Catching the cheats

C&I Issue 7, 2016

Athletes have been using substances to enhance their performance for decades. However, as David Mottram, emeritus professor of pharmacy at Liverpool John Moores University, UK, and editor of Drugs in sport, now in its sixth edition, speaking at the SCI in April, said: ‘Landmark events in the 20th century brought home the extent and seriousness of doping in sport.’

In 1967, British cyclist Tommy Simpson, died having taken amphetamines; throughout the 1970s and 1980s, state-controlled doping went on in the old German Demographic Republic; in 1988, at the Seoul Olympics, Ben Johnson was stripped of his gold for testing positive for the anabolic steroid, stanozolol – revealing that the extent of the problem went beyond just power-lifting athletes; and the Festina affair at the 1998 Tour de France showed that it was not just individuals who were involved but also teams of athletes taking drugs.

The Festina affair, explained Mottram, proved to be a trigger for the formation of the World Anti-Doping Agency (WADA) in 1999, which brings together the various sporting bodies and governments from around the world to monitor and tackle the problem. Funded equally by the International Olympic Committee (IOC) and the national governments to the tune of $30m/year, WADA now has in place five international standards, covering: prohibited substances; therapeutic use exemptions; testing and investigations; protection of privacy; and accredited laboratories – of which there are 35 around the world, including one at Kings College London (KCL), UK. WADA’s standards are high. In June 2016, the agency suspended the accreditation of the Rio laboratory for ‘non-conformity’, thus prohibiting the Olympic and Paralympic hosts from carrying out all anti-doping analyses on urine and blood for the games. As C&I went to press, it was not known which WADA accredited laboratory would be doing this work. 

The 2016 Prohibited List is extensive. Some classes of drug are prohibited at all times – anabolic agents, peptide hormones, growth factors, beta-2-agonists, hormone and metabolic modulators, and diuretics and other masking agents. Other substances are prohibited in competition only, such as stimulants, narcotics, cannabinoids and glucocorticoids – for example,  anti-inflammatories – and others, such as alcohol and beta-blockers. The manipulation of blood and blood components, chemical and physical manipulation of samples, and gene doping are prohibited at all times. Importantly, athletes are responsible for any prohibited substance found in their system, whether or not there was an intention to cheat, and the Prohibitive List is monitored and reviewed annually. Sometimes drugs previously taken off the list are put back on if new evidence suggests otherwise.

The extent of the problem is a moot point, said Mottram. The latest statistics from WADA find that of the 283,304 samples analysed by its accredited labs in 2014, 3866 gave adverse results, suggesting that just 1.36% of athletes were using prohibited drugs. This, he said, is a much lower figure than the media would have us believe, although the truth probably lies somewhere in between.

Elite athletes are by nature determined people and some will experiment with any substance that they think will give them the winning edge. ‘The BALCO scandal in California – involving a ‘back street lab’, which supplied anabolic steroids and supposedly “undetectable designer drugs” to professional athletes highlighted the fact that they would even use drugs which hadn’t gone through any safety checks,’ said Mottram. And cyclist Lance Armstrong  – who claimed he was the world’s most tested athlete in the world  –  managed to cheat the system for years by using drugs like EPO and testosterone, which occur naturally in the body and were at the time difficult to detect.

But things have changed since then and several factors are coming together to help WADA and its scientists keep apace, and often one step ahead, of the cheats.

Over the past 15 years, WADA has pumped some $60m into research to develop new and improved detection methods for prohibited substances and methods, as well as into investigating emerging threats such as gene doping. Funding from WADA, other agencies and industry, has, for example, allowed David Cowan, head of the Drug Control Centre at KCL and his group, not only to detect previously undetectable drugs, such as anabolic steroids, testosterone and growth hormone, but also to develop new methodology.

‘With financial backing from GSK, we developed a new approach to testing samples at the London 2012 games,’ said Cowan. ‘This involved using liquid chromatography (LC)–high resolution MS for routine screening of samples for the wide range of WADA prohibited substances in urine.’ Until then, he said, scientists had used targeted drug screens – looking for specific compounds, which was time-consuming and costly.

At the London Olympics, analytical chemists were able to screen for 100s of substances in just one sample, and around 400 samples could be tested in one day; any negative results were fed back to WADA and the IOC within 24 hours. The technique is accurate to four to five decimal places of mass unit. Second generation LC-HRMS, using methods developed at Kings, explained Cowan, is expected to be in place for Rio 2016, providing even more sensitive and faster detection capability.

