"Explore Your Options, Take A Chance"

Roderick MacKinnon delivered the keynote address at Tufts University's
Medical and Sackler School Commencement ceremonies.

Medford/Somerville, Mass. [05.20.02] -- Graduates of the School of Medicine and the Sackler School of Biomedical Sciences, congratulations. This is your day, a day that marks the end of one period of your lives and the beginning of another. It is an honor and a privilege to be here to address you on the occasion of Tufts 150th anniversary.

   I was last here at Tufts twenty years ago, in May 1982, when with my graduating class I took the oath of Maimonedes and received the degree of Doctorate in Medicine. How could I ever forget it, as I approached the platform to receive my medical degree my mother shouted from the audience, 'Here is my son the doctor', I was horrified. At that time my aspiration was to become a family doctor, to practice general medicine. That is the reason I immersed myself in the study of medicine for four years, completed three years of clinical training as a primary care Internal Medicine Resident at the Beth Israel Hospital, and became a board certified Internist.

   But something happened to me along the way. My path took an unexpected turn. Today I'm a biophysicist who studies the atomic structure of the electrical circuitry of living organisms. My life is quite different than what I originally had planned. I still find myself working late into the night, sometimes all night, just like when I was a medical resident. But instead of spending the hours with patients and medical charts I am engaged in different activities, like carrying out all night experiments at high-energy synchrotrons in order to determine the structures of ion channels, the proteins responsible for generating the electrical signals inside of us, the signals that underlie the rhythm of our hearts and the processing of information in our brains.

   Twenty years ago I could not have imagined that my career would take such an unexpected turn from clinical to basic research. I want to tell you how this happened, but first I feel compelled to tell you that along with the feeling of privilege and honor for being asked to be here, I have a strong feeling that I don't really deserve to be here.

   I was convinced that my former teachers, mentors and classmates from the School of Medicine considered me a failure for having deviated so far from my first aspirations of becoming a physician and caring for patients: my stated mission upon entry into medical school. At least that's how I saw it so I was surprised to say the least when I received a call from Dean Harrington and then from President Bacow informing me that I had been selected to receive an honorary degree from Tufts and to address you here today.

   My first thought was, they must have confused me with someone else! I failed my original mission; how could I possibly deserve to address the graduating classes of 2002? My insecurity was only intensified by my wife Alice's response to the news. At first, when I told her, she said, oh what a wonderful honor. A few days later, after hearing my repeated concerns about what I should say, Alice asked what are you worried about? When they give you the honorary degree, tell them how honored you are, thank them, and sit down.

   I explained that such a response would be insufficient for a commencement address. She then gave me a most puzzled look and said, commencement address? You? I nervously said yes, commencement address, me. At that she put her hands on her head, rolled her eyes back, and said oh my god! With that needed injection of support I spent my next several days trying to figure out how I would explain to the Dean and the President that they had made a big mistake and might wish to reconsider!

   Sensing my predicament, Alice, in her inimitable way, had a follow-up comment: just think about what the commencement speaker said when you graduated from Tufts. She was with me at the graduation and knew exactly what my response would be: Are you kidding? I can't remember a thing my commencement speaker said. At which point Alice responded, exactly, they're not going to listen to you anyway, so don't be so worried.

   But as I thought about it further, I began to wonder, really for the first time, how did it all happen? How did I change from the aspiring physician to the biophysicist, carrying out activities that are very far from the bedside? How did my medical education set me on this course? In searching for the answers to these questions I realized that there are some things that I would like to tell you about, a perspective that probably would have been useful for me to hear twenty years ago when I graduated from Tufts Medical School.

   I will tell you a personal story about my own career path. It isn't my intention to bore you with my personal details, but I use my own story as one example of how your medical education, clinical or scientific, has given you many choices in life, probably more than you realize, and to emphasize that what is most important is that you not be afraid to explore your options.

   In medical school I was fascinated by the biochemical and physiological processes that we learned about in classes and readings, and I wanted to know more and more about the mechanisms underlying disease processes. Most of all I remember wondering how the complex machinery of living cells could ever work at all - it seemed simply marvelous.

   It was clear to me at the time, as I am sure it is to you now, that there is so much we do not understand. The thought definitely occurred to me while in my first two years of medical school, the basic medical science years, that perhaps I should stop, focus on one aspect of what I was learning, and pursue research in order to understand it at a deeper level.

