Building a better mouse

Breeding the mice is just the first step. Because such a small portion of the genome is currently understood, Xu’s next project is figuring out what effect each disabled gene will have on the development, health, and behavior of the mice. And diagnosing the problems is a complex business, because Xu’s method of knocking out genes is random. Unlike the molecular biologists who disable a selected gene because they think it may be related to diabetes or cancer, Xu has no way to control which genes will be deactivated by his breeding process. So when each mouse is born, he needs to test it for a whole battery of different abnormalities.

Back at Yale, Xu is at work creating the “most advanced mouse hospital on earth.” Parts of that hospital are already functional, in his current lab at the Boyer Center for Molecular Medicine. A miniature CT (computed tomography) scanner sits in the corner of a laboratory room, along with a hot plate (used to detect pain response) and other mouse-testing equipment. But the mouse hospital will soon be a part of Yale’s new West Campus, where substantial mouse vivarium space will be devoted to Xu’s project. “I was trained as a PhD in genetics to become a mouse doctor,” Xu jokes.

Yun You, an associate research scientist at Yale who is managing the mouse testing effort, says the diagnostic work begins even before the mutant mice are born. About 15 percent of genes appear to be so vital to survival that mice without them die in utero. Some of those that survive will have visible problems: they won’t grow normally, or they have patchy fur, or they grow tusks. Others require more advanced testing. Every mouse has its blood drawn and its heart rhythm scanned. The mice get colonoscopies, X-rays, and CT scans. Motor control is tested on tiny balance beams. Mouse memory is tested using special mazes. Behavior tests look for depression, fearfulness, obsessive-compulsive disorders, and trouble with breeding. Xu hopes this method will reveal many more genes of medical importance than would have been discovered the old way, by guesswork.

As the lab learns more about the function of each gene, Xu and his colleagues will publish scientific papers and enter the information about each mouse into a central Internet database. That website is already live with about 1,200 known genes. Scientists can use the site as a sort of catalog, then contact Xu with an order if a particular mutant would aid their research. Xu wants to create a shopping-cart system, so that scientists can search for traits and genes and order frozen embryos or live mice in a few simple steps.

“They’re all available,” says Jon Soderstrom, managing director of the Yale Office of Cooperative Research, who is helping Xu patent the mice and set up a for-profit corporation to manage the mouse-selling effort. “They’ll all be cataloged, and you’ll be able to go online and click through and put your order through.”

That concept is similar to a website the NIH has built for its knockout mouse project, but is vastly different from how knockout mice were obtained for research in the past. Until recently, there has been no comprehensive database listing knockouts and no reliable way for scientists to put in requests, even for those mice that were ready. Though Yale’s plan is to make money from mouse distribution, the project’s overall goal is to make mice widely available, at lower prices than those of most labs that currently offer mutant mice to researchers.

Stefan Somlo, a nephrologist who works across the street from Xu, read an early published report about Xu’s mutants, and found a mouse that was perfect for his own work on a common inherited kidney disease that causes cysts and kidney failure. He hopes the transposon-created mouse will help him find out whether therapies that turn the gene on and off will influence the progress of the disease. “This is an enabling technology for us,” he says.