1998: Robert J. Lefkowitz, MD

Robert J. Lefkowitz, MD Howard Hughes Medical Institute Investigator James B. Duke Professor of Medicine and Biochemistry Duke University Medical Center

Cells in our body are constantly exposed to a variety of chemical signals—hormones, neurotransmitters, growth factors, and sometimes even drugs—that they need to interpret and translate into a response. This task is handled by receptors that dot cell membranes. Robert Lefkowitz has essentially defined the field of receptor biology through his work with G protein–coupled receptors, the largest and most pervasive family of cell receptors. A thousand or more of these receptors are known to exist throughout the body, playing critical roles in sight, smell, and taste, and in regulating heart rate, blood pressure, pain tolerance, glucose metabolism, and virtually all known physiological processes.

Surprisingly, Lefkowitz never fully intended to make research the focus of his career. As a child growing up in the Bronx, he read medical fiction and detective stories, and decided in third grade that he wanted to become a physician. He went to medical school at Columbia University, finishing first in his class. But during a two-year fellowship at the National Institutes of Health from 1968–70, he got hooked on receptor biology, a field that was then in its infancy.

At that time, experiments in other laboratories had only suggested the presence of cell receptors, but no one had ever proved their existence. Lefkowitz, however, was convinced they were real, and he set out to isolate them. Beginning with the ß₂-adrenergic receptor in 1982, Lefkowitz isolated eight of the nine subtypes of adrenergic receptors and determined their complete amino acid sequences. The ß-adrenergic receptors are among the most common G protein–coupled receptors, regulating the body’s fight-or-flight response by responding to epinephrine.

Lefkowitz also discovered two new families of proteins that desensitize G protein–coupled receptors—a finding that has helped scientists understand, in molecular terms, how receptors become tolerant to certain drugs. The first is a novel family of enzymes called the G protein–coupled receptor kinases (GRKs) including the ß-adrenergic receptor kinase (ßARK), and the second is a group of proteins called arrestins. Both protein families, he has shown, are widely distributed, and their actions are not limited to the ß-adrenergic receptors.

Understanding the actions of arrestins and GRKs eventually may lead to new treatments for human diseases, including heart failure, Lefkowitz predicts. One of his current research projects involves restoring heart function in mouse models of heart failure by effectively blocking ßARK. He has shown that a ßARK inhibitor originally developed in his laboratory by then postdoctoral fellow Walter Koch (now at the Center for Translational Medicine, Jefferson Medical College) can keep heart cells sensitive to epinephrine stimulation when normal heart cells would have become desensitized. They also have demonstrated that expression of the ßARK inhibitor in the heart can markedly improve cardiac function, relieve heart failure, and lower ßARK levels—results that suggest this strategy may also improve cardiac function in patients with heart failure.

In addition to three decades of discoveries in the laboratory, Lefkowitz is widely recognized for his dedication to mentoring and his tireless devotion to his students. Over the years, he has trained some 175 graduate students and postdocs in his laboratory. While acknowledging that there is no recipe for turning out successful researchers, Lefkowitz admits he is very much a “hands-on” mentor, one who enjoys daily interactions with those working in his laboratory. In small group meetings held three or four times a week in his office, he discusses results and plots strategy with students working on related projects.

When it comes to his own research, Lefkowitz says he remains fascinated by the way it “continuously renews itself and always feels fresh. I come to work every day with a sense of great anticipation and curiosity about what new discoveries and insights will come our way. Every question that we can answer poses several new ones that seem even more interesting than the one we’ve just answered.”

Robert Lefkowitz’s research program is concerned with the molecular properties and regulatory mechanisms that control the function of plasma membrane receptors for hormones and drugs under normal and pathological circumstances.

This information was copied from www.hhmi.org/research/investigators/lefkowitz_bio.html on August 14, 2006