Here Is a Human Being (28 page)

Former Clinical Genetics fellow and now-attending doc Joe Thakuria arrived ready to perform a skin biopsy on me in George’s office. He wore a threadbare sweater and wire-rimmed glasses; his olive skin came courtesy of his Indian father and half-Filipino mother. In kindergarten Joe was diagnosed as severely autistic. His parents were urged to put him in special education, which they opted not to do. In Catholic secondary school he vaulted to the top of his class and stayed there. He began college at sixteen and med school at twenty. When he was finishing his residency at Penn in 2001, his younger brother died in his sleep from a cardiac arrhythmia. He was twenty-four. Given his brother’s general good health, Joe intuited that his death was likely caused by something genetic. “It seemed clear to me that in the future medicine would (or at least should) be able to screen, identify, and save patients like him.” He has since become convinced that his brother had Brugada syndrome, a genetic condition that causes arrhythmias and puts one at high risk for sudden cardiac death.
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In 2009 he approached his family and proposed exhuming his brother’s body to get a DNA sample for testing, but “for emotional reasons” his family had been slow to act on this idea.
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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.”
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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.
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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.
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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.
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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.
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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.”
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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.
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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.”
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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”:

1. Thank you.
   

2. Today is a start, not a final product.
   

3. The PGP is research, not a genetics service.
   

4. 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.
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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 utility
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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.”