At least two personal genomics companies included APOE as part of their SNP-based scans (Green consulted with them pro bono).7 As genes go, APOE is arguably the most powerful one yet discovered that contributes to complex traits mediated by multiple genes and the environment. This is probably why both Jim Watson and PGP-10 participant Steven Pinker declined to learn their APOE genotypes (though, as we saw in chapter 7, successfully not knowing was not always so easy to accomplish).
Time was short. The National Human Genome Research Institute (NHGRI) folks were about to pay a visit to the Church lab in anticipation of George submitting a renewal for his big grant, one of ten such genome grants in the country. The site visit would not be a make-or-break; indeed, it would not be evaluative at all, only advisory. The NIH wanted to know what progress the Molecular and Genomic Imaging Center had made over the last five years and what George’s team was planning for the next five. The idea was to maximize the grantee’s chances for success going forward. George thought the stakes were fairly low and refused to get worked up about it the way Bob Green and Jason Bobe had done. “The only tricky thing,” George conceded, “will be getting the PGP right.”8
“Tricky” was an understatement. From the moment the NIH notified George that it would fund every aspect of the imaging center except the PGP, rhetoric and accusations flew back and forth between the Church camp and NHGRI. From what I could glean from these exchanges, the NIH saw George as a brilliant scientist, a world-class biologist, and a sharp and incisive mind that had always rewarded the public’s investment in him. Perhaps even more important, he was a card-carrying inventor and precocious technology developer who had a knack for seeing the future. It would be stupid not to make him a centerpiece of the institute’s efforts to realize the thousand-dollar genome. “We ignore George Church at our peril,” a powerful genome scientist once said. On the other hand, there were parts of the Churchian future that the NIH simply could not stomach. His views about genetic privacy, for example, which he began to spell out in the original 2003 Molecular and Genomic Imaging Center proposal:
The core question is: How may the gathering of increasing amounts of genetic information be made compatible with ethical and legal requirements for privacy? Anything approaching a comprehensive genotype or phenotype (including molecular phenotypes) ultimately reveals subjects’ identity in our increasingly wired world as surely as conventional identifiers like name and social security number… . This raises numerous specific questions:
Are current informed consent practices sufficient to give human subjects adequate understanding of the potential that their identity may be discernible in large genetic data sets …?
Is enough protection afforded by allowing researchers open access to such data sets so long as they agree not to take the analytical steps that would link these data to a specific person …?
Is there a kind and level of genetic information for which it would be virtually impossible for a researcher … to link it with a specific person?9
For George, the answer to each of these questions was a resounding no. DNA was the ultimate digital identifier, after all: a Social Security number was nine digits, while a genome was 3 billion. George believed the NIH was balking at paying for the project (despite having approved every other aspect of his $10 million genome technology grant) because he refused to do it under the ethical paradigm set forth by the agency—that is, one in which subjects give informed consent and in return are promised, more or less, privacy and confidentiality.
And what about the long list of privacy breaches involving health and genetic information?10 To NIH, these might have been noteworthy anecdotes that raised potentially provocative questions about the privacy of genomic data. Such questions were certainly worthy of study. But their answers were in no way self-evident. It was one thing for the Church team to come up with faster ways to sequence human DNA or better ways to interpret what those sequences meant. It was quite another to start sequencing healthy humans, sharing every detail of their genomes with them, and not even trying to keep their identities secret.
In early 2007, Jeff Schloss, the National Human Genome Research Institute’s point person on sequencing technology grants, reluctantly granted me a brief telephone interview. His main point was that George had not made the case, either in his 2003 grant application or in three years’ worth of subsequent correspondence, as to why the PGP should be carried out under different rules of informed consent. “We need hypotheses,” Schloss said. “We need to know what scientific ideas he’s going to be testing.”11
“We’re doing hypothesis generation, not hypothesis testing,” countered George. “What hypothesis were we testing when we sequenced the first human genome? When he sold the Human Genome Project to Congress, Jim Watson didn’t say we were going to test hypotheses, he said we were going to cure cancer.”12
A few weeks later I tagged along to a meeting of the various ethics centers funded by NHGRI. There an NHGRI administrator gave a presentation outlining the institute’s plan to sequence five to ten humans in the next one to three years. It was never clear to me what NIH hoped to gain from this, as there was no discussion of scale-up or data analysis. Multiple companies had, like George, already begun to sequence humans to demonstrate the power of their technologies. But NIH itself was not in the technology development business—it gave money to academic scientists and start-ups to do that. And clearly NHGRI was not excited about publicly identified genomes. During the Q&A someone asked about the PGP-10 and how it was different from what NIH was proposing. An administrator said that George insisted on sequencing highly educated geneticists and seemed to imply that this was elitist, celebrity genomics. The interlocutor, an ethicist familiar with the PGP, said she thought that the education requirement was something that had been demanded by Harvard. The administrator said no and insisted it was George’s idea. I had interviewed Rabbi Terry Bard, a member of the Harvard Institutional Review Board that oversaw the human subjects aspects of the PGP. He told me that having the PGP-10 be highly credentialed was indeed the IRB’s stipulation, not George’s.13 Yet in the coming months I would hear the same charge leveled at George from several people affiliated with NHGRI.
