For the past dozen years or so, any-one even vaguely interested in sci-ence has followed the Baltimore case with all the fascination of witnessing a slow-motion pileup of cars on a foggy freeway. Headlines have alternated between declaring that the Nobel laureate David Baltimore and his co-worker Thereza Imanishi-Kari were either guilty of scientific fraud or cleared of all charges. Federal oversight committees also alternated between finding Baltimore and Imanishi-Kari innocent and guilty. Congressional hearings claimed to expose a rot that was affecting science at its very roots. Baltimore’s colleagues joined in defending or attacking him. Such controversies in science puzzle the general public. Why are these scientists behaving so badly? Scientists are supposed to be dispassionate seekers after truth. Why all these charges and countercharges?
Quarrels in science are chiefly of two sorts—those that concern credit and those that concern accuracy. In the early days of science, all that scientists could hope to receive for their years of work was the acknowledgment of their contributions by their peers, the people who know most about the value of their work. In science the first person to make a discovery public gets the credit—all the credit. There are no silver medals in science. This system was devised to force scientists to publish their findings so that others could use them. A scientist might postpone publishing a crucial result so that he could mine it for additional discoveries, but only at the peril of being scooped. This system has worked well; but in the rush to publish, too much gets published too quickly.
In most cases of disputes over priority, only the people working in the relevant scientific community decide who gets credit for which discoveries. However, once in a while claims of priority become of more general interest because the discovery is so momentous or because large amounts of money are involved. The dispute between Robert Gallo and Luc Montagnier over who first discovered the AIDS virus combined both factors. When hundreds of thousands of people are dying, how could these two scientists take up so much time and so many resources bickering over who discovered the virus first? Of course Gallo and Montagnier want credit for their contributions. But in the face of the newest and probably most lethal plague human beings have ever known, mightn’t these two scientists have bent their individual ambitions and lust for money a bit for the greater good?
To many people quarrels among scientists over credit appear a bit unseemly. Quarrels over empirical matters such as the accuracy of data strike us as more important. That is what science is all about—finding out what causes AIDS, deciding the role that genes play in alcoholism, working out the implications of “strings” in physics, etc. When scientists and students of science claim that science is self-policing, this is what they mean. Scientists use each other’s work. If it helps them with their own research, well and good, but if it contains faults, scientists try to find out why. If they trace the error back to you, you are in real trouble. The worst thing that one scientist can say about another is that you can’t trust his results. The reason that scientists police each other as well as they do is that it is in their own best self-interest to do so.
Numerous disputes over alleged faults in science have become very nasty down through the years, but I think that what has come to be known as the Baltimore affair has blown up into the biggest controversy over fraud and accuracy that we have ever known. The controversy grew out of a paper published in 1986 in Cell by David Weaver, Moema H. Reis, Christopher Albanese, Frank Constantini, David Baltimore, and Thereza Imanishi-Kari.1 In 1986 the immune system was the hottest topic in biology, not just because of AIDS but because of its inherent interest. Nobel prizes seemed to be lying in wait for anyone making a major contribution to unraveling the complexities of the immune system.
The experiment that produced all this controversy was conducted by Imanishi-Kari and her co- workers, in particular Moema Reis, in one of the labs supervised by David Baltimore at the Whitehead Institute of the Massachusetts Institute of Technology. The immune system produces vast numbers of antibodies and, in certain strains of mice, antibodies display a distinctive chemical feature called an idiotype that is akin to a birthmark and can be used to tell one antibody from another and to study the inheritance of genes that produce the antibody. All but a small number of antibodies are reabsorbed in the body without ever having encountered an antigen, but very rarely the binding site of an antibody matches some part of an antigen. Immediately this particular antibody is reproduced in huge numbers and attacks the antigen. In most cases, the attack is successful, the organism survives, and the immune system returns to its former quiescent state.
The experiments performed by Imanishi-Kari and Reis started with two strains of mice, one black, one white, that were so highly inbred that they had lost most of their genetic heterogeneity, although quite obviously not all of it because the genes for coat color differed from one strain of mice to the other. Moreover, the genes in their immune systems that coded for particular antibody types were different. A gene that codes for a particular antibody missing in the black mice was extracted from white mice and transplanted into the fertilized eggs of black mice; it was thereafter termed the transgene, and the mouse that now carried the gene in every cell of its body was called a transgenic mouse.
To the surprise of Imanishi-Kari and her co-workers, the antibody normally produced by the transgene appeared in the newly born black mice. How come? Although several explanations presented themselves, the one that was emphasized in the ensuing paper was “idiotypic mimicry.” The transgene itself, Imanishi-Kari said, did not turn on and produce these foreign antibodies but somehow caused the immune system of the black mice to produce antibodies that mimicked those of the white mouse. Although this paper was only one small step toward understanding the immune system, its implications for treating damaged immune systems looked promising. The results of this research were published in the April 25, 1986, issue of Cell.
