How Lexi Walls' graduate school research put us ahead in the fight against COVID-19

Little was known about coronaviruses five years ago when Lexi Walls made them the focus of her doctoral research

To read Lexi Walls’ dissertation now is an eerie exercise in watching someone predict the future with precision.

“The tremendous pandemic potential of coronaviruses was demonstrated twice recently by two global outbreaks of deadly pneumonia,” Walls wrote in 2019, referring to coronavirus outbreaks of SARS in 2002 and MERS in 2012.

Despite the threat coronaviruses posed, Walls found that there was very little information about the structure of the virus, which made it difficult to understand it, treat it, or come up with a vaccine.

That’s why Walls spent the past five years of graduate school understanding what coronaviruses looked like and how they infected people. Walls studied the structure of coronavirus spike proteins using cryo-electron microscopy and learned how they disguised themselves from a body’s immune system.

As Walls completed her doctorate in biochemistry in December of 2019, a still nameless virus was just beginning to spread in Wuhan, China. What the world would soon learn was a novel coronavirus would soon live up to the “tremendous pandemic potential,” Walls had just written about. Her work would soon prove critical in helping scientists understand and research treatments for COVID-19.

Walls at her doctoral defense in 2019, presenting five years worth of research on coronaviruses.

Walls’ research received the Distinguished Dissertation Award in the biological sciences from the Graduate School this year, reflecting the global and even life-altering importance of graduate student research.

“The fact that I worked on this understudied virus for five years prior to the pandemic really set us up for moving quickly and learning things about this virus at unprecedented speed, which highlights the need to study and fund all types of research, because you never know what the next pandemic — or pandemic equivalent — is going to be,” Walls said.

No one had solved the structure of coronavirus spikes when Walls began studying them a few years ago. There were a few reasons for that, Walls said. One, cryo-electron microscopy — a method to view molecules at a high resolution — was just becoming more accessible to scientists in 2015, when Walls began her studies. Two, coronaviruses were not known to be deadly to healthy adults until the SARS outbreak in 2002, making them less well studied and therefore, less understood.

But seeing their pandemic potential, Walls got to work solving the structure of the spike protein on a coronavirus, the now widely portrayed image of a red protrusion on the exterior of the virus. Understanding the structure is an important step to figuring out how to create treatments and vaccines.

Walls presents a poster on coronaviruses at the 68th Lindau Nobel Laureate Meeting on June 27, 2018, in Lindau, Germany. Among her audience here is Nobel winner Martin Chalfie, left. (Photo credit: Christian Flemming/Lindau Nobel Laureate Meetings)

Working in Associate Professor David Veesler’s lab, Walls started studying a prototypical coronavirus that infects mice, called mouse hepatitis, and then moved on to a coronavirus, named NL63, that infects humans with the common cold.

Using cryo-electron microscopy, Walls took images of the protein to reconstruct what it looked like in 3-D. This helped her understand how each amino acid connected to the next, what that meant for the protein structure, and what she could infer the function might be.

She also studied what that protein looked like at different phases of its lifecycle as well as how it used sugars called glycans to disguise the spike protein from a body’s immune system.

The final part of Walls research was to look at the spike protein of SARS and MERS; at the time, the only two known deadly coronaviruses to humans.

Walls and Xiaoli Xiong, a postdoc in the lab, solved these structures in conjunction with the structure of antibodies from human survivors of these viruses. That helped them understand how the immune system could beat a coronavirus spike protein.

Walls talks with market goers at the U-District farmers market event, “Science at the Market” in Seattle (a pre-COVID-19 event). UW IPD Photo / Ian Haydon

After completing her doctoral degree in December of 2019, Walls began working as a postdoctoral fellow in Veesler’s lab. By the end of the month, it was revealed that the novel virus spreading through Wuhan was a coronavirus, so Walls quickly shifted focus to studying what she had years of experience with: the spike protein, but this time, the one on SARS-CoV-2, the causative agent of COVID-19.

It was a surreal experience for Walls, whose entire graduate school experience had been preparing her for this moment. From February to June, she and her 10 labmates worked long hours, seven days a week, studying the spike protein, antibodies and how the immune system responded to it. The Veesler lab collaborated with other groups around UW, including the Institute for Protein Design and King Lab, jumping on video calls to divide the work and share what they’ve learned.

But their arduous efforts paid off: This month, the team announced that they’d developed a vaccine that was effective in mice and nonhuman primates.

“Lexi designed a subunit vaccine eliciting potent neutralizing antibodies which we hope will participate in ending the pandemic and bring the world back to normal,” said Veesler, Walls’ advisor, calling Walls “a very talented scientist who made seminal discoveries” on coronaviruses.

Amidst all her work studying coronaviruses, Walls has also taken time to share her learning with others. She joined a video call to talk with 100 students in her Massachusetts high school about the work she’s done this past year, as well as locally at North Seattle College. Professors at UW have remarked on how she prioritizes teaching and mentoring undergraduate students as well as her peers in the lab.

Walls said sharing science with others is the best part of the job.

“Your science is only good if you can share it,” Walls said. “If you can teach others, you’ve succeeded.”


Story by Kate Stringer, UW Graduate School

Originally published Sept. 8, 2020