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/-------------------- advertisement -----------------------\ FOR YOUR CONSIDERATION: IN AMERICA - IN THEATRES NOVEMBER 26 Fox Searchlight Pictures proudly presents IN AMERICA directed by Academy Award(R) Nominee Jim Sheridan (My Left Foot and In The Name of the Father). IN AMERICA stars Samantha Morton, Paddy Considine and Djimon Hounsou. For more info: http://www.foxsearchlight.com/inamerica \----------------------------------------------------------/ Decoding a Steroid: Hunches, Sweat, Vindication November 2, 2003 By JERE LONGMAN and JOE DRAPE Last June 13, a test tube of clear liquid arrived by overnight mail at the Olympic drug-testing laboratory at the University of California, Los Angeles. The liquid included residue from a syringe that a tipster said contained an undetectable anabolic steroid. In 21 years as director of the laboratory, Dr. Donald H. Catlin had never encountered a smoking gun like this. He had believed for several years that some athletes were cheating with impunity by using designer steroids, and now he had a chance to prove it. Over the next three months, using high-tech screening devices and low-tech tools like pencil and paper, Dr. Catlin and a team of eight chemists cracked the chemical code of the steroid, tetrahydrogestrinone, or THG, synthesized it and developed a test to catch those who used it. The result has been a billowing scandal. Urine samples from five track athletes, including Regina Jacobs, the perennial top American women's miler, and Dwain Chambers, Britain's top sprinter, who trains in California, have shown THG in preliminary tests, according to officials familiar with the results. The athletes did not knowingly take a prohibited substance, their lawyers have said. The federal authorities are investigating a nutritional supplement company, the Bay Area Laboratory Cooperative, or Balco, which one anti-doping official called the likely source of the steroid. Subpoenas to appear before a grand jury have been issued to baseball stars like Barry Bonds and Jason Giambi, and reportedly to dozens of other athletes including various professional football players, the boxer Shane Mosley and the sprinter Marion Jones. A lawyer for one of the athletes said the authorities were investigating the sale and distribution of THG, along with possible tax evasion by Balco. Victor Conte, Balco's president, has denied being the source of the THG. Apparently for the first time in a game of pharmacological cat and mouse that has spanned four decades, an unknown performance-enhancing drug has been identified, a test for it has been developed and urine samples have been re-examined before any athletes who might have used the drug were aware that the authorities knew the steroid existed. It has left the scientists who detected THG with a bittersweet sense of enormous accomplishment and dread. "It's really nice to be able to solve an important, complex problem," Dr. Catlin, 65, a professor of molecular and medical pharmacology, said in a telephone interview. On the other hand, the existence of the steroid would undoubtedly not be known if a track coach who has not been identified had not stepped forward. He gave the syringe to anti-doping officials in Colorado, who sent it to Dr. Catlin. There must be other undetected steroids out there, Dr. Catlin believes, made by clandestine labs without regard to approved safety standards or federal laws. "I do shiver a lot," Dr. Catlin said in contemplating a prospect he calls horrifying. Dr. Caroline Hatton, a chemist at the U.C.L.A. lab, agreed. "It's pretty chilling," she said. "It's like our worst nightmare was just proved. This might just be the tip of the iceberg. We hope to learn more in a few days, weeks, months. We're a little afraid of what we don't know and may never learn." A Longstanding Problem Dr. Hatton and Dr. Catlin work in a low-slung building abutting an auto body shop two miles from the main U.C.L.A. campus. There is no sign on the door to identify it as the Olympic Analytical Laboratory. If the outside is nondescript, though, the inside contains one of the world's foremost laboratories for the research and testing of performance-enhancing drugs. Each year, 25,000 tests are conducted here for clients like the United States Olympic Committee, the National Collegiate Athletic Association and the National Football League. The laboratory opened in 1982 and served as the official drug-testing center for the 1984 Summer Olympics in Los Angeles; later it provided screening for the Games in Atlanta and Salt Lake City. The U.C.L.A. laboratory is one of 30 worldwide accredited by the International Olympic Committee, and the only one in the United States. "Frankly, I didn't know much about the problem when I first started," Dr. Catlin said. He had grown interested in the drug issue while helping to treat heroin addicts as a young doctor in Washington but had heard little of the abuse of performance-enhancing drugs in sport. "I didn't believe it," Dr. Catlin said. "Why would a sportsman take drugs?" As the 1984 Games approached, Dr. Catlin read all the literature he could find and learned about steroids by visiting with bodybuilders on Venice Beach in Los Angeles. "I learned enough to know they worked," he said. His suspicions about designer steroids grew last year when Dr. Catlin tested a cyclist's urine and found norbolethone, a steroid that had been developed by a drug company in the 1960's but never marketed. If people were synthesizing steroids from arcane literature published 40 years earlier, Dr. Catlin reasoned, they might also be designing undetectable drugs. He was determined to catch them. "He is like a tractor, always grinding forward in low gear," Ed Williams, a lawyer representing Ms. Jacobs, said of Dr. Catlin. In mid-June, upon receiving a test-tube sample of the still-unknown drug, contained in the solvent methanol, Dr. Catlin performed a standard test known as gas chromatography-mass spectrometry. A droplet of purified sample was injected into a sophisticated oven, where it was vaporized in temperatures approaching 400 degrees and was swept by helium gas along a coiled column 50 feet long. Next, the substance was bombarded with electrons and fragmented, creating a molecular fingerprint. The drug had been forwarded to the U.C.L.A. laboratory by the United States Anti-Doping Agency, a nonprofit organization that receives federal funding and enforces drug testing in Olympic-related sports. Armed with a grant of about $100,000 from the anti-doping organization, Dr. Catlin and his team went to work trying to identify the substance. Within two or three days, the scientists knew the drug belonged to the steroid family. Steroids are synthetic versions of the male hormone testosterone