Hope, peril in gene therapy

Altering: Genetic engineering may conquer diseases and birth defects. It may also lead to the ultimate form of doping by athletes.

Medicine & Science

September 06, 2004|By Alan Zarembo | Alan Zarembo,LOS ANGELES TIMES

Dr. Jim Wilson never intended to create supermonkeys.

A pioneer in genetic engineering, he was experimenting with a way to insert single genes into muscle cells, a technique that could someday be used to treat a variety of genetic illnesses.

He chose a gene that boosts levels of erythropoietin, or EPO, a key hormone in the production of oxygen-toting red blood cells and a convenient marker to measure the success of his experiment.

But EPO has long had another claim to fame. Its synthetic version, created in the 1980s to treat anemia, is one of the most notorious performance-enhancing drugs in competitive sports, able to increase endurance by raising the oxygen supply to muscles.

In less than two weeks, many of Wilson's rhesus monkeys had red-cell counts greater than those of world-class runners who train at high altitude.

By three weeks, they had a higher concentration of red cells than even the worst EPO abusers in sports. And no drug was ever injected.

As the sports world vainly struggles against the epidemic of illegal drugs, science has already opened the door to the next frontier in fraud: gene doping.

By introducing specific genes, the experimental technology has created bigger muscles, faster metabolism and greater endurance in laboratory animals. Hidden in cells, gene enhancements in humans would be much harder to detect than drugs.

"We know that gene therapy at some point will be abused," said Olivier Rabin, the director of science for the Montreal-based World Anti-Doping Agency.

There is no evidence that any athlete has tried genetic alteration, but the agency added it last year to the international list of "banned methods" and has begun funding research to detect gene abuse. The temptations for athletes are high. But they are not without risks. For example, all eight monkeys in Wilson's experiment are dead.

Wilson, a boyish-looking professor of medicine at the University of Pennsylvania, knows the highs and lows of gene therapy, a field barely three decades old.

He led one of the earliest trials in humans - an effort to introduce genes to cure cystic fibrosis. In 1992, at 37, he became the first director of the university's Institute for Human Gene Therapy.

But seven years later, he found himself at the center of gene therapy's biggest disaster. Jesse Gelsinger, an 18-year-old from Tucson, Ariz., with a rare liver disorder, enrolled in one of Wilson's clinical trials. He received a genetic injection, which his body rejected. Four days later, he was dead.

The university shut down the institute. The Food and Drug Administration, which ruled that Wilson should have stopped the experiment sooner, moved to bar him from leading human trials.

Despite the setback, Wilson and other scientists are pushing ahead. There have been nearly 1,000 gene therapy clinical trials worldwide.

The field remains one of medicine's best hopes in the fight against disorders caused by defects in genes, such as diabetes and Parkinson's disease.

The concept of gene therapy first appeared in the late 1960s. As scientists learned how to manipulate DNA, they came to believe that genetic defects could be fixed by installing new genes.

To accomplish that, they had to figure out how to deliver the therapeutic genes to cells. The leading method today uses viruses, which naturally invade cells. Researchers snip out the harmful parts of the virus and splice in the new gene.

These "viral vectors" are typically injected into the body. In some cases, they are designed to permanently merge the new gene into the subject's DNA so that it is replicated and passed on when cells divide. In other cases, the virus deposits the new gene as a self-contained ring of DNA in the cell nucleus, where it remains for the life of the cell.

The problem is the interactions among genes are poorly understood and the therapeutic genes do not always land where scientists intend.

In humans, success has been limited and sobering. The most-cited example is the treatment of a fatal immune disorder known as X-linked SCID - severe combined immunodeficiency or "bubble boy" disease - in 10 children in France. Eight recovered. Two developed leukemia after the new gene landed in a dangerous spot.

It could be years or decades before viable therapies are on the market. Most clinical trials are conducted on terminally ill patients seeking a last resort.

Despite the risks, it didn't take long for sports officials to recognize the potential for athletes to abuse genetic technology.

How much is an extra tenth of a second worth?

The week that H. Lee Sweeney, a physiologist at the University of Pennsylvania, announced that he had genetically engineered a group of freakishly muscular mice, he received a call from a high school football coach.

Could Sweeney inject the team with the gene he had used to bulk up the mice? Later came a similar request from a wrestling coach.

Sweeney's mice, which had been given a muscle-building gene, developed hind limbs that rippled like mini-Mr. Universe thighs. They were up to 30 percent bigger than those in their unmodified cousins. No exercise was required.

Sweeney explained to both coaches that the gene had never been tried in humans, and that using their athletes as guinea pigs could land them in prison. He had little interest in helping athletes. His research seeks to slow the muscle breakdown that occurs with aging and degenerative diseases such as muscular dystrophy.

What if gene therapy becomes a standard method of treating injuries? Should an athlete given a muscle-building gene to repair an injury be banned from competing?

Technologies on the distant horizon further blur the debate.

In the meantime, the phone keeps ringing in Sweeney's office. He receives a few calls every week, mostly from power lifters and wrestlers.

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