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PROFILE: Laureate in The Lab

Laureate in The Lab

Nobel Prize Winner Barry Sharpless Pushes the Boundaries of Chemistry in Search of a New Way to Develop Drugs

BY MARION WEBB

Staff Writer





Little more than a year after winning the Nobel Prize in chemistry, Barry Sharpless is hardly resting on the laurels of being a laureate.

“I work as hard as ever,” Sharpless says, though seemingly frustrated by the obligations of his elevated status to intellectual sainthood, which have for the most part kept him out of the lab.

Judging from the looks of his office at the Scripps Research Institute in La Jolla, one would think otherwise.

The piles of paper scattered across the carpet are so high that Sharpless needs to step lightly to maneuver around them.

The conference table is similarly cluttered; among the items are a six-pack of Diet Coke, some half-dozen bottles of chemicals, mail, and more notes.

By contrast, his team of young chemists, dressed in pristine lab coats, provide a picture-perfect image of diligence.

Vlad Litosh, a postdoctoral student from Russia, admits he likes the idea of working for a Nobel laureate and believes Sharpless may well be on his way to another breakthrough discovery. Sharpless certainly thinks so.

“I think we’ve found something that’s more useful than anything I have worked on to date , a simple yet new way to discover and develop better medicines,” Sharpless says.

Sharpless adds he and his colleagues have found a compound that could potentially lead to a better drug for Alzheimer’s disease than existing drugs.

Genius Discovery

Some people believe the technique may be as powerful as the “Sharpless Asymmetric Epoxidation,” which won him the Nobel Prize.

The asymmetric epoxidation uses tools to synthesize molecules that may become a drug without producing their sometimes dangerous mirror images.

Most natural molecules exist in mirror image forms. But nature prefers to make and use just one of the two possible images.

The non-natural form can sometimes be dangerous.

One example is the drug thalidomide, used by pregnant women in Europe in the late 1950s to control nausea. One form of the drug is effective against nausea while the mirror image can produce birth defects. The drug was sold as a mixture of the two forms, which led to malformation in newborns.

Sharpless’ discovery has saved drug makers cash and time, because his tools speed up the drug discovery process.

Sharpless, 60, in his button-down shirt, casual slacks and eyeglasses, fits the role of a chemist. Yet he still muses about his lifelong fantasy of demystifying the sea, forever comparing his laboratory adventures to fishing.

“I would have loved to have been Captain Cook or (Ferdinand) Magellan , that’s real discovery.”

Born on April 28, 1941, in Philadelphia, Sharpless spent much of his childhood at the New Jersey shore where his mother’s family established a fishery after emigrating from Norway.

At 14, Sharpless landed a job as first mate on his cousin “Uncle Dink’s” boat.

Dink, he recalls, was irresponsible, a Yale University dropout, a former prizefighter and womanizer , but Sharpless loved everything about him.

One day, Sharpless says, they took some clients, a young couple, out to sea to fish.

The young Sharpless helped the husband, who was seated in the fighting chair at the back of the boat, hook a 150-pound tuna. Meanwhile, Dink and the wife were alone, out of sight on the bridge.

“It was an amazing thing,” Sharpless recalls. “This guy was stuck down there for 2 & #733; hours and his wife was up there on the bridge with Casanova.”

Sharpless could hardly relate. Like most scientists, he was a shy kid who buried his nose in books behind closed doors.

At Friends Central School, a Quaker high school, Sharpless shined with intellect, but shunned football.

His younger sister, Gay, was the opposite, a born athlete, but not intellectually gifted like her brother.

“She is smart in her own way but she had a tough time in school, because she was always compared to me,” Sharpless says about Gay, who is a teacher, mother and the caretaker of their 91-year-old father.

Sharpless says he was always good with the “smaller things,” like molecules.

“I found I understood molecules and think I had some gift for wanting to understand and understanding what they might do to each other in a new circumstance,” he says.

Stanford Science And Marriage

At Dartmouth College, a chemistry professor by the name of T.A. Spencer persuaded the undergraduate to delay medical school and try a year of graduate school instead.

It was a good decision, Sharpless admits.

“I am good with dogs and I am good with molecules, but I don’t put myself in other people’s shoes very well.”

Sharpless has to thank his Stanford University Ph.D. professor, E.E. van Tamelen, for shifting his passion for fishing into science.

Stanford was also the place where Sharpless met his wife of 36 years, Jan.

They met at a beach party at San Gregonio State Beach in November 1963.

At the time, Sharpless was a first-year chemistry graduate student and Jan was an undergraduate majoring in creative writing.

Their first evening out wasn’t a real date.

Jan was supposed to meet Sharpless’ roommate for the Cal-Stanford game, but he left town when the game was canceled following the assassination of John F. Kennedy.

Sharpless recalls “crying in his beer about some Smith woman” , an old girlfriend from back East.

But he quickly forgot about her. A year-and-a half later, Sharpless and Jan were married secretively with only their best friends present.

“She lived in the dorm and I lived with friends and neither parents knew we were married at first,” Sharpless says, adding “I gave her a motor scooter so she could come visit.”

After receiving his Ph.D. in chemistry in 1968, he stayed on at Stanford as a postdoctoral research student. In 1969, he moved to Boston to spend another year as a postdoctoral research student at Harvard University.

Sharpless began investigating chemical reactions that can produce mirror images when he joined the Massachusetts Institute of Technology in 1970 as an assistant professor.

Jan worked as a public relations account executive and later started her own company.

In 1976, the couple had their first child, Hannah, who is now a teacher in Boston. William, born in 1978, wants to become a medical doctor; Isaac, born in 1980, is studying in Italy.

Click Chemistry

Sharpless returned to Stanford in 1977 as a professor of chemistry, where he met a gifted postdoctoral student named Tsutomu Katsuki.

Three years later, the two scientists discovered the asymmetric epoxidation (AE) reaction, which was hailed as a breakthrough in chemistry.

In 1981, the discovery translated into the first commercial product used by the U.S. government for insect control.

Sharpless returned to MIT in 1982 and remained there until his arrival at the Scripps Research Institute in 1991.

At Scripps, Sharpless created ways to synthesize chemicals, including flavors, insecticides, fragrances and a variety of drugs, which is related to his earlier asymmetric catalysis studies.

Hartmuth Kolb, who worked as a postdoctoral student in Sharpless’ lab in the early 1990s, has a simplified analogy of what chemists refer to as “click chemistry.”

“We click things together like Lego pieces to assemble new compounds that are then tested by big pharmaceutical and biotechnology companies,” Kolb said.

Kolb is now vice president of chemistry at Coelacanth, a New Jersey-based chemical firm founded by Sharpless, Seth Harrison, a venture capitalist, and Alfred Bader, who founded Aldrich Chemical Corp.

Coelacanth was acquired by Lexicon Genetics in July 2001, and is now Lexicon Pharmaceuticals.

Kolb says he’s never met a more creative human than Sharpless, calling him a “chemical-thinking machine.”

“Most people have a linear way of thinking , he thinks outside the box , and jumps left and right,” Kolb says of his former mentor.

Though Sharpless remains “a down-to-earth guy” despite his celebrity status, Kolb says, he’s probably as determined as ever.

Indeed, Sharpless says he wants to prove to the rest of the world that his way is the right way.

The results of his ongoing collaborations with biological teams targeting cancer, HIV, even anthrax, remain to be seen.

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