2012 Lucian Award
In its more than 45-year lifespan, the Louis and Artur Lucian Award has recognized scientists who tear down walls.
“The researcher who stays in his silo may be doomed. The ones who can pop off the lid and open the walls are the ones who will make the new discoveries,” said Jacques Genest, MD, Chair of the Lucian Award Committee.
The 2012 Lucian Award winner, Garret FitzGerald of the University of Pennsylvania, left the silo long ago, Dr Genest said, building a resume of creative accomplishments, and now formulating a multidisciplinary strategy for drug discovery and personalized medicine.
“Garret FitzGerald is perpetually riding the crest of a wave and never coming down,” Dr Genest said. It makes him just the kind of researcher the Lucian Award was meant to recognize when, in 1965, the late Olga Leibovici created a $2 million bequest at McGill University to honor her brothers, Louis and Artur Lucian. She stipulated that the award go to the best cardiovascular research published that year. Since the first award in 1978, it has recognized seminal advancements in our knowledge of cardiovascular function. One recent sign of the award’s distinction: In 2012, the Nobel Prize in Chemistry went to 1999 Lucian Award Winner Robert J. Lefkowitz, MD.
“It’s wonderful how this philanthropic gift allows the university to recognize excellence,” Dr Genest said. “For instance, the G-coupled proteins identified by Lefkowitz, and inhibitors of these receptors, led to a revolution in cardiovascular medicine.”
Lucian Award winners, selected by a committee of former Lucian award winners and McGill researchers, receive $60 000 (CDN), and an invitation to spend a minimum of a week at McGill and to deliver the annual Lucian Lecture.
This year’s winner can point to accomplishments in several arenas, including advances in the field of prostanoid biology revealing the metabolic pathways of prostaglandin synthesis, and the discovery that the prostaglandin F receptor may play an important role in blood pressure control, renin release, hepatic glucose formation, and atherosclerotic plaques. His work contributed significantly to the development of low-dose aspirin to prevent cardiovascular disease, based on his description of aspirin’s dose-dependent suppression of thromboxane and prostacyclin.
Garret A. FitzGerald, MD, began his premedical studies at University College, Dublin, National University of Ireland, in 1968, where he also completed his medical degree in 1974. After internships at St. Vincent’s Hospital Dublin, he completed graduate work in statistics at Trinity College Dublin and the University of London, as well as clinical pharmacology fellowships at the Royal Postgraduate Medical School in London and the Max Planck Institute in Cologne, Germany. He became a research fellow and instructor at Vanderbilt University in Nashville, Tennessee, in 1980, and rose eventually to Chief of the Division of Pharmacology in 1988. That same year he was named Director of the Training Program in Clinical Pharmacology. In 1991 he returned to Ireland to chair the Department of Medicine and Experimental Therapeutics at University College Dublin. He also served as Director of the Center for Cardiovascular Science. Three years later he returned to the United States as Professor of Medicine and Professor of Pharmacology at the University of Pennsylvania, Philadelphia, and became the founding Director of the Center for Experimental Therapeutics, a post he held for 10 years. In 1996, he was named chair of the Department of Pharmacology, a position he continues to hold. In 2004 he added assignments as Director of the Institute for Translational Medicine and Therapeutics and Associate Dean for Translational Research, both of which he still holds. In addition to prostanoid biology, his laboratory has focused on clock biology and the role of internal clocks. In 2001 he published the first report of a clock in the cardiovascular system and how a hormone could reset a peripheral clock.6 This year, the FitzGerald laboratory showed an independent role for peripheral clocks in the coordination of energy homeostasis. In a paper published in Nature Medicine7 in November, Dr FitzGerald’s laboratory showed that mice with the molecular clock component, Arntl, disabled in adipocytes not only gained more weight while consuming the same number of calories as control mice, they also were more likely to eat in daylight—the rodent version of human night-eating syndrome, which is associated with obesity. Disrupting the adipocyte clock altered the timing of plasma concentrations of polyunsaturated fatty acids, with a corresponding change in neurotransmitters responsible for appetite regulation in hypothalamic feeding centers. This altered the timing of feeding behavior and resulted in weight gain. This change took place without affecting the function of hypothalamic circadian clock genes, including Arntl, showing the direct effect of the peripheral clock on the hypothalamic feeding center. Such research comes at a critical time, as obesity threatens to undo the advancements in cardiovascular medicine. “We are now faced with a huge biosocial epidemic, not just in North America, but in the world over, and that is the increased consequence of obesity,” said Dr Jacques Genest, MD, Chair of the Lucian Award Committee. “We’re going to see cardiovascular disease rising again,” making questions of obesity of increasing importance in the cardiovascular field.
