Of mice and men: Lab rodents react differently to male researchers than female

April 29, 2014 – It turns out the best-laid research plans involving mice and men have a bit of a wrinkle ­– the lab rodents appear to react differently to male scientists during experiments than they do to females.

And that could skew results of numerous medical studies in which the critters are used as stand-ins for humans, suggests Jeffrey Mogil, a professor of behavioural neuroscience at McGill University, whose lab set out to test the responses of mice to male versus female experimenters.

Mogil directs a group of scientists who focus on pain, including its
genetic and neurological underpinnings. Part of their work involves
inducing discomfort in lab mice with the ultimate goal of finding drugs
that can relieve pain in humans.

But a funny thing kept
happening: sometimes, the mice didn't react as expected when given an
injection in a limb meant to induce pain and pain behaviours, including a
specific set of facial expressions known as the mouse grimace scale
previously developed by Mogil's lab.

Initially, the experimenters thought there was something wrong with the inflammatory agent they had injected.

Yet
when they left the room, the mice would start exhibiting signs they
were in pain, suggesting that the experimenters themselves were somehow
causing pain inhibition – or analgesia – in the animals.

“This
was something that people had sort of whispered about at (scientific)
meetings for years, but as far as we can tell, no one ever tried to
investigate whether it was true,” said Mogil, who asked his lab to
conduct dozens of studies to determine whether the suspicion had any
validity.

“And to our great surprise it was true, but only
half-true because it was only male experimenters and not female
experimenters (that affected the mice),” he said from Montreal.

In their study, published online in the journal Nature Methods,
Mogil's team showed that lab rodents become stressed in the presence of
male researchers. Stress leads to the release of chemicals in the body
that act as pain suppressors.

And the underlying reason for this rodent response? Males smell different than females.

“We
found that this was olfactory because we could replace the male
experimenter with a T-shirt worn by a male and that also produces
analgesia,” he said. “And it has nothing specifically to do with humans,
because you can use bedding from almost any animal, as long as it's
male and has testosterone.

“They're not analgesic to bedding of
mice they know. They're only analgesic to bedding of mice they don't
know or guinea pigs or rats or cats or dogs, it doesn't matter.

“What's
driving this effect are olfactory stimuli that are released from the
armpit, specifically ones that are released from the armpits of men in
higher concentrations than in women.”

The finding is important
because researchers need to be aware that the sex of an experimenter may
alter the outcome of tests – and that could potentially invalidate
research conclusions.

“There's been a lot of wringing of hands
and gnashing of teeth over the last year or so about the idea that
pre-clinical research doesn't replicate,” said Mogil, explaining that
scientists have not been able to reproduce the findings of some
high-profile studies involving animal models like lab mice.

Being
able to repeatedly get the same results when studying an experimental
drug or procedure from one study to another is the gold standard of
medical research.

So when animal research findings can't be
replicated, some researchers conclude they must be invalid, caused
perhaps by false-positive test results.

“What these data suggest
strongly,” Mogil said of his lab's findings, “is that there's another
explanation, that they're not false positives at all. What it is is that
different laboratories have slightly different environments where their
studies are conducted.

“So I think this provides a big part of
the reason why it's so hard to replicate. You change any little thing in
the laboratory environment and your results will be different.”

Douglas
Wahlsten, a genetic neuroscientist who has studied mouse behaviour
extensively, says the McGill paper shows “very strong evidence” that
chemical odours emanating from males can influence test results.

But
Wahlsten, a professor emeritus at the University of Alberta, said
similar studies need to be done using different strains of lab mice, as
well as in different laboratory environments to see if the findings hold
up.

“The way a lab is built and set up, the way the air
circulates… are really critically important when you want to study
odours,” he said from Salt Spring Island, B.C., where he now lives.

Wahlsten
believes the McGill study will have some influence on other
researchers, and he noted the so-called experimenter effect “needs to be
taken very seriously.”

“I think that the gender of the person
doing the test is a factor, and they've shown this,” he said. “It's
something we need to be aware of and we need to control for it to the
extent that we can.”

Mogil said the study obviously doesn't mean
that scientists should get rid of male experimenters and hire only
females, but should take the gender difference into account when
analyzing data and reporting results.

“This is an example of
things we should be taking into account, but we don't. People simply
don't put in the methods section (of their published studies) what the
gender of the experimenter was.

“But these data suggest that starting now, they really need to.”

The goal of studies like this is to show scientists how to do better research, no matter what issue they are examining, he said.

“This is a finding that's going to make scientific research better, more reliable than it's been before.”