The world of sports doping is a high-stakes, hi-tech game played out at race tracks and in labs. But as the Olympics approaches, scientists hope a raft of new techniques will give them the edge in the battle to catch out unscrupulous athletes.

He thought he had got away with it. In August 2008, track and field athelete Rashid Ramzi stood on the Olympic podium in Beijing to collect a gold medal for the men's 1500m. The Moroccan native was competing for Bahrain, and his victory gave his adopted country its first-ever Olympic medal. But 15 months later, he had been stripped of his win and his running career was all but over.

It was a major coup for the International Olympic Committee (IOC), and proof that so-called retrospective testing for banned substances worked. But that was nearly three years ago and the world of sports doping moves quickly. Experimental compounds are traded on the internet and at the race track before they are even approved for use in humans, whilst increasingly complex compounds and techniques are used to give athletes a crucial edge and hide the evidence. As the London Olympics approaches, the authorities are once again preparing to do battle with the dopers. And this time the scientists hope a raft of new techniques and measures will tip the balance in their favour.

These systems have been refined over decades of drug use. In the mid-nineteenth century, for example, there were various reports of athletes using drugs as diverse as nitro-glycerine, opium, cocaine and caffeine – all of which were considered an acceptable part of competition. But that changed in 1967 when, spurred on by rising levels of use, the IOC banned all performance-enhancing drugs. Just one year later, Swede Hans-Gunnar Liljenwall was the first to be caught out by the new rules after downing a couple of beers to steady his nerves before a pistol shooting competition. From those relatively innocent days, doping – and anti-doping – has become a hi-tech, high-stakes game of cat and mouse.

In London there are plans to conduct 5,000 drug tests – 500 more than were done in Beijing – covering nearly half of the 10,500 athletes competing, and including each and every medallist. “We’ll provide most negative results in 24 hours and positive ones in 48 hours,” says Jonathan Harris, head of anti-doping for the Games.  In order to process so many samples, the testers have partnered with pharmaceutical giant GlaxoSmithKline, which has technology that can look for more than 60 illicit substances in a single test. “We’ve brought the world of pharma a little closer to the world of anti-doping,” he says.

Black market trade

But it is not just the scale of the operation that has changed. Where drug testing was once reactionary – officials would wait for an indication that athletes were using a new drug, then move to prohibit it and then develop a test – officials at organisations like the World Anti-Doping Agency (Wada) now aim to get ahead of the curve.

The agency maintains a detailed list of prohibited substances and methods, and it has devised the list to address not only specific drugs, but categories of potential drugs and methods to ensure that rules cover new methods not yet known to them. As a result, any drug that has not been approved for human use is automatically banned, as are substances with similar chemical structures or biological effects to other abused substances, such as hormones and growth factors.

“What’s really changed in recent years is that we want to predict what people will use next,” says Daniel Eichner, laboratory director of the Sports Medicine Research and Testing Laboratory, a Wada-accredited drug testing lab in Salt Lake City, Utah. “So we scour the medical and scientific literature, look at drugs that are in the research and development pipeline at pharmaceutical companies, and see if there’s any kind of application they may have in the future for doping.”

For instance, since the late 1980s unscrupulous competitors have used erythropoietin (EPO), a hormone that stimulates the production of oxygen-ferrying red blood cells. The drug increases the blood’s oxygen capacity, boosting endurance and stamina by as much as 15%. When drug testers finally developed a test for EPO, dopers turned to next-generation versions of the drug, originally developed to treat severe anaemia in cancer patients.

But this time, Wada was ready. Recognising that it was all but inevitable that rogue athletes would turn to versions of EPO still under development, WADA had begun collaborating with companies to ensure that it would have a test waiting. “We recognise the need to anticipate trends,” says Wada’s director Olivier Rabin.

While legitimate scientists aren’t developing drugs specifically for performance enhancement, numerous researchers are working on disease-fighting medications that might also boost athletic performance, and many of them have received calls from coaches or athletes seeking to obtain such drugs before they’re approved or publicly available. These requests are usually rebuffed, yet some of these early stage drugs (or products claiming to contain them) still make their way to the black market.

“There are a lot of people out there who are willing to be the human guinea pig,” Eichner says. As evidence, he points to the proliferation of products for sale on the internet that purport to contain myostatin inhibitors. Myostatin is a hormone that regulates muscle growth. “If you knock that out or inhibit myostatin, then your muscles just keep growing,” Eichner says. Belgian bulls lack myostatin, resulting in extreme musculature – they look like bovine Arnold Schwarzeneggers.

Researchers are studying myostatin inhibitors for the treatment of obesity and diabetes, but no products have been approved for use yet, and some research suggests they may make users more prone to muscle and tendon injuries. But none of this has stopped would-be dopers. “Are they available for clinical use? Not yet,” says Eichner. “But you can still buy them on the black market.” The regulation of such sales falls to agencies like the Food and Drug Administration in the US, but Wada has reacted by reaching out to researchers and companies studying substances like these to recruit their help with detection.

For instance, GlaxoSmithKline has signed an agreement with Wada to give the Agency advance warning about the development of products that cheats might try so that anti-doping officials can get ahead of the curve. Myostatin inhibitors are listed on Wada’s prohibited list and they are already detectable using standard laboratory techniques. Working quietly with drug developers allows Wada to maintain an element of surprise and keep cheaters on alert. “When an athlete cheats, our goal is to catch them. If we tell them about a new test ahead of time it defeats the purpose,” says Rabin.  

