Among other athletes I asked about their interest in ApoE testing was Glen Johnson, a professional boxer with seventy-one fights, including wins in 2004 over Roy Jones Jr. and Antonio Tarver. Johnson knew that getting hit in the head—and not simply a particular gene—was the primary factor for brain damage, but says, “I’d never hide from extra information.”
Former New England Patriots linebacker Ted Johnson, who suffered a series of concussions that led him to retire and later suffered from amphetamine addiction, depression, memory problems, and chronic headaches, says: “I would be the first person signed up for a test. I wouldn’t even hesitate. I know it’s no guarantee just because you have this gene, but if it’s true that you are potentially at greater risk than the average person, I would do it in a heartbeat. When I was playing we had no information. . . . This kind of information would be incredible to have if you’re a current player.” One Alzheimer’s researcher at Mount Sinai Hospital in New York has noted that the dementia risk of having a single ApoE4 copy is roughly similar to the risk from playing in the NFL, and that the two together are even more dangerous.
But because the precise degree of additional risk is impossible to quantify, doctors I spoke with almost uniformly felt that ApoE testing should not be offered to athletes. “This is a very controversial area,” says Robert C. Green, a BU neurologist who collaborated on the REVEAL Study, which examined how people who volunteer for ApoE screening react when they get bad news. “The world of genetics for decades has suggested that there’s no reason to give people genetic-risk information unless there’s something proven you can do about it.” REVEAL found, though, that people who learned they had an ApoE4 variant did not experience undue dread. Rather, study subjects who got bad news tended to increase healthy lifestyle habits like exercise, which doctors told them might help, even though there is no proven remedy for delaying the onset of Alzheimer’s.
Still, the doctors’ hesitation is understandable. “If we have a gene we know increases your risk of blowing out your knee, if that got into the wrong hands, somebody could decide not to sign a player,” says Barry Jordan, the former New York athletic commission medical officer. “That would be a potential problem.” (Of course, teams already go to great lengths to guess that same information using physical examinations and medical histories.)
Actually, genes have been identified that appear to alter one’s risk of blowing out a knee. Biologists at South Africa’s University of Cape Town have been leading the way in identifying genes that predispose exercisers to injuring tendons and ligaments. The researchers focused on genes like COL1A1 and COL5A1 that code for the proteins that make up collagen fibrils, the basic building blocks of tendons, ligaments, and skin. Collagen is sometimes referred to as the body’s glue, holding connective tissues in proper form.
People with a certain mutation in the COL1A1 gene have brittle bone disease and suffer fractures easily. A particular mutation in the COL5A1 gene causes Ehlers-Danlos syndrome, which confers hyperflexibility. “Those people in the old days of the circus who used to fold themselves into a box, I bet you in most cases they had Ehlers-Danlos syndrome,” says Malcolm Collins, one of the Cape Town biologists and a leader in the study of collagen genes. “They could twist their bodies into positions that you and I can’t because they’ve got very abnormal collagen fibrils.”
Ehlers-Danlos syndrome is rare, but Collins and colleagues have demonstrated that much more common variations in collagen genes influence both flexibility and an individual’s risk of injuries to the connective tissues, like Achilles tendon rupture.* Using that research, the company Gknowmix offers collagen gene tests that doctors can order for patients.
“All we can say to an athlete with a particular genetic profile is that you are at increased risk of injury based on our current knowledge,” Collins says. “It’s no different than saying that smoking a cigarette increases your chance of lung cancer. The difference is that you can stop smoking, but you can’t change your DNA. But there are other factors which you can change. You can modify whatever training you’re doing to reduce risk, or you can do ‘prehabilitation’ training to strengthen the area that is at risk.”
A gaggle of NFL players have already availed themselves of testing for “injury genes” that may predispose them to Achilles tendon injuries or torn ACLs in the knee. Duke University’s football team, as just one example, sought university approval to submit players’ DNA to a researcher on campus who would look for genes that predispose players to tendon and ligament injuries.
