BioEd Online

With the Olympics Games fast approaching, headlines about drug-taking athletes stripped of their medals will surely not be far behind. So, away from the arena, a rather different race is being run - between the dopers and the officials trying to catch them out.

"The competition between testers and abusers is an ongoing cat and mouse game," says Norman Taylor, a biochemist at Guy's, King's and St Thomas' School of Medicine in London. And it is a battle that will probably never be won, says Vivian James, a chemical pathologist who advises UK Sport, the government agency that runs Britain's national anti-doping body. James acknowledges that the illicit chemists who make new drugs will probably always be one step ahead of the analysts.

"It's not too difficult for a competent chemist to change a drug's chemical structure to make it difficult to detect. It might take them only a week or two to develop a new steroid that could not be tested for," James says. But he emphasizes that it is much harder to determine whether these chemical tweaks affect the drug's effectiveness.

Although there are many different types of drugs used in sport (see 'The drug cheat's medicine cabinet'), steroid abuse has garnered the most headlines in the last few years because it has been linked with high-profile sprinters such as Dwain Chambers, who tested positive for the synthetic steroid tetrahydrogestrinone (THG). THG's muscle-building action was probably discovered by accident, says James, and its unusual chemical structure meant that it evaded detection for years before a tip-off from a coach alerted the US Anti-Doping Agency in the summer of 2003.

Drug testing was first introduced to the Olympics in 1968 and was used to detect about 20 drugs. The roll-call now numbers more than 150, and is still growing. But the number of illicit substances is probably even larger: "We simply don't know how many designer drugs there are out there," says James.

How much is too much?

A positive result on a test for a synthetic drug immediately implies guilt, but detecting abnormal levels of the steroids that occur naturally in the body is far tougher. "It's certainly a much bigger challenge," says Taylor. Nandrolone, which occurs naturally in the body in tiny quantities, is an anabolic steroid: it helps to build muscle mass. Tests for nandrolone actually look for molecules that are produced when the body breaks down this steroid.

Doping labs must then make a judgement about whether the level of a certain body chemical has been artificially elevated. Human beings exhibit a very wide range of body chemistry, and world-class athletes often find themselves at the extremes of that range simply because of a mixture of genetics and training. This has led to a string of appeals against recent bans for alleged nandrolone doping, which damage the credibility of both the athletes and the doping labs.

"I think the doping labs are being too stringent," says John Honour, a steroid chemist at University College London. The current limit for nandrolone is just two nanograms per millilitre of urine; if it is any higher than that, an athlete's career could be destroyed by the scandal of a positive drug test. But traces of the breakdown products from nandrolone are sometimes found in diet supplements that are frequently used by athletes. These traces would be insufficient to affect their performance, but enough to put them over the doping limit. Honour argues that this is no different from being banned for the traces of opiates found in the body after eating a poppy-seed bagel.

Honour thinks the answer is long-term monitoring of athletes to check for continuous use of banned substances such as steroids, which generally only benefit performance if used regularly for months.

The latest thing

Doping labs will soon have to deal with new and even more evasive enemies. "There's going to be a whole bunch of new compounds around the corner," Honour says.

He points to non-steroidal anabolic agents, a totally new class of compound that doping labs cannot yet detect. One example is Bicalutamide, a commercial drug used to treat cancer of the prostate, and he says there are a handful of others. "Although quite a lot is known about steroid action, you can still be surprised by molecules that on paper shouldn't work, but do," adds Taylor. This makes it difficult to anticipate the drug cheats' next molecular move.

The use of human growth hormone also seems to be on the rise, Taylor says. The hormone is legitimately manufactured for the treatment of muscle-wasting diseases and to boost stature in unusually short children, but some finds its way on to the black market.

'Gene doping' could be a realistic prospect in just a few years, says Geoffrey Goldspink, molecular biologist at the Royal Free and University College Medical School, London. Rather than injecting human growth factor to boost muscle size, gene doping would go straight to the source by giving an athlete extra genes so that they make more of the growth factor themselves. Goldspink's experiments with mice have already shown that injections of a gene that produces a muscle growth factor can boost muscle mass by about 25% in a matter of weeks¹. Honour says the doping agencies "are scared of it".

Although gene doping has not been tried in humans yet, the development of gene-injection treatments is progressing at breakneck pace. Experts remain hopeful that they can discover a smoking gun for gene doping, perhaps by studying how the genes' products are processed. Ultimately, the anti-doping agencies have to tackle every new method that rears its head, says Honour, alongside the hundreds of chemical tests they already carry out. "I don't see where it ever stops," he sighs.