Learning from the mice

Nicolas Rasmussen, University of New South Wales

Karen Rader Making Mice: Standardizing Animals for American Biomedical Research, 1900-1955, New Jersey, Princeton University Press, 2004 (pp. 312). ISBN 0-69101-636-4 (hardcover) RRP $127.95.

When you think of a scientist, is the first thing that springs to mind a contemplative, wise man, like Einstein, surrounded by arcane mathematical figures? Or do you conjure up someone in a white lab coat actively experimenting, perhaps pouring bubbling chemicals from one flask into another? If theory and practice represent opposite poles on our Western action-contemplation (hand/eye, body/mind) axis, trends in English-language philosophy of science have sharply reversed over the past 25 years or so, in favour of practice. Since the collapse of the nineteenth-century project of positivism, which aimed to build sound scientific knowledge out of pure empirical facts, right through the 1970s, theory dominated philosophical understandings of science for over half a century. Thomas Kuhn’s work can be seen as the apogee of theory-first visions of science: for him scientific change only came with a change in theoretical perspective, and experimental observations could not bring about that change. An old theoretical frame or ‘paradigm’ was only discarded when someone found a new and different way of seeing the world. The most any new observation could do is hasten change when it fitted poorly with the established paradigm by making the old picture unstable or uncomfortable. But it could not significantly alter the picture and when a new paradigm finally replaced the old, the change was not incremental but revolutionary.

There were many problems with this theory-dominated notion of science. For one thing, it turned scientists into philosophers building world systems by mere cogitation. This neglects exactly what has made science distinct from and, in society’s estimation, more valuable than philosophy for the four centuries since Descartes. Scientists don’t just speculate, they experiment and act upon the world in novel ways that go beyond theory, and which connect science with technological advances. Philosophical work by Ian Hacking and others has striven to right this wrong by restoring experimental practice to a place of prominence. The basic insight is that scientists, like the rest of us, learn about the world by interacting with it, not by constructing castles in their minds. The world is known by what tricks we can make it perform, and how it resists our manipulative efforts. Entities—real things—are known by a list of characteristics they exhibit when we interact with them; theory plays a secondary role as an account, always provisional, of how these performance characteristics relate to each other.

Another problem with old-school philosophy of science was the way philosophers assumed there is just one thing properly called ‘science’, not an implausible assumption if one’s contact with what actually happens in the sciences is remote. Naturally drawn to abstraction, philosophers concocted general formulas to explain and improve science as a whole. The trend in the philosophy of science now is to follow scientific research much more carefully, and to treat as an empirical question any generalisation about what various sciences, past and present, have in common. This less presumptuous approach proposes that philosophers ought to learn from, rather than dictate, what scientists actually do. One can no longer understand how science arrives at knowledge without understanding experimental materials and methods—reading the introduction and conclusions of the journal articles won’t do.

Thomas Kuhn’s work can be seen as the apogee of theory-first visions of science.

Since Kuhn went out of fashion, the trend to emphasise practice over theory has also swept the history of science. Historians have turned their attention to those factors other than the strictly intellectual that also play a role in shaping scientific fact. Broad socio-economic and cultural forces—the staples of explanation in mainstream history—are fairly popular, as are the disciplinary and institutional settings in which scientific knowledge is pursued (Kuhn had a place for these latter as the paradigm ‘matrix’). But increasingly, historians have focused on the material, and especially technological, conditions of scientific knowledge. For example, influential work by Peter Galison has shown how certain questions and theoretical frameworks are attached to distinct instrument-based traditions in particle physics, while in the historiography of the life sciences, Robert Kohler has demonstrated the same for genetics. In Kohler’s study of the foundational Morgan school of Drosophila genetics, he shows how the geneticists working on this particular organism developed a particular style of experimental work, of theory, and of scientific community, based (in part) on the particular biological characteristics of their fruit fly. Flies captured from the wild were quickly transformed through selective breeding to display the phenomena which interested geneticists, and as the flies evolved to suit the biologists so the culture of the biologists co-evolved with the fly. The inbred fruit fly was their instrument—their particle detector or microscope—and like any instrument, it was largely the creation of the scientists using it, even as its characteristics shaped their own work.

