Stuart Schreiber was about to become a college dropout after three weeks at the University of Virginia when he snuck into a chemistry lecture. He'd been told not to take the class because he'd skipped high school chemistry. But when the instructor drew the innards of atoms in colored chalk, Schreiber was enthralled. He ran to the bookstore, bought a chemistry text, and decided to stay put. "Sitting in on one class made me decide what the rest of my life would be like," says Schreiber. That revelation led him to the forefront of chemical biology, which makes novel small molecules and determines their effects on cells.
Studying for his Ph.D. at Harvard during the late 1970s, Schreiber synthesized copies of natural chemicals, using traditional methods. But after reading about biological discoveries in publications such as Scientific American, he realized he was missing something by focusing on small molecules alone. He therefore taught himself the techniques of biochemistry, molecular biology, and cell biology.
After joining the Yale faculty in 1981, he developed new methods to make complex small molecules and to test their effects on biological systems. One of the highlights was making a cockroach's antenna twitch when he applied a new chemical. "That caused a light bulb to go off in my head that ended up changing my career again," he recalls. "I decided to turn my attention to the ways in which small molecules function in living cells by interacting with macromolecules such as DNA and proteins," he says.
Schreiber's last two years at Yale were frustrating because he had observed that a fungal product, FK506, suppressed a key signaling pathway in the body's immune response, but he was unable to determine its molecular action. A week after joining the Harvard faculty in 1988, however, he discovered an unknown protein that FK506 interacted with. Dubbed FKBP for FK506-binding protein, it appeared to help transmit signals to the gene for interleukin-2, which stimulates the growth of certain immune system cells.
On the other side of the country, Stanford University scientist Gerald Crabtree (now an HHMI investigator) discovered a different protein that directly regulates the same gene. Picking up the phone to quiz him about this finding, Schreiber discovered that Crabtree had also grown up in Virginia's Shenandoah Valley. After talking for three hours, the two men became fast friends, and have collaborated ever since.
In the first two years of their association, Schreiber and Crabtree discovered one of the first examples of a pathway that transmits signals from the cell membrane to the nucleus. The calcium-calcineurin-NFAT (nuclear factor of activated T cells) pathway, which FK506 blocks, is involved in the development of the brain, heart, and skeleton. "It is probably the pathway that evolution stumbled upon to give us the vertebrates," Schreiber says. "And when it goes awry, it leads to a number of human diseases, including diabetes and heart failure." Today, FK506 is sold as the drug tacrolimus, a powerful immunosuppressant.
During this time, Schreiber devised a new way to synthesize a variety of small molecules. Instead of making them one at a time, as chemists are apt to do, he systematically made structurally diverse compounds simultaneously, using a high-throughput process called diversity-oriented synthesis (DOS). With such a collection in hand, it was possible to expose cells to a huge number of new compounds without preconceived ideas of which proteins would be targeted. DOS begins when the same small molecule is placed on a collection of plastic pegs. Each peg is treated with a series of different reagents so it eventually contains a chemical backbone that differs from all the others. Further chemical reactions spawn new families of molecules.
Schreiber's group has developed an extensive robotic system to efficiently screen these diverse chemicals for their effects on living cells. In 1991, for example, they studied a molecule, now called trapoxin, which altered the shape of cells and bound to an unidentified protein. After several years of work, they realized that this protein modifies chromatin, the complex of protein and DNA that condenses into chromosomes. "The last fabulous 10 years have been spent exploring many fascinating facets of chromatin and its role in gene regulation," Schreiber says.
More than 200 groups around the world have made use of the lab's screening system. In 1997, Schreiber decided it was time to make these data publicly available. Therefore, Harvard's Broad Institute, which Schreiber helped found, created a database, analysis tools, and visualization tools. In 2003, it launched ChemBank, which makes these tools available on the Web (http://chembank.broad.harvard.edu) and posts data one year after they are obtained. ChemBank 2.0, launched in 2006, documents the biological actions of hundreds of thousands of small molecules tested in thousands of small-molecule screens. "It offers the possibility that many other laboratories will take the science in directions we never dreamed of," Schreiber says.
Meanwhile, Schreiber has taken his own work in new directions by cofounding Vertex Pharmaceuticals, Ariad Pharmaceuticals, and Infinity Pharmaceuticals, all based in Cambridge, Massachusetts. Each company uses a different flavor of chemical biology to find potential drugs. Many of the compounds have been tested in clinical trials, and the U.S. Food and Drug Administration has approved several for medical use. For example, Vertex discovered a small molecule that is now used to treat AIDS. "In the past, our laboratory focused almost entirely on the biological [actions of small molecules]," Schreiber says. "But over that period, we learned an awful lot about the cellular circuitry that goes awry in human disease. The existence of those probes and of DOS to make and optimize them increasingly caused us to think about their therapeutic potential. That was yet another unexpected turn of events."