Mighty Mice

Gene transfers create giants

It was the sort of biological alchemy that abounds in science fiction. Take a trait from one species, genetically transfer it to another species, and voila!: a hybrid emerges that nature could never have produced. In last week's issue of the British journal Nature, scientists at four American institutions announced that they had actually accomplished this remarkable, first-of-its-kind feat. A gene carrying the DNA code for growth hormone was taken from rats and incorporated into mouse embryos. The result: mice that grew to be nearly twice the normal size. The super-mice not only produced large quantities of rat growth hormone in their bodies, but in some cases even passed on this trait to a second generation of giant offspring.

The experiment was the culmination of years of genetic tinkering by three biochemists: Richard Palmiter, of the University of Washington in Seattle, and Ronald Evans and Neal Birnberg, of the Salk Institute in La Jolla, Calif. The gene they prepared for insertion into mice was a carefully crafted composite. It consisted of a rat growth-hormone gene plus part of a mouse gene. The mouse portion served as a switch to activate the rat gene.

Copies of the composite gene were shipped to the University of Pennsylvania's School of Veterinary Medicine in Philadelphia, where they were inserted into 170 mouse embryos. The embryos were implanted into foster-mother mice, which produced litters last May. The yield was typical for such experiments: 21 apparently normal baby rodents.

The size achieved by each mouse was dependent on how many copies of the rat gene it happened, by chance, to have received. One mouse with 20 copies had 800 times the normal level of growth hormone in its blood. It grew to be almost twice the size of litter mates that had no copies of the rat gene.

The implications of the experiment for medicine, agriculture and biological research are enormous. The most obvious application would be the creation of giant pigs, sheep and cattle, capable of yielding vast quantities of meat and milk. "If we can make bigger mice," says Microbiologist Ralph Brinster, of the University of Pennsylvania, "we can make bigger cows."

The extraordinary levels of hormones produced by the giant mice also suggest the possibility of "genetic farming," that is, using animals to produce large quantities of medically useful substances. Genetic engineers have already reprogrammed simple organisms like bacteria and yeast to produce insulin and growth hormone, but these have not proved to be fertile ground for producing blood-clotting agents needed by hemophiliacs. Harvesting such substances from large animals could be more fruitful.

Although the researchers are skeptical about any immediate medical applications, there is little doubt that the new technique for gene transfer will shed some light on certain inherited disorders. "In a sense," says Palmiter, "the big mice are models of pituitary giantism in humans." It may also help scientists unravel the mysteries of how a fertilized egg becomes a living organism and how gene regulation goes awry in cancer. Concludes Brinster: "This study provides another system in which we can examine the regulation and control of genes, and that is one of the most important issues in biology."

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