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The completion of the Human Genome Project last year marked a milestone in medicine. The detailed mapping of the entire set of human genes was a decade-long project worked on by some of the best minds in biology. But in many ways it was only the beginning of the real medical challenge: understanding the million or so proteins that are the molecular workhorses of the human body. Genes are really just the programming code that tells cells how to synthesize proteins; almost all the biological action occurs among these large, complex molecules.

When proteins misbehave they can destroy our health in myriad ways, from the amyloid proteins that gum up the brains of Alzheimer’s patients to the proteins that cause runaway cancer-cell growth. Battling disease more effectively means getting a better grip on how proteins work and interact-and fail. The most important emerging tools in reading the vast protein library are micro-arrays, small chips containing thousands of protein samples that can be analyzed quickly and cheaply. “This is where people will get answers about how disease develops, how drugs work, and how to find new drugs,” says Peter Wagner, chief technical officer of Zyomyx, a Hayward, CA-based protein-chip startup.

Zyomyx has nearly a dozen competitors, including Large Scale Proteomics, Ciphergen Biosystems, Packard BioScience and Phylos. The industry’s first products are expected on the market in a year, and while technologies vary, the new biochips are generally two-dimensional grids of proteins or protein fragments attached to a solid support.

When the protein microarray is exposed to biochemicals or solutions of other proteins, some of those molecules will stick and some will wash off; the ones that stick can be identified by various markers, such as fluorescent tags. Molecules that adhere strongly to specific proteins are valuable leads in the search for new drugs, because that binding ability is what makes pharmaceuticals effective. And for diagnostics, measuring abnormally high amounts of telltale proteins in a blood sample using these biochips could be a fast method for early detection of heart attacks and cancer.

The idea of microchips is nothing new in biology. The manufacture of DNA chips has been one of the hottest areas of biotech since the early 1990s, when innovative researchers took the robotics and lithographic-patterning technology used in making silicon microelectronics and applied them to DNA analysis. They were able to attach thousands of pieces of genetic material to glass slides or plastic wafers and use these “chips” to identify DNA in a sample of interest. These DNA chips are now widely used in medical research.

But making a protein chip is far more vexing. While DNA is pretty sturdy, proteins are shrinking violets. Proteins are exquisitely folded strings of subunits called amino acids, and a lot of what proteins do depends on the precise three-dimensional pattern that the string folds into. Outside of a narrow range of environmental conditions, proteins will “denature”-the amino-acid chain will lose its three-dimensional structure, collapsing like a pile of overcooked spaghetti. In making microarrays, researchers have to keep the proteins in a watery solution at just the right temperature the whole time.

Despite these challenges, the future of protein biochips is unfolding rapidly. “There is a clear understanding everywhere in the [biotech] industry now that you’ve got to focus on proteins,” says Zyomyx’s Wagner. According to a recent report by BioInsights, a biotech consulting firm in Redwood City, CA, sales of protein biochips will likely rocket to half a billion dollars in 2006.

And the eventual impact of the technology may be felt far outside the biological research community. “Useful protein chips for diagnostics should be available in a couple of years,” says N. Leigh Anderson, CEO of Large Scale Proteomics. “It won’t take as long as some people think.” That might be an optimistic prognosis, but if he’s right, packages of small protein chips may soon be just as ubiquitous as tongue depressors or rubber gloves in your doctor’s office. 

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