Here Is a Human Being

by Misha Angrist

  So now Hugh had a set of sequence data from all of the genes that were expressed or “switched on” in Bea’s white blood cells.* In this case, that meant about fifteen thousand distinct bits of RNA, about two-thirds of which coded for protein. And he knew to what extent any given gene was expressed in those cells. “Why would that matter?” I asked. Hugh pointed to the glowing computer screen where he had aligned his, Lisa’s, and Bea’s data—a seemingly infinite series of colored peaks and valleys measuring gene expression. In most cases, the peaks were of similar height in all three. Although the conventional wisdom at the time was that humans’ gene expression profiles would vary widely, Hugh’s family suggested otherwise—the diagonal lines showing levels of gene expression were almost identical for the three of them, even though he and Lisa were not related—certainly not closely. But the patterns were not perfectly correlated, either: Hugh pointed to a variant in a gene he was scrutinizing that had two versions (alleles), G and C. He and Lisa both had one of each: they were both genotype G/C (heterozygous). Bea, on the other hand, inherited a C from each parent: she was genotype C/C (homozygous). So what, I thought. “Ah,” Hugh said, anticipating my skepticism. “Look at the difference in expression between the two alleles.” The peak representing the G allele towered over the tiny peak representing the C allele; the G version was expressed tenfold more strongly than the C version. Bea, therefore, appeared to make a tiny fraction of this particular protein compared to the amount her parents made.68

  Hugh would have to chase down this lead as he would thousands of others, one gene at a time: checking for differences in expression levels, looking for new mutations that neither he nor Lisa carried (he had found several possibilities), looking for known pathogenic variants, trying to guess whether variants he saw that had not yet been reported might be capable of causing Bea’s condition, and all the while enlisting pro bono help from academic scientists who analyzed gene expression data for a living. And there was a mountain of data: instead of setting his computer’s sequence analysis filters to be extremely stringent, Hugh kept his filters loose and inclusive, lest he miss anything among the millions of base pairs scrolling by. It seemed like an impossible long shot.

  He smiled. “That’s why I call it hand-to-hand combat.”69

  As we sat in the Bat Cave, Hugh picked up a child’s acoustic guitar and began to play a sure-handed version of “Fly Me to the Moon.” Later we harmonized on “I Will” by the Beatles. As the kids ate dinner in the kitchen, Hugh sat on the floor munching carrot sticks and telling me about his decision to become a conscientious objector during the Vietnam War. I reckoned I liked him because he came across as a smarter, better-looking version of what I imagined myself to be on my best days: a dedicated father, an enthusiastic dilettante, an iconoclast, and a bit of a troublemaker.

  A couple of years earlier, at the National Marfan Foundation Annual Conference in Palo Alto,70 not far from his home, Hugh went to a workshop intended for people and families who had Marfan-like features but lacked a diagnosis. He saw it as an opportunity to represent Bea’s point of view and to learn something. There were a fair number of patients and a doctor, Dianna Milewicz of the University of Texas Health Science Center in Houston, who served as interlocutor.71 Each patient told his/

  her story, many of which involved frustration with the medical system. Many went something like this: “I have long fingers, a heart murmur, and the insurance company won’t pay for the echo.” Or: “I have a high arched palate and narrow feet, long fingers, my father died at age thirty-five, and my physician will not order the genetic test for Marfan.” Hugh found it heartbreaking to encounter so many people stuck in the same netherworld of not knowing what their symptoms meant, and without his financial and scientific resources.72

  Finally it was his turn. “I have a daughter,” he began, “and she has some of the important features of Loeys-Dietz, but she doesn’t have any evidence of vascular disease. I reasoned that maybe she had a TGF beta problem, or that she had a problem in some other member of that gene family. So I sequenced a few of her genes.”73 At that point, according to Hugh, Milewicz stopped him, turned to the rest of the participants, and said that none of them should ever attempt this—it was just too difficult.74

  Hugh was taken aback. “Who the fuck is this person?” he thought, shocked at the paternalism of a fellow doctor, especially given the current, pre-reform state of health care. “I’ve never seen a better example of a physician being contemptuous of a patient’s own initiative. I live in a world where the patient-doctor relationship is a collaboration. That’s how I was trained. These people need a diagnosis. Without a diagnosis they can’t get coverage. And sometimes once they do get a diagnosis they’re screwed anyway because suddenly they have a preexisting condition. But getting a diagnosis is the foundation of everything else: prognosis, management, reimbursement … and understanding.”75

