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Sense/Antisense Creeping Down the Pipeline


By John S. MacNeil

“Am I suggesting that all NIH researchers become drug developers?” asked Francis Collins at the annual BIO meeting this summer. Although he answered himself with an emphatic “No!”, that he asked the question at all is noteworthy. In a paper published in Nature last April, Collins first raised the idea of the National Human Genome Research Institute participating more actively in early-stage drug discovery. At BIO he made the institute’s plans more explicit.

Collins is referring to an interest he and others have in seeing NIH researchers screen small molecule compound libraries for inhibitors for many, if not all, of the proteins encoded by the human genome. At the very least, he said at BIO, NHGRI scientists could identify small molecules that modulate the behavior of proteins and investigate protein function — experiments loosely grouped under the term chemical genomics.

Two things seem to be motivating NHGRI’s push into early-stage compound identification: the need to address orphan diseases and the desire to justify the continued existence of NHGRI by deriving drugs from the completed human genome. “What we’re talking about is simply moving a small degree along the drug development pipeline, doing a little bit more work in the public sector than has traditionally been done, to help triage the genome for therapeutic purposes,” says Chris Austin, senior advisor to the director for translational research at NHGRI.

This approach makes sense for several reasons. Profit-driven pharma and biotech companies are unlikely to invest significant resources in finding a cure for rare genetic diseases; a public effort to do so would be welcome. And compound libraries are cheaper, and therefore easier to obtain, than they once were, making a public-sector distributed chemical genomics effort feasible now. Given NIH’s mandate to address issues of public health, not to mention its budget windfall of recent years, early-stage drug discovery would make prudent use of NHGRI-generated genomic data.

To be sure, NHGRI is not the first public-sector institution to tread this route. Aside from NCI, which has several programs to encourage researchers there to identify new targets and lead compounds, schools such as Harvard University are establishing core facilities for compound screening, as is the Fred Hutchinson Cancer Research Center in Seattle. Researchers and administrators involved with these programs share NHGRI’s drive and say the institute’s initiative is well-founded, but also point out a few caveats.

Ross Stein, who is directing the Laboratory for Drug Discovery in Neurodegeneration at Harvard, says that while compound libraries and chemistry expertise may be cheaper than they used to be, they’re still expensive. Adds Julian Simon, a molecular pharmacologist engaged in early-stage drug discovery at Fred Hutchinson, these resources shouldn’t come at the cost of more basic science research for public labs. “There’s certainly an argument to be made that we shouldn’t take resources away from basic science in order to do drug discovery, just because most of drug discovery is going to be a failure,” he says. Smart oversight would also help avoid conflicts of interest, says Ed Harlow, a molecular biologist at Harvard working with Stein to establish a screening core. “What you don’t want is research in academia directed by industry,” he adds.

Can NHGRI raid drug discovery territory and get away with it? Perhaps. A chemical genomics effort that identified clinically successful new drugs would certainly help to justify NHGRI’s existence at a crucial time, given the recent call to combine NIGMS and NHGRI (see Markers, p. 17).

But how much of the drug development burden should taxpayers take on if the bulk of the profits from any compounds that succeed as therapeutics end up in the pockets of big pharma? Austin says NIH has couched the argument in terms of what it can do to serve the public: “We would be amiss if we didn’t ask what we could do to make new drugs available faster,” he says. Adds Simon, “We want industry to do it, we just want to give industry a broader palette to do it with.”


John S. MacNeil, a senior editor at Genome Technology, can be reached at [email protected] His Sense/ Antisense column, which covers government research policy and regulatory issues, will appear bi-monthly.

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