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The mouse house: From old to new

In the spring of 2003, ORNL's new Mouse House will open, replacing the old Mouse House that dates back to 1948. The new Mouse House (officially called the Laboratory for Comparative and Functional Genomics) will hold 60,000 mice. It will be located in ORNL's new Marilyn Lloyd Environmental and Life Sciences Complex.

The mice in the old Mouse House, including those allowed to grow old there, will not be moving to the new Mouse House. The mice in the new Mouse House will indeed be new. But the genetic heritage of many of the newly bred mice will be traceable back to the old Mouse House.

Using cryopreservation techniques, some of which were pioneered by former ORNL biologist Peter Mazur and his colleagues, staff in ORNL's Life Sciences Division (LSD) are freezing and preserving eight-cell mouse embryos, sperm, and egg-containing ovaries. "We already have 450 stocks of frozen mouse embryos," says LSD's Eugene Rinchik.

"Genetic characteristics and other information on each mouse stock have been entered into a computerized database. If needed for new experiments, any of these embryos can be thawed out and implanted into new female mice brought to the new Mouse House. The mice born to the surrogate mothers will have the same mutant genes as mice now in the old Mouse House."

The current ORNL Mouse House is a valuable research resource. Its colony of mice is of special interest because they represent a variety of mutations to genes, including those that cause obesity, diabetes, skin and stomach cancer, leukemia, cleft palate, polycystic kidney disease, chronic hereditary tyrosinemia, neurological dysfunctions, seizures, and a wide variety of birth defects. All of these diseases and disorders are similar to human afflictions.

For research on the effects of aging, some mutant mice are being allowed to grow old. "In our lab, we are putting four males and four females of some of our mouse families on the shelf and letting them age to 18 months, which is the equivalent of 75 years in humans," says Dabney Johnson, head of LSD's Mammalian Genetics and Genomics Section. "As these mice approach old age, we screen them for late-onset diseases.

"So far our tests of non-mutant older mice in mazes show that they have less agility with age but that activity levels and memory are the same as in younger mice. If we find abnormal older mice, we will determine which gene is associated with the later-onset abnormality."

"We are also working with our partners in the Tennessee Mouse Genome Consortium to examine older mice, which carry mutations induced at ORNL, for late-onset diseases and disorders," Rinchik says. "The diseases of interest include, but are not limited to, cancer, diabetes, obesity, memory problems similar to Alzheimer's disease, neurological problems similar to Parkinson's disease, and inner-ear or other neurological problems that cause loss of balance, lack of coordination, or even deafness.

"We are trying to find out if we can recognize mutations that cause effects in older animals but not necessarily in younger ones. Most new inherited disorders are currently identified in younger animals, and we are trying to extend that observation period to older mice carrying mutations. One goal is to determine if we can recognize good models for old-age diseases in our mutant mice."

There are various ways to produce mutations in mice. One way is to expose them to radiation and chemicals, including a powerful mutagenic chemical called ethylnitrosourea (ENU), first used by Bill and Liane Russell at ORNL. A newer way is to use DNA recombinant technology or ENU to alter genes in embryonic stem cells from mice.

In one of Rinchik's approaches to breeding mutant mice, numerous males are exposed to ENU and mated with females that have a known mutation that results in an easily identified abnormality (e.g., unusually hairy ears). Such "visible markers" allow geneticists to track the mutated chromosomes through subsequent generations. Various tests are then performed on the descendants of these mice, to determine if they have recessive or dominant mutations that result in changes in behavior, biochemistry, physiology, or anatomy, or that render them more susceptible to other diseases.

Using mice for medical research is an old idea, but the benefits of this kind of research to humans are likely to improve as resulting research at ORNL and elsewhere yields new discoveries. The new Mouse House will allow ORNL researchers to carry on the Laboratory's long tradition of mouse genetics.

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