Ronald Evans realized the word was out when scores of strangers, some fit and some fat, started showing up at his biology lectures around the country. Soon, via email and voicemail, they were hounding him at all hours. Was it true, some wanted to know, that he had pills that could vaporize fat? Could the pills really, others asked, increase athletic endurance by 70 percent? Would he be interested in coming over and doping a racehorse?
During a lecture for a crowd of 200 in Montreal, a pair of college athletes took the mic and peppered Evans with questions about the pills’ potential impact on the effectiveness of human growth hormone and erythropoietin. They ignored his interjections that those two performance-enhancing drugs were banned by most athletic rule-making bodies.
That was 2007. Evans was finishing up a study showing that mice taking the drug, an experimental GlaxoSmithKline Plc compound called GW501516, vastly increased their fat burn and athletic performance, even with minimal exercise. Some mice demonstrated the kind of endurance that would normally require intense training. Evans, a researcher at the Howard Hughes Medical Institute and the Salk Institute for Biological Studies, warned repeatedly that the pills weren’t ready for human consumption when he published the study in 2008. They were just a proof of concept, he said, using some potentially dangerous substances. There were no studies showing they’d work on humans, no data on possible side effects.
His caveats didn’t make it into the headlines. By 2009 enough athletes had been caught using GW501516 (aka Endurobol) that the World Anti-Doping Agency banned it. By 2013 so many had been caught that WADA took the rare step of issuing a health notice. Human trials with the drug had been abandoned because of “serious toxicities,” the oversight body noted. Among the side effects in mice: cancerous tumors. “For a lot of athletes, winning is more important than their intrinsic health or the risk they are taking,” says Evans, who at 67 has a lean runner’s build, tight black curls, and a thin goatee that’s peppered with a lot more gray than it was in ’08. “So I guess I’m not surprised they were taking it. They want to win.”
His story is an object lesson in what happens when the world can’t wait for the science to catch up with the hype. “The drug companies got way ahead of our understanding of the biology,” says Daniel Kelly, director of the Cardiovascular Institute at the University of Pennsylvania. “That kind of soured the field. The biology now has caught up.”
Just about, Evans says. In July, almost a decade after that first study, his company, Mitobridge Inc., in partnership with Astellas Pharma Inc., began testing MA0211, a new drug that he’s betting can safely upgrade human cellular metabolism. The six-year-old company has received $45 million in venture funding to make it happen, much of it earmarked for development and trials targeting those in the greatest need. The first treatment is aimed at Duchenne muscular dystrophy, a genetic protein mutation that affects 1 in 5,000 men, causing a progressive loss of muscle and killing most by the age of 26. Given the severity of the disease, Mitobridge and Astellas can expect speedy approval from the U.S. Food and Drug Administration if their study, the first phase of which will be finished within a year, shows even some promise of building muscle in Duchenne sufferers.
Seated in his third-floor office at Salk on the bluffs of La Jolla, Calif., where he’s had a stunning view of the Pacific for 38 years, Evans is already thinking about what comes next. “A drug that promotes the benefits of fitness could have widespread applications,” he says with more than a little understatement. Beyond tackling obesity, a pill that replicates the benefits of exercise could help reduce the risk for chronic inflammation, diabetes, even cancer. From behind a desk buried in a pile of awards, DNA models, and photos of his twentysomething daughter, Lena, Evans insists the previous efforts failed only because they were based on incomplete pictures of the human body. “When you’re gaming a genetic system, if you overgame it, you activate genes outside your target, causing side effects,” he says, rising from his chair. He walks past the two acoustic guitars in his office and picks up a recent scientific paper. “Our molecule is completely different.”
Evans’s record sets him apart from the hucksters who’ve been peddling get-fit-quick schemes and weight-loss pills since the dawn of footwear. A pioneer in molecular biology, he was the first, three decades ago, to discover nuclear receptors. These microscopic proteins, sticking out from the surface of a cell’s nucleus like antennae, can be triggered to switch cellular processes on and off. These switches became the principal means by which scientists learned to manipulate genes. Ten years later, in 1995, Evans found the receptor that appeared to control the storage and metabolization of fat, known as a peroxisome proliferator-activated receptor, or PPAR-alpha. A few years after that, he identified PPAR-gamma and PPAR-delta, related receptors that appear to activate fat-burning.
The study published in 2008 started there. In 2003, Evans and his team tweaked mouse genes to turn the fat-burning switches on permanently in fat tissue, and their mice slimmed down dramatically. A year later he flipped the fat burners on in muscle tissue, and the mice developed Type 1 muscle, the kind found in marathon runners and endurance cyclists. These mice lasted an hour longer on the treadmill than normal ones and ran twice as far. The downside was burnout, says Michael Downes, a senior scientist who’s been working with Evans since the 1990s. Permanently flipping all of the cellular switches on made the mice’s muscles grow faster than any known medication had.
Big Pharma had seen all it needed to charge ahead. “Drugs were built pretty quickly, because there was enthusiasm for new targets,” says Evans, meaning such targets as obesity and heart disease. For the 2008 study he principally used GlaxoSmithKline’s GW501516, along with a less potent drug that worked in a similar way. GW501516 allowed the mice to run 75 percent farther than normal mice before collapsing from exhaustion. But by the time Evans published the study, bringing a stream of obsessive athletes to his door, Glaxo had abandoned efforts to test GW501516 on humans. Only later did published papers link its testing in mice to development of tumors in the liver, bladder, stomach, and skin.