The Superhero Genes One scientist is on a quest to find the genetic mutations that make athletes elite — which may lead to new treatments for the rest of us.

At 14, Caitlin Gregg had never run a real race. But here she was, pink socks pulled over black-and-red spandex, a white bib displaying her official number, 69, about to run not just any race, but an uphill-downhill test of endurance in Vermont’s Mad River Glen, an outcropping of the Green Mountains. A vertical climb of more than 2,000 feet loomed ahead — no trails, no markings — followed by a descent, for a total of more than three miles. Gregg was in middle school. She had never shied away from a new sport — she’d once entered a pogo-stick competition at her dad’s urging — but she felt anxious about this particular event.

“I remember thinking it was going to be long and hard,” she told me recently. She hadn’t trained. She’d never competed in any sort of en­dur­ance sport. She was terrified of running out of steam partway through and having to walk. So she ran. Slowly at first, conserving her energy. More quickly as she realized that, while many racers slowed down or walked uphill, she could pass them and not feel tired. “I remember thinking, This is pretty awesome,” she said. “I could push a lot harder than the people around me.” She ended up outperforming far more seasoned and older runners. In fact, she came in ahead of even the 20- and 30-somethings in the race. Today, Gregg, a compact, Nordic-looking 35-year-old, is a four-time NCAA All-American in running, an Olympian, and a 2015 world-championship bronze medalist in cross-country skiing. It turns out she has something the vast majority of us, even those who are athletically able, do not: a biological advantage that has allowed her to become one of the world’s most elite athletes.

It starts with a single gene, out of some 20 to 25,000, coding for the more than 30 trillion cells in a human body. Take the length of the DNA in those cells, unravel it, and you have a distance of more than 400 lengths from the sun to the Earth. The human genome has 6 billion data points of information. Six billion ways for something to go incredibly right — or incredibly wrong. Sorting through these possibilities is the job of Stanford University scientist Euan Ashley. The 45-year-old Scotsman is a cardiologist, a systems biologist, and one of the leaders of a new, integrated approach to the science of genetics. He led the first team to clinically interpret a full human genome; he’s involved in attempts to sequence cancer genomes for personalized treatment and to analyze the genomes of individuals who have rare and unknown diseases. But for the last several years, his work has focused on a specific mystery. He is looking for superhero genes: the minute variants in the genome that help make people like Caitlin Gregg who they are. Ashley is tall and wiry, with dimpled cheeks, dark hair, and an ebullient manner. At times, he seems like a jack-in-the-box whose springs are about to snap into action. When we met at his Stanford lab, a pristine circle of glass with offices arranged around it, he was in the midst of vetting athletes for his study, which is known as the ELITE study. “We’re interested in truly the fittest people on the planet,” he explained. Though there are many factors that may make someone elite, his team made the decision to select athletes on the basis of a single, objective physiological variable: the maximum amount of oxygen a body can use, or VO 2 max. VO 2 max is considered one of the most important markers not only for athletic success, but for overall health: It’s such a crucial indicator of cardiovascular function that it is used to determine whether someone requires a heart transplant. VO 2 max has also been measured in the same way for half a century, which means it can be a useful comparative point. “We can go back historically and look at people who were world class and analyze their DNA now,” Ashley said. To be a part of the study, men need to test at a VO 2 max that exceeds 75 milliliters of oxygen per minute; for women, the cutoff is 63. Fewer than .00172 percent of the population qualify. In the lab, I watched as Kyle Peter, who is widely considered among the best ultra-endurance adventure racers in the U.S., prepared to test his VO 2 max. Peter, who has won two adventure-racing world cups in the past year with only a few weeks’ break in between, is a three-time national champion and currently heads the third-highest-ranked ultra-endurance team in the world. He can race two days without sleep and has been known to machete for 20 hours through Brazilian wetland to complete a course. Peter, a stocky, self-effacing, bearded 31-year-old, was dressed in runn­ing shorts and a very loose T-shirt: He explained that during his most re­cent race in Belize, he had acquired a jungle rash that reacts whenever his body heats up, as it would on the treadmill that day. The pacing of the test was calibrated to Peter’s last 10K running time of 37:30 minutes. The test would last between six and ten minutes. The goal is for the athlete to go until he feels he cannot possibly go any farther, speeding up until the pace is unsustainable. Peter started at a jog. Soon, as he sped up, his face changed from relaxed to determined to altogether grim. When he finally grabbed the handlebars and collapsed on a chair, he was unable to speak for several minutes. His VO 2 max for the test: 60.6. Not close to qualification. To put the cutoff in perspective, the 11-time Olympic medalist and multiple-record-holding swimmer Ryan Lochte reportedly comes in at 70 milliliters per minute, meaning he is out of contention. “We’re starting at the top,” Ashley said. “Getting the most elite first.” To optimize the chance of finding true genetic markers of performance outliers, you need to set incredibly high limits.

