php pdoping,Gene Doping 关于基因兴奋剂

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

News, send it to editors@sciencenews.org. Please include your name

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.