Abstract
Several review articles in immunology indicate that while we have an increasing body of knowledge about the immunology of the mouse, this is translating very poorly into clinical outcomes for humans. This raises several issues for the scientific community, including some related to the apparent inadequacy of the mouse as a model for understanding and predicting human immunity. This paper has two purposes. First, we offer an explanation for why the typical approach to animal model research will most likely fail to produce satisfying clinical outcomes for human immunology. The standard approach to this problem focuses on the lack of similarity between the genes and molecular pathways of model and target systems. Our analysis focuses instead on differences in the ways in which model and target organisms interact with and adapt to their respective environments. We argue that in order to find a proper model organism for studying human immunity we need to think outside the mouse. Second, we advocate abandoning purely reductionist, gene-centered research, giving greater importance to observational studies of humans, and using new emerging technologies for information-processing for in vivo observation.
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- 1.
This section deals with model systems and with inference from these to target systems. As such, it could apply to a wide range of physical systems. But our focus is on biomedical research, more specifically on inference from research on animal models to conclusions about humans, in the area of immunology. Unless otherwise specified, you can assume that the expressions “model” and “target system” refer respectively to “animal model” and “human.”
- 2.
Please note that there is a vast and active literature trying to figure out how the inference from animal models to other target systems really works—e.g., Overmier and Carroll (2001), Gachelin (2006), and Volume 26, Number 2 (1993) of the Journal of the History of Biology. But the main idea we are drawing on here is quite uncontroversial.
- 3.
Lymphocytes are small white blood cells. There are two main types of lymphocytes, T and B cells. Both are involved in the production of antibodies (immunoglobulins)—B cells by making them and T cells by regulating their production by B cells. Neutrophils are white blood cells that ingest and destroy bacteria. (National Institute of Allergy and Infectious Diseases, http://www.niaid.nih.gov/topics/immunesystem/Pages/default.aspx)
- 4.
Biodefense Workshop Summary: Humanized Mice, 2005, Clarion Bethesda Park Bethesda, Maryland Abstract; http://www.niaid.nih.gov/topics/immuneSystem/Pages/frontiers.aspx
- 5.
National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/topics/immunesystem/Pages/default.aspx
- 6.
The rate of mutation in somatic hypermutation is approximately 10 − 3 /bp/cell division, which is 106 fold higher than the average mutation rate of structural genes (Odegard and Schatz 2006).
- 7.
Parham is not the only one to bring this critique to immunology. Shanks and Greek (2009) is another, much more articulated example of this claim. But it is also interesting to note that the clonal selection theory discussed by Parham has been interpreted in Darwinian terms since its early articulation in the late 1950s by Sir Frank Macfarlane Burnet (1899–1985). Before that point, immunologists believed that lymphocytes, the antibody producing cells, were instructed what antibodies to produce from the antigen exposure. Burnet, inspired by Jern’s 1955 hypothesis, suggested that lymphocytes were not instructed, but rather selected by the organism on the basis of a positive reaction between the antibody that they were carrying on their surface and the antigen presented to them. This somatic selection produces more cells of the same type, i.e., clones, and thus results in an increased capacity of the organisms to fight the pathogen. In the extended version of his theory, Burnet (1959) explicitly characterizes this process as a form of Darwinian selection.
- 8.
Another well-known example of reductionism is the attempt to explain consciousness in terms of the capacities of neurons.
- 9.
This idea of the fixity of the internal milieu was a precursor of the notion of homeostasis still accepted today.
- 10.
We are not implying here that experimental research should be left aside. In an ideal world, one could simply bring more resources towards clinical research. But resources are limited, so furthering observational studies would most likely mean a change in the resources allocated to lab research.
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Desjardins, E., Barker, G., Madrenas, J. (2014). Thinking Outside the Mouse: Organism-Environment Interaction and Human Immunology. In: Barker, G., Desjardins, E., Pearce, T. (eds) Entangled Life. History, Philosophy and Theory of the Life Sciences, vol 4. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7067-6_9
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