Ashley grew up in a small town in Scotland, where his father was a general practitioner and his mother a midwife. They lived on the border between the affluent and the poor parts of town. His father worked primarily with the former; his mother covered the latter. It was “a real education,” Ashley said. At 13, before he knew that humans had a code of their own, he wrote a computer program that could calculate the taxes of his father’s medical practice. “You have to understand that miniaturization came from computing to biology,” Ashley told me, “from chips to genome studies.” Next he turned to a game of horse racing: On his ZX Spectrum, he programmed horses to respond to presses of two rubber keys. Later, he’d discover that his little experiment in the speed with which you can alternate key presses was a perfect measure for sprinting ability. He eventually turned his attention to cardiology, hoping to understand heart failure; Scotland has one of the highest rates of cardiovascular disease in the world, and he took it as a personal affront. His first step toward the ELITE project came in the Scottish Highl­ands in the summer of 2001, in something called the Adrenaline Rush Adventure Race — a 300-mile ultra-endurance event where participants bike, climb, row, and swim nonstop for several days. Ashley was interested in seeing what such extreme conditions would do to healthy hearts. Athletes had blood drawn and underwent echocardiograms and other testing to show how fatigue and extreme exertion affected their cardiac function. “The winning team for this event won in 84 hours and slept a total of two hours each night,” Ashley said. “Sleep deprivation becomes almost a bigger challenge than the actual racing. They start literally hallucinating. They talk about giant bunnies and dinosaurs.” Ashley was expecting dramatic results, showing severe physiological strain, “because people push themselves so far in these conditions.” But in some of the athletes, he found nothing. “It went from supernormal to just above normal. The change was quite small.” It’s not that the heart didn’t get tired; it’s that it recovered phenomenally quickly after exhaustion. The results were astounding, and so Ashley ran some genetic tests. He looked at a gene related to cardiac function — the angiotensin-converting enzyme, or ACE , which is involved in increasing blood pressure. What he found was that a tiny polymorphism in the gene could predict the extent to which heart function would decline — or remain stable. In that finding, something seemed to click: ACE had previously been linked to an increased rate of heart attacks. Could the same gene, in different manifestations, cause disease and lead to superior performance? The question itself wasn’t new, but the lens of extreme athletes was, and there were other examples that bolstered Ashley’s idea. Consider Eero Mäntyranta. The champion Finnish skier won seven medals over four Olympic games — three gold, two silver, two bronze. At the time, it was an unparalleled feat. So unparalleled, in fact, that he was accused of blood doping. Testing seemed to provide confirmation: The percentage of his blood made up of red blood cells, which carry oxygen to the muscles, was multiple deviations away from the average range. It would soon turn out, however, that the accusations were false. The skier was clean. He simply had a mutation in a receptor that controls how many red blood cells are produced and allowed to remain in the blood. In Mäntyranta’s case, a tiny change had hugely shifted the balance. The same mutation was eventually found in his extended family. “It was as if he had an accelerator down on his red-blood-cell-manufacturing plant permanently,” Ashley said. “He was a genetic superhero.” Mäntyranta’s mutation, however, can also cause polycythemia, a red blood cell disease. (Mäntyranta actually had polycythemia, though it didn’t manifest with negative symptoms.) Understanding the performance-­enhancing change, Ashley thought, could lead to treatments for people with cardiovascular problems. “You can short-circuit normal drug discovery,” Ashley said, “by creating a drug that mimics that.” It’s a transition in thinking that has begun to crop up in other treatments. Sharlayne Tracy, an aerobics instructor in Texas, became medically famous for her impossibly low levels of cholesterol, ones that exercise and diet could not explain. Healthy levels of cholesterol are usually less than 100. Below 50 is considered exceptional. Tracy’s was 14. When Tracy’s genome was sequenced, geneticists found a mutation in a gene that is a sort of cholesterol trash collector: It tells the body when to remove excess cholesterol from the blood and when to go home for the night and let the trash pile up. Tracy’s mutation, Ashley explained, was the equivalent of giving a sedation shot to the head of the trash-collection agency. He’s knocked out cold, so he never tells his team to go home. They stay out all day collecting that trash — and cholesterol levels remain abnormally low. The finding has led to two new drugs for treating high cholesterol. “We learn a lot of things by looking at extremes,” Ashley told me. “The fittest and the most failing in the world — the power of the genome speaks to more than one system.” This is the logic that governs his work: He’s on a quest to use the healthiest people in the world to help the least healthy, and, perhaps, those of us who fall somewhere in between.

