The Jackson Laboratory’s Scientific Director Dr. Nadia Rosenthal in her lab. PHOTO COURTESY OF JAX

Mouse research aids COVID-19 response

By Ezra Sassaman

[email protected]

BAR HARBOR Over the past year, COVID-19 has wreaked havoc across the country, causing shutdowns, social isolation, and, as of press time, more than 430,000 deaths. But there are many reasons for cautious optimism looking forward, including here on Mount Desert Island. The Jackson Laboratory in Bar Harbor is on the forefront of research that could help better understand and hopefully defeat coronavirus. 

In 2020, the lab was awarded over $100 million in federal, foundation and other grant funding. A portion of this money went toward research related to the SARS-CoV-2 virus, which causes COVID-19. 

The Islander talked to Nadia Rosenthal, Ph.D., FMedSci, FAAHMS, who is the scientific director of The Jackson Laboratory. She was awarded a contract from the National Institutes of Health last year to develop mouse models to more effectively study COVID-19. Her work in this area has focused on using mice to model the genetic diversity found in humans. 

Much of the lab’s research is based on creating mice that are as genetically similar to each other as possible.  

“With purebred mice, there’s a level of knowledge and security in your product. We want to study the same genetic variant of mouse as our colleagues in Germany, for example, so we can compare notes,” said Rosenthal. 

Working around the globe with the same purebred mice allows for reliable results, providing scientists with a shared testing template that increases scientific accuracy and reproducibility. 

It’s also useful for isolating the effects of specific diseases. A mouse strain specifically bred to trend towards obesity, for example, can be useful in pinpointing the causes and effects of that disease. 

A molecular model of the spike proteins (red) of SARS-CoV-2 binding to the angiotensin-converting enzyme 2 (ACE2) protein, the receptor (blue) that is its entry route to the target cell.

But to study SARS-CoV-2, The Jackson Laboratory needed to focus instead on breeding mice which resembled the genetic diversity of human beings. Unlike the lab’s carefully controlled mouse populations, random mating between humans makes every person (with the exception of some identical twins) genetically unique. 

“All humans are ‘mutts,’ which is a good thing,” said Rosenthal. Parents that are too genetically similar might produce children more susceptible to certain diseases by doubling a negative recessive trait. But when genetically dissimilar humans mate, these traits are much less likely to find their pair. 

Understanding the genetics behind coronavirus infection risk is important. “We know that some people are extremely susceptible to COVID-19, while others are asymptomatic,” said Rosenthal. 

“We don’t know exactly why yet, but we know that genetics plays a major role, because it plays a major role in other disease research.” 

Waiting for random mutations to happen on their own would take a long time, so Jackson Laboratory undertook controlled breeding to create mouse “mutts.” As Rosenthal explained, “If we know who the original parents were for each mouse, we can find the specific genetic features that render some mice more susceptible to COVID-19 and others asymptomatic.” 

Rosenthal outlines the challenges she and her team had faced undertaking this task. Bats and humans share the cell protein that binds to COVID-19’s protein “spikes” that can be seen on visual renderings of the virus. But mice, lacking this specific protein, are not naturally susceptible to SARS-CoV-2 infection. 

Fortunately, the lab had access to a genetic variant of mouse that had been engineered to research the SARS virus. That mouse strain “came out of the freezer” and was used as a starting template for COVID-19 research. 

At first, the virus proved fatal to these mice at a rate that far exceeded human reactions to SARS-CoV-2 – mice were dying in just five or six days after being infected. After this realization, Rosenthal and her colleagues decided to put the same COVID-friendly protein in several types of mice with different genetics and study them. 

The Jackson Laboratory does not virally infect mice in Bar Harbor because of the danger it would present to other mice in the lab as well as people in the surrounding community. Instead, it ships them to Rocky Mountain Labs, a high-containment facility in Montana.  

“We sent out eight different types of mice out to test at the beginning of last summer,” said Rosenthal. 

By the middle of the summer, Rosenthal and her team saw that the mice with different genetics responded in different ways, just as they had expected. Some mice were asymptomatic, some got sick and survived, and some died from severe respiratory issues or thrombosis. These findings have been corroborated by COVID-related human fatalities from the same conditions. 

Now, Rosenthal and her Jackson Laboratory colleagues are expanding their vistas to better understand “what genetic features might track with one of these outcomes.” She hopes the findings in their mice “will allow us to predict human responses to the virus,” enabling people to determine on a genetic basis who will be asymptomatic and who needs to exercise extra caution. 

Genetics has a role to play in estimating vaccine effectiveness as well, especially as other virus strains threaten humans around the world.  

“Ideally we’d rely on these variable models to represent genetically diverse human populations when assessing the safety and efficacy of vaccines and potential treatments for emerging strains,” Rosenthal said. 

Despite her progress, Rosenthal cautions that we still don’t know the long-term effects of coronavirus.  

“We’re not out of the woods yet. This disease is going to be haunting us for a long time as a human race.”  

But she hopes her mice will help provide a ray of hope for humanity moving forward. 

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