Daniel Kevles’s The Baltimore Case is an immensely detailed chronicle of the people and politics surrounding the genesis of this paper and its eventual fate. No one in the future is likely to match Kevles’s scholarship, let alone surpass it. Kevles begins his book with objective, disinterested descriptions of who did what to whom, but as the injustices to Baltimore and Imanishi-Kari begin to pile up and the behavior of some of their opponents becomes tawdry, he cannot even pretend to be a detached observer hovering above the battlefield. Increasingly he describes contradictions in testimony, lapses in memory, the hypocrisy of some of Baltimore’s critics, and the duplicity of the politicians and bureaucrats who became involved in the case. His heroes are not the whistle-blowers who criticized the research for the Cell paper but the two scientists who stood their ground against unrelenting and increasingly powerful persecution.
Kevles begins by introducing his three main characters, along with several others who played less important parts. David Baltimore taught himself molecular biology while an undergraduate at Swarthmore College and earned a doctorate at Rockefeller University in 1964, when he was twenty-six. His first job at the Salk Institute was cut short after he became politically active in opposing the Vietnam War. In 1967, Kevles writes, “when several pieces of art were removed from an exhibit…because they were said to use the American flag improperly, he quit, protesting censorship”; and he then went to work at the Massachusetts Institute of Technology. In 1970 both he and Howard Temin published papers in the same issue of Nature reporting the discovery of reverse transcriptase, a crucial enzyme in the process by which a certain kind of virus—a retrovirus—invades a cell and commandeers its molecular mechanism to make hundreds of copies of itself.
The “simultaneous” discovery of this enzyme independently by two different researchers might have led to a nasty dispute over priority. Even though Temin had anticipated Baltimore by a matter of days, neither man attempted to take sole credit for himself. Instead they published their findings simultaneously, and both received the Nobel Prize for their joint discovery in 1975. One wonders whether had Gallo and Montagnier behaved in a similar way they too might have won the Nobel Prize long ago, instead of battling over who stole what from whom. Once they realized that this behavior was ruining any chances that either man had for being awarded the prize, they published a joint paper, but by then the damage had been done in the eyes of the Nobel Committee, and no prize was forthcoming.
Imanishi-Kari’s journey to MIT was as circuitous as Baltimore’s was direct. Her parents were Japanese immigrant tenant farmers who worked a plot of land near São Paulo, Brazil, and ran a small fleet of rickety trucks. They opposed further schooling, beyond college. Eventually, however, Imanishi-Kari was allowed to go to Kyoto University to do graduate work in biology. While completing her graduate training in Finland, she married a Finnish architect, Markku Tapani Kari. Next she moved to Cologne, Germany, for her postdoctoral work. In 1981 she was hired by MIT as an assistant professor. By then she had a daughter and her marriage was beginning to unravel. When Imanishi-Kari first took the job at MIT’s Whitehead Institute, she was warned that it was a “sea full of sharks” and that getting tenure would prove to be quite difficult. In fact, in 1985 she was informed that she would not be awarded tenure at MIT, but by then she already had the promise from Tufts University of a job that could lead to tenure.
The person who was central in transmuting Kevles’s story into a tragedy is Margot O’Toole. In 1973 O’Toole graduated from Brandeis University with honors in biology. Instead of proceeding directly to graduate school, she worked as an assistant to a young immunologist at Harvard University for a year. She then began her graduate training in 1974 at Tufts University Medical School, working with the respected immunologist Henry Wortis. In 1978 O’Toole married Peter Brodeur, one of Wortis’s graduate students, and in 1979, after receiving her Ph.D., O’Toole and her husband began postdoctoral studies at the Fox Chase Cancer Research Center in Philadelphia. Her work in Donald Mosier’s labs did not go well, and she moved on to work with Melvin and Gayle Bosma. In a story that is all too familiar, O’Toole had a baby and followed her husband back to Tufts when he was offered a tenure-track job. Wortis got her some temporary space at Tufts until her postdoctoral fellowship ran out. It was at this point that O’Toole was introduced to Imanishi-Kari, who offered her a one-year “postdoc” at MIT. As O’Toole remembers their conversation, Imanishi-Kari also promised to help her get a tenure-track position at Tufts when her postdoc job came to an end.
David Weaver, Moema H. Reis, Christopher Albanese, Frank Constantini, David Baltimore, and Thereza Imanishi-Kari, "Altered Repertoire of Endogenous Immunoglobulin Gene Expression in Transgenic Mice Containing a Rearranged Mu Heavy Chain Gene," Cell 45 (April 25, 1986), pp. 247-259.↩
David Weaver, Moema H. Reis, Christopher Albanese, Frank Constantini, David Baltimore, and Thereza Imanishi-Kari, “Altered Repertoire of Endogenous Immunoglobulin Gene Expression in Transgenic Mice Containing a Rearranged Mu Heavy Chain Gene,” Cell 45 (April 25, 1986), pp. 247-259.↩