Leading animal models are powerful tools for translational research, but they also present obstacles. Poorly conducted preclinical research in animals is a common cause of translational failure, but even when such research is well-designed and carefully executed, challenges remain. In particular, dominant models may bias research directions, elide essential aspects of human disease, omit important context, or subtly shift research targets. Recognizing these stumbling blocks can help us find ways to avoid them: employing a wider range of models, incorporating (...) more realistic environmental conditions, better aligning studies between animals and patients, and focusing on human biology and therapeutic goals. Such changes are costly; but insisting it would be impractical or unrealistic to change strategies offers no way out of the current impasse. Rather, we must acknowledge the obstacles as well as the advantages presented by core models, and direct some of our investments in translational research toward getting around them. The dominance of biomedical research by a handful of animal models introduces subtle but significant obstacles to translation. Recognizing these obstacles is a critical first step toward finding ways around them; this paper describes how dominant models can create roadblocks, and suggests strategies to improve the efficiency of translation from animal models to humans. (shrink)

This paper responds to a recent challenge for the validity of extrapolation of neurobiological knowledge from laboratory animals to humans. According to this challenge, experimental neurobiology, and thus neuroscience, is in a state of crisis because the knowledge produced in different laboratories hardly generalizes from one laboratory to another. Presumably, this is so because neurobiological laboratories use simplified animal models of human conditions that differ across laboratories. By contrast, I argue that maintaining a multiplicity of experimental protocols and simple (...) models is well justified. It fosters rather than precludes the validity of extrapolation of neurobiological knowledge. The discipline is thriving. (shrink)

Animal models have long been used to investigate human mental disorders, including depression, anxiety, and schizophrenia. This practice is usually justified in terms of the benefits (to humans) outweighing the costs (to the animals). I argue on utility maximization grounds that we should phase out animal models in neuropsychiatric research. Our leading theories of how human minds and behavior evolved invoke sociocultural factors whose relation to nonhuman minds, societies, and behavior has not been homologized. Thus it is not (...) at all clear that we are gaining the epistemic or clinical benefits we want from this animal-based research. (shrink)

It is one of the central aims of the philosophy of science to elucidate the meanings of scientific terms and also to think critically about their application. The focus of this essay is the scientific term predict and whether there is credible evidence that animal models, especially in toxicology and pathophysiology, can be used to predict human outcomes. Whether animals can be used to predict human response to drugs and other chemicals is apparently a contentious issue. However, when one (...) empirically analyzes animal models using scientific tools they fall far short of being able to predict human responses. This is not surprising considering what we have learned from fields such evolutionary and developmental biology, gene regulation and expression, epigenetics, complexity theory, and comparative genomics. (shrink)

ArgumentThis article uses four historical case studies to address epistemological issues related to the animal model of human diseases and its use in medical research on human diseases. The knowledge derived from animal models is widely assumed to be highly valid and predictive of reactions by human organisms. In this contribution, I use three significant historical cases of failure (ca. 1890, 1960, 2006), and a closer look at the emergence of the concept around 1860/70, to elucidate core (...) assumptions related to the specific practices of animal-human knowledge transfer, and to analyze the explanations provided by historical actors after each of the failures. Based on these examples, I argue that the epistemological status of the animal model changed from that of a helpful methodological tool for addressing specific questions, but with precarious validity, to an obligatory method for the production of strong knowledge on human diseases. As a result, there now exists a culture of biomedical research in human disease that, for more than a century, has taken the value of this methodological tool as self-evident, and more or less beyond question. (shrink)

The seminal 1993 article by LaFollette and Shanks “Animal Models in Biomedical Research: Some Epistemological Worries” introduced an influential taxonomy into the debate about the value of animal experimentation. The distinction they made between hypothetical and causal analog models served to highlight a concern regarding extrapolating results obtained in animal models to human subjects, which endures today. Although their taxonomy has made a significant contribution to the field, we maintain that it is flawed, and instead, we offer (...) a new practice-oriented taxonomy of animal models as a means to allow philosophers, modelers, and other interested parties to discuss the epistemic merits and shortcomings, purpose, and predictive capacities of specific modeling practices. (shrink)

Neuronal ceroid lipofuscinoses are a group of lethal inherited neurodegenerative disorders in humans and many animal species. Critical reflections on a range of ethical issues concerning NCL have been instigated by my research on sheep and cattle affected with NCL, the claim that these sheep and cattle are useful models for the disease in humans, and engagement with families and support groups. My reflections on moral status of animals and validity of animal models are outlined in this paper.

