Here Is a Human Being

by Misha Angrist

  Joe lightly numbed my arm with a shot of lidocaine and made a three-millimeter hole near my tricep. A skin biopsy is better than a sharp stick in the eye, but based on my experience, I’m not sure how much better—my arm was tender for almost two weeks. I don’t think the procedure was Joe’s forte, but why would it be? Clinical geneticists, after all, don’t really do “procedures"; they spend most of their time talking to people, just as psychiatrists do. Thus, Medicare and insurance companies were not all that inclined to pay for their services. And this, among other reasons, is why geneticists have long dwelled at or near the bottom of the physician food chain, which I happen to think is a shame.

  Joe was relaxed and seemed to radiate the placidity that good physicians do when they’re in their element. I thought he would have been beaten down by having had to sort through thousands of genes and decide which ones were important. This meant setting up stringent filters in the software to remove all the noise and the “normal” sequence that did not vary from the reference sequence. I learned later that he had been up until all hours combing through the data and preparing for our consultations—maybe his tranquility was just exhaustion.

  Soon George appeared in a brown corduroy jacket, his hair still wet. He turned to me and spoke in a low voice. “You get to watch me fail in real time on a national stage.”62 I smiled at his self-deprecation, though I didn’t quite understand what he meant. Ting arrived to sit in on their consult with Joe. People were calm and talked in hushed tones, but a nervous energy was present in the room. Marilyn studied her schedule and gave terse, sotto voce directions to her crew. The “First Family of Genomics,” minus daughter Marie, took their places at the small circular table in the center of George’s office.

  “You have four variants that are most concerning,” Joe said to George and Ting, “ … which are not really all that concerning. Of the four, there is a variant associated with susceptibility to multiple sclerosis.” Ugh, here we go with the MS again, I thought. “I’ve enclosed three research papers and one commentary on the specific variant.” Ting furrowed her brow. “I would not lose sleep over it,” Joe said. They talked about the small sample size of the study indicting this variant and its relatively high frequency (84 percent) in the population. If it were truly bad news and powerful enough to do damage in youngish people, then most of us wouldn’t have it—this is both the beauty and the cold indifference of natural selection. George asked if he was heterozygous, that is, had just one copy rather than two. He was. Joe noted that this variant was associated most often with MS in younger females (most MS patients develop the disease prior to age forty; George was fifty-two). And, Joe said, its contribution to MS appeared to be relatively weak. “Is there any MS in your family?” asked Ting. “I don’t think so,” said George.63

  Not an auspicious start. They moved on. George—and several of us, it turned out—carried a variant that appeared to cause an increased susceptibility to tuberculosis in West African populations. As with the MS allele Joe had identified in George, the major risk allele in the tuberculosis susceptibility gene had a frequency of greater than 80 percent. But with the possible exception of James Sherley, none of us had obvious West African roots. What was going on here? Joe, it seemed to me, had made his choices about what to discuss with us based on the strength and validity of the science in each case more so than on the likelihood we would actually develop these conditions. Fair enough, but none of these polymorphisms was likely to have a dramatic—or even undramatic—effect on our lives.

  Variant number three was thought to be associated with ovarian hyperstimulation syndrome and longer menstrual cycles. Hoo boy. This was starting to feel like an early Woody Allen movie. “It could be relevant to our daughter, though,” said Ting, always ready to see the beaker as half full.64

  She and George bantered about whether there might be mosaicism, a phenomenon whereby some cells in the body are genetically different from other cells. George mused on it, thinking aloud about the prospect of comparing skin to blood. “That’s a level of sophistication we’re not quite at yet,” he said.65

  George struck me as willing to play his part in celebrating the fact that we were having actual genomic consultations, even though this approach would not be scalable to one hundred thousand. But he also knew that this whole exercise was mostly for show. “The database fields for frequency, penetrance,* and research quality are pretty much empty,” he said.66

  My own consult followed George’s and proved no more scintillating than his. George’s was such a nonevent that I suppose I should have been suspicious about mine. All the SNPs Joe went over with George and Ting were from the Affymetrix chip harboring five hundred thousand markers. This was information I’d already seen via SNPedia and, to some extent, Navigenics, six months earlier. Joe handed me my folder, asked me if there was anything I didn’t want to know, and confirmed that my phenotypic data were indeed my phenotypic data. Yes yes yes, I thought. I’m overweight and depressed—get on with it! On a piece of paper before me were three markers. They all had “affx” in their descriptors, which meant they were from the Affymetrix 500 SNP chip. Been there, done that. I felt like the bride-to-be at her wedding shower and I had just been handed a pair of lacy underwear I already owned and frankly wasn’t sure I really wanted to wear again.

