June 10th, 2013

Research During Fellowship: Perspectives from the Protégé and the Mentor


In the first part of this post, CardioExchange’s John Ryan writes about the research he performed during his cardiology fellowship under the mentorship of Stephen Archer. In the second part, originally delivered at the Resident Research Day at Queen’s University, at which he is Professor and Head of the Department of Medicine, Archer gives his “elevator speech”, explaining what it means to start a career in research.

John Ryan: When I was looking for a cardiology fellowship, I was told that I should think about it as a form of apprenticeship. Tom Ryan told me, “Think about when Paul Dudley White started them originally. People would come to work with him one-on-one over the course of a few years.” With that in mind, I was hooked when I met Stephen Archer during my interview day at the University of Chicago and he told me the things we could do in the world of pulmonary arterial hypertension (PAH). Admittedly, I had no idea what he was talking about as he discussed mitochondria, how they divide and rejoin and how they play a role in disease processes such as cancer, heart failure, and PAH. But his enthusiasm, expertise, and interest in me seemed to equate with what Tom Ryan advised me to look for.

After finishing my clinical years of fellowship, I entered into the Archer lab without any identifiable basic science skills. Many months went by, with a lot of failed experiments and contaminated RNA. Despite the mistakes, I had to present my data week after week at every lab meeting, flawed though it was. It took about 6 months before I had reproducible results. Then about a year into our work, I noticed a change. I travelled to a series of meetings to present our preliminary results. I found that I was able to talk the language of the other investigators. I felt like I had completed an immersion course and was now able to converse with the locals. I was far from fluent but I was able to get my point across and, more importantly, understand what they were saying.

This past month our work was published in the Blue Journal. We showed that animal models of PAH could be reversed by fusing the mitochondria of pulmonary artery smooth muscle cells. Furthermore, we showed that the increased rates of proliferation seen in pulmonary artery smooth muscle cells could be repressed by shifting mitochondrial dynamics and metabolism towards a more normal phenotype. Obviously this is all preliminary data, and there is a lot to be done before this translates into clinical practice, if ever. However, that was just part of what I discovered while I did my PAH basic science work. I also learned how to maintain the diligence to see a project to completion, how to problem-solve failed experiments, and — most important — how to develop an awareness that the truth is indeed out there.

Choosing a fellowship is not easy and there are a lot of moving parts, such as geographic considerations, the ability to get “your level 2s”, as well as US News and World Report rankings. But Tom Ryan was right. The most important aspect of fellowship was having someone who was interested in my career and my thought process, because that is what I now use every day.

Stephen Archer: This is my “elevator speech.” A friend in Chicago taught me this term. The elevator speech is the quick headline you tell your boss when he/she asks you, “What are you up to?” It is meant to be quick, concise, and to convey your big idea before you exit the elevator and your boss glides on upward to the penthouse. With that introduction, here are my thoughts on research for medical residents considering a career with a significant research component.

Research is a disruptive process of discovery conducted by skeptical scientists who believe the conventional wisdom is wrong, or at least incomplete. The questions may be practical or exotic but in the process of testing a hypothesis, the ball of knowledge is almost always moved a little further down the field. Over the ages researchers have often found themselves on the wrong side of state and church. Research challenges governments and religions, putting the sun in the center, revealing the relatedness of humans and animals, and even allowing manipulation of our genetic code.

In the past, scientists were defenestrated, excommunicated, and mocked. In the modern era, scientists have been more often lionized for their discoveries, which have lifted us into space, developed treatments for many lethal diseases, given us unprecedented creature comforts, and prolonged longevity. However, even now, science in Canada is under threat with insufficient funding and an ill-informed government agenda to prioritize research, which is “practical” in the very short term.

Each of you has the potential to perform research, to discover, to perfect, and, in so doing, to enrich your community, country, and make a contribution to future generations. It matters not whether the questions you ask are of the molecular, physiologic, medical, ethical, or historical genre. If your question is precisely framed, the measurements and analysis rigorous, and you let the data speak without bias, you are treading the scientific trail.

It’s not easy to be a scientist in an era where fewer than one in five grants is funded. It is particularly difficult to live the divided life of a clinician-scientist, answering both to the patient and the scientific muse.

Of course, not all scientists are inspired and being “in the game” does not make you a genius. A certain rare combination of talents is required for truly great discovery. As Denis Diderot, French enlightenment philosopher and author, noted in the mid-18th century how we discover:

“We have three principal means: observation of nature, reflection, and experiment. Observation gathers the facts, reflection combines them, and experiment verifies the result of the combination. It is essential that the observation of nature be assiduous, that reflection be profound, and that experimentation be exact. Rarely does one see these abilities in combination. And so, creative geniuses are not common.” Denis Diderot, Pensees sur l’interpretation de la nature 1753, XV

For your efforts, conducted in the wee hours and often presented to wee audiences, you will garner that great satisfaction of knowing how things work, of knowing things that others do not, and of changing how we understand our world. You may face rejection, skepticism, and perhaps ridicule. In defense of your sanity, seek out supportive environments that value discovery and innovation. If you are at the beginning of your journey, find a mentor; there’s too much to learn on one’s own. A mentor can give you a sober critique of your approach and your science; often delivering the clear message to change course or improve quality. At all stages of your career, find collaborators and groups of colleagues with whom you can discuss, refine, reject, and perfect ideas. Scientific discovery whether epidemiologic, clinical, qualitative, translational, or molecular builds on the shoulders of fellow scientists who preceded us. As Stella Didacus (Diego de Estella), noted in the mid-16th century:

“Pygmaeos gigantum humeris impositos, plusquam ipsos gigantes videre. (Dwarfs on the shoulders of giants see further than the giants themselves.)”

Research is about independence, honesty, and a belief in the value of fumbling toward a distant truth that may be more than a lifetime’s journey. Science is not about prizes, it is not guided by politicians or clerics, it is not defensive of its errors, and it is not the possession of one people, one country, or one gender. The best of scientific spirits knows that the high-impact discovery of 2013 will be at best partially correct a century on, and more often than not a source of amusement for future generations.

Today is a celebration of your research efforts. Your mentors are proud of you and, as Department Head, I am inspired by your enthusiasm. Today you join scientists through the ages and perhaps share the common experience of Discovery, as summarized by Albert Einstein,

“In the light of knowledge attained, the happy achievement seems almost a matter of course, and any intelligent student can grasp it without too much trouble. But the years of anxious searching in the dark, with their intense longing, their alterations of confidence and exhaustion, and the final emergence into the light – only those who have themselves experienced it can understand that.”


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