But it was Dr FitzGerald’s research on cyclooxygenase-2 (COX-2) inhibitors that inspired him to create a multidisciplinary research consortium aimed at improving the synthesis of research data with the goal of developing personalized medicine. Dr FitzGerald is the Director of the Institute for Translational Medicine and Therapeutics at the Perelman School of Medicine.
The COX-2 story began in Dr FitzGerald’s laboratory >15 years ago, when he was on the trail of metabolites of the evanescent prostacyclin, PGI-M. “I guess it began with some human pharmacology studies where we made the discovery—which was surprising to us—as we looked at a product of prostacyclin,” Dr FitzGerald said. They found PGI-M levels depressed under the influence of the COX-2 inhibitor, celecoxib.
The result was simply odd. It didn’t fit anywhere. As far as anyone knew, COX-2 played no role in producing cardioprotective prostacyclin. The potent vasodilator was believed to be produced solely by COX-1, with which celecoxib did not interact.
Now it appeared that COX-2 was intimately involved in prostacyclin signaling. Referring to research by Michael Gimbrone Jr, MD (Brigham & Women’s Hospital, Boston, MA), regarding the effect of laminar flow on vascular signaling, Dr FitzGerald suggested a similar mechanism at play. “We hypothesized that normal blood flow upregulated COX-2 in the endothelium,” leading to prostacyclin expression, Dr FitzGerald said. “Therefore, if you gave a COX-2 inhibitor, you were suppressing the cardioprotective ligand.”
The January 1999 publication of these findings in the Proceedings of the National Academy of Sciences1 proved flammable. It “coincided precisely,” Dr FitzGerald said, with Pfizer Inc’s release of Celebrex, that is, celecoxib, the first COX-2 inhibitor to hit the market. “Down on top of me came a lot of criticism,” Dr FitzGerald recalls.
Some questioned the finding based on the use of PGI-M as a marker for prostacyclin action. It wasn’t clear, they said, that the PGI-M metabolite actually reflected vascular cell activity. Dr Fitzgerald’s laboratory followed the PNAS paper with another in May 1999 in the Journal of Pharmacology and Experimental Therapeutics,2 showing prostacyclin suppression by another of the COX-2 inhibitors, rofecoxib.
As pharmaceutical companies slowly released data from postmarket clinical trials that suggested a link between COX-2 inhibition and adverse cardiovascular events, many resisted Dr FitzGerald’s mechanistic explanation. The first postmarket study compared rofecoxib (Vioxx) to the traditional NSAID, naproxen, in some 8000 patients and found an increase in the number of myocardial infarctions in the group taking the COX-2 inhibitor—20 in the Vioxx group (0.5%) compared with 4 in the naproxen group (0.1%). Although numbers that low can be explained away as a function of chance, 4 years later, Merck released the full data set. The thrombic events in the Vioxx group were more than double the number in the naproxen group (47 versus 20).
The company attributed the difference to a previously unrecognized cardioprotective effect of naproxen, and makers of other COX-2 inhibitors said that if there was a problem, it was with Vioxx, not with their drugs.
