The Explainer: Gene, gene, the doping machine

Dear Readers,
First off, we did get a good response from many of you regarding a possible point-counterpoint with Padraig over the issue of stop-as-yield, the policy that would allow cyclists to simply slow down at STOP signs. I have some great input on readers on the topic, but Patrick is a little banged up this week, so we’re going to put that idea on hold for a little while.

Second, I want to thank long-time reader Ed Rubenstein for sending me an absolutely wonderful press release from the Police Department of Bethlehem, Pennsylvania. The department is honoring two local citizens for their efforts to stop a hit-and-run driver from scampering away from the scene after he struck cyclist Frank Pavlik.

I won’t spoil the end by describing the events. Instead, just watch the video… indeed, you ought to scroll down and watch the video before reading the press release. While I am not normally a fan of those overly intrusive cam’ systems that seem to be popping up everywhere, this is one of the cases for which I am more than willing to make an exception.

The good news is that Mr. Pavlik was not injured in the incident.

Now, back to work.

Gene Doping?
Dear Explainer,
I am gonna take a shot and see if you’re willing to end your ban on doping questions.

So, I have been reading a lot about the “progress” researchers are making in the detection of illicit doping products – like CERA, EPO and NESP – and even the manipulation of blood counts by monitoring through the Biological Passport. Now, I’m beginning to wonder if all of that is worth the trouble, since it seems like the new thing in the 21st century is gene doping.

Is it detectable? If not, what the hell are we wasting millions on doping controls when the real cheaters aren’t being caught?
– Martin

Dear Martin,
Okay. I have to admit, I like the topic, too. It’s a little disheartening to constantly discuss the subject, but I do really find it fascinating. So, okay, I’ll try to tackle this one … and I’ll make a habit of answering future questions on the subject, if readers are interested.

Doping has been such a common subject of dinner time discussions in our house that I even got a copy of Angela Schneider’s and Theodore Friedmann’s book “Gene Doping in Sports: The science and ethics of genetically modified athletes” for Christmas a few years back. (And you probably thought I was tough to buy for.) A lot of progress has been made in the field since that book first came out in 2006, but the field is still in its infancy and I continue to believe that it may be some time before we see gene doping making an appearance in competitive sport.

That said, the day is getting closer.

As “traditional” doping is the unwanted off-spring of progress in pharmacology, gene-doping is the evil spawn of the new science of gene therapy. Instead of altering DNA to resolve an existing mutation or attack a disease, cheaters are hoping to trigger genetic changes that will result in enhanced athletic performances.

Case in point, is something I was planning to write about last summer, right after the Tour was over (but things came up that distracted me for a few months). Researchers at the University of Pennsylvania published an interesting article in the August edition of the Journal of Clinical Investigation. If you’re into that sort of thing, it’s worth trying to work your way through “Loss of IL-15 receptor á alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles.”

The short hand version is that the authors found the “negative regulator” of endurance. The absence of a specific gene actually allowed test subjects – in this case lab mice – to run more than six times farther than their counterparts who had the regulatory gene.

Another obvious approach, of course, is the effort to manipulate an athlete’s genetic structure in an effort to produce greater amounts of erythropoietin. Research has already shown that we could all become our own little EPO factories, cranking out red blood cells to our heart’s content.

And there’s the rub. At this point the science is still new. A few years ago, a study at France’s University of Nantes did show that genetic manipulation could “flip the switch” on erythropoietin production in mice. The problem was, however, that researchers hadn’t found the “off switch,” and the genetic manipulation resulted in the over production of red blood cells to the point the animals died of circulatory failure, heart attacks or strokes.

Of course, it may only be a matter of time before that regulatory mechanism is found. Already there are gene therapy drugs for anemic patients being produced in China and under preliminary review here in the U.S. I sure wouldn’t want to risk it, but others probably would. For long-time cycling fans, you might recall the spate of mysterious deaths of cyclists in the early ‘90s when some took a more-is-better approach to EPO and raised their hematocrit levels to 60 percent and beyond.

Testing?
Assuming the safety issues are truly resolved, the problem then comes down to one of detection.

One big advantage that testers have in the effort to monitor genetic manipulation is that such gene therapies take time. The result is not instantaneous as the body undergoes gradual changes as it begins to adapt to the new genetic sequence.
The World Anti-Doping Agency has announced that it is refining and finalizing a testing method to be used in time for the 2012 Olympics in London. Financed by WADA and developed at the Universities of Tübingen and Mainz, in Germany, the test is said to be able to detect genetic manipulation that took place up to 56 days before a sample is submitted. [Gene Therapy 18, 225-231 (March 2011)]

WADA is attacking the question on several fronts and has established a “Gene Doping Expert Group,” headed by the aforementioned Theodore Friedmann. The group is overseeing the development of testing protocols and, like its Biological Passport counterpart, will be heavily involved in decisions as to whether a sample is to be flagged as positive.

Is it going to be effective? Time will tell. I remain hopeful (some have said “clueless”) but no matter what, I would reject the idea that we abandon the very notion of testing and throw open the doors to cheaters, simply because the technological stakes are constantly being raised.
— Charles

P.S. – Back to racing, folks. I will be here – and on my own site, LiveUpdateGuy.com – providing up-to-the-minute reports on the action in tomorrow’s edition of Paris-Roubaix. I hope you can join me and the guests who may, or may not, wander through while we’re “on the air.”
— CP

The Explainer is a weekly feature on Red Kite Prayer. If you have a question related to the sport of cycling, doping or the legal issues faced by cyclists of all stripes, feel free to send it directly to The Explainer at Charles@Pelkey.com. PLEASE NOTE: Understand that reading the information contained here does not mean you have established an attorney-client relationship with attorney Charles Pelkey. Readers of this column should not act upon any information contained therein without first seeking the advice of qualified legal counsel licensed to practice in your jurisdiction.

