Mark Krasnow thinks learning about the genetics and physiology of the mouse lemur could help humans as well as preserve the endangered animals.

The group spent several nights in the summer of 2010 scanning the tall trees for all types of lemurs, but they were most interested in the grey mouse lemur, Microcebus murinus (see Web extra sidebar, “Meet Microcebus murinus”). The big-eyed, bug-eating lemur from Madagascar’s west coast is one of the world’s smallest primates. And, more importantly for Krasnow’s group, mouse lemurs’ DNA has diverged from humans only half as much as the DNA of mice.

At the field station, in Ranomafana National Park, Krasnow talked with Malagasy biologists about the potential of mouse lemurs as a model for human disease. “They had grown up with lemurs but had never thought about model organisms,” Krasnow says. They loved the idea that mouse lemurs could help cure diseases, he says, but they were concerned that the lemurs—and the country—not be exploited in the process.

Moving Beyond the Mouse

During the past half century, biomedical research has focused on a handful of model organisms, as research communities have developed tools that make in-depth studies possible. The most widely used models include the mouse, the roundworm, the fruit fly, and, more recently, the zebrafish. For disease research, mice have been the focus; introducing genetic changes, scientists have made great leaps in understanding disease and basic biology (see Web extra sidebar, “Model Redefined”).

		Model Redefined A model organism doesn’t just mean a mouse or fruit fly anymore. Read More In the Wings: Model Organisms Ready to Take the Stage Play Slideshow

But mice can’t do it all. A 2008 analysis by University of Michigan scientists showed that in 40 percent of genetic defects known to cause human disease, researchers either do not see symptoms in mice or cannot identify an equivalent gene. “The mouse has revolutionized medical research, but it is necessarily limited by its biology,” Krasnow says.

Physician-scientist Michael Welsh had been studying cystic fibrosis (CF) for many years when it became clear that the field needed a new way to understand the disease. In humans, the single gene mutation that causes CF induces problems throughout the body, especially the lungs and gastrointestinal system. In mice, the mutations fail to produce typical CF disease.

“To understand the pathogenesis of a human disease, a model can be critical. If the model does not reproduce features seen in human disease, making progress can be a challenge. And if you want to develop new therapies, and the model does not manifest those key defects, you have nothing to correct,” explains Welsh, an HHMI investigator at the University of Iowa. “It was frustration and the lack of an ability to make sufficient progress that led us to develop another model of cystic fibrosis.”

Welsh’s team settled on the pig, and their new CF model develops disease like that of humans. “It is a very exciting time,” Welsh says. “We are able to answer questions and approach persistent problems that have been plaguing the field.”

Failure to replicate human disease isn’t the only problem with mouse models of disease. “There have been some very expensive long-term clinical trials based on mouse models that just didn’t turn out the way they did in mice,” says immunologist Mark Davis, an HHMI investigator at Stanford University. “The real test of a model is whether there is any predictive ability, and I think there is often a disconnect between mouse data and human disease.”

Photo: Ramin Rahimian

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