HHMI and Duke Celebrate the Lefkowitz Chemistry Nobel

As discussed in my previous post, I took a personal day off from work yesterday to bask in the excitement of a university community celebrating a Nobel prize for one of its most beloved researchers, Dr. Robert "Bob" Lefkowitz, MD. He joined Duke in 1973 when, he says, "it was not the powerhouse it is today." Lefkowitz will share the prize with his former trainee, Brian Kobilka, MD, now at Stanford University. I had the honor of joining his laboratory's champagne celebration in the morning and the Duke University press conference in the early afternoon. (The full 47-minute press conference streamed live and is archived here at Duke.). I live barely three miles from Duke and had no idea when or if I'd ever have the chance to be so close to such an event. The Lefkowitz prize is particularly meaningful to me as he is a biochemist physician-scientist who also considers himself a pharmacologist. So, I write this not so much as a journalist but rather -- as Duke Research Communications Director Karl Leif Bates put it -- a fan boy.

Fan boy? Nope. Not me. Credit: Ashley Yeager/Duke News & Communications

Dr. Lefkowitz is officially designated as an investigator of the Howard Hughes Medical Institute and James B. Duke Professor of Medicine and Biochemistry at Duke University Medical Center. The New York City-born-and-bred Lefkowitz is an exceedingly proud graduate of the Bronx High School of Science, which counts him as the eighth graduate to receive a Nobel prize. Yes, eighth. The vast majority of universities cannot count that many graduates and faculty put together as Nobel laureates. After earning his Bachelor of Arts degree in 1962 from what was called Columbia College, trained originally as a physician at the Columbia University College of Physicians and Surgeons where he received his MD in 1966. He stayed there for a year each of internship and general medical residency. But he was bitten by the research bug while at the National Institutes of Health during the final third of the Vietnam War (1968-1970), with a reamrkable group of physician-scientists. During the Duke news conference, Lefkowitz remarked that among his NIH class of eight fellows, "four or five" have since won Nobel prizes. "I was the schlep of the group," quipped Lefkowitz. Lefkowitz then moved to Massachusetts General Hospital, the Harvard University affiliate, for his cardiology training. He wasn't looking to leave Harvard. But while giving talks at the American Heart Association annual meeting and other national cardiology conferences, he caught the eye of Dr. Andy Wallace, then chief of Duke's cardiology division and later CEO of the hospital. When Wallace and other Duke administrators tried aggressively to recruit him, Lefkowitz said that he really had no particular desire to leave Harvard. The proposed annual salary of $24,000 would certainly go farther in Durham, NC, than in Cambridge and Boston. So, he put together a list of demands that, he says, were well beyond what one should expect at that early stage of an academic career. Duke responded with agreement to all of his terms and resource requests. And while he hadn't objected to the salary, they increased it by a third to $32,000. Lefkowitz has been at Duke for the last 39 years, training over 200 scientists and fellows, many who have gone on to stellar research careers, department chairs, and deanships. Lefkowitz is also the longest standing investigator of the Howard Hughes Medical Institute (since 1976), whom he credits immensely for their support. While the HHMI is well-recognized, less known is the fact that its flagship program is an organization of 330 investigators spread of 70 universities, medical schools, hospitals, and other research entities. While HHMI investigators maintain their institutional appointments, the Hughes aspect operates independently of the administration of the host institution. Currently, HHMI investigators support over 700 postdoctoral fellows and 1,000 graduate students. (This is not the only HHMI program - see here for details.) The chemistry prize Much hullabaloo has transpired as to whether the work of Lefkowitz and Kobilka is deserving this chemistry Nobel. One could argue that since work on the natural ligands that bind to G-protein-coupled receptors have historically garnered Nobel prizes in Physiology or Medicine that this one should have followed similarly. The father of the chemblogosphere, Derek Lowe, held forth yesterday on why this is a chemistry prize. Indeed, the X-ray crystallographic work of Brian Kobilka is clearly a chemical technique use for all manner of so-called biological research. But there is one aspect to the GPCR work that I believe also qualifies these two gentlemen for the chemistry prize. During the news conference, someone beat me to the question of how his cardiology training led Lefkowitz to pursue this avenue of research. His most obvious answer was that the adrenergic receptors -- those that bind epinephrine and norepinephrine -- are the most critical receptors and neurotransmitters in cardiology. But in the early 1970s, some scientists were still unconvinced that receptors could be these specific entities that bound these chemicals and triggered some reaction in cells to get them to do something. So, it was the second answer from Lefkowitz that most acutely caught my attention. And this is the section that you should cut-and-paste for your blog: Lefkowitz noted that adrenergic receptors were the group of receptors most amenable to laboratory research because the chemical probes and biological tools were most readily available. Remember, he started doing this research as a NIH fellow in 1968. We did not have the ability to clone the genes encoding receptors and determine their structural similarity and differences. We couldn't just use degenerate PCR primers to amplify from the genome the relatives of these so-called alpha and beta receptors. In fact, how did physiologists ever define α and β receptors in the first place? In work leading to a legendary 1948 paper in the American Journal of Physiology, Raymond Ahlquist at the University of Georgia used structurally similar chemicals to demonstrate that some had better stimulating or inhibiting activity in isolated organ systems. Yes, this physiological advance required biologists to have access to specifically-designed small molecules.

