Research Reflections: Professor Dan Drucker on Lizard Venom, Serendipity and the Rigours of Reproducibility

U of T Medicine hosts the Smithies Lecture, honouring the work of genetics pioneer and Nobel laureate Oliver Smithies, and supported since 2008 by Sanofi Aventis. The October 2017 lecture offered an engaging look at the career of one of Canada’s pioneers in the treatment of Type 2 diabetes. Professor of Medicine Daniel Drucker is a Senior Scientist  at  the Lunenfeld-Tanenbaum  Research  Institute,  Sinai Health System, and holds a Canada  Research  Chair  in  Regulatory Peptides, as well as  the  Banting  and  Best  Diabetes  Centre-Novo Nordisk Chair in Incretin biology. He was named an Officer of the Order of Canada in 2015.

Professor Drucker’s 30-year career investigating a group of metabolic hormones called incretins has led to the development of two classes of FDA-approved drugs, GLP-1 receptor agonists and DPP-4 inhibitors for the treatment of diabetes, with one GLP-1 therapy also approved for obesity. A second peptide therapy based on GLP-2 action, teduglutide, has also been approved for the treatment of short bowel syndrome. U of T Med’s Linda Quattrin caught up with Professor Drucker after the Smithies Lecture.

You covered a lot of ground in your talk – from your early days in Boston, coming back to Toronto in 1987 and moving into the world of transgenic models of disease. What was the environment like in Toronto that gave rise to such a productive genomics cluster?

I was recruited into the Division of Endocrinology by Gerry Burrow (who went on to become Chair) with early mentorship from (former Chair) Charles Hollenberg. At that time, there were few colleagues in the clinical departments doing work in molecular biology or mouse genetics. I was very fortunate that Lou Siminovitch at the Lunenfeld found the time to read my grants and offer advice grounded in his broad perspective of evolving science. It brought home how generous mentors, often outside one’s immediate circle or comfort zone, can be so valuable in shaping careers and providing direction.

I love the story about heading over to the Royal Ontario Museum in search of lizard venom when you were working on the first GLP-1 treatment for diabetes in 1995. Bob Murphy is still there – he’s head of herpetology, in fact. How did he help you out and what did a salivary gland have to do with regulating blood glucose?

We needed to try and obtain the right kind of lizard DNA to start our cloning efforts. Turns out, Bob had a freezer full of various DNA samples that were very useful in helping us get started. However, after a while, it was clear that we needed to find a real lizard, and they are largely domiciled in the southeastern United States. I needed a bona fide lizard expert to help us with all of the various steps required to obtain a lizard from the United States, and “Dr. Bob”, the lizard expert, was invaluable in helping us along the way. And from that we were able to clone the gene for exendin-4, which ended up being the first GLP-1-related peptide approved for the treatment of Type 2 diabetes.

Tech entrepreneurs often talk about failing – and failing fast – as a badge of honour. You have been incredibly successful in translational research:  multiple classes of FDA-approved drugs, and newer versions of these drugs under clinical development. I imagine you’ve had great trainees and collaborators over the years but there must be more to it. What’s your secret weapon?

First, it is important to note that many amazing scientists all over the world, working in academia and in industry, made dozens of key contributions enabling the development of GLP-1, GLP-2 and DPP-4 inhibitors. I would never take sole credit for discovery of these drugs; that would simply be disingenuous. Translational success involves hard work, collaboration, a great deal of failure, solving road blocks, and yes, lots of good luck and serendipity. We have also developed a fondness for rigorous reproducible science, particularly for testing potential drugs in multiple species, using different experimental models, at varying doses. This kind of science can seem tedious and boring to some colleagues and journal editors, but broadly reproducible data is essential to move molecules successfully along the drug development pathway.

With GLP-1 agents now FDA-approved for the treatment of Type 2 diabetes, what are some of the other effects that look promising for potential future uses?

We are seeing increasing interest in developing more potent GLP-1-based drugs for the treatment of obesity. I think we may see improvements in this area that start to catch up with the impressive weight loss achieved through bariatric surgery. There is also excitement about the clinical results to date in testing GLP-1 therapy in people with Parkinson’s disease. Additional trials are ongoing in populations with Alzheimer’s disease as well as separate trials assessing GLP-1 effects in patients with liver inflammation and fibrosis. So it seems the full therapeutic potential of GLP-1 may yet be realized, but we need to wait conservatively, with cautious optimism, for the clinical trial results.

You mentioned a side interest in reproducibility in translational research. This is a big problem in science. What do you think is at play here – and what does it mean for the public as we interpret the results of any one new study?

We live in an age where much of the world is fascinated with science, as well as advances in medicine. New results are communicated daily, with breathless enthusiasm, often without context. As a result, we may have created huge expectations based on hype, yet the public is increasingly aware that many of the highly touted “breakthroughs” they read about seem to vanish and never materialize. Part of the problem is reproducibility. Scientists, institutions and journals are quick to hype new and exciting findings, for many reasons. We are less willing to keep tabs on which results endure, versus which findings are just not reproducible over time. We risk engendering a loss of trust in science, and in turn, a reduced willingness to invest in science, unless we make changes to our scientific culture at multiple levels.

Finally, a pop quiz: I did a PubMed search to see the scope of your publications – 17 pages of search results, 333 papers. Do you remember your first publication? (Hint: CMAJ, May 15, 1982)?

It was “Smoking Habits in Hospital” with Cheryl Rosen, my girlfriend in medical school, who was finally persuaded to become my wife in 1981. Last time I checked the dates, it seems we have been married a little more than 36 years. Cheryl did a research project on smoking cessation and public health. I think we wrote a letter to the editor together about this topic that was published in 1982 when we were both still trainees. We later went on to publish a few more papers together on the intersection of molecular biology and dermatology. I always considered becoming a dermatologist but instead veered off into endocrinology. Happily, my wife, and later our oldest son, pursued dermatology as a career, and I think these decisions have worked out well for all of us.