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The Fine Print

No proteomics companies have agendas that come anywhere near the type of comprehensive analysis favored by the Alliance for Cellular Signaling. But the companies’ bold pronouncements about their projects would seem to indicate otherwise. Myriad Genetics of Salt Lake City, for example, announced in April that it had formed an alliance with Hitachi and Oracle “to map the human proteome in less than three years.” Large Scale Biology is compiling a Human Protein Index that it boasts is “the protein equivalent of the Human Genome Project, in which all the proteins expressed by every human cell type are being documented.” Celera’s founder, J. Craig Venter, once declared that his company’s proteomics division would work through “every tissue, organ and cell.”

Many proteomics researchers blanch at these declarations. “Those are exaggerated claims, and you have to read the fine lines,” says Human Proteome Organisation president Hanash.

What the fine lines reveal is that the more than 70 companies involved with proteomics are each exploiting limited technologies and therefore have sliced relatively small pieces of the human-proteome pie. Myriad’s definition of proteomics, says executive vice president of research Sudhir Sahasrabudhe, is cataloguing all of the interactions between proteins that it can discover with yeast two-hybrid and mass spectrometry approaches. So much for a map of the human proteome in less than three years. In fact, Myriad has no intention of cataloguing all of the proteins in a human and their modifications. “The technology for conducting a comprehensive inventory of all proteins in a biological model is not there,” says Sahasrabudhe. “You really just begin to skim the surface.”

Meanwhile, Large Scale Biology has catalogued 115,000 proteins derived from 157 “medically relevant” tissues in its Human Protein Index. Yet no one knows just how many medically relevant tissues there are. “We’re in a quandary about that,” acknowledges Anderson. “It’s going to be an elastic concept,” he says, based on the definition of what a separate tissue is. But whatever the definition, the effort seems far short of the boast of “the protein equivalent of the Human Genome Project.” Anderson stresses that his company’s goal is to develop new diagnostics and drugs rather than to know everything that can be known. “The Human Protein Index is trying to get down to a rational point that means something,” he says.

Celera, too, now has much more circumscribed goals than finding all of the proteins from every tissue, organ and cell. Instead, the company studies tissues and cells from people with specific diseases and hunts for proteins found in the membranes that surround cells; such proteins are often susceptible to drugs. “We’re looking in a very targeted way for potential therapeutics,” says Patterson.

Other proteomics companies bill themselves-at least in the fine print-in relatively restricted terms as well. Some target proteins that work as enzymes, the molecular scissors that can cut other proteins and either cause or prevent disease. Other companies hunt for antibodies, the Y-shaped immune warriors that can glom onto dangerous proteins and render them harmless. Some, like Rockville, MD-based Human Genome Sciences, look for proteins secreted from cells (see “Consulting Biotech’s Oracle,” p. 70). Still others carve out a bioinformatics niche, combing the literature to create novel protein databases, developing software to make sense of huge databanks, or helping companies design experiments to quickly find promising drug candidates.

And a dozen companies have invested heavily in developing the next hot assay in proteomics, protein affinity arrays (see “Protein Chips,” TR May 2001). These protein chips set up microgrids of protein fragments or molecules like antibodies that can trap proteins; one day, they may offer a fast, reliable way to compare hundreds of proteins found in, say, healthy and diseased tissue, giving researchers clues about how diseases develop and how drugs work.

Sydney Brenner, building on the oft-used analogy that the human genome data resemble the names and addresses found in a phone book’s white pages, says all of these proteomics research efforts are attempting to compile yellow pages. “It’s classification: we’re trying to find all the plumbers,” says Brenner. But he emphasizes that a true “global understanding” of the proteome will require much more. “We have to begin thinking about getting beyond the mere lists and the interactions,” says Brenner. “That’s as opaque as the original data. That’s going to be the critical thing for biology. And it’s not going to happen overnight.”
The University of Geneva’s Hochstrasser similarly sees the task as daunting. “It’s funny when you think about it,” Hochstrasser says. “People have sent a man to the moon. We have the entire human genome sequenced. But we do not know how many proteins we have in blood.” And we may never know. “It’s like the DNA world is finite, but maybe the protein world is infinite,” he says.

So proteomics researchers may never enjoy their version of June 26, 2000, a day where they bask in the glory of heads of state exclaiming over the completion of their “map.” But already, proteomics is revolutionizing the way scientists hunt for new medicines, and given the many diseases for which no good treatments exist, the ultimate payoff could be much larger than crossing a finish line.

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Tagged: Biomedicine

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