How much control can we really have in studies on animals?

Animal studies have long been invaluable in advancing biomedical research, allowing us to probe the physiological and biochemical mechanisms underlying disease in powerful ways that currently aren’t possible with human or in vitro studies. Among their many advantages, they afford a high level of experimental control, right down to animal habitats, feeding habits, and even genetic profiles. And yet, when it comes to living, feeling, thinking beings, can we ever have complete control? And if not, how should that fact affect our perspective on results from in vivo investigations?

Can animals’ emotional well-being affect their physiology?

Recently, my attention was brought to a study, published in 1980, in which the authors investigated how laboratory rabbits’ social environment and psychological state impacted their development of atherosclerosis. For the experimental groups, a researcher bonded with the animals with multiple sessions each day devoted to petting, playing with, and speaking to each rabbit. The control groups, in contrast, received more typical laboratory care from the same researcher, with no intentional bonding or dedicated sessions for play and petting. The groups received the same cholesterol-fortified diet and were subjected to weekly blood pressure and serum cholesterol measurements, and after 5-6 weeks, the animals were sacrificed to measure the presence of atherosclerotic lesions along the aorta.

Remarkably, despite having no significant differences between groups in serum cholesterol or blood pressure, the experimental animals were found to have a reduction in lesioned aortic surface area of over 60% relative to controls (P < 0.05). The authors state that this difference is at least as great as that observed in many studies using specific atherosclerosis interventions in hypercholesterolemic rabbits.

It’s a charming and heartwarming study, and it suggests that our own human social relationships may reduce our risk of atherosclerosis – though data on human cardiovascular risk as a function of social interactions are very limited and fraught with confounding variables. But beyond inspiring us to hug our friends and family (and pets), this study has important implications for interpretation of animal studies more broadly, suggesting that a lack of attention to sociopsychological factors might underlie certain instances of conflicting results. In other words, if one research group shows their rabbits a little love over the course of the study while another does not, the two may find divergent results from a given intervention, but since there are no standard approaches for promoting or reporting animal emotional well-being in research, those reading the study would be unaware of the potential psychological cause for the discrepancy.

Animals have personalities

So is the solution simply to set standards for controlling and reporting the socioemotional environments of research animals, just as we have standard mouse genetic lines and report their housing environments and diet composition? If we all agree that no one will ever take time to pet research animals, then they would all be in the same emotional state across all labs and studies, right?

Hardly. As anyone who has ever owned a pet or worked closely with animals will swear, they have complex and individualized personalities just as surely as humans do. Many of the species used most frequently in animal research – including mice, rats, and rabbits – are no exceptions, and their individual differences in temperament, emotional state, sociability, and preferences all may affect their physiology in myriad ways. However, as in humans, the underlying causes of these differences aren’t fully understood and likely reflect complex interactions between genetics and subtle differences in experience, so no single, standard protocol can completely eliminate the variation.

We have less control than we assume

Of course, such individual variation makes animals a closer model of human populations, but it follows that animal studies are likewise subject to many of the potential pitfalls and confounds which we typically associate only with human studies. Because we can’t control for (or currently know) every variable that may impact animal psychology, we can’t be certain that the average temperament of a group of animals in one facility is equal to the average at another facility, just as we can’t be certain that a human cohort in Japan will yield similar results as a human cohort in Tanzania. This is true even for genetically identical mouse strains, for which countless variables such as litter size, cohabitant temperament, or even building or cage location can impact the animals’ emotional baseline. (A colleague of mine noted that during her graduate work, animal technicians found that mice housed on the bottom shelves of cage racks tended to be more stressed than mice housed on top shelves, which they eventually concluded was due to extremely subtle floor vibrations caused by nearby subway trains. Now how does one control for that?)

Keeping perspective on animal research

I’ve often cautioned against placing too high a value on animal studies when it comes to predicting effects in humans. One reason for my skepticism is simply that animals aren’t humans – they have different biology which may or may not have sufficient overlap with our own to provide useful information on human diseases and treatments. But another reason concerns quite the opposite problem: in some ways, animals are more similar to humans than we often give them credit for. This 1980 paper serves as a simple reminder of the fact that these creatures are complex and experience emotions and social connections in ways we may not yet fully realize, let alone understand. Far from mindless clones, research animals reflect the variations in personality seen in human populations – and come with the same potential for confounds from subtle differences in innate qualities or experience.

So in the end, we can take two key lessons from this study. First, we must remember that although animal studies may allow us to investigate biological pathways and physiology beyond what would be possible in humans or cell culture, they are not without their own limitations and we cannot control them completely. And second, we can see that when it comes to animals, a little love can do the heart a lot of good – perhaps for humans, too.