Contents

The People

Prologue

Act One

Scene One

| Something wicked comes this way

Scene Two

| Code breakers

Scene Three

| The bed, the patient and the student doctor

Act Two

Scene One

| A daring attempt to secure Singapore

Scene Two

| T cells: An elegant defence

Scene Three

| Tracing the future

Act Three

Scene One

| Quelling the flames of inflammation

Scene Two

| Facing up to a hundred battles fearlessly

Scene Three

| From the imagination of clinician-scientists

Epilogue

The Pandemic

Prologue

Standing at the State Lectern, Singapore’s Prime Minister Mr Lee Hsien Loong addressed the nation: “My fellow Singaporeans, our fight against COVID-19 has reached a major turning point. We will be making a decisive move towards living with COVID-19.”

It was Thursday, 24 March 2022.

Precisely 814 days earlier, on 31 December 2019, the World Health Organisation had received a report about a cluster of pneumonia cases with no known cause from the Wuhan Municipal Health Commission in China. This report heralded the beginning of the biggest crisis to hit the planet since World War II.

Just 11 days after that first report, Chinese scientists identified the virus causing the pneumonia. It was a coronavirus, a cousin of the viruses behind SARS and MERS. In the days that followed, doctors detected cases in Japan, South Korea, Thailand and the United States. On 23 January 2020, doctors added a pin for Singapore to the map tracking the virus’ global spread.

***

Set up in the wake of the 2003 SARS outbreak, Duke-NUS Medical School had been conceived to train a new generation of research-minded clinicians and pursue translational research in fields that are relevant to the population and people across Asia. Situated in Southeast Asia, a region that stands out for its diverse fauna, flora and population density, Duke-NUS would study emerging infectious diseases through one of its five research programmes and contribute to any disease outbreak response. This very eventuality—mobilising an effective response to a potential pandemic—formed the bedrock of the Emerging Infectious Diseases (EID) Programme.

“While we talked a lot about wartime and ensuring that our teams were prepared, our recruitment efforts focused on bringing in the right people to do the best research in the area of emerging infectious diseases,” said Senior Vice-Dean for Research Professor Patrick Casey, who had joined the School when it was still only a blueprint.

Together with the programme’s founding director, Emeritus Professor Duane Gubler, and subsequently Professor Wang Linfa, who took over from Gubler in 2012, they assembled a team of scientists who specialised in studying different kinds of infectious diseases, from mosquito-borne diseases like dengue and Zika to respiratory viruses like influenza, as well as how these pathogens interact with their hosts—be they mosquitoes, bats or humans.

***

So, as the world ushered in a new decade, scientists at Duke-NUS readied their teams, studying the first sequence from China, ordering the necessary testing materials and, in Wang’s case, sharing first-hand experience of the situation in Wuhan.

The morning after the first case was reported in Singapore, Casey called for an urgent meeting. Ten experts from the the safety team and the EID Programme met in a conference room. Interrupting their breaks and conference trips, another handful phoned in to the meeting—virtual meetings had yet to become the norm.

“We met around the table in the conference room about 10 o’clock to talk about what we could do, because the EID professionals were chomping at the bit to study the virus,” recalled Casey.

And during that meeting, just twelve hours or so after the first case of the novel coronavirus had been detected in Singapore, this group of inadvertent avengers assembled, ready to step up to serve the nation and the world.

What everyone around the table wanted was to identify and study the virus. They wanted to isolate it. Culture it. Sequence it. To unlock treatments, vaccines, diagnostics and determine from where it had come.

“We knew we couldn’t begin mitigation protocols until we had the wherewithal to determine the identity of the virus,” said Casey.

On the ground, the EID professionals adjusted their work to focus on this new threat, while the liaison with the Ministry and the university fell to the School’s head of safety. With the Chinese New Year holiday just around the corner, Casey remembered the speed with which the School scrambled to respond.

“The next 72 to 96 hours were really crazy,” said Casey.

Reflecting on the work that arose out of those intense early days, Casey said: “I am terribly proud of what our folks did and how everyone stepped up to the plate. These were the individuals who, during the Circuit Breaker, worked 14 to 16 hours a day”, singling out the teams who worked in the high security lab while sealed inside their “space suits” or personal protective equipment.

“Never once did I have to remind anybody to do their bit,” he added. “In fact, I had the opposite.

What I had was people stepping up to the plate, asking what more they could do.”

***

Duke-NUS’ research response had already been fully mobilised when at lunchtime on Friday, 7 February 2020, the multi-ministry taskforce announced that the nation’s Disease Outbreak Response System Condition or DORSCON level would be raised from yellow to orange.

This announcement meant that all clinical training was suspended with immediate effect.

“That Friday afternoon, after we were told by the Ministry of Health, ‘That’s it; clinical training’s suspended’, we met all the classes to tell them ‘Right. Go collect your things from the hospitals, because you won’t be allowed back in for the time being’,” Vice-Dean for Education Professor Ian Curran, said candidly. “And then we had one hell of a busy weekend working out what we’re going to do.”

All of a sudden, a well-thought-out response was needed; indeed, re-envisioning and re-assessing became imperative. The School’s education teams had the weekend to work out the first contingency plan. That was first of many revisions to the School’s curricula—“75 curriculum iterations” Curran likes to say—that would become necessary over the next two years.

“It would become the really demonstrated the professionalism, determination and flexibility of the education teams both within the School and across our clinical training partners who came up with creative, imaginative and effective solutions throughout the pandemic,” said Curran.

These constant revisions ensured the safety of patients, faculty and students while enabling students’ uninterrupted progression through their training as the pandemic evolved.

“Healthcare systems and the human response to disease are inherently complex adaptive systems. They’re constantly evolving. We, too, had to evolve and adapt with them to meet our educational mission,” explained Curran.

During the first six months of the pandemic, Duke-NUS transitioned to full e-learning for classes with more than 50 students, developed virtual alternatives to clinical clerkships and worked closely with the Ministry of Health and the other medical schools to return students to hospitals and clinics across the country as soon as it was safe.

After sitting their final exams in March 2020 under full COVID-19 restrictions, the final-year students were able to return to clinical training as early as April just as the country entered its national Circuit Breaker.

“This meant we had to ensure our students were fully trained in using personal protective equipment and prepared for entering a completely transformed clinical environment,” said Curran.

Despite the challenges and curveballs, the students successfully completed their clinical training and graduated—even joining the frontlines two weeks earlier than had been planned.

“We prioritised the clinical training and final exams for the fourth-year students as we were keen to demonstrate that our students had met all the required clinical, professional and academic standards that ensured they could practise as safe and competent doctors,” added Curran.

For students in their earlier years, the education team designed bespoke solutions to keep their learning on track.

“We took the bold decision to bring forward the research activity for two year groups,” said Curran. “That move allowed those cohorts to remain actively engaged and progressing through the course while the clinical settings were off-limits.”

Two classes of medical students, then, would in due course complete all components of the world-class Duke-NUS curriculum, albeit in a uniquely sequenced way, thereby cementing their place alongside the other graduated cohorts in the School’s history.

***

In the Acts that follow, Duke-NUS educators, clinician-scientists, researchers and alumni share their stories of the pandemic years, reflecting on their personal experiences and professional accomplishments. Their work was invaluable to the public; they provided much-needed trained manpower to restore the medical frontlines; and throughout, progressed medical education practice and made scientific discoveries that helped chart a way out.

Act One

It was December 2019. While most people were looking forward to the New Year, something ominous began to spread. Unbeknownst to the world, the SARS-CoV-2 virus and a long pandemic “era” awaited.

As the virus spread to all corners of the world, the Duke-NUS community rallied. Scientists stepped up their efforts to lead humanity’s fight back, educators flexed and adapted so that medical training could continue uninterrupted—all of them drawing deep on experiences accumulated over a lifetime to deliver innovative solutions.

Act One | Scene One

Something wicked comes this way

The night air was cold as Professor Wang Linfa alighted from a car outside the Wuhan Tianhe International Airport. After checking in for his flight back to Singapore, he headed for the departure hall.

Something awful is coming, Wang realised as he saw a fortified temperature monitoring station manned by airport medical and security staff, kitted out in full personal protective equipment.

“Usually, you’d just walk through,” said Wang, who leads a lab at Duke-NUS that investigates emerging infectious diseases and bat biology. But this time, a long queue of people had built up.

“They controlled the flow of people so that only four in a group walked slowly past the three cameras. Most people had to do that twice.”

He, too, was asked to repeat the process.

“That immediately gave you that fearful feeling that something serious is going on,” added Wang, who rapidly revised his initial perception of the novel coronavirus outbreak that had erupted in Wuhan.

It was Saturday, 18 January 2020.

Wang had never, in all his 30-plus years as a researcher, experienced anything on this level, not even during the 2003 SARS outbreak.

How do I protect myself? Wang wondered instantly. I’m not wearing a mask.

Once onboard the Singapore-bound plane, he cleaned his seat handrail with the little wet towel provided. The flight would take five hours, and Wang spent the entire time staying put, interacting as little as possible with the other passengers and cabin crew. He gained a newfound appreciation for his business-class seat—with no one next to him, he could reassure himself that he was at least within his own airflow space.

***

Wang had originally trained as a biochemist, working in the United States before taking up a senior tutor role with Monash University’s Biochemistry Department in Australia in the late 1980s. While working there, he came across a job advertisement that would set him on a new course in his career, one that would lead him to become one of the world’s foremost experts in emerging infectious diseases and bat biology.

The Australian Animal Health Laboratory (now the Australian Centre for Disease Preparedness) under the state-run Commonwealth Scientific and Industrial Research Organisation (CSIRO) had put out a call for a PhD scholar with a molecular biology background to study infectious diseases. A Masters researcher, skilled in either biochemistry or protein chemistry, was sought for as well. The listing gave him, and his wife, pause.

“It felt almost like insider trading. The advertisement was like it was written for the two of us,” Wang recalled saying to his wife. “And it was a permanent job.”

Wang’s career blossomed at CSIRO, where he traced the origins of the Hendra virus in Australia and helped curb a Nipah virus outbreak in Malaysia. In 2005, he reported that horseshoe bats are major reservoirs of SARS-like coronaviruses.

Wang rose through the ranks from research scientist to CSIRO Office of the Chief Executive Science Leader before joining Duke-NUS in 2012 as the director of the Emerging Infectious Diseases Programme.

Here, he leads research teams examining how animals—particularly bats—transmit diseases between each other and humans, studying why these otherwise innocuous flying mammals harbour a kaleidoscope of viruses. He also teaches undergraduates, supervises PhD students and communicates science to the public through media appearances.

***

Within days of his return from Wuhan, Wang’s research expertise, as well as his inadvertently first-hand experience, became sought after by the School, government ministries and international health bodies.

By that time, the confirmed number of novel coronavirus infections had risen to 581 cases, with all but ten from China. But those ten included infections reported as far afield as the United States and South Korea, hinting at the global spread that was already underway.

On 22 January 2020, the day before Singapore reported its first case of the novel coronavirus, Wang attended a meeting called by the government. It was the first meeting of the newly convened COVID-19 Research Workgroup, where Wang was asked to spearhead the virology research.

Recalling that meeting, Wang said, “Then I said, ‘Personally, I think serology’s important, and I don’t mind leading that, too.’” Serology is the study of antibodies in blood. And for Wang, it was a tried-and-tested strategy to get answers long after a virus had moved on.

“And people said, ‘Oh. That’s good. Yeah. Just add that in.’”

With these two duties settled, Wang did what he had always done—make sense of the unexpected.

With intuitive foresight, Wang could already picture the necessity for a serological kit to rapidly detect exposure to SARS-CoV-2, that could be safely used outside of a top security lab to trace the virus’ path.

“We envisaged very early on that neutralising antibody testing would be important,” noted Wang about the anticipated bottleneck in testing. “And we just wanted to do something that’d solve that issue.”

So, he had, while still in Wuhan, alerted his team, including then-research fellows Drs Chia Wan Ni and Tan Chee Wah, to be ready to search for these neutralising antibodies. With the genome published on 11 January, they had ordered the reagents needed for such serological investigations. Now they just needed samples.

“In any major disease outbreak, you’ll have different phases. In the initial phases, molecular testing is important,” explained Wang. “But later, serology is much more powerful. Because the virus is gone, but we can still trace its spread.”

In the context of SARS-CoV-2, which did not trigger any outward symptoms in some people, a serological test that detects neutralising antibodies to the virus would let experts like Wang understand just how many people had been infected, how fast the virus was spreading, how fatal it was, and which population segments were especially resistant or susceptible to it.

Meanwhile, as Wang was sharing his insights with Duke-NUS’ leadership, Singapore’s newly set up multi-ministry taskforce and the World Health Organisation’s COVID-19 International Health Regulations Emergency Committee, he knew that a new phase of the outbreak was imminent.

“All this was happening before the Chinese New Year. So, every other day, there were a few hundred people directly travelling from Wuhan to Singapore,” noted Wang.

His tone was firm. It was that of a man who already knew that he and his colleagues would, in the months and years to come, face one of the toughest challenges of their careers.

After all, he was bringing all his experience as a virus hunter to the fight against COVID-19.

***

Wang names the Hendra outbreak as the moment when the full potential of serology became clear to him. Still at CSIRO’s then-Australian Animal Health Laboratory, Wang led a team investigating a disease outbreak in the Brisbane suburb of Hendra that was killing horses and humans. The virus, named by Wang after the suburb, causes haemorrhages, meningitis and respiratory dysfunction such as a build-up of fluid in the lungs.

Hendra’s transmissibility from its natural reservoir to humans, though, was not understood initially. Polymerase chain reaction or PCR tests of tissues taken from different animals, which the research team collected in order to study the virus’ origin, all turned up negative.

“So, I said, ‘Serology’. Let’s go searching for Hendra virus antibodies and we’ll test as many different animals as possible,” said Wang. “We tested 42 different animals. Koalas, snakes, birds—everything. Eventually we found an antibody in bats.”

And they found these antibodies in a particular type of bat called flying foxes. With this knowledge, more precise laboratory research and public health measures were implemented against Hendra.

Some five years later, Wang brought this expertise to curb the deadly Nipah virus outbreak which killed 109 out of 276 people infected in Singapore and Malaysia between 1998 and 1999.

But as Wang pursued serological testing, he also came up against its limits.

“In our field, we always say that the gold standard is the virus neutralisation test. But for virus neutralisation tests, you need a live virus for the base,” explained Wang.

For diseases like Hendra and Nipah, that meant Wang and his team could only handle them in the most secure biocontainment facilities, making the job so much harder.

“I needed something that was a surrogate so we could mimic this,” said Wang. “So, instead of using the whole virus, we just used a piece of its protein.”

In 2007, Wang published the concept, developed using the Nipah virus, in the Journal of Virological Methods to little fanfare.

***

As he had anticipated, by February 2020, Wang’s team was busy using serology to support Singapore’s contact tracing efforts, proving its value when they uncovered the hidden link between the two largest COVID-19 clusters at the time—never mind that he was at that time serving a self-imposed three-week home quarantine, even before it was mandated for people coming or returning from Wuhan and Hubei Province.

That achievement earned Duke-NUS as well as a number of government agencies public commendations from Singapore’s Prime Minister and Deputy Prime Minister.

All the while, Wang had been fine-tuning his 2007 concept. In early March 2020, Wang sketched his idea for a surrogate SARS-CoV-2 virus neutralisation test for the then-Senior Associate Dean for Innovation and Entrepreneurship Associate Professor Christopher Laing, asking whether this should be patented.

“I told him, ‘I have something really exciting—a potentially revolutionary test,’” recalled Wang.

This surrogate method would make testing for viruses easier, doing away with the need for a live virus, which in turn, would unlock more data at a faster rate for policymakers, doctors and other researchers. And make contact tracing through serology more accessible.

The patent was filed on 24 March 2020.

“I felt really excited. We were solving a bottleneck for COVID-19. Scientifically, it was a brilliant idea and now commercially there may be a future as well,” said Wang.

By May 2020, Wang was working with A*STAR’s Diagnostics Development Hub and biotech company Genscript Biotech to co-develop and manufacture his invention, which was trademarked cPassTM.

Just six months later, on 9 November 2020, the United States Food and Drug Administration (FDA) announced its decision to authorise cPass for emergency use.

“It took me six months and many 3 am meetings to convince the FDA,” said Wang.

“In the history of the FDA,” he went on, “they have never approved serology to measure neutralising antibodies. Not just for SARS-CoV-2—but for any virus. The reason is that testing traditionally can only be done with live agents—live viruses and live cells. So how can you regulate this to make sure that the assay is performed identically in a thousand different labs? There’s no way. Quality assurance is impossible when you have a live virus in a live cell. ‘Wow,’ I thought, ‘that’s a very high bar to cross.’”

But since cPass does away with this need, it can be used to reliably measure immunity in the community, trace close contacts and evaluate vaccines and therapeutics.

“We still don’t really know how this pandemic started and we didn’t know how we could get out. That became my focus,” said Wang. “Because if we don’t know how it started, we cannot prevent another pandemic.”

“And,” Wang paused for emphasis, “the old, powerful serology, it’s highly specific. The serological approach can play a key role in addressing those problems.”

In February 2021, Wang was among 65 international experts elected to the American Academy of Microbiology, the honorific leadership group within the American Society for Microbiology, recognised in the field and relied upon for authoritative advice and insights on critical issues in microbiology.

***

By then, new variants had been protracting the course of the pandemic. So, Wang and his team upped their search for a neutralising antibody that could perhaps take out not just SARS-CoV-2 and its current variants but help boost immunity against its close cousins, too.

They and their clinical collaborators returned to a unique group of people—people who had been infected with SARS-CoV-1 in 2003 and vaccinated against SARS-CoV-2.

Using an advanced, multiplex version of their surrogate virus neutralisation test, the team discovered that this group of people produced neutralising antibodies that could knock out up to ten coronaviruses from a group called sarbecoviruses. This group includes SARS-CoV-1, SARS-CoV-2 and all its variants, as well as several coronaviruses identified in bats and pangolins that have the potential to infect humans.

Speaking at a news conference announcing the discovery held on 18 August under embargo, Wang said that this could become an alternative to variant-specific booster strategies, called third-generation coronavirus vaccines (3GCoVax).

“We think this provides the scientific foundation to try a new boosting strategy—we call that 3GCoVax—to combat different variants including the current four and future ones,” said Wang, adding that the same principle could be used to produce therapeutic antibodies.

He went on to note that the World Health Organisation was targeting to have the majority of the global population vaccinated with existing vaccines in a year’s time.

“If we boost that population with the 3GCoVax, we also potentially can be ready to fight and prevent the next pandemic of SARS-3 or SARS-4,” added Wang, whose discovery has since been licensed to start-up biotech company CoVBio for further development.

In December 2021, he received the President’s Science Medal “in recognition of his stellar contributions to the field of bat biology and emerging viral diseases”. And, in particular, his success in translating his discoveries into biomedical innovations and pandemic responses that have helped combat several viral outbreaks, including COVID-19.

But Wang believes that he can play an even bigger role.

“The dream for me is that one day—one day—people can treat viruses and pandemics totally apolitically. Treat them as a common enemy,” he declared. “And then, in peacetime, build up an intelligence, resource and knowledge-sharing network. That, to me, is the only way to prevent the next pandemic.”

As part of Wang’s lab at Duke-NUS, Drs Chia Wan Ni and Tan Chee Wah were instrumental in accomplishing the lab’s many breakthroughs. Aligning to their supervisor’s commitments, they divided into groups—one to focus on virology and another on serology—and both had to scale up their output.

“When Professor Wang said, ‘Okay, we really need manpower; we need to bring a lot of manpower to cope with this,’ a lot of people volunteered,” recalled Chia. “The PhD students said, ‘Okay. I’ll stop doing my PhD work. I’ll help.’”

And they did. Tan and Chia worked alongside them during morning, afternoon and, inevitably, impromptu night-time shifts. The Linfa lab, as Wang’s lab is affectionately known, was in research-and-response mode, responding to requests from various ministries to examine suspected SARS-CoV-2 clusters while also scrutinising the virus and sharing their latest discoveries with the world.

One day, while Wang was still self-quarantining in February 2020, the team received instructions to run conventional serological tests on a particular set of samples to determine if they contained antibodies to SARS-CoV-2. As the test needed to be done with a live virus, Chia headed to the biosafety level 3 (BSL3) lab.

Tan, Chia’s lab mate, explained: “They want you to go in blind and just work on the sample. After that, whether it turns out positive or negative, you’ll have seen the truth.”

This bias-free approach to testing turned up a milestone discovery: the missing link between the SARS-CoV-2 clusters involving two churches. The resulting chain of infections totalled 31 people. And it was the first time in the world that serology was used like this.

“When Professor Wang explained the entire backstory, we were, ‘Whoa! O-kay! This is a first in the world?’” Chia smiled, remembering.

Besides contact tracing, serology would also enable the team and others to check the levels of immunity in the community as well as develop vaccines and therapeutics.

But working with a live virus in highly secure facilities meant that the process was slow, time-consuming and expensive. Faced with this bottleneck, Tan and Chia helped Wang develop his idea for a surrogate virus neutralisation test, which eventually evolved into cPass.

These months, understandably, became the career highlight for them.

“It was the first time I’ve done research and come up with a [commercial] product,” said Tan. “I can’t explain the feeling.”

He laughed. “Maybe this might happen only once in my life.”

***

All things considered, Chia and Tan never expected to become so intimately involved with SARS-CoV-2—or, indeed, any respiratory disease. Chia’s previous work focused on malaria. Tan had researched mosquito-borne flaviviruses and enteroviruses that cause hand-foot-and-mouth disease.

They had joined the Linfa lab not long after each other—Chia in late 2016 and Tan in March 2017. Here, they built upon their existing specialties, but swapped virus reservoirs. Instead of mosquitoes, they focused on bats and the threats that lurk within the only flying mammal, a change Chia welcomed.

“Emerging infectious diseases are a lot closer to my heart,” Chia shared.

Shifting their focus to this particular virus, accordingly, came naturally to the pair.

“We work very well together as a team. I was mainly taking charge of all the response stuff. Chee Wah was doing all the research,” explained Chia, who became the main point of contact between the lab and external stakeholders.

And it wasn’t just external contacts who would reach out. Chia became a “COVID help desk” for her extended family. She debunked rumours from social media and explained the reasons behind different measures. Tan, similarly, had to reassure his wife about his work in the BSL3.

“My wife was worried. She asked, ‘Can you catch the virus in the BSL3?’ I told her that, in some ways, it’s safer working in the BSL3 environment than the BSL2,” he said, referring to the more common type of lab, where the requirement for personal protective equipment is considerably lighter.

***

And it wasn’t just cPass that the pair were instrumental in developing.

By August 2021, they were in possession of another discovery that had to be kept under wraps until it was published in The New England Journal of Medicine.

“Once we published this New England paper, all the people who had access to it would immediately start their experiments to prove us right. Or prove us wrong,” said Chia. “So, we were competing with the whole world.”

“That’s science, right? You must master a bit of competition. Then you become better,” added Tan.

The paper that had both of them so excited provided the first glimpse of broadly neutralising antibodies produced by SARS-CoV-1 survivors who had received the Pfizer-BioNTech mRNA vaccine—never mind that the SARS-CoV-1 infections took place almost two decades ago in 2003.

“If our science leads to a real product—like a real vaccine that actually can be used for boosters—then…” Tan trailed off, leaving the enormity of the thought unspoken.

“If it works, that means our science is true. And correct,” Chia chimed in. “It’s a good feeling to be validated by others.”

They laughed, in mixed satisfaction and disbelief, at how their work had escalated since the start of the pandemic.

First, they were just doing their own research. Then their serological testing methods helped Singapore’s health authorities link two of the largest SARS-CoV-2 clusters; and the cPass serological test kit for the rapid detection of SARS-CoV-2 neutralising antibodies followed. Now, this New England paper; their laugh simply meant: Is this big breakthrough really happening? To us?

But after the long hours in the lab and at their desks, as well as that frenzy of writing up the data and the month-long peer-review process, they felt like they were suddenly put on hold as they impatiently waited for news from the journal.

Tan shook his head. “When our paper was first accepted in principle, I kept asking Prof Wang, ‘When are they officially accepting our paper? Are they going to reject us or what?’ Then after the official acceptance, I kept asking Prof Wang, ‘When are they publishing our paper?’ It was a very long wait.”

Because until it was published, they could not share their excitement with the wider world nor receive the validation of other labs corroborating their findings.

“I think every one of us has our secret tree hole to tell all these things to,” mused Chia.

Secret tree holes aside, the team could, at least, rely on each other.

“It’s good to have someone to talk to, and just hash things out, and just feel amazed at the whole situation,” she concluded.

Also, the New England paper did not, Chia pointed out, mean the end of that particular research avenue for them. In fact, in August 2022, Chia moved on to her next adventure, working for CoVBio, the start-up that has since taken over the development of these findings.

The Linfa lab, then, was no longer just a lab where researchers work on their research. They were part of a larger, nationwide, even global, research network intervening against the pandemic.

A quietly satisfied Tan summed it all up, saying: “We contributed to the country. And that’s good.”

Act One | Scene Two

Code breakers

I hope they manage to lock that down was Professor Gavin Smith’s first thought when the news broke in December 2019 that a novel virus was spreading from Wuhan.

“Because if they don’t, it’ll probably become a pandemic.” But they couldn’t. And it did.

The transportation hub was finally closed to the outside world on 23 January 2020.

By then, 286 people around the globe were already suffering from—and spreading—the highly infectious novel coronavirus.

By then two of these virus carriers, travellers from Wuhan, were already warded in isolation facilities in Singapore.

By then, Smith had already deployed his team.

***

The professor with Duke-NUS’ Emerging Infectious Diseases Programme is a multi-disciplinary researcher renowned for his expertise in respiratory viruses. His team is trained in fieldwork, biosafety level 3 (BSL3) research and the genomic mapping of viruses—making them well-equipped to sequence respiratory pathogens.

Moreover, the team had worked on human coronaviruses—“the regular ones,” said Smith—before SARS-CoV-2.

“Preparation is what we do every day,” declared Smith.

They travel around the world, training and working with partners to conduct robust surveillance of the viruses circulating in animals, particularly bats and small mammals like rats, both hotbeds for disease X.

They work wearing protective coveralls, N95 masks and even respirators. They are accredited N95 mask fitters. They are experts at handling and studying all kinds of pathogens.

“This kind of research builds capacity,” Smith continued. And capacity was precisely what was needed.

***

When the novel coronavirus erupted in early 2020, the immediate ask of Smith and his team was to sequence the novel virus once it hit Singapore’s shores and examine the 30,000 bases that make up this giant of a virus.

They readied themselves by scrutinising the first sequence of the novel coronavirus released to the world, comparing it to existing sequences of similar viruses from animals and humans. They studied how the four chemical bases in the virus’ RNA—its guanines, cytosines, adenines and uracils—repeat to form a unique chain that can be compared with other chains from the same virus.

“We immediately started comparing that sequence with other known coronavirus sequences so that we were prepared for when the first sequences came from patients in Singapore,” said Smith.

“Our focus was on trying to generate the sequencing data as quickly as possible and making sure that we weren’t messing it up.

