It was late summer, and the grey towers of the Salk Institute in San Diego shaded seamlessly into ocean fog. The marble-paved central courtyard was deserted; the south lawn, too, was lifeless. But through the vents built into its concrete border, you could detect a slight ammoniac whiff from the 2,000 or so cages of laboratory rodents below. In a teak-lined office overlooking the ocean, the biologist Ronald Evans introduced me to two specimens: Couch Potato Mouse and Lance Armstrong Mouse.
Couch Potato Mouse had been raised to serve as a proxy for the out-of-shape everyman. Its daily exercise was limited to an occasional waddle towards a bowl brimming with pellets of laboratory-standard “Western Diet”, which consists of fat and sugar and tastes like cookie dough. The mouse was lethargic, with rolls of fat visible beneath its thinning fur.
Lance Armstrong Mouse had been raised under the same conditions, yet its body was lean and taut, its mind alert. The secret to its youthful energy, Evans explained, was a daily dose of GW501516 (or 516 for short) – a drug that confers some of the benefits of exercise without the recipient needing to move a muscle.
Mice love to run, Evans told me. When he puts a wheel in their cage, they typically log several miles a night. For the rodents, these nocturnal drills are not simply a way of dealing with the stress of laboratory life. When scientists left a training wheel in the corner of an urban park, their camera footage showed it was in near-constant use by wild mice. Even though their daily activities – foraging for food, avoiding predators – provided a more than adequate workout, the mice chose to run. (Several slugs also made use of the amenity, possibly by accident.)
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Still, as the example of Lance Armstrong Human makes clear, sometimes exercise alone is not enough. When Evans started giving 516 to active mice, he found that, after just four weeks, they had increased their endurance by 75 per cent. Meanwhile, their muscle composition ratio shifted towards slow-twitch fibres, which predominate in distance runners. In human terms, this would be like a recreational jogger waking up with the body of Mo Farah.
The drug works by mimicking the effect of exercise on the gene PPAR-delta. Like all genes, PPAR-delta issues instructions in the form of chemicals that tell cells how to behave. By altering the message the gene sends, 516 boosts, among other things, the signal to burn fat instead of sugar. Evans’s doped mice ran further, in part, because their muscles had been told to torch fat and save carbohydrates. As a result, they took longer to “hit the wall” – the painful sensation encountered when muscles exhaust their glucose store.
Although Evans understands the mechanism behind 516’s effects, he doesn’t yet know exactly how these processes are triggered naturally during exercise. No one does. This is the most significant challenge facing anyone who wants to develop an “exercise pill”. For all the known benefits of a loop around the park, scientists are largely incapable of explaining how exercise works.
The compound 516 was developed in the late 1990s by the chemical biologist Tim Willson in the laboratories of GlaxoSmithKline. Its ability to lower levels of insulin and triglycerides initially made it seem a promising treatment for metabolic syndrome, a cluster of conditions (including obesity and increased blood pressure) that is a precursor to heart disease and diabetes. In 2007, however, GlaxoSmithKline shelved 516 following the results of a long-term-toxicity test. Mice that had been given doses of the drug over the course of a lifetime (two years for a lab rodent) developed cancer at a higher rate than their dope-free peers. The only way to prove conclusively that it would not have a similar effect on humans was to run a 70-year trial.
Elsewhere, however, work on the drug continued. At Salk, Evans began his own trials in the same year that GlaxoSmithKline’s researchers abandoned theirs. Since then, he has developed a new version – one that he hopes will be less toxic.
But 516 is not the only exercise pill in development. Ali Tavassoli, a professor of chemical biology at the University of Southampton, came across Compound 14 more or less by chance while designing a way to screen a new class of cancer drug. He seems somewhat bemused that his lab is now a front-runner in the race to develop an exercise pill. Compound 14 has been shown to rebalance the blood-sugar levels of obese mice, while melting away 5 per cent of their body weight. It works by fooling cells into thinking that they are running out of energy, causing them to burn through the body’s reserves.
Meanwhile, the Harvard cell biologist Bruce Spiegelman is researching his own compounds. When I visited his lab, he invited me to look through a microscope at a Petri dish of muscle fibres – a kind of mouse tartare. They twitched spasmodically. “It’s spontaneous,” Spiegelman said. “The membranes are electrically active. It’s almost like static on a radio.” The experiment – in effect, exercise in a dish – is an efficient way of screening chemicals before selecting the most promising candidates for trials on intact mice.
Other researchers are tackling the problem from the opposite direction, attempting to document all of the chemical reactions that exercise unleashes to create a sort of road map for drug development. This year, the US National Institutes of Health will embark on an ambitious five-year study to measure every major molecule changed by exercise.
Maren Laughlin, who is leading the programme, explained that the technology to create a molecular snapshot of the body in motion has only become available in the past decade. “We’ve studied human metabolism for many years, but almost always at rest,” she said. It’s as if our knowledge of how the brain works had come from observing only people who were asleep.
London’s red double-decker buses are famous around the world. Less well known is that the first systematic medical study of exercise took place aboard them. In the 1940s, a young epidemiologist named Jerry Morris was looking through the postmortems of an East End hospital when he noticed an alarming increase in the frequency of heart attacks. Nobody had an explanation, but Morris suspected it might correlate with sedentary occupations – so he turned to the double-decker bus. Of the thousands of drivers and conductors working on London’s buses at the time, most came from a similar social background. The only substantial difference between them was their activity levels. The drivers sat, on average, for 90 per cent of their shifts; the conductors ran up and down the stairs all day, taking tickets.
Morris spent hours on the double-deckers, monitoring the busmen’s activity. Then he went through their medical records. He was stunned by how powerfully the data bore out his hypothesis: the sedentary drivers were almost twice as likely as the mobile conductors to drop dead of a sudden heart attack.
When the papers presenting these findings appeared in the Lancet, Morris’s conclusion – that exercise was medically important – was met with disbelief. “Puzzling,” the Aberdeen Evening Express declared, noting that Morris’s studies failed to take into account what were then generally accepted risk factors for heart attacks, such as a temperamental propensity toward “nervous strain”.
Up to this point, historical attitudes towards exercise had varied. The ancient Greeks were big fans; medieval Europeans regarded it as a distraction from the more important work of improving the soul. Until the Victorian era, vigorous exercise was more commonly cautioned against, thought to lead to fatigue and an untimely death. Of course, for most people throughout human history, not moving hasn’t been an option. Only since industrialisation, which made physical exertion a choice rather than a necessity, have scientists begun to quantify its virtues – and, in the process, to increase the burden of guilt on those who fail to squeeze in enough of it.
In the six decades following Morris’s work, the benefits of exercise have been confirmed in study after study, and physical activity is now linked to the prevention of more than 40 chronic conditions, from constipation and colon cancer to depression and diabetes. Such is the weight of evidence today that, if something could be developed to mimic the benefits of exercise safely, it would likely be the most valuable pharmaceutical in the world. At the same time, the sheer range of those benefits suggests it is unlikely that any single drug could have such wide-ranging effects.
The real problem, according to Evans, lies in the term “exercise”, which is too general to be useful. “You have to be more granular about it,” he told me. He suspects that a mere handful of biochemical pathways will prove to be responsible for the majority of exercise’s benefits. Among the current field of exercise-pill competitors, Evans is the closest to the finish line. Last year, his company, Mitobridge, launched phase I trials of 516 in humans.
Risk and Reward
Of course, “lack of exercise” is not currently recognised as a disease in its own right. Anyone who wants to market an exercise pill must therefore get it approved as a treatment for a disease that meets the criteria of the US Food and Drug Administration (FDA). Evans pointed out that statins were initially approved specifically for people who had experienced a heart attack; three decades later, they are routinely prescribed for tens of millions of people who have high cholesterol. With this in mind, Mitobridge is testing its drug as a treatment for Duchenne muscular dystrophy, a genetic muscle-wastage disease. “The economics of getting a drug approved make Duchenne a good target,” Evans said. “It’s a disease for which there are no good drugs, and those who have it will all die young. That’s an easier sell to the FDA.”
Both Evans and Spiegelman are confident that legal drugs mimicking some of the effects of exercise will be available within the next 15 years. Ali Tavassoli, the Southampton researcher, is more sceptical. “Newspapers always get me in to be the cynical Brit,” he said, laughing. His main work lies in cancer research, and he is all too aware that significant changes in metabolism are linked to the growth of tumours. His fear is that artificially increasing the rate at which muscle cells burn energy cannot help but have long-term consequences: “Not all of them are going to be good news.”
All drugs have risks. The issue is whether the benefits make them worthwhile. For someone with Duchenne, taking 516 would make sense. But the cost-benefit analysis is more complicated for the majority of us who don’t meet the government’s target of 150 minutes of exercise each week. Inactivity is one of the most significant problems of the 21st century. One study found that it was responsible for 7 per cent of all deaths in Europe in 2008 – more than twice as many as were caused by obesity. “Which is better for those people?” Willson asked me. “Being told, again, to exercise – or taking a pill?”
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You could respond with another question: why can’t humans be more like mice? Or why do so many of us choose to skip exercise in favour of more time on the sofa? One explanation is that much of human evolution has been motivated by the imperative to conserve energy and, over time, different species tend to develop neurochemical reward systems that make movement more – or less – appealing. Instead of designing a pill to replace exercise, then, perhaps a pharmaceutical aid to boost motivation would be more useful.
A taste for exercise, I gradually realised, was something that all of the pill researchers had in common. Spiegelman follows a strict regimen of kick-boxing, running and lifting. Tavassoli is a surfer; Evans is a cyclist; Willson recently completed his 11th Half Ironman. “I love that discipline of having to exercise regularly,” he told me. “It’s part of my personality.” Taking a pill, he said, would feel like cheating.
“In a lot of people’s eyes, the development of an exercise pill is a bad thing,” Evans said. “They say we’re trying to undermine exercise.” But the more accurate charge is that his research may redefine exercise, in much the same way that nutritional research has redefined food. During the 19th and 20th centuries, as scientists discovered vitamins and minerals, “food” was transformed into “nutrients”. That conceptual shift paved the way for RDAs and the rise of the so-called superfoods. In the coming years, as research provides us with new ways of quantifying physical activity, our relationship with exercise will surely change. A morning jog will be reclassified as a good source of beneficial chemicals; sports may be redesigned to optimise their molecular outcomes. But will a scientific understanding of the parts come at the expense of appreciating the immeasurable whole?
Although 516 has not yet been approved, people are taking it. Once the structure of a new compound has been published, laboratories are free to synthesise it for sale, “for research purposes only”. The earliest adopters were elite athletes. The World Anti-Doping Agency added 516 to its list of prohibited substances in 2009; since then, at least six cyclists have been suspended after taking the drug. More recently, 516 has become popular among the kind of men who frequent message boards with names such as “Think Steroids”, “Swol HQ” and “Juiced Muscle”. In this corner of the internet, guys whose avatars typically feature headless selfies are dosing themselves with 516 and sharing their reactions.
I joined a couple of forums to ask these men about their experiences. Most were unwilling to talk, but eventually one member agreed to correspond with me, on the condition that I refer to him by his online handle, Iron Julius. He told me he was a father of three and that he began taking the drug in 2012. “It wasn’t very popular yet but the little info there was made it sound like something I might like,” he wrote. His wife had been trying to persuade him to start running with her, but his bulk had made him hesitate. Still, he signed up for a 5K race to support her. He started taking 516 five days before the race. “I was planning to walk a good bit,” he wrote. “But I actually ran with her the entire time. It blew my mind how good I felt.”
Iron Julius still takes 516, although lately he has noticed a decrease in the drug’s quality. “I’m a volunteer firefighter so stamina is very important,” he explained. “Many police and firefighters are on some form of performance-enhancing substance, as the jobs are sometimes physically demanding.” Iron Julius told me that around a third of the people he sees at the gym are using 516. When I asked whether he would recommend it, his response was, “Hell, yeah, man. Try it! It don’t mess with hormones and it increases performance.”
So I ordered some. A few weeks later, a 20mg bottle arrived, containing a cloudy white liquid with a faint smell of nail-polish remover. A label instructed me to “see accompanying information” for dosage instructions. There weren’t any.
I called Tim Willson, the drug’s designer, to ask whether he would take it. “No,” he said, without hesitation. I contacted the other researchers and found that none of them had ever taken an exercise pill, in any form. I put the bottle to one side of my desk while I pondered not only the advisability of ingesting a likely carcinogen but also the fact that I actually enjoy exercise. Since then, the bottle has sat on my desk, undisturbed. During the past month, its contents appear to have developed a faint, yellowish tinge.