Viewing entries in
Gene Doping

Genetically Modified Olympians? (2008, July 31)

Genetically Modified Olympians?Jul 31st 2008 From The Economist print edition

On the eve of the Beijing Olympics, we examine the prospect of athletes using gene therapy to enhance their performance—and of catching them if they try

FOR as long as people have vied for sporting glory, they have also sought shortcuts to the champion’s rostrum. Often, those shortcuts have relied on the assistance of doctors. After all, most doping involves little more than applying existing therapies to healthy bodies. These days, however, the competition is so intense that existing therapies are not enough. Now, athletes in search of the physiological enhancement they need to take them a stride ahead of their opponents are scanning medicine’s future, as well as its present. In particular, they are interested in a field known as gene therapy.

Gene therapy works by inserting extra copies of particular genes into the body. These extra copies, known as “transgenes”, may cover for a broken gene or regulate gene activity. Though gene therapy has yet to yield a reliable medical treatment, more than 1,300 clinical trials are now under way. As that number suggests, the field is reckoned to be full of promise.

As far as sport is concerned, the top transgene on the list, according to Jim Rupert, an anti-doping expert at the University of British Columbia, is the gene for erythropoietin. EPO, as it is known for short, is a hormone that regulates the production of red blood cells. It is already available as a drug (it was one of the first products of biotechnology companies in the late 1980s), and it has been used widely in endurance sports such as long-distance cycling. But if an athlete’s body could be stimulated to make more of it that would—from the athlete’s point of view—be better than taking it in drug form.

No dopes The reason is that EPO, like most performance-enhancing drugs, is banned. However, bans work only when they are enforced, and that requires a test which can distinguish synthetic EPO from the natural hormone made by an athlete’s body. At the moment, this is possible. The EPO from a biotechnology company’s vats has a slightly different chemical structure from the natural sort. But the evidence suggests that EPO produced as a result of gene therapy will be far harder to distinguish.

In fact, EPO doping may already have happened. In 2006, during the trial of Thomas Springstein, a German coach accused of doping his underage charges, it transpired that Repoxygen, an experimental gene-therapy product containing the gene for EPO, was already making the rounds on the black market. Repoxygen causes a controlled release of EPO, but only when the body senses a lack of oxygen. Or at least it does so in mice.

Whether black-market Repoxygen has won any races is unknown. But several other genetic therapies being tested in mice also look as if they may interest the sort of men and women who feel their athletic performance needs a little boost.

Like EPO, vascular endothelial growth factor spurs red-blood-cell formation and thus helps to supply tissues with oxygen. The gene that encodes this protein is the subject of several medical studies, and is thus a prime candidate for sporting use.

IGF-1 is also a growth factor—though it promotes brawniness in muscle rather than the production of blood cells. Inject the gene that encodes it into a particular muscle and you can affect that muscle and no other. Such specificity might be of interest to people like tennis players and javelin throwers. Meanwhile, a gene called MSTN encodes a protein called myostatin, which limits rather than enhances muscle development. In this case, therefore, the doping is designed to switch the gene off. The result is what have been nicknamed “Schwarzenegger” mice.

Once brawny muscles have been acquired, whether licitly or illicitly, other genes might then be used to tune their activity. Tweaking PPAR-delta, for instance, alters the way muscles obtain their energy. The individual fibres that comprise a muscle can run in one of two modes. In slow-twitch mode they burn fat, and are less prone to fatigue. In fast-twitch mode they burn sugar. That makes them prone to fatigue, but is useful for delivering short bursts of power. Both modes are valuable to athletes, but in different types of event. The ability to make muscle fibres specialise in one mode or the other would thus be of great benefit to unscrupulous coaches. PPAR-delta controls the switch.

Finally, animal studies on the genes for natural pain-killers called endorphins suggest that these could be used to limit the perception of pain—another desirable trait for athletes. That might consign the adage “no pain, no gain” to the history books.

There is thus a lot of potential. And although—the Springstein incident aside—there is no evidence that any of these techniques have made their way into real athletes, the authorities are taking no chances.

The World Anti-Doping Agency (WADA), sensed several years ago which way the wind was blowing. In 2003 it issued a proclamation banning “the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance”. It followed this by putting its money where its mouth was. Since much of gene doping’s allure derives from its alleged undetectability, WADA committed $7.8m—a quarter of its research budget for 2004-07—to 21 projects intended to develop ways of detecting it. Now another $6.5m is up for grabs.

Broadly, there are two ways of spending this money usefully. The direct approach focuses on improving ways of detecting differences between truly natural and “therapeutically enhanced” proteins or, failing that, on detecting the “vector” used to inject the transgenes into the places where they will operate. Such vectors are often particular sorts of virus.

The indirect approach seeks second-hand signs of the transgene or its vector. Viruses, for example, may produce a characteristic immune response that can be detected. Meanwhile the transgenes themselves may alter the body’s proteome (the set of proteins active in it at any given time) or its metabolome (a list of all the by-products of the chemical reactions that go on in each cell). Changes to either of these “-omes” can, in principle, be detected in blood or urine. What is needed are points of comparison. This requires working out the typical “biosignatures” of elite sportsmen as a group, or indeed of each individual, as a baseline.

Testing times Whether gene doping will make its debut in Beijing remains to be seen—or perhaps not, if it is as hard to detect as its protagonists hope. Theodore Friedmann of the University of California, San Diego, who heads WADA’s Gene Doping Panel, reckons it probably won’t happen this time. He does not think there is, yet, a form of gene therapy that could easily be used to enhance performance. As for Dr Rupert, he says, “I would be surprised. But I have been surprised before.” It would be ironic if the first successful application of gene therapy were to people who are among the fittest on the planet. But it is possible.

Copyright © 2008 The Economist Newspaper and The Economist Group. All rights reserved.

Fairly safe Jul 31st 2008 From The Economist print edition

What athletes may or may not do ought to be decided on grounds of safety, not fairness

ANOTHER Olympics, another doping debate. And this time it is a fervent one, as recent advances in medical science have had the side-effect of providing athletes with new ways of enhancing performance, and thus of putting an even greater strain on people’s ethical sensibilities.

This is especially true of gene therapy. Replacing defective genes holds out great promise for people suffering from diseases such as muscular dystrophy and cancer. But administered to sprightly sportsmen, the treatment may allow them to heave greater weights, swim faster and jump farther (see article). And that would be cheating, wouldn’t it?

Two notions are advanced against doping in sport: safety and fairness. The first makes sense, the second less so—particularly when it comes to gene therapy. For instance, some people have innate genetic mutations which give them exactly the same sort of edge. Eero Mantyranta, a Finn, was a double Olympic champion in cross-country skiing. His body has a mutation that causes it to produce far more of a hormone called EPO than a normal person would. This hormone stimulates the production of red blood cells. A synthetic version of it is the (banned) drug of choice for endurance athletes.

Mr Mantyranta was allowed to compete because his advantage was held to be a “natural” gift. Yet the question of what is natural is no less vexed than that of what is fair. What is natural about electric muscle stimulation? Or nibbling on nutrients that have been cooked up by chemists? Or sprinting in special shoes made of springy carbon fibre? Statistically speaking, today’s athletes are unlikely to be any more naturally gifted than their forebears, but records continue to fall. Nature is clearly getting a boost from somewhere.

Given that so much unnatural tampering takes place, the onus is surely on those who want to ban doping (genetic or otherwise) to prove that it is unusually unfair. Some point out, for instance, that it would help big, rich countries that have better access to the technology. But that already happens: just compare the training facilities available to the minuscule Solomon Islands squad alongside those of mighty Team America. In druggy sports it may narrow the gap. One condition of greater freedom would be to enforce transparency: athletes should disclose all the pills they take, just as they register the other forms of equipment they use, so that others can catch up.

The gene genie is already out of the bottle From this perspective, the sole concern when it comes to enhancing athletic performance should be: is it safe for the athletes? Safety is easier to measure than fairness: doctors and scientists adjudicate on such matters all the time. If gene doping proves dangerous, it can be banned. But even then, care should be exercised before a judgment is reached.

Many athletes seem perfectly willing to bear the risks of long-term effects on their health as a result of their vocations. Aged Muhammad Ali’s trembling hands, for example, are a direct result of a condition tellingly named dementia pugilistica. Sport has always been about sacrifice and commitment. People do not admire Mr Mantyranta because he had the luck of the genetic draw. They admire him for what he achieved with his luck. Why should others be denied the chance to remedy that deficiency?

German TV reporter turns down Chinese request for help investigating stem-cell doping (2008, Jul 28)

German TV reporter turns down Chinese request for help investigating stem-cell doping

BEIJING (AP) -A German television reporter turned down a request from Chinese authorities Monday to help identify a Chinese doctor filmed in a documentary offering stem-cell therapy to athletes.

In a documentary aired last week by German ARD television, a man identified as a Chinese doctor offered stem-cell therapy to a reporter posing as an American swimming coach. The episode was filmed with a hidden camera, the doctor's face was blurred and the hospital was not identified.

Although Chinese officials have offered evidence in recent months that they are cracking down on doping before the Beijing Olympics open, the TV documentary suggests that China is still a major center for the illegal production and distribution of performance-enhancing drugs.

"Can you provide us with some information about what specific agency or entity was involved in the report done by ARD,'' Yan Jiangying, spokeswoman for the state food and drug administration, asked ARD correspondent Jochen Graebert.

Graebert, attending a Monday media conference with three dozen other journalists, turned down the request.

"No I can't,'' he replied, adding that he did not have the details. He said even if he did, he would probably not offer them.

"We are not prosecutors, we are journalists,'' he added. "It's not our duty to follow people and see if they get punished or not. ... It's not up to me to tell you.''

Sitting alongside Yan, a spokesman for the health ministry didn't dispute the incident took place, but he said the Chinese doctor was probably duping his would-be client.

"According to the view of the experts I consulted, such a technology in China and internationally is not operational,'' said Mao Qunan, the health ministry spokesman.

"Whether the doctor tricked the reporter, or the story mislead the general public, we are waiting for the media to give an explanation about the specific report about China offering gene doping to athletes.''

Du Jijun, general director of China's Anti-Doping Agency, said the country conducted 10,238 doping tests on Chinese athletes in 2007 - 74 percent out-of-competition. He said only 0.4 percent were positive. These included two athletes who were given life-bans earlier this year: swimmer Ouyang Kunpeng and freestyle wrestler Luo Meng.

A third Chinese athlete, race walker Song Hungjuan, was handed a four-year ban this year by track and field world governing body the International Association of Athletics Federations.

Du said six other Chinese athletes had failed recent doping test, but said they were young or provincial-level athletes and he did not name them.

John Fahey, head of World Anti-Doping Agency, has lauded the new Beijing laboratory that will conduct 4,500 tests for banned substances during the Beijing Olympics - 25 percent more than at the 2004 games.

The next step in doping (2008, Jul 27)

Sunday Focus | The next step in dopingBY LINDA ROBERTSON Imagine the Olympics of the future, perhaps the New Delhi Games of 2040. Then, as now, some athletes will cheat to win gold medals. Picture discus throwers with custom-built arms. Or swimmers with modified legs. Or marathon runners with enriched blood. Or gymnasts and basketball players with injury-proof joints. Or archers with brains designed for hyperconcentration. No longer will they rely on such primitive substances as steroids or worry about drug tests. They will be able to alter their own DNA.

Is this science fiction? It's called gene doping, and it might make its debut at the Beijing Olympics.

The science of implanting genes to boost the body's performance has been called the next frontier in illicit sports doping. Unless it already is happening.

''I predict multiple people will win in Beijing who have been gene-doped,'' said John Leonard, executive director of the American Swimming Coaches Association in Fort Lauderdale. ``It's not just experimental. It's been in use for four years.''

Other doping experts doubt the problematic technique of gene transfer has worked on any athlete. But the World Anti-Doping Agency, which banned gene doping in 2004, believes it is a threat to the integrity of sports and is trying to develop a detection test.

''We have no evidence that people have tried it successfully,'' WADA science director Olivier Rabin said. ``We've heard rumors. We investigate, but so far it's led nowhere.''

EASILY AVAILABLE

The technology, explained in numerous scientific articles, is available and relatively easy to implement, although the dangers include heart attack or cancer. Not just Olympians but pro baseball, football and basketball players and athletes in other major sports would benefit from increased strength and endurance. Throughout history, unethical athletes have shown a willingness to be guinea pigs if it meant the difference between winning and losing.

''Thousands of labs around the world with reasonably trained people in molecular biology have the capability,'' said Dr. Theodore Friedmann, a gene therapy expert at the University of California-San Diego. ``There is so much money in sports. Put a couple unscrupulous people together, and it wouldn't surprise me if an athlete attempted gene doping.''

H. Lee Sweeney is a scientist at the University of Pennsylvania researching cures for muscle-wasting diseases who used growth hormone to bulk up his ''Schwarzenegger mice'' and is now increasing muscle mass in dogs by 20 percent by inhibiting myostatin production. He has been contacted by various athletes, coaches and trainers, mostly in football, weightlifting and body building.

''The inquiries never stop,'' Sweeney said. ``They ask if they can be treated. They're ready to volunteer for any experiment. Some even say they'll pay me.''

No wonder because gene doping has potential to not only be effective but invisible. Why inject synthetic EPO to increase red blood cell production when you can inject the EPO gene itself? Athletes wouldn't have to bother with detectable drugs if their own cells could be stimulated to produce a natural stream of performance-enhancing proteins.

Gene doping is the bastardization of gene therapy, which is used to change traits in diseased people. This is how it works:

Human DNA is made up of 20,000 genes. They contain codes that tell cells how to function. To worm a gene into the body, a virus, like the one that causes colds and pink eye, is hollowed out and implanted with new genes for, say, stronger muscles or super-oxygenated blood. The ''vector virus,'' a little bag of protein with the gene inside, is then injected into target tissue, where it attaches to cells and dumps in the gene. The cells with new DNA replicate.

VARIETY OF USES

''Viruses can be engineered to express a whole variety of genes,'' said Dr. Richard Snyder, associate professor of molecular genetics and microbiology at the University of Florida and director of the Center of Excellence for Regenerative Health Biotechnology. There are genes to improve reaction time and increase alertness, although tinkering with cognitive functions is farther down the road, Snyder said.

A Harvard professor has located a gene that he hopes would prevent osteoarthritis and create sturdier joints. He has tested it on lame horses.

A simpler, cheaper but uncontrollable method would involve injecting a piece of DNA into a muscle to prod the pituitary gland to release growth hormone.

''It worked pretty well in pigs, which they grew faster so they could take them to market faster,'' Sweeney said. ``But they didn't want these pigs to live for 20 years. You can turn the gene on, but what happens if you can't turn it off?''

The first sign that gene doping wasn't just a Frankensteinian fantasy came before the 2006 Torino Olympics. E-mails found during an investigation of German track coach Thomas Springstein detail his efforts to obtain Repoxygen, developed to treat anemia, then taken off the market. It helps the body produce EPO.

In the shadowy subculture of sports doping, underground websites and black market labs advertise gene therapies for sale. WADA's Rabin posed as an athlete and ordered what was touted to be Repoxygen from a company in Southeast Asia. Tests showed it was synthetic EPO.

SUSPICIONS

In the TV documentary ''Doping in the Middle Kingdom,'' broadcast Monday on Germany's ARD network, a journalist posing as an American swimming coach was offered stem cell treatment for his athlete by a Chinese doctor for $24,000. During the segment, filmed by hidden camera inside a Chinese hospital, the doctor recommended ''four intravenous doses, 40 million stem cells, perhaps twice that, the more the better'' over two weeks.

''Quite frankly, this surpasses my worst fears,'' WADA's Patrick Diel told the filmmakers, who also interviewed a Chinese swimmer, now coaching in South Korea, who said the 1988 and 1992 Chinese swimming teams were fueled by steroids.

Fort Lauderdale's Leonard, a watchdog for swimming, has heard of alleged gene doping during his travels in China. Many in his sport are curious about the fate of the so-called ''Baby Army,'' a group of young swimmers from Hunan Province posting world-class times and the ''lost children'' from that group who are training in secrecy. He said the country, given its totalitarian government, well-funded sports school system and sophisticated sports science program, has the means, the will and the numbers to try new treatments.

''China is obsessed with athletic success, and there are huge political, economic and personal ramifications,'' Leonard said. ``In China's system, athletes aren't always able to say no.''

But China has made much-publicized bans on athletes who have tested positive and crackdowns on companies distributing doping products. Sweeney believes China wouldn't risk the embarrassment of hosting anything other than the ''Clean Games'' it has promised. The International Olympic Committee will conduct 4,500 tests for banned substances, a 25 percent increase over 2004 and a 90 percent over 2000.

However, Sweeney also believes an ambitious centralized government may not be able to resist the temptations of gene doping.

''If the East German sports machine was still in place, they could perfect gene doping,'' he said. ``Who would have dreamed up BALCO? Athletes are crazy and will try anything if they have someone to help them.''

But he doesn't believe gene doping would work now, at least not without serious health consequences. Most of the hundreds of gene therapy trials over the past 20 years have been unsuccessful or inconclusive, with a few striking breakthroughs, such as one for treatment of childhood blindness.

''It's a difficult and controversial field,'' Friedmann said. ``If anyone proceeded on an athlete it would be malpractice. Things can and will go wrong.''

SERIOUS SIDE EFFECTS

Monkeys injected with EPO genes developed blood the consistency of sludge. Some had clots, strokes and heart attacks. In others, bone marrow shut down and they died of anemia.

The ''marathon mice'' created at the Salk Institute died young. Other animals developed huge muscles that caused tendons, ligaments and bones to snap.

''Race horses are bred for traits of speed and power, but with no trait for bone strength they shatter those spindly legs,'' Friedmann said.

In France, three boys who had gene therapy for immune deficiencies got cancer.

''We've seen several cases of leukemia where the inserted gene hit a cancer-regulating cell,'' Rabin said.

In the U.S., a boy who volunteered for a study on genetic liver disease died.

''If gene therapy worked as well on humans as it does on monkeys or dogs it would be thriving,'' Sweeney said. ``The problem is that humans have an immune reaction to the virus vectors. Gene doping would be like an organ transplant. . . . It's heavy duty.''

To deter cheaters, WADA aims to have gene doping tests ready by 2012 for the London Olympics and for major sports leagues.

At Snyder's lab in Gainesville, research funded by WADA is focused on a blood test that would distinguish between the genes a person is born with and extra, ectopically introduced genes.

Friedmann's tests would find the antibodies that react to the viruses or identify a molecular signature for genetic changes.

Friedmann and WADA know they are in a race against ingenious dopers.

By the time a method or substance gets unmasked -- such as BALCO's ''designer'' THG -- another is in vogue.

''I love the beauty of sport,'' Friedmann said. ``But when the competition is not between athletes but between their molecular biologists and the technological companies behind them, that is not pretty.''

No gene therapy for athletes allowed in China (2008, Jul 25)

Ministry of Health: No gene therapy for athletes allowed in China

www.chinaview.cn 2008-07-25 01:03:17

BEIJING, July 24 (Xinhua) -- China has never approved any hospital to offer performance-enhancing stem-cell therapy, a Ministry of Health official said here on Thursday.

He made the remarks in response to a German TV report that some Chinese hospitals offered what is described as performance-enhancing gene therapy treatment.

"China has never allowed medical institutions or staff to provide stem-cell therapy aimed at improving athletes' performance," he said.

Any medical institution or medical worker doing so would be severely punished under the law, he stressed.

The official added he welcomed media scrutiny and clues to help the government's anti-doping efforts.

In gene doping, athletes put a second copy of certain cells into their bodies to try to increase muscle mass or improve endurance.

As early as March 2004 China had implemented its Anti-Doping Code. Over the past two years, the country had launched several special investigations into performance-enhancing drugs to ensure a fair Olympics.

In these aggressive campaigns, 23 companies were punished for illegal drug trade, or selling sports performance enhancers that shouldn't have been available over the counter since last year.

In addition, three drug makers were ordered to suspend production of relevant drugs, while another 18 had their licenses revoked. Another 321 websites containing illegal drug trading information were shut down.

The race against gene doping (2008, July 27)

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.”

Bioengineering the perfect athlete (2008, Jul 16)

Bioengineering the perfect athleteLast Updated: Wednesday, July 16, 2008 | 8:04 AM ET By Matthew Herper Forbes Athletes can develop amazing strength and abilities without drugs, but world-class comptetitors are now operating near the limits of human physiology. (Ron Staton/AP)Will scientists ever create the perfect athlete?

Sure, someday. But creating drug-enhanced superhumans along the lines of Captain America or the Russian boxer who beat up Sylvester Stallone in Rocky IV is a lot harder than you'd think.

In fact, the most talked about super-steroid, a drug designed to treat muscular dystrophy, failed in a clinical trial earlier this year and has been discontinued by Wyeth, its maker.

Some drugs can dramatically improve the performance of weightlifters, sprinters and cyclists, and many current world records were probably achieved with the help of man-made chemicals. Steroids and Erythropoietin (EPO), a hormone manufactured to combat anemia in cancer and kidney dialysis patients, clearly increase strength and endurance, respectively. And because world-class athletes operate near the limits of human physiology, tiny differences add up. Tufts researcher Roger Tobin has estimated that a 10 per cent increase in a baseball player's muscle mass could double the number of home runs he hits.

But the number of really effective performance-enhancing drugs may stop there. Many athletes who dope could be loading their blood with placebos, or worse.

Human growth hormone (HGH) has been at the center of the doping scandal in baseball. But there is little evidence it actually works. When Stanford researchers pooled placebo-controlled clinical trials of HGH involving 300 patients, they found no benefit for muscle strength. Another placebo-controlled study conducted at the Garvan Institute of Medical Research in Sydney, Australia, found that athletes' performance improved whether or not they were taking real HGH because of the psychological impact of thinking they were taking strength-boosting meds.

Nine out of every 10 medicines that drug companies put into human testing fail, either because they're not safe, or because they aren't effective. Those studies may have involved too few patients to pick up an improvement in athletic performance from HGH, or athletes might need to take it for years at a time to get a meaningful improvement. In reality though, creating a new drug to do anything is tremendously difficult. Nine out of every 10 medicines that drug companies put into human testing fail, either because they're not safe, or because they aren't effective. In search of super-steroids Performance-enhancing drugs for athletes are no different. Steroids were invented 75 years ago. EPO sold by Amgen and Johnson & Johnson for its legitimate uses came around in the early 1980s, as did HGH, which is sold by Pfizer and Genentech. Scientists are trying to develop other drugs that athletes might choose to abuse, including gene therapies, a spate of experimental medicines that turn normal rodents into mighty mice, and new growth hormones. But no flood of super-steroids has yet emerged.

One of the most promising ways of increasing strength is by blocking a protein called myostatin that slows down muscle growth. Belgian blue cows, which lack the myostatin gene, are so covered with bulky, rippling muscles that they look like something out of a bovine superhero cartoon. Mice engineered to lack myostatin get far bulkier than if they are given steroids. In one documented case where a human baby lacked the gene to make myostatin, he was unusually strong. At age four he could hold a 7-pound barbell in each outstretched hand, according to the New England Journal of Medicine.

Given all that biological evidence, a drug that blocks myostatin would seem like a slam dunk as a treatment for muscular dystrophy — and as a drug ripe for abuse by athletes. Wyeth, one of the world's largest pharmaceutical companies, created a myostatin-blocking drug and put it into clinical trials for Duchenne muscular dystrophy, a muscle-wasting disease that kills hundreds of men each year before they reach their mid-thirties. Over-the-counter supplements that claimed to block myostatin took off with weightlifters.

But earlier this year, Wyeth published disappointing results about its myostatin blocker, MYO-029. And then, deep in a filing with the U.S. Securities and Exchange Commission, Wyeth quietly announced that it had canceled all testing of the experimental drug.

Se-Jin Lee, the molecular biologist at Johns Hopkins University who discovered myostatin in mice in 1992, says it's "disappointing" that MYO-029 is dead, but he still believes blocking myostatin holds promise. Acceleron, a Cambridge, Mass.-based biotech firm, is still pursuing the approach. As for those dietary supplements, "They must be bogus."

But what really disappoints Lee is that discussion of a promising treatment for a devastating disease becomes entangled in discussions of doping. The benefits go far beyond the Duchenne muscular dystrophy, a disease that is diagnosed in only 600 American boys a year, to diseases like cancer and AIDS. Such drugs could even have a big effect on the muscle weakening that comes with aging.

"Everybody gets old; everybody is going to lose muscle mass," Lee says. "If you look at the benefit of buying people five more years of independent living, it seems a little out of whack to be worrying about sports records."

And despite all the difficulties inherent in drug development, medicines that could enhance athlete performance are still moving forward. Acceleron and some other companies are working on several different drugs that hit myostatin. And Affymax, a Palo Alto biotech firm, is working on what may be a cheaper, easier to use version of EPO.

These are baby steps, but also reminders that someday, performance-enhancing drugs will be able to really push the limits of what the human body can do — like it or not.