Thus the turn to material practice and especially to instruments is a major recent development in the history of science, and in the history of biology this has meant a spotlight on the ‘model’ organisms like the fruit fly from which almost all our experiment-based knowledge of life is actually derived. Some historical work along these lines has taken the form of a kind of ‘biography’ of the experimental organism, such as Rachel Ankeny’s study of the nematode worm C. elegans, and Angela Creager’s book on the Tobacco Mosaic Virus, once the workhorse of molecular genetics (back when solving the puzzle of the gene was considered a problem in high-resolution protein biochemistry). In these approaches the organism in question is treated as a protagonist endowed with agency at least on par with the human actors. Likewise Kohler, with his extended use of the co-evolution concept, shows how the scientific community and insect population shape one another equally. In the latest contribution to the model organism literature, Making Mice, Karen Rader takes a more standard historiographic approach, focusing on a scientist (Clarence Little) and his institution (Jackson Laboratories), which together did far more than anyone else to make mice into standard laboratory instruments. Thus the mouse as model organism, particularly in cancer research, is but one of three main actors on stage in this tale, sharing the limelight with Little and his lab.

The turn to material practice is a major development in the history of science.

Little was a member of the first generation of biologists trained completely in the new science of Genetics by one of its founders, Harvard zoologist and eugenicist William Castle. Little began his studies under Castle looking at the inheritance of coat colour, but in 1916 he switched focus to heritable cancer susceptibility while working with medical researcher EE Tyzzer, who was already looking at this eugenic problem in mice. Immediately after military service in the First World War, Little followed in Castle’s footsteps with a post at the Cold Spring Harbor Station for Experimental Evolution, America’s premier lab for eugenics and related biological disciplines. There he worked to establish breeding colonies of various mouse strains and of the new mutant strains that inevitably emerge during breeding work, and to help maintain and collect such mutants he organised the Mouse Club of America, a breeder’s network of the same type that the fruit fly geneticists already had established to great advantage. In an uncharacteristic display of communalism, American geneticists had found that the field as a whole benefited when all experimenters who discovered a new mutant form of their organism would share it with others (at least after they published an initial description). When progress in breeding experiments depended crucially on access to as many strains as possible, it did not pay to be known as one who did not share.

Though an accomplished experimenter, Little soon became best known as a spokesman and champion of inbred, genetically defined mice for medical experimentation generally, and especially in the cancer field. In 1922, Little moved to Orono, Maine to become president of the state’s growing University there, and in 1925 he became president of the University of Michigan, but these involvements in administration did not mean the end of his direct contributions to mouse genetics. Not only did he maintain his own mouse breeding research on the side during his presidential tenures, these influential positions allowed him to advance his vision of medical mouse genetics on an institutional level. At Bar Harbor, Maine there was a summer colony enjoyed by wealthy families, including some from Detroit, as well as a biological research station associated with the state University. During summer research at Bar Harbor, Little came to know this group, among them Roscoe Jackson, president of the Hudson Motor Car Company. It was through Jackson and the other Detroit summer visitors that Little became president at Michigan, and it was ultimately Jackson who supplied most of the funding for the mouse genetics laboratory bearing his name, founded in 1929. Little was clearly a talented, entrepreneurial administrator—devoted, according to Rader, to advancing the values of cooperation, efficiency, and social conscience—and his Jackson Laboratories would provide him and the mouse geneticists with a platform to pursue cancer research against a drastically changing context for American biomedical research over the next 27 years.

