Gene Doping
Will athletes go for the ultimate high?
Christen Brownlee
In 1998, the press jumped on H. Lee Sweeney's
first study showing that gene therapy could enhance mouse muscle.
Soon, the calls and e-mails started flowing in, first as a trickle,
then as if from a fire hose. They're still coming, Sweeney says.
Some people beg him to reverse their muscle degeneration caused by
disease or aging. However, about half of the calls and
e-mails come from healthy individuals—professional power
lifters, sprinters, and weekend wannabe athletes of all stripes.
They want bigger, higher-performing muscles. One caller offered
$100,000 for muscle enhancement, and a high school football coach
asked Sweeney to treat his whole team.
The requests from healthy athletes "really caught me off guard,"
says Sweeney, a physiology professor at the University of
Pennsylvania in Philadelphia. His goal had been to stave off the
muscle wasting that comes with muscle dystrophy and just plain
aging.
Now, Sweeney finds himself in the middle of what could become
the sports world's next serious dilemma: Should gene
enhancement, or doping, be permissible for athletes attempting to
improve their performance? And if not, how can it be
prevented?
Gene doping could someday provide extra copies of genes that
offer a competitive advantage, such as those that
increase muscle mass, blood production, or endurance.
The products of gene doping would be proteins similar, if not
identical, to the body's versions and would therefore be less
detectable in an athlete than are performance-enhancing drugs such
as steroids and insulin. Consequently, rules against
gene doping might be difficult to enforce.
Heading off what they see as an inevitable problem for the
future, the Montreal-based World Anti-Doping Agency (WADA), which
works with Olympic officials to prevent athletes from using
performance-boosting drugs, already has banned genetic
enhancement.
Some researchers predict that gene doping might become a
problem as early as the next summer Olympics, in 2008.
"Gene doping is going to happen because technology is going
to ripen in the gene therapy setting," says Ted Friedmann,
director of the Human Gene Therapy Program at the University of
California, San Diego and a consultant for WADA. "Of course, it's
going to be too tempting for athletes to avoid."
Natural healing, baby
The roots of gene doping lie in gene therapy, the
decades-old idea of inserting genes into the body's cells to
correct genetic flaws that cause diseases such as juvenile
diabetes, hemophilia, and cystic fibrosis. Although simple in
concept, gene therapy has been tricky to carry out reliably in
patients. Scientists can count only one success: a 2000
study that cured nine French infants of severe combined immune
deficiency, also known as "bubble-boy syndrome" (SN: 4/29/00, p.
277: Available to subscribers at
http://www.sciencenews.org/articles/20000429/fob3.asp). Even then,
two of these patients developed leukemia 2 years later, a
mystery that scientists have yet to fully explain.
Some biologists currently are developing new methods to
introduce target genes into cells by using electricity, chemicals,
or pressure. But for now, researchers typically infect cells with a
virus, nature's mastermind at getting foreign genetic material past
stringent cellular defenses.
The viruses that scientists have modified for use in gene
therapy are vastly different from those that circulate in
nature. Researchers pare down the viruses' genetic code,
trimming away the genetic material that enables the agents to cause
disease. They retain only the genes associated with the proteins
making up a virus' outer coat.
Such stripped-down viruses can transform cells into factories
that churn out empty shells, "like hollow M&Ms," said James
Mason, director of the Gene Therapy Vector Laboratory at the
Institute for Medical Research in Long Island, N.Y. Then,
researchers paste a human gene—such as one for a blood-clotting
protein that a patient lacks—within the virus' remaining genetic
sequence to craft a vector that shuttles a therapeutic gene into
the patient's cells.
The original idea behind gene therapy was to replace a missing
or damaged gene, thereby providing an essential substance that the
patient had been lacking. Many scientists have taken this
initial concept one step further, says Sweeney. Instead
of simply supplying a copy of a missing gene, he and others
realized that gene therapy could also fortify muscle, bones, and
other tissue at the first signs of disease or aging. This
approach could slow the progress of muscle wasting from aging or
diseases, such as muscular dystrophy and osteoporosis, he says.
It's not a big technical leap from gene therapy to gene
doping. "The sorts of things you'd want to do to help make
muscle stronger or repair itself better in a diseased or old person
would also make a healthy young person's muscles stronger and
repair faster," Sweeney says.