Dr FitzGerald, however, argued that his laboratory’s work showed that this was a class effect, not just Vioxx’s bad luck. A 2002 paper he published in Science3 showed that mice without the prostacyclin receptor had an amplified response to vascular injury. In the same paper, this amplified response was eliminated when neither the thromboxane receptor nor the prostacyclin receptor were functional. “It was the first evidence that prostacyclin mattered in a nonredundant way,” Dr FitzGerald said.
Meanwhile, others found that COX-2 plays a crucial role in protecting the heart against ischemia/reperfusion injury—a finding that changed the understanding of the role of COX-2 in cardiovascular biology.4 Further studies by FitzGerald in which one copy of the prostacyclin receptor gene was eliminated showed an intermediate phenotype of susceptibility to thrombosis, strengthening the notion that the COX-2 inhibitors, which suppressed COX-2 by some 60% to 70%, led to cardiovascular vulnerability. COX-2 knockout mice in other studies developed salt-sensitive hypertension, cardiac hypertrophy, and severe cardiac fibrosis.
“The arguments were beginning to run out,” Dr FitzGerald said. “These people, besides being predisposed to thrombosis, are predisposed to heart failure.” Still, “all of the companies were saying, ‘We don’t know how this happens,’” Dr FitzGerald recalls. In the meantime his laboratory continued to show just how it happens.
The last arguments fell in May 2012, with a publication in Science Translational Medicine,5 which showed that nitric oxide could not counter any cardiovascular effect caused by prostacyclin inhibition. In fact, NO synthase expression proved to be under the control of COX-2. The paper also demonstrated that PGI-M accurately reflected what happened in the vasculature (Figure).
“That was where the loop was closed,” Dr Fitzgerald says. “Although there are always people who will believe in a flat earth.”
His experience with COX-2 inhibitors demonstrated an urgent need for “more people who can integrate basic science and clinical research.”
In the COX-2 debates, “To my surprise, I found myself one of the few people who actually dealt with and could understand the power and limitations in cell biology and models in fish and mice, as well as clinical pharmacology and the strengths and limitations of observational studies,” he said.
“The lesson from Vioxx is you actually have to put together these different forms of evidence to understand what’s going on,” he said. This lies behind his efforts toward a “new approach to drug discovery and development” with the founding of the Personalized NSAID Therapeutics Consortium, PENTACON. (http://www.pentaconhq.org). The organization received an $18.5 million grant from the National Heart, Lung, and Blood Institute in August. Its mission is to integrate the many layers of data available toward a more personalized approach to NSAID use.
The paradigm under development will synthesize data from deep drug-interaction phenotyping studies in humans, with screens for on- and off-target effects in yeast, high-throughput screens in mammalian cells, genetic and chemical modifier screens in zebrafish, systematic studies of COX biology, and genetic screens in mutant mice. The end product will be clinical hypothesis testing with randomized controlled trials of individualized therapy.
It’s a little like putting together the Hubble Telescope for biology, Genest said.
“Setting up a platform to integrate huge data amounts in, I would call it the science of integratives, is one of his important contributions,” he said.
“There is no such thing, in my view, as a cardiovascular researcher,” Dr Genest said. “People have to step outside of their comfort areas to make huge inroads. Dr Fitzgerald’s done that. He’s an absolutely stellar scientist.”
Jacques Genest Jr, MD
Chair, McGill University, Canada
Roberto Bolli, MD
University of Louisville, United States
Dirk L. Brutsaert, MD, PhD
Universiteit Antwerpen, Belgium
José Jalife, MD
University of Michigan, United States
Richard J. Novick, MD
University of Western Ontario, Canada
Jean L. Rouleau, MD
Université de Montréal, Canada
Avril V. Somlyo, PhD
University of Virginia, United States
Duncan J. Stewart, MD
University of Ottawa, Canada
Yves Clermont, PhD
McGill University, Canada
Anthony R.C. Dobell, MD
McGill University, Canada
Samuel O. Freedman, MD
McGill University, Canada
- © 2013 American Heart Association, Inc.
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