Related articles - Gene cheats

Drug scandals in sport would be nothing compared to the potential for genetic engineering to create "super-athletes". Christie Aschwanden investigates

A TENSE HUSH falls on the Olympic stadium as the sprinters crouch on the starting blocks for the men's 100-metres final. With the 2008 Olympic games in full swing, athletes have shattered records as never before, usually by an ample margin. Television ratings are soaring, and as the finalists prepare to compete for the title of world's fastest man, the crowd expects the winner to obliterate this record, too.

Though the Olympic flame still burns in the stadium, these athletes are nothing like their heroic predecessors. Athletes of old honed their bodies with toil and sweat, but at the 2008 games most of the champions have altered their genes to help them excel at their sport. Weightlifters' arms and sprinters' thighs bulge as never before, and long-distance runners have unparalleled stamina—all the result of a few crucial genetic upgrades. Officials are well aware that such "gene doping" is going on, but as the practice is virtually undetectable, they are powerless to stop it.

This may sound like the ultimate sporting nightmare, but the technology to make it come true could well arrive even before 2008. Scientists around the world are working to perfect gene therapies to treat genetic diseases. Soon, unscrupulous athletes may be able to use them to re-engineer their bodies for better performance.

Need more endurance? Add a gene to bolster delivery of oxygen to labouring tissues. Want bigger muscles? Inject them with a gene that will make them grow. Both techniques are under development, and if they work in humans as they do in lab animals, they will change the face of nearly every sport. But at what cost? Knowing how to boost performance is one thing; knowing how to do it safely is quite another. If athletes do turn to gene therapy, these genetically enhanced champions risk paying for their success with heart disease, strokes and early death.

Genes matter when it comes to sport. At the 1964 Winter Olympics in Innsbruck, for example, Finnish sportsman Eero Mäntyranta won two gold medals in cross-country skiing. Though his training programme wasn't radically different from those of his teammates and rivals, Mäntyranta had a distinct advantage: he was born with a genetic mutation that loaded his blood with 25 to 50 per cent more red blood cells than the average man's. Since these cells shuttle oxygen from the lungs to the body tissues, Mäntyranta's muscles got more of the oxygen they needed for aerobic exercise, so he could ski faster for longer.

Mäntyranta got his extra red blood cells because of a mutation in the gene that produces the receptor for the hormone erythropoietin (epo). The kidneys normally churn out epo when oxygen levels in the body's tissues drop, as they do at high altitude, where the air is thin. Epo commands the body to manufacture new red cells, which raises the blood's capacity to carry oxygen. Once oxygen regains its normal level in the blood, the epo receptor should shut down epo production. But Mäntyranta's mutation turned off this crucial feedback, so his body kept making more red cells.

Mäntyranta's mutation is exceedingly rare. But anyone can boost their red cells simply by adding more epo to their bloodstream. In 1989, the biotech company Amgen began marketing Epogen, an injectable form of epo produced by recombinant bacteria, as a treatment for severe anaemia—a serious problem in patients with AIDS or kidney failure.

Athletes were quick to exploit the drug, even though such doping is banned in most sports. At the 1998 Tour de France, for example, French officials caught an employee of the Festina cycling team with a carload of performance-enhancing drugs, including epo. The scandal exposed a dirty secret: "Doping is part of the business of cycling," Swiss rider Alex Zulle told reporters after he confessed to taking epo and other banned drugs.

Secret weapon

Cycling isn't the only sport sullied by allegations of epo use. At the Australian Open tennis championships a year ago, the player Jim Courier told reporters that he suspects epo use is rampant in the game. "I can't play 35 weeks a year and God knows how many matches and keep going. I just can't do it and I don't think anybody else can, either. But they are." Courier says epo makes such superhuman performance possible. Athletes in cross-country skiing, football and track and field athletics are also rumoured to use the drug. "The fact is, we only reward winners, and drugs work," says Charles Yesalis, an epidemiologist at Pennsylvania State University who has interviewed more than a thousand athletes who have admitted to taking banned drugs. With epo rumoured to make athletes run up to 20 per cent faster, the drug's allure is hard for many to resist, he says.

The problem may grow even more widespread if athletes can insert a gene that makes their bodies produce extra doses of the hormone. Instead of injecting themselves with epo several times a week, athletes could use this "gene therapy" to acquire the equivalent of Mäntyranta's super-gene with a single shot. The technology may be just around the corner, as several academic groups and a handful of biotech companies hammer out ways to use epo gene therapy to treat anaemia.

The gene-therapy techniques under development use viruses to carry the epo gene into cells. Researchers remove the genes that make a disease-causing virus harmful and insert the epo gene in their place. "The virus acts as a taxicab," says Philip Whitcome, chairman of the biotech company Avigen in Alameda, California. "You need to get these instructions inside the cells to the machinery that can follow the instructions and make the protein."

