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A lengthy but good read.
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How Doctors Help The Dopers
New ideas from medical research are being plundered by athletes looking for a boost. In Athens, the drug cops will be in hot pursuit
Every morning, he starts the day by taking two blue tablets, and every night before bed, he takes another, making sure no less than 12 hours have elapsed since the first dose. Since he started taking the pills, he can run faster and longer, and tests of his muscle strength confirm what he already knows: he is getting stronger.
It may sound like the routine of another conniving athlete preparing for Athens, but it's the way an 11-year-old boy in Menlo Park, Calif., is fighting muscular dystrophy. Starting in 2002, the youngster began taking low doses of albuterol, a popular asthma drug, as a participant in an experimental study at UCLA. The lead investigator of the trial got the idea for testing albuterol by searching the Internet for references to muscle-building drugs, which soon linked her to sites for body builders. The body builders had learned about the drug's effect from combing the journals of agricultural science, in which veterinarians frequently reported on the bulging muscles they saw in cattle after injecting them with albuterol. It turns out that the drug blocks an enzyme that chews away at muscle. Beef begat beefcake.
Welcome to the emerging reality of competitive sports, where high stakes and high technology are combining to push the limits of human performance often without leaving chemical evidence that science is helping nature. Scientists and athletes increasingly find themselves in symbiotic research, both driven to achieve the same goal of enhancing physical ability, but with polar-opposite motivations. Scientists want to treat debilitating diseases, while elite athletes look to the labs for a competitive edge.
At the Athens Games, which begin this week, the cat-and-mouse contest between dopers and detectives will be sharper than ever. Athletes will be policed by the World Anti-Doping Agency (WADA), an independent testing body created in 1999. WADA will forward its results to the International Olympic Committee (I.O.C.), which can then bar athletes from competing if they test positive for any of hundreds of illegal or prohibited drugs. Since its inception, WADA has been playing catch-up with better-informed and better-equipped athletes, some of whom can pay their way into the world of designer drugs created to evade detection. But the agency has started to close the gap. At the 2002 Winter Games, WADA tested the arriving athletes and surprised them with a more sophisticated test to detect darbopoeitin, a bioengineered hormone that dopes blood by increasing its oxygen content. On the basis of those results, the I.O.C. stripped three athletes of their eight medals.
There is speculation, which WADA won't deny, that the organization will pull the same trick in Athens with a test for synthetic human growth hormone (HGH), which stimulates muscle and bone growth. It's popular among competitors because unlike easily detected steroids, excess HGH levels are difficult to distinguish from normally circulating levels. And WADA is also reserving the right to nab dopers after the fact the I.O.C. will keep the samples from Athens and subject them to detection methods WADA may deploy over the next few months.
Yet the dopers will have their own new tricks too. What WADA may have trouble getting a handle on is the rapid development of gene-based compounds, which are souped-up versions of muscle-building and blood-boosting cells. The latter would enhance the performance of endurance athletes. The former would help strength competitors, notably sprinters, a group made infamous by Ben Johnson, disqualified for steroid use in 1988. This year two U.S. sprinters have been suspended by the U.S. Anti-Doping Agency (USADA) for doping. And track and field's governing body has recommended suspension for world 100-m champion Torri Edwards. Others, including defending gold medalist Tim Montgomery, are under investigation.
Gene-based compounds will be much harder to track than a synthetic steroid like andro or a stimulant like ephedrine. That's because compounds delivered directly to muscle generally remain corralled there, rarely reaching the bloodstream or urine, where they could be traced. Though genetic treatments are not yet out of the lab, WADA has enlisted the help of researchers who have provided them with ideas for identifying competitors taking advantage of the new therapies. (Here's a hint: start with the record breakers.) "I don't think anyone will be competing in Athens with genetic enhancement," says Dr. H. Lee Sweeney, chairman of the department of physiology at the University of Pennsylvania School of Medicine and a consultant to WADA. "But I wouldn't be willing to make the same bet about Beijing."
By the Beijing Games in 2008, Sweeney predicts, athletes may be availing themselves of a genetic treatment designed for muscular dystrophy, years ahead of safety and efficacy trials, and years ahead of when patients may have access to the remedy. "I'm sure there are going to be scientists willing to set up illegal clinics to treat athletes who want genetic enhancement if they pay enough money," he says.
