John Oates: A closer look
Seeing beauty in the complexity of wildflowers and clinical pharmacology
Editor’s Note: This profile, first published in 2005, has been updated.
The experience 15-odd years ago sparked him to enroll in a photography course and to add wildflower hunts to his global travels.
“It is certainly true that I’ve had a fascination with the intimate detail of wildflowers—details that elude the view from a distance,” he says during a conversation in his office at Vanderbilt University Medical Center. He’s silent for a long moment before launching into a quote from Henry David Thoreau’s Walden, slowly at first, then with growing confidence.
“The scenery of Walden is on a humble scale, and, though very beautiful, does not approach to grandeur, nor can it much concern one who has not long frequented it or lived by its shore…”
Leaning back in his chair, he’s careful to note that Thoreau’s comment didn’t inspire him, but that it fits.
“What he’s saying is that the beauty isn’t something you spot while driving by—like the Rocky Mountains—it’s only apparent to the people who frequent the shores… to those who become intimately acquainted with it,” Oates says.
Oates frequents the shores—of wildflowers, of biological signaling pathways, of the discipline of clinical pharmacology. He looks closely and sees deeply.
His dossier is thick with achievements: discoveries that shaped the field of research related to biologically active molecules called prostaglandins; activities that built the foundations for the discipline of clinical pharmacology and made its principles central to drug development.
“I think he’s one of the greats of Pharmacology and of American medicine,” says Garret A. FitzGerald, M.D., chair of Pharmacology at the University of Pennsylvania School of Medicine.
Now in his mid-70s, John A. Oates, M.D., the Thomas F. Frist Sr. Professor of Medicine at Vanderbilt, could easily choose to relax his intense gaze. But there are too many biological complexities yet to understand, too many wildflowers yet to behold.
Among them: the link between the cyclooxygenase (COX) enzymes—which produce prostaglandins and other products—and Alzheimer’s disease. Oates and his colleagues are trying to understand how acetaminophen and aspirin interact with the COX enzymes to block activity, and why those drugs are more effective in some cell types.
A broad grin creeps across his face when he is asked how long he’ll keep all this up. “As long as I’ve got ideas,” he chuckles.
Sowing the seeds
The ideas started coming early. As a young medical student at the Bowman Gray School of Medicine of Wake Forest College, Oates had the option of writing a paper or doing a research project for the physiology course.
“A group of my friends and I decided to test whether or not peritoneal dialysis would be beneficial for kidney failure,” he recalls. “At the time, that idea hadn’t been introduced clinically.”
The group had only limited access to laboratory equipment, but the physiology department had an excess of electrocardiogram machines. The bright medical students reasoned that they could use the EKG to look for effects of elevated potassium—one way that kidney failure leads to a fatal outcome.
Their experiments in dogs showed that peritoneal dialysis prevented elevated potassium following renal failure. The taste of research whet Oates’s appetite, and he went looking for more.
What prompts a medical student to seek opportunities to study potassium and the heart?
“I guess I was always curious,” Oates says, recalling his eastern North Carolina childhood spent exploring, camping, sailing and reading adventure novels.
“I think he’s much more curious than most,” says Robert A. Branch, M.D., chief of Clinical Pharmacology at the University of Pittsburgh, who worked closely with Oates for 20 years. “He’s logical; he’s well-informed; but primarily I think his driving force is curiosity.”
“He has an inquisitive mind—a very, very inquisitive mind,” says L. Jackson Roberts II, M.D., professor of Pharmacology and Medicine at Vanderbilt.
When in 1955 one of the cardiologists at Wake Forest turned down his research proposal, Oates approached the chair of the Biochemistry department, Camillo Artom, M.D., Ph.D.
“I was a naïve student who thought I could do anything,” Oates says.
Artom listened politely, told Oates his ideas were interesting, and then redirected him to work on phospholipids—the fatty molecules that constitute the cell’s membrane and are the starting materials for the production of many signaling molecules.
The seeds were sown. Both cardiovascular biology and lipid biology would become recurring themes in Oates’s research career.
His time in the Artom laboratory was likely responsible for his success in obtaining an internship position at Cornell Medical Center, Oates says. “I wasn’t the top student in my class ... and that was a great institution.”
He applied and was offered a clinical associate position at the NIH.
“I think I was fortunate that I was in a house staff program where there were bright people who were interested in research and one of them put me onto this opportunity at the NIH,” Oates says.
The move to Bethesda proved to be a key one.
