Stanford Scientists: They Were Willing To Take Bets

STANFORD-- CALIF—Irving Weissman is a risk taker. He doesn’t mind losing bets: A bottle of wine here, a beer there. It’s a small price to pay for the progress of science. The last bet the Stanford University immunologist lost was with postdoc Mike McCune over whether a complete human immune system could be transplanted into a mouse. “I said, ‘Great idea, fantastic, but I’ll bet it doesn’t work,’ “ Weissman recalls. “Well, I was wrong and he was right.” It’s been a good year for the Weissman lab. The September 23 publication in Science (page 1632) of their paper describing mice with a human immune system—the first true animal model for studying AIDS—came on the heels of another long-sought breakthrough: the isolation from mice of stem cells, the precursors that give rise to the entire immune system. If the isolation procedure can be repeated in humans, it could revolutionize bone marrow transplants. Unlike the mixture of stem cells and differentiated blood cells now used in transplants, pure stem cells, which do not yet have the specificity to recognize self versus nonself—would not attack the recipient and cause the deadly graft-versus-host disease. These two heady developments come one right after the other. But it is not single-minded determination that has brought these successes, say team members and colleagues; rather, it is Weissman’s receptivity to novel ideas, along with his 25-year investment in understanding the immune system. Weissman maintains a diverse lab by giving his people freedom to pursue their interests. It’s not a management style that wins races to clone and sequence the latest hot gene in immunology, but Weissman is less interested in a scientific footrace than in innovative ideas. He is not one to squelch hare-brained schemes. “I make bets all the time,” he laughs. “But that is to be sure the experiments get done, not to prevent them.” So the risks Weissman and his team take are worthwhile whether he wins his bets or not. Mike McCune is a perfect example, says Weissman, of the kind of independent thinker he seeks in a postdoc. After two years of treating AIDS patients while a resident at San Francisco General Hospital, McCune, an M.D./Ph.D. trained in immunology began looking for a lab where he could study how retroviruses like HIV infect the immune system. McCune learned that Weissman had been managing research on mouse leukemia viruses in the Stanford laboratory of the late Henry Kaplan, who died in 1984. He approached Weissman, and in January 1986 joined the group, intending to work on leukemia viruses but quickly delving into his real interest: N.W. Working on a hunch that HIV is like other envelope-coated viruses that he worked on as a graduate student, McCune found a surface protein of NW that must be cleaved before the virus can enter the cell. If he could identify the cleaving enzyme, and find a way of inhibiting it, he might have an AIDS treatment. But any inhibitor should be tested in animals, and N.W. only causes disease in humans. “It was an exciting line of work that would reach a dead end, unless we had an animal model,” says McCune. McCune began pestering Weissman about a pet idea: Why not put the whole human immune system into immune-deficient mice? He had heard about a strain of mice that completely lack an immune system. The mice, called SCID mice due to their severe combined immunodeficiency, die of Pneumocystis carinji pneumonia, the disease that kills many AIDS patients. With no immune system of their own, McCune reasoned, the mice would not reject a transplanted human one. Weissman was skeptical because he had tried a similar experiment in the 1960s with mice that had been irradiated to destroy their own immune systems. But, says McCune, “If Irv thinks that something’s not going to work, he doesn’t discourage you.” As the experiment took shape, McCune found the Weisasman group full of the expertise he needed. A key to the experiment was the fetal thymus, the organ in which T-cells mature. Reiko Namikawa, a visiting Japanese professor, taught McCune to dissect the tiny one-millimeter-long thymus from the remains of nine-week-old fetuses. Research asso- ciate Miriam Lieberman specializes in transplanting thymuses into mice, next to the kidneys, where they are nourished by a rich blood supply. As a source of stem cells to produce the new immune system, McCune injected the mice with homogenized fetal liver, the home of the blood-cell progenitors. The first SCID mice arrived in March 1987, and by summer the team had produced amazing results. As later experiments would show, each stage of immune system development was occurring correctly. But the first result said it all: Mice that got the human tissues lived. The others succumbed to PCP. Later versions of SCID-hu mice, as they are called were given fetal human lymph nodes as well—these are important for the maturation of antibody-producing cells. In these mice, a complete human immune system develops from scratch, says Weissman, making them an exciting tool for basic research. As a system for studying AIDS, they provide a complete range of developing blood cells, any of which might be the target for HIV And the general principle may work with other human organ systems for the study of diseases such as diabetes. Advances like those of the past several years come from filling the lab with the best minds, says Weissman, and having a thorough understanding of one’s system. “Biology is messy,” he says. “But as you get closer and closer to the truth, it gets cleaner and cleaner. It’s very satisfying, once in a while, to bring out of a complex system a simple, clean truth." Marcia Barinaga is a freelance writer based in Berkeley, Calif.

Stanford Scientists: They Were Willing To Take Bets

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