in my shoes
Catching the bad sports Don Catlin has made a career of developing techniques that strike out athletes who use illicit performance-enhancing drugs.
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kept the new lab busy, but from “the summer of 1984 to the summer of 1985, there was no work. Nobody was doing any testing,” says Catlin. “The staff I had went from 30 to 1.” But then the USOC asked him to reopen the lab, and the National Collegiate Athletic Association and the National Football League became clients. The lab continues to operate today.
Test for testosterone JEFF MINTON, COURTESY OF THE UCLA OLYMPIC ANALYTICAL LABORATORY
he big sports doping scandals are hard to miss when they hit the headlines: Barry Bonds, BALCO, and designer steroids; Floyd Landis and testosterone; Lance Armstrong accused of taking erythropoietin (EPO). But who helped to develop the tests that uncover such cheating? Don Catlin of the Anti-Doping Research Institute (ADR) has been a key figure in the fight against sports doping. From 1982 to early this year, he was the director of the University of California Los Angeles (UCLA) Olympic Analytical Laboratory. During his tenure, that lab was instrumental in identifying the designer drugs that the supplement company Bay Area Laboratory Co-operative (BALCO) was distributing to elite athletes. He and his colleagues developed the test that caught Floyd Landis’s use of synthetic testosterone in the 2006 Tour de France. And it was Catlin who predicted the abuse of EPO, which boosts production of red blood cells, in sports. If the 1984 Olympic Games hadn’t been held in Los Angeles, Catlin says, he wouldn’t have entered the field of sports doping. Catlin—a onetime army doctor and an expert on drug addiction—was a faculty member at UCLA’s medical school in 1982, when the U.S. Olympic Committee (USOC) was searching for someone to start up a lab to test samples from athletes during the games. “My name popped up because of some things I had written; I had been in the army, done some work on drug abuse, and had an appointment in pharmacology at UCLA,” says Catlin. “The USOC people came to visit, and they had a long list of drugs. I looked at it and said, ‘Well, I really don’t know all these drugs, and I don’t understand chemistry all that well.’” His answer was no. But the USOC members returned, and this time, they explained that they were offering a $1.3 million grant. “If I took on the job, I
Don Catlin has been a major player in the development of analytical techniques to catch sports doping.
would be the recipient of the grant,” says Catlin. “That led to discussions with UCLA and my department chairman, and to make a long story short, we decided to go for it.” Gears shifted for Catlin. “I had to sit down and brush up not only on my chemistry but also on my instrumentation. As a director of a lab that was going to do the 1984 Olympics, I had to know mass spectrometry,” he says. “I learned enough to be able to seriously discuss it and know the differences between instruments, the principles, and so forth. In the early days, I wrote software to detect drugs, and I really got into it on an everyday basis. But then my medical practice suffered!” The Los Angeles Olympic Games
By the late 1980s, Catlin’s group had established methods for detecting the performance-enhancing drugs that were completely foreign to the human body. But that drove up the stakes. “Athletes who wanted to dope needed a different handle on the situation,” says Catlin. Testosterone seemed perfect for cheating athletes, because the synthetic hormone is identical to natural testosterone. MS can detect testosterone in urine, but spectra of the natural and synthetic hormone look the same. But Catlin and colleagues soon figured out that nature put a marker on synthetic testosterone. “A group of us were sitting around, 1986 or 1987, batting around some ideas. We started saying, ‘Gee whiz, maybe it’s got a different carbon isotope ratio,’” remembers Catlin. Synthetic testosterone isn’t made from scratch. Pharmaceutical manufacturers carry out a partial synthesis in which they start with a precursor plant compound, typically from yams, and do a few synthesis steps to convert it into testosterone. The plant compound happens to have a different carbon isotope ratio from human testosterone. But it took the investigators 15 years to develop the test based on carbon isotope ratio. “It was a hard sell,” says Catlin. “It’s really hard to describe to sports funders what you’re trying to do. They’re not the [National Institutes of Health]. They have no idea what you’re
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doing. It was, ‘Who are you, and how credible are you? You want a $300,000 instrument?!’” Catlin finally managed to establish a partnership with a lab in France and get equipment to develop the carbon isotope ratio method for testosterone. His
differ from the natural ones—with the right instruments and techniques, he thinks a reliable test is possible. He’s aiming for a urine test, because doping control is almost entirely based on urine tests; blood is only taken during Olympic Games. But skepticism exists about a urine test for growth hormone. “If you read around, a lot of people say it can’t be done,” Catlin says. “It’s a research project. I have ideas. I’m not divulging all of them, but we’ll see.”
Cyclists caught using EPO and other drugs reduced the 1998 Tour de France to the “Tour de Shame”. Lance Armstrong, a seven-time winner of the Tour de France, has been dogged by accusations of taking EPO, though he has never tested positive.
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BALCO and THG
Barry Bonds was among the athletes caught up in the 2003 BALCO scandal.
efforts bore fruit when the Olympic Movement Anti-Doping Code recognized the test in 1999. The test apparently caught Floyd Landis, the winner of the 2006 Tour de France, and Justin Gatlin, the U.S. sprinter who won gold medals in the 2004 Olympic Games. “It’s not an easy technique to do, but it works,” remarks Catlin.
