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Secrets of my DNA: Behind Raymond McCauley's cut-rate gene sequencing

16 Feb 2011













Consumer genomics expanded at prodigious speed after the announcement from the Human Genome Sequencing Center in Houston, Texas, in May 2007 that DNA pioneer James Watson had become the first person to have his entire genome sequenced. The first direct-to-consumer genome tests appeared on the market a few months later, and after that a steady trickle of individuals' genomic information began appearing online. Initially it was curated by a handful of geneticists -- including George Church of Harvard Medical School, whose Personal Genome Project has so far made publicly available the complete genomes of 12 men and women, and Hugh Rienhoff, a doctor and biotech entrepreneur who in October 2007 founded as part of his attempts to discover more about the illness afflicting his daughter Beatrice. But by June 2010, an estimated 100,000 people had sent spit samples and cheek swabs to companies including 23andMe, Navigenics, Pathway Genomics and Decodeme for mail-order DNA analysis.

Although these tests offer only a selective analysis of the most useful chunks of DNA, a few dozen wealthy individuals have also gone directly to labs such as Knome or Illumina and paid to have sequenced their entire genomes -- all six billion letters of genetic code, each representing a single nucleotide base, either an A (adenine), C (cytosine), T (thymine) or G (guanine). Among the tech elite and early adopters of Silicon Valley, having your DNA sequenced has become as socially valued as being early to the iPad or driving a Tesla. And, of course, the more of the genome you've had decoded, the more impressive it is: "It's, 'Have you had 23andMe done? Just a fraction of a per cent?'" Raymond McCauley explains one evening in San Francisco. "'Have you had the whole thing done?'

That's swank."

But as the sophistication of sequencing increases and its price plummets, the process is becoming democratised. The decoding of Watson's DNA in 2007 took four months and reportedly cost the lab $1 million; to have the same thing done now would take less than a week, for a retail price as low as $20,000. Speed and price continue to fall, outstripping even the pace of advances in printed circuits. "It beats Moore's Law with a stick," says McCauley, who believes that the $100 genome is only three years away. "It's going to be so cheap that it will be a choice between, 'Do I want to buy a pizza tonight or should I go ahead and get my genome sequenced?'"

The reach and impact of personal genomics could revolutionise the way that we approach healthcare; almost anyone will be able to learn the contents of their thousands of lines of DNA code, without even making an appointment with a doctor. Yet the decoding alone is of little use without the means or knowledge to interpret it. "At that point you're going to have all the data but no information,"

McCauley says. "That's what got me started. How do I make all of those As, Cs, Gs and Ts useful? I know that I've got a C and a T here, but what does that matter? And what difference is that going to make to me in my life?"

The answers may come from a small group of individuals such as McCauley who, armed with their own genomic data, have become citizen scientists -- amateur biologists who are part of a wider trend towards what Melanie Swan, a Silicon Valley futurist who recently founded DIYgenomics, an online start-up dedicated to crowdsourced clinical trials and personal-genome apps, calls "health hacking".

Health hackers, Swan says, are using online resources such as PubMed -- the US Library of Medicine's colossal database of biomedical literature - to help conduct experiments upon their own bodies with the same ease that anyone with access to the internet can now trade stocks and shares. "Twenty years ago, you had to have a stockbroker. Now there's enough information and tools available on the internet, you can dig into it yourself and experiment. The same is true for health," says Swan.

Increasingly, health hackers with access to their own DNA analysis are intervening more directly in their healthcare. Rather than having to rely on general information from books and clinical studies designed to draw median conclusions about the population in general, Swan and McCauley want to customise their own drug and diet regimens. They hope to devise preventative treatments for themselves based on their personal genetic predispositions towards everything from disease to drug response. "It's enabling people to know not just what's in their genome, but to figure out what that means -- instead of waiting for some scientist to do a study that may relate to them," says McCauley.