Adenoviruses, like the ones that cause the common cold, are a favourite delivery system for gene therapy because they are relatively large and can carry big genes in their payload. However, they are easily recognised and destroyed by the immune system. "There's a race going on to see if the immune system will destroy the taxi before it delivers its passenger to the inside of the cell," says Whitcome. So to evade the body's defences, Avigen has patented the use of adeno-associated viruses (AAVs) for delivering epo. Smaller than an adenovirus, an AAV can't carry as much cargo but is less vulnerable to attack from the immune system, says Whitcome.

Both viral types have shown exceptional results in early tests of epo gene therapy. In 1997, a group led by Jeffrey Leiden, then at the University of Chicago, used an adenovirus to deliver the epo gene to mice and monkeys. After the scientists injected the virus into the animals' muscles, it infiltrated their cells, inserting the epo gene and spurring the cells to pump out the protein. This boosted mouse hematocrits (the proportion of the blood volume made up of red blood cells) from 49 per cent to 81 per cent, while the monkeys' hematocrits rose from 40 per cent to 70 per cent or more (Human Gene Therapy, vol 8, p 1797). A single injection elevated hematocrits for over a year in the mice and for 12 weeks in the monkeys.

Researchers at the biotech company Chiron in Emeryville, California, reported similar results in a 1998 trial that used AAVs to deliver the epo gene to two baboons (Gene Therapy, vol 5, p 665). After 10 weeks, their hematocrits had risen from 38 per cent and 40 per cent to 62 and 75 per cent, respectively, and stayed at those levels for the entire 28 weeks of the study.

Promising though these results appear, gene therapy may not be risk-free. Last autumn, an 18-year-old patient died after receiving gene therapy for a rare liver ailment, delivered via an adenovirus. It is still uncertain what went wrong, but scientists are anxiously re-examining the safety of gene therapy in the light of this incident.

Unless safety turns out to be an insuperable problem, we could see clinical trials of epo gene therapy within the next few years. And if the trials prove successful, athletes would inevitably be tempted to hike up their hematocrit - and thus their endurance - with a single injection. But elevating the red blood cell count is a risky business, as the blood thickens when it is packed with so many red cells. "The heart has to pump sludge blood through small vessels, and that puts you at high risk for high blood pressure and stroke," says Leiden. In one family with a mutation similar to Mäntyranta's, for example, the father died of a stroke in his 50s, and a son suffered a heart attack at age 40, notes Josef Prchal, an epo researcher at the University of Alabama in Birmingham.

Even successful gene therapy could still lead to problems, mainly because there's no way to turn the gene off once it has been inserted. "Some of the monkeys in our experiment made too much epo, and we had to bleed them to thin their blood and keep them alive," says Leiden. Healthy athletes who indulged in epo gene therapy might likewise require frequent bleedings to keep their hematocrit low enough to prevent strokes—and they'd still have a heightened risk of high blood pressure and atherosclerosis, says Prchal.

If epo gene therapy can give athletes added endurance and stamina, a different sort of gene therapy can give them the muscles to match, says Geoffrey Goldspink, a biologist at Royal Free and University College Medical School in London. Scientists believe that hard exercise, the kind that leaves you sore the next day, builds muscle by inducing microscopic damage to the muscle fibres. These "micro tears" are repaired by beefing up the fibres with extra proteins so they will be adapted to the exercise the next time. A protein called insulin-like growth factor 1 (IGF-1), which is turned on by mechanical signals such as stretch or exercise overload, seems to play a role in this repair process. IGF-1 exists in at least five different forms, whose parts are spliced together in different ways. All the forms are produced by a single gene.

Pumping genes

Goldspink's group is working on gene therapy that uses a form of IGF-1 called mechano growth factor (MGF) to treat muscle-wasting diseases such as muscular dystrophy. Since MGF is made in muscle tissue and doesn't seem to circulate in the blood, Goldspink expects its effects to be localised to muscle. His group has tested MGF gene therapy in mice, with impressive results. The researchers gave mice a single injection of the MGF gene, and two weeks later the injected muscles had grown by 20 per cent. "We seem to have found the magic potion that makes muscles grow," says Goldspink.

Across the Atlantic, researchers are having similar success with another form of IGF-1 which is made in the liver as well as in muscle. When it circulates in the blood, IGF-1 raises blood sugar levels. But when it is in muscle tissue, "IGF-1 seems to be mainly involved in repairing and building muscles," says Lee Sweeney, a physiologist at the University of Pennsylvania.

Sweeney and his colleagues used an adenovirus to deliver the IGF-1 gene into the leg muscles of mice. Their results, published in December 1998 in Proceedings of the National Academy of Sciences (vol 95, p 15 603), made headlines and caught the attention of bodybuilders everywhere. After three months, the mouse leg muscles injected with the IGF-1 gene had grown by 15 per cent, even though the animals had not taken any special exercise. Sweeney is convinced that similar IGF-1 gene therapy could allow people to custom-build their physiques.

