Blogging the Human Genome

The Nasty Fight Between Scientists That Resulted in the Sequencing of the Human Genome
Each one has a story
July 11 2012 6:00 AM

Blogging the Human Genome

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The nasty fight between scientists that resulted in the sequencing of the human genome.

Chromosome 19

Illustration by Andrew Morgan

James Watson and Francis Crick made DNA famous in 1953 with their elegant double helix model. However beloved, though, the double helix revealed nothing about how DNA actually makes proteins—which is kind of the whole point of DNA. To understand protein production, scientists actually had to shift focus to RNA, DNA’s chemical cousin. Soon after illuminating the structure of DNA, in fact, Watson and Crick joined a fledgling scientific group called the RNA Tie Club.

Physicist George Gamow founded the club in 1954. Although a physicist moonlighting in biology might sound odd—Gamow studied radioactivity and Big Bang theory by day—other carpetbagging physicists like Richard Feynman joined as well. RNA not only offered an intellectual challenge, but many physicists were appalled by their field’s role in creating nuclear bombs. Physics seemed life-destroying, biology life-restoring. Overall, 24 scientists joined the Tie Club—one for each amino acid, plus four honorary members, for each DNA base. Club members sported green wool ties with an RNA strand embroidered in gold silk, which cost $4 from a haberdasher in Los Angeles. Club stationery read, “Do or die, or don’t try.”

By the early 1960s Tie Club members and other scientists had puzzled out how DNA and RNA could make proteins, and had confirmed that the same basic DNA-to-RNA-to-protein process ran every living thing on earth: guinea pigs, E. coli, frogs, tulips, slime molds, U.S. Congressmen, whatever. But again, knowing how the process worked in general told biologists only so much: They’d discovered how to build proteins in general, but not what kinds of proteins a life form actually did build. For that, they had to start sequencing genes—that is, determining the order of a creature’s As, Cs, Gs, and Ts.

Early sequencing attempts attracted only the bravest scientists, for they had to endure truly staggering amounts of boredom. In the 1970s, British biologist Frederick Sanger, already a Nobel laureate, finally developed a usable, three-step method to sequence DNA. I won’t go into the gritty details (you can get your fingernails dirty here), but Sanger had to tally the sequence by hand, one letter at a time. His first full genome, the 5,400 bases and 11 genes of the virus φ-X174, so impressed his colleagues that Sanger won a second Nobel in 1980. Not bad for someone who once confessed he could never have attended Cambridge University “if my parents had not been fairly rich.”

Though it wowed them, Sanger’s work also deflated some colleagues. He’d taken years to sequence the few thousand bases of a virus, which isn’t even technically alive. Even the lowliest bacteria have millions of bases, making the labor thousands of times harder. In the mid-1980s, two biologists in California automated Sanger’s method with lasers and computers, which made large-scale sequencing more plausible. But it was still a heck of a leap to the 3 billion letters in the human genome.

Everything changed in the early 1990s, when a neuroscientist at the National Institutes of Health got fed up with chromosome 19. He was looking for a few brain genes on it, and after two years of ungodly tedium picking through a 100,000-letter stretch, he threw up his hands. There has got to be, decided that neuroscientist, Craig Venter, a better way.

There was. Venter had heard about a method to quickly identify some of the RNA that cells use to make proteins. While cruising above the Pacific Ocean at 38,000 feet one night, returning from Japan, Venter sat up in his chair with an even better idea. Again, to make proteins, cells first transcribe DNA into RNA. So by capturing and reading that RNA, Venter realized he could then reverse-transcribe it and determine what the original DNA sequence must have been. This method had some technical limitations, but at least Venter could find most genes quickly. By automating the technique, he cut down the price for detecting each gene from around $50,000 to $20, and within a few years he’d claimed discovery of a whopping 2,700 human genes.

Venter’s method caused immediate controversy. (He had a talent for that.) The U.S. government’s Human Genome Project—an effort to sequence all human DNA—had recently rumbled to life, and the HGP didn’t appreciate being scooped by an upstart. One observer basically called Venter a rotten cheat, comparing his gene-detecting shortcut to Sir Edmund Hillary taking a helicopter up Mount Everest.* While testifying in a U.S. Senate hearing on the HGP, James Watson, the project’s first leader, dismissed Venter’s operation—with Venter sitting right there—as something that “could be run by monkeys.” Rhetoric aside, scientists harped on Venter because they thought his shortcuts would produce a sloppy, incomplete outline of the human genome—a charge that continued to dog Venter in later years.

Venter left his government job for the private sector not long afterward, then flung a gauntlet at the HGP by proposing to sequence the entire human genome himself, way faster and way cheaper. (When announcing his plans, Venter reportedly told HGP leaders that they still could find important work to do. Like sequencing mice genes.) The ensuing genome war, and the whole multidecade, multibillion-dollar HGP saga, occupies a chapter in my new book, and I came to believe that it’s as much a morality tale as a scientific one. If you ask a biologist about the HGP, in fact, you can get a pretty good handle on her values. Does she admire the HGP government scientists as selfless and steadfast, or dismiss them as stumbling bureaucrats? Does she praise Venter’s challenge as heroic rebellion, or condemn it as self-aggrandizement? Does she think the project succeeded or harp on its disappointments? Like any epic story, the sequencing of the human genome can support multiple readings.

Regardless of what you think, Venter’s challenge—and the HGP’s rousing response—led to a veritable avalanche of DNA data, data that has uncovered whole hosts of lost stories about human history. Blitzkrieg sequencing made modern genetics, and we have the tedium of tiny chromosome 19 to thank.

Correction, July 11, 2012: This article originally misspelled Sir Edmund Hillary's last name. (Return to the corrected sentence.)

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