Basic Research Leads to Profitable Bay Area Industry
by Mika Pringle Tolson
Dr. Leslie Z. Benet
Oral drug delivery and availability has been a problem confounding the medical profession for decades. Until recently, the problem was believed to be physico-chemical: either the drug wasn't soluble enough, or it couldn't pass through the cell membrane. All previous drug delivery solutions worked on solving these two problems. But Dr. Leslie Z. Benet, a professor of Biopharmaceutical Sciences at UC San Francisco and investigator for the UC Toxics Substances Program questioned this conventional wisdom. Like many successful investigators, his career path took a few twists. Dr. Benet started his educational career at the University of Michigan, where he received a Bachelor's Degree in English. As the son of dermatological drug company owners, he seemed destined for pharmacy, but Benet had wanted to attend Yale. Because Yale had no pharmacy school, to comply with his parents' wishes he attended the best university that also had a pharmacy school, and that was the University of Michigan. After receiving his degree in English, he applied to graduate school, but before embarking on his graduate education, he spoke with a creative writing professor that he admired very much, who was also a well known poet at the time. This professor advised Benet that "he'd do well in graduate school and be a great professor, but he'd never be a very good creative writer." Benet aspired to be a poet, but accepted this honest evaluation of his capabilities and returned to the University of Michigan to finish a second undergraduate degree in Pharmacy. This led him to a master's degree in Pharmaceutical Chemistry, also from U of M, and eventually to his Ph.D. at UC San Francisco in 1965. Benet became an Assistant Professor in Pharmacy at Washington State University immediately following his doctorate and then accepted a faculty position in 1969 at UCSF, where he currently chairs the Department of Biopharmaceutical Sciences and conducts his research.
Benet's initial research focused on physical chemistry and mathematics applied to pharmaceutical systems. It wasn't until he became an Assistant Professor at Washington State University that he started doing biological studies - looking at theory about what happens in the intestines related to pH. Since he had done work on pH before, the accepted theories of toxics metabolism didn't sound logical, so it stimulated his interest in the biological mechanisms against toxicity. And thus began his work that led to the discovery contradicting current views on drug bioavailability. Benet and his team at UC San Francisco realized that there were many drugs that didn't have solubility or permeability problems, yet the absorption rate was just as dismal as other drugs. They discovered the real problem was that these drugs were either being metabolized in the intestine, or they were being pumped back out of the cells by a transporter once they got absorbed. Benet's research group uncovered the major obstacle to reliable drug absorption: the body's protective mechanism against toxicity - the teamwork of the intestinal enzyme cytochrome P450 (CYP3A) and the transporter Pglycoprotein. The enzyme destroys the drug by metabolism, and the transporter pumps any absorbed drug molecules back into the intestine to come in contact with the enzyme again and again. It is this process that reduces the bioavailability of many drugs to a percentage of their original dose. More than half of human drugs can be metabolized by CYP3A, so the potential implications of Benet's discovery are enormous.
While he was conducting his research, Dr. Benet came across an Indian study in the Journal of Nutrition and Cancer on how diet, specifically Indian spices, affects the cellular toxicity of aflatoxin. The study didn't mention anything about the spices being inhibitors of CYP3A, which activates the toxicity of aflatoxin, but Benet suspected that was what was happening. Anecdotal evidence for his hypothesis was presented when a staff member of Benet's told him her story. She had been taking a drug for her jaw pain, and because the drug was fairly toxic, she had to go to the hospital periodically to be monitored. After a while, she found that the drug was no longer working as well, and a coworker offered her a Chinese herbal tea that was supposed to help with the pain. She drank the tea, and sure enough, her pain went away. When she went back to the hospital for monitoring, they found toxic levels of the drug in her body. Benet believes that the tea contained a potent inhibitor of CYP3A, which kept the drug from being metabolized and allowed much higher levels into the bloodstream, leading to its toxicity. Our diet seriously influences drug absorption; it has been known for a few years in the AIDS community that taking medication with grapefruit juice increases its effectiveness. Why? Because grapefruit juice contains high levels of an unidentified substance which inhibits CYP3A.
