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Genetic Linkage

Should Gene Doping Studies Be Published?

In late 2011, creation of a lab strain of of H5N1 influenza capable of spreading easily among ferrets, and presumably us, sparked heated debate about whether and when to publish scientific research that could do harm. The same could be said for gene doping.

Consider a report about use of IGF-1 (insulin-like growth factor-1) to enhance athletic performance, from researchers at the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy, published in Human Gene Therapy. (“Enhanced athletic performance upon multi-site AAV-IGF-1 gene transfer coincides with massive modification of the muscle proteome.”) The report concerns gene therapy to deliver the DNA instructions to make the molecule, not the IGF-1 itself.

The article title doesn’t indicate that the improved athletes were of the rodent variety (see my next blog in a few days). But the researchers injected 100 billion adeno-associated viruses harboring human IGF-1 genes into several leg muscles of 4-6 week old male mice. The little beasts were then placed in a 200 liter bathtub-like contraption with a shovel at one end that makes waves, like a wave pool at an amusement park, pushing the animals to exhaustion.

Thirty days after the gene therapy shots, each of several dozen mice took a 15-minute swimming lesson, repeating it every other day for 2 weeks. This was the training before the exhaustion test, like taking your kids to the Y for swim lessons before throwing them into a swim meet. For said exhaustion test, each mouse had metal wires attached to his tail, in case the task wasn't challenging enough. The outcome measure was “maximum swimming time before submersion,” but fear not, the animals were quickly scooped up, warmed, and returned to their cages. Their unfortunate mates who were part of earlier studies to track metabolism were sacrificed on day 15 or 30 so their muscles could be sliced and studied for evidence of telltale molecules of anaerobic respiration.

Muscle samples taken at various time points and subject to RNA analysis, which reflects the active genes, revealed what was happening. The subheads in the article, which I read aloud to my husband the former marathoner, had him panting for more:

“Profound changes in skeletal muscle structure and metabolism”

“AAV-IGF-1 remarkably improves muscle performance”

The mouse muscles grew, knit themselves new blood vessels, and converted fast-twitch (sprinter) muscle fibers to slow-twitch (endurance), to which my husband paid particular attention. Swimming endurance increased 3-fold.

Will IGF-1 join the ranks of other hormones and growth factors reinvented as performance enhancement drugs? EPO anyone? HGH?

Indeed, the article ends with: “Thus, our model fully supports the concept that IGF-1 gene delivery can be considered a realistic way to achieve a greater athletic performance.” Like the headline and subheads, the statement fails to distinguish between lesser mammals and the people they model.

I wasn’t so sure the findings could safely apply to humans, despite the fact that ads for IGF-1 have been on the Internet for years. So I e-mailed the researchers. And here’s what Mauro Giacca, MD, PhD, answered: “We never tested the effect of IGF-1 long term. However, there is published evidence that transgenic mice overexpressing constitutively this factor have important cardiovascular problems. I would definitely not recommend to take IGF-1 as a nutritional supplement for prolonged periods of time.”

But a warning like that isn’t in the actual article. The closest is the final sentence at the end of the abstract: “Collectively, these results give important insights into the biological response of muscles to continuous IGF-1 expression in vivo and warn against the potential misuse of AAV-IGF-1 as a doping agent.”

I think the ambiguity of that conclusion may do more harm than good to those looking for a competitive advantage, validating the ability of IGF-1 to boost performance – at least if you are a mouse.
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