According to Thomas Murray, president of the Hastings Center in
Garrison, N.Y., and chairman of WADA's ethics panel, gene
doping crosses an ethical line. The traditional draw of athletics,
he says, is the combination of an athlete's natural talents with
complementary virtues such as determination and
discipline.
"What's chilling about the prospect of gene doping is that it
arguably changes a person's natural abilities," Murray says. "It
violates our understanding of what should make for success in
sports."
Mighty mice
When his work attracted athletes' attention, Sweeney had been
focused on the problem of muscle-mass depletion that occurs with
aging. He and his colleagues had noted that when a
protein called insulin growth factor 1, or IGF-1, interacts with
cells on the outside of muscle fibers, the muscles grow.
The researchers reasoned that if they could insert the gene
responsible for making IGF-1 inside muscle cells, those cells would
then proliferate and increase the muscle's size.
HEAVY WORKOUT. This rat, injected with a muscle-enhancing
gene, boosts its strength by lugging weights up a
ladder.
Courtesy Sweeney
To test this idea, Sweeney's group injected a virus carrying the
gene for IGF-1 into the leg muscles of mice and then monitored the
animals. The scientists found that when the mice became senior
citizens, at about 20 months of age, the animals retained the
muscle strength and speed of their early adult days.
After that promising start, the researchers made an even more
startling observation. Young mice injected with the gene
grew stronger and more muscular, even without exercise. In
a later study, Sweeney noticed that rats' strength could be
boosted further by a training regimen in which the animals
climbed ladders after weights had been tied to their tails.
The genetic and physiological modifications that led to these
"Schwarzenegger mice," as they became known in news reports, could
prove intriguing to weight lifters, wrestlers, and
other athletes whose sports hinge primarily on
strength.
Another set of experiments, by scientists at the Salk Institute
in San Diego, produced mouse muscles that just keep going
without fatiguing. This result has obvious implications
for long-distance swimmers, runners, and others
for whom endurance is pivotal. Ronald Evans and
his colleagues had started out with the intention of engineering
mice that stay trim. To do this, the researchers inserted
genes that code for a fat-burning protein called
PPAR-delta.
The mice that resulted stayed slender, even when fed a high-fat
diet, but also developed an unusually large number of
slow-twitch muscle fibers, the type the body
relies on during extended exertion. "This change produced the
'marathon mouse,' able to run twice the distance
of its normal littermate," Evans says.
Genetic engineering differs from gene therapy in many ways,
including that the genetic modifications are passed on to
offspring. However, Evans predicts that eventually gene therapy
could similarly enhance endurance.
Lethal legacy
Sweeney has developed a stock response to athletes who contact
him. "I basically say this is experimental. It's in
animals, and even if I had it available to give to humans, it has
to go through clinical trials to make sure it's safe," he
says.
Ascertaining the safety of gene therapy—and its gene-doping
offshoot—couldn't be more important to Jim Wilson, a professor of
medicine at the University of Pennsylvania in Philadelphia. He
presided over the clinical trial in which 18-year-old Jesse
Gelsinger died in 1999 after suffering a massive immune reaction to
the virus used to deliver a target gene.
In a recent study designed to test the effectiveness of several
viral vectors, Wilson discovered another deadly result. He and his
colleagues injected macaque monkeys with different strains of the
same virus that carried a gene for making erythropoietin (EPO), a
protein that signals bone marrow to produce red blood cells. EPO is
manufactured for patients with anemia resulting from kidney
failure. It is also used as a doping agent among athletes because
with bonus red blood cells, the body can absorb extra
power-generating oxygen. Wilson chose EPO because it's easy to
detect.
In his experiment, as expected, the high concentrations of EPO
produced so many red blood cells that the macaques' blood thickened
into sludge. As they had done in previous experiments, the
researchers remedied this by drawing blood from the primates at
regular intervals to thin the remaining blood enough to circulate
properly. But as the experiment wore on, Wilson's team noticed
an unusual response in some of the macaques. Rather than
remaining at high concentrations, EPO concentrations in these
animals' blood plummeted, leading to severe anemia.
After autopsying these monkeys, Wilson and his colleagues came
to a troubling conclusion: The animals' immune systems had
cleared out not only EPO produced by the inserted gene but also the
macaques' natural EPO.
