Hunting the secrets of the cell in San Francisco, and game fish across the globe

John D. Baxter, M.D. ’66, HS ’68, has an imposing presence. At 64, he is a tall, strongly built man with shaggy hair, an affable Kentucky drawl and a passion for the specialized hunt. As often as he can, he packs his gear and heads for Alaska, the Seychelles or the South Pacific to go fishing. He goes after marlin, tarpon, bonefish, trout, salmon and sailfish, and if you want to see him beam, ask him about the five world records he holds. But Baxter doesn’t go out with powerhouse rods and tackle; that would be too easy. No, he goes after the biggest fish in the sea with only a fly rod and delicate test line, tools requiring an artist’s touch.

“I love Alaska,” Baxter says, kicking back in his office at the University of California, San Francisco (UCSF), campus. “And I’m very passionate about my fishing.”

For the past three decades, Baxter has also passionately devoted himself to another specialized hunt: he has been trying to decipher the delicate mechanisms by which hormones, proteins and receptors interact inside our cells. Here, too, he has bagged some impressive trophies. In 1977, he, Peter H. Seeburg, Ph.D., Howard M. Goodman, Ph.D., and John Shine, Ph.D., were the first to isolate and clone the human growth gene. That led to the creation of the first synthetic drug to stimulate growth in children of short stature. It also led to drugs that increase milk production in dairy cows. Then Baxter and a UCSF research colleague, Robert J. Fletterick, Ph.D., became the first to reveal what a nuclear receptor looks like when it is binding to a hormone, a breakthrough that led to new structures in drug design. In 2003, in recognition of his pioneering research, Baxter was named to the National Academy of Sciences.

Now he believes he may be on to his biggest catch yet. Working with Thomas S. Scanlan, Ph.D., another colleague at UCSF, Baxter has developed GC-1, a new compound that is showing great promise in preventing and treating high cholesterol, heart attack and stroke. By working on multiple sites in the liver, GC-1 could prove far more effective in lowering cholesterol than the statins that most doctors prescribe today. Baxter says it also shows promise in reducing obesity and diabetes, especially the highly prevalent type 2 form.

“This compound is about 1,000 times more potent than the statins,” Baxter says. “It will not replace the statins. If it works out, it will probably be used in conjunction with the statins. It attacks a different part of the cholesterol pathway, so they’d work phenomenally well together.”

If GC-1 does fulfill its promise, it will crown for Baxter a lifelong quest. He was born and raised in Lexington, Ky., and did his undergraduate work at the University of Kentucky on an athletic scholarship, majoring in chemistry and graduating Phi Beta Kappa. When he entered Yale in 1962, it was quite a shock: “Even though I had a good education at Kentucky, I was not prepared for the Ivy League. I had a significant adjustment, adapting to the Eastern intellectual establishment. I thought my Kentucky accent was just fine, but that was not the prevailing view at Yale.”

Baxter struggled in his first two years, but then he found his legs, thanks in large measure to Philip K. Bondy, M.D., the head of endocrinology. “He was a wonderful mentor,” Baxter recalls. “By the time I graduated in 1966, Dr. Bondy was head of medicine. So I elected to stay on at Yale and do an internship and residency in internal medicine.”

Yale left a deep imprint on Baxter. “When I look back, the most wonderful thing about Yale was that it was patient. I struggled and Yale put up with me. And I’ll forever be indebted to Yale for that,” Baxter says. “And I could not have gotten better training. Once I got out and mingled with the guys who went to Harvard, Johns Hopkins, wherever, we guys who came out of Yale were quite competitive.”

After leaving Yale in 1968, Baxter joined the National Institutes of Health and began probing the inner workings of nuclear receptors. In 1970 he went west to UCSF, where his work on receptors led him into the field of human growth hormones. After he and his colleagues cloned the human growth gene, Baxter teamed with Fletterick to show how hormones bind to their thyroid receptor proteins. “That has had all kinds of implications for helping us design things that ultimately become pharmaceuticals. It has really paid off.” In 1979, Baxter was named chief of endocrinology at UCSF and director of the UCSF Metabolic Research Unit, and continues today to lead a team of researchers.

Baxter was among the first university researchers to create biotech startup companies. Not everyone approved. “At a time when interactions with industry were highly controversial in the university setting, John started biotech companies, several of which were very successful,” says Jan-Åke Gustafsson, Ph.D., M.D., professor and chair of medical nutrition at the Karolinska Institute in Stockholm. “Although he received scorn from his academic colleagues, John kept working in new directions and thereby substantially contributed to modernizing the thinking in academia.”

Bert W. O’Malley, M.D., professor and chair of molecular and cellular biology at Baylor College of Medicine in Houston, says that even greater renown for Baxter may be in the offing. “Although GC-1 is not being tested on humans yet, it looks very promising,” O’Malley says. “It could rival or exceed the importance of John’s work with human growth hormone.”

In conversation, John Baxter comes across as a man fulfilled. For the past 40 years he has been married to Lee, his Kentucky sweetheart, and the couple has two grown daughters. Clearly, though, Baxter is a man who still dreams of sailing distant seas and hooking even bigger fish, and right now those dreams are riding on the wings of GC-1. “You go to medical school to be a doctor and make a difference. If this thing could ever work and not be bad for some unforeseen toxicity, that would be a very satisfying thing.”