When he saw the preliminary results, Duke University research scientist Alejandro Berrio Escobar couldn’t believe his eyes. He was staring straight into the future of the pandemic.

It was a few weeks into the COVID-19 lockdown, and Berrio Escobar, who specializes in evolutionary biology and computational genomics, had made a major discovery: SARS-CoV-2, the virus that causes COVID-19, not only was diverging from the previous strain, but it was also diverging and evolving into new versions of itself.

“I felt a deep sense of purpose when I saw this bug evolving in real time,” Berrio Escobar says.

His early observations would ultimately lay the groundwork for one of the largest COVID-19 genome sequencing initiatives in the nation.

By this summer, Duke’s COVID-19 genome sequencing efforts, also known as the COVID-Seq project, were in full swing. In Duke’s Sequencing and Genomic Technologies Core Facility—housed within the Duke Center for Genomic and Computation Biology at the Chesterfield Building in downtown Durham—a group of genomics researchers has closely monitored the evolution of SARS-CoV-2 in the Duke community for the past year and a half. By sequencing the viral genomes of positive COVID test results, they have provided valuable data for the university administration to stay one step ahead of the pandemic.

Early discoveries

Like most modern genome sequencing facilities, the Duke core facility, equipped with over $2.5 million worth of state-of-the-art sequencing machinery, is capable of sequencing the full genomes of anything with a genetic code. The genome—the sum total of genetic information within an organism—consists of a sequence of four distinct chemical bases that make up a DNA molecule. DNA is the most common molecule for storing genetic information, but certain viruses, such as SARS-CoV-2, also store this information in a molecule called RNA. DNA genomes range in size from millions of bases to over three billion in the case of humans, and sequencing is essentially the process of “reading” every single base within the total genome.

Today, the core sequencing facility at Duke can sequence 80 human genomes simultaneously in a matter of 48 hours. Using similar principles as human genome sequencing, the core facility was transformed to sequence thousands of samples of SARS-CoV-2, and, as variants emerged, samples could be analyzed and assigned as a specific variant.

As the project got underway, Berrio Escobar was working in Duke scientist Gregory Wray’s lab, which focuses primarily on researching human and sea urchin genomes. But Wray, who heads Duke’s Center for Genomic and Computational Biology, saw promise in the COVID-19 project. Berrio Escobar had quickly started uncovering distinct regions of interest within the virus’s genome that explained why it was so infectious, including genes that coded for the infamous spike proteins.

Wray and Steve Haase, Wray’s colleague in Duke’s biology department, convinced the university’s administration to carry out regular COVID-19 surveillance testing for students entirely in-house, an anomaly among universities at the time. As a comprehensive, campus-wide testing effort got underway, the question of what to do with the positive results became paramount.

The virus evolves

By fall of 2020, Berrio Escobar, Wray, and several Duke scientists realized they needed to begin sequencing viral genomes from the broader Duke community to understand the virus’s evolution.

These SARS-CoV-2 samples were a treasure trove of data that researchers could utilize to understand how the pandemic was unfolding. The emergence of distinct COVID-19 variants was still months away, but the rate and magnitude of mutations in the spike protein region concerned the researchers enough to push for a comprehensive sequencing project.

The task ahead was enormous.

Between Duke students, faculty, staff, and patients at Duke University and Duke University Health System (DUHS), and additional staff and patients from the Durham VA Health Care System, the number of individuals included in the weekly testing protocol exceeded 60,000.

And while many of these systems were under the Duke umbrella, their needs varied significantly.

“DUHS did their own thing, the university did their own thing, and I had to communicate different things to both institutions based on their needs,” Berrio Escobar says.

Duke delivered funding for the COVID-Seq project in February 2021. During its initial stages, much of the analytical work was undertaken manually.

“The first two months of 2021 were hard,” recalls Berrio Escobar. As new variants started emerging, he and his colleagues gathered a team of Duke engineers to automate the process of assigning a variant to each sequenced SARS-CoV-2 genome. With each new variant more transmissible than its predecessor, understanding the viral composition of Duke would provide vital feedback on the state of COVID-19 at Duke and in the surrounding Durham community.

Tracking infections

The unfolding results from this sequencing facility directly impacted Duke’s COVID-19 policies, including its decision to keep classes in-person for a majority of the 2021–22 academic year. Last August, however, the vision was considerably more uncertain. As thousands of students arrived from around the world to start their fall semester, they brought with them hundreds of new COVID cases, including the highly infectious Delta variant. The sequencing facility saw a huge spike in incoming positive results. Questions arose about whether in-person classes would still be feasible.