Early last year, Swan and McCauley began contributing to the development of Genomera, a website founded by Silicon Valley entrepreneur Greg Biggers to enable health hackers to share their genetic and experimental data. Biggers had visited Hugh Reinhoff's attic laboratory but was appalled at how antiquated and laborious the analysis of DNA data remained. He recognised an opportunity: no longer were huge quantities of complex data restricted to scientists in the new era of consumer genomics. So consumers would pay for a service that helped them. "User experience is going to be huge in a way that wasn't necessary for the phase of biology in which it lived in laboratories," he says. As a result, Genomera has been designed with a simple interface and community features that Biggers hopes will soon turn healthcare into a social activity. "It's Facebook for genomes," Melanie Swan explains over coffee one afternoon in a café in Palo Alto.

And when mass sharing of DNA data does arrive, citizen geneticists will play a key role. "I think of all the things that citizen scientists can do -- astronomy, weather, geology, fossil-hunting -- this is probably the one with the biggest impact on peoples' lives," says George Church. "If you find another tyrannosaurus, that's kind of cool -- though it's not a life-or-death matter. But if you find some family that has somehow escaped the ravages of Huntington's, even though they have the Huntington's allele, that would be a really big impact. If you found a family that avoided diabetes, despite having all the risk factors, that would be even bigger. It's something that scientists can't just do sitting in a laboratory. This is one of the few things where scientists really need citizen-science."

At 6ft 2in and 113kg, Raymond McCauley is a big man. But he used to be much bigger, he tells wired one October afternoon in the small, cluttered upstairs room he uses as an office in his house in Mountain View, California. "I was a 300lb [136kg] guy," he says. "Really big." At the end of 2008, McCauley began making drastic changes to his diet, switching from burritos and hamburgers to fresh fruit and yoghurt, slashing the number of calories he consumed by two-thirds. In the first two weeks he lost 4kg through water loss alone; by March 2009 he had dropped four clothes sizes and lost tens of kilos.

The dramatic change in McCauley's weight is the most visible result of the citizen-science project he has been pursuing since the arrival of his 23andMe data at the end of 2007. Weight loss was not exactly a scientific leap in the dark: on his father's side, the family had endured a long history of heart trouble, and for years McCauley's doctor had been telling him to eat less and exercise more. But he had simply ignored the advice. "I was like, yeah, yeah, yeah, OK," he says. But when McCauley saw the elevated risks of a trial fibrillation and diabetes in his DNA profile, "I decided that the most actionable, important thing I could do was to lose weight -- if I wanted to live longer."

He procrastinated about actually embarking on a diet ("I delayed it as long as I could," he admits). He connected a digital scale to his home computer and began poring over research journals that told him essentially what he already knew. ("Most of it basically came down to: eat less, exercise more".) Yet McCauley remained preoccupied with the one outstanding risk he had found in his genetic data: his high chance of developing the creeping blindness of age-related macular degeneration.

His first stop to find out more about AMD was the Mayo Clinic website -- "They've got articles on everything from removing a splinter to the different forms of brain surgery," he says. There, he had found advice about avoiding smoking and UV light. He discovered a self-diagnostic tool, the Amsler Grid -- a pattern of bold lines and a dot that a patient is required to print out on a piece of paper and then stare at. If you notice that the lines begin to distort and warp after a few seconds, then you've probably got AMD.

Seeking more information -- "doing the scientist thing" -- in mid-2008 he took a trip to Stanford University to visit a research ophthalmologist conducting clinical trials on AMD. McCauley wanted to hear news from the cutting edge of work on the disease and its links to genetics, and to put himself forward as a subject for long-term study. But he was told that although researchers were very interested in the genetic markers of the disease, nobody at Stanford had considered conducting genomic testing for AMD.

McCauley was certainly the only person who had ever arrived bearing their own DNA information. His offer to become a subject for study was politely declined. "It was, 'Gosh -- thank you. It's really interesting that you're proactive about this, but we don't really do that.'"

Back at home, McCauley considered taking vitamins as a preventative. He discovered a clinical study which suggested that the chances of contracting the disease were significantly reduced in patients who had taken a special mix of supplements, including B12, zinc and lutein. The results of the trials seemed conclusive.

Even McCauley's doctor -- "One of these guys who says, 'Vitamins?

Vitamins are really good for giving you expensive urine,'" he explains -- saw its value and advised him to begin taking the supplements.

