by Dan Ariely
Having spent a career shaking up paleontology, Horner seems perfectly happy with the idea that even considering a chickenosaurus shakes up biologists. “Paleontology is ossified,” says Nathan Myhrvold, the former Microsoft CTO who now dabbles in a bunch of different sciences and has worked extensively with Horner. “The methods haven’t changed substantially in a hundred years.” Yes, researchers know more about dinosaurs and other extinct creatures now than they did a century ago—and Myhrvold has been a coauthor of several academic papers that contribute to that supply of knowledge. But he sees Horner’s work as the first real push to bring the tools and insights of molecular and developmental biology into the paleontological fold. “Normally, paleontologists go out and walk around until they find fossils,” Myhrvold says. “But it turns out that there’s a place to look that’s just as good as the badlands of Montana, and that’s the genome of living relatives.”
And if Horner is right, do we get the joy of real dinosaurs menacing the San Diego suburbs? “A lot of people say, ‘You worked on Jurassic Park, you should know better,’” Horner says with a laugh. “But contrary to Steven Spielberg’s movies, animals don’t want to get even with us. We actually could have dinosaurs running around and they wouldn’t be any worse than grizzly bears and mountain lions.” That might seem like scant reassurance to those who spend less time wandering the badlands than Horner does. But for now, Horner has no intention of letting any of his experiments hatch. (Just give him a few years and some funding.) And because he intends only to manipulate developmental signals, without altering any DNA, any offspring of a chickenosaurus would be a normal-looking chicken. So what could possibly go wrong?
One project, if it ever happens, could give us an idea. In 2008, researchers at Penn State announced that they’d sequenced most of the genome of the woolly mammoth, extinct for 10,000 years, from samples of its hair. That prompted the Harvard geneticist George Church to claim that for around $10 million he could resurrect the mammoth. He’d take a skin cell from an elephant, even more closely related to mammoths than humans are to chimps, and then reprogram the elephantine bits of its genome into something more mammothy. Convert that into an embryo and bring it to term in an elephant uterus. No problem.
If Church were ever to try it—and there are no signs that he will—the project would have a few advantages over Horner’s. DNA can last for around 100,000 years, so researchers actually have mostly intact genetic material from mammoths, avoiding the Jurassic Park degraded-DNA problem. And from a genetic perspective, elephants are practically mammoths already, whereas chickens have diverged pretty significantly from, say, a velociraptor. But the important point is that the technology to do this kind of work didn’t exist ten years ago. It’s now possible, for example, to make thousands of modifications to the genome in a single cell. Genomics has gone from an artisanal craft to something more akin to the mechanical looms of the early industrial revolution. Sure, to realize his reverse-evolution dream, Horner needs to take the technology even further. But the trend lines do seem to point in the right direction.
Back in his office, he picks up a heavy introductory developmental bio textbook from his desk. “All these books are about flies,” Horner says, arching his eyebrows. “Flies are great. They’re very interesting, and you can learn a lot by studying them. But . . .” He tosses the book onto a chair and stands up, walks down a long hallway to his crammed collection room and a drawer filled with every imaginable sort of bird skull—a toucan with its giant orange bill, a parrot’s hooklike mouth, the flattened beak of a spoonbill. “Birds are pretty amazing, too,” he says.
Developmental biologists talk about the regulatory machinery they study as a biological toolkit, a small set of mechanisms and processes that evolution uses to construct new and wonderful bodies. “Well,” Horner says, “they’ve found the toolkit. But what good is a toolkit if you don’t use it to build something?”
MICHAEL BEHAR
Faster. Higher. Squeakier.
FROM Outside
BACK IN THE EARLY 1960s, when the architect Louis Kahn designed the airy layout of the Salk Institute—a collection of stark concrete towers aligned like teetering dominoes on a Pacific Ocean bluff in La Jolla, California—he oriented the buildings so that robust sea breezes would waft through the upper floors. But as I descend four flights of stairs to enter a sprawling subterranean lab, the sweet ocean air turns sour. Researchers at Salk are conducting cutting-edge experiments in genetics, biology, neuroscience, and human physiology. At the core of this futuristic work are six thousand old-fashioned, defecating rodents, stacked in shoebox-size plastic cages, creating an odor far too potent for Kahn’s ingenious ventilation scheme to handle.
Despite the funk, the facility is meticulously clean. Wearing powder-blue scrubs, a surgical mask, a bouffant cap, and cloth shoe covers, I enter through a sterile clean room closed off between double doors. A whitewashed hallway adjoins various smaller labs, where some mice are being injected with performance-enhancing compounds and forced to sprint on tiny treadmills. Others have had bits of their DNA reprogrammed to make them better runners. There are paunchy mice gorging on high-fat diets and svelte mice getting low-cal meals. Hunched over a metal table, a technician sorts through a squirming posse, plucking out prime studs for breeding and banishing aggressive males to solitary confinement. Mice are sacrificed and their muscles examined. Blood is sampled, hearts are inspected, kidneys and livers prodded.
This busy little world is the multimillion-dollar endeavor of Ron Evans, a sixty-one-year-old molecular and developmental biologist who’s trying to crack the code of human endurance. With help from a team of thirty-five scientists, Evans has an ambitious goal: to develop the first-ever performance-enhancing drug that can radically boost physical endurance in humans.
The “exercise in a pill” project began during the summer of 2007, when Evans made a stunning announcement. While investigating obesity, he stumbled upon a genetic switch that unexpectedly turned his lab rodents into superathletes. In August 2008, Evans published the findings in Cell, a prestigious scientific journal, claiming that in some cases his augmented mice could run 90 percent farther than ordinary critters. By comparison, it’s considered extraordinary when a human athlete’s performance jumps by only 3 percent. Evans’s breakthrough would be like transforming a dawdling weekend jogger into an Ironman contender overnight. And, as Evans assures me, “This wouldn’t require you to actually exercise muscle to gain a benefit.”
In the now famous Cell paper, Evans and his coauthors—a collaborative multinational team based at research institutes in California, Massachusetts, and South Korea—confidently announced that they had found a way “to enhance training adaptation or even to increase endurance without exercise.” Physiologists who’d spent their careers deconstructing the sophisticated mechanics of exercise and its numerous benefits were skeptical, dismissing the notion of pill-popping your daily workout as ludicrous.
But that didn’t stop every major media outlet—including the big four networks, cable news channels, the New York Times, and the Wall Street Journal—from declaring the breakthrough a “couch potato’s dream.” Nova scienceNow, a PBS program, interviewed Evans, who said that “the benefit of exercise alone and the benefit of the drug [are] almost exact” and predicted that athletes would be the earliest adopters.
Though it may be years before doctors are writing prescriptions that turbocharge your training, serious people are aiming at that goal. Evans’s group is a frontrunner in the race, but there are others: independent teams around the world developing naturally derived and synthetically engineered compounds that in preliminary animal experiments—and a few human tests—have measurably increased overall fitness.
Obviously, there will be hurdles. One is convincing biotech firms to back the costly studies required to create a marketable drug. Another is the U.S. Food and Drug Administration, which won’t green-light a new treatment that exists solely to help people run farther. (Scient
ists would first have to show that the drug can cure a real disease.) Even so, Evans believes that we’re heading toward an inevitable day in which a pill will supplement and, in many cases, entirely replace exercise.
I first heard about Evans on the NBC Nightly News, shortly after slogging through a forty-minute treadmill run at my gym. When a smirking Brian Williams flashed the onscreen headline EXERCISE IN A PILL, my bullshit meter redlined. So I phoned Evans, who amiably assured me that his research was legit and invited me to visit his lab, where I could see his supermice firsthand.
Now, over the course of an introductory two-hour chat in his oak-paneled fifth-floor office, Evans, a southern California native who’s tan and slim and looks far younger than his age, does his best to simplify the science. When it comes to genetics and pharmacology—subjects I’ve covered for more than a decade—I’m usually a quick study. Not so today. Listening to Evans delve into the complexities of cellular nutrient transfer makes my brain hurt.
Evans is goateed and wears frameless specs, designer jeans, a crisp blue oxford shirt, and black retro sneakers. On the windows, across the glass, he’s scribbled elaborate equations that almost completely obscure the ocean view. Academic honors in elegant frames crowd the walls, with overflow awards aligned neatly along baseboards. On a shelf are three bobbleheads—one of Evans beside James Watson and Francis Crick, the legendary scientists who in 1962 shared a Nobel Prize with Maurice Wilkins for mapping the structure of DNA. There’s a stainless-steel yo-yo on his desk and a half-empty bottle of Jose Cuervo on a coffee table. I ask about the tequila, but Evans, a wicked tennis player and avid swimmer, can’t remember how it got there and would rather talk about Lance Armstrong’s quads.
To be an endurance athlete like Armstrong, Evans explains, your leg muscles need lots of slow-twitch fibers. “Energy is stored in the chemical form of ATP, adenosine triphosphate,” he says. “The mitochondria, the powerhouses of the cells, break down sugar and fat to create ATP.” Every endurance athlete knows what comes next: when ATP stores run dry, you bonk, hit the wall—kablooey.
Exercise creates more slow-twitch fibers and fuels a process known as mitochondrial biogenesis. Put simply, train hard and your mitochondria multiply like microbes. More mitochondria equals more ATP and, whoosh, you’re running sub-three-hour marathons. Among exercise physiologists, the consensus has always been that the only way to increase mitochondria was through intense, prolonged physical activity.
“Endurance is a matter of real-time generation of ATP, and it was thought that exercise was the only way to get the system to work better,” says Evans, who accepted this idea until 1998. That’s when he began exploring the role of genes in obesity, homing in on a genetic switch called peroxisome proliferator-activated receptor delta, or PPAR-delta, a protein known to regulate metabolism and fat burning. When your body demands fuel, PPAR-delta can influence whether it chooses glucose (sugar) or lipids (fats).
At rest, PPAR-delta is dormant. But during exercise it awakens to sustain a metabolic chain reaction that produces muscle fibers with slow-twitch properties, which feed on body fat. Vigorous exercise isn’t an option if you’re morbidly obese, though. So Evans wondered: what if we exercised the gene and not the muscle? Activate PPAR-delta, his thinking went, and fat-eating slow-twitch fibers would materialize like blades of grass sprouting from a freshly watered lawn.
In his first experiment, Evans coded the PPAR-delta gene to activate only in fat cells, where he thought it would have the most impact on weight loss. “We reengineered PPAR-delta in mice to be permanently on, like a light switch,” he says. “What happened was a bit of a miracle. The animals slimmed down and were resistant to weight gain even on a high-fat diet.” Fat cells in the mice had become more oxidative, similar to what happens when you blow air over smoldering coals and they erupt into flames. The cells could, quite literally, vaporize excess blubber.
Impressive results, but Evans wasn’t satisfied. By 2004 he’d figured out how to tweak the PPAR-delta gene to fire in muscle cells. If the muscle became oxidative, as it did in the fat-cell experiment, it would cultivate the growth of mitochondria-rich slow-twitch fibers, essential for endurance.
Recalling all this, Evans grins broadly, eager to reveal the outcome. “We got marathon mice—an entire strain of animals that had become long-distance runners without ever having had to run,” he says. “We proved that endurance could be genetically engineered through this particular switch. And the switch stayed on and could be passed on as a genetic trait. You could have a whole lineage of long-distance-running mice.”
While we talk, Evans sits cross-legged in a sage-colored lounge chair, fiddling with pencil-thin paper wands that resemble giant chopsticks. He makes them by rolling together discarded Post-its. “Humans and spotted hyenas are endurance predators. They wear their prey out,” he says, delving into a tangential discussion of fast-twitch muscle fibers in primates. I nudge him back on topic. “So we wanted to find a drug that could activate the PPAR-delta switch by injection or pill,” he says, “because genetic engineering is impractical.”
At this point Evans leaps from his chair and starts pacing in front of a large whiteboard. He grabs a red marker and draws a box. Inside he writes GW1516. “This is a Glaxo compound,” he says, referring to the pharmaceutical giant GlaxoSmithKline, which, Evans learned, had created GW1516 more than a decade ago, later making it publicly available for biotech researchers. “They were developing it to trigger the PPAR-delta switch, because they had observed that in obese primates it tripled HDL levels, the good cholesterol.” Glaxo test subjects had been receiving GW1516 in intermittent doses—enough to increase HDL but not a lot else. GW1516 was available commercially, so Evans ordered up a batch and fed it to his mice every day for five weeks, a dose that far exceeded amounts given in any previous experiments. “The effect was huge!” he says.
It sure was. Couch-potato mice could eke out a lame two-thirds of a mile. The same was true for mice given GW1516 that didn’t train. Mice that didn’t get GW1516 but did ten-minute daily stints on a treadmill eventually hit 1.1 miles. But mice that had both—training and GW1516—easily hit 2.3 miles.
In short, the drug had doubled the normal performance-enhancing effect of regular endurance training. Unlike mice with genetically altered PPAR-delta, GW1516 had no impact on sedentary animals. Exercise, it seemed, was an essential part of the equation, though Evans didn’t know why.
He submitted the results to Cell in 2007. But the editors wanted more and initially refused to publish his paper. “We had ended the story with a drug working in the context of exercise, and the Cell reviewers said, ‘Look, you can’t leave us hanging, because if what you’re saying is correct, then the real breakthrough would be to completely replace exercise.’ They wanted us to take it to the next level, to find a drug that could enhance performance without any exercise. That was something nobody had done before, and we didn’t think it was possible.”
Evans persisted, searching for another substance to flip the PPAR-delta switch. The winner was a chemical compound called AICAR (pronounced aye-car), which had been around since the 1980s and was being used in clinical trials for the treatment of ischemic reperfusion, a rare complication of coronary bypass surgery that occurs when blood flow restored to previously damaged arteries causes inflammation and damage to heart tissue.
“We knew AICAR could stimulate a more oxidative metabolism,” Evan says. “There were reports that it had been given to people, and activity in muscle had been measured. But these studies were all based on single injections. They weren’t giving it once a day for thirty days. When we did that, the results were beautiful.”
Once again, here was an experimental compound readily available to scientists—but one that nobody had thought to test in a high-dose way. Mice that hadn’t done any exercise but were given AICAR could run 23 percent longer and 44 percent farther than sedentary mice that didn’t get the drug.
Sure, it wasn’t the doubling of enduran
ce seen with GW1516. But the AICAR mice hadn’t trained at all. They’d become remarkably fit by doing nothing.
Once word got out about AICAR and GW1516, Evans figured that human athletes would jump the gun and start ingesting the stuff. Before Evans published his Cell paper, he tipped off the World Anti-Doping Agency (WADA), the Montreal-headquartered outfit that sets drug-testing and enforcement policies adopted by every Olympic and many non-Olympic sports. WADA asked him to devise a test to detect the drugs in urine and blood and added both compounds to its list of banned substances. It didn’t take long for the drug to make news: the French Anti-Doping Agency alleged that AICAR had been used by riders in the 2009 Tour de France, though it never came forward with specific allegations or named names.
Meanwhile, on supplement-oriented Web forums like RxMuscle.com, the buzz grew quickly. “I can’t wait!” one poster declared. “Give me some of that GW1516!” Another wrote: “AICAR is already available on the grey market.” There’s also an online clearinghouse, aicar.co.uk, which provides AICAR data and calls the compound “a new dawn in dieting and fitness . . . the revolutionary AICAR and GW1516 are the newest buddies of athletes.”
Other studies have shown that a healthy abundance of mitochondria can mitigate aging and make it easier to lose weight, factors that will likely extend AICAR and GW1516 use well beyond a handful of zealous endurance athletes. And as Evans points out, “These compounds are easy to make or obtain.” He shows me a Web site where a licensed research institute can buy GW1516 online; AICAR is also available from biotech suppliers. “Type ‘purchase AICAR’ into a search engine,” Evans suggests. I quickly find some, though it’s not cheap: a thousand bucks for ten grams, about twenty times the street price of cocaine.