The Sports Gene: Inside the Science of Extraordinary Athletic Performance

by David Epstein

  •

  Just across the Charles River from Boston’s Fenway Park is another structure of brick and steel. But rather than flags commemorating World Series wins, snaking down three stories of the exterior of this building are two winding metal ribbons, an artistic depiction of the DNA double helix.

  Inside the building—the Harvard-affiliated Partners HealthCare Center for Personalized Genetic Medicine—geneticist Heidi Rehm directs the Laboratory for Molecular Medicine. Rehm and her lab staff identify new HCM mutations by the week. In the early 1990s, it was thought that HCM came from any one of seven different mutations on a single gene, the MYH7 gene, which codes for a protein found in heart muscle. By the time I visited Rehm’s lab in 2012, there was a database that included 18 different genes and 1,452 different mutations (and counting), any one of which can cause HCM. Most of the mutations are in genes that code for proteins found in heart muscle, and around 70 percent of people with HCM have a mutation on just one of two specific genes. (To make matters extremely complicated, though, two thirds of the different HCM mutations are “private mutations.” That is, each one has only been identified in a single family.) The most common cause of HCM is a DNA spelling error known as a “missense” mutation. A missense mutation occurs when a single letter is swapped in the DNA code, but in such an important place that it changes the amino acid that goes into making the resulting protein.

  HCM mutations can occur randomly in someone with no family history of the disease, but most HCM gene variants are passed from parents to children. Some, however, don’t make it down family lines. One particularly dangerous HCM gene variant only ever appears as a spontaneous mutation in a single individual in a family. “That’s because it’s reproductive lethal,” Rehm says. “No one ever survives to an age to reproduce and pass it on.”

  Other mutations can be so mild as to go entirely unnoticed over a lifetime, like the “Trp-792 frameshift,” which sounds like it’s out of an NFL playbook, but is actually a mutation found specifically in Mennonite people.

  In most instances, though, it’s difficult to tell whether a particular mutation puts an HCM patient at risk of sudden death. In Kevin’s case, the disease was only diagnosed after he died and his heart was examined. Kevin’s autopsy showed that his heart was a gargantuan 554 grams. An average adult male heart is around 300 grams. Kevin had no obvious signs of disease, other than that he had once been told he had a heart murmur. But so had I, and so have hordes of athletes who have been at the flat end of a stethoscope. As with any muscle, the heart gets stronger with exercise, and athletes often have nondangerous heart murmurs that go away when they’re out of shape.*

  Given her family history, Eileen Kogut had all her children’s hearts checked regularly from the time they were little. Her son Jimmy, who played basketball and lifted weights, had occasionally complained of shortness of breath. He was told he had asthma, a common but dangerous misdiagnosis for someone with HCM, because asthma inhalers can prompt lethal heart rhythms in HCM patients. In 2007, as he was getting set to start junior year at the University of Pittsburgh, Jimmy had a genetic test and learned that he has one of the most common HCM mutations, on a gene that helps to regulate heart contraction. Like his hazel eyes and freckles, he got it from Eileen. With the family mutation identified, Eileen decided to have her other children, Kyle, then eighteen, Connor, then sixteen, and Kathleen, then twelve, tested, even though they weren’t showing symptoms. In March 2008, she took the kids for genetic screening and prayed that she hadn’t passed the mutation to any more of her children.

  But the tidings were bad. Connor and Kathleen both came up positive. “I was devastated,” Eileen says. “I don’t know what I expected. I expected to hear good news. It was not an easy pill to swallow . . . I was angry at the lab. I was not coping well. I just thought, ‘Why did I ever do this? They’re young, what was I thinking? It’s going to ruin their childhood.’”

  Cardiologists who study HCM recommend that people with the disease abstain from extremely rigorous activity, because the increase in adrenaline may spark a deadly heart rhythm. After the diagnosis, Jimmy underwent surgery to have a defibrillator implanted in his chest. About the size of a matchbox, the tiny device has wires that reach into the heart and stand guard, waiting for an abnormal heart rhythm. If one is detected, the defibrillator automatically fires an electrical shock to jolt the heart back to a normal pattern. Jimmy returned to college life as usual, minus the basketball. And weight lifting was restricted to nothing overhead or that could stress his left side so much that it might damage the defibrillator wires.