The amazing adventures of gene doping man (2008, Jun 21)

The amazing adventures of gene doping manDan Silkstone June 21, 2008 THE breakout star of this year's Beijing Olympics just might be a name you've never heard before.

Ladies and gentlemen, please welcome to the winners' podium . . . Gene.

Gene is neither man nor woman, athlete nor coach.

Gene doping is a sophisticated method of cheating and a phrase you'll be hearing a lot more of soon.

It is the stuff of comic books - superhumans born from laboratory experiments, incredible bulk, designer viruses and alien incursions into human DNA.

If it all sounds a little far-fetched, you haven't been keeping up as science streaks past science fiction.

Many experts believe gene doping is already happening and warn that tinkering with human DNA to boost performance could seriously injure or even kill those who try it.

Oh, and a test to detect it is years away - perhaps as much as a decade.

At stake is the integrity of sport itself.

Only years after Sydney's 2000 Olympics do we realise that the Games some dubbed "friendly" were more like pharmaceutical.

Many of the best-known medallists, particularly in athletics, have handed back their medals as investigation of the infamous BALCO laboratory and other cheat rings uncovered systematic doping.

Since Sydney, the possibilities offered by science have multiplied rapidly.

Now the question is: could the biggest dopes of all, this August, be the hundreds of millions expecting a fair contest? Dr Peter Larkins is a former head doctor for Australia's athletics team and past president of Sports Medicine Australia.

"I think it is happening now," he says of gene doping.

"I can't believe that 10 years after gene therapy has been proven and we have mice that grow muscles twice the size of normal mice and mice that are called marathon mice because they run all day, I can't believe the scientists who have been unethical enough to help athletes cheat for the last 30 years aren't giving that technology to some people.

" Associate Professor Bob Stewart, a drugs-in-sport expert from Victoria University, is also pessimistic.

"We just have to accept the fact that athletes and biochemists are a jump ahead of the WADA (World Anti-Doping Agency) testers," he says.

"In sport, there is enormous incentive to pursue that competitive edge ...

There is no evidence at all that these Games are going to be clean.

The context hasn't changed, the rewards for getting an edge in performance are as high as ever.

The testing is not better for the substances that are out there.

" WADA is taking the threat seriously.

Gene doping has been banned since 2003, when it was still just a fanciful idea.

In the past fi ve years, $8 million has been spent by WADA, fi ghting against it.

Earlier this month, Russia £ once the world capital of state-sponsored drug cheating - played host to the third WADA conference on gene doping.

Warnings rang out that the practice posed a massive threat to the integrity of elite sport as the anti-drug body called for urgent action from the world's scientists.

Dr Olivier Rabin is WADA's science director.

He says his duty is to try to anticipate the future of drug cheating and be ready.

"Gene therapy is currently making huge progress at addressing many illnesses and is better and better mastered by the experts," he says.

"That leads to what we call gene doping.

" Almost all doping originates as legitimate medical treatment.

When technology offers the sick and infirm new ways to rebuild wasted tissue or replace red blood cells, it seldom takes long for rogue scientists and desperate athletes to muscle in on the game.

The gold medal question: is it happening already? "Nobody knows," Rabin admits.

It is a startling admission from the man who is a world expert on the subject.

Rabin says there is no clear-cut evidence of gene doping.

"We have heard rumours.

There is a German coach being investigated.

" German athletics coach Thomas Springstein was sacked by his club in 2006 after he was caught supplying steroids to his athletes.

When Springstein's computer was seized, authorities found emails discussing the purchase of repoxygen - a gene treatment, developed for anaemia, that makes the body produce erythropoietin (EPO).

"We work on the assumption that it will happen one day, if it has not already," Rabin says.

As it waits for a test, WADA has worked hard to build links with the labs developing gene therapy for illnesses such as muscular dystrophy and motor neurone disease.

"Some of them tell us that following scientifi c symposia or workshops, they are being approached by athletes and coaches interested in the technology and asking if it is possible to inject their athletes," Rabin says.

"We have even had a case of a coach approaching a scientist and asking if his whole team could be treated, so we know there is a huge interest from some athletes in this and from the part of the sport community interested in doping.

" Clearly, there are athletes who want gene doping technology.

There are also people who wish to sell it.

It is the scientists who don't talk to WADA who are the most worrying.

Rabin made contact last year with one such lab over the internet.

Posing as an athlete, he purchased repoxygen.

But when the substance was received and tested, it proved to be standard EPO - sold at an inflated price.

There are, Rabin says, trends and fashions in doping.

Cheating athletes want the latest, undetectable substances.

Ultimately, though, athletes are not stupid.

"They will use a drug if they believe it will work and they believe they are not going to get caught.

If it does work, they will keep going.

" How close are we to a test? Larkins says "about 10 years" but Rabin says preliminary work shows gene doping does leave a detectable "signature".

"It is clear today that we do not have a test and are still at a research level. But things can move fairly quickly ∑ it could be weeks or it could be years."

Australia is at the forefront of the search.

In a laboratory at the quaintly named National Measurement Institute in Sydney, Dr Kerry Emslie and her team are working hard. "It is a needle in a haystack we are looking for. It is not easy," she says.

Emslie says a reliable test is probably years away but thinks the signs are encouraging. She wrote a paper last year for the Government, assessing the potential threat posed by gene doping. Lose the initial fight, she warns, and as technology improves, we will see more and more genetic manipulation and enhancement.

So how does it work?

First, the gene that governs a certain desirable function is isolated ˜ the source is usually another person. Then, in a laboratory, it is amplified ˜ made more powerful. The gene is then inserted into a viral vector, a virus that has had the harmful part of its structure deactivated but which retains the ability to penetrate and colonise human cells. It is a sort of biological Trojan Horse.

Adenovirus ˜ a common cause of respiratory problems ˜ is most often used but other viruses such as herpes simplex or even HIV are being looked at. The vector is injected into the athlete and begins to take over cells. Once inside, the altered gene becomes part of the cell's DNA and recodes it to behave differently ˜ producing, for example, more and stronger muscle or creating EPO, which in turn creates more red blood cells.

The virus colonises cells at the same rate it would if carrying disease. Once the gene is embedded, it will be expressed. There is no turning back.

Emslie thinks the viral vector leaves a trace that could be the basis for a test. But so little of the vector is required to start the process that searching for it is extremely difficult. Another option is to search for the body's immune reaction to the virus. At the moment, the only way to test for genetic manipulation is to take a muscle biopsy ˜ an invasive procedure that athletes would never submit to.

The search is annoyingly slow. Anyone charged with doping will automatically challenge the finding in court and a testing regime considered untried or experimental would not withstand legal scrutiny. While the cheats may gamble with untried and cutting-edge technology, the drug testers must be certain.

Rabin says that as testing for synthetic EPO gets better, the focus of cheats will shift to gene doping. Currently, athletes must be tested soon after administering EPO. When they remove themselves to distant training locations, they are hard to uncover. But WADA has been cracking down on such practice and is now forcing athletes to continually disclose their whereabouts. Time is running out for the EPO cheats.

Dr Harry Rothenfluh is national testing manager for the Australian Sports Anti-Doping Authority. He says the lack of a test does not give potential gene dopers a free pass. "Finding a test is going to be a real challenge but we also have intelligence functions looking at information coming in and seeking information."

The organisation now has an intelligence staff of six scientists and former law enforcement people. They trawl internet sites where athletes seek information, forge close ties with labs and try to predict where illegal medical technology might be found. "We aren't just relying on testing because we don't know how far away a test will be."

If this brave new world all sounds a little Frankenstein, Larkins says we should have seen it coming. "We've always known genetics determines talent and genetic selection of athletes has gone on since the 1960s," he points out.

Ian Thorpe endured a doping scandal in 2007 because his natural production of hormones was abnormal. Thorpe was a genetic freak. It's easy to see how a rival might be tempted to cheat. No matter how hard you train, the Thorpes of this world have an inbuilt genetic advantage. Why not redress that imbalance?

Larkins says it is a tragedy for sport and a danger for its future that we simply will not know until years after Beijing who, if anyone, was cheating.

"If anyone performs too well in Beijing, the cloud will be over them for the next 10 years. Every fantastic performance now is tainted ∑ it is a really sad thing for sport."

Blood samples taken during the Games will be frozen for eight years and retested once new detection methods are developed. A star two months from now could be unmasked as a cheat two years hence.

Because of the cost and scientific complexity, it is unlikely that huge numbers of athletes are gene doping. But, as the BALCO case showed, it is those near the top who have the most reason to use such methods and the best means of accessing them.

There are plenty of ethical problems with gene doping. But far more pressing are the medical questions surrounding the embryonic science. Experiments and trials over the past decade have demonstrated an impressive capacity to retool human bodies by tinkering with DNA. They have also uncovered some terrible side effects.

And while accessing substances from a legitimate laboratory is one method of gene doping, once research is published, it can be relatively simple for others to "follow the recipe" and replicate gene treatments in secret labs.

"Doing this is much more complicated than injection of EPO," Rabin says. "We know that from experiments conducted on animals that if you cannot regulate correctly expression of the EPO gene, then you die. Your blood becomes so thick that it coagulates."

If you think that is enough to scare athletes away, think again. Rabin estimates that during the late 1990s, when EPO abuse was in an early phase, 20-30 young cyclists died from the substance. "We know people will take the risk . . . when you are an athlete in your 20s, you feel invincible."

ASADA's Rothenfluh says human trials of gene therapy are still in the early stages and it is vital that athletes realise the danger. "There have been some pretty high-profile cases. A young man in the US died as a result of his body reacting to the virus inserted and there were some kids in another trial for whom the treatment accidentally activated leukaemia. There are some pretty major risks but the lesson of history is some athletes won't care."

Rothenfluh says there is a quantum leap between traditional drug cheating and gene doping. With traditional doping, an athlete can stop taking the drug if harmful side-effects become apparent. Quit taking steroids, EPO or human growth hormone and there's a fair chance your body will recover. "But once you've put a gene inside a viral vector into your system, it is not really possible to get it back out."

Larkins also fears the consequences. "You are manipulating your cells' biology at a micro level," he says. "In the studies of this, more mice die than actually survive."

But the mice that do survive have 30% bigger muscles, more power and more strength, he says, or can run all day without ever training.

Victoria University's Stewart says the effect of gene doping on the coming Games is uncertain, but says gene doping, coupled with next-generation EPO products, means there is now a distinct gap between the cheats and the testers.

He proposes a radical solution ˜ opening the doors to supervised and controlled doping. "It's really a matter of finding policy measures that aren't as punitive and are based around education, harm-minimisation and protecting the health and wellbeing of athletes and not worrying too much whether someone has an unfair advantage.

"As fans, we pretend and fantasise about naturally gifted athletes and sheer hard work but we already use genetics to identify athletes for sports, then we target them and train them up and feed them specific diet. There's not much accident in it."

It's an interesting idea but unlikely to happen soon and it hardly seems fair to the overwhelming majority of athletes who do not cheat. Instead, it seems, we are in a new era where gold medals will be provisional and world records arrive with asterisks attached.

It's not ideal to catch drug cheats years after the event, WADA says. But it is better than not catching them at all.

Gene genie is out of the bottle, and cheats may escape Dan Silkstone June 21, 2008 "It is clear today that we do not have a test and are still at a research level. But things can move fairly quickly ∑ it could be weeks or it could be years."

Australia is at the forefront of the search.

In a laboratory at the quaintly named National Measurement Institute in Sydney, Dr Kerry Emslie and her team are working hard. "It is a needle in a haystack we are looking for. It is not easy," she says.

Emslie says a reliable test is probably years away but thinks the signs are encouraging. She wrote a paper last year for the Government, assessing the potential threat posed by gene doping. Lose the initial fight, she warns, and as technology improves, we will see more and more genetic manipulation and enhancement.

So how does it work?

First, the gene that governs a certain desirable function is isolated ˜ the source is usually another person. Then, in a laboratory, it is amplified ˜ made more powerful. The gene is then inserted into a viral vector, a virus that has had the harmful part of its structure deactivated but which retains the ability to penetrate and colonise human cells. It is a sort of biological Trojan Horse.

Adenovirus ˜ a common cause of respiratory problems ˜ is most often used but other viruses such as herpes simplex or even HIV are being looked at. The vector is injected into the athlete and begins to take over cells. Once inside, the altered gene becomes part of the cell's DNA and recodes it to behave differently ˜ producing, for example, more and stronger muscle or creating EPO, which in turn creates more red blood cells.

The virus colonises cells at the same rate it would if carrying disease. Once the gene is embedded, it will be expressed. There is no turning back.

Emslie thinks the viral vector leaves a trace that could be the basis for a test. But so little of the vector is required to start the process that searching for it is extremely difficult. Another option is to search for the body's immune reaction to the virus. At the moment, the only way to test for genetic manipulation is to take a muscle biopsy ˜ an invasive procedure that athletes would never submit to.

The search is annoyingly slow. Anyone charged with doping will automatically challenge the finding in court and a testing regime considered untried or experimental would not withstand legal scrutiny. While the cheats may gamble with untried and cutting-edge technology, the drug testers must be certain.

Rabin says that as testing for synthetic EPO gets better, the focus of cheats will shift to gene doping. Currently, athletes must be tested soon after administering EPO. When they remove themselves to distant training locations, they are hard to uncover. But WADA has been cracking down on such practice and is now forcing athletes to continually disclose their whereabouts. Time is running out for the EPO cheats.

Dr Harry Rothenfluh is national testing manager for the Australian Sports Anti-Doping Authority. He says the lack of a test does not give potential gene dopers a free pass. "Finding a test is going to be a real challenge but we also have intelligence functions looking at information coming in and seeking information."

The organisation now has an intelligence staff of six scientists and former law enforcement people. They trawl internet sites where athletes seek information, forge close ties with labs and try to predict where illegal medical technology might be found. "We aren't just relying on testing because we don't know how far away a test will be."

If this brave new world all sounds a little Frankenstein, Larkins says we should have seen it coming. "We've always known genetics determines talent and genetic selection of athletes has gone on since the 1960s," he points out.

Ian Thorpe endured a doping scandal in 2007 because his natural production of hormones was abnormal. Thorpe was a genetic freak. It's easy to see how a rival might be tempted to cheat. No matter how hard you train, the Thorpes of this world have an inbuilt genetic advantage. Why not redress that imbalance?

Larkins says it is a tragedy for sport and a danger for its future that we simply will not know until years after Beijing who, if anyone, was cheating.

"If anyone performs too well in Beijing, the cloud will be over them for the next 10 years. Every fantastic performance now is tainted ∑ it is a really sad thing for sport."

Blood samples taken during the Games will be frozen for eight years and retested once new detection methods are developed. A star two months from now could be unmasked as a cheat two years hence.

Because of the cost and scientific complexity, it is unlikely that huge numbers of athletes are gene doping. But, as the BALCO case showed, it is those near the top who have the most reason to use such methods and the best means of accessing them.

There are plenty of ethical problems with gene doping. But far more pressing are the medical questions surrounding the embryonic science. Experiments and trials over the past decade have demonstrated an impressive capacity to retool human bodies by tinkering with DNA. They have also uncovered some terrible side effects.

And while accessing substances from a legitimate laboratory is one method of gene doping, once research is published, it can be relatively simple for others to "follow the recipe" and replicate gene treatments in secret labs.

"Doing this is much more complicated than injection of EPO," Rabin says. "We know that from experiments conducted on animals that if you cannot regulate correctly expression of the EPO gene, then you die. Your blood becomes so thick that it coagulates."

If you think that is enough to scare athletes away, think again. Rabin estimates that during the late 1990s, when EPO abuse was in an early phase, 20-30 young cyclists died from the substance. "We know people will take the risk . . . when you are an athlete in your 20s, you feel invincible."

ASADA's Rothenfluh says human trials of gene therapy are still in the early stages and it is vital that athletes realise the danger. "There have been some pretty high-profile cases. A young man in the US died as a result of his body reacting to the virus inserted and there were some kids in another trial for whom the treatment accidentally activated leukaemia. There are some pretty major risks but the lesson of history is some athletes won't care."

Rothenfluh says there is a quantum leap between traditional drug cheating and gene doping. With traditional doping, an athlete can stop taking the drug if harmful side-effects become apparent. Quit taking steroids, EPO or human growth hormone and there's a fair chance your body will recover. "But once you've put a gene inside a viral vector into your system, it is not really possible to get it back out."

Larkins also fears the consequences. "You are manipulating your cells' biology at a micro level," he says. "In the studies of this, more mice die than actually survive."

But the mice that do survive have 30% bigger muscles, more power and more strength, he says, or can run all day without ever training.

Victoria University's Stewart says the effect of gene doping on the coming Games is uncertain, but says gene doping, coupled with next-generation EPO products, means there is now a distinct gap between the cheats and the testers.

He proposes a radical solution ˜ opening the doors to supervised and controlled doping. "It's really a matter of finding policy measures that aren't as punitive and are based around education, harm-minimisation and protecting the health and wellbeing of athletes and not worrying too much whether someone has an unfair advantage.

"As fans, we pretend and fantasise about naturally gifted athletes and sheer hard work but we already use genetics to identify athletes for sports, then we target them and train them up and feed them specific diet. There's not much accident in it."

It's an interesting idea but unlikely to happen soon and it hardly seems fair to the overwhelming majority of athletes who do not cheat. Instead, it seems, we are in a new era where gold medals will be provisional and world records arrive with asterisks attached.

It's not ideal to catch drug cheats years after the event, WADA says. But it is better than not catching them at all.

Hustle and muscle (2008, June 14)

Hustle and muscleSaturday June 14 2008 21:45 IST

Praveen Raja

Early in 2008, when Olivier Rabin, science director at the World Anti-Doping Agency (WADA) was quizzed on whether WADA had developed dope tests for both Selective Androgen Receptor Modulators (SARMs) and Myostatin inhibitors, he nodded in the affirmative.

“In fairness to athletes who stay clean, we don’t say when detection tools are available,” he had said. “We say when we detect the first athletes using the drugs.”

We have to wait to tell if that optimism was feigned. But we already know what these two doping agents can do. These two new classes of drugs, which have made WADA’s 2008 list of prohibited substances, have super powerful muscle-building capabilities.

Unlike testosterone and other tried and tested steroids, SARMs and myostatin inhibitors target individual muscle groups.

Here’s how SARMs gets their name. An androgen is a male sex hormone (such as testosterone). Androgens bind to chemicals on the surface of certain muscles, and initiate cellular processes, like inhibiting or regulating muscular growth. An SARM molecule can activate certain chemicals in the muscle without affecting others. In effect, SARMs can safely ‘switch off’ certain fibres of muscles from bowing to heredity. The muscle just keeps growing. Athletes could build strength, and increase muscle mass or bone density without harmful side-effects or getting caught.

Myostatin inhibitors get the job done in a different way. They block Myostatin, a naturally occurring protein in the body that stops growth of skeletal muscle. An experiment was performed on mice whose myostatin genes had been disabled and they turned into what scientists called ‘Schwarzenegger mice’.

In WADA’s own words: “Based upon their mechanisms of action and early clinical results in humans, these compounds have the potential to be used as doping substances.”

WADA has reasons to be wary. No one could have forgotten the case of disgraced German coach Thomas Springstein, who was accused of gene doping athletes, including minors. The substance used was Repoxygen, a substance that stimulates the production of red blood cells. That infamous substance joined the WADA list in 2006 and still remains one of the most elusive of drugs to detect.

If experts are to be believed, in the future, an athlete could point to any of his muscles and simply ask his coach or doctor to ‘supersize it’ — like in a McDonalds. The same experts also warn that the ‘X-men’ athlete could debut at the 2008 Olympics. The future is now.

suvheart@gmail.com

Gene doping - sport's next big challenge (2008, Jun 12)

Gene doping - sport's next big challengeMatt Slater 12 Jun 08, 01:06 PM

What links sheep's testicles, Scandinavian fungi , strychnine and fine cognac?

Are they the contents of the cupboard under my kitchen sink? Vague memories from my stag do? The honourable way out for a rural Swedish chemist with a well-stocked drinks cabinet?

No. They are all things athletes (or Vikings) have tried to enhance performance.

Of course, they've also tried lots of amphetamines, steroids and naturally-occurring substances to help them go citius, altius and fortius , and that has made things quite tricky for those trying to maintain fair play.

No matter how many pills, rubs and potions the sporting authorities ban, the inescapable feeling is that they are slamming barn doors after the horse has bolted.

Sisyphus and his big stone , the Forth Rail Bridge 's maintenance team, Fabio Capello ...they've got nothing on sport's anti-doping regimes when it comes to endless and thankless tasks.

But at least they're still trying. And it was with this noble cause in mind the World Anti-Doping Agency (Wada) held its third Gene Doping Symposium in St Petersburg this week.

For those of you who don't know what that is, a symposium is a big chinwag...only kidding...gene doping is the evil twin of gene therapy and has been described as a doper's dream come true and curtains for clean sport.

Now I'm no scientist but I think I get the basic idea behind gene therapy : let's cut out the middleman (drugs) and get the body to heal itself. If a gene isn't working properly (and causing problems), let's change, manipulate or repair it.

The potential benefits to sufferers of illnesses like cystic fibrosis, muscular dystrophy or sickle cell anemia are huge. Be it encouraging the production of blood cells, boosting muscle growth or controlling the production of a certain hormone, genetic manipulation could be the answer.

Can you see why this might interest fit and healthy people who want to run faster, throw further, ride longer, but don't fancy the complications and risks of taking drugs?

Can you see how testers might be worried about how they're going to tell the difference between oxygen-bearing red blood cells or testosterone the body has produced naturally, and oxygen-bearing red blood cells or testosterone the body has been engineered to produce naturally?

And they are worried, there's no doubt about that.

This was made clear to me by Professor Theodore Friedmann , the head of Wada's gene doping panel and perhaps the world's foremost authority on gene therapy, when I spoke to him earlier this year.

"Gene doping is clearly an issue that will come to us sooner or later - so we should be worried in a general sense," he explained.

"If the question is should we be worried about it clouding the Beijing Games the answer isn't at all clear and is probably closer to no than yes.

"But Wada is taking it very seriously. They want to stay ahead of the question, they want to shape the issue rather than just respond to it.

"And anybody tempted to cheat should count on it being detectable. People in legitimate gene therapy need to be able to track genes and detect their action. New things are coming and we have promising evidence we can find things that way."

Friedmann also stressed just how foolish it would be for any athlete to dabble in what remains a very experimental area.

"Sport represents the first opening to gene transfer that is not for disease management but for the enhancement of human traits," he said.

"Any attempt to use genetic tools of this sort in sport would first of all be fraught with danger, and secondly would, in my view, be medical malpractice or professional misconduct if carried out by a medic or trainer.

"But there is a possibility of illicit use anywhere in the world. Trying to develop a legitimate clinical application for human beings is complicated but making disabled viruses or moving genes around in animal studies is within the grasp of several thousand laboratories in the UK alone. It's not that complicated.

"Illicit use in sport won't be concerned with the niceties of safe clinical research - they won't go to those extremes. So it will be done and it will be done badly.

"You are going to find mishaps and catastrophes before you find real efficacy in sport performance, I'm afraid."

So gene doping looks set to become the next line in the sand for those willing to follow Tom Simpson 's infamous maxim, "if it takes 10 to kill you, take nine and win".

The British cyclist was the BBC's Sports Personality of the Year in 1965. Two years later he died on the climb up Mont Ventoux during the Tour de France 's 13th stage.

Dehydrated by a stomach bug, he had been so doped up on amphetamines and brandy he rode beyond the pain barrier and didn't stop until his body shut down.

His death shocked sport but nothing much actually changed - cyclists, and other athletes, continued to take risks and it wasn't too long before more of them started dropping dead for wanting sporting glory too much.

But Simpson's case and gene therapy's potential benefits pose another dilemma.

Would the 1965 world road race champion have been so weakened that day if he had access to modern (and legal) sports medicine? Would today's sports drinks, supplements and vitamin shots have helped? Would he have died if his team were tracking his heart rate from the team car?

Probably not, but these are legitimate scientific advances, aren't they?

Yes, but then so is Prozac , Viagra and hormone replacement therapy . Should we deprive today's athletes of medical improvements many in society take for granted?

"The long-term question is how we answer all these questions when gene transfer technology is better understood and the tools are safer," said Friedmann.

"Athletes should not be deprived of real therapeutic tools, even preventive tools. Do we want to see sport go in that direction?"

And with that hospital pass to Wada's ethics panel I will leave you.

Matt Slater is a BBC Sport journalist focusing on sports news. Our FAQs should answer any questions you have.

