How to Catch Olympic Cheats

Athletes aren't the only ones racing against the clock this week in Beijing. A team of skilled scientists is working 24 hours a day at a drug-testing lab in Beijing's Olympic Sports Center, analyzing approximately 4,500 blood and urine samples for banned substances. Their work is part of an ever-evolving arms race between scientists and sports cheats who try to stay one step ahead of the latest detection methods.

On Monday, the International Olympic Committee (IOC) announced the first athlete to fail a drug test in Beijing: Spanish cyclist Maria Isabel Moreno, who tested positive for the red-blood-cell-boosting hormone erythropoietin (EPO). But IOC president Jacques Rogge has predicted that 30 to 40 athletes will test positive during the games.

EPO is used therapeutically to treat anemia, but it also boosts blood oxygenation in healthy people, and it has proved troublesome for scientists to detect. For one thing, traces of the drug are quickly eliminated from the body. "When the drug is gone, the urine test becomes negative, but the effect of the drug lasts longer and the athlete is still enhanced," says Don Catlin, founder of Anti-Doping Research, a nonprofit research institute based in Los Angeles that is helping oversee drug testing in Beijing during the games. "Therefore, athletes game the test, trying to figure out the dosing regimens that will keep them beneath the radar."

In an attempt to catch those athletes out, the Olympic antidoping lab has dramatically stepped up testing compared with previous games, conducting 1,000 more tests than in Athens in 2004 and double the number at the Sydney games in 2000. That increase comes largely from greater numbers of tests per sample, rather than from an increase in the number of samples collected.

The IOC and the World Anti-Doping Agency (WADA) are also developing new testing techniques, although they won't give details about any new tests that they plan to run at this year's Olympics. "We need the elements of secrecy to try to be ahead of the game," saysCatlin.

This secrecy won WADA a dramatic victory at the Tour de France last month. Its drug-testing lab caught several cyclists using a longer-lasting form of EPO called CERA. Soon after the athletes were caught, it was revealed that the agency had been working with Swiss drugmaker Roche to develop a test to detect CERA while the drug was still being tested by the U.S. pharmaceutical company Amgen.

Unfortunately, generic versions of the drug are popping up all over the world. And because each has a chemical composition slightly different from the original version, scientists must design a new test for each variety. (Scientists detect the different forms of EPO using a standard laboratory technique called electrophoresis, which separates molecules based on their charge. The man-made versions have a different charge than the peptide made naturally in the body.)

Catlin says that many more versions of EPO are likely to emerge, as well as a related class of drugs called next-generation erythropoiesis-stimulating agents, or ESAs. One of those, Hematide, is already in late-stage clinical trials. "As soon as that's out, it will find its way into the hands of sportsmen and -women," Catlin says.

He ultimately hopes to use mass spectrometry, the gold standard in analytical chemistry, to detect all forms and variants of EPO with a single test. Mass spec measures the unique spectral profiles generated by different molecules, giving an unambiguous method of detection. While the technique is already used to detect other banned drugs, the chemical structure of the EPO molecule makes it difficult to measure using traditional mass spectrometry. "It is a complex drug with glyco groups hanging off it," says Catlin. "We have to get rid of these groups or find a way to characterize the whole intact molecule."

Another significant challenge for the antidoping authorities is human growth hormone (hGH). This drug is virtually identical to the most common form of growth hormone produced naturally by the body. It is made by inserting the human gene for the growth hormone into bacteria.

The current test for hGH was first used at the 2004 games in Athens, and it will be used more broadly in Beijing. The test analyzes the ratio of different forms of the hormone in the blood. "If an athlete uses recombinant hGH, which is identical to the major isoform of natural hGH, the ratios that normally occur are influenced and significantly altered," says Mario Thevis, a professor of preventive doping research at the German Sport University Cologne. "This can be measured and visualized, and enables the detection of hGH misuse." Thevis is also working on a more sensitive test that can detect different varieties of hGH.

And while WADA prefers to stay mum on the specific details of new tests currently under development, the agency has disclosed details of a broader new approach that might overcome some of the challenges associated with detection of EPO and hGH. Using new technologies, such as microarrays, which can simultaneously measure changes in the expression of thousands of genes, proteins, and other biomarkers, scientists can quickly search for biological changes induced by such drugs. "The new armamentarium doesn't look for drug X; it looks for the effects of drug X," says Theodore Friedmann, a physician scientist at the University of California, San Diego, who is working with WADA. Thanks to this approach, altering a drug so that it becomes invisible to testing will no longer be possible, he says.

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