Mayo Team Of MD's Advances Field Of Vascular Biology

In the medical research arena, the M.D.'s have generally stuck with their stethoscopes, leaving the work of discovering to the Ph.D.'s. But at the Mayo Clinic in Rochester, Minn., a research group led by cardiologist John C. Burnett, Jr., and composed entirely of medical doctors is charging ahead to decipher the physiologic role of endothelin, a peptide that causes narrowing of the blood vessels. For the most part, endothelin has been the focus of investigations by molecular biologists and biochemists--not clinicians. During the past year, however, Burnett and his team have added a new dimension to endothelin research; a dimension that has received considerable attention from the rest of the research community. John Burnett's team has been on a winning streak in the past few months as the Mayo group of clinicians had two more endothelin studies accepted for publication: one appeared in the August issue of the American Journal of Physiology (P.G. Cavaro, et al., "Endothelin in experimental congestive heart failure in the anesthetized dog," 259:F312-17, August 1990), and one is to be published in the January 1991 issue of Circulation. The team also presented a third paper at the Central Society for Clinical Research conference in Chicago two weeks ago. Using a dog model to mimic human heart failure, the team has shown that plasma endothelin levels are elevated more predictably than other hormones associated with this disease, such as renin and aldosterone. Furthermore, when healthy animals were given endothelin to equal the plasma concentration observed in the sick dogs, coronary, renal, and systemic vasoconstriction were observed. These findings demonstrated endothelin's potency. The team's original research (W.L. Miller, et al., Journal of Clinical Investigation, 83:317-20, 1989) indicated a pharmacologic effect, says Burnett, while the subsequent work has shown endothelin to have a biologic activity at one-tenth the dosages administered in the first study. In addition to using dog models, the team has also investigated endothelin's role in the human body. Cardiology fellow Amir Lerman presented the results of the human study this fall. The researchers found that endothelin levels were significantly elevated among patients with symptomatic atherosclerosis. "One of the actions of endothelin in addition to its being a vasoconstrictor," says Burnett, "is that it causes smooth muscle proliferation, which is part of the natural history of atherosclerosis, and that serves in part then to build up this plaque and obstruct the arteries." According to Burnett, damage to endothelial cells may disturb the homeostasis between endothelin and endothelial-derived relaxing factor (EDRF), a vasodilator. "If you damage an endothelial cell, one thing it does is produce more endothelin and less EDRF, and there is evidence to suggest that EDRF can inhibit the release of endothelin," he says. "Clearly, circulating endothelin is much higher in patients with atherosclerosis. So at the very least, it may be a marker for endothelial damage. And the intriguing thing is that it may also contribute to some of the complications." The Mayo Clinic research team is also studying endothelin's therapeutic potential. In a syndrome known as endotoxic shock, caused by bacterial infection, tremendous vasodilation occurs. "Indeed, it appears that that type of shock is caused by an over-release of EDRF," says Burnett. "Endothelin may be a unique agent to treat that." Ultimately, the researchers hope to develop the ability to regulate endothelin levels in the body. Burnett says that manipulating the receptors may prove too difficult. Inhibiting the converting enzymes that cleave the precursor peptides is a more promising approach, he says, as there are already converting enzyme inhibitors for angiotensin II. "I'm sure there are some reasons why we have endothelin that are not quite clear to us," says Burnett. "I think we know a lot more about its molecular biology than we know about its physiology and biology"--an imbalance in knowledge that Burnett and his team are determined to shift. --P.K. According to Burnett, director of the Mayo Clinic's Cardiorenal Research Laboratory, the team's strong interest in clinical investigations is the propulsion behind its success. "What drives us is an interest in hypertension and heart failure. So our fellows are usually strong M.D. investigators," he says. "In this day and age," when most research teams do not have a clinical focus, "that does set us apart. By taking an integrative approach, the work has a more immediate application to a clinical problem." Adds team member Ken Margulies, a fellow at the Mayo Clinic, "If there is anything unique about this lab, it's that we're all M.D.'s. A lot of us are drawn to basic research and basic physiology, but with a clinical eye." Burnett and his team are using integrative, whole-body models to determine the role the potent vasoconstrictor endothelin plays in diseases such as congestive heart failure, hypertension, and atherosclerosis. "We have an interest in peptides and an interest in cardiovascular disease," says Burnett. "This looked like a good gamble. The feeling was that this should pay off." And indeed, it did pay off for Burnett and his team (see accompanying story). Fellows laud the integrative approach advocated by Burnett as well as his clinical expertise. "John Burnett is a tremendous clinical investigator," says pulmonary fellow and team member Mark Perrella. "He has excellent insight into what are very important topics. He is not afraid to expand his horizons. He's a cardiologist. This is a cardiorenal lab. He's interested in renal physiology; he's had nephrology fellows in the lab, he's had endocrine fellows in the lab, and he's had pulmonary fellows in the lab. So he takes suggestions on new topics very well, and he expands