Ashley’s ELITE lab team is an eclectic mix of people, including a scientist who also happens to be a champion ultra-endurance athlete and another who is an Olympic gold medalist. Over the past months, they’ve assembled a 650-person (and growing) cohort of superathletes. They’ve also secured a trove of data from Claude Bouchard, a geneticist who, many years ago, gathered athlete DNA from all over Europe, and another trove from Japan, provided by colleagues of Izumi Tabata of the famed Tabata Protocol, an interval-training technique that has given rise to many of CrossFit’s methods. (During my stay, Tabata himself was visiting Ashley from Kyoto, eager to see what the study might yield.) Overall, 19 centers in 11 countries have collaborated to create the largest gathering of elite athlete DNA in the world. The data analysis will take many years — there are too many possibilities to sift through them all — but the ELITE team has already isolated some 9,200 genetic variants that may explain preternatural athletic ability. “Our first focus is on the heart,” Ashley said, “but then we’re searching for variants across the whole genome.” One early contender, flagged just before my visit, is a gene known as DUOX . A mutation in the gene essentially confers what many nutrition gurus tout as the health benefits of antioxidants, mitigating the damaging effects of our usual cellular metabolism. In the past, DUOX mutations have been identified in a very specific population: People who’ve managed to adapt to living at extremely high altitudes — in the Andes, in particular — show the mutation, suggesting a possible link to increased pulmonary function. Could DUOX -targeting therapies help in hypoxia? Could they help with tissue repair, since the amount of oxygen in wounds is a crucial factor for speed of recovery? Then there’s NADK , a gene involved in fatty acid synthesis. If you have lowered NADK , your body could be better at using fat as fuel, making you more powerful over time. So far, two athletes in the sample have the mutation, a high hit rate given its rarity. Could this be a weight-regulating therapy in the making? Another intriguing variant found in several athletes is RUNX3 — though, as with all of these mutations, the data are quite preliminary and any conclusions likewise so. Originally, the gene came to light in cancer research. Normally, it suppresses tumors, but in mutated form the suppression function is lost and increased cellular growth ensues. If you’re an athlete, cellular growth can be good: The better your muscles and heart grow, the more quickly you respond to training. The mutation, however, can also lead to tumors. There’s a finely calibrated and fungible line between overperforming and underperforming, between what makes us healthier and what puts us at risk. It’s tempting to see Ashley’s work and imagine a Gattaca-like future in which the revelations of the genome help not just the diseased, but those of us who are average — a time when this information could take all of us from normal to elite. That has worrying implications: not only the fears that accompany any genetic interference, but a further fear, of health ramifications. As the RUNX3 variant suggests, playing with these genes is a hazard the healthy probably won’t want to risk, since tweaking the genome could take us from benefit to harm in an instant. Even maximizing our abilities could give us more than we bargained for. You would think that the fittest people on Earth would also be the healthiest; you would be wrong. If you compare Olympic athletes with the average human, you would indeed find that they live longer and are healthier. But when compared with people who are generally fit, who exercise at levels that are more recreational and don’t push their bodies to extremes, research has found that Olympians die at a younger age. Being elite is an honor, but it may be a complicated one.