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New, Improved Mini Me
by Mary Beth Gardiner
Mouse models of human cancer help Tyler Jacks explore biochemical pathways regulated by cancer-associated genes.
Kevin P. Campbell used to study muscular dystrophy by analyzing small pieces of thigh muscle from a child with the disease. Today, there's a better option. Campbell can now mimic the biochemistry of muscular dystrophy and test its effects in mice—rather than children struggling with disease—and evaluate tissues that could never be tested before.
"With a patient," says Campbell, an HHMI investigator at the University of Iowa Roy J. and Lucille A. Carver College of Medicine, "you never biopsy the diaphragm, but it's a very important muscle because most patients die from respiratory problems. With the mouse, one can test the diaphragm to study the pathogenesis or the response to particular therapies."
An astonishing 99 percent of mouse genes have comparable versions in the human genome, and many of them appear in the same order in the two organisms' chromosomes. "We also have similar reproductive systems, similar physiology, very similar nervous systems, and so forth," says HHMI investigator Mario R. Capecchi, professor of human genetics at the University of Utah School of Medicine. "For all these reasons, the mouse model is a good representation of human biology."
In the last century, the mouse became the premier mammalian model system for genetic research. Now, the creation of mouse models is "like a cottage industry," says Capecchi. "There are literally thousands of labs all over the world making mutations in mice."
Capecchi pioneered "gene targeting," a technology that has revolutionized scientists' ability to use the mouse to model human disease. This advance of the late 1980s allowed researchers, in their attempts to re-create the possible genetic cause of a specific disease or study the function of a particular gene of interest, to "knock out" the function of that gene or modify its activity.
Since then, researchers have refined gene targeting to create strains of mice with mutations in virtually any gene. They can direct gene mutation so that it occurs in every cell of the body or only in certain tissues or cell populations. And they can control when that mutation occurs—right away, or later in the animal's life span. They can even inactivate combinations of genes, independently of each other, within the same animal.
Photo: Flynn Larsen