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Do Chimeras Have Minds?

The Ethics of Clinical Research on a Human–Animal Brain Model

Published online by Cambridge University Press:  22 September 2017

BENJAMIN CAPPS
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Abstract:

Suppose that a colleague proposed a fantastic experiment: to introduce human stem cells into a neonatal mouse so that its entire brain developed into “human-like” neuronal structures. The colleague claimed it would still be a mouse, and that its chimeric brain would be nothing like a “human” one. It would not, as a result, have a moral status beyond its nonhuman animal origins. Thus, the “human neuron mouse” would allow scientists to tinker with human-like neurology in ways that would be precluded if it were a human being, and that would promise to lead to substantial understanding of the destructive and incurable brain diseases that befall humanity. The colleague does admit, however, that for reasons of comparative fidelity, experiments in human patients would be scientifically preferable, although in this case, neither ethically justified nor legally permitted. For that reason, it might be desirable to create a human brain in a nonhuman primate, where it would be more likely that significant human-like neuronal development would occur, but still could not become a person. This article explores the significance of a “human neuron chimpanzee,” and suggests that contradictions in the design of the experiment make it unethical to proceed in either murine or primate models.

Keywords

chimeraanimal modelprimateanimal ethicscomparative biology
Type
Articles
Information
Cambridge Quarterly of Healthcare Ethics , Volume 26 , Special Issue 4: Clinical Neuroethics , October 2017 , pp. 577 - 591
Copyright
Copyright © Cambridge University Press 2017 

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References

Notes

1. In the following, I refer to “humans” (or human beings), nonhuman animals as “animals,” and nonhuman primates as “primates.” I use person and agent interchangeably, although the former is often used to denote a member of the human species (of which not all are agents). I will refer to “patients” as being human unless otherwise indicated.

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6. European Commission Scientific Committee on Health and Environmental Risks. The Need for Non-Human Primates in Biomedical Research, Production and Testing of Products and Devices. Brussels: European Commission; 2009.

7. A number of definitions have been used under the umbrella term of “human–animal combination.” I use “chimera” to define an entity that contains two or more species’ distinct cell populations.

8. National Institutes of Health. Request for Public Comment on the Proposed Changes to the NIH Guidelines for Human Stem Cell Research and the Proposed Scope of an NIH Steering Committee’s Consideration of Certain Human–Animal Chimera Research. Notice Number: NOT-OD-16-128; Release Date: August 4, 2016.

9. “Consciousness” is shorthand for the mental capacities contained within minds; see generally: Baars B. In the Theater of Consciousness: The Workplace of the Mind. Oxford: Oxford University Press; 1997. Consciousness in an analogy to mental states, because whereas consciousness is experienced, such states indicate subjective motivational or affective states that may or may not be experienced by another. My reference points for “consciousness” will be: (1) mice having minimal capacities of sentience; (2) primates (depending on species) having “higher consciousness”; and (3) “human consciousness.” Human consciousness here refers to the capacities for reason: an inward process of awareness of and reflection about the world and our place in it. Although these categories might be controversial—I am not saying, for instance, that primates do not reason—they suffice for my purposes. See generally: Allen C, Bekoff M. Animal minds, cognitive ethology and ethics. The Journal of Ethics 2007;11:299–317.

10. For a description of the experiment see: Greely, H, Cho, M, Hogle, L, Satz, D. Thinking about the human neuron mouse. American Journal of Bioethics 2007;7:27–40, at 32.CrossRefGoogle ScholarPubMed

11. That the being might have rights could be reason enough to object to the experiment; if it were plausible that it did have rights, then the experiment would be unethical. This requires a defensible agency-neutral theory of rights, such as: Gewirth A. Reason and Morality. Chicago. Chicago University Press; 1978.

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16. The proposed experiment was ethically reviewed in an internal report. I presume that the arguments presented in the Report are the same as those in Greely H, et al. 2007, see note 10. When I refer to the “Report,” I am indicating the arguments represented in that article.

