Embracing Variability

Beyond3Rs > Research > Embracing Variability

Harmonizing animal and human study design is a paradigm shift for biomedical research.

Traditional animal research practices promote controlling and standardizing as many things as possible, which can lead to spurious results that do not generalize to other contexts. Adopting clinical research practices used in human research (referred to elsewhere as "treating animals as patients") means recognizing that individual variability exists in animals and cannot (and should not) be removed. Embracing individual variability is the future of animal research, just as embracing variability has been central to human research and clinical practice for decades.

Viewing animals as patients creates new experimental approaches for researchers:

The world is one enormous ongoing natural experiment, and epidemiology allows us to study it. Epidemiological approaches (observational population studies, rather than direct manipulation) can identify risk factors for disease, behavior, and well-being issues. Epidemiological studies have improved the quality of life of animals, identified new options for improved veterinary care, and led to the development of new models.
Studies on spontaneously and naturally developing diseases in lab, companion, and farm animals can help improve our understanding of human and animal pathology without experimentally inducing disease.
Harmonizing experimental design and data analysis allows our approach to animal studies to match our approach to human studies (e.g. controlled heterogeneity of subjects) and optimizes the likelihood of reproducibility and translation.
Appropriate housing and husbandry can reduce confounding stressors (e.g., provision of nesting material to mice supports a behavioral need and allows for individual control over thermoregulation).
Biomarker-based and personalized medicine models cannot exist without individual variation between animals. Viewing animals as patients has led to exciting innovations including successful first-in-human biomarker-based drug trials.

In this new paradigm, better science, animal well-being, reproducibility, and translation are all fundamentally connected. We can go Beyond3Rs by adopting gold standard clinical research practices when working with animals. These include accounting for the psychological impacts of experimentation, appropriate use of blinding during data collection and analysis, recognizing and utilizing variation among research animals, and adopting a mindset of treating animals as patients. This has far-reaching implications for human health — one major reason why in vivo experiments fail to translate to humans is because they do not account for natural variation within the population.

Research: Embracing Variability in Preclinical Trials

When we are used to seeing mice in barren standardized environments, with standardized chow, and standardized genetics, it is easy to fall into the trap of thinking of them more as little furry test tubes ... If we think of animals as patients, not tools, it forces us to think about all the aspects of the experimental background that differ from humans that we might otherwise ignore.

From "Introducing Therioepistomology"

The epidemiology of fighting in group-housed laboratory mice

Jacob H Theil, Jamie Ahloy-Dallaire, Elin M Weber, Brianna N Gaskill, Kathleen R Pritchett-Corning, Stephen A Felt, Joseph P Garner (2020), Scientific Reports

Injurious home-cage aggression (fighting) in mice affects both animal welfare and scientific validity. It is arguably the most common potentially preventable morbidity in mouse facilities. We performed a point-prevalence epidemiological survey of fighting at a research institution with an approximate 60,000 cage census. Fighting was almost exclusively seen in group-housed male mice. Approximately 14% of group-housed male cages were observed with fighting animals in brief behavioral observations, but only 14% of those cages with fighting had skin injuries observable from cage-side. Thus simple cage-side checks may be missing the majority of fighting mice. Housing system, genetic background, time of year, cage location on the rack, and rack orientation in the room were significant risk factors predicting fighting. Of these predictors, only bedding type is easily manipulated to mitigate fighting. This study emphasizes the need to invest in assessing the welfare costs of new housing and husbandry systems before implementing them.

Introducing Therioepistemology: the study of how knowledge is gained from animal research

Joseph P Garner, Brianna Gaskill, Elin Weber, Jamie Ahloy-Dallaire, Kathleen Pritchett-Corning (2017), Lab Animal

For the first time, the scale of the reproducibility and translatability crisis is widely understood beyond the small cadre of researchers who have been studying it and the pharmaceutical and biotech companies who have been living it. Here we argue that an emerging literature, including the papers in this focus issue, has begun to congeal around a set of recurring themes, which themselves represent a paradigm shift. At the macro level, it is a shift from viewing animals as tools (the furry test tube), to viewing them as patients in an equivalent human medical study. We feel that we are witnessing the birth of a new discipline, which we term Therioepistemology, or the study of how knowledge is gained from animal research. In this paper, we outline six questions that serve as a heuristic for critically evaluating animal-based biomedical research from a therioepistemological perspective.

A "Pedi" Cures All: Toenail Trimming and the Treatment of Ulcerative Dermatitis in Mice

Sean C Adams, Joseph P Garner, Stephen A Felt, Jerome T Geronimo, David K Chu (2016), PLoS One

Ulcerative Dermatitis (UD) is the most common cause of unplanned euthanasia in mice used in research, with prevalence rates reported between 4 and 21%.There is a growing body of evidence that suggests a behavioral component to the onset, maintenance, and progression of UD lesions. Scratching behavior in response to the intense pruritus associated with UD lesions may be an effective target for interventional therapies. We hypothesized that interfering with scratching behavior by trimming the toenails of mice with UD, would resolve UD lesions. This is the first report of a highly effective treatment for one of the most serious welfare issues in laboratory mice.

Behaviour and the standardization fallacy

Hanno Würbel (2000), Nature Genetics

Behavioural phenotyping of mouse mutants has become an important tool in the search for biological roles of single gene products in complex mammalian traits, such as memory, aggression, anxiety and addiction. Because specific strains of mice, husbandry practice and test protocol may influence behavioural effects of mutations in unpredictable ways, scientists strive for consensus on rigorous standards to maximize reproducibility of results across laboratories. Increasing reproducibility of results through standardization, however, accentuates and obscures the problem of reporting artefacts that are idiosyncratic to particular circumstances. Using a single standardized genetic or environmental background or test situation for the characterization of mutants makes it impossible to distinguish artefacts from informative effects. Systematic variation is the only means to determine the nature of genetic effects on behaviour.

Preventing, treating, and predicting barbering: Oxidative stress in a mouse model of Trichotillomania

Giovana de L T Vieira, Amy C Lossie, Donald C Lay Jr, John S Radcliffe, Joseph P Garner (2017), PLoS One

Barbering, where a "barber" mouse plucks hair from its cagemates or itself, is both a spontaneously occurring abnormal behavior in mice and a well validated model of Trichotillomania (TTM). N-Acetylcysteine, (NAC) a cysteine derived food additive, is remarkably effective in treating TTM patients, but its mechanism of action is unknown. We hypothesized that barbering is a disease of oxidative stress, whereby ROS and/or a failure of antioxidant defenses leads to neuronal damage that induces barbering in susceptible animals. We conclude that NAC is effective in preventing and/or curing barbering at least in part by promoting GSH synthesis, thereby preventing oxidative damage.

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