Yet McCauley also remembered reading research into diabetes treatments, which suggested that large doses of vitamin B9 are important. The study mentioned that some patients with a specific genetic defect could not absorb the most widely available form of vitamin B9. To overcome this, diabetics were prescribed an active form of the vitamin, L-methylfolate. McCauley began to wonder if the same defect might affect him, and what the basis might be for the usefulness of taking L-methylfolate: "Is it snake oil or is it really helping people? How do you test it? How do you test if this is really working?"

He searched for information about the genetic defect, and for something that would tell him about his own potential response to vitamins, any study from which he could personalise his treatment, based on what he knew from his own DNA make-up. By crossreferencing what he found on PubMed with what he had been told by other subscribers to the 23andMe message boards, he was eventually led to a single gene, methylenetetrahydrofolate reductase (NAD(P)H), the status of which directly affects the body's ability to metabolise vitamins B9 and B12. The gene provides the body with instructions to manufacture an enzyme crucial to the chemical reaction by which one specific amino acid is processed into another. Its official name is usually abbreviated to MTHFR. Noting the opportune sequence of consonants in the initials, McCauley and a friend began referring to it as "Samuel L Jackson's favourite" -- or, often, in a less oblique and more coarse way. And so, when they eventually found their focus, Raymond McCauley's citizenscience experiments would close in on the ten variants of what he had come to know as "the motherfucker gene".










'aha!' moment for me."









Genetic research was, in McCauley and Swan's first home-brew clinical trial, being conducted to answer a question that had become increasingly important to McCauley in the months since he first saw his 23andMe results: was there any link between individual genotype and vitamin metabolism? Specifically, could they prove a connection between variants in the MTHFR gene and the ability to metabolise B vitamins, one that might affect McCauley's efforts to head off AMD? They decided to find out with a series of simple experiments using the two forms of the vitamin, followed by blood tests. In the tradition of scientific pioneers of the past, they selected themselves as initial test subjects. They needed more -- and discussed conducting the trial through a university lab where Swan had connections and could canvass a sample of student volunteers. But they quickly realised that wasn't the point: they didn't just want to conduct a single experiment that answered questions about B vitamins, they wanted to build a model trial that could be easily replicated by citizen scientists anywhere, with the minimum of effort. If the vitamin study were a success, they could post their findings online and invite anyone who was interested to help them repeat it on a larger scale, or to investigate any number of genetic questions about ageing, athletic performance, skincare products -- anything at all.

The experiment required five test subjects. In addition to themselves, McCauley and Swan solicited help from friends and acquaintances who had taken the 23andMe test. They signed up Chris Hogg, director of commercial strategy at a California biotech company, and Aaron Vollrath, a doctoral biology student living in the Bay Area. The fifth slot went to McCauley's partner, Kristina Hathaway. The experiment took place in three stages, starting with a two-week period during which the group took no vitamins at all.

This was followed by a fortnight during which they all took Centrum multivitamins, then another fortnight taking the active form of vitamin B9, L-methylfolate. During the third period they took both supplements at once, followed by the "washout phase" when they took nothing. As each phase ended, they took a blood test to monitor each individual's level of homocysteine, the undesirable amino acid that is converted into a more benign substance if the body is efficiently absorbing B vitamins.

This proved the most potentially expensive part of the experiment: in California, drawing blood may be done only by a licensed technician, at a cost of around $100 for each test. So when, in April last year, Swan discovered a local lab running a three-day, two-for-one offer on blood tests, they decided to start the trials immediately. By the beginning of June, they had all uploaded their results, Wikipedia-style, to Swan's website.

Relying on such a small sample, the findings of the experiment were hardly definitive. But they did confirm McCauley's suspicions about his genotype, which -- "homozygous at both SNPs that coded for MTHFR", according to a recent report in the journal Nature Medicine -- proved to be unique among the five people tested. The four other participants in the study responded well to taking both forms of B-vitamin supplement (Centrum and L-methylfolate), which reduced their levels of homocysteine by almost a third. But during the Centrum phase of the trial, the amount of the hormone in McCauley's blood actually rose; only when he began taking L-methylfolate did it fall. This suggested that if he wanted to have any benefit from taking B vitamins he would have to take the active form of it after all. For everyone else, the study demonstrated that taking vitamins certainly had at least one positive, quantifiable effect.

