Here Is a Human Being (9 page)

Or so he thought. In June 2008, California followed New York’s lead and sent cease-and-desist letters to thirteen companies, including the Big Three (Navigenics, 23andMe, and deCODEme), some of which claimed to be in compliance with state law, while others stopped offering their services in the state, at least temporarily.
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The California Department of Public Health complained that 1) the clinical labs used by the companies to perform the genotyping were not appropriately certified; and 2) as in New York, the companies could not offer their tests directly to consumers in California without a physician’s order. These companies were, according to California officials, “scaring a lot of people to death.”
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That summer the Secretary’s Advisory Committee on Genetics, Health, and Society convened its biannual meeting. SACGHS was formed in 2002 (an outgrowth of an earlier committee on genetic testing) by then-HHS secretary Tommy Thompson, and asked to consider the impact of genetic technologies on American society.
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The meetings took place in the Hubert H. Humphrey Building, a singularly ugly 1970s edifice that serves as the headquarters of the Department of Health and Human Services and lives in the shadow of the Capitol. Day one of the meeting was as boring and Kafkaesque a gathering as I’d ever attended, devoted to a dissection of the process by which the committee would decide what its priorities were; I thought I’d stumbled into a scene from the film
Brazil.
Two hours into the session my posterior was numb and I could feel my eyes rolling back in my head. Worst of all, the building didn’t seem to have wireless Internet available to civilians; I made a mental note to bring an Ethernet cable, some sudoku, or something to read next time.

Day two, unassumingly titled “Session on Personal Genome Services,” was the antithesis of the previous day’s sleepy proceedings. On three sides of the rectangular assemblage of tables sat committee members—academic physicians, geneticists, biotech executives, law professors, theologians, social scientists, and assorted bureaucrats. At the head of the room were empty chairs reserved for the leading lights of the new wave of personal genomics: Dietrich Stephan (Navigenics), Linda Avey (23andMe), Jeff Gulcher (deCODEme), Ryan Phelan (DNA Direct), and George Church (Personal Genome Project; Knome [about which more later]). There was a cacophony of excited chatter beforehand. By the time the chairman asked people to take their seats it was standing room only.

At this stage of the game, eight months since the launch of the first commercial “Saliva Diviners,” the blogosphere had, for the most part, warmed to personal genomics.
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Customers were comparing results from different companies;
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some were writing their own software to interpret it.
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But the folks in white coats remained unimpressed: the backlash against the companies by the medical establishment was almost immediate. Not only are these companies doing more than dispensing “information,” the critics said, they are practicing medicine, and indeed, they are practicing—in the immortal words of Bon Jovi—
bad medicine.
These tests are inaccurate, they don’t measure what they are supposed to measure, they are not actionable, they will lead to the “wrong” actions, they will lead to unnecessary anxiety, they will rob medicine of valuable resources, physicians will not be able to handle the data deluge, and they are frivolous manifestations of important science.
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(Perhaps the unkindest cut was “recreational genomics,”
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a label Navigenics gave to 23andMe and one that, much to Linda Avey’s chagrin, had stuck.)
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When it threw down the gauntlet in January 2008, the
New England Journal of Medicine
encouraged doctors to tell patients that the information derived from these services was essentially useless and that patients should “ask again in a few years.”
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One of the authors of that editorial was Muin Khoury, director of the National Office of Public Health Genomics at the Centers for Disease Control and Prevention. He was also on the Secretary’s Advisory Committee and expected to be a sharp interlocutor at the July meeting. He didn’t disappoint.