  I followed George outside into the hallway between his office and lab. “Your sequencing run failed,” he said apologetically. Now I understood the remark about getting to watch him fail in public. “Only six of the ten will get their sequence data today.”67 And, I would come to find out, even that sequence data was of fairly low quality and woefully incomplete. The moment of truth turned out to be a false alarm or, at best, a dress rehearsal. He could see that I was crestfallen (even though I had no right to be) and started to apologize again (even though he had no reason to). He assured me that all ten of us were in the queue for a full genome sequence from Complete Genomics. “No no, it’s okay, George,” I said. Marilyn interviewed me and to her I defended George and said yes, I’m disappointed but hey, shit happens. I said I felt “our” disappointment was because the PGP-10's expectations had been raised, because we were so intimately involved with the project, and because I had talked to so many people about the PGP, about the technology, about the ELSI aspects, etc. And because in twenty-four hours the world was supposed to hear all about the glory of seeing our own genomes.

  I would have to wait a few more weeks or, more likely, months or years. Knowing that I had SNPs that slightly altered my risk for prostate cancer and tuberculosis was hardly a revelation. Nor was learning that I was a carrier for trimethylaminuria, aka “fish-odor syndrome,” although that was interesting in a 23andMe and Beavis & Butt-Head kind of way. Because I carried a mutation in the gene encoding the enzyme flavin-containing monooxygenase-3, if Ann were to carry a mutation in the same gene, then our kids would each have been at 25 percent risk of stinking: their urine, sweat, and breath would be replete with aminotrimethylamine, a nitrogenous base that also happens to be a product of decomposing plants and animals.68 It smells like rotting fish. I admit to being biased (everyone thinks their own kids tend to walk on water), but to my nostrils, my children smelled no worse than any of their peers and almost always better than me. Curiously, though, I can’t stand eating fish and am repulsed by the way they smell. More evidence of self-hatred, perhaps. In any case, I was relieved that I’d chosen a freshly scented mate who wasn’t a fish-odor carrier: my family dodged a bullet there. Persons with trimethylaminuria really do suffer—some so much so that they commit suicide.

  Much later I asked Joe to reflect on what exactly went on during those initial consults. “That was definitely a dress rehearsal in some respects,” he wrote. “That date in 2008 had been set before we had any data from your exomes. If I were doing a consult today, I wouldn’t even mention any of those high-frequency, probably benign variants. We’ve gotten a lot better at eliminating that type of noise.”69

  The day after my
consult the ten of us met on the third floor of HMS’s New Research Building, fifteen months after we’d last met. We sat around the same table: Rosalynn, Keith, John, George, Kirk, Esther, James, and me, nowjoined by Stan Lapidus and Steven Pinker.

  There were smiles all around. I suspect we were all happy to be there, with the possible exception of George. His MO was lowering expectations. But how could he do that with the New York Times, Boston Globe, and Wired in the room, to say nothing of a sound crew and a cameraman, and a press conference to follow?

  He tried. “This is really about listening,” he said. “We know there are still a lot of rough edges.”

  He put up a slide titled “Major Points”:

  Thank you.

  Today is a start, not a final product.

  The PGP is research, not a genetics service.

  We are providing some interpretations, but mainly to initiate study and discussion. Decisions about releasing one’s data should be largely based on other considerations.

  He put up our mug shots, the ones where we sported pieces of measuring tape on our foreheads. As always, our photos were labeled with our Coriell Institute accession numbers in case anyone wanted to order our cells or DNA.

  We went around the table and gave little speeches again. I don’t remember what I said other than that I was thrilled. And for the most part I was.

  Kirk, still smarting from the sperm donor fiasco, I imagined, compared the arrival of the PGP to the emergence of widespread vaccinations in the nineteenth century and said we should expect backlashes.

  Esther: “My feeling is today shouldn’t be exciting. We don’t understand this yet. We know ninety words of Russian and we’ve just been handed War and Peace.” (That’s Bo$$Ha $$ M$$p to you, comrade.) I agreed with her, but the truth was the PGP-10 had hardly been given the whole of War and Peace … more like a few dog-eared pages; an outline, or the CliffsNotes at best.

  James said he hoped we would try to lead first with education and that people would come to recognize the importance of genomic information—we were all products of it, after all. And with immortalized cell lines, genomes of individuals could now be propagated through time.

  Steve Pinker emphasized that his interest was largely scientific: “Behavioral genetics and twin studies have underscored the importance of genes in our psychological makeup. What’s missing are links between an individual’s genome viewed holistically and that individual’s makeup. The answers have implications for brain function and how we evolved. Even identical twins are distinguishable. Why? What is the role of chance? What is the role of ontogeny?”

  We talked a little about “crowd sourcing.” To what extent would all of these questions be answerable when we had data on one hundred thousand people and the world was free to peruse it?

  Robert Green gave a talk about the REVEAL study: Risk Evaluation and Education for Alzheimer’s Disease. Despite the fact that many of us had heard his shtick before, his data were so compelling and his delivery so engaging, we all sat there rapt as he told us, once again, that hearing one was at high risk for a devastating, untreatable, late-onset disease was very unlikely to cause permanent emotional or psychiatric harm.

  He also said that we were now witnessing the early stages of a war between scientific and unscientific approaches to the genome. “We’ve already lost a similar war in nutraceuticals,” he said. I stole a glance at Rosalynn to see if the founder of a nutrigenomics company would flinch. She wouldn’t.

