Cyclist
Should all dopers be banned for life?
Alejandro Valverde cut a divisive figure throughout the second half of his 20-year professional career. In January 2010, the then 31-year-old Spaniard was stripped of his number one world ranking and banned for two years after being implicated in Operation Puerto, a blood-doping ring in Spain involving more than 50 riders and, though not officially indicted, athletes from other sports including football and tennis.
Valverde returned to the WorldTour at the 2012 Tour Down Under, won stage five and went on to add a further 72 victories to his pre-ban palmarès of 60 before retiring in 2022. Those 73 post-ban wins included two victories at Liege-Bastogne-Liege (2015 and 2017), plus four Flèche Wallonne titles (2014-2017) and the world road title in 2018. Impressive. And potentially fuelled by a continued illegal competitive advantage as a persuasive, and growing, body of evidence suggests that those who dope still benefit from their nefarious activities after stopping. It begs the question: should dopers be banned for life?
Let’s give Valverde some slack as he’s clearly not the only cyclist who followed the oft-ridden path of succeed, suspend, succeed. Others include Ivan Basso, who was also caught up in the Puerto scandal and went onto win the 2010 Giro d’Italia. Closer to home (if you live in the UK, that is), there was David Millar, who served a two-year doping ban from 2004. On the Brit’s 2006 return, he’d win 12 times for a professional career tally of 30.
Millar, in particular, became a vocal anti-doping advocate, telling the world’s press that it was possible to win clean. ‘I want everybody to understand, even my fellow professional cyclists and the fans who love cycling, that I am doing this on nothing, solely bread and water,’ Millar said after winning stage 14 of the 2006 Vuelta a España.
To that, infers Claire Traversa, of McGill University in Canada, Millar should add his doping muscle memory. Traversa recently penned a perspective piece in the journal Drug Testing and Analysis that examined the phenomenon of skeletal muscle memory from an anti-doping perspective.
‘My PhD is in muscle physiology, so WADA [World Anti-Doping Agency] approached me to investigate the subject,’ she says. ‘They’re clearly interested in the idea that athletes can potentially benefit from doping once they’ve stopped.’ And they’re particularly interested in the myonuclei…
Myonuclear domain advantage
Myonuclei are the nuclei of your muscle fibres. ‘Muscle cells contain multiple nuclei,’ says Traversa. ‘These are where the transcription process begins that creates new, structural proteins, so the more nuclei you possess, the more proteins you can create and the more proteins you can create, the greater the cell will grow, which induces muscle hypertrophy.’
The idea stems from the 2000s where researchers noted that satellite cells – stem cells found in skeletal muscle – turned into myonuclei after resistance training. Vis-à-vis: hit the gym, squat and your muscle cells might see nuclei increase from a hypothetical five to a hypothetical ten. In short: lift weights, increase strength. Nothing groundbreaking there, you might think. But it’s what happened once training ceased that raised a few anti-doping eyebrows.
‘Not surprisingly, when they stopped training, they suffered muscle loss,’ says Traversa. ‘That was both visible by eye and ultrasound technology, where the researchers noted the cross-sectional area of muscle had shrunk. What hadn’t changed, however, was the additional myonuclei gained from the training. They remained at the same number.
‘Now, if an athlete were taking, for example, steroids for the purposes of muscle growth, they’d have gone beyond their body’s natural limits and reached a supra-physiological level. You wouldn’t see that in an athlete training natural.’
The dopers would have raised what’s termed ‘the transcriptional ceiling’ – in other words, to use a Spinal Tap classic, their potential for growth and power had cranked up from 10 to 11.
‘It has connotations for the doping world,’ says Traversa. ‘If Johnny doped five years ago, served his sanction and comes back clean, does he still have the unnaturally high myonuclei that he can access, whereas someone who has never doped and consistently trained is still only able to reach a lower level? Is that fair? We can certainly hypothesise that athletes who’ve served their sanctions and returned clean are still benefitting from when they doped. There are certainly many cases of athletes returning from a suspension and performing on the world stage when they say they’re clean.’
Take research by The New York Times, which showed that of the 11,000 athletes who competed at the 2016 Rio Olympics, at least 120 had served suspensions or had to return medals because of doping but were reinstated in time for the Olympics. So, around one in 100 competitors.
Of the 974 medals awarded, 35 were won by athletes who’d served suspensions for doping. Twelve of those were in weightlifting, seven in track and field with one in cycling, that being France’s Grégory Baugé on the track, who won bronze in the team sprint. In January 2012, it was announced that Baugé had received a backdated 12-month suspension for three missed doping tests.
Were these medallists benefitting from their doping history? There’s no way of knowing as there’s no evidence that any of the 35 physically benefitted from previous doping offences (there’s also no evidence Baugé doped). But WADA is convinced of the science and is investing in myriad muscle memory studies.
