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An illustration of lab mouse hiking in nature.
Illustration by Laurie Rowan
Annals of Inquiry
The Case for Free-Range Lab Mice
A growing body of research suggests that the unnatural lives of
laboratory animals can undermine science.
By Sonia Shah
February 18, 2023
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The experiment that became known as the Elephant Man trial began one
spring morning, in 2006, when clinicians at London's Northwick Park
Hospital infused six healthy young men with an experimental drug.
Developers hoped to market TGN-1412, a genetically engineered
monoclonal antibody, as a treatment for lymphocytic leukemia and
rheumatoid arthritis, but they found that in just over an hour, the
men grew restless. "They began tearing their shirts off complaining
of fever," one trial participant, who received a placebo, told a
London tabloid. "Some screamed out that their heads were going to
explode. After that they started fainting, vomiting and writhing
around in their beds." The heads of some of the subjects swelled to
elephantine proportions. Within sixteen hours, all six were in the
intensive-care unit suffering from multiple organ failure. They had
narrowly survived a potentially fatal inflammatory response known as
a cytokine storm.
The trial grabbed headlines and sent a "shock wave" through the
scientific community, as one of the developers of the drug later
wrote. A subsequent review found a few sloppy medical records and an
underqualified physician associated with the study, but nothing that
could explain a central mystery: the drug had already been tested on
rodents and monkeys. Lab animals had tolerated doses that--after
adjusting for the animals' weights--were five hundred times greater
than the ones that nearly killed the young men. Why did animal
experiments fail to warn scientists that TGN-1412 was dangerous?
Because so many of our genes are shared with other vertebrates,
scientists have generally assumed that whatever harms lab animals is
likely to harm humans, too. The Food and Drug Administration requires
preclinical tests, traditionally on two species of non-human animals,
before drugs can be tested on people. Yet a 2014 analysis of more
than two thousand drugs found that animal tests were "highly
inconsistent" predictors of toxic responses in humans and "little
better than what would result merely by chance." More than eighty per
cent of novel drugs fail in Phase I and Phase II trials--when they're
first tried in healthy volunteers and patients--and others fail in
Phase III, which are large-scale efficacy trials; as of 2009, these
unsuccessful human trials were consuming seventy-five per cent of
drug-research and development costs. Fifteen per cent of drugs,
including blockbuster remedies for conditions such as depression and
arthritis, turn out to have dangerous toxicities even after they're
approved by the F.D.A.
When lab-animal studies fail to predict human responses, scientists
typically scrutinize them for mistakes (maybe lab workers
contaminated cell lines; perhaps they failed to authenticate
reagents) or blame the differences between species. "A mouse is not a
person" has become a running joke. The problems with animal
experimentation, however, go deeper than that: some studies of
standardized lab animals can't even be replicated on identically
standardized lab animals. In 2012, a Nature paper revealed that
scientists at Amgen, a multibillion-dollar biotech company, had spent
a decade trying to repeat landmark animal studies and had succeeded
only eleven per cent of the time. The following year, at an N.I.H.
review board meeting, Elias Zerhouni, a pharmaceutical executive who
had directed the N.I.H. during the Bush Administration, likened
science's reliance on lab-animal research to a mass hallucination.
"We all drank the Kool-Aid on that one, me included," he said. "It's
time we stopped dancing around the problem." (Later, after an outcry
from advocates of the biomedical-research industry, Zerhouni walked
back his comments.)
The global animal-testing industry is worth billions of dollars and
counting. Scientists experiment on some hundred and twenty million
lab mice and rats per year. But, as the industry continues to grow,
problematic results continue to emerge. Last May, European scientists
reported in the journal PLOS Biology that they had conducted an
identical experiment on identical mice in three separate labs. They
found that the mice behaved differently in each setting, a result
that they could only attribute to Rumsfeldian "interactions between
known but also unknown factors we are not even aware of." Can animal
experiments still be trusted?
