Here Is a Human Being (33 page)

On his current thinking on personal genomics: “We have a long way to go before we can say that all of this is going to provide serious positive-outcome opportunities as opposed to just ‘curiosity satisfactions.’ But I guess I’m more on the side of, ‘Let’s go full speed ahead and empower the people interested in having this information sooner rather than later while still making sure we’re providing the kind of support they’re going to need.’ ”
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Why was he so optimistic? “The most significant reason is that the science has finally gotten to the place where the predictions are not fanciful. Admittedly they are relatively modest risks [in most cases], but they’re not made-up. The other thing that’s given me an increased sense of confidence is GINA. So we have better science, we’re giving out better information, and we have better protections against the most egregious misuses. That really changes the landscape. I think that’s why I feel primarily positive versus two or three years ago when I felt primarily negative.”
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I suggested that, given these developments, the current medical genetics paradigm was not up to the task of dealing with personal genomics and all that it entailed. To my surprise, he agreed. “We know that most common illnesses have heritability that’s in the neighborhood of fifty percent. If we had all [of those genetic factors in hand] then the idea that we could just go on with business as usual in medical genetics, which is largely built upon rare Mendelian conditions and chromosomal disorders, is not going to be sustainable. Frankly I’m very worried about my own specialty of medical genetics, a field I’m deeply attached to.”
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Why has medical genetics not kept up? “We have not succeeded in attracting young, energetic, visionary physician scientists to join us. Here we are on the brink of a revolution where genetics is driving the entire medical profession, yet there are fewer applicants today to medical genetics fellowships than there were twenty years ago! Medical students look around and they don’t see a lot of geneticist role models because there are so few of us. We’ve never been able to catch the wave and build it up. I’m not sure the leaders [in medical genetics], most of whom were trained in an earlier era, are actually all that comfortable with the idea that they need to blow up their profession and start over.”
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What would you do to fix it? “For starters we really have to renovate the training programs to make them attractive to the best and brightest of the next generation of physician-scientists. [Genetics] ought to be the kind of profession that lots of cerebral young physicians would like to join. Right now we’re doing what we’ve done for the last fifty years: [Trainees] see newborns with birth defects and go to the clinic and see people with [rare] Mendelian conditions. There’s not a sense that this is the new genetics—this is the
old
genetics. I think the medical genetics profession [has] more people who are ready to deal with dysmorphology [assessing people with congenital birth defects] than are ready to deal with a genomic sequence that needs to be sorted out. There’s still a ‘two cultures’ problem.”
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I asked him about “the incidentalome.” What happens when people learn potentially worrisome things about their genomes and start to pursue them at great cost and effort only to find out that most are meaningless? Collins said that that was a serious concern. “That’s the part I’m most wondering about when it comes to complete genome sequences. For these rare variants it will take decades before we have a sufficient ‘encyclopedia’ of them to know whether they matter. [In the meantime] we’ll be leaving a lot of ambiguity hanging in the air.”
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We were running out of time before the morning sessions of the meeting would commence. I had caught Collins at a professional inflection point, but his embrace of personal genomics was only the beginning. In the coming months he would establish a foundation meant to address the culture war between science and faith in the United States.
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He would indeed write a book.
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In July 2009 he was nominated for the directorship of the NIH.
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A few weeks later he was confirmed unanimously by the Senate.
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Had his decision to resign from NHGRI been part of some master plan to become top boss at NIH?

Shortly after his confirmation, he laid out his priorities. First on the list was using hi-tech approaches to discover the genetic bases of diseases.
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Whatever one’s view of Collins, his confirmation was unequivocal proof that genomics had reached the head of the class. And I expected it to stay there: Collins has long been interested in a large cohort study of genes, traits, and environments in the U.S. population akin to the UK Biobank.
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There was another, smaller reason I was optimistic that Francis Collins—onetime would-be villain of this book—would do right not only by genomics writ large, but by our flagging health-care system and those who have been ill-served by it. A week after he was nominated to lead NIH I found myself in Washington, D.C., for Genetics Day on the Hill, a day of gentle lobbying of our elected representatives on issues pertaining to genetics or, as was the case in 2009, health care in general. We were given talking points—mostly of the mom-and-apple-pie variety—and we were broken up into teams of three to six people with whom we would visit our senators and congresspeople.

My team included a fifty-something guy from Lawton, Oklahoma, named Dennis Pollock. In 1993 Dennis was diagnosed with alpha-1-antitrypsin deficiency; he had served on the board of the Alpha-1 Association for many years. Alpha-1-antitrypsin is a protein produced mostly in the liver. Its main job is to protect the lungs from an enzyme that digests damaged or aging cells and bacteria. Without alpha-1, the enzyme will attack healthy lung tissue.
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As a young man Dennis had a double lung transplant. He described himself as completely healthy, although it was clear that schlepping from one congressional office building to another in the July Washington heat took its toll upon him. Being from Oklahoma, Dennis was represented by Republican senator Tom Coburn,

aka “Dr. No.” Among legislators, Coburn was probably the one most allergic to legislation. In 2007 he single-handedly blocked or slowed more than ninety bills, including GINA.
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Dennis repeatedly came to D.C. to press Coburn about GINA, going so far as to organize a phone blitz on his office. Not long after this—and following a couple of concessions on the part of the bill’s sponsor—Coburn lifted his hold on GINA. Dennis’s activism won him admirers, including Francis Collins. The two became friends, Dennis told me; Pollock stayed with Collins and his wife whenever he was in the area.
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I had heard Collins talk about reducing health disparities on many occasions. It was gratifying to know that it wasn’t just talk.