Benet realized the major implications of the results of his basic research and wrote a patent application through UCSF in early 1994. He decided to put the patent to work and founded his own company, AvMax, Inc. (Maximum Availability) to continue research on the enzyme and transporter and to search for specific inhibitors that can be added to approved drugs to increase absorption. The result will be safer, more effective drugs, with a decrease in the volume and frequency of dosage needed for effectiveness. AvMax opened its labs in January of 1995. The company is currently headquartered in Berkeley and has 8 employees, 6 of whom are scientists. Three of the scientists work on the enzyme, and three on the transporter. Dr. Vince Wacher, who was a postdoctoral researcher in Benet's lab until 1995, heads the group that studies the enzyme, and an expert on the transporter, Dr. Jeff Silverman, was recently recruited from NIH; he has two technicians that work with him on testing different inhibitors. The remaining employees are business oriented: the CEO, Mr. David Leech, and the operations manager, Mr. Reed Benet, Dr. Benet's son, a graduate of Harvard Business School. AvMax hopes to increase their arsenal of scientists to 18 in the next 6-8 months, and move to a larger facility in the Bay Area. The company was originally funded with a small amount of venture capital, and then some joint research agreements with pharmaceutical companies. Says Benet, "We're boot strapping it because there are near term products. Most pharmaceutical companies would take 10-15 years before you can see anything. What we're doing actually has the potential to have products in 3-4 years."
As company founder, Dr. Benet is Chair of the Board, but he is not an employee of the company. He continues to do research at UCSF on different aspects of the enzyme and the transporter because, according to Benet, "it works all kinds of other places in the body that are real important". You may be wondering how a University of California professor can start his own business and not be in a potential conflict of interest. As a longtime member of the UCSF Conflict of Interest Committee, Benet has firsthand experience with the policies and procedures guiding Universitylndustry relations. Because the inital research that spawned the company was done at UCSF and the patent was written through UCSF, the University has an equity position with the company and receives royalties. As Benet puts it, "the University benefits as well as the individuals."
How common is this sort of thing? Consider the entire biotechnology industry. Most of the major companies thriving today were spawned from various UC campuses and universities like Stanford. For example, COR Therapeutics, Inc., a company that develops platelet aggregation inhibitors to treat arterial thrombosis, was founded by Dr. David Phillips, a UCSF researcher who first identified and characterized the glycoprotein CPllb-llla that controls platelet aggregation. And it's not only the biotech industry that benefits from UC research. The computer chip industry has received many boosts from electrical engineers at UC Berkeley and elsewhere. Says Benet, "You've probably heard more about companies coming out of Stanford and UCSF because it's health related. I'm not sure we do more. I think you just hear more about it because it's the kind of thing papers like to write up. They don't write up so much about making an electron go faster through a board, even though the implications are probably better. But who wants to read that in a newspaper? If I can say I can cure breast cancer because I understood this receptor, it's going to get into all the public papers."
One of the University of California's major contributions to the state, as well as the rest of the world, is its ability to apply the results of laboratory research to solving the problems of everyday life. Basic research can lead to very lucrative links to industry - it doesn't always have to take the path of applied research with matching funds from industry. The two approaches are probably equally unpredictable in their outcomes. Programs like the UC TSR&TP that fund basic research and provide seed funding for new ideas may be the link to more industries in the future. Dr. Benet's research has been funded both directly as an individual investigator and indirectly through the Health Effects Component of the UC TSR&TP. The UC San Francisco portion of this component has added strengths in molecular biology and pharmacology to the public health & epidemiology aspects from the UC Berkeley campus. As Benet says, "What we thought we could contribute at UCSF was a perspective, both from a clinical and basic science aspect that translated into what happens in people."
So what's in the future for Dr. Benet? More research is needed. As he says, "there's an addiction to research because you're looking at basic things and you're trying to figure out what's going on and when you do that's really exciting. Some people when they start companies leave the University and run it, but it's too much fun doing this. I have a really good job. I like what I'm doing. I like teaching, and I like training young people. My objective is to make more discoveries."
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