How Two Immunology Teams Made Headlines

“Human Immune Defenses Are Transplanted in Mice” beckoned the headline on a front page of the New York Times last month. It announced a story arousing high expectations for a powerful new medical research tool Independently, two teams of researchers had shown that rodents having no immune systems of their own could be made to serve as true models of the human immune system, and this promised to open many doors in the study of human disease—offering insights into some cancers, for example, and AIDS. But of the scientists themselves and of the secrets to their success, the Times said little. Who were they, and exactly how did they achieve what no scientists before them had ever done? Beginning on page 24, The Scientist takes a close look at them. The excitement engendered by their achievements spurred a number of major newspapers in addition to the Times to run prominent stories on the same day—September 15, to be precise. This spate of publicity, The Scientist learned, produced some unwanted side-effects: It befuddled some of the scientists involved and caused a flap in the science publishing community as one journal broke its embargo allowing one team to publicly discuss its work before it was published. Lost in all the hoopla were special talents of the scientists themselves. We ask the question: What special ingredients in their management and research styles made these teams click? And, as is so often the case, we find that the scientists in each group cite very different strategies as the keys to their success. One team, for example, attributes its success to the serendipitous na- ture of interactive science. Researchers at the Medical Biology Institute in La Jolla, Calif., which reported on its work injecting mice with purified lymphocytes from normal human adults, say that a friendly argument led them to try something they never expected would work so well. Members of the other team—from Stanford University—credit, among other things, their leader’s enthusiasm for long-shot experiments. His brand of supportiveness, they say, provided great inspiration as the team went about transferring the entire human defense system into mice, by transplanting blood-forming and immune system cells from human fetal tissues. The special stories of both groups, along with a separate article on Science’s breaking of its embargo, are presented below. What Prompted Science To Lift Embargo? The journal Science has traditionally been a big enforcer of news embargoes. Thus it was something special when the New York Times and other major newspapers ran the story of a Stanford University immunology research team’s innovative work with mice more than a week prior to the journal’s exclusive Sept. 23 publication of the team’s report. For a variety of reasons, not the least of which is a desire to scoop the competition, journals such as Science and Nature frequently enforce embargoes on upcoming research papers. That is, they issue advance information on a paper scheduled to appear in a forthcoming issue so that reporters from other publications can do background research and interview scientists in preparation for writing articles on the research; but they do so only on the condition that the journalists will not file their stories until the journal’s publication date at the earliest. Science editor Dan Koshland defends the embargo rule’s role in enforcing accurate and fair reporting but says that his magazine has over the years made a few exceptions. He notes, for example, that his magazine might decide not to hold back advance notice of research that may be vital to government decision makers or to national public health. Such a decision, Koshland says, led to prepublication release in 1981 of research to be published in Science concerning the discovery of the AIDS virus. Potential Model It first became apparent that the Stanford team’s work might fall into that category on Thursday, Sept. 8, when Irv Weissman, head of the team, was startled to read in the New York Times that the White House was considering an executive order banning research using fetal tissue. HHS secretary Otis Bowen was given until Sept. 9 to reply to the White House memo, the Times reported. Weissman, Koshland, and Don Kennedy, president of Stanford University, all agreed that it was important for Washington decision makers to know that Weissman’s research, which depended on fetal tissues, provided a potential animal model for AIDS research. Later in the week, Weissman learned that, while the White House had decided to wait on an executive order, a panel of scientific consultants was scheduled to meet at the NIH from Sept. 14 to 16 to discuss the issue of fetal research. Again, Weissman and Koshland discussed whether they should make the work known to members of the panel. They realized that their action could result in leaks to the press, but they were prepared, if it leaked, to lift the embargo. Then, a few days later Weissman got a call from a “prominent science reporter” who said he had a press release from the Medical Biology Institute in La Jolla, Calif., as well as a copy of a report that was scheduled to appear in the Sept. 15 issue of Nature, a major Science competitor. The report mentioned the Stanford team’s work, the reporter said. Weissman had received a preprint of the paper a couple of weeks earlier from Donald Mosier of the MBI team, but says it did not include a publication date and he’d had no idea when the report would be released. Weissman explained to the reporter that because of the embargo rule, he could not discuss his research yet. But the reporter pressed him, saying that the paper would write about his work whether he talked about it or not— it was his choice. Then other science reporters also began to call. “As the barrage [of phone calls from reporters started coming in, we realized it was impossible to hold it back,” says Weissman. It was this combination of pressures—the meeting of the panel on fetal tissue research, and the fact that news of the Science article had leaked to journalists, that finally convinced Dan Koshland to go ahead and lift the embargo. “I felt it was bad for the magazine, and bad for science in general, to say we won’t release this information that was very important for AIDS, and for other research, on the basis of just having an embargo,” Koshland says. On Sept. 14, Stanford University put out an eight-page news release onthewire service. That day and the next day, both the La Jolla and Stanford teams held press conferences at their respective institutions. Still, when news of the Stanford team’s work appeared in the newspapers the same day as reports on the La Jolla team’s work, it caught the La Jolla group by surprise, because Mosier knew the Stanford team’s report wasn’t due to be published in the journal Science until later. Mosier’s colleague Darcy Wilson was in Rome attending a meeting when the two studies were released. At breakfast he opened the International Herald Tribune and saw a headline referring to the La Jolla team, which delighted him. As he began reading the story, though, “they start talking about the Stanford group and I got really pissed off,” Wilson laughingly recalls. The two teams actually have a fairly gentlemanly relationship. They had been in touch with each other, but not in collaboration since March of this year, and the La Jolla team had even visited the Stanford labs. Mosier said that had he been asked, he would have agreed with Science’s decision to lift its story embargo to influence the federal committee’s discussion of fetal research, an area which Mosier feels is important and should continue. However, the simultaneous release of the Nature and Science articles did result in Mosier’s getting caught up in the fray. After one newspaper confused both projects, Mosier found himself the target of some misdirected fury. An aide to Sen. Jesse Helms (R-N.C.), a staunch opponent of abortion, called Mosier to interrogate hin about his team’s involvement in fetal research, though Mosier’s work made no use of fetal tissue. And Time magazine concluded that Mosier’s research suggested that fetal research such as Weissman’s was unnecessary Mosier says that is wrong, that the Stanford team’s experiment explored different questions than that of the La Jolla team, and couldn’t have been done without fetal tissue. “I think (scientists) should be using fetal tissue for research,” Mosier says. “I think it’s somewhat unfortunate that our results are being used by the wrong side to counter Irv’s position.” Stanford Scientists: They Were Willing To Take Bets MARCIA BARINAGA 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.

How Two Immunology Teams Made Headlines

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