Radical View | September 2017

Francis J. Miller, MD
Duke University

DOT: Tell us about your professional background.

While in high school, I decided that I wanted to become a physician. However, since neither of my parents had attended college, I had no idea what the requirements were or what professional options were available to doctors. I was first introduced to research through the honors project I completed in a developmental biology lab while pursuing my undergraduate degree at the University of Iowa in Iowa City. I enjoyed the challenges of research but wanted to be a surgeon, so I attended medical school at the University of Iowa. Once I was on my clinical rotations, I realized that internal medicine was a better fit for me and chose the University of Texas Southwestern Medical Center for my residency. Three years later, I was back at the University of Iowa for fellowship training in cardiology. I had to decide at that point whether to pursue additional clinical training and become an interventional cardiologist or to develop a career in discovery bench research. I wasn’t initially sure that a research career was an ideal fit for me, but I knew that if I didn’t do it then, it would be difficult to re-enter the research field later. I decided to give academic cardiology and research a couple of years, thinking that if it did not work out I would go into private practice.

My initial research was in vascular physiology, specifically nitric oxide-mediated vasodilation in disease. The ability of superoxide to decrease the bioavailability of nitric oxide had only recently been described, and adenoviral-mediated gene transfer to blood vessels was in vogue. My entry into free radical biology was through my examination of whether gene transfer of superoxide dismutase improved endothelial function in disease. Based on this work, I was soon measuring superoxide levels and studying the NADPH oxidases in the vessel and in vascular cells. I was fortunate to get an American Heart Association Postdoctoral Fellowship, which led first to an NIH K08 award and then to NIH R01 and VA Merit Awards. This fellowship and these awards inspired me to continue in the field and gave me confidence. Meanwhile, I continued to practice clinical cardiology and enjoyed being able to spend my mornings seeing patients in the Coronary Care Unit or performing diagnostic cardiac catheterizations and my afternoons discussing new research findings with students or performing mouse surgeries. I have been able to maintain a good balance between clinical and research time, though it sometimes feels as though I have two very different, yet complementary, jobs. I moved to Duke University in the spring of 2016 after more than twenty years on the faculty at Iowa, having benefited from a rich collaborative research environment, including colleagues in the Free Radical and Radiation Biology Program (Drs. Oberley, Spitz, Buettner, and Domann).

DOT: Briefly describe your research interests and what is the most notable research achievement from your lab.

My research has focused on examining the role of reactive oxygen species in vascular cells and the regulation and function of the NADPH oxidases. Early in my career, I was struggling with a negative result and realized that there was not an assay to obtain the type of data I needed to determine the topographic distribution of superoxide levels throughout the vessel wall. Consequently, we developed an assay using dihydroethidium on frozen sections, which allowed the assessment of superoxide levels in the different layers of vascular tissue. This study became highly cited, not because of its primary findings but because of the method we described. This is how I first broke onto the scene of vascular redox biology in 1998. Another memorable “aha moment” was when we were trying to identify the location that Nox1 NADPH oxidase generated superoxide and why its function was dependent on the ClC-3 Cl-/H+ antiporter. I was looking at cells under the confocal microscope after incubating with OxyBurst, a redox-sensitive fluorescent dye conjugated to cell impermeable albumin, when I noticed fluorescent dots in those cells with ClC-3 and no fluorescent dots in cells without Nox1 or ClC-3. This was the first recognition that Nox1 was generating superoxide within endosomes. I happened to be working in the coronary care unit at that time and was so excited about this finding that later that afternoon, I shared it with my patient, James Van Allen, the famous physicist from Iowa who discovered the radiation densities in the atmosphere known as Van Allen Belts.

DOT: What are the most significant elements that have shaped your career?

My supervising cardiologist during my third-year cardiology clerkship was Dr. Melvin Marcus, an internationally recognized coronary physiologist with an entertaining personality. As he stood one day at the blackboard enthusiastically explaining the biology and importance of platelet plugging in the microvasculature, I had an epiphany that physicians can do research and still see patients. By that time in my third year, I was questioning my plans to become a surgeon. With Dr. Marcus’ help, I obtained an American Heart Association Medical Student Fellowship, which allowed me to take a year off of medical school to do research and decide which medical specialty I would pursue as a next step. It was an exciting time to be at Iowa, and during my year off I had frequent contact with a distinguished group of cardiovascular investigators, including Mel Marcus, Michael Brody, David Harrison, Don Heistad, David Gutterman, Allyn Mark, and Frank Abboud. That experience sparked my interest in vascular biology and cardiology and set me on the path to where I am today.

DOT: What has changed the most about scientific research during your time as a physician-scientist?

There have been significant changes in both the clinical and research expectations for being a physician-scientist. From the clinical perspective, it has become more difficult to balance the increasing demands of clinical work, teaching and research. Whereas in the past, a physician-scientist could spend a couple of hours a day doing clinical work and focus on research for the rest of the day, now the documentation and supervisory expectations of clinical duties can consume most of the day. With respect to research in my field, experiments moved away from a focus on vascular physiology toward a focus on studying cellular molecular biology with the expectation of uncovering molecular mechanisms. These two changes, combined with increased competition for funding, have necessitated more time devoted to grant writing. The other noticeable change has been the increasing degree of team-based research.

DOT: In your mind, what is the best way to bridge basic science, clinical research and medicine?

Earlier in my career, a single principal investigator and a team of graduate students, postdocs or technicians collected most of the data for a given research project. This traditional structure has changed over the past several years, especially in biomedical research, such that research projects require contributions from multiple investigators with different and complementary skills and knowledge. This team science approach is even more necessary when bridging basic and clinical science. The organization of the research lab needs to include opportunities for a diverse collection of investigators to sit around the same table to pursue a common goal. The basic scientist needs to become familiar with the pace, culture and challenges of treating patients, and the clinician needs to appreciate the approach, limitations and challenges of basic research. The most successful biomedical research involves an integrative team of investigators working together.

DOT: What are your hobbies outside of your career?

With three children and a wife who is also in medicine, I have tried to adopt those hobbies and activities that I could do with my family, including boating, water skiing, snow skiing, traveling and golfing. For many years, I delegated much of my free time to my kids’ athletic practices and tournaments, music and dance performances, and school-related activities.  Now that they are out of the house and live in different states, I will have to find something else to do when we’re not together.

DOT: How do you feel SfRBM has contributed to your successes?

For me, the most valuable aspect of SfRBM has been the annual meetings that have introduced me to other free radical investigators, many of whom work in different research fields that I would otherwise never have met. In these meetings, I have generated new ideas, gained new collaborators and made new friends.