Wilson notes that unpredictable results such as these are common
in the field of gene therapy, which is why the strategy is still
experimental.
"[Gene therapy's] potential to treat disease is substantial, but
we're now in a phase where we're still working on the technology,"
Wilson says. "We ought to pay attention to these kinds of immune
responses not only for EPO but for other kinds of gene therapy."
In other words, athletes who try gene doping could find
themselves dead rather in the winners circle.
Unethical advantages
Despite the dangers now inherent in gene therapy, some
researchers worry that unprincipled scientists will inevitably gene
dope unscrupulous athletes. "You have to remember that most of
these athletes are very young, in their twenties, and so they have
feelings of invincibility," says Olivier Rabin, scientific director
of WADA.
The financial reward that accompanies athletic success adds
to the incentive to try an untested procedure. "There's so much
money in sports today, and when you see what a national title or
gold medal around your neck will bring in your life, some are
mentally ready to bear the risks," Rabin says.
He reports that, besides working with legislators and athletes,
WADA is encouraging scientists to develop tests that could catch
gene-doped competitors. Some researchers have feared
that because an inserted gene's products can be extremely similar
to the body's natural chemicals, routinely snagging rogue athletes
could prove impossible. The only way to test for gene
doping, some surmised, would be to biopsy muscles or other
tissues into which gene vectors had been injected. The biopsy
would require a surgical procedure right before competition.
However, a new study published in the September Molecular
Therapy raises the likelihood that a test might be
possible. A team led by Francoise Lasne and
Philippe Moullier at the National Anti-Doping Laboratory in
Chatenay-Malabry, France, found that monkeys
doped with the gene for EPO by muscle injections produced a protein
slightly different from their native EPO. These small
differences could, in part, underlie the disastrous immune response
that Wilson's team observed in some of the macaques in their
study.
Although the scientists aren't sure why the doped EPO is
different, they suspect that cells in various tissues might not
make the same modifications to the protein after it is produced.
Kidney cells normally produce EPO, but in response to the gene
doping, muscle manufactured it too. Distinctive modifications by
these organs eventually might provide a basis for detecting EPO
from gene doping.
Someday, says ethicist Murray, gene doping might become
widespread and even acceptable in all sports, Making such tests
unnecessary. But he and other experts don't expect that to
happen anytime soon.
"When we think about the meaning of sports, these days,
it's about natural talents and virtues," he says. "I can't tell you
what your grandchildren and great grandchildren will believe, but I
hope that there will still be meaning in perfecting natural
abilities."
Letters:
In this article you wondered, "Should gene enhancement, or
doping, be permissible for athletes attempting to improve their
performance?" Sure, but in separate competitions.
Athletes would register as either "doped" or "clean."
The problem with doping is not the doping, it's the
cheating.
Sam Cox
Loveland, Colo.
If you have a comment on this
article that you would like considered for publication in Science
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and location.
References:
Barton-Davis, E.R. . . . and H.L Sweeney. 1998. Viral mediated
expression of insulin-like growth factor I blocks the aging-related
loss of skeletal muscle function. Proceedings of the National
Academy of Sciences 95(Dec. 22):15603-15607. Available at
http://www.pnas.org/cgi/content/full/95/26/15603.
Gao, G. . . . and J.M. Wilson. 2004. Erythropoietin gene therapy
leads to autoimmune anemia in macaques. Blood 103(May 1):3300-3302.
Abstract available at
http://www.bloodjournal.org/cgi/content/abstract/103/9/3300.
Lasne, F. . . . P. Moullier, et al. 2004. "Genetic
doping" with erythropoietin cDNA in primate muscle is
detectable. Molecular Therapy 10(September):409-410.
Abstract available at
http://dx.doi.org/10.1016/j.ymthe.2004.07.024.
Wang, Y.-X. . . . and R.M. Evans. 2004. Regulation of muscle
fiber type and running endurance by PPAR-delta. PLOS Biology
2(October):1532-1539. Available at
http://dx.doi.org/10.1371/journal.pbio.0020294.
Further Readings:
Seppa, N. 2000. 'Bubble' babies thrive on gene therapy. Science
News 157(April 29):277. Available to subscribers at http://www.sciencenews.org/articles/20000429/fob3.asp.
From Science News, Vol. 166, No. 18, Oct. 30, 2004, p.
280.