July-August 2017, Volume 14, Issue 4
Shifting the Focus of Medical Research From the Bench to the Bedside
Published on: July 01, 2017
Unlike other commentators who have been featured in these columns, I had no role models to guide me in my career path because clinical research, as we know it today, was not being performed in the mid-1960s. Instead, clinician researchers focused their efforts on understanding the pathophysiology of disease and not on solving the problems that they encountered in clinical practice; their research in the laboratory was disassociated from their activities in the clinic.
After I graduated from medical school at Melbourne University in Australia, in 1959, I completed four years of residency training in internal medicine and an additional year in laboratory hematology. It was then that I developed an interest in research, but I had no idea how to go about obtaining the necessary training. I sought advice from Professor Carl de Gruchy, a prominent Australian hematologist, who suggested that I specialize in thrombosis. He said that thrombosis bridged hematology and cardiology and would become an important field in medicine. He encouraged me to locate suitable training positions, so I applied for, and obtained, research fellowships at Washington University in St. Louis, Missouri, where I worked with Drs. Sol Sherry and Tony Fletcher; the London Post Graduate School in London, U.K., where I was fortunate to be Professor John Dacie’s sole trainee; and in Toronto, Canada, where I worked for Dr. Fraser Mustard. These researchers were giants in their fields, and of the many lessons that I learned, two stand out and continue to serve me well: First, to succeed in research, a person requires passion, “stick-with-it-ness,” and stamina. Second, don't give up on a problem because you lack the expertise to solve it.
In 1968, I returned to a faculty appointment at Melbourne University in the Department of Medicine headed by Professor de Gruchy. I chose venous thromboembolism (VTE) as my clinical field and used the training received overseas to set up a platelet/coagulation/fibrinolysis laboratory. My laboratory research was opportunistic and mainly phenomenological, though I did use the laboratory to support clinical studies with anticoagulants and with streptokinase. I was shocked to realize that almost all patient management decisions lacked a firm scientific basis. Even more shocking to me was that physicians caring for patients were unaware of the flimsy evidence on which they made many of their clinical decisions. Venous thrombosis and pulmonary embolism (PE) were diagnosed on clinical grounds, and anticoagulant management was haphazard and not standardized. It was then that I decided that I would focus my research on problems that I encountered in my clinical practice and that I would use my laboratory to complement patient management. This shift in research philosophy, in which the research question is driven by patient-important problems and in which the laboratory is used to help explain unexpected findings in clinical trials was novel at the time and provided the basis for evidence-based medicine.
I performed clinical studies which convinced physicians that they should use standardized diagnostic testing to confirm a clinical suspicion of VTE. I introduced (and personally performed) venograms to confirm a diagnosis of deep vein thrombosis. I standardized heparin monitoring, switching from the whole blood clotting time to the activated partial thromboplastin time, and I standardized prothrombin time monitoring for warfarin. I obtained local funding for a nonrandomized trial that showed that streptokinase was much more effective than heparin in lysing PEs. I also performed an experimental study in pregnant rabbits to determine the optimal time to switch from warfarin to heparin in pregnant mothers (with prosthetic heart valves) to limit bleeding in both mothers and their fetuses.
My clinical colleagues were very cooperative, supportive, and collegial. I was hailed as a success in Melbourne, but I sensed that my clinical research lacked rigor. Then, in 1969, my life changed! I was invited to pay a visit to the newly formed Faculty of Health Sciences at McMaster University in Hamilton, Ontario. When I visited, I was impressed with the energy, enthusiasm, creativity, and other outstanding qualities of the founding members. I was offered an appointment but was torn by obligations to my family and colleagues in Melbourne. Two factors swayed me. My wife told me that we should “go for it.” Additionally, I had several long discussions with Dr. David Sackett when I visited McMaster. David, who at my age (mid-30s) was founding Chairman of the Department of Clinical Epidemiology and Biostatistics, was the missing link that I was seeking in order to perform worthwhile clinical research. He taught me how to focus my research on patient-important questions and outcomes and to design rigorous clinical studies required to change clinical practice. Soon after I moved to McMaster (in December 1969), I met Dr. Michael Gent, a mathematician who morphed into an outstanding biostatistician. The three of us became firm friends and colleagues, each with our own growing research groups, but sharing a common aim to perform clinical research that improves clinical practice. Dave and Mike collaborated with and advised many faculty members in a variety of specialties, but my group and I concentrated on clinical research in thrombosis.
The McMaster environment was enormously supportive of our research, as was the Canadian funding scene. Throughout a 45-year period I mentored, advised, and collaborated with numerous outstanding clinical investigators, some of whom stayed and joined the McMaster faculty and others who moved to Faculties in Canada, Australia, Europe, Asia, and the United States. Some of my earlier fellows and recruits such as Drs. John Kelton, Jeffrey Weitz, and Mark Levine branched out into their own fields and became international leaders in their respective areas. Others such as Drs. Russell Hull, Graham Turpie, Jeffrey Ginsberg, Harry Buller, Giancarlo Agnelli, Phillip Wells, Gary Raskob, Agnes Lee, Mark Crowther, David Anderson, Clive Kearon, and John Eikelboom remained in clinical thrombosis research and became famous in their own right. Working with collaborators and trainees during a span of almost 50 years, I performed research that changed clinical practice. I established clinical standards for the laboratory monitoring of warfarin and heparin and introduced the international normalized ratio in North America. We demonstrated the benefit of aspirin in stroke prevention, established standards for the short- and long-term treatment of VTE, the diagnosis of venous thrombosis and PE, and the out-of-hospital treatment of venous thrombosis. We performed pivotal studies on the prevention of venous thrombosis with anticoagulants and mechanical devices, and my group was one of three that demonstrated the clinical advantages of low-molecular-weight heparin. More recently, we were involved in some of the pivotal studies with direct acting anticoagulants in the prevention of stroke in atrial fibrillation, and in the prevention and treatment of VTE.