The crucial role of animal models in biomedical research calls for philosophical investigation of how and whether knowledge about human diseases can be gained by studying other species. This Element delves into the selection and construction of animal models to serve as preclinical substitutes for human patients. It explores the multifaceted roles animal models fulfil in translational research and how the boundaries between humans and animals are negotiated in this process. The book also covers persistent translational challenges (...) that have sparked debates across scientific, philosophical, and public arenas regarding the limitations and future of animal models. Among the are persistent tensions between standardization and variation in medicine, as well as between strategies aiming to reduce and recapitulate biological complexity. Finally, the book examines the prospects of replacing animal models with animal-free methods. The Element demonstrates why animal modeling should be of interest to philosophers, social scientists, and scientists alike. (shrink)

Polycystic kidney disease (PKD) is one of the most prevalent causes of heritable renal failure. The disease is characterized by the occurrence of numerous fluid‐filled cysts within the parenchyma of kidney. The cysts are epithelial in origin and expand in size, leading to crowding of normal kidney tissue. Ultimately, there is gross enlargement of the kidneys with loss of normal functions, and death usually occurs because of complications related to renal failure. Animal models of polycystic kidney disease are proving (...) to be extremely useful for studying the molecular basis of renal cyst formation and for the isolation of genes carrying the mutations. This article describes the various animal models of polycystic kidney disease, spontaneously and experimentally derived, that have recently been identified. (shrink)

This paper provides a historical analysis of a shift in the way animal models of mental disorders were conceptualized: the shift from the mid-twentieth-century view, adopted by some, that animal models model syndromes classified in manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM), to the later widespread view that animal models model component parts of psychiatric syndromes. I argue that in the middle of the twentieth century the attempt to maximize the (...) face validity of animal models sometimes led to the pursuit of the ideal of an animal model that represented a behaviorally defined psychiatric syndrome as described in manuals such as the DSM. I show how developments within psychiatric genetics and related criticism of the DSM in the 1990s and 2000s led to the rejection of this ideal and how researchers in the first decade of the twenty-first century came to believe that animal models of mental disorders should model component parts of mental disorders, adopting a so-called endophenotype approach. (shrink)

Anorexia nervosa is an eating disorder characterized by intense fear of gaining weight and a distorted body image which usually leads to low caloric intake and hyperactivity. The underlying mechanism and pathogenesis of anorexia nervosa is still poorly understood. In order to learn more about the underlying pathophysiology of anorexia nervosa and to find further possible treatment options, several animal models mimicking anorexia nervosa have been developed. The aim of this review is to systematically search different databases and provide (...) an overview of existing animal models and to discuss the current knowledge gained from animal models of anorexia nervosa. For the systematic data search, the Pubmed—Medline database, Embase database, and Web of Science database were searched. After removal of duplicates and the systematic process of selection, 108 original research papers were included in this systematic review. One hundred and six studies were performed with rodents and 2 on monkeys. Eighteen different animal models for anorexia nervosa were used in these studies. Parameters assessed in many studies were body weight, food intake, physical activity, cessation of the estrous cycle in female animals, behavioral changes, metabolic and hormonal alterations. The most commonly used animal model is the activity-based anorexia model in which typically young rodents are exposed to time-reduced access to food with unrestricted access to a running wheel. Of the genetic animal models, one that is of particular interest is the anx/anx mice model. Animal models have so far contributed many findings to the understanding of mechanisms of hunger and satiety, physical activity and cognition in an underweight state and other mechanisms relevant for anorexia nervosa in humans. (shrink)

A moral dilemma exists in biomedical research relating to the use of animal or human tissue when conducting scientific research. In human ethics, researchers need to justify why the use of humans is necessary should suitable models exist. Conversely, in animal ethics, a researcher must justify why research cannot be carried out on suitable alternatives. In the case of medical procedures or therapeutics testing, the use of animal models is often justified. However, in forensic research, the justification (...) may be less evident, particularly when research involves the infliction of trauma on living animals. To determine how the forensic science community is dealing with this dilemma, a review of literature within major forensic science journals was conducted. The frequency and trends of the use of animals in forensic science research was investigated for the period 1 January 2012–31 December 2016. The review revealed 204 original articles utilizing 5050 animals in various forms as analogues for human tissue. The most common specimens utilized were various species of rats, pigs, mice, and rabbits although different specimens were favored in different study themes. The majority of studies were conducted on post-mortem specimens. It is, however, evident that more needs to be done to uphold the basic ethical principles of reduction, refinement and replacement in the use of animals for research purposes. (shrink)

Crespi & Badcock (C&B) present an appealing and parsimonious synthesis arguing that schizophrenia and autism are differentially regulated by maternal versus paternal genomic imprinting, respectively. We argue that animal models related to schizophrenia and autism provide a useful platform to explore the mechanisms outlined by C&B. We also note that schizophrenia and autism share certain risk factors such as advanced paternal age. Apart from genomic imprinting, copy number variants related to advanced paternal age may also contribute to the differential (...) trajectory of brain development associated with autism and schizophrenia. (shrink)

