The race against gene dopingOfficials expect a new form of sports cheating to appear: gene transfer ... and they have turned to this UCSD researcher to help detect it. By Scott LaFee UNION-TRIBUNE STAFF WRITER July 27, 2008 Past controversy has not made this year's Tour de France scandal-free. Cycling's premier event, which ends today, has again been marred by busts for illegal doping, with at least three riders thrown out and entire teams quitting. The Summer Olympics begin Aug. 8, and rumors of illicit drug use are likely to be rampant there, too.

For the World Anti-Doping Agency, or WADA, eliminating the use of banned substances to boost performance in sports is a difficult, endless challenge – and a job likely to get tougher. Agency officials expect a new and more problematic form of sports cheating to soon appear. It's called gene transfer or, more commonly, gene doping. They have turned to University of California San Diego researchers for help.

To date, no athlete has been caught gene doping, which involves injecting genes or genetic material into the body to make it stronger, faster or more resilient. In fact, there's no solid evidence any athlete has tried it, “though I wouldn't be surprised to hear somebody had,” said Dr. Ted Friedmann, director of the Center for Molecular Genetics at UCSD. “Drugs in sports isn't going away, but gene (doping) is the next big thing.”

Friedmann is a leading authority on gene doping and a pioneer in gene therapy – the evolving medical technology that inserts healthy or modified genes into the body to treat serious, often deadly diseases such as cystic fibrosis, cancer and immune system deficiencies.

In the fight against sports doping, the metaphor is often a race, with the cheaters usually one step ahead of the watchdogs. This time, authorities want a head start. In the last few years, WADA has funded basic research programs into how athletes might use – and abuse – gene transfer, and how to detect it. Helping lead the effort is Friedmann, who will oversee a new clearinghouse for data derived from WADA-funded studies and labs around the world.

“If the idea is to pick needles out of a haystack, WADA wants all the hay in one place,” said Friedmann, who has worked with the organization since 2000. “It wants a centralized bioinformatics effort that can result in a unified approach.”

Currently, Friedmann said, there isn't much cross-talk among researchers investigating gene transfer in sports. “And there's no lab that's equipped to handle all of the data being produced.” But with help from scientists at the San Diego Supercomputer Center, Friedmann said the UCSD-based program will pull together all of the data generated, organize it, collate it and help disseminate the findings.

It's an unprecedented effort. Previous and current sports drug-testing programs have tended to be reactive, responding to revelations about the abuse of new drugs (or versions of old ones) with new, targeted tests.

In recent years, the focus has been on anabolic steroids, human growth hormone, known as HGH, and such banned drugs as erythropoietin, or EPO, which boosts blood-oxygen content. Rigorous blood and urine testing appears to have reduced steroid use. There is no widely available, effective test for HGH, but experts say one is imminent.

On June 8, highly ranked cyclist Riccardo Ricco was thrown out of the Tour de France after testing positive for Cera, a third-generation version of EPO. Authorities said Ricco may have thought his variant of Cera was undetectable, but WADA investigators had developed a test for it in collaboration with the Swiss maker.

Gene doping presents different and greater challenges for sports sentinels. Broadly speaking, it involves introducing genetic material into an athlete's cells or tissues to help them work differently or better. Usually this means making muscles grow stronger, regenerate faster or break down more slowly.

The introduced material is indistinguishable from its natural counterpart and found only in affected tissues. There is nothing to detect in blood or urine.

Friedmann said the UCSD research effort is aimed, in part, at developing a knowledge base of how gene doping affects the athlete's whole body. “We won't look necessarily for the suspect agent, but for its broader effects,” he said. “Are there specific changes in the way targeted genes are expressed or how proteins work that can be conclusively linked to gene doping?”

In medicine, the goal of gene therapy is to find an effective treatment. In sports, the goal is to generate a competitive edge.

But at what cost? The history of gene therapy has been marked by serious setbacks, including patient deaths. In 1999, Jesse Gelsinger, an 18-year-old with a rare, inherited liver disease, died from a massive immune response to the viral vector used to deliver genetic material to his cells. In 2002 in France, doctors used gene therapy to treat 12 boys with X-linked severe combined immunodeficiency, or “bubble-boy disease.” The technique effectively treated SCID, but at least three boys developed leukemia and one died.

Despite the setbacks, progress in gene therapy is being made. Dozens of clinical trials are under way, with researchers reporting varying degrees of success in treating cancers and heritable diseases.

“Gene therapy works. The proof of principle is there, but it will take decades more to refine it,” said Friedmann, who helped originate the idea in the 1970s. “Throwing genes around in a human is highly experimental. There are surprises around every corner. It's full of dangers. It should be limited only to very serious diseases.”

More to the point, no one really knows what the short-and long-term health effects of gene transfer are in a healthy human. Animal models have produced some eye-popping results. In the late 1990s, H. Lee Sweeney, a physiology professor at the University of Pennsylvania, discovered how to inactivate a protein called myostatin, which tells muscles when to stop growing. Sweeney subsequently was able to create lab mice with twice the normal muscle mass even though the rodents didn't exercise much.

Bad things happen, too. In 1997 and 1998, researchers injected synthetic EPO into monkeys and baboons. The idea was to see if boosting the oxygen-carrying capacity of the animals' blood would result in greater physical stamina and endurance.

Initially, things looked good. In both species, red blood cell counts nearly doubled within 10 weeks. Then, wrote Sweeney in a 2004 Scientific American account, the animals' blood became “so thick it had to be regularly diluted to keep their hearts from failing.”

With the right tools and know-how, Friedmann said gene doping isn't hard to do.

“The basic biology is easy. On this campus, there are probably 1,000 people who could do it. What is hard is doing (gene transfer) well and safely, and knowing what the outcome will be.”

It may be impossible to stop gene doping. “Sports is the camel's nose under the tent,” Friedmann said. “Genetic enhancement will likely touch many aspects of future life, but one of the first will probably be sports.”

Thomas H. Murray, president of The Hastings Center, an independent bioethics research center based in New York, predicted gene-doping probably wouldn't be a significant issue at the Beijing Olympics, aside from the whispers and rumors. But after that, he said, it's a different story.

As it now stands, Murray said, gene doping violates WADA rules and the general sense of what constitutes fair play. “It's ethically wrong, no different from illegal drug use,” he said.

Some observers have argued that gene transfer is OK, that it simply levels the playing field, potentially providing every athlete with roughly the same biological equipment.

Murray argues otherwise. Even if gene transfer were to become widely available and commonly used, he said the technology would have no place in sports. Who would decide which inherited, physical characteristics could be genetically altered, he asked. And where would the line be drawn?

More troubling, Murray said, “doping distorts the meaning of sports, which has nothing to do with the size of molecules or whether to use a pill or an injection. What matters here is what athletes and the people who watch athletes believe sports to be about, what they believe the whole enterprise is trying to do. Sports isn't about genetic modifications.

“If people lose heart and give in to doping,” Murray said, “sports will be changed, and not for the better.”