The Violinist's Thumb: And Other Lost Tales of Love, War, and Genius, as Written by Our Genetic Code (42 page)

The two papers outlining the rough draft of the human genome appeared in early 2001, and history should be grateful that the joint publication fell apart. A single paper would have forced the two groups into false consensus, whereas the dueling papers highlighted each side’s unique approach—and exposed various canards that had become accepted wisdom.

In its paper, Celera acknowledged that it had poached the free consortium data to help build part of its sequence—which sure undermined Venter’s rebel street cred. Furthermore, consortium scientists argued that Celera wouldn’t even have finished without the consortium maps to guide the assembly of the randomly shotgunned pieces. (Venter’s team published angry rebuttals.) Sulston also challenged the Adam Smith–ish idea that the competition increased efficiency and forced both sides to take innovative risks. Instead, he argued, Celera diverted energy away from sequencing and toward silly public
posturing—and sped up the release only of the “fake” rough draft anyway.

Of course, scientists loved the draft, however rough, and the consortium would never have pushed itself to publish one so soon had Venter not flipped his gauntlet at their face. And whereas the consortium had always portrayed itself as the adults here—the ones who didn’t care about speedy genomic hot-rodding, just accuracy—most scientists who examined the two drafts side by side proclaimed that Celera did a better job. Some said its sequence was twice as good and less riddled with virus contamination. The consortium also (quietly) put the lie to its criticisms of Venter by copying the whole-genome shotgun approach for later sequencing projects, like the mouse genome.

By then, however, Venter wasn’t around to bother the public consortium. After various management tussles, Celera all but sacked Venter in January 2002. (For one thing, Venter had refused to patent most genes that his team discovered; behind the scenes, he was a rather indifferent monomaniacal capitalist.) When Venter left, Celera lost its sequencing momentum, and the consortium claimed victory, loudly, when it alone produced a full human genome sequence in early 2003.
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After years of adrenalized competition, however, Venter, like a fading football star, couldn’t simply walk away. In mid-2002 he diverted attention from the consortium’s ongoing sequencing efforts by revealing that Celera’s composite genome had actually been 60 percent Venter sperm DNA; he had been the primary “anonymous” donor. And, undisturbed by the tsk-tsking that followed his revelation—“vainglorious,” “egocentric,” and “tacky” were some of the nicer judgments—Venter decided he wanted to analyze his pure DNA, unadulterated by other donors. To this end, he founded a new institute, the Center for the Advancement of Genomics (TCAG, har, har), that would spend $100 million over four years to sequence him and him alone.

This was supposed to be the first complete individual genome—the first genome that, unlike the Platonic HGP genome, included both the mother’s and father’s genetic contributions, as well as every stray mutation that makes a person unique. But because Venter’s group spent four whole years polishing his genome, base by base, a group of rival scientists decided to jump into the game and sequence another individual first—none other than Venter’s old nemesis, James Watson. Ironically, the second team—dubbed Project Jim—took a cue from Venter and tried to sweep away the prize with new, cheaper, dirtier sequencing methods, ripping through Watson’s full genome in four months and for a staggeringly modest sum, around $2 million. Venter, being Venter, refused to concede defeat, though, and this second genome competition ended, probably inevitably, in another draw: the two teams posted their sequences online within days of each other in summer 2007. The speedy machines of Project Jim wowed the world, but Venter’s sequence once again proved more accurate and useful for most research.

(The jockeying for status hasn’t ended, either. Venter remains active in research, as he’s currently trying to determine [by subtracting DNA from microbes, gene by gene] the minimum genome necessary for life. And however tacky the action might have seemed, publishing his individual genome might have put him in the catbird seat for the Nobel Prize—an honor that, according to the scuttlebutt that scientists indulge in over late-night suds, he covets. A Nobel can be split among three people at most, but Venter, Collins, Sulston, Watson, and others could all make legitimate claims for one. The Swedish Nobel committee would have to overlook Venter’s lack of decorum, but if it awards him a solo Nobel for his consistently excellent work, Venter can claim he won the genome war after all.
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)

So what did all the HGP competition earn us, science-wise? Depends on whom you ask.

Most human geneticists aim to cure diseases, and they felt certain that the HGP would reveal which genes to target for heart disease, diabetes, and other widespread problems. Congress in fact spent $3 billion largely on this implicit promise. But as Venter and others have pointed out, virtually no genetic-based cures have emerged since 2000; virtually none appear imminent, either. Even Collins has swallowed hard and acknowledged, as diplomatically as possible, that the pace of discoveries has frustrated everyone. It turns out that many common diseases have more than a few mutated genes associated with them, and it’s nigh impossible to design a drug that targets more than a few genes. Worse, scientists can’t always pick out the significant mutations from the harmless ones. And in some cases, scientists can’t find mutations to target at all. Based on inheritance patterns, they know that certain common diseases must have significant genetic components—and yet, when scientists scour the genes of victims of those diseases, they find few if any shared genetic flaws. The “culprit DNA” has gone missing.

There are a few possible reasons for these setbacks. Perhaps the real disease culprits lie in noncoding DNA that lies outside of genes, in regions scientists understand only vaguely. Perhaps the same mutation leads to different diseases in different people because of interactions with their other, different genes. Perhaps the odd fact that some people have duplicate copies of some genes is somehow critically important. Perhaps sequencing, which blasts chromosomes into bits, destroys crucial information about chromosome structure and architectural variation that could tell scientists what genes work together and how. Most scary of all—because it highlights our fundamental ignorance—perhaps the idea of a common, singular “disease” is illusory. When doctors see similar symptoms in different people—fluctuating blood sugar, joint pain, high cholesterol—they naturally assume similar causes. But regulating blood sugar or cholesterol requires scores
of genes to work together, and a mutation in any one gene in the cascade could disrupt the whole system. In other words, even if the large-scale symptoms are identical, the underlying genetic causes—what doctors need to pinpoint and treat—might be different. (Some scientists misquote Tolstoy to make this point: perhaps all healthy bodies resemble each other, while each unhealthy body is unhealthy in its own way.) For these reasons, some medical scientists have mumbled that the HGP has—kinda, sorta, so far—flopped. If so, maybe the best “big science” comparison isn’t the Manhattan Project but the Apollo space program, which got man to the moon but fizzled afterward.

Then again, whatever the shortcomings (so far) in medicine, sequencing the human genome has had trickle-down effects that have reinvigorated, if not reinvented, virtually every other field of biology. Sequencing DNA led to more precise molecular clocks, and revealed that animals harbor huge stretches of viral DNA. Sequencing helped scientists reconstruct the origins and evolution of hundreds of branches of life, including those of our primate relatives. Sequencing helped trace the global migration of humans and showed how close we came to extinction. Sequencing confirmed how few genes humans have (the lowest guess, 25,947, won the gene sweepstakes), and forced scientists to realize that the exceptional qualities of human beings derive not so much from having special DNA as from regulating and splicing DNA in special ways.

Finally, having a full human genome—and especially having the individual genomes of Watson and Venter—emphasized a point that many scientists had lost sight of in the rush to sequence: the difference between reading a genome and understanding it. Both men risked a lot by publishing their genomes. Scientists across the world pored over them letter by letter, looking for flaws or embarrassing revelations, and each man had different attitudes about this risk. The
apoE
gene enhances our
ability to eat meat but also (in some versions) multiplies the risk for Alzheimer’s disease. Watson’s grandmother succumbed to Alzheimer’s years ago, and the prospect of losing his own mind was too much to bear, so he requested that scientists not reveal which
apoE
gene he had. (Unfortunately, the scientists he trusted to conceal these results didn’t succeed.
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) Venter blocked nothing about his genome and even made private medical records available. This way, scientists could correlate his genes with his height and weight and various aspects of his health—information that, in combination, is much more medically useful than genomic data alone. It turns out that Venter has genes that incline him toward alcoholism, blindness, heart disease, and Alzheimer’s, among other ailments. (More strangely, Venter also has long stretches of DNA not normally found in humans but common in chimps. No one knows why, but no doubt some of Venter’s enemies have suspicions.) In addition, a comparison between Venter’s genome and the Platonic HGP genome revealed far more deviations than anyone expected—four million mutations, inversions, insertions, deletions, and other quirks, any of which might have been fatal. Yet Venter, now approaching seventy years old, has skirted these health problems. Similarly, scientists have noted two places in Watson’s genome with two copies of devastating recessive mutations—for Usher syndrome (which leaves victims deaf and blind), and for Cockayne syndrome (which stunts growth and prematurely ages people). Yet Watson, well over eighty, has never shown any hint of these problems.

So what gives? Did Watson’s and Venter’s genomes lie to us? What’s wrong with our reading of them? We have no reason to think Watson and Venter are special, either. A naive perusal of anybody’s genome would probably sentence him to sicknesses, deformities, and a quick death. Yet most of us escape. It seems that, however powerful, the A-C-G-T sequence can be circumscribed by extragenetic factors—including our epigenetics.

T
he prefix
epi-
implies something piggybacking on something else. Epiphyte plants grow on other plants. Epitaphs and epigraphs appear on gravestones and in portentous books. Green things like grass happen to reflect light waves at 550 nm (phenomenon), yet our brains register that light as a
color,
something laden with memory and emotion (epiphenomenon). When the Human Genome Project left scientists knowing almost less than before in some ways—how could twenty-two thousand measly genes, fewer than some grapes have, create complex human beings?—geneticists renewed their emphasis on gene regulation and gene-environment interactions, including
epi
genetics.

Like genetics, epigenetics involves passing along certain biological traits. But unlike genetic changes, epigenetic changes don’t alter the hardwired A-C-G-T sequence. Instead epigenetic inheritance affects how cells access, read, and use DNA. (You can think about DNA genes as hardware, epigenetics as software.) And while biology often distinguishes between
environment (nurture) and genes (nature), epigenetics combines nature with nurture in novel ways. Epigenetics even hints that we can sometimes inherit the nurture part—that is, inherit biological memories of what our mothers and fathers (or grandmothers and grandfathers) ate and breathed and endured.

Frankly, it’s tricky to sort out true epigenetics (or “soft inheritance”) from other gene-environment interactions. It doesn’t help that epigenetics has traditionally been a grab bag of ideas, the place scientists toss every funny inheritance pattern they discover. On top of everything else, epigenetics has a cursed history, littered with starvation, disease, and suicide. But no other field holds such promise for achieving the ultimate goal of human biology: making the leap from HGP molecular minutiae to understanding the quirks and individuality of full-scale human beings.