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Venter's reputation as a creative thinker was made back in the late 1980s. He was studying genes at the National Institutes of Health when he came to a humbling realization: while the greatest minds in biochemistry still hadn't figured out how to locate a gene efficiently, cells do it all the time. Cells, moreover, tap into only those genes they need and ignore the rest.
That was fine with Venter, since the strips of DNA that are actually being used as blueprints for constructing a protein are where the action is. So Venter decided to concentrate on these active parts. He focused on the so-called messenger RNA, or mRNA, which ferries instructions from DNA over to the cell's protein-making machinery. This is the essence of the gene, and it was these stripped-down genetic instructions--copied into a more stable form known as cDNA--that he fed into an automated gene sequencer he'd acquired for his lab.
Decoded cDNA began tumbling out of his machine. A portion of these decoded regions were used as tags--he called them expressed sequence tags (ESTs)--to help scientists distinguish one gene from another and identify related genes even in other species. "His invention of ESTs was inspired," says Victor McKusick, a geneticist at Johns Hopkins University who is often called the father of genetic medicine. In June 1991, when Venter published his first paper based on this work, scientists had identified only about 4,000 genes, each one representing years of painstaking labor. In one day, Venter added 347 new genes to the list. Soon he was finding 25 a day.
Officials at the National Institutes of Health were delighted that one of their own had struck the mother lode, and they rushed to patent Venter's genes. But across the NIH campus, James Watson, who had won a Nobel for his co-discovery of the structure of DNA and who was then running NIH's Human Genome Project, was outraged. This wasn't science, he insisted. "Virtually any monkey" could do that work, Watson fumed in the opening salvo of a battle that would rage for months--and which smolders to this day. To patent such abbreviated genetic material, said Watson, was "sheer lunacy" that would entangle genetic research in legal issues and slow it to a crawl. When the battle was over, the NIH had withdrawn the patent proposal and Watson was no longer head of the genome project. Gone too were Venter and his wife and collaborator, Claire Fraser.
Freed from the confines of the NIH, Venter took an offer from a venture capitalist to head his own research facility, which he named The Institute for Genomic Research--TIGR, or "tiger." The private sector gave him the resources to find genes as fast as he could.
But in 1994 Johns Hopkins Nobelist Hamilton Smith challenged Venter to do more. At the time, Venter was using a technique called shotgunning. In essence, shotgunning amounts to putting DNA into a chemical Cuisinart. High-frequency sound waves shred the long stringy molecule into tiny fragments. The fragments are cloned in bacteria, and then, following what has become standard gene-mapping procedure, the bugs are ripped open and their DNA is run through a gene-sequencing machine.