Moreover, WADA laboratories now hold onto urine samples for up to 10 years after an event so that retrospective testing can be done as the technology improves. ‘With the full scan approach, and data storage technology, we can do more retrospective testing without having to go back to urine or blood samples and reanalyse them – giving us a very powerful forensic tool,’ said Cowan.

The introduction of Registered Testing Pools (RTP) and athletes’ biological passports have also gone some way to stop would-be dopers. Athletes who compete at the highest levels now have to be in a RTP, maintained by the International Federations (IFs) and National Anti-Doping Organisations (NADOs). As part of this programme, they have to go online every three months and state where they will be for one hour of every day for the next three months for random testing. ‘The biological passport is a record of an athlete’s haematological and steroidal profiles in their urine and blood over a period of time and useful for highlighting possible use of difficult to detect substances such as EPO and testosterone, which occur naturally in the body,’ explained Mottram. While other testing protocols compare one athlete against another, here the athletes act as their own control, so longitudinally monitoring their samples shows up any abnormalities, which would then lead to an investigation by a panel of experts.

But analytical prowess is only part of the solution. Increasingly scientists are gaining invaluable information on drug use from intelligence-based sources. WADA now cooperates with law enforcement agencies – both national and international – and border agencies for information on drug trafficking. The agency also collaborates with pharmaceutical companies to find out if there are any products in the pipeline that are likely to be licenced in coming years, which could have the potential for performance enhancement. The Internet and the media also have a role to play – investigative journalists have highlighted potential dopers, which anti-doping agencies have gone on to investigate.

For Rio 2016, some people speculate that gene doping could make the headlines. A spin-off of gene therapy – where genes are manipulated to restore some function – athletes would be looking to manipulate specific genes to improve their performance. To-date, a host of genes have been identified, albeit in mouse studies, that might be used to sporting advantage, including ones for the production of EPO and growth hormone. Genes that either inhibit the production of the protein myostatin or block its receptor would increase muscle size and therefore also be attractive to a wide range of athletes.

However, as Dominic Wells, professor in translational medicine at the Royal Veterinary College, London, UK, who researches gene therapy for neuromuscular disease, comments: ‘There’s a lot of talk about gene doping but as yet there is no evidence that anyone has done it, nor is likely to be able to do it for at least five to 10 years. We don’t actually know that what we’ve seen in genetically-modified mice would translate to an effect following gene-doping in man. And that’s currently a significant limitation.’ 

There are also detectable differences, for example, between the genes that express EPO – and other sporting chemicals – when injected into the circulation, compared with those produced endogenously, he said.

And there’s a big difference of scale in producing viral vectors, which carry the modified genes to cells, for lab mice and for humans. The latter, he explained, would require bioprocessing facilities capable of making hundreds of litres, which would put the technology beyond any back street laboratory. But he acknowledges developments are being made all the time, so it is right that WADA makes clear that gene doping is against the rules and develops the necessary tests.

Recently, ground-breaking research by Jerry Mendell at Nationwide Children’s Hospital, Ohio, US, has shown that it is possible to transfer viral vectors to babies who have the genetic defect that leads to the fatal condition of spinal muscular atrophy. ‘It’s early days for this stunning work,’ said Wells, ’but it does tell us there is potential for vector systems to work in man and therefore could eventually be used as a way of gene doping’.

Again, though, he emphasises that the amounts of material needed would be a limiting factor and even if it could be done, the adverse health effects are likely to outweigh the benefits. The effect of such vectors on the adult immune system could be devastating and more research needs to be done here.

Perhaps the more pressing problem for Rio is the use of supplements by athletes. As Mottram pointed out, supplements are still used by athletes at all levels not necessarily to enhance their performance but to maintain a certain level of health, as the Sharapova case highlighted. Significantly, however, figures from three national doping agencies – in the US, UK and Australia – find that between 6 and 9% of doping violations for the period 2005 to 2013 were associated with supplement use. ‘They are simply not safe for athletes to use,’ said Mottram. ‘Supplement producers are not regulated; some of the labelling can be misleading; and there is the possibility of contamination with prohibited substances during the manufacturing process. It’s a big education issue that still needs to be addressed.’

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