This evolutionary biologist-turned-virus-decoder finds that a quarter of Singapore’s diseases stem from a virus variant, and that her daughter helped a classmate through a difficult COVID situation.
There’s a big chunk of sequences missing in some of the SARS-CoV-2 samples from Singapore, realised then-Assistant Professor Yvonne Su as she stared at the next-generation sequencing data displayed on her screen one afternoon in February 2020. She had started compiling the sequences from her lab’s SARS-CoV-2 samples soon after the first case was detected in Singapore. This shouldn’t be happening.
The result had been perplexing. Until then, the sequences had all matched those obtained from the early infections detected in Wuhan; a particular set of adenines here, another string of guanines there, and this short chain of cytosines and uracils clustered exactly where it should. The missing, or deleted, chunk of the virus’ RNA, however, could mean a change in the virus’ behaviour.
But Su took some convincing of her own finding. “My first instinct was is this a sequencing error,” recalls Su, who double-checked her work on different samples. The deletion appeared over and over again.
Still not ready to believe the data, she fired off an email to the lab lead Professor Gavin Smith — this is odd, could it be a mistake?
After careful review, Smith and Su decided the anomaly was worth investigating further.
They designed specific primers and retested the sequences to pinpoint and verify exactly which sequences were missing. And it was a necessary caution—the general public and scientific community deserved the most accurate information possible.
“We wanted to verify this observation. Whether it was true or not. Because once it’s out in the world, we can’t recover it,” says Su. “It was exciting, but we were very careful—very cautious!—in interpreting our results.”
Their careful work identified a particular SARS-CoV-2 deletion, called Δ382—named for its missing 382 nucleotides or building blocks—that was found in 23.6 per cent of novel coronaviruses locally by February. This deletion was concentrated in a portion of SARS-CoV-2 known as open reading frame (ORF) 8.
Deletions in the same area of the viral genome had also been observed in Australia, Bangladesh, Spain and Taiwan. However, unlike those deletions which appeared to decrease the virus’ ability to replicate, Su and the team found that their variant appeared to be more transmissible than the original, or wild-type, virus but less severe.
Lessons from previous pandemics
In her work, Su had been focusing on the evolution, emergence and transmission of respiratory viruses, primarily seasonal influenza. She studies the whys and hows of these viruses as they transmit between hosts, as well as the seasonal outbreaks which result.
The H1N1 influenza virus subtype which caused the 2009 global swine flu pandemic had been one of her key research projects.
“That was the year when my daughter was born. And in 2010, we all moved to Singapore,” Su remembers; Smith is her husband. “We were fortunate to get the funding for studying the evolution of the H1N1 pandemic.”
They had received thousands of these H1N1 samples from hospitals including Singapore General Hospital and the National University Hospital. Su and her team ended up testing each one individually in order to sequence the full genome. Never mind that each experiment needed more than 20 pairs of primers and many repeat attempts—and that these results did not show any evolution.
“All the virus sequences from the first two years of that pandemic that we extracted were very similar to each other. I panicked a bit,” says Su. “There was nothing for me to work on here.”
Instead of focusing on the differences between sequences in Singapore, Su adopted a larger perspective and started comparing the Singapore H1N1 sequences with those of the rest of the globe. A very clear picture emerged—the spillover event for H1N1, where the virus had first began transferring from swine to human, was marked by “a lot of random mutations”. Two to three years down the line, however, only certain variants had survived to recirculate in human populations.
Su received the SingHealth/Duke-NUS Research Team Award in 2018 for her work on the H1N1 pandemic, and her experience guided her research against SARS-CoV-2 and its variants.
Handling a giant
Adept at handling the series of nucleotides that make up the influenza genome, tackling the giant genome of SARS-CoV-2 had required a deeper breath.
“Influenza’s about 13,000 RNA bases. But SARS-CoV-2’s genome is nearly 30,000,” she notes. “That’s double the size.”
The other challenge had been the explosion in genome sequences uploaded onto the international genome database GISAID. When Su had started on the project, she had just 130 other sequences to compare her data with.
“By the time we were revising the manuscript, there were more than 13,000 genomes,” says Su.
So, they relied on their computational shortcuts developed while studying influenza, which enabled them to randomly select sequences for comparison. Even so, it was a stressful time.
“We had the pressure to write up the paper and get it published,” says Su, who remains grateful for the unstinting commitment from the team who readily pulled long shifts in purposeful excitement of making a difference.
Their findings were published today, but, Su and the team were already getting to grips with their next project: to track the evolution of the virus within the same host over time.
“We wanted to see what the changes are over time within the same host. Some patients may carry the virus longer than others,” says Su. “In influenza, for example, we found intra-host diversity that correlates with other factors such as age and weight.”
Sharing knowledge to help others
During the early months of any pandemic, the many unknowns can easily cause wide-spread fear.
Seventeen years ago, Su hadn’t made the jump to working on viruses yet. When SARS struck Hong Kong, where she lived at the time, life was scary. At the same time, safe distancing measures, split shifts and other measures were not widely used.
“I was more panicked. I didn’t know much about viruses,” recalls Su, remembering the pervasive fear she’d felt of inadvertently bringing the virus home.
This time around, Su felt better equipped. She was assured by the Singapore government’s control measures. And now working on viruses herself, the threat seemed less abstract.
It was also a topic of conversation at home. Whenever her daughter Abigail, then a young tween, asked about the virus, Su and Smith talked to her about it. They reassured her that it’s not as scary as it sounds.
This at-home education planted good seeds.
“One day at work, I received an email from her schoolteacher,” Su shares. “Saying she wanted to thank my daughter Abigail for giving comfort to a classmate whose parents were infected with COVID-19. The parents were in hospital for weeks.”
“My daughter didn’t tell me that story,” says Su proudly. “When I got that email, I thought ‘Okay, we’re not just doing basic science in the lab. We’re educating our next generation as well.’”
With Su and Smith both working long hours and weekends in the lab particularly during the early months of the pandemic, family time remained at a premium.
“I’m fortunate to have two lovely children who don’t complain when we are working for long hours, plus the support of a very good helper. She gives me peace of mind when I am at work, basically,” says Su. “It’s a sacrifice we’ve had to make since the start of the pandemic, and it’s a good opportunity for us to help out.”
She thinks for a while.
“We’re not like staff in hospitals — they’re really dealing with pandemic patients. I admire those frontline workers for their contributions and efforts,” she continues. “For us as scientists, we’re just doing basic science. I’m very honoured to be part of the pandemic response.”