The Trouble with Animal Models in Brain Research

Johnson, L. Syd M

doi:10.1007/978-3-030-31011-0_16

Cited by 8 publications

(6 citation statements)

References 46 publications

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“…This leads to a justificatory dilemma : the use of NHPs (over other NHAs) on the basis of their similarity to humans stands in tension with the intuition that humans deserve more moral consideration than NHPs. 153 This tension is eased by the prospect of using long-term or chronic recording techniques to produce more robust data in rich experimental contexts with fewer NHPs (and other NHAs) required. However, the data scientific practices that are well suited to making the most of NHP research will likely raise further ethical considerations when applied to human subject research.…”

Section: Perspective On Ethics Considerations: Protections For Nhps A...mentioning

confidence: 99%

Large-scale multimodal surface neural interfaces for primates

Belloir¹,

Vargo²,

Ahmed³

et al. 2023

iScience

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Section: Perspective On Ethics Considerations: Protections For Nhps A...mentioning

confidence: 99%

Large-scale multimodal surface neural interfaces for primates

Belloir¹,

Vargo²,

Ahmed³

et al. 2023

iScience

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“…These considerations do not support a conclusion that the development of nonhuman models of neuropsychiatric disorder is wholesale scientifically unjustified (though some commentators, on similar grounds, do take that stance 32 ). We should be open to the possibility that certain instances or experiments are or will be designed, executed, and analyzed in ways that proximally produce knowledge worth having and more distantly contribute to the amelioration of human suffering.…”

Section: Toward Changementioning

confidence: 95%

Threats to Benefits: Assessing Knowledge Production in Nonhuman Models of Human Neuropsychiatric Disorders

Neuhaus¹

2022

Hastings Center Report

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November-December 2022/HASTINGS CENTER REPORT A key finding from the work group deliberations of The Hastings Center's project Actionable Ethics Oversight of Human-Nonhuman Chimeric Research is that more analysis is needed on what it means for chimeric research to be scientifically justified and how to assess the benefits of such research. This finding is supported by a literature review of how benefits are typically understood in publications on harm-benefit analyses of experiments involving nonhuman animals. 1 The same literature review called for deeper analysis of benefits and how they are assessed.This essay responds to this gap as it applies to humannonhuman chimeric research that seeks to model human neuropsychiatric disorders such as schizophrenia, obsessive-compulsive disorder, depression, or autism. This is not a merely futuristic or theoretical concern. A recent report from the National Academies of Sciences, Engineering, and Medicine, The Emerging Field of Human Neural Organoids, Transplants, and Chimeras, specifically points out the promise of human neural transplants and chimeric models to ameliorate suffering due to autism spectrum disorders, depression, and schizophrenia. 2 Additionally, recent scientific papers report the creation of chimeric organisms to model-and treat-neuropsychiatric disease. 3 Papers that report chimeric models of Alzheimer disease indicate interest and progress among the neuroscientific community in chimeric models of brain disorders generally. 4 The benefits to humans who suffer-now and in the future-from devastating neuropsychiatric disorders are supposed to justify the harms imposed on nonhumans used in research and humans affected by that research. Benefits may include improved understanding of underlying pathology, preventative measures, and new treatments. But various factors affecting studies' results and conclusions may threaten the production of benefits and thus the underlying ethical justification for this research. 5 After providing a general framework for classifying the benefits of biomedical research, I will focus on two factors that directly impact-and threaten-the production of knowledge in research that models neuropsychiatric disorders. Given that nearly 90 percent of behavioral neuroscience results fail to translate to humans, 6 an understanding of these threats must be included in the ethical analysis of chimeric research. Joseph Garner, a scientist critical of current methods for developing nonhuman models of human disease, states, "At the end of the day, the failure of animal results to translate is arguably the greatest laboratory animal welfare issue for our day." 7 For this special report focused so centrally on animal welfare, the conceptual issues surrounding how to understand benefits and the practical problems with benefits' assessment and production demand attention.

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“…Overall, replicating brain disorders in animal models has been difficult. The biological differences inherent between species impact the external validity of animal models for brain disorders, making translation of laboratory findings rare and of minimal impact [ 5 , 6 ]. Furthermore, behavioral analysis in animal models of monogenic conditions can produce highly variable results [ 7 , 8 ].…”

Section: The Complexity Of the Disease Process And Utility Of Genetic...mentioning

confidence: 99%

The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model

Mukherjee

LaConte

Srivastava

2022

Cells

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Most human disease manifests as a result of tissue pathology, due to an underlying disease process (pathogenesis), rather than the acute loss of specific molecular function(s). Successful therapeutic strategies thus may either target the correction of a specific molecular function or halt the disease process. For the vast majority of brain diseases, clear etiologic and pathogenic mechanisms are still elusive, impeding the discovery or design of effective disease-modifying drugs. The development of valid animal models and their proper characterization is thus critical for uncovering the molecular basis of the underlying pathobiological processes of brain disorders. MICPCH (microcephaly and pontocerebellar hypoplasia) is a monogenic condition that results from variants of an X-linked gene, CASK (calcium/calmodulin-dependent serine protein kinase). CASK variants are associated with a wide range of clinical presentations, from lethality and epileptic encephalopathies to intellectual disabilities, microcephaly, and autistic traits. We have examined CASK loss-of-function mutations in model organisms to simultaneously understand the pathogenesis of MICPCH and the molecular function/s of CASK. Our studies point to a highly complex relationship between the potential molecular function/s of CASK and the phenotypes observed in model organisms and humans. Here we discuss the implications of our observations from the pathogenesis of MICPCH as a cautionary narrative against oversimplifying molecular interpretations of data obtained from genetically modified animal models of human diseases.

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The Trouble with Animal Models in Brain Research

Cited by 8 publications

References 46 publications

Large-scale multimodal surface neural interfaces for primates

Large-scale multimodal surface neural interfaces for primates

Threats to Benefits: Assessing Knowledge Production in Nonhuman Models of Human Neuropsychiatric Disorders

The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model

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