Of Mice and Men and Environments

Here is one of the most important issues we face. It effects a wide array of scientific research. But it also has vast implications for our lives and our entire society. It is about the power of environments, including even the slightest of differences.

A mouse’s house may ruin experiments
Environmental factors lie behind many irreproducible rodent experiments.
by Sara Reardon, Nature Journal

It’s no secret that therapies that look promising in mice rarely work in people. But too often, experimental treatments that succeed in one mouse population do not even work in other mice, suggesting that many rodent studies may be flawed from the start.

“We say mice are simpler, but I think the problem is deeper than that,” says Caroline Zeiss, a veterinary neuropathologist at Yale University in New Haven, Connecticut. Researchers rarely report on subtle environmental factors such as their mice’s food, bedding or exposure to light; as a result, conditions vary widely across labs despite an enormous body of research showing that these factors can significantly affect the animals’ biology.

“It’s sort of surprising how many people are surprised by the extent of the variation” between mice that receive different care, says Cory Brayton, a pathologist at Johns Hopkins University in Baltimore, Maryland. At a meeting on mouse models at the Wellcome Genome Campus in Hinxton, UK, on 9–11 February, she and others explored the many biological factors that prevent mouse studies from being reproduced.

I came across this issue in a book by David Shenk, The Genius in All of Us. The book is about genetics and IQ. But he brings up many other issues, such as the difficulties and problems of research.

He discusses a mouse study that demonstrates the power of environmental factors. It is far worse than the above article indicates. Even when all known factors are carefully controlled, the results can still be far different, to the point of being divergent in particular areas.

Below is the passage from Shenk’s book (Kindle Locations 1624-1657). I’ve shared before, but it bears repeating.

To say that there is much we don’t control in our lives is a dramatic understatement, roughly on the order of saying that the universe is a somewhat large place. To begin with, there are many influences we can’t even detect. In 1999 , Oregon neuroscientist John C . Crabbe led a study on how mice reacted to alcohol and cocaine. Crabbe was already an expert on the subject and had run many similar studies, but this one had a special twist: he conducted the exact same study at the same time in three different locations (Portland , Oregon; Albany, New York; and Edmonton, Alberta) in order to gauge the reliability of the results. The researchers went to “extraordinary lengths” to standardize equipment, methods, and lab environment: identical genetic mouse strains, identical food, identical bedding, identical cages, identical light schedule, etc. They did virtually everything they could think of to make the environments of the mice the same in all three labs.

Somehow, though, invisible influences intervened. With the scientists controlling for nearly everything they could control, mice with the exact same genes behaved differently depending on where they lived. And even more surprising: the differences were not consistent, but zigged and zagged across different genetic strains and different locations. In Portland, one strain was especially sensitive to cocaine and one especially insensitive , compared to the same strains in other cities. In Albany, one particular strain— just the one— was especially lazy. In Edmonton , the genetically altered mice tended to be just as active as the wild mice, whereas they were more active than the wild mice in Portland and less active than the wild mice in Albany. It was a major hodgepodge.

There were also predictable results. Crabbe did see many expected similarities across each genetic strain and consistent differences between the strains. These were, after all, perfect genetic copies being raised in painstakingly identical environments. But it was the unpredicted differences that caught everyone’s attention. “Despite our efforts to equate laboratory environments, significant and, in some cases, large effects of site were found for nearly all variables,” Crabbe concluded. “Furthermore, the pattern of strain differences varied substantially among the sites for several tests.”

Wow. This was unforeseen, and it turned heads . Modern science is built on standardization; new experiments change one tiny variable from a previous study or a control group, and any changes in outcome point crisply to cause and effect. The notion of hidden, undetectable differences throws all of that into disarray. How many assumptions of environmental sameness have been built right into conclusions over the decades?

What if there really is no such thing? What if the environment turns out to be less like a snowball that one can examine all around and more like the tip of an iceberg with lurking unknowables? How does that alter the way we think about biological causes and effects?

Something else stood out in Crabbe’s three-city experiment : gene-environment interplay . It wasn’t just that hidden environmental differences had significantly affected the results. It was also clear that these hidden environments had affected different mouse strains in different ways— clear evidence of genes interacting dynamically with environmental forces.

But the biggest lesson of all was how much complexity emerged from such a simple model. These were genetically pure mice in standard lab cages. Only a handful of known variables existed between groups. Imagine the implications for vastly more complex animals— animals with highly developed reasoning capability, complex syntax, elaborate tools, living in vastly intricate and starkly distinct cultures and jumbled genetically into billions of unique identities. You’d have a degree of GxE volatility that would boggle any scientific mind— a world where, from the very first hours of life, young ones experienced so many hidden and unpredictable influences from genes, environment, and culture that there’d be simply no telling what they would turn out like.

Such is our world. Each human child is his/ her own unique genetic entity conceived in his/ her own distinctive environment , immediately spinning out his/ her own unique interactions and behaviors. Who among these children born today will become great pianists, novelists, botanists , or marathoners? Who will live a life of utter mediocrity? Who will struggle to get by? We do not know.