I paid a visit to the fortress itself. On the NIH website there was a warning about “new security procedures.” I showed up early, which was a good thing. I drove into the car inspection line and queued up, and a succession of orange-vested people approached my window. The first brandished a metal detector wand, which she waved over my steering wheel. The next collected my driver’s license. The third placed a sheet of paper on my dashboard saying that my car had been inspected and would I please open the trunk. The fourth asked me to step out of the vehicle and walk through a metal detector.
I should say that, through the entire process, there was not an ounce of DMV- or airport-security-style surliness. Judging by my experience at the entrance gate, NIH was populated by Shiny Happy Civil Servants. They preempted one’s inclination to get mad at them. They had to do this all day in the sweltering heat—so if they weren’t irritated, how could you be? I returned to my car and a smiling orange vest came back with my license and a badge with my name on it. Then I sat and waited. And waited. And waited some more.
Eventually I was waved through. I found Building 49 and waited for Les Biesecker to come downstairs and guide me over the final security hurdle. Biesecker ran the Genetic Disease Research Branch at NHGRI. He was tall with short gray hair and glasses on the end of his nose. Biesecker was in charge of ClinSeq, which its website described as an attempt to “pilot large-scale medical sequencing in a clinical research setting.”14 He told me that he and his colleagues wanted to bring genomics to bear on medical problems. The idea was to find a population with a medical condition and sequence a couple of hundred genes in each patient where there’s likely to be a “hit”: a mutation or mutations that are important in that disease. The National Heart, Lung and Blood Institute bit on this idea: cardiovascular disease would
therefore be ClinSeq’s initial focus.15
Like the PGP, ClinSeq would return results to participants. But unlike the PGP, it would return them only if they were clinically relevant. This meant 1) known genetic variants that led to known clinical manifestations; 2) variants that appeared to be severe because they stopped a complete protein from being made, they inserted/deleted sequence, or they drastically rearranged the gene; and 3) more ambiguous changes that altered amino acids within a protein but whose effects were not known. “Those will be tough,” said Biesecker of the last category. “The good thing is that for cardiovascular disease, there are interventions, so if there is bad news then there are potentially things that can be done [in those cases].”16 For each gene analyzed then, ClinSeq staffers would have to investigate the variants they found and decide if a case could be made for returning results from that gene to subjects.17
“Why not return all of the variants or even all of the sequence data back to participants who want it?” I asked.
“I’m not interested in the genome as entertainment,” he said.18
When I got back to my car, I noticed a sign on the top floor of the parking garage. ATTENTION: OVERHEAD LEAKS OR BIRD DROPPINGS MAY STAIN CAR FINISHES. PARK AT YOUR OWN RISK.
In my twenty-five years of parking I had never seen such a sign. I imagined it was dreamt up by a government lawyer somewhere as some form of preemptive legal strike against angry drivers. But maybe that was too cynical—maybe it was just full disclosure: “Here are the possible consequences of parking here. If you park here then you consent to the possibility of bird shit on your car.” Okay, good to know—two cheers for NIH. But bird droppings or unspecified overhead leaks were not in the same league as genomic information. Given the gauntlet one had to traverse just to pay a visit to NIH, it was easy to understand why the institutes appeared to have zero interest in health information altruism or open consent. Openness implied risk. In acknowledging how little we know about what any of the information written in our genomes means, Amy McGuire once said we must learn to consent to uncertainty.19 But bird poop notwithstanding, that was a lesson our government seemed unlikely to assimilate anytime soon. Uncertainty was still Kryptonite.
While fighting for NIH acceptance, George continued to pursue private funding sources. Although George would not discuss it, others familiar with the PGP told me that at one point Google was poised to infuse tens of millions of dollars into the PGP to help develop sequencing technology and use the project as a showcase for Google Health, the company’s new Web-based platform for central storage and management of all of one’s health information. Before pulling the trigger, however, Google higherups wanted to solicit the opinions of other thought leaders. What effect would public disclosure of DNA and trait data have on the public’s view of a company whose unofficial motto was “Don’t Be Evil"? The PGP brain trust had a sit-down with NHGRI leadership, a few bioethicists, and a couple of senior Googlers. According to a PGP affiliate who was there, “It was clear we were walking into a hornets’ nest.” After the meeting, sources told me, NHGRI leadership followed up with an email to someone on Google’s board of directors saying that if Google went ahead with the PGP it could set personal genomics back twenty years. At that point the collaboration was all but dead.
George was distraught. He had imagined Google Genomes taking its place alongside Google Books, Google News, and Google Maps. Admittedly, the PGP still had a million bucks from the company. But that is all it would get for the foreseeable future.
“For one brief shining moment,” said Ting, “it was Camelot. George had gotten to be good friends with the Googlers. It had become kind of an extended lab situation. So when it ended it was hard.”20
All of this pushback made the inclusion of the PGP in George’s grant renewal proposal a piping hot potato. George still desperately wanted NIH’s approval for the project, but after four years of supplication, argumentation, butting of heads, and politicking, he was no longer sure how to get it.
