August 9, 2002

“Work of high distinction” merits Grant Wilkinson D.Sc. degree from University of Manchester

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Grant R. Wilkinson, Ph.D., admired the academic bonnet of the D.Sc. degree as an undergraduate; almost 40 years later he was at his alma mater to receive the degree.

“Work of high distinction” merits Grant Wilkinson D.Sc. degree from University of Manchester

A young student’s admiration of a fancy cap and gown turned into a self-fulfilling prophecy, nearly forty years later, for one of Vanderbilt’s most well-published pharmacology researchers. Grant R. Wilkinson, Ph.D., professor of Pharmacology, returned to his alma mater last month to don such academic regalia himself as he accepted the esteemed D.Sc. degree from the University of Manchester.

"I was an undergraduate at a ceremony when I saw somebody walking down the steps," Wilkinson recounted, "and they had a bonnet on, rather than a mortar board. I asked, ‘What’s that?’ Somebody said it was a D.Sc. and I thought, ‘I’d like one of those one day!’ This was before I’d even decided to go into research."

Wilkinson did pursue a career in medical research, finishing his B.Sc. in Pharmacy with Honors at Manchester in 1963, earning a Ph.D. in Pharmaceutical Chemistry at the University of London in 1966, and completing an NIH post-doctoral fellowship in the department of pharmacology at UCSF. He joined Vanderbilt’s faculty in 1971.

Conferred in recognition of "published work of high distinction," the D.Sc. degree is awarded by the University of Manchester only to former graduates or affiliates. According to Manchester’s specifications, the published work must reflect research that "constitutes a substantial, sustained, and original contribution to science or engineering, and has established the candidate’s authoritative standing in his/her subject."

The meritorious degree mirrors the salute made recently by ISI Citations, which named Wilkinson one of its top 100 Highly Cited scientists for his work over the past 20 years in the area of pharmacology.

Asked whether seeing his inches-thick, leather-bound collection of works gave him a sense of satisfaction, he answered with characteristically dry British wit, "Well, it does make you feel that you haven’t been just pottering about."

Wilkinson’s research, since he’s been at Vanderbilt, has centered on trying to understand better why individual patients respond differently to drugs. Drugs are typically effective in only 20-60 percent of patients, and each individual responds differently. The reason, according to Wilkinson, has to do with what happens between when you take a medication and when it leaves the body through various processes of elimination.

People differ in the rate at which the body handles a drug — determining its concentration in the bloodstream over time, for example — and in the responsiveness of the drug target to a particular concentration. Drug effectiveness, then, is dependent on a combination of pharmacokinetics — getting the drug in and out — and pharmacodynamics — what happens when the drug is at the target site.

The research reflects, to a large extent, a group activity over many years, Wilkinson said. Much of the work has been done through a Program Project Grant that’s just been renewed for the 20th year, in which he and his colleagues study interindividual differences, particularly how drugs are broken down in the body during the process of drug metabolism.

According to Wilkinson, the differences, which may be a thousand-fold, are often associated with genetic problems or variations, causing a metabolizing enzyme to either be present or not. Even in those who do have the enzyme, activity can also vary, so a standard drug dose may be too little for some patients and too much for others.

In the late 1970s and early 80s, the group identified a genetic condition where certain people in a population lack a metabolizing enzyme, later named CYP2C19, which is a member of the major family of liver enzymes known as cytochrome P450. Over the following 15 years or so, he and his colleagues explored how absence of the CYP2C19 enzyme affects drug metabolism and defined the molecular defects that lead to the enzyme’s absence.

Wilkinson continues to study the cytochrome P450 family of enzymes, and is currently focused on CYP3A. The presence of this key enzyme in the gut and liver determines how much of a drug given orally actually enters the bloodstream. To make matters worse, the same cells that have CYP3A also have a counter-transporter, called P-glycoprotein, that pumps any drug that does get into the cell right back out. Wilkinson, along with colleagues Alastair Wood and Richard Kim, are studying how genetic variants and modulation of the P-glycoprotein pump can affect its function in various parts of the body, including the blood-brain barrier.

Accepting the award at the University of Manchester’s July 5 graduation ceremony, Wilkinson said he got a new perspective going through the commencement a second time, after so many years.

"Overall, it had changed surprisingly little," he said. "It was interesting, of course, because you’ve matured and you’re older and you’re comfortable being in public. At 21 or 22…the actual ceremony was just a blur. It was interesting to step back and observe all the details. And also to see young people still going through the cycle, and wondering how their lives and careers would develop."