This Duke-NUS virologist aims to break SARS-CoV-2 infection cycles at a molecular level.
Assistant Professor Ooi Yaw Shin had not been back to visit his loved ones in Penang ever since the pandemic began. This even though the Malaysian island is merely a 90-minute flight away from Singapore.
“One of the reasons I moved back to this region was that I would be closer to home,” says Ooi, who had moved from Stanford to Duke-NUS in December 2019. “I remember calling my mom when I arrived, telling her: ‘Yeah, I just started my lab. I may not be coming home this Chinese New Year but I promise I’ll definitely come back in April or May for Qing Ming.’” Referring to the Chinese festival where families pay their respects to the deceased at their tombs.
“I never got the chance to leave,” Ooi finishes, deadpan.
Instead, he buried himself in work, researching fundamental questions about SARS-CoV-2: How exactly does the virus get into human cells?
“If we know which doors and windows a virus uses to break into our cells, we may be able to design new drugs, and perhaps improve vaccine designs,” he explains.
Ooi and his team with Duke-NUS’ Emerging Infectious Diseases Programme specialise in identifying the factors that enable viruses to flourish within host cells. They turned to dissect the mechanics of a SARS-CoV-2 infection, searching for any weak links in the viral infection processes.
Tracing the path of invasion
Leveraging the latest gene-editing tool CRISPR, Ooi zooms in on virus-host interaction at the cellular level.
“With CRISPR, we can switch each of the 20,000 genes off or on in the human genome,” explains Ooi.
Like a surgeon with a scalpel, Ooi cuts the genetic material of cells to introduce or remove genes with precision, searching for candidate genes that are associated with the body’s susceptibility to viral infections.
“By finding out which genes are important and drugging them, we may potentially stop SARS-CoV-2 from infecting us,” he says.
Which is what he and his team set about to uncover.
Bringing everything to bear
With his years of experience, Ooi has always taken a broad approach to tackling viral threats. And so he studies a range of viruses — including respiratory viruses such as seasonal coronaviruses, human parainfluenza viruses as well as arboviruses such as the mosquito-borne dengue and chikungunya viruses.
“If we can find a feature shared by multiple viruses, the interventions we discover could be helpful across a range of viruses,” he explains. “Our director, Gavin Smith, he’s a world-class expert on respiratory viruses. He’s already worked on human seasonal coronaviruses before this outbreak so he had all the samples we could use and study.”
While coronavirus research is currently experiencing a surge in interest and funding, things had not always been that way.
Before COVID-19 hit, Ooi could name fewer than five laboratories across the world that were active in coronavirus research.
There was simply not enough public interest and funding, he shares, as previous coronavirus outbreaks had been limited in scale — and in the case of SARS, the virus vanished completely, perhaps because of effective containment strategies, or maybe a bit of luck. And the remaining coronaviruses that circulate in the human population as common colds were just not priorities.
But with its potent mix of transmissibility and infectivity, COVID-19’s unprecedented economic and social damage transformed the global public health agenda.
“Let me put it this way: a lot of the worst-case scenarios we predicted in decades of scientific papers and grant proposals had unfortunately become a reality,” remarks Ooi grimly.
A sneaky pathogen
Even for experienced virologists like Ooi, COVID-19 research was tough.
The widespread pandemic lockdowns had resulted in laboratory facilities being shut, assay turnaround times bottlenecked, and reagent shipments delayed.
“With lockdown delays, we got scooped multiple times as studies like ours were published. While we are confident that we still have unique findings to report, it is a constant race to get our findings validated and published,” he reveals.
But that doesn’t mean he and his team were idle. Far from it. While they battled supply chain issues, they also set about consolidating a comprehensive review of the intra-cellular goings-on that unfold when a SARS-CoV-2 virus infiltrates a cell.
Unlike most viruses Ooi had studied, which are faithful to a single mode of entry into human cells, SARS-CoV-2 turned out to have access to a side door, too.
As everyone soon learnt, it latches onto cells using the angiotensin-converting enzyme 2 or ACE2 receptor and merges with the cell surface membrane. Once inside the cell, the virus dumps its genetic material, which hijacks host cells’ machinery to generate copies of the virus for release.
But SARS-CoV-2 can also wiggle its way into cells when it is taken up by cells after binding to receptors on its surface, a process called endocytosis.
“SARS-Cov-2 just waits for its endocytic elevator ride to arrive and hijacks this mechanism to get in. It’s a very patient and sneaky pathogen,” Ooi says with a laugh.
Research that matters
Despite the initial setbacks, his team was soon doing what they are best at: getting busy decoding the threats posed by viruses and tapping the support the SARS-CoV-2 spotlight had brought.
To this end, he is part of a group of scientists from Duke-NUS led by Gavin Smith, who received funding to research human parainfluenza viruses, which cause respiratory infections like the influenza virus. Unlike influenza, there is no vaccine that currently protects against parainfluenza infections.
“This is a really good sign,” Ooi says. “It means we can hopefully continue to do good science over the next five to ten years — before attention fades and people lose sight of why this research matters.”
And while he looks forward to what’s to come, being at the forefront was at times a double-edged sword.
“In February, I could see the infection trend in Malaysia going up. And my extended family — my father’s side — they still wanted to throw a big Chinese New Year party like every year,” says Ooi, who had to play the “bad guy”. “I told them ‘Please don’t. All 50 unvaccinated people having lunch or dinner together is going to be disastrous.’”
“And they said, ‘OK, we’ll discuss among the senior folks in the family.’ Then, ‘Thank you for your suggestion. We’ll look into it’,” he shares.
Ooi’s relatives did eventually cancel that large gathering.
Having been apart for more than 18 months now — their big Chinese New Year reunion would be all the more joyous for the wait. While Ooi waited for that to happen, work in his lab continued, generating intel that would give us an edge against infectious diseases like COVID-19.