Robert J. Lefkowitz (New York, United States; 1943) graduated from Columbia University College of Physicians and Surgeons in 1966 and served as Clinical and Research Associate at the National Institutes of Health from 1968 to 1970. Upon completing his clinical training in 1973, he was appointed Associate Professor of Medicine and Assistant Professor of Biochemistry at the Duke University Medical Center. In 1977, he was promoted to Professor of Medicine, and in 1982 added the post of James B. Duke Professor of Medicine. An Established Investigator of the American Heart Association from 1973 to 1976, he has been an Investigator of the Howard Hughes Medical Institute since 1976.
He has served as president of the American Society for Clinical Investigation and of the Association of American Physicians, and on the council of the U.S. National Academy of Sciences, where he is also an elected member.
Lefkowitz received the Nobel Prize in Chemistry in 2012. Further recognitions for his professional achievements include the Gairdner Foundation International Award (1988), the Association of America Medical Colleges’ Biomedical Research Award (1990), the American Heart Association’s Basic Research Prize (1990) and its Research Achievement Award (2009) and the 2007 National Medal of Science, bestowed by the U.S. government.
Speech
Biomedicine, 2nd edition
Robert J. Lefkowitz grew up in the Bronx borough of New York, the grandson of Eastern European immigrants. His vocation came to him at an early age through his idol, the family doctor: “He did home visits, which is very uncommon now. From the time I was small I wanted to cure people like he did.” His other major professional influence has similar childhood roots: “I loved novels where the hero was a doctor.” His high grades earned him a place at a public secondary school specialized in science, after which he was able to train in the prestigious College of Physicians and Surgeons at Columbia University (New York) with the help of his family and some scholarship money.
And so began the career of the man who discovered the molecules targeted by over half of today’s prescription drugs, and now winner of the BBVA Foundation Frontiers of Knowledge Award in the Biomedicine category. A researcher, and cardiologist, whose insights have found application in the treatment of numerous diseases, including such common ailments as arterial hypertension and diabetes.
This summary may give the impression that Lefkowitz pointedly and clear-sightedly orients his research toward clinical aims. Not so. Lefkowitz has left most of his professional choices to intuition. “When I think about my career” he muses, “I feel I’m not guiding it at all. It’s like a wild horse galloping along with me holding onto the neck like crazy and trying not to get thrown off.”
The metaphor suggests – correctly – that Lefkowitz’s research area is a hive of activity: “It is certainly a competitive field and has been since I started in it almost forty years ago.” The field he refers to is the study of how cells receive signals from their environment and process them internally. More concretely, the study of cell receptors, the gateway through which compounds enter the cell. What has made Lefkowitz the leading light in receptors is largely his boldness as a researcher. In the 1970s, when many scientists doubted such molecules even existed, he was the first to prove them wrong.
“Back then, the idea that cells had specific receptors, molecules that could bind to drugs and hormones, was pretty controversial. But for me it was clear that they had to exist. I never doubted, not even for a moment, that I would be successful; perhaps out of what I would now call youthful arrogance,” he explains. “I saw it as a mature field, where there were important results to be achieved. I didn’t even view it as a particularly courageous thing to do; it was just a question of developing the right techniques. You know how it is. When you’re young you have this certainty that you are right. At times I think if I’d known how difficult it would be, I would never have dared, but then, at age thirty-two, it all seemed easy.”
Lefkowitz showed that receptors are in fact proteins dotting the cell membrane, which change shape when a specific chemical signal fits inside them – like a key inside a lock. The signal is thus detected and channelled through to the inside of the cell. This is the way pharmaceutical drugs work.
In 1973, Lefkowitz set up his own research program at Duke University, where he still serves as James B. Duke Professor of Medicine and Biochemistry. In a few short years, he was able to isolate the genes of all known adrenergic receptors. He chose this kind of receptor because of his work as a cardiologist:
“I wanted to study receptors that had an immediate effect on cardiovascular diseases, and adrenaline receptors fitted the bill.” This led to the discovery that adrenergic receptors are proteins that weave back and forth across the plasma membrane seven times, i.e., crossing the cell wall at seven points. But there was more to come. Lefkowitz encountered a similar structure in around one thousand other receptors. Nowadays these ubiquitous molecules go by the name of seven-transmembrane-spanning receptors and we know that they regulate “virtually every known physiological process,” Lefkowitz continues. They are the “locks” permitting entry to numerous drug types, among them beta-blockers, angiotensin receptor blockers, antihistamines or the body’s own adrenaline.
Seven-transmembrane-spanning receptors also play a part in processes like smell and taste, sensations of pleasure and pain, and aspects of visual perception: for instance, the receptor for the rhodopsin molecule, which detects when light strikes the retina, is made up of seven segments. Is this a case of the organism finding a structure that works and exploiting it for all it’s worth? “These are complex processes, but there is also an elegant simplicity in the fact that all these receptors respond to the same principles,” says Lefkowitz. “It’s been a continuous amazement. I never dreamt that there could be about a thousand different receptors all belonging to the same large gene family, sharing the same structural properties.”
Lefkowitz has also discovered the reason why so many drugs gradually lose effect. Receptors are not immutable, and are in fact transformed by the substances with which they interact. He and his team have found new protein families that are able to desensitize seven-transmembrane-spanning receptors, which could explain, for instance, the diminished efficacy over time of epinephrine or morphine.
Robert Lefkowitz has worked as an investigator at the Howard Hughes Medical Institute since 1976, and continued to practice as a clinical cardiologist until his sixtieth year. Mentor to over 200 graduate and postdoc students over the last three decades, he has authored more than 850 original papers cited on more than 95,000 occasions. He has also acted as advisor to various pharmaceutical or biotechnology companies and holds around twenty patents, although this is very much a second-string activity: “I don’t know the exact number of patents I own or precisely the stage they are at. That gives you some idea of my priorities. My heart has always been in the academic world,” he confesses. “What I most value is the freedom to pursue whatever scientific goal I feel drawn to at each moment, and you can’t do that in a commercial context.”
Hence his reluctance to do research directly for industry or, as he puts it, to “go over to the other side.” Or at least to work for others, because two years ago, he co-founded a biotech company, Trevena, that has just started clinical trials of an anti-heart failure drug: “It’s a nice outlet to have more of a direct hand in translating my basic research into the clinical arena.”
