Of Mice as Stand-Ins for Men

By John Langone

For years, laboratory mice have served well as substitutes for humans in studying diseases or testing new drugs or vaccines. But in many areas, mice have not always proved up to the job of acting as surrogate humans -- in studies of the dauntingly complex and specific human immune system, for example, and in research into how the deadly AIDS virus works to cripple the body's defenses. Last week, however, mice and men suddenly seemed more alike than different, at least in some critical aspects of biology.

In a pair of remarkable studies, one reported in the journal Nature and the other to be published in Science this week, researchers at the Medical Biology Institute in La Jolla, Calif., and at Stanford University, working separately and using different methods, successfully transplanted elements of the human immune system into mice. The achievement meant that such animals may soon serve as stand-ins for human beings in the study of AIDS and a host of other diseases, including leukemia and hepatitis. The mice could also be used to test drugs that would be unsafe to test in humans and to study the mysteries of the immune system with a precision never before possible. Declared Dr. David Katz, who is head of the La Jolla institute: "This potentially rivals gene-splicing technologies in its impact. It has redefined what bioengineering can be about."

The Stanford scientists announced their findings, which involved transplanting human fetal tissue into the mice, just as a special advisory committee of the National Institutes of Health was meeting in Bethesda, Md., to consider the scientific and ethical issues surrounding the use of human fetal tissue in experimental research. The reason: to develop recommendations that may influence the Reagan Administration's proposed ban on such federally funded research.

The work with fetal tissue was by far the more elaborate of the two research efforts. Led by Stanford's Dr. Mike McCune and Irving Weissman, the scientific team actually reconstituted a human immune system in mice that lacked their own immune systems. Because of a genetic abnormality known as SCID (for severe combined immunodeficiency), these mice usually die at an early age, often of pneumocystis pneumonia, the disease that kills many AIDS patients. The researchers implanted some 300 of the defective mice with tissue taken from human fetal thymus, where certain immune and blood cells develop, and with blood-forming cells from fetal liver. The implanted tissues soon produced mature human T cells, specialized white blood cells that help provide immunity against disease. Mice that additionally received fetal lymph tissue -- needed for the functioning of some immune cells -- also developed mature human B cells. All fetal tissues were obtained from legally aborted fetuses with the consent of the mothers.

After more than a year, the Stanford mice are still thriving. Their new immune systems, however, must be sustained by injections of fetal liver cells every eight to twelve weeks. In addition, researchers are not sure whether all the parts of the human system are functioning in the mice. "We'll find that out," says Weissman, "but we'll have to do every known test for human immune cells. These mice open ways of studying human systems, normal or diseased, under experimental circumstances that were impossible before."

The La Jolla team also used SCID mice. By comparison, however, their approach was simple. Circulating white blood cells taken from human adults were injected into mice. Almost immediately, the mice began replicating the cells. Within three weeks they had human immune systems with nearly correct proportions of all the major types of white cells found in human blood. Moreover, when the researchers injected these mice with tetanus toxoid, most of the animals produced human antietanus antibodies, further proof that their new immune systems were functioning as though they were naturally human.

Because SCID mice lack immune systems, the scientists did not expect them to reject the transplanted human cells. Researchers also suspected that the human fetal cells, since they are too immature to distinguish themselves from foreign cells, would not reject the mice in a graft-vs.-host response. But, surprisingly, the adult human cells used in the La Jolla research did not reject the mice either. "That these human cells recirculate around in the mice without caring is astounding," said Dr. Donald Mosier, head of the La Jolla research team.

There was yet another unexpected consequence of the experiment. After being injected with human immune cells, many of the mice suddenly developed rapidly growing cancers, perhaps caused by a virus in the blood of some of the donors; mice injected with cells not exposed to this virus did not develop the tumors. The implications for cancer research could be enormous: the rapid growth -- in eight to 16 weeks -- would afford scientists a rare opportunity to track the emergence and spread of cancer. Said Mosier: "This is an extraordinary breakthrough. We may be able to dissect that tissue week by week to see what happens to these cells."

Mosier's research bore some relevance to the discussions under way at the NIH meeting. While the Stanford work with fetal tissue appeared to be a powerful argument for continuing such experimentation, the La Jolla studies seemed, however unintentionally, to offer an alternative. Still, Daniel Koshland Jr., editor of Science, who admitted to releasing the Stanford results a week early in order to coincide with the NIH meeting, strongly backed the scientists' right to continue their research. Said Koshland: "This is an excellent example of careful, scientifically controlled use of fetal tissue to attack major human disease." Moreover, the fetal-tissue transplants give the mice a more complete human immune system, which should provide a better model for studying the progression of AIDS and other diseases.

With reporting by Scott Brown/Los Angeles and Barbara Dolan/Chicago