A walk on the wild side

TECHNOLOGY FEATURE A walk on the wild side Dustin M. Graham Springer Nature © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Dirty mice are helping researchers clean up translational science, but their wild ways create risks for institutions more accustomed to the prim and proper. For most immunologists, the big red barn that sits on a farm near Princeton, New Jersey, would be an odd place to store data. It has no lab benches or freezers. The inside walls are covered in cobwebs, and overhead, dusty blue tarps stretch across the rafters, arched downwards from the weight of petrified bat guano. But standing on the barn’s floor is a server, humming away as it collects wireless data from a unique source outside. The source is a circular 1,500 square-meter open-air enclosure sitting in a field at the farm’s edge. This is where LabAnimal the wild(ish) things are, and where Andrea Graham is about to start the safari. Graham, an evolutionary ecologist at Princeton University, hops over the enclosure’s fence and gathers her students for their weekly reconnaissance. Walking through the weeds, she inspects the Longworth traps her team laid out the night before, seeing if any have been tripped. Longworth traps are designed for behavioral ecologists to capture, without injury, small wild mammals, such as mice. But as Graham explains, the mice they are searching for on this farm aren’t exactly wild, not yet at least. “These guys were bred in a lab at New York University, actually, so they’re big city mice.” Spotting a trap with some movement inside, Graham scans the first catch of the day, making use of the radio-frequency chip implanted in each mouse for tracking. “Mouse 51-51-57,” Graham announces. “We caught it last time,” says Sriveena Chittamuri, a visiting undergraduate. “We have enough poop samples, but we still need urine.” Volume 46, No. 11 | NOVEMBER 2017 423 Springer Nature SAFE HAVEN | Pie plates tied across strings above the outdoor enclosure help keep away birds. The group carefully moves the mouse to a clean cage to collect fresh excreta for microbiome analysis. Afterwards, they open the cage, and the mouse, no worse for the wear, scampers back into the weeds that are full of life, but free of predators. Graham says that for the next two months, she and her students will repeat this unique ‘catch-and-release’ strategy in the outdoor enclosure with the same group of lab mice. Her students will collect samples from the mice every 10–14 days, to quantify changes in the mice’s microbiomes after exposure to a microbial world they have never seen before, but one that most other animals, including humans, come into contact with everyday. “We’re basically asking, how rapidly can we convert a hygienic lab mouse into a more natural mouse,” says Graham. “We call it ‘rewilding’.” By taking lab mice from Manhattan and setting them free on a farm in New Jersey, Graham hopes to better understand how changes in the microbiome can impact immune system mechanisms regulating parasitic worm infections. More broadly, she wants to see if adding a touch of the real world into her immunology experiments can affect genotype-phenotype relationships in mouse models of human disease, which could reveal their potential for translatability. But given the controlled confines that biomedical research t ypically operates with424 Volume 46, No. 11 | NOVEMBER 2017 in, mucking around with mouse models— and their environments—can get messy. Feral phenotypes Stephen Jameson and David Masopust, immunologists at the University of Minnesota, have also been dirtying up their lab mice to see how it impacts immune phenotypes, but rather than taking their mice into the wild, they’ve been bringing the wild to them. In a recent paper published in Nature, their teams compared the immune systems of clean lab mice with dirty pet shop mice and found that not only did pet shop mice have immune systems that better mimicked those of adult humans, but when used as ‘dirty roommates,’ pet shop mice could transfer their adult human-like immune system phenotype to previously clean lab mice, demonstrating a role for the microbiome in driving the changes1. Eleanor Riley, Director of the Roslin Institute at the University of Edinburgh, calls results like these “immunology’s dirty little secret.” For years she’s done research on infectious disease in humans and also in lab mice, and has been “aware for a while that the results you get in mice, just like in humans, really depends on where they come from.” In a recent paper with collaborator and helminth parasitemia expert Mark Viney, from the University of Bristol, she looked at the immune systems of feral mice from all over the UK—including farms and the London Underground—and compared them with clean lab mice 2. In line with Masopust’s and Jameson’s work, they found several quantitative and qualitative differences in dirty (wild) vs. clean (lab) mice immune systems, differences that she believes need to be taken into account by more translational scientists. “We see in humans that a difference in environments really helps to calibrate our Springer Nature © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. TECHNOLOGY FEATURE TRAPPER KEEPER | An example Longworth trap used for catching mice in the enclosure. www.nature.com/laban immune response, and that’s exactly what we’re seeing in lab vs. wild mice. And so by extension, when you’re translating a drug from a lab mouse to a human, you’re jumping from very clean to dirty environments, as well as across species, and I think that complicates the translation.” Adding some studies with dirty animals before clinical trials, Riley says, could help spot treatments earlier in the pipeline that work only under artificially neat and tidy conditions; conditions unlikely to be encountered by most humans. But even if adding a little dirt can go a long way towards improving the translatability of disease model research, it’s difficult to know how it will impact a study’s reproducibility, another hot-button issue in biomedical research. “Everyone wants reproducible results,” Riley says, which usually means eliminating variables, not adding more of them. Biomedical research has adopted the reductionist approach with great success, she says, and going out into the wild (or bringing it into the lab) might help to improve translation, but needs to be balanced with reproducible outcomes. “There’s a kind of tension between getting highly reproducible data, which I absolutely understand, and the need to have a more real-world solution.” Nowhere is that tension greater than in the animal care facilities that house the models used for research. After thirty years and millions of dollars spent cleaning up these facilities, institutions are hesitant to roll out the red carpet for dirty animals. A culture of clean When Masopust’s and Jameson’s pet shop paper came out in Nature, says Ken B (...truncated)