So specific genes have now been implicated in sudden death, brain damage, and injury on the field. And now researchers have begun to identify genes that undergird another unpleasant and unavoidable aspects of sports: pain. Genes, it seems, influence our very perception of it.
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In the waning years of a career that spanned thirteen NFL seasons, 3,479 carries, a bevy of broken ribs, several separated shoulders, a couple of concussions, a torn groin muscle, a bruised sternum, and a legion of knee and ankle surgeries, 255-pound running back Jerome Bettis developed a Monday-morning tradition. He would sit at the top of his staircase and scoot down toward breakfast on his butt, one step at a time.
On Sundays, the Steelers expected Bettis to run through people. “That was my skill set,” he says. “It wasn’t like I could run away from them.” In one game against the Jacksonville Jaguars, a defensive player’s thumb came through Bettis’s face mask and broke his nose. Team doctors taped the nose and stuffed it with cotton. That helped, until a head-on collision late in the game propelled the cotton up through his nasal passage, down his throat, and into his stomach. “It was like, ‘Guys, wait a second, the padding is gone,’” Bettis says. “It was the worst.”
No wonder Bettis was unable to walk down the stairs on Monday mornings. The pain was so intense at times that he figured he would have to miss the next game. But once he stepped on the turf Sunday, he never backed down. “When you get on the field, it’s not even a question mark,” Bettis says. “You do your job, by any means necessary.”
Bettis was renowned for his toughness, but he says there are athletes, even in the NFL, who struggle to manage discomfort. “I think some people’s bodies kind of shut down from the pain, and it doesn’t allow them to still have peak performances,” Bettis says. “I saw that problem at times.”
Pain tolerance and pain management are as central to most high-level sports as running and jumping, and just why some people tolerate pain better than others is a topic of research at the Pain Genetics Lab at McGill University in Montreal. One room in the lab is stacked from floor to ceiling with clear tanks that house mice, all bred for the study of genes that influence how they (and humans) experience pain, and how that pain can be ameliorated.
In one tank are mice missing oxytocin receptors. They are used in the study of pain, but the mice also have deficits in social recognition. Put them with mice they grew up with and they won’t recognize them. In another corner is a tank of raven-haired mice that were bred to be prone to head pain, that is, migraines. They spend a lot of time scratching their foreheads and shuddering, and they are apparently justified in using the old headache excuse to avoid mating. “This experiment has taken years,” says Jeffrey Mogil, head of the lab, of the work that seeks to help develop migraine treatments, “because they breed really, really badly.”
On another shelf is a tank of mice with nonfunctioning versions of the melanocortin 1 receptor gene, or MC1R. In plain language, they’re redheads. It’s the same gene mutation that is responsible for the ginger locks of most human redheads. Mogil found that both people and rodents with the redhead mutation have higher tolerance for certain types of pain, and require less morphine for relief.
MC1R was among the first genes identified that influence how humans experience pain. Another was discovered by scientists who followed the theatrical talents of a ten-year-old Pakistani street performer.
Medical workers in Lahore knew the boy well, because after he stuck knives through his arms and stood on burning coals he would come in to get stitched back together. But they never treated him for pain. The boy could feel no pain.
By the time British geneticists traveled to Pakistan to study him, the boy had died, at the age of fourteen, after jumping off a roof to impress his friends. But the scientists found the same condition in six of the boy’s extended relatives. “None knew what pain felt like,” the scientists wrote, “although the older individuals realized what actions should elicit pain (including acting as if in pain after football tackles).”
The “older individuals” were just ten, twelve, and fourteen. People born with congenital insensitivity to pain tend not to live very long. They don’t shift their weight when sitting, sleeping, or standing as the rest of us do instinctively, and they die from the joint infections that result.
Each of the Pakistani relatives with pain immunity had a very rare mutation in the SCN9A gene. The mutation blocked pain signals that normally travel from nerves to the brain. A different mutation in SCN9A causes those who carry it to be hypersensitive to pain, bothered by warmth so easily that they won’t wear shoes. In 2010, the British geneticists teamed up with researchers in the United States, Finland, and the Netherlands for a study that reported that much more common variations in SCN9A influence how sensitive adults are to common types of pain, like back trouble. Genetic variation among individuals, it seems, ensures that none of us can truly know another’s physical pain.
The gene that has been most studied for its involvement in pain modulation is the COMT gene, which is involved in the metabolism of neurotransmitters in the brain, including dopamine. Two common versions of COMT are known as “Val” and “Met,” based on whether a specific part of the gene’s DNA sequence codes for the amino acid valine or methionine.
In both mice and humans, the Met version is less effective at clearing dopamine, which leaves higher levels in the frontal cortex. Cognitive testing and brain imaging studies have found that subjects with two Met versions—both animals and humans—tend to do better on and require less metabolic effort for cognitive and memory tasks, but that they are also more prone to anxiety and more sensitive to pain. (Anxiety, or “catastrophizing,” is a strong predictor of an individual’s pain sensitivity.) Conversely, Val/Val carriers seem to do slightly worse on cognitive tests that require rapid mental flexibility, but may be more resilient to stress and pain. (They also get a better boost from Ritalin, which increases dopamine in the frontal cortex.) Additionally, COMT is involved in metabolism of norepinephrine, which is released in response to stress and has a protective effect.
David Goldman, chief of the Laboratory of Neurogenetics at the NIH’s National Institute on Alcohol Abuse and Alcoholism, coined the phrase “warrior/worrier gene” to describe the apparent tradeoffs of the two COMT variants. Both versions are common everywhere in the world they’ve been studied. In the United States, Goldman says, 16 percent of people are Met/Met; 48 percent are Met/Val; and 36 percent are Val/Val, leading him to suggest that both warriors and worriers are needed in every society, so there is widespread preservation of both forms of the gene. “We’ve never done the study,” Goldman says, “but I predict if I took a big group of NFL linemen that they would tend to have the Val genotype, because they’re in the trenches every day and they’re exposed to pain and they just have to have this super resilience and toughness.” *
In fairness, studies of the COMT gene have often been contradictory, and the gene’s relevance to pain sensitivity is hotly debated among pain researchers. But the idea that genes involved in emotional regulation might alter pain sensation is uncontroversial. Morphine, after all, doesn’t so much decrease pain intensity, but rather reduces the emotional unpleasantness that results from pain. “The pain circuitry is shared so strongly with the circuitry of emotion,” Goldman says, “and many of the neurotransmitters are too. As you modify emotion, you strongly modify pain response.”
And sports can be strong modifiers.
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Haverford College psychologist Wendy Sternberg was giving a lecture on stress-induced analgesia—the brain’s ability to block pain in high-pressure situations—when a student told her that it sounded just like what happens to athletes in competition.
A 2004 Ultimate Fighting Championship heavyweight title fight is an excruciating example. Brazilian jiu-jitsu black belt Frank Mir caught 6'8" Tim “The Maine-iac” Sylvia in a joint lock called an armbar. Mir grabbed Sylvia’s extended right arm, braced the elbow joint against his hip, and pulled backward so forcefully it looked as if he were heaving back a train brake.
The pop of Sylvia’s shattering arm was audible on television. Referee Herb Dean rushed in to separate the fighters and shouted for the match to stop. Sylvia set to cursing and demanding that the fight continue. Only later, as he sat on a gurney en route to the hospital, did Sylvia begin to feel pain and realize that his attempt to keep fighting had been ill considered. It took three titanium plates to rig his arm back together. “[The ref] probably saved my career,” Sylvia says, because in the heat of battle he couldn’t perceive the pain on his own.
Says Sternberg, “Under conditions of acute stress the brain inhibits pain, so you can fight or flee without worrying about a broken bone.” A system to block pain in extreme situations evolved in the genes of all humans, and even quotidian sports settings tap into it.