In 2022, WADA approved funding for a study by the University of Copenhagen’s Morten Hostrup, head of studies and associate professor of human physiology, around the topic: muscle memory after treatment with anabolic substance clenbuterol and resistance training in humans – myonuclear addition, hypertrophy and myocellular reprogramming.
Cyclist contacted Hostrup for further detail; he said, ‘Our team is currently conducting multiple studies examining various anabolic substances, including testosterone, clenbuterol and albuterol. We’re at a stage where we cannot share specific data. However, I’d be happy to keep you informed once our results are published and available for public discussion. The myonuclear domain hypothesis and its potential implications for anti-doping policies is indeed a crucial area of investigation that could significantly impact our understanding of long-term athletic performance advantages.’
WADA is also funding research by Fabio Pigozzi, professor at the University of Rome, entitled ‘Identifying the mechanisms and biomarkers of anabolic steroid-induced muscle memory in mice and humans’.
The MMAAS Project has even been set up to focus squarely on this topic. MMAAS stands for Muscle Memory and Anabolic Androgenic Steroids Study, and is an international collaborative study developed by the University of Brighton, University of Rome and Murdoch Children’s Research Institute in Australia.
Overcoming funding hurdles
There’s a current groundswell of interest and, more importantly, research into this topic but, Cyclist asks Traversa, why now? The BBC ran a news story about athletes potentially benefitting from steroids for a decade after use off the back of what’s seen as the first major study into this area back in 2013. Back then, a team led by Professor Kristian Gundersen discovered that mice injected with steroids saw a significant increase in muscle mass and nuclei. The drug was then withdrawn for three months (the equivalent of ten human years), the muscle mass returned to normal, but the nuclei persisted. When the muscles were then subjected to overload, they grew by 30% over six days, while the control mice grew insignificantly.
In the intervening years, there was little progress, apart from occasional studies like in 2019, where Professor Lawrence Schwartz showed similar results. As is often the case with anti-doping progress, further research in this area stalled due to funding.
‘I think WADA would concede they’re behind the gun with this, but these are expensive studies to conduct,’ says Traversa. ‘For instance, in a study like this we might use deuterated water. One litre costs $1,200. You’d need many bottles for a study of this kind. In fact, we mapped out a study where you’d administer a substance for 12 weeks and the cheapest we could get the study down to was $850,000.’
Deuterated water is a stable isotope that labels amino acids and other substrates in the body, allowing the likes of Traversa to trace a human’s metabolism through a biological system. ‘Since it’s an isotope of water it can be consumed like water (orally ingested), unlike traditional stable isotopes that need to be infused through an intravenous [IV] catheter for several hours,’ she says. ‘It allows you to monitor a participant in “free-living” conditions over days or even weeks as opposed to only a few hours while being bound to an IV pole with the infusion tracers.’
Studies also involve biopsies, which means slicing off a piece of the subject’s muscle. That’s not appealing to the general public let alone athletes who are seeking to maximise muscle output, not scythe it off. And then there’s the ethical side. Ethics committees aren’t too keen on injecting subjects with potentially dangerous substances.
‘It’s why many of the subjects analysed in studies of this kind are athletes who’ve doped and have self-reported,’ says Traversa. ‘That means you’re getting a hodgepodge of volunteers. Someone might apply saying they’ve taken growth hormone, another might be testosterone, another glucocorticoids. The most popular cohort are bodybuilders, for a couple of reasons: they’ve generally taken steroids and they’re honest about it.’
It’s common knowledge that many bodybuilding bodies don’t drug test. It’s why in October 2022, the International Federation of Bodybuilding and Fitness (IFBB) was confirmed to be non-compliant with the WADA code.
Does EPO leave an imprint?
But arguably the greatest reason bodybuilders act as subjects in these studies is that they’re about muscle memory, of the long-lasting effects on the muscle of steroids, which are essentially manufactured forms of testosterone. While that does have ramifications in cycling – at Valverde’s appeal in the Court of Arbitration of Sport in 2009, former teammate Jesús Manzano testified that Valverde took testosterone, while Millar admitted using testosterone patches – significant muscular growth (certainly, significant muscle mass) isn’t wholly desirable when faced with the mountains where watts per kilo rides roughshod over absolute power. That, says Traversa, has anti-doping research repercussions.
‘We haven’t really looked at drugs like EPO or the impact of blood boosting because that’s less about a huge change in muscle architecture, like power sports, and more about resistance to fatigue, which heavily stems from changes in things like oxidative capacity.’
Oxidative capacity is the maximal amount of oxygen consumed per gram of muscle per hour. Its proficiency, and subsequent elevation of endurance performance like road cycling, is down to factors such as the number of mitochondria (the cell’s energy powerhouse) and how a cell uses fuel. Whether it’s reliant on fast-burning glucose and glycogen or slow-burning fat, for instance.
