Overabundant skepticism about genetic manipulation in sports may be as dangerous as the hype that heralded its arrival.
Alexis Madrigal
After Ye Shiwen shocked the Olympics with her performance in the 400 meter individual medley, swimming the last 50 meters faster than Ryan Lochte, the men's champion in the event, a long-time American coach ominously hinted that perhaps a new kind of performance enhancement had arrived on the athletic scene."If there is something unusual going on in terms of genetic manipulation or something else, I would suspect over eight years science will move fast enough to catch it," John Leonard, the American executive director of the World Swimming Coaches Association, said.
It's important to note that there is no evidence that Ye engaged in any doping practice, let alone something as new and high-tech as genetic manipulation.
But, the fact that genetic manipulation was even on the table or in the ether as the example Leonard gave in his accusation is remarkable. So I set out to find out how scientifically plausible it might be for Ye -- or any athlete -- to enhance his or her performance with current gene doping technology.
The context here could not get larger. Ever since humans deduced the powerful nature of DNA and all the associated molecules that do work in our cells, people have wondered: how long before we can simply change our own genes? On the one hand, all kinds of genetic diseases could be cured. On the dark side, if genetics sets the limits of human action, how long before we create genetically enhanced humans? And, like many things in bioethics, these thoughts are never very far away from the long shadow of the Nazis' eugenics program.
These fears and hopes have traveled with all kinds of work on the genome from Watson and Crick through the Asilomar Conference on Recombinant DNA to the earliest gene trials and the sequencing of the human genome. But until very recently, we had no evidence that transferring genes into human cells was helpful at all. In the early 2000s, gene therapy suffered a series of setbacks, including the high-profile death of a young patient. In the words of the Mayo Clinic, "The possibilities of gene therapy hold much promise. To date, however, that promise has not been realized."
Given that background, I was planning to write a story about how it was sort of nuts for John Leonard to talk about genetic manipulation, not because athletes wouldn't try it, but because it's unlikely to be effective.
But then I called up Richard Snyder, a University of Florida biologist who has a grant from the World Anti-Doping Agency to create reliable blood tests for gene doping. As as result, he's intimately involved in both what might be possible with current gene transfer technology -- and how we might detect any kind of illicit practice.
Snyder told me that gene doping of exactly the kind you'd expect high-level athletes to use is already effective in animals and that in the last few years, therapeutic gene therapies in humans have started to experience and sustain success, particularly in treating hemophilia and certain types of congenital blindness. And right now, there's no available test for gene doping. Put those three facts together and the idea that someone might be transferring genes into his or her body doesn't sound so outlandish.
"In the last five years, there have really been some dramatic examples of gene transfer being efficacious in humans. What we've been seeing in animals for a long time is coming to humans. We've optimized the delivery routes and the viral gene transfer vectors themselves. We understand the diseases better and know what genes we need to deliver to treat people," Snyder said. "This technology can also be usurped for illegitimate means."
He sent me over a paper his team published last year in the journal Gene Therapy, and began to walk me through how gene doping -- and his method of catching it -- could work.
How Gene Doping Works
Here is the basic idea of gene doping. First, you need a virus. Viruses work by going into the cells of your body and hijacking the machinery in there to make more of whatever they want, which in many cases is more viruses.
Second, you need to modify that virus. Scientists have been defanging viruses for a while and turning them into DNA delivery machines that they call vectors. These viruses are loaded with a "cassette" (this is actually what they call it) of DNA that the viruses then insert into cells within the mammalian body.
That DNA is the blueprint for whatever protein you are trying to make. In the case of doping, there's a protein hormone that your kidneys make called Erythropoietin, or EPO. Hormones control a lot of things in your body; in this case, EPO stimulates the production of red blood cells (erythrocytes). Because red blood cells carry oxygen, having more of them means more oxygen carrying capacity, a key factor in athletic performance. Simply put: inject yourself with EPO and your body starts cranking out more red blood cells.
There's a measure for the percentage share of blood that is composed of red blood cells. It's called hematocrit. Normally, it's about 40-45 percent, but by taking EPO people can boost that count to 50 percent or more. In fact, the only way to catch EPO cheaters for a while was to look for people with very high hematrocrit numbers. There are now more sophisticated ways to tell synthetic EPO from naturally occurring EPO, and people get caught even if their hematocrit numbers are in the normal range.
So here's the illicit promise of gene doping: your cells already make EPO, so what if you could get them to make more? Then, the EPO would be "natural," right?