The irony in the story which Rader tells is that the more Little succeeded in making his inbred mice a standard experimental tool, the less he and his Laboratory were able to use their breeding work to explore the basic genetics of the organism. In the Depression years Little was able to keep his genetics lab afloat with help from the Rockefeller Foundation, which made the modernisation of medical research its top philanthropic priority. Little’s appeal was twofold: only careful experimentation using genetically well-defined strains could reveal the role of heredity in cancer, and the mouse strains produced at his Jackson Laboratories were the only ones sufficiently well-defined to do any proper medical research upon. Thus it was essential to fund his Lab to conduct research, and the strains of animals the Lab produced could be supplied to other experimenters. From the start, the Rockefeller Foundation found Little’s second argument—that his stable, inbred mouse strains were like the pure chemical reagents that any scientist needed to have on the shelf if they were to produce trustworthy results—more compelling. The Jackson Lab was indeed funded to produce mice for other labs, and whatever research on cancer genetics that it might manage along the way was a bonus.

Karen Rader focuses on Clarence Little and his Jackson Laboratories, which together made mice into standard laboratory instruments.

This problem of balance between animal supply and genetics research became even worse for Jackson Labs after the Second World War, when the United States government began pouring prodigious support into medical research generally (as a symbolic substitute for the universal medical insurance scheme waylaid by lobbyists in 1948-1950 despite its massive popularity), and particularly into a NIH cancer chemotherapeutics program that consumed massive numbers of mice and rats. The demand for standard inbred mice and other rodents skyrocketed, and for the Jackson Labs to remain at the centre of the mouse genetics field, the institution had to scale up production to meet rising demand. Otherwise, it would have had to cede a central role to other institutions that could supply the needed animals. But meeting these new demands meant devoting an ever-greater proportion of the institution’s efforts to production. Thus what had been an adventitious survival strategy ultimately became the main role of the Jackson Laboratories.

There is an element of tragedy here, in that what had been a field of research throwing important light on our knowledge of life, genetic experimentation on mice and their cancer susceptibility, became a mere instrument or commodity—the inbred mouse of a standard strain, cancer research’s living test-tube. The people making these mice were transformed, over the course of decades, from cutting-edge medical researchers to factory farm workers in white coats. This trajectory is common, if not universal, however. When a new method or instrument first is introduced to science, either it fails to produce anything interesting and is thus left behind, or else it helps produce knowledge valuable to scientists in the field. If it works, more and more scientists build the instrument or technique into their research programs. Soon it becomes commonplace, and thus loses its power as a special ingredient in research programs that can provide an edge over other approaches. Continued improvement in the instrument or method can stave off this day, if the masters of the technique retain an edge over everyone else. Perhaps this explains why 70 years after the first cyclotrons and radio telescopes, versions of these instruments are still required for progress in certain experimental fields. But sooner or later, there awaits the fate of the geiger counter, the microscope, the spectrometer, and all the other instruments bought from a catalogue and otherwise taken for granted. And as William James argued, it is the same for knowledge as it is for such pieces of scientific technology: once an important fact is accepted as true, it becomes so universal that it becomes invisible—even though it remains essential to all later facts. These are the ancient shoots that mature into limbs on the tree of knowledge, no longer green or flowering, but all the more crucial for supporting the growing tips. James’s point is confirmed in the very fact that we now take genetic experiments on mice for granted as a reliable basis of knowledge about what our genes do. There is no surer science than that which we have come to depend upon.

REFERENCES

Ankeny, R. 1997, ‘The Conqueror Worm: An Historical and Philosophical Examination of the Use of the Nematode C. elegans as a Model Organism’, Ph. D. dissertation, University of Pittsburgh, Pittsburgh, PA.

Creager, A. 2002, The Life of a Virus: Tobacco Mosaic Virus as an Experimental Model, 1930-1965, University of Chicago Press, Chicago.

Galison, P. 1997, Image and Logic: A Material Culture of Microphysics, University of Chicago Press, Chicago.

Kohler, R. 1994, Lords of the Fly: Drosophila Genetics and the Experimental Life, University of Chicago Press, Chicago.

Nicolas Rasmussen is Senior Lecturer in the School of History and Philosophy of Science at the University of New South Wales.