  It was an epiphany. People had no idea what genetics and genetic testing were about and the medical establishment didn’t seem all that interested in telling them. Hugh was. He went home and wrote down everything he’d done for Project Bea. And he began talking. “If you can make a good soufflé, you can sequence DNA,” he told the Economist.76 He and Bea graced the cover of Nature.77 They appeared in Make, the do-it-yourselfer magazine.78 In 2009 they were in Wired.79 A presentation Hugh gave showed up on YouTube.80

  And he launched MyDaughtersDNA.org, a website that pointed visitors to various accounts of Bea’s journey and invited parents, patients, and physicians “to describe for the other users of the site a case that needs some help.” A few of them have told their stories and shared their expertise.81 A geneticist in St. Louis read a description that a Bulgarian man had posted of his twelve-year-old daughter who lacked the ability to cry and suggested that she might have an extremely rare endocrine disorder known as Triple-A syndrome. She did; shortly thereafter she began hormone therapy. “To see a complete stranger solve another person’s problem,” said Hugh. “That was nice.”82

  But the broader goal was to inform. Everything he’d written down went on the website: how to do PCR, how to pick primers, where to get something sequenced, how to navigate genomic databases. “I felt that just understanding what the steps were would demystify the process. Maybe no one would actually go from beginning to end, but people could understand every little step along the way. A lot of people don’t have the benefit of seeing a geneticist, let alone know what it is a geneticist does.”83

  But just as Milewicz considered the Rienhoff approach a bad idea, so too did Bea’s own doctor, Hal Dietz. “I could imagine some parents diverting financial resources away from physical therapists and other health-care professionals in order to access the great promise of genomics and sequencing. I could imagine tragic consequences to that decision. I think Hugh is uniquely prepared to understand and deal with the complexities of his daughter’s situation. But I can’t imagine parents with no scientific background really knowing what to do with the information they would get.”84

  Hugh deferred to Dietz. “When the discouraging word came from Hal, I immediately switched from being the ‘bad boy of genetics’ to being Bea’s dad who did not want to jeopardize her relationship with her doctor, which at that time was tender and new. I’m not condemning Hal. I just decided that maybe I wouldn’t tell the world how to make an A-bomb and blow up academia. And besides, it’s all out there already anyway, right? I was just consolidating the information. And putting a human face on it.”85

  Eventually Dietz came around … at least somewhat. When Hugh and Bea came to Baltimore in 2009, Dietz fully endorsed keeping her on losartan. And when Hugh brought him reams of transcriptome data, Dietz did not roll his eyes; Hugh hoped that this would be the beginning of yet another collaboration on Project Bea. He speculated that his “Tom Sawyer” approach to science might finally be working.86

  When Hugh called from his cell phone the following summer, he was still pursuing any number of hot candidate gene
s. But he was even happier that Bea was thriving, if not putting on weight. Her echocardiograms continued to come back clean. She was being a champ about remembering her losartan pill and taking it on her own.

  And she was living the life of any other happy five-year-old. She had started to read and learn math. She attended science camp with her older brother Mac and came home ebullient about the experiments they’d done; one sensed the pride in her hypothesis-generating old man. Maybe she would make it to Hopkins as a student one day instead of a patient.

  Meanwhile, Bea and Mac had become close: Mac treated her like a peer, teased her as only a big brother can, and stuck up for her when necessary. “Bea’s not above kicking a boy in the cojones,” reported Hugh. “She got into a fight the other day at camp with a boy who was much stronger than she is. Macky had to step in and defend her. She’s got to learn to take what she dishes out. But … chivalry is good, too, I suppose.”87

  Hugh had gotten off Highway 101, the perpetually clogged artery in and out of Silicon Valley, and we began saying our good-byes. Where was he headed?

  “My ambition is to eat lunch. After all,” he said, “you gotta have ambition.”88

  * By exposing DNA fragments to an electrical charge, it is possible to separate them by size in an agarose gel. Small fragments run faster than larger ones.

  * RNA, as you’ll recall, is the intermediate between DNA and protein; it is the “messenger” that instructs the protein synthesis machinery exactly what to make. Genomic DNA—the 3 billion base pairs you inherit from each parent—is full of extra stuff that doesn’t code for protein. If you are interested in which genes a cell or tissue is actually using, you would want to look at RNA, nearly all of which does something useful. First, however, you would enzymatically convert it to its DNA counterpart, complementary DNA (cDNA). Why not just sequence RNA directly? It can be done, but people generally don’t because it is very fragile. The half-life of RNA is usually measured in minutes. And it’s very easy to contaminate. DNA is much hardier and easier to work with.