Because of their particular focus, muscular-dystrophy labs stand to provide a rich pipeline of potential doping agents. Muscular dystrophy is a genetic condition in which muscle can no longer repair the tiny abrasions that come from normal wear and tear, and begins to waste away. The disease mimics an exaggerated form of the stress that highly trained athletes inflict on their muscles. To restore the balance in favor of regeneration, researchers are isolating the myriad growth factors and other biochemical compounds that regulate the musclemaking factory.
So far, two major strategies hold the most promise: boosting levels of a hormone called insulin-like growth factor 1 (IGF-1), which encourages muscle repair; and removing myostatin, the body's natural check on uncontrolled muscle growth. Versions of IGF-1 are already available at pharmacies and nutritional-supplement stores, where they are marketed as muscle boosters, but scientists know that taking this oral form of the hormone does very little for building muscle and can have harmful effects on the heart. That hasn't stopped some athletes from trying it. "I'm convinced that some athletes are using a combination of IGF-1 and human growth hormone," says Nadia Rosenthal, an IGF-1 researcher at the European Molecular Biology Laboratory in Rome. The theory behind the combo is that human growth hormone signals the liver to secrete more IGF-1, keeping blood levels high. "These athletes know a little bit about how [the hormones] work, and for them, a millisecond could be the difference between gold or nothing," she says. What they don't seem to realize is that circulating IGF-1 is less effective, and more dangerous, than the version that is concentrated in the muscle.
The key, then, to using IGF-1 safely and effectively in muscular-dystrophy patients lies in getting enough of the hormone directly to the muscle. So Sweeney's group is perfecting a version of gene therapy, the most efficient way to dump a large amount of genetic material into a tissue as extensive as muscle (about 40% of body weight comes from muscle). He packs the IGF-1 gene into a harmless cold virus and injects the entire package directly into muscle. Once the IGF-1 gene inserts itself into the genome of the muscle cell, it begins to churn out the insulin-like growth factor that activates muscle expansion. Muscles in mice injected this way grew up to 30% larger than in normal animals, even when the mice didn't exercise. And as the animals aged, their muscles remained strong, as vigorous as if they belonged to far younger mice. In the coming months, Sweeney plans to inject IGF-1 into dogs to learn more about how the added growth factor would operate in a larger, mammalian body that more closely resembles that of humans.
Boosting IGF-1 levels is only half the story. Sweeney is also trying to tip the balance by shutting down myostatin, a compound that inhibits IGF-1 activity in the muscle. The pharmaceutical maker Wyeth Ayerst is testing a myostatin blocker in early trials of healthy humans, and hopes that it may become a new treatment option for those with muscular dystrophy or for the elderly who have become frail from the normal muscle wasting that occurs with aging.
Other labs are taking a different approach, focusing on enhancing the supply of oxygen that fuels everything the muscle cells do. And here too, athletes are eagerly dogging the footsteps of medical researchers, specifically those working to treat chronic anemias, conditions in which red blood cells dwindle to dangerously low levels, starving tissues of oxygen. In athletes, prolonged exertion leads to oxygen depletion in the muscles, which causes fatigue.
When researchers found a way to bioengineer a version of the human hormone erythropoeitin (EPO), which acts as the body's trigger to create more red blood cells, it didn't take long for athletes with perfectly normal red-blood-cell counts to exploit the technology. French cyclists were caught using EPO in the 1998 Tour de France; Olympic officials began testing athletes at the Sydney Games in 2000.
EPO may shunt more oxygen to the muscles, but it comes at a price. "If you take too much EPO," explains WADA's Dr. Gary Wadler, professor of clinical medicine at New York University, "the production of red blood cells is excessive, and the blood becomes viscous it's like sludge." In the late 1980s, when EPO became available, nearly 20 European cyclists died of causes that some experts suspect were linked to EPO.