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21. The point being that the chimeric mouse might not now be “human,” but have a level of consciousness that makes it analogous to that expected in a person. See: Karpowicz P, Cohen B, van der Kooy D. Developing human–nonhuman chimeras in human stem cell research: ethical issues and boundaries. Kennedy Institute of Ethics Journal 2005;15:107–34.

22. See note 10, Greely et al. 2007. As already stated, this article is a reiteration of the Report, which itself appears not to have been made public.

23. Greely H. Cho M, Hogle L, Satz D. Response to open peer commentaries on ‘Thinking about the human neuron mouse.’ American Journal of Bioethics 2007;7:W4–W6.

24. Quoting Sean Wu, in: Begley S. Human–animal chimeras face new ethical scrutiny. STAT; available at https://www.statnews.com/2015/11/05/human-animal-chimeras-face-new-scrutiny/. November 5, 2015. (last accessed 29 Mar 2017).

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26. See note 5, Sharma et al. 2015.

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28. See note 10, Greely et al. 2007, at 38.

29. See note 10, Greely et al. 2007, at 37.

30. See note 27, Greely 2014.

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32. See note 10, Greely et al. 2007, at 36.

33. See, for example, ‘“We’re too big. We cost too much. You can’t slice us up at will,” said Greely. “If you want to study how human neurons react to disease agents, to drugs, to chemicals, to radiation, et cetera, there are very, very grave limits on what you can do looking at those human neurons inside human beings”’; Levine D. Working on chimeras could put scientists in the doghouse. San Francisco Business Times; available at http://www.bizjournals.com/sanfrancisco/stories/2006/05/15/newscolumn5.html?page=1%2520 (registration%2520required). May 14, 2006. (last accessed 29 Mar 2017).

34. This kind of argument is one that may be offered by the utilitarian who is less inclined to morally count animal pains and pleasures (not all are). See generally: Bass R. Lives in the balance: Utilitarianism and animal research. In: Garrett J, ed. The Ethics of Animal Research: Exploring the Controversy. Cambridge: MIT Press; 2012:81–105. Also see, for example: Arnason G, Clausen J. On balance: Weighing harms and benefits in fundamental neurological research using nonhuman primates. Medicine, Health Care and Philosophy 2016;29:229–37.

35. See note 27, Greely 2014, at 14.

36. Cheshire W. The moral musings of a murine chimera. American Journal of Bioethics 2007;7:49–50.

37. I will return to Greely’s posturing, by way of “precaution,” subsequently; and indeed, his should not be the last word, as against; for example, Steel S. Philosophy and the Precautionary Principle: Science, Evidence and Environmental Policy. Cambridge: Cambridge University Press; 2015.

38. Apart from sensational reasons, one might try to replace and systematically repopulate the brains of animals to model cephalic disorders of humans, to provide evidence of generation of “human”-like functional regions in whole organs, and to create other biological and clinical curiosities for study.

39. See note 14, Bai 2005; note 15, Clark 2002, at 12.

40. Carbone L. The utility of basic animal research. Hastings Center Report 2012;42:S12–S15, at S12.

41. Weissman, as far as I know, never proposed conducting the experiment in a primate.

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44. See note 3, IOM 2011, at 4.

45. However, there are arguments that such experimental models are fundamentally flawed; see Garner J. The autistic mouse and other unlikely stories. New Scientist 2016;232:42–3.

46. See also: Collins F. Reengineering translational science: The time is right. Science Translational Medicine 2011;3:1–6.

47. Editorial. Animal farm: Europe’s policy-makers must not buy animal-rights activists’ arguments that addiction is a social, rather than a medical, problem. Nature 2014;506:5.

48. Greely’s group only considered the “young mouse”; however, I find such limited context curious (and even they realized that “the analysis may have broader implications”): if human brain study is the desired end, then nonhuman primate factors should be relevant to the scientific purpose of the experiment. The mouse experiment seems to be the easy case.