“Because in the early days, the sequencing data would be crucial for contact tracing, so that we’d know whether the virus was spreading in the community and could monitor how it was adapting to being transmitted by humans,” explained Smith.

***

Then on 30 January 2020, researchers at Duke-NUS successfully extracted the virus from a patient sample in Singapore, making Duke-NUS the third institution in the world to culture SARS-CoV-2.

It took them just seven days from when the first case of SARS-CoV-2 was detected in Singapore.

“It was an achievement and it shows that we have the capacity to do this work,” affirmed Smith.

“More importantly, it meant we had the virus and we could start to study it.”

The live virus was a precious resource for testing whether therapies and vaccines could work in humans and developing better and faster ways of detecting it.

“It was key for [Professor Wang] Linfa developing the cPassTM assay that’s become widely used. That was very satisfying,” said Smith.

And with that data, Smith and other scientists could then trace the virus’ journey and identify new mutations over time. Comparing the sequences with clinical outcomes, they could determine whether the virus was evolving to infect people faster or cause more severe disease.

While they were monitoring the evolution of SARS-CoV-2 in Singapore, Smith’s team discovered a large deletion in one of the virus’ key genes, called open reading frame 7b and 8 or ORF7b and ORF8.

“It was a massive deletion that was quite unexpected,” recalled Smith, who worked with Su to confirm these findings which they would publish in two papers in mBio and The Lancet.

***

By March 2020, it had become clear that the world faced an escalated threat, one that kept on confounding even the highest echelons of public health officials with its unpredictability.

A senior World Health Organisation official, for example, stated during this time that the asymptomatic transmission of the virus was “very rare”; more senior officials from the health body backtracked on the comment the following day.

“What really surprised me was the number of assumptions that were made,” Smith recalled, “that led to definitive statements which were really unhelpful, especially at a time when no one really had a clue.”

That was not the only challenge he and others had to deal with.

Home-based learning would soon be added to the mix as the outbreak transformed into a rampant pandemic.

“We were struggling to work out what was going on with the home-based learning, particularly as we were still in the lab every day,” said Smith.

However, with his first-hand experience of working with the virus, it was satisfying to be able to reassure his children—seven and eleven at the time—when they brought home the latest talk from the classroom.

“They would come home from school and tell us what they’d heard from their friends,” Smith smiled.

“Then we just say, ‘Oh, you know that’s not quite what’s going on. This is really what’s happening.”

Together with his wife, Yvonne Su, a then-assistant professor with the Emerging Infectious Diseases team, he would reassure them.

Yes, this virus is a problem. Yes, it is real. No, you don’t need to be scared.

Were his kids ever scared for their parents?

“No, they don’t have any such concept of what our work involves,” chuckled Smith.

“They would forget about it for a while and then a month later, you’d get the same question. We’d say, ‘You do know we work on this, right?’

“And they go, ‘Oh? Really?’

“At the same time, we were doing this extra job supporting the national effort to sequence early virus samples that we’d been given, while also still having to do all the regular work and look after the team because everybody was uncertain about what was going on. It was really stressful.”

***

The pandemic also brought pleasant surprises. With its mix of bat researchers, immunologists, virologists and vaccinologists, Duke-NUS’ Emerging Infectious Diseases Programme, though small compared with other infectious diseases teams, packed a solid punch.

“In hindsight, that was a very effective unit to have. Given how small our department is, we made an oversized contribution both nationally and internationally to the COVID response,” said Smith, who, in 2022, was appointed to lead the programme.

He was especially impressed with the “amazing” research on the immune system’s T cells by immunologist and a fellow professor with the Programme, Antonio Bertoletti, and how Bertoletti contributed a new understanding of how these cells might counteract the severity of a SARS-CoV-2 infection.

***

Throughout the outbreak, Smith stuck to one guiding principle: science should make for a world free from the pandemic.

“Contrary to what some on social media claimed, scientists are overwhelmingly good people,” he shared.

“We do this type of stuff because we’re interested in helping.”

“And so, even though people were completely burnt out, they still felt that it was their duty to try and find solutions.”

Reflecting on the best-case scenario of how this pandemic could trail off, Smith said: “The ideal situation is that as immunity builds globally, whether through vaccination or natural infection, the overall severity of the disease becomes less.

“It’ll hopefully settle down to a level of severity that’s no greater—but hopefully less—than flu. But even then, it is still a big deal. It is an enormous cost to society.”

And looking to the next pandemic, Smith mused: “Pandemics aren’t rare. If you look at the exposure of humans to pathogens in animals, it is enormous.”

While most such exposures or spillovers don’t trigger a pandemic, they happen all the time. And it only takes one virus that happens to be readily transmissible between humans to spark the next outbreak.

With this constant threat, the only response is preparedness.

“We have all sorts of disaster plans, right? Fires. Earthquakes and tsunamis. Floods.”

“We now must have a pandemic preparedness plan that should be updated to match the capacity and skills of the team,” he said.

“Before this, the idea that a department or a school should have a pandemic preparedness plan was kind of laughable, right?”

He gestured, already knowing the answer. Yes, it was. But not anymore.

When Yvonne Su first spotted “that massive” deletion in her SARS-CoV-2 sequence one afternoon in February 2020, she simply stared at the next-generation sequencing data, not trusting her eyes.

This shouldn’t be happening.

***

An evolutionary biologist-turned-virus-decoder, 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.

But these latest results were perplexing.

The initial sequences obtained from patients in Singapore 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.

This missing, or deleted, chunk of the virus’ RNA however, could mean a change in the virus’ behaviour—a change that would need to be investigated.

With the potential for far-reaching consequences, Su took some convincing of her finding.

“My first instinct was, ‘Is this a sequencing error?’,” recalled 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,” said Su.

“It was exciting, but we were very careful—very cautious—in interpreting our results.”

***

During the early months of any pandemic, the many unknowns can easily cause widespread fear. The H1N1 influenza virus which caused the 2009 global swine flu pandemic had been one of Su’s key research projects.

“That was the year when my daughter was born. And in 2010, we all moved to Singapore,” said Su, who is married to Smith. “We were fortunate to get the funding for studying the evolution of the H1N1 pandemic.”

They had received thousands of H1N1 samples from hospitals including Singapore General Hospital and the National University Hospital. Su and her team ended up testing each one individually to sequence the full genome. Each experiment needed more than 20 pairs of primers and many repeat attempts. Yet the 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,” remembered 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 from the rest of the world. A very clear picture emerged: the spillover event for H1N1, where the virus had first begun 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 and her team received the SingHealth Duke-NUS Research Team Award in 2018 for this work, and her experience guided her research against SARS-CoV-2 and its variants.

***

While adept at analysing the series of nucleotides that make up the influenza genome, tackling the giant genome of SARS-CoV-2 required a deep breath.

“Influenza’s about 13,000 RNA bases. But SARS-CoV-2’s genome is nearly 30,000,” she noted. “That’s double the size.”

The other challenge was the explosion in genome sequences uploaded onto the international genome database GISAID. When Su 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,” said Su.

So, she and her team relied on the computational shortcuts they had developed while studying influenza, which enabled them to randomly select sequences for comparison.

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 ORF7b and ORF8.

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 was associated with less severe disease.

Still, the continuous influx of sequences made for a stressful time.

“We had the pressure to write up the paper and get it published,” Su said.

She remains grateful for the unstinting commitment from the team who readily pulled long shifts in purposeful excitement, knowing they were making a difference. Their findings were published on 21 July 2020 in mBio with a follow-up piece in The Lancet one month later.

By then, 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,” said Su, who was promoted to associate professor in July 2022.

“In influenza, for example, we found intra-host diversity that correlates with other factors such as age and weight.”

***

Seventeen years ago by contrast, when SARS struck, Su hadn’t made the jump to working on viruses yet. And living in Hong Kong at the time, life was scary. Safe distancing measures, split shifts and other measures were not widely used.

“I was more panicked. I didn’t know much about viruses,” recalled Su, remembering the pervasive fear she felt of inadvertently bringing the virus home.

One thing that was markedly different for Su in 2020 was that this time round, she felt better equipped. She was assured by the government’s control measures. And now, working on viruses herself, the threat seemed less abstract.

The pandemic was also a topic of conversation at home. With Su and Smith both working long hours and weekends in the lab 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 long hours, plus the support of a very good helper. She gives me peace of mind when I am at work, basically,” she said.

“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.”

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 was not as scary as it sounded.

This at-home education planted good seeds.

“One day at work, I received an email from her schoolteacher saying she wanted to thank my daughter for giving comfort to a classmate whose parents were infected with COVID-19. The parents were in the hospital for weeks. My daughter didn’t tell me that story,” Su said 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.’”

Su and Smith’s work started after the team at Duke-NUS had successfully cultured the virus, an achievement that molecular virologist Martin Linster had a hand in. So it is no surprise that for him, the first few days and weeks of the pandemic had been particularly intense.

Okay, we really can’t mess this one up.

That was Linster’s main thought whenever he or one of his colleagues collected Singapore’s first few SARS-CoV-2 samples from hospitals across the island.

The way he narrated it, those errands were straight out of a heist movie.

During those times, the team’s circuit started at Singapore General Hospital around 3 pm before proceeding to the basement loading bay of the National Centre for Infectious Diseases.

“We even got with the courier the first weeks of the outbreak. We went into the dispatch driver’s lorry just to make sure the samples were safe,” recalled Linster.

At both stops, they’d swap iceboxes full of triple-sealed patient samples for a signature.

Then, once they were suited up and fitted with a respirator, the team—including Linster—would examine the contents of their iceboxes in the safely contained zone of the BSL3 lab.

***

Linster was a senior research fellow then with the Emerging Infectious Diseases Programme at Duke-NUS, with years of experience handling dangerous viruses to find out how they infect cells, mutate and—importantly for these uncertain days—multiply.

His previous targets had been “less newsworthy”, said Linster. He studied the human parainfluenza virus in Vietnamese children in 2009, showing that a particular strain was responsible for most of the cases, and that diverse virus strains were entering Vietnam.

In 2014, Linster researched how far away an H5 avian influenza is from mutating into an airborne pathogen that readily spreads among its hosts. He found that five positions in the viral genome could be changed so that the virus binds to and infects cells of the new host.

Upon joining Duke-NUS in the mid-2010s, Linster had not planned to resume BSL3 work. He already had a decade’s worth of investigations within these high-security containment facilities under his belt; it’d be good, he thought, to work elsewhere in the field of emerging infectious diseases after all that.

But after a few years, he started missing the work, and it took little convincing for Linster to join his first Duke-NUS BSL3 project in 2019. When the pandemic hit, he was accordingly in a prime position to contribute his expertise.

“You start up slowly again,” said Linster of his return. He had to re-acclimatise to the sealed-off environment of the BSL3 with its ventilation and noises.

“It’s a bit like doing your first scuba dive,” he remarked.

“Then you go full speed when the pandemic hits.”

***

The courier journeys, iceboxes and strictly regulated BSL3 were necessities—the Duke-NUS team’s work called for samples and security because they had no room for “messing it up”.

The carefully guarded samples should offer the key to unlocking vaccines, treatments and policies to help the world fight the virus. But there was always a question.

“How good was your patient sample?” Linster explained.

“Did you manage to keep the cold chain?”

Maintaining the cold chain in this case meant keeping the samples from SARS-CoV-2 patients at a low temperature. Break the chain and the virus dies. SARS-CoV-2, it turned out, was pretty unstable outside the human body in tropical Singapore.

After some initial fine-tuning of the experiments, a clear pattern emerged.

The team put the virus samples into a carefully selected cell line that allowed the virus to thrive, infecting the cells and replicating itself—all under the watchful eyes of people like Linster.

“You look under the microscope,” said Linster. “And you see cell death.”

But this effect was not unwelcome.

Such cell death is what virologists term a “cytopathic effect”. This happens when a pathogen invades a cell and causes structural damage.

And Linster and the team didn’t just see their cells die.

They watched them bursting all over each other.

Such an uncontrollable and messy death typically results from a major injury to cells and is consistent with how viruses affect them. This was a key clue.

Now, they had to wait for their tests to finish running to make sure that this was indeed the work of a virus.

“You think, ‘Okay, this doesn’t look normal, but was there a bacterial contamination or anything?’” he remembered.

“Then you look at the screen for half an hour just to convince yourself and the rest of the world that this is really positive if you do it over again. Because you could’ve done something wrong.”

In the end, the team’s findings proved accurate; yes, this was all the work of a virus, and here was its genetic code in full, waiting to be extracted from the living virus.

It had taken the team less than a week to complete this feat, which would unlock opportunities for the rest of the scientists at Duke-NUS and beyond to develop tests, treatments and vaccines.

With such an important discovery in their possession, the team was swift to publish their data. They were the third lab in the world to do so, after ones in China and Australia.

“As a scientist, you want to do something new, right?” Linster said.

“You say, ‘Okay, I’m number three?’ Personally, I’m not too much interested in being that hamster on the treadmill.”

Research papers and national and international collaborations resulted regardless.

“There were surprises every day. That was the essence of what kept us going,” said Linster.

For him, one of the most exciting projects to follow was a collaboration with the lab of Antonio Bertoletti, a colleague and professor with Duke-NUS Emerging Infectious Diseases Programme, who specialises in the study of T cells.

“Characterising the T-cell response, we found something rather unexpected that was met with strong interest from the world,” said Linster of what they discovered.

***

And it wasn’t just work that brought exciting discoveries during the pandemic. On 12 February 2021—just as the Year of the Rat made way for the Ox—Linster and his wife, Marina, welcomed their baby daughter, Norah.

Norah was the first Lunar New Year baby delivered at Singapore General Hospital in the Year of the Ox. She is the Linsters’ second child and little sister to Bruno, then three years old—and another reminder after the hectic months of the pandemic that people were waiting for him, outside of the BSL3.

“You should at least sit at the breakfast table with everybody before you leave again,” mused Linster about life’s unstoppable flow.

“You can’t have the people who love you waiting forever.”

***

Exciting new opportunities aside, Linster, who was promoted to assistant professor in 2021, believes that the lessons from this pandemic will help us respond more efficiently when the next pandemic strikes.

He also advocates that the global scientific community—and virologists in particular—should work together on an easily accessible catalogue of crucial viral mutations that could underpin the next outbreak. It would be a timely tool for researchers by researchers.

Such a collaborative effort would, he expects, save lives during any future pandemic. “It is a lot of effort, but it’s crucial,” said Linster. “We seriously want to prevent the next pandemic from happening on a scale like the current one.”

Act One | Scene Three

The bed, the patient and the student doctor

“So, I started with Duke-NUS on 10 February 2020, and Singapore had just gone into DORSCON Orange,” remembered Ms Kirsty Freeman about the first day of her new job in a new country; a country that had just raised its national disease alert level, the Disease Outbreak Response System Condition or DORSCON, to its second-highest level.

“I didn’t know what that meant. But I came to work, and there was this bustle—this unusual sort of vibe.”

Freeman discovered why later that day.

The School had just been told to withdraw every single medical student from hospitals and clinics—all clinical environments suddenly off-limits.

It was a necessary precaution. SARS-CoV-2 had spread to Singapore and the hospitals were on high alert. Would this be a replay of the 2003 SARS outbreak?

This measure, however, meant no more opportunities for students to learn from doctors, nurses and patients in a real clinical setting. And no way for clinical supervisors to assess if these students had mastered the required clinical skills.

As the incoming lead for the Clinical Performance Centre at Duke-NUS, Freeman had been hired to make sure that students could take medical theory out of textbooks and put it into practice. There would be gaps in learning opportunities now, she knew, with students removed from healthcare institutions.

Freeman’s personal plans to watch and learn “for probably the first six months” to get “a feel for how the School does things” were out of the window.

“On that first day, I realised my next six months were going to be a little different from what I’d thought.”

***

Singapore’s DORSCON framework has four colour-coded levels: green, yellow, orange and red. They represent, in that order, the increasing severity of an infectious event in Singapore as well as the steps needed to contain it.

DORSCON Orange meant that the disease was severe and spreading easily among people, but also that it was being contained. Such containment necessitated moderate disruptions to daily life, including temperature screening and quarantines.

Additional sector-specific precautions—learnt from the previous SARS outbreak and the H1N1 pandemic in 2009—were also rolled out, including the cohorting of healthcare professionals and visitor restrictions in hospitals.

Gatherings of students, too, were capped at 50 per group. The solutions that Freeman and the education team developed over the coming months needed to be in line with these measures.

***

Right from the start, the School had been clear that despite all the restrictions, the students would sit their high-stakes clinical exams in March 2020, by which point they would have to be competent in all the prerequisite clinical, procedural and professional skills.

Freeman, a fellow of the United States Society for Simulation in Healthcare, had to draw deep on her knowledge and experience, acquired over nearly 20 years of delivering simulation-based education, assessment and research. But finding ways to simulate clinical environments is Freeman’s area of expertise and passion.

“I love simulation as a tool to take theory out of the books and put it into practice,” she shared. “Simulation ensures that when students have the privilege of interacting with real patients, they are prepared and ready to deliver really great care.”

To maximise training opportunities for students while making sure that group sizes remained within the permitted limits, her team ran simulations on weekends and late into the night.

“I was so proud of all our staff,” she beamed.

“We completely re-envisaged our work life to meet the needs of our students.”

And for those times when in-person became just impossible, Freeman and the team created fully online learning opportunities.

“I loved our can-do attitude,” she shared.

“Everyone rallied together and said, ‘Who’s got ideas? We don’t know how that’s going to work, but let’s do it!’”

The Clinical Performance Centre, along with the wider Duke-NUS education team, also worked closely with healthcare organisations and the Ministries of Health and Education to obtain critical equipment and resources such as personal protective equipment and hand sanitisers so that students could continue learning, even if that learning had to be brought back to the School’s campus.

***

But even with their can-do attitude, they were challenged at times as week by week, the goalposts kept changing.

“You were never on solid ground,” said Freeman.

“We would come up with a great plan but then a couple of days later—guess what? We couldn’t do that any more because now everyone must be so many metres apart. Or must now have masks and face shields on.”

She didn’t let that discourage them. She shrugged—this was the way things were, and we got on with it.

So as the measures continued to evolve, the educators and examiners were put to the test.

“It was a new directive almost every other day—each a highly sensible new precaution—but each drove a big red bus through our curriculum plans,” Vice-Dean for Education Professor Ian Curran chuckled, recalling those early months.

“We had to flex and adapt constantly. Often with just a few hours’ notice. You’re told, mid-afternoon on a Sunday, that you couldn’t rotate your students on Monday.”

As for following the trend started by medical schools overseas of doing away with the exams? Unthinkable.

“We felt it was important to validate our students’ own sense of knowing that they’ve made the grade and met the standard,” asserted Curran, who like Freeman is a fellow of the Society for Simulation in Healthcare.

“We also needed to demonstrate to our clinical stakeholders and partners that our students were good to graduate and fit to go into practice.

“These constant challenges demonstrated the true professionalism, creativity and adaptiveness of our educators, as well as the resilience, grit and determination of our students. All characteristics that would stand us and them in good stead to navigate the challenging years ahead as we adapted to the new normal.”

***

When the Circuit Breaker was announced, the team knew they had to rethink their protocols again for the final round of clinical exams.

“I felt like MacGyver,” Freeman said, referencing the fictional undercover agent, known for his nifty invention and engineering skills.

“We just had to use what was on hand.”

And the Circuit Breaker made necessity the mother of invention.

“How could we position cameras to capture images? Who had duct tape and bits and pieces to bring in from home? Could we stick stuff on walls or lean tablets against equipment for a different angle? It was creative,” she laughed.

Freeman and Curran, along with their colleagues, went on to publish their approach in MedEd Publish. The two case studies were downloaded thousands of times as educators looked for ways in which to pandemic-proof exams around the world.

***

The secret ingredient to their successful transformation, Freeman revealed, was going social.

She credits informal sharing networks for bringing the medical simulation community together and preventing educator burnout. For instance, she actively crowdsourced best practices and exchanged tips on topics such as manikin sanitation and hygiene protocols.

“Social media was such a great tool for everyone to share their stories. It was the little things like what is it that we must do and how do we do it. The simulation community was coming up with processes and policies and guidelines to keep everyone safe.”

And this sharing enabled Freeman and the Duke-NUS team to adapt quickly.

“We could learn how someone tried something, and we could build on their successes and failures. That’s how we were able to respond so quickly and implement things effectively.”

On 29 May 2020, 62 medical students—part of the uniquely-trained Duke-NUS Class of 2020—graduated. Even with their graduation they chalked up another first for the School and Singapore: reciting the Hippocratic Oath in a virtual ceremony.

***

But what of Freeman’s own needs? The plan had been for her, her family and friends to fly between Australia and Singapore for regular visits.

Her husband, too, would fly in from Perth around the middle of the year. Then, they would build their life in Singapore.

“That didn’t happen,” stated Freeman.

“I remember sharing with him—it was changing on a weekly basis—this great plan. A couple of days later, that was up.”

Border restrictions soon cancelled all travel and grounded planes. Freeman’s husband would remain in Australia until an unknowable someday.

So, Freeman focused on what she could do.

The “busyness” of work and the creative delight of pottery classes helped.

The new bonds forged online—through Zoom catch-ups and spontaneous notes of reassurance—with others in the medical simulation community sparked joy and provided much-needed encouragement and inspiration too.

“There are so many people within Duke-NUS and our larger community here in Singapore who have been more isolated due to the pandemic,” said Freeman.

“And we should be reaching out to each other every now and then to say, ‘Hey, guess what? Thinking of you today.’”

And she always started her day by sharing a virtual cup of tea with her husband, who had had to remain in Australia.

“We set our alarms early. Before our working day,” she shared.

“Starting at 6 o’clock every morning, we’d meet each other on video and have breakfast together.”

They would check in on each other during these virtual sessions, asking about their friends and families. It became the way they maintained their relationship for a long time, also because constant interaction in relationships is part of Freeman’s larger approach to life.

***

Despite the many scuppered plans and constant need to respond and adapt, Freeman has no regrets.

“You know what got me through?” asked Freeman. “I have a job where I felt like I’m making a difference. I was surrounded by like-minded people who were passionate about medical education and providing access to great healthcare. All that kept me going.

“Looking back now, it’s energising to know that we can provide solutions to challenges that other people might be facing too,” she continued. “None of us are alone in this.”

She considered the students who graduated during the first year of the pandemic again, with proprietary pride.

“We delivered incredibly robust education while adhering to safety restrictions. We can say—with hand on heart—that our students were ready for the workforce. I think that’s spectacular.”

Act Two

From an outbreak, COVID-19 spiralled into a pandemic. Governments closed borders, rolled out public health measures to contain and later mitigate the impact of the virus. With vital information now at hand—and new data constantly adding to the rapidly emerging situation—researchers, clinician-scientists and health services research experts at Duke-NUS began delving deeper into the immune response,developing vaccines and modelling many what-ifs.

While addressing the world’s urgent need for answers and better tools, global health experts also started tracing the contours of the shadow pandemic that loomed.

Act Two | Scene One

A daring attempt to secure Singapore

The gravity of what was to come first hit infectious diseases expert Professor Ooi Eng Eong in January 2020.

Oh no, will this be a repeat of 2003? was Ooi’s initial thought.

The 2003 SARS outbreak—standing out for its long days and short weekends—had been testing for Ooi. He had run experiments in one of Singapore’s two biosafety level 3 (BSL3) labs, the high-security facilities needed to study airborne pathogens, for anyone in search of answers. He also shared inactivated viruses with colleagues for use as a control to ensure diagnostic equipment was returning accurate results.

This experience made Ooi, a clinician-turned-scientist, feel confident that Singapore was better prepared this time.

After all, SARS had been a watershed moment, bringing in its wake a robust infection control infrastructure, one that even had a dry run in 2009.

“But the SARS label was also a bit of a red herring because we all thought that we should be able to control this outbreak as quickly as we had SARS,” he said.

Even as he authored one of the first close-ups of the inflammatory and immune responses of patients infected with this newer SARS virus, he still thought—hoped—the outbreak could be contained.

“Those were the first three cases and I thought that would be it,” he laughed, fully aware of how wishful that thinking had been.

“That turned out to be wrong.”

Instead, as SARS-CoV-2 infections spread through undetected networks of presymptomatic and asymptomatic carriers, the usually buzzing Duke-NUS campus fell silent. Students learnt online. Researchers met virtually to hear about each other’s work. The building felt deserted.

“Those of us who worked on COVID-19—we were the only ones in the building at one point,” Ooi recalled.

***

Ooi knew that as the co-director of the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS), he could—and should—intervene on a larger scale.

“It is not unreasonable for countries to buy insurance in the form of vaccines to protect lives and livelihoods,” he mused.

“But better still would be for a country to be self-sufficient. We should be able to make our own vaccines.”

And he did more than muse.

Putting his thoughts into action, Ooi leveraged his experience with dengue and SARS, as well as his lab’s deep know-how about what makes an effective vaccine to embark on a quest to enhance Singapore’s vaccine expertise, and test-drive processes and protocols with the hopes of producing a new COVID-19 vaccine for the world.

That know-how also made him and his long-time collaborator, then-Associate Professor Jenny Low, a logical choice for the Economic Development Board (EDB), which had been in discussions with a biotechnology company from the United States about producing a vaccine against this novel virus.

“It was mid-February 2020 when the EDB asked if we would collaborate with a company they’d been talking to,” said Ooi.

Arcturus Therapeutics had a self-replicating mRNA SARS-CoV-2 vaccine concept and ready candidates that needed to be assessed, optimised and tested.

“We thought we could contribute because of what we’ve been doing with dengue and yellow fever. We understood what attributes to look for in a vaccine candidate,” explained Ooi.

Discussions between Duke-NUS and Arcturus started roughly a fortnight later. In March 2020, confident they could complement each other, both parties agreed to embark on the project together.

“After that, life became very busy,” deadpanned Ooi.

***

Right from the start of the pandemic, Ooi was also acutely aware of the need to communicate what was known about the virus to the public—another way in which he could intervene on a larger scale.

Because in the absence of a reliable source of knowledge, mis- and disinformation about SARS-CoV-2 had quickly filled the void, spreading worldwide through social media and conspiracy websites. The situation had become so grave that by February 2020, World Health Organisation Director-General Dr Tedros Ghebreyesus noted that the world was “not just fighting an epidemic; we’re fighting an infodemic.” Fake news was spreading faster and more easily than the virus.

“Let’s say there was a misunderstanding, or a myth or whatever that was being circulated. If we as professionals didn’t speak up, then we were lending credence to that belief system,” said Ooi.

“So, every time I saw a journalist, I felt that I should do this. Because if I didn’t, then from where else would the public get their information?”

***

With the collaboration sealed, Arcturus shipped their vaccine candidates to Ooi and his team for analysis. Unlike other mRNA vaccines, the self-replicating nature of this vaccine meant that the mRNA in the vaccine could be amplified in the body to produce spike proteins, prompting the immune system to produce antibodies and other immune cells to fight off the spike protein’s simulated infection then and there while forming a lasting memory of the threat.

After carefully and systematically studying the different candidates’ attributes, Ooi and his team identified ARCT-021 as the most promising. In their preclinical studies, the self-replication process boosted ARCT-021’s performance markedly when compared with other mRNA vaccines.

But it was also the one part of the vaccine that had not been tested in humans yet.

