By Yehudis Kundin, Staff Writer
Rodent models have been crucial to biomedical research for more than 150 years. Rats and mice are anatomically similar to humans and share around 95% of their genes with us. They therefore prove to be ideal models for studying biological processes and diseases in humans in addition to testing drugs and treatments. However, in recent years, a discrepancy seems to have been found between drug efficiency in lab mice and humans. Scientists believe this may be due to the extremely isolated conditions of laboratory mice. Mice that are raised in “safe, shoebox-sized cages” are more anxious than mice living in the wild, for example. Researchers have found that their artificial environment gives rise to psychological differences that greatly impact the transferability of research outcomes to humans living in the natural world.
In a famous 2006 case, a new drug, TGN1412, was shown to effectively boost the immune system in preclinical rodent trials but induced life-threatening symptoms in humans. Andrea Graham, an evolutionary ecologist at Princeton University, discovered that this was likely due to the immunological difference between lab and wild mice. Mice that live in the wild experience enhanced differentiation of T-cells, which are crucial in the immune response. Subsequent research demonstrated that while this drug was effective in lab mice, the opposite was true of wild mice, whose symptoms mimicked the disastrous effects the drug had on humans.
Matthew Zipple, a postdoctoral researcher at Cornell University, sought to establish the existence of a clear gap between lab animal models and humans, which he believes is due to the “artificial, standardized environment in which lab animals are kept.” It seems that wild mice actually mimic the human condition much more accurately than laboratory mice do, both physically and socially. They are constantly on the go, foraging for food, seeking shelter and avoiding predators. Additionally, they build hierarchical social structures, using sounds and body language to communicate with one another. Lab mice, on the other hand, spend their entire day in a small cage with two or three same-sex siblings, having food and water provided for them on a regular schedule. According to Zipple, testing drugs on these mice is akin to studying how drug efficiency works on prisoners in solitary confinement. The results of such experiments would not be generalizable to the broader population.
Therefore, Zipple and his colleagues aimed to compare the psychology of two groups of mice: one group that lived in a lab and another that lived in an outdoor enclosure, with grass, dirt and exposure to the sky. They compared the groups’ psychology by measuring their behavior in an elevated plus maze, an enclosure with two open arms and two enclosed arms. Typically, upon first exposure to the maze under a bright lab light, mice explore the open arms, find them terrifying and avoid venturing there again. This is exactly how the lab mice in the experiment behaved. However, the wild mice showed no signs of fear or anxiety upon entering the open arms. They continued exploring them throughout subsequent experiments, all while under the bright light. Zipple and the other researchers then exposed some of the lab mice to the outside enclosure for a week and repeated the experiment. These mice, which had previously demonstrated anxiety when in the open arms under the lab light and thus avoided them, now explored the open arms twice as much as the lab mice that remained in cages.
While this study simply demonstrates that outdoor exposure in mice seems to decrease anxious behavior, it has broader implications. It highlights a fundamental flaw in rodent research: lab mice don’t reflect the human condition accurately enough to serve as effective subjects in drug trials. As Graham puts it, it is inefficient to continue to test drugs on mice that are kept in “immunologically boring, psychologically boring environments.” While redesigning traditional animal model protocols will increase costs and take more effort, Zipple says, it will increase efficiency in the long run, expediting the search for drugs that are more likely to translate from the lab to the clinic.
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