It is stylish (and expedient) at present to emphasize the ‘translational’ aspects of biomedical research and to act as though such projections/predictions of what might go from ‘bench-to-bedside’ were readily made. As anyone who does this work for a living knows, they are not. Whatever successes in translation characterize the research described here are the result of asking one big question—‘how is body weight regulated in humans?’—and then using whatever tools (physiology, genetics, cell and molecular biology) and ‘models’ (animals, humans and cells) are available to answer the corollary questions that arise from the big one: what are the physiological responses to weight perturbation?; what genes mediate the defense of body weight?; how do these genes act in concert?; what developmental and post-developmental processes influence the underlying neural substrates for this homeostasis? It seems to me that students often do not get the message that a good way to do research is to pick an important question, and to pursue it relentlessly over time, trying to avoid experiments that are doable, but not so important, in favor of the more difficult, time-consuming and risky experiments that are likely to move one closer to the big answer. There are good, even urgent, reasons to ignore/invert this advice in service of one’s CV and career. But that strategy also deprives one of some of the thrills inherent in ‘big picture’ research. Einstein’s advice is relevant here: ‘I have little patience with scientists who take a board of wood, look for its thinnest part, and drill a great number of holes where drilling is easy.’
Note: The views expressed in this historical review are mine, but reflect the important intellectual interactions I have had over 30 years with many mentors, associates, students and collaborators. Among these are Jack Crawford, MD, who introduced me to ob mice as a pediatric endocrinology fellow at the Mass General in 1973–1975; Jules Hirsch, MD, who pioneered in the study of the functional anatomy of adipose tissue and who provided me with the opportunity and protected time to learn adipose tissue biology, energy metabolism and mouse genetics; Jules also secured funding from the Rockefeller University to start the mouse project that led to the cloning of ob and db; Jeff Friedman, MD, PhD, who had the courage as a starting assistant professor to engage in the collaborative effort that, over a period of 9 years, led to the identification of the ob and db genes; and to Doug Coleman, who provided expert advice, some critical animals, and steady encouragement. Extraordinary students and fellows who worked on the ob/db and fa projects included Nathan Bahary, MD, PhD, Wendy K Chung, MD, PhD, Yiying Zhang, PhD, Don Siegel, PhD, Streamson C, Chua, MD, PhD, Gary Truett, PhD, Jordan Smoller, MD, and others, and a large number of dedicated young technicians. My longstanding associate, Mike Rosenbaum, MD, for the past 20 years has led virtually all of the clinical studies related to bioenergetics of weight homeostasis, and the physiology of leptin in that context. More recently, Joy Hirsch, PhD at Columbia, has collaborated with us on functional magnetic resonance-imaging studies in weight-reduced subjects. Other collaborators on these studies include Rochelle Goldsmith, MD, Bo Bogardus, MD, Eric Ravussin, PhD, Krista Vandenborne, PhD, Louis Aronne, MD, and Laurel Mayer, MD. Members of the New York Obesity Research Center—Xavier Pi-Sunyer, MD, Steve Heymsfield, MD, Dympna Gallagher, PhD, Harry Kisileff, PhD, and Carol Boozer, PhD, have all helped me and my associates in various ways throughout the years. Extraordinary nursing staff and research dietitians have likewise been critical to our studies of energy homeostasis in human subjects. Finally, our research subjects themselves (human and otherwise) have contributed selflessly to our efforts to understand the molecular physiology and molecular genetics of obesity.