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The Screen Machine

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About a year ago, scientists from Illinois State University and the NIH's Chemical Genomics Center published results of a major effort to find compounds that might be used as therapeutics for the parasitic disease schistosomiasis. While the work itself was considered to be of great importance, the real point of interest for CGC's Christopher Austin was that the project went from "an idea to in vivo validation in the mouse model in about two years. It's unheard of."

Austin, who joined the National Human Genome Research Institute in 2002, has been building a massive screening center to make possible exactly that kind of pie-in-the-sky research. From designing assays to generating and analyzing data to chemistry optimization, Austin says the pieces are finally in place. "It is an absolute machine," he says.

That machine has gotten a serious boost in recent years as Austin has wrapped up a major phase in building "an unprecedently large collection of drugs that are approved for human use by regulatory agencies in [the US] or elsewhere," he says. The CGC collection now has virtually every drug that's been approved by FDA or its counterparts in Europe, Canada, and Japan. The idea is to take assays for rare diseases that are unlikely to spark the interest of pharma, scan them against the collection, and find drugs that can be repurposed for those diseases. "We can test every drug that's approved for human use in an afternoon," Austin says. "That fundamentally changes the way you think about translational screening."

Now his goal is to feed the beast. Austin's modus operandi is for his team to partner with biologists whose work could be given a serious boost by having a solid chemical assay. Many of the partnerships focus on rare diseases — about 30 percent of assay development goes toward cancer-related projects, Austin says.

Most of the collaborations begin with someone getting in touch with Austin or another member of the CGC — occasionally it's someone who has a specific assay in mind, while the vast majority of scientists who contact Austin have simply made an interesting observation in the lab and have a vague idea that using a chemical probe to manipulate a target would be helpful.

"We ask everybody to give us a 20-minute presentation about the biology," Austin says of potential partners, who also report on whatever types of tests they're currently using, whether they have positive controls, and more. "We are looking for folks who really know their biological system, from basic chemistry up to animal physiology, if possible," he says. Another essential quality of good partners is being eager "to be deeply collaborative on an ongoing basis with a group whose expertise is quite distinct from their own," he adds — and over a long period of time. Generally speaking, CGC scientists will spend six months to two years developing an assay.

For most biologists, signing on with the CGC means working with unfamiliar technology and new concepts — in other words, "working outside their comfort zone," Austin says. But in some of the great partnerships he's experienced so far, Austin says both groups recognize that they are "completely depending on each other" to move the project forward.

The CGC isn't meant to be a facility that generates data like a service provider and then tosses it over to the scientists. When Austin's team works with biologists from another institution, the collaborative aspect drives the strength of the project. Scientists at CGC trade data back and forth with collaborators, constantly honing assay development and eventually moving into assay validation, secondary assays, and work in different physiological systems, Austin says.

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