   But I wanted to be a physician and recognized the importance of a broad, comprehensive education. Any feelings that perhaps I should pursue a research career were pushed aside during the clinical years of medical school, as I thoroughly enjoyed working with patients. In working with patients it also became clear that there is little room for error in the practice of medicine: ignorance can lead to disaster. The narrow margin of error in medicine taught me to be disciplined, compulsive, and to pay close attention to detail.

   In addition, I found that clinical training introduced me to an unusual kind of learning: I was thrown into the middle of very complicated situations and I'd better learn fast. Many of you know the feeling that I am talking about: sink or swim. Suddenly it was not as simple as reading certain books and knowing what was in them, the kind of learning that was familiar to me. In taking caring of patients I had to be very resourceful, to learn to teach myself by asking questions and by reading. There was so much to be learned.

   The point I wish to make is that to survive and excel as medical students we become masters of self-education. During residency thoughts of scientific research surfaced again. I don't quite know why. I found patient care very rewarding, even to the extent that I chose the primary care track of my residency program. But I found myself wondering more and more about the mechanisms underlying what I was seeing.

   Why do certain drugs such as quinidine, used to treat ventricular arrhythmias, sometimes cause a worse ventricular arrhythmia called Torsade de Pointes? I saw this happen and wondered what is the mechanism. Many such observations fascinated me, and raised questions in my mind about basic principles, and what it would be like to study them. I had no illusions whatsoever that research would be a more useful pursuit than clinical medicine, in fact quite the contrary, but I had this curiosity that wouldn't go away.

   By the beginning of my last year of residency, when my peers were making final plans for medical practice or specialty training I began to entertain seriously the possibility of basic medical research on the subject of how cells make electrical signals. It really fascinated me. I had a few serious problems with this plan, however.

   First of all, I had just spent the last seven years of my life preparing myself to practice medicine, and I enjoyed it very much. Would I be throwing it all away? Basic medical research didn't make any sense at all for me. What could I possibly be thinking? Second, as a practical matter I had accumulated a significant financial debt, not as large as it might have been because Alice had been working as a chemist to support our household during my medical training, but nonetheless, it was about time for me to 'get a real a job' as a friend put it, as I had obligations, responsibilities. And third, I did not have the usual background education to go and study what makes electrical signals in cells.

   I had become very interested in the problem, but I had been studying clinical medicine, not the more typical course of study, such as courses in physics and chemistry. These realities, on top of the fact that I was nearly thirty years old - which seemed old to me at the time - nearly prevented me from listening to a little voice inside that told me I should pursue my fascination. But I finally reasoned that when I'm seventy, thirty will seem young, and no matter what, if I'm pursuing my fascination I will be a happier person than if I'm not. Or at the very least I would have only myself to blame for unhappiness!

   With Alice's support I began studying the molecules that make electricity in cells - ion channels - by entering postdoctoral research studies. That of course meant a salary decrease from the relatively meager amount I had been making as a medical resident. Over the years, I have given Alice many opportunities to hold her head and roll her eyes!

   Perhaps I did not have the formal scientific background of many biophysicists, but my medical education had prepared me in a different way. The self-discipline, resourcefulness, and ability to assimilate information through teaching myself, characteristics that had become a way of life through my medical training, all came to bear on my new problem.

   When I needed to learn about the theory of random processes to make sense of the electrical signals that ion channels produce, I just did it. It seemed evident to me that electrical engineers must know a lot about the analysis of electrical signals so I read extensively in that subject. My approach afforded me a fresh perspective and soon I found that I had a deeper grasp of theory and a way of thinking about the problem than most scientists around me.

   At the same time, while I studied ion channel biophysics I also studied molecular genetics because it was clear that a combination of biophysical and genetic approaches would be needed for real progress. And I noticed something strange. At that time, in the late 80s, there were biophysicists and there were geneticists, but not scientists who were experts in both areas. It made no sense to me at all. Why not just learn everything you need to solve the problem?

   That's what my medical education taught me, to teach myself, to be inventive. In little more than three years I became Assistant Professor at Harvard Medical School and my research proceeded nicely. I was quickly promoted to professor; by most measures things could not be better. But I was not satisfied.

   Despite more than fifty years of research in the field, no one had ever succeeded in visualizing an ion channel. In a sense ion channels were theoretical entities that conducted ions across the cell membrane to make electrical signals. Their existence was deduced and a number of their properties were known through the signals that they produce. But what does an ion channel look like and how does it work?