Most importantly, the MTHFR study was a perfect proof-of-concept trial for other citizen scientists interested in contributing to the experiment, or to guide them in devising their own. For the price of a handful of vitamins and some budget blood analysis, anyone could repeat the MTHFR test for themselves and add their results to the wiki at With each contribution, the overall study would become statistically more significant.

When Swan and McCauley mentioned to Greg Biggers, whom they both knew from conferences and Silicon Valley health-hacking meetings, that they wanted to build a new interface to cope with the volume of data necessary to scale up these contributions into a clinically valid study, he told them not to bother. They could use the one he was already building. The result, Genomera, is still in beta testing, but promises to provide a place where individuals can upload their decoded genomic information to share and compare with other users, and gain easy access to medical databases where they can find information related to their DNA profiles. 23andMe has already shown the scientific benefits of consumers sharing their DNA data, with an analysis of its customers' information that revealed previously undiscovered connections between genetic variations and traits such as freckles. But Biggers plans to enable users to create and upload their own research data and provide fields for simple comparison, creating a truly interactive global platform for citizen science.

The second phase of the MTHFR study will be the first such open-participation experiment available on Genomera: anyone with their genomic data can participate for what Melanie Swan estimates will be around $500 each. McCauley has been surprised by the response. "I thought this was a narrow, geeky project," he says, adding that he's now heard from people who are planning to have a gene scan just so they can participate. The next stage Swan has planned is a long-term ageing study, which she hopes will involve 10,000 people.

Beyond that, McCauley sees citizen-science genetic experiments expanding as far as broadband will take them. At the discussion group in San Francisco where I first meet him, he's asked to introduce himself to the room in three words. "Genomics for grandmas," he replies.

Back in his office, McCauley says he understands that the small scale and modest aspirations of his investigation of the motherfucker gene make it easy to dismiss. "In some ways, what we're doing with this little experiment is not a big deal. It's high-school science. Instead of building a volcano or measuring the temperature in the garden, we've got genomic information and some blood-test info."

But he says that the power of citizen genomics lies, by definition, in how personal its appeal is. Someone need be motivated only by self-interest -- "Does Centrum work for me?" -- to contribute their valuable genetic data to a study that might have consequences for everyone, and could otherwise have cost millions. "Scientists are not people with degrees," he says. "Scientists are people who have questions and they're trying to find answers. I guess my big thing here, beyond asking if vitamins work, is that if you want a democratic, technological society you have to have people who understand how science really works. To me, that's what this is. If somebody does this and doesn't get a good result, or they look at it and never participate but read up about it a little, they've asked a question. They understand, viscerally, how the scientific method works and how people really apply it with today's technology. I think that's a big deal. If we don't do more of it, I think we're doomed."

A few weeks later, McCauley writes to say that he has decided to leave his job at Illumina, to take up a full-time position with Genomera. "Helping people understand what's going on in their bodies, in their lives," he says in an email. "That's a good life's work."

Meanwhile, McCauley's home science has ensured that he's taken steps to offset his increased risks of developing AMD. He wears spectacles that reduce his exposure to ultraviolet light. And every afternoon he takes 1,000mcg of L-methylfolate and other vitamins.

The chances are he'll be fine, and it remains possible that the vast areas of the genome about which we still know nothing might contain a variation that counteracts the one linked to AMD. "It's a crap shoot," he says. "Most of it's unknown." But in case none of his preventative measures works, he's taking out one more piece of insurance. On his computer, he has a checklist of places he wasn't expecting to visit until after he'd retired, but now wants to make sure he sees while he can still fully appreciate them. "The Grand Canyon, from the river, or Mount Fuji... I don't want to look at it out of the corner of my eye. I'm gonna go ahead and do some [of that] stuff now."

Adam Higginbotham is a writer based in New York. He wrote about wireless electricity in 11.10