Some athletes are banking on a different strategy: gene therapy. Researchers have developed techniques to insert EPO-producing genes into cells so they can generate additional amounts of EPO long term. But again, says Wadler, "since overproduction of red cells is potentially lethal, this technique requires a pharmacological on-off switch." Researchers are using various techniques to devise controllable EPO delivery systems, in which genes inserted into the skin can be turned on and off either by taking a pill or rubbing a chemical on the skin. Other scientific groups are encapsulating genetically engineered EPO-producing cells in man-made biological carriers and implanting these microbioreactors into tissue, where they deliver a controlled low-dose supply of the hormone.
Enhancing oxygen delivery is a broad frontier. The process theoretically can be manipulated at many points. "It is inevitable that other pharmacological avenues to stimulate red-cell production will be explored and exploited," says Dr. Michael Ashenden, project coordinator for a global blood-doping research consortium funded by WADA and USADA. "Putting in an EPO gene is only one way to get the same result."
Instead of finding novel ways of delivering EPO, for example, some researchers are hoping to harness modified versions of hemoglobin, the oxygen-carrying workhorse in red blood cells. Artificial blood has long been a dream of doctors who face perpetual blood shortages, and in recent years that dream is closer to becoming reality. One promising approach involves extracting hemoglobin from living cells and using it alone as an oxygen transport system. Unfortunately, naked hemoglobin is quickly broken down in the body. Housing the hemoglobin in an artificial cell, or modifying the hemoglobin so it remains stable, could solve this problem. Two such artificial hemoglobin-based blood products in the final stages of development are already rumored to have made the rounds in the track-and-field community.
Beyond hemoglobin, there are totally synthetic blood substitutes like perfluorocarbon (PFC), a cheap, inert molecule with an enormous capacity to carry oxygen. Those fluids behave like an additional reservoir of oxygen for the body to utilize during exercise. However, because PFC has a short half-life and is effective only when individuals breathe abnormally high concentrations of oxygen, it will probably remain a very difficult technology to abuse.
For athletes tempted to cheat, a word of caution: advances in technology cut both ways. Ashenden's group is researching a powerful new tool able to precisely measure a person's metabolic profile. "Athletes who are doping are altering their metabolism, whether it's by taking a drug or inserting a gene," Ashenden says. "So if we can look at their metabolic profile and see it isn't normal, then that's evidence they have doped even if we might not know what exactly they've done."
That may be wishful thinking, but what we can be sure of is that as long as there is a pipeline of medical innovation, athletes will continue to feed off its bounty despite potential health or legal consequences. And researchers will obviously not be deterred by the possibility that their work will be exploited. "I'm not going to let an insane athlete keep me from curing muscular dystrophy, that's for sure," says Jeffrey Chamberlain, director of muscular-dystrophy research at the University of Washington in Seattle. Patients, after all, have more to lose than a gold medal.
HOW THE BODY'S MUSCLES WORK AND HOW TO ARTIFICIALLY ENHANCE THEM
The human body contains about 650 muscles, which are made of fibers that either relax or contract in response to central nervous system impulses
RELAXED MUSCLE
Muscle cells are cylinder-shaped fibers bundled along with connective tissue and fat. These fibers are made up of many myofibrils, or muscle proteins. The two proteins that allow muscles to contract are myosin and actin, which operate together in units called sarcomeres
CONTRACTED MUSCLE
During contraction, the myosin grabs onto the actin and pulls the filaments past it, shortening the sarcomere. The contraction signal is synchronized through the fiber, causing all the myofibrils that make up the sarcomere to shorten at the same time
NORMAL MUSCLE GROWTH
When we exercise, microscopic tears in muscle fibers activate a chemical alarm that summons satellite muscle-repair cells to the tear. These stem cells divide and multiply before they fuse with the muscle fiber, leaving it bulkier than before it was injured
GROWTH THROUGH GENE TAMPERING
Injecting a synthetic gene into a healthy muscle can simulate growth-and-repair signals by producing a protein that tells the satellite cells to proliferate and become new muscle cells
ENDURANCE INCREASED WITH OXYGEN SUPPLY
Erythropoietin is a natural protein that stimulates the production of oxygen-carrying blood cells. When a synthetic version called EPO is injected, a person produces more red blood cells, which carry more oxygen to the muscles, increasing stamina
SOURCE:
______________________________________
How Doctors Help The Dopers
New ideas from medical research are being plundered by athletes looking for a boost. In Athens, the drug cops will be in hot pursuit
Every morning, he starts the day by taking two blue tablets, and every night before bed, he takes another, making sure no less than 12 hours have elapsed since the first dose. Since he started taking the pills, he can run faster and longer, and tests of his muscle strength confirm what he already knows: he is getting stronger.