them nicely and groups them into an integrative, total-system type of relationship. We don't just look at the heart, we don't just look at the kidney, we don't just look at the lungs--we integrate the entire package." Perrella, who met Burnett on his cardiology rotation, is investigating the role of endothelin and endothelial-derived relaxing factor (EDRF) in the control of pulmonary circulation. Spirited by the discovery in 1988 of the vasoconstrictor produced by vascular endothelial cells by Masashi Yanagisawa and his group at the University of Tsukuba in Japan (M. Yanagisawa, et al., Nature, 332:411-5, 31 March 1988), Burnett and his team published their first study on endothelin in January 1989 (W.L. Miller, M.M. Redfield, J.C. Burnett, "Integrated cardiac, renal, and endocrine actions of endothelin," Journal of Clinical Investigation, 83:317-20, 1989). This research showed that endothelin elevates systemic blood pressure and depresses cardiovascular and renal functions in anesthetized dogs. "That first article [Yanagisawa's] was so good and so comprehensive," says Margulies. The research that followed Yanagisawa's original discovery "really unfolded most of the molecular biology," he says. "It really put the challenge out to physiologists: `We've done our stuff; we defy you to find out its physiologic role.' And I think physiologists have taken the bait." Margulies adds that part of the reason the field has moved quickly is that so many effective protocols already existed for studying cardiorenal peptides like atrionatri-uretic factor and renin. As for his own lab, Margulies notes the enthusiasm of Burnett as a spur for solid research. "Dr. Burnett is an incredibly dynamic thinker," he says. "He's an enthusiastic guy who generates a lot of action and motivation from the people around him." Senior faculty member Wayne Miller, assistant professor of medicine, concurs: "John is good at focusing the group on the right questions to ask and try to answer." Mayo medical school graduate Debra Fett, currently an intern at the clinic, describes Burnett as a persistent questioner in the lab. "On a day-to-day basis, he's always asking, `What do you think about this experiment? What do you think about this other guy's lecture?' " Fett also credits the team's success to the way Burnett runs the weekly lab meetings, in which, she says, medical students are treated as equals. "It's unique in that it's not a dictatorship. The meetings are more like a forum than a lecture." "What characterizes our group is that we're very decentralized," says Burnett. "We've run the laboratory in a very open manner in which all the fellows, even the medical students, have an equal voice at the weekly meetings when we talk about the projects, ideas, and directions. Everyone is quite free to bring up their ideas. There is no hierarchy in the discussion." Idea Exchange This "freedom of ideas" atmosphere has helped attract a growing number of researchers over the last four years, allowing Burnett's team to grow considerably. Three senior faculty members, seven research fellows, and a number of students and technicians coordinate their efforts on the biochemistry and molecular biology of endothelin as well as the animal and human studies. Familiarity is another ingredient in the Mayo team's success. Says cardiology fellow Amir Lerman, "Most of the other fellows in this lab are graduates from here. We know each other from the program." Lerman adds that the group members' familiarity with each other makes individuals more comfortable about sharing experiences with each other when evaluating protocols. Also, knowing one another increases his colleagues' accessibility to each other after normal working hours. Those prior relationships help Burnett in his goal to run a decentralized lab with freely flowing information. He encourages cross- fertilization from the fellows who have different scientific backgrounds as well. "Everyone has his or her own project, usually with another member of the lab associated with it. All the experiments are done in one room, the analysis in another, and the computers for analysis in another," says Burnett. "People are always in groups, so there's lots of discussion." At this stage in the research, the team is committed to the hypothesis that endothelin is a circulating hormone, although they're unsure of the principal organs directing its production. "We're all confused; I think it's unclear," says Burnett. "The fact that the message is there doesn't necessarily conclusively demonstrate that it's being secreted by those cells. One can find message for a number of peptides in which there is no evidence that there is active secretion taking place. Plus, messenger RNA for endothelin is also present in nonvascular tissue. It's present in the brain, it's in kidney cells. So it's in epithelial tissue as well. The fact that we see endothelin in the plasma, and that it goes up in various disease states, strongly suggests that it can operate as a circulating hormone." True to Burnett's claim that the group welcomes differences of opinion, however, Miller gently disagrees on the issue of endothelin as a circulating hormone. "It's circulating," he says, "but I'm not sure we're not just seeing the excess of it. Maybe its role is that of a local modulator." Whatever the physiologic role of endothelin, Burnett's team could very well play a key part in unraveling it with the group's integrated approach and decentralized, family- style system. "We treat everyone the same," says Burnett. "Everyone gets to go to the same meetings, everybody gets the same perks. There's not a lot of jealousy. We're a family here. We follow the old Midwest tradition: You either get along or you go to the woodshed." Paul Kefalides is a freelance writer based in Merion, Pa.

Mayo Team Of MD's Advances Field Of Vascular Biology

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