"What happened in our mice is that they are essentially expressing IGF-1 as if they had just been exercising hard. They are enormous, and they have no body fat," says Nadia Rosenthal, a geneticist at Massachusetts General Hospital in Boston who also worked on the study. Though the mouse muscles don't need the extra IGF-1, they do much better with it, she says. Sweeney believes IGF-1 could even account for the difference between weaklings and muscle men. "It may be that some people naturally make more IGF-1. That might explain why some people can build muscle more easily than others," he suggests.

IGF-1 gene therapy promises to be relatively safe because the protein produced by the newly added gene seems to stay in the muscle that receives the injection. "We didn't find any IGF-1 circulating in the animals' bloodstream, and so that suggests that it was in fact being made and used locally in the muscle," says Rosenthal. That's important, because it means that IGF-1 injected in, say, a tennis player's biceps won't lead to an enlarged heart, nor will it alter blood sugar levels.

The ability to target IGF-1 therapy at specific muscles could be especially enticing to athletes. "A 20 per cent increase in muscle mass is probably pretty easy with IGF-1 alone. If we start adding in other growth factors it could be as high as 50 per cent," predicts Sweeney. "This could give you the ability to grow new muscle on demand. Because its effects are local, you could just inject the IGF-1 gene directly into the muscle you want to enlarge. You could potentially re-engineer your body."

Sweeney speculates that IGF-1 therapy might be available as soon as two years from now. Rosenthal, however, warns that several problems stand in the way. "Mice are not humans. We have already determined that a completely different protocol would be necessary for larger animals because it's harder to access the inside of a large muscle," she says.

Even if IGF-1 therapy does work, there's no guarantee that it will last over the long haul. "It might wear off more quickly in athletes because they damage the muscle more often than sedentary people. When you damage the muscle through exercise you run the risk of losing the genes that you've put in there," Sweeney says. "These issues are a big unknown because no one really knows to what extent people turn over their muscle cells. Every cell that's in your heart when you're born is there when you die, but we're not sure if that's true of other muscles."

If an athlete's gene therapy does stop working, there's no guarantee that a second dose will have the same effect as the first one. "There's a problem with repeated dosing: your body will build antibodies against the virus that inserts the gene into your cells, so if you give another injection with the same virus, your body's immune system may very well wipe out the virus before it can deliver its genes," says Sweeney. But athletes and their doctors aren't likely to be put off so easily. They might, for example, be able to get around this problem by turning to alternative viruses for delivering their illicit genes.

Catching cheaters

So does this mean that the authorities will finally lose their long battle against drugs in sport? Don Catlin, a biochemist who studies gene therapy abuse at the Olympic drug testing lab at the University of California in Los Angeles, has little doubt that athletes and their doctors will resort to gene doping. "I don't like what they do - it's dirty - but I have to admit I'm impressed with the sophistication of doctors on the 'other side'," he says.

Detecting abuse won't be easy. The big problem is that proteins made by engineered genes look identical to the ones the body makes naturally. About the only way scientists might detect illicit gene therapy would be to find traces of the virus that delivered the gene. "If you were looking for MGF or IGF-1, you could take a biopsy from the muscle and look for viral DNA. But you would have to know exactly where it was put in. You're essentially looking for a pinprick in the body," says Goldspink. The same method could detect epo therapy, but again you'd have to know where the gene was injected, says Leiden.

No one seriously expects athletes to line up for muscle biopsies before they go out to compete at the Olympics, so clearly a less invasive strategy must be found. One approach would be to look for abnormally high levels of a gene's product. "You could get the athlete to remain inactive for, say, 12 hours, and then test for MGF," says Goldspink. "If the levels were still high you would have a good indication that you've got a gene that's been switched on all the time instead of being induced by natural activity." But he admits: "Athletes are probably the people least likely to stay inactive for 12 hours, and even that may not be long enough."

This approach might be more useful for detecting epo gene doping, however. People with plenty of red blood cells should have little or no epo circulating in their blood, so if testers found epo in those circumstances, says Leiden, "you'd have a pretty good indication that something was going on." But even there, testing could not separate illegal gene dopers from athletes who carry natural - and presumably legal - mutations such as Mäntyranta's.

If history is any guide, scientists will have a tough time staying ahead of the cheats. That, at least, is nothing new. "There's a lot of money at stake, and drug tests are easy to circumvent," say Yesalis, who thinks many of the records set in the past 30 years have been drug aided. "Users have kicked butt on the drug testers for 40 years. What makes anyone think that's going to change?"

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Genetically modifying muscle cells

Christie Aschwanden

From New Scientist magazine, 15 January 2000.

© Copyright New Scientist, RBI Limited 2001