Scientists have been experimenting on animals for centuries to solve
anatomical and physiological mysteries. In the twentieth century,
researchers used animals to calibrate therapeutic doses: one "rabbit
unit," for example, was the amount of insulin required to produce
convulsions in a rabbit. However, animals from the same species
varied in their responses to drugs, in part because scientists
acquired them from pet breeders and hobbyists. One study in the
forties found that a batch of diphtheria antitoxin protected some
guinea pigs from the disease, but not others, depending on whether
they'd been reared on green vegetables or beets. The British Medical
Journal published an article with the title "Wanted--standard
guinea-pigs."
Many mid-century scientists viewed lab animals as lower creatures,
even automatons; some hoped to breed them into "pure" and "uniform"
animals, as the geneticist Clarence Cook Little put it during a
congressional hearing in 1937. They assumed that variation between
animals was determined by genes and germs, so they bred mouse
siblings with one another, shielded the mice offspring from a range
of microbes, and then repeated the process for many generations of
inbreeding. (James A. Reyniers, who was later nominated for the Nobel
Prize in Physiology or Medicine, went so far as to surgically remove
animals from the wombs of their mothers and rear them in airtight
steel chambers; in 1949, Life published photographs of monkeys in his
lab and declared, "The research possibilities are virtually
limitless.")
Commercial suppliers marketed lab animals to all manner of
scientists--geneticists, immunologists, neuroscientists,
oncologists--in thick catalogues that described their technical
specifications as though they were test tubes or Bunsen burners.
Standards for the certification and transportation of lab animals
were codified by UNESCO. Experiments on standardized lab animals
spread across the globe and led to new insights into human biology,
accelerated the development of breakthrough medical products such as
vaccines and cancer drugs, and earned lab-animal researchers dozens
of Nobel Prizes.
Animal experiments rested on the notion that humans and other mammals
are kindred creatures, but for many scientists that kinship was
solely physical, not mental. They tended to dismiss the idea that
animals have minds and emotions that are comparable to our own, which
Charles Darwin argued in the nineteenth century, or that "each and
every living thing is a subject that lives in its own world," as the
Estonian biologist Jakob Johann von Uexkull wrote, in 1934. Such
beliefs were even caricatured as symptomatic of "zoophil-psychosis,"
a supposed psychiatric condition defined in 1909 as "an inordinate
and exaggerated sympathy for the lower animals" and the "delusion
that they are persecuted by man."
This may be why puzzling irregularities in early studies did not
prevent lab-animal experiments from becoming an industry standard. A
1954 Nature paper, for example, reported that when scientists
injected inbred mice with sedatives, the inbred mice took wildly
different times to fall into a stupor, whereas hybrid mice reacted to
the drugs within a more predictable window of time. Just because two
mice have near-identical genes does not mean that they will develop
the same physical traits, the authors wrote; they may even be
"strikingly more variable" than genetically diverse mice. That same
year, another paper reported that lab animals with nearly
indistinguishable genes had dramatically different skeletal
structures--a finding that British geneticist Hans Gruneberg vaguely
blamed on "intangible factors" and "accidents of development." But as
long as animal studies were unlocking new biomedical insights and
therapies, there were few incentives to contemplate the lives of lab
mice.
The idiosyncrasies of lab animals garnered new attention after the
explosive Amgen paper in Nature, in 2012. In a wave of subsequent
papers, other scientists described failures to reproduce published
research in medicine, psychology, and many other fields. In 2014, as
concern about a "replication crisis" grew, a cover story in the
medical journal The BMJ declared animal research a "shaky basis for
predicting human benefits." A growing body of evidence was suggesting
that a variety of subtle, uncontrolled factors affected lab animals'
bodies and behaviors.
Rodents respond differently to experimental drugs depending on the
levels of phytoestrogens in their chow--levels that can vary between
different batches from the same vender. Their microbiomes, which
contribute to their immune function, vary from vender to vender and
from lab to lab. Many lab mice today come from an inbred strain known
as C57BL/6, or Black 6, which originated with a pair who were mated
in the nineteen-tens or twenties. Yet "there is no such thing as a
Black 6 mouse," Joseph Garner, a professor of comparative medicine at
Stanford, argued recently when we spoke via Zoom. "There's the Black
6 mouse in my lab, on my diet, in my cages, with my noise exposure,
my light exposure, and my technician. And literally in the lab down
the hall, the Black 6 mouse is different." The dream of scientists
like Little, of animals that had completely lost their individuality,
never came true.
Standardized laboratory conditions turn out to affect the animals
that scientists are trying to study, potentially distorting the
results. According to a recent meta-analysis co-published by Georgia
Mason, the director of the Campbell Centre for the Study of Animal
Welfare, at the University of Guelph, who mentored Garner, the
standard lab-mouse cage--a plastic container the size of a
shoebox--sickens its inhabitants and increases their risk of death.
These cages can make its inhabitants cognitively pessimistic, mess up
their sleep, and reduce their physiological resilience, compared with
rodents who are given the opportunity to burrow, explore, and
exercise. Researchers have also found that mice experience a spike in
stress hormones when their cages are moved, and their behavior can
change depending on the height at which their cages are stacked. The
ambient temperature in lab-animal facilities, though comfortable for
humans, inflicts chronic thermal stress on rodents; Cindy Buckmaster,
a former director of the Center for Comparative Medicine at Baylor
College of Medicine, compared their experience to that of a human
unclothed in forty-five-degree-Fahrenheit weather. Imagine a study in
which subjects are chronically cold, sleep-deprived, inbred, and held
captive in cramped conditions. If the subjects were human, the
scientific establishment would dismiss such a study as not only
unethical but also irrelevant to normal human biology. Yet, if the
subjects were non-human, the study could be treated as perfectly
valid.
Jeffrey Mogil is a neuroscientist at McGill University who studies
pain perception. In 2010, he and his collaborators filmed mice before
and after they received shots of pain-inducing acetic acid. They used
the footage to develop a "Mouse Grimace Scale," which uses mouse
facial expressions to measure their level of pain. Then, in 2014, one
of his postdocs told him about a strange occurrence in the lab. The
postdoc had administered a pain-inducing chemical to lab mice, but
the mice had failed to lick themselves in response. Then he turned
his back to depart, and they started licking. "They were just waiting
for me to leave the room," he told Mogil.
The mice's pain response, Mogil said, seemed to be more than a
mindless reflex: they seemed to adjust it in response to a human's
presence. "People at meetings for a number of years had sort of
whispered about this," Mogil told me. In a series of subsequent
experiments, his team observed fewer "pain behaviors" when a man--or
even a T-shirt that a man had worn--was nearby. An editorial
accompanying these findings noted their "extremely wide-ranging
implications for physiological and behavioral research." When Mogil
went back and analyzed his past work, he found that in all his
experiments, the mice had shown a higher threshold for pain when
handled by male researchers. If so, animal studies of painkillers or
drugs with painful side effects could contain systematic errors,
simply because of the makeup of a laboratory's staff.
We will probably never know all of the factors that influence the
lives of lab rodents. Some rodents can sense magnetic objects and
ultrasounds that go undetected by humans. Even animals that have
lived indoors for hundreds of generations, under artificial light and
in hermetically sealed cages, notice the seasons and adjust their
behavior accordingly. "Are they detecting odors that come in through
the outside air, and they can, like, smell the smell of new leaves?"
Mason asked. "Is it something to do with sunspots? I've got no idea."
Animal-welfare specialists such as Mason and Garner argue that
scientists should worry about these hidden variables not only because
they could influence research but also because of their ethical
implications. If even an inbred and microbially sterile lab mouse,
living in isolation, has subjective experiences that go beyond human
detection--something that Darwin and von Uexkull may have argued long
ago--then perhaps we need to treat the lab animal as more than
biological machinery. Perhaps we should see her as a sentient being
entitled to our moral attention.
There's no straightforward way to purge the literature of the
innumerable lab-animal studies that in retrospect seem suspect. "It's
like the Titanic," a retired pharmaceutical-industry insider, who
requested anonymity to speak openly about problems in lab-animal
research, said. "We found it, but getting it up from the bottom of
the ocean is gonna be impossible." Flawed studies may have smothered
life-saving insights and interventions, because animal experiments
rendered a misleading negative result. Others have likely sent
researchers down scientific dead ends. "Young researchers could base
an entire career on that path and then find out much, much later,
'Well, wait a minute, I can't replicate this,' " Buckmaster told me.
"What if your whole career was based on what was found previously,
and you've got hundreds of papers? Do you have to retract those
papers? Do you lose your job? Do you lose your reputation and
standing?"
Still, some critics of animal experimentation have difficulty
imagining a future without any lab-animal experiments. When
scientists try to understand complex biological systems by
simplifying them--an approach known as reductionism--an experiment on
standardized lab animals can sometimes work "beautifully," Mason told
me. Mice share a large majority of their genes with humans and suffer
many of the same illnesses, and they can be bred cheaply and have a
conveniently compressed lifespan. It's true that many lab-animal
experiments render indeterminate results, Buckmaster told me. But
"there's this sort of small percentage of really translatable stuff
happening," she said, which is why "millions and millions of people
are still alive and healthy." She argued that incremental refinements
in study design and animal husbandry could boost that percentage, and
also improve animal welfare.
Over time, scientists have adopted expensive and complicated
safeguards to separate fact from fiction: increased sample sizes,
elaborate statistical techniques, arduous peer review. Papers that
survive this gantlet are subject to follow-up studies in other labs,
using different protocols and different species. At the same time,
government agencies have acknowledged the need to reduce reliance on
animal experiments. The F.D.A. has set aside five million dollars in
funding aimed at developing reliable alternatives to animal trials,
such as in-vitro experiments and "organs on a chip," which are
three-dimensional organoids grown from human stem cells. The N.I.H.
encourages biomedical researchers to use fewer lab animals and
minimize their suffering, if it's possible to do so without impinging
on scientific integrity--and also recommends that the rest of us
temper any starry-eyed expectations of sweeping scientific progress.
"All research is not expected to translate to human treatments, as
there is no perfect model," a working group that advises the N.I.H.
on animal research declared in a 2021 report. "Scientific process is
as much about failure as it is about success."
A few scientists are experimenting with a more radical approach. In
2013, Stephan Rosshart, then a postdoc at the N.I.H., tried to find
out why animal experiments had failed to warn scientists about
TGN-1412, the experimental drug in the Elephant Man trial. He
wondered whether sterile lab conditions had stunted the animals'
immune systems, so he developed a new kind of lab mouse by trapping
wild female mice, implanting lab-mouse embryos into their wombs, and
raising the offspring in a remote quarantine facility in Poolesville,
Maryland. His superiors probably saw him as "one crazy postdoc,"
Rosshart told me--but his mice, which he dubbed "wildlings" after
independent tribes in "Game of Thrones," proved him right. When he
exposed them to TGN-1412, the level of cytokines in their blood
spiked, just as it had in the unfortunate volunteers at Northwick
Park Hospital. His wildlings also correctly predicted the human
response to an experimental sepsis treatment, which had appeared
effective in standard laboratory mice but had failed when tested on
sepsis patients. If researchers had these mice, they "could have
potentially prevented these trials from happening," Rosshart, who now
directs the department of microbiome research at the University of
Freiburg Medical Center, in Germany, said at a recent conference.
Early successes like Rosshart's suggest a striking possibility--that
in some cases, scientists could learn more about human biology from
animals that live less sterile and more natural lives. A handful of
scientists have co-housed lab mice with pet-store mice, or have given
them fecal transplants from wild mice to naturalize their immune
systems. At the University of Utah, the biologist Wayne Potts
unleashed some of his lab mice into barn-like structures, where they
can socialize and mate; so far, his cage-free mice have accurately
predicted the health effects of high-fructose corn syrup, the statin
Baycol, and the antidepressant Paxil. (They failed to predict side
effects to a discontinued arthritis drug, Vioxx.)
Neither Rosshart nor Potts is calling for an end to traditional
experiments on caged lab animals, which they still consider useful
for reductionist research. Still, their vision of the uncaged lab
animal acknowledges that lab animals have many of the same needs as
humans--which could undermine the usual justifications for
standardizing their bodies and their lives in the first place. What
if the best animal to model our shared biology is one that lives a
relatively unconstrained life, like we do? Garet Lahvis, a
neuroscientist who abandoned animal experiments a few years ago, has
urged his former peers to move lab animals into "research barns," and
to treat them as sentient beings, not "psychologically inert
automatons." Mogil, the McGill neuroscientist, told me, "I do see a
day where we might be able to do experiments without ever
interrupting the normal or semi-normal social life of the animals
we're testing." Such animals would suffer less; humans might learn
more.
On a gold-tinted morning last July, I visited Andrea L. Graham, a
Princeton evolutionary immunologist, at her field site in the hills
of central New Jersey. We stood by a waist-high fence that encircled
a clearing in the woods. Graham, who wore a floppy hat and purple
examination gloves, told me about the mice that live here. Just a few
weeks ago, their cages were stacked in the basement of a biology
building at Princeton. Graham had whisked them away in a white van
and, in a process she describes as rewilding, released them into her
grassy enclosure.
Graham's team had risen at dawn to collect mice from traps inside the
area. Afterward, Alec Downie, a gangly graduate student with a bushy
red ponytail, sat at a folding table and inspected a small female
mouse with soft, gray-black fur. "Yeah--this is non-standard
procedure," Downie told me.
As the mouse furiously sniffed the air, I thought about the smooth
plastic walls within which she and hundreds of generations of her
ancestors had spent their entire lives. In this clearing, she had
smelled fresh air and felt rain on her fur for the first time.
Exactly how these experiences might have changed her was not
immediately apparent. But Graham's team would extract some of the
mouse's blood, test it in a field lab that they had set up in a
nearby barn, and compare the results with the blood of laboratory
mice that had never been outdoors. So far, Graham has found that even
brief spells in natural settings transform the immune systems of lab
mice, making them more like the immune systems of humans. The
difference between a rewilded mouse and a lab mouse can be even more
dramatic, she told me, than the difference between two lab mice from
separate genetic lines. In a 2021 review paper, Graham called on her
colleagues to venture beyond their immaculate labs and "go where the
wild things are."
When their field work wound down for the day, Graham's team fetched
cans of seltzer and retreated to folding chairs. As they relaxed, a
sharp call emanated from the trees.
"That's a weird noise," Graham said quietly. "It sounds like a
raptor."
The group visibly tensed. A few put down their seltzers and craned at
the foliage; one offered that the call might have come from a
harmless blue jay. Graham, unconvinced, called out to any predators
that might be nearby: "Go away!" But there's only so much that can be
done to protect a rewilded animal.
That day, despite the team's best efforts, about a third of Graham's
free-range mice eluded recapture. Perhaps some were hiding in the
leaf litter or had fallen victim to birds of prey. Later that week,
the team would try to retrieve more. This was not the shining vision
of limitless science that once appeared in Life magazine but a murky
thicket in which animals themselves were helping to inscribe borders
around what science can know. I imagined lab mice that had dug into
the soft earth, tunnelled under the metal fenceposts, and slipped
into the woods. They took their data with them, and were lost to
science forever.
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Sign up for our daily newsletter to receive the best stories from The
New Yorker.
Sonia Shah is a science journalist in Baltimore and the author of
five books, including "The Next Great Migration: The Beauty and
Terror of Life on the Move" and "Pandemic: Tracking Contagions, from
Cholera to Coronaviruses and Beyond."
More:ScienceMedicineHealthAnimalsLab RatsAnimal Testing
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