Sports Doping Researchers to Tackle Mount Everest (2008, May 26)

Sports Doping Researchers to Tackle Mount Everest HILDEN, GERMANY, May 26, 2008 (MARKET WIRE via COMTEX) ----In the run-up to the Olympics scientists use live mice for the first time on the "roof of the world" to develop new tests for gene doping Hilden, Germany / Everest Base Camp, Nepal - May 26, 2008 - In the run-up to the Summer Olympics, scientists are taking an innovative approach to develop new molecular testing methods for performance manipulation on the genetic level. A team of researchers from the University of Pennsylvania today is attempting to climb Mount Everest, taking with them for the first time live mice to the "roof of the world". The effort is being supported by the World Anti-Doping Agency (WADA) and the molecular diagnostics company QIAGEN. The purpose of the researcher's historic climb is to investigate tissue and blood samples from the mice to create a molecular signature for altitude-induced hypoxia. The scientists' ultimate goal is the development of novel testing methods for gene doping by comparing such natural molecular signatures with induced signatures that would be created by gene doping. Such practices have been listed on WADA's index of banned substances since 2003, but the identification of athletes using gene doping is still not possible. Accordingly, experts consider gene doping to be one of the most urgent problems in sports today.

The scientific team headed by Prof. Dr. Tejvir S. Khurana and Dr. Gabriel Willmann is specifically looking to find those genes that are active in a low-oxygen environment and thus enable the organism to adapt to the altered environmental conditions. In general, hypoxia has a positive influence on the body's performance as it stimulates the creation of erythropoietin (EPO), a naturally occurring hormone that promotes the production of red blood cells. When applied artificially, EPO can be easily discovered. However, if gene activity is manipulated in a way that the body produces more "natural" EPO and therefore more red blood cells without being exposed to a low oxygen environment, existing doping-detection methods prove ineffective - at least so far. Now, the University of Pennsylvania scientists intend to solve this problem by developing markers for a test that can discriminate between naturally induced activations and activations induced through gene doping.

"We are very excited that the attack on the summit is now beginning. From a research point of view, a major challenge of this endeavor will be the extraction of samples from the mice under these extreme conditions," said Dr. Gabriel Willmann, one of the initiators of the research project. "The cooperation with QIAGEN, as the world's leading provider of sample and molecular testing technologies, will help us enormously to successfully collect, process and analyze the samples. Therefore, we are confident that first results will be ready for presentation shortly after our return."

According to Peer Schatz, Chief Executive Officer of QIAGEN, this expedition shows how molecular biology is increasingly helping to find solutions for critical issues in many areas of our daily lives: "We are very pleased to partner with the team from the University of Pennsylvania in this exciting project, in which our sample and assay technologies will be used for the development of testing methods in the harshest of conditions. We are also proud to be contributing to the team's so important goal of making anti-doping controls more effective."

In addition to new testing methods for the identification of doping offenders, the scientists also hope to generate new data that may lead to a better treatment of muscular dystrophy. The incidence of this genetic disease is comparatively low, yet it is also incurable and leads to a significant loss of expectation of life. As the disease also affects respiratory muscles, patients in an advanced stadium experience a level of hypoxia comparable to the effects of exposure to extreme altitudes.

Background Gene Doping

Gene doping as defined by the WADA encompasses the non-therapeutic use of cells, genes, genetic elements, or of the modulation of gene expression, having the capacity to enhance athletic performance. An example for such doping approaches is a method to increase the organism's own production of EPO using an active agent called HIF-stabilizers. Usually, a protein called hypoxia-induced factor (HIF) ensures the sufficient supply of oxygen to cells as it stimulates the production of EPO in low oxygen environments. When the oxygen concentration rises, both the production of HIF and of EPO decreases. This process is driven by an enzyme called HIF-PH, which reduces HIF. So called HIF-stabilizers can be used to stop the enzyme from functioning, resulting in a slower reduction of HIF and thus higher EPO levels. New products for the treatment of anemia currently under development tackle exactly this mechanism using HIF-stabilizers.

Note

Photos of the expedition, info graphics explaining the application of molecular tests and pictures describing the principles of gene doping can be ordered from: pr@qiagen.com.

Background QIAGEN

QIAGEN N.V., a Netherlands holding company, is the leading global provider of sample and assay technologies. Sample technologies are used to isolate and process DNA, RNA and proteins from biological samples such as blood or tissue. Assay technologies are used to make such isolated biomolecules visible. QIAGEN has developed and markets more than 500 consumable products as well as automated solutions for such consumables. The company provides its products to molecular diagnostics laboratories, academic researchers, pharmaceutical and biotechnology companies, and applied testing customers for purposes such as forensics, animal or food testing and pharmaceutical process control. QIAGEN's assay technologies include one of the broadest panels of molecular diagnostic tests available worldwide. This panel includes the only FDA-approved test for human papillomavirus (HPV), the primary cause of cervical cancer. QIAGEN employs more than 2,700 people in over 30 locations worldwide. Further information about QIAGEN can be found at www.qiagen.com. Contact: Public Relations QIAGEN Tel.: +49 2103 29 11826 Mail: PR@qiagen.com Copyright Copyright Hugin AS 2008. All rights reserved.

SOURCE: Qiagen N.V.

Gene doping is next frontier of performance enhancers in sports (2008, May 11)

Gene doping is next frontier of performance enhancers in sportsBy SAM MELLINGER The Kansas City Star S cientists have seen the future of sport. It involves mice that can lift three times the average, humans who can run 90-minute marathons, and ligament tears that can be fixed by injection.

It is genetic engineering, therapy and doping, and it is the arrival of the bionic athlete. At the extreme, this is either the advancement or end of the human race. At the minimum, it is the unavoidable change to the way our sports — baseball, football, the Olympics, you name it — are played.

They used to talk about this in whispered tones, with only the occasional mention in mainstream media. Five years ago, the experts said gene doping wouldn’t be a concern for another five years. More and more, that sci-fi, futuristic threat is now.

“The upcoming Olympics,” says Ron Evans, a genetics professor at the Salk Institute, “it’s probable that right now, someone is training on this.”

Evans knows. He led a team of geneticists who created “the marathon mouse,” a rodent that ran twice as long as normal mice with one-third of the weight gain.

The goal of Evans’ work is to cure obesity, diabetes, certain kinds of heart disease, and all sorts of noble endeavors. But you know who calls him? Athletes. Coaches. Even a horse trainer.

A couple of snapshots:

A German track coach charged with supplying steroids to underage athletes is proven in court to have the knowledge and desire to purchase Repoxygen, a substance that activates a gene that stimulates the body’s production of red blood cells. One cell biologist refers to this as the “crossing of the Rubicon” into the world of gene doping.

China holds science fairs in which it shows off rabbits with human ears, and a mutant fish that matures into adulthood in half the time, setting off alarms around the globe about what else that country may be up to.

This is not the apocalypse of life as we know it. Genetic engineering’s base is in saving lives, which it has done already. Children suffering severe anemia have already benefited from still-risky experimental treatments that injected genes to boost red blood-cell production.

But this could be the apocalypse of sports as we know it. The abuse of this technology may forever change our games. This is real, experts say. It’s happening soon, if not already.

The competition may be drifting to labs in a way that could make BALCO look quaint. Gene doping has the potential to have much more impact on sports than steroids or HGH ever did.

“Absolutely,” says Gary Green, a UCLA physician who advises Major League Baseball on its drug policy. “It could really redefine everything we think about sports. You could end up with 10 different competitions, the genetically natural and the genetically unnatural. It’s a really dangerous thing.”

•••

Your local grocery store sells the benefits of gene therapy. Those greenhouse tomatoes, the ones that are smooth and plump and beautifully red even out of season? Yeah, they’ve been genetically altered.

The world of genetic engineering creates possibilities for all sorts of medical miracles. There are between 250,000 and 300,000 ACL injuries per year in America — the vast majority away from professional sports — and they may soon be treated with an injection that would heal the ligament. No more surgery.

Researchers at Baylor used genetic modification to boost the size of pigs by 20 percent while cutting down on fat and avoiding the debilitating side effects produced by more traditional treatments.

It’s not a huge leap to see the potential gold mine here for athletes.

“Whether it is promoting an endurance-enhancing gene or increasing muscle mass,” says Andy Miah, a Scottish doctor and expert in bioethics. “There are many applications, but no direct ways to test for it.”

To get an idea, consider the case of Eero Mantyranta, a three-time Olympic gold medalist for Finland in cross-country skiing in the 1960s.

He was accused of blood doping — even back then — but was proven to have a natural genetic mutation that gave him more red blood cells than the average person. More cells to carry oxygen from the lungs means more aerobic stamina.

Mantyranta’s case illustrates the difficulty of catching dopers, because some of these mutations can happen naturally. They can also happen through genetic alteration, giving athletes superhuman physical ability.

“You take a normal human,” says Theodore Friedmann, a board member for the World Anti-Doping Agency health medicine research committee, “and you make him better than normal.”

If confined to natural training, elite athletes are said to be now using 99 percent of their natural physical capacity, compared to just 75 percent in 1896, the year of the first modern Olympics. Given those parameters, academics say there would be no new world records after the year 2060.

But that’s in a world with no genetic engineering. Scientists think a series of gene-doping breakthroughs could boost endurance by up to 10 percent and, according to one study, allow a runner to complete a marathon in 90 minutes — more than a half-hour faster than the current world record.

Consider that your favorite basketball and football players could enhance their genes to become faster, stronger, even taller, avoid the natural slowing down that comes with age — and do it with virtually no risk of being caught by a drug test.

LeBron James could be dunking into his 50s, Josh Beckett dropping nasty curveballs 20 years from now, and Brett Favre making broadcasters coo in the year 2025.

Scott Rodeo is an orthopedic surgeon at the Hospital for Special Surgery in New York. His work centers on using gene therapy to treat the recovery of rotator cuff tears. His team has completed work on sheep, but if it goes where they hope, this is literally life-changing stuff for baseball pitchers everywhere.

“The healing between tendon and bone is a slow process,” Rodeo says. “What we’re doing, this could potentially hasten recovery time. You could certainly diminish the failure rates, which are distinct.”

•••

There is an unavoidable ethics question here. It’s the kind of thing that physicians and philosophers could spend days debating, with no consensus.

What if doctors say your child will grow to be 4 feet tall, but a genetic alteration could make your kid 5-2? Wouldn’t you take it? So how long before someone wants their 6-2 son to be 6-8 and play college ball?

Molecular genetic engineering holds the most promise in curing muscular dystrophy in children. So how long before those same effects are used by an athlete to accomplish what otherwise wouldn’t be possible?

We utilize all kinds of enhancement already, from pills that make us feel better to plastic surgery that makes us look better. Genetic alteration may provide the same benefits, only without the drugs or risk of surgery.

“If you’re a philosopher,” Friedmann says, “you might ask, ‘If we accept it through pills, why don’t we accept it through genes?’ And the answer isn’t absolutely clear to me.”

In the sporting world, there are plenty of examples of dependence on engineering: race cars, golf clubs, even baseball bats. Maybe it shouldn’t be a surprise that someday — today? — our athletes will be engineered, too.

The effects here go way past sports, straight into everyday life. Should parents be able to choose the sex of their baby? What about hair color? Eyes? Physical attributes like height and build?

Medical researchers have come to expect that their advancements, aimed at treating disease, will eventually be used for less-than-noble purposes. After all, AIDS patients sometimes sell their prescription HGH to bodybuilders.

But sports leagues and organizations are scrambling to come up with answers to how they can deal with a problem that is potentially more pervasive and less detectable than anything we’ve seen involving steroids and HGH.

“We’re going to have to start looking at patterns, rather than just what’s there at this present time,” says John Lombardo, a 30-year veteran of sports medicine and the NFL’s advisor on performance-enhancing drugs. “You look at what somebody’s pattern or profile does over years, then use that as a mechanism. Not just a positive test, but be able to say, ‘Well, this is altered and this doesn’t happen naturally.’ ”

•••

Nine Paris boys were diagnosed with the same fatal disease as the Texas Bubble Boy. Beginning in 1999, doctors experimented and gave each boy transplants of his own bone marrow cells corrected by a gene transfer.

All immediate indications were positive. After about three years, one had developed a leukemia-like disease. Three months after that, another. Both boys died, sending emergency halts to other gene therapy projects around the world.

So it doesn’t take Friedmann long to answer what the dangers are that we’re working with.

“Death,” he says. “Death is a danger. You don’t play with these methods.”

This is a dangerous spot we’re in right now, where there’s enough knowledge to mess with genes but not enough history to know what the effects will be. Experimentation right now could be fatal.

They say the technology is so immature that the only certainty here is that something will go wrong. Deaths are the price of progress when trying to treat fatal disease, but hardly justified when trying to improve athletic performance.

One experiment involved altering the genes of monkeys to boost their red blood cells, which allowed them to test off the charts in endurance tests. Unexpectedly, and without warning, the floor fell out of monkeys’ blood production and they eventually died of anemia.

There is no “off switch” in much of what these gene alterations do. Which is why one scientist warned athletes to only genetically enhance the muscles they don’t really want, so that the flesh could be cut out if it grows too big or too fast or both.

In time, genetic engineering may very well be safer than steroid or HGH use. But that time is not now, not yet.

“I think if athletes really paid attention to what it means to change a gene,” Lombardo says, “they’d be very hesitant to do it. At least the state of the art right now. Most of the studies have been done in medical conditions, and most of them haven’t been real successful.”

•••

The future of gene engineering is the future of sports, and vice versa. As Rodeo says, “you’re talking about the next frontier of doping.”

There is no way of knowing just where this is going, but already there are people trying to figure out how we’ll deal with it all once it’s here. Since there would be no drug to test for, some want in-depth DNA and gene readings done early on athletes to establish known baselines.

There are calls for strict governmental oversight, medical tags on gene alterations that would show up in tests, or just regulation — not prohibition.

Others say forget that, let’s create two divisions: the natural and the enhanced. Kind of like in bodybuilding.

“Athletes are already posthuman cyborgs and we celebrate this,” says Miah, the Scottish doctor. “It is likely that greater use of this technology will seep into other aspects of culture, as we begin to embrace more and more enhancements.

“Sports might soon become peculiar for resisting such developments and, in the meantime, will be placing athletes at greater risk by forcing them to enhance behind closed doors.”

Miah has studied the trend of performance enhancers in sports and says one of the favorite lines of leagues and sports organizations is to acknowledge a pending threat, but say it’s still down the road.

That’s essentially what Green and Lombardo — the doctors working with MLB and the NFL, respectively — said in separate interviews for this story.

Evans and other experts say the future is closer to now, if it hasn’t already arrived. Evans has been approached too many times by too many people in sports to think it isn’t possible that a gene-altering version of BALCO is up and operating somewhere, working to unleash a new generation of superior athletes.

Parents, coaches and athletes themselves want to know as much as they can about the process and the benefits and the risks. Knowing that gene alteration is still — at best — in its adolescence and potentially fatal doesn’t seem to scare anyone.

After a recent speech, Evans was approached by a college basketball player he didn’t want to identify. These weren’t surface, just-to-understand-better questions, either. And this athlete is not alone in his curiosity and willingness.

“They’re not embarrassed by asking,” Evans says. “If they think someone’s cheating, and they have to race against that person, that’s a decision they have to make. And it’s not an obvious decision for athletes.

“Look, it’s definitely early. But the games are on. Athletes are emerging in their awareness.”


How gene doping works Experts say gene doping is the next great threat to professional sports, and that the impact could far outweigh what we’ve seen with steroids and HGH. Here are three ways doctors say athletes could abuse the technology:

Injection of a gene to boost production of the hormone erythropoietin, known as EPO. This increases red blood cell production, which increases aerobic capacity. The procedure is meant for patients who suffer severe anemia, but could also benefit healthy athletes — and is why some predict a 90-minute marathon.

Insertion of muscle-building genes into muscle cells. This is the method designed for those with conditions like muscular dystrophy but, again, can be abused by healthy athletes to target specific muscles they want to enhance. Like a sprinter’s legs, a linebacker’s chest or a pitcher’s arm.

Insertion of genes to grow new blood vessels. This treatment is mostly for elderly people with arterial disease. The new gene would boost production of new vessels, which would provide more oxygen and other nutrients to the tissues of athletes. This is the part that would give muscles, lungs and the heart more stamina, both in the short and long term.

To reach Sam Mellinger, sports reporter for The Star, call 816-234-4365 or send e-mail to smellinger@kcstar.com <mailto:smellinger@kcstar.com> | Sam Mellinger, smellinger@kcstar.com <mailto:smellinger@kcstar.com>

One club wants to use a gene-test to spot the new Ronaldo. Is this football's future? (2008, April 26)

One club wants to use a gene-test to spot the new Ronaldo. Is this football's future? Screening could help teams looking for talent · UK Sport has 'no power' to prevent use of technique

Matt Scott <http://www.guardian.co.uk/profile/mattscott>  and Paul Kelso <http://www.guardian.co.uk/profile/paulkelso> The Guardian <http://www.guardian.co.uk/theguardian> , Saturday April 26 2008

This article appeared in the Guardian <http://www.guardian.co.uk/theguardian>  on Saturday April 26 2008 <http://www.guardian.co.uk/theguardian/2008/apr/26>  on p3 of the Top stories <http://www.guardian.co.uk/theguardian/2008/apr/26/mainsection/topstories>  section. It was last updated at 00:37 on April 26 2008.

For decades the task of identifying emerging football talent has been considered an art rather than a science, exclusively the preserve of wise old pros and sharp-eyed scouts and dependent on a large slice of luck. Now, however, it seems leading football clubs are turning to cutting edge laboratory techniques to aid their search for the next David Beckham. According to a leading sports scientist, at least one football club has explored the possibility of using genetic screening to separate prospective Ronaldos from those destined to join the Sunday morning hackers on Hackney Marshes.

Dr Henning Wackerhage of the school of medical sciences at Aberdeen University told the Guardian that a professional club had made contact with him about the possibility of screening players to discover whether they have a genetic predisposition to athletic excellence.

Wackerhage prepared an academic paper earlier this year highlighting experiments that had produced enhanced physical performance in mice and rats, and the possibilities offered by gene doping and screening for enhanced athletic performance. He has since suggested that it might be possible to produce the human equivalent of a formula one car by using genetic mutations. His research was picked up by the unnamed club, which got in touch hoping to exploit nascent gene-screening technology, already freely available in Australia, which tests athletes for a number of genes considered indicative of top-level performance.

"A football club was interested in doing genetic testing of athletes," he said. "It was a genetic performance test. My advice was that there are questions of legality with an employer doing genetic tests on its employees. They wanted to conduct a test that is specific to genetics."

Australian company Genetic Technologies offers a A$100 (£47) test that claims to identify whether customers have the fast-twitch muscle function gene ACTN3, which is found in leading sprinters.

There are other genes associated with athletic ability including PPARdelta, which governs slow-twitch muscle growth; IGF-1, which controls human growth; and genes that regulate erythropoietin, a hormone that affects the production of red blood cells.

Finding and developing players who will help clubs win titles and reap large profits on the transfer market is the holy grail of football development. Manchester United's achievement in developing half a team of international players in the shape of Beckham, Ryan Giggs, Paul Scholes, Nicky Butt and Gary and Phil Neville is the benchmark for talent identification, and English professional clubs spend £50m a year trying to achieve similar success.

Wackerhage said he was not in favour of using the screening method but said the technology had potential. He also gave a speech earlier this month suggesting that genetic modification could reduce the world record for the marathon, currently just over two hours, to 90 minutes.

"The aim of the talk was to highlight the fact of genetic research on mice and humans. It shows why there are different natural variations in sporting ability," he said. "The mice are made to be different because their DNA is changed. Sometimes it doesn't cause disease but leads to fitter specimens, better storage of glycogens, a massive heart etc. The idea of the talk was as a thought experiment that would consider combining all the mutations to see if you got a superathlete."

Huw Jennings, youth development manager at the FA Premier League, said screening could have a role to play in identifying athletic talent but was unlikely to establish whether youngsters would make the grade as professional footballers.

"While you may be able to identify athletic ability, the road from promising youngster to top professional is far from smooth, and it doesn't necessarily follow that talented athletes will become talented footballers," he said.

UK Sport, the body that governs drug testing in Britain, said it had no power to prevent clubs using genetic screening on players as it was not prohibited by the World Anti-Doping Agency.

Doping for a cause (2008, April 4)

Doping for a cause: Brain-enhancing drug use by academics could improve research - as long as it doesn't lead to unfair competitionBy: Christina Domenico

Will academics be the baseball players of tomorrow, testifying on Capitol Hill about their alleged performance-enhancing drug use?

That's the question right now, as "brain doping" becomes the sister buzzword to "human growth hormone" and "anabolic steroid," - words popularized by the doping scandals that plague the sports world. Some neuroscientists believe that academia is about to enter an era of drug-induced brain enhancement.

But unlike baseball, in which a batter facing Roger Clemens' over-inflated shoulder can claim that the game's unfair, academia - and society as a whole - can benefit from the use of cognition-enhancing drugs.

As Stanford law professor Henry Greely points out, sports are a zero-sum game - when someone gets better, someone else gets worse - and players who have enhanced themselves with the use of drugs tip that balance in their favor.

Academia, however, doesn't work that way. One researcher's success is not hampered by another's performance. Greely added that "it's rare to have head-to-head competition" among academics - so the sports analogy doesn't hold up.

Cognitive-enhancing drugs such as Adderall and Provigil can affect a user's mental abilities by allowing them to concentrate completely on one task or giving them a period of alertness. There's also already a widely-used drug out there that produces similar effects - it's the caffeine you consumed in your morning cup (or two) of coffee.

Many researchers and students enjoy a daily caffeine fix to help keep them alert.

So, as Arthur Caplan, director of the Penn Center for Bioethics, pointed out in an e-mail, "if it is OK to drink three Red Bulls or six cups of coffee or tea to stay awake to get a paper written or corrected, why is it inherently wrong to do so with a pill?"

There are legitimate concerns, of course. Greely noted that the most pressing issues are safety, fairness and coercion. If the drugs have negative health effects, it's a bad thing. If they harm hiring practices or foster competition and inequality between universities, it's a bad thing. If an employee is forced to take them to work better, it's a bad thing.

But if an academic decides to give himself a boost by taking Adderall and consequently produces better research - well, that's a good thing. In essence, it's no different than stopping by Starbucks for a triple-shot latte, no foam.

Their use can improve the ability of academics to discover new things about the world. And that's the main goal of research.

And if academic research gets better, there's a social benefit attached to it. "The idea of doing things that lead to better research and the production of knowledge is a good thing, with all other things being equal," Greely told me.

I'm not saying that cognition-enhancing drugs are a necessity in any case. Rather, it's an individual's choice to use them, and we shouldn't be so quick to shout out against something that can yield such positive results.

If the era of "brain doping" really is on the horizon, there naturally will be concern about its future and consequences. And rightly so, as with any new trend. But unlike in the sports world, improving the ability of scientists and researchers to do their job effectively betters the world we live in.

If one day, a researcher whose heightened mental ability because of a pill finds a cure for AIDS, are we really going to sit him down in front of a Senate committee to question him about how he achieved such an incredible feat?

I would hope the answer to that question is a resounding "no."

Christina Domenico is a College junior from North Wildwood, N.J. Her e-mail is domenico@dailypennsylvanian.com. The Undersized Undergrad appears on Fridays. © Copyright 2008 The Daily Pennsylvanian

Building better bodies (2008, March 22)

Building better bodiesSome athletes willing to use untested therapies that scientists are developing for patients

Curtis Eichelberger Bloomberg News

Saturday, March 22, 2008

Chris Rosa has spent 26 years in a wheelchair awaiting a treatment for his muscular dystrophy. Within the next five years, even before new drugs are approved for him, athletes may try using them to cheat, sports doping authorities and scientists say.

"I get angry about it," said Dr. Se-Jin Lee, the Johns Hopkins University scientist who discovered a protein being developed for diseases including muscular dystrophy. "The scientific potential to make people's lives vastly improved is incredible. And all we talk about is whether some athlete can use it to hit a baseball farther."

Wyeth, Amgen Inc. and closely held Acceleron Pharma Inc. are experimenting with spurring muscle growth by suppressing a chemical called myostatin, found by Lee in 1997. Doing so would reverse atrophy caused by wasting illnesses and aging -- and create a hard-to-detect, non-steroid shortcut for increasing the size of healthy tissues.

Agencies that police sports for performance-enhancing substances say myostatin blockers may reach athletes as soon as this year's Olympics and certainly by 2012. The World Anti- Doping Agency has banned them even before they have been fully tested. Meanwhile, that group and sports organizations including Major League Baseball are monitoring other treatments known as gene doping, in which cells are reprogrammed to enlarge muscles.

The Montreal-based anti-doping group, created in 1999, has already spent $6.5 million on finding ways to detect athletes using gene-altering technologies. The group plans to work with companies making myostatin inhibitors when trials are more advanced, according to Olivier Rabin, the agency's science director.

"We have to prepare ourselves for misuse in sport soon," Rabin said in a telephone interview. Some athletes might try to use the new muscle-building medicines as soon as the 2012 Olympic Games in London, he said.

The new drugs may be particularly difficult to detect because they are injected directly into the targeted tissues and could be designed not to show up in urine and blood tests, researchers say.