  Ultimately, Eileen overcame her dismay and is glad she had her children tested, even though it meant certain lifestyle changes. As she had learned in the cruelest way, the only outcome worse than losing one brother is losing two. And the only fate worse than that would be losing two brothers and a child. Says Rehm, “I got totally hooked on this area of genetics because it really is an area where you can make a difference in patients’ lives—to be able to figure out the cause of their HCM, and predict it in other family members. Sometimes you get bad outcomes, sometimes you get good outcomes, but at least you can understand it and predict it.”

  A definitive determination of HCM is particularly important in athletes, because the most conspicuous sign of HCM is an enlarged heart, which is normal for athletes. It often takes a true HCM expert—of which there are precious few in the world—to tell whether the enlargement is the result of the athlete’s training or a sign of HCM. Martin Maron, Barry Maron’s son, a cardiologist at Tufts Medical Center in Boston and an expert on sudden death in athletes, says that the specific enlargement depends on the sport the athlete plays. Cyclists and rowers, for example, have enlargements in the heart chambers and walls from their training, whereas weight lifters have thicker walls but not chambers. Each sport has its signature pattern.

  In a normal heart, the wall that divides the heart chambers is usually thinner than 1.2 centimeters, and the left ventricle chamber is typically smaller than 5.5 centimeters across. If either the wall or chamber is greatly enlarged, it’s a sign of disease. But if there is only some enlargement—a wall between 1.3 and 1.5 centimeters, and a chamber between 5.5 and 7 centimeters—then “that’s a gray zone for athletes,” Maron says. That is, the enlargement could be due either to training or to disease, and some athletes who are in the gray zone are cleared to play sports on the assumption that their large hearts are a training adaptation, only to then drop dead on the field. If, instead, the athlete is genetically tested and revealed to have a known mutation for HCM, no more gray zone.

  This is one area where personalized genetic testing is making an impact on athletes in the present day—although they aren’t always eager to take advantage of it.

  In 2005, center Eddy Curry was leading the Chicago Bulls in scoring when he was sidelined with an irregular heartbeat. Curry missed the end of the season and the entire playoffs while he was being evaluated.

  At the suggestion of Barry Maron, the Bulls—hoping to avoid a situation where Curry might die in front of television cameras, as the NCAA’s reigning scoring and rebounding leader Hank Gathers did during a game in 1990—added a genetic testing clause to the $5 million contract offer that was on the table for Curry. If a test showed that Curry had a known HCM gene variant, the Bulls would not allow Curry to play, but would pay him $400,000 per year for the next fifty years. Curry refused the test, and the Bulls subsequently traded him to the Knicks. “As far as DNA testing, we’re just at the beginning of that universe,” Curry’s attorney, Alan Milstein, told the Associated Press. “Pretty soon, though, we’ll know whether someone is predisposed to cancer, alcoholism, obesity, baldness and who knows what else . . . Hand that information to an employer and imagine the implications.”

  Today, the situation would be different. After thirteen years of haggling over genetic privacy, the U.S. Congress passed into law the Genetic Information Nondiscrim
ination Act of 2008, or GINA. The law took effect in late 2009, and barred employers from demanding genetic information, and both employers and health insurance companies from discriminating based on genetic information. (GINA does not, however, prohibit discrimination by providers of life, disability, and long-term care insurance.)

  Plenty of athletes, even knowing they carry a dangerous mutation, choose to continue playing. In a 2009 moment immortalized on YouTube, Anthony Van Loo, then a twenty-year-old defender on the Belgian soccer team SV Roeselare, crumpled to the pitch like a marionette whose strings had been cut. Van Loo was in cardiac arrest. Seconds later, he jerked violently and then sat up, as if nothing had happened. Van Loo’s implanted defibrillator had fired and literally yanked him back from death’s door. He was lucky, as implantable defibrillators aren’t built to withstand the wear and tear of vigorous sports.