  * Admittedly, if one or more genes responsible for Bea’s condition were not turned on in white blood cells, one would never see them. This is clearly a limitation of transcriptomics.

  10 “Take a Chance, Win a Bunny”

  The first PGP-10 meeting was both baby shower and brainstorming session. George expressed his gratitude to us. The other seven of us who could attend sat around a table and made speeches, wish lists, and plans for our genomes. Filmmaker Marilyn Ness was there to capture it, having scraped together enough money to shoot documentary footage of us for a few hours. After a day of offering paeans to George and getting to know one another, fanciful musings, and gentle arguments, five of us adjourned to George and Ting’s unassuming Brookline house with the pond in the back for food and drink. The next day we scattered, full of ambition and hope for the project.

  The second annual gathering was intended to be both a bigger deal and more substantive: PGP-10ers would see their data fresh from the Polonator, they would consult with a clinical geneticist about it, and they would make decisions about how much of it they were willing to share going forward. The press would be invited to learn about the PGP, its participants, and how genetic information need not be toxic.

  It was just after 5 a.m. on Sunday. I sat in the Raleigh-Durham airport anticipating a nap as I waited to board an American Eagle flight to Boston. It was hard to believe that the last two years of running around the country had brought me to this, the presumptive crucible of my entire personal genomics experience. Amy Harmon, the Pulitzer Prize–winning New York Times reporter who covers “The DNA Age” for the paper, had called me nearly every day for the last week to ask me questions for a story that would coincide with the Big Event: Why did you do this? What do you hope to learn? What does your family think? What would you redact? I danced around, but I didn’t really have any hard-and-fast answers for her. To my own surprise, I was torn. Should I let it all hang out, as I had said I would over and over with studied insouciance, and thereby demonstrate my solidarity with the other nine and my loyalty to the open-consent ethos? Or should I heed my colleague Bob Cook-Deegan and all the other cautious pre-Facebook, pre-Twitter people I knew and opt for the old privacy norms?

  At the beginning of my involvement with the PGP, I had longed for my genome to be something more than someone else’s lab experiment, more than a set of anonymous data, more than an abstraction. The lesson I failed to heed, of course, is to be careful what you wish for. But before revisiting that theme, a little concrete backstory.

  In 1976, at age forty-two, after months of denying the existence of the growing mass in her chest, my mother was diagnosed with breast cancer. I was twelve and don’t remember it well, perhaps because I was such a burgeoning pothead at that age. I do recall fidgeting in the backseat of my parents’ Plymouth Valiant and listening to my older brother, whom I idolized, trying to impress upon me the gravity of the situation: “Mom could die.” For once I knew he had to be wrong.

  My mother opted for a radical mastectomy. Twelve years later, after her doctor found a thickening of cells in her remaining breast, she went back to the hospital for another one. Years later, when I asked her about this decision, she smiled and said, “I already had one breast gone, so I figured why not make it even. If you don’t have breasts, you can’t get breast cancer.”1 When it comes to her own health, she has always been a practical woman (less so when it comes to her children’s and grandchildren’s health).

  Given her young age at diagnosis and her heritage, there’s a decent chance my mother carries a mutation in either the BRCA1 or BRCA2 gene. Five to 10 percent of breast cancers in white women are due to aberrant versions of one of these genes. In Ashkenazi Jewish women with hereditary breast cancer, three mutations in particular account for as much as 90 percent of the disease burden, perhaps more. Females with one of these mutations have an 80 percent lifetime risk of developing breast cancer.2 The chances of me or my brothers developing breast cancer were fairly remote: about 1 percent of U.S. breast cancers occur in males. We are “hormonally hostile” to breast tumors.3 But these genes are not on the sex chromosomes; thus, men can transmit BRCA mutations to their offspring just as well as women. I could have passed it to either or both of my two daughters, who turned seven and ten in 2009.