The thrill of discovery
One night in 1959, Oates headed back into the lab at the National Heart Institute—now the National Heart, Lung, and Blood Institute—with the sense that he and his team were onto something big. The graph he charted from the day’s data didn’t let him down. He called one of his colleagues at home at 11 p.m. to relate the news: the drug they were studying appeared to lower blood pressure.
It was the first time Oates remembers feeling the thrill of discovery, and he was hooked.
“It’s incredibly exciting, to be working on something for a long time, and then all of a sudden—bang!—it’s there, something new that nobody has ever seen before,” he says. “In this case, it’s fair to say that we all had hoped the drug might have an effect on blood pressure in humans, but there was no precedent for it in prior animal studies.”
The drug was methyldopa. At the time of Oates’s discovery, there were no effective drugs for treating patients with severe hypertension—the subset of hypertensive patients who are most susceptible to stroke, heart attack, and kidney failure. Methyldopa, developed and marketed as Aldomet by Merck, became the first.
The NIH group, headed by Albert Sjoerdsma, M.D., Ph.D., and Sidney Udenfriend, Ph.D., had not set out to discover methyldopa’s usefulness as an antihypertensive drug. The drug from Merck was simply an experimental tool, part of ongoing efforts to understand the biochemistry—synthesis and metabolism—of aromatic amines like norepinephrine and serotonin, as a way to gain information about hypertension and its treatment.
Aldomet was one of the major treatments for severe hypertension for about 15 years, Oates says. It was replaced by a newer generation of antihypertensive agents, but it is still used for certain indications, including high blood pressure in pregnancy.
Oates’s experience in the Sjoerdsma-Udenfriend unit set his career trajectory, he says.
“I think one of the most important things you can do as a young person entering science is to work with the right mentor—somebody’s who’s successful and having fun with it. Science is like most things in life: you win some and you lose some. In order to sustain through the ups and downs, you have to have tasted success in science and had the thrill of a discovery, or two, or three ...
“At the NIH there were a lot of young scientists my age who were really having a ball doing research, and it was because of the senior leaders who were creative, energetic, had good ideas, and were committed to clinical research. I was fortunate for having landed in a group like that,” Oates says.
It was in this dynamic and uniquely productive environment—where discoveries and approaches from the laboratory were applied to clinical research—that Oates’s vision for clinical pharmacology germinated. His ideas sprouted and took form in the Vanderbilt Division of Clinical Pharmacology, which Oates founded in 1963 and directed for 25 years.
Growing a discipline
“Clinical pharmacology became what those five or so investigators took it to be,” says David Robertson, M.D., director of the Elliott V. Newman Clinical Research Center at Vanderbilt. “They all knew each other, and they met and called themselves the ‘non-society of clinical pharmacology.’
“They were each great scientists in their own fields, and they insisted on carefully controlled studies. I think if John had an ideology with which he approached research, it was that measuring things carefully and thinking properly about study design was the way to make discoveries.”
At Vanderbilt, Oates found a confluence of the right ingredients for a successful program, including a pharmacology chairman, Allan D. Bass, M.D., who was committed to the idea and a thriving clinical research center, one of the first NIH-funded centers in the country.
“Allan Bass had a vision that the scope of pharmacology ought to include clinical investigation and human pharmacology,” Oates recalls, “and that was unique at the time.”
So with Bass’s enthusiastic support and an early award from the Burroughs Wellcome Fund, Oates set about building a world-class clinical pharmacology program—a division of the Department of Medicine with strong connections to the basic scientists in the Department of Pharmacology. His efforts met with stunning success.
“I think John’s extraordinary talents have been in having a vision for the field of clinical pharmacology and in recruiting and retaining people who have very complementary skills and creating an environment in which they flourish,” says FitzGerald, who served as the second director of Clinical Pharmacology at Vanderbilt.
“Those talents have been why, under John’s leadership, this model of what we call translational research now really flourished at Vanderbilt in a way that I don’t think it did anywhere else, and that’s really his great gift to that institution and to the country.”
“The most important thing was the atmosphere of getting enterprising people to be enterprising,” Branch says. “He didn’t tell people what to do. He had foresight in putting together infrastructures, like the mass spectrometry resource. He understood the mechanics of networking and cooperative multidisciplinary research way before it became popular and a buzzword at the NIH.
“In the first generation of clinical pharmacology centers, as the leaders retired, the centers fell apart. John’s is the only one, that when he moved on to become chairman of Medicine, continued to grow. And it’s the most substantial clinical pharmacology unit anywhere.”
From the vantage of this influential division, Oates shaped clinical pharmacology’s impact. He has served as a scientific advisor over the years to various pharmaceutical and biotechnology companies, including Merck.