Follow me on Twitter: @Charles_Pelkey

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7 comments

  1. Rp

    What does “Clean” look like?
    I like your passion for cycling and of course the explations you porvide. I was intrigued by the “Gene” article, which led to a thought when you mentioned the mice could not be turned off once started.
    We have seen a peloton with doping and your gentic explanation leads to a future of dna doping, but before we go there, what would one (peloton) look like without doping?
    Would there be a variety of winners vs one strong man, who would be younger or would experience play the significant role?
    I ask the question, because I’m not sure whether I would recognize a “clean” peloton … I have been fooled so many times in the past thinking the athlete I was cheering for was “unassisted”.
    So, before we break the bonds of genetics and jump into the future, can you attempt to answer this … what does a ‘clean’ peloton look like?
    thanks
    Rp

  2. Skippy

    Happy Easter to you and your family , and also your readers .

    Regardless of offence to some my POV on doping and ” generic Manipulation ” is that i hope they find NO method of turning OFF the dangers to those choosing to practice ” Sporting Fraud “!

    Reading the comments in a variety of ” forums ” leads me to believe that those that voice an opinion , choose to believe that there is no such thing as a ” clean Peloton “, nor that it ever existed ! Having cycled alongside so many of the ” stars ” on rest days and out of competition encounters i can tell you that i would not be able to detect the difference between ” clean ” or ” doped ” athletes . Of course , i watch and hopefully emulate their tactics and observe a variety of physiques put to use in training situations but i am sure there are other responses when racing .

    Pantani arrived in Madonna di C. in 1999 looking to me drained but within minutes he was looking really well in the Press Room . What had taken place between times , if anything , other than a washup by his soigneur ?

    Imagine what could be the future situation when ” Genetically Modified Athletes ” take their place in the peloton ? Mayhem for the most part ! No follower of cycling will rest easy and those placing money on the results , would be ” sheep to the slaughter ” , treated with the same disrespect as those that contributed to an infamous ” FFF ” that is now being investigated by the authorities that COULD lead to fraud charges in the near future .

    GREED will no doubt cause the death of more ” Athletes ” , whilst the pharmacists TRY to reduce the ” hazards ” of genetic manipulation . Thankfully i am reaching the point where those that i fancied and supported are now retired or near to doing so .

  3. Chris

    Firstly, I think, as has always been the case, some athletes will leave no stone unturned to try to derive a benefit. As such, gene doping, will be (or maybe already is) an issue in the pro peloton.

    A couple counterpoints, though, from my perspective as a molecular biologist. First, evidence of genetic manipulation would very likely, be detectable in the athlete for ever. The “Did he, didn’t he?” fiasco we have with Lance could be resolved 5, 10, 20 years after a cyclists retirement. It’s very difficult to get ride of the tell-tale sings of genetic manipulation. I think WADA needs to make in clear to athletes now that if they gene dope, they will be caught – even if it takes 20 years.

    Secondly, as a means of fighting viruses and other rogue genetic elements in our genome, our cells are very adept at shutting off many types of DNA sequences if they don’t belong there. This means an athlete might benefit from their new, improved genome for a season but would have to go back for frequent tweaks during their career.

    This might make their performance inconsistent, and would likely make their biological passport data look like a stage profile from last year’s Giro.

    In short, I don’t think gene doping will be any more of a game changer, or a blow to anti-doping efforts, than EPO was. If the authorities do the right things now rather than sticking their heads in the sand, hopefully we can avoid the debacle we had with EPO.

  4. Charles Pelkey

    Chris,
    Thank you. I appreciate your perspective. I have long been wary of claims that gene doping was to be the death knell of efforts to control “bio cheaters” (pharma and genetic).

    Might I assume that the ability to detect 20 years down the road would require the establishment of a baseline at the outset of one’s career? A simple DNA sample might suffice, but wouldn’t one, nonetheless, have to have something against which to compare?

  5. Chris

    Hi Charles,
    I don’t think a baseline would be necessary in this instance for a couple reasons. First, gene therapy/doping work by incorporating a piece of DNA right into the genome. You can either target the “doped” gene so that it replaces the normal gene – this is called a knock-in – or you can incorporate it elsewhere so you end up with an extra copy.

    Once the human genome was sequenced a dozen or so years ago, we know where all the genes live, and who their neighbours are. If you find the gene in a different neighbourhood, it’s a proverbial smoking gun.

    In the case of the knock-in, the gene is in the right spot, but has to be modified somehow to confer a performance advantage. The DNA sequence would have tell-tale signs of having been tinkered with so would also tip off a tester.

    Further, in both of these cases, not all the cells would be modified. So if you found that the athletes blood carried one copy of a gene, but a mouth swab gave a different result, once again, he’s busted.

    There are potentially ways of gene doping that would not leave of multi-decade trace, but these would be inherently short-lived and would show up on the biological passport.

    Granted I’m not an evil genius and haven’t spent hundreds of hours trying to come up with ways to foil testers, but gene doping is not the end game, it’s just the next stage in the arms race between cheaters and testers.

  6. Boy_Howdy

    The one good news with regard to IL-15 is that if you indeed somehow engineer a way to ‘knock it out’ in a human, the health consequences would be dire. You’d have a real difficulty fighting infection, and a likely increase in the chance for cancer. So they’d be dead dopers. We can get behind that, right?

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