As a U.S. House of Representatives subcommittee probed the use of steroids in professional sports, witnesses at hearings in January and February warned that next-generation drugs may enable athletes to rewrite record books.

"When we think we have a problem solved, there are chemists creating new problems," said Bud Selig, the commissioner of Major League Baseball, told the House panel Jan. 15. Baseball "hired the best experts that we can" on gene doping, he said. Selig didn't address myostatin blockers.

Drugs to inhibit myostatin are being developed to help patients like Rosa, 40, who is the director of student affairs at City University of New York. He was diagnosed with muscular dystrophy at age 14. He remembers spending childhood summers playing stickball in the shadows of New York's Shea Stadium and the winters emulating St. John's basketball player Chris Mullin.

"I can't dream about my future without worrying about how this disease might skew my life expectancy," Rosa says.

In healthy people, muscle mass is determined by need. As exercise tears fibers, the cells instruct the tissues to rebuild themselves bigger and stronger to handle increased workload.

Patients like Rosa lose muscle and never rebuild it. The same process affects people with amyotrophic lateral sclerosis, also called Lou Gehrig's disease, after the New York Yankees Hall of Fame baseball player whose career it ended. Others lose muscle as they age, affecting stability when walking.

In 1997, Lee at Johns Hopkins in Baltimore created mice lacking a gene to make the protein myostatin and showed that they developed more muscle. He and other scientists later showed that the substance regulates growth of the tissues. Michael Bloomberg, the majority owner of Bloomberg LP, is a former chairman of the Johns Hopkins board of trustees, and the university's school of public health is named for him.

Wyeth, based in Madison, New Jersey, and Amgen, based in Thousand Oaks, California, are testing myostatin blockers in humans. Neither company would discuss the drugs' potential for abuse by athletes. "Amgen's mission is to serve patients," said spokeswoman Anne McNickle.

Wyeth, the fifth-largest U.S. drugmaker, is developing MYO- 029, an antibody molecule that attaches specifically to myostatin and blocks the signal instructing muscles to stop growing. The results of an early study, with more than 100 patients in the U.S. and the U.K., will be published this year, said Michael Lampe, a Wyeth spokesman.

Amgen, the world's largest biotechnology company, has started a safety trial for a myostatin blocker called AMG-745. McNickle declined to how say many patients are participating.

Acceleron, in Cambridge, Massachusetts, will begin safety trials this year for its myostatin treatment, ACE-031, said Steven Ertel, vice president of corporate development. Acceleron has reported that rodents given the substance had a 60-per-cent increase in muscle growth and primates, at least 10 per cent.

"What I care about are the five-year-old children diagnosed with muscular dystrophy who will be in a wheelchair by 12 and oftentimes dead by their early 20s," said John Knopf, Acceleron's chief executive officer."The focus here isn't on athletes."

Nonetheless, participants in sports are following the development of myostatin inhibitors. Lee, the Johns Hopkins School of Medicine molecular scientist, recalls putting down a test tube one day about two years ago to take a phone call from a Brazilian bodybuilder who had e-mailed for weeks with questions about the substances.

"I was explaining that we were still in the testing phases and that a drug Wyeth has in trials, and he interrupted me and said, 'MYO-029?' " Lee said during an interview at his laboratory. "He said, 'I have some right here. I just want to know if it's safe to take.' "

"I warned him against taking something that hadn't been thoroughly tested," Lee said. "It was a shocking conversation."

Geneticists Lee and Alexandra McPherron discovered myostatin when they were studying how cells send signals to each other. The material was one of the communicating molecules they identified. Lee later found that while the protein plays a predominant role in controlling muscle growth in mice, it is just one of many regulators in humans, and might not even be the most important, he says.

In Philadelphia, Dr. Lee Sweeney is developing a different, gene-based approach to increasing muscle mass. Sweeney, the chairman of the physiology department at the University of Pennsylvania's School of Medicine, recalls watching his grandmother struggle with muscular atrophy in her final years, until she was unable to care for herself.

In the late 1990s, he injected mice with a synthetic gene that produced IGF-1, for insulin-like growth factor 1, and saw a 30 percent gain in muscle. Later, rodents were genetically engineered to overproduce IGF-1 in their skeletal muscle. These sedentary mice experienced increased muscle mass of as much as 50 percent. The substance instructs the tissues to grow.

U.S. newspapers and magazines picked up on medical journal reports of his work, and football coaches started calling, Sweeney says. One offered his own athletes as test subjects.

"I kept telling them that my research had only been done on mice and that it could potentially kill a person," Sweeney said. "I finally had to hang up on some of them."

Sweeney's research has graduated to dogs from mice. It's a big step, because the dog's immune system is more similar to that of a human, he says. Treatments that safely alter the muscle mass of a mouse might trigger a canine's immune system to attack tissues injected with new genetic instructions.

That's why the medicines aren't yet safe enough for athletes or anyone else to try, Sweeney says. He worries that a rogue lab could be built for as little as $500,000 to turn out untested materials to meet athletes' demands, he says.

"You have athletes out there who want to become champions so badly that they are willing to risk their health and their lives," Sweeney says.

Designing Improved Humans (2008, March 16)

Designing Improved Humans Playing Cat and Mouse with Genetic “Enhancement”

Henry I. Miller, M.D.

The well-publicized use by athletes of performance-enhancing drugs including androgenic steroids and human growth hormone has gotten more people than ever before thinking and talking about the subject. But the issue is neither new nor limited to a small number of people.

Few of us are strangers to using chemicals to enhance our mental state. No, I don’t mean alcohol or marijuana—just good old No-Doz caffeine tablets and coffee to stay awake while cramming for a final exam or driving late at night.  Medicine has also made great advances in the use of cognition-enhancing drugs, which doctors prescribe to treat cognitive disabilities and improve the quality of life for patients with neuropsychiatric disorders and brain injury. These prescription drugs are now being used more widely, including for shift workers and for jet lag. The ethical issues and risk-benefit considerations are the subject of a commentary published in December in Nature.

Technology will soon offer even more extreme possibilities for enhancement. Scientists, using gene therapy to increase the levels of a single enzyme, recently created a strain of mice with increased physical abilities by genetically altering a gene that affects metabolism. By injecting an active form of the gene PEPCK-C into an embryo, the scientists found that the mouse more efficiently burns body fat for energy and produces less lactic acid during exercise.

These “mighty mice” run much faster and longer than their nongenetically engineered cohorts. “They are metabolically similar to Lance Armstrong biking up the Pyrenees,” said Richard W. Hanson, Ph.D., the Case Western University biochemist who directed the research. Although the mice eat 60% more food than controls, they remain fitter and trimmer and live and breed longer than mice in a control group. (Humans share the same gene.)

The appearance of these mice represents a sort of laboratory-created evolutionary balancing act, following by several years, the creation of enhanced cats. (The good news for rodents is that the felines aren’t smarter or faster but they are less allergenic to humans.)

These experiments have reinvigorated a long-running debate about the ethics of creating designer humans. “We’re in an era when breakthroughs in biology and intelligence are outpacing the culture’s capacity to deal with the ethics,” said Joe Tsien, Ph.D., the Princeton University molecular biologist who directed the development of a “smart mouse” almost a decade ago. “There will be issues of access and who can afford it and whether the social wealthy class will have the intellectual advantage over poor people.” As though attending M.I.T. instead of Florida A&M doesn’t confer an intellectual advantage.

Molecular biologist Lee Silver, Ph.D., of Princeton University has written thoughtfully about these issues. He speculates about the emergence of two biological classes, the “Gen Rich” and “Naturals.”  Comprising perhaps 10% of the population, the Gen Rich will include businessmen, musicians, artists, athletes, and intellectuals, all of whom have been enhanced with specific synthetic genes that allow them to perform at levels not possible for those who have access only to nature’s lottery. They might be thought of as the logical successors to Mark McGwire and Marion Jones, who were able to use only crude chemical means to enhance their athletic prowess.

Who then, should dictate when and how such procedures can be used? Economist Francis Fukuyama thinks the answer lies in greater government regulation. In Our Posthuman Future he writes: “The FDA is not set up to make politically sensitive decisions concerning the point at which selection for characteristics like intelligence and height ceases to be therapeutic and becomes enhancing or whether these characteristics can be considered therapeutic at all. The FDA can disapprove a procedure only on the grounds of effectiveness and safety, but there will be many safe and effective procedures that will nonetheless require [additional] regulatory scrutiny.”

Therefore, Fukuyama proposes “a new agency to oversee the approval of new medicines, procedures, and technologies for human health,” which would exert broader control than current regulation by including “other societal voices that are prepared to make judgments about the technology’s social and ethical implications.”

This additional interference with decisions that should be left to consumers and physicians smacks of antilibertarian nanny-statism of the worst kind. Moreover, it ignores the fact that our society now affords wide latitude to those who choose to enhance their appearance or health in other ways. For example, drugs are commonly tested and commercialized for relatively trivial indications such as modest obesity, stuffy nose, age spots, and baldness. The injectable drug Botox, widely used to treat nothing more ominous than wrinkles, is one of the best-selling drugs in the U.S., and there have been numerous clinical trials of appetite suppressants, memory- and performance-enhancing drugs, and human growth hormone for hormonally normal but short children.

Gene therapy is an extension of drug and surgical treatments and part of a continuum of medical interventions that introduce or modify DNA or modulate genes’ activity.  Among the therapies on the continuum are organ transplantation (for genetic-deficiency diseases), vaccination (which precipitates irreversible changes in white blood cells’ DNA, initiating the synthesis of antibodies), and drugs (to stimulate the activity of dormant genes in sickle-cell anemia, for example).

For over half a century, these therapies have raised many medical and ethical questions similar to those of gene therapy, and physicians, ethicists, patients, and society at large have had to confront them. Issues such as whether a patient suffers from a condition that warrants treatment, the kinds and magnitude of risks, and equal access to therapy are fundamentally no different for gene therapy than for other interventions. Therefore, even when used for enhancement, gene therapy should not be treated differently from other medical interventions.

Arguments against testing gene therapy for enhancement should be weighed against society’s permissiveness toward experimental medical and surgical interventions in general and those intended for nontherapeutic purposes in particular.

An array of entities at several levels of government regulates gene therapy. This intensive and highly duplicative oversight offers a stark contrast to the scrutiny of a radical new surgical procedure, for example, which might be completely unregulated or subject only to the approval of a hospital-based committee.

Patients’ psychological well-being and freedom to choose are also important considerations. “Mere” enhancement is not trivial to the adolescent boy who is six inches shorter than anyone else in his class or to many adults of either sex who suffer hair loss.  One need look no further than the huge societal demand for cosmetics, cosmetic surgery, tanning salons, and health clubs to know that people consider it  important to look and feel good.

In a 1992 editorial, The Economist posed the critical question, “What of genes that might make a good body better, rather than make a bad one good? Should people be able to retrofit themselves with extra neurotransmitters to enhance various mental powers? Or to change the color of their skin? Or to help them run faster, or lift heavier weights?” Its admirably libertarian answer: “Yes, they should. Within some limits, people have a right to make what they want of their lives.”

In view of what people want and what society permits in other realms, should not those limits be very wide?

Henry I. Miller, M.D., a physician and molecular biologist, is a fellow at Stanford University’s Hoover Institution. From 1979 to 1994, he was an official at the FDA. E-mail: miller@hoover.stanford.edu.

World Anti-Doping Agency Gene Doping Symposium (2005)

WADA gene doping Symposium4-5 Dec, 2005, Karolinska Institutet

Welcome

improve people's health. misuse of medical tes

Richard Pound

banbury conference

wada

OM contributions shared by NOCs - but..

gene doping research $3m

gene doping panel in WADA, help with detection

new results - WADC, mar 2003 -

ME: who are stakeholders of gene doping?

Olympic charter amended stating that only countries signed to  WADC can participate in Olympics

UNESCO convention Oct 19 2005 120 supporting states, observed by all 191 states

gov actions - now wider gov support

gov can do sth sports cannot sports cannot address trafficking, seizing, regulation of med professionals

trying to widen network of stakeholders recently, an athlete committee athlete outreach committee

gene doping inevitable

athletes believe they are immune to risk and their entourage seem not to care

New Trends in Anti-Doping Arne Ljungqvist

need to be ahead of the game first time in history

purpose - describe recent developments

some key years 1960 olympic games in rome - danish cyclist died in 100km road race. ioc took action, as first televised Olympics. athlete dying in front of ioc 1961 ioc mc 1964-72 testing for stimulants 1972 munich first serious case, us athlete ephedrine, controversial, still claims medal 1974 testing for AAS - tentative for 76 games in montreal 1983 IOC labs 1988 seoul -arne gave press  conference in rel to  johnson's positive. huge press. death of sport question. response was that this should be stopped. led to unified global effort. iron curtain drop changed this. 1999 ioc code, wada - changed med code into antidoping code 2004 wada code 2005 unesco convention

arne was olympian in1952 and nothing then,

doping code explanation

doping is definedas...

violation new 4. inadequate whereabouts information 8. administration, assisting, encouraging

prohibited list - wada publish each year

criteria - enhance, health risk, spirit of sport

(two of three)

doping need not be cheating to be banned

could say that any substance could be on list, and this is a legal prob

need common sense

substances w similar structures likewise banned, but legal difficulty to try

prohib method enhancement of oxygene trtansfer

distrib of substances 2004 - 36% anabolic 0.1% oxygen transfer enhancement

TUE

anti-doping strategy - info, educatioo, doping control,research

wada allocates 25-30% of budget to research vasst improvement since 2000

ioc never took this responsibility

strategy of doping controls - in comp - unanncounced out of comp - random - targeting (intelligence)

ME: what is current status of intelligence on gene doping?

need to improve intell

ME: how?

recent negative envts

- salt lake city experience, tendency  to make use of most recent advancements. 3 cross country skiers on aranesp - The Sweeney Experience' 2002: first reported that athletes had been contacting him to see how they could benefit; - The BALCO affair 2003; shows illegal production jsut for doping - The Athens experience 2004; first olympics at whch people banned for non-analytic positive; greek athletes; were using artif device for urine - Further designer drugs 2005; don catlin found further egs

The maked Machine false urine

REcent positive evens

SLC2002 -showed that we are close to athletes; these were subsrtances that had been on market for some months - Athens - pursued cheats successfully - WADA Code - UNESCO convention - Research fund - Proactive initiatives

whycontinue fight? - in ethics session. must be unbiased ME: this is too far. to pose all or nth is mistaken.

funl facts must be mentioned 1. no support for such an idea in t sports communioty - there was a debate. but it no longer exists. everyone agrees 2. wada andunesco convention, political estab has reinforced support 3. athletes themselves dont want it. athletes commisions are strongest

ME: when asking athletes about their feelings, hat do you think they are rejecting?

President of K: what are legal conseqs for med professionals?

AL: any person assisting may be banned. will not receive accreditation to be Olympic doctors. but we have limited legal action in civ law. at World Championships some years ago, some finnish professionals weree encouraging, investigation into law. found that action could not be taken. no legal ground .this changed the law.

The Irrefutable Success of Gene Transfer for Therapy of Human Disease) Concepts and techniques of gene therapy - applicationsv to doping in spoprt Ted Friedmann

give overview of underlying baasis of justif for potential of gene doping

rationale is direct outgrowth of gene therapy itself a controversial and difficult field

now a real area of cliincal research basis to think that direct attack can be and has been therapeutic

gene based doping - realstic poss imminent threat to sport - same pressure  that sustain drug doping  will lead to gene doping - based on advances in gene therapy

Evol and current state of gene therapy -controversial history - tools and concepts still immature - clinical reality, effective treatment, poss  cure -- serious risks, tolerable in context of therapy -- still subject to oversight and regulation

gene therapy for human genetic disease science, 1972, mar 3, 172, n 4205 friedman and robin

Proposal for human gene theerapy - needed - technically diffi -use disabled viruses as gene transfer vectors - many ethical and policy problems - reqs local and nationaal oversight - likely to be used for non-therapeuticapplics (enhnacmenet)

dark side broader than gene doping - enhancement of human traits in a eugenic sense.

LeRoy Walters, Kennedy Institute, Georgetown - somatic cell - germ cell

two major technical advances

recombinant DNA -cohen and boyer, 1973 - first efficient transfer tools (engineered viruses), 1981-1982; retrovirus vectors - Temin, Weinberg, Scolnick

retrovirus 1981-2 random integratioon, insertional mutagenesis adenovirus adeno-associate virus liposomes naked dna

ref: j biological chemistry; 1984, 25 12, 7842-9 - restored gene function and reversed phenotype

optimisms - beginnings of human clinical studies - 1989-90 - high expectations - exaggerated promises

gene transfer trials by year crash in 2000

ME: why? at the time of HGP completion

photo of jesse gellsinger

gene directly injected into liver

3 or 4 days later after injection, died react to vector not gene

Uni of Pennsylvania OTC study - a patient death -1999 - adenovirus vector to transfer ornithine transcarbamylase gene (OTTC) directly to liver - patient (JG) developed explosive

visible depression in Society of Gene Therapy

yet, heard of a diff technique

Paris study, Fischer, Great Ormond St LondonX- SCID

photo of Bubble Boy syndrome child - protect from inections

X-linked SCID,sevcombined immunodef dise - mutations in..

ex vivo study

introduiced to bone marrow cells

REF: NEJM article ,Fischer, Alain, lead Hacein-Bey-Abina, S -sustained correction of X-linked severe combined immuno

complete recovery - complete immunecorection 14 patients - some >6 yrs

but at high cost - 3 cases of T-cell leukemia -direct result of treatment - responsive to chemotherapy but reqd eventual one marrow transplantation - one death 2004

other two aree still alive and no evidence of residual disease. but diff to ustd

three cases of leukemia during effective treatment of x-scid deficiency

LMO2 oncogene has been disrupted - this is why we have leukemia

Why is this result imp? - proof - can be therapeutic - all previous studies ,potential or marginal benefits ,theoretical risks - no risk/benefit -X-SCID -quantifiable beenfits - gene transferrresearch becomes gene therapy - opens new era for med

legitmately therapy not just gene transfer

current successful therapies - X-SCID - q14 patients ,3 leuk, 1 death - ADA-SCID - 4 patients - prolonged - chronic grnaulomatous disease -2 patients

addl imminent and probable successes - cancer vaccines - introdcue genes (GM-CSF, CD40) to cancer cells to enhnace immune response (melanoma, CML, others) - restore tumour suppressor fn (p.53) - some photoreceptor degeneration andblindness -restored sight in blind dogs by gene transfer into retina - coronary artery disease

intra-tumoral...

CNS prophylaxis, new chemo agents

additional info into genome, which maintains mutant gene

now, te to fix defect - to change to wildtype gene from mutant

emerging tes - siRNA for gene modulation -especially for dominant diseasee - vector targeting -gene deliv - targetd gene modifi -zinc finger delivery of transcription factors ,transgenes

so, darker side -therapy is poss, what about enhnacement?

socially and ethically 'acceptable' enhnacement -we already do pharma, so why not gene - reelvant genes are becoming identified - tf, applic of gene tools to non-disease traits seem inevitable -

extension to sport - one of most imminent - unlikely to conform to standards of human clinical research -safety, informed voluntary consent

ME: why is informed vol consent unlikely?

sport or bioengineering? is it still sport?

ME: yes ,good photo, the q might be whether he would have been ahigh jumper if he had info about his genes

germ cell -therapy or enhance?

eugenics - old eugenics of late19th and early  20th C - new eugenics based on genetics - new potential for restrictive ,discrimintory

conclusions - all human gene transfer  -immature ,exptl clinical research, not standard of care -but if i had a child with X-SCID, i would opt for genetic approach - proven concept ,truly therapeutic - many dangers, known and unknown,reqs oversight

risks tolerable in light of disease ,but for healthypeople?

conclusion -sport may lead the way - opp to define social atts and responses

in US, not entertaining proposals for enhancement

discussion

how is read out monitored ?/ dosage? how follow efficacy of therapy? if so, might be poss to detect.

ME: what lev of cooperation is expected from biotech industry?

change position but

Goldspink Kathy Howe, killing off cells. factor 9 expt study shelved becuse of immune response to vector

holy grail is sequence correction

goldspink:

tom: surprised by one thing, which  was your optimism. I sat on FDA committe which looked at gene transfer when French study began.  what is your assessment of the science. is it  likely that LMO2 will not be repeated.

Ted: it hasnt in

Olivier: you refereed to over 700 studies, by RAC. do we have idea of success rate? are we aware of  some genes, neverr been poss to transfer. some genes more capable of expression than others. how long to go from animal model to human.

Ted: not all of 700 studies led to clinical. need to learn much more about how to turn genes on and off.

Olivier: side effects?

Ted: dont see them until you see effect.

Olivier: procedure itself not harmful?

Ted: in Gelsinger it did. will not see ath going wrong until see sth happening

Q: state for muscular.

Q: leukemia. single gene as key factor .also v shiort period - 3-4 years. usually cancer 10yrs. sth peculiar of case , it is activation of agene. are ways to avoid activation.

Ted: but not activitation, but disruption

Q: 3rd case special since dif

Odile: transgene role is enormous. cannot claim thatt there are no te that could counteract potential activations.

Chair: what is view on detection of gene transfer? willl this stop? or need legislation on other level?

Ted: no, wont be enough ,but will be strong deterrent.

Coffee

Effects on organ systems/tissues

Heart -    bigger, greater stroke vol -    inc maximal cardiac output

Blood vessel (heart and trained skel musc) -    more capillaries -    improved dilatory capacity

Blood -    ic total amount of red blood cells -    evevn larger expansion of plsma vol, reduced blood count in a blood sample

Adipose tissue -    reduced amount

Connective tissue/bone cartilage -    inc amount/strengthened

efects on organs systs

endocrine system -    insulin sensitivity -    catecholamine and gH response to ex

skin

imune systt

lungs

nervous system/brain -    inc capillaries more utilised

what factors influe performance

bouchard, C. et al 2005 -    gene map -    summarise what has happened in last year -    prediction of health or fitness -    no agreement yet on ‘key genes’ using popn genetics -    difficult to validate – separate population studies reqd

how study human muscle ‘phenotype’? -    skeletal muscle. -    How dna, to mRNA to protein -    Strength and endurance mapped to samples

Considerations -    species -    type/duration/intensity of intervention o    aerobic, resistance, inactivityy -    acute or repeated -    sampling site and time(s) -    amount needed -    mRNA and/or protein -    localisation -    housekeeping genes/normalization procedures o    complicates, regulation -    method – broad or narrow?

ReF: fluck et al 2005,

REF: Mahoney FASEBJ 2005 -    after acute ex, more genes activated in sets -    limited by number of biopsies you can take. Scientists would ilke one every hour -    but used 3h and 48hr

Generating a human endurance ‘transcriptome’ -    24 sedentar subjects -    240 musc biopsies -    24hr post ex -    measured phenotypic by important

500 genes ‘activated’ by ex in humans - COL3A1, FABP4, IGF-1, TGFBR2

what prdicts for improved cycle performance following 6 weeks training?

What genes regulate -    better oxy deliv

Timmons et al FASEB K, 2005

Gene ontology analysis

PGC-1 inc by training in following hours

Ameln et al FASEBJ 2005 -    HIF-1 drives expresion of epo. -    And VEGF -    At protein levvel, was regulated by acute ex, bound more to Dna, drives target genes,

Does epo play role in muscle? -    perhaps, protective or androgenic -    thus, epo might have systemic and local eeffects beneficial for performance

receptors of VEGF go up – inc to manipulate receptor side

5wks of training, VEGF goes up

to develop gene therapy fully, must understand cocktail of things that are going on

in gene therapy, CV side things are going on, but must know more to grow complex structues such as vessels

Targets of interest at geen level -    transcription factors, angiogenic, mit biogenesis, hypertrophyt

cell doping -    naked cells -    encapsulated – put into tissue, then remove. – safe for cheater, since no trace. Can be done with epo and inserted anywhere. -    sooner than one might expect. As many cell trials. And move towards gene modified cells. -    Yesterday, venture capitalist in san diego, using fibroblaysts, for parkinsons

Questions and Answers

Question: focused on up regulation, but what was freq v down reg

A: usually more up regulated, but perhaps a quarter, 3-4times more up than down

Question: how do trained, elite athletes differ?

A: some surprising, some expected. Not easy to predict.

Question: can distinguish

A: no of subjects needed to study polymorphisms v high, often differe considerably. W n24, impossible

Question: important?

A: extremely. But every thousand base is … bypassed polymorphy by looking at integrated response

Question: study in male, not female? Same for female? Each react differently to training

A: what would you expect?

REsponse:

Response: total of 16mins, can dramatically inc endurance performance, no gender related differences. Might depend on ex mode.

Olivier: concern of cell therpay, problem earlier than gene doping. Today, company proposing use of tendon cells to strengthen repair of horses. So is coming at commercial level soon. One key element in detection is time window we have. You have observed some transformation at mRNA level. What is order of magnitude of change?  Concern that signature will be lost.

