Alumni Gazette
CHEMICAL CATALYST: First introduced to the chemical compounds known as statins as a scientist at Rochester, Roth later developed Lipitor, the cholesterol-lowering statin that has become one of the bestselling drugs in history. (Photo: AP Images for Rochester Review)Medicinal chemists like Bruce Roth ’82 (Flw), the inventor of the molecule that became Lipitor, are an optimistic lot. Most of the time, they fail in their attempts to synthesize compounds. Even among those molecules that get created, only a small percentage move on to clinical trials. Fewer still actually reach the pharmaceutical marketplace.
But when medicinal chemists succeed, the impact can be huge. Lipitor, which lowers blood cholesterol, is the world’s largest-selling statin, a drug that has lowered the risk of cardiovascular disease for millions worldwide.
“As a chemist, you learn to live with failure,” says Roth, a senior director of discovery chemistry at Genentech, the research firm whose offices at 1 DNA Way overlook San Francisco Bay. “Almost everything you make has flaws, and it fails. So you need to stay optimistic because the next compound you make will solve the problem. Finally, you succeed, and you are buoyed by the few successes you have.”
On a visit in late spring, Roth, a trim, affable man with red hair, wire-rimmed glasses, and a mustache flecked in gray, stands by a white board and sketches the chemical equation for atorvastatin, the compound that became Lipitor. That day, he’s wearing khaki slacks and a black polo shirt with the company’s logo stitched to the breast. Many Genentech employees are wearing similar shirts because it’s the day the biotech company agreed to be purchased by Roche, the international pharmaceutical company.
It wasn’t the first time Roth had been caught up in a pharmaceutical industry acquisition. He was senior director for atherosclerosis and inflammation chemistry at Warner-Lambert when pharmaceutical giant Pfizer purchased it in 1999. With the new company, he rose to vice president of chemistry before moving to Genentech in 2007.
At Genentech his research unit includes about 90 researchers and chemists at Genentech’s sprawling South San Francisco campus. There, the group is working to develop compounds to combat neurological degenerative diseases such as Alzheimer’s.
“The culture at Genentech has a focus on great science,” he says. “It’s freewheeling, and there’s not a lot of process. We’re nimble and you feel like you can make an impact.”
Roth likes to make an impact. He holds 43 U.S. patents; he’s the author or coauthor of 50 manuscripts, 35 published abstracts, and nine book chapters.
The son of a grocery store manager, Roth was raised in Media, Pa., in suburban Philadelphia, and earned his undergraduate degree in 1976 at St. Joseph’s College in Philadelphia. Instead of entering the food business, he decided to pursue science, studying organic chemistry at Iowa State University, where he earned his doctorate in 1981.
The foundation for Roth’s success in creating Lipitor was set at Rochester in 1981 and 1982 when he worked as a postdoctoral fellow in the laboratory of Andrew Kende, now the C. F. Houghton Professor Emeritus of Chemistry. Roth had learned of Kende’s lab from George Kraus ’72, his PhD advisor at Iowa State, who had studied with Kende and thought Roth would be well served to continue his research at Hutchison Hall.
At Rochester, Roth worked alongside Kende, Robert Boeckman Jr., now the Marshall D. Gates Jr. Professor of Chemistry and chair of the chemistry department, and Richard Schlessinger, a professor of chemistry for three decades at Rochester who died in 1997. There, he began experiments to replicate highly complex fungal products, called statins, which were thought to block cholesterol.
Like many postdocs in chemistry, Roth spent long hours in Hutchison, showing up daily by 9 a.m. and typically working until 10 p.m. or even midnight, seven days a week. Roth says some of the professors were often there that late as well.
“That’s how you learn the chemistry that you need,” says Roth. “You learn the chemist’s work ethic. You learn there is a sweat-equity piece to it. Being a doctoral student or postdoc in chemistry is like being in a sprint. Once you are in industry, it’s more like a marathon.”
Kende recalls Roth’s leadership, good nature, and productivity that year, when he published three papers to document his work.
“He was intellectually engaged, not only in his own research, but the research of others in the group,” says Kende. “He was, for many of us, an intellectual sounding board. In his Midwestern, good-humored way, he was usually ready to give good suggestions to those who sought them. It was because he was so engaged, bright, and highly creative that he was really fun to work with, and he was ready to discuss chemistry at all times.”
By the early 1980s, the pharmaceutical industry was just discovering the promise of statins in the fight against heart disease. As Kende prepared to travel to a seminar at the pharmaceutical firm Warner-Lambert, he asked Roth for his CV to pass along to the company’s recruiters. Roth was hired in 1982 to work at the company’s research facility in Ann Arbor, Mich.
Soon after arriving on the job, he met his wife-to-be, Michelle, who had been hired there a week earlier. They were married in 1984, and have four children—David, Sarah, Rebecca, and Aaron. The Roths live in San Jose, where Michelle teaches biotechnology at Valley Christian Schools.
After three years of research at Warner-Lambert, Roth had developed several promising compounds, including a molecule called CI-981 that became Lipitor. But that molecule wasn’t Warner-Lambert’s first choice for a cholesterol-fighting medication. In fact, Roth called Lipitor, “the drug that almost wasn’t.”
“They were about to begin animal trials with one compound,” he says. “Then there was a patent problem, and it fell through. We had this molecule sitting on the shelf.”
Although the molecule showed promise in early tests, after several years in development, animal studies indicated that it would be no more effective than cholesterol-reducing drugs already on the market. But Warner-Lambert moved forward in 1990 with clinical trials on humans, hoping to reduce low-density lipoprotein, or LDL, the so-called “bad cholesterol” that’s associated with heart disease.
The results were earthshaking, with the new drug reducing LDL significantly more than its competitors.
In 1997, Lipitor hit the market with a splash. By 2008, Lipitor had annual sales of $13 billion worldwide.
“It wasn’t until we entered the clinical trials that we really understood what we had made,” says Roth. “With 20-20 hindsight, everything seems obvious, but in 1982, it wasn’t clear whether lowering plasma cholesterol would have a benefit or that we could do it safely.”
Roth holds the patent for Lipitor. But since the drug was developed when he was at Warner-Lambert, he receives no royalties.
He has, though, earned considerable acclaim within the field. In 2008, he was named one of the American Chemical Society’s “Heroes in Chemistry” for the discovery and development of Lipitor.
He still enjoys the challenge that chemistry provides and remains upbeat that the hard work that goes on in his labs will improve the lives of those suffering from debilitating illnesses.
“You are lucky if one in 20 compounds that is a candidate for clinical trials ever makes it to market,” he says. “But you have to remain optimistic, and bring that attitude to work with you every day.”
David McKay Wilson is a New York–based freelance writer.
