Why a manipulated mouse is a central focus of Cornell's genomics plan

Photo: Robert Barker

Cornell researchers in a range of scientific disciplines view an on-campus facility for breeding mice as a crucial project for the university's Genomics Initiative.

Indeed, it is viewed as so vital that one-third of the $15 million proposed for implementing the initiative would be earmarked for renovating the present mouse facility. And the price tab on a future new home for the breeding of thousands of Cornell mice in pathogen-free conditions is put at $25 million.

The focus of this big-ticket spending is the so-called transgenic mouse, which the initiative report describes as the model system for virtually all new gene discoveries in mammals. "It is the only animal in which embryonic stem cells can be readily cultured and genetically manipulated," says the report.

The high cost of this research results from the expense of keeping mice in the required sterile conditions. However, researchers say, the benefits of having this facility are great. Currently, 25 percent of all research grants sponsored by the National Institutes of Health (NIH) employ the mouse model, and this percentage continues to grow rapidly. NIH has embraced the mouse as the preferred model for both basic and biomedical research.

The mouse is a major tool for research because it lends itself to genetic manipulation at the earliest stages of development -- when the mouse embryo is just a cluster of undifferentiated stem cells. This can involve the transfer of genes from other organisms to make transgenic mice. Or it can mean the removal of particular mouse genes to produce "knockout mice" after the genetically altered embryos are returned to the mother mouse.

The mice can be used to identify the function of genes in a living animal model, as well as to identify and clone new genes. But the major function of this "living test tube" is to act as an easily manipulated "stand in" for the human body in researching diseases, from cancer to neurological defects. For example Patrick Stover, an assistant professor of nutritional biochemistry, is using transgenic mice to examine the dual roles of prenatal nutrition and genetics in neural tube defects, such as spina bifida.

At present, Stover's Division of Nutritional Sciences laboratory is the only one generating transgenic mice at Cornell. However, concerned researchers say, a campuswide facility is needed for the specialized work of generating and breeding the mice. "Various supply and biotechnology companies exist that offer limited genetic services for mice," says Stover. "However, these services tend to be very expensive, and they do not include custom transgenic services with tailored genetic manipulations that an investigator requires."

Anthony Bretscher, a professor in the Section of Biochemistry, Molecular and Cell Biology, looks ahead to complete sequencing of the human genome, when the next challenge will be to determine what all the gene products do.

"That is functional genomics," Bretscher says. "Altering the closely related genes in the mouse will allow researchers to evaluate the role of each gene product. For example, we have identified a protein, called 'ezrin' in honor of Ezra Cornell, and now we need to know the role it plays in the structural organization of cells in a whole animal. If a modern mouse transgenic facility were available, we could immediately start with mice with altered forms of ezrin and add a whole new dimension to our research," he says.