As we collected our trays, Collins asked what I would do with my genome. “What are you going to do when you encounter a SNP no one’s ever seen? You will have some
breathtaking
mutations … because we all do. You’ll be thinking [about what they mean for] yourself, for your kids. What are you going to do with that?”
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What indeed.

B
y the end of the summer of 2009, I was in a pickle. Not only was I on deadline—that is to say, a year late—for this book, but I was getting regular invitations to speak. “O Great Genomeboy, yea, though thou hast walked through the valley of the shadow of death, thou hast feared no evil. We beseech you. Tell us, please: What is it like to have Your Genome Sequenced?”

The truth was, I still had no idea. It had become clear to me that a complete exome, much less a complete genome, was not going to be forthcoming from the Church lab any time soon. While the quality of the Harvard sequence data had gotten better, after two and a half years, I had access to only some 5 percent of my exome, or about 0.002 percent of my genome. This was unlikely to yield the stuff from which deep insights into oneself would be gained. George’s lab was an incubator—a place where ideas were born, tested, and published. It was a workshop, not an assembly line. The notion that it would generate thousands of exome sequences like clockwork was simply unrealistic, at least in the near term. It was clear that George needed technical help to bring his grand visions to fruition, but at the moment it was unclear as to when and from whom he would get it outside of his own group. For my own selfish reasons (personal genomics: it’s all about me), I needed to look elsewhere.

I began to bug David Goldstein. David is a colleague and friend, and for both relationships I am grateful. He’s one of the smartest people I’ve ever met, and to be honest, I don’t have very many really good friends, probably because I have not made time for them, and because I am insecure and afraid that they will reject me. I suspect David doesn’t have many close friends, either, though not out of fear of rejection. He is a brilliant geneticist but extremely competitive, sure of himself, convinced that he’s right, not one to shy away from a scrap, and not always blessed with the gift of tact. Indeed, he really doesn’t “give a toss” (he lived in the United Kingdom for many years and has retained some of the vernacular) about whether you like him. God knows that if he did give a toss, he’d be a mess: over one two-week period, half a dozen people on campus complained to me about him. The general tenor of their complaints was “Who does he think he is?” When I told him of this, he seemed curious about who the aggrieved parties were, but assumed that they were people who, at least on a professional level, did not really matter to him all that much (for the most part he was right).

David grew up in California in a middle-class but broken home, and on the way to fulfilling a passion for marine biology he stumbled into genetics in college. He completed a graduate degree and postdoc with highly esteemed population geneticists, and took a job at University College in London. There he began working in the nascent field of genetic anthropology—that is, using genes to understand where historical populations lived, where they went, whom they mated with, and perhaps something about their culture. A half-Jew who had spent time in Israel when he was young and impressionable, David wondered if genetics could be used to elucidate some aspects of Jewish history. It could. He became a leader of the group that identified a signature (a set of genetic markers) on the Y chromosome strongly associated with the Cohanim, the ancient Jewish priests of the time of Christ and before, and whose descendants are presumed to carry surnames like Cohen, Cohn, Kahn, Kagan, etc. David and his colleagues also found results that supported the claims of a Bantu tribe (the Lemba) to have Jewish roots. And they used mitochondrial DNA (passed on only by females) to understand how and where Jewish communities were founded.
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Years later his lab found a signature that correlated perfectly with Ashkenazi Jewish ancestry among people who self-identified as Jewish.
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But David had long since grown bored with the pursuit of human history via genetics, feeling that he had taken the science as far as it could go and wanting to do work that was more clinically relevant. He dug into another burgeoning field, pharmacogenetics: the idea that genes have a lot to do with how well (or how poorly) people respond to medications (see chapters 2, 6, and 10). David reasoned that if we could understand the genetic mediators of responses to drugs, then we couldn’t help but learn something about the diseases those drugs were used to treat.
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Particularly in the areas of epilepsy and infectious disease, his hypothesis has turned out to be correct.
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He also became an early proponent of genome-wide association studies (GWAS), the approach whereby geneticists collect DNA from thousands of cases with a genetic disease, and thousands of controls without it.
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By typing, say, a million markers across the genome in hundreds or thousands of cases and controls, one could often find markers that were clearly associated with the trait or disease of interest. Indeed, David and his collaborators (including Duke infectious disease specialist Jacques Fellay and sequencing and genotyping czar Kevin Shianna) used this approach to identify genetic markers that determined how well HIV-infected people handled the virus and the amount of time until they would become sick, if ever.
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GWAS quickly became au courant and these studies identified markers associated with scores of diseases. The money continued to flow from NIH to fund them.
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But because he is honest, because he is often prescient, because he is apt to see the dark side in just about everything, because he is David Goldstein, by 2008, even as his own GWAS were starting to yield compelling results, he was simultaneously telling the world that the emperor had no clothes and chomping on the hand that fed him. With few exceptions, he said, GWAS was a profound disappointment and he was hereby tendering his resignation from the amen chorus. “There is absolutely no question,” he told the
New York Times,
“that for the whole hope of personalized medicine, the news has been just about as bleak as it could be.”
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The problem, as geneticists had come to realize, was that we could find variants associated with any given disease, but they didn’t explain very much of the disease and so weren’t very predictive. “For schizophrenia and bipolar disorder, we get almost nothing; for type 2 diabetes, [we’ve found] twenty variants, but they explain only two to three percent of familial clustering, and so on,” said David. If schizophrenia was 80 percent genetic, then why couldn’t anyone find any genes that played a major role in causing it? Geneticists began wondering where the missing heritability of supposedly genetic diseases could be hiding.
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Unless it could be found, bringing the genome to the clinic in a meaningful way would be difficult, if not impossible.