Engineering a win (2007 Oct)

Engineering a winIssue 17 of Cosmos, October 2007 <> by Dominic Cadden <> Sporting prowess at the flick of a gene? In the race to be the best, some athletes are even prepared to toy with their DNA.

Doping in sport is big business. Fierce competition drives athletes to extreme measures to improve their performance, while sports institutions employ ever more comprehensive tests to screen for the most commonly abused steroids and drugs.

The next paradigm in doping for those who can afford (and stomach) it may lay in illicitly manipulating their own DNA for a range of benefits, from increased stamina and reduced fat to larger muscles. 'Gene doping' exploits the ability to splice or 'cut and paste' useful genes resulting in athletic benefits ˆ and unknown side effects ˆ that last a lifetime.

A substance linked to gene doping was first detected at the 2006 Winter Olympics and there's now concern the practice could be used in the 2008 Beijing Olympics.

Gene doping is a spin-off from gene therapy, which is being investigated to treat hereditary disorders such as cystic fibrosis by replacing a patient's faulty genes with functional ones. Doctors have had some success with transferring genes into harmless viruses, which are injected into the body. With luck, these viruses replicate within target cells and copy themselves into the body's strands of DNA.

"The skills involved aren't that difficult," says Daniel Eichner, scientific manager for the Australian Sports Anti-Doping Authority in Canberra. "There are scientists who are willing to do anything for money, and a lot of athletes are willing to put their body on the line, no matter what the danger."

Even in medical gene therapy, however, two major dangers exist. The first is the risk that a manipulated gene can't be controlled or turned off. The second is that gene therapy could trigger cancer. One seemingly successful French trial for treating severe combined immunodeficiency disorder was halted in 2002 when some of the 11 patients developed leukaemia. However, despite the risks, the temptations will be hard to resist.

Since the full publication of the human genome in 2004, a handful of the 25,000-odd genes detected so far have been found to have some role in athletic performance. One example is the IGF-1 or insulin growth factor gene, says geneticist Damien Abarno of the University of South Australia in Adelaide. Scientists have already had some success getting this gene to 'take' in animals and, unlike steroids, "it increases the number of muscle cells, not just the size of them," he says.

And there are many more genes that could be useful to athletes. Boosting the expression of the gene for MGF, or mechano-growth factor, could limit fatigue and improve muscle repair. The AMPK gene affects how muscles accumulate glycogen, and therefore impacts endurance. The ACE-1, or angiotensin-converting enzyme gene, can be deleted for increased strength or inserted for greater endurance, and has an effect on blood pressure and how muscles use oxygen.

Only a few of these genes have been extensively tested for side effects. However, animal trials with one gene called HCP have highlighted some of the potential risks. One common method of improving performance is increasing red blood cell numbers, which boosts the transport of oxygen from the lungs to the muscles, improving stamina and performance. The conventional method of boosting red blood cell count is with the hormone erythropoietin (EPO), although this is now easily screened for in athletes. Similar effects can be gained by inhibiting the function of the gene HCP, which itself regulates blood cell distribution. However, trials in monkeys were unsuccessful, and often fatal, says Albarno. "The problem was that the [red blood cell count] increased rapidly up to levels where it turned the blood to jelly."

This side-effect was avoided with a different gene therapy treatment, for anaemia. Tested in 2002, but never produced commercially, Repoxygen works by increasing levels of the body's own EPO. This, in turn, boosts red blood cell production, but only in response to very low levels of oxygen that might be experienced with anaemia or during intensive exercise.

It was Repoxygen that German athletics coach Thomas Springstein was accused of attempting to obtain prior to the 2006 Winter Olympics in Turin, Italy. Springstein and another trainer in Germany are under investigation by the World Anti-Doping Authority (WADA), which outlawed gene doping in 2003. The WADA is now working with geneticists to find effective screening techniques.

"Close to US$8 million has been spent in the WADA research program for gene doping, representing a significant portion of the entire budget," says geneticist Theodore Friedmann at the University of California in San Diego, USA, and chair of WADA's gene doping panel.

One proposal has been to genetically map athletes and then periodically re-screen them to detect changes, says Robin Parisotto, a Canberra-based consultant to Sport Knowledge Australia, who helped establish a test for blood doping with EPO. "But when do you do that? Before they become elite athletes, as a child, or soon after birth?" Parisotto asks.

Friedmann says that scientists working under the WADA banner have studied a number of the side effects that occur with changes to genes and to metabolism. If researchers can put these together to create a 'signature', eventually it may be possible to detect this signature in saliva samples, he says. "In exactly the same way that DNA technology has added so much in forensic science and crime detection, it will add very powerful new tools to detect doping."

With the 2008 Beijing Olympics looming, the clock is ticking to find tests capable of detecting the practice.

"Realistically, it will be very difficult to have a test up and running before Beijing", says ASADA's Eichner. But this doesn't mean GM cheaters will manage to remain undetected ˆ WADA rules allow samples to be tested for up to eight years after an event. 

Dominic Cadden is a freelance science and physiology writer based in Sydney, Australia.