“Where is the balance between waiting and validation?” he wanted to know. The development of valid cholesterol testing, he pointed out, took many years. “What is the value added by genes versus pure family history and traditional risk factors?” Later, he answered his own questions with a sharp rhetorical flourish: “This information is not ready for prime time. Replication is not clinical validity. When you [panelists] talk about value to consumers and clinical utility, I talk about balance of harms and benefits. The problem is lost in translation.”
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The companies had also appeared a couple of months earlier at the Cold Spring Harbor meeting. There, at a session moderated by Francis Collins on commercial personal genomics, Dietrich, Linda, and deCODE’s Kari Stefansson were downright deferential to the assemblage of scientists. They wanted to know how they could work with scientists. They acted not like competitors, but like colleagues—even deCODE’s notoriously cantankerous Stefansson made nice.
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At the SACGHS meeting two months later, the companies were still “on message”: they were doing everything they could to cooperate with the state health departments in New York and California, they were going to meet to hammer out standards, and they were actively soliciting advice from all of the stakeholders in personal genomics.
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If there was a panelist who exuded above-the-fray gravitas at the SACGHS gathering (as opposed to Gulcher’s slight hostility and George’s phlegmatic indifference), it was DNA Direct CEO Ryan Phelan. Like Linda Avey, she was a Silicon Valley veteran. She was married to Whole Earth Catalog author and counterculture/cyberculture icon Stewart Brand; the pair lived on a tiny tugboat in Sausalito.
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Phelan came to genetics well into her career. But DNA Direct preceded and was wholly distinct from the Big Three and other personal genomics SNP-chip companies; it was in essence a clearinghouse for traditional, one-disease-at-a-time genetic testing. When I met her for lunch in San Francisco not long after the 23andMe and deCODEme launches, Phelan had already sussed out what the new companies would mean for her business. “Both 23andMe and deCODEme are drawing a line and saying, ‘We’re just health information. We’re going to give you some interpretation but not a whole lot. And we’re also going to tell you that what we do is not a medical diagnostic. So if you really think you’re at risk for something [like breast cancer], you need a follow-on DNA diagnostic.’ DNA Direct can be a service to those customers.”
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Looking ahead, Phelan saw an opportunity in the arrival of whole-genome sequencing: interpretation. “The core competency I want to add is helping people to utilize this cool new technology.”
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After the regulatory crackdown, the DNA Direct website included a statement from Phelan:

“DNA Direct has not received a cease & desist letter from the California State Department of Health. And DNA Direct has no reason to expect to receive any such letter. Our company fully complies with all applicable state and national regulations for genetic information services, including facilitating genetic test requests.”
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Clearly the company was not in the crosshairs of regulators the way the genome scanning firms were.

Kevin FitzGerald, a SACGHS committee member and perhaps the only person in the world who was both a trained molecular biologist and an ordained Jesuit priest, asked the assembled purveyors of personal genomics, “Would you sacrifice your bottom line for the sake of health care?” Phelan didn’t hesitate: “From an investor’s perspective, we have
always
sacrificed the bottom line.”
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Linda Avey chimed in that while 23andMe was a business, it also had a social mission. Jeff Gulcher said deCODEme was genotyping some people at cost. Dietrich seemed piqued by the question. “Implementing genotyping as a service doesn’t fit as a not-for-profit model. What portion of medical infrastructure operates as not-for-profit?”
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It’s doubtful the meeting changed any minds. During a break I heard geneticist Jim Evans, who had earlier compared personal genomics to astrology, say to some attendees, “I don’t care if they want to make a buck. They just shouldn’t pretend like they’re doing something else.”
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But even if there had been an understanding between personal genomics companies and the feds on that day in July, political reality made it extremely unlikely that anything meaningful would happen before President Bush left office six months hence. Because everyone knew that, much of the day’s later proceedings had a relaxed, valedictory feel. Not only did Francis Collins make his last appearance as an ex officio committee member before stepping down as director of the National Human Genome Research Institute in August 2008, but HHS secretary Mike Leavitt himself turned up unannounced (it was
his
committee, after all). And like any capable politician, Leavitt managed to make people feel good while saying absolutely nothing of substance. When asked how he thought we might move ahead with direct-to-consumer genetic testing, he said that he would not weigh in on either side but that the matter represented “a positive struggle.” When asked politely by Collins when reimbursement for preventive health-care measures would be implemented, Leavitt admitted that it was indeed a pressing issue. But, he said, “It’s not likely to happen in the next one hundred and ninety-seven days.”
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A month earlier, molecular biologist Steve Brenner of the University of California at Berkeley organized a dinner at a swanky San Francisco hotel aimed at helping to realize his vision of a “Genome Commons.” Brenner’s idea arose from the need to “specifically address the incredible difficulty of integrating and interpreting multiple variants in an individual, each associated with a given trait.”
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In other words, we will soon have tens of thousands of genomes … how in the hell will we even begin to interpret them? As an example of what not to do, he pointed to the 2007 paper announcing the completion of Craig Venter’s genome,
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and especially the “inscrutable” table therein that was meant to relate his genotypes to his traits, but contained only a smattering of random phenotypes and susceptibilities (for example, “evening preference,” “novelty seeking,” “tobacco addiction,” “Alzheimer’s”), a sort of 23andMe lite. “What did we learn [about Craig Venter’s phenotype from that paper]?” said Brenner. “Nothing that was worth even reporting correctly.”
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Among others at the dinner were the Big Three: Gulcher from deCODEme, Avey from 23andMe, and Stephan from Navigenics. At that time it seemed that wherever one was, you could find the other two. Geneticist Hugh Rienhoff (whom we will meet again later) opined that most of the variants the companies were reporting to customers didn’t pass the “so what” test. A variant that raised one’s risk for any given disease from one in a thousand to one and a half in a thousand, for example, was not clinically meaningful. And even when changes in risk were large, physicians still weren’t getting the message, said Rienhoff; in fact, they probably didn’t care.

