A growing number of people are opting to find out. With some trepidation, I became one of them.
* Unless you’re an identical twin.
† Despite our best efforts, a “whole” human genome in 2010 is actually only about 93 percent; the other 7 percent has resisted our best efforts to sequence it.
* An allele is a version of a gene. For every gene, we inherit one allele from our mothers and one from our fathers; those alleles may or may not be the same. If they’re the same, we are said to be homozygous for that allele. If they are different, we are said to be heterozygous.
2 “His Own Drum”
Like a character on Lost, John Halamka has arrived from the future.
Wearing all black and brandishing his BlackBerry, he looks the part. And he lives it. As chief information officer at Harvard Medical School and CareGroup Healthcare System, he is responsible for the information needs of three thousand doctors and the health records of two million patients. He is conversant in twelve computer languages. He is a self-taught mycologist: if you find yourself in the ER after having ingested a wild mushroom, it is likely to be Halamka who gets called to figure out which of the twenty-five hundred North American mushroom species you ate and what to do about it.1
He is also apt to be mistaken for a shoplifter at Home Depot.
After the Food and Drug Administration approved the technology in 2004, Halamka had a bean-sized Radio Frequency Identification chip implanted in his right triceps. The RFID contains his medical record identifiers.
In part his interest was personal: An avid mountain and ice climber, Halamka was concerned that if he fell off a cliff and lost consciousness, his would-be rescuers would not be able to identify him. Now by scanning his arm they could. The downside is that the same ISO-standard 134.2 KHz RFID scanner at the mall may occasionally confuse him with a roll of duct tape or a garden hose.2
Visit Halamka in his feng shui corner office on Harvard Medical School’s Longwood campus and chances are you’ll find him serenely clacking away at his computer, his desktop as clean as the day it left the office-furniture showroom. His lunch is all vegan, probably eaten with chopsticks and great dexterity. Send him an email and you’ll likely get a response within minutes, just like the hundreds of others who’ve emailed him that day, including the ER docs wondering whether the mushroom little Billy swallowed is going to be lethal, hallucinogenic, or merely vomit-inducing. Listen to Halamka talk in his calm, measured cadences and it’s not hard to imagine his flat Iowa accent booming out from your local public radio station.
When I visited, his office inside the Center for Educational Technology was emblematic of the rest of the medical school these days: an incongruous mix of Boston Brahmin stateliness and sleek hi-tech utility. Outside his door, banks of computers lined long tables in an otherwise open area, like a bullpen in a brokerage firm, only without the manic buying and selling, just the basal hum of conversation and the HVAC. Clad in his usual onyx ensemble (“At 3 AM halfway around the world, you do not have to think about color matching”3), hands folded on his lap, Halamka emphasized that his participation in the RFID trial was about more than just preparing for some hypothetical mountaineering accident. He saw it as both part of his job description and a moral obligation. Having the chip implanted allowed him to answer questions that might someday be relevant to his patients: Does an RFID hurt? (No, but there is some discomfort upon implantation.) Would it lead to infection? (Not so far.) Would it place any limitations on his activities? (Other than getting rung up for $27.99 at big-box retailers, no.)
There was the stalker, however. “This guy thought that RFID tagging was the mark of the beast. He basically devoted his life to blogging about me.” Rather than antagonize his “fan,” Halamka began a dialogue with him. “He said his name was Bob, he lived in Kansas City, he was disabled, and that following me was going to be his daily activity.” After a while Bob went away.4 Even the mark of the beast can get tedious.
Did the stalking episode dampen Halamka’s appetite for early adoption? Hardly. Stalking him is now an utterly trivial exercise on par with checking the weather forecast: He has an application on his BlackBerry that tracks him via GPS and produces Google maps of his whereabouts. Anyone with a username and password can locate him anywhere on the planet.