A: presume that gene copying intensively is more stable and chronic than when you train. I would guess there is an elevation of gene doping product.

Olivier: what level should we detect?

A: problem is legal. Ban people that have strange pattern? Cell therapy been around for long while. Blood transfusion for over 100yrs. Bone marrow transplant since 70s, skin transplant, etc. cell therpay not new, but gene modified cells is novel and cells that are hidden.

Olivier: cells that grown and reinjected

A: yes, like cell

Andren Sandberg is rapporteur

Lunch

Session 2

Chair: Odile Cohen-Hagenauer

Vectors and Delivery Methods C. I Edvard Smith, Karolinska

Gene therapy -    gene could be 10,000 base pairs -    virus contains maybe 3,000 base pairs -    human genome, thousand books with thousand pages

today, cannot fix gene, but put in an extra one

concept oif a gene

if cell goes through many divisions and gene is in episome, will be lost. So if need to put in cells that divide many times must go for integration. Only way to ascertaint hat will be in cell.

Problem with going from outside of cell to nucleus

Local and systemic gene therapy

Gene transfer techniques -    non-biol methods (plamids, oligonueclotides) o    liposomes and polycations (lipofections) o    electroporation o    in situ naked dna injection o    gene gun (biolistics) -    biol methods o    transduction (virus-mediated transfer, most efficient)

drawbacks to viruses

DNA complexes – plasmids or oligonucleotides -    insert size no limit (can use long stretch of DNA, makes possible sequences, marker of normal) -    episomal – normally this; outside chromosome -    short-term expression -    broad host range -    unstable in vivo

is possible to remove all foreign elements. Ie design genes that do not carry any foreign elements, so  harder to trace

Virus as a vector for therapeutic genes, eg hiv

How use a virus?

Concept: the packaging cell line

IMAGE

Empty particles – allow introduction

Packing cell line 2nd generation

There are a number of viruses that can be used -    ecah has benefits and drawbacks

Concept: RNAi – how does it work?

IMAGE

Recent phenomenon, a decade, first observed in plants. If introduce double stranded rna has different features

In mammalian cells, if, instead of long dsRNA sequence, use short siRNA molecule, can have same effect. Si = short interferring

Regulates gene expression

Can achieve stable expression – deliver shRNA

Vectors contain unique sequences that can be trace Provided you know where and how to look Apart from t vectors there are their products

Questions and Answers

A: when expresss siRNA, is v short.

Question: if do cell culture, get up to 10,000 fold interference.

Question: will day come when can do entirely in vitro?

A: yes, should be. But viruses also have problems. They rely on cellular machinary, so good but also limitations – must use normal process of making proteins. If do invitro can avoid regulatory problems.

Vectors and delivery methods – vector and transgene vector detection H. Haisma

www.rug.nl/farmacie/tgm

in non-viral vectors, mostly have much chemical stuff added to them to allow entry to cell

adenovirus

shedding data, gene therapy stdies

shedding

excreta – semen, stool, saliva, urine, blood germ line – sperm, ovum

environmnent – next of kin

if people treated with gene therapy, can find vectors in almost any of tissues

do not find anything in germ line - ie no transfer to next generation

Gene doping detection

IMAGE OF TABLE

Dna – muscle – no shedding - months For adenovirus, shed in serum, saliva and urine, but only last days AAV – muscle – serum saliva urine – weeks Retrovirus – iv blood – semen (probably through prostate) – weeks

Vector: -    protein – no, requires biopsy -    dna, rna – yes, blood, urine -    chemicals – no, requires biopsy -    antibody response – yes, blood

clearance of free dna IMAGE OF GRAPHS

Even if inject into muscle and leaks into circulation, no way of finding. -    goes to liver and is broken down – perhaps find 10% of it in blood, after 30mins

dna detection?

Baterial is immunogenic

CpG dna: -    unmethylated CpG motifs are abundant in bacterial DNA -    the frequency of t CpG motif is supporess and highly methylated in mammalian DNA

detection?

Transgene -    protein o    human original, yes, elevated blood, urine o    new modified, yes if in blood, urine o    human modified, yes if in blood urine -    effect – yes, if in blood, urine

use effect as most promising

specific detection?

IMAGE

Isoelectric patterns of epo

REF: Lasne F et al Mol Ther 2004, 10:409-10 -    can see difference in number of glucose; same gene, same protein looks different from muscle or kidney -    possible fror detection

detection?

Specific – every potential drug needsa  specific sampling and analysis method – also detect other doping General – profiling allows t determination of (major) changes in gene expresion pattens by: gene array or proteomics

Genetic interventions IMAGE

Serum Protein Pattern diagnostics IMAGE

DETECT MAJOR CHANGE

Proteomics IMAGE

Establshes normalised picture of sports people on proteomic level, then look for major changes

Detection by proteomics

May be indication of gene doping – ME: WHAT else might it be

Post translation modifs

Mann and Jensen, Nature Biotech, 21, 255 (2005)

Gene expression profiles

IMAGE

Alreay used for cancer patients -    sample from tumour, isolate its rna, then matched on a chip, comparative analysis from arrays -    in sport, chip would convey change, 25,000 patterns on chip

Gene Array

IMAGE OF CHIP

Discussion -    gene doping vectors will be undetectable -    proteomics and gene expression profiling are powerful generally applicable methods and will be part of diagnosis and therapy in t future -    requires fresh tissue, urine or blood sample of good (RNA or protein) quality -    logistic (handlig, storage) -    global change in sampling handling is needed

Questions and Answers

A: once gene is active, no way of shutting it down.

Chair: Problem, because need 100% proof to commit someone

A review of current gene transfger models relevant to athletic performance

Haematological system and red cells in particular O. Cohen-Hagenauer

Launched European Society of Gene Therapy

Mainly deal with EPO

What matters, detection of EPO or that carry more level of EPO than rules permit? -    v costful

do you want to detect exogenous and transgeneand rEPO, or have world athlete not go beyond a certain threshold

Epo gene transfer -    can easily be monitored in vivo (hematocrit) – as hematocrit will just increase -    not supposed to induce an immune reaction -    therapeutic indications: epo sensitive anemias, eg chronic renal failure

epo gene transfer 1.    state of t art of vector systems 2.    regulatable expression – pharmacological control 3.    adverse effects – alluded to by haisma 4.    detection of abuse and gene doping

state of art of vector stys

state of art of vector systs 1.    dna electroctransfer of plasmid dna in rate muscle- just need needle, introduce gene in muscle, then electric field and dna will stay in. 2.    polymer encapsulation of xenogrenic or allogenicc fibroblasts or myoblsasts engineered to secrete epo 3.    sub-cutaneous implantation of microdermis biopump 4.    IM injection of epo-recombinnt AAV

IMAGES

AAV-mediated epo gene transfer 1.    long term expression (over 6 yrs) 2.    fatal polycythemia (excessive levels) 3.    regulatory system reqd – pharmacological control by an orally administered drug 4.    adverse event: auto-immune anemia 5.    detection of abuse and gene-doping

regulatable expressoin (3)

companies now investing into this sector

Questions and Answers

Coffee

Gene doping and the regulation of skeletal muscle hypertrophy Lee Sweeney

Skeletal muscle

Gene delivery into muscle -    primary targets are post-mitotic (non-dividing) nuclei of mature muscle fibers -    gene delivery vectors o    naked (plasmid) o    virus •    aav serotypes 6 and 8 are most efficient •    capsule modified lentiviruses o    non-viral dna conjugates o    adult stem cells •    muscle and bone marrow derived

adeno-assoviated virus mediateed gene transfer -    readily infects skel musc -    accommodates <4.7kb synthetic gene -    delayed onset of expression (Biut self compleent and high titrs decreates) -    no viral gene expressio -    no immune response in mice /capsid immune response in larger animals -    no integration (?) into post-mitotic nuclei – better for FDA safety -    long duration of xpression (likel years to decades) – but depends on usage, since only hitting postmitotic. Eg. Normal sedentary mouse loses no expression, but if hypertrophy, then lose in matter of months o    in monkeys that are not exercising, expression remains

efficiency of aav gene transfer -    50-95% of fibers show expression of reporter gene (LacZ) delivered by AAV1 -    transduction of -200% of all muscle in mouse possible w high levels -    looks possible for dogs now.

So, enhancement?....

potential appliocs for sskel musc -    primary musc diseases, duchenne beckeer, muscl dyst -    loss of muscle function during aging -    secration of therpaeutic proteins into t blood (factor 9 for haemophilia)

loss of muscle function during aging (sarcopenia) -    progressive loss of muscle mass and force beginning in fourth decade of life -    slowed, but not prevented by exerccise -    negatively impats health and quality of life -    occurs in all mammals -    may be due to progressive failure of skel musc to repair damage (decline in regenerative capacity) o    prob with ageing when satellite cell fusion doesn’t occur as well

Muscle Growth and regeneration. -    Various growth factors, HGF (hamatocrit) -    IGF-1 one of key factors – imp property (most inhibit maturation of muscle cells, so if over express, would inhibit muscile) but igf-1 drives proliferation, then XXXX

IGF-1 -    drieves protein synth -    reduces protein degred -    stimulates sat cell different

GH-IGF-1 axis - local synthesis decreases with ageing

Will inc IGFF-1 expression im muscl promote growth and refgernation pathways?

IGF-1 expression targetd to muscle -    utilize aav to achieve efficient skel musc delivery -    utilize musc specific promoter (MLC1/3) to limit expression to skel -    igf-1 over exzpresiosn should promote growh -    injected legs did not have age related loss -    also stopped loss of power

hyp -    igf1 overexpres should promote musc growth ad repair leading to t following outcomes

IGF-1

Conclusions – -    igf1 ocer express prevents age-relationship atrophy and loss of skel musc function -    skel musc regen i\

20% or more depending

prevented fibrosis due to severe injury

would it lead to enhanceemnt for athletes? If combined w trainig?

IMAGES

Igf-1 effect local- -    avoids harmful side effects, since blood levels of igf-1 not eleveanted -    decteion difi or impossible without biopsy, unless surrogate markers. -    But difficult to seee surrogate

Could systematic delivery of any ageny provide a similar effect to that achieved w local prodn of igf-1?

-    a TF-beta family membner, myostain antagonise igf-1 action, limiting skeltal musc growht. With igf-1 trying to create a balance. So knock down myostat to create effect on igf-1 -    possible cardiac toxicity -    relatively speciic to skeletal musc -    decreases fat -    loss or inhjib or myostat inc musc mass -    wyeth is in phase 2 clin trials w anti-myosttin antibodies for multiple types of muscle dystrophy – scarey note: all have dlated cardiomyopathy – could exacerbate cardiac condition, but speculative at this stage. Beginning to see effects. In obse patient, marked decrease in fat

Muscle growth and regen -    would inhibit prolif of sat cells, igf inrceases

myostatin inhib could allow systemic delivery -    antimyostat antibody injections into t blood of mice result in muscle hypertrophy -    viral delivery to liver or peripheral skel musc could generate screaion of anti-myostatin inhib in blood o    could look in blood for trace -    should result in inc growth and repair -    not clear if harmful side effects. Not clear would prov all benefits of igf-1 especially during senesence

gene doping could be detected by screening

myostatin KO Mouse -    wild type v myostatin null -    in any athlete, would not want total knock out

belgian bull

young child -    parents, mother is competitive athlete

conclusion -    gene transfer could be used for skel musc

nuber of properties could be changed -    strength, but repair, better muscle mass, strength and speed, maintainence of mass and strangth during disue, inc endurance

is genetic enhancement going to be a reality? -    inevitable -    banned on safety and fairness o    but safety sufficient -    if used in widespread for preventing aging, then harder to ban in athletic population. Especially when earlier better for intervention. -    Genetic profiling of athletes ‘ raise issues of genetic ‘fairness’ -  If someone has genetically decreawed myostatin, then is also unfair

Where are we now? -    can do this today o    naked dna o    direct injection o    vasula injection o    regulated gene expression

acknowledgement -    elizaeth barton, linda morris, rosenthal, farrar

Questions and Answers

Question: these are small animals. But how many injections for thigh muscle of human?

A: we are moving away from injection, rather vascular delivery. But problem is immune response in vector

Geoff Goldspink

Animal gene transfer model Interested in musc regulation

Looking at XXX, derived from IGF-1

IMAGES

Biol actions of gh/igf1

Mgf seems to cause sat cells to inc in no –then goes away

Igf1 also involved, but later in process

Damage

Real outcome is muscle force

With knockout myostatin not strong – lacking in functionality

35% inc in mujscle strength within 3 weeks

already company on internet creating mgf – Phoenix pharmaceuticals

ME: how did you find this?

Splicing can be induced by siRNA

Prediction

IMAGE

Put

Detection -    rapid screen mas spec

confirmatory tests -    antibody methods and o -    cell signalling using differeential gene expression

Questions and Answers

Tom: difference of view about what happens to myostatin knockout. Does it give strenght or not?

A: JHU argue that 17% increase in Arnold Schwarzenegger mice. Not a good balance in extra weight.

Lee: agree, if knockout altogether then not much strength .

Odile: but mujst increase other body parts

Lee: bones do compensate, do get larger. But not looked at tendons. But would assume they would hypertrophy as well

Geoff: myostatin KO; if keep putting into req state, can activtate w mgf, but if keep knocking out myostatin, energy pool diminishes over time. Athletes might use on short term, .

Lee: child born with KO liely to have problems, but mother doesn’t.

Question: shown that athletes using steroids get inc in sat cells, so can detect by muscle biopsy.

Geoff: butler brown in paris when taking biopsy from steroid using athletes, telelle length – life of sat cells – diminished – whereaas we might live to 180 efore run out of sat cells, athletes and exessive exercise might run out

Mitochondrian power plants: target for performance enhancing gene therapy Doug Wallace

Mit genome -    1500 chromosomes, 37mtdna genes -    all key energy genes

african

expressed through oocyte

males do not contribute

life = structure + energy

Schriner s et al 2006, science, 308, 5730, 11… -    increased lifespan by 20%, assoc w marked decrease in mtDNA

mtDNA, since maternally inherited, can only change over long period of time -    difference between everyone in room influences level

women started in africa about 200,000 years ago move to asian then to northern and then to americas

highly correlated w geographic origin – specifically latitude – because of temperature

mtDNA have specific point mutations that change coupling from ATP to decreasing work efficiency, hbut increaseing heat efficiency

changing of coupling efficiency

excess calories burned as heat

A nieme and k majamaa, 2005 Euro j hum gen 13 965-969 - mt dna genotypes correlates w finnish elite endurance versus sprinter athletes - functional difference between type one or two nucleotides

can radically change performance

possible that might be strand invasion of nucleiotide -    if switch from tightly to loosely coupled, would introduce muation, change 1 polymorphic base, inrcease performance 5-10%

Questions and Answers

Question: what is importance of mt ….?

A:

PPAR and the creation of the Marathon Mouse Ronald M. Evans, Salk Institute

What are they? -    peroxisome proliferator-activator receptors, comprise set of three related nuclear hormone receptors, that control broad aspects of lipid metabolism -    expresed in different tissues and are naturally activated

Fat storage and burning -    determined by relative levels of ppars,

revving up metabolism -    synthetic ligand GW1516

created marathon mouse (ppar)

transgenic mouse -    now expresses ppar-delta

muscling in on endurance -    will also treat wildtype (ie. Normal) littermates w orally active PPARd specific rdug

red muscle increased transgenic mice -    pink – glycolytpic fast twitch type ii -    - suggest switch to type 1 myosin rich fibres (slow twitch) -    from carbo burning to fat burning

A – better B – worse C – same

?

treadmill challenge

improved exercise performance in transgenic mice -    80% more time and distance capacity what about ppard null mice? -    Total running time only 20min, compared to wildtype of over 1hr and transgenic of more than 2hrs

Under study – does GW1516 enhance performance in mice?

Future – magic pill?

Clinical -    muscle wasting -    weight loss mec related to inc oxidative meabolism

opp for abuse -    inquiries from athletes, coaches, a horse trainer

conclusions -    ppar-delta directed metabolic changes produces a mouse w a long distance running phenotype -    possible to alter single component of compplex system –ie muscle fiber en burning ) to enttrain t rest of physiologic network -    genetically produced ‘delta’ muscle fibers confer high performance even in absence of exercise (training) -    exercise physiology can be predictively manipulated -    ppar-delter receptor

lead by Yongxu Wang – now running own lab at U Mass.

Gene Doping -  possible orthopedic applications Chris Evans, Harvard Medical School, Boston, MA, USA

Inflammation/arthiritis – phase I

And repair of: Bone Cartilage Ligament and tendon

Arthiritis is chronic, requiring long term gene expression, the other 3 are not – repair, then stop

Gene tansfer to the synovial fluid of joint

ex vivo and in vivo

Some success with ex-vivo

ex-vivo preclinical -    safe feasible in rabbits, rats, dogs, mice horses -    levels of expresion sufficient to inhiit animal models of RA

use retrovirus

phase 1 study in knuckle joint w rhumatoid arthiritis

put into joints that were due for removal

PAHSE I RA STUDY conclusion  (N=2) -    gene transfer to human joints is safe and feaible -    intra-articular gene expresion occurs -    patients accept procedure well -    reported relief, but not fully documented -    phase II studies merited    , BUT which vector

not progressed due to lack of funding. Big pharma wont touch it, small biotech don’t have enough money, millions just to treat small number f patients, but made progress by going around with it.

REF: Evans et al PNAS 102 8698-8706,2005

Targetted genetics company in seattle study.

Also in dusseldorf on modifications to determine clinical response. First year patients respnonded dramatically.

Horses Colorado state uni collab Experimental study in horse wrist joint, experimental model. Remove cartilage and inntroduce chip, measure effects of XX.

Induced disease at day 0, introduced vector after 2 weeks, disease under way, therapeutc not prophlyactivc, at end of experiment untreated joint shows erosion of articular cartilage

Absent from horse who recent therapy

Now bone

Direct injection of adenovirus – BMP-2

V responsive to gene transfer

Do this by making hole in animal’s bone and intro virus (BMP-2)

Rate undergo surgery, where femur exposed and external XX attached 5mm defect in femur would not heal if now use adenovirus and inject 40micro ltirs

after 8 weeks,good healing

Wolf’s law – how bone responds to load

After pins removed normal mineral content returns

Effectively repairing bone that would otherwise not occur

Concluding that we can do this

Cartilage

No intrinsic ability to heal

If partial injury to articular cartilage will not repair

If goes through to bone bone marrow defect

Trying to take adv of fact

Use with rabbit

ligament and tendon -    healing initiated by forming of blood clot -    gene transfer to healing ligament

see if enhance healing

gel-mediated gene transfer -    ad GFP placed into migration model gel -    1 week -    after 3 seeks more cells transduced

Presnet status

Indication – status – relevance to doping Inflam/arthiritus – phase1 clinical – high Bone – advanced preclin - ? Cartilage – preclin - ? Tendon/ligament – experimental – high tendon-muscle

If uses it when injured, then goes back to track, is horse doping?

Overlap between legit medical use – do have arthiritis – but overlaps with doping, since reason for arthiritis is due to over-traiing, so we increae their ability to train

Questions and Answers

Arne: Different between doping and treatment is already in use as TUE. Sports peple should be able to benefit. Problem is when it may go beyond.

Monday

Chair: Friedmann Standard in medical doping involves looking for assays

Don’t worry about looking for epo if you are interested in finding it

Look for local effects Systemic Homeostatic

Need un-biased global assays Changes in gene expression patterns in distal non-target tissues

WADA Perspectives on Gene Doping in Sport Olivier Rabin

Anti-doping analyses started in 60s based on detection of drugs in urine (stimulants and anabolic steroids) Progressive incorporation of -    immunassays: hcG (1987); LH (1997); hGh (2004) -    electrophoresis/focusing: EPO (2000); HBOCs (2004) – human blood oxygen carriers -    flow cytometry: blood transfusions in 2004 trend evolving from pure chemical analysis to incorporate more biochemistry and biology

evolution of rules -    from imperative need to detect and characterize t doping substance(s) in athlete’s biol specimen -    to -    possibiilty to use markers of abuse of substances to report doping -    as long as scientifically validated (concept and method)

markers approach already in final development phase for hGh detection: -    IGF-1 (liver) -    P-III-P (bone) Abnormal markers variation are used to qualify doping Hwr, almost 10 yrs of research and more than $4m

Fundamental concept

Abuse: substance – extra gene -    non physiological modification (imbalance) – change in homeostasis -    detection: where to look? o    Genomic o    Transcriptomic o    Proteomic o    Meabonomic

What to look for? -    signatures of changes unique to doping classes of substances

cannot say one substance equals one specific signature, but can make claims about relationships

limits in -    interpretation of gene modifications -    protein and peptide knowledge -    interpretation of metabolic changes

some gene regulations not fully understood

where to look? -    accessible cells or biol fluids w minimal invasiveness (urine? Blood cell lines, buccal cells; ) -    imaging (changes, markers, radiolabeled tracers)

challenges faced -    identification of right target: where, what how, interpret? -    Accessibility to measurable modifications (invasiveness, time window, ethical methods) -    Eliminate other explanations than doping (gender, age, diseases, enviro, ethnicity) -    Development of specific tools for anti-doping -    Extremely sophisticated constructs w fine modulation already in animal models -    Approaches may well work for gene doping or some substances, but what about cell therapy, in partic autoloous cell transplants – eg. Tendon strengthening in horses – extremely difficult to monitor. Looking for same cells in same organ. Already in application -    Costs. o    Money we can invest has limits. o    Also limit of cost we can ask for analysis. -    Layman accessible! – particularly lawyers.

Hope -    epo study in monkey showed genetically transferred epo still detectable o    not endog -    microarrays and SAGE appear to reveal target genes or mRNA. Proteins are promising. Metabonomics will grow. -    Combination of discriminant factors o    Projects ongoing on physiological markers that can be followed by biochem o    Have longitudinal XXX of athletes and detect unusual variations o    Doubt in future that can test every athlete for gene doping. Must start

Pragmatism -    science is likely to deeliver the antidote. When and how? -    Resources can be v demanding on anti-doping and beyond capability. Need to partner. -    Anti-doping market is limited. -    Partner with academic or private org -    Hope for some large scope methods, not too narrow in application -    Even if gene doping applied, limited chance of success, delay in significance impact in sport, though success will come…

DHEA is an anabolic steroid like testosterone and THG: Global gene expression analysis F Labrie

Use of microarrays applied to DHEA (hormone mutant)

Thg includes a genomic signature typical of a potent anabolic steroid J of Endocrinology 2005, 184, 427-33 Labrie, …. Claude Labrie

What is DHEA? -    precursor of all androgens -    from adrenal or food supplement (will argue against food supp) -    dhydroepiandrosterone (DHEA) -    leads to DHT dihydrotestosterone

The anabolic steroid control Act of 2004 has amended the US controlled substant act to include androstenedione, but it excluded DHEA.

‘ther term anabolic steroid means any drug or hormonal substance chem or pharm relationship to testost (other than estrogenes, progestins, cortico…’

JAMA 280, 1565-1566, 1998 -    qual control of DHEA dietary supplement products

HFL Jane Roberts

Difficulties, always new pharma drugs

Current methods cannot detect gene therapy

But if devevlop, perhaps could apply to other things, proteins/peptides, etc

Gene therapy to gene doping -    non-therapeutic use of genes, genet elements, and/or cells that have capacity to enhance -    muscular, anaemia, pain relief

alternative testing strategy -    surrogate marker approach (biomarker)

cell tissue, organ, organism -    complete ensable of biomolecules -    reflects influecnes of t enviro introduce exogenous substance

biomarkers -    transcripts -    proteins -    metabolites

transcriptomics vs proteomics

transcrcipts (mRNA) -    cellular material o    white blood cells o    urine epithelial cells -    differential gene expression -    complementary to proteomics

proteins -    serum/plasma -    secreted proteins -    includes PTM -    simpler assay -    sample stability?

Surrogate marker approach

Screening approaches

1.    pattern recog (uncharac markers) a.    transcriptomics i.    microarrays ii.    PCA, PC-DA b.    Proteomics i.    Gels, mass spectra ii.    ANNs (WADA Grant) – artif neural networks

2.    biomarkers assays (charac markers) a.    transcriptomics, proteomics b.    characterise proteins c.    development panel assays (multiplexing)

1.    pattern recog

sample prep is key- proteins in serum

Questions and Answers

Question: 4% cvould make world performance difference. Can array technology detect sorts of changes to give improvements of performance. Also legal issues – if athlete tested with array, about 36% of affeymetrix, not confident.

A: at proof of principle stage. Relies on probability

Proteomics J Yates, The Scripps Research Institute

Used for biol discovery

Ideas have been to apply technology to understand how proteins come together

Achieve total protein charcaterisation

Driven by mass spec

Single protein vs shotgun proteomics

Quantification

Global method: Would not stand up in court of law

Questions and Answers

Question: mentioned 20-30% SD, how about if shipped around world?

