The Violinist's Thumb: And Other Lost Tales of Love, War, and Genius, as Written by Our Genetic Code (40 page)

Scientists could possibly identify Darwin’s ailment with a DNA sample. But unlike Lincoln, Darwin died meekly of a heart attack, leaving no bloody pillowcases. And so far Westminster Abbey refuses to allow DNA sampling of Darwin’s bones, partly because doctors and geneticists can’t agree what to test for. Complicating things, some doctors conclude that Darwin’s illness had a serious hypochondriac edge, too, or sprung from other causes that we can’t pin down so easily. Indeed, our focus on Darwin’s DNA might even be misplaced, a product of our times. It should serve as a warning that when Freudianism was ascendant, many scientists saw Darwin’s illness as the consequence of an Oedipal struggle: the claim was that, unable to overthrow his biological father (an imposing man), Darwin instead “slew the Heavenly Father in the realm of natural history,” as one doctor gushed. To such thinking, Darwin’s suffering “obviously” derived from repressed guilt for this patricide.

Perhaps our groping about in DNA sequences for the roots of illnesses like Darwin’s will look equally quaint someday. And regardless, this groping about misses a deeper point about Darwin and others—that they persevered, despite their illnesses. We tend to treat DNA as a secular soul, our chemical essence. But even a full rendering of someone’s DNA reveals only so much.

C
onsidering its scale, its scope, its ambition, the Human Genome Project—a multidecade, multibillion-dollar effort to sequence all human DNA—was rightly called the Manhattan Project of biology. But few anticipated at the outset that the HGP would be beset with just as many moral ambiguities as the venture in Los Alamos. Ask your biologist friends for a précis of the project, in fact, and you’ll get a pretty good handle on their values. Do they admire the project’s government scientists as selfless and steadfast or dismiss them as stumbling bureaucrats? Do they praise the private-sector challenge to the government as heroic rebellion or condemn it as greedy self-aggrandizement? Do they think the project succeeded or harp on its disappointments? Like any complex epic, the sequencing of the human genome can support virtually any reading.

The HGP traces its pedigree to the 1970s, when British biologist Frederick Sanger, already a Nobel laureate, invented a method to sequence DNA—to record the order of the A’s, C’s,
G’s, and T’s and thereby (hopefully) determine what the DNA does. In brief, Sanger’s method involved three basic steps: heating the DNA in question until its two strands separated; breaking those strands into fragments; and using individual A’s, C’s, G’s, and T’s to build new complementary strands based on the fragments. Cleverly, though, Sanger sprinkled in special radioactive versions of each base, which got incorporated into the complements. Because Sanger could distinguish whether A, C, G, or T was producing radioactivity at any point along the complement, he could also deduce which base resided there, and tally the sequence.
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Sanger had to read these bases one by one, an excruciatingly tedious process. Nevertheless it allowed him to sequence the first genome, the fifty-four hundred bases and eleven genes of the virus φ-X174. (This work won Sanger 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.”) In 1986 two biologists in California automated Sanger’s method. And instead of using radioactive bases, they substituted fluorescent versions of A, C, G, and T, each of which produced a different color when strummed by a laser—DNA in Technicolor. This machine, run by a computer, suddenly made large-scale sequencing projects seem feasible.

Strangely, though, the U.S. government agency that funded most biology research, the National Institutes of Health, showed zero interest in DNA sequencing.
Who,
the NIH wondered,
wanted to wade through three billion letters of formless data?
Other departments weren’t so dismissive. The Department of Energy considered sequencing a natural extension of its work on how radioactivity damages DNA, and it appreciated the transformative potential of the work. So in April 1987, the DoE opened the world’s first human genome project, a seven-year, $1-billion effort centered in Los Alamos, across town from the site of the
Manhattan Project. Funnily enough, as soon as NIH bureaucrats heard the B-word,
billion,
they decided sequencing made sense after all. So in September 1988 the NIH set up a rival sequencing institute to scoop up its share of the budgetary pie. In a scientific coup, it secured James Watson as the institute’s chief.