“I think somebody has to do these experiments,” he said of the Personal Genome Project. “We need to get a dataset and figure out what all the implications of this stuff could be.”5
Halamka was probably destined to become Subject Number Two: like him, the PGP was another Harvard-based bit of self-experimentation and potential compromises in personal privacy. That’s not to equate the two. For all of their potential applications, in the early 2000s RFIDs and GPS devices were really nothing more than LoJack for human beings—fancy dog tags. But if Harvard geneticist George Church had his way, the Personal Genome Project would raise the stakes by making public thousands of identifiable human DNA sequences. Church came to Halamka’s attention several years ago after Church posted his own medical records online.6
We would like to invite you to participate in a research study. You have been asked to participate because you are a healthy individual with sufficient training in human genetics and human subjects research to be able to give informed consent for a public and open-ended study.
The main scientific goal of this study is to explore ways to connect human genotype and phenotype information, i.e., human genome sequence, medical records, and nonmedical physical traits… . The ethical and human goals include educating participants and the general public about the risks and potential alternative pathways that genetics can take… . We also hope to discover what consumers, clinicians, and researchers might want and not want and why.7
Researchers have long been interested in the relationship between genome and—in the trendy parlance—phenome, that is, how what’s encoded in our DNA interacts with the environment to give rise to traits ranging from height to athletic prowess to behavior to assorted health conditions, be they cancers or various forms of male-pattern baldness.8 Datasets have gotten larger and the DNA sequencing industry has become a multibillion-dollar behemoth.9
The Personal Genome Project’s initial goal was to recapitulate the Human Genome Project; the HGP was the effort by both government and private-sector scientists to decode the entire complement of human DNA. The PGP would sequence the DNA of ten individuals, that is, ten persons’ entire collection of 6 billion base pairs,* a task that by 2009 would take any properly equipped and extremely well-funded molecular genetics lab no more than a few weeks and a few hundred thousand dollars.10 But statistically speaking, ten people is not that much different from one person or even zero people, which is to say, it’s not much at all. Most if not all of the insights from those ten genomes would have to be replicated in a much larger sample, an undertaking that would not commence in earnest for a while yet. But in the early days when George Church discussed the PGP with me, he often began sentences with the phrase “When we get to a million.”11 Even though many of us rolled our eyes at that (and even its less ambitious interim successor, “When we get to a hundred thousand”), the premise was fundamentally correct: the real promise of genomics resides in large numbers. Only by studying thousands of people (and corralling a collection of supercharged computers and really smart people) can we begin to detect the subtle and meaningful DNA variants that affect complex and common traits like heart disease, arthritis, and diabetes. Those traits have been among us for millennia, but the technology capable of identifying their molecular underpinnings did not reach fruition until twenty-odd years ago. (Whether what we find will be at all helpful is another question entirely.)
Church, the PGP’s Grand Pooh-Bah, is a tall man in his early fifties often hunched over the tiny netbook he carries with him everywhere. With his thick beard and backswept hair he reminds one of a healthier, pre-Appomattox Robert E. Lee crossed with a younger incarnation of the Band’s keyboardist Garth Hu
dson, and perhaps a touch of Gandalf: a gnostic, gentle giant. He smiles and laughs easily. He is at peace with what he admits to be an idiosyncratic view of the world. When students and postdocs ask if they should share some juicy piece of data with other labs, his answer is almost invariably yes. His voice is a mellifluous baritone with a trace of twang; he has the air of a southern gentleman who’s amused and beguiled by most of what he sees. His bright green eyes do not betray madness exactly, but the mischievous twinkle is undeniable.
According to his official online PGP profile, he’s six feet four, 245 pounds. He takes statins (hyperlipidemia; his personal Web page cites a heart attack in 1994). He is narcoleptic. He has had squamous cell carcinoma. He takes vitamins.12
Every morning George walks the 0.8 miles from his house in Brookline to his office and lab in the unimaginatively named New Research Building in the Longwood Medical Area, a sleek glass edifice that could work as a setting for a science fiction movie. It is clean and new. Security is tight: two guards sit at the entrance. They greet visitors and monitor the goings-on via sixteen digital cameras. The restrooms are “smart”: enter and the lights turn on. Upstairs they are identified by the male and female karyotypes: XY and XX chromosomes, respectively. George’s office is spacious but not ostentatious. It’s moderately bright: surrounded by glass on two sides, but nestled among tall buildings and parking garages. Children’s Hospital is visible at the end of the access street two blocks away. Immediately below the window is a small green space that was recently invaded by a phalanx of geese (“More geese poop!” said George13). A welder’s sparks tumbled from above—yet another parking garage was going up next door.