In fact, this is the premise of Snyder's work. In the 2011 paper, he and his team injected monkeys with different doses of a virus carrying an EPO cassette. They are effectively transferring not the hormone itself, as in traditional doping, but the machinery to make the hormone inside the body. You can see what happened to one of the monkeys in the chart here. Remember that what dopers want to do is increase their hematocrit because that means they have greater oxygen carrying capacity. That's accomplished by increasing the amount of EPO in the blood. Both things occurred in this monkey. After the administration of the gene transfer, the monkey's hematocrit jumped from around 40 to between 50 and 60 percent.
This makes gene doping for EPO look possible, certainly. But the same study tells a cautionary tale, too. Another animal in the study was given a larger dosage. Initially, its hematocrit shot up as EPO production kicked in. But as the production kept climbing, the hematocrit stalled out and then crashed.
"What happened there is the animal mounted an immune response against the EPO that was being made off the vector and that also wiped out the EPO that it made on its own," Snyder explained. If that happened to a human, it would be life-threatening.
"Because then you're like a kidney transplant patient who has to take a lot of EPO," he said. "I don't even know if that's recoverable, even if they were injecting themselves with EPO."
When I expressed my surprise at the study and related my skepticism about gene transfer as a strategy for doping, Snyder told me, "You went into this thinking gene transfer vectors and gene therapies don't do anything, but it can have quite the opposite effect if you don't dose correctly."
With that kind of danger in gene doping, the globe's anti-doping agencies are trying to figure out how they're going to test for this kind of cheating. Snyder said that his lab, working with others in Germany and France, had found a way. It's a tiny bit technical, but bear with me.
When your body naturally makes proteins from its DNA code, there are long sections between the actual coding sequences called "introns." When your body goes to transcribe that section, it knows to leave out those parts and create a copy with just the "exons." But when people use viruses to do gene therapy, they do the intron cutting step beforehand. So, the compact DNA sequence that gets loaded into the vector is shorter than the version that's in the cells of your body. Snyder and his team latch on to that difference to sort out naturally occurring DNA (endogenous) from the DNA they've injected (exogenous).
"We've showed that in primates, if we inject them into the muscle, we can still detect the sequences in their blood months after the injection," Snyder said. They hope to transform this science into an actual working detection system by 2016. "Our primary focus is to develop technology that can be utilized on a wide scale for the direct purposes of screening athletes," he said. "Our push is to try to get them out for the next Olympics."
Which might be when this issue really breaks into the mainstream doping conversation. All those hormones that people directly inject? Hypothetically, at least, it would be possible to produce them in human bodies in the same way that EPO was produced in these macaques. "The most likely biological targets for cheating are erythropoietin, the protein enhanced by Repoxygen; genes for the production of myostatin and insulin-like growth factor I, which affect muscle production (as in the lower mouse in the photo); and peroxisome proliferator-activated receptors, a family of proteins that regulate metabolism," Brandon Keim noted in Wired a couple years back.
Are Athletes Already Gene Doping?
Given the state of the experimental science, the big question now is whether anybody is actually trying to succeed with gene doping. Don Catlin, a pharmacologist at UCLA, told Nature News that gene doping "is not a good idea, but I wouldn't be surprised if someone's out there trying it." That seems to be roughly Snyder's position as well.
Out in the world, there's very little evidence one way or another that athletes or coaches are actively seeking out gene doping with one major exception. Repoxygen is a gene therapy drug developed by an Oxford biomedical company that is also supposed to stimulate the production of EPO. (It's based on a different virus from the one Snyder works with.)
Well, in 2007, a German trial of track coach Thomas Springstein revealed that he'd sent an email to a Dutch doctor in which he wrote, "The new Repoxygen is hard to get. Please give me new instructions soon so that I can order the product before Christmas."
Wait. The *new* Repoxygen?! This seemed like a smoking gun, opening the door to a shadowy world in which gene transfer methods aren't just used but are practically old hat. Nonetheless, no Repoxygen was ever found on Springstein and a New York Times article claimed it was "unlikely that Springstein ever got hold of [the drug]."
Still, that was five years ago. Gene transfer methods have improved a lot since then. "As much negative press and as much lack of results in humans that there was from the late 90s through the mid-2000s in gene therapy," Snyder said, "scientists were still plugging away trying to make better vectors, trying to understand what went wrong, trying to understand the genetic components that need to go into this, trying to understand the dosing, trying to understand all the parameters that go into gene transfer."
And now that they do, and so does everybody else. "I don't want that to sound too academic, like we're not really interested in the actual use of this technology," Snyder concluded. "Our primary focus is to develop technology that can be utilized on a wide scale for the direct purpose of screening athletes."
Gene doping may have arrived later than some thought -- the World Anti-Doping Agency banned it in 2003 -- but an overabundance of skepticism about its impacts may be as dangerous as the hype that heralded its arrival.
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