‘The problem, when it comes to investigating markers for anti-doping, is that these changes tend to be temporary,’ adds Traversa. For instance, if you’re injecting EPO, your haematocrit (percentage of red blood cells in your blood) goes up, meaning you can carry more oxygen to fuel working muscles, and ride faster and longer, but once you stop taking EPO, haematocrit levels drop, meaning the scene of the crime is now clean.
It’s a sentiment echoed by the WADA spokesman: ‘[When it comes to memory] It wouldn’t be appropriate to group all illegal ergogenics into a single classification. While there is evidence that some ergogenic aids, such as anabolic-androgenic steroids, can offer longer-term effects [once stopped], for many others (eg, EPO, stimulants, narcotics) the effects would be transitory.’
Not everyone agrees with that, however. According to an overview piece in the summer 2021 issue of the Physiology News Magazine, Dr Einar Eftestol of the University of Oslo and Professor Jo Christiansen Bruusgaard of Kristiania University College, also in Norway, suggest that ‘an environmental stimuli can lead to epigenetic memory in haematopoietic stem cells (makers of red blood cells), meaning an epigenetic memory response to erythropoietin abuse seems plausible’.
What’s the implication? That when you ride, genetic pathways related to endurance adaptations like energy production and proficiency of burning fat for fuel are upregulated. That means genes for improving cycling performance are switched on. Do this enough and you’ll change the way a gene works to, in this case, be more conducive to optimum endurance performance. Throw EPO into the mix and, as per the Spinal Tap 11 reference, you’ll have artificially raised your gene ‘performance ceiling’. Unlike genetic changes (mutations), epigenetic changes are reversible and don’t change the sequence of DNA bases, but they can change how your body reads a DNA sequence.
Could this leave an ever-lasting imprint and be detected even after EPO injection is stopped? We’re certainly aware of research by Professor Yannis Pitsiladis that detects changes in the expression of genes that are triggered by blood doping, such as EPO or blood transfusion. We actually covered this several years back and know Pitsiladis was becoming frustrated through that common WADA bugbear: lack of funding. We reached out to Pitsiladis, who recently moved from the University of Brighton to Hong Kong, for his thoughts on this EPO memory but received no reply. He is still active in this field though, contributing to a 2023 study into metabolomic profiling when an athlete has taken EPO. The aim remains to create a failproof blood test that detects the genetic markers of cheats.
What’s clearer, argues Traversa, is that EPO abuse will leave a memory that’ll last generations. ‘The epigenetic theory says that if you’re constantly exposed to a gene that’s turned on in your lifetime, you’ll pass that onto your offspring.’ So, if a rider’s doped with EPO, they’d leave an imprint that rolls down the family lineage.
‘We’re not saying if you take steroids forever, you’ll produce a child who looks like the Hulk,’ she says. ‘But you might produce a child who has a high amount of a gene involved in muscle hypertrophy. Ultimately, what are the “downstream” effects of doping on a genetic level, be it steroids or EPO? We’re not 100% sure and it’d be near impossible to trace. Thankfully, I’m not a geneticist so I won’t be taking studies like that on.’
Lifetime ban for all?
Where does that leave us? Lifetime bans for all of those who cross the ethical line because they can still benefit when ‘clean’? Ban athletes from birth whose parents doped?! Understandably it’s too early to make such an extreme call, says Traversa. More research must be done, which, in fairness to WADA, is happening. WADA told us that, ‘Anti-doping penalties must be proportionate, and lifetime ineligibility is reserved for only the most serious violations or for repeat offenders. In Article 10, the World Anti-Doping Code outlines which offences can lead to lifetime bans. WADA feels that the four-year period of ineligibility, which is the standard sanction for non-specified substances, offers an appropriate sanction and deterrent.’
We also sought the input of a former doper, first to see if he’d enjoyed any lingering performance benefits post-doping and then to seek his thoughts on lifetime bans: ‘I cut my cycling right down when I tested positive, so it’s impossible to know,’ says Joe Papp, convicted doper and dope dealer but now behind the anti-doping movement. ‘And arguing for lifetime bans based on an incomplete scientific understanding of how the persistence of changes in muscle nuclei density might translate into a definitive, permanent competitive advantage seems overly punitive.
‘I’m more concerned about negative long-term health consequences of doping for myself and others, and whether there’s an increased risk of cardiovascular disease due to doping-altered cholesterol levels. Without going into excruciating detail, I need to lower my bad cholesterol. But is that because I doped? Or is it hereditary? Or is it because my lifestyle’s now too sedentary?’
Like with sport and anti-doping in general, there remain many open-ended questions that need answering.
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