Blood lines

Not every new testing method gets adopted quietly, however. Wada’s most ambitious detection method had a very public inception. “The biological passport has changed the paradigm,” Rabin says. The passport – essentially an electronic record – stores snapshots of an athlete’s physiological parameters at various times in the season to establish an athlete’s normal values and look for discrepancies between tests that could indicate doping. Instead of looking for a particular substance in the blood or urine, the passport reveals the tell-tale physiological effects that a given substance or method provoke.  The technique is already in use and will provide a crucial component of the London 2012 testing programme.

The concept arose from a growing recognition among anti-doping researchers that cheaters were gaming the system. Although Wada has instituted random, out-of-competition testing in addition to traditional post-event drug screens, most of these tests can only detect doping agents within a small window of time, and savvy athletes can use this to their advantage, for instance, taking drugs in microdoses that clear the system quickly without spiking levels.

The passport has a number of different modules, which cover different markers in different parts of the body. For example, the first one to be used – the blood passport – aims to identify blood dopers via markers that fluctuate when someone takes a blood transfusion or a blood-boosting drug. Concentrations of haemoglobin – the protein in red blood cells responsible for transporting oxygen around the body – provide one such marker, says Eichner. If someone who normally produces a value of around 14 suddenly spikes up to 18 or 19, this suggests doping and would flag the athlete for further testing for EPO or a blood transfusion – a common way of increasing the number of oxygen-transporting blood cells in the body and increasing performance.

Another marker the passport covers is the concentration of baby red blood cells called reticulocytes. “If you take a drug to increase red-blood-cell production, you’re going to get a spike in reticulocytes,” Eichner says. Conversely, if an athlete takes a transfusion their body suddenly has a lot a more blood than it needs, and it shuts down production of red blood cells and reticulocyte concentrations drop.

A strength of the passport is that each athlete serves as his or her own reference. “We’re using mathematical models to, in a sense, predict for each athlete what the next values should be,” says Rabin. “If the next value is in the same ballpark, we can say that’s normal. If it moves significantly up or down, then we say there’s something abnormal.” It can also spot minor changes that may alert anti-doping authorities that the athlete is worth watching.

Gene tricks

But as drug testers develop better ways to detect doping substances, there is an increasing fear that cheaters will seek ways to turn their bodies into doped-up versions of themselves via genetic manipulation. Such an approach, dubbed gene doping, would turn on specific genes that are known to enhance athletic performance.

The process is similar to gene therapy, which aims to treat diseases by inserting a healthy version of a gene into a human to replace a faulty one. This is commonly done using a vehicle, such as a virus, to deliver the desired gene to targeted cells, where it can do its work. It has had some success in treating conditions such as severe combined immunodeficiency (SCID, also called “boy-in-the-bubble syndrome”). But it is still a relatively new technology with unknown risks. For example, it produced disastrous immune responses and provoked leukaemia in some patients. And in 1999, 18-year-old Jesse Gelsinger died from a severe immune reaction he developed after receiving gene therapy.

But groups like Wada believe that it is not a case of if, but when someone turns to gene therapy in sport. Genes that promote muscle gain, such as IGF-1, are an obvious target for gene doping. “Some in the muscle field have been approached repeatedly, asking what’s new and what’s available,” says Theodore Friedmann, a gene therapy researcher at the University of California, San Diego. Genes that turn on EPO are another obvious target.

The problem with gene therapy, Friedmann says, is that once initiated, it may be difficult or impossible to turn off. This could prove fatal, for instance, if an athlete who took gene therapy to raise red blood cell production developed blood too thick for the heart to pump.

No one thinks that gene doping is rampant, at least not yet, but its inherent dangers may not be enough to deter would-be users. In 2007, German track coach Thomas Springstein sent an email to a Dutch doctor asking for advice on how to acquire Repoxygen, a gene therapy designed to turn on the body’s production of red blood cells. Its developer, pharmaceutical firm Oxford Biomedica, was looking to develop Repoxygen as an anaemia treatment, but the drug has never been tested in humans, and it is not clear that Springstein ever got his hands on it. Still, the development is worrying because it shows how reckless dopers are willing to be, says Friedmann.

“It’s not rocket science,” says Friedmann. “Someone who wants to gene dope could easily gather people well-enough trained in molecular biology to do it.” Given the troubles that have plagued legitimate gene therapy, the results of rogue gene doping is likely to be disastrous. “There’s money to be made there, and lots of [researchers] who can’t find jobs might be convinced to try it,” Friedmann says.

Wada has had a gene doping research program since 2002. “A lot of people told us it would never be possible to detect gene doping, but we’ve we achieved some major breakthroughs,” Rabin says. He’s not revealing too much yet, but regardless of how far such tests have come, would-be dopers of any stripe cannot rest easy.

That’s because retrospective testing – the kind that caught out Rashid Ramzi after the 2008 Beijing Games – is now standard. At the time of Ramzi’s win, there was no test for the blood-boosting hormone he had used in the run up to the Games. But when that changed shortly after the fireworks of the closing ceremony, the IOC decided to retrospectively test hundreds of samples, catching him and five others out.

Officials with the London Olympics have already announced plans to store samples taken during the 2012 Games for eight years, allowing them to be retested as new technologies become available. “We can’t promise that these will be cleanest Games ever, but if people are cheating here, we will catch them,” says Jonathan Harris. Dopers could steal the glory of standing on the podium in London, he says, but they will spend the next eight years looking over their shoulders wondering when the testers will catch up.

(18/04) The article has been updated to correct inaccuracies about gene therapy.

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