A: 20-30 is within sample.

Question: what preventive measures to keep stable.

Question; had possible to look at disease or treatment?

A: if biomarker, than one that shows dramatic. PSA doesn’t show much variation across sick and normal.

Question: Haima – not easy to detect in mass spec because some proetins don’t fly very well

A: at peptide level are problems

Proteomics as a tool to tdetect gene doping: intro to protein profiling C C King, San Diego, UoCalif, dept of pediatrics

How can embryonic SCs be used for …

Proteome complete set of proteins in a defined cell type, their relative quantitiates…

Outline -    2D electrophoresis: analysis and pitfalls -    establishing positional databases of proteins for analywsis -    frcaction -    applics for wada

2D gel electrophoresis -    few do this, since pattern recog alone does not give much diagnostic information -    but does offer possible to analyse specific proteins

coffee

Research Report on studies Geoff Goldspink

Exercise -    knee extensor weightlifting exercise -    3 sessions per week

using muscle biopsy

with elderley people

if give growth hormone and then exercise, leads to substantial inc in MGF -    related to inc in cross-sectional area of muscle fibres -    these old people are hormone deficient (drop by 2/3 from teenage to 70+)

relationship between MGF and muscle

studied young people next -    n16 -    give growth hormone, then 4 week washout, then placebo -    take biopsies before and at wk2 and wk8 with blood samples -    untrained indviduals

repeated with trained athletes -    blood levs went up considerably

been taking muscle cells in culture and putting serum on them

use muscle cells in culture

IGF-1 gene transfer

3 Different types of IGF-1 in muscle tissue

actually 6 types (2 classes of 3)

with placebo, inc in class 2 with Gh wen down

with MGF of Class 2,

can now purchase human muscle cells

with GH, get inc in Class II with MGF, mainly class 2

Class II MGF trascripts in cells treated w Human Serum Samples -    clear distinction

Present project with NHFL Newmarket and Nott Trent Uni -    human and murine serium samples for o    biosensor o    other markers o    proteomics – mass spec/neural network

Study 2 Trained Subjects Experimental protocol -    n15 -    from uni exercise science dept -    in training -    randomised o    GH + training o    or Placebo + training,

concern that they might be disqualified from sport

Currently collab

1.    mice receiveing hgh delivered using a mini osmotic pump

mass spec can distinguish

detection -    rapid screening using mass spec -    confirmatroy w o    antibody o    cell signalling using differential gene expression

present and future challenges in detecting enhacneing substances -    synthetic/recombinant analogues -    generic sbstances -    new methods of admin -    gene doping

providing we have good methods, it’s almost immaterial whether gene doping or not

Transcriptional and proteomic effects of IGF-1 Ted Friedmann

Does igf-1 casue sig molecular changes useful for detecion? -    changes? Basis for detection?

Model systems – in vitro and in vivo -    initial studies in in-bred mice – avoid problem of indivd variability, polymorphisms -    cultured murine and human muscle cells o    C2C12 o    Primary human muscle cell -    In vivo, IGF-treated mice o    Muscle, blood, urine, saliva, other organs

Exptl design – short term

I. transcriptional response to IGF-1 - microarray, affymetrix

candidate of genes that can be used to detct

approach to screening for IGF-1 -    identify genes most markedly regulated by IGF-1

Application of microarray technology for the detection of changes in gene expression after doping w recombinant human growth hormone Rene Stempfer…. Christa Nohammer

Goal: development of target dna microarray to identify specific change sin blood cell gene expression related to t admin of hgh

Present project -    feasibility study o    in vitro – different blood cells o    in vitro -  peripheral blood mononuclear cells

microarray procedure

Application of cellular chemistry and proetomic approaches to t detection of gene doping Jane roberts

Objectives -    identify and validate protein expression patterns (fingerprints) o    GH IGF-1 protein gene construct o    Mouse model o    Applic to humans y2-3

Yr1 -    show that genetic manipulation results in change in genetic fingerprint -    can detect w pattern recog

Doping analysis relevant for potential application to gene doping detection James Segura, Biomedical Research Park, PRBB, Barcelona

Oxymoron -    a thetorical figure in which an epigrammatic effect is created by t conjunction of incongrous or contradictory terms -    eg. Not-for-profit drugs; research and physician

detection of doping substacnes -    problem w substances identical to t endogenous ones (endogenous-like substances) is it possible to detect non-natural traits in natural substances?

Gene doping makes this problem harder

Peptide hormones

Indirect markers -    physiological effects -    popn studies: probability

direct markers -    subtle chemical difference between t admin drug and t natural hhormne produced by t b -    difficult to find direct markers

indirect dtection of GH

liver metabolism -    igf-1, igfbp-2 and 3, als

bone metab -    osteocalcine, p-III-p ; picp; ictp

gene expression of gh isoforms

need further verificaiton that change derives from gene therapy and not something else -    use non invasive imaging that shows expression in an unexpected tissue o    IMAGENE

A long way to go before detection

Potential for non-invasive imaging in anti-doping efforts Kurt Zinn

Outline -    background -    imaging -    potential -    points for consideratoin

potential imaging targets -    direct o    transferred genee o    products from gene -    indirect o    change in metab due to chronic exposure to transferred gene products o    changes in anatomy due to chronic exposure to transferredgene products o    inflamm arising from gene transfer or expresed gene product o    reporters of pathway activation

imaging modalities -    radioactive-based -    gamma-ray imaging -    posittron empission tomography -    xray computer tomography -    magnetic resonance imagine -    light-based imaging -    ultrasonography

imaging that maybe immediately applicable to gene doping

Roussel et al, Fig1, J app physio, 94, 1145-1152, 2003

Richardson et al Biochem Soc Trans, 30, 2002 232-237

Potential methods -    direct o    imaging gene transfer agent o    imaging protein gene product o    eg

meausrement of firefly gene for light if mouse produces light, then gene is being expressed

Imaging tc-99m-ad-luciferase

Particle goes to liver

Shows light ommision from liver of mouse

Questions and Answers

Lunch

Session 4

Tom murray

Screening a worry

Matt

T culture of sport Natural talent and effort Natural variation of talent is intrinsic to sport – if your body doesn’t fit, then do something else

New types of sport have developed that appreciate natural talents – where certain body types suit

Equal opportunities -    not part of culture of sport

cannot complain that

does not imply that sport activity is result of genetic lottery -    there is no genetic lottery, but evolution of natural talent combined with effort

fair chance – if different heights where height is relevant, then is unfair – so we divide in groups -    age differences, sex

limits of accessibility on fair innings argument

need sufficient number of competitors to make it worthwhile

natural variation –s mostly self-regulation

people w extreme gene mutations not become elite athletes

limits of genetic screening

gene doping for improvement talent and level of effort -    opening for fair innings – set up games where GM athletes complete, but should we?

The phenotype routlette -    natural phenotype is t result of a delicate balance in order to master o    genetic program o    epigenetic instabilities o    biological chance o    environmental challenges

for safety reasons -    major reason against -    keepin athletes healthy is difficult enough at such extremes of performance. With gene doping more complicated -    delivery, expression and safety -    protect athletes from their own winner instincts -    protect next generation from manipulating their health -    health expenss for sports moveement will likely sky rocket

if we assume safety? -    natural mutations have many advantages appreciated and accepted -    some can be screened for -    hwe, where draw line, w gene doping, one has to screeen for many genetic variants in order to meet t same requirement

snowballing inflation -

rules of fair play -    sport activities presume a pre-competition agreement about rules -    winning is essnetial but so is also fair play

fairness as equal opp not part of sport

as fair share of innings – part of sport with rough measures

as fair play – intrinsic

protecting privacy -    can we protect, with testing -    it can, if understand what privacy is all about -    often willing to give up privacy in certain conditions o    enjoying sport activities is one of those conditions

gene testing – includeed in rules of fair play -    accepted part of different practices -    research, medical treatment, sport activities -    need to regulate. How reliable? Who has access? How handle safely

yes to gene technology -    no to gene doping is consistent w a yes to medical treamtnet

aging of muscles problem – fear that cannot set limits -    distinc between gene transfer in care of patient, always balancing – benefits v risk -    patients are closely mointored to correct for unforeseen -    v different thing to do this on healthy people, where not monitoring closely

these questions not new, many drugs that used on old people that we would not use on younger

eg. Morphine good for people at end state, does not mean that give to anyone in pain

ethics and t challenge of t potential use of genetic technology in sport. Angela Schneider

Summary of effort, talent and fair play -    sport is rule governed -    action against rule is cheating -    should thre be a rule against – yes -    hwr, important practical and ethical problems

Winning the genetic lottery -    is it fair to compensate for those who have lost t genetic lottery from a sport perspective but still wish to compete in elite sport by enhazncing -    Hannson ‘why not allow gene doping’

Need to answer some important concepts

Contested distinctions -    natural and unnatural (artif) -    point of sport is to measure difference o    we have allow naturally differences to affect outcomes o    hwe, we wil not allow t potentially fairere gnetic equalization that would occur through enhancement. Do we have good grounds?

Ethical foundation -    preventing avoidable harm -    paternalism -    performance enhancement -    vision of sport and how gene doping fits within this context -    sport for humans not humans fro sport -    contested

do not design humans for sport

ME: but we do

Sport exhibits values -    leadership must choose which values -    eg. Equity of access; implications of genet therapy for those who currently live with disease or disability; specific sport oriented issues

Laser eye surgery -    language is intructive – if describe as removing normal variation, status as enhancement clear. But if removing abnormalities, more like correction

LASIK -    used in some sports. Should it be? -    Enhances

Comparison w rules against doping -    one point of rules is to limit risk -    risk of laser eye, 5-10%, possible risk -    how much risk is too much? -    Not clear why sport should accept any degre of risk for beyond performance – ie enhancement -    Most relevant value is definition of health

Consistency and credibility of rules In anti-doping have analogous substances

Principle at stake

Distinction between enhancement and repair -    restorative and addtive distinction (fost)

repair is unprobc

incidental improvement -    Tommy John elbow injjury – generalyl accepted

Surgery in absense of defect is enhancement

But Tiger Woods – laser eye

Laser correction public use now

Not like cheating in way that steroid use is

Practice doesn’t cause sufficient harm But this sets bar high

Things that are acceptable elsewhere, not aceptable elsewhere

What do with grey zones? -    arbitrary, but

with strict liability

privacy issues and access to genetic information -    genetic information especially private -    indicative of identities in special way -    puzzle – genetic make up not indicative

social question -    maintaining privacy of personal genetic information  vs potential role of sport community becoming wedge used to derive greater geneal

wituhout moral support, sport will not be able to preserve humanizing influecnce s if sport recognises and re

genetic modification and improving humans -    enhancement

sport conflronst problems

if sport faces problems

who decides?

Sport is leading by saying we will regulate

Ethics, enhancement and sport Tom Murray

Meaning of soprt as a human activity: why the world loves the olympic games

Excellence in sport as expression of -    natural talents -    virtuous perfection of those talents

Aristotle – eudamonia -    full good natual ilfe

there are unvirtuous ways of getting these

objections to doping control in sport -    claim of incoherency -    line drawing problem -    resistance Is futile -    appeal to individual liberty -    romantic/promethean view

ME: but this ignores game theory. It’s not about the rules. It’s about the intended test.

incoherency claim -    no cnpcetual ethical or practical distinction among different means of enhancement sport performance o    the marathoner’s shoes

response -    hypothetical

Line Drawing problem -    all possible lines are arbitary -    aribtrariness is fatal flaw

conflates two meaning of arbitrary -    as unprincipled, indefensible -    as reasonable response when o    drawing SOME line is defensible o    placing line IN THIS PLACE likewise

athletic virtues – fast.

Why 5 players Why not 50 players, look like rugby -    ME: not really. Dimensions of playing field,

But this would not have any of the characteristics of bball

Why draw in this place? -    why not 6 in team? Or 4? No 1 on 1

would not have a game of bball

ME: tom is not distinguishing different kinds of rules – he is talking about constitute rules, not regulative rules

Resistance is Futile -    not a first-order ethical claim -    primarily two empirical predictions o    control will be impossible o    bad conseques ensue -    control is never perfect -    depends upon o    public consensus o    effetive enforcement

ME: he is now switching to regulative rules

ME: breaking some rules is not bad in intelf

there are silly rules – prohibition in us

So must have a public consensus in support of rules

In sport, if ban certain things but do not enfocre

Argument from Individual Liberty

Presumption in favour of liberty Paternalism difficult to defend w adult athletes Hasting Center project -    coercive impact of drugs in sport: the unlevel field

doping control done well provides level playing field

argument from liberty fails to

romantic/promethean view -    humans as self-creators -    understand cultural and philosophical context and implications -    valorizes unfettered will and self-manipulation -    relation to human flourishing? -    Case of anorexia o    ‘anorexia is t cultivation of a specific image as an image – it is purely artficial rceation and that is why it is so admired. Will alone produces it and maintains against considerable odds’ noelle casky, 2003, 129

Triump of Performance Principle -    max performance by any means at any cost -    power lifting: drug free and? -    Unavoidable conseq of refusing to set limits o    Greatly increased risk    rules governing a practice not equal indefensible parternalism -    Threat to spirit of sport

No longer throw people to lions

ME: so the level of risk in sports is just right?

Ethics of enhancement in context -    non-trembling neurosurgeon -    point of practice: spirit of sport -    not t means per se, rather their relationship to t goals of t practice, values and human flourishing

imagine drug with no side effect

imagine drug diminishes hand tremour and neurosurgeons see benefit

let’s also assume that mperson you love most in world needs operation

2 surgeons, one says biomedical enhancement always ethically wrong, never use tremour reducing, and second says, I use it all the time

you would choose one w best results

first surgeon missed practice of surgery

point of sport is natural excellence

point of surgery is to make well

different kinds of human activity calls for different kinds of rules -    partic to circum of relevance

not bad to prevent muscle wasting , but still suspect as use in sport

because of goals and values of practice

challenge of genetic enhancement in sport

what do we value in sport? -    natural talents -    virtuous perfection of talents

what do we disvlaue -    distortion of relationship between natural talent, virtue

what makes a talent natural?

Complex phenotypes -    genome as ecosyst o    genes interact complexly w each other genes, w external environment -    genetic difference in general not rigidly determinative for human behaviour o    see behavioural genetics report at hastings center website

child who has been engineered prenatally, natural?

ME: ecosyst argument – just a complexity argument?

Differences in natural talents? -    as vicious inequalities to be redressed? 1.    Vonnegut’s ‘handicapper general’ •    Disable smart -    As expression of human of human variaton to be celebrated? -    Olympic movement opts for t latter? 1.    Alternative romantic/promtehan, triumph of performance principle

ME

Final session

Jacque Rogge

Test to check for drugs for neurosurgeon

Need clear rules for world of sport

Fairness – but is life fair?

Sport is arbitrary in some ways

Can this be accepted?

Is it fair that kenyan athlete born at 2000m of altitutde has special diet, runs 10km twice a day? Fair to compare with swedish athlete

Laser eye surgery, but would any physician accept to do that? Any ethical physician would refuse operation without pathology

Look at high-jumpers

Achilles tendon most fragile for fosbury

If in 10-15yrs, cell therapy to heal tendon and grow by 10% more and allow better training, forbid? – yes it should, but I need advice.

Paternalism -    we cannot have been told to decide for -    gov put strong warnings on sale of tobacco. But athletes do not know what is dangerous for their health.

Basis of beliefs

850million people practcising sport, 750million recreational

every recreational is competing with self

only 150million in sports contest

we believe that this pyramid provides great educational tool, for body and mind

sport taches social sskills- achieve more in a team, than alone

respct sport, respect society

sport integrates

sport brings health

sport shapes identity

we know life and soc is unfair, but social value of hierarchy – doping destroys ranking system

we believe that protect health, even if paternalism

believe in one example – that fight against doping is important for keeping explemar of sport

different between nature and nurture -    virtuous perfection is essence of sport -    everyone wants to reach limits – leaves sense of accomplishment -    important anser against existential fear that everyone has – who am i?

recruitment -    social aspect -    champion is admired -    not everyone born with talents, but way athlete behaves and lead life is important to protect. Genetic doping would destroy

doping rules are imperect

compensation theory -    compensate up to normal level, but then are cheating, but allowing less effort athlete to be compensated, then penalising the champion

my plea is please give us clear rules – must be crystal clear

enhancement not be allowed

where draw line must be done with ethicists and scientists

Stockholm Declaration Arne Ljungqvist

Composed of olivier, ted, and arne

Today, several human genetic diseaes can be succesffuly reated by gene transfer Gene transfer is still a very immature and it is still an exptl field of human medicine

Challenge?

Change serveal to  ‘a few’

Extensive and rigorous regulatory mechanisms need to ensure safety of research subjects and patients

Gene transfer procedures must -    follow code and principles of human exptn and clinical research -    be performed strictly in accord w local and national rules and regulations for gene transfer in clinical research

Comment: these are more general reseacrh

Tom: human beings?

Lee: clinical trials

Tom: clinical research aimed at dealing with human disease, but some of this will not be about disease. ‘Follow codes and principals governing research to human subjects’

Matt: follows nuremberg, etc

Tom: these are minimal conditions, we can elaborate

Lack of compliane w standards an rules of gene trasnfer procedures must be considered as medical malpractice and/or professional mis-conduct

Development appropriate sanction mechanism for illegal application of gene transfer in sport

Gary: who will develop?

Comment: since no legal, ma

Maybe unethical or illicit

Illegal implies court of law

Unethical and/or illegal

Promote public discussion issues on THE PROSPECT OF gene based enhancement and develop education progrms

Be developed

Comment: this implies it exists

Olivier: can argue this in animal models

Odiele: reservations, since education can be spreading

scientficic progress made through resarch projects supported by WADA and others suggest that new detecion and screening methods are likely to emerge in t near future, which will help to keep sport untainted by gene based doping methods

Cell doping? It is covered if we move entirely towards gene.

Delete ‘near’?

Lee: must emphasise need for research

Support research programs instituted by WADA and other anti-doping organizations

Comment: ‘should be supported’ at end remove support

academic and private research organizations to dedicate resources to further progress in gene doping research should be encouraged

Larry: deter, not just detect – progress to ‘deter’ gene doping

Gary:  government?

Academic, government and private research

Genetic and denomic charcaterisation of athletes to determine genetic traits is contrary to the principles of sport

Rogge: contradiction with screening

Odiele: when speak of genetic trait, must speak of interited trait

Dave: might be reasons to screen for genetic traits in medicine

Tom: say something about unwise nature, but not sure contrary to principles of sport. Not because against principle of sport, but because of potential harm

Lee: must specify athletic traits, not genetic

Ted: not determination of trait, but use of it to exclude. Ie. To determine eligibility

Peter Fricker: this research has been done. Issue here is about discrimination. Need to look at genes and risk of illness.

Tom: use of genetic information about putative athletic ability to discriminate against athlete, should be strongly discouraged.

Add to ‘select’ or discriminate

Peter: must allow ethical reseearch must proceed to validate role of genetic information

Enhance awareness of potentiall illicit use of gene transfer techniques in sport

Promote knowledge on medical and physical dangers associated with gene doping

Odiele: woiuld we like to put forward idea that there are dangers?

Olivier: dangers alone?

Odiele: why not ‘misuse of gene transfer’

Olivier: risks or dangers?

How about potential risks?

Olivier Rabin

ME: why not inter-governmental rules and regulations? As well as local and national

Sports and Genes (2004, Geneva)

Sports and GenesAISTS 2004-09-22

Bengt Kayser

Rankinin, Perusse, Rauramaa, Rivera, Wolfarth, Bouchard – Human gene map for performance and health related fitness phenotypes: the 2003 update Med, Sci. Sport, Ex, vol 36 9 1451-69,

Altitude tents, induce endogenous production of red blood cells

Marathon mice engineered for extra endurance CNN Aug 23

Schuelke et al. Powerful Genes – myostatin rgulation of human muscle mass, Journal p..2682-88 Mcnally, e.m. -    four year old child with unusually large muscle mass

should we exclude this person from comp?

Geneticists engineer marathon mice Helen pearson news@nature.com 2 strains – one dies, the other runs faster for longer

Bob Goldman, 1984, Death in the Locker room

Lane, T. www.theage.com A future of jocks, genes and jingoism Peter fricker – Athens Olympic Team -    identifying athletic genes

Iannis Pitsalidis International Centre for East African Running Science

Why do Kenyans and Ethiopians Win all the time?

Why do Kenyans and Ethiopians win Most of the Time!

Last time an African won marathon was in 1968

Though performances are remarkable

Can genetics explain t dominance of east Africans in world athletics?

Scott,  … and Pitsiladis Med, and Science in Sports and Ex 35 (102) 1727-1732, 2003

Heile Gebraselasie I’ve been running since I was 4 or 5, for us life was a kind of sport

Methodology

Environmental Analysis -    place of birth -    lang -    distance oand method of travel to school

Genetic analysis: mtDNA -    mitochondria are major energy producers of t body -    mitochond fn imp in ex

MtDNA useful in popn genetics -    maternal inheritance, no recombination -    ….

Wildman, DE, Uddin, M., Liu, G, Grossman, Goodman Prot Natl Acad SCi 100 12  7181-8, 2003 -    genetic difc between humans and chimps

Demographic expansion analysis

Peter Forster (2004) Ice ages, and mtDNA chronology of human dispersals Phil Trans R. Soc. Lond. B -    origins of mitochorndria and movement of genes around world

Human mtDNA tree -    many branches of tree, various mitochondrial types and we want to see whether African athletes are part of one branch specifically

MtDNA qs If mt DNA polymorp im in enduance performance..

Contral mtDNA tree -    all different types in Ethiopia – tf. Heterogenous popn -    but did not find that – no common mtDNA -    remarkable distribution -    some amazing athletes who  have genes common among Europeans, than Africa

Conclusions (mtDNA studies) -    Ethiopian athletes distinct enviro relative to ethipian -    Deep commn maternal ancestry

Human karyotype – chromosomes

Why Y? -    patrilineal inheritance -    never 2 ys in 1 cell o    fnal changes immediately subject to selection o    no recombination

Conclusions -    like mtDNA y haplotypes spread throughout tree -    ethiopian y haplotypes show assoc with elite athlete status -    how can t y be having such an effect? -    Direct effect of a genen on t y chromosome? -    Unknown subgroup of popn?

Can genetics explain dominance? -    no genetic evidence found to date! o    So far have not looked too far

They have to run back to school, otherwise they would be caned -    mm

Alex Mauron Sports, Genes, Brains and Ethics

Thomas Murray

Just deserts (1) Purely scholastic process not sport – gambling not sport Largely predictable process not a sport – treadmill test

Nothing more basic to idea of sport than notion that successs or failure ‘sufficiently’ reflects inherent merit of indiv athletes or teams

Ethics of spectator sports -    must be fun to watch in market economy -    needs to be ‘sufficiently’ fair to satisfy yearning for justice

conventional ethics of sports -    let best win -    talent, effort luck

what it means for doping -    chemistry or genetics moral shortcut -    doping disturbs ‘level playing field’

doping immemorial (iliad, chapt 23)

sport has always attracted cheating

‘Citius Altius Fortius…Purius?’ NY Acad Sci, Mgazine, aug, sept 2004-09-22- race between doping and testing

Dilemmas in doping ethics -    prevention best with practical and conceptual difficulties

doping vs honest medical treatment

increasingly doping -    uses substance naturally present in human body -    involves substances also need in bona fide medical treatment -    involves methods that are synergistic with, not alternative o, intensive training

one of major intuitions against dopingis that we substitute something easy – doping – with something that is difficult – training -    may not be true now -    requires sophisticated knowledge

doping vs honest medical treatment not possible

doping vs privacy -    doping prevention requires all-round surveillance of athletes and invasion of privacy -    incly resembles crime control, except in sport you are guilty until proven innocent

The Red Queen -    in Alice’s wonderland you have to run fast just to stay where you are, because landscape moves with you. In fact, t evolutionary arms race between predator and prey is called t Red Queen phenomenon by biologists o    used as metaphor for c-evolution of predator and prey -    sport is full of Red Queen phenomena

running 100m I less than 3 sconds -    thre is arguably an asymptotic levelling-pff of certain sports achievements, as basic human limits are increasingly tested -    puts prob of enhancement in radical light -    will  enhancement of natural hman performance become necessary to remain interesting Red Queen race between dopers and testers -    increasingly costly -    National Centre of Addiction and Substance Abuse (CASA) at Columbia Uni calls for research effort for doping prevention costing hundreds of millions of dollars -    Unforeseen ethical dilemma: would they divert funds from health-related research? If so, is sport so imp?