It may sound like the routine of another conniving athlete preparing for Athens, but it's the way an 11-year-old boy in Menlo Park, Calif., is fighting muscular dystrophy. Starting in 2002, the youngster began taking low doses of albuterol, a popular asthma drug, as a participant in an experimental study at UCLA. The lead investigator of the trial got the idea for testing albuterol by searching the Internet for references to muscle-building drugs, which soon linked her to sites for body builders. The body builders had learned about the drug's effect from combing the journals of agricultural science, in which veterinarians frequently reported on the bulging muscles they saw in cattle after injecting them with albuterol. It turns out that the drug blocks an enzyme that chews away at muscle. Beef begat beefcake.
Welcome to the emerging reality of competitive sports, where high stakes and high technology are combining to push the limits of human performance often without leaving chemical evidence that science is helping nature. Scientists and athletes increasingly find themselves in symbiotic research, both driven to achieve the same goal of enhancing physical ability, but with polar-opposite motivations. Scientists want to treat debilitating diseases, while elite athletes look to the labs for a competitive edge.
At the Athens Games, which begin this week, the cat-and-mouse contest between dopers and detectives will be sharper than ever. Athletes will be policed by the World Anti-Doping Agency (WADA), an independent testing body created in 1999. WADA will forward its results to the International Olympic Committee (I.O.C.), which can then bar athletes from competing if they test positive for any of hundreds of illegal or prohibited drugs. Since its inception, WADA has been playing catch-up with better-informed and better-equipped athletes, some of whom can pay their way into the world of designer drugs created to evade detection. But the agency has started to close the gap. At the 2002 Winter Games, WADA tested the arriving athletes and surprised them with a more sophisticated test to detect darbopoeitin, a bioengineered hormone that dopes blood by increasing its oxygen content. On the basis of those results, the I.O.C. stripped three athletes of their eight medals.
There is speculation, which WADA won't deny, that the organization will pull the same trick in Athens with a test for synthetic human growth hormone (HGH), which stimulates muscle and bone growth. It's popular among competitors because unlike easily detected steroids, excess HGH levels are difficult to distinguish from normally circulating levels. And WADA is also reserving the right to nab dopers after the fact the I.O.C. will keep the samples from Athens and subject them to detection methods WADA may deploy over the next few months.
Yet the dopers will have their own new tricks too. What WADA may have trouble getting a handle on is the rapid development of gene-based compounds, which are souped-up versions of muscle-building and blood-boosting cells. The latter would enhance the performance of endurance athletes. The former would help strength competitors, notably sprinters, a group made infamous by Ben Johnson, disqualified for steroid use in 1988. This year two U.S. sprinters have been suspended by the U.S. Anti-Doping Agency (USADA) for doping. And track and field's governing body has recommended suspension for world 100-m champion Torri Edwards. Others, including defending gold medalist Tim Montgomery, are under investigation.
Gene-based compounds will be much harder to track than a synthetic steroid like andro or a stimulant like ephedrine. That's because compounds delivered directly to muscle generally remain corralled there, rarely reaching the bloodstream or urine, where they could be traced. Though genetic treatments are not yet out of the lab, WADA has enlisted the help of researchers who have provided them with ideas for identifying competitors taking advantage of the new therapies. (Here's a hint: start with the record breakers.) "I don't think anyone will be competing in Athens with genetic enhancement," says Dr. H. Lee Sweeney, chairman of the department of physiology at the University of Pennsylvania School of Medicine and a consultant to WADA. "But I wouldn't be willing to make the same bet about Beijing."
By the Beijing Games in 2008, Sweeney predicts, athletes may be availing themselves of a genetic treatment designed for muscular dystrophy, years ahead of safety and efficacy trials, and years ahead of when patients may have access to the remedy. "I'm sure there are going to be scientists willing to set up illegal clinics to treat athletes who want genetic enhancement if they pay enough money," he says.
