Photo: Stanley Rowin

Return to the Wild "Faster, faster," urges Stuart Schreiber, perched on the passenger door of the rented Jeep that his sister Renee Crackel is maneuvering down a mountainside during a family vacation in the French Caribbean. Crackel hugs the hairpin curves as Schreiber hangs out the window, taping the ride for a homemade DVD. They zip down the winding road, picking up speed, until an inattentive motorist chatting on a cell phone forces Crackel to swerve to the right—just as a rocky outcropping juts into their lane. Read more... Related Stories: Stuart Schreiber, Career Highlights Eric S. Lander, Ph.D. Angela Koehler: Hands-on at Harvard Manolis Kamvysselis: Pursuing New Challenges Visit the Schreiber Lab's website

Stuart L. Schreiber, Ph.D.
By Karen Hopkin

Stuart Schreiber has always been a hard-working guy. "I can count on one hand the number of days in the past 22 years that I haven't done something related to work," he notes. Even in his youth, Schreiber worked for what he wanted: mowing lawns, pumping gas, painting houses, and waiting tables at the local pizza parlor to pay for his first motorbike, his first car, and his college expenses.

Industrious as he was, however, young Schreiber was not exactly "academically oriented." In fact, he never opened a book in high school. "Each year they gave me some books and a locker and a combination. So I put the books in the locker," recalls Schreiber. "Then at the end of the year, they asked for the books back. So I had to ask for the combination."

Schreiber was too busy with sports, cars, and girls—or "raising hell and getting in trouble," as he puts it—to seriously hit the books. Enrolled in a work-study program, Schreiber loaded his class schedule with courses on automotive repair and "bachelor wardrobe planning"—the guy's version of home ec. His sole exposure to chemistry came from a movie shown in the school auditorium. In this film, Walt Disney explains how atoms are like the solar system, says Schreiber, "with something in the middle, like the sun, and things that spin around it, like planets." The image was not inspirational.

"I had no interest in going to college when I was a boy," notes Schreiber, who was planning on becoming a carpenter, "but I heard there were lots of pretty girls there." So he took the SATs. "To my surprise, I did really well," says Schreiber. The questions were logical, like a puzzle, and he actually enjoyed working through the answers.

Because of his high SAT scores—and the fact that his sister had paved the way with her academic achievements—Schreiber got accepted to the University of Virginia. There he decided to major in forestry because he wanted to work outdoors. The catch: He had to take chemistry. To postpone that fate, Schreiber instead signed up for a literature class. But he soon found himself frustrated. "I thought it was utter nonsense," says Schreiber. Three weeks later, he phoned his sister to announce that he was dropping out.

Somehow, Schreiber's sister convinced him to tackle the chemistry. "And that day I walked into a class that changed my life," he says. The instructor was at the blackboard drawing some large lobular structures—electron orbitals, it turns out in blue and white chalk. "I remember looking at this thing—I had no idea what it was—and thinking that it was breathtakingly beautiful," says Schreiber. "It was nothing like the Walt Disney image of chemistry I had in my mind."

Schreiber was smitten. He aced the exams and immediately bought the text for the second-year course. Over the summer, Schreiber read that organic chemistry book, cover to cover—twice. He then informed the department chairman that he intended to become a synthetic organic chemist at a major East Coast university. "He laughed at me," says Schreiber. "But I had no doubt about what I was going to do. I had it all mapped out. And I basically stuck to it."

His first stop was Harvard, where Schreiber worked on his Ph.D. with R. B. Woodward, the father of organic chemistry. Finishing his degree in three years, Schreiber landed a faculty position at Yale straight out of graduate school. He moved to New Haven at the end of May and hit the ground running. Arriving at 7 a.m. and working through the night, Schreiber managed to publish his first Yale paper before his official start date of September 1. "It was like playing," he says. "I didn't want to sleep. I just wanted to stay in the lab."

As a synthetic chemist, Schreiber got to act as a sort of molecular choreographer. "I was learning how to make molecules dance." But he soon discovered that there was more to chemistry than designing graceful structures. "I realized I could make substances that are produced by living organisms—or substances I could use to understand living organisms. Chemistry could give me the tools I needed to study life."

In his first foray into biological chemistry, Schreiber synthesized a pheromone that cockroaches use to attract a mate. To determine whether his synthetic pheromone was active, Schreiber plucked the antennae off some of Yale's finest roaches, attached them to a set of electrodes, and puffed his compound over this makeshift bioreactor. To Schreiber's delight, his molecule interacted with the antennae, generating an electrical impulse. "It was like a religious experience," he says. But he failed to figure out how the compound drives insects to distraction. "In the chemistry world, it was considered a success," says Schreiber, "but it wasn't the success I was looking for."

That kind of success would wait until Schreiber was lured back to Harvard—the mecca of organic chemistry. There, he became interested in studying the properties of compounds that affect the immune system. One molecule, called FK506, is made by a bacterium. It can suppress the immune system of animals and humans—a property that surgeons can exploit to keep their patients from rejecting organ transplants. But how does FK506 work?

Because most drugs interact with cellular proteins, Schreiber set out to determine which proteins bind to FK506. He anchored FK506 to a solid support and then used the compound as molecular bait to fish its binding protein from a gruesome soup of minced calf thymus and brain. He then determined the structure of this protein, dubbed FKBP (for FK506 binding protein), and found that when complexed to FK506, it inhibits immune function by shutting down the molecular signaling pathway that allows white blood cells to recognize foreign tissue.

This triumph with FKBP was the start for Schreiber in what scientists now call chemical genetics—using small molecules, such as FK506, to study how proteins work in living systems. Now Schreiber, named an HHMI investigator in 1994, is scaling up his efforts, working to synthesize millions of small molecules that can be used to study the function of every protein in the cell. A $40 million grant from the National Cancer Institute—earmarked for the establishment of Harvard's Molecular Target Lab—should help him to accomplish just that.

Schreiber may have been seduced into chemistry by the voluptuous curves of a well-drawn set of electron orbitals, but his talent, enthusiasm, and dedication allowed him to stay the course. Now he enjoys helping others find their way. "The best part of science is that you get to work with bright young people in this amazing period in their lives, when they're in transition and full of ideas. When I have people come back to me and say, 'I have a better life because you steered me in the right direction,' I get goose bumps. I'm in tears."

Chemistry, it seems, has the power to transform more than molecules. "I think I'm the luckiest person on the planet," concludes Schreiber. "I love what I do every day."

© 2013 Howard Hughes Medical Institute. A philanthropy serving society through biomedical research and science education.
4000 Jones Bridge Road Chevy Chase, MD 20815-6789 | (301) 215-8500 | email: webmaster@hhmi.org