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Completeness and accuracy were the Human Genome Project's twin mantras from its formal start in 1990. At that point, researchers had already painstakingly identified more than 4,000 of the 100,000 genes that serve as the blueprint for a functioning human being--each gene carrying instructions that tell cells how to produce a specific protein. Scientists had located about 1,500 genes, in a rough way, on the 46 chromosomes--the long, twisted strands of DNA cradled in protein at the heart of every human cell. But they had deciphered, or sequenced, only a handful of the many-hundred-word "sentences" that each gene represents--sentences made up of three-letter "words" built in turn from four available molecular "letters," represented by A, T, C and G.
The project's $3 billion mandate: sequence the entire 3 billion-letter human genome with high precision as a prelude to figuring out eventually what protein each gene produces and for what purpose (see diagram). The process can be likened to mapping out a route from San Francisco to New York City by walking the entire distance and noting every hill and valley along the way. It's slow but precise. After eight years, some 7% of the human genome has been sequenced in encyclopedic detail.
But while the genome project has been methodically chronicling the details of human cells--including long stretches of DNA, amounting to some 97% of the total, that contain no genes at all--private companies have opted for a very different approach. Their maps are more like satellite photographs that take in the entire route but concentrate only on the highlights. "The thing people are highly interested in," says Randal Scott, president and chief scientific officer at Incyte Pharmaceuticals, based in Palo Alto, Calif., one of the players in the private-sector gene-mapping game, "is where all the cities are. You don't need to document all the trees and gullies and ditches." Once those landmarks are identified, scientists assume, they can focus on them in greater detail.
Scott's rivals at Genset, based in France, are taking a similar approach: their map, to be completed in early 2000, will highlight just 60,000 of some 10 million biochemical "beacons" found along the human genome. By comparing the DNA of many individuals in and around these signposts, Genset hopes to pick out specific genes whose malfunctions actually cause disease. It has already begun to work. Using this technique, says Genset chief genomics officer Dr. Daniel Cohen, the company has found two different genes involved in prostate cancer. Cohen points out that the 20 most common diseases, which kill about 80% of the population, are probably linked to some 200 genes out of the body's 100,000. It only makes sense, he says, to look first at those genes.
As narrowly focused as their efforts are, Cohen and Scott are using gene-mapping techniques that are not very different from the Human Genome Project's. Craig Venter, on the other hand, has taken a radical approach, one that resembles paper shredding more than it does mapmaking.