Enter Robert Green. In preparation for the site visit, he began meeting with George and Jason Bobe several times a week. If this proposal were to succeed, he told George, the PGP would have to be scaled down by at least two orders of magnitude. He laid out some ground rules:
No use of the phrase “100,000 people” (500 max, or better yet, 250)
No discussion of asking participants to pay their own way
No insistence on a total lack of privacy for participants
Come up with a very modest plan to collect trait information
Rehearse your PowerPoint presentations ad nauseam
“If George’s goal is to get NIH funding for a portion of the PGP,” Green said, “there really isn’t any choice. You have to play this game. One has to abide by the standards of scientific proposals that have become the norm at NIH.”21
Under Green’s tutelage, the Church team fell into line. Everyone dutifully made slides and practiced their talks while Green sat in the audience and played the role of hostile questioner. But the dry runs seemingly paid off: the new, scaled-down incarnation of the proposal—now with the even more unwieldy moniker, “The Human Gene/Environment/Trait Technology Center” (HGETTC)—was ready. Two days prior to the site visit, Jason was giddy. “This is going to be like Gettysburg,” he said, invoking a George metaphor.
“You mean a bloodbath?” I teased him.
“No,” he laughed. “A turning point!”22
• • •
Gail Henderson had never heard of George Church. And even after reviewing the materials that had been sent to her, she still didn’t know quite what to make of the Personal Genome Project. But since she was the member of the site-visit team responsible for ethical, legal, and social-issues (ELSI), all eyes were on her. Henderson was professor of social medicine at the University of North Carolina Chapel Hill, about ten miles from where I work. “Durham is a full day’s journey from Chapel Hill,” she told me half jokingly over beers, referring (I think) to both the cultural divide between Duke and UNC and the increasingly snarled traffic on the highway connecting the two cities.23
Henderson may have been new to the PGP, but you would have been hard-pressed to find anyone who knew more about ethics and biomedical research. She had long studied how scientists, patients, and ordinary people perceive genetic research and genetic medicine. And now, as director of UNC’s Center for Genomics and Society (an ethics center funded by NHGRI), she had turned her attention to ethical and regulatory issues posed by new genomic technologies and the big science that came with them. The PGP was right in her wheelhouse. “Our center’s theme is about exactly this: What are the ethical, legal, and social issues when you start to scale up?”24
The night before the site visit, Henderson caught a plane from Raleigh to Boston. When she arrived she felt tired, out of breath. Her heart raced whenever she stood up. She thought she was exhausted from traveling and stress: after the site visit she had a meeting in D.C. and from there was scheduled to go to China, where she was to continue her studies of the Chinese health-care system. She reached the Best Western near Harvard Medical School and went straight to the restaurant—maybe she just needed to eat something. She sat down … and promptly passed out and fell to the floor. When she came to, two strangers were kneeling over her. They called an ambulance, which didn’t take long. “If you’re gonna pass out,” Henderson said, “the place to do it is directly across from Brigham and Women’s and Beth Israel Deaconess hospitals, right?”25
She was experiencing a slow but massive gastrointestinal bleed, though she did not fully apprehend its severity at the time. “I had this idea that this was nothing,” she said. “I talked to the NIH and said I’m sure I’ll be out of here soon; put me on the agenda for tomorrow afternoon.”26
Once word spread that Henderson was in the hospital, there was concern on both sides, not only for her health, but for what this would mean for the site visit. The Broad Institute’s Chad Nusbaum, a member of the NHGRI team who
se job was to evaluate the sequencing technology, was worried that he would be called upon to have “intelligent opinions on ELSI matters.”27 Jeantine Lunshof, the philosopher/bioethicist who had helped George articulate the rationale for open consent, fretted over the prospect of not having a fellow ethicist in the room.28 And Jason Bobe feared the worst. “I thought this was a sign that NHGRI wanted to bump this part of the proposal altogether.”29
Robert Green sensed the apprehension and decided to act. “It’s always good to meet people face-to-face,” he said. “The value of the site visit was that we were going to be able to talk person to person. It was not a calculation, but an instinct. I went to her hospital room and found her fully lucid and ready to talk. We started to go through the slides, but she stopped me and said, ‘Why don’t you just tell me about this?’ And that turned into a conversation that went on for over an hour.”30
By the time Henderson was piped into the meeting by phone, most of her reservations about the PGP seemed to have been assuaged. “[When she addressed the meeting], she ended on this enormously positive note,” said George. “The impression I got from NHGRI was that they thought we were really doing our homework on the ELSI.”31
What about everything else George wanted to accomplish? What about the RNA, immunogenetics, the microbiome—i.e., the collective genomes of the thousands of microorganisms that live inside of us? What about adult stem cells? “They said we were being too ambitious,” remembered James Sherley, who, in addition to being one of the PGP-10, was collaborating with George on the adult stem cell project. “This is the weakness of NIH and I think even NIH itself recognizes it. It’s been designed to support work that has a high probability of success. That makes it hard to support things that are truly visionary.”32
Here Is a Human Being Page 18