In 1998, prompted by her student’s suggestion, Sternberg tested the sensitivity of Haverford track athletes, fencers, and basketball players to cold and heat pain two days before they competed, on the day of a competition, and two days later. She found that basketball players and runners were less sensitive to pain than their nonathlete peers to begin with, and that all of the athletes were least sensitive to pain on game day. “I think athletic competition can activate the fight-or-flight mechanism,” Sternberg says. “When you get in a competition that you care about, you’re going to activate it.”
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Pain can be modified by a game situation or by the emotions of an athlete, but the genetic blueprint for pain in the body is encoded in the brain, whether or not that body even exists in its entirety. (People who are born without limbs or who have them amputated nonetheless often experience pain in those “phantom limbs.”) Still, pain must be practiced in the first place.
In the 1950s, Canadian psychologist Ronald Melzack was working toward his Ph.D. at McGill under psychologist D. O. Hebb, who was studying how extreme deprivation of life experience affects intellect. Hebb was experimenting on Scottish terriers.
The dogs were well cared for, groomed, and fed, but they were totally isolated from the outside world. Hebb was interested in how that would alter their ability to navigate a maze. (The answer: very negatively.) But it was in the holding room, before the maze, where Melzack made the observation that started him down the road to becoming the most influential pain researcher in the world. “The water pipes in the room were at head level for the dogs,” Melzack says, “and these wonderful dogs would run around and bang their heads right into the pipes, as if they felt nothing. And they kept running around and banging their heads on the water pipes.”
Melzack was a smoker at the time, so he struck a match. “I held it out, and they’d put their nose in it,” he says. They’d back up, “and then come back and sniff it again. I’d put it out and light another match, and they’d sniff it again and again.” The dogs obviously had normal cerebral hardware, but had missed the critical developmental window for downloading the brain’s pain software. They never learned to be deterred by the flame. Just like language, or hitting a baseball, even though each of us may be born with the requisite genetic hardware, if we miss the window for acquiring the software, the genes are of little use. Adds Jeffrey Mogil, of McGill’s Pain Genetics Lab: “The fact that something like pain would have to be learned at all is pretty
surprising.”
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Pain is innate, but it also must be learned. It is unavoidable, and yet modifiable. It is common to all people and all athletes but never experienced quite the same way by any two individuals or even by the same individual in two different situations. Each of us is like the hero in a Greek tragedy, circumscribed by nature, but left to alter our fate within the boundaries. “Maybe if you’re a worrier by genotype, it’s a better idea not to be a warrior by profession,” says Goldman, the neurogeneticist. “Then again, it’s hard to say, because people overcome so much.”
Like most traits discussed in this book, an athlete’s ability to deal with pain is a braid of nature and nurture so intricately and thoroughly intertwined as to become a single vine. As one scientist told me: without both genes and environments, there are no outcomes.
It reinforces the idea that any notion of finding an “athlete gene” was a figment of the era of wishful thinking that crested a decade ago with the first full sequencing of the human genome, before scientists understood how much they don’t understand about the complexity of the genetic recipe book. What, exactly, most human genes do is still a mystery. Sure, the ACTN3 gene may tell a billion or so people in the world that they won’t be in the Olympic 100-meter final, but chances are they all already knew that.
If thousands of DNA variations are needed to explain just a portion of the differences in height among people, what are the chances of ever finding a single gene that makes a star athlete? Slim? Or none?
And yet . . .
16
The Gold Medal Mutation
It is December 2010, and human civilization in northern Scandinavia is temporarily reduced to a layer of sediment beneath the snow. Excavation will come only with spring. The last few days have seen record snow and a constant -15 degrees Fahrenheit at the Arctic Circle in Finland—the Napapiiri, as the Finns call it—where I am now. There’s no wind, so the first crunching step outside each morning is deceptively placid, before nose hairs morph into ice daggers.
The Sports Gene: Inside the Science of Extraordinary Athletic Performance Page 28
