By Jim Shamp, News & Publications Editor
“Wow! Talk about being in good company! This is really something,” said Duke University research pioneer Robert Lefkowitz during a recent BT Catalyst interview. Lefkowitz will accept the National Medal of Science at the White House September 29 from President Bush.
But Lefkowitz, a Howard Hughes Medical Institute investigator at the Duke University Medical Center, wasn’t referring to President Bush in his outburst of “good company” enthusiasm. Instead, he was referring to the research scientists who had preceded him in winning the honor.
“They give two of these a year in the biological sciences,” grinned the professor of biochemistry, immunology and medicine, who is also a basic research cardiologist in the Duke Heart Center. “When I look back over the previous winners, it’s really an awesome list. And I don’t think there’s been a winner in the past 40 years I didn’t know.”
Come Monday, Lefkowitz, 65, will be part of that august group. It’s one of the few major science prizes he hadn’t won after a lifetime of discovery and teaching. That, and the Nobel Prize in Medicine, which many of his colleagues expect him to also bring home to North Carolina, a la the University of North Carolina at Chapel Hill’s Dr. Oliver Smithies’ feat last year.
“I’ve won a scad of awards in my career,” Lefkowitz said. In fact, he’s garnered more than 50. “My office is covered with ‘em. But response to this one has been unreal. There’s been a huge outpouring of interest, way beyond anything before. I think it’s because it’s given out by the President and it’s very high-visibility. I don’t think there’s any money with it, but I’ve gotten more interviews and congratulatory messages this time than when I won $1 million last year with the Shaw prize.”
Lefkowitz also won the Albany Medical Center Prize in Medicine and Biomedical Research last year, sharing that $500,000 prize with two other researchers.
He’s been collecting all that cash and hardware for his discoveries on how some of our most prevalent and fundamental cellular hardware – proteins called receptors – operate in the body.
Receptors work like ignition switches to accept only certain "keys," usually hormones, that float by with the correct "cut." When a hormone fits a receptor, it "turns on the ignition" and produces a chemical reaction within the body.
Lefkowitz found that some of these receptors – branded as "beta adrenergic" – respond to the hormone adrenaline, for example. When the adrenaline "key" inserts itself into the beta adrenergic receptor "ignition switch," the cells hosting those receptors produce the chemical cascade we commonly know as an "adrenaline rush," replete with increases in heart rate, blood pressure, breathing and metabolic energy production. Another hormone, histamine, causes allergic reactions when it binds with its receptors.
Lefkowitz also found that some important forms of these receptors have a unique formation, "sewing" themselves back and forth through the outer layer of a cell seven times, almost like a quilting stitch, with one end inside the cell and the other end outside. He called them "seven-transmembrane-spanning receptors."
The work by Lefkowitz and approximately 200 young scientists he has mentored during his three decades at Duke has contributed to the development of a wide array of drugs to treat disorders, including heart disease, high blood pressure, asthma and pain.
Some of those drugs, called agonists, are "cut" by their designers to look like hormones so they'll fit into targeted receptors to create desired chemical reactions. Other drugs designed using Lefkowitz’ findings are called antagonists. They fake their way into receptors with a perfect fit, but they're designed to go no further and not "start the ignition." By plugging up possible landing sites of unwanted hormones, they prevent problems from happening. Antihistamines are familiar antagonists, as are beta blockers, which plug up the receptors for adrenaline so the patient taking them doesn't have an over-stimulated heart.
Lefkowitz is one of the most oft-cited scientists in the world’s biology literature. And his receptor discoveries have been linked to the therapeutic activity of more than 40 percent of the pharmaceutical products on the market today.
But despite his gravitas, Lefkowitz is highly popular among students and colleagues. Known for his sense of fun and passion for fast cars, the father of five grown children has been a Blue Devils basketball season ticket-holder for his full 35 years at Duke. Born in England, reared in New York, trained at Harvard but married to a Durham native, the former Lynn Tilley, Lefkowitz considers himself a North Carolinian through-and-through.
“I think this award is a wonderful distinction for the state,” he said. “In our area there’s so much pride that our basketball teams are on the national radar that sometimes the citizenry forgets that we also have some of the nation’s top research universities here.
“I think sometimes when we’re recruiting people here to our universities we still encounter people who say, ‘Who the hell wants to move south, to the sticks, to Podunk?’ We’re a real powerhouse when comes to academics and research, but I still encounter some resistance. I have some friends who’re just inveterate city dwellers, who can’t understand this. But I think it’s nice to be able to live in the middle of woods and be 10 minutes from work. I spent my first 25 years of life in New York City, then lived in Washington, D.C., then around Boston. But I love this way of life in North Carolina. All five of my kids went to public school here.”
Lefkowitz has recently helped start a biopharmaceutical company, Trevena, with R&D facilities in Research Triangle Park and headquarters near Philadelphia.
“Drug development isn’t easy in an academic setting” he said. “Nor is it appropriate. So my colleague here at Duke, Howard Rockman, and I are into my first commercial venture with Trevena. It’s funded by four venture capital firms and staffed mostly by senior postdocs who’ve transitioned from my lab to the new place. The goal to develop drugs that will work according to the principles I’ve been talking about.”
“To me, I’m as excited in what I’m doing now as I ever have been,” he said. “Sure, sometimes I ask myself if I’ve lost half a step or whatever, and I probably don’t work with the same insane intensity of 25 years ago, but that’s probably a good thing. To me, I see the entire body of my research as sort of like building a house. I can see the outcome and structure I have in place and continue to put floors on the building, even though I don’t know how many floors it’s going to have.
“But what’s amazing is that every ‘X’ number of years, we’ll make interlocking discoveries that take us in new directions, bring new life. And because they’re discoveries, by definition, there’s nothing in them we can predict. I love it.”