“He understood what was required to work out how well drugs worked, and why they worked, and who they worked in,” says David Shand, M.D., Ph.D., a retired pharmaceutical company executive who was on the Vanderbilt faculty in the 1970s.
“He has been instrumental in our way of thinking about groups of drugs and drug interactions; it’s really a style of thinking that he’s contributed to the drug discovery and development process,” Branch adds.
Putting together the pieces
Clinical pharmacology, perhaps more than other biomedical research disciplines, has an obvious link to the pharmaceutical industry, Oates says.
Methyldopa was one such “tool” that allowed Oates and colleagues to illuminate aspects of blood pressure regulation. The team’s research on guanethidine, another blood pressure medication, identified drug interactions as an interesting and important area in clinical pharmacology, Oates says.
Studies of a drug candidate that never made it to market also had a major impact on concepts in drug metabolism.
The drug candidate, code named SU-13197, was being investigated as a potential antiarrhythmic drug when the global chemical company Ciba enlisted Oates’s assistance in studying its metabolism and human pharmacology.
“It was just the beginning of the era of realizing that it’s important to investigate metabolic fate early in the process of drug development,” Oates recalls.
Oates and his colleagues followed the availability of radiolabeled SU-13197, discovering that only a fraction appeared in the systemic circulation following oral administration compared to intravenous administration. It was the first solid evidence of what came to be known as “first pass metabolism”—the clearance of an orally delivered drug by the liver on the drug’s “first pass” through the body.
The team also found evidence that drugs with a high first pass metabolism, like SU-13197, had a high degree of inter-individual variation, a concept that continues to shape drug discovery and development now in the genomic era.
The late Grant R. Wilkinson, Ph.D., who joined the faculty in 1971, and Shand went on to develop what Oates describes as “elegant clearance concepts.” But that would not have happened were it not for a “very proactive” interaction with industry.
“It’s just one example of how our involvement with industry gave us the tools to make discoveries,” Oates explains. “Once we had those tools, the opportunities for creativity opened.”
Oates has been “a trailblazer” for the development of new methodologies that contributed to the teasing apart of the components of prostaglandin physiology, Branch says.
Prostaglandins are members of a large family of molecules called eicosanoids that are derived from fatty acids, predominantly arachidonic acid, and that have varied and profound physiological and pathophysiological effects. The eicosanoid field started with the discovery of two compounds and now boasts over 2,000 family members, Roberts says.
“His group would develop a new method that would allow that area to be developed, and then they would develop another new method and so on. It was painstaking work, and they put a lot of pieces of the jigsaw puzzle into the prostaglandin-eicosanoid story,” Branch says.
The Oates team defined the role of prostaglandins in renin release by the kidney, demonstrating the importance of prostaglandins as a pathway parallel to the adrenergic nervous system in controlling renin release and regulating blood pressure.
The group also discovered that the prostaglandin PGD2 is the principle prostaglandin mediator in human mast cells. That finding is being explored in drug development for allergic rhinitis and asthma, Oates says.
As to his current research projects, he says they’re at a “speculative stage,” and with a sly chuckle adds, “these are exciting times.”
A lasting legacy
Oates’s contributions have been honored many times over. He is a member of the prestigious Institute of Medicine of the National Academies of Science, the adviser to the nation on matters of biomedical science, medicine and health. He is a Fellow of the American Association for the Advancement of Science.
He singles out two awards as most meaningful to him, one from early in his career: the American Society for Pharmacology and Experimental Therapeutics Award for “Outstanding Basic Pharmacologic Investigations in Man;” and one from just last year, an Award of Excellence in Clinical Research from the General Clinical Research Centers Program of the NIH. These awards applaud the hypothesis-driven clinical research that has distinguished his career.
Central to such research is the patient, and Oates has never lost sight of his calling as a physician.
Robertson is one of the more than 300 fellows who have trained in the Division of Clinical Pharmacology at Vanderbilt. About a third of them have gone on to leadership positions in either academia or industry related to drug discovery and development.
This legacy of success will be extended in the John A. Oates Institute for Experimental Therapeutics.
“This institute recognizes Vanderbilt’s commitment to growing the kind of science that John made famous here—understanding how drugs work in the body, why not everyone responds to drugs the same way, and how we can use that information to make better use of the drugs we have and to develop new drugs,” says Dan M. Roden, M.D., director of the Oates Institute and former director of Clinical Pharmacology.
As the new institute blooms and begins to flourish, Oates will be watching.