Lefkowitz is a clinician who still makes hospital rounds. After more than 30 years in the laboratory, he now hopes to help improve the treatment options for heart patients.
Photo: Scott Dingman

Pursuing Receptors and Heart Disease
in North Carolina

By Karyn Hede

Bob Lefkowitz doesn't simply walk into a room, he bounces in. On one sunny summer day, he arrives in his office carrying giant yellow and green rubber bands and accompanied by a postdoctoral fellow. "We're doing a little PT [physical therapy] here," he announces, as he ties one end of a band to a table leg and inserts a sneakered foot into the loop at the other end. "Here's what I've been doing," he says to the postdoc, and proceeds to swivel his foot to the right and then to the left. She responds with a few pointers.

"When you've been running as long as I have," he offers, "it starts to catch up with you."

At 57, Lefkowitz is an energetic man, lean and angular. He carries a mere 158 pounds on his six-foot frame. But appearances deceive, and you would never guess by looking at him that what he's been running from is coronary heart disease. His father died at age 63, following his fourth heart attack, and his mother had a heart attack at age 59. It's a disease he knows intimately.

"I knew I had it coming from both sides," he says, but he just pushed it to the back of his mind. Too many other things to think about—and Lefkowitz is not your ordinary heart patient. He can tell you in minute detail exactly what's going on when the heart starts to labor against arteries filling with fat-laden plaque. He helped define what it means, with molecular precision, when the heart starts to fail. He laid the basis for understanding the intimate details, the biochemical drama that silently weakens and then saps the life of 400,000 people a year in the United States alone.

But when his own number came up, well, the mind plays tricks on even the nimblest of brains. "I developed angina," he said. "But interestingly, I could only bring it on by running."

Didn't he, a trained cardiologist and consummate biochemist, realize what was happening? "You know, and you don't know," he responds with his distinctive Bronx accent, still quite recognizable after 27 years in North Carolina as an HHMI investigator at Duke University Medical Center. It was only after nine months of denial that he could ignore the symptoms no longer and, in June 1994, had a quadruple bypass operation.

Since then, he has maintained a strict vegetarian diet, continues to run—despite nagging injuries—and now, from all appearances, leads a charmed life. He is the man who essentially defined receptor biology through his work with b adrenergic receptors, the molecules that translate hormonal signals into cellular responses in the heart and other organs throughout the body. Lefkowitz is largely responsible for decoding all of the a and b receptors. He was the first to isolate the b₂ adrenergic receptor (bAR) in 1982; the first to clone the b₂ receptor in 1986, the b₁ receptor and all the a₁ and a₂ receptor subtypes (there are nine known adrenergic receptor subtypes); the first to identify and clone the G protein-coupled receptor kinase: b adrenergic receptor kinase (bARK) or GRK2, the major regulator of bAR activity; and the list goes on. A member of the National Academy of Sciences, Lefkowitz's office walls are papered with plaques and certificates attesting to his achievements. (See "Mentor and Data Junkie")

"One of the things that I think has categorized my research throughout the years, and something which I have delighted in, is how hard it is to categorize," he says. "I've had fellows in my lab from every [medical] discipline."

Reprinted from the September 2000 HHMI Bulletin, Vol. 13, No. 3, pp. 26-33.

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