Scientists kill 192 million lab mice each year. Is there a better way?

Scientists stress out lab mice, a lot. Inducing chronic stress and anxiety in these furry critters is how scientists explore the bodily and cognitive effects of stress and discover anti-anxiety medications for humans.

There are two primary ways researchers stress out a lab mouse: immobilization and restraint. As described in the Encyclopedia of Stress (Second Edition), immobilization involves “taping the four limbs of a rat or mouse to mounts secured to a metal frame using hypoallergenic tape. A pair of metal loops attached to the frame limits the range of motion of the animal’s head…The duration of a single episode of immobilization usually varies from 5 to 120 min or more. In addition, animals in chronic stress protocols may be immobilized each day for many weeks even months.”

Psychologist Richard McCarty described the effects in the journal Psychoneuroendocrinology.

“The struggling that is typical of the first several minutes of an immobilization session places great pressure on the four limbs and animals are often physically exhausted at the end of an immobilization session.”

Other than immobilization, scientists might elect to stress out lab mice via restraint, in which critters are “secured in a plastic tube or a wire-mesh container that is small enough to prevent the animal from moving about or turning.” Mice are forced to endure this protocol for hours a day over weeks.

The bigger picture

Scientists are not bad people. For most, their overarching goal is to uncover new knowledge that betters the human condition and the broader world. But in that noble pursuit, they sometimes do things that fall into an ethical gray zone. Animal research is one of them. And 95% of all the animals involved are rats and mice.

Beyond psychological stress, scientists expose lab mice to starvation, pain, physical harm, and death. Blood is drawn in a variety of ways — sometimes deadly, sometimes not. Tails are snipped, holes are punched in ears, and toes are severed. Researchers and lab technicians carry out these activities all the time, for genotyping, identification, and data collection. This day-in and day-out doesn’t just take a toll on the animals, but also on their handlers.

Dr. Bernard E. Rollin, a professor of philosophy and animal sciences at Colorado State University, called attention to their mental health in a 2011 paper.

“Many research technicians… go into the field of animal research to help the animals, yet their day-to-day work ends up being the killing of animals or being complicit in creating pain, distress, disease, and other noxious states demanded by the research Enterprise.”

A good death?

Perhaps the most traumatizing part of the lives of lab mice, for both researcher and animal, is ending them. An estimated 192 million rodents, mostly mice, are studied and sacrificed each year in labs worldwide.

Lab mice meet their ends in a variety of ways, all of them regulated to be humane (though approved methods differ depending upon the country). Overdose of anesthetic, concussion by blunt force trauma, cervical dislocation, decapitation, exposure to carbon dioxide (CO2), and microwave irradiation are the most common. But if you’re of the opinion that “humane death” is an oxymoron, there’s a plethora of evidence to support you.

“The majority of rodents are conscious during handling and the application of killing methods and are therefore capable of experiencing negative states (e.g. pain and fear) until they lose consciousness,” a trio of UK-based animal researchers wrote in a thorough 2022 review of the practice of killing laboratory rodents.

They note that cervical dislocation, which involves “placing the finger or an instrument behind the base of the skull while pulling the tail firmly to achieve rapid separation of the high cervical vertebrae” is widely considered “to induce rapid unconsciousness due to concussion and damage to the brain.” But at the same time, there’s very little scientific evidence to actually support the view that the act produces a humane death — or even a reliable one.

“Work to date concurs that cervical dislocation is particularly susceptible to a high failure rate and that proper technique is crucial,” they wrote.

Then there’s decapitation, often carried out on conscious lab mice using small guillotines. Studies tracking the brain activity of mice indicate that the animals maintain consciousness for anywhere from three to 14 seconds after beheading, a disturbing notion.

Carbon dioxide exposure is by far the most commonly used technique to extinguish laboratory rodents.

“Some systems are fully automated and enable the animals to be killed in their home cage along with their cage mates, which offers several advantages over physical methods, such as its high-throughput and non-contact nature, elimination of stress associated with handling, isolation and restraint, as well as minimizing the impact of operator error,” the authors noted.

But this method has problems, too, which the reviewers say warrants discontinuing its use, unless lab researchers are “exploiting its high-throughput advantage”.

Chief among them, new evidence suggests that mice killed with carbon dioxide experience breathlessness — and worse — “air hunger,” the conscious appreciation of an urge to breathe, which humans find to be uniquely and primally uncomfortable.

Moreover, lab mice exposed to carbon dioxide have been observed running around, jumping, rearing, gasping, defecating, and urinating before death finally relieves them of their overt distress.

Mice lives matter

Is there anything that can be done to improve the welfare of lab mice? For starters, marking animals for identification doesn’t need to be a traumatic experience. Painless methods involving special dyes and markers are available. Second, antiquated methods of inducing stress, like the aforementioned immobilization technique, could be prohibited. Most importantly, lab mice can be granted quick, painless deaths. Current methods don’t do this reliably.

Novel techniques for sacrificing lab mice are rolling out now. Focused beam microwave irradiation is one of them. It involves rapidly heating the rodent brain with a high-energy beam. Mice reportedly lose consciousness in less than half a second. Unfortunately, the equipment for granting mice this swift end is costly, limiting wide adoption.

Hypobaric hypoxia, gradually decreasing the pressure in a chamber, causing death by lack of oxygen, is a cheaper alternative. In a study published last year, scientists compared it to carbon dioxide exposure. They found that while hypobaric hypoxia took longer to result in death — just over six minutes vs. under four minutes — the lab mice displayed fewer signs of pain and anxiety.

But while some researchers focus on bettering the lives of lab mice, others look to replace them entirely.

No more mice?

Professor Paul A. Locke is a Professor of Environmental Health and Engineering at Johns Hopkins Bloomberg School of Public Health, affiliated with the university’s Center for Alternatives to Animal Testing (CAAT). CAAT’s ultimate aim is to minimize the number of animals used in scientific research. Still, Locke thinks that animal models are useful and that the scientists who use them should not be vilified.

“We don’t always know as much as we would like to know about the underlying biology,” Locke told Big Think. “We’re shining a flashlight into a dark cave. While animal models don’t give us the information that we always need, unfortunately right now they’re one of the few tools we have.”

Scientists use lab mice to develop new human medicines, ensure that consumer products and environmental chemicals are safe, and uncover new biological knowledge that could lead to useful advances down the road. While those are all worthwhile aims, the general public isn’t convinced that animals should be used for them.

Polling firm Morning Consult surveyed 2,205 adults in September of this year. More than eight in ten respondents agreed with the statement: “Animal experimentation should be phased out in favor of more modern research methods.”

In step with public opinion, in 2022, President Biden signed a bill doing away with a longtime requirement that every new drug seeking FDA approval first be tested on animals. This year, the National Institutes of Health is launching a $300-million fund supporting the development, validation, and testing of alternatives to animal research.

And there are very promising alternatives. Models based on human cells and tissues grown outside the body attract a lot of attention. One researcher at Johns Hopkins University uses blood samples from Alzheimer’s patients to create stem cells. She then turns these into brain organoids, which eventually show signs of Alzheimer’s. Scientists can then test drug candidates on the organoids.

There are also microphysiological systems, so-called “organs-on-a-chip.” These contain engineered or natural miniature tissues grown inside microfluidic chips. Each emulates the physiology of a certain organ, like the liver or kidneys.

Computer simulations also show potential. In what’s been dubbed “in silico testing”, data scientists can task computers with analyzing the structures of drug candidates and predicting how they will affect living systems. Rapidly advancing artificial intelligence will surely speed up progress in this area.

We’re not there yet

To be clear, these novel approaches can’t replace lab mice yet. Locke noted that animal testing has been ended for a lot of consumer products, particularly cosmetics. Moreover, a Congressional rewrite of EPA’s Toxics law (TSCA) has put the agency on a path towards phasing out animal research for toxicology purposes in the next few decades. However, we’re nowhere near being able to remove lab mice from drug discovery and basic research.

That’s mostly because those two areas use the most lab mice, not necessarily because lab mice are better than animal-free alternatives. As Thomas Hartung, the Doerenkamp-Zbinden Chair Professor of Environmental Health and Engineering at Johns Hopkins and the Director at CAAT, noted in a review paper published earlier this year, animal studies are far from perfect, and often highly misleading. They frequently result in false negatives and false positives, and miss safety risks later discovered in human trials.

A host of factors limit the accuracy of animal studies, Hartung explained. These include biological differences, molecular differences altering drug effects, and the simple fact that what mice eat and how they live differ drastically from human lifestyles. Moreover, many mouse studies are small and short, and high dosing of tested substances can trigger irrelevant effects.

While animal research has in the past been considered essential to the drug discovery process, the reality is that roughly 90% of novel drugs that work in animal models fail in human clinical trials. That’s because rodents are not humans. Though mice and humans share 92% of their DNA and have identical genes, our bodies behave differently to the same substances. In one recent study, researchers compared the expression of individual genes within the same cell type in both mice and humans. They found that two-thirds of all genes shared between mice and humans are expressed differently.

The researchers working on alternatives are convinced that we can do better and that these alternatives will save time, money, and the lives of both humans and rodents. Emerging evidence is backing this rosy outlook, but Locke says that regulatory agencies at the federal level are currently not doing enough to accelerate change. The Food and Drug Administration has not yet accepted alternative data for drug discovery applications. And the National Institutes of Health needs to reform training grants so young scientists can be educated on animal alternatives.

“The federal government needs to take the lead here and they’re not exerting the leadership now that they should,” Locke said.

“Law and science are fellow travelers. You’re not going to have advances in science unless you have advances in law and policy. The scientists can’t do it alone. They need help. We have to put pressure on our federal agencies to be leaders in this area.”