The culture of the Church lab is reminiscent of the best labs I worked in. It is characterized by an utter lack of pretentiousness. People wear jeans, T-shirts, and sandals or flip-flops along with their lab coats, goggles, and latex gloves. Elaborate drawings of molecular biology experiments appear on wipe boards next to cartoons of superheroes and deep-sea divers, and cutouts of rock stars. There is conversation, but mostly it is quiet. Everyone has his or her experiments to do. The British-born geneticist and Nobel laureate Oliver Smithies,14 famous for discovering a bunch of things, including how to knock out single genes in mice in order to see what traits those genes control, continued—and for all I know, continues—to go to his lab at the University of North Carolina every day well into his eighties. When I asked him why, he likened the lab to a monastery and told me that good scientists more or less take a vow of poverty in order to do science: they must renounce most of the rest of their lives.15 My sense is that George would never regard it as a solemn vow. Science is fun, so why not do it?
When George was born, his biological father, Henry Stewart McDonald III, was working as a clown. At various times he was a race car driver, actor, model, auto mechanic, aircraft pilot, movie producer, writer, TV commentator, and champion water-skier.16 After a public address announcer introduced him as “Barefoot McDonald” because of his disdain for wearing shoes, the name stuck. The resistance to footwear, however, was not an act: A 1971 Sports Illustrated profile described his infamous ejection from a Las Vegas casino under protest. “Whaddaya mean, bare feet? You’ve got broads in here wearing dresses without any backs. Some of the dresses don’t even have any fronts.”17 In 1992, at the age of sixty-seven, McDonald was inducted into the Water Ski Hall of Fame.18 Indeed, there is an adorable picture of seven-month-old George sitting on a tiny chair that has been fastened to a tabletop and is being pulled through the water by his father. “My mother was beside herself with terror,” George recalled. “My father was convinced I was enjoying it.”19
When George was two, McDonald left his mother, Virginia Anne Strong, who went on to marry twice more. George’s wife Ting Wu attributed much of her husband’s success to his mother’s influence. “An amazing woman,” she said of Strong. “She was brilliant—a lawyer, a psychologist, and an artist. And like George she was extremely flexible and optimistic. I don’t think I ever heard her say a negative thing. I think George grew up knowing he could weather anything.”20
George lived in Tampa and Clearwater, Florida, until he was a teenager. His second stepfather, a doctor and Phillips Academy Andover alum, suggested George might like the prestigious boarding school. George excelled at Andover, both in academics and on the varsity track and wrestling teams. He applied to and was accepted at Harvard and Duke, went to Duke, and finished an undergraduate degree in zoology and chemistry in two years. He received a predoctoral fellowship from the National Science Foundation and dove into graduate work in microbiology.
Within a year he had flunked out.