  Whether to let an athlete with HCM participate in sports is a dilemma for doctors, who are frequently left guessing if their particular HCM patient is one of those who is at risk of sudden death, or one of those who will live to ninety with no serious symptoms.

  Certain HCM mutations are known to be more dangerous than others, but it’s an inexact science. “I see some kids, and they don’t have a family history of death and they don’t have symptoms or a very thick heart, and I don’t think a lot of them are at great risk,” says Paul D. Thompson, a cardiologist at Hartford Hospital and a competitor in the 1972 U.S. Olympic marathon trials. “I usually say to them, ‘I don’t think you’re at great risk, but I have to sleep at night, and I can’t take a chance with you, so I’m prohibiting you.’ For some acne-stained seventeen-year-old who’s accepted at that high school because he’s a good linebacker, to tell him that’s gone is a load.”

  It’s better, though, than the linebacker himself being gone. When I went home for my friend Kevin’s funeral, I visited the indoor track where he died. One of the white lines that demarcates a track lane was covered in penned messages: “LUV YA 4 LIFE”; “HOPE TO SEE YOU ON THE OTHER SIDE”; “WHEN THE TIME COME, YOU GOING TO LET US ALL KNOW WHY YOU DIED.” When I visited again, a year later, the messages were there, in the floor with Kevin’s sweat and dreams, but they were invisible beneath a fresh coat of paint.

  •

  Kevin never knew he had a time bomb inside his chest. But what if he had? At his funeral, friends emphasized that he died doing what he loved. Kevin did love to race. But he loved other things too, like computers. Racing might have been his scholarship ticket, but I have no doubt that he would have stopped running and eagerly rechanneled his competitive energy elsewhere. For me, there is scant solace in the poetic detail that he died running.

  While the issue of whether to preemptively restrict an athlete is beset with emotional and legal barbs, cardiologists agree that when an athlete is clearly at risk of dropping dead on the field, the recommendation should be to avoid the field. (Though some athletes ignore the advice and play anyway.) But what if the athlete was just at risk of damage? Sports are inherently risky. Like flying fighter jets, no one participates for too long without an injury. But what if scientists could tell that some athletes are at greater risk than others?

  Right now, they are beginning to be able to do just that, as researchers probe genes associated with some of the most high-profile medical risks in all of sports.

  •

  On a brisk November afternoon in Manhattan, Ron Duguay had just finished several hours of cognitive testing when he settled into a chair overlooking Park Avenue South to await news from Dr. Eric Braverman. Beginning in 1977, Duguay played twelve seasons in the NHL, primarily as a center with the New York Rangers. Duguay was a good player—he made the ’82 All-Star Game—but was better known as hockey’s rock star.

  Duguay didn’t wear a helmet, and the curly brunette locks that fluttered behind him when he skated made him a sex symbol in the 1980s. Even today, in his fifties and married to erstwhile supermodel Kim Alexis, Duguay’s hair is thick and curly, and he is friendly and easy to talk to. In Braverman’s office, though, he’s nervous. He fiddles with his gleaming Rangers pinkie ring when he mentions that friends often tell him he should write a book about his hockey days. “I’d have to call up my teammates,” he says. “There’s a lot I can’t remember.” That’s why Duguay is here. He thinks he suffered undiagnosed concussions during his career, and he knows he took scores of lesser hits to the head from sticks, elbows, and the occasional puck.

  Braverman appears and flatly tells Duguay that he flunked three of the tests meant to gauge his memory and brain processing speed. “He’s a mess compared to his old self,” Braverman says.

  As part of the testing, Braverman also ordered a genetic test to see what versions Duguay has of a gene known as apolipoprotein E, or ApoE. Duguay’s grandmother died from Alzheimer’s disease, and another family member has been having memory problems. Studies of Alzheimer’s patients indicate that a particular version of the ApoE gene substantially increases an individual’s risk of getting the disease.

  The gene comes in three common variants: ApoE2, ApoE3, and ApoE4. Everyone has two copies of the ApoE gene, one from Mom and one from Dad, and a single ApoE4 copy increases the risk of Alzheimer’s threefold. Two copies increases the risk eightfold. Around half of Alzheimer’s patients have an ApoE4 gene—compared with a quarter of the general population—and those who do tend to develop the disease at a younger age.

