Author: [AUTHOR] Published on 5/1/2021 12:00:00 AM

Dan Roden, MD, Professor of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee

What professional accomplishment are you most proud of?
I have been very fortunate to have spent my career in an environment that has trained me and allowed me to grow new science and clinical work in my own group and across our institution. So I don’t want to point to one specific accomplishment, but rather highlight how my training as a clinical pharmacologist has always forced me to ask “why” and “how,” to question conventional dogma, and to think about how to apply emerging experimental paradigms—at the bench and in people—to understand a fundamental question in clinical pharmacology: Why not everyone responds to drug therapy in the same way.

I’ll describe two ongoing themes in my work. The first theme is very specific, and that is studies of the drug‐induced long QT syndrome. I remember seeing a patient with quinidine‐induced polymorphic ventricular tachycardia (torsades de pointes) and being told that this was an odd arrythmia, and its mechanism was a mystery. I was a fellow at Vanderbilt working with Dr. Ray Woolsey at the time and we were studying NAPA, the active metabolite of procainamide, as a potential antiarrhythmic, and we had a case of NAPA‐induced torsades. Later, Ray supported my excursion to Dr. Brian Hoffman’s lab at Columbia to learn the rudiments of basic electrophysiology. I was thinking about a project and I knew that Hoffman’s group had shown that NAPA and slow simulation rates and low extracellular potassium— those are the clinical conditions under which torsades with quinidine. I won’t forget the day I actually saw my first quinidine‐induced EAD!

That’s not the end of the story. We had recruited Luc Hondeghem, a leader in thinking about drug effects on individual ionic current in the heart, to Vanderbilt, so I spent a year in his lab learning how to record individual currents, ultimately showing that quinidine prolongs action potential by blocking a current we now call IKr. I was also tutored around that time on how to clone ion channel genes by Tamkun, another new recruit to Vanderbilt. Then in the early 90s, Al George, a former Vanderbilt chief resident who had left to learn nephrology and ion channel biology, was recruited back, and that started a 25‐year collaboration focusing on the functional consequences of ion channel mutations. It was Al who suggested we start collecting DNA from patients with drug‐induced arrhythmia. I think that’s because cardiac repolarization is a pretty complex biologic system, so a subclinical acquired or even genetic lesions are present. I coined the now widely used term “repolarization reserve” to describe this idea in 1998, and we continue to try to understand why some patients have reduced repolarization reserve and how to identify those patients. That work involves generating induced pluripotent stem cells from patients with torsades and studying IPSC‐derived myocytes, looking at the functional consequences of ion channel variants in very large DNA banks (including Vanderbilts’s BioVU), and some very exciting new work studying the functional consequences of hundreds of mutations in ion channel genes using new techniques in high‐throughput functional genomics.

The second theme I’d like to highlight is the development of our biobank BioVU to advance an agenda in Personalized Medicine at Vanderbilt and nationally and internationally. I’ve served as institutional PI for BioVU since we started planning in 2004. BioVu now houses 250,000 DNA samples coupled to electronic health records (EHRs), making it the largest such collection at a single academic institution worldwide. The idea had its roots in our strengths in clinical pharmacology, and in particular in pharmacogenomics, as well as an early implementation of an HER based on institutional strengths in Biomedical Informatics. The initial driving vision was that increasingly cheap genotyping and sequencing would allow us to deliver to every patient and their HER important pharmacogenetic variants even before a culprit drug was prescribed. To enable that vision, we needed the biobank to address questions like which variants are important, and how to store and deliver them. BioVU has enabled a new generation of faculty and trainees to be proficient in Big Data analysis, and that in turn has enhanced our ability to be leaders in an emerging science that uses the HER as a phenotyping and data delivery platform for personalized medicine. And Clinical Pharmacology is a key component of that vision.

What is the most important leadership lesson you have learned the hard way?
I think the most important thing that leaders do is to create environments for people around them to succeed. Easy to say, much harder to execute. In my leadership positions, I have been struck by how much time and effort I have had to devote to keeping things running smoothly—thinking about space, faculty development, funding. When things are working no one notices—it is only when something does not work that people notice, and notice in very loud ways sometimes. Leading a large enterprise of any kind means there will always be issues—underperforming or unhappy faculty or staff, funding gaps, overperforming faculty who are being lured away. One lesson is real crises are few and far between and each issue has to be thought through, deliberately and dispassionately. Keep your eye on the long‐term goal—where do we want to be, and how will we get there?

Who has inspired you in your career?
We are all a product of a complicated environment. As I reflect, I understand increasingly that my worldviews were formed first and most importantly by my parents, holocaust survivors who made a new life in Montreal. In university, I was a math major, but mostly a rabble‐rousing college journalist, something my parents did not embrace. My dad was a doctor, and I always thought medicine could combine science and a people‐helping mission (I still think that). After college I was working as a reporter at the Montreal Gazette when I was accepted into medical school—I told my father I’d try it for a couple of weeks, and here I am.

When I was a resident, I did an elective rotation in Clinical Pharmacology, which was very clinically oriented. I really enjoyed it so I decided to try a fellowship in clinical pharmacology for a year or two to learn more about things like drug interactions and pharmacokinetics. I was fortunate that Canadians who came out of the medical division as leaders at Vanderbilt, John Oates and Grant Wilkinson, were willing to take a chance on someone like me who really had no research experience to speak of.

So how did I get to where I am? Support from my family, great mentors, colleagues, and trainees, and a wonderfully supportive environment. It really helps to be able to enjoy writing, and I think I do that pretty well—that is a product of high school and college.

When you aren’t working, how do you spend your free time?
In ordinary times, we like to travel to visit exotic places, friends around the world, and mostly see kids and grandkids. COVID‐19 has changed all that so my free time is devoted to making sure I get my 10,000 steps just about every day. I have always been a crossword puzzle fan and my wife and I now collaborate. We are getting pretty good at solving even the Friday and Saturday New York Times puzzles in less than a half an hour. She knows fashion and contemporary culture better than me and I help with the science geek stuff. I took up golf a couple years ago and look forward to re‐taking it up. I’m really terrible, but it is great relaxation.

Dr. Roden has been a member of ASCPT since 1982.