and are illicitly used to build muscle and recover quickly from injury and strenuous workouts. Dr. Catlin, though, still had no idea exactly what anabolic steroid he had on his hands. He checked a routine computer program that identifies known steroids and came up empty. He and his laboratory associates began referring to the substance as Compound X. Typically, when a steroid is sent through the long column of the gas chromatograph, its identity can be viewed on a computer screen as a sharp peak. The peak corresponds with the steroid's retention time in the column. In this case, Dr. Catlin saw not one peak but a forest of 25 or 30 peaks, which indicated Compound X's impurity, complexity and insidious elusiveness. Essentially, the substance disintegrated during drug screening and thus was not detectable. "There are two hypotheses," Dr. Catlin said. "One is that it was deliberately designed and tested, that people knew it was not going to be detectable. We have some reason to believe that way. The other is that they made it and it came out undetectable, just a happy occurrence." Finding the Solution Now the real chemical sleuthing began. To identify Compound X, Dr. Catlin had to make it more stable, so that it would not disappear during testing. He and his associates began adding various chemical groups to the four carbon rings that serve as the backbone of a steroid molecule. The desired stability was achieved by adding a group called methyl-oxime, or MOX, to one site on the molecule and another group called tri-methyl-silyl, or TMS, to a second site. Now, a single sharp peak appeared when Compound X was sent through the gas chromatograph, but the substance remained unknown. Next, Dr. Catlin examined the drug's chemical fingerprint, a pattern of fragmented particles produced by bombardment in the mass spectrometer. These fragments appear on a computer screen as lines in a kind of stick diagram. Essentially, they are jumbled pieces of a molecular puzzle. To know exactly what molecule they were dealing with, Dr. Catlin and his team had to assemble these scattered pieces into a coherent whole. The first step was to draw a prospective molecule, the way sketch artists draw pictures of suspected criminals. Dr. Hatton, the chemist, said of Dr. Catlin: "One of the things I admire is that he's always had vision, hunches. I've wanted to say many times he's crazy or paranoid, but it turns out he's right." By July 1, two and a half weeks after receiving the sample of the mystery substance, Dr. Catlin and his associates had drawn such a prospective molecule. Next, they had to make a batch of the drug, to see whether it matched Compound X. Two days later, Dr. Catlin synthesized the steroid. It was a match. The drug's formula of carbon, hydrogen and oxygen atoms (C21H28O2) resembled two well-known steroids: gestrinone, used therapeutically to treat gynecological problems, and trenbolone, used by ranchers to beef up cattle. The scientists named the steroid tetrahydrogestrinone. Dr. Catlin consulted a worldwide database to see whether anyone else had synthesized THG or written about it. "Nothing came up," Dr. Catlin said. He was dealing with a previously undetectable steroid. "I had suspected this for years," Dr. Catlin said. "Suddenly, we were confronted with proof." As part of a peer review, a second laboratory synthesized THG. Now a test had to be devised to detect the steroid in urine samples provided by athletes. Because THG could not ethically be given to a human, a test was arranged to have it injected into another primate, in this case a baboon. Urine samples provided by the baboon over the course of three or four days all showed the presence of the drug. Putting Theory Into Action By September, the laboratory protocol was sufficiently refined to conduct a test for THG in human urine samples. At the anti-doping organization's request, Dr. Catlin's lab retested 550 refrigerated urine samples. They had been provided at the United States track and field championships three months earlier, collected in out-of-competition tests or forwarded by the world governing body of track and field. On Oct. 16, Terry Madden, chief executive of the United States Anti-Doping Agency, announced the existence of THG, saying that positive drug tests signaled a "conspiracy involving chemists, coaches and certain athletes using what they developed to be undetectable designer steroids to defraud their fellow competitors and the American and world public." In the past, some sports federations might have resisted a retesting of urine samples. But the anti-doping organization has controlled testing in the United States since October 2000, and it was eager for another examination. As accused athletes defend themselves, some seem likely to challenge whether proper procedure was followed before the urine samples were resealed after the initial tests weeks earlier. "Clearly, it will be an issue," Mr. Williams, the lawyer for Ms. Jacobs, said. Over the past 15 years, Dr. Catlin has grown by turn encouraged and disheartened as he witnessed doping scandals involving the Tour de France and the sprinter Ben Johnson and observed the debate over the use of legal steroid precursors by the former home run champion Mark McGwire. Dr. Catlin is bothered by a poisoned environment in which remarkable performances bring immediate suspicion. "As athletes move up and begin to win, everyone says they must be on drugs," Dr. Catlin said. "That's grossly unfair." Yet he is also disturbed that no test exists to detect human growth hormone, a substance that athletes are widely believed to be using. Dr. Catlin's friends ask why he remains in such a messy business, and he admits that he has wondered whether the drug problem is unsolvable. He has considered getting out, but he stays, convinced that most athletes do not cheat and that the top levels of sport can be made clean. Scientists could confront designer steroids more aggressively, he said, anticipating their use and devising tests for them. But Dr. Catlin and other scientists say it would take $50 million or more over the next five years to address doping in sports adequately. It is uncertain whether sports organizations and governments are willing to pay. Even with more aggressive testing, scandals persist. "I'm interested to see how sport responds," Dr. Catlin said. "If it takes a deep, hard look at this, there could be fundamental changes. I don't want to be finding another big bust in five years. I'm fearful of that." http://www.nytimes.com/2003/11/02/sports/02STER.html?ex=1068775461&ei=1&en=93f27f1069417b3f --------------------------------- Get Home Delivery of The New York Times Newspaper. Imagine reading The New York Times any time & anywhere you like! 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