Mans sana (?) in corpore not so sano perhaps -    sports turned into another health problem, when sport was supposed to be health promoting

health vs hyperhealthTM -    doping prevention relies on conventional distinction between o    medical treatment – restoration of normal species-typical functioning o    enhancement – augment bodily functions (beyond normal)

distinc between therapy and enhancement in bioethics -    asked in rel to gene therapy

gene therapy – initial debate 1980s -    somatic : ok -    germline: not ok -    therapeutic: ok -    enhancement: not OK

1990s -    gene therapy failures -    normalisation of somatic gene therapy – similar to other innovative chemotherapy (pradigm of AND medicament – axel kahn) -    but normal doesn’t mean harmless (see Gelsinger)

gene doping and gene therapy -    debate concludes that somatic gene therapy on same footing as pharma therapy -    same apply to gene doping v pharma doping -    tf gene doping objectionable on same grounds

treatment ok, enhancement not ok -    no need for genetic exceptionalism

gene doping to neurodoping -    other form of doping, such as neurocognitive could becme practical before gene doping

mens ampilificata in coropre amblificato -    one of promising avenues for sports o    eg modafinil – anti-sleeping pill o    for sports involving complex tactical tasks with motor performance (tennis), neurocog enhancement (of woring memory, executive functions, motivation) by pharma means may become incly appealing neurophilosophy

3 years ago – san Francisco – neuroethics

another basic problem -    common unreflected intuition that natural = good, artificial  = bad o    fuels some of the disapproval -    does not help – sports science is highly technicised

sociologists in france – Andrieu, Rauch) -    ritual nture of intensive training -  less to do with health

another problem -    success in sports depends on talent -    first order capacitites (musculation potential, bone structure, lung capacity, etc) -    second order capacities (somatopsychic characrs such as relative intensivity to pain, endurance and the like) -    such capacities are undeserved and unequally distributed, almost by defn -    level playing field problematic

skating on thin ice- thick conceptual distinc be treatment and enhacement probc, emphasis on fairness as THE ethical motivn for doping prevention become less persuasive -    equal doping for all not appealing proposition

real reason for doping prevention less to do with fairness -    has to with health (more of a threat than intensive sports training)

Enjoy the freaks -    mark Lawson, guardian, june 7, 2003

Non-cynical -    need a more secure basis for ethics of sport -    ethical basis of doping position, relies on ethical framework for sport

Q&As

Redefine health and disease How notion of performance has evolved through time?

Whose responsibility is sport ethics?

Dietary supplements

Mattias Kamber Instit of Sport Science, Federal office of sports, Magglingen switzerland Anti-(gene)doping: The Swiss and WADA’s approach He is member of ethics and education working committee

Voices of gene doping

Devel of doping -    1807: arsenic, strychnine, opiate, alcohol, cocaine, cannabis, hypnosis -    1936: stimulants (amphetamine, ephedrine) -    1958: anabolic steroids (dianabol, testosterone) -    1968: diuretics (chlorthaldone, furosemide) -    1976:betablockers (atenolol, propranolol) -    1980: peptide hormones (HCG, hGH, EPO, insulin) -    20XX: gene doping?

Why be concerned? -    misuse of therapeutic medicine

are we ready? -    current anti-doping tools based on science applied to urine o    non-invasive o    concentration of substances (but limited info) -    anti-doping labs started biochemical methods (EPO and HGHG) and new matrix (blood)

not yet ready for genomic or proteomic analyses

challenges -    organisations and governments -    detection and research -    athletes and support personal -    pharma companies and ‘back yard labs’ -    defn and refulations

same topics as ever but more challenges

governments -    misuse of undemocratic states – need instruments – we have this from other aspects of politics – e.g. arms control,

ME: if I am an athlete who uses doping and tries to get around the rules, is that wrong? Sport relies on this

Detection and reearch -    took more than 10 yrs to develop a test for EPO from urine -    break through for hGH and blood doping in short time (blood samples)

more research (and grants) are needed -    what type of biological samples?

Athlete and support personnel -    Victor Comte, BALCO -    THG

We do not know if it is a safe drug or not?

ME: but no form of clinical trial will tell us, since ‘enhancements’ are not studied

Pharma Companies -    detection of ARANESP at OG in Salt Lake withhelp of AMGEN -    new drugs are in devel and clinical studies e.g. RSR13, CERA, DYNEPO -    pharma compnies not forthcoming in assisting sports world

early cooperation with pharma companies is essential

Laws and regulations

Gene doping has been on list since 2003. International conventions Defn of gene doping and medical application will be challenging

Pillar principle

Controls, education and information, research Doping statut of swiss Olympic Law promoting gym and sport

The government fights against doping It promotes doping prevention Formulates a doping list Trafficking, distributing, prescribing…of medication and methods for use are forbidden -    but not easy to apply -    if trafficker claims they are not elite athlete, then not legally compromised Government supports Swiss Olympic financially to carry controls Minimal standards for controls are formulated

Swiss Workshop 2002 -    create an observatory for scientific research results and its possible application for doping -    national level, we are aware of it

WADA -    now doping is most prominent threat -    no structured independent anti-doping organisation until recently -    Council of Europe was not sufficient – not international -    Banbury conference o    Conclusions and recommendations •    Gene transfer technology is beginning to show results •    Potential for misuse in sport •    Collective efforts required •    Compliance with international standards involving human subjects that prevent unethical research is essential •    Broad public discussion and devel of social and policy frameworks before abuse occur, not after •    After Tour de France, survey whether should ban it? 34% suggest we should liberalise it under medical supervision o    Swiss Assoc of Medical Doctors developed code of conduct, now for 1year, doctors have regulations for treating athletes

WADA sport specific conclusions -    if therapy, then ok

WADA calls on govs to consider: -    req detailed record-keeping in respect of all applications of gene transfer technology with independent audit -    expand standards of medical and professional behav to prohibit improper use of gene transfer -    extend civil criminal limitation periods in respect

Legislation -    close rel with govs and international orgs (Unesco, WADA) to adapt internatona and national laws to prohibit gene doping

CCES\ -    if magic pill, what would be point of sport? -    But it is not a magic pill -

ME: what should be role of ethics committee, what political importance does it have in WADA – how do others perceive its role, what is it doing?

Cost of urine test – out of comp: 200CHF, 300CF in comp – depending on substance

Sandro Rusconi Gene Doping: Not yet possible?

Now, gene doping can be used to improve performance

What is a gene? -    one gene = many functions

what is therapeutic ‘gene trasnfer’? -    transfer of functions(s), ‘somatic’ rather than germline, targeting

how far has gene therapy progressed?

Which possibilities would exist for doping with gene transfer? Conclusions and perspectives

Elite sport has become a job with dangerous side effects

Mythos ‘gene’ in good or bad sense

It has become difficult to frankly and objectively discuss about real perspectives of gene technology

Myths -    only against hereditary disease -    transmission gene alteration -    transfer must reach 100% of cells

myths gene doping -    better than conventional doping -    transmissible gene modification -    prenatal design of athletes

DNA – RNA – Protein

Genes ‘segments’ of DNA

1cm3 = 1,000,000,000 cells

the motto ‘one gene one function’ is outdated -    2-5 functions?

100,000 genes = 300000 functions

side effects of gene transferdepend on number of alternative functions of gene product -    for most cases not known

what is a gene: a regulatable nano-device for the production of RNA and proteins -    to be effective gene segment shall include o    sequences for gene regulation o    signas for manipulation/transport of RNA o    signals for translation into protein

space – regulatory – coding spacer –

reductionist paradigm of molecular biologists

gene transfer can imply- transfer of new fn or -    transfer of a compenasating, f -    or transfer of an interfering function

4 big eras of molecular medicine

1980s – genes as probes -    prenatal diagnostics -    is someone predisposed to something?

1990s – genes as factories -    biopharmaceuticals -    take segments of genome and place into cell cultures (e.g. epo)

2000s -    genes as drugs

2000 + post genomic improvements of former technologies

gene transfer – logical consequence of former progress

somatic gene therapy NFP37 somatic gene therapy www.unifr.ch/nfp37

definitions of SGT correction disoreer by somatic gene transfer -    in gene therapy genes are used directly as drugs

Pharmacological considerations difcs conventional and moleculartherapy

Classical drugs -    mw 50-500 daltons -    synthetically prepared -    rapid diffusion/action -    oral -    cellular delivery -    readily revesible

Protein drugs – from genes as factories -    mw 20000 – 100000 DA -    biologically prepared -    slower diffusion -    oral delivery not possible -    cellular delivery o    act extra cellularly -    reversible

Nucleic acids -    mw n x 1000000 Da -    biological -    slow diffusion -    slowly or not reversible

Therapies with nucleic acids (DNA) -    req special formuation -    morec complicated than conventional

Risk / benefit balance -    depends on adopted therapy and targeted disease

why somatic? -    germ line cells: hereditary -    somatic: all other cells

4 qs about gene therapy -    efficiency of gene transfer -    specificity og gene transfer -    persistence of gene transfer -    toxicity of gene transfer

variables? -    which disease/gene/vector/organ/tissue/delivery method

3 main anatomical

ex-vivo -    bone marrow (allows to reconstitute immune system)

in-vivo -    local delivery o    cancers o    e.g. brain, muscle, eye, joints, tumors -    systematic delivery o    egs intravenous, intra-arterial, intra-peritoneal

2 classes of vector -    non-viral o    transfection o    nuclear envelope barrier! -    Viral o    Infection

Why viruses so attractive? -    they know better how to transfer DNA than us

Efficiency of transfection with recombinant DNA compared to infection with recombinant viruses

Mini-list of popular gene transfer vectors -    adrenovirus -    adreno-associated v -    retrovirus -    lentivirus -    Naked DNA o    Liposomes

Recap: limitations of current transfer vectors - can contain only certain amount of DNA in virus

there is no perfect vector

costs of each path through to clinical phase III to registration $80m -    still don’t know if would be registered – only 1 in 4 is registered

trends of clinical GT experimentation -    as of june 2003, 918 cumulative protocols -    4500 treatments -    www.wiley..com/genetherapy

1990, 1993, 2000 / ada deficiency f Anderson, m blasé, c bordignon

1997, 2000 j isner, I baumgarter, 1998, 2000

1998 restenosis v dzau

2000 hemo.. m kaey Jan 2004 – first product gendicine, by Sibiono inc 2004

No god medication without side effects

Most feared side-effects -    immune response to vector -    immune response to new or foreign gene product -    gen toxicity of viral vectors -    adventitos contambinants in recomb viruses -    random intergration in genome (inserational mutagenesis = cancer risk) -    side effects of newly acquired gene products -    contamination of germ line cells

material side effects still virtual when GT was in early phase

5 bitter adverse situations, still only one certified deat

NY ma, 1995, R Ccrystal

Upenn, sept 199 j Wilson Jesse gelsinger

Paris oct 2 2002 a fischer Retro virus x-SCID

Paris jan 14 2003 a fishcer

Pittsburgh, may 2004 K high Aav treatment factor IX hemofphilia, patients develop anti-fix antibodies

Acculutatio of hypes and loaws: roller-coaster drive

Gene doping possible? -    gene therapy o    treatment not heritable principle works o    not yet generally available o    high risk for virtually all  types of diseases

still unreachable

3 levels of doping -    before comp (anabolic) -    during comp (performance enhancers) -    after comp (repair)

which gene transfer? -    ex vivo hematopietic -    invivo – example muscle – growth factor, anti-myostatin

doping with gen transfer, many concrete possibilities

Lee Sweeny, J. App Physiology, 96, 1097 ff (2004) – march publication -    transferred gene method -    igf-1 growth factor -    aav vector,, intra muscular -    rat model

Is rat easily transferable to humans?

Side effects of gene transfer?

Short term -    autoimmunity -    hyperimmunity -    toxic shock

long term -    fibrosis -    cancer, conventional side effects of admin factors, inaccessibility to future gene therapy interventions

Specially dangerous: -    improper procedure (unsuitable vector, insuff competence) -    inapprop material (not GMP (good manufacturing practice) conform) -    insufficient follow-up

objective limitations -    viral gene transfer (immune probs, lmited readmin, gen toxicity) -    n

most likely will not be effective and harmless

Detection? -    antibody detection -    r-nucleic acids detection -    anatomically difficult to detect, but leaves permanent genetic marking -    might require tissue biopsy

foreign gene traces short-lived in body fluitds foreign genes can be in biopsies abnormal gene products oft detectable -    if expressed in wrong tissue, can be seen

adv/disadv of gene

gene doping loses

Is big talk about gene doping just one of many psych bluffs to intimdate lower-tech adversies?

Conclusions -    gebe doping higher health risks -    biggest problem is not intrinsic to technology but bears as usual on human greed and over-ambition

sanro.rusconi@unifr.ch

Prf. Dr. Hidde J Haisma Gene doping is possible? University Center for Pharmacy Rijksuniversiteit Groningen www.rugnl/farmacie/tgm

gene therapy is protein therapy, but using genes -    when give epo as gene or protein, is same thing

genomics -    identification of genes and gene expression -    caterpiller and buttergly – have same genome, but expression is different -    same with human variation – 99% we are all same

genetic manipulation -    GMOs -    Modern biotechnology

Genetic Manipulation Herman (1989-2004) -    dutch transgenic bull -    transgene = lactoferrine to be secretedin milk

genetic manipulation of humans -    delivery for therapeutic purposes -    we don’t have pills yet – and probably would not have this

good news and bad news on gene therapy -    gene therapy works on some patients

FDA stops researchers human gene therapy expt, by deb nelson and rick weiss, wash post, marc 2 200, pa08

December7 1999, Nytimes Successful gene therapy on hemophilia

March 2 200 Nytimes Hint of success indicated in gene therapy

2982000

indications addressed by gene therapy clinical trials J Gene Medicine www.wiley.co.uk/genmed/clinical monogeneic diiseas 9.8 (n=90)

requirements

genetic material to treat disease -    dna, rna

method of delivery -    viral or nonviral

how to get the dna? – internet!

How to get dNa of erythropoietin Go to anymolecular boil sites and it tells you Chromosome 7, location 7q22, geneID 2056

Gene therapy vectors

Vector – adv – diasdv Naked dna – no limitation on size – low transduction efficiency, no integr Liposomes – no lim on size – low trans and eff, no integration Retro

Gene therapy vectors Non-viral

Monogenic diseases

Factor IX in haemophilia B 9 different factors to induce clotting -    one missing or too many cause problems

Kay et al nature genetics, 2000 -    intro of Factor IX into muscle -    shows that it leaves the muscle cells and goes into the blood -    muscle secretes factor IX into blood -    (if this hormone like treatment occurs, you cannot tell where we injected this factor – detection not possible)

Use in sport – increased healing after trauma -    muscle injuries -    ligament and tendon ruptures -    meniscal tears -    cartilage lesions -    bone fracture

this would not be gene doping

misuse -    alternative to protein drugs -    protein identical to human endogenous protein (not possible to detect) -    gene therapy vector present locally

gene doping -    inc hematocrit, by epo -    increase blood flow by vegf -    inc muscle strength using igf-1 -    inc mucle size by inhibition of moystatin -    decrease pain by endorphins o    ME: check his refs

Some things we cannot do -    steroids not on list, since no steroid gene o    steroids made by many genes, not that far yet -    can only make proteins

Gene Doping

gene – potential – risk controlled – risks uncontrolled

epo- ++++ - +/- - ++++ IGF-1 = ++ - - - ++++ VEGF, FGF - + - /- ++++ Growth hormone - + - - - ++++ Myostatin / follistatin - ++++ - ? - ++++ Endorphins, enkephalins - + - ? - ++++

Very easy to make DNA, but might not be safe if uncontrolled

Epo -    glycoprotein hormone that stimulates production of red blood cells -    used to treat anemia resulting from o    cancer chemo o    chronic renal failure -    boost red blood cells prior to elective surgery -    is a gene we produce ourselves -    produced in kidney – stim bone marrow – inc red blood cells -    if you put in a gene, the signalling doesn’t take place -    need to ensure signalling to regulate

ye et al, science, 283:88, 1999 -    epo

IGF-1 -    greatly improved repair fn of dystrophic muscles -    promote skeletal muscle hypertrophy in young mice -    prevents muscle loss in old mice -    synergistic effects with weight-training -    rat ran up ladder, with weights on tale -    improve muscle force by 30-40%, combined with weight training, even more

Can IGF-1 over expression enhance athletic muscle performance? -    inc even without ex -    inrease rate and extent of repair following injury -    better maintenance of muscle mass, strength and speed during ex, during aging -    inc end of skeletal muscle, speed of skeletal muscle

how can we deliver this? -    inject our muscles?

Some vectors show it is possible -    systmetic delivery AAV-6 -    Anti-dystrophin lavelled muscles ffrom mice adminisrtered 1x 10E13 vector genomes of rAAV6-CK6 -    Microdystrophin and VEGF, mice we examined at 6 weeks after treatment -    Gregorevic et al, Nature Medicine, 2004

Gene therapy – risks

Person risks -    disease (vector, transgene), mutagenesis -    offspring

Mileu risks -    people: spouse, next of kin -    environment: infectious disease

as long as we treat somatic cells, no transfer to offspring

gene therapy and doping risks -    vector (contamination, replication competent virus) -    transgene (duration, amount of gene expression, auto-immune response)

detection? -    vector o    vector constitutents – requires biopsy o    vector dna – requires biopsy

-    transgene o    protein (e.g. epo, unless natural product) – yes, if in blood o    effect  - yes, if in blood

detection by proteomics -    physiological profiling o    serial blood sampling o    assessment of protein markers o    using protein maps, can see if changes have occurred o    people are within a certain range

WADA currently do not see drugs they are not looking for – profiling could help Rather than develop new assay for each new potential drugs, profiling could highlight anomalies

Preventatve measures

Regulation (gov, IOC, WADA) Codes of conduct (pharma ind, scientists) Education (athletes, supp staff, public) Detection (assay development)

When and where? -    genes and vectors are available -    plain dna is easily produced -    illlegal drugs produced and used

where? -    human and animal sports

can make epo DNA for €10-€25 -    quality control and marketing much more

ICSSPE Pre-Olympic Congress (2004, Thessaloniki)

ICSSPE Pre-Olympic Congress,Thessaloniki, August, 2004-08-07

Bengt Saltin Energetic limits to performance

Leo Hsu

Concept of the good foul Bsketball Soccer

Good foul unethical -delib interfere - no equal opp for contest -    not agreed on

good foul not cheating -    cheating: intention to deceive and unfair adv -    good foul: intention to break rules  plus unfair adv

simon ‘strategic foul’ -    intention and action -    penalty might become adv cheating\break rules deilib avoid penalty inend to deceive win or gain adv

good foul breaking written rules delib expect to accept penality win and gain adv

a good player… -good intention act rightly keep spirit

concl good foul -    not cheating -    against purpose of sport -    morally wrong act -    indicates deficiency of rules -    violates spirit

Q&A Scott: opponent stalling – good player wants to play good game, so breaks a rule in order to create a good game. Is this good foul? -    response: NO

Sigmund: Good foul morally wrong act, but ethos

Leo: depends on defn of morally right: - if ethos is morally justified, then ok, but if not, then is morally wrong.

Heather

Beauty of Olympic sport typically allow more than one way of playing the game Not clear whether poss to decide between beautiful and corrupt -    elitism, sexism, racism

need to estab criteria for changing sports practices

set out Rawls’ method reflective  equilibrium

narrow -    justif ororig posn, if match -    choose strongest convictions as fixed points then work backwards

wide -    demonstrate why justified to apply in  specific contexts, by increasing breath of test

benefits -    clarification, systematic, democratic

going through process of wide refl equilib help clarify views

can uncover more systematic

democratic: in context of other beliefs. Where conflicts with other values, then indication of problem

disadv with this method -    uniersal and cross Cultural undemocratic -    indivs and their interests

diving or shirt pulling in elite soccer, decision could include everyone in debate as to whether is acceptable – these people unlikely to be aware of internal goods of game -    they’re likely to have limited knowl of game (HMMM) -    to follow wide refl  equilib

abstraction is undemocratic, since must disconnect from cultural context

democracy not about truth

while wide refl equilib is useful – it is too thin, since too far removed from sports practices to have any normative force -    could not determine which ethos is most justified.

Tradition practice bound reasoning: -    Which criteria? -    Who ought to evaluate?

Liberal interpret of practice community allows spectators, etc -    only views about goods internal to game count -    a limited  democracy, providing correct credentials

Gunnar: -    would work in new sports, with fast developing ethos -    would rely on imagination of people to a much higher degree

Mike -    liberalism v communitarianism

Sigmund Loland Fairness in spor t- critical comments on Olympic competitions

Not Fairness as indiv obligation, but ‘structural’ fairness -    when is a competition fair,not when is a competitor fair

fairness in sport -    competitions -    relevant and non-relevant inequalities -    fairness ideal -    implementation of fairness in practice

gen principles of fairness -    eliminate or compensate for inequals that exert SIGNIF influ on performance o    indivds cannot control and influt o    for which cannot be held responsible

-    conseqs for Olympic  sport?

Inequalities -    ext conditions -    person-dependent inequalities: INCLUDING GENETIC MAKEUP, BODY SIZE, ETC -    system inequalities

ext cond -    direct competition – standardisation -    indirect comp (outdoor) – seeded groups, drawing of positions

person depdendent -    sex and age, over-clasficiation (sex classification seems reasonable in some sports – where biological differences are significan, though in others, they are not justified) o    – ME: interesting analogy for genetics, would we seek to ensure athletes are all the same age? To what degree? Where it seems to have some influence on performance, we should. -    body weight – under classification

CAN SPORT SUPPORT ADDITIONAL CLASSES AND DISTINCTIONS AND DO YOU THINK IT POSSIBLE TO LOOK TOWARDS PARALYMPIC DISTINCTIONS TO IMAGINE HOW IT MIGHT FUNCTION? - A QUESTION ABOUT THE SPORTING SPECTACLE AND ITS VALUES

TALENT IDENTIFICATION IN SPORT

What makes a Champion?

Talent -    natural endowment or superior ability -    single most imp factor contributing to achievement -    other factors include

identified developed selected science or art?

Intuition, rolling dice, magic, sport science (multidisciplinary, evidence based)

Nature v nurture

Genetic endowment -    intrinsic potential 46xy -    structure, function, behav -    genetic manipulation -    next doping frontier?

Environmental influence -    extrinsicfactors

Suzuki Method -    all  Japanese children speak Japanese -    inborn greatness or mediocrity not known -    advanced ability can be nurtured  in any child

Why does it matter? -    parental imperative -    Olympic imperative -    Financial imperative

Jason Gulbin -    South Australian Sports Institute -    AIS -    National Coordinator of Talent Search -    Published on athlete profiling, ex induced muscle damage

Thomas Reily -    Liv John Moores -    President-elect of Int. Soc Adv. Kinanthropometry

Darlene Kluka -    Grambling State University -      Volleyball talent

Jason Gulbin Paradigm Shifts in Talent Identification National Talen Search Coordinator, AIS

Concerned about young athlete and talent identification – but much of the work is also on older athlete

Terminology Talent (identification/detection) – athletes from outside of the sport (non-specialist, quasi scientific approach, to examine predisposition for a specific sport) Talent Selection (within the sport, watching athletes) Talent Development (vital to process)

Intentiaonal Search for answers Ireland (NCTC) 2001 -    factors prpmoting and inhibiint  success of H Performance players and athletes n=207

USOC 2002 Talent id and devel of US Olympians

AIS 2003 How do elite Athlete develop n=681

NZAS 2004 Linking promise to t podium taskforce report

Why such a focus on this area?