Several universities around the country, including in the Triangle, were sending students home; meanwhile, many Duke professors had elected to teach virtually out of safety concerns.

Before jumping to conclusions, the researchers wanted to know: Where were people getting infected? By comparing the different viral samples’ genomes in the lab, they stumbled on an interesting observation: people who were infected by the same host had genetically identical SARS-CoV-2 genomes.

During August and September, the researchers found many viral samples with nearly identical sequences, meaning a few super-spreaders were shedding virus to several people, most likely at large indoor gatherings. The researchers singled out Shooters II, a popular nightclub among Duke students that had remained open at full capacity during the first few weeks of the fall semester, as a major contributor to spread of the virus. Through Duke’s existing contact-tracing framework—interviewing infected students and contact tracing—they traced large numbers of infections to Shooters and other off-campus events, while virtually no infections were happening in classes, likely due to strictly enforced mask mandates.

“This was the key observation that convinced leadership that transmission rarely happened in the classroom,” Wray says.

The core facility’s sequencing work continued to provide Duke with vital insights throughout the Delta wave. To keep up with the heavy caseload—it takes technicians 48 hours to fully sequence around 400 samples—the facility hired two full-time technicians.

At the height of the Delta wave, they saw “anywhere from 800 to 1,000 samples per week,” says Sarah Clarke, the facility’s main COVID-Seq technician. Looking at the composition of viral samples, researchers could predict which variants would soon predominate at the university, predictions that helped guide Duke’s masking policies, contact-tracing guidelines, and event organizing decisions.

Omicron emerges

With every new variant, however, came an entirely new set of challenges, including the emergence of the highly infectious Omicron variant last winter. Omicron caused some of the highest infection totals that the administration had seen thus far, and, during its peak, the facility was sequencing well over 1,000 positive samples per week.

“The DUHS nurses had to stop contact tracing during Omicron,” Berrio Escobar recalls. “The number of cases made it impossible.”

In the early stages of the Omicron wave, Devjanee Swain Lenz came on board as the facility’s associate director. A former postdoctoral fellow in Wray’s lab, Swain Lenz recalls frequent 12-hour workdays. Eventually, some of the testing sites, particularly in DUHS, stopped sending all of their positive samples because there were simply too many.

On top of managing the acute caseload of Omicron, Swain Lenz’s long-term goal was to formulate a strategic vision for the future of the core facility.

“We were never meant to be a COVID-19 sequencing facility,” she says. “Our main mission is to support academic research, a definition which has obviously shifted a lot in the last two and a half years.”

Looking ahead

The future of the core facility has become a balancing act between the needs of researchers and the needs of administration. In this demand-centric model, Swain Lenz cites COVID fatigue as a major determinant of the facility’s activity.

“Fewer and fewer people are testing for COVID-19 regularly,” she says. Duke has opted for a voluntary testing protocol for the upcoming fall semester. Students will still be required to take an entry test prior to arriving on campus, though they will not need to submit results to Duke administration.

“Things have slowed down naturally, but we will see what happens,” Swain Lenz says.

Indeed, a new Omicron BA.5 subvariant has become the dominant COVID-19 strain across the United States. Highly infectious, even among recently infected individuals, BA.5 may stretch Duke’s COVID-19 protocol once again. But the researchers approach concern about increasing cases with a healthy dose of curiosity.

Berrio Escobar says the students’ return will be something of a bellwether for the rest of the nation.

“We usually have a great idea of what’s going on in the entire country when students come back,” he says.

The researchers’ contributions to both Durham’s health and the broader scope of academia are striking when considering their background. As Wray notes, no one on the COVID-Seq team had any training in virology or public health. What they did have, however, was a keen understanding of how things evolved. And harnessing and predicting these evolutionary trends would provide an essential lifeline to Duke’s pandemic response.

“It’s basic biology. You work with sea urchins and genes, and you wonder when your research may impact the public,” Berrio Escobar says.

No estimate currently exists of the number of lives saved because of the COVID-19 sequencing initiative and its resulting policy decisions. For a disease that has taken away so much, the affirmation of central evolutionary principles has revived this team’s faith in the healing powers of science and even in the twisted dogmas of the natural world.

“Biological entities don’t have to be beautiful or wonderful to evolve,” Berrio Escobar says.

While that may be the case, the response to evolution certainly can be. 

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