July 11, 2003

Wells retires after 31 years of service

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Jack Wells

Wells retires after 31 years of service

When Jack N. Wells, Ph.D. first came to Vanderbilt 31 years ago, he intended for his sabbatical here to last only one year.

“You’re supposed to return from sabbaticals,” he said recently. “I went back to Purdue to tell them I wasn’t returning.”

He had such fun working with Dr. Earl W. Sutherland and Joel G. Hardman, Ph.D. in the department of Physiology, he recalled, that when they asked him to stay on, he jumped at the opportunity. Wells retires at the end of July after 30 years as a faculty member. He was named professor of Pharmacology, Emeritus at the spring commencement ceremony in May.

The department of Pharmacology celebrated Wells’ career last week with a symposium and reception in his honor. Symposium speakers included Wells and longtime colleagues Dr. Italo Biaggioni, professor of Medicine and Pharmacology, Lee E. Limbird, Ph.D., associate vice chancellor for Research, and Elaine Sanders-Bush, Ph.D., professor of Pharmacology and Psychiatry.

Hardman, professor of Pharmacology, Emeritus and chair of the department from 1975 to 1990, made a surprise visit from his home in Maine to make closing remarks at the symposium. Charged with “roasting” Wells, Hardman razzed him about his fishing tales.

“Jack’s been running this scam for a long time, about catching fish,” Hardman said. “I went fishing with him once, and he assured me we would get a lot of bites. And we did — from the mosquitoes.

“Seriously though, Jack’s thoroughness and self-critical approach in research and his unreserved help clearly have made him a pillar of this department and of this school,” Hardman said.

Wells got his educational start in a one-room schoolhouse in Kansas. He went on to graduate from Park College in Missouri with a double major in chemistry and biology. This combination set the stage for his career, which has “melded chemistry and biology in a wonderful way,” said Heidi E. Hamm, Ph.D., Earl W. Sutherland Jr. Professor and Chair of Pharmacology.

Wells intended to attend medical school, but an early fascination for chemistry research landed him in graduate school at the University of Kansas. He moved with his mentor, the famous medicinal chemist Joseph Burckhalter, to the University of Michigan where he earned his Ph.D. in medicinal chemistry. Following a short postdoctoral fellowship, Wells joined the faculty at Purdue University where he remained for nine years before the fateful Vanderbilt sabbatical that lured him away.

During the course of his education, he was honored with membership in Phi Beta Kappa, Sigma Xi, Phi Lambda Upsilon, Pi Delta Sigma and Rho Chi. He received the Lederle Faculty Research Award at Purdue and was an Established Investigator of the American Heart Association from 1976 to 1981.

Throughout his career, Wells has stayed true to his roots as a medicinal chemist, generating small molecule chemical compounds that interact with biological targets of interest and that might be good therapeutic agents.

Early on, Wells and colleagues synthesized more than a hundred “xanthine” compounds — inhibitors of enzymes called phosphodiesterases — and studied their effects on smooth muscle relaxation and contraction. At the time, phosphodiesterases were not considered to be good drug targets, but Wells and colleagues showed that these enzymes played an important physiological role.

“I take quite a bit of pride in the fact that I think we awakened the pharmaceutical industry to the idea that if you inhibit phosphodiesterase, you accentuate the effects of hormones,” he said. “We got a lot of attention after that, from the pharmaceutical industry, from the people that were designing drugs. Their subsequent research efforts on inhibiting phosphodiesterases led to the development of Viagra and cardiotonic agents like amrinone and milrinone.

It also changed my career very quickly,” he added. “When three or four big pharmaceutical companies go after a target, then a single academic medicinal chemist better step out, or he’s going to be left behind. And I think that’s the purpose of academic research in medicinal chemistry — to make breakthroughs that can be utilized for the betterment of clinical medicine.”

Wells didn’t have to look far to find other uses for his collection of xanthine compounds. It was known that two xanthine-type chemicals — caffeine and theophylline — were blockers of adenosine receptors. He and graduate student Betsy Martinson began to evaluate their modified xanthines on these receptors.

“Betsy made what is still the gold standard antagonist for the A1 adenosine receptor,” Wells said. The A1 receptor is one of four “subtypes” of adenosine receptors. “We showed that it was possible to selectively inhibit a single form of the receptor.”

Another of their inhibitors, this one for the A2B adenosine receptor, has been patented and licensed to a company called CV Therapeutics. The compound, and a newer one related to it, could prove to be potent asthma medications, an area that has been pursued by collaborator Biaggioni. In addition, Biaggioni said, blocking the A2B receptor could prove useful in blocking pathological angiogenesis associated with tumor growth, for example.

For Wells, the patenting of his compound was a triumph.

“You work all your life as a medicinal chemist to get a patent, to get a compound that might become a drug,” Wells said. “And then in the last two years of your career, it finally happens. It’s a good note to go out on.”

But Wells hasn’t rested on these laurels. In the last few years, he’s taken up molecular biology — under the tutelage of Dr. Alfred L. George Jr., Grant W. Liddle Professor of Medicine — and embarked on a project to define the amino acids in the “binding pocket” of the A1 adenosine receptor protein.

These efforts are a critical prelude to drug design based on molecular modeling. “If we know the amino acids that are facing the binding pocket, then we have data that must be accommodated by models of the A1 adenosine receptor,” Wells said. “That would give me a lot of confidence that I could take that model and dock imaginary experimental compounds and develop a specific drug for that protein.”

The conclusion of these studies, expected in the next few months, will be a “really wonderful and important contribution,” Hamm said.

More so than his many scientific achievements, Wells points to the mentoring he has done over the years as his most important contribution. “I’m absolutely most proud of the 20 Ph.D. students I had the privilege of mentoring,” he said.

“Why did so many students flock to Jack Wells?,” Hardman said. “I think the reason is, students select first, people who are good scientists. And second, people who are known to sincerely care for students and who support them not only scientifically, but personally. Jack has done that.”