Medicine Has a Rat Problem

It’s stranger than you think.

a green rat on a zig-zag background
Daniel Zender / The Atlantic; Getty

Thirty years ago, antidepressant research seemed on the verge of a major breakthrough. Years of experiments with laboratory rats and mice—animals long considered “classic” models for the condition—had repeatedly shown that a new drug called rolipram could boost a molecule in the rodent brain that people with depression seemed to have lower levels of. Even guinea pigs and chipmunks seemed susceptible to the chemical’s effects. Experts hailed rolipram as a potential game changer—a treatment that might work at doses 10 to 100 times lower than conventional antidepressants, and act faster to boot.

But not long after rolipram entered clinical trials in humans, researchers received a nasty surprise. The volunteers taking rolipram just kept throwing up. Terrible bouts of nausea were leading some participants to quit taking the meds. No one could take rolipram at doses high enough to be effective without experiencing serious gastrointestinal distress. Years of hard work was literally getting flushed down the tubes. Rolipram wasn’t alone: Over the years, millions of dollars have been lost on treatments that failed after vomiting cropped up as a side effect, says Nissar Darmani, the associate dean for basic sciences and research at Western University of Health Sciences.

The problem in many of these cases was the rodents, or, maybe more accurately, that researchers had pinned their hopes on them. Mice and rats, the world’s most commonly used laboratory animals—creatures whose many biological similarities to us have enabled massive leaps in the treatment of HIV, cardiovascular disease, cancer, and more—are rather useless in one very specific context: They simply can’t throw up.

Vomiting, for all its grossness, is an evolutionary perk: It’s one of the two primary ways to purge the gastrointestinal tract of the toxins and poisons that lurk in various foodstuffs, says Lindsey Schier, a behavioral neuroscientist at the University of Southern California. But rodent bodies aren’t built for the act of throwing up. Their diaphragm is a bit wimpy; their stomach is too bulbous, their esophagus too long and spindly. And the animals seem to lack the neural circuits they’d need to trigger the vomiting reflex.

And yet, rodents make up nearly 40 percent of mammal species and have colonized habitats on every continent on Earth except Antarctica—including homes laced with delicious, bait-laden rodenticides. Part of their secret might be pure prevention. Rodents have exquisite senses of smell and taste, which work as “gatekeepers of the gastrointestinal tract,” says Linda Parker, a behavioral neuroscientist at the University of Guelph. They’re also extremely wary of new foods, and their memory for a sickening substance is strong. “They’ll avoid it for months, years, maybe even their whole life,” Parker told me. “It’s probably the strongest form of animal learning we know.”

Any noxious stuff that does enter rodent bellies can also be waylaid. The animals may get diarrhea, or delay their absorption of the harmful substances by slowing digestion, or swallowing materials such as clay. These tactics aren’t perfect—but neither, to be fair, is vomiting, which is “very violent,” says Bart De Jonghe, a nutritional-science researcher at the University of Pennsylvania. The act requires the diaphragm and abdominal muscles to clench around the gut, and can leave animals physically drained and dehydrated. Maybe rodents are spared quite a few costs, says Gareth Sanger, a pharmacologist at Queen Mary University of London.

It’s still a bit unclear just how much of an anomaly rodents are. Only so many mammals—among them, cats, dogs, ferrets, primates, and pigs—have thrown up in human sight. Researchers can’t always tell if the creatures that haven’t are unable, shy, or just wise about what they consume, making it difficult for biologists to trace vomiting’s evolutionary roots.

Yates is one of several experts who suspect that throwing up is a relatively recent development, manifesting mainly among carnivores and primates, creatures that perhaps could not afford to snack slowly and warily as rodents do. But others disagree, hypothesizing instead that ancestral mammals had an emergency brake in their gut. Maybe rodents (and, apparently, rabbits) lost the gift, while the rest of us kept it around, Sanger told me. The act’s origins could be more ancient still: Some evidence suggests that even creatures from the Jurassic era may have occasionally lost their lunch.

Labs interested in studying vomiting directly have long relied on creatures outside of the rodent family, among them dogs, cats, and ferrets—though high costs of upkeep and intermittent pushback on companion-animal testing from the public have made that work tough, Darmani told me. Nowadays, some of the most promising research takes place in shrews: small mammals that resemble rodents in size and ease of care, but can throw up. The animals have helped researchers such as Darmani and Parker make big advances in figuring out, for instance, how cannabinoids might help curb the urge to vomit—findings that could provide major relief for people undergoing chemotherapy, radiation treatment, and more.

Still, rodents haven’t been written out of digestive research just yet. Parker and others have found that rats and their relatives are great models for nausea, which has historically been far harder to define and treat. Give a shrew a drug to induce vomiting, and it will work—making the brief moments when their equivalent of nausea might manifest quite tough to study. A rodent, meanwhile, must stew in its digestive distress, potentially giving researchers crucial insight with every gape of the mouth, or wrinkle of the nose.

The work isn’t without its challenges. Nausea is, by definition, subjective. “You can ask a room full of 30 people what nausea is, and I guarantee you’ll get 30 different responses,” De Jonghe told me. Among nonhuman creatures, the problem is worse: “You cannot ask an animal if they feel this way or that,” Schier said. Many researchers are adamant that no animal models for nausea exist at all.

But nausea-esque behaviors, even if not totally equivalent to ours, can offer important clues. Rodents, like us, get majorly turned off by gross foods; they, like us, get woozy, trembly, and sluggish after they’ve been swirled around. And when researchers spot such reactions in their lab animals, they can check what hormones spike in their blood, and what microscopic switches get flipped in the circuits of their brain—observations that could help us map nausea’s precise pathways, and perhaps block them with drugs.

Understanding that topography is urgent. “Twenty years ago,” Sanger said, “vomiting was the most feared side effect” in many of the patients he saw. But with the advent of several generations of vomit-curbing drugs, “now it’s nausea.” Our current approaches for addressing motion sickness aren’t up to snuff either: Many of them are hit or miss; others are so broad-acting that they drug people into sleepy stupors—muting not only their digestive discomfort but a bunch of other basic functions as well. The medications are “sledgehammers,” Yates told me, when a “tiny little hammer” will likely do.

All of that means that rodents’ big gastrointestinal shortcoming could end up being far more valuable than once thought. The weirdness of their guts and respiratory tracts might end up being key to making future train rides and boat trips less sickening, and migraines and morning sickness more bearable—even cancer treatments less brutal. With enough understanding, maybe we’ll be able to mimic rodents’ best responses to bad foods, and none of their worst.