There’s been a lot in the media in recent weeks about the use of performance-enhancing drugs – especially in Australian sport. “Supplements”, “peptides” and other forms of doping appear to have been used in a number of sporting codes and cycling, of course, has attracted more attention than any other. But all of these drugs – erythropoietin (EPO), human growth hormone, “peptides” – could well become obsolete in years to come.

In the first post in this series called Blood Doping 101, we discussed the basis of blood doping and which variables can be manipulated in an athlete’s aerobic capacity. There are many ways to cheat, but in endurance sports – such as cycling – the most effective way of doping is to increase haemoglobin mass. It’s all about blood.

READ: Blood Doping 101

In that first post we suggested there are two ways of artificially increasing haemoglobin mass: by taking EPO or by blood transfusion. But there is actually a third way which is currently in clinical trials for medical usage – EPO gene therapy.

This post has been adapted from conversations I’ve had with a haematologist and fellow cyclist (who prefers to remain anonymous) and materials he’s given me. This has also been checked for accuracy by two doctors who specialise in the field of blood.

The holy grail of doping?

The next step forward in terms of cheating in endurance competition is very likely to come from the genetic arena. Could this be the holy grail of doping?

Everything in medicine has moved towards targeted therapy. In cancer treatment, for example, doctors no longer just use chemotherapy to target both the normal and abnormal cells. Because they have a better understanding of the mechanisms involved in the disease, they can target, more specifically, the abnormality itself. The consequence – or side effect, whichever way you look at it – is that you can use targeted therapy to your benefit.

In the first post we talked about EPO which, as a reminder, is a hormone that controls red blood cell production. Athletes have used EPO as a performance-enhancing substance for many years, though exclusively by receiving injections of the hormone. Recent studies suggest it may be possible to introduce another EPO gene into an animal in order to increase EPO production endogenously – that is, by getting the body to produce more EPO on its own.

A benefit of EPO gene therapy is that it can consistently elevate red blood cell production, rather than providing a short-term burst as with injecting EPO or blood doping. As a result EPO gene therapy is less likely to be picked up using a regular biological passport technique or by testing urine samples.

Banned, but used?

Given its potential for enhancing performance, gene doping was banned by the International Olympic Committee in 2003. Despite the ban, athletes and coaches may be using gene-targeting therapies.

In 2004, German track coach Thomas Springstein was caught after unsuccessfully trying to score Repoxygen, an experimental gene therapy drug that boosts red blood cell production. And at the 2008 Beijing Olympics, an unidentified Chinese doctor offered stem cell injections to a German journalist who was posing as a swim coach.

The effects of gene doping in healthy humans aren’t currently known. But healthy animals have suffered drastic side effects, from fatal anemia caused by an immune reaction to blood vessels clogged with overproduced blood cells.

EPO gene therapy is still very much in the research domain though early clinical trials are underway. Once it becomes widely available, dopers are likely to take advantage of this strategy. New detection methods will have to be developed and validated before they can be introduced for routine testing, providing a window of time that may stretch to years before offenders can be caught.

There are, however, new therapies emerging all the time as blood-boosting agents remain a keen focus for drug development. It is at the cutting edge of this research that dopers can count on new candidates for performance-enhancing drugs, such as “HIF stabilisers”.

So what is HIF and what are HIF stabilisers?

HIF – Hypoxia inducible factor

During mountain stages of the Tour de France you’ll often hear Phil Liggett use the term “oxygen debt” – when the muscles lack an adequate amount of oxygen due to high-intensity anaerobic efforts. Oxygen debt is more formally known as hypoxemia.

The most important mediators of the cellular response to hypoxia are “transcription factors” (proteins which influence which genes are used in which cell) called HIFs (or hypoxia-inducible factors).

HIF activates the genes that influence adaptive responses to hypoxia, including:

– the production of EPO

– the way the cells generate energy

– the creation of veins and blood vessels (called VEGF: vascular endothelial growth factor)

– the supply of iron (important for red cell production).

From this list, it is clear that the HIFs have the potential to improve the performance of an athlete. Does that mean administering HIFs will have an immediate effect on performance?

The short answer is no, because the HIFs are targeted for degradation in the absence of sustained blood hypoxia, so providing an external source isn’t the best way to increase their activity. Instead HIF stabilisers can be used to prolong the activity of the HIFs and provide ongoing production of natural EPO when there is no biological need for it (i.e. when oxygen levels are normal in the blood).

HIF stabilisers

As mentioned above, HIFs also stimulate the formation of new blood vessels (a process called angiogenesis) and therefore HIF stabilisers will improve this process. For an endurance athlete, this means more blood vessels supplying the muscle, which are normally generated over time in response to training.

By using HIF stabilisers, an athlete may be able to decrease the training period required to improve the blood supply to the muscles from weeks or months to a matter of days. Think about this: More oxygen-rich blood being delivered to more blood vessels generated within new muscle tissue. Add to this an improvement in carbohydrate metabolism and you have a very attractive performance-enhancing drug. You can quickly see the consequences (or benefits) here.

HIF stabilisers are still being developed for routine use in humans but they are being tested in clinical trials now. These drugs are small chemical compounds that can be delivered in an oral pill and they are difficult to detect in blood and urine samples.

A Human Limit?

When we exercise to our limits, approximately 90% of our oxygen is being sent to the muscles being used. The remainder is sent to the brain, heart, and gut (that’s why those bars sometimes don’t digest well when you’re working hard up a climb). When the body has already maximised the oxygen supply, the only way to improve performance is to blood dope.

As history (and reasoned decisions) have shown, athletes are willing to explore every option to improve the oxygen-carrying capacity of their blood with blatant disregard for the risks involved. Too much exogenous EPO or too many blood bags will thicken the blood to the point where it will come to a standstill during sleep, with obvious consequences. In short, our bodies have evolved to operate within a set of standard specifications that are difficult to exceed without endangering the function of the entire system. Performance-enhancing drugs challenge the body’s normal specifications and that’s why they pose so many risks to dopers.

EPO gene therapy carries the same risks as exogenous EPO and blood bags, including the development of circulatory abnormalities leading to internal bleeding and even death. HIF stabilisers also influence the expression of more than 200 genes – many of which we simply don’t understand yet – so there is enormous potential for serious unwanted side effects. As yet, these effects have yet to be defined in gory detail, but such concerns are unlikely to enter the head of an athlete after they hear about the benefits.

EPO gene therapy is certainly possible but much remains unexplored with respect to efficacy, safety, and the way it affects the immune system. Thankfully, gene therapy doesn’t appear to have entered the sports scene yet, but is it only a matter of time?

Upcoming articles in series:

– How testers detect EPO and transfusions and how athletes beat the tests

– Short term and long term risks of Blood Doping