By the 1980s, Watson had developed a reputation as the “Caligula of biology,” someone who, as one science historian put it, “was given license to say anything that came to his mind and expect to be taken seriously. And unfortunately he did so, with a casual and brutal offhandedness.” Still, however much he repulsed some of them personally, Watson retained the intellectual respect of his colleagues, which proved crucial for his new job, since few big-name biologists shared his enthusiasm for sequencing. Some biologists disliked the reductionist approach of the HGP, which threatened to demote human beings to dribbles of data. Others feared the project would swallow up all available research funds but not yield usable results for decades, a classic boondoggle. Still others simply found the work unbearably monotonous, even with machines helping. (One scientist cracked that only incarcerated felons should have to sequence—“twenty megabases [each],” he suggested, “with time off for accuracy.”) Most of all, scientists feared losing autonomy. A project so extensive would have to be coordinated centrally, and biologists resented the idea of becoming “indentured servants” who took orders on what research to pursue. “Many people in the American scientific community,” one early HGP supporter moaned, “will support small mediocrity before they can even consider the possibility that there can be some large excellence.”

For all his crassness, Watson assuaged his colleagues’ fears and helped the NIH wrest control of the project from the DoE. He canvassed the country, giving a stump speech about the urgency of sequencing, and emphasized that the HGP would sequence not only human DNA but mouse and fruit fly DNA, so
all geneticists would benefit. He also suggested mapping human chromosomes first thing, by locating every gene on them (similar to what Charles Sturtevant did in 1911 with fruit flies). With the map, Watson argued, any scientist could find her pet gene and make progress studying it without waiting fifteen years, the NIH’s timeline for sequencing. With this last argument, Watson also had his eye on Congress, whose fickle, know-nothing members might yank funding if they didn’t see results last week. To further persuade Congress, some HGP boosters all but promised that as long as Congress ponied up, the HGP would liberate humans from the misery of most diseases. (And not just diseases; some hinted that hunger, poverty, and crime might cease.) Watson brought in scientists from other nations, too, to give sequencing international prestige, and soon the HGP had lumbered to life.

Then Watson, being Watson, stepped in it. In his third year as HGP director, he found out that the NIH planned to patent some genes that one of its neuroscientists had discovered. The idea of patenting genes nauseated most scientists, who argued that patent restrictions would interfere with basic research. To compound the problem, the NIH admitted it had only located the genes it wanted to patent; it had no idea what the genes did. Even scientists who supported DNA patents (like biotech executives) blanched at this revelation. They feared that the NIH was setting a terrible precedent, one that would promote the rapid discovery of genes above everything else. They foresaw a “genome grab,” where businesses would sequence and hurriedly patent any gene they found, then charge “tolls” anytime anyone used them for any purpose.

Watson, who claimed that no one had consulted him on all this, went apoplectic, and he had a point: patenting genes could undermine the public-good arguments for the HGP, and it would certainly renew scientists’ suspicions. But instead of laying out
his concerns calmly and professionally, Caligula lit into his boss at the NIH, and behind her back he told reporters the policy was moronic and destructive. A power struggle ensued, and Watson’s supervisor proved the better bureaucratic warrior: she raised a stink behind the scenes, Watson alleges, about conflicts of interest in biotech stock he owned, and continued her attempts to muzzle him. “She created conditions by which there was no way I could stay,” Watson fumed. He soon resigned.

But not before causing more trouble. The NIH neuroscientist who’d found the genes had discovered them with an automated process that involved computers and robots and little human contribution. Watson didn’t approve of the procedure because it could identify only 90 percent of human genes, not the full set. Moreover—always a sucker for elegance—he sneered that the process lacked style and craft. In a hearing before the U.S. Senate about the patents, Watson dismissed the operation as something that “could be run by monkeys.” This didn’t exactly charm the NIH “monkey” in question, one J. Craig Venter. In fact, partly because of Watson, Venter soon became (in)famous, an international scientific villain. Yet Venter found himself quite suited to the role. And when Watson departed, the door suddenly opened for Venter, perhaps the only scientist alive who was even more polarizing, and who could dredge up even nastier feelings.

