DENY, DENY, DENY. Gene doping: the future of theatre?

Deny, Deny, Deny is written by Jonathan Maitland and is due to open at the Park Theatre, London on November 2^nd. I was the scientific advisor for this play, which deals with a female sprinter tempted into experimenting with gene doping. I wrote a short piece for the program notes, which I reproduce below [note that the last line does not mean I particularly think any athlete is currently gene doping, although this possibility can’t be ruled out entirely].

“In 2006 anti doping agencies got the information they had always feared.  Police raiding the home of famous German athletics coach, Thomas Springstein, found this email on his computer: The new Repoxygen is hard to get. Please give me new instructions soon so that I can order the product before Christmas.” Repoxygen was an experimental drug developed by UK biotechnology company Oxford Biomedica. It was designed to treat anaemia by injecting extra copies of the human erythropoietin (EPO) gene.

EPO is a small protein that increases the number of oxygen carrying red blood cells in the body. Activating the EPO gene increases the levels of EPO protein, increasing the number of red blood cells, enhancing oxygen delivery and improving performance in long distance “aerobic” sports. Clean athletes try to increase their own levels of EPO by altitude training. Others, like the cyclist Lance Armstrong, injected synthetic EPO directly - a process explicitly banned by the World Anti Doping Agency. Synthetic EPO is detectable, albeit with difficulty. It also needs multiple injections. How much better coach Springstein thought to inject the EPO gene itself? This gene would continue to make increased undetectable levels of EPO, creating a gene doped super athlete!

We don’t know whether Springstein ever got hold of his black market Repoxygen. We do know that Oxford Biomedica stopped making it; a combination of poorer than expected animal trials and the ready availability of new versions of cheap, synthetic EPO protein made further development uneconomic. Market forces, rather than the vigilance of anti doping agencies saved the day for clean sport in this instance.

Gene doping sits at the heart of Deny, Deny, Deny. So what is it and is the plot scientifically feasible? Gene doping is the bastard child of gene therapy. It uses the same molecular tools but aims at different outcomes. Whilst gene therapy attempts to cure genetic diseases such as cystic fibrosis and thalassemia, gene doping aims to improve how well elite athletes can run, swim or throw.

In the 1970s gene therapy was touted as heralding a new age of medicine. Is gene doping a similar game changer in sports cheating? The basic science is scarily cheap. You can teach students the principle in a school project and even get them to make a “dummy” gene construct. There is an analogy here with nuclear weapons. Everyone knows the basic theory of how to make one. But the problem - and expense - lies in the fine details of the engineering. In gene therapy the multi million pound expense is not in creating the new gene, but in making the final product effective and safe. As a result there are only a handful of genetic diseases that are currently treated by gene therapy; the cost of gene therapy per patient runs into the hundreds of thousands of pounds.

It is easy to envisage gene doping increasing the speed of female sprinters. It would only require injecting a gene that causes a slight increase in levels of testosterone – the natural male anabolic steroid - to increase female muscle mass and enable a sprinter to power to victory in the 100m or 200m. But given the costs is gene doping too expensive and impractical to be successful without the backing of Big Pharma or a rogue state? I think not. If you had “looser” ethics and were willing to trade off safety for low cost and high performance, it is easy to envisage an unscrupulous coach persuading a scientist to inject a gene that would increase the performance of a female sprinter. Perhaps they already have …….”

Bloody Olympics: Rio, 2016, and the history of illegal blood doping

The below is a reprint of a bog I wrote for Oxford University Press to coincide with the Olympics. Nothing new really, but it was nice to put things in a historical context. To see the original story (with pictures) go to http://blog.oup.com/2016/08/rio-2016-history-blood-doping/

Throughout history blood has been imbued with magical properties. Drinking blood was viewed as a source of power for many mythical beasts centuries before the invention of the modern vampire myth. In Greek mythology Odysseus can revive the dead by giving them blood to drink. But all blood is not the same – the blood from the veins on the left side of the snake-headed Gorgon Medusa is deadly, that from the right side is life-giving. In 1489 the Italian philosopher Marsilio Ficino, proposed that drinking the blood of healthy young men could rejuvenate the sick and elderly. Indeed it seems that an attempt was made to cure Pope Innocent VIII of his stroke by giving him blood from three ten year old boys. More dramatically the Hungarian princess and serial killer, Countess Elizabeth of Bathory, was alleged to have drained all the blood from over 600 young girls to feed her restorative blood baths.