  The importance of the ApoE gene extends beyond Alzheimer’s to how well an individual can recover from any type of brain injury. Carriers of ApoE4 gene variants who hit their heads in car accidents, for example, have longer comas, more bleeding and bruising in the brain, more postinjury seizures, less success with rehabilitation, and are more likely to suffer permanent damage or to die.

  It is not entirely understood how ApoE influences brain recovery, but the gene is involved in the brain’s inflammatory response following head trauma, and people who have an ApoE4 variant take longer to clear their brains of a protein called amyloid, which floods in when the brain is injured. Several studies have found that athletes with ApoE4 variants who get hit in the head take longer to recover and are at greater risk of suffering dementia later in life.

  A 1997 study determined that boxers with an ApoE4 copy scored worse on tests of brain impairment than boxers with similar length careers who did not have an ApoE4 copy. Three boxers in the study had severe brain function impairment, and all three had an ApoE4 gene variant. In 2000, a study of fifty-three active pro football players concluded that three factors caused certain players to score lower than their peers on tests of brain function: 1) age, 2) having been hit in the head often, and 3) having an ApoE4 variant.

  In 2002, at age forty, former Houston Oilers and Miami Dolphins linebacker John Grimsley began to show signs of dementia. His family noticed that he would repeat the same question, that he could not remember what groceries to buy without a list, and that he would ask to rent movies he had already seen.

  Though an experienced hunting guide, Grimsley accidentally shot and killed himself in 2008 while cleaning one of his guns. Grimsley’s wife, Virginia, had long wondered whether the concussions her husband suffered had anything to do with his mental deterioration, so she donated his brain to Boston University’s Center for the Study of Traumatic Encephalopathy.

  It was the first of many brains belonging to former NFL players that the BU researchers would examine en route to increasing awareness of the danger of brain trauma in sports. The researchers at the center found an extensive buildup of protein in Grimsley’s brain, characteristic of chronic traumatic encephalopathy, or CTE. The condition has now been found in scores of brains from college and pro football players. The BU scientists also found that Grimsley—like just 2 percent of the population—had two copies of the ApoE4 gene variant.

  In 2009, the BU researchers made national headlines (and headaches for the NFL) when they reported on dozens
of cases of brain damage in boxers and football players. What went entirely unmentioned in media coverage, though, was that five of nine brain-damaged boxers and football players who had genetic data included in the report had an ApoE4 variant. That’s 56 percent, between double and triple the proportion in the general population. Brandon Colby, a Los Angeles–based physician who treats former NFL players says of those patients: “Of the ones who have noticeable issues from head trauma, every single one had an ApoE4 copy.” Colby now offers ApoE testing of children to parents who want to weigh the risks of playing football.

  Neurologist Barry Jordan, coauthor of the 2000 study of fifty-three football players, and former chief medical officer of the New York State Athletic Commission, once considered making genetic screening for the ApoE4 variant mandatory for all boxers in New York. “I don’t think you can stop an athlete from participating,” Jordan says, “but it might help just in monitoring them closely. [An ApoE4 gene variant] doesn’t seem to increase the risk of concussion, and I wouldn’t expect it to, but it may affect your recovery following concussion.”

  Ultimately, Jordan decided not to implement mandatory genetic testing, primarily because he was concerned about how the information could be used. “Even with [the Genetic Information Nondiscrimination Act],” Jordan says, “you never know. Information still gets out. I think genetic testing is something you can educate athletes about. But I’m not sure how interested people would be in it. Some people don’t want to know.” Or, as James P. Kelly, a neurologist who was on the Colorado State Boxing Commission, put it: “With ApoE4, some would argue that knowledge is not power.”

  It’s fraught territory, but most current or former pro athletes to whom I explained an ApoE4 test seemed eager to take one, provided the information would be kept from teams, insurance companies, and potential future employers.* Weeks after his visit to Dr. Braverman, Ron Duguay learned that he did indeed have an ApoE4 variant. Had he known of this potential additional risk factor for cognitive impairment, Duguay says he “would’ve seriously considered wearing a helmet” during his playing days.