Oak Ridge researchers build mouse community to mimic human diversity

Associated Press • Mar 31, 2007 at 11:33 AM

OAK RIDGE, Tenn. - In one corner of the vast Oak Ridge National Laboratory, they aren't interested so much in building a better mousetrap, but in creating a vast colony of closely crossbred mice.

At the Russell Laboratory for Comparative and Functional Genomics, commonly known as "the mouse house," researchers are building a mouse collection that resembles the human population in its diversity, group leader Elissa Chesler says.

This first-of-its-kind, international project could become a platform for "a new way of looking at human biology using the mouse as a model," said geneticist David Threadgill at the University of North Carolina at Chapel Hill.

Mice have long been used as laboratory substitutes for humans. They reproduce quickly, are easily mutated and on a genetic level are about 85 percent identical to people.

Since the late 1940s, Oak Ridge researchers have used mice to establish the biological effects of radiation exposure and establish dose limits for humans.

They made the fundamental discovery here that gender in mammals is determined by the Y-chromosome, and helped identify genes associated with birth defects, cancer and other diseases.

But researchers say the approach used in those studies at Oak Ridge and elsewhere - examining one gene at a time - fails to address the genetic and environmental complexity of human diseases and conditions such as obesity, diabetes, alcoholism and aging.

"It is like saying, ‘Do you want a blurry picture of Saturn? Or do you want to see the space between the rings?'" Chesler said. With the so-called "Collaborative Cross" mouse project, "we can get down to that level of detail."

The project is the result of a collaboration between some 300 geneticists from around the world. Their plan is to create 1,000 distinct lines of mice from eight original breeds. It will require more than 20 generations of carefully plotted, though randomly selected, crossbreeding and inbreeding.

But the result will be like taking "representatives of each racial group from each geographical region and putting them together" and then being able to "reproduce those same individuals over and over," Threadgill said.

The potential breakthrough is to be able to study multiple genetic factors simultaneously, aided in part by the Oak Ridge National Laboratory's supercomputers. It also could be the basis for decades of accumulated research by scientists from around the globe on the same mouse pool.

"This is a very exciting project," said Marvin Stodolsky of the Department of Energy's Office of Biological and Environmental Research.

"It will reflect the sort of diversity that we have in the human population, which for some technical reasons and largely political reasons (stem cells) we cannot yet harvest and use," he said. "Well, the mice are not in a position to complain."

The $14 million Russell Lab, which opened in 2004, was selected as the main site for this work. Oracle CEO Lawrence J. Ellison's medical foundation, which has a particular interest in age-related diseases, is providing funding support.

Companion projects are under way in Israel and Australia, funded by the Wellcome Trust in Jerusalem and the University of Western Australia in Perth. The Russell Lab offers cushy accommodations for up to 80,000 resident rodents. Filtered air, filtered water, climate-controled cages in rooms virtually sealed off from the outside world, and equipment for cryogenically freezing their embryonic offspring. Since the Collaborative Cross work began in 2005, a little over 400 mouse strains have been created in Oak Ridge. Scientists believe they will need about 1,500 crossbred lines to yield 1,000 viable ones. The reproduction work could take three to five more years to complete, though researchers could begin using the mouse pool in as little as 18 months. Threadgill already has grant applications in to the National Institutes of Health to use the Collaborative Cross mice to study health effects of stress, for instance. Geneticist Rob Williams at the University of Tennessee Health Sciences Center in Memphis, a founding member of the collaboration, views complex mouse work as the only way to achieve "individualized medicine." The concept is that everyone will one day have a credit card containing their genetic history that their doctor can use to fine tune their treatment. "We will need a tremendous amount of information in order to predict ... outcomes and risk factors," Williams said. "If we can do predictive medicine (on mice), then the prospects are really great for very effective predictive and preventative medicine for human populations. "But we still have a long way to go," Williams said.

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