Drinking fresh blood was supposed to give you strength, maybe eternal life if you were a vampire. Even in the post-enlightenment age, the first blood transfusions had nothing to do with the modern notion of enhancing oxygen supply; instead they were supposed to heal by replacing old bad blood with strong healthy animal blood.

Sport has long had a fascination with blood. The blood of the Roman gladiators, moppped by a sponge from the arena, fed a profitable business; perhaps the athlete’s ultimate commitment to promoting their brand? Today blood is even more relevant to sport. Indeed arguably its use and abuse in sport today has come close to destroying the Olympic movement.

The modern fascination with blood in the Olympics arose from the new discipline of sports science in the 1960s and 1970s.  A key driver was the 1968 Mexico City Olympics where physiologists recognized the difficulty of getting sufficient oxygen to tissue in the rarefied 2km high air. Red blood cells transfusions increase the amount of oxygen given to people suffering from trauma or anaemia. It was therefore argued that healthy athletes could be given “excess” blood to increase their ability to deliver oxygen to tissue, and hence enhance their performance in endurance sport?

Scandinavian scientists were first to prove this - in 1972, Björn Ekblom at the Institute of Physiology of Performance in Stockholm, showed a 25% increase in stamina after a transfusion. It was subsequently alleged that Scandinavian athletes were putting this laboratory method into practice. Lasse Viren won double gold medals on the track in 5,000m and 10,000m at the 1972 and 1976 Olympics. Unproven allegations of blood doping dogged Viren, who always denied them claiming that altitude training and “reindeer milk” were the keys to his enhanced performance. Some of his teammates did later confess to blood doping, however, most notably Kaarlo Maaninka at the 1980 Olympics. Maaninka received no sanction, which might surprise today’s readers given that blood doping is one of the main reasons we will not see the Russian track and field team competing at these Olympics. However, although in the 1970s and 1980s blood doping was viewed as morally dubious, it did not break any rules. The anti doping effort of the time focussed more on amphetamines and anaboloic steroids.

This would change in the 1980s. The LA Olympics in 1984 was the watershed event. There was extensive use of blood transfusions including by several members of the highly successful US cycling team. Again no rules were broken, but the IOC had had enough and banned blood doping in 1985. However, they had no way of testing for this form of cheating, so it presumably continued in secret. In fact the ready availability of genetically engineered EPO in the late 1990s, a difficult to detect drug that increases the number of red blood cells more gradually and naturally than a blood transfusion, undoubtedly increased the use of banned methods. I could fill most of the rest of this article with a list of Olympic athletes who are confirmed or strongly suspected of using EPO and/or blood transfusions to aid their performance.

So where are we now? Blood is a part of the Olympics and always will be. Whilst not imbuing you with the mythical life giving properties of Odysseus, optimizing your number of red blood cells is a key part of success in endurance events. I can guarantee that every medal winner in a long distance endurance event will have had their blood measured frequently by support scientists to conform the success of their training program, whether that program uses permitted (altitude training, sleeping in low oxygen tents) or banned (EPO, blood transfusion) methods.

So much for Rio, what about PyeongChang and the Winter Olympics? This is, if anything, an even richer source of stories than the summer games.  There are claims of athletes chosen for ski teams solely so that are the right blood group to donate blood to their team leader; in 2006 a disgraced ex Austrian ski coach crashed his car into a roadblock in the Italian alps, whilst attempting to escape the police. But that’s a blog for two years time ……..