Because of their particular focus, muscular-dystrophy labs stand to provide a rich pipeline of potential doping agents. Muscular dystrophy is a genetic condition in which muscle can no longer repair the tiny abrasions that come from normal wear and tear, and begins to waste away. The disease mimics an exaggerated form of the stress that highly trained athletes inflict on their muscles. To restore the balance in favor of regeneration, researchers are isolating the myriad growth factors and other biochemical compounds that regulate the musclemaking factory.
So far, two major strategies hold the most promise: boosting levels of a hormone called insulin-like growth factor 1 (IGF-1), which encourages muscle repair; and removing myostatin, the body's natural check on uncontrolled muscle growth. Versions of IGF-1 are already available at pharmacies and nutritional-supplement stores, where they are marketed as muscle boosters, but scientists know that taking this oral form of the hormone does very little for building muscle and can have harmful effects on the heart. That hasn't stopped some athletes from trying it. "I'm convinced that some athletes are using a combination of IGF-1 and human growth hormone," says Nadia Rosenthal, an IGF-1 researcher at the European Molecular Biology Laboratory in Rome. The theory behind the combo is that human growth hormone signals the liver to secrete more IGF-1, keeping blood levels high. "These athletes know a little bit about how [the hormones] work, and for them, a millisecond could be the difference between gold or nothing," she says. What they don't seem to realize is that circulating IGF-1 is less effective, and more dangerous, than the version that is concentrated in the muscle.
The key, then, to using IGF-1 safely and effectively in muscular-dystrophy patients lies in getting enough of the hormone directly to the muscle. So Sweeney's group is perfecting a version of gene therapy, the most efficient way to dump a large amount of genetic material into a tissue as extensive as muscle (about 40% of body weight comes from muscle). He packs the IGF-1 gene into a harmless cold virus and injects the entire package directly into muscle. Once the IGF-1 gene inserts itself into the genome of the muscle cell, it begins to churn out the insulin-like growth factor that activates muscle expansion. Muscles in mice injected this way grew up to 30% larger than in normal animals, even when the mice didn't exercise. And as the animals aged, their muscles remained strong, as vigorous as if they belonged to far younger mice. In the coming months, Sweeney plans to inject IGF-1 into dogs to learn more about how the added growth factor would operate in a larger, mammalian body that more closely resembles that of humans.
Boosting IGF-1 levels is only half the story. Sweeney is also trying to tip the balance by shutting down myostatin, a compound that inhibits IGF-1 activity in the muscle. The pharmaceutical maker Wyeth Ayerst is testing a myostatin blocker in early trials of healthy humans, and hopes that it may become a new treatment option for those with muscular dystrophy or for the elderly who have become frail from the normal muscle wasting that occurs with aging.
Other labs are taking a different approach, focusing on enhancing the supply of oxygen that fuels everything the muscle cells do. And here too, athletes are eagerly dogging the footsteps of medical researchers, specifically those working to treat chronic anemias, conditions in which red blood cells dwindle to dangerously low levels, starving tissues of oxygen. In athletes, prolonged exertion leads to oxygen depletion in the muscles, which causes fatigue.
When researchers found a way to bioengineer a version of the human hormone erythropoeitin (EPO), which acts as the body's trigger to create more red blood cells, it didn't take long for athletes with perfectly normal red-blood-cell counts to exploit the technology. French cyclists were caught using EPO in the 1998 Tour de France; Olympic officials began testing athletes at the Sydney Games in 2000.
EPO may shunt more oxygen to the muscles, but it comes at a price. "If you take too much EPO," explains WADA's Dr. Gary Wadler, professor of clinical medicine at New York University, "the production of red blood cells is excessive, and the blood becomes viscous it's like sludge." In the late 1980s, when EPO became available, nearly 20 European cyclists died of causes that some experts suspect were linked to EPO.
