Here Is a Human Being

by Misha Angrist

  When 454 approached him about Project Jim, did he have any hesitation? “Oh no. I never thought twice about it.”

  When I asked about his reluctance to know his APOE status he said simply that his grandmother died of Alzheimer’s at eighty-three and he didn’t want to spend the rest of his life worrying that any lapse in memory he might experience would be the onset of dementia. So was he nervous about discovering anything else that might lurk in his genome? “Not at all,” he said.

  What did he say to Francis Collins about all of this? “I told him how much more reassured I was having had my genome sequenced. And he looked uncomfortable.” He laughed, eyes wide.

  I asked about the value of sequenced human genomes. “I think we will have a more compassionate, better society because of them,” he said. “They will be useful to explain why people are the way they are, why some people don’t fit in. My son has schizophrenia, for example. He never wanted to go to work or to school because he couldn’t fit in. Maybe genomics can explain that. We are all different. We all have different abilities. Some people can’t sing or dance. Why should we make them go out on the dance floor? I think it’s better to understand people’s limitations. If we understand the biological basis of those limitations, then I believe we will treat people better.”

  Did he get permission from his children? “No,” he said. “They might have said no.”45 He laughed again. I recalled George’s lament that because of Watson’s bull-in-a-china-shop approach, perhaps Watson was not a good choice to start with for personal genomics.46

  I asked about the concerns some people had about informed consent and individual whole-genome sequences. He was unmoved. “If we get ourselves wrapped up in this, then no information will ever be released.” And what about charges of elitism? “It’s crap! Not everyone can afford an automobile. Does that mean the rest of us shouldn’t be allowed to drive? People who want these types of restrictions on genetics don’t like genetics. They see genetic determinism everywhere and they think it’s an evil worse than fascism. No competent geneticist can believe in genetic determinism.”47

  I regretted not asking him why, then, if he were not a genetic determinist, he would be so discomfited by knowing his status for APOE, which, after all, is only a susceptibility gene. While it alters one’s risk for Alzheimer’s, in its worst guise it is still well short of a guaranteed death sentence. (Persons carrying two copies of the APOE4 allele have a fifteen-fold increased risk for developing Alzheimer’s.)

  Every time Watson flitted away and I thought the discussion was over, he drifted back with an addendum. The conversation caromed from Michael Crichton (“He told me he was on his fifth wife—I thought that explained a lot”) to religion (“I don’t hate God the way Francis Crick did”) to psychiatrists (“They don’t know very much”).

  Finally he signaled he was really leaving, but not before imparting some literary advice. “I wouldn’t spend more than twenty-five pages of your book on George Church,” he said. “He’s not that interesting … though he’s very tall. He can be one character … but you need more. You need a villain if you’re going to compete with the Michael Crichtons of the world. Who’s your villain?”

  I hesitated. “Gosh, I don’t know,” I said.

  “You have to have a villain,” he insisted.

  “Well … right now I suppose it’s Francis,” I said without much conviction.

  “Aha! That’s good. So now you’ve got at least two thousand readers.”48 I looked around nervously—there were chortles of affirmation from some of the other folks who’d gathered on the veranda and were eavesdropping if only to hear what outrageous thing Watson might say next. One scientist assured me that if Francis Collins were indeed my bad guy then she would be among the two thousand. I started to talk with her; when I looked up Watson was gone.

  Later that afternoon, the organizers of the meeting grudgingly gave him a forum to talk about his genome. The feeling seemed to be that this was a nonevent, though I wasn’t quite sure why. Maybe because human genomes were still not taken seriously—they weren’t “real” science; rather, they were thought of as tiny blips of data that added up to nothing. Maybe because Watson was likely to say something outrageous (a pretty safe bet). Maybe because it had simply become too much work for the veterans of these meetings to manage and minister to him. A longtime CSHL denizen had seen this tug-of-war before and offered a note of sympathy for Watson. “It’s hard being ex-emperor when people have been saying yes to you for sixty years.”

  Watson made it clear that his genome—and all human genomes—should be cause for celebration. Having them would make us better, healthier people. “If there had been a genetic diagnosis for my son Rufus,” Watson told the audience, “we would have raised him differently and not expected him to go to Exeter… . I’m not hesitant to say we’re playing God. Someone should.”49

  Ting Wu gave a congenial laugh at the notion of her husband as an elitist. “I think when people get to know him that thought will vanish. He’s very modest. People won’t be able to miss it.”50

  When I raised the issue with George, he patiently explained—again—that we ten were not really important. We would be among the first, sure, but he reminded me that his premium was on scalability, that is, getting to a million. Thus he opted to sequence only our protein-coding 1 percent, our exomes—at least for now. “If you give me a hundred million dollars,” he told me, “I would rather spend it on ten thousand or one hundred thousand exomes than on one hundred complete genomes.”51 In other words, he would rather have 1 percent of the genome from one hundred thousand people than 100 percent of the genome from a hundred people. To paraphrase The Incredibles, once everyone’s genome was super, then no one’s would be.

  But to scale up meant moving beyond the limited pool of master’s-level geneticists willing to share their genomic information (there are only a few hundred board-certified medical geneticists in the United States and only about 2,500 master’s-level genetic counselors).52 George therefore wanted to replace the credential requirement with an exam that all PGP subjects from any walk of life would have to pass before being allowed to enroll. “A test could help prove they know what they’re doing and might even have a psychosocial component to make sure they’re not pathologically exhibitionistic or likely to react in a depressed way to news about, say, Huntington’s disease.” What else would it cover? “Interactions with insurance companies. Things like ‘Do we think having reporters in our living room is a good thing or a bad thing?’ And ‘How much do we think our cells are worth?'”53

  George saw money less as something that would taint and commoditize personal genomics than as a means of altering the subject-researcher power dynamic. Indeed, he suggested he might be willing to blur the scientist-subject distinction altogether. While some bioethicists have argued that returning genetic research results to subjects is a good idea, it’s not clear how many feel that way. (Some have issued “consensus” statements,54 but as far as I can tell, while putting out consensus statements is a favorite pastime for bioethicists, it tends to correlate poorly with actual consensus.) For their part, all the data say that participants would very much like their results back.55

  Certainly there are good reasons not to give experimental results back: research is just research, after all—it has not been clinically validated. Do the researchers even know what the data mean, especially if they’re not clinicians? And what if the information they give is wrong—can they be counted on to clean up the fallout from results that mislead or, more likely, just don’t pan out?

  George didn’t buy it: he had long thought disclosure of genetic and genomic results to subjects was the natural thing to do. He said he would like to make PGP subjects true partners in the outcome of his project. Yes, they would bear the risk of eating from the tree of genomic knowledge,

  however bitter and uncertain that might taste, but they would also reap the rewards. “We’re hoping everyone in the study will not only know what’
s going on, they will actually be working with us to analyze their own data. You could be so informed you might even qualify as a coauthor.”56

  He said that returning results to subjects was imperative because it would give them the information they needed to make the single most important decision about the PGP that other human genetics protocols did not: when to quit. “I think the opt-out clause of most consent forms is a mirage,” he told me. “It’s a fake. If you don’t get your information back, then how would you know you have a Huntington’s mutation and don’t want that to be in the public domain or even a private database? Ideally, opting out means that that type of information would be erased from everything. But if you don’t know it to begin with, then you can’t ask the investigators to erase it.”57

  “So what will you do with your exome?” I asked him in early 2007.

  “Um … what do you mean? I’m going to study it.”

  “Okay. But will I be able to study it?” I felt like a six-year-old boy at summer camp: I’ll show you mine if you show me yours.

  He demurred and suddenly sounded more like the modest, private man Ting described to me. “I’m not going to be superfast in putting mine in the public domain. I intend to, but I think I would like to be a guinea pig for the phasing process where I’ll look at it myself as much as I can with software, and then get some experts involved who are inside the PGP and look at it with them with moderate security. And then together if the PGP subjects and the PGP researchers feel that there’s anything that needs to be redacted, then we will redact it either from the genotype or the phenotype or both. We will leave behind a scar that says ‘this was redacted.’ We won’t say, ‘Oh no, George doesn’t have schizophrenia.’ We will say, ‘We’re not saying whether George has schizophrenia or not.’ And those scars will be revealing in a certain sense, but they may not be actionable. We’ll work with ELSI scholars and genetic counselors and genetic experts to try to proactively redact, and not just for me but for everybody else in the PGP who wants to do this.”58

  George told me his daughter wanted her personal genome—or some approximation of it, anyway—for her sixteenth birthday; he and Ting had tentatively agreed. I met her at the first PGP barbecue at the Church-Wu home. She was a tall, striking teenager with her mother’s jet-black hair and her father’s liquid, penetrating eyes. And while she didn’t like school (“not my thing”), she seemed to share her parents’ propensity for creativity and overachievement. She is an artist: her abstract photos, paintings, and multimedia creations adorned the walls of the house. She told me the plate I was eating off of was one of hers. She designs clothes. And she’s a fashion model (“I’m trying to sign with a big agency”).

  She shared three short-term goals. “On my birthday I’m gonna go to school and tell them I’m not coming anymore, I’m gonna get a tattoo, and I’m gonna get my genome done.” Why did she want her genome? “I’d really like to know what’s coming. If I’m gonna have a short life or if there will be uncomfortable things in my future, I really wanna live now.” This was the flip side of Jim Watson: he needed not to know at the end of his life, she needed to know at the beginning of hers. They seemed to share a fatalistic, deterministic view of their genomes.

  I asked if she thought she was unique or whether her friends were thinking about their personal genomes, too. She assured me they were, but qualified her answer like a true scientist. “This is Brookline,” she said. “Harvard is right down the street. So this isn’t a random sample of teenagers. A lot of my friends know about it because of my dad and also because their own parents are aware of it.”

  “How much of your and your friends’ interest in personal genomics is related to MySpace and Facebook—people just putting everything on the Internet?”

  “I really don’t think any of it has to do with that,” she said. “I just think we’re a more informed generation because of the Internet in general. Anyway, MySpace is out now—it’s all old men and creepy people.”59

  “Playing in bad rock bands,” I offered.

  “Pretty much.”

  George said that five thousand dollars for a set of genotypes (the projected price for a scan of a half million genetic markers in mid-2007) was not much of a lifetime investment to make on behalf of a teenager. And pretty soon, everyone would be doing it.

  Even before the recent explosion of personal genomics, there were signs that the ossified, neglected, backwater specialty of medical genetics was about to change. Jason Bobe started the blog The Personal Genome: Genomics as a Medical Tool and Lifestyle Choice in 2003.60 In early 2007, just before taking a job helping George to manage the PGP, he told me he was planning to launch a new website, GenomeHacker.com, designed to give young people crude ways of interrogating their genomes without the benefit of fancy lab equipment. He expected they would be able to infer things about their DNA simply by studying their own phenotypes; for example, if they couldn’t drink coffee late in the day without being up all night, it was likely they were slow metabolizers of caffeine and therefore harbored a genetic variant in one of the major genes that encodes a drug-metabolizing enzyme. “Ten years from now there’s going to be a whole bunch of fourteen-year-olds developing tools for parsing their genomes,” said Bobe. “It’ll be a new after-school hobby for kids, I imagine.”61

  Bobe, a curious and precocious guy who turned thirty in 2009 and has become a friend, was enthusiastic about technology and life as depicted in the pages of Wired. He liked to send emails at 4 a.m.; his Gmail status message often revealed how many unanswered emails were currently in his inbox (two hundred to four hundred seemed to be the norm). He was stocky and still spoke with a midwestern twang; he credited his blog with rescuing him from the Indiana cornfields.

  I never doubted the viability of his idea: genome hacking as an after-school endeavor. But it had already become clear that it was not going to take ten years. Or five. Or even one. Neither kids nor their parents would have to infer their genotypes from their phenotypes. They could go right to the source.

  * As I discuss in chapter 10, my mother was diagnosed with early-onset breast cancer at age forty-two—she eventually had two radical mastectomies. She is an Ashkenazi Jew, which means there’s a pretty good chance she carries a high-risk mutation in one of the two major familial breast cancer genes, BRCA1 or BRCA2. If so, that means I have a fifty-fifty chance of carrying that mutation while my young daughters each have a 25 percent chance of carrying it. If they carry it, they would likely have an 80 percent lifetime risk of developing breast cancer versus the 15 percent lifetime risk for most American women.

  * “Common” because the rules were agreed to by an unprecedented number of government agencies.

  * A good journal, yes: Nature . . but not until April 2008—nearly a year after the announcement of the completion of Watson’s genome. A genomics muckety-muck told me the initial data were not of very high quality and the 454/Baylor team was told by reviewers to go back and polish it.

  * Gelsinger had a rare, genetically caused enzymatic deficiency. He died in 1999 at age eighteen while enrolled in a gene therapy trial at the University of Pennsylvania. The lead researcher was cited by the Food and Drug Administration for flouting several rules. Gelsinger’s death is widely acknowledged to have single-handedly derailed the gene therapy field for years.

  4 “But When Is It Mature?”

  When I met Matt Crenson on an overcast Wednesday morning, his deep, raspy voice belied an affable manner, which was appropriate: his employer, the Mountain View, California–based company 23andMe, had for the last several months taken great pains to portray itself as friendly and nonthreatening—the anti-Gattaca. George Church, who was on the company’s scientific advisory board (he was on some eighteen other such boards, too; God knows how he found the time), often described 23andMe as “playful.” The lobby of the company’s home in a nondescript Silicon Valley office building looked something like a hipster toy store that was building up its inventory before officially openin
g its doors for business.

  The atmosphere—a basal bustle of twenty-somethings, occasional peals of laughter echoing among the cubes and glass offices—harked back to the dot-com era: there were shelves filled with Day-Glo-colored squishy rubber balls while the otherwise Spartan lobby was scattered about with cute stickers, buttons, and plastic packages of Mike & Ike’s red and green candies festooned with the company logo and its catchphrase, “Genetics Just Got Personal.” (I stuffed several in my bag for the plane ride home.) 23andMe thought of itself not as a health-care company or as a biotech, but rather as an Internet start-up. “Web 2.0” was the descriptive phrase one heard over and over from its employees.

  23andMe officially launched in November 2007, just a couple of days after the first commercial entrant into the personal genomics market, deCODEme, which was an outgrowth of Icelandic genetics-meets-pharma firm deCODE Genetics. Both companies began by offering customers access to what I will call “the variome.” If your genome is all 6 billion DNA base pairs (the function of most of which we don’t understand), and your exome is the 20,000+ genes (about 60 million base pairs) that code for protein, then your variome is a smaller subset still: it is an assortment of markers more or less evenly spaced across the genome that tend to vary from person to person; some markers fall within genes, but most do not. By early 2010 researchers had identified nearly 13 million of these markers; from 2007 to 2009 the companies typically typed 500,000 to 1 million of them (about 1–2 million base pairs total). These marker sets (called single nucleotide polymorphisms, or SNPs—"snips”) were thought to capture much of the variation in human DNA, although they represented no more than 0.05 percent of the entire genome.* But they were relatively cheap to type given that such endeavors would have cost hundreds of thousands of dollars in the 1990s; both 23andMe and deCODEme began by charging customers a thousand dollars. Customers entered their credit card number online, waited for their kits, spit in a tube, put it in the mail, and a few weeks later could log onto a secure website and look at their variomes.