One lab is digging into its freezer to thaw out the archived sperm of SARS-susceptible mice. Another is anesthetizing ferrets so they don’t sneeze when the new coronavirus is squirted into their nostrils. Yet others are racing to infect macaques, marmosets, and African green monkeys.

Those animals could prove critical for understanding how Covid-19 works — and for concocting vaccines and treatments to stop its sweep. Every day, it seems another company announces an attempt to make its own virus-fighting vials. But to test an experimental formulation, scientists can’t just jump from Petri dishes into people. They need to try it in critters first, to check that the stuff is safe and effective.

Now, researchers are rushing to figure out which creatures work best, a task that could take months. “We’re at the ‘Uh oh, it’s complicated’ stage,” said Lisa Gralinski, a microbiologist and assistant professor of epidemiology who studies coronaviruses at the University of North Carolina at Chapel Hill.

advertisement

The trouble is, labs can’t just use whatever animal they have lying around to start testing their shiniest Covid-19 vaccine. Not every animal is susceptible to the virus, and those that are may not show signs of disease. Even if they do get sick, that doesn’t mean their symptoms match the ones doctors hope to prevent and treat in humans, which can run the gamut from almost unnoticeable cough to life-threatening lung injury.

An infected but asymptomatic animal can tell scientists whether drugs or vaccines effectively fight the pathogen. Yet because severe disease might be partially driven by the human immune system itself — a violent inflammatory response to a viral intruder — those creatures that can slough off this coronavirus without looking any worse for wear can’t tell us everything.

advertisement

Support STAT: If you value our coronavirus coverage, please consider making a one-time contribution to support our journalism.

“If you don’t have animals getting sick, it’s hard to know what you’re doing,” said Stanley Perlman, a University of Iowa pediatrician and microbiologist who specializes in coronaviruses. “We know that if you clear the virus and don’t deal with the clinical disease and host immune response, you may still have a sick animal or a sick person.”

Past outbreaks can provide some guidance, but what worked then won’t necessarily fit the bill now. With SARS — another coronavirus that passed from animals into humans and caused a serious outbreak, starting in 2002 — the pathogen could infect run-of-the-mill mice, but only to a limited extent, and didn’t cause the same sort of respiratory disease it did in people. A similar pattern was seen in macaques, marmosets, and African green monkeys, as well as ferrets. From a virus-replication standpoint, at least, researchers at the National Institutes of Health found the golden Syrian hamster “an excellent model.”

But then, when MERS emerged, likely from camels, about a decade later, the coronavirus responsible seemed especially comfortable infecting primates and hoofed relations of its animal reservoir — with lung infections less severe in marmosets than macaques, nasal drip observed in camels but not alpacas. Mice, ferrets, and hamsters, meanwhile, simply weren’t susceptible.

So the first question to sort out is what kinds of cells the Covid-19 virus can infect — an issue that has its roots in the pathogen’s architecture.

As specks of genetic material inside a protein envelope, viruses wobble on the edge of being alive. Their metabolic machinery only truly fires into action when they get inside a cellular host. To do that, they use a molecule on the outside of a cell as a kind of portal, like burglars slipping in through a skylight or fire escape.

“Viruses tend to coopt these molecules and use them as their receptors,” explained Kanta Subbarao, director of the World Health Organization Collaborating Centre for Reference and Research on Influenza, in Melbourne, Australia, who spent years doing coronavirus animal research.

Because those receptors evolved differently from one species to another, depending on the purpose they’re supposed to serve within the body, the viral proteins that can unlock a human cell can’t necessarily do the same in a macaque or mouse.

Virologists hoped the new virus would multiply in mice. They’re cheap and plentiful and easy to work with, meaning that important experiments could get started quicker. No such luck, it seems. When a group in Wuhan led by virologist Shi Zheng-Li adorned cells with receptors from a variety of mammals, the team found the virus could latch onto those of horseshoe bats, civets, and pigs — but not mice.

There are ways around that: One is to repeatedly pass the virus through mice, until it evolves to infect them. The other is to give the rodents human receptors, either inserting the molecules locally in the respiratory tract or breeding mice that have virus-susceptibility wired into the entire body’s DNA.

While scientists were disappointed to see that everyday mice may be resistant to the virus that causes Covid-19, it has given them a lucky break: There’s evidence that it uses the same receptor as the SARS pathogen. In other words, the animals they made during that outbreak may be relevant. But they aren’t necessarily ready to use.

About 15 years ago, Perlman’s lab engineered some mice to have the receptors SARS coopts to gain entry into our cells. But maintaining that colony was work in and of itself. Lab members had to keep propagating them, swiping skin and tail samples to check that they still had the desired genetic makeup.

By 2009 or so, long after the SARS outbreak had died down, that seemed like a waste of resources. “We kept them for an extra five years and decided, ‘We are not using these mice, no reason to keep them,’” Perlman said. So his team collected some sperm, froze it down, and sent it off to Jackson Labs for safekeeping. Then they got rid of the colony.

Early this year, Gralinksi’s lab was preparing to do the same with mice left over from SARS work. “We were about a week away from killing all of them and cryopreserving the line,” she said. Her team had started the necessary paperwork when they heard news of a strange sort of pneumonia popping up in Wuhan, China — a coronavirus, people said. “It was like, ‘All of those mice, we need to set them up as breeders immediately,” she recalled. “So our colony is in the growing phase right now; we’re not ready to do experiments.”

At Jackson Labs, in Maine, Perlman’s mouse sperm has given rise to a new generation — but it’s not ready to be infected with the virus yet, either. As Cathleen Lutz, senior director of the mouse repository at the non-profit’s rare and orphan disease center, wrote in an email to STAT, “Our first litters have been born just days ago.”

Gralinksi’s mice should be ready for studies by April, Lutz’s by May. “I must get two emails a day asking for the mice,” Perlman said.

Some researchers in Beijing have posted promising but preliminary and unreviewed results online after showing that the virus infects these modified mice and injures their lungs, while at the NIH, researchers are testing a Covid-19 vaccine from Moderna Therapeutics on normal mice to check whether it generates an immune response — yet it will take longer before animals are ready for evaluating the safety and efficacy of drugs and vaccines.

In the meantime, Perlman is also working on delivering human receptors into the lungs of rodents, using a different, harmless virus as a Trojan horse. He knows those quick-fix animals may allow for some studies on fighting virus replication, but probably won’t be much help in understanding the progression of disease.

Just as virus susceptibility can change from animal to animal, so can the accompanying symptoms. That’s why researchers are beginning to test a whole menagerie’s worth of species.

“To understand what goes on following infection in humans, we need a model that reflects that severe pneumonia and acute lung injury,” explained Rudragouda Channappanavar, a veterinarian who studies coronaviruses at the University of Tennessee Health Sciences Center, “especially for severe patients that are in the ICU.”

In Saskatoon, Canada, tests to see the effects of the coronavirus in ferrets began last week. “If you infect ferrets with some influenza viruses, they get very similar symptoms to what humans get,” said Darryl Falzarano, a research scientist focusing on coronaviruses at the Vaccine and Infectious Disease Organization’s International Vaccine Centre, at the University of Saskatchewan. “They actually cough and sneeze. They have similar lung pathology. But that’s flu.” He isn’t yet sure that that’ll be true of the new virus.

With many of these animals, the plan is to sample different tissues and fluids at different time points, to check that the animal was indeed infected, and if so, where the virus is hanging out in which species, and for how long.

“This initial study is just to find out whether these species of animals can be infected, whether they demonstrate the clinical signs, whether they have an immune response … where the virus is shed, whether it’s in urine, tears, feces, blood,” said Skip Bohm, chief veterinary medical officer at Tulane University’s National Primate Research Center, in Covington, Louisiana.

Last week, scientists there received a sample of the virus that causes Covid-19, swabbed from a patient in Seattle and shipped in a vial within a leak-proof, Tyvek-sleeved bag, within a rigid outer box, as per Department of Transportation requirements. They’re now waiting for regulatory approval to start experiments.

In the meantime, they’re working to reassure the lab’s neighbors that their research will help combat the outbreak rather than worsen it. “What typically has been expressed is just the idea of bringing coronavirus into the area, the idea that it’s not here yet, there have been no cases, and we’re bringing it into the area — that has been the concern,” said Bohm.

They’ve been reaching out to nearby schools and local officials to explain what goes on behind the locked doors of the center. “What we’ve seen is a lot of positive response … to our part in developing vaccines,” Bohm said. “Because everybody wants that.”

As with many labs around the world, though, it’s still up in the air exactly when that work will begin.

  • No animals should be used. There is a difference between mice being able to carry and transmit coronavirus, and being able to get sick from the virus. The line between the two is being blurred deliberately by those who have weaponized mice and rats to carry and transmit a virus. They may have intended at first to research a vaccine or cure, however somewhere along the line, someone turned loose some of those super spreader rodents.

  • so, Thanks Living in Italy and have ferret fermale, and dog have risk?? Thank You

  • when will you start using people to treat people? if you wouldn’t do it to a human, why do it to another animal, hypocrites?

  • Allow death row inmates to choose whether they want to volunteer for human testing in exchange for clemency or even going free, if they survive. People say test it on prisoners, however it should not be required like in China. Most inmates charged with nonviolent crimes or even some violent crimes should be able to earn early release for risking their lives in such service to society.

  • Animal Testing is a SIN, Heinous, Cruel and UNNECESSARY!! Drugs for humans, or ANY testing for human issues, SHOULD BE TESTED ON HUMANS!! It is a FACT, that humans and animals DO NOT react the same to outside influences; our bodies are NOT THE SAME!! If you want to TEST products for human compatibility, then TEST ON HUMANS!! Put those most violent and heinous criminals to good use for our society, TEST ON THEM!! We better hope and Pray if there is other life in the universe, and they discover US, that they don’t look at humans the way WE LOOK AT OUR ANIMALS!! “Do unto others” SHOULD mean ANY OTHER, NOT just humans!!

    • That’s what Hitler did. Tested on people. If your going to get offended by people trying to help why don’t you organize a group of people willing to be tested on, on the chance that they might die. And if you can’t find them would you have them be forced to partake in your dangerous ideas?

    • Awwww Melanie, you don’t want your place at the top of the food chain? Go for a wilderness trip in a mountain park – you’ll figure it out as you get eaten.
      Thank you Dr. Jones for your spot-on reply.

    • So with that statement I’m guessing you’ve already signed up for the first (probably premature) human drug trials?
      If not I hope your not alluding to just grabbing random ppl off the street are you?
      I’m in no way saying that the idea of lab animals isn’t heartbreaking, but if it’s a ferrets sacrifice vs the health and well being of my family, I know my family is going to win every time………… maybe there’s 2 members that scientists can use I guess

    • They are beginning to make tests on british volunteers for 4000 €. So it’s possible. It is easy to use animals which cannot say NO. There is unbearable usings animals

    • We cant test on animals because of there cute, furry and almost human nature affects SOME of us. And we cant test on the doctors HELPING us fix this because then they will get sick, and then who will help us now. Stop fighting and pick one, our doctors and researchers HELPING us, and then they get sick so no one can help us, or a few animals. I would pick the animals over the WHOLE human race dying. But what am I saying were dying already, global warming, coronavirus, bla bla bla.

Comments are closed.

Sign up to receive a free weekly opinions recap from our community of experts.
Privacy Policy