Some athletes are banking on a different strategy: gene therapy. Researchers have developed techniques to insert EPO-producing genes into cells so they can generate additional amounts of EPO long term. But again, says Wadler, "since overproduction of red cells is potentially lethal, this technique requires a pharmacological on-off switch." Researchers are using various techniques to devise controllable EPO delivery systems, in which genes inserted into the skin can be turned on and off either by taking a pill or rubbing a chemical on the skin. Other scientific groups are encapsulating genetically engineered EPO-producing cells in man-made biological carriers and implanting these microbioreactors into tissue, where they deliver a controlled low-dose supply of the hormone.
Enhancing oxygen delivery is a broad frontier. The process theoretically can be manipulated at many points. "It is inevitable that other pharmacological avenues to stimulate red-cell production will be explored and exploited," says Dr. Michael Ashenden, project coordinator for a global blood-doping research consortium funded by WADA and USADA. "Putting in an EPO gene is only one way to get the same result."
Instead of finding novel ways of delivering EPO, for example, some researchers are hoping to harness modified versions of hemoglobin, the oxygen-carrying workhorse in red blood cells. Artificial blood has long been a dream of doctors who face perpetual blood shortages, and in recent years that dream is closer to becoming reality. One promising approach involves extracting hemoglobin from living cells and using it alone as an oxygen transport system. Unfortunately, naked hemoglobin is quickly broken down in the body. Housing the hemoglobin in an artificial cell, or modifying the hemoglobin so it remains stable, could solve this problem. Two such artificial hemoglobin-based blood products in the final stages of development are already rumored to have made the rounds in the track-and-field community.
Beyond hemoglobin, there are totally synthetic blood substitutes like perfluorocarbon (PFC), a cheap, inert molecule with an enormous capacity to carry oxygen. Those fluids behave like an additional reservoir of oxygen for the body to utilize during exercise. However, because PFC has a short half-life and is effective only when individuals breathe abnormally high concentrations of oxygen, it will probably remain a very difficult technology to abuse.
For athletes tempted to cheat, a word of caution: advances in technology cut both ways. Ashenden's group is researching a powerful new tool able to precisely measure a person's metabolic profile. "Athletes who are doping are altering their metabolism, whether it's by taking a drug or inserting a gene," Ashenden says. "So if we can look at their metabolic profile and see it isn't normal, then that's evidence they have doped even if we might not know what exactly they've done."
That may be wishful thinking, but what we can be sure of is that as long as there is a pipeline of medical innovation, athletes will continue to feed off its bounty despite potential health or legal consequences. And researchers will obviously not be deterred by the possibility that their work will be exploited. "I'm not going to let an insane athlete keep me from curing muscular dystrophy, that's for sure," says Jeffrey Chamberlain, director of muscular-dystrophy research at the University of Washington in Seattle. Patients, after all, have more to lose than a gold medal.
HOW THE BODY'S MUSCLES WORK AND HOW TO ARTIFICIALLY ENHANCE THEM
The human body contains about 650 muscles, which are made of fibers that either relax or contract in response to central nervous system impulses
RELAXED MUSCLE
Muscle cells are cylinder-shaped fibers bundled along with connective tissue and fat. These fibers are made up of many myofibrils, or muscle proteins. The two proteins that allow muscles to contract are myosin and actin, which operate together in units called sarcomeres
CONTRACTED MUSCLE
During contraction, the myosin grabs onto the actin and pulls the filaments past it, shortening the sarcomere. The contraction signal is synchronized through the fiber, causing all the myofibrils that make up the sarcomere to shorten at the same time
NORMAL MUSCLE GROWTH
When we exercise, microscopic tears in muscle fibers activate a chemical alarm that summons satellite muscle-repair cells to the tear. These stem cells divide and multiply before they fuse with the muscle fiber, leaving it bulkier than before it was injured
GROWTH THROUGH GENE TAMPERING
Injecting a synthetic gene into a healthy muscle can simulate growth-and-repair signals by producing a protein that tells the satellite cells to proliferate and become new muscle cells
ENDURANCE INCREASED WITH OXYGEN SUPPLY
Erythropoietin is a natural protein that stimulates the production of oxygen-carrying blood cells. When a synthetic version called EPO is injected, a person produces more red blood cells, which carry more oxygen to the muscles, increasing stamina
SOURCE:
