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By Malorye A. Branca

September 15, 2003 | The nay-sayers who warned it would take 100 years to complete the Human Genome Project (HGP) will have plenty to fret over about the latest proposal percolating at the National Human Genome Research Institute (NHGRI). Its chemical libraries plan has all the breadth and potential of the HGP and raises similar questions about focus and feasibility. But the plan also moves the National Institutes of Health (NIH) into territory that has traditionally been restricted to industry – high-throughput screening and small-molecule development. Indeed, some biotechs are voicing concern that it might seriously limit their own prospects for success.

NHGRI Director Francis Collins has been testing the idea on a variety of audiences over the last year. The project, which Collins calls “the centerpiece” of the agency’s new five-year plan (see The New House of Genomics, Feb. 2003 Bio-IT World, page 14), would establish several NIH-based centers for high-throughput screening of small molecules.

The proposal already has many NIH supporters, including director Elias Zerhouni, whom Collins says is “strongly in favor of it.” Zerhouni has made the development of chemical libraries an NIH-wide priority. According to Collins, each of the 15 institutes is interested in the project.

Chris Austin, senior advisor to the director for translational research at NHGRI and an architect of the chemical library plan, says that NHGRI will primarily use the libraries to “determine function and therapeutic potential of genes and to define molecular networks.” While NHGRI hopes to pull new drug targets from the genome, other institutes will seek targets for specific medical conditions, including orphan diseases — typically neglected by industry ( see Orphan Drugs: For Love or Money? Aug. 2003 Bio-IT World, page 29). “Some of those [chemical] probes just might turn out to be good drug candidates,” says Collins.

Costs are not yet available, but the first concrete steps could happen within a year. NHGRI would start by acquiring small-molecule libraries and assembling information on functional assays and chemical synthesis protocols. Scientists would submit screening assays, and collaborate in the development of high-throughput platforms. “Search algorithms analogous to BLAST for gene sequences” would allow researchers to trawl for useful compounds, says Austin. Samples of small molecules will also be made available.

The ultimate goal is to have a small-molecule modulator of every human gene product, but that could take decades with current technologies. However, a simultaneous goal is to develop novel tools for high-throughput screening, chemical diversity generation, bioinformatics, and functional assay development.

Biotechs have no problems with the technology development aspect of the project. “Having more smart people working on this is bound to help – I’m excited about that part of it,” says Exelixis Chief Science Officer Geoffrey Duyk. But he and others are concerned about some aspects of the proposal.

A major worry is that researchers new to screening will overreact to early results, clogging the scientific literature with manuscripts “talking about hits, and with a tagline implying that ‘cures are around the corner,’” Duyk says. Most active molecules found through high-throughput screening do not pan out as drug candidates. “Hits have long been sold as a milestone in screening,” says Anton Fliri, research advisor in Pfizer’s CNS technology group. “But if you take 100 hits, you may come up with only one drug.”

“The unintended consequence [of the libraries plan] could be a lot of noise in the literature and not many practical results -- and another wave of genome hype,” echoes Joshua Boger, CEO of Vertex Pharmaceuticals, wary of the suffering biotechs have experienced from investors’ overblown expectations.

Intellectual property (IP) is another problem. Boger has a “free-floating anxiety” that this project could shrink the pool of commercially exploitable targets. “Once things come into the public domain, even if they are not already patented, it could be harder to claim a novel use for them,” he says.

Specific high-throughput “friendly” functional assays are also extremely valuable. But getting even academics to part with them could be tough. “Certain academic institutions take a hard line on intellectual property,” says Mark Namchuk, head of high-throughput screening at Vertex.

Plan architects agree that the IP issues are complicated. “We don’t have a final decision on how to proceed, but we believe they can be worked out,” Austin says. He adds that NHGRI is committed to giving all interested parties, including industry, freedom to operate with the probes in their collection. The agency hopes that researchers will recognize the community benefits that sharing resources brings.

Tom Insel, director of the National Institute of Mental Health (NIMH), supports the initiative, saying, “We want to bring the power of academic researchers into this effort.” (See The Case for Chemical Libraries.) That would be researchers like Huda Zoghbi, at Baylor College of Medicine. Her group identified the gene for spinocerebellar ataxia type 1, and is looking for modulators of that gene product. The NHGRI screening plan, “could help us,” says Zoghbi, “but it depends on what type of molecules they have in the library.”

Perception Problem
A further concern is whether this is the best use of NHGRI resources. Drug makers contend that screening isn’t the slow point: The real pain lies when they move from hits to drugs, trying to find improved ways of characterizing “druggable” and elucidating pathways in animal models. “It would be nice if NHGRI was addressing some of the really hard problems in drug discovery,” says Nat Goodman, a senior research scientist at the Institute for Systems Biology. “This is an interesting project, but it’s not an obvious choice as a centerpiece.”

The NHGRI, meanwhile, is struggling against the perception that its charter goal has been met with the completion of the HGP. Recently, a joint National Research Council/Institute of Medicine report recommended merging NHGRI with the National Institute of General Medical Sciences (NIGMS) – a suggestion Collins has tactfully deflected for the moment. Zerhouni’s office, meanwhile, says it is still considering the document.

But finding new drugs was always a goal of the HGP, and now there is more pressure for that to happen than ever. “Everyone involved with the genome project, including Congress, is anxious to see that translation take place,” says Austin.

As part of the plan, the agency will recruit medicinal chemists to refine leads into drug candidates, but will rely mainly on industry collaborators for subsequent steps. Collins says industry should see the plan as “complimentary, not competitive,” particularly since the data will be freely available. “Would we use the data? Of course we would,” says Pfizer’s Fliri. “It all depends on how good it is.”

Clearly many researchers are being seduced into small-molecule research. Guiding that process, says Collins, would be a “transforming opportunity” for NHGRI. “Isn’t it our job to look into the future to identify areas of intense promise that need further development?” he asks rhetorically.

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