October 2001

Speeding Drug Discovery

Continued from page 3

By Gary Taubes

Biology on the Fly

What Lexicon is attempting to achieve with mice, a South San Francisco company called Exelixis is trying to do with fruit flies, worms and fish. These organisms have also established themselves over the years as workhorses in genetics labs, but Exelixis's innovation was to put them to work on an industrial scale in order to elucidate the functions of genes and identify promising drug targets. As the Whitehead's Altshuler puts it, "Flies and worms may not get diabetes, for instance, but they do sugar metabolism, and they do it pretty damn similarly to the way we do it. So you can find all the genes that affect sugar metabolism in the fly, find out if they're relevant to humans, figure out their function and do drug discovery."

Exelixis was founded by a trio of fruit-fly geneticists hoping to leverage the evolutionary conservation of genes and cellular circuitry that underlies these similarities-not to mention the arsenal of genetic tools honed by the decades of geneticists who have worked on flies, worms and fish. Since these organisms mature in just days or weeks, "You can rewrite their genetic code very quickly, so you can ask all the appropriate questions very quickly," says Exelixis chief scientific officer Geoffrey Duyk. At Exelixis, those inquiries usually start with flies, and so Exelixis has amassed a collection of knock-outs covering most of the 13,000 or 14,000 genes of the fly genome. Using that library, for example, Exelixis researchers are investigating angiogenesis, the process by which new blood vessels are formed. This is one of the hottest areas of cancer research, because a tumor will spur the growth of blood vessels to feed its proliferating cells. Find a way turn off angiogenesis, the argument goes, and you can choke off the cancer. Fruit flies could help researchers tease apart the genetic underpinnings of angiogenesis, even though they don't have blood vessels. What flies do have is a trachea: a system of branching vessels that carry air through the body. The development of the trachea is controlled by a process known as branching morphogenesis, which turns out to be the same process that creates blood vessels in humans.

The Exelixis researchers started studying branching morphogenesis in flies a year ago and expect to identify as many as 200 genes crucial to the process-all potential drug targets. The next step is to take these genes, find their counterparts in zebra fish, and then knock them out of the fish to see which are, indeed, involved in creating and maintaining blood vessels. Unlike flies, zebra fish do develop vasculature systems, just like mice and humans. And unlike mice and humans, zebra fish are, well, fish: their eggs develop outside the mother, and within 24 hours the body plan and all the organs are not only formed but visible, because the embryos and even the adult zebra fish are translucent. "You can follow in real time the development of the vasculature system in the embryo just by looking through a microscope," says Felix Karim, who runs the Exelixis angiogenesis program.

The research to elucidate exactly what these genes do and how they cause disease then proceeds by a process Karim describes as "ping-ponging" between studying the genes of interest, or their absence, in flies, worms, zebra fish, mice and even humans-all done in parallel for maximum speed. The entire discovery process, from fruit fly to validation of a promising target, might take only a couple of months.
The same approach can also be used to identify the genetic targets of existing drugs or promising compounds, which is what Exelixis is now doing for Pharmacia, Bayer, Bristol-Myers Squibb and the National Cancer Institute. "Once we identify the molecular target," says Duyk, "we can develop alternative compounds with the same target but which may have more optimal therapeutic and pharmacological properties."