound effects. We won't go through all them, but let's just consider the liver

GLP-1 drugs are in phase three trials for NASH. There are no GLP-1 receptors expressed in hepatocytes. There are GLP-1 receptors in the brain that enable weight loss, there are GLP-1 receptors on a few gamma-delta T cells in the liver that might reduce inflammation. But none on hepatocytes themselves. This is a general theme in the space: often, we don't find a lot of GLP-1R in places that we know are affected. It is likely that there is inter-organ communication, often involving the nervous system. The brain may send GLP-1 signals through efferent autonomic branches to other tissues, which may not have a lot of GLP-1 receptors themselves. It is challenging to study these complex systems.

If you simply take out the liver and apply GLP-1 to study it’s function-- good luck to you, because you will see nothing. In these cases one needs to unfortunately revert to whole animal and human physiology. There are some promising new technological developments in organoids.  But for the most part, these will not be very helpful in understanding most GLP-1 actions because these systems don’t recapitulate indirect effects of inter-organ communication. There are techniques for interrogating neurological pathways: chemogenetics, optogenetics and viral tracing. I don't know anything about these: but one of the themes of my lab is “jack of all trades, master of none.” We're not afraid to get help to learn how to do stuff to answer these questions. That is part of the fun of science: learning new techniques and collaborating with people.

Maybe the study of GLP-1 will move to the realm of neuroscience over the next few years…

There is a lot of excitement about ongoing studies with the GLP-1 drugs in Parkinson's and Alzheimer's. When I was in medical school, I said: “I'm never working on the brain. It is way too complicated. There are all these pathways, it's an electrical organ with different neurotransmitters. It’s too hard.” Now we have mouse models of Alzheimer's, and we're looking at neuroinflammation. We're really trying to figure this out. The most important thing about being a good scientist is asking good questions. The techniques are around if you're at a good university: you'll find expertise and collaborate with really smart people who can bring novel techniques. But asking good questions is the key to having a successful research career.

6.  What do you view as the remaining barriers to widespread adoption of GLP-1R agonists for obesity? How do you predict these drugs will be used clinically in the coming years?

There are a couple of very important clinical issues. The history of medical therapy in obesity has been frustrating: many treatments were not effective at all. Several drugs were withdrawn from the market because they were ultimately not safe. This has engendered a degree of mistrust by clinicians. I often see my colleagues quoted when they're asked about semaglutide: “it’s just another obesity drug that produces weight loss and may not be safe. We've seen this story before.” I understand why they say that, but I don't agree with that sentiment. We have an 18-year track record of clinical safety. Nonetheless, I think there is a cloud over the obesity field.

Novo Nordisk has sponsored a big study that will report in a few months called the SELECT trial, which evaluates cardiovascular outcomes in people living with obesity treated with semaglutide. Trials like these are important to address ongoing resistance to pay for these drugs. Many insurance plans will not reimburse drugs for obesity, because they view weight loss as a “lifestyle” choice. We need to prove that there is long term health benefit for patients and the healthcare system. We don't have evidence of that yet. The SELECT trial will go a long way to answering: is there a real cardiovascular benefit? What is the number needed to treat to achieve meaningful benefit?

These drugs still may not be cost-effective. Rightly or wrongly, companies are aware that they can make a lot of money selling these drugs. I think cost [of GLP-1 drugs] will be an issue. Most of us would like to live in a world where there is not a division between haves and have nots: in the U.S. people who are struggling to make a living often do not have access to the same medicines [as wealthier people].

I do think tolerability of these drugs is still an issue. Some people can’t tolerate the mild nausea, diarrhea, and occasional vomiting. Though most of the time these side effects go away over a few weeks, it would be nice to have newer versions that were not as challenging to introduce. I mentioned earlier that Amgen has a new drug in clinical development. It's a once monthly, injectable drug. In the GLP-1 field, we have gone from twice a day, to once a day, to once a week to now once a month. Wouldn't it be great to eventually have a drug that is given once every six months? This is in development by Intarcia and will be back in front of the FDA later this year. I think there are always ways to make medicines more effective--greater weight loss, greater hemoglobin A1c reduction, new indications. But I think there are also many ways to enable a larger number of people to safely access these medicines and improve their health.

[On oral GLP-1 drugs]

There are also multiple small-molecule, oral GLP-1 receptor agonists in clinical development—with one drug in phase 3 trials. This will be yet another generation of medicines. We have to learn more: these drugs are certainly activating the GLP-1 receptor, but their pharmacokinetics are totally different. They have a different Cmax, different peak and trough concentrations than traditional GLP-1 drugs. These small molecules will also probably produce more side effects initially, because they're not buffered like the long-acting GLP-1 drugs. Ultimately, the cost of goods however should be much cheaper. We may then be able to make these medications more widely available to patients. I view small molecule agonists as a very exciting development that's ongoing in the field.

7. Which areas of science, outside of your direct field, are you most excited about seeing develop in the next 5-10 years? 

I’m very excited about regenerative medicine. I work in the diabetes field. With type 1 diabetes, we've had astounding advances from engineers to make continuous glucose monitoring, and closed loop systems so that people with diabetes no longer need to stick their fingers for blood glucose several times a day and inject insulin. So that's amazing progress.

But even better would be a safe cell-based therapy to replace the beta cells that were previously destroyed by disease. One can also extend cell-based therapies to many different diseases. If you're interested in neurology, you could think about Parkinson's or stroke. I think that cell-based therapies, regenerative medicine or even gene editing for monogenic disorders are all exciting areas with huge potential.

8. What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries? Any advice specific to physician-scientists?  

Surround yourself with really good people who are smarter than you. That's a recipe for learning. You never want to be the smartest person in the room—whether you're the President of the United States, or the head of a lab. You only get better by being challenged and listening to really important ideas.

Sometimes they will be different than yours, and you have to think things through. I’ve done this in my career. When I was deciding where to intern, I chose Johns Hopkins. I wanted to see how I measured up. I felt the same way for my fellowship at Mass General. Surrounding yourself with smart people helps you learn immediately, in the short term and accomplish your goals. But in the long term these environments also provide you with a network and lifelong colleagues.