“I find every paper that’s published in the
New England Journal
about [genetic] association studies to be almost completely useless for the reader,” said Rienhoff. “And the [intended] reader is the clinician! But he doesn’t understand the statistics, he doesn’t understand the technology, and it won’t make any difference for ten years.”

“But that’s what the missing piece is,” Avey shot back. “We don’t have a way to translate this into the clinic.”

“Well,” said Rienhoff, “I think it’s premature, to be honest with you.”

“It’s premature,” echoed Avey. “But when is it mature?”
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This was—and still is—the question for commercial personal genomics, the same one posed by Rabbi Hillel some two thousand years earlier: If not now, when?

Both 23andMe and Navigenics were born of this frustration and impatience. And both companies may have shared a catalyst.

In November 2006, a
Wall Street Journal
article about Augie Nieto, inventor of the Lifecycle exercise bike, described his tragic diagnosis of amyotrophic lateral sclerosis, or Lou Gehrig’s disease, at the age of forty-eight.
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Like breast cancer, ALS is mediated mostly by genes of strong effect in 5 to 10 percent of cases and partially mediated by a collection of much weaker genes in the other 90 to 95 percent. Even had Lou Gehrig never made his extraordinary “luckiest man on the face of this earth” speech, ALS would still be among the most heart-wrenching of diseases. While the body breaks down, the limbs atrophy, and one loses the ability to move and speak, the mind remains intact. It is an agonizing, inexorable process; most ALS patients die within five years due to respiratory failure.
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Nieto, however, had financial resources most other ALS patients didn’t. He was not going to succumb without a fight. He assembled a team of physicians and scientists, and through his newly hatched ALS foundation, “Augie’s Quest,” sponsored research into the genetic basis of the disease with the explicit goal of finding a cure. Among the researchers was Dietrich Stephan, then at the Translational Genomics Research Institute in Phoenix. At Nieto’s urging and with his financial backing, TGen collected 1,250 ALS samples in three months. The TGen team then typed the samples for hundreds of thousands of markers and assembled a list of twenty-five promising ALS susceptibility genes. Nieto’s doctor asked for his patient’s genotypes. Stephan wanted to oblige him but found that he could not.
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There were two main issues. “The genotypes were done in a research environment and not in a CLIA environment."
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In other words, TGen’s lab was not a certified clinical diagnostic lab and therefore the institute was forbidden from returning results to research participants. “Second, the IRB mandates total de-identification of research subjects/samples.”
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The Institutional Review Board (IRB), that is, the ethical review board charged with approving, monitoring, and reviewing TGen’s biomedical research on humans (every hospital and academic medical center has one or more IRBs; I serve on Duke’s), demanded that research samples be kept anonymous in order to protect subjects’ privacy and confidentiality. Whether the subject wanted to waive that right was immaterial. Augie Nieto could not view his own genetic data.