Craig Venter started raising hell in childhood, when he’d sneak his bicycle onto airport runways to race planes (there were no fences) and then ditch the cops that chased him. In junior high, near San Francisco, he began boycotting spelling tests, and in high school, his girlfriend’s father once held a gun to Venter’s head because of the lad’s overactive Y chromosome. Later Venter shut down his high school with two days of sit-ins and
marches to protest the firing of his favorite teacher—who happened to be giving Venter an F.
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Despite a GPA well below the Mendoza Line, Venter hypnotized himself into believing he would achieve something magnificent in life, but he lacked much purpose beyond that delusion. At twenty-one, in August 1967, Venter joined a M*A*S*H-like hospital in Vietnam as a medic. Over the next year he watched hundreds of men his own age die, sometimes with his hands on them, trying to resuscitate them. The waste of lives disgusted him, and with nothing specific to live for, Venter decided to commit suicide by swimming out into the shimmering-green South China Sea until he drowned. A mile out, sea snakes surfaced around him. A shark also began thumping him with its skull, testing him as prey. As if suddenly waking up, Venter remembered thinking,
What the fuck am I doing?
He turned and scrambled back to shore.

Vietnam stirred in Venter an interest in medical research, and a few years after earning a Ph.D. in physiology in 1975, he landed at the NIH. Among other research, he wanted to identify all the genes our brain cells use, but he despaired over the tedium of finding genes by hand. Salvation came when he heard about a colleague’s method of quickly identifying the messenger RNA that cells use to make proteins. Venter realized this information could reveal the underlying gene sequences, because he could reverse-transcribe the RNA into DNA. By automating the technique, he soon cut down the price for detecting each gene from $50,000 to $20, and within a few years he’d discovered a whopping 2,700 new genes.

These were the genes the NIH tried to patent, and the brouhaha established a pattern for Venter’s career. He’d get itchy to do something grand, get irritated over slow progress, and find shortcuts. Other scientists would then denounce the work as cheating; one person compared his process for discovering genes
to Sir Edmund Hillary taking a helicopter partway up Mount Everest. Whereafter Venter would strongly encourage his detractors to get bent. But his arrogance and gruffness often ended up alienating his allies, too. For these reasons, Venter’s reputation grew increasingly ugly in the 1990s: one Nobel laureate jokingly introduced himself by looking Venter up and down and saying, “I thought you were supposed to have horns.” Venter had become a sort of Paganini of genetics.

Devil or no, Venter got results. And frustrated by the bureaucracy at the NIH, he quit in 1992 and joined an unusual hybrid organization. It had a nonprofit arm, TIGR (the Institute for Genomic Research), dedicated to pure science. It also had—an ominous sign to scientists—a very-much-for-profit arm backed by a health-care corporation and dedicated to capitalizing on that research by patenting genes. The company made Venter rich by loading him with stock, then loaded TIGR with scientific talent by raiding thirty staff members from the NIH. And true to its rebellious demeanor, once the TIGR team settled in, it spent the next few years refining “whole-genome shotgun sequencing,” a radicalized version of Sanger’s old-fashioned sequencing methods.

The NIH consortium planned to spend its first few years and its first billion dollars constructing meticulous maps of each chromosome. That completed, scientists would divide each chromosome into segments and send each segment to different labs. Each lab would make copies of the segment and then “shotgun” them—use intense sound waves or another method to blast them into tiny, overlapping bits roughly a thousand bases long. Scientists would next sequence every bit, study how they overlapped, and piece them together into a coherent overall sequence. As observers have noted, the process was analogous to dividing a novel into chapters, then each chapter into sentences. They’d photocopy each sentence and shotgun all the copies into random
phrases—“Happy families are all,” “are all alike; every unhappy,” “every unhappy family is unhappy,” and “unhappy in its own way.” They would then reconstruct each sentence based on the overlaps. Finally, the chromosome maps, like a book’s index, would tell them where their passage was situated overall.