Mice can't catch COVID-19, so a UA lab is making new kind of mouse

Arizona researchers working on a vaccine for COVID-19 would like to test their work on mice. But there's a problem: Mice don't get sick from the new coronavirus.

Their solution? Create a mouse that does.

"A special mouse needed to be developed that mimics the way the virus infects humans," the University of Arizona's Teodora Georgieva wrote in an email.

Georgieva is the director of the UA's Genetically Engineered Mouse Models (GEMM) Core, which creates genetically engineered mice for research. Since late March, GEMM Core has been working on making mice that can get sick with COVID-19.

Out of at least 300 attempts, GEMM Core successfully created seven such mice and are now breeding them to make more, Georgieva said. She is expecting the first litter of mice pups to be born soon and hopes to distribute the engineered mice to researchers by the end of the month.

So far, researchers in at least 10 different labs at the University of Arizona want to use the mice in COVID-19 research. One lab is testing possible vaccines for the disease.

Before the labs can advance to human clinical trials, some may need to conduct experiments on animals to prove that the treatments are safe. 

"Researchers study what they can with cells in Petri dishes and by observing human patients, but a pandemic with so many unknowns and this unprecedented level of complexity requires use of an animal model," Georgieva said.

Mice are the preferred animal for testing because they are cheap, easy to maintain and reproduce quickly.

GEMM Core is not the only lab doing this type of work on mice. The Jackson Laboratory, a Maine-based nonprofit that breeds and sells research animals, has been breeding genetically modified mice for COVID-19 research since March. 

The Jackson Laboratory has been inundated with requests for mice from researchers, and breeding enough mice to meet the demand takes time.

Mice typically start reproducing once they are six to eight weeks old and give birth after being pregnant for about three weeks.

"We found out it would be several months at least before they could provide the mice to researchers in Arizona," Georgieva said. Such a delay could unnecessarily prolong the pandemic as scientists work on treatments and pandemics.  

"We wanted to make it faster and cheaper," she said.

How the mice were made

A normal mouse doesn't develop symptoms from the novel coronavirus because of differences in how the virus attaches to mice cells.

To infect a host, the spikes on the outside of the novel coronavirus need to bind to the right receptor on a cell, much like a key and a keyhole. 

In the case of COVID-19, the virus binds to the ACE2 receptor, the same receptor used by a related strain of coronavirus known as SARS, or Severe Acute Respiratory Syndrome.

Mice have a differently shaped ACE2 receptor than humans, making it harder for these viruses to attach. Essentially, the keyhole for the mice cells is the wrong shape for the virus to open.

In response to the 2003 outbreak of SARS, Stanley Perlman, a coronavirus expert at the University of Iowa's medical school, genetically modified mice to give them the human version of the ACE2 receptor. 

Georgieva reached out to Perlman, who agreed to send GEMM Core the genetic material needed to create mice with a humanized ACE2 receptor.

GEMM Core has injected the genetic material into hundreds of mice embryos — a difficult process involving microscopes and extremely small injectors.

"The embryos are tiny," Georgieva said. "I mean, you cannot see them with the naked eye."

Because researchers don't target specific sections of the mouse's DNA, or genetic code, the injected genetic material can sometimes wind up in the wrong place and do nothing, according to David Besselsen, the university's attending veterinarian and director of animal care.

"Because you're relying on the cell, a cell process called homologous recombination, and it doesn't happen at a high frequency, the success rate is low," he said.

Additionally, microinjections can sometimes damage the mouse embryo so that it is no longer viable. 

Even successfully injected embryos still need to be transplanted into female mice before they can develop into healthy pups. Because of this, Georgieva estimates the overall success rate of this method can vary from between 10% to 50%.

"It's a very complex procedure, which is why this type of facility does not exist at every university," she said. "We're very fortunate to have this facility."

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Why mice in the first place?

Some labs have been experimenting with the use of other animals, such as monkeys or ferrets, but those animals are not understood as well as mice, and they take much longer to reproduce, which can slow down the research process.

"Mice are the most well studied mammals outside of humans," Besselsen said. "That's why mice are so widely used in research."

Another reason mice are preferred, Besselsen said, is that animal researchers typically try to reduce animal testing on primates like monkeys and only use such animals during the last stages of research.

Genetically modified mice in particular have proven to be useful in a number of studies in the past, according to Georgieva. Since GEMM Core was started around 2007, the facility has used techniques such as gene editing to create over 150 different mouse models for research. 

Many of these models helped researchers study genetic disorders. In one case, Georgieva said GEMM Core created mice with the same unique genetic mutation that caused muscular dystrophy in a young female patient to help study her disease and research treatment options.

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Animal testing regulations

While some companies have skipped animal testing altogether to go straight to human clinical trials, they are typically experimenting with treatments originally developed for other diseases and that have already been proven to be safe.

For many new drugs and new treatments, the FDA requires animal testing data that shows the treatment is safe before allowing researchers to begin human clinical trials.

Though some may disagree with the idea of animal testing, Besselsen said there are many rules and regulations in place to ensure that the work is necessary, impactful and respects the welfare of the animal.

The University of Arizona is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AALAC), a nonprofit that advocates for the humane treatment of animals in science research.

"That is the gold standard for animal care and use programs in the world," Besselsen said.

Every study is also reviewed by the university's Institutional Animal Care and Use Committee, which ensures that appropriate painkillers, anesthetics and euthanasia methods are used, according to Besselsen.

Any work with animals infected with the virus must also be done in animal biosafety level 3 laboratories, which have tight security to ensure the safety of the researchers and to prevent accidental escape of animals, according to Georgieva.

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Of the seven genetically engineered mice for COVID-19, five are female and will hopefully give birth by the end of June.

A typical litter size is around seven pups, according to Georgieva, but some newborn pups may not inherit the genetic trait of having humanized ACE2 receptors. If they don't, they won't be used in research.

Those that do inherit the trait will be given to University of Arizona researchers first, but Georgieva said in the future GEMM Core might consider providing mice to other COVID-19 researchers in the state or around the world.

Amanda Morris covers all things bioscience, which includes health care, technology, new research and the environment. Send her tips, story ideas, or dog memes at amorris@gannett.com and follow her on Twitter @amandamomorris for the latest bioscience updates.

Independent bioscience coverage in Arizona is supported by a grant from the Flinn Foundation.

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