49. For now, I leave this moral value blank; but see note 11.

50. This point is disputed in Pound, Bracken 2014 (see note 13).

51. “Implausible” is obviously an empirical question, as much as it is a belief: no one knows the end state of MChimera because the experiment has yet to be conducted.

52. If 6 is false, then a diametric conclusion would preclude the experiment.

53. Noting that human beings often have mental states at the edges (or vacuous) of personhood.

54. See note 27, Greely 2014.

55. See note 27, Greely 2014, at 13.

56. See note 27, Greely 2014, at 14.

57. Kass L. Ageless bodies, happy souls: Biotechnology and the pursuit of perfection. The New Atlantis, Spring 2003;9–28, at 20.

58. Pluhar E. Beyond Prejudice: The Moral Significance of Human and Nonhuman Animals. Durham: Duke University Press; 1995.

59. See note 31, Tooley 1998.

60. Greely’s scepticism extends to the “vast ignorance of the daunting neurobiology… We know even less about what one would have to do to create such consciousness or characteristics in nonhuman animals. If I were trying to do such a thing, I suppose I would try to put human brain-forming stem cells into a very early embryo of a nonhuman great ape and see what would happen. But I wouldn’t expect success.” see note 27, Greely 2014, at 14.

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63. Leiber J. Can Animals and Machines be Persons?: A Dialogue. Indianapolis: Hackett Publishing Company; 1995.

64. The Cambridge Declaration on Consciousness, July 7, 2012.

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67. Fenton A. Can a chimp say “No”? Reenvisioning chimpanzee dissent in harmful research. Cambridge Quarterly of Healthcare Ethics 2014;23:130–9.

68. But on this point, I concede, we cannot know with respect to the brain.

69. In the preceding format, H(human) → HChimera.

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78. Masson, J. When Elephants Weep: The Emotional Lives of Animals. New York: Delta Books; 1995.

79. See note 42, Pattinson, Beyleveld 2010.

80. See note 10, Greely et al. 2007, at 34.

81. Loveless S, Giordano J. Neuroethics, painience, and neurocentric criteria for the moral treatment of animals. Cambridge Quarterly of Healthcare Ethics 2014;23:163–72, at 164, my emphasis.

82. See especially: Williams B, Smart J. Utilitarianism: For and Against. Cambridge: Cambridge University Press; 1973:248–50.

83. See, for example, Non-randomized, Open-labeled, Interventional, Single Group, Proof of Concept Study With Multi-modality Approach in Cases of Brain Death Due to Traumatic Brain Injury Having Diffuse Axonal Injury; ClinicalTrials.gov Identifier: NCT02742857, April 2016; available at https://clinicaltrials.gov/ct2/show/NCT02742857?ter (last accessed 29 Mar 2017); Steinberg GK, Kondziolka D, Wechsler L, Lunsford L, Coburn ––M, Billigen J, et al. Clinical outcomes of transplanted modified bone marrow–derived mesenchymal stem cells in stroke: A Phase 1/2a Study. Stroke 2016;47:1817–24.

84. See note 2, Bailey, Taylor 2016.

85. See, for example, Chen D, Miller F. Rosenstein D. Enrolling decisionally impaired adults in clinical research. Medical Care 2002;40:V-20–29.

86. See also: Walde V, Kurzban S. Paying human subjects in research: Where are we, how did we get here, and now what? Journal of Law, Medicine and Ethics 2011;39:543–58.

87. A working group report chaired by Sir David Weatherall. The Use of Human Primates in Research. London: Academy of Medical Sciences; 2006.

88. Regan T, Singer P. Animal Rights and Human Obligations. Upper Saddle River: Prentice Hall; 1989.

89. That is not to say that we have not learned a great deal by studying nonhuman animals, often in highly intrusive and invasive ways. The point is whether this progress outweighs any ethical arguments against the use of nonhuman animals in research. We cannot turn the clock back. However, for some, in considering how far we have come, and where we can go, this is a distinctly utilitarian consideration in favor of continued invasive studies to further elucidate neurocognitive functions that have relevance to our own species.

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