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by: david warmflash

After theDavid Warmflash Zika virus, the next most popular health topic trending during the recent Olympic Games in Rio de Janeiro, Brazil, was designer drugs. This term refers to gene doping, use of gene therapy to boost athletic performance, which the World Anti-Doping Agency (WADA) has prohibited since 2001.

In the final days of Rio 2016 in mid-August, the International Olympic Committee (IOC) warned that anyone considering designer drug use should think twice. “We will store [athletes’ urine and blood] samples,” said Richard Budgett, the IOC medical chief. “ If someone thinks they have designer drugs eventually they will be found…The message for all those cheats out there is ‘beware you will be caught.’ I am confident we have the deterrents that should lead to the protection of clean athletes.”gene_doping_500

Currently the IOC radar screen is on the prospect of gene therapy directed at giving an athlete extra copies of the gene encoding erythropoietin (EPO), a hormone that stimulates bone marrow to increase production of red blood cells (RBCs). This is the logical next step from a more traditional doping tactic of injecting recombinant EPO. The latter is fairly easy to detect, because blood levels change with pharmacokinetics that you’d expect from any injected agent. The same is true for recombinant human growth hormone (rhGH) which is also a notorious sports doping agent. Normally, one’s naturally-occurring EPO genes are stimulated to increase output as a physiological response to increased demand for oxygen delivery—as occurs after significant blood loss, or spending time at high altitude. However, giving a person extra copies of the gene means that baseline production of EPO will be higher than average. However, in contrast with direct use of recombinant EPO, the changes in EPO blood levels will look natural.

Gene therapy currently requires enormous amounts of vectors—virus particles, lipid spheres, or other particles to contain the therapeutic genes and deliver them through the blood to target tissues. Consequently, screening tactics for gene doping include new tests that detect vector remnants. Furthermore, while particular vectors can be selected to deliver genes to specific tissues, with a commonly used vector called AAV, a few of the therapeutic genes may reach white blood cells as an unintended consequence. Inside the white blood cells from samples of athletes who have received the therapy, the extra copies of the EPO genes would be easy to spot since they’d exist as episomes—pieces of DNA separate from the chromosomes.

Available tests and the IOC warning notwithstanding, gene doping with the EPO gene may be just the beginning. Gene therapy is developing extremely rapidly and delivery tactics may change in the years to come. Athletes may consider a range of body functions to alter. They might tamper with the gene for myostatin, for instance. This is an enzyme that inhibits muscle growth. Eliminating both copies of the gene causes muscles to bulk up, though with increased rigidity, but losing one of the two copies makes the muscle grow and also perform better.

(a) Delivery vectors for intracellular delivery of nucleic acids. Apart from viruses, synthetic cationic vectors such as cationic polymers, branched dendrimers, cell-penetrating (CP) peptides and cationic liposomes can be used to deliver genes into cells. (b) Properties of an engineered synthetic vector for gene therapy in the future. In addition to exhibiting good biocompatibility, loading capacity and transfection efficiency, a future synthetic vector may also be designed to have a desired intrinsic biological activity that would enhance the effects of gene therapy. (Reused with permission from Nature, doi:10.1038/sj.gt.3302692)

(a) Delivery vectors for intracellular delivery of nucleic acids. Apart from viruses, synthetic cationic vectors such as cationic polymers, branched dendrimers, cell-penetrating (CP) peptides and cationic liposomes can be used to deliver genes into cells. (b) Properties of an engineered synthetic vector for gene therapy in the future. In addition to exhibiting good biocompatibility, loading capacity and transfection efficiency, a future synthetic vector may also be designed to have a desired intrinsic biological activity that would enhance the effects of gene therapy. (Reused with permission from Nature, doi:10.1038/sj.gt.3302692)

The advent of CRISPR-Cas9 genome editing may enable enough control for planned knockouts of one yet not the other copy of the myostatin gene. Gene therapy using CRISPR might also be employed to change muscle phenotype. Power athletes, such as sprinters, excel when their muscles have high ratios of white (fast-twitch) fibers versus red (slow-twitch) fibers; whereas, high red-to-white ratios confer benefits for endurance sports. Thus, depending on their sports, would-be gene dopers might opt to switch fibers over to one type or the other.

Treatment might be administered directly to the target muscles, avoiding the bloodstream in which case IOC might be compelled to demand muscle biopsies, which elite athletes may not welcome. Furthermore, CRISPR could be used to add genes very accurately in particular locations in chromosomes. All of this paints a picture of a future in which genetic modification of athletes may be extremely difficult to detect, or at least unreliable enough to be useful as evidence of cheating.

David Warmflash, M.D., is an astrobiologist, science writer, and physician. He is principal investigator on a Planetary Society-sponsored investigation of the effects of the space environment on organisms.