I remain involved in clinical practice and retain my passion for discovery and for teaching new fellows. My students have become my teachers. Drs. Sackett and Gent (who were never my students) taught me methodology and the rudiments of biostatistics. Dr. Weitz taught me biochemistry, and Dr. Gordon Guyatt refined my knowledge of grading evidence and convinced me of the importance of including patients’ values and preferences in clinical decision-making. Now at the age of 82, I am fortunate to belong to an outstanding research group led by one of my former students, Dr. Eikelboom, and I continue to mentor and learn from fellows and new faculty who are members of our group.
Of course, I have other passions. I love spending time with my wife of 54 years and family made up of three children, four grandchildren, and two great-grandchildren, whose ages span nine to 55 years. I have always loved participating in sporting activities and have graduated from playing tennis and squash to the more sedate (but fiendishly difficult) game of golf, to which I am moderately addicted. I enjoy reading history, science, and good mysteries.
Finally, I showed this piece to two of my colleagues, each whom told me that it was too light on showcasing myself and too strong on highlighting my colleagues. But, they missed the point. I was not being overly generous. My success in research has been strongly dependent on three factors: my passion for learning; my ability to attract smart young researchers and provide an environment that entices them to stay; and the wonderfully supportive environment at McMaster University, which was unparalleled.
Thoughts From a Protégé
I was completing fellowship training in the United States when I became aware of the innovative research studies coming from McMaster University. When I visited the campus and spoke with potential supervisors, I met Dr. Jack Hirsh and immediately fell under his spell. Jack was made for the role of “mentor,” even long before the actual concept of mentorship became popular. It seemed impossible to me that such a modest person could simultaneously have a crackling intellect, an intense curiosity, and an energy level well beyond the Tasmanian devil of his home country. Jack was also nice — terribly nice.
When I first met Jack, I had a foundation in basic science, but I had not acquired the ability to align bench research with patient care. In the area of translational research, Jack Hirsh was a master without peer. He did not invent the concept of evidence-based medicine, but he was certainly one of the first clinician-scientists to harness its remarkable power to answer important clinical questions. Each week, the clinical and research fellows would update their research at our meetings. The educational experience was remarkable. Jack taught us that a failed experiment was often as informative as a successful one. Above all, he showed us the power of unbridled optimism in a field where most experiments fail and some patients are beyond our help. We made our pilgrimages to Jack’s office where he would assume his characteristic posture: leaning forward, listening intently, one hand under each thigh, legs swinging below the chair. Like bloodied fighters, the research fellows would explain our (often) failed experiments, while Jack asked questions. Throughout this process, our initial pessimism (often a sense of pending doom) turned into faint hope, and then miraculously into outright optimism. We came to believe that we were on the threshold of success, and only a few more experiments in a slightly different direction could lead to victory. A key principle of research that Jack taught me is, “What is the question?” Those four plain words represent not just the question of that particular experiment, but the value of the research itself. Our ability to ask and answer Jack’s trademark question is what separates workmanlike experimentation from truly important research.
I have learned through a nearly four-decade-long career in medicine that this is not a solo sport. Everything depends on the people around you. They set the circumstances, the examples, and occasionally the limits that define our professional progress. At McMaster, Jack was building a team. He was the force that built a team of achievers, consecutive clusters of McMaster health scientists who went into the worlds of academia and medicine and became leaders. He made research a team sport by the sheer force of his example and leadership. I can count at least fifty scientists, half a dozen departmental chairs, and at least three medical school deans scattered across Canada and the United States who owe big parts of their careers to Jack. I am one of them.
Jack’s intensity in research also extended to sports. With each passing decade, Jack picked up and invariably conquered a new sport, taking them on with a ferocity that exhausted everyone, except of course himself. I watched him cycle through one sport per decade, including tennis, squash, and jogging. All the same. All predictable. Seldom did Jack’s energy wane. Instead, it would take about a decade for accumulated injuries to impose a switch. Jack’s current sport is golf. I recall playing with Jack in the first few years he took up the sport. He was extoling (with some authority) the value of a natural swing. To the casual observer, the swing could only be called natural if shoulder entrapment prohibits raising the club face higher than waist-level. That day, I defeated Jack, and vowed never to play him again since I knew I could never replicate the outcome. His swing has improved, his game has improved (he often scores his age), and his former students receive the frequent news that he has added to his collection of holes-in-one. He’s up to four. From the white tees.
—John G. Kelton, CM, FRSC, MD
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Executive Director, Michael G. DeGroote Initiative for Innovation in Healthcare; Dean Emeritus, Michael G. DeGroote School of Medicine; Dean & Vice President Emeritus, Faculty of Health Sciences; McMaster University, Hamilton, Ontario, Canada