The neuropsychopharmacological methods and theories used to investigate the nature of depression have been viewed as suspect for a variety of philosophical and scientific reasons. Much of this criticism aims to demonstrate that biochemical- and neurological-based theories of this mental illness are defective, due in part because the methods used in their service are consistently invalidated, failing to induce depression in pre-clinical animal models. Neuropsychopharmacologists have been able to stave off such criticism by showing that their methods are context (...) and domain-sensitive, and that the worth of an animal model is relative to its purpose – thereby creating logical space for the question of whether there could ever be a “good” animal model of depression. I contend that this sort of response implicitly leans on Feyerabendian principles in the philosophy of science, and exemplify this connection using a standard taxonomy of behavioral models of depression. I then take one central Feyerabendian principle – methodological and theoretical pluralism – and show how it maps onto the neuropsychopharmacological research tradition as it is currently practiced. (shrink)

Educational institutions have a responsibility not only to provide a solid theoretical background on scientific phenomena, but to also frame them within the wider social context and highlight their numerous ethical implications. It is fundamental that tomorrow’s scientists be encouraged to develop an informed and critical approach towards scientific issues that, as in the case of animal experimentation, bring undeniable advantages to our society while carrying highly controversial moral implications. However, despite the considerable social and scientific relevance of the (...) use of animal models in biomedical research, there is a scarcity of scholarly literature exploring the topic from a pedagogical standpoint. The case study presented in this paper aims to investigate the effectiveness of role play simulation in promoting critical understanding of the use of animal models in biomedical research and its ethical implications. A simulation was set up in which first year undergraduate students took the role of delegates to a conference purportedly organised by the United Nations Ethics Office. The simulation included two electronic voting sessions, an open debate, and a keynote lecture. Post-session feedback indicated that most students found the simulation more engaging than a conventional lecture. A comparison of self-assessment questionnaires compiled at the start and at the end of the session indicated that students’ understanding of, and confidence in, the topic of animal experimentation had considerably increased after taking part in the simulation. (shrink)

Educational institutions have a responsibility not only to provide a solid theoretical background on scientific phenomena, but to also frame them within the wider social context and highlight their numerous ethical implications. It is fundamental that tomorrow’s scientists be encouraged to develop an informed and critical approach towards scientific issues that, as in the case of animal experimentation, bring undeniable advantages to our society while carrying highly controversial moral implications. However, despite the considerable social and scientific relevance of the (...) use of animal models in biomedical research, there is a scarcity of scholarly literature exploring the topic from a pedagogical standpoint. The case study presented in this paper aims to investigate the effectiveness of role play simulation in promoting critical understanding of the use of animal models in biomedical research and its ethical implications. A simulation was set up in which first year undergraduate students took the role of delegates to a conference purportedly organised by the United Nations Ethics Office. The simulation included two electronic voting sessions, an open debate, and a keynote lecture. Post-session feedback indicated that most students found the simulation more engaging than a conventional lecture. A comparison of self-assessment questionnaires compiled at the start and at the end of the session indicated that students’ understanding of, and confidence in, the topic of animal experimentation had considerably increased after taking part in the simulation. (shrink)

The ways in which other animal species can be informative about human biology are not exhausted by the traditional picture of the animal model. In this paper, I propose to distinguish two roles which laboratory organisms can have in biomedical research. In the more traditional case, organisms act as surrogates for human beings, and as such are expected to be more manageable replicas of humans. However, animal models can inform us about human biology in a much (...) less straightforward way, by being used as measuring devices—what I call their instrumental role. I first characterize this role and provide criteria for it, before illustrating it with some examples from biomedical research, especially cancer research. In such an instrumental role, phenotypes are not expected to phenocopy human phenomena, but instead have the purely instrumental value of detecting or measuring differences. I argue that the instrumental role is more prevalent than might first be suspected, and that some characteristics of contemporary biomedical research are increasingly shifting the use of laboratory organisms to the instrumental role. Finally, in light of the distinction proposed, I discuss the meaning of the expression “animal model”. (shrink)

Single-cell studies of monkey posterior parietal cortex (PPC) have revealed the extensive neuronal representations of three-dimensional subject motion and three-dimensional layout of the environment. I propose that navigational planning integrates this PPC information, including gravity signals, with horizontal-plane based information provided by the hippocampal formation, modified in primates by expansion of the ventral stream.