  And Green said that yes, genomic information should have the traditional attributes—analytical validity, clinical validity, and clinical utility—in order to be used in medical testing.70 In other words, genetic tests should measure what they say they measure, they should be predictive of something, and whatever that something is should be treatable somehow. But he also put forth the idea of “personal utility,” a phrase he credited to the University of Washington geneticist Wylie Burke. The personal utility71 argument goes something like this: “Maybe I don’t care whether or not my samples have been typed in a CLIA-certified lab. Maybe I just want to know where my family came from and/or the genetic basis of how my pee smells after I eat asparagus. Maybe I can’t do anything about Alzheimer’s and maybe the test isn’t perfect, but I’d like to know as much about my risk as I possibly can. You may deride those sorts of things as silly or bad ideas, but for me, they represent information I am interested in and they are no one else’s business.”

  Stan Lapidus, the founder of Helicos and the same guy who’d imagined opportunities for “positive eugenics” when I spoke to him a few months earlier, was wearing a bow tie and looked as though he might have stepped out of an earlier era. He asked George if we could review “redaction opportunities.”

  “We consider these difficult exercises,” George said with characteristic diplomacy. “APOE will be in the next set of data you receive. Watson found his out, even though he said he didn’t want to. If you redact one thing, it is likely there will be something even scarier later on.”

  George then reminded us that even if we did redact certain portions of our genomes, anyone from a research institution could order our cells, grow them in culture, extract DNA from them, and then sequence whatever he or she wanted. We would be fully identifiable.72

  I had heard this refrain both from George and from others when I mentioned the possibility of redacting my breast cancer genes: “Today it’s breast cancer,” they said. “Who’s to say tomorrow we won’t find something worse in your genome?” A fair point, but I had a strong family history of breast cancer and a high likelihood of carrying a single gene variant that would strongly predispose my kids to it. Wasn’t family history still “the gold standard"? At the press conference that afternoon, Pinker said he did not want to know his APOE status. He and I were the lone potential redactors of anything in our genomes. Everyone else but us gave the PGP carte blanche to put the entirety of his or her data on the Web. I said only that I wanted to see mine before I released it.

  But redaction, as it turned out, had practical, catch-22ish consequences. By asking to see my data so that I could decide whether to redact a small piece of it, I had further delayed the day when I would actually see my data. Steve Pinker and I were now at the back of the sequencing line. Jason said it was too hard to segregate our data and our cells. Redaction was not scalable. “Redaction poses logistical issues,” he wrote to me. “It’s not clear that we can honor such requests and manage all of the upfront costs and downstream consequences right now. We’re at a point in our development of infrastructure, protocols, and quality control that, like in the early days of the Model T, you can get it in any color you want … as long as it’s black.”73

  “Getting sequenced requires being comfortable with the cell lines being distributed and with the unknown part of the sequence being released,” George told me. “Watson surprised me by redacting APOE, but everything since then has been unsurprising. I feel that if you’re gonna get your genome sequence and make it public and you know a modicum of genetics, then you know that one gene is just the tip of the iceberg. Frankly the PGP-10 were not recruited to get a homogeneous set of opinions. I think if anything we failed to get enough skeptics among you nine. It’s a trade-off—if someone is ambivalent, then we’re not satisfying the IRB. But if everyone is drinking the Kool-Aid, then we’re not getting any useful feedback.”74

  Graduate student Sasha Zaranek, a soft-spoken, Russian-born, and Canadian-raised guy who managed the sequencing data pipeline, said that because of our reluctance to release our data without strings, my sequence information and Pinker’s had been encrypted in order to protect it and us; therefore the other eight PGP-10ers would get their data first. “It’s just practical for us to do it that way,” he said. “The one thing we don’t want to do is to get your wishes wrong.”75

  He told me that the PGP had an ongoing internal debate about whether to release rough data often or to release polished data less frequently. The former approach hewed more
closely to the PGP ethos of openness. On the other hand, shitty data could actually do more harm than good. Could he give me an example? “Halamka has been blogging about things we think are sequencing errors,” he said quietly.76

  “Listen, I’m not trying to be a dick,” I said. “But I was consented eighteen months ago, George long before that, and there’s still almost no real, high-quality exome data on any of us.” Other groups were starting to publish exomes and whole genomes they’d knocked out in a much shorter time.

  “We’re all frustrated with the pace,” Sasha assured me. “We’ve been working at this for years. But as George says, we’re eventually going to sequence six billion people, so what does it really matter where we are on this exponential curve?”77

  Touché. What was my hurry? Was being among the first really so important (other than to my editor, who wanted a draft of this godforsaken book)? I had been naïve in the extreme. When I strolled into Harvard in 2006 and saw the XY and XX chromosomes denoting the men’s and women’s restrooms, respectively, and began reading about the PGP, going to meetings about personal genomics, and listening to people discuss it in breathless terms, I envisioned the PGP to be the Six Million Dollar Man of human genomics: better, stronger, faster. And maybe it would be someday. Maybe in a couple of years, instead of just the ten of us eating carryout vegan Chinese in a Harvard Medical School conference room, tens of thousands of us would converge on Fenway Park and celebrate the PGP database busting at the seams.