Squeaky clean mice could be ruining research

Cassandra Willyard in Nature:

On an unseasonably warm February morning, Mark Pierson takes a 20-minute drive to one of Minneapolis’s larger pet shops. Pierson, a researcher in an immunology laboratory at the University of Minnesota, often comes here to buy mice, so most of the staff know him. Today he asks for ten, and an employee fishes them out of a glass box. Pierson requests the smaller mice because they’re typically younger, but he isn’t too picky. They probably all have what he wants: germs. These mice are about to enter one of the most tightly controlled labs in the country, a facility normally reserved for studying dangerous pathogens such as tuberculosis and chikungunya virus. The rodents probably don’t carry serious human infections, but they do harbour diseases that pose a grave threat to the hundreds of other research mice in the building. The pet-shop mice are about to get new room-mates. Each one will bunk with a group of shiny black lab mice, sharing food, water, bedding and, most importantly, pathogens. Until now, the lab mice have been kept in a squeaky clean environment, free from most diseases, so some will fall ill and die. The rest will develop more robust immune systems, more like those of wild mice — and, arguably, humans.

What Pierson is doing breaks the rules. For more than 50 years, scientists have worked to make lab mice cleaner. In most labs today, the animals’ cages are sanitized, and their water bottles and food are sterilized. “We really go to great lengths to keep natural infectious experience out of the mouse house,” says David Masopust, an immunologist at the University of Minnesota who heads the lab where Pierson works. Those efforts have paid off: with the confounding effects of pathogens controlled, mouse experiments have become less variable.

But a raft of studies now suggests that this cleanliness has come at a cost, leaving the rodents with stunted immune systems. In a quest for standardized and spotless mice, scientists have made the creatures a less-faithful model for human immune systems, which develop in a world teeming with microbes. And that could have serious implications for researchers working to usher treatments and vaccines out of the lab and into the clinic. Although it’s not yet possible to pin specific failures on the impeccable hygiene of standard mouse models, Masopust thinks the artificial environment must have some effect. It’s no secret that the success rate for moving therapies from animal to humans is abysmal — according to one estimate¹, 90% of drugs that enter clinical trials fail. “You have to wonder if you might sometimes get misinformed simply because you’re in a clean environment,” says Masopust. That’s why he and other researchers are developing dirtier models that better replicate how the immune system develops in the natural world. Some groups have given their mice infections^2,3, others a more natural microbiome^4,5. But housing the dirtier mice can be risky. Pet-shop mice carry so many infections, it’s as if they came from “a Dickensian orphanage”, says Aaron Ericsson, a microbiome researcher at the University of Missouri in Columbia. Lab-animal caretakers take biosecurity very seriously and mice are a precious resource. “The last thing you’d want to do is have some sort of an outbreak.”

More here.