Why Many Mice Studies Are Meaningless
Earlier this year, Australian researchers touted a new ultrasound treatment for Alzheimer's disease that restored memory function in 75 percent of mice treated. Professor Jürgen Götz, the study's co-author, was positively glowing in his assessment.
"The word ‘breakthrough’ is often misused, but in this case I think this really does fundamentally change our understanding of how to treat this disease, and I foresee a great future for this approach."
Götz' findings were widely disseminated in the popular press to much fanfare. But, while one hopes that his team's fantastic findings will translate to humans, odds are, they probably won't.
In 2006, a team of scientists from the University of Toronto reviewed 76 of the most highly cited animal studies published between 1980 and 2000, the vast majority published in prestigious journals like Cell, Science, and Nature. The reviewers found that only 37 percent of the works had been replicated in randomized trials on humans. Of the remaining 48 studies, 14 were contradicted in further trials and 34 remained untested more than a decade after being published.
"Patients and physicians should remain cautious about extrapolating the findings of prominent animal research to the care of human disease," the team concluded.
The outlook for successfully translating cancer treatments from animals to humans is much worse. Only eight percent usually make the cut. The rate for stroke may be even more abysmal. When Malcolm Macleod, a Scottish neurologist at the University of Edinburgh, went hunting for new stroke therapies back in 2003, he and his colleagues found 603 drugs which had been tested on animals. Of those, only 97 ended up being tested in humans, and just one worked.
"Animal models are limited in their ability to mimic the extremely complex process of human carcinogenesis, physiology and progression," McMaster University scientists Isabella Mak, Nathan Evaniew, and Michelle Ghert, wrote in 2014. "Therefore the safety and efficacy identified in animal studies is generally not translated to human trials."
While the systems that regulate gene activity are generally the same in mice and humans, there are key biological differences in other areas that prevent successful results from applying to humans. Transcription factor binding sites, where information is passed on, differ for between 41 and 89 percent of the genes that our species share. Moreover, unlike humans, mice used in studies are often highly inbred. The mouse immune system is also drastically different compared to a human's. Laboratory rodents are also often overfed and sedentary. Thus, the positive effects of some drugs might result from improving factors associated with an unhealthy lifestyle rather than the drug counteracting the disease, itself.
Considering the sizable gulf between mice and men, it doesn't help that rodent studies are often poorly conducted. Reporting on the problem for Science Magazine in 2013, Jennifer Couzin-Frankel noted, "For ethical and cost reasons, researchers try to use as few animals as possible, which can mean minuscule sample sizes. Unblinded, unrandomized studies are the norm." One of the scientists she interviewed described the methodology in mice studies as "stone-age." A prime example of an outdated practice is how mice are "randomly" selected.
"You stick your hand in a cage, and pull out a rat," Ian Roberts, a professor of epidemiology at the London School of Hygiene and Tropical Medicine, told The Scientist. "The rats that are the most vigorous are hardest to catch, so when you pull out 10 rats, they're the sluggish ones, the tired ones, they're not the same as the ones still in the cage, and they're the control. Immediately there's a difference between the two groups."
Problems may also arise after the groups are selected. Research published this week to PLoS Biology suggests that as much as 42 percent of stroke and cancer studies lose animals from treatment groups during the course of experiments. This loss could lead to a treatment's effectiveness being overstated by as much as 175 percent.
While inherent biological differences between mice and humans cannot be reconciled, methodological drawbacks can be easily remedied. Investigators can start by simply applying the same level of rigor demanded by a human clinical trial. We need to truly treat our furry friends as we would be treated.