Mixing things has always come naturally to chemists. But just a decade ago, mixing chemistry and genetics did not always stir an optimistic reaction from many authorities in either discipline.

Fortunately, for those suffering from cancer, neurological disorders, tissue rejection or autoimmune diseases — to name just a few — UCSF's Kevan Shokat likes risks. And in following his instincts, the professor in the department of cellular and molecular pharmacology has created a technique that allows researchers to track the path of distinct chemical signals as they move from the surface of a cell toward its nucleus.

By so doing, Shokat and his colleagues have not only made it possible to follow the chemical cascade of what are known as signal transduction pathways, but also to explore and ultimately point the way to new and more effective drugs that might dramatically improve human health.

To the uninitiated, following the chemical trail of cell signals may seem an esoteric route to such a grand payoff. But consider the benefits of tuning in a clear channel in what is otherwise a sea of static. In the human genome, there are approximately 35,000 genes coding for approximately 70,000 proteins. Since proteins are responsible for constructing our body's physical components (everything from our heart to our hair), as well as maintaining and managing the internal environment that sustains them (the immune system is one good example), they must stay in constant communication as they move around both inside and outside the body's 10 trillion cells. Sorting out the details of this communication network, which involves the selective action of one molecule upon another, has been difficult, if not impossible. Until now.

"Everyone said it couldn't be done," says the 38-year-old Shokat, a Bay Area native, who will be part of the first wave of scientists moving from the main UCSF campus on Parnassus Heights to UCSF Mission Bay in early 2003. "But since I was trained as an organic chemist, I like to synthesize, test and tinker."

Shokat's tone is self-deprecating, yet what he and his colleagues accomplished in just two years and first published in 1997 — two years before Shokat's recruitment to UCSF from Princeton — has created a new field known as chemical genetics. At the same time, Shokat and his team have introduced an entirely new technique for observing how disease may develop at the molecular level.

"The simplest way to explain our work," says Shokat, "is to say that we mutated enzymes (those cut-and-paste proteins that speed up chemical reactions), specifically the protein kinases, which are central players in all signal transduction pathways. We then designed tailor-made molecules that only fit into these mutated enzymes — and not into naturally occurring ones."

Kinases work by removing a phosphate group from the cell's "battery," a molecule known as adenosine triphosphate or ATP, and transferring its energy to a variety of different proteins. This triggers a process that fuels and regulates a variety of other important cell machinery. "Think of it as a gradient of on-and-off switches," Shokat explains. The problem in studying kinases is that there are so many of them in humans - around 500 in all. Worse, for scientists like Shokat who were trying to distinguish the individual roles of kinases, each one has almost the very same active site — an area on the surface that binds with another molecule.

Normally, genetics with its precision for interrupting individual genes, would solve this problem of redundancy. Yet for kinases, it didn't work well. As Shokat explains, the technique had a way of producing such global abnormalities in normal cellular development that the information gleaned was of questionable value.

Shokat continued to ponder the problem and eventually realized that it could only be solved by changing the question. "We were all concentrating on what was different about each kinase. I realized that the foothold into the problem was concentrating on what was the same." And what was the same was that all kinases act upon, or bind, ATP. From that starting point, he theorized that if the active site of an individual kinase could be altered genetically so that its shape would change in a way scientists could predict, while still binding ATP, the researchers would then be able to introduce an inhibitor to shut it — and only it — down. Once shut down, there would be consequences. And in knowing what the consequences are, scientists could learn what role each kinase played in that careful balance of chemical reactions we define as good health.

Indeed, experiments conducted in yeast cells and mice over the last few years have shown that this "knockout equivalent" technique not only works on different kinases — cancerous tumor growth was suppressed in mice — but in different protein families as well. Moreover, Shokat has found a family of plant hormones that seem to perform this inhibition function naturally, validation of sorts that there is an evolutionary precedent to what he has engineered artificially. This opens the door to what drug developers call "target validation" and "target prosecution." In essence, Shokat has found a way to make perfectly selective inhibitors of single proteins and then watch what happens when normal signals are disrupted. Such a method is key to crafting any effective pharmacological approach, particularly one that limits side effects.

Along the way, this father of three (who also holds a joint appointment in the chemistry department at UC Berkeley) has also helped to raise the profile of UCSF chemists. His move to Mission Bay signals another opportunity as well. "The six chemistry labs (of Pam England, Kip Guy, Paul Ortiz de Montellano, Jack Taunton and Tom Scanlan) will all be together for the first time. I expect a real chemistry culture to develop."

There's another reason for Shokat's enthusiasm too. "I look forward to cutting my UCSF - Berkeley commute in half."

Source: Jeff Miller

Last updated January 28, 2005

Kevan Shokat

Kevan Shokat has created the field of chemical genetics by developing a technique for studying individual signaling pathways inside cells. Photo by Majed.