Compounds used in Ahlquist's legendary work. From the Introduction to Ahlquist R. A study of the adrenotropic receptors. Am J Physiol 1948;153:586-600.

Ahlquist's stroke of genius was observing that the ranking of their order of potency in each tissue system seemed to differ. Specifically, these chemicals fell into two groups. Some of these chemical probes were superb at stimulating heart rate but less active in causing constriction of blood vessels, both effects of epinephrine and norepinephrine (remember, these were originally called adrenaline and noradrenaline, respectively). This different "rank order of potency" led Ahlquist to conclude that tissues whose chemical responses grouped with blood vessels had one type of adrenergic receptors, or "adrenoceptors," which he called α. Those tissues whose potency order of chemical responses grouped with the beating heart had another type that he called β.

These two tables summarize of an exhaustive series of whole animal, tissue, and organ studies first defined receptor subtypes. Ahlquist R. A study of the adrenotropic receptors. Am J Physiol 1948;153:586-600.

  Alhquist passed away in 1983, precisely on the date of Dr. Lefkowitz's 40th birthday. In contrast, Alhquist never won a Nobel prize although he did received the Albert Lasker Award in 1976, a US honor also bestowed on Lefkowitz that often precedes a Nobel. Ahlquist left a couple of nice reminiscences on this and his subsequent work, here in the Journal of Autonomic Pharmacology and here in the old ISI Citation Classics.   We don't need no stinkin' cloning; we have chemicals! But stay with me now, especially the chemists. Ahlquist lamented that he didn't have access to any compounds that blocked the effect of norepinephrine on beta-receptors. Sir James Black, later a 1988 Nobel laureate in Physiology or Medicine, seized upon the value of chemistry and took a chemical structure-activity approach in coming up with the first beta-blocker, propranolol. Propranolol (Inderal) marked a new era in the treatment of hypertension and other cardiovascular diseases. We now know that multiple subtypes of beta-receptors exist but, again, we knew it long before gene cloning was possible. But discerning between beta1- and beta2-receptors took until 1967-1968, almost another 20 years after Alhquist's 1948 work. Why? Because the compounds necessary to discriminate between beta1 and beta2 receptors did not yet exist. It took physiologists and pharmacologists working with chemists to make this happen.

Sir James Whyte Black in front of tissue bath setups on the day his Nobel Prize in Physiology or Medicine 1988 announcement. The photo comes from his obituary the Royal Society of Chemistry -- yes, chemistry -- recognizing that chemistry was essential to his physiological and receptor approach to drug discovery.

By the way, Sir James took the same chemical approach when he was at SmithKline in the UK to find receptor-selective histamine antagonists to block gastric acid secretion for the treatment of gastric ulcers. He seized on the observation that the effects of histamine could be blocked by diphenhydramine (Benadryl) in every tissue except the stomach and the uterus. He had his chemists start with histamine itself to work up to chemicals such as cimetidine (Tagamet) that had the selectivity to block histamine at this second type of receptor, the histamine H2 receptor. (You'll not be surprised that when Sir James received the Albert Lasker Clinical Medical Research Award, he shared it with Ahlquist!) Remember that this was now about the time that Lefkowitz came into his NIH research training about this time (1968-1970). Again, he remarked yesterday chose cardiology research because the tools existed for him to embark on his work. Those tools were chemical tools. As Dr. Lefkowitz works on his autobiography and Nobel lecture leading up to the December ceremony in Stockholm, I hope that he reflects on that era - he'll certainly remember it far better than I can piece together from the literature. More later. . .  I'm still not done - I'll have another blogpost on this Nobel prize tomorrow, a bit more of the personal side.   In the meantime, my Duke News & Communications colleagues, many who've contributed to the upcoming annual meeting of the National Association of Science Writers later this month, have set up this portal to six features on Dr. Lefkowitz and the Nobel prize. Well done, folks!  

Author: David Kroll

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