That was considered the holy grail of bioelectricity. Without knowing the chemistry and structure of ion channels the hope of developing new therapies for the treatment of cardiac arrhythmias, epilepsy, and numerous other disorders on the basis of ion channel pharmacology would be very difficult indeed. The problem, determining the atomic structure of an ion channel was considered impossible. There were several good reasons for that attitude.

   Ion channels are suspended in the membrane of cells; they are known as membrane proteins. To solve the structure of a protein you first have to crystallize it, and very few membrane proteins had ever been crystallized, none of them valence selective ion channels. Despite the supposed impossibility, structure determination was essential and I decided to take a chance and attempt it. Any other approach, it seemed to me, would be a waste of my time.

   Again, I encountered a few logistic problems. First, I was not trained in X-ray crystallography, but then again I had not been formally trained in anything I was doing after I left clinical medicine. I again began to learn through reading, asking questions, and doing. The second problem was a practical one. Where would I get the research funds to do this? The National Institutes of Health, the main government agency for funding biomedical research, was not about to support a proposal written by me, a scientist with no track record in X-ray crystallography, to do something that was considered impossible anyway.

   But if you really want to do something you find a way, and I did. By giving up my professorship at Harvard and going to a new university, Rockefeller, I had the promise of several years of research support to get me going. Of course, when I described my grand plan to Alice you can imagine her response. It went something like this. Let me see, now that you have made it to full professor at Harvard and everything is nice you are telling me you want to sell the house and move to New York City where we have no family or friends so that you can work on the structure of an ion channel? Yes, I told her. How many of your lab members are willing to join you on this adventure? Probably none. I can see her holding her head and rolling her eyes. Come to think of it, Alice should be the one receiving the honorary degree today!

   I moved to Rockefeller University to concentrate on determining the structure of a valence selective ion channel and I was comforted by my closest colleagues' warnings that I had lost my mind and that my successful career would be destined for failure. At some level, I figured, they're probably right, but it still seemed worth trying. Fortunately, the problem was not impossible - is any problem really impossible?

   In a little more than two years we had produced the first atomic structure of a potassium ion channel in 1998, and of a chloride ion channel in January of this year. As you might imagine, being the first to see these marvelous constructions of nature, and to begin to understand how they produce electrical signals was thrilling beyond description. My work is, in fact, bringing me to closer to understanding the chemical basis for how quinidine binds to a potassium channel, where it can alter the electrical signals in the heart, as well as many other issues that I wondered about when in clinical training - the issues that inspired me to become a medical scientist.

   I tell you this story not to suggest that those of you receiving MDs become research scientists and those receiving PhDs become clinicians. Rather, I tell you my story for two reasons, first, to heighten your awareness of the many possibilities that your education has prepared you for, and second, don't be afraid to take chances in your career.

   Many of you have known for a long time exactly what it is you want, your sights are set on a goal, and you will get there. Some of you may still be considering your options. Others may think you know but will eventually come to a fork in the road, as I did. What you should all know is that you are still undifferentiated, like pleuripotent stem cells, with a wide field of possibilities in front of you.

   Your training in medicine and in medical science has created these possibilities. So keep an open mind and take advantage of it. Whether you someday choose a career in medical practice, teaching, scientific research, administration, writing, or forensic criminology, to name just a few possibilities, your medical education will serve you well and give you a unique perspective.

   You might wonder why is it that medical school, probably more than any other formal training, prepares an individual for so many fields? One reason is that a medical education is very broad, covering subjects ranging from molecular biology to ethics: you learn to think in scientific terms and at the same time you think about people, the needs of individuals as well as society as a whole. A second reason why medical education creates opportunities is that society in general holds medical doctors and medical scientists in high esteem.

   Let's face it, health is one issue that concerns most of us at some point in our lives; the interested audience is very large. For this reason, doors will open more readily for you because of your training. Finally, and I think most importantly, your education as doctors and as medical scientists has begun to teach you how to live a rigorous intellectual life, as it has taught you an approach to problem solving that is just as important as the factual information that you learn. This approach will serve you well in any endeavor.

   A last point that I would like to make is that if you develop a fascination, hear a little voice inside telling you to take a road that was not anticipated, don't be afraid to listen to the voice and follow the road. Whether that voice is pointing you to a career change that is different than what you had planned, not the expected route, or telling you to take an unconventional approach within a discipline, don't be afraid to take a chance.

   What is most important is that you find your passion and pursue it. Your medical education has given you many options; do not be afraid to explore them.