Mark Mattson knows a lot about mice and rats. He's fed them; he's bred them; he's cut their heads open with a scalpel. Over a brilliant 25-year career in neuroscience—one that's made him a Laboratory Chief at the National Institute on Aging, a professor of neuroscience at Johns Hopkins, a consultant to Alzheimer's nonprofits, and a leading scholar of degenerative brain conditions—Mattson has completed more than 500 original, peer-reviewed studies, using something on the order of 20,000 laboratory rodents. He's investigated the progression and prevention of age-related diseases in rats and mice of every kind: black ones and brown ones; agoutis and albinos; juveniles and adults; males and females. Still, he never quite noticed howfat they were—how bloated and sedentary and sickly—until a Tuesday afternoon in February 2007. That's the day it occurred to him, while giving a lecture at Emory University in Atlanta, that his animals were nothing less (and nothing more) than lazy little butterballs. His animals and everyone else's, too.
Mattson was lecturing on a research program that he'd been conducting since 1995, on whether a strict diet can help ward off brain damage and disease. He'd generated some dramatic data to back up the theory: If you put a rat on a limited feeding schedule—depriving it of food every other day—and then blocked off one of its cerebral arteries to induce a stroke, its brain damage would be greatly reduced. The same held for mice that had been engineered to develop something like Parkinson's disease: Take away their food, and their brains stayed healthier.
How would these findings apply to humans, asked someone in the audience. Should people skip meals, too? At 5-foot-7 and 125 pounds, Mattson looks like a meal-skipper, and he is one. Instead of having breakfast or lunch, he takes all his food over a period of a few hours each evening—a bowl of steamed cabbage, a bit of salmon, maybe some yogurt. It's not unlike the regime that appears to protect his lab animals from cancer, stroke, and neurodegenerative disease. "Why do we eat three meals a day?" he asks me over the phone, not waiting for an answer. "From my research, it's more like a social thing than something with a basis in our biology."
But Mattson wasn't so quick to prescribe his stern feeding schedule to the crowd in Atlanta. He had faith in his research on diet and the brain but was beginning to realize that it suffered from a major complication. It might well be the case that a mouse can be starved into good health—that a deprived and skinny brain is more robust than one that's well-fed. But there was another way to look at the data. Maybe it's not that limiting a mouse's food intake makes it healthy, he thought; it could be that not limiting a mouse's food makes it sick. Mattson's control animals—the rodents that were supposed to yield a normal response to stroke and Parkinson's—might have been overweight, and that would mean his baseline data were skewed.
"I began to realize that the 'control' animals used for research studies throughout the world are couch potatoes," he tells me. It's been shown that mice living under standard laboratory conditions eat more and grow bigger than their country cousins. At the National Institute on Aging, as at every major research center, the animals are grouped in plastic cages the size of large shoeboxes, topped with a wire lid and a food hopper that's never empty of pellets. This form of husbandry, known as ad libitum feeding, is cheap and convenient since animal technicians need only check the hoppers from time to time to make sure they haven't run dry. Without toys or exercise wheels to distract them, the mice are left with nothing to do but eat and sleep—and then eat some more.
That such a lifestyle would make rodents unhealthy, and thus of limited use for research, may seem obvious, but the problem appears to be so flagrant and widespread that few scientists bother to consider it. Ad libitum feeding and lack of exercise are industry-standard for the massive rodent-breeding factories that ship out millions of lab mice and rats every year and fuel a $1.1-billion global business in living reagents for medical research. When Mattson made that point in Atlanta, and suggested that the control animals used in labs were sedentary and overweight as a rule, several in the audience gasped. His implication was clear: The basic tool of biomedicine—and its workhorse in the production of new drugs and other treatments—had been transformed into a shoddy, industrial product. Researchers in the United States and abroad were drawing the bulk of their conclusions about the nature of human disease—and about Nature itself—from an organism that's as divorced from its natural state as feedlot cattle or oven-stuffer chickens.
Mattson isn't much of a doomsayer in conversation. "I realized that this information should be communicated more widely," he says without inflection, of that tumultuous afternoon in Atlanta. In 2010, he co-authored a more extensive, but still measured, analysis of the problem for the Proceedings of the National Academy of Sciences. The paper, titled " 'Control' laboratory rodents are metabolically morbid: Why it matters," laid out the case for how a rodent obesity epidemic might be affecting human health.
Standard lab rats and lab mice are insulin-resistant, hypertensive, and short-lived, he and his co-authors explained. Having unlimited access to food makes the animals prone to cancer, type-2 diabetes, and renal failure; it alters their gene expression in substantial ways; and it leads to cognitive decline. And there's reason to believe that ragged and rundown rodents will respond differently—abnormally, even—to experimental drugs.
Mattson has seen this problem in his own field of research. Twenty years ago, scientists started to develop some new ways to prevent brain damage after a stroke. A neurotransmitter called glutamate had been identified as a toxin for affected nerve cells, and a number of drug companies started working on ways to block its effects. The new medicines were tested in rats and mice with great success—but what worked in rodents failed in people. After a series of time-consuming and expensive clinical trials, the glutamate-blockers were declared a bust: They offered no benefit to human stroke patients.
Now Mattson has an idea for why the drugs didn't pan out: All the original test-animals were chubby. If there's something about the brain of an obese, sedentary rodent that amplifies the effects of a glutamate-blocker, that would explain why the drugs worked for a population of lab animals but not in the more diverse set of human patients. This past June, he published apaper confirming the hunch: When he put his test mice on a diet before administering the glutamate-blockers, the drugs' magical effects all but disappeared.
Many promising treatments could be failing for the same reason, Mattson argues, and other trials should be re-examined—but that's unlikely to happen anytime soon. "It comes down to money and resources," he says. "There's some fraction of studies that may have been compromised by [these] issues, but there's no way to know unless one does the experiment with the proper controls."
That's the drawback of the modern lab mouse. It's cheap, efficient, and highly standardized—all of which qualities have made it the favorite tool of large-scale biomedical research. But as Mattson points out, there's a danger to taking so much of our knowledge straight from the animal assembly line. The inbred, factory-farmed rodents in use today—raised by the millions in germ-free barrier rooms, overfed and understimulated and in some cases pumped through with antibiotics—may be placing unseen constraints on what we know and learn.
"This is important for scientists," says Mattson, "but they don't think about it at all."
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