January 1, 1970 (Vol. , No. )

Zachary N. N. Russ Bioengineering graduate student UC Berkeley

When it comes to games, the Olympics are probably as far as you could get from a friendly match. Worldwide sporting events are matters of national pride and offer life-changing prizes of fame and fortune to the victors. With high stakes and stiff competition, it is a natural consequence that contenders will do what they can to succeed, utilizing both legitimate and illegitimate means.

Another high-stakes game, the Graduate Record Exam (GRE), acts as the gatekeeper to graduate schools. The GRE was featured in last month’s news for the cheating rings that have formed around it: students taking the exam would memorize questions and pool them with other students to generate pirated copies of the exam.

Where students might hire tutors and use practice books, Olympic teams have members who have been training as long as they can remember with the best coaches and nutritionists. If admission to graduate schools and fellowships can attract a sophisticated network of cheaters, imagine what the Olympic gold could draw.

A Card Up the Sleeve

It doesn’t take much of an imagination. Over the decades, amphetamines, anabolic steroids, erythropoietin, self-transfusions, and gonadotropins have been used to improve performance in the Olympics and other international competitions.

It’s almost a given that the discovery of a new medical treatment will find its application in performance enhancement. Even investigational drugs such as Andarine (a selective androgen receptor mediator), GW1516 and Acadesine (AMPK activators) are available on the online black-market and could be used as anabolic steroids and endurance boosters, respectively.

While many of these drugs are relatively easy to detect, manifesting themselves as anomalous compounds or metabolites that can be detected via GC/MS or LC/MS, drugs that mimic naturally occurring molecules such as erythropoietin (EPO) or human growth hormone (hGH) prove to be a little more difficult.

ELISAs to detect pharmaceutical formulations of the molecules are one option. PEGylation and domain being are the major structural differences for EPO varieties. But hGH is a more difficult challenge, and detecting administered hGH may rely on the ratio of its naturally occurring isoforms or other protein levels that may be affected by a sudden dose.

Shuffling the Deck

The real challenge is what’s coming next. Gene doping makes use of drugs that work through increasingly roundabout pathways: Instead of administering EPO directly, they use an inhibitor (HIF-stabilizer) to shut down the negative feedback systems in the hypoxia pathway.

This creates pseudohypoxia, where cells behave as if they were under hypoxic conditions, leading to increased production of EPO. Using a drug to create pseudohypoxia is cheating; training at high altitudes to create hypoxic effects is not. Distinguishing the two isn’t always so easy as finding an odd compound like hGH; secondary biomarkers have to be examined.

In developing an assay, an academic (University of Pennsylvania and University of Tübingen) and corporate-sponsored (Qiagen) team took mice to the peak of Mount Everest to gain a baseline example of natural hypoxic behavior.

Ultimately, it seems as if the only way to detect gene doping is noting the perturbations doping causes in biological systems. While the agents themselves may become undetectable through their diversity or subtlety, the abnormal biological responses will remain conspicuous. Studies on pseudohypoxia biomarkers and similar endeavors will contribute to better models, advancing knowledge of disease states as well as antidoping research.

Knowing When to Fold

While catching a gene-doping cheat with the ripple-effects of their treatment might be feasible for the more blatant cases of abuse, variations in individual physiology and diet put a lower bound on what can reliably be detected. Furthermore, accounting for individual variation by profiling athletes over time just means they can continue with the same doping regimen they were using when the profile began.

If permanent human genetic modification becomes a reality, the gene doping discussion becomes moot. Athletes could pick up polymorphisms such as myostatin dysfunction, which results in greatly increased muscle mass and strength, or perhaps upregulated copies of the erythropoietin gene.

Athletes would no longer have to play with the cards nature dealt them, and it would be unreasonable to ban someone from competing because of their genes. The question of fairness would no longer be “Why should these few be permitted to alter their physiology?” but instead, “Why can’t everyone else?”

Even if the health risks of doping disappear and fairness permits reshuffling the genetic deck, there’s still one point against doping:

“There is no gene for the human spirit.”—Gattaca (1997 film tagline)

Zachary N. Russ ([email protected]) is a bioengineering graduate student studying synthetic biology at UC Berkeley.

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