To hear George tell it, microbiology was the wrong home for someone with a passion for biochemistry. And when he switched to biochemistry, he found that his new department was not terribly interested in him, either: the orphan narrative, it seemed, had followed him to the academy. And then there was the course work. George often read his assigned textbooks cover to cover by the first or second week of class. After that, there wasn’t much point in showing up; after all, he could be using that time to do actual hands-on research rather than simply read abstract accounts of what had already been done. He refused to take “baby science courses” just to fulfill curricular requirements. Recalling this, he gave a sheepish laugh and shrugged. “I guess I should’ve told them I wasn’t going to attend classes.”21
His academic problems did not prevent him from beginning to get his name on papers, including a first-author publication in Proceedings of the National Academy of Sciences at the age of twenty-two.22 After Duke wished him luck elsewhere, he reapplied to Harvard, stated in his application he wanted to work with renowned molecular biologist Walter Gilbert on a new approach to decoding DNA, and was accepted. In an interview, Gilbert maintained that Harvard’s admissions policy at the time did not consider incoming students’ preferences for faculty, let alone require them. He was willing to believe, however, that George flunked out of Duke. “He always marched to his own drum.”23 George began his doctoral studies at Harvard in the fall of 1977, just a few months after Gilbert and graduate student Allan Maxam published a paper on how to sequence DNA,24 for which Gilbert would go on to share in the 1980 Nobel Prize.25
It was at Harvard that George met his future wife and Harvard colleague Ting Wu, also then a graduate student in genetics. The two were in a class together on the structure of chromatin, the essential but still somewhat mysterious molecular scaffolding found in chromosomes, an irony not lost on her. “Chromatin is one of the aspects of inheritance not entirely coded for by DNA.”26
Her first impressions? “I remember noticing that this guy knew everything. Someone mentioned that an interesting article had just come out but couldn’t remember what journal or who the authors were. George always knew: ‘It’s in PNAS, volume such and such, page so and so.’ But when he said those things it would never come off in a know-it-all kind of way. He was just a nice guy. And even when I first I met him he was fascinated by sequencing.”27
“When I got to Wally’s lab in ‘77 I was already thinking about it,” George said. “It just wasn’t rational thought.”28
The first quasi-complete sequence assembled by the public Human Genome Project (HGP) in 2003* was actually a composite of several anonymous people who were recruited via ads in the Buffalo News in 1997.29 One sample known as “RP11” appears to have been overrepresented (George told me that reporters have since gone to Buffalo to try to learn the identity of RP1130). In parallel to the publicly funded HGP, Craig Venter used his own DNA as part of a private sequencing effort led by the company he once ran, Celera,31 and subsequently by his own research institute. Venter’s entire sequence was published in 200732 and represented the first complete human reference genome from a single individual.* In any case, depending upon when one marks the start date, obtaining that first composite sequence took something like thirteen years and $3 billion in public funds plus the hundreds of millions spent by Celer
a and its stockholders.
Until 2006 or so, few gave the idea of personal genomics much consideration, rational or otherwise. Yes, sequencing had already gotten much cheaper by the early 2000s, but until about 2005 a human genome was still going to cost you tens of millions of dollars.
Since his arrival in Harvard Yard in the late 1970s, Church has spent his time there (and at various companies he’s helped found) looking for ways to make sequencing cheaper and easier. In 2003, Genome Technology magazine suggested he would make “a good candidate for a lifetime achievement award in genome sequencing.”33 He and later his small army of students and postdocs found clever chemical shortcuts and cost-savers. Over the last few years, much of his lab’s attention has been on polymerase colonies, or “polonies,” a method that uses enzymes to amplify billions of short DNA fragments and stitch those together into a form that can be sequenced.34 Polony technology has since been licensed to several companies. As we’ll see, Church has teamed up with an engineering firm to make and sell a polony sequencer (“the Polonator”) for significantly less than other companies in the sequencing business.35 Among DNA sequencers, it was and is a thing of beauty: even the beta testers who couldn’t get it to work admired its aesthetic qualities. The Polonator has a robotic arm inside humming along and dispensing chemicals, and a platform that holds the slide upon which sits the DNA. An expensive camera takes pictures of the samples. The whole apparatus sits inside a slightly Daliesque warped blue cube about the size of a small clothes dryer.
For the last few years sequencing costs have been in free fall, thanks in no small part to George’s work. In 2007 he told me he expected that soon his lab would be able to use the Polonator to sequence the entire human exome, that is, the protein-coding 1 percent of the human genome, for as little as a thousand dollars. In reality this was still more than two years away, but I came to learn that this type of error is a chronic occupational hazard for an incurable optimist such as George.
Here Is a Human Being Page 2