Tackling EPO and growth hormone Catlin’s medical training led to his hunch that EPO—a drug originally designed to help patients on chemotherapy and with chronic renal failure— would spell trouble in sports. “When I read about EPO being developed by Amgen back in the 1980s, I thought, ‘Oh my goodness, this is going to be a doping agent for athletes,’” he says. “I didn’t know at the time how extensive the use would be. Nobody did. But sure enough, I started picking up signals that it was being used as early as 1988 and 1989, just as it was coming out of Amgen. It went on for 10 years until people really got on to it.” 3964
Françoise Lasne and colleagues at the French National Anti-Doping Laboratory were first to describe a urine test for EPO (Nature 2000, 405, 635). It is based on isoelectric gel focusing, in which the sugars on synthetic and natural EPO produce different bands on the gel. But the method is cumbersome, takes 3 days, and only works if the athlete is tested within 2–5 days of taking the drug. One of Catlin’s goals at ADR is to come up with a more effective detection technique. “We would like to go directly to MS, enzymatically degrade EPO, and look for specific combinations of amino acids that are particular for recombinant human EPO,” he says. ADR has leased an Orbitrap mass spectrometer, which Catlin hopes will be the key to a better test. Besides EPO, Catlin wants to develop a urine test for growth hormone. No mass spectrometric test for the drug currently exists, because the recombinant protein is identical to the human product. However, Catlin says, isoforms found in recombinant growth hormone
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Perhaps the biggest sports doping scandal Catlin was involved in was the 2003 BALCO case. BALCO was a service for blood and urine analysis and food supplements. But federal agencies started getting tips that Victor Conte, the founder and owner of BALCO, and his cronies were providing high-end athletes and their coaches with designer steroids. Jeff Novitzky, a federal investigator, approached Catlin for help. Novitzky spent nights in the dumpsters behind the BALCO lab, looking for empty vials and package inserts. Catlin says, “He’d call and say, ‘Dr. Catlin, I have this thing I really can’t pronounce. It’s eery-thro-po-ee-tin.’” Novitzky’s nightly forages produced evidence that BALCO dealt in all kinds of steroids. In addition, the U.S. AntiDoping Agency received a spent syringe with a tiny drop of liquid from a locker room floor; an anonymous source said the syringe contained a BALCO product. The agency rinsed the syringe out with methanol and gave the rinse to Catlin. Catlin and colleagues analyzed the liquid by GC/MS, the analytical standard in sports doping. “We saw a hundred peaks, a forest. There wasn’t a single unimolecular peak. It was just a big mess,” says Catlin. Whatever they were looking at fell apart at the heated inlet of the gas chromatograph, but the investigators knew they were on to something. Soon, they obtained a good spectrum without derivatization, but they knew that was a short-term solution. So they switched to LC/MS/MS. Sure enough, they identi-
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fied a designer anabolic steroid, tetrahydrogestrinone (THG), known by athletes as “The Clear”. Barry Bonds, Jason Giambi, Marion Jones, and other BALCO clients got embroiled in the scandal. The probe soon extracted guilty pleas from Conte, Bonds’s trainer Greg Anderson, BALCO vice president James Valente, and track coach Remi Korchemny. The sophistication of THG forced Catlin’s lab and other anti-doping labs to incorporate LC/MS methods into their arsenal along with GC/MS and immunoassays. “There really was no choice. In this business, if you find something like THG, then it’s out there,” says Catlin. “You’ve got to block it somehow; otherwise you have a giant hole in your [testing] program. The only way to block it is to have LC/MS.”
A paradigm shift Besides developing new detection methods at ADR, Catlin wants to induce a paradigm shift in sports. His Volunteer Program removes the cat-and-mouse element of the business—instead of hunting down athletes to test them for drugs, Catlin is requesting athletes to volunteer to be tested regularly to show that they’re clean. “We will follow biomarkers much as a doctor would follow a patient by measuring their blood pressure. Some of these biomarkers would be related to doping. For example, we would follow the blood level of growth hormone, which we can do with an immunoassay,” explains Catlin. If an athlete’s biomarker levels shoot up because of doping, the athlete will be excused from the Volunteer Program but not accused of anything. Catlin says this approach will
avoid the litigation that takes up energy and money in sport. The main purpose of the program is to protect the athletes who do compete fairly and cleanly. Catlin asks, “What kind of industry is it where you train hard and finally excel to get to the Olympic level, but somebody says, ‘Oh, you must have cheated. How else could you get here?’” He also points out that the arms race between cheating athletes and anti-doping agencies can’t continue—the drugs get more sophisticated every time, as do the tests to catch them. It’s time to approach the problem differently, and Catlin wants to experiment with the Volunteer Program. “I want to see if sport and clients will support the program. If they do, we’ll do just fine,” he says. “And if not, well, we tried.” a —Rajendrani Mukhopadhyay
Editor-in-Chief Royce W. Murray and the Associate Editors of Analytical Chemistry express their sincere thanks to the many reviewers for the journal.
With 64,301 total citations and an ISI® Impact Factor of 5.635, Analytical Chemistry is the most cited and highest impact journal in the field of Analytical Chemistry as reported in the 2005 ISI® Journal Citation Reports.
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