Animal models of human disease play a central role in modern biomedical science. Developing animal models for human mental illness presents unique practical and philosophical challenges. In this article we argue that existing animal models of psychiatric disease are not valid, attempts to model syndromes are undermined by current nosology, models of symptoms are rife with circular logic and anthropomorphism, any model must make unjustified assumptions about subjective experience, and any model deemed valid would (...) be inherently unethical, for if an animal adequately models human subjective experience, then there is no morally relevant difference between that animal and a human. (shrink)

Attention deficit hyperactivity disorder affects children, adolescents, and adults. Research suggests ADHD has a heritable component. The present article presents and assesses several genetic animal models of ADHD. The paper reviews the literature involving the following genetic animal models of ADHD: the spontaneously hypertensive rat ; the Wistar–Kyoto hyperactive rat; the coloboma mouse; the fast kindling rat; the acallosal mouse; the whirler mouse; and the genetically hypertensive rat. Research investigating animal models of ADHD has concentrated on hyperactivity, (...) but impulsiveness, learning, and attention are also being examined. The use of animal models allows for the control of possibly confounding variables and has proven very useful in the screening of new therapies. These models have not been shown to be the equivalent of the human disorder, and no model encompasses all of the symptoms of the human disorder, but they are useful nevertheless. (shrink)

Animal Models in the Light of Evolution provides persuasive evidence that animal models should be used with great caution when applying the results to human diseases. Mice and other model animals are both similar and different, in their biology, to humans.

Reviews the book, Animal models of human psychology: Critique of science, ethics, and policy by Kenneth J. Shapiro . The principle focus of most of this text is on the present-day use of animals in psychological research. In particular, Shapiro examines contemporary animal models of eating disorders, showing how psychology came to rely so heavily on animal models in the first place and how prevalent scientific attitudes about the use of animals in the laboratory have taken shape (...) over the past several decades. In addition, he traces the recent rise of the animal rights movement and highlights the several philosophies upon which it is based. Drawing upon certain historical and empirical analyses, as well as certain themes in contemporary sociology of knowledge, Shapiro attempts to navigate his reader through the twin minefields of impassioned rhetoric and insufficiently examined conceptual commitment to a better understanding of the core issues surrounding the role of animals in scientific psychological investigation. 2012 APA, all rights reserved). (shrink)

Over the past two decades, research on neural transplantation in animal models of neurodegeneration has provided provocative in sights into the therapeutic use of grafted tissue for various neurological diseases. Although great strides have been made and functional benefits gained in these animal models, much information is still needed with regard to transplantation in human patients. Several factors are unique to human disease, for example, age of the recipient, duration of disease, and drug interaction with grafted cells; these (...) need to be explored before grafting can be considered a safe and effective therapeutic tool. (shrink)

BackgroundCurrent policies regulating the use of animals for scientific purposes are based on balancing between potential gain of knowledge and suffering of animals used in experimentation. The balancing process is complicated, on the one hand by plurality of views on our duties towards animals, and on the other hand by more recent discussions on uncertainty in the probability of reaching the final aim of the research and problems of translational failure.MethodsThe study combines ethical analysis based on a literature review with (...) neuropsychiatry-related preclinical research as a case study.ResultsBased on the analysis and the case study we show that neuropsychiatry-related preclinical research is an especially interesting case from an ethical perspective. The 3R principles are used to minimize the negative consequences for the animals used in research. However, neuropsychiatric research is characterized by specific challenges in assessing the probability of success of reaching the final aim, due to our limited mechanistic knowledge of human neuropsychiatric illness. Consequently, the translational value of the currently used animal models may be difficult to prove, which undermines the validity of these models and complicated the ethical assessment.ConclusionsWe conclude that a combined approach that deals with both science and the ethical dimensions is necessary to address the problems of validity and translation in neuropsychiatry-related preclinical research. We suggest this approach to comprise first, improved experimental methods, e.g. by using systematic reviews, second, a more patients-based approach that leads to models that reflect interindividual variation better, and third, more interdisciplinary cooperation. (shrink)

In general, we endorse Aggleton & Brown's thesis that the neuroanatomy of amnesia comprises two functionally distinct systems, but we are disappointed in the lack of detail regarding the critical functional contribution of the hippocampus. We also take issue with the characterization of the cortical areas surrounding the hippocampus, particularly the decreased emphasis on the cortical input to the hippocampus.

Animal Models in the Light of Evolution provides persuasive evidence that animal models should be used with great caution when applying the results to human diseases. Mice and other model animals are both similar and different, in their biology, to humans.

Critics of animal modeling have advanced a variety of arguments against the validity of the practice. The point of one such form of argument is to establish that animal modeling is pointless and therefore immoral. In this article, critical arguments of this form are divided into three types, the pseudoscience argument, the disanalogy argument, and the predictive validity argument. I contend that none of these criticisms currently succeed, nor are they likely to. However, the connection between validity and (...) morality is important, suggesting that critical efforts would be instructive if they addressed it in a more nuanced way. (shrink)