Of (Transgenic) Mice and Men

By Natalie Angier

Some appear perfectly pedestrian, with the warm white fur and beady pink eyes of pet-store mice. Others are clearly extraordinary, waddling about on paws shaped like miniature dolphin flippers or swollen to the size of their larger relative, the rat. They are called transgenic mice, and in a nobly selfless fashion, they are revolutionizing modern biology. Hidden somewhere along the twisting chain of DNA found in every cell of their bodies are alien genes, injected by biologists. The study of these mutants and the effects of the interloping genes may help provide answers to such fundamental questions as what switches DNA on and off, and how a single cell blossoms into a complex organism like a mouse or a human being. Someday the new technology could yield treatments for diseases such as cancer, thalassemia and sickle-cell anemia. In short, an increasing number of biologists and geneticists agree, the field of transgenic mice is hot. Says Rudolf Jaenisch, a molecular biologist with the Whitehead Institute for Biomedical Research in Cambridge, Mass.: "Everybody wants to jump on the bandwagon because it's such an interesting wagon to ride."

Ever since the 1970s, when scientists first learned to snip individual fragments from the hundreds of thousands of genes in the nuclei of mammalian cells, the behavior of the isolated segments interacting with cells in a laboratory dish has been studied extensively, an approach with obvious limitations. "A new gene in cell culture can't walk funny or think strange thoughts or do what it had planned to do," says David Baltimore, director of the Whitehead Institute and a Nobel-prizewinning biologist. "You need to trace its course through a living, breathing organism."

Yet getting foreign genes into a living, breathing mouse and then activating them turned out to be extremely tricky. A dramatic success occurred in 1982, when Ralph Brinster of the University of Pennsylvania School of Veterinary Medicine, Richard Palmiter of the University of Washington in Seattle and their colleagues concocted a sort of two-part genetic mongrel. They fused a gene that produces rat growth hormone to a powerful regulatory switch cleaved from a mouse gene. That construct in hand, the scientists mated normal male and female mice, and then removed the fertilized eggs from the female before the egg and sperm nuclei had combined. Viewing the cell beneath a microscope and wielding a glass micropipette less than the width of a human hair, the researchers injected their fusion construct into the larger male nucleus and then implanted the manipulated eggs into foster mothers.

Their strategy worked beautifully. The growth-hormone gene was incorporated into the DNA of about a third of the mouse pups and, most important, was activated in a variety of tissues. These offspring, spurred on by the extra portion of growth hormone, ballooned to twice the size of normal mice. What is more, because the new gene was present in all their cells, including their sex cells, it was passed along to the next generation. Says Brinster: "We're now doing work on the seventh generation of Supermouse."

In a somewhat subtler series of experiments, Baltimore and his colleagues are studying how genes for disease-fighting antibodies are coordinated to respond to thousands of different invading microbes. They tailor-made a mouse gene for producing antibodies and inserted it into the DNA of a normal mouse. Although the antibody gene was bequeathed to every cell of the transgenic mouse, it was turned on (expressed) only where antibody genes normally operate: in the white blood cells. Now the scientists can determine just what gives the gene a preference for one tissue type over another, a crucial step in determining how cells diversify.

To understand better the genetic basis of cancer, Philip Leder, a molecular geneticist at the Harvard Medical School and his colleague Timothy Stewart, have bred a line of transgenic mice that may someday serve as a model for human breast malignancy. He designed a DNA hybrid consisting of a gene called c-myc, which has been implicated in animal and human cancer, linked to a regulatory segment of another gene that is expressed in developing and lactating breast tissue. Soon after female mice with the injected gene give birth and begin nursing, they grow sizable tumors in their breasts. Perhaps more remarkable still, when these transgenic mice are interbred, their offspring occasionally have a startling sort of limb deformity, fused leg bones, for example, and three digits instead of five. The reason is that some of the descendant's own genes have been disrupted by the inherited but foreign c-myc DNA. "This approach will certainly help us understand limb development and what can go wrong with it," says Leder. "Why, for example, did Anne Boleyn have six fingers?"

Although transgenic technology is still in its infancy, some scientists hope that they can use it soon to reap medical benefits. If cancer genes can be so readily turned on, for example, the new technique may reveal ways to turn them off. And what is learned about gene expression could be applied to human gene therapy, in which people born with defective genes will have a "good" gene introduced into their bone marrow to produce the missing proteins. If all goes well, such therapy will begin on victims of blood disorders and enzyme deficiencies within five years. --By Natalie Angier. Reported by David Bjerklie/New York

With reporting by Reported by David Bjerklie/New York