Cracking the Secrets of Human Coronaviruses

Growing up in rural western Massachusetts, Lisa Gralinski was in high school when she first encountered what a career as a biomedical researcher might look like. She attended a summer research experience running microbiology experiments at Smith College and read the real-life thriller about an Ebola outbreak, The Hot Zone by Richard Preston. These peeks into life as a virus-hunter set Gralinski on a path that would take her through Haverford’s outstanding biology program, including the celebrated “Superlab” class, to become one of the leading U.S. scientists working with human coronaviruses. Having investigated closely related coronaviruses during the past 12 years, Gralinski was uniquely poised to tackle scientific questions swirling around the new coronavirus that emerged as the culprit in the global COVID-19 pandemic. 

Now an assistant professor, Gralinski’s laboratory group at the University of North Carolina at Chapel Hill (UNC) has been working nearly around the clock to chip away at the mysteries of SARS-CoV-2, the virus that causes the respiratory infection COVID-19. Suited up in protective suits and respirators in a Biosafety Level 3 laboratory, Gralinski and her colleagues have probed how a patient’s immune cells react to the virus and how an individual’s genetic variation may change those interactions, altering the course of their illness for better or worse. Their work could lead to improved treatments for COVID-19 and a better understanding of the virus’s stealthy path to infection—and ways to block it.

How did your Haverford experience shape your career?
When I toured the campus as a prospective student, I got to see the “Superlab” class for biology majors. This class, which is two long lab afternoons each week, lets students dive into the fundamental experi- mental methods that are standard in biology research. That really grabbed my attention.

For my independent research senior year, I worked at the nearby Wistar Institute investigating cancer cell signaling with Steve McMahon. That hard-core lab experience showed me that the lifestyle of a biomedical researcher absolutely did appeal to me. I would struggle with a traditional office job—the hands-on aspect of my laboratory work is something I really enjoy.

What led you to study human coronaviruses?
After completing my Ph.D. in micro-biology and immunology at the University of Michigan, I began looking for postdoctoral positions. I was really interested in how viruses cause human disease, especially those that greatly impact human health.

In 2008, I joined the research group of Ralph Baric here at UNC, which was studying the virus that causes SARS, or severe acute respiratory syndrome, the only coronavirus known to infect humans and cause severe disease at that time. Then in 2012, MERS, or Middle East respiratory syndrome, suddenly emerged, also caused by a coronavirus. Both were animal viruses that had evolved the ability to infect humans. In this field, we fully expected this meant that another new human coronavirus was also likely to emerge.

Both SARS and MERS got our groups interested in looking at what antiviral medicines might be effective against coronaviruses. Before the new virus emerged to cause COVID-19, Dr. Baric’s group had shown that the antiviral drug remdesivir could lessen severity of SARS infections in mice. The drug disrupts the virus’s ability to replicate in the body. Remdesivir is now being tested in clinical trials to see if it can also help improve human COVID-19 infections.

The current pandemic is so beyond what we could have imagined that watching it unfold in real-time is kind of baffling. But it is also fantastic to be in a position to try to help.

What are you investigating about this new coronavirus?
I am interested in how viral diseases are modified by the human’s immune response. For coronaviruses, we know that it is not simply a matter of your body clearing the virus, but rather your immune system’s response can go well or go poorly, and that affects your outcome.

My work also looks at how natural genetic variation in the hosts—usually mice in the laboratory that we infect with coronavirus—could contribute to how the disease develops. Obviously, how much of a virus dose someone is exposed to, their underlying health conditions, and their age are also important contributors to this. But in the 1918 flu pandemic, genealogy records show clear genetic effects on the outcomes of flu infection in people with different genetic backgrounds.

By using mouse models, we can ask which specific mouse immune genes, when turned off or over-activated, can make a difference in the outcome of the mouse’s disease. If we find a gene modification that makes the disease less severe, then we can think about developing treatments that mimic that. In other words, can we turn up or turn down a particular part of the immune response to better fight off the infection?

What else can you learn in the laboratory about this coronavirus? 
We can also ask questions about some of the unexpected complications of COVID-19 that doctors are seeing. In some patients, blood-clotting side effects, such as strokes and microclots forming in the lungs, are happening after patients are sent home from the hospital. We can study COVID-19 infections in mice to see how those blood-clotting problems arise.

Why can the course of COVID-19 infection be so variable—from no symptoms to fatal—in different people?
Part of the answer is: We don’t know yet. But part of the answer comes from our work on SARS and MERS. These viruses are really stealthy at the beginning of the infection. They set up replicating themselves and make lots of copies before the human cells recognize the infection. A whole 24 hours can go by before that happens, which is equivalent to more than 250 generations of virus being born. This stealthiness is very different from what we see in influenza infections.

We don’t know if the same is true yet for COVID-19 infections, but if so, it gives the virus time to build up in the body before the host immune response kicks in to fight the infection.
      
What’s been the biggest challenge of doing coronavirus research during a pandemic?
It is something we deal with in science all the time, and that is: What is the appropriate balance of work? Science has never been a 9-to-5 contained job. Experiments happen at weird hours, especially when dealing with cells and mice. In the midst of the pandemic, our lab group has been working when campus is otherwise shut down. We are trying to generate high-quality data as fast as possible, because a lot of people are counting on this work.

There is always more work to do that is important, but so is being able to work safely in the Biosafety Level 3 containment laboratory. After all, when suited up in there, you eventually reach this unhappy mix of dehydration and needing to use the bathroom! If we are too tired or distracted by world events, then we need to recognize that and take a day off to reconnect with family or take care of the home front.

How have you coped with the intensity of work and the lockdown at home?
I take breaks and moments for myself. If I know that I have to work late, I take my dinner in and I make sure that I take a real dinner break, usually catching up on social media with my friends. If I work late one night, then I might go in later the next morning and just sit and pet my cat (Rascal) to relax a bit. My husband, Mike Kingery, and I do Saturday morning garage CrossFit workouts. I go for walks around campus, and I call friends from Haverford or graduate school to check in.

What’s one surprise you’ve learned from this pandemic?
You never know when research into something that seems very basic is going to be incredibly important for human health. A few months ago, people would have said that research into the spread and velocity of a human sneeze was not that relevant.

Haverford set me up really well for this current situation, giving me the abilities to think critically and independently. Also the emphasis on communicating my research to a new and broad audience was incredibly important. It doesn’t matter what you discover unless you can convey your discovery to other people. That’s never been more relevant. 

Learn more: Lisa Gralinski was interviewed by David Wessel '75 as part of our Fords on the Front Lines video series.