Australian Typical spending patterns ($AUS)

Costs $37m for a gold medal

$8m for any medal

(Hogan and Norton, 2000)

reducing costs isa  huige bonus

US Census Bureau 2000

Population for Oz significantly less than other countries, so identification critical

National Talent Search Program 10 yr programme www.ais.org.au/talent in each academy, talent search coordinator phase 1: ask pe teachers in highschools to collect data for basic phys test phase 2: submitted to talent search coordinator phase 3: if athlete good, invited to talent devel programme

program  issues -    growth and devel conundrum (too much to measure, children of same age too different) -    labour intensive  (reject around 95% of data from schools) -    athlete acceptance uncertainty (not all kids want to do selected sport) -    variable enthusiasm of schools/teachers -    information privacy concerns (now, they use id numbers, rather than names) -    inability to respond to immediate needs of coaches in age group ( -    emerging adulthood and retention

paradigm shifts -    broad – focussed -    young – older -    novice – experienced -    schools - public domain -    TID

e.g Cycling -    ad in paper for talented female cyclists for 500m event -    females 18-26 -    non-cyclists -    explosive leg power -    competition history -    recruitment via the media -    initial screening n=247 applicants -    peak power, 30 sec av power, vertical jump test -    selected 26 girls -    age 16-29 (played various sports: bball, rock climbing, athletics, rowing, netball) -    lab performance: peak power: (1300w, av power: 700w; 10+yrs),  these athletes peak power: 1134W, av power: 625W – after 6weeks (gardner et al, 2002) -    performance in less than two years, 5 athletes when on to win national comps

Paradigm shifts -    simple – complex models -    from physical to physiological -    focused cohort of 32 selected, based on: o    water ‘feel’ o    school grades o    parental background (molecular biological approach will be critical in advancements)

paradigm shift -    centralised – decentralised -    generalist – specialist

Regional postgrads -    offer maters by research (cycling) – fee-free position plus stipend, to assist talent search coordinators and also develops local support

Summary Consider maximising talent harvest by supplementing traditional TID approaches

KIM SCHIMMEL Deep Play – political hierarchies  in  new Olympics

Reconstitution of Olympic space -    nato resources -    70000 troops -    greek forces -    us coast guard -    us special forces

private security entitites and gov alliances

eyes and ears of the games

cancellation insurance -    first time in Olympic history -    $170m coverage/$6.8m premium  usd -    terrorism, earthquake, landslides (not construction delay)

Olympic Spirit -    if terrorism threat to Olympics real, then why stage it in  modern world (july 26, 2004, b KI Angelopoulous)

www.anti2004.net

current cost of Athens 2004  6billion euros, 1% of Greece gross product

Beijing 2008

Kristine Toohey -    (Sporting) Legacy of Sydney (Cashman) -    economic (direct and indirect) -    vbuilt environment (nonsport) -    info and education -    public life, politics and culture -    sport o    elite, mass (FOCUS ON MASS SPORT IN THIS PRESENTATION), financial, built infrastructure -    symbols memory history

Mass particpation as Olympic legacy (grassroots sport) – theory/intent -    de Coubertin -    Olympic Charter -    IOC invlve with sport for all, since 1983 (samaracnch) -    IOC Sport for aLL commission -    IOC WHO 5th World SFA congress 1994 -    SFA congress declarations sponsored by IOC, Seoul, 1996, bcn 1998, quebec 2000 -    IOC Legacy symposium 2002 (Hein Vergruggen) – to remain educational -    55 papers: mass participation addressed in 3 (2 winter sports)

Ressearch Q -    given intent, does hosting OG boost mass sport particpation in host communities?

Past Olympics -    international conf held in late 1980s in seoul, korea -    reps from 5 previous Olympics -    agreed that mass participation most imp -    but little evidence that actually happens -    2 exceptions o    LA 1984: AAFLA – runs number of programmes o    BCN (Truno, 1995) o    Sport paritipation in BCN •    1+ per week •    1983 36%

Sydney 2000 -    in aus $60m dollars per gold medal

Houlihan from ASC

Centre for East African Running (2004, Glasgow)

Glasgow University Symposium Possible Causes of Success of East African Distance Runners March 8, 2004.

Keith Johnson – genetics dept

‘Off the track, in the field’ Yannis Pitsiladis

Dr. Bezabeh Wolde, Sec Gen Ethiopian Olympic Committee

Sampled entire Olympic team Team trains together

Kotebe College of Teacher Education, Addis Most of athletes from Shewa and Arsi (central part of Ethiopia) -    altitude 3000m (Addis Ababa is 2400m) Bekohi, Aris Province -    deratu tulu -    kenenisa bekele children’s journeies to school by foot/running/cycling World Champs Paris, 10000m -    gold, silver, bronze all Ethiopian

Kenyan First Olympic Gold – Neftali Temu, Mexico Olymmpics Mike Boit, bronze medal 800m 1972 Munich, Olympics Commonwealth Gold, Edmonton, 1978 Nambi? Nandi? province Rift Valley St. Patrick’s High school – boys school -    many Olympians from here tea break – important? Itigo Girls High School Pupils running to school Morning, for lunch, and afternoon (parents must find food for them) Kaptagat Training Camp – Patrick Sang -    Global sport sponsorship -    Joseph Chelimo, Head Coach -    Eliud Kipchoge – gold 5000m World Champs, Paris 2003 -    Richard Limo – Gold 5000m, Edmonton 2001 -    Camp has no electricity -    Cooking fone in pots

IOC Consensus Statement on Sport Nutrition 2003 All cooking done on fires, very precisely

Daily diet -    average carbo 606g -    body weight on average 58.6 -    near perfect ratio

Fluid intake

Eliha Lagat (boston marathon)

IOC Camp – Kipchoge Keino (most well known of Kenyan athletes)

Chirchir training camp -    sampled athletes -    tea important again -    ran in morning without breakfast, and return to have tea with 3 slices of bread

Chepkoilel Stadium Kaptagat Camp (FILA) -    moses tanui -    unpasteurised milk for tea

Amos Biwott (3000m gld, Mexico 1968)

Fatwell Kimaiyo Gold 110m 1976, hurdles

Commonwealth games perth 1962, seraphina antao, gold

“whether there is money in it or not, running is in the children’s blood” school teacher

Acknowls John robertson bequest, uni of glasgow EOC, EAF, Wellcome Royal Soc Carnegie Scotland Event sponsored by Glasgow City Council, Abgene, WWR International, Cranlea

Used Bleep test – had not heard of this test before. -    results under analysis -    1000 kids tested in Nairobi

no obese kids in nandi, but plenty in nairobi

agali (staple part of diet) -    similar structure to rice

John Bale

Pre-colonial period Cultures of running Myth of natural athlete

FAM Webster arranged comp between spear throwing and javelin

Modern period When running became racing Refute idea that these Kenyans emerged in 1972 from nowhere those performances had roots in 1900s earliest recording sportised event was in 1902 one of first timed events – modern notin of recording

influence from Muscular Christianity through missionaries 1924 bureaucratisation of Kenyan running organised African Olympics records from the 1930s best performance for mile measured to second 1951 formation of African Amateur athletic federation

joy adamson – anthropoligist, research on athletic body, Masai

1954 kenyan began to engage with international comp, NOT 1968 Mexico Olympics

Kenyan Olympics, won medals in high jump, javelin, and sprinting Diversification of athletic production imp At Vancouver Empire Games, team was 2 runners in 440m, 1 in 880m, 1 in 3, 6 miles, … -    no suggestion that this was a running team at all went on into 1960s

present time… -    how does this history help explain Kenyan running? -    Need to take a global perspective -    Can Kenyan running be partly explained by the absence of success in the West -    As West declines in interest in this kind of activity, for various reasons – range of alternative activities, which has led to diminution of people taking part in long distance events. In part, this explains the success of Kenyans. -    There are poor results in these events in the west Has slope in improvement of these records declined? Things are slowing down in those events in the west

Interesting to examine how Kenyans react to this running phenomenon and how Kenyans view the western view of this -    neo-colonialism -    need a Kenyan voice

mtDNA Haplotypes and Demographics f Elite Ethiopian Athletes Robert Scott

Why do some people perform better than others?

Proposed explanations for greater success -    favourable physiology -    altitude adaptation -    running long distances to school -    psychl advantage (and cultural = ME: but actually doesn’t mean this) -    favourable genetic endowment

believes tha genetics is important, but not in way that people have considered

Majority of human genetic diversity is within populations rather than between -    more within East Africa than in Europe

more than skin colour needs to be considered -    ok, so what then?

Ethiopia

Methodology

Enviro analysis -    place of birth -    language -    distance and method of travel to school

genetic analysis: mtDNA -    mitco are major energey producers -    mito function imp in ex

mtDNA useful in population genetics -    maternal inheritance: no recombination -    fast mutation rate (D-loop) -    Maternal ancestry can be traced through branches of tree

MtDNA genome separate from

Buccal swabs from 109 control and 114 elite athletes MtDNA extracted and classifieid -    HVS-1 polymorphism -    Coding region polymorphism

Compare distrib of mtDNA types amongst athletes and controls

Ethiopian Regions -    arsi is over-represented in succeses

Place of birth results

Slightly more from Assis Ababa for elite athletes Large increasee for 18%

Might show that athletics is more prevalent in Arsi

Language Results

Possible that different ethinic goups have different frequencies of gene variant

Might be to do with popularions

Distance travelled to school results

Evidence that this might be influential

Students running some 5-10km to school, and even some running marathon distances.

MtDNA questions -    if mtDNa polymorphisms are imp in endurance performance, will t linage on whch they occur be more common amongst t athletes? -    Might this explain t dominance of East African athletes in distance running?

Contrls’ mtDNA tree -    Mitochondrial Eve

Athletes’ mtDNA tree -    relatively similar distribution -    not significantly different

Conclusions -    Ethiopians are of a distinct enviro background relative to Ethiopian popn -    Athletes have a very deep common maternal ancestry -    Athletes are not a genetically distinct population as defined by mtDNA

How does the ACE I/D polymorphism affect athletic performance, especially in East African athletes? Richard Wilson, Molecular Genetics, IBLS, Glasgow University of Paisley

Why t ACE gene? -    is a major target for blood pressure controlling therapies, and has other less well-understood activities

Why geontype athletes? -    athletes with extremes of physiological performance may help elucidate t physiological variation of normality

why genotype Africans? -    African populations contain more genetic variation than European-derived populations

What does ACE I/D do?

Lots apparaetly -    publications showing effects ranging through, o    – muscle performance in response to training skeletal muscle fibre type (in young Japanese), endurance performance (UK Olympians), high altitude adaptation, survival to 100yrs old (in France); kidney responses, insulin sensitivity, etc

How does ACE (I/D) do all this?

ACE -    activates Angiotensinl to AngiotensinII (which raises blood pressure) -    inactivates Bradykinin (removing a factor which lowers blood pressure) -    Two ACE activities so far, is it all this simple?

ACE is DCP1

ACE is a dipeptidase, cutting two amino acids off peptide hormones -    angiotensiI DRVYIHPF HL -    Bradykinin RPPGFSP – FR -    Haemoregulatory peptide AcSD – KP

Ace is an enxzyme that clips other peptide hormones

High affinity for hameo

Ace is found attached to endothelial cells and soluble in blood plasma Form of ACE is found in sperm -    In mice, where have engineered out sperm type, but not other, sperm no longer functions properly, no longer capable of fertility -    Link to cleaning vaginal secretions, which kill sperm (possible fertility link)

Functional genomics of the human ACE / DCP1 gene -    t full ACE protein has two active sites -    33 ACE isoforms o    som – DCPi – link – DCPi – anchor o    som – DCPi – link I DCPii o    tes – DCPii – anchor (male form)

ACE can do a range of things and is collecticated

Variations in the Human ACE gene -    over 70 common variants (SNPs) in 30000 DNA bases of human ACE Gene -    less than 10 of these ACE SNPs chang t functioning of the ACE gene -    human ACE gene shows t signature of recent natural selection (haplotypes / linkage disequilibrium) -    The famous ACE I/D polymorphism is almost certainly non-functional o    Is in region of gene that is removed

The ACE I/D polymorphism -    is easy to test for -    in Caucasians, ACE I/D is associated with 40% of opulation variation in circulating ACE levels (I low, D high) -    Is ace I/D hitch-hiking with t real functional change? (haplotypes) -    if look for other markers on ACE gene, knowing that how different versions have been shuffled around 22982AG is t best functional candidate, I is always found with 22982A in Caucasians, D with 22982G

DNA sampling at Kaptagat Training camp -    sample using swabs -    can diagnose people’s genotype, to carry out genotyping

An ACE blood sampler -    removed from Kenyan population, -    Kenyan, no longer regulated in same way that they are in Caucasians

ACE I/D PCR -    Extract DNA, and amplify small pieces of it

Can genotype for most markers in the ACE gene -    Roberts and others have set-up assays

ACE activity and I/D -    ethio: 40% variation -    Kenyan: 7%

ACE activity and 22982AG -    real causative agent for circulating ACE levels

Conclusions -    22982AG (not I/D) is t functional polymorphism regulating circulating ACE levels -    Kenyan / African population genetics have modified t assoc between ACE i/D and 22982AG

Few people who came out of africa historically, cold not carry the level of variation that existed in Africa -    expains why we do not see this variance in other locatioes

Is ACE I/D asoc with excelenct in Ethopian -    genotyped 114 (… -    no strong assoc with ACE I/D or 22982AG

Ethiopian ACE/ID data -    not clear that ID is solution for talent searching.

ACE I/D might work differently in males and females

Little effect of ACE ID and other polymorphisms on elite endurance Cannot use it as predictive test, May subtly affect training response Tell everyone they’ve got the ACE gene (placebo effect)!

Any evidence that ACE gene involve with other aspect of performance

Best studies are small groups of people, where have looked at small aspects of physiology , rather than assoc with large athlete cohorts.

Y Chromosome haplotypes and the African endurance Athlete Colin Moran

Overview Existing theories (including genetics) Why Y? -    what is t Y chromosome? -    Y chromosome consortium YCC) tree -    Global distrib

Techniques and subject groups Analysis -    by major clades -    by haplotypes

In the beginning -    Rome Olympics, 1960s -    Atlanta Olympics 1996 -    Sydney Olympics 2000 -    37 of top 40, 10k times

Explanations for Success -    diet -    culture -    genetics o    mtDNA o    ACE o    Alpha-actinin 3 (ACTN3) o    Y chromosome

Now around 100 genes associated with human performance

Human Karyotype -    picture of chromosomes -    23rd ppair of chromosomes are sex chromosomes (smallest) why Y? -    patrilineal inheritance -    never 2 y’s in 1 cell o    functional changes immediately subject to selection o    no recombination

haploid (because only one copy of it)

different types of y chromosome in different proportions around the world, because it is a dynamic chromosome

Summary -    Group analysis: o    Control groups not different o    Some difcs between athlete groups and control groups

-    indiv haplotype anaylsis o    4 haplotypes showed as o    sev haplotypes that we may have expected to showed no assoc •    African specific clades, A and B •    E3b*/E3b4 similar to E3b1 •    J(xJ2) which had apparent

Conclusions -    some Ethiopian Y haplotypes show assoc with elite athletes status, though not really a predictor -    Athletes are more distinct from the Arsi control population than the Addis control o    Arsi control truly representative? •    Town v country?

-    how can t y be having such an effect? o    Direct effect of a gene on the Y chromosome o    Unknown subgroup of the population?

Thanks LeicesterUniversity of Paisley    - mark jobling

Demographic characs of elite Kenyan endurance runners Vincent Ochieng Onywera

The Kenyan Runners: In search of Olympic Glory Mike Boit, Kenyatta University

Olympic boycotts and lack of exposure, performance in Kenya declined significantly

Top runners left or stopped

Kenyan Athletes in top ten of world 1968-72: 1 73-76: 4 77-80: 3 81-84: 1 85-88: 4 89-92: 9 93-96: 6

we are still not at human potential in sport – still not training enough

set backs -    inadequate facilities -    less than minimum sports funding -    lack of sophistication in coaching -    lack of expertise in nutrition -    lack of institutional training -    lack of systematic talent identification plans and implementation programme

CULTURAL traditions -    cattle radigin expedition practices (hugh demand for endurance), suallly taken as sports for the young warriers -    male circumsision (process of instilling high discipline, agresiveness, etc; ability to withstand pain)

would be prudent to assist athletes in providing alternative to taking drugs that could enhance their performance

Genetics and Sport (2003, Sept 30, Geneva)

Genes in Sport, Geneva, Sept 30 2003 GATTACA -    crucial point in film where two brothers are swimming against each other and the GM brother says to his brother ‘we cant see the shore, we have to turn back’. This moment is very  interesting because it reveals the relative importance of that contest in comparison to their broader dispute (which was what gave rise to the contest). -    Hero is not merely the ‘natural’ athlete, but also the benevolent and ‘injured’ GM athlete.

Bengt

Bob Goldman (1984) – if take drugs, big success, then death, would you =52% said yes

Lane, T. 2003 Jan A future of jocks, genes and jingoism.  www.theage.com

Veronique L. Bilat Why do Kenyans run so well?

Wolfarth, B. Genes and sports performance: what do we know today, what will we know tomorrow?

GENATHLETE study

ACE and Performance

NOS3 and Performance

Aerobic performance and trainability -    which genes are involved -    what are major intermediate phenotypes for aerobic performance and regulation? -    Poss to predict aerobic performance and trainability levels using genetic markers?

ACEII (not a strong candidate gene) -    cardiac contractility -    cardiac and vascular hypertrophy -    vasoconstriction -    Rigat, B. et al NAR20: 1433, 1992 -    Inertion-/Deletion -    Montgomery, HE Nature (1998) -    ACE in the HERITAGE study o    Cannot support concept that ACE locus plays a contribution to training

No difference between genotypes of trained and untrained athletes, with respect to ACE I/D –polymorphism.

Outside of sport related research (e.g. hypertension), similar findings

ACE I/D also asso with left ventricular hypertrophy -    Landry et al JAMA 1985 254, 1 -    Kupari, 1994, Am J Physio -    Montgomery (1997, Circulation, 96(3) 741-747

Material and Methods LVM (Left ventricular mass)

LVM and LVMI of different ACE I/D genotypes and allele carriers -    any differences between genotypes and carriers? o    No overall association between ACE I/D and LVMI •    But new studies using higher sample o    For carrier status, a small significant difference between I carriers and D carriers •    But I carriers had higher mass (Montgomery concluded that D is responsible for training)

NOS (Nitric oxide synthase) -    REF: McAllister, RM Med Sci sport Exercise, 27 -    Nadaud et al, 1994, -    Nakayama et al 199 – hypertension and left ventric hypertrophy o    Found link between patients with hypertension and left ventric hypertrophy had allele o    Perhaps play a role in endurance o    4 polymorphisms in NOS3 genes analysed o    no different between EEA and SC o    no signif in overall distribution o    but higher proportion for 164 base pair allele •    why? Not sure yet. Might be marker  for variant in surrounding genes, need to screen gene for variants

Perusse, tankinen, Rauramaa, migual rivera, wolfarth, bouchard Human gene map for performance and health related fitness phenotypes: the 2002 update, Med Sci Sport Exercise , Vol 35, no.8

Sandro Rusconi Dept of Medicine, Biochemistry, Uni of Fribourg

Basic understanding of genes -    what is a gene, molecular biology dogma, genetic diseases, environmental factors, ageing

Essential concepts

DNA – RNA - Protein 100000 genes, more than 300000 functions

no such thing as a genetic disease, except for monogenic ones, e.g. muscular dystrophy, where genetic component is dominant

other conditions are significantly environmental and bahvioural -    Familiar breask cncer, poradic breast cancer, lung cancer, obesity, atherosclerosis, alzhiemers, parkinsons, dru abuse, homosexuality

Genes important but cannot define them because they are multi-functional

Science-grade material can be prepared easily Clinical-grade material is more difficult (i.e. GNP prepared vectors for patients) Millilitre of XX is 1franc, for GNP is 10000Francs (safety measures)

Molecular medicine -    prevention, diagnosis, therapy

Four eras of molecular medicine -    eighties: genes as probes (pre-natal diagnosis) -    nineties: genes as factories (isolate gene and put back to work into cells, e.g. yeast, growth factors, pharma products, many of which save lives) -    Y2K: genes as drugs – inject gene into body to correct -    Post-Y2K: post-genomic era

If we live long enough we all get Alzeimers and Cancer! -    these are part of ageing process

Somatic gene transfer

Definition of FT – use of genes as drugs (correcting disorders by somatic gene transfer

Chronic, acute, preventive Hereditary and acquired disorders Loss of function, gain of function

Why somatic? -    somatic gene transfer is a post-natal treatment aiming at somatic cells o    does not led to a hereditary transmission of genetic alteration •    Is not a Genetic selection

Four fundamental questions -    efficiency -    specificity (which kind of tissue to address) -    persistence (acute or rapid treatment) -    toxicity (how toxic is treatment)

Pharmacological considerations

Classical drugs -    synthetically prepared, rapid diffusion,oral delivery poss, cellular delivery, can be delivered as soluble molecules, rapidly reversible treatment

Protein drugs -    e.g EPO -    biggermolecules -    cannot enter into cells -    act exocellary -    if stop using, effect will go away

Nucleic acids -    larger -    biologicall prepared -    slow diffusion -    oral delivery inconceivable -    cellular dlivery: no membrane, no nuclear, no biological import -    must be delvered as complex carrier particles -    slowly or not reversible

therapy with nucleic acids -    reqs particularted -    more complex -    different degrees of reversibility

3 classes of physio gene delivery -    exvivo (bone marrow, liver cells, skin cells) -    invivo (topical delivery) e.g. brain, muscle, eye, joints, tumours) -    invivo (systemic delivery) intravenous,inttra arterial, intra peritoneal o    bigger implications

2 classes of gene transfer -    non viral transfer (transfection) Nuclear envelope barrier, see Nature Biotech, Dec 2001 -    Viral gene transfer (infection)

Popular vectors -    Adenovirus o    No persistence o    Limimited packaging toxicity -    adeno-associated Very -    retrovirus (include. Hiv) o    limited package, random insertion,

Gene Therapy in Clinic -    cancers main

A of Sept 2002, 599 registered protocols, 4000 treated patients -    86% phase I -    13% phase II -    1% phase III

Genetic milestone -    gives overview of recent science -    all experimental

(Road runner cartoon, cayote on drugs)

currently, side effects would and should ethically limit science

3 levels of doping

possible treatments -    Before the competition anabolic enhancers -    During competition – performance enhancers -    After competition – repair enhancers

Anti-TNF factor, BMPs

Current limitations Viral gene transfer (immune problems, limited readmin, gen toxicity Nonviral (inefficient Strategy-indep (laborious, long term different to control, irreversible

Side effects -    short – mid term, autoimmunity, hyperimmunity, toxic shock -    long term: fibrosis cancer, inaccessibility to other interventions

Intrinsic to reckless apliaction (problem biggest danger) -    malpractice (unsuitable vector administration route) -    non-clinical grade material (pathogens or allergens)

Detection -    antibody detection (viral antigens) -    r-nucleic acids

Anatomoically difficult to detect

Need muscle biopsy -    before permit, need strong suspician!

Gene based doping versus drug or protein based doping -    drug protein is most possible -    gene doping detection is difficult or impossible

odds speak against adoption of gene-based doping -    b tu this applies to common-sense clinical practice and this aspect is not guaranteed in doping field

entire  sector of sport where doping is not rigorously controlled

major risk is with premature application

5-10 yrs before effects has been a lot of bad science and Stock market crash has got rid of bad scientist -    follow this up!

Alex Mauron Gene Doping

Ethics of human gene manipulation Convention vs gene doping, ethical differences? Doping and ethics of sport Doping and ethics of human enhancement

Gene therapy: initial ethical debate 1980s -    somatic, and therapeutic OK -    germ-line and enhancement, NOT OK

enhancement is called doping -    not correct: non-medical therapy is characterised as enhancement. That’s all.

1990s many clinical trials of somatic gene therapy, often for polygenic diseases few successes ‘normalisation’ of somatic gene therapy, that is increasingly felt to be similar to any innoivative chemotherapy (paradigm of DNA medicine – A. Kahn) normal doesn’t mean harmless (the Gelsinger case)

Gelsinger case largely misunderstood -    reaction was ‘gene therapy is dangerous’ -    actually, clinical research is dangerous, not just genetics! (whenever system of ethical process breaks down, then it becomes dangerous)

still, messing with genes of humans remains highly controversial. Why?

Genomic metaphysics -    genome represents ontological hardcore of organism, determining both its individuality and species identity -    Mauron, Genomic metaphysics J Mol Biol, 219, 2002 -    Mauron, Is t genome t secular equivalent of soul, science, 2001, 291:831-832

Gene therapy debate concludes that somatic gene therapy is ethically similar to pharma therapy

Same relationship to gene doping and pharma doping

Therefore gene doping would be objectionable on same grounds as doping -    ME: not true: doping is typically associated with anti-social behaviours and a negative sporting culture. Gene doping doesn’t have that context, but if we make it illegal, then we imbue it with that framework

Back to therapy./enhanement distinction

In gene therapy, ethics just as in sport ethics, therapy ok, enhancement is not.

Standard ethics of sport -    let best win -    to bethe best, ought to result from virtuous combintion of innate talent of personal meirt and effort, plus some degree of luck -    chemistry or genetics represent moral shortcuts that substitute undeserved facility where there should be meritorious effort and excellece -    doping disturbs the ‘level playingfield’  need for a fair competition

doping is immemorial -    ME: this is reason to question the moral discourse running through it

Be it through genetics, drugs, or divine intervention, sports has always attracted cheating

Notion of level playing field may be an illusion -    talent: includes genetic differences -    first order capacities (muscultaion potential, bone structure, lung capacity, etc) -    second order capacities (somatopsychic, insentitivity to pain, endurance etc) -    such capacities are unequally distributed almost by definition real reason of prohibition has little to do with fairness, actually has to do with the threat to health of athletes (threatens it more severely than intensive sports training does) -    ME: how do we make this conclusion? -    Well I agree, but this is a partial reading of the situation. Anti-doping is poltically more entrenched than the health issue

What is the merit in sport?

What is merit in scientific training? -    ME: hmmm, it is not easy, as our first presentation indicated

Difference between sports and other competitive human activities -    ME: not sufficient

Our concepts of fairness and merits have been honed by other human activities, and have been applied to sports in appropriately

Conclusion

Enjoy the freaks, Mark Lawson, The Guardian, June 7, 2003.