  At the dinner banquet that closed the first annual Cold Spring Harbor Personal Genomes Meeting, I sat next to the doyenne of breast cancer genetics herself, Mary-Claire King. She was and is a brilliant thinker and tough-minded professor at the University of Washington. She gives off maternal charm and empathy. She is a tireless crusader for human rights; in the 1980s, her lab used molecular genetics to prove kinship among Argentine families in which the parents had been imprisoned by the military dictatorship and the “orphan” children were being adopted out surreptitiously.4 In 1994, King lost the race for the two major breast cancer genes with such grace and humility that her already-stellar aura only grew.5 Years later she would find dozens of novel mutations in those two genes, mutations that Myriad Genetics, the company with a monopoly on genetic testing for breast cancer, had missed.6 I told Mary-Claire my story and asked for an on-the-record interview with her, but she quickly recognized that, with the PGP meeting less than two weeks away, what I really wanted was genetic counseling. And she was happy to give it. She suggested that I redact several million base pairs around BRCA1 and BRCA2 before going public; if my BRCA carrier status weren’t public then I would not have to lie to my daughters. If I didn’t have a mutation, then no harm, no foul. If I did, then Ann and I could talk to the girls when they were older. It all sounded so simple.7

  Ann and I agreed that at the very least, I should find out whether I carried a breast cancer mutation before putting my entire genome on the Web. If one or both girls were at high risk for developing breast cancer later in their lives, we wanted them to hear it from their parents when they were ready, and not from some intrepid blogger while they were still i
n elementary school. I had already discussed my risk with Elissa Levin at Navigenics, but her company was not offering BRCA mutation results—she could only quote me risks based on my family history. Thus I hoped the next PGP trip to Boston would bring some clarity to the whole business.

  But without sequence data neither this nor any of the other promised moments of genomic truth could happen at the October gathering, and back in Polonatorville, all was not well. At the end of 2007, the machine was reportedly ready to ship. By the time of the Marco Island meeting the following February it had become a source of conversation, fascination, and maybe even buzz: an open-source sequencer from George Church’s lab that was one-third the cost of the next cheapest commercial competitor! But the truth was, at that time the Polonator was more about promise than it was decoding actual nucleotides from people’s genomes. It was a good-looking, well-engineered box that didn’t have working software: Mr. Spock without a brain.

  Rich Terry, a boyish, thirty-four-year-old engineer from Boston, and grad student Greg Porreca—short, close-cropped hair, New Jersey accent—had devoted much of the previous year working seven days a week trying to breathe life into the Polonator. Terry spent his days tweaking design problems, thinking about microfluidics (extremely tiny channels that carried chemicals in and out of the machine), and, together with Porreca, writing code that would get the moving parts to go where they needed to be at each step. Had Terry known that this is what his life was going to be like, I wondered, would he still have taken the job toiling in the Church lab? He paused … and then he groaned … and then he laughed. “Noooooo!” he said. “I don’t know … Last summer was tough. I like to ski, though, so I don’t mind being indoors in the summer.”8

  I asked him and Porreca about other next-gen sequencing technologies. They handicapped the field and more or less stuck to the conventional wisdom of the day: Illumina/Solexa was the tentative front-runner, 454 Life Sciences had squandered its early lead by being too expensive to run, and Helicos charged too much for its instrument and was late to the party. Both also said that ABI’s SOLiD platform was essentially an earlier version of the Polonator—the primitive tangle of wires hooked to a microscope, named after Simpsons characters, and known as the D.05—in a box.9 “It’s very similar,” agreed George.10 In one sense, this was true: in the early 2000s, Agencourt Personal Genomics licensed the key Church-lab patent that described the nuts and bolts of polony sequencing, which meant sequencing short stretches of DNA in massively parallel fashion using the enzyme ligase, whose raison d'être is to stitch together DNA fragments.11 ABI, the dominant purveyor of the Sanger sequencing technology that had conquered the Human Genome Project a few years earlier, was in danger of falling behind up-and-comers 454 and Illumina; it had to make a move. After evaluating more than forty next-generation sequencing technologies, the company in 2006 settled on George’s sequencing-by-ligation; it bought Agencourt for $120 million.12 Kevin McKernan, who was CEO of Agencourt and subsequently became senior director of scientific operations at ABI13 (which itself merged with Invitrogen in 200814), said it was a logical choice given the promise of the method and its source. “George’s mind is always in a lot of different fields at once. He pulls from nanofabrication, microfabrication, and computer technologies. He often has very simple ideas, but they are fundamentally different from the way other people are thinking about things. And his lab got the proof-of-principle done.” McKernan conceded the Polonator machine was similar to the SOLiD instrument, but emphasized that the “chemistry is very different.”15