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From humanized mice to human disease: guiding extrapolation from model to target

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Abstract

Extrapolation from a well-understood base population to a less-understood target population can fail if the base and target populations are not sufficiently similar. Differences between laboratory mice and humans, for example, can hinder extrapolation in medical research. Mice that carry a partial or complete human physiological system, known as humanized mice, are supposed to make extrapolation more reliable by simulating a variety of human diseases. But what justifies our belief that these mice are similar enough to their human counterparts to simulate human disease? I argue that, unless three requirements are met in the process of humanizing mice, very little does. My requirements are not meant to provide necessary and sufficient conditions that guarantee a particular outcome. Instead, they serve as a heuristic for guiding scientific judgments involving extrapolation. In developing each requirement, I engage with philosophical issues concerning the nature of model-based science and the mechanistic approach (and its limits) to making generalizations in the life sciences.

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Notes

  1. Other works on the topic of extrapolation in biology include Ankeny (2001), Bechtel and Abrahamsen (2005), Bolker (1995), Burian (1993), Cartwright (1989), LaFollette and Shanks (1996), Love (2009), Schaffner (1986, 2001), Weber (2005), and Wimsatt (1998).

  2. The difference between computer climate simulations and mouse simulations of human disease is that in the latter the base and target already share some similarities inherited from a common ancestor. However, this fact doesn’t guarantee that the one is a good model for the other, since characteristics not inherited from a common ancestor may still differ (cf. Steel 2008).

  3. It might seem that the process of humanizing mice begins with modifying the recipient to prevent it from rejecting transferred parts, e.g., weakening the immune system of the mouse. While this is sometimes the actual first step, it is not the first step in the design of the experiment. One must first determine which parts will be transferred in order to know how to modify the recipient.

  4. Throughout the article, I analyze scientific experiments with the aim of providing criteria for judging their outcomes (at least the ones that aspire to humanize mice). My aim is not to criticize these experiments.

  5. Although the details of the evolutionary history of a trait may not be readily available, this requirement is not beyond reach. There is a growing initiative to incorporate the study of evolution into medicine given the benefits of an evolutionary perspective for understanding and treating human diseases such as diabetes, obesity, autoimmune diseases, cancer, diseases of aging, etc. (cf. Stearns and Koella 2008; Nesse et al. 2010).

  6. Although I agree with Waters that having access to a multiplicity of outcomes helps in identifying causes that make a difference, I also think such access is constrained by practical considerations. For example, parts that are easily manipulated in the laboratory are more likely to be identified as difference-makers than parts that are not easily manipulated (cf. Gannett 1999).

  7. There is a worry here that one may not be able to apply Waters’s concept of a difference-maker prospectively, since one cannot know what parts make a difference if one has not yet constructed the model. However, in order to simulate a human disease in mice, some knowledge of the causes behind the disease must be available up front. Waters’s concept of a difference-maker provides one principled way of selecting which causes to replicate in the model and which to ignore, even if this knowledge is sometimes unavailable.

  8. Of course, transferring an entire chromosome does not guarantee analogous gene expression, since trans-elements that regulate gene expression may be located on other chromosomes.

  9. The exception is parts of organisms that are integrated into the organism but are at the same time relatively autonomous with respect to other parts of the organism, i.e., modules (cf. Wagner et al. 2007).

  10. The aim of creating “immunodeficient mice” is to eliminate some of these differences (cf. Shultz et al. 2007).

  11. I take it that Moss (2012) is expressing a similar worry when he writes “Whether, and in what way, some process and the material components of said process can be reckoned as a ‘mechanism’ is never an intrinsic feature of any such process and its components, but is rather a function of its relationship to the living (i.e., self-purposive) system” (p. 166).

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Acknowledgments

Special thanks to Steve Downes, Matt Mosdell, Daniel Steel, Jim Tabery, and several anonymous reviewers for their careful reading and constructive criticism. In addition, I would like to thank Matt Haber, Anya Plutynski, Emanuele Serrelli, Mike Wilson, Rasmus Winther, members of the audience at ISHPSSB 2011 in Salt Lake City, and the editor of this journal for valuable comments. I gratefully acknowledge financial support from the American Association of University Women, Marriner S. Eccles, and Obert C. and Grace A. Tanner Fellowships.

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  1. Philosophy Department, Florida International University, DM 347, 11200 S.W. 8th Street, Miami, FL, 33199, USA

    Monika Piotrowska

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Piotrowska, M. From humanized mice to human disease: guiding extrapolation from model to target. Biol Philos 28, 439–455 (2013). https://doi.org/10.1007/s10539-012-9323-5

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