Rio Olympics 2016 and doping stories

Most of the interest for me happened pre the Games of course and the "will they, won't they" allow Russia to compete saga. Not surprisingly during the games my TV and radio interviews weren't about science, but about athletes response to other athletes. The extent of finger pointing was unusual for the Olympics,  but less extreme than has happened at some other events e.g. Paula Radcliffe unfurling her "EPO cheats out" banner at the 2001 World Championship [1]. Still it was the Olympics so news outlets inevitably focussed on incidents such as the finger wagging between Yulia Efimova and Lilly King [2]. Until of course the light relief/black comedy provided by Ryan Lochte and his co-conspirators [3].

The main story in my opinion though was the IPC being brave enough to ban Russia completely from the Paralympics. The world didn't end and the ban was even upheld by the Court of Arbitration for Sport.  This rather put the lie to the IOC's passing of the buck to the national sporting organisations with its ridiculous one week timescale and wilful misreading of the nature of the McLaren WADA report [3].

I didn't get asked much about the IPC decision  though I did try to bring the contrast with the IOC into some of my interviews. Still I am now really looking forward to the Paralympics. Not clean, but cleaner......

[1]  https://www.theguardian.com/sport/2001/aug/10/athletics1

[2] http://www.independent.co.uk/sport/olympics/rio-2016-yulia-efimova-and-lilly-king-show-how-swimmings-code-of-honour-is-shot-to-pieces-by-ioc-a7179891.html

[3] http://www.breitbart.com/video/2016/08/22/john-oliver-destroys-ryan-lochte-labels-him-americas-idiot-sea-cow/

[4] https://www.theguardian.com/sport/2016/aug/04/richard-mclaren-ioc-wada-russia-rio-2016-

Sharapova, Pound and Seppelt: Tacking Doping in Sport 2016

I’ve just come back from this two-day conference at Twickenham stadium. To get there I waited once again at the bus stop I used to spend my teenage life hanging around – a situation made me feel both strangely young and old at the same time. But what of the conference? You might expect a set of talks from regulators and lawyers to be dry and drab. However, at times more sparks flew than even at the most vitriolic academic meeting. Actually the latter are usually sedate – though intellectually stimulating events – with tempers and egos well in check (at least until the bar opens).

So what caused the fuss at Twickenham? Surprisingly it wasn’t the Maria Sharapova meldonium affair. This just led to incredulity as to how someone would keep taking a drug – for whatever reason – when it was so clearly advertised as coming on to the banned list and an effective test had clearly been developed. The fact that Sharapova has been joined by 99 other athletes in the space of a few months suggests either a massive breakdown in anti doping education or a significant level of stupidity amongst dopers.

So who did get everyone excited? Not Dick Pound for once with his usual erudite exposition of Russia’s recent failings. Not even Jonathan Taylor from Bird & Bird who did his best to wind up – well everyone really. No they were both upstaged by the showing of Hajo Seppelt’s new ARD documentary; this revealed that banned coaches were still active in Russia. He followed this up with some direct barbs at the WADA president, Sir Craig Reedie, accusing him of firing one of his top investigators and having a conflict of interest between his role at WADA and the IOC (where he is a Vice President).

I felt a little bit sheepish giving my own talk immediately after Hajo’s Tour de Force. Especially as what I was talking about essentially amounted to studying not doping. I discussed whether much of doping’s effectiveness could be due to the power of the placebo effect i.e. the athlete runs faster because they believe they have a secret advantage. This contrasts with the nocebo effect, where the athlete runs slower because they believe their opponent is doping and hence can’t be beaten. The problem is to do the definitive placebo doping study I would need to give EPO to a elite athletes whilst telling them I was giving them a meaningless injection. This would reveal exactly how much of EPO’s benefit is due to its biological, rather than its psychological effect. But it is hard to see a research ethics committee agreeing to this level of deception. Such a pain when morality gets in the way of a good piece of science!