Some people are lean, others more Rubenesque. Ron Evans has discovered that, to some degree, the difference between a couch potato and a marathon runner lies in the activity of a family of genes that controls the storage and burning of fat.
By exploring the function of these key regulatory genes, Evans hopes to deepen our understanding of the molecular basis of obesity-related diseases such as diabetes and syndrome X, a disorder characterized by high blood pressure, heart disease, and insulin resistance. Ultimately his studies could lead to the development of drugs that might help people slim down and improve their overall health.
“Follow the energy—that’s my story,” says Evans, an HHMI investigator at the Salk Institute in San Diego. “It’s all about the energy.”
The focus on energy applies equally well to both Evans’s science and his personal philosophy. In the lab, Evans explores the regulation of metabolism: how cells balance their energy input and expenditure. But his investigations are powered by his enthusiasm, curiosity, and irrepressible energy. “I was a real lab rat,” says Evans of his early days at the bench. “Fifteen- or 16-hour days were pretty normal. It was work, work, work—and I loved it.”
That degree of dedication is not unusual, says Evans. “When you’re engaged in a scientific adventure, it really gets your juices flowing.” And science has been working its charms on Evans since he was in high school. “I was good at it,” he says, “and I think I had a good feel for it.”
Evans signed on as a graduate student to work with UCLA researcher Marcel Baluda. The lab was studying tumor-causing viruses that use RNA as their genetic material. What Baluda—and his competitors—were trying to figure out was how these viruses convert their RNA to DNA, a feat that they perform after infecting a host cell but that runs counter to the way all other organisms operate.
Baluda and his lab got scooped. Two other biologists—Howard Temin and David Baltimore—discovered the enzyme that transforms RNA into DNA, work that eventually earned them a Nobel Prize. Evans plowed ahead. “My goal—and it wasn’t necessarily the most lofty goal—was to get a Ph.D. fast.” Evans’s efforts paid off. He published half a dozen papers in under four years and was well positioned to secure a good postdoctoral fellowship.
His first choice was the lab of “the arch nemesis, David Baltimore,” says Evans. But when Evans went for a visit, he discovered that Baltimore was preparing to go on sabbatical to Rockefeller University to work with molecular biologist James Darnell. Evans decided to go there as well.
“That was an exciting time and an ideal choice,” he says of his stay in Darnell’s lab. He began studying a problem that would hold his interest throughout the rest of his career: how cells control the activity of their genes, a process central to life. Although Evans started out studying viruses, which were easy to work with, he really wanted to work with mammalian genes. In particular, he wanted to determine how the growth hormone gene is regulated by steroid and thyroid hormones. Researchers believed that receptor proteins that bind to these hormones could function as a genetic switch to control gene activity. To find the switch, Evans first needed to isolate the growth hormone gene. The only problem was that scientists had imposed a moratorium on manipulating cellular genes until they could sort out the relevant ethical and safety issues.
While they debated, Evans prepared the proper facilities for handling mammalian DNA and got all his reagents ready. Finally the moratorium was lifted. “At midnight on the day you could start cloning,” he says, “we made the first library”—a collection of fragments that represents all the genes in an organism. Within days, they’d found the growth hormone gene, which Evans packed up and took with him to the Salk Institute, where he started his own lab.
With the gene in hand, Evans next focused his attention on identifying the genetic switch that turns it on. “It was extremely difficult,” he says, “because nobody really knew how to do it.” In addition to his effort, several labs around the country were taking different approaches to find the molecules that would help unlock the secrets of gene control. This time, Evans got there first. He and his colleagues were able to isolate the gene for the glucocorticoid receptor, the first of a series of related switches that allow hormones to control genes.
In short order, Evans found two more receptors capable of regulating the gene for the growth hormone, and more soon followed. Each works in a similar way. It binds to some sort of activating molecule—a hormone or vitamin—and then heads for the nucleus, where it finds the proper chromosomes and tweaks gene activity. The first dozen receptors form what Evans calls a “nuclear receptor superfamily.” And these were just the beginning.
Evans knew that when he searched the genome for genes that were similar to those that encode these nuclear receptors, he could see “faint signals” indicating their presence. “We knew there were more receptors out there.” He and his team decided to chase them.
To date Evans has turned up nearly 50 receptors that are part of this nuclear receptor superfamily. Two of these receptors, PPAR-gamma and PPAR-delta, play key roles in regulating the storage and burning of fat. PPAR-gamma snatches fat from the blood and squirrels it away inside fat cells. Its sister protein, PPAR-delta, regulates how muscles burn fat. When kept on a high-fat diet, mice that lack PPAR-delta become obese. Mice that are engineered to produce an overactive version of the receptor in their muscle tissue remain sleek and lean. PPAR-delta revs up cellular fat-burning pathways and beefs up the animals’ slow-twitch muscle mass. And the engineered animals put this muscle to good use. When placed on a rodent-sized treadmill, these “marathon mice” will run twice as far as their normal relatives.