The genes of mice are remarkably similar to those of humans, despite an evolutionary distance of 75 million years between the two species. Unlike humans, however, mice are small, handy, and remarkably fecund: two months after her own birth, a female mouse can produce ten new babies. Mice live only two to three years, allowing researchers to follow disease processes from beginning to end in a relatively short time.

So it's easy to understand why mouse genes have become prize tools for finding and studying human genes, including disease genes. Scientists can also use mouse models to test drugs, devise novel therapies, and study the physiology and biochemistry of genetic diseases in ways not possible in humans.

The Jackson Laboratory in Bar Harbor, Maine, maintains 2,000 strains of mice with a wide variety of genetic mutations and apt names. The "stargazer" mutant, for example, has a neurological disorder that forces it to throw back its head and look at the sky. "Twitcher," "shiverer," and "quaking" mice have damaged nerve fibers and abnormal gaits. "Dwarf" and "little" are lacking growth hormones. Most of these mutations arose spontaneously, and at least 20 new mutants are identified each year. Using various breeding tricks, the scientists are able to perpetuate the mutant strains in stable colonies.

Despite such progress, researchers still lack animal models for most human genetic diseases. But this is changing rapidly as scientists learn that they no longer have to wait for Mother Nature to make their mutants—they can create them to order. By inserting foreign genes into animal embryos, they can produce "transgenic" animals whose cells follow the instructions of the interloper genes as well as those of their ancestral genes. The result is an explosion of new information on how genes work in specific cells and how they go about promoting health and disease in both mice and humans.

In 1982, Richard Palmiter, an HHMI investigator at the University of Washington in Seattle, Ralph Brinster of the University of Pennsylvania, and their colleagues injected a modified rat growth-hormone gene into a fertilized mouse egg. The researchers attached the gene to promoters, regions of DNA that control which tissue expresses a gene, and redirected the gene's expression to cells where it would be freed of normal controls and would produce large quantities of growth hormone. Then the scientists implanted the egg into a mouse foster mother. She gave birth to normal-sized pups that grew at an unusually rapid pace to become giant mice, nearly twice the size of their litter mates. The picture of one of these super mice was splashed across newspapers and magazines throughout the world.

This experiment paved the way for the first attempt to cure a genetic disorder, dwarfism, in transgenic animals by gene therapy. The mice "patients" were undersized because they lacked sufficient growth hormone. By inserting a modified growth-hormone gene into them, the researchers and Robert Hammer, who was then at the University of Pennsylvania and is now a senior associate in the HHMI unit at the University of Texas, Southwestern Medical Center, corrected the genetic defect. The correction was so good that the mice grew slightly larger than normal.

Since that seminal experiment, geneticists have been striving to find permanent cures for a variety of genetic diseases. But first they have to understand the basic biology of the diseases. To produce models of human diseases, scientists inject hundreds of copies of an abnormal gene into fertilized mouse eggs. The pups born of these eggs are examined to see which by chance has incorporated the human gene into one or more chromosomes. Those with the gene are then mated in the hope that the the trait will be passed on to the next generation.

In this manner, cancers of the eye, breast, lymph tissues, pancreas, and other organs have been induced in mice by cancer genes and combinations of cancer genes. This work is fueling one of the most important revolutions in twentieth-century medicine—the ultimate understanding of cancer as a genetic disease.

Until recently, researchers faced a major problem: They could not specify where in the animal's DNA the foreign gene would become integrated. If a gene is taken up at the wrong spot, it may disrupt a native gene or even cause a lethal mutation; if taken up in the right spot, it may cure a disease. Researchers also learned that they wouldn't get uniform results. One animal might integrate hundreds of copies of the gene, while another animal, under the same experimental conditions, might integrate only a single copy. Another problem was that researchers could only add genes to the animal's own genome. They could not create models of mice that lacked a particular gene.

A new technique overcame these limitations and opened up a whole world of possibilities for making almost any wished-for animal model. It is called homologous recombination, or more loosely, gene targeting, and it is awesomely precise. In homologous recombination, a desired gene finds an identical, or homologous, sequence of DNA in the animal's genome and swaps places with it.

Homologous recombination allows scientists to carry out a new type of research with transgenic mice: knockout experiments, in which a native gene is eliminated by replacing it with a defective gene.

This technique should prove very useful in studying human diseases, points out Mario Capecchi, an HHMI investigator at the University of Utah and a pioneer of gene targeting. "For example, you can put a gene under the control of a switch so that if you inject a certain drug, the gene is turned on—or turned off." Almost any disease process can now be studied in animals in this way.

— Sandra Blakeslee

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A giant mouse (left) grown from an egg injected with rat growth-hormone genes weighs nearly twice as much as its normal sibling. This experiment was a major step toward creating animal models of human disease.

Photo: Ralph Brinster, University of Pennsylvania School of Veterinary Medicine, Nature Vol. 300, pages 611-615, 16 December 1982, ©1986 by Macmillan Magazines Limited.

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