“My worry was that no matter how well we looked at it during the preclinical stage, there would still be a surprise when it went into humans, resulting in unexpected side effects,” said Ooi.

After stringent and extensive testing, the company and regulators greenlighted the first phase of human trials, which started just after Singapore’s National Day in August 2020.

Despite that, Ooi and Low, who is also a senior consultant with the Department of Infectious Diseases at Singapore General Hospital (SGH), kept a careful watch for possible side effects in the volunteers.

“I was very nervous,” confessed Ooi.

“I think I was nervous throughout the entire Phase I.”

During the first phase of human testing, the clinical trial team, led by Low, administered escalating doses of ARCT-021 to the volunteers. They stopped when those who received the highest dose showed the first side effects. Then, it was over to Arcturus with the data and on to the next phase.

“The initial set of data was enough to support the start of Phase II trials,” said Ooi.

And on 28 December 2020, the Singapore Health Sciences Authority gave the green light to proceed with the next phase. Around the same time, Ooi and his team also began delving deeper into the data to decode the immune response, so they could be better prepared in the fight against the coronavirus, as variants of concern continued to emerge.

Reflecting on his involvement in the most hotly contested race in human history, Ooi admitted that “it had been a bit daunting” to be working on one of more than 100 vaccine candidates that had commenced development by April 2020.

With only a fraction of these eventually progressing to Phase I trials, he had not known what to expect.

“We were able to take it through to the next stage of trials,” he sighed with relief.

“Each new phase of testing uncovered new lessons for us and we’re now consolidating these lessons to explore ways in which to create other vaccines,” he added.

With hindsight, would he have done anything differently?

“The one thing that I wish we could have done,” considered Ooi, “was to have the resources to do more than one vaccine.

“But other than that, I wouldn’t change anything. Because we were given an opportunity to use what we had learnt to benefit Singapore and the world.”

***

Ooi along with Low and Drs Eugenia Ong and Ruklanthi de Alwis shared their experience of developing the vaccine in a documentary, called “The Vaccine Quest”, which aired in March 2021.

But even before that, Ooi’s role as a public face of science and vaccine development in particular had earned him two awards from The Straits Times. He was among a group of six individuals, dubbed the virus hunters, who were honoured with The Straits Times’ Asians of the Year Award in December 2020.

And just two months later, in February 2021, he received the Singaporean of the Year Award from the same paper as a representative, along with four others, of COVID-19 frontliners from the healthcare, research, security and public health sectors.

***

Ooi sees the experience gained from his work on ARCT-021 as propelling future and longer-lasting healthcare solutions for the region. He hopes that countries will invest in even more robust medical research ecosystems.

“Countries need to put aside a certain sum of money to keep the infrastructure going,” he explained, “so that when you need, you can tap into that science.”

A science that will undoubtedly be called on again soon as a slide Ooi is fond of showing suggests. The slide charts a stark sense of the inevitable: the first 21 years of the 21st century alone have seen eight major disease outbreaks. That means one outbreak every two-and-a-half years, which means the next one might be just around the corner.

“We need to invest in preparedness,” asserted Ooi, noting that talk about improvements and measures always abounds during outbreaks.

“We need to be self-sufficient. In Southeast Asia, we should not have to continually rely on shipping vaccines from Europe or North America. To meet our needs, we should be able to make our own. And distribute it to our neighbours.”

Like Ooi Eng Eong, Dr Jenny Low, a then-associate professor with the Duke-NUS Emerging Infectious Diseases Programme, had seen a number of outbreaks flare up before being quickly contained.

Even the first SARS outbreak in 2003—although devastating—lasted only a matter of months before life went back to normal.

“There was no way that any one of us anticipated that it would grow to the kind of scale that we saw,” she reflected.

“But most of us came to the realisation that we would have to live with this for a long time to come.”

While the sheer scale of COVID-19 may have surprised some, Low and her colleagues at Duke-NUS and across the road at SGH, where the clinician-scientist practises, were prepared for the outbreak.

“We always knew that these events are ‘whens’ not ‘ifs’, so mentally we’re prepared,” she shrugged.

***

Low—like most other healthcare workers and infectious diseases scientists—had been on high alert as the new decade was ushered in. Bolstered by the lessons from the 2003 SARS outbreak, the infectious diseases community reviewed infection control protocols and kept abreast with the latest scientific reports and news about the outbreak while the robust screening system ensured that symptomatic patients were quickly identified, isolated and tested.

Just around Chinese New Year, with the number of suspected cases snowballing, Low—who divided her time between clinical work and research—had to take on full-time clinical duties; her colleagues were already away on long-planned trips across the Malaysia-Singapore border and would have to quarantine once they returned.

“I was doing calls 24 hours for four days in a row,” she recalled.

“And at night, my phone was going off every 15 minutes. People wanted to know what to do with all these suspected cases, what risk factors to consider, whether these cases should be isolated.”

And in this way, the early days flew past.

“Comparing this experience with working through SARS, I definitely had a lot more energy back then,” Low mused.

“I didn’t have kids either, but now I have four! There was a difference in my energy level, stamina and time.”

Despite being pressed for time, Low, who co-directs ViREMiCS with Ooi, and their collaborators managed to share their early experiences of dealing with this novel virus in a slew of publications, which included a report on the first three cases admitted to SGH as well as a larger report about the disease in 18 patients, which was published in JAMA.

***

By April 2020, she was finally able to focus on her research duties, joining the fray by recruiting patients for a range of clinical trials to evaluate potential treatments and other interventions to help people suffering from COVID-19, as well as to examine the immune response of and disease progression in infected individuals.

“I was having to deal with the speed needed to accelerate the research,” she laughed.

“It was crazy. I was really racing against time and racing against everyone else.”

The most demanding leg of that race involved shepherding the Arcturus vaccine candidate, ARCT-021—Singapore’s first locally tested vaccine project against the virus—through early phase clinical testing.

“It was a very exciting time,” said Low, who also heads SingHealth’s early phase clinical trials unit, the Investigational Medicine Unit.

But while Ooi was on tenterhooks as the first doses were administered, Low felt quietly confident.

“By the time we started working on the vaccine with Arcturus, they had been recruiting children with a rare inherited disorder in New Zealand for a trial using this platform and had safety data from their early phase study. Since we were using the same platform, I didn’t foresee much of an issue,” said Low.

Still, as the first doses were administered, Low remained on hand, vigilant for signs of an anaphylactic reaction in her participants. She did the same whenever the dosage was increased.

In the end, out of the more than 100 volunteers, all but two adverse events experienced by the participants were mild or moderate. And the vaccine candidate was greenlighted for further testing at the end of 2020.

***

Just as the vaccine entered the next phase of testing, the frontrunners were shipped around the globe for real-world use. While that proved to be a bittersweet moment, Low was glad that the world had access to vaccines that could prevent severe disease and help communities emerge from the pandemic.

“The world got lucky. We had a ready platform that had been developed for cancer that could be designed into vaccines,” she observed, pointing to the need for continued innovation.

“If we look around us to see what was happening in the world, there quite clearly weren’t enough vaccines for the short term,” added Low.

“So, with more vaccines on the market, ones that could be administered as a single dose, those would help benefit more people.”

And the faster vaccines could be made available, the better, as the long tail of the pandemic was starting to take its toll on people’s wellbeing.

The intermittent tightening and loosening of safe distancing measures had resulted in corresponding changes to work routines and school life. And home itself became an added source of mental stress.

“It was very difficult managing work plus home-based learning,” recalled Low.

“I think for all of us, the difficulty lay more in coping with just how long the pandemic was lasting.” But she knew that after the vaccines were rolled out, there was a good chance that the situation in Singapore could return to some semblance of pre-COVID life.

“The more people were vaccinated, the faster we could get to a level of immunity that would allow the healthcare system to handle small outbreaks without having to reimpose restrictions,” she reflected.

As it turned out, the wily virus required a close-to-perfect vaccination rate to adequately cushion its impact on an exhausted healthcare system and fatigued economy before safety measures were significantly relaxed.

***

As for Low, she continued to pursue projects that helped to profile immune responses to vaccines and infection to gain a better understanding of the evolving virus.

Colleagues, too, tapped her expertise for other research projects—including saliva testing and N95 mask re-usage. It was fulfilling, purposeful work and resulted in, as Low said, “many publications and fantastic research achievements”.

But she would trade a normal 2020 for all these accomplishments any day.

“It made me realise that I missed so many things that I could do in normal times.”

Thinking about the things she was going to do differently after the heat of the pandemic dissipated, Low listed: “I’ll do more travelling. I obviously wasn’t taking enough breaks. I wasn’t spending enough time with family. Maybe I’ll catch up on all this.”

She laughed with a touch of self-deprecating awareness: “I guess the whole world thought the same.”

But like all wounds, Low knows that the ones gouged by the pandemic will heal with time.

By the time the COVID-19 pandemic becomes a peculiar memory of the past, Low hopes that the medical community’s recommendations will guide individual behaviour more.

“We have always strongly advocated masking up, yearly flu vaccination and pneumococcal vaccines and staying away from crowded places to our at-risk patients with damaged and vulnerable lungs,” she said.

“Hopefully, people will be convinced.”

Dr Eugenia Ong, a then-senior research fellow with Duke-NUS’ Emerging Infectious Diseases Programme, studies gene expression in human samples in response to infections, vaccines and treatments.

As part of the team at ViREMiCS, she was also at the coalface of the outbreak from the day the first patient was detected. It fell to her and the ViREMiCS team to help shed light on the immune system’s reaction to this new threat.

“The complication came because we didn’t know very much about this virus.”

Facing an unknown threat, Ong worked with the team on how to safely study these samples. Mitigating steps included treating the samples with heat and “chemical cleans” that killed the virus but kept everything else intact. They also included wearing two sets of gloves, disposable gowns and N95 masks on top of the usual safety gear required in the lab.

While Ong worked out the rapidly growing number of experiments the team wanted to do and responded to a deluge of emails, patient samples kept coming from the hospital.

“So the first few days and weeks, we were just collecting and freezing the samples while we waited for the approvals to come in,” she recalled.

Once they received the green light, Ong, who works closely with Ooi Eng Eong and Jenny Low, started by studying the gene expression of patients over the course of their illness until they had recovered.

“It is one of the most highly cited papers that I have,” laughed Ong.

“It gained quite a bit of traction. There was a lot of interest around what was happening on a molecular level in these patients.”

At the same time, other projects came online and samples from various clinical trials kept arriving throughout the day.

***

“It started to feel more intense when we went into the Circuit Breaker,” remembered Ong.

“With the split team arrangement, we had to do a lot of coordinating.”

At the same time, Ong was onboarding Ayesa Syenina, who had just successfully defended her thesis and was now joining the lab as a full-time staff member. Between the two of them, they oversaw the coordination and tracking of clinical trial samples, with Ong taking the morning shift and Syenina covering the afternoon.

“But she really had to hold her own during those days,” said Ong.

“We had regular catch-ups in the evening. They were long days.”

Alongside mentoring new colleagues, Ong and the team geared up to start on the human trials of the vaccine, ensuring they had all the necessary reagents and tests ready and spelling out the finer points of how the samples would be transferred between the trial site and the lab.

At least by then, the Circuit Breaker had had its desired effect.

“Starting on the vaccine project was a nice transition as we had stopped sampling patients from the hospital with numbers so low by then,” recalled Ong

***

By National Day 2020, Ong and the team at ViREMiCS were ready. It was the last moment of calm before the storm hit.

“It was pretty intense and intensive after that point in time,” remembered Ong.

“We wanted to get everything right. Because really, with clinical trial samples, you need to get it right the first time.”

The last tube of blood from the final follow-up visit of the first human trial was drawn in January 2021, capping an intense four-month period.

“It was a lot of work, I won’t underplay that,” she said, her tone suggesting that it was also hugely satisfying work.

“We had these moments, when we were the first to see results and the patterns that emerged,” offered Ong by way of explanation.

***

“What is interesting is the contrast between this virus and SARS,” she mused.

“I remember SARS, because I was in secondary school then. We got an extra week of June holidays because they were trying to keep everyone at home. That disease was more severe,” Ong continued.

“Because of that, more people died.”

Bringing that virus to a hard stop.

“SARS-CoV-2, though, is a different beast. There was a lot more effective transmission that we were seeing with the variants that kept coming up,” she went on to explain.

“And the question was: Would the vaccines protect against these variants?”

For Ong, that question led to further investigations into the immune response and whether it differed between vaccination and infection; and whether age, gender and health mattered.

“We started a follow-up study with some of the participants from the Phase I study to look at long-term immunogenicity from the vaccine, looking specifically at T-cell responses to find out how long these responses actually last,” she elaborated.

“In parallel, we were also looking at healthcare workers who received the mRNA vaccine,” Ong added, explaining that they were tracking the incidence of side effects and investigating the molecular triggers behind them.

“Running these in parallel allowed us to really dissect what happened at the molecular level in participants.”

And like her mentor Ooi Eng Eong, she felt duty bound to share her knowledge of the vaccines with the public.

“There’s a small pocket of the population that was hesitant; they were resistant to taking vaccines,” said Ong.

“Because often you have one or two people who write something, and send it out on social media. And you know social media. It gets passed on from one to a billion other people.”

Whether it was a family member, friend or journalist who reached out, Ong was always happy to help.

“I was always happy when someone asked me about vaccines and whether they should take them. It gave me a chance to explain,” she said.

That motivation underpinned her participation—along with the rest of the team—in the documentary “The Vaccine Quest”.

While the documentary may have been one of the more in-depth pieces of media coverage, the team were joined by other faculty members in the fight against misinformation.

The most important piece of advice Ong gave out during that time?

“If you don’t know where the information came from, and if you don’t know if it’s true,” stressed Ong, “Don’t spread it.”

Twenty-twenty is going to be an amazing year, Dr Ruklanthi—or Rukie—de Alwis recalled thinking as she and her husband trekked in the Himalayas in late 2019, even as their respective Twitter feeds filled with news of a pneumonia of unknown cause.

Soon, the cause began to be attributed to a SARS-like virus.

De Alwis, a then-senior research fellow with Duke-NUS’ Emerging Infectious Diseases Programme, had been looking forward to studying the human antibody response to viruses that cause neglected tropical diseases like chikungunya and dengue to advance the search for effective vaccines.

In particular, she was keen to shed light on the different signals that emanate from the stem of the Y-shaped antibody. These signals beckon other parts of the immune system to help protect against infection.

At least that’s how they are supposed to work.

“The plot thickens because that stem portion can either protect or make the infection more severe,” said de Alwis, who was also part of the ViREMiCS team.

“And that is something that has not been very closely studied.”

***

But as the first weeks of January rolled by, the novel coronavirus started to take root in Singapore, spreading beyond holidaymakers to the community.

As de Alwis watched cases creeping up, she felt agitated; an urgency to lend her skills was building in her. Sitting dispirited at the café at Duke-NUS, de Alwis was spotted by a principal investigator (PI) whom she admires.

“When I confided in this PI, she told me to just ask, giving me that push that I needed,” recalled de Alwis, who works closely with Ooi Eng Eong, Jenny Low and Eugenia Ong.

“I was sure I could help out somehow as we knew nothing about the antibody response patients were having,” said de Alwis. She had been developing a series of antibody tests using her National Medical Research Council Young Individual Research grant.

“I had these easily adaptable tests ready,” she added.

Plucking up the courage, de Alwis approached Ooi.

Yes, of course! was Ooi’s response and de Alwis plunged into the preparatory work for a new vaccine project Duke-NUS was embarking on with Arcturus Therapeutics.

***

The weeks and months that followed were a blur of activity, filled with scientific discussions on what and how many constructs to test, reading up on the literature from SARS to find the best leads, organising reagents and ensuring all the necessary supplies were on hand for the moment the contract was signed.

While they waited for the go-ahead, de Alwis and Ooi delved into a concern that had been niggling at the back of their minds. Some early reports of preclinical studies had hinted at antibodies possibly going rogue, sending signals—or effector functions as they are known—that helped the invading pathogen. Similar effects had been observed in preclinical work for some vaccine constructs that had been developed against the SARS-CoV-1 coronavirus.

“There were some reports that instead of having all these beautifully protective functions, the virus uses the same portion of the antibody to get into an immune cell, causing an infection in the immune cell,” she explained, adding: “And at that point we knew very little about SARS-CoV-2.”

Reflecting on the resulting review, de Alwis was glad that the antibody-dependent enhancement effect didn’t materialise in subsequent studies.

“We didn’t see the same effect in our preclinical vaccine studies, fortunately,” she said.

***

In April 2020, just as Singapore entered the Circuit Breaker, the vaccine work unfurled in earnest, setting de Alwis and her colleagues off on a rollercoaster ride. With limited reagents and even less time, de Alwis and the team were under pressure to make every experiment count. Frequent and detailed discussions with the whole team and their partners were the norm.

So, despite being assigned to the afternoon shift, de Alwis’ day would start early, her morning filled with meetings with teams in the United States, analysing the latest data and planning the next steps. Around 2 pm, she would begin her shift in the lab.

“Sometimes, there were days when I’d stay till 1 am or 2 am,” she recalled.

“We were running on adrenaline.”

One bright spark during those sleep-scarce rollercoaster days was the company of her family. Based in Sri Lanka, which is two-and-a-half hours behind Singapore, she would video call them as she worked late into the night, the gentle chatter helping her stay focused on her work.

Like the joy her family brought, the shared excitement and enthusiasm from the team in Singapore was another source of happiness.

“It was nice to have the team to discuss the data with. For the vaccine development project, seeing any signal was so exciting, we were literally jumping.”

“That doesn’t happen in peacetime,” de Alwis laughed.

***

While excitement ran high, the need to validate the science required the team to run the same experiments for each clinical trial participant at different time points to ensure they had a complete picture. This meant that the team had to stay focused.

“I’m very much an academic scientist,” she admitted.

“So, if there is something super interesting, I want to follow it. But when you’re doing a clinical trial, there is one goal and you got to stay focused. That was the hardest part of it.”

They couldn’t lose sight of the goal. Reaching their goal required them to meticulously document every sample and each step of their experiments—even as they raced against time.

“It was a highly stressful time,” said de Alwis.

“But I also learnt a lot in the process and it showed me that I had skills I could contribute, making it a very fulfilling experience.”

***

Her experience, too, was immortalised through the documentary “The Vaccine Quest”. Like the vaccine development project, it was another new experience for de Alwis, who would in the past have passed on such an opportunity, valuing her privacy more.

“I was thinking that if sharing my experience motivates more young scientists to do this sort of thing, then why not,” she said.

She also wanted to help in the bigger fight against rumours that were playing out on social media. De Alwis realised that in those instances shutting people down would do more harm than good as many rumours hijacked legitimate concerns.

“So, I really tried to listen to their concerns first because maybe with some I could still reason,” she said.

“I started taking the time to explain. I tried to engage. I made sure that the science was true and yet simplified in a manner that anyone could understand.”

***

As for her own scientific ambitions, the pandemic lent a wider focus.

“It has increased my focus on regional development,” shared de Alwis, who realised that to see a vaccine through its full development journey, she would have to find a role that takes her beyond Singapore. Because by the time Phase III trials were due to start, Singapore had implemented an effective nationwide vaccination programme and successfully lowered its community transmission rates—“essentially making Singapore at the time no longer a suitable location for testing a COVID-19 vaccine in Phase III trials,” added de Alwis.

This thought sparked the embers of another dormant passion of de Alwis’: a desire to give back.

“I come from Sri Lanka, and I really want to be able to give back all that I’ve learnt,” said de Alwis.

So, when she learnt that Duke-NUS was setting up a new centre—a centre that would work with low-resourced partners around Asia to ensure humanity’s defences against the next outbreak are strengthened—she saw a perfect opportunity.

“The pandemic showed us that we have a long way to go before everyone has equal access to healthcare,” she said.

“And right now, we have an opportunity to strengthen the region in terms of tracking diseases, developing vaccines and fortifying our regional health security.”

The Centre’s director Professor Paul Pronyk was keen to bring her on board and within days, had offered her a new appointment: as an assistant professor with the Emerging Infectious Diseases Programme and the new Centre for Outbreak Preparedness as its deputy director, effective from the third quarter of 2022.

“With these two complementary roles, I now act like a bridge, helping our research folks translate their discoveries into meaningful impact through our partners across the Asian region,” she explained, “a bit like a matchmaker.”

She added: “I do miss lab research, but this is just as exciting—I’m creating research opportunities, opportunities that I’ve benefitted from, for others.”

Act Two | Scene Two

T cells: An elegant defence

“I did not think it could spread so fast, in such a short time,” admitted immunologist Antonio Bertoletti when asked about his first reaction to the news of a novel virus spreading in China.

“Then everything exploded.”

By 20 April 2020, the daily case count in Singapore had spiked, hitting 1,426 new cases that day alone. At the same time, Bertoletti’s hometown in Italy became one of the worst-affected areas. It was no longer a theoretical threat. But it had stopped being that even before then.

***

“I was amazed that initially—the first two to three months—everybody was only speaking about antibodies,” said Bertoletti, who is a professor with the Emerging Infectious Diseases Programme at Duke-NUS.

Because focusing on antibodies as the single most important measure of immunity failed to capture the whole story. To fully understand the body’s response to viruses like SARS-CoV-2, Bertoletti pointed to a usually sidelined group, the underdogs, of immune cells—T cells.

These white blood cells perform two roles. Helper T cells, or CD4 T cells, patrol the body for foreign invaders or pathogens and stimulate the production of antibodies. Killer T cells, or CD8 T cells, destroy cells that have been infiltrated by viruses before they can replicate, alerted to the cells’ distress by the viral antigens hoisted like flags on the surface of these cells. Killer T cells can eventually turn into memory T cells, ready to strike if the same pathogen appears again.

Put simply, T cells target and clear an infection after it has occurred, complementing antibodies that prevent the virus from infecting the cell. A robust T-cell response, therefore, can make the difference between mild or severe illness.

“Antibodies are easy to test, T cells are a little more complicated to test,” said Bertoletti, whose interest—or “first love” as he likes to joke—is studying T cells in chronic infections caused by the hepatitis B virus. “But that doesn’t mean they don’t exist.”

***

So when Associate Professor Tan Yee-Joo from the National University of Singapore, a long-time collaborator of the Bertoletti lab, reached out to him in March 2020, asking whether Bertoletti could help test COVID-19 patient samples, the answer was a resounding “yes”.

And Bertoletti’s team was well-positioned to start testing immediately. Having studied the T-cell response to SARS-CoV-1, also with Tan, they had on hand all the necessary reagents.

To understand how the body defends itself against SARS-CoV-2, they used an enzyme-linked immunosorbent spot (ELISpot) assay, a method for detecting T cells that actively secrete specific signalling proteins or antibodies.

“We ran the first ten samples and the response was fantastic,” Bertoletti enthused.

On 6 April 2020, the lab tweeted a picture of their ELISpot results, with the question: An alternative to the antibody tests? The post attracted hundreds of comments and more than 150 retweets.

“It was one beautiful ELISpot,” stressed Bertoletti. “And it was the first one in all the world, basically.”

The interest of other researchers and clinicians was piqued.

That ELISpot flagged off a frantic three-month-long sprint by the team to investigate the T-cell response of three groups of people: those who had recovered from SARS some 17 years previously, those who had been infected with SARS-CoV-2 and a third group of healthy volunteers who had had neither SARS nor COVID-19.

The race ended on 15 July 2020, with their findings published in Nature. Like the tweet in April, the paper, titled “SARS-CoV-2-specific T-cell immunity in cases of COVID-19 and SARS, and uninfected controls”, attracted immediate attention from around the world. And the then-National Institutes of Health Director Francis Collins even cited it in his blog on 28 July 2020.

And it quickly became one of the most popular articles published by Nature, cementing its place in the top one per cent of tracked articles of a similar age well into the months and years to come.

***

But Bertoletti’s “romance” with SARS-CoV-2 was far from over; his “first love” would have to wait a little longer.

Questions on the relationship between the severity of disease and T-cell responses required addressing. With novel vaccines on the horizon, how these stimulate T cells was another piece of the puzzle. And what kind of T-cell response could be detected in the noses of people who have been vaccinated or vaccinated and then infected?

So, the team set about decoding the T-cell response to SARS-CoV-2. They demonstrated that people who had only mild COVID-19 symptoms produced the strongest virus-specific T-cell response early on in their infection, suggesting that T cells play an important role in the rapid control of the infection.

They also found that people who had asymptomatic SARS-CoV-2 infections produced a similar number of SARS-CoV-2-specific T cells compared with people who experienced symptoms. But unlike in symptomatic individuals, the T-cell response in asymptomatic people was more efficient.

For Bertoletti, the next step was clear: finding a way to measure T cells easily in a healthcare setting without needing specially trained staff or expensive equipment.

Applying the principles used in monitoring T cells by proxy in infections like tuberculosis, he and his team developed a SARS-CoV-2 test. Their test detects a signal that is released by T cells when they come into contact with small fragments of the SARS-CoV-2 spike protein. All that is needed is about half a teaspoon of blood to perform this fast, easy and accurate test.

“This discovery means we now have a way to conduct studies that track T-cell activity more quickly without the need for specialised or expensive equipment,” emphasised Bertoletti.

Called a cytokine release assay—named for the signalling molecule that it detects—the test is now being commercialised by innovation-based biotech company Hyris.

But they did not stop there. In collaboration with partners from the United States, Spain, Italy and the United Kingdom, they developed a rapid polymerase chain reaction or PCR test that needs less than 1 ml of blood to measure and quantify SARS-CoV-2-targeting T cells.

“What makes this discovery so impactful is that it can now be adapted to test the T-cell response to any infection,” said Bertoletti.

But it wasn’t just the testing front that Bertoletti and his team advanced through their innovative work. They also collaborated with a team that opened the possibility of a T-cell-triggering COVID-19 vaccine.

“We found that people who had been exposed to SARS-CoV-2 but never became infected still produced T cells that targeted a protein that is essential in the early stages of the SARS-CoV-2 replication cycle,” explained Bertoletti.

In the lab, these very specific T cells could be triggered to multiply and abort an infection.

“Designing vaccines that activate these T cells could possibly protect us not only from current coronaviruses but ones that have yet to emerge,” he added.

***

All this work meant that Bertoletti became an active and prolific member of a collaborative global effort to understand the contours of the pandemic.

“Before, we were much more niche, more isolated,” he observed, noting that much of the recognition for his previous work on hepatitis B had come from Asia, where the virus is more prevalent.

His pandemic projects put him in contact with SARS researchers around the world and fostered new collaborations with many others.

“The community of immunologists working on SARS-CoV-2 is now very active. We have nice discussions,” he shared.

That thriving sense of community was evident in his own team and enabled them to press ahead with their research even when restrictions in Singapore were at the highest level.

“We were very, very united. We still are,” Bertoletti said, while acknowledging the pressure they were under.

“It was a little bit stressful. The pace was so fast, and if you want to be on the cutting edge, it was difficult. But we were there, and are still there.”

Recalling that first glimpse into the T-cell response to SARS-CoV-2, Ms Kamini Kunasegaran, a then- research assistant with Antonio Bertoletti’s laboratory at Duke-NUS, explained: “We deal with hepatitis B, so we don’t usually see a big response. So, the SARS-CoV-2 response was really big to us.”

“That really was the turning point,” added her lab mate Ms Adeline Chia, a senior research associate. “Everyone got so excited.”

Kamini and Chia were referring to that “beautiful ELISpot” that had ignited the Twittersphere in April 2020.

“The ELISpot lit up like a Christmas tree” was Kamini’s description of those first results.

***

Prior to the pandemic, Bertoletti’s team—including Chia and Kamini—had been investigating the behaviour of T cells in chronic hepatitis B virus (HBV) infection, where the continued presence of the virus elicits a countermeasure response from the body’s T cells. These continue to patrol the bloodstream in low numbers; perhaps one per 10,000 T cells is on the lookout for HBV. With neither side winning, the body reaches a stalemate which the team were investigating.

But when SARS-CoV-2 struck, they turned their well-honed expertise to studying T cells in SARS-CoV-2 infections. While that pivot posed no technical difficulties for them, the team had to adapt to the challenges of an unprecedented pandemic.

***

With the Circuit Breaker looming over them, having everyone together in the laboratory was off the table—this at the precise moment when they needed all hands on deck. Instead, the lockdown and its associated safe-distancing measures whittled the on-site team down to a crew of eight.

“It was chaos in the beginning,” recalled Kamini, who was assigned to the skeleton crew that worked in the lab over the months that followed.

Those who were allowed back into the lab were further divided into morning and afternoon shifts. Getting their work done in that short span of time added immense pressure and demanded clear communication.

The team kept in close contact, so they could easily pick up from where the other shift had left off, digging beyond antibodies to discover more about the immune system’s response to SARS-CoV-2.

“Having a long enough working relationship was important for times like these,” stressed Chia, who coordinated the on-site team.

But it wasn’t an easy task. Not for any of them.

“Those colleagues with children had to come to work. But their kids were at home doing home-based learning—how did they?” wondered Kamini.

“It was a nightmare,” added Chia. “And researchers were also anxious to know if they could come into the lab or not.”

“But that was not because no one wanted to come in,” said Kamini. “We all wanted to do our bit.”

It turned out to be a steep learning curve. Even while they navigated the new restrictions, the pace of research accelerated. Studying SARS-CoV-2, unlike HBV, meant responding to a dynamic and unpredictable situation.

And unlike the frozen HBV samples the team was used to handling, they were new to working with fresh blood samples.

“We had to collect the samples, process them and do the experiments straight away,” explained Kamini.

“If the sample came in at 5 pm, in our HBV work, we could have left it till the next morning before starting our experiments. But with fresh samples, we had to process them immediately.”

Processing alone took about two hours, and only then could they start with their experiments. Long shifts became the norm.

With the samples coming directly from patients at Singapore General Hospital and other collaborating institutions across Singapore, the team was unable to anticipate the quantity and quality of samples on any given day. There could be a glut, or not a single one.

And without a scheduled pool of samples, they were unable to plan ahead. Day to day, the priorities for what to test in each set of samples varied.

“It all depended on the samples, and at that point, what question we wanted to ask,” said Kamini.

Chia chimed in: “Sometimes the decision could only be made on the spot, about what exactly we would do with these precious samples.”

But it was in this crucible of stress, that the team forged a greater sense of cooperation.

“The teamwork is more pronounced now,” reflected Chia. “We’re all working towards a common goal, and there is a lot of help between people.”

***

That first breakthrough captured on an ELISpot in April 2020 opened the floodgates to new opportunities.

“The project exploded,” said Chia. “We began collaborating with even more people, and we had even more samples coming in. But the good thing was, our staff were even more well-trained.”

Collaborations with scientists around the world led to advances in the understanding of T-cell responses in asymptomatic, mild and severe infections. They also designed novel—and more practical—ways of detecting these elusive fighters so that doctors assessing an individual’s immunity could get a better measure of them.

Reflecting on the speed with which the study progressed—it went from idea to publication in just three months—Kamini remembered her surprise: “Whoa, that was fast.”

Surprised despite the fact that she had been one of the engines driving the team, playing an instrumental role in orchestrating the team’s pivot from HBV work to SARS-CoV-2 projects—a role for which Kamini received a special COVID-19 Hero Award at the Asian Scientist Lab Tech of the Year 2021 awards.

For Chia, it was one of those “little blips of excitement”, made all the more thrilling because it proved their strong collaborative spirit.

“It was the first time there were so many people from the lab in a paper. Looking back, it really does feel like a big collective effort.”

Act Two | Scene Three

Tracing the future

“It was all about the exit strategy,” declared Professor Marcus Ong, the director of the Health Services and Systems Research (HSSR) Programme at Duke-NUS. How to prepare Singapore—and its healthcare system—for the transition to living with COVID-19.

Because right from the start, Ong’s models predicted only three ways in which things could end. The virus could, as had happened during the first SARS outbreak, trigger one tidal wave of infections—“about 50–60,000 cases”—before petering out. Or it could release repeated but progressively less intense waves over the next two to three years, where vaccines and new treatments coupled with safe distancing measures would be key.

“The last scenario was pandemic moving to endemic. Which was what we ended up in, where it has become like tuberculosis or seasonal influenza and we have to live with it,” finished Ong, who took no satisfaction from having called the pandemic’s trajectory correctly from the outset.

“I would have been happy to have been proven wrong,” reflected Ong.

***

Ong had had his finger on the pulse of this pandemic and the public health measures necessary to tackle it since the start of 2020. And his estimates came backed by data—concrete figures extracted from the healthcare system—which he fed into simulations to predict the likely impact of different “what ifs”.

“Ten years ago, we would not have been able to pull this off. During SARS, we were using Excel spreadsheets, best guesses and consensus by experts. But this time we could play with things in the virtual world before testing them out in the real world,” explained Ong.

To do that, the entire HSSR Programme came together, driving a four-pronged research approach called the COVID-19 Virtual Disease Health System Outbreak Model for Singapore, aptly abbreviated to CoViD-SOS. Through it, they modelled the impact of the pandemic on the entire care system—from its impact on vulnerable people and mental health to the virus’ impact on hospital services and the effectiveness of different public health measures—generating actionable insights.

“We demonstrated that health services research can address an issue of national value and that helped bring this field into the realms of operations, decision-making, clinical policy and treatment,” he added.

Ong and his team’s simulations helped Singapore prepare for vastly different eventualities. They influenced the pandemic response strategies at the hospital and national levels.

“I think I can help people more at a systems level, a population level,” said Ong, who also works regular shifts as a senior doctor in the emergency department of Singapore’s largest hospital, Singapore General Hospital.

“Research, innovation and education are just as important as our clinical service.”

***

Ong’s concerns about the pandemic’s impact on the national healthcare system stemmed from personal experience: SARS. H1N1. And a deep understanding of the mechanics at work in a complex, multifactorial healthcare system.

“You can’t just leave the healthcare system to fight this battle alone,” he said, thinking about his fellow clinicians and frontline healthcare providers, who, like Ong, worked extra shifts to keep services running.

“They will get overwhelmed. That’s what happened in many other countries.

“In some countries, the rest of the population did their own thing and left the frontline healthcare system to carry on alone—that’s not sustainable.”

Indeed, the overload of hospitals in the United States, the plea by the United Kingdom’s government to stay home to protect the National Health Service during the 2021 holiday season and contradictory public healthcare responses in certain Asian countries, all bore out his warning.

“Singapore showed that it’s a combination of three things,” said Ong about the nation’s success in keeping people safe during the pandemic. “Healthcare system. Leadership. Social capital.”

He pointed to the fact that “if your government response and your social capital are poor, it’s still a disaster”.

And preparedness, especially, made this combination work.

“All the hard work, preparation and planning. Having stockpiles of equipment, personal protective equipment and drugs. Having legislation in place that we can pull up to effect quarantine,” listed Ong.

“All these served Singapore well. If we had not had these, we wouldn’t have been able to have such a comprehensive response.”

***

As the country eyed a future of living with SARS-CoV-2, a paradigm shift was required—a balancing act that protected vulnerable groups while maintaining the capabilities of the healthcare system.

“In the emergency department, we already had a new paradigm for managing all our patients. Red, yellow, green,” said Ong about the newly expanded triage protocols. These protocols run in parallel to existing Priority I, II and III classifications that identify patients by the seriousness of their condition upon admittance at the emergency department and run all the way to general inpatient and isolation wards.

Red is for high-risk infected cases who need treatment in isolation-type facilities where air, for safety, flows in rather than out. Green is for low-risk patients and yellow—a new lane introduced with COVID-19—is an intermediate risk rating.

“It’s for those with some kind of respiratory infection or contact history. Lower risk, but you still need some precautions,” said Ong, who predicted in mid-2021 that such stratification would become commonplace.

***

Looking back, 2020 was the toughest year of this clinician-scientist’s life. No downtime. Additional shifts at the emergency department. Running and repeating simulations to predict the virus’ next move. And some challenges on the family front, as his daughter, who has Tourette’s Syndrome, was struggling to come to terms with the condition while preparing for the Primary School Leaving Examination (PSLE).

“She had lost interest in everything she used to enjoy. She would come home from school, head into her room and slam the door,” remembered Ong. “The last straw was when she developed selective mutism and didn’t utter a word to me for months because she couldn’t express herself.”

Yet, when the Circuit Breaker saw Ong’s overseas work and conference travel grind to a halt and his two sons return home—the older one from law school in the UK and the younger one from the student dorms of the Singapore University of Technology and Design—he noticed an unexpected effect on his daughter.

“She is very close to her older brothers, but both had been away at university,” recalled Ong. “So, when the Circuit Breaker came, they came back and she could talk and joke with them.”

“The other big benefit for her was that she didn’t have to spend hours travelling to school. She was happy to learn at home and by the end of the year, she exceeded all our expectations during PSLE,” added Ong.

Family time also improved. Ong could regularly prepare lunch for his daughter and read the Bible with her at night.

But the biggest and most unexpected pay-off was that all these changes helped ease the pressures and stresses on Ong’s daughter and she could open up again.

“The Circuit Breaker gave me my daughter back, God works in mysterious ways!”

While he enjoyed his family time, Ong also credits the support he drew from the men’s cell group he leads at church, where he saw everyday examples of resilience and courage—from the retrenched regional manager, who pedalled through Grab deliveries to feed his three children, to the university graduate clawing back his life after years of incapacitation with mental health issues.

“Resilience is knowing that you’ve been knocked down yet still having the courage to stand up,” said Ong.

“You don’t give up. That is the quality of resilience, and I learned resilience from these guys.”

***

Indeed, by mid-August 2021, mitigation strategies were applied to social gatherings and travel, so that Singapore could get back to life as normal while protecting the vulnerable.

Public and political discussions were, as Ong noted, all about the exit strategy from the pandemic, about Singaporeans picking themselves up, dusting themselves off and getting back in the saddle.

“You can survive for 40 days without food, probably one or two days without water and about ten minutes without oxygen,” said Ong.

“But you can’t survive without hope. And we have hope by sharing a common purpose which is beyond just yourself.”

For Marcus Ong’s colleague, global health expert Professor Tazeen H Jafar, one of the main concerns was the impact of the pandemic on people’s mental health.

“Mental health is a huge issue,” stressed Jafar. And the practising kidney specialist was particularly concerned for her patients.

“Optimal cardiovascular and metabolic disease risk reduction requires addressing mental health, as well as other pharmacological and lifestyle interventions because mental health impacts how they take care of themselves,” she explained. “So, even minor things will lead to people not being as productive, not reaching their potential. This could have a very negative impact, potentially, from a long-term perspective, unless—and until—we intervene,” warned Jafar.

So, her move to studying the impact of the pandemic on mental health was a natural extension.

“COVID unfortunately attacked and impacted people with cardiovascular disease risk factors, with hypertension and diabetes disproportionately,” she explained.

In 2021, Jafar and her team published the results of a systematic review and meta-analysis that synthesised the results of 68 studies involving 288,830 participants from 19 countries. What Jafar got was a snapshot of the global mental health situation, spanning low-, middle- and high-income countries.

“Our findings were quite alarming,” reflected Jafar. “We under-appreciated how severe these issues were.”

They found that one in three adults suffered from psychological distress during the pandemic. With COVID-19-induced lockdowns, quarantines and social distancing, as well as job losses and other stressors, this “shadow pandemic” knew no boundaries.

While she had initially expected some countries to emerge more resilient than others, her results showed that the mental health crisis was truly a global one. Roughly 33 per cent of the general population was anxious. And 30 per cent experienced depressive symptoms.

“It was an eye-opener,” she said of the study. “It screamed, ‘Gee, people need help.’”

***

Her findings had implications for almost all parts of society, but highlighted that among those most likely to experience anxiety and depression were women, younger adults, individuals of lower socioeconomic status and those living in more rural areas.

The consequences were going to be long-lasting and far-reaching, economic and societal, she worried.

“If you have a large proportion of the population who won’t be able to reach their full potential, the impact will be felt at the national level,” she declared.

All the more so as this shadow pandemic was playing out in the context of very performance-driven societies, creating a negative spiral where the rise of unhappiness could feed the rise of chronic illnesses like diabetes and cardiovascular diseases.

“It was a very unhealthy setting both in the short and long term,” added Jafar.

The coronavirus also disproportionately impacted those with existing conditions, influencing the severity of disease, need for intensive care and even the probability of death. Jafar’s kidney transplant patients, who take immunosuppressive medication, were extremely vulnerable. And her study showed that those at higher risk of severe infection were more likely to experience anxiety and depression.

More robust treatment plans could target these intersecting problems by offering mental health support alongside lifestyle management and pharmacological interventions.

With her own patients, Jafar assessed their mental health regularly, providing counselling and coping strategies whenever she could.

“Measure and intervene, measure and intervene,” she affirmed. “That’s what we have to do; that’s how we make a difference.”

Jafar hopes that the wider medical community will also adopt such a strategy.

“A comprehensive, optimal cardiovascular and renal risk reduction strategy requires addressing mental health in addition to the pharmacological and other lifestyle interventions,” she stated.

More importantly, such holistic care has to be available to everyone.

So, she uses her board seats at funding and advisory bodies, such as the Medical Research Council in the United Kingdom, to advocate for large-scale programmes that tackle mental health disorders, calling for more recreational activities and healthcare resources to be directed to high-risk populations.

A concerted effort is necessary to reduce the rural-urban, socioeconomic and gender disparities in psychological distress created by the pandemic, she noted.

But for programmes to scale up, policymakers and institutions would have to address the shortage of qualified counsellors, psychotherapists and health workers with different levels of mental health expertise.

“We need to train more people going into these fields and we need to create awareness,” she emphasised.

***

At the heart of all of Jafar’s work, though, is an unflinching focus on public health equity—the belief that everyone should have access to quality medical care.

“I’ve done large programmes,” she said. “What I want next is a big non-communicable disease or a chronic disease control programme which brings things together holistically. How can we deliver packages that are uniform, so that they can be applied in both high-income countries and low-income countries?”

“Programmes that are customisable; but not something that’s just only going to be for that one little population of one hospital,” she continued. “I want things that can go to the masses. To the public; so that the vast majority of people can benefit from it and that are cost-effective.

“I want to eliminate the disparities. That’s my dream.”

Like Tazeen H Jafar, health economist Eric Finkelstein, a fellow professor with the Health Services and Systems Research Programme at Duke-NUS, was concerned about the impact of the pandemic on mental health.

“The one thing that I’m qualified to study and interested in is the mental health aspect of COVID,” he said.

Long before SARS-CoV-2 had entered the lexicon of everyday language, Finkelstein had already assessed Singapore’s receptiveness to lockdowns, using previous pandemics in Asia such as the H1N1 pandemic in 2009 and the 2003 SARS outbreak as a basis.

What he and his colleagues found was that overall, Singapore residents willingly supported government restrictions if these restrictions reduced transmission, with respondents split into two key groups: the mortality-averse and the tax-averse.

To gain support from both groups, public health measures needed to stress the necessity of lockdowns to reduce mortality, while minimising the economic impact on society.

Thus, even though mental health had not been his initial research focus, Finkelstein, with his extensive experience in surveying public health behaviours, was uniquely placed to analyse the impact of COVID-19 on Singapore’s population, from both economic and behavioural perspectives.

***

“So, I did a study to get at the incidence of depression and anxiety during the pandemic. The idea was to generate data to develop interventions aimed at addressing mental health needs in Singapore,” expanded Finkelstein.

“I wanted to find the unmet need for people who have these mental health conditions, but who are not accessing the health system to see if there might be opportunities to follow up and provide access to care.”

The responses to his study were varied but had one thing in common—more and more, people were experiencing mental health issues.

“That’s a hidden problem in Singapore,” said Finkelstein.

Indeed, the Singapore Association for Mental Health reported a 50 per cent increase in calls made to its helpline between February and March 2020 compared with the average it received between April 2019 and January 2020.

“Now is that because of this pandemic? Or because of the interventions that have been put in place? It’s hard to know,” said Finkelstein.

Nonetheless, between lockdowns, lost work opportunities and the devastating effects of social isolation, it was clear that COVID-19 was taking its toll.

Unlike tallying COVID-19 case numbers, exposing the damage to a nation’s collective mental health was a trickier task—not least because the team had to adapt quickly to a new way of working when the Circuit Breaker restricted movement.

Used to interviewing people in clinics or their homes, Finkelstein and his team pivoted to conduct interviews remotely.

The transition to phone interviews, though, meant that the team had to re-centre their interviewing techniques around the nuances of voice-only responses.

“It’s not as good. You can’t read body language or faces,” explained Finkelstein. “We survey a lot of patients. We look for signs of fatigue, we look for signs of distress.”

“When you’re on the phone, you just don’t have that same ability,” he continued.

“But the team adapted and did the best they could.”

***

Despite the challenges of remote work, the impact of COVID-19 on mental health was clear. Out of 897 participants, 23 per cent reported moderate to severe anxiety, significantly higher than previous mental health surveys.

Younger people, people with chronic conditions, children or those with a lower trust in government had higher levels of anxiety about COVID-19 and a higher perceived risk of being infected.

However, the risk perception of these participants was also skewed. Nearly half feared they would be admitted to the intensive care unit if they were to contract COVID-19; just under a third believed they would die.

The study also found that 40 per cent of people with chronic conditions had missed a healthcare appointment for fear of contracting COVID-19.

“I think COVID has shed some light on the high rates of undiagnosed mental health problems in the region,” said Finkelstein. “But this problem existed before COVID and will exist after COVID.”

Keen to quantify the total economic burden of COVID-19’s mental health impact, Finkelstein would go on to field a survey to explore just that in April 2022. Between reduced productivity, increased healthcare spending and days missed from work, what exactly was the financial aspect of this shadow pandemic?

***

Before that, another topic rose to the fore. By mid-2020, novel mRNA vaccines were racing through testing with promising results, offering a new means to help fight the pandemic. But with a catch: only if people were willing to take them.

Drawing on his expertise in assessing how financial and behavioural incentives impact obesity, weight loss and palliative care, he set up an online survey about people’s willingness to be vaccinated.

“The willingness or unwillingness of people to vaccinate was definitely an interesting topic,” mused Finkelstein, who is also the director of the Lien Centre for Palliative Care at Duke-NUS.

In an online poll on vaccination, 22 per cent of the respondents answered that they would never get vaccinated. Most countries encountered a stubborn percentage of the population who were refusing to budge on this issue. So, what held those people back?

“It’s what economists call ‘elasticity’—their willingness to vaccinate and to what extent we need to ‘bribe’ our population,” explained Finkelstein, adding that if the vaccine was free, people didn’t rush to get it because they knew they could get it later.

In the end, it took Singapore extensive vaccination-differentiated measures as well as a new variant that caused more severe disease to achieve the vaccination rates necessary for re-opening.

***

Reflecting on the first year of the pandemic, Finkelstein said: “I think by the end of 2020, we’d done a great job in arresting the spread of the pandemic, but I think it came at a pretty high cost.

“If you look at mental health services in Singapore, certainly, you can see that rates of depression or mental illness were way up.”

He wrote commentaries highlighting that circuit-breaker measures were delaying tactics. Because as Finkelstein saw it, this globalised world meant that SARS-CoV-2 would always be lurking.

So, while public health measures would always be necessary, it was similarly important to prioritise individual mental health measures.

Finkelstein said it is about how we learn to live with COVID-19. It is how governments and communities improve treatment options, reduce the mortality rate and encourage vaccination.

“You can’t live your life in your basement forever,” he remarked.

And the world didn’t. By 2022, exit strategies to enable countries to live with SARS-CoV-2 were rolled out across the globe. Singapore, too, embarked on its new normal, where people and the virus would co-exist.

“Once you realise that these variants will be around indefinitely, at some point you’re going to realise that and recognise that you can mitigate those risks, but you can’t reduce them to zero.”

For Sean Lam, balancing the needs of patients, hospital capacity and infection control measures became the focus as the pandemic unfolded.

“The first thing we were asked to model was how a surge in patients would affect the hospitals and the overall patient load,” remembered Lam, who heads the data science team at the SingHealth Duke-NUS Academic Medical Centre.

Having spent more than a decade modelling the day-to-day operations across Singapore’s largest healthcare cluster and developing predictive algorithms for clinical and management use, Lam—a then-assistant professor with Duke-NUS—and his team of data scientists and analysts were quick to respond when SARS-CoV-2 reached Singapore.

They adjusted their models and fine-tuned them with the rapidly emerging and evolving information on the virus—models that would help hospital executives and operations managers plan where to focus resources so that the health system could weather the surge in patients.

“We developed a model and shared that with the Ministry of Health,” recalled Lam about that early modelling. “They took some of those recommendations.”

This model made the best use of the scattered data from published sources on hand at that time—Big Data, after all, had to start smaller somewhere.

With some additional resources from the Ministry, Lam, as part of the Health Services and Systems Research team at Duke-NUS, put forward the comprehensive multi-pronged modelling approach called COVID-19 Virtual Disease Health System Outbreak Model for Singapore, or CoViD-SOS.

***

By April 2020, they were working flat out on these projects, which for Lam meant supporting healthcare operations teams at SingHealth in their resource planning through dynamic modelling that could forecast different scenarios accurately even as the data evolved.

“Our systems dynamics model could consider more complex interactions, the feedback effects, loops, etc., leading to the ability to uncover emergent behaviours and unforeseen consequences. We also brought in a variety of other considerations such as public health interventions, workflow modifications and even social behaviours,” explained Lam.

“We built our simulation models at the micro and meso levels to get the most accurate estimates for a variety of problem statements.”

As policy and treatment courses changed over the following months, Lam’s models, too, evolved.

“There were policy changes like the introduction of step-down and community care facilities.

Those, as well as new policies implemented at the hospital level, would all affect our predictions.”

By 23 June 2021, five million doses of the SARS-CoV-2 vaccine had been administered to residents in Singapore. Around the same time, the government announced a further acceleration of the vaccination programme that would come into effect on 26 June.

“That meant new numbers needed to come into play all the time,” said Lam.

“We would have to watch the evolution carefully. What the impact on morbidity and mortality would be as well as the easing of some of the restrictions.”

Throughout the pandemic, Lam shared his insights with the SingHealth Disease Outbreak Committee as well as other hospital-level operational committees. He and his team also published some of their models and solutions in journals including Frontiers in Public Health and International Journal of Medical Informatics.

But it wasn’t just the direct effects of COVID-19 on hospitals that concerned Lam. He also studied the impact of delayed and cancelled routine surgeries, and the impact on patients who faced delayed care or were unable to visit the hospital. And how the hospital could plan for resumption of business as usual.

“How could we plan to best manage the backlog of surgeries but ensure that we would have enough beds, operating theatre capacity, diagnostic facilities and the necessary healthcare manpower,” explained Lam.

Those models helped Singapore General Hospital resume its operations and effectively tackle the backlog that had been caused by the delays imposed by the pandemic.

***

Reflecting on the most intense period of the pandemic, Lam found satisfaction from his behind-the-scenes perspective, knowing the what-ifs that were avoided.

When COVID-19 cases were high, Lam’s models painted a grim picture. Without any intervention, he saw towering peaks almost shooting off the charts. In the end, events unfolded differently.

“It was good to see that the interventions were effective and that we avoided the worst-case scenarios completely,” said Lam.

It also felt good to return to work that had been set aside to free time for COVID-19 projects. These projects included ongoing studies on how to optimise healthcare resources for pandemics or disaster management.

“Some of the other research activities are related to respiratory medicine, cancer screening and diagnosis, diabetes and chronic diseases. The team has also been deep in the trenches working to implement the next-generation data science platform for SingHealth,” he said.

***

Pandemic-era research on SARS-CoV-2 had a noticeable and immediate impact. It was driven by an existential urgency—the virus spread rapidly, impelled lockdowns, overwhelmed unprepared health systems and caused mass deaths.

Yet, Lam approached these social and institutional anxieties unfazed. After all, there’s no better time to prepare for war than during peacetime.

“If you’ve not been doing this data modelling, and suddenly you’re called to do something like it—it’s like starting in a whole new research field during the middle of a pandemic. You’d better not take it up,” said Lam, who was promoted to adjunct associate professor at Duke-NUS in July 2022.

“But here, we’ve been doing this all along. So, whenever we’re called up to do this, we are always ready to take up the challenge.”

Act Three

Singapore’s national Circuit Breaker emptied roads, offices, restaurants and shopping malls. Even the Khoo Teck Puat building fell silent. Despite the absence of students and many staff, and research teams split across shifts, the sense of collegiality—teamwork, resource sharing and peer support—suffused the campus.

Reaching warp speeds, the teams raced around the clock to deliver answers, identify new treatments and create inventions that would help save lives and chart a way towards a pandemic-era exit strategy. At the same time, Duke-NUS’ latest graduates readied themselves to join the healthcare frontlines.

Act Three | Scene One

Quelling the flames of inflammation

SARS-CoV-2’s inflammation profile was something quite unique, immunologist Associate Professor Ashley St John realised early in February 2020. While most resources had been diverted to contain the pandemic and uncover the first building blocks in humanity’s response—such as the genomic sequence of the virus—St John knew she, too, could contribute and make a difference.

All of the information’s coming out on preprints, she realised after reading another wave of journal reports for early insights on SARS-CoV-2. And people didn’t always know how to evaluate the quality of that data.

***

Offering preprints of SARS-CoV-2 research papers was how academic journals and researchers responded to the urgency of the pandemic, particularly in its initial stages. These papers skipped journal queues and backlogs, making research on the virus immediately accessible to—and actionable for—the medical and research community.

The pandemic, however, triggered a torrent of medical research papers churned out faster than normal. This growing torrent of data needed a macro-level overview, especially during those early, furious months of the pandemic. Too much information would lead to confusion, sending scholars down pointless paths and avoidable dead ends.

And so, St John, who is with Duke-NUS’ Emerging Infectious Diseases Programme and investigates immunity and immune pathology, set out to make all these early insights into the novel coronavirus accessible and verifiable.

“The one thing I could do was go through it all,” reflected St John.

“I told myself, ‘I’ll learn, and I’ll put it all in context.’”

“All” here meant sifting through thousands of preprints and published articles before focusing on the most pertinent ones, which St John and her co-author—Abhay PS Rathore, a then-postdoctoral research scholar from Duke University—systematically reviewed. A robust immune response is vital for determining how a disease develops and resolves, yet there weren’t any reviews on SARS-CoV-2 immune responses at that time. New work was simply coming out too quickly from labs and hospitals across the globe.

More so, these papers mainly informed their readers that this particular result had been observed in this particular lab and that these results were (or were not) consistent with those from another lab.

“A lot of the early literature was highly descriptive,” remembered St John.

“Many of these preprints that were coming out of China very accurately described the types of changes in the immune cells that you see.”

But with papers coming out at breakneck speed via preprints, St John and Rathore didn’t want to necessarily exclude important new information from their review either.

“Those that hadn’t been peer-reviewed, we made sure to flag as such in the text,” said St John.

Their review, then, provided a contextual guide to different ways of thinking about—and intervening against—SARS-CoV-2.

“We’re lucky that these first researchers did it right. So, our review was right,” observed St John, whose analysis has been backed up by a good number of publications since.

The resulting review paper, which was published on 8 June 2020 in The Journal of Immunology, was exhaustive and exacting.

One of its key observations was that SARS-CoV-2 may have long-term effects on the immune system.

While SARS-CoV-2 patients had varied immune responses, some quite notably had a weakened immune system containing fewer white blood cells even weeks after their hospital discharge. Others experienced inflammatory symptoms such as swelling and pain even after recovering from SARS-CoV-2. And some patients were at risk of kidney damage—SARS-CoV-2 particles were present even there, potentially provoking similar inflammatory symptoms.

***

With the review published, St John’s focus shifted back to potential vaccines and therapeutics. Separate collaborations with Duke-NUS’ parent university in North Carolina, and with the pharmaceutical industry, were imminent possibilities.

“While the initial steps in a pandemic were very competitive, unanswered questions would continue to challenge scientists,” she said.

Here, her previous experience of applying her expertise during the Zika outbreak had given her the confidence to take the plunge this time and investigate a familiar target: mast cells, the type of white blood cell that is responsible for immediate allergic reactions in the unfamiliar landscape of COVID-19.

“So, my goal was to ask specific questions and establish the systems to address more questions as we learnt more about the virus,” said St John.

She split her focus between finding ways to make less successful vaccines work better and investigating new therapeutic options that could help reduce or avoid the inflammation that SARS-CoV-2 can trigger in the lungs by focusing on mast cells.

***

For those COVID-19 patients who suffered from widespread and long-lasting inflammation, mast cells likely play a key role.

“Mast cells are these really beautiful huge cells—they have lots of granules inside them. They’re kind of like an arsenal,” explained St John in a feature published in Duke-NUS’ magazine, MEDICUS.

These granules are packed with inflammatory mediators such as histamines and chymase. And when mast cells encounter an invading pathogen, St John said: “They explode and release these mediators.”

Once released, these mediators swiftly clear the invader by recruiting other immune cells to the fight. But in people with severe COVID-19, the inflammation doesn’t always recede after the virus is cleared.

Instead the mast cells linger, ever vigilant, causing swelling and build-up of fluid, leading to laboured breathing.

“A lot of these symptoms were very similar to the respiratory distress experienced by people with asthma,” she explained.

Counteracting the flood of inflammatory products released by activated mast cells could provide a way to help patients breathe easier. And St John already had a lead for a treatment option. She’d been conducting a clinical trial to assess the effectiveness of a mast cell-stabilising drug in the management of dengue, particularly to prevent the vascular leakage triggered by severe infection.

This drug, used in the management of asthma and other allergies for more than 30 years in the United Kingdom, Europe and other countries, works by blocking mast cells so that they cannot inflame or irritate the lung tissue unnecessarily.

“We think we can quieten them, help the tissue recover and prevent the coughing and laboured breathing,” explained St John of the benefit she hoped the drug could have in COVID-19 patients.

***

By mid-2020, St John was ready to test her hypothesis about the role of mast cells in severe COVID-19. But by then, she had to look to international partners as COVID-19 infections in Singapore were dropping rapidly.

Given her strong ties to Duke University, she started engaging clinicians there to see whether they would be interested in pursuing this project with her.

As she was pitching her idea, life-science start-up Sen-Jam Pharmaceutical Partners reached out to her on Twitter. They had had a similar idea and wanted to test an approved non-steroidal anti-inflammatory drug.

“They kept messaging me,” she laughed.

It wasn’t just Sen-Jam who had reached out. She had been inundated with requests. But St John wanted to identify the right partners whose science was sound. The support from the School’s Centre for Technology and Development (CTeD) was invaluable during that process.

“The CTeD team was super supportive in helping to manage all these inquiries,” said St John, crediting the CTeD team with brokering the successful deal with Sen-Jam that was announced on 12 August 2021.

The partnership meant that St John’s mast cell-stabilising drug would be combined with a non-steroidal anti-inflammatory drug to tackle severe COVID-19 infections. Duke University, too, would come on board to advise on the clinical trial.

“It was really hard keeping all of this secret until all the paperwork was done,” confessed St John.

Then on 18 February 2022, authorities in Nepal greenlighted a clinical trial of this novel combination therapy.

***

All the while, she did her media rounds, where she’d break down the latest medical news for everyone to understand because it was not only researchers who needed accurate information about the pandemic. Her clear communication helped journalists as well as writers at the School distinguish fact from fiction and gain a richer understanding of this virus and complex disease.

On 4 December 2020, St John was awarded the Young Researcher Award from the National University of Singapore (NUS)—not just for her translational research accomplishments but also for her passion for communicating science and outstanding mentoring of graduate students.

In his citation, Professor Chen Tsuhan, NUS Deputy President for Research and Technology, remarked: “Ashley is a brilliant young scientist who is already recognised among the top researchers in her field. As a viral immunologist, Ashley studies immune responses to viral infections and her work has significant translational impact.”

Serving as a role model for other young women in science was also important for St John. Women in general are underrepresented in science leadership.

“This award made me feel challenged to continue contributing to science and making research advances that are meaningful. I hope that other young researchers who are just starting their careers, and particularly young women in science, can see that there are many rewards to pursuing research even as it requires significant effort and resilience,” she said.

In this regard, St John has been resilient, ensuring that her efforts have shown young women that research is a rewarding path—one that a researcher can shape for themselves.

“Sometimes I just have to do my own thing,” summed up St John. “And, you know? It works out. It works out.”

Act Three | Scene Two

Facing up to a hundred battles fearlessly

“One of the reasons I moved back to this region was so that I would be closer to home,” said Assistant Professor Ooi Yaw Shin. He had moved from Stanford to Duke-NUS in December 2019, so he would only be a 90-minute flight away from his family in Penang.

“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.’” He was referring to the Chinese festival where families pay their respects to the deceased at their tombs.

“For two years, I never got the chance to leave,” Ooi finished, 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 explained.

Using his experience, Ooi and his team with Duke-NUS’ Emerging Infectious Diseases Programme hunt down the factors that enable viruses to flourish within host cells. Taking a broad approach, they study 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 elaborated.

So, they turned their expertise to dissecting the mechanics of a SARS-CoV-2 infection, searching for any weak links in the viral infection processes.

***

Before he could get started, though, Ooi had to set up his lab—right at a time when widespread pandemic lockdowns had resulted in laboratory facilities being shut, assay turnaround times bottlenecked and reagent shipments delayed.

“For the first five months or six months because of COVID, I’m setting up the lab, and it was a royal pain,” remembered Ooi about how it all began for the host-virus interaction lab that he leads.

“We could not receive the equipment. We couldn’t…,” he trailed off.

“My ex-lab from Stanford, they wanted to ship me some reagents, so that I could start working in the lab,” he continued about the broken international supply chain.

“But then we had the Circuit Breaker here. And over there, they had an order for residents to shelter in place.” Such orders are typically used during moments of danger in the United States, mostly to protect people from natural disasters such as hurricanes, and require everyone to remain indoors until they are given the all-clear.

“So, SFO [San Francisco International Airport] was shut down and it was a mess,” said Ooi.

Everything was significantly delayed.”

He brightened up: “Luckily, [Ooi] Eng Eong and [Wang] Linfa—Gavin [Smith] as well—they shared their resources with me. I could kickstart some basic stuff.”

“Our now director, Gavin, 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.”

Leveraging the latest gene-editing tool CRISPR, Ooi zoomed 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,” he explained.

Like a surgeon with a scalpel, Ooi cut the genetic material of cells to introduce or remove genes with precision, searching for candidate genes 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 said.

Which is what he and his team set about to uncover, joining the international research race in the fight against COVID-19.

“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 revealed.

At the same time, Ooi and his team 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 said with a laugh.

His review of the intra-cellular goings-on of SARS-CoV-2 infections made the cover of the October 2021 issue of Current Opinion in Virology.

***

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 shared, 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,” remarked Ooi grimly.

And being at the forefront of COVID-19 research was at times a double-edged sword.

“In February 2021, 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,” said 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 shared.

Ooi’s relatives did eventually cancel that large gathering.

***

Despite all this, his team was soon doing what they are best at: getting busy decoding the threats posed by viruses and tapping the renewed support the SARS-CoV-2 spotlight had brought the field.

On this front, Ooi is now part of a group of scientists from Duke-NUS led by 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 said.

“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.”

Act Three | Scene Three

From the imagination of clinician-scientists

As a cancer surgeon specialising in head and neck cancers, Assistant Professor Rena Dharmawan had been deployed, along with droves of other specialists, to dorms across Singapore.

Their task?

To conduct nose swabs for intensive SARS-CoV-2 testing while ensuring that the tests were performed accurately and without injury to patients.

The shifts meant long hours in full-body hazmat suits and N95 masks to protect against infection. Each clinician saw up to 130 patients per shift, starting at 9 am and ending at 5 pm. Dharmawan recalled that almost all were COVID-positive.

Frontliners were keenly aware that they risked not just their safety but that of their families.

“It was worrying,” said Dharmawan, who admitted that the uncertainty of the pandemic made her feel very uncomfortable.

“I have two young kids, and I really didn’t want to expose them to the virus.”

In times of crisis, the speed of innovation can make or break a nation’s response. The pressure was building as Singapore experienced its first large-scale outbreak.

As infections spread, the need for testing—not just those at risk of having the virus in the community but travellers too—skyrocketed.

And Dharmawan, a serial innovator, was clear about one thing: if she could harness the power of automation, she would be able to develop a better, more efficient and cheaper way of conducting these tests on a large scale.

“Why should nasopharyngeal swabs be only done by doctors or specialists? Couldn’t swab tests be as simple as getting a check at an optometrist? Step into a booth, put your head here, get your nose swabbed, and get your results. That was the grand idea,” Dharmawan explained.

Being an enthusiastic innovator with a background in bioengineering, who is “addicted”—as she calls it—to innovation, the Duke-NUS Class of 2011 alumnus did not stop there.

Having already co-founded several successful Singapore-based startups, she had built a formidable network using her multiple hats. Among her many appointments, Dharmawan was a then-associate consultant with the department of head and neck surgery in the division of surgery and surgical oncology at Singapore General Hospital and the National Cancer Centre Singapore (NCCS) as well an assistant professor of clinical innovation with the Duke-NUS Office of Innovation and Entrepreneurship. All that equipped her with the necessary know-how, network and confidence to act.

After discussing the idea with her innovator-mentor, Dharmawan and a group of SingHealth clinicians banded together with medical robotics company Biobot Surgical. The company had previously developed a surgical robot with a probe that was similar to what Dharmawan had in mind.

It took them a mere three weeks to develop a prototype.

“Of course, it was more of a metal skeleton then,” remarked Dharmawan, “but it worked.”

The team’s target development timeline was ambitious.

“What I wanted to prove was that amidst COVID, we could build a commercially viable solution in just a few months,” she said.

The biggest roadblock Dharmawan had to navigate was the requirement back then for wet ink signatures on agreements and contracts.

“These are COVID times, and electronic signatures exist; so why did we need to bring documents to people’s houses to get signatures in person?” she recalled, shrugging.

She was once again operating ahead of the status quo, which would soon see electronic signing implemented across the School.

After a few trans-island journeys, Dharmawan and her team secured the documents required. By July 2020, the world’s first patient-controlled nasopharyngeal swab robot—SwabBot—was ready for clinical trials.

Dharmawan still remembers the reaction of a senior urologist when she presented her innovation at a SingHealth COVID-19 taskforce meeting. His first comment, Dharmawan recalled, was: “‘You know that your team basically did in four months what took us ten years to do, right?’” He was referring to the iSR’obot Mona Lisa prostate biopsy robot, which had also been developed in collaboration with Biobot and contained the mechanism central to Dharmawan’s prototype.

“SwabBot is much simpler, and obviously Biobot’s experience counts,” acknowledged Dharmawan.

“But it’s still a miracle that we pushed this through in four months.”

***

White, sleek and about the size of a large house cat, the SwabBot prototype looked friendly and was easy to use. Users would take a seat, rest their hands on its handles, place their nose against the disposable nose piece and gently press their chin against a conveniently located button. In just 20 seconds, the swab was done. Throughout the process, the user was in full control, and able to start and end the swab at will. And because SwabBot users retained full control throughout, they reported less discomfort.

“Just like how you can’t tickle yourself, you experience less pain when you are fully in control compared to having someone twirl a swab in your nose,” Dharmawan explained.

While swabbing pressure varies with human swabbers, SwabBot’s touch sensor was calibrated to the delicate sensitivity of a surgeon performing microvascular surgery.

“It retracts upon encountering resistance, and if it is not a good quality swab, it tells you to please do it again until you pass,” said Dharmawan.

All this meant that SwabBot yielded swabs of consistently high quality. This while offering to decrease the swabber’s exposure risk and reduce the need for trained manpower.

***

Despite the benefits, healthcare has traditionally been among the last industries to adopt new technologies and innovations. But the pandemic shook this state of affairs, accelerating digital health innovation as virtual consultations and digital platforms became commonplace.

And credit for Singapore’s growing biotech and medtech innovation space goes to institutions such as Duke-NUS and SingHealth, said Dharmawan.

“They are making it a lot easier for anyone with a promising idea to navigate the research ecosystem.”

Indeed, the surgeon-innovator was herself successful in leveraging the pandemic, proving that even in the field of healthcare, new ideas can rapidly be turned into innovations.

With SwabBot in the hands of Biobot, Dharmawan embarked on the next project: a programme for Duke-NUS medical students to discover the innovation bug, just as she had.

Offered to Duke-NUS third-year medical students, Dharmawan’s programme would bring them together with peers from NUS’ business and engineering programmes, clinicians and industry partners to conceptualise, develop and prototype an innovation.

“By bringing products to market, be it through startups, licensing or multi-national company spinoffs, we can create a multiplier effect that impacts the lives of our patients,” she said, hoping that, like her, these students would grow into similarly passionate innovators.

Called the Duke-NUS Health Innovator Programme, it would be officially launched on 23 September 2022.

While she started with medical students, she hopes to engage residents—clinicians who are pursuing their specialist training—in the future, too.

“They are young and savvy. If they see the light when their idea is licensed or spun off, I think they could get hooked and carry on even as they become consultants,” explained Dharmawan, who was, at the same time, pursuing an Executive MBA, a qualification she anticipates will further boost her projects.

Eventually, she aspires to develop a sustainable funding pipeline not just from public grants but also private funding.

Her moonshot goal?

To build an independent laboratory that drives innovations, works closely with industry and engineering stakeholders and delivers a training programme that feeds into a sustainable ecosystem of clinician-innovators.

And with the launch of the Health Innovator Programme and her promotion to Assistant Dean for Innovation Education and Ecosystem Development in 2022, she is well on her way.

“To me, that would be the dream.”

Just as Rena Dharmawan was thinking about how to automate the swabbing process, her fellow alumnus Dr Danny Tng (Class of 2019) was musing about the bottleneck created by the nation’s polymerase chain reaction, or PRC, testing capacity.

“Everyone was talking about PCR testing,” said Tng, who was then working as a medical officer with the radiation oncology department at NCCS.

“But with the volume of testing required, we felt convinced that there had to be a simpler and cheaper way to do it. Maybe even one that was totally non-invasive.”

“We wanted to create an alternative ART using saliva,” said Tng.

ARTs—or antigen rapid tests—using nose swabs would be widely used as part of routine rostered testing in many sectors as the pandemic dragged on. And like PCR swabs, they were often eye-wateringly uncomfortable when done as instructed.

***

When he enrolled at Duke-NUS, Tng had come armed with a Bachelors in Electrical Engineering and a PhD where he gained crucial knowledge about nanomaterials. He was nearing the end of his PhD, working on nano-based cancer therapeutics, when the self-confessed tinkerer had an epiphany.

“During the final year of my PhD, it hit me that the bulk of scientific research does not make it beyond a paper,” summed up Tng.

“I realised I wanted to focus on research that can be translated into something tangible.”

***

At the time, available saliva-based ARTs had one key limitation: they could only generate reliable results if done after an overnight fast because only then enough virus particles would have accumulated in the saliva.

So by June 2020, Tng and his mentor from NCCS, Professor Soo Khee Chee, with whom he had been working on detecting cancer proteins, started to explore this idea in earnest.

The pair reached out to Associate Professor Melvin Chua also from NCCS, virologist Professor Ooi Eng Eong from Duke-NUS’ Emerging Infectious Diseases Programme as well as then-Associate Professor Jenny Low, a practising infectious diseases physician at Singapore General Hospital (SGH) and clinical researcher—all of whom were equally passionate about the idea.

“Everyone chipped in some resources, a little lab space, a few reagents,” recounted Tng.“All chipping in small parts to make it happen. That was a real demonstration of the support from the faculty and staff around here.”

Armed with a set of new targets identified by Ooi, Tng used his engineering knowledge and handy DIY skills to build a test that could work, trying different approaches.”

“But those initial ideas all had a flaw—one had too many steps, another needed people to time the test precisely and yet another required users to refer to a table to decipher their result.”

So, they narrowed it down to just one target and to help boost the signal that they could pick up, Tng added an amplification step to the test. To ensure their test generated reliable results time after time, batch after batch, they brought a materials expert from the National University of Singapore on board.

“Professor Zhang Yong helped us identify the right parameters needed for the kind of virus detection and amplification we wanted to do,” said Tng, “where the particles were just the right size to create a clear signal.”

In all, they tried six different configurations of gold nanoparticles before they found their Goldilocks spot.

With a working blueprint and prototypes in hand, Tng—who by then had joined the Department of Infectious Diseases at SGH—and the team started clinical testing in May 2021, validating their test on samples of more than 100 study participants. The results, which were published in December 2021, showed that the parallel-amplified saliva rapid point-of-care test—or PASPORT—worked, and worked very well. Its sensitivity in detecting the virus was 97 per cent and its specificity, 90.6 per cent, compared with the PCR test’s more than 99.5 per cent sensitivity and 100 per cent specificity.

“From bench to hand. That’s the greatest sense of satisfaction,” reflected Tng on what this meant to him as the lead inventor. “It doesn’t just exist as a paper, it is real.”

Singapore-based company Digital Life Line licensed the technology, announcing in July 2022 that they would explore its use beyond infectious diseases in areas including cancer and metabolic disorders.

***

All this was a long way from the moment during his first year at Duke-NUS when Tng was on the verge of throwing in the towel. Having joined the School to combine his passion for innovation with clinical application, he worried that he would not be able to pursue such projects.

“Thankfully, Professor Soo took me under his wing and showed me all the opportunities that existed—even for medical students,” recalled Tng, who kept engaged in research throughout his medical school years, working on detecting proteins in cancers.

When asked what he thought Soo saw in him, Tng laughed. “You’ll have to ask him that! I’m just an ordinary guy.”

Ordinary or not, he is already making a mark as a clinician-innovator on the SGH campus. And there is one thing that he has grown to value as he combines his clinical work with research.

“You can do your clinical work and then, straight away, go do your science. It is that close,” said Tng, who is also an adjunct research fellow with Duke-NUS’ Emerging Infectious Diseases Programme.

But that is not the only benefit.

“Everyone is very supportive. In medicine, when you have a good idea, people will jump in to help. And that is very rewarding.”

Epilogue

The pandemic took the world by surprise, especially in the magnitude of its spread, severity and duration. But at Duke-NUS, we—and in particular our Emerging Infectious Diseases team—were prepared and trained for just such eventualities. So as the worst-case scenarios unfolded, we were quick to respond emphatically. Looking back now on those harrowing times, I am tremendously proud of all that we have achieved.

We contributed to Singapore’s decisive and effective actions to fight COVID-19. Our educators demonstrated their creativity and strong collaboration with clinical partners to ensure that the training and assessment of students could continue with minimal disruption. Our students, too, responded with resilience, grit and compassion, looking out for each other when the going got tough.

Our scientists—including our clinician-innovator alumni—created new tools to help us assess immunity and devise effective exit strategies. They crunched numbers and modelled scenarios that prepared the healthcare system for the immediate and longer-term challenges. They shared their expertise with national and international bodies—allowing us to punch well above our weight.

It is certainly possible that the flames of the pandemic flare again as the virus continues to smoulder in our midst. Accordingly, as we learn to live with SARS-CoV-2, we must heed the lessons from this global crisis—understanding where the gaps are, where we can do better as a School and as a member of the global research community.

On 10 June 2022, we launched the Duke-NUS Centre for Outbreak Preparedness, which will leverage our ties with our parent universities, Duke University and the National University of Singapore, as well as Singapore government agencies and key local and regional partners. To be truly prepared for future pandemics, the Centre aims to collaborate with partners such as Singapore’s National Programme for Research in Epidemic Preparedness and Response or PREPARE, A*STAR’s Bioinformatics Institute, the National Centre for Infectious Diseases and international bodies such as the World Health Organisation.

We also partnered with the Bill and Melinda Gates Foundation to develop the Asia Pathogen Genomics Initiative, expanding genomic sequencing capacity across 11 countries in South and Southeast Asia, so we can collectively keep a closer eye on the viral threats carried by bats and other small mammals.

And our commitment to a better-prepared future doesn’t end there. In 2021, a team of our scientists identified broadly neutralising antibodies powerful enough to fight off current SARS-CoV-2 variants as well as SARS-CoV-1, along with other subgroups of coronaviruses. In September 2022, this discovery was licensed to a Singapore start-up company, CoVBio, to be further developed into third-generation booster vaccines and monoclonal antibody treatments.

At the same time, our T-cell experts continue to advance T-cell testing technologies so that frontline clinicians can assess the full spectrum of their patients’ immune responses.

Over three Acts in this book, we’ve shared the stories of our clinicians, scientists, and educators, capturing their response to the pandemic. In these accounts, they shared ideas and experiences that enabled them to innovate during this time of crisis.

But they also candidly discuss their personal highs and lows—how they coped with the Circuit Breaker, keeping relationships alive across continents and even making space—and time—to welcome new family members.

Their stories are a testament to our unique place in the Singapore biomedical ecosystem—as a world-class graduate-entry medical school and research powerhouse that is committed to our academic pursuits in partnership with SingHealth, our academic medicine partner, to prepare for a safer and more resilient future.

Professor Thomas Coffman
Dean
Duke-NUS Medical School

Preface

The COVID-19 pandemic created significant challenges for Duke-NUS Medical School: sustaining medical training for students while ensuring safety and compliance with national protocols; managing research safely; and like everyone else, learning how to work and teach remotely.

Despite the challenges, Duke-NUS pivoted to be a thought leader and exemplar in so many areas, under its excellent and creative leadership team which ensured operations continued with minimal or no disruptions.

The education team deployed many innovations to sustain teaching and assessments even as safety restrictions continued to evolve, and their papers on these experiences were widely read and cited.

The School also played a significant role in the national response to COVID-19, in particular through the exceptional Emerging Infectious Diseases (EID) Programme. The EID team’s innovations and discoveries were impactful and timely. Moreover, their expert advice was sought after worldwide.

This crisis has validated the foresight of the Singapore government in establishing a research-focused graduate-entry medical school in 2005, stress-tested the School and proved its clinician-scientist model as a critical component of healthcare education and research in Singapore, as well as its value and significance globally.

To ensure we do not forget the lessons from this defining period, the Duke-NUS communications team chronicled the many accomplishments in this half of the book, called The Pandemic. They also interviewed the people who pursued answers and innovated education, retelling their stories in The People.

I hope their stories will reinforce the convictions of aspiring scientists and clinicians to pursue science and discovery for the public good; show them that research and innovation have the power to alter the course of diseases and affect lives across our planet; and inculcate the necessity of teamwork when dealing with complex medical emergencies.

These accomplishments and the many highlights that mark Duke-NUS’ 17-year heritage are impressive. The challenges ahead are exciting, and continued support from Duke University, the National University of Singapore and SingHealth, as well as the Singapore government and the School’s many local, regional and global partners is encouraging.

Even as we emerge from this crisis, we cannot be complacent, and so the School launched the Duke-NUS Centre for Outbreak Preparedness in collaboration with regional partners to strengthen surveillance, early detection and to build capacity.

I feel privileged to lead the School to successful outcomes and innovations that benefit and impact communities in Singapore and beyond. Because that is how the School transforms medicine and improves lives.

Mr Goh Yew Lin
Governing Board Chairman
Duke-NUS Medical School

“During COVID-19, Singapore demonstrated that its research ecosystem has matured, delivering scientific breakthroughs with international impact. Duke-NUS Medical School played a key role in strengthening the nation’s response to the pandemic, punching above its weight as the personal stories and milestones documented in this two-part book clearly show. Many scientists, educators, clinician-scientists and alumni from the School, together with colleagues from the National University of Singapore (NUS) and the Singapore research community, stepped forward to heed the nation’s call—driving impactful research, sharing their expertise and serving on the clinical frontlines. Along with a global pandemic, they also fought the spread of misinformation with equal alacrity. The accomplishments here are but some of the many successes that are a testament to the vision of a research-focused graduate-entry medical school. Bolstered by its deep academic medicine partnership with SingHealth, as well as collaborations with the rest of NUS and Singapore, I am confident Duke-NUS will continue to champion innovative translational research and strategic initiatives in academic medicine to ensure better protection against disease X not just for Singapore but for all of humanity.”

Professor Tan Eng Chye
President
National University of Singapore

“Throughout the COVID-19 pandemic, Duke-NUS researchers partnered with Singapore’s public officials to identify and trace the virus, saving countless lives. The School also continued to excel in its research and educational missions, simulating real-world patient encounters for students unable to access the clinical environment. I am extraordinarily grateful for our partnership and the faculty, staff and students at Duke-NUS who dedicated their time and talent to respond to the pandemic.”

Professor Vincent E Price
President
Duke University

Introduction

As 2019 drew to a close, the SARS-CoV-2 pandemic began to unfurl. For the next two-and-a-half years, Singapore—along with most of the world—would live directly under the umbra of the pandemic, with COVID-19’s full shadow stretching well into 2022 and beyond.

But it is the frantic early days and months, when the world scrambled to respond and Duke-NUS Medical School’s researchers, clinician-scientists, educators and alumni first stepped up to serve, that are our focus here.

Complementing the stories told in The People, in The Pandemic, we retrace the journeys of ideas, discoveries and innovations as they progressed from the imagination into the public domain. We chronicle the milestones and accomplishments, as well as accolades that describe Duke-NUS’ contributions to the fight against SARS-CoV-2.

Our timeline ends with Singapore’s decision to move from a pandemic state to living with the virus. While that moment signalled a turning point in many people’s lives and work, it did not spell the end of the virus nor was it the end of COVID-19 research at Duke-NUS because more answers are needed if we are to protect ourselves from the virus and future outbreaks alike.

We invite you to visit our virtual timeline to continue following our story via the QR code.

▸31 December 2019

A cluster of severe pneumonia cases is reported

On 31 December 2019, China’s health authorities informed the World Health Organisation of a cluster of pneumonia cases of unknown cause that had emerged in the central transport hub city of Wuhan.

The initial report noted that 27 people had been infected, with seven in serious condition. Symptoms were mainly fever while a few also experienced shortness of breath.

Within weeks, the entire world would be drawn into what was to become the largest global crisis since World War II and Duke-NUS would find itself in the very eye of the storm.

▸7 January 2020

New type of coronavirus behind outbreak

Scientists from China’s National Institute of Viral Disease Control and Prevention confirmed that the  novel coronavirus, first isolated four days earlier, was the cause of the viral pneumonia of unknown cause that had been spreading in Wuhan.

They noted that Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-1) and Middle East Respiratory Syndrome coronavirus (MERS-CoV) are this virus’ closest antecendents.

Just four days later, on 11 January 2020, the first sequence of the virus’ genome was published by scientists in China, who would be joined in the days and weeks that followed by scientists from Australia and Singapore.

▸23 January 2020

Novel coronavirus hits Singapore shores

This evening, less than 24 hours after Singapore’s outbreak strategy had been launched, the Ministry of Health confirmed the country’s first case of the novel coronavirus. The new coronavirus had already killed 17 people and infected more than 570 in China.

Singapore’s first reported case, a 66-year-old Chinese man from Wuhan, had arrived in the city state with his family three days earlier.

On 21 January, he developed a fever and cough, and was diagnosed with pneumonia at Singapore General Hospital the following day. He was isolated and remained in a stable condition.

His nine travelling companions were quarantined for 14 days. A second suspected case was also reported that night.

Earlier that day, Duke-NUS’ leadership and senior management had discussed the immediate safety implications of the novel coronavirus on the School’s operations during the first monthly operations meeting for 2020.

It was the calm before the storm.

“The team at Duke-NUS worked with other researchers and also with the National Public Health Laboratory on developing diagnostic test kits to detect the SARS-CoV-2 virus and COVID-19 infection. This early work was instrumental in allowing us to have a diagnostic test kit very early on, even before the first case came to Singapore, to diagnose COVID-19 with confidence. This was very different from SARS, which we encountered a decade before, when the diagnosis of SARS infection was often made clinically and based on epidemiological history, without the benefit of any confirmatory diagnostic test.”

Associate Professor Kenneth Mak, Duke-NUS Governing Board Member, and Director of Medical Services, Ministry of Health

▸24 January 2020

Prepared for this eventuality, Duke-NUS activates its response plan

The morning after the first case was reported in Singapore, about ten experts from Duke-NUS’ safety department and Emerging Infectious Diseases (EID) Programme met in a conference room for an urgent meeting. Another five or so dialled in via phone, interrupting their breaks and conference trips—virtual meetings having not yet become the norm.

“We didn’t really know about Zoom then,” says Professor Patrick Casey, Senior Vice-Dean for Research at Duke-NUS. “So, we met around the table in the conference room about 10 o’clock to talk about what we could do, because the EID professionals were chomping at the bit to study the virus,” he recalls.

This very eventuality—mobilising an effective response to a potential pandemic—formed part of the bedrock of the EID Programme, which had been conceived in the wake of the first SARS outbreak. Casey recalls many discussions with the Programme’s founding director, Professor Duane Gubler, and subsequently Professor Wang Linfa, who took over from Gubler in 2012, about the necessity of being ready for wartime.

“While we talked a lot about wartime and ensuring that our teams were prepared, our recruitment efforts focused on bringing in the right people to do the best research in the area of emerging infectious diseases,” explains Casey, who had joined the School when it was still only a blueprint.

Together, they brought in a team of scientists who specialised in studying different kinds of infectious diseases—from mosquito-borne diseases like dengue and Zika to respiratory viruses like influenza—as well as how these pathogens interact with their hosts—be they mosquitoes, bats or humans.

And during that meeting on 24 January, just twelve hours or so after the first case of the novel coronavirus had been detected in Singapore, this group of inadvertent avengers assembled, ready to step up to serve the nation and the world.

What everyone around the table wanted at that point was to be able to identify and study the virus. They wanted to isolate it. Culture it. Sequence it. To unlock treatments, vaccines, diagnostics and determine from where it came.

“We knew we couldn’t begin mitigation protocols until we had the wherewithal to determine the identity of the virus,” says Casey.

On the ground, the EID professionals would adjust their work to focus on this new threat, while the liaison with the Ministry and the university fell to the School’s head of safety.

“The next 72 to 96 hours were really crazy,” remembers Casey.

Reflecting on the work that would blossom out of those intense early days, Casey is fiercely proud.

“I am terribly proud of what our folks would go on to do and how everyone stepped up to the plate. These were the individuals who, during the Circuit Breaker, would work 14 to 16 hours a day,” he says, singling out the teams who would go on to work in the high security lab while confined in their “space suits” or personal protective equipment.

“Never once did I have to remind anybody to do their bit,” he says. “In fact, I had the opposite. What I had was people stepping up to the plate, asking what more they could do.”

▸30 January 2020

Duke-NUS scientists successfully culture SARS-CoV-2

Just one week after Singapore detected the first case of SARS-CoV-2 on its shores, scientists at Duke-NUS made a breakthrough. The team of specialised virus hunters successfully cultured the coronavirus from the sample of an infected patient.

This milestone came through collaborations with clinicians and scientists from the National Centre for Infectious Diseases, Singapore General Hospital and the Ministry of Health.

The Duke-NUS culture of this highly infectious virus would go on to underpin many medical interventions against SARS-CoV-2—from diagnostics to treatments—and contribute to monitoring and surveillance studies.

A team of scientists working in the biosafety level 3 laboratory at Duke-NUS was among the first three in the world to successfully culture the virus.

Healthy monkey kidney cells (left) died after infection with the novel coronavirus (right).

“This is a crucial step forward for Singapore and neighbouring countries in response to the evolving coronavirus outbreak,” said Professor Wang Linfa, the then-Director of the Duke-NUS Emerging Infectious Diseases Programme in a statement. “We will continue our efforts and do our best to serve the nation, the region and the world in controlling this outbreak.”

“This significant breakthrough exemplifies the strong collaborative culture we have with SingHealth, our Academic Medicine partner, as well as the National Centre for Infectious Diseases and the Ministry of Health,” commented Professor Patrick Casey, Senior Vice-Dean for Research at Duke-NUS. “It will continue to be important in providing insights on potential diagnostics and therapies for this coronavirus outbreak.”

By this time, China had already reported more than 9,000 confirmed infections and 213 deaths.

In Singapore, 13 cases had been confirmed by 2 pm that day while results for a further 49 cases were pending.

▸7 February 2020

Singapore raises disease threat level

DORSCON—or Disease Outbreak Response System Condition—is a colour-coded framework that tracks disease situations in Singapore, spanning four levels of increasing disease severity: green, yellow, orange and red.

The announcement that DORSCON had changed to orange indicated that COVID-19 was severe and spreading from person to person but had not been spreading widely. The last time that DORSCON had been raised to orange was during the 2009 H1N1 pandemic.

With the raised alert level, moderate disruptions to daily life came into effect while hospitals recalibrated operations to reduce the risk of spread. For a medical school like Duke-NUS, the disruption was immediate and far-reaching, testing the School’s adaptability and flexibility.

▸7 February 2020

DORSCON Orange: Responding, re-imagining and re-thinking medical education

It was Friday lunchtime when the news came through that clinical training across Singapore’s healthcare system was suspended with immediate effect.

All Duke-NUS medical students in clinical postings would be recalled to campus. The School’s education teams had the weekend to work out the first contingency plan; the first of many revisions to the School’s curricula—“75 curriculum iterations” as Vice-Dean for Education Professor Ian Curran likes to say—that would become necessary over the next two years.

“This really demonstrated the professionalism, determination and flexibility of the education teams both within the School and across our clinical training partners to come up with creative, imaginative and effective solutions throughout the pandemic,” reflects Curran.

These constant revisions would ensure the safety of patients, faculty and students, as well as enable students’ uninterrupted progression through their training.

“Healthcare systems and the human response to disease are inherently complex adaptive systems,” Curran explains.

“They’re constantly evolving. We, too, had to evolve and adapt with them to meet our educational mission.”

After they received the news, Duke-NUS educators and administrators immediately communicated to students and faculty the new DORSCON Orange rules announced that day, as well as the need for significant and profound changes to their curricula.

“That Friday afternoon, when we were told by the Ministry of Health, ‘That’s it; clinical training’s suspended’, we met all the classes to tell them ‘Right. Go collect your things from the hospitals, because you won’t be allowed back in for the time being,’” Curran shares candidly. “And then we had one hell of a busy weekend working out what we’re going to do.”

It was the first of many such weekends to come. Under the evolving restrictions, Duke-NUS would, in the days, weeks and months that followed, transition to full e-learning for classes with more than 50 students, develop virtual alternatives to clinical clerkships and work closely with the Ministry of Health and the other medical schools to return students to hospitals and clinics across the country as soon as it was safe to do so.

After sitting their final exams in March under full COVID-19 restrictions, the final-year students would return to clinical training as early as April just as the country entered its national Circuit Breaker.

“This meant we had to ensure our students were fully trained in using personal protective equipment and prepared for entering a completely transformed clinical environment,” says Curran. This group would go on to successfully complete their clinical training and graduate on time.

“We prioritised the clinical training and final exams for the fourth-year students as we were keen to demonstrate that our students had met all the required clinical, professional and academic standards that ensured they could practise as safe and competent doctors,” expands Curran.

For students in their earlier years, the education team would come up with bespoke solutions to keep their learning on track.

“We took the bold decision to bring forward the research activity for two-year groups,” adds Curran. “That move allowed those cohorts to remain actively engaged and progressing through the course while the clinical settings were off-limits.”

Two classes of medical students, then, would in due course complete all components of the world-class Duke-NUS curriculum, albeit in a uniquely sequenced way, thereby cementing their place alongside the other graduated cohorts in the School’s history.

▸11 February 2020

From Hendra to Wuhan: Lessons in emerging zoonotic viruses

“Although the source of 2019-nCoV is yet to be confirmed, early findings suggest a high possibility of a bat origin,” wrote Professor Wang Linfa from Duke-NUS’ Emerging Infectious Diseases Programme, and a team of international infectious disease experts in The Lancet.

In the article, Wang and his co-authors offered guidelines for managing emerging zoonotic virus outbreaks similar to what the world was about to face. Drawing on six similar outbreaks from the previous 25 years and incorporating the first lessons from this novel coronavirus outbreak, they put forward four key points:

1. A next-generation sequencing-based reporting system

The genome of the suspected novel coronavirus was released before live samples had been isolated. Such early flagging can lead to timelier medical and scientific interventions. A contemporary next-generation sequencing-based reporting system could, therefore, quickly alert the population to suspected outbreaks.

2. Clear guidelines for communicating information to the public

Balanced communication about suspected emerging zoonotic virus outbreaks is crucial. Clear communication guidelines must be in place to determine what must and must not be reported to avert panic and enable balanced leadership.

3. Need for a “One Health” approach to outbreak responses and control

A “One Health” intervention strategy unites experts from various disciplines to solve public health problems. A comprehensive “One Health” team should be involved in future emerging zoonotic virus investigations, and devise wider impact measures for preventing transmissions.

4. Name viruses with care

Location-based names for viruses, such as “Wuhan virus” and “China virus”, are socially and culturally insensitive. This particular virus should, Wang and the World Health Organisation experts suggested, be named “Han acute respiratory syndrome” (HARS-CoV). This, as with SARS and MERS, foregrounds the disease as a symptom. Such a re-emphasis would reduce blame and discrimination during media usage.

▸17 February 2020

Simulating COVID-19’s effect on Singapore’s health system

Would there be enough beds? What about nurses? What would the impact be on patients who didn’t have COVID-19? Questions like these drove a multi-disciplinary Duke-NUS research team as they set about planning for the likely effects of COVID-19 on Singapore’s healthcare system.

The project, which brought together the full Health Services and Systems Research (HSSR) team at Duke-NUS and the Health Services Research Centre at SingHealth would inform top-level health policy decisions as the pandemic unfolded.

The team’s first key intervention involved using computer simulations to evaluate the impact of different healthcare policies on Singapore’s rates of disease, mortality, and use of medical services.

These simulations would also evaluate hypothetical policies, enabling the 11-strong SingHealth Duke-NUS team to predict a policy’s effectiveness in three distinct possible scenarios: COVID-19 remains under control, becomes difficult to control with local clusters or results in a full-blown local epidemic.

“You can test out policy A, where ‘Okay, I’m going to convert 50 per cent of the beds [to isolation beds],’” says Professor Marcus Ong, the director of Duke-NUS’ HSSR Programme, about how the hospital network would need to respond to COVID-19.

“Or policy B, where I’m conservative; I’m going to convert about 20 per cent of my beds.”

These simulations were timely. A steady flow of data from public electronic health records would inform and shape their trajectories. And Ong and the team would add qualitative data when running them, inputting stakeholder views and policies to nuance their models.

Key work streams in this research project, called COVID-19 Virtual Disease Health System Outbreak Model for Singapore, or aptly abbreviated to CoViD-SOS, would focus on understanding how the virus affects the workflow of emergency departments, intensive care units, operating theatres and the needs of medically vulnerable patients.

“This is where health systems research came to the forefront and showed its value,” adds Ong, who is also a senior consultant with Singapore General Hospital’s Emergency Department. “By nature, health services research is multidisciplinary, cross-boundary and collaborative.”

“Our overall goal was—and continues to be—to minimise the impact of the evolving COVID-19 disease outbreak on Singapore’s healthcare systems.”

The HSSR team investigated how different health policies would impact Singapore, taking into consideration challenges and other societal factors faced during the pandemic.

▸25 February 2020

A world first: Duke-NUS’ serology test links SARS-CoV-2 clusters

Serological testing uncovered the hidden link between SARS-CoV-2 clusters associated with two churches in Singapore at a time when the nation was focused on containing the rapidly growing threat of the new virus.

Thought to be the first such use in the world, a team from Duke-NUS assisted local contact tracers by analysing the blood of a married couple who had not previously been diagnosed with SARS-CoV-2 but had been in close contact with the index case of Singapore’s largest church-related SARS-CoV-2 cluster at Grace Assembly of God.

Having successfully cultured the virus, the Duke-NUS team used the virus and its genetic material to develop tests to accurately detect virus-specific antibodies that remain in people’s blood long after they recovered from the infection.

With these, the team determined that the couple had previously been infected with the novel coronavirus. Contact tracers were then able to trace the source of the infection, which originated with two travellers who had arrived from Wuhan in January. The visitors had attended a church gathering where they interacted with the couple. The couple, who were not initially linked to the resulting cluster, then met the index case of the Grace Assembly of God cluster.

The final chain comprised 31 people, accounting for a third of all reported infections at that time.

▸25 February 2020

PM and DPM commend Duke-NUS, contact tracers

Linking the two church clusters drew plaudits from Singapore’s Prime Minister Mr Lee Hsien Loong, who wrote on his Facebook page: “This breakthrough would not have been possible without close cooperation among the Ministry of Health, Singapore, Singapore Police Force and researchers from Duke-NUS Medical School, who developed the serological test, the world’s first, here in Singapore. My thanks to all of you for a job well done!”

The following day, Deputy Prime Minister Mr Heng Swee Keat echoed the PM’s commendation in a post on Facebook, in which he wrote that the Duke-NUS team had “done Singapore proud” by developing the tests. He added that the team did this just weeks after scientists and researchers from A*STAR and Tan Tock Seng Hospital developed a diagnostic test kit for screening suspected SARS-CoV-2 cases.

“This is a world’s first—using serological testing to link different clusters of COVID-19 cases,” DPM Heng wrote. “Well done to all the scientists and researchers who worked on the diagnostic test kit as well as the serological test—you have made a difference!’’

“Despite being a relatively small institution, Duke-NUS was at the forefront of Singapore’s battle against COVID-19. The willingness of the scientists there and at NUS to serve the country and the world was impressive. They exceeded my expectations with their commitment to science and service. They provided us with a great deal of knowledge, showed us how to navigate a pandemic, and helped us realise what we can achieve as a team when we collaborate openly.”

Professor Ho Teck Hua, Duke-NUS Governing Board Deputy Chairman, and Provost, National University of Singapore

▸1 March 2020

A dynamic immune response shapes COVID-19 progression

As the first cases of a novel coronavirus were detected in Singapore, a team of clinician-scientists from Duke-NUS and the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS) closely tracked patients’ immune response to help shed light on how this virus interacts with the human immune system.

Studying blood and throat swabs from three SARS-CoV-2 patients, Professor Ooi Eng Eong, from Duke-NUS’ Emerging Infectious Diseases Programme and co-director of ViREMiCS, who was joined by then-Senior Research Fellow Dr Eugenia Ong and then-Associate Professor Jenny Low, tracked these patients’ inflammatory and immune responses.

Unlike many other studies carried out around the same time, which would take snapshots at fixed time points, the team decided to collect samples every day.

“We looked at the genes that were turned on or off and whether that could be the underlying reason why some people went on to develop severe disease while searching for some starting points for therapeutic approaches,” Ooi explains.

“We were able to get a nice pattern of what the immune response looked like,” adds Ong. “We detected pro-inflammatory signals through gene expression profiling that correlated with the severity in clinical outcomes, showing that inflammation was a key driver in disease severity.”

With so little known about the virus, they decided to submit their observations on 1 March to Cell Host & Microbe, which would go on to publish the report a month later. It was one of the first—if not the first—paper to do that.

What was the biggest takeaway from that work?

“That the whole process is very dynamic,” says Ooi. “And that we needed to be a lot more specific about what we’re talking about instead of lumping everyone into the same bucket.”

▸4 March 2020

Duke-NUS and Arcturus Therapeutics join forces to develop an mRNA-based vaccine with a difference

The collaboration combined Arcturus’ STARR technology with Duke-NUS’ rapid screening platform developed by Professor Ooi Eng Eong’s team. The hope was to create an effective, single-dose vaccine in Singapore.

Ooi Eng Eong and his team have built deep expertise in understanding what causes vaccination side effects, knowledge that made them an ideal partner for Arcturus.

Ooi, a dengue researcher at heart, would be the lead Principal Investigator for the preclinical studies, to which he would apply his expertise and deep understanding of vaccine development to serve the nation.

“We’d been studying how humans respond to the yellow fever vaccine and found the causes of common vaccine side effects and the genes that need to be switched on or off to produce immune responses that give durable protection. And that’s what we want from a vaccine,” says Ooi.

“With a solid scientific foundation, we knew what milestones to look out for,” he adds; milestones that would give the team the confidence that they were on the right track in the quest for a COVID-19 vaccine.

“Duke-NUS has been on the frontline in the fight against COVID-19, developing the first serological tests for the infection, and was among the first groups to isolate and culture the virus. The partnership with Arcturus Therapeutics combines complementary strengths as we work together to fight this global outbreak,” said Professor Thomas Coffman, Dean of Duke-NUS, on 4 March 2020 when the deal was announced.

This collaboration came about after just weeks of fast-paced talks between Arcturus, Duke-NUS and Singapore’s Economic Development Board.

Commenting on the partnership, Ooi said at the time, “There is a tremendous urgency to develop an effective prevention for the current coronavirus crisis. The Duke-NUS and Arcturus partnership could expedite a solution to this pressing need as we utilise STARR technology to bring a vaccine candidate for clinical testing in the shortest time possible.”

▸11 March 2020

COVID-19 declared a pandemic

The disease was no longer local—it had hit more countries. The World Health Organisation’s announcement came about six weeks after the COVID-19 outbreak was declared a Public Health Emergency of International Concern, amid worries about its growing severity and rapid spread.

That same day, Singapore announced its 166th confirmed case, while contact tracing had revealed links between previously announced cases that would lead to another milestone for the nation and Duke-NUS.

▸12 March 2020

Treating COVID-19 with your ‘own’ immune cells

More often associated with the treatment of cancer, immunotherapy could also be used to treat infectious diseases, suggested a team from Duke-NUS.

In a commentary published in the Journal of Experimental Medicine, Professor Antonio Bertoletti and Senior Research Fellow Dr Anthony Tanoto Tan from Duke-NUS’ Emerging Infectious Diseases Programme made the case that T cells could be extracted and engineered to recognise a viral threat before being reinjected into the blood stream.

Such engineered T cells when fitted with either artificially recreated receptors called chimeric antigen receptors (CARs) or naturally occurring ones called T-cell receptors (TCRs) can recognise cells infected either by a specific cancer or virus.

“We demonstrated previously that T cells can be redirected to target the coronavirus responsible for SARS,” said Bertoletti at the time.

“Our team has now begun exploring the potential of CAR/TCR T-cell immunotherapy for controlling the COVID-19-causing virus, SARS-CoV-2, and protecting patients from its symptomatic effects,” Bertoletti would go on to say in a media statement issued by the School on the commentary on 21 April 2020.

The Bertoletti lab had been studying this method to treat chronic hepatitis B infections and hepatitis B-related liver cancer. The scientific concept was licensed to local biotech start-up, Lion TCR, which brought it to the clinical trial stage in 2018 for liver cancer patients whose cancer had recurred even after transplant.

“This commentary was largely written before the pandemic, but some aspects turned out to be pretty predictive of what was to come,” reflects Bertoletti. “For example, we have since gone on to develop SARS-CoV-2 TCR-redirected T cells and are testing the possibility of using this strategy to treat immunocompromised patients with COVID-19.”

▸27 March 2020

And they shall pass: Duke-NUS’ COVID-safe clinical exams lead the world

A MedEdPublish case study of how Duke-NUS planned and conducted its final-year clinical skills exams under pandemic-era conditions showed that it was possible—even in trying and safely distanced times—for students to complete their exams and graduate as planned without compromising competency.

The authors of the case study, which included Duke-NUS educators Ms Kirsty Freeman, who leads the Clinical Performance Centre, and Vice-Dean for Education Professor Ian Curran, noted that there were no reports of COVID-19 infections by any person who participated in the three-day Observed Structured Clinical Examinations (OSCEs).

This was achieved by dividing the 56 students undergoing the exams into four separate cohorts with specific faculty and administrative staff assigned to each. Freeman, Curran and the rest of their team noted that “at no time were students, staff or examiners from different circuits allowed to mix, and all were also given strict instructions about avoiding meeting and socialising” beyond their time in the School.

The educators also noted that having actual patients participating in the pandemic-era OSCEs was challenging. Patient volunteers who had healthcare contact during the preceding 14 days were disallowed. While those patients allowed on-site were initially fearful of being infected with COVID-19—the team, conversely, had to consider the risk of these patients spreading COVID-19 to the other OSCE stakeholders.

To mitigate any risk and assure patients, Duke-NUS involved only patients with chronic conditions, minimising their on-site changeovers and screening patients for travel histories, as well as sick family members during the fortnight leading up to the OSCEs.

The Duke-NUS operational measures would go on to guide other medical schools in designing and implementing rigorous clinical skills examinations that, at the same time, minimised the risk to key stakeholders.

Less than two months after this, the team would once again have to re-evaluate these measures to be able to conduct the final set of exams during Singapore’s Circuit Breaker, the most restrictive period in Singapore’s fight against COVID-19.

▸7 April 2020

Singapore announces Circuit Breaker to curb COVID-19 spread

The government’s key measure to minimise the spread of SARS-CoV-2 saw most businesses, except essential services, adopting a work-from-home model. Schools shifted to home-based learning.

All social gatherings were banned, except for visiting elderly relatives needing assistance. Originally planned to last till 4 May 2020, the Circuit Breaker would be extended until 1 June 2020 and restrictions further tightened.

At Duke-NUS, work shifted to home for a majority. Among the exceptions were the teams pursuing COVID-19-related laboratory research. But even they had to pare down their numbers, running their studies with a skeleton crew.

On 19 May 2020, the authorities would announce that the nation would exit the Circuit Breaker in three phases, with the first phase of reopening starting on 2 June 2020.

▸16 April 2020

The good and bad of plasma therapy and plasma-derived vaccines: what we know so far

During the early stages of the COVID-19 pandemic, plasma-based therapies were a low-hanging fruit that held the potential of yielding effective treatments against this then-unknown virus and even vaccine candidates as they could be moved from bench to bedside fast.

This approach, which was first used as a treatment in the late 1800s, makes use of plasma derived from the blood of people who have recovered from the infection—which is rich in antibodies against the virus. The plasma-derived treatment is then injected into an uninfected individual as a vaccine or an infected person to help fight the infection.

“But some initial preclinical studies showed that in certain situations, some SARS-CoV-1 vaccine candidates could make the infection worse,” says Dr Ruklanthi de Alwis, a then-senior research fellow from the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS).

This happens when antibodies in the plasma that are supposed to fight the virus go rogue and enhance the viral infection instead.

“And because we’ve been studying the mechanisms that make these antibodies go turncoat, we wrote this mini review about the good and bad of this kind of approach,” explains de Alwis, who wrote the review together with Professor Ooi Eng Eong from Duke-NUS’ Emerging Infectious Diseases Programme and co-director of ViREMiCS.

Drawing on their experience of working with antibodies in all kinds of diseases including dengue where antibodies can switch sides when people are re-infected, they summarised what was known then, what to look out for and how to mitigate this risk. Their review was published in the journal eBioMedicine.

They concluded that because of the nature of the data available, the risks appeared to be low, an assessment they would subsequently confirm.

“In terms of antibody-dependent enhancement, we did not see that in subsequent SARS-CoV-2 preclinical studies,” says de Alwis.

Looking back at the role that plasma-based interventions would end up playing, de Alwis says that early hopes of an effective plasma therapy were quickly dashed.

“It still holds true for monoclonal antibodies. If given very early on in an infection, they can be protective against severe disease,” she says. “But plasma therapy, unfortunately, has not shown a lot of protection from disease.”

▸29 April 2020

National research effort to tackle COVID-19 on three fronts

Scientists and clinicians in Singapore embarked on three national-level studies targeting different segments of Singapore’s population, namely healthcare workers, children and people at high risk of COVID-19 exposure.

All three studies would be based on standardised antibody tests, which would be carried out at a single centralised laboratory at Duke-NUS. Such standardisation would allow for valid comparisons across various populations despite different sampling methods.

In addition to experts from Duke-NUS, the studies assembled medical researchers and clinicians from Singapore’s public health institutions, the Ministry of Health, DSO National Laboratories and A*STAR.

“At this critical juncture, it is important to know the extent of COVID-19’s exposure in the community, given potential asymptomatic infection and herd immunity,” said Professor Wang Linfa from Duke-NUS and a member of the national COVID-19 Research Workgroup when the studies were launched.

As the virus could spread around the community through asymptomatic and therefore unhospitalised individuals, these studies would provide insights such as the extent to which such cases are underdiagnosed, and how they may contribute to the spread of COVID-19.

Data from these studies would let policymakers map how best to control the long-term spread of COVID-19, identify segments of the population at risk of infection and who would benefit from a vaccine once one became available.

Singapore would be one of the first countries in the world to conduct such tests on a large scale.

▸15 May 2020

Singapore unveils the world’s first rapid test for SARS-CoV-2 neutralising antibodies

Duke-NUS, A*STAR’s Diagnostics Development Hub (DxD) and global biotechnology group GenScript joined forces to develop cPass™, a surrogate virus neutralisation test that can detect whether someone has previously been infected with SARS-CoV-2.

The test offered to be more impactful and faster than existing antibody tests. It detects neutralising antibodies which clear SARS-CoV-2 viral infections by preventing coronavirus spike proteins from entering the host body’s cells.

Other SARS-CoV-2 tests simply detect the overall presence of antibodies—including those which do not necessarily block infections.

cPass also detects these SARS-CoV-2 neutralising antibodies within an hour. Other kits and laboratory procedures can take several days to produce results as they have to be carried out in biosecure facilities by personnel specially trained to handle the live virus safely.

“The cPass kit developed by our team can be used for contact tracing, reservoir or intermediate animal tracking, assessment of herd immunity, longevity of protective immunity and efficacy of different vaccine candidates,” said Professor Wang Linfa, the principal investigator of this collaboration, in a statement issued at the time.

“It does not require a biosafety containment facility, which makes it immediately accessible to the global community, including many developing nations,” added Wang, who is also an emerging infectious diseases expert from Duke-NUS’ Emerging Infectious Diseases Programme.

In the media statement issued at the time, Ms Sherry Shao, President of the Life Science Group at GenScript, commented that “the collaboration with Duke-NUS is a key example of how global industry and academia work together to make things happen”.

Echoing her sentiments, Professor Thomas Coffman, Dean of Duke-NUS, added, “This innovative platform developed by our researchers will be extremely useful for quick and reliable surveillance to determine how widely a population has gained immunity to SARS-CoV-2. The partnership with GenScript and DxD Hub combines complementary strengths as we work together to fight this global outbreak.”

▸29 May 2020

Duke-NUS’ virtual Hippocratic Oath ceremony: Another first in Singapore!

The Duke-NUS Class of 2020 graduated on 29 May 2020 while the nation was still in circuit-breaker mode. But far from being a muted affair, the event became another first in the School’s—and Singapore’s—history by bringing students and faculty together for a virtual declaration of the Hippocratic Oath.

The Oath is a traditional code of ethics, whereby individual physicians collectively pledge to uphold the highest personal and professional standards in their conduct and practice. They promise to “apply, for the benefit of the sick, all measures that are required”. By reciting the Oath, newly minted doctors pledge their commitment to the welfare of their patients as they step into their new roles as doctors—high ideals and values that were never more critical than during Singapore’s fight against the pandemic.

The Class of 2020 faced a difficult final semester before their graduation. The threat posed by the pandemic had forced the Ministry of Health to suspend all clinical training from 7 February 2020 when the national disease outbreak alert level was raised to orange.

The impact of COVID-19 on clinical training was significant as Professor Ian Curran, Vice-Dean for Education at Duke-NUS, explains: “On a normal ongoing basis, we would have two years out of four in clinical training at any one time. And now all bar the final-year students were back on campus. Our educators flexed rapidly to provide creative and high-quality surrogate learning experiences for all four of our medical cohorts.”

It fell to educators at Duke-NUS like Ms Kirsty Freeman, the lead for the Clinical Performance Centre at Duke-NUS, and others across the

“The education team rose to the challenge posed by the pandemic, delivering a curriculum while also focusing on students’ mental wellbeing. Many clinical faculty members led by example, demonstrating how to live during a pandemic as a doctor or researcher. When the next pandemic strikes, I have faith that our students will be ready to step up and become role models themselves.”

Professor Ho Teck Hua, Duke-NUS Governing Board Deputy Chairman, and Provost, National University of Singapore

SingHealth Duke-NUS Academic Medical Centre, to make sure that these medical students had the closest analogue to real-world clinical experiences as was possible under the circumstances.

Freeman and the wider team at Duke-NUS had organised exams through video-conferencing, installing cameras on invigilation room walls and using duct tape and pieces of wood to prop up iPads, so examiners could assess the students fully whilst maintaining all necessary safety measures.

“We were really cognizant of what must we do,” says Freeman reflecting on those days. “To both operate within the restrictions, but still provide students the opportunity to graduate in the expected timeframe.”

Speaking at the virtual ceremony, Professor Thomas Coffman, Dean of Duke-NUS, remarked, “Now, you’re officially doctors who have endured some unprecedented times. Also, probably a little nervous about what comes next, but I can assure you that you’re well prepared for this next phase of your postgraduate clinical training.”

“You’re truly a historical class. You will forever be known as the first Duke-NUS Class to graduate virtually,” he added. “But more importantly, as the Class who graduated in the midst of the COVID-19 pandemic.”

Following their send-off, Duke-NUS’ newest alumni would go on to start work two weeks earlier than originally planned, bolstering the staff numbers of the frontline healthcare workforce as Singapore continued to battle the pandemic.

▸15 June 2020

Bringing the intensity and sound of an emergency room online

Virtual telesimulation lessons can be effective alternatives when in-person teaching is not possible, medical researchers including Ms Kirsty Freeman, the lead for the Clinical Performance Centre at Duke-NUS, found.

Their findings, published in The Asia Pacific Scholar, showed that if used correctly, telesimulation lessons can sharpen non-tactile aspects of clinical care such as history-taking, executing treatment algorithms and team communication.

With stringent controls on movement and gatherings still in place and high-risk clinical areas like the emergency room (ER) still off limits to students, the team from Duke-NUS along with colleagues from across the SingHealth Duke-NUS Academic Medical Centre transformed a four-week emergency medicine clerkship into a virtual experience for Duke-NUS medical students.

And even with the time and resource crunch, Freeman’s team did not spare any attention to detail.

“An ER is a noisy place,” she noted.

So, her team honed students’ psychological readiness by layering on medical equipment noises for fidelity—this ensured that students were immersed in as life-like an environment as possible, and that they could transition more smoothly into real-world practice.

More than 95 per cent of students who provided feedback agreed that participating in the simulations was interesting and useful. Thirty-eight felt that telesimulation provided a good grounding before beginning their real-life clinical work.

However, the student respondents indicated that the limitations of telesimulation included an inability to examine patients, perform procedures and understand non-verbal cues of team members and patients.

Freeman and her team found, too, that designing the telesimulation according to defined objectives and scheduling it after theory teaching contributed to a successfully executed lesson. Having faculty skilled in debriefing techniques that enable the learner to critically reflect on the telesimulation lesson was also advantageous.

The team, as such, recommended that educators who wish to implement a telesimulation programme should pay particular attention to the learning objectives and debriefing methods.

The simulation experience created by Kirsty Freeman and her colleagues ensured students had as life-like an experience of the busy and noisy environment of an emergency room as possible.

▸28 June 2020

A global calamity with more than 500,000 deaths; in excess of 10 million infections

Half a million people across the globe had died from COVID-19, and more than 10 million infections were straining hospitals and clinicians, according to the Johns Hopkins University tracker.

At the same time, the world hit a record number of daily infections—more than 189,000 in 24 hours.

In Singapore, the Circuit Breaker along with swift infection control measures, had been effective at lowering the community spread of COVID-19. So on 19 June 2020, Singapore had entered the second phase of reopening and researchers were returning to the Duke-NUS campus in greater numbers again.

▸15 July 2020

Turning the spotlight on T cells

In one of the first publications on this topic, a team of Singapore scientists, led by researchers from Professor Antonio Bertoletti’s lab at Duke-NUS and collaborators from healthcare institutions including Singapore General Hospital, discovered that people who recovered from COVID-19 or had previously been infected with its precursor SARS-CoV-1, retained long-lasting memory T cells that could confer some level of cell-mediated immunity.

T cells, a key part of the immune system, are activated when an infected cell calls for help. They find the cell in trouble and destroy it before the threat within can spill out of control.

What’s more, the team found that even people who had never been infected by either virus generated SARS-CoV-2-specific T cells.

The findings, published in Nature, suggested that previous infections from SARS-type viruses could confer some level of long-lasting protection against SARS-CoV-2, potentially making people less susceptible to severe infection from this virus.

ELISpot result showed the presence of large numbers of T cells in COVID-19-recovered patient samples. Credit: Bertoletti lab

Studying 96 human donor samples, the researchers found SARS-CoV-2-specific T-cell activity in all the 59 patients who had recovered from SARS-CoV-2 and SARS-CoV-1; never mind that the SARS-CoV-1 infections took place some 17 years ago.

Just over half—19 out of 37—of the individuals who had never been infected with a SARS-type virus exhibited T-cell activity against SARS-CoV-2.

“This finding, in particular, has attracted a huge amount of interest from the scientific community because it shows that coronaviruses can induce long-lasting immunity that might have a protective effect. This is an area of huge controversy and with great impact on the management of the COVID-19 pandemic,” said Bertoletti in an interview with Duke-NUS’ MEDICUS magazine.

And indeed, it would. The paper would become one of the most highly cited and then-Director of the National Institutes for Health Dr Francis Collins would write in a blog that this study showed that past coronavirus infections may play a role in COVID-19: “Bertoletti’s team and others are pursuing this intriguing lead to see where it will lead—not only in explaining our varied responses to the virus, but also in designing new treatments and optimised vaccines.”

“The pandemic has taught us that you need the foundations. The foundations must be good, built on strong partnerships forged in peacetime. And inherent in that is trust within the Academic Medical Centre and the knowledge of the different pockets of expertise. That put us in a good place to adapt and innovate.”

Professor Ivy Ng, Duke-NUS Governing Board Member, and Group Chief Executive Officer, SingHealth

▸21 July 2020

First trial for moonshot vaccine approved

The first clinical trial for LUNAR-COV19 (as ARCT-021 was then called) received the green light from Singapore Health Sciences Authority. The study would evaluate several dose levels of this self-replicating mRNA vaccine in more than 100 healthy adult volunteers.

In preclinical data, a single 0.2 µg dose of ARCT-021 promised to generate a robust immune response.

ARCT-021 was jointly developed by Duke-NUS and Arcturus Therapeutics and the first dose would be administered in just under a month, on 11 August 2020.

▸23 July 2020

First evidence of the power of a new serology test

Less than six weeks after announcing the commercialisation of a novel serological test, Duke-NUS scientists reported the first testing data.

Invented by Professor Wang Linfa’s team from Duke-NUS and co-developed with A*STAR’s Diagnostics Development Hub and biotech group GenScript, the test was validated with two cohorts of SARS-CoV-2 patients from Singapore and China. The results, published in Nature Biotechnology, showed that the surrogate virus neutralisation test had 99.3 per cent specificity and 95 to 100 per cent sensitivity.

The other major advantage of this invention is that as a surrogate test, it does not require the live virus, and can be completed in as little as an hour in a standard biosafety level 2 laboratory.

This surrogate virus neutralisation test contains 96 wells for testing on a plate, which are coated with angiotensin-converting enzyme 2 (ACE2) receptors that the SARS-CoV-2 virus uses to enter human cells. To this, researchers add a mix of serum from the patient and a solution containing just the part of the virus’ spike protein that binds to the receptor, called the receptor-binding domain, which is fitted with a chemical signal. The signal lights up blue if the viral fragment was able to attach to the ACE2 receptor in the wells, indicating that neutralising antibodies are not present in the serum.

This kit represents a key intervention against SARS-CoV-2 for clinicians as well as researchers. It can be used to determine infection rates, herd immunity, predicted humoral protection and vaccine efficacy during clinical trials.

The School’s commercial partner, GenScript, had also filed for Emergency Use Authorisation with the United States Food and Drug Administration.

▸1 August 2020

Ascertaining the true lay of the land

Preprints were being uploaded at a fierce rate. Faced with this tsunami of information, Associate Professor Ashley St John from Duke-NUS’ Emerging Infectious Diseases Programme and then-Postdoctoral Research Scholar Abhay PS Rathore from Duke University published a review synthesising what was known at that point about the immune response in the lung to draw out deeper insights.

The insights of this review, which was published in The Journal of Immunology, could assist in developing a vaccine that protects from SARS-CoV-2 infection without triggering inflammatory immune reactions, the authors hoped. Excessive inflammatory reactions can lead to severely—or even fatally—damaged lungs.

St John and Rathore further described how recovery from SARS-CoV-2 may also be associated with persistent immunological changes. Some patients continued to have reduced numbers of lymphocytes and eosinophils—a type of white blood cell that curbs infection and boosts inflammation—in the weeks after hospital discharge. Others experienced inflammatory symptoms persisting even after recovery. They also reported that pre-existing antibodies against coronaviruses did not necessarily work against SARS-CoV-2.

Unlike other coronaviruses which typically infect cells in the airways, SARS-CoV-2 could also infect endothelial cells, or the single-layer cell lining of blood vessels. The review noted that data showed virus particles observed within endothelial cells of the kidney, highlighting that inflammatory immune responses could be far reaching and trigger organ damage well beyond the lungs. SARS-CoV-2 was also observed to infect secondary lymphoid organs, which, in turn, could cause the white pulp of the spleen, which contains immune cells, to wither.

The review found that the collated risk factors for more severe SARS-CoV-2 infection outcomes included low blood oxygen during a patient’s initial admission for treatment, as well as hypertension, smoking, coronary heart disease, cerebrovascular disease, diabetes, and pre-existing lung diseases. Chronic infections, such as hepatitis B and tuberculosis, were other factors associated with worse infections. Men generally exhibited more severe SARS-CoV-2 infections than women.

▸11 August 2020

First volunteers join in moonshot mission for a Singapore-developed COVID-19 vaccine

The first doses of ARCT-021, an investigational self-replicating mRNA SARS-CoV-2 vaccine, developed by Duke-NUS and Arcturus Therapeutics, were administered to a group of healthy volunteers in a trial in Singapore.

The first group of younger volunteers, aged 21 to 55, had all been injected with a dose of the vaccine candidate which became better known as ARCT-021. This marked the beginning of the Phase I/II trial that would evaluate the safety of the vaccine. As well as safety, the longitudinal immune responses and T-cell response data would be monitored and inform which dose regimens would be selected for the second phase of the study. That phase would include cohorts in both younger and older adults, aged 56 to 80.

“The attention had shifted away from only developing local diagnostic tests to developing effective therapeutics and vaccines against COVID-19. Again, Duke-NUS made strong contributions in the research space, with innovative research performed to develop our own local vaccine. It was and remains challenging to develop a vaccine in Singapore.

While non-human research work may be initially performed in Singapore, it is difficult to launch local studies on the efficacy and safety of vaccines because you need large numbers of participants in Phase II and III studies, as well as a relatively high incidence of COVID-19 infection with sufficient numbers of COVID-19-infected persons to be able to study the effect of vaccinations against infection. In the later years once the national COVID-19 vaccination programme started, it became difficult to recruit local participants into the study who had not received other vaccinations under the national vaccination programme.”

Associate Professor Kenneth Mak, Duke-NUS Governing Board Member, and Director of Medical Services, Ministry of Health

▸18 August 2020

Mutation unmasks the virus to the immune system

At a time when few genetic changes of SARS-CoV-2 had been described, researchers from Duke-NUS, A*STAR and the National Centre for Infectious Diseases published two papers describing a new variant of the SARS-CoV-2 virus detected in Singapore, which resulted in milder infections compared with wild-type or ancestral virus infections.

The studies, which were published in the journals mbio and The Lancet, showed that out of the 92 patients with the wild-type virus, 26 required supplementary oxygen, 15 needed admitting to the intensive care unit, and ten were placed on mechanical ventilation.

None of the 29 patients infected with the new variant, however, needed these interventions. Not only that, they also experienced a lower degree of fever, had more effective T-cell responses and better platelet regulation during the early phase of infection. Only when it came to sore throats did those infected with the new variant fare less well when compared with the group which was infected with the wild-type virus.

Research on the evolution of the virus, which led to discoveries like the ORF8 deletion by Gavin Smith and Yvonne Su, demonstrates how viruses adapt to their hosts through transmission.

This variant had been identified by its deletion of 382 nucleotides, or RNA building blocks, in a section of the viral genome known as open reading frame (ORF) 7b and ORF8. A similar deletion of 29 nucleotides in ORF8 of the original SARS virus had been observed during the 2003 outbreak, resulting in a less infectious SARS-CoV-1 variant, though its severity had not been examined.

However, evidence suggested that the ORF8 gene, a mystery protein of unclear function, could help the virus evade the immune system and its deletion may have, therefore, helped uncloak it.

The researchers, Professors Gavin Smith and Wang Linfa, and then-Assistant Professor Yvonne Su from the Emerging Infectious Diseases Programme at Duke-NUS among them, noted that patients infected with the variant also had lower concentrations of widely released pro-inflammatory cytokines, chemokines and growth factors that are strongly associated with severe COVID-19.

“These studies provide the first convincing data showing that an observed genetic change in SARS-CoV-2 has affected the severity of disease in patients,” said Smith in a statement issued at the time.

“This further highlights the importance of tracking the genetic diversity of SARS-CoV-2 as the virus continues to evolve,” added Smith.

Elaborating on the significance of a deletion such as this, Smith explains, “Strains like this—which make the virus less dangerous—have the potential to be used for human challenge studies”, referencing a type of study where healthy volunteers are deliberately infected with a mild or weakened virus to test vaccines and treatments.

▸31 August 2020

Duke-NUS young scientist honoured as trailblazer

Prestige Singapore named Dr Eugenia Ong, a then-senior research fellow both with Duke-NUS’ Emerging Infectious Diseases Programme and the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS) in its list of Singapore’s most successful, innovative and influential young people.

Ong made the 2020 list for her role in leading the development of novel molecular tests that shortened the bench-to-bedside timeline for vaccines and drugs against infectious diseases such as COVID-19, as well as for helping ViREMiCS attain ISO 15189 (Medical Testing) accreditation in 2019.

▸21 September 2020

The robot will swab you now

Six months after serial entrepreneur and cancer surgeon Assistant Professor Rena Dharmawan first conceptualised the idea, she along with a team of clinicians from the National Cancer Centre Singapore (NCCS) and engineers from local medical robotics company Biobot Surgical unveiled SwabBot, the world’s first automated nasal swab robot.

The robot prototype, which was about the size of a large house cat, promised to be fast but gentle—its entire collection process lasting just 20 seconds, half the time of a manual swab test. Despite its mechanical appearance, it had a soft touch, delivered with surgical precision. It would be fully controlled by the person being tested, making the experience less uncomfortable.

“When patients are empowered and fully in control of the swabbing process, they are mentally prepared and experience subjectively less pain,” said Dharmawan, a then-associate consultant at NCCS and then-Entrepreneur-in-Residence with Duke-NUS’ Centre for Technology and Development, in an interview at the time.

The promise of SwabBot was to reduce the risks and costs of manual swabbing. Nasal samples would be more accurate, while swabbers would be less likely to be exposed to the virus.

“SwabBot never needs to stop for lunch and never suffers from fatigue,” commented Dr Luke Tay, one of the project’s team members and a consultant at Singapore General Hospital at the prototype’s demonstration.

“Furthermore, the sample quality remains consistent even though nose structures can vary in size and shapes.”

“When you are in the thick of the action on the healthcare side of the house, you see the gaps almost immediately—what do we still need to know, what can we do better—and on the Duke-NUS side of the house, you have expertise in areas like emerging infectious diseases and innovation; and when you bring all this expertise together, you get many achievements.”

Professor Ivy Ng, Duke-NUS Governing Board Member, and Group Chief Executive Officer, SingHealth

▸5 October 2020

The first look at the impending sea change

The first B1.671 genome was uploaded to international database GISAID. This new variant, which had originated in India, was thought to be about twice as infectious as the original, or wild-type, SARS-CoV-2. People infected with it were more likely to need hospitalisation.

The variant would go on to be named Delta and become the dominant strain around the world in 2021.

▸24 October 2020

Uncovering hidden vaccine hesitancy

Twenty-two per cent of Singapore residents said that they would never choose to get vaccinated, a survey led by Duke-NUS health economist Professor Eric Finkelstein found. Herd immunity, resultingly, may be difficult to achieve locally without a vaccine mandate, Finkelstein and his colleagues argued in an opinion piece published in The Straits Times.

And the refusal the scientists observed was not only driven by price. Participants had been asked to respond to different scenarios, including opting for an immediate and free vaccine, paying a randomly-varied price two months later or never be vaccinated.

Forty-two per cent of respondents said that a S$100 price tag would make them get vaccinated for free immediately, Finkelstein and colleagues noted. Another 35 per cent would wait for two months—and pay the vaccine provider—in order to gauge the safety and efficacy of the vaccine. A S$6,000 price tag, on the other hand, had a double-sided effect: it would increase the immediate take-up of the vaccine to fifty-two percent, but also drive up the percentage of people who would completely refuse a vaccine.

The low exposure rate in Singapore, resulting from measures such as quarantines, safe distancing and contact tracing, indicated that a vaccination rate below 70 per cent—generally accepted as the threshold for herd immunity—would be insufficient for stopping the spread of SARS-CoV-2.

“[Vaccine] uptake could be increased by public health messaging campaigns reminding Singaporeans that although vaccination is an individual choice, vaccination benefits all of us due to herd immunity,” Finkelstein and his co-authors wrote. “Combating COVID-19—by heeding measures such as keeping a safe distance from others and wearing masks—is truly a community effort.”

By the end of August 2021, Singapore would become the world’s most vaccinated country.

Eric Finkelstein’s survey of public opinion about COVID-19 and vaccination found that many believed they had a high chance of being infected despite low community transmission rates at the time. Despite this, many remained skeptical about vaccination.

▸6 November 2020

World’s first surrogate virus neutralising antibody test gets green light

The United States Food and Drug Administration (FDA) authorised the emergency use of cPassTM, a world-first kit for detecting antibodies that neutralise SARS-CoV-2 easily, efficiently and quickly.

Where similar tests can take up to several days, cPass returns results within an hour. It requires neither live virus nor complex laboratory procedures and is easy to use.

cPass was invented by Professor Wang Linfa’s team from the Emerging Infectious Diseases Programme at Duke-NUS and co-developed with biotechnology group GenScript Biotech and A*STAR’s Diagnostics Development Hub.

“FDA approval of cPass as ‘the first test that detects neutralising antibodies (against SARS-CoV-2)’ is an important landmark in the fight against the COVID-19 pandemic. As the first and only commercial kit with such capability, this serological test will have wide-ranging applications and is another demonstration of the high-quality science and translational research that distinguishes Duke-NUS and Singapore,” said Professor Thomas Coffman, Dean of Duke-NUS, in a statement.

The addition of cPass to the arsenal of diagnostics was timely as it could be used to help verify the efficacy of vaccines, determine infection levels in different communities and support contact tracing measures as many countries were battling a surge in COVID-19 cases.

Reflecting on the moment when he received the news, Wang says, “The beauty of cPass is that it is such a simple concept but one that can have a huge impact. I was both relieved and incredulous that we had done what no one had done before by getting the FDA to approve a serological test for neutralising antibodies.”

“This is an incredible recognition for our team and the Singapore research and biotech landscape,” adds Wang. “The total critical mass of Singapore’s biomedical R&D is less than one per cent of the world’s, and yet we are the international leader in this area for COVID-19.”

▸4 December 2020

Top NUS award for rising young research star

“SARS is gone and it won’t be coming back, so this is a waste of money,” was the comment immunologist Associate Professor Ashley St John still recalls receiving many years ago when she had applied for funding for a SARS-CoV-1 vaccine project. “It seems unbelievable now.”

So, she had focused instead on flaviviruses such as dengue that have a large burden and display an interesting immunological basis in their disease progression. A choice for which St John from Duke-NUS’ Emerging Infectious Diseases Programme was rewarded with the Young Researcher Award from the National University of Singapore (NUS). She was one of two researchers under the age of 40 who were recognised for their impact and promise in research.

“Ashley is a brilliant young scientist who is already recognised among the top researchers in her field. As a viral immunologist, Ashley studies immune responses to viral infections and her work has significant translational impact,” said Professor Chen Tsuhan, NUS Deputy President for Research and Technology in his citation.

One example of the translational impact of St John’s work was the clinical trial of a novel therapeutic strategy against dengue that came out of her studies on vascular leakage.

Being singled out among her colleagues across NUS is humbling, said St John.

“This award also makes me feel challenged to continue contributing to science and making research advances that are meaningful. I hope that other young researchers who are just starting their careers, and particularly young women in science, can see that there are many rewards to pursuing research even as it requires significant effort and resilience,” she said at the time.

In bestowing the award on her, Chen also cited St John’s passion for science communication and outstanding mentoring of graduate students, something that is central to her philosophy. During the pandemic, St John often spoke—and would go on to speak—to different media outlets, transforming complex scientific concepts into easy-to-understand soundbites.

The University Awards recognise excellence in educating and nurturing talent, advancing knowledge, fostering innovation and contributing to country and society.

▸5 December 2020

Duke-NUS professor among six heroes named ST Asians of the Year

For his role in spearheading vaccine development, Professor Ooi Eng Eong from Duke-NUS’ Emerging Infectious Diseases Programme, was one of six individuals honoured with The Straits Times’ Asians of the Year Award. Collectively known as Asia’s virus busters, these scientists played instrumental roles in advancing the fight against SARS-CoV-2, representing the entire trajectory of the pandemic response.

Already in its ninth run, The Straits Times’ Asians of the Year Award honours an individual, a group of people or an institution that has made the news and significantly contributed to their society, country or Asia as a whole.

▸14 December 2020

Singapore is first Asian country to approve mRNA vaccine

The Singapore Health Sciences Authority approved the Pfizer-BioNTech mRNA SARS-CoV-2 vaccine for pandemic use, with the first batches due to arrive by the end of the month. The vaccine would be made available free to citizens and long-term residents.

Singapore was one of a handful of countries worldwide to approve the vaccine.

“When you get yourself vaccinated, you are not just protecting yourself,” said Prime Minister Lee Hsien Loong in a special address broadcast live to the nation. “You are also doing your part to protect others, especially your loved ones.”

Sixteen days later, on 30 December 2020, Singapore would become the first Asian country to start its mass vaccination programme, with more than 30 healthcare workers from the National Centre for Infectious Diseases receiving their first dose.

▸28 December 2020

Who needs mental health interventions the most?

One in three adults experienced COVID-19-related psychological distress. These were the findings of a research team led by clinician-scientist Professor Tazeen H Jafar from the Health Services and Systems Research Programme at Duke-NUS. Published in PLOS ONE, the team’s findings particularly focused on gender, age, residential area and socioeconomic status.

Those at higher risk of COVID-19 infection, such as older people and those in hard-hit areas, were understandably more prone to psychological distress. But the study also revealed that younger people, mainly those below the age of 25, had higher odds of feeling distressed because this was most likely their first experience of an outbreak, and they had greater exposure to media dispensing COVID-19 updates including information from unreliable sources.

Other groups that were particularly vulnerable included women and people in lower socioeconomic strata, particularly those with lower income and fewer years of education. They were prone to anticipate bearing financially disastrous medical expenses and loss of income. Rural dwellers also faced greater anxiety compared with urbanites due to their poorer healthcare infrastructure, as well as less-developed economic, sanitary and educational resources.

“Understanding these factors is crucial for designing preventive programmes and mental health resource planning during the rapidly evolving COVID-19 outbreak,” said Jafar in a media statement issued on 28 January 2021.

The findings were the result of a meta-analysis of 68 studies conducted during the pandemic, encompassing 288,830 participants from 19 countries. Here, the team systematically reviewed factors associated with psychological distress among the predominantly general population. This contrasted from the majority of other research studies, which were largely centred on the mental health of healthcare workers.

The report, Jafar hoped, would help policymakers identify the urban-rural, socioeconomic and gender disparities in COVID-19-related psychological distress and ensure equitable healthcare across population segments.

▸28 December 2020

Singapore moves into Phase III of re-opening

The most significant allowances among Singapore’s Phase III re-opening measures included eight-person social gatherings, increased capacity limits for malls as well as religious services of up to 250 persons.

Phase III came about through effective safe management measures, sufficient SARS-CoV-2 testing capabilities and high adoption of the TraceTogether contact tracing app.

▸21 January 2021

T cells key to preventing severe COVID-19 infections

Comparing T-cell responses between different groups of COVID-19 patients, researchers from Duke-NUS found that people who had mild symptoms produced the strongest virus-specific T cells early on in their infections. The researchers, who published their findings in Cell Reports, also noted that the immune response in those people who had more severe disease was dominated by a rapid appearance of large quantities of antibodies.

The secretion of interferon-gamma-secreting SARS-CoV-2-specific T cells, in particular, characterised the immune response in those with mild infections. Interferon-gamma (IFN-?) is the primary activator of macrophages, which play a key role in fighting foreign pathogens, including viruses. It also recruits other immune cells, including a type of T cell, known as natural killer cells, and neutrophils.

“Our data supports the idea that SARS-CoV-2-specific T cells play an important role in the rapid control of viral infection and eventual clearance of the disease,” said Dr Martin Linster, a then-senior research fellow with Duke-NUS’ Emerging Infectious Diseases Programme and the co-author of this study in a media statement.

The quantity of these IFN-?-secreting T cells also increased progressively while the SARS-CoV-2 infection resolved. Their peak was detected within 15 days after onset of symptoms in eight of the 12 patients studied.

The most robust functional T-cell response was detected in patients with mild symptoms who cleared the virus early.

When the study was published, Professor Antonio Bertoletti, the corresponding author of this study, called for more efforts to adopt a more holistic view of immune responses to SARS-CoV-2: “It is time that T-cell monitoring should be considered in providing a comprehensive understanding of the immune response against SARS-CoV-2. This would also mean that a vaccine will likely be more effective if a concurrent induction of both antibodies and T cells occurs.”

▸27 January 2021

Worldwide infections top 100 million

Even as local cases continued to drop in Singapore, the global tally of infections crossed the 100 million mark.

World Health Organisation Director-General Dr Tedros Ghebreyesus reiterated the importance of vaccine equity: “The stakes could not be higher. Every moment counts.”

▸3 February 2021

Duke-NUS professor among frontliners awarded Singaporean of the Year 2020

In an award that recognised all the “selfless workers and volunteers who stepped forward” during the first year of the pandemic, The Straits Times recognised Professor Ooi Eng Eong from Duke-NUS’ Emerging Infectious Diseases Programme, for his contribution to the development of vaccines.

Ooi was part of a group of five COVID-19 frontliners from the healthcare, research, security and public health sectors, who received the honour in the name of all who fought the SARS-CoV-2 virus on the frontlines.

▸9 February 2021

Study: Many SARS-CoV-2-like coronaviruses lurk in Southeast Asian bats and pangolins

SARS-CoV-2-related coronaviruses are circulating in wildlife across Southeast Asia. This finding stemmed from a study of bats and pangolins in Thailand.

Published in Nature Communications, the international team of researchers led by Duke-NUS experts found that 13 out of the 100 horseshoe bats studied tested positive for these SARS-CoV-2-like coronaviruses. These positive results all contained a particular genetic sequence that is 95.86 per cent identical to the corresponding section in human SARS-CoV-2, 96.21 and 94.48 per cent identical to the bat-borne CoV-RaTG13 and CoVRmYN02 viruses, respectively.

When testing for past infections using the Duke-NUS-invented surrogate virus neutralisation test cPassTM, the team further found that one of ten pangolin serum samples screened showed a strong surrogate virus neutralisation test (sVNT) reading, exceeding 90 per cent. This corroborated published findings that pangolins are susceptible to infection by such viruses.

The research team, which included Professor Wang Linfa, then-Senior Research Fellows Drs Tan Chee Wah and Chia Wan Ni from the Emerging Infectious Diseases Programme at Duke-NUS, was confident that this finding demonstrates that coronaviruses with a high degree of genetic relatedness to SARS-CoV-2 are widely present in bats across many nations and regions in Asia.

The team additionally also observed that these coronaviruses have been detected in bats across an area of approximately 4,800km, spanning from Iwata Prefecture in Japan in the north and Zhejiang province in China in the east to Yunnan in the southwest of China and southward in Chachoengsao, Thailand.

The great genetic diversity and plasticity of these viral genomes suggested to the team that the immediate progenitor virus of SARS-CoV-2 could be, with intensified and internationally coordinated surveillance, traceable.

“We need to keep a finger on the pulse through regional networks. It is critical to share knowledge and collaborate—not just about the pandemic, but helping each other design infrastructure, services and building trust. You then have feelers out to get first-hand information about changes during a crisis like this.”

Professor Ivy Ng, Duke-NUS Governing Board Member, and Group Chief Executive Officer, SingHealth

▸18 February 2021

Duke-NUS’ ‘batman’ elected to American Academy of Microbiology

Among the 65 new fellows inducted into the American Academy of Microbiology, Professor Wang Linfa from Duke-NUS’ Emerging Infectious Diseases Programme was perhaps a more unusual candidate.

The trained biochemist won over members of the Academy, which is the honorific leadership group within the American Society for Microbiology (ASM), following a highly selective peer-review process of how much his scientific achievements and original contributions have advanced microbiology.

“I am delighted and deeply humbled by this honour. I look forward to being a part of ASM’s mission to promote and advance microbial sciences,” said Wang when he received the news.

Wang played a pivotal role in deepening our understanding of the likely origins of the COVID-19 pandemic. During the early days of the pandemic, his team was among the first in the world to culture the SARS-CoV-2 virus from patient samples and develop serological antibody tests to identify an important missing link between two major COVID-19 clusters in Singapore. His team also invented cPassTM, the world’s first surrogate SARS-CoV-2 serological test to rapidly detect neutralising antibodies that does not require containment facilities or live biological materials.

Professor Thomas Coffman, Dean of Duke-NUS, said at the time, “We are extremely proud of Linfa for being elected to this prestigious Academy. This is a testament to his passion, leadership and tremendous contributions to the field of infectious diseases. I look forward to his continued success and seeing more of our young scientists follow in his footsteps.”

Fellows in the Academy represent all subspecialties of the microbial sciences and are involved in basic and applied research, teaching, public health, industry and government service. The Class of 2021 hailed from Australia, Canada, Singapore, China, France, Ireland, Sweden, Slovenia, Mexico, the United Kingdom and the United States.

▸1 March 2021

SARS-CoV-2 triggers immune response even without symptoms

The body’s ability to mount a virus-specific T-cell response is not necessarily linked with symptom severity, found a new study by Duke-NUS researchers and colleagues from the Saw Swee Hock School of Public Health at the National University of Singapore.

People who were infected with SARS-CoV-2, but showed no symptoms of infection, produced virus-specific T cells in a similar quantity compared with those who did experience symptoms, the researchers discovered.

But unlike in symptomatic individuals, the T-cell immune response in asymptomatic people was more efficient, releasing more signalling molecules, called cytokines, which are important for viral control, in particular interferon gamma and interleukin-2.

These findings, published in the Journal of Experimental Medicine, were the first to show, through direct comparison, that SARS-CoV-2-specific cellular immune responses were more efficient in asymptomatic than symptomatic individuals.

Speaking at the time of the paper’s publication, Professor Antonio Bertoletti from Duke-NUS’ Emerging Infectious Diseases Programme, who is also the corresponding author of the study, observed, “It would be good news for patients to know that they are developing an efficient cellular immune response after a symptom-free infection. Our study opens the door for further large-scale T-cell testing, which could match the speed of antibody testing.”

▸14 March 2021

“The Vaccine Quest”: Going behind the scenes of Singapore’s search for a vaccine

The first episode of “The Vaccine Quest”, a two-part documentary, aired on CNA. The documentary followed the researchers and clinician-scientists from Duke-NUS and SingHealth, as well as staff of the United States-based mRNA medicines company Arcturus Therapeutics, on a quest for a vaccine.

In the first episode, Duke-NUS and SingHealth experts ready this novel vaccine candidate for human trials.

A week later, the second episode of was released, in which the story picks up with the team one step closer to the finish line. But as human clinical trials were underway, other vaccine candidates were being shipped for real-world use.

“While our scientists and doctors were fighting the virus on the frontlines, it was essential to educate the public on how the war was being fought. Seeing our scientists make time to educate people and help make sense of the situation was really gratifying. They created value by making everyone smarter and safer. This empowered all of us to become responsible citizens.”

Professor Ho Teck Hua, Duke-NUS Governing Board Deputy Chairman, and Provost, National University of Singapore

▸30 April 2021

SARS-CoV-2 is officially airborne

The acknowledgment from the World Health Organisation (WHO) came a week after The Lancet published a letter from researchers urging a change in position.

The WHO’s update stated that “the virus can spread from an infected person’s mouth or nose in small liquid particles when they cough, sneeze, speak, sing or breathe. These particles range from larger respiratory droplets to smaller aerosols.”

▸30 April 2021

Singapore hits the first hurdle to full re-opening

As the Delta variant continued to spread rapidly, a cluster of COVID-19 cases emerged at one of Singapore’s largest hospitals.

Along with rising cases in the community, the multi-ministry taskforce announced precautionary measures to minimise outward transmission from the hospital cluster.

Calling on the community to remain vigilant, the taskforce asked everyone to minimise their social interactions to help break the chain of transmission. Other curbs affecting malls and outdoor attractions were also introduced while BBQ pits and campsites were closed.

The curbs were initially planned to last for two weeks, till 14 May 2021. However, on 4 May 2021, the multi-ministry taskforce announced a further tightening of restrictions, extending beyond the original end date.

▸10 May 2021

Delta variant a global concern

Early research showed that Delta, known as B.1.617, was spreading faster and more easily than the original, or wild-type, SARS-CoV-2 virus.

Today, it became the fourth variant to be classified as of global concern after Alpha, Beta and Gamma.

A day earlier, Singapore had announced special COVID-19 measures for air and sea ports. These came in the wake of a local outbreak, driven by the Delta variant that had seen the nation re-instate previously eased restrictions.

On 16 May 2021, further curbs to “decisively arrest” the rise in community cases came into effect.

Among the latest safe distancing measures, group sizes were further cut to two people and dining-in at food outlets was banned, with the measures planned to run until 13 June 2021.

▸22 June 2021

US allows cPassTM patent application in record time

cPassTM, the novel surrogate virus neutralisation test (sVNT) invented by Duke-NUS and co-developed with A*STAR’s Diagnostics Development Hub and GenScript Biotech, received notice of allowance for its patent application.

cPass offers a marked improvement over other SARS-CoV-2 tests as it specifically detects SARS-CoV-2 neutralising antibodies and produces reliable results within an hour. It also needs neither a live virus nor the stringent biosafety level 3 measures required for other tests.

“Instead of using the whole virus, you just use a piece of protein,” explains Duke-NUS Professor Wang Linfa, lead inventor of the test. “So, you have the receptor and the key part of the viral spike protein that docks onto the receptor. And you can mimic the live virus neutralisation test in a test tube.”

While Wang and his team had invented cPass, GenScript optimised and refined it into a commercial product, tapping its global network and manufacturing capacity to launch cPass, which would become used across the globe.

“It took only 14 months to receive the notice of allowance, which we view as a strong validation of the innovative sVNT detection methodology,” said Dr Li Zhu, executive director and chief strategy officer at GenScript in a statement.

▸9 August 2021

Global entity adds ARCT-021 to its Phase III study

ARCT-021 was selected by a global entity as a vaccine candidate in a multinational Phase III trial.

The vaccine candidate ARTCT-021, which was identified through a collaboration between Arcturus Therapeutics and Duke-NUS, would be evaluated in tens of thousands of people as a single dose regimen.

▸18 August 2021

Duke-NUS scientists identify powerful neutralising antibodies ready to take out more than SARS-CoV-2

By studying the neutralising antibodies of SARS survivors who had been vaccinated against SARS-CoV-2, a cross-disciplinary research team led by Professor Wang Linfa from Duke-NUS’ Emerging Infectious Diseases Programme identified powerful antibodies that could neutralise not just SARS-CoV-1 and SARS-CoV-2 but also similar viruses in the same sub-genus of coronaviruses.

Published in The New England Journal of Medicine, the researchers—Drs Tan Chee Wah and Chia Wan Ni among them—reported that while most survivors of the 2003 SARS-CoV-1 outbreak retained neutralising antibodies, these antibodies were not able to neutralise SARS-CoV-2. It was only after being vaccinated with an mRNA vaccine that they produced these broadly neutralising antibodies.

Using an advanced version of the surrogate virus neutralisation test, which in its original format had been commercialised as cPassTM, the team confirmed that these neutralising antibodies could knock out up to 10 different coronaviruses that belong to the same sub-group, which includes SARS-CoV-1 and SARS-CoV-2, as well as several pre-emergent viruses identified in bats and pangolins.

Speaking at a news conference announcing the discovery, Wang said that this could become an alternative to variant-specific booster strategies, called 3GCoVax.

“We think this provides the scientific foundation to try a new boosting strategy—we call that 3GCoVax—to combat different variants including the current four and future ones,” said Wang during the press briefing, adding that the same principle could be used to produce therapeutic antibodies.

“We have been thinking on our feet and reacting to the virus. What we need to do is move ahead of the curve. So, a vaccine that can address current and future variants—that is the way to go because we need to be two steps ahead of this virus and the same applies to disease X.”

Professor Ivy Ng, Duke-NUS Governing Board Member, and Group Chief Executive Officer, SingHealth

He went on to note that the World Health Organisation was targeting to have the majority of the global population vaccinated with existing vaccines in a year’s time.

“If we boost that population with the 3GCoVax,” he said, “we also potentially can be ready to fight and prevent the next pandemic of SARS-3 or SARS-4.”

From diagnostics to a dream vaccine, Wang Linfa’s team used their novel surrogate virus neutralisation test to identify powerful antibodies that fight more than just SARS-CoV-2.

▸21 August 2021

“If you know the enemy and know yourself, you need not fear the result of a hundred battles”, not even with the SARS-CoV-2 virus

By August 2021, the world was once again in the midst of a rapidly swelling wave of SARS-CoV-2 infections, with new information and insights continuing to come out at an exponential rate.

Taking a leaf from the ancient Chinese general Sun Tzu, researchers from Duke-NUS who specialise in studying the human response to viral infections decided to review all that was known about the intra-cellular goings-on in the human body as SARS-CoV-2 infects cells. Their review article, published in Current Opinion in Virology, they hoped, would help consolidate what was known about the virus and spur the development of new vaccines and antiviral therapeutics.

The team, led by Assistant Professor Ooi Yaw Shin from Duke-NUS’ Emerging Infectious Diseases Programme, laid out the sequence of events in a SARS-CoV-2 infection cycle: SARS-CoV-2 infections begin when the virus’ spike protein locks onto receptors such as the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of cells. Two main entry routes, then, become available for SARS-CoV-2: the virus either fuses directly with the membrane coating the cell or it is taken into the cell after binding to certain receptors. Either way, success is achieved once the virus matures and fuses with the cell membrane.

Once that happens, the virus unloads its RNA genome in the cell’s cytoplasm, where the viral RNA payload hijacks the cellular copying mechanism to generate viral proteins. Some of these proteins are assembled into new viruses, while others seize control of the machinery in the infected cell, forcing the cell to channel its resources into synthesising more viruses.

Accordingly, existing drugs that target pro-viral factors could potentially be repurposed, the researchers pointed out, to forestall SARS-CoV-2 infection. Such a repurposing could form the primary line of treatment for COVID-19; with new drugs taking time to invent, trial and be approved for human use, the researchers noted.

They added that “selecting a suitable host target essential for a virus, but dispensable for a host remains challenging.”

Ooi Yaw Shin studies which genes are hijacked by SARS-CoV-2 and what the virus needs to infect a human cell and spread to other cells.

▸29 August 2021

Singapore: The world’s most vaccinated country

The nation became the world’s most vaccinated country with 80 per cent of its 5.7 million population fully inoculated. That was the threshold set by the government for considering easing of pandemic control measures in place at the time.

▸1 September 2021

A new and fast way to track an elusive part of the immune system

For the longest time, the study of T cells remained the domain of specialist research laboratories like Professor Antonio Bertoletti’s lab at Duke-NUS. With an acute frontline need for a full picture of the body’s immune response to SARS-CoV-2 infection and vaccination, Bertoletti and his team developed a simple and rapid method to measure the T-cell immune responses to SARS-CoV-2.

Their discovery, published in The Journal of Clinical Investigation, applied the principle of monitoring T cells by proxy that is used in the diagnosis of diseases like tuberculosis. When the researchers added small fragments of the SARS-CoV-2 spike protein to blood from people who had been vaccinated against or recovered from SARS-CoV-2, the T cells in the sample released signalling molecules called cytokines that can easily be detected.

Building on that, they showed that the test, called a cytokine release assay, could reliably identify and quantify specific T cells in these samples.

Antonio Bertoletti and his team’s work on T cells led to the development of a test that can reliably detect SARS-CoV-2-specific T cells, offering the potential for a large and rapid expansion of T-cell studies.

They validated the test using blood from more than 200 patients recruited with the help of the team’s clinical partners at Singapore General Hospital, National University Hospital and the National Centre for Infectious Diseases.

“This discovery allows a rapid and large-scale expansion of studies to track T-cell activity across the world, while not requiring specialised or expensive equipment,” emphasised Bertoletti at the time the paper was published.

“The study results confirm that the level of antibodies against SARS-CoV-2 in blood samples does not always correlate with the T-cell response. With this rapid test, we can help define the correlates of protection from T cells and antibodies for the development of COVID-19 vaccines.”

To bring this discovery to clinics around the world, Duke-NUS licensed the assay to Hyris, an innovation-based biotechnology company.

▸7 September 2021

Formation of a national pandemic preparedness programme announced

Speaking at the second anniversary celebration of the National Centre for Infectious Diseases (NCID), Deputy Prime Minister and Coordinating Minister for Economic Policies Mr Heng Swee Keat highlighted that preparing for the next pandemic would be a key area of the national Research, Innovation and Enterprise 2025 plans.

“We will be developing a national R&D Programme for Research in Epidemic Preparedness and Response, or PREPARE in short,” he said. “PREPARE will further strengthen our capabilities to prevent, prepare for and respond to future epidemics, by working with our local research partners, including NCID, and building a regional network to foster collaborations.”

In the months to come, Duke-NUS Professor Wang Linfa would be appointed to helm this new programme as its executive director.

“Having an established Emerging Infectious Diseases Programme meant that we had research facilities, as well as the critical mass of scientific talent already available at Duke-NUS when COVID-19 emerged. This was clearly a farsighted move which has benefited us as these scientific and research resources have contributed to our national effort to combat COVID-19. And when we’re looking to improve and expand our national research infrastructure for pandemic preparedness, Duke-NUS scientists are again at the forefront, contributing in this area.”

Associate Professor Kenneth Mak, Duke-NUS Governing Board Member, and Director of Medical Services, Ministry of Health

▸5 November 2021

COVID-19 researchers celebrated for excellence

At the National Medical Excellence Awards this evening, members of the COVID-19 Research Workgroup were honoured for their notable efforts in shaping the pandemic response in Singapore. The group’s findings had helped improve infection control methods, public health policies and the development of diagnostics and treatments.

This large, multi-disciplinary and inter-institutional group included Dr Chia Wan Ni, a then-research fellow with the Emerging Infectious Diseases Programme at Duke-NUS, along with experts from the National Centre for Infectious Diseases and A*STAR. They received their National Clinical Excellence Team Award from Minister for Health Mr Ong Ye Kung at an event held at the Shangri-La Hotel in Orchard.

“Everyone contributed very significantly at the highest level and I am proud of what our group at Duke-NUS has contributed to the national fight against COVID,” said Chia, who represented Professor Wang Linfa’s entire team that night.

▸10 November 2021

A T-cell-triggering COVID-19 vaccine?

In a Nature paper, scientists from University College London together with collaborators from across the United Kingdom, Europe and Singapore, reported that boosting T cells that target a highly conserved region of the SARS-CoV-2 genome can supplement spike-specific antibodies in next-generation vaccines against emerging coronaviruses.

Putting the findings in simple terms, Professor Antonio Bertoletti from Duke-NUS’ Emerging Infectious Diseases Programme, who was one of the senior authors on the paper, explained that what this study found was that people—in this instance healthcare workers—who had been exposed to SARS-CoV-2 but never became infected nonetheless produced T cells that targeted a protein that is essential in the early stages of the SARS-CoV-2 replication cycle, called polymerase.

And these very specific T cells could be made to multiply to abort an infection in lab tests.

“Designing vaccines that activate polymerase-specific T cells could add a further layer of protection and be more effective in the early containment of the virus compared to spike-only vaccines as the polymerase protein is synthesised early after infection,” said Bertoletti in a tweet issued by the School at the time.

▸8 December 2021

Saliva-based rapid test provides hope for sensitive sniffers

SARS-CoV-2 testing had become an integral part of life in Singapore. With access to anti-COVID pills from primary-care settings on the horizon, the eye-watering, sinus-stinging experience of an antigen rapid test (ART) swab looked like it might even stay on beyond the need for routine testing.

To spare everyone’s sniffers, a team of scientists from Duke-NUS, its academic medicine partner SingHealth and the National University of Singapore developed a saliva-based SARS-CoV-2 ART that showed promise in early clinical testing, nearly matching the sensitivity of the gold standard Polymerase Chain Reaction (PCR) test. And requiring only saliva pooled in the mouth, the test was simple and easy to use.

Dubbed the parallel amplified saliva rapid point-of-care test, or PASPORT, the technology leverages a proprietary on-kit amplification technique to produce results from a saliva sample in minutes.

Like other ARTs, PASPORT uses nanoparticles to bind the virus. But it is also coated with a second type of nanoparticle. These bind to the first set in order to amplify the signal. Because of its two-stage amplification, PASPORT can detect the virus at much lower viral loads, making it more sensitive at flagging SARS-CoV-2.

This also meant that it could be used any time of the day, even after eating or drinking. The results of a clinical study involving more than 100 participants, which was published in Microchimica Acta, showed that PASPORT’s sensitivity in detecting the virus was 97 per cent and its specificity, 90.6 per cent.

“A reliable and painless saliva antigen test that is affordable and convenient to perform would encourage more [people] to be tested, and more frequent testing,” said lead inventor Dr Danny Tng, a medical officer with the Department of Infectious Diseases at Singapore General Hospital, and an adjunct research fellow with Duke-NUS’ Emerging Infectious Diseases Programme at a briefing for media.

Tng, who graduated from Duke-NUS in 2019, added, “This may enable us to manage COVID-19 more effectively not only at the point of care, but also in settings such as airports, conventions and even at home.”

Duke-NUS and SingHealth filed intellectual property protection for the invention, and entered into a licence agreement with Digital Life Line, a Singapore-based company. The inventors hoped that through close collaboration with commercial partners, the product could be out in the market as soon as possible as countries around the world moved to making treatments available faster and in primary healthcare settings.

“[Oral antiviral drugs] will need to be given as early as possible after illness onset for maximal benefit,” said Professor Ooi Eng Eong from Duke-NUS’ Emerging Infectious Diseases Programme during the press briefing.

“A test that can be self-administered or used on-site in the primary care setting may mitigate the need for cases to be managed at the hospitals.”

“We want people who are not only excellent doctors, schooled in their trade, who put their patients’ best interests first, but also students who understand how to conduct research and who can reap the benefits of research to derive clinical applications. They will, therefore, be able to contribute beyond delivering clinical care. They are the students who are willing and courageous enough to push the boundaries, not just in traditional areas of research, but in areas of innovation. These distinctives are a very strong part of the heritage of Duke-NUS.”

Associate Professor Kenneth Mak, Duke-NUS Governing Board Member, and Director of Medical Services, Ministry of Health

▸10 December 2021

Duke-NUS’ ‘batman’ honoured with the President’s Science Medal

Singapore’s President Madam Halimah Yacob presented Professor Wang Linfa with the award at the 2021 President’s Science and Technology Awards in recognition of his global leadership in addressing the SARS-CoV-2 pandemic and advancing our understanding of bat biology and emerging infectious diseases.

▸10 February 2022

Half the world vaccinated against SARS-CoV-2

It took just over two years from SARS-CoV-2’s emergence for half the world’s population to be fully vaccinated against the virus, according to Our World in Data. In Singapore, 93 per cent of the eligible population—that was everyone aged five and older—had received two doses of the vaccine.

This global milestone coincided with a surge in Omicron cases. Unlike during previous waves, hopes were high that hospitalisations would remain low this time.

▸18 February 2022

Nepal green-lights trial of novel combination therapy co-developed by Duke-NUS

A novel combination therapy received the green light to proceed with testing from regulators in Nepal. The project resulted from a collaboration between Sen-Jam Pharmaceutical Partners, Duke-NUS and Duke University School of Medicine. The partnership was first announced in August 2021.

The Phase II study will test the efficacy of an oral combination therapy of an antihistamine and a non-steroidal anti-inflammatory drug to mitigate severe symptoms and hospitalisation due to COVID-19. The researchers—including Associate Professor Ashley St John from Duke-NUS and Professor Alexander Limkakeng from Duke—believe that in combination the two will disrupt the body’s inflammatory process.

“We are a key node in the global pandemic preparedness network. This means that we feed and receive information to empower people to act quickly and decisively when a threat like SARS-CoV-2 emerges. It is our duty to maintain and grow this network of partners and collaborators. We must also continue to invest in research on emerging infectious diseases so that we can respond even faster and better to the next pandemic.”

Professor Ho Teck Hua, Duke-NUS Governing Board Deputy Chairman, and Provost, National University of Singapore

The drug cocktail being tested consists of two drugs, including one whose mast cell-stabilising properties, Ashley St John believes, could help tackle severe COVID-19 infections.

▸24 February 2022

Kidney transplant patients and donors in Singapore less distressed than healthy people around the world

Kidney transplant recipients and donors in Singapore felt less distressed during the COVID-19 pandemic than the general population around the world, reported clinician-scientist and kidney specialist Professor Tazeen H Jafar, from the Health Services and Systems Research Programme at Duke-NUS, and her colleagues.

While some 14 per cent of donors and recipients reported feeling anxious, stressed or depressed during the pandemic, Jafar and her colleagues, including Drs Sobhana Thangaraju and Terrence Kee from SingHealth, found that this was almost two times lower than the global average of 30 per cent of the general population and almost four times lower than high-risk individuals living with pre-existing conditions such as cancer, type 2 diabetes and COVID-19.

In the paper published in BMC Nephrology, Jafar and her team placed this overall resilience to pandemic-induced psychological distress in the context of Singapore’s health policies and resources, attributing their findