Scientists Breed a Tougher Mouse

A group of mice bred in a laboratory are leaving their peers in the dust.

"Marathon mice," genetically engineered by Howard Hughes Medical Institute researchers, can run twice as far as their unaltered buddies. Previously, the only known way to increase endurance was through training.

With no previous running experience, most mice can run about 900 meters before exhaustion. But the genetically altered mice can run 1800 meters (more than a mile) before running out of steam, and keep it up for two and a half hours -- an hour longer than unaltered mice can run.

"Records are broken on a fraction of a percent," said Ron Evans, the head researcher in the mouse experiment and a professor in the Gene Expression Laboratory at The Salk Institute. "A few percentage points is like a minute or two in a race. This was a big change: 100 percent."

To perform the genetic enhancement on the mice, researchers injected a human version of a protein called PPAR-delta attached to a short DNA sequence. The injection permanently incorporated enhanced PPAR-delta production into the mice' genomes. The change is transgenic, meaning the mice will pass down the trait to future generations.

The mice were also resistant to weight gain, even when fed a high-fat diet that caused obesity in other mice, according to research published online in the Aug. 24 issue of the Public Library of Science Biology.

It's too late for next week's Olympic marathon competitors in Athens to take advantage, but, coincidentally, GlaxoSmithKline is developing an oral drug that activates the same protein in humans (called PPAR-delta) that was stimulated in the marathon mice.

GlaxoSmithKline has completed the first phase of three human trials necessary for FDA approval to market the drug as a good cholesterol, or HDL, booster. (Increased HDL can help prevent heart attacks.) Evans said researchers at GlaxoSmithKline were surprised when told about the other benefits he and his colleagues had found were associated with increased levels of the protein.

"We learned it may be good for weight gain, good as an insulin sensitizer and it may change muscle performance," Evans said. "The (company researchers) became very excited."

Evans was just as surprised by the results. He knew that PPAR-delta increased fat-burning. But he was surprised to see an increase in certain muscle fibers. GlaxoSmithKline plans to study the marathon mouse further, Evans said.

"If you put those things together in a product for human beings, you can imagine the market that would open up," said Paul Root Wolpe, a bioethicist at the Center for Bioethics at the University of Pennsylvania. "A dietary control drug is something that's been the Holy Grail for researchers spending millions of dollars for a long time."

Several modifications in animals have shown that altering certain genes can make animals stronger, particularly in work by Lee Sweeney, associate professor of physiology and medicine at the University of Pennsylvania.

But the fact that the researchers changed various outcomes by altering just one gene is unexpected, Evans said. Most physiologists believe that enhancing performance is a complicated process during which several genes coordinate changes throughout the nervous system, the cardiovascular system, and the muscle itself. But this single change seems to have rewired the entire system.

That could be good news for people who are confined to a wheelchair or suffer from muscle-wasting diseases like AIDS or muscular dystrophy. The discovery could also lead to treatments for diabetes and obesity, because the mice also had lower levels of intramuscular triglycerides, which are associated with insulin resistance and diabetes in obese people, the researchers said.

If athletes were to use the "marathon" gene alteration to their advantage, sprinters would want to steer clear. The genetic alteration increased "slow-twitch" muscle mass, which run on energy stored in fat and are fatigue resistant. But mice had fewer "fast-twitch" muscle fibers, which rely on glucose for fuel and fatigue quickly.

Having more slow-twitch muscle appeared to protect the mice from weight gain on a high-fat diet that made other mice obese. The result led Evans to believe that long-distance runners can likely fend off weight gain even when they're not exercising because of the muscle they've built up.

But the fact that just one genetic change had such a widespread effect also presents an ethical quandary. While mice are much easier to genetically alter than humans, if genetic modification is perfected in humans, this could lead to an easy way to enhance sports performance.

"The world is about to change dramatically," Wolpe said. "It's one thing to say there are going to be certain banned substances. It's another thing to say people are not going to be able to manipulate their bodies in certain ways."

Genetic alterations will also be more difficult to detect than drugs, Wolpe said.

"Are we going to perform sophisticated genetic tests on people? What if you were born that way? Will you have to document the fact that its 'natural' rather than an induced trait? Or are we just going to throw out the whole idea that human sports achievement has to be done with some sort of notion of the natural?"

By Kristen Philipkoski

Wired News