'Everything we’ve been training for is happening now'

Dr. Tyler Starr was standing in the hallway outside his lab, nursing a coffee and thinking about his research when his mentor, Fred Hutchinson Cancer Research Center virologist and evolutionary biologist Dr. Jesse Bloom, strolled up with a suggestion.

The first U.S. case of COVID-19 had made headlines the previous week, but Starr was focused on his work examining how specialized immune proteins interact with HIV. Bloom wondered if Starr could use the system he’d spent a year and a half perfecting to study the virus behind COVID-19 instead?

At the time, Bloom’s question was prompted by scientific interest in what seemed like an unusual virus causing problems in just one corner of the world. But as COVID-19 swept around the globe, it quickly became clear how much we needed to know — but how little we did.

Starr and Bloom weren’t the only virologists and antibody experts at Fred Hutch who jumped to help close the knowledge gap. Many young scientists at the center had chosen to study viruses with an eye toward improving human health. Applying their expertise to the novel coronavirus, SARS-coronavirus-2 or SARS-CoV-2, seemed like the best reaction to the burgeoning pandemic.

“I happened to be in the viral immunology field and this is like the Super Bowl for us: Everything we've been training for is happening now,” said Meghan Garrett, a grad student in the lab of Hutch HIV expert Dr. Julie Overbaugh, who directs the office of graduate education and holds the Endowed Chair for Graduate Education.

Before tackling coronavirus, Garrett had previously focused on the antibody response to HIV, another pandemic virus.  

“I was completely primed,” Garrett said. “I had spent two years doing this with HIV. By the time we had it all figured out with HIV, it was just super fast to continue with working with coronavirus.”

Dr. Caitlin Stoddard, a postdoc in Overbaugh’s lab, was also able to transition quickly. Prior to the pandemic, she had been implementing a method to chart antibody binding to the Zika virus. For Stoddard, too, transitioning to SARS-CoV-2 work felt like a natural progression. She had initially focused on Zika virus, which began marching around the world in the mid-2000s. In February — even before the disease had taken hold in the U.S. — Overbaugh suggested that Stoddard study the newly emerging coronavirus.

“I said, 'Sure, why not?' We have all the infrastructure in place, I'm doing these experiments anyway. … Then as [the novel coronavirus] spread throughout the globe, we realized that this should be the number one priority,” Stoddard said.

Starr, however, didn’t immediately see the point in switching research topics.

After joining Bloom’s team in 2018, he’d spent the first year or so troubleshooting a yeast-based method to study how changing the building blocks of antibody proteins alters their ability to bind and block HIV. It wasn’t until late 2019 that he got his first real results. Just a few months later the pandemic hit, and that day in the hall, Bloom suggested what felt like a complete re-route.

Bloom had seen that others had used yeast to produce a key segment of the SARS-CoV-2 spike protein, called the receptor-binding domain or RBD, which determines which hosts the virus can infect. Mutations in this area helped SARS-CoV-2 jump species and become the dangerous human pathogen it is today. And it’s important to a protective immune response: Many of the antibodies that block SARS-CoV-2 infection target this area.

So, Bloom asked, did Starr think he could use his yeast-based system to produce the SARS-CoV-2 RBD as a first step toward studying how mutations affected its ability to bind ACE2?

It seemed worth trying, Starr recalled, but not as a main project: “I was happy to do that first test, but I didn’t really want to get distracted. I was still in antibody mode.”

But a weekend of reading up on the RBD quickly revealed many interesting, unanswered questions. Within months, Starr and Bloom Lab M.D./Ph.D. student Allison Greaney had published a study that examined how changing every possible amino acid in the SARS-CoV-2 RBD changed its ability to bind ACE2.

This kind of information could be quickly used by other researchers hoping to halt coronavirus spread by developing a vaccine. That was an important consideration for Starr, who’d found himself confronted by a question about his science that he’d never had to answer before.

“OK, we can do this — does that mean we should?” Starr said. He and other virologists recognized, more than most, how much they risked getting or transmitting coronavirus every time they came to lab.

To enable scientists to study coronavirus, the Hutch kept the specialized core facilities, which give scientists across the center access to cutting-edge technology, open while implementing stringent risk-reduction measures. The safety of the scientists staffing these cores was very much on his mind, Starr said: “If we're doing this work, it needs to be a project that's important to do at this time.”

As an evolutionary biologist, he had been immediately drawn to questions about how SARS-CoV-2 had evolved — scientifically interesting, but not a question whose answer would help slow a pandemic. At the pandemic’s height, they weren’t worth putting others at risk, he said. He’s just now returning to it.

Kate Dusenbury Crawford, a grad student in Bloom’s lab, had quickly pivoted from studying Lassa virus, Ebola and rabies, to develop a method that scientists could use to safely and easily measure how well antibodies block, or neutralize, SARS-CoV-2. The strategy quickly garnered international interest and has already been cited by other scientists in their work, she said.

She and other investigators who decided to study SARS-CoV-2 now face a looming question: Return to their previous projects, or commit to coronavirus work — perhaps permanently?

“There has been a worry that all of this other research isn’t going to happen, because we’re so focused on coronavirus,” said Dusenbury Crawford, who a few months into the pandemic considered jettisoning her other projects to focus her thesis solely on SARS-CoV-2. Ultimately, she decided to continue her other projects.

“I’m excited to work on coronavirus, but I didn’t want to drop this other important work,” she said.

Balancing risks with scientific opportunities

Each person’s risk calculation is slightly different and sometimes that calculation can feel odds with the calculations of others working alongside you — even for scientists.

For example, many young researchers at Fred Hutch support the Black Lives Matter movement and have been balancing their choice to protest with their understanding of the potential for viral transmission. In the Overbaugh Lab where Stoddard works, some people attended protests. And others were frightened by the heightened risk. 

“It becomes sort of a personal health decision to come into the lab and a values decision to go to a protest — that you usually don't have to reconcile,” Stoddard said. “It was just a very complicated question. It sorted itself out and we all just agreed as a lab to take precautions if we’re going to protests, and to try to take stock of our exposure risk and be wise about that.”

To limit her exposures, Garrett had moved into her boyfriend’s apartment for the first three months of the pandemic. None of his roommates were fellow researchers.

“That was my entire [interpersonal] interaction — those four boys, just completely disconnected from the science world,” Garrett said. “Everybody else at the house felt very cooped up and it actually was super refreshing to be able to go in [to the lab]. But it was very nerve-wracking in the beginning. …  I was so nervous about bringing [coronavirus] back to the house and I was nervous about bringing it to work.” (Editor's note: So far, there are no cases of coronavirus being spread among researchers at the Hutch.)

Starr’s response to the stress of the pandemic was to throw himself into his work.

“I think it was a coping mechanism with the anxiety of coronavirus, just working incredibly hard at the project,” Starr said.

While others watched the pandemic from the sidelines, scientists who took on coronavirus work knew they had to make their time on the field count.

“I know that it was very, very challenging for other people in the lab to be stuck at home,” Stoddard said. “I was trying to take advantage of the fact that I was being given this opportunity. I recognized that it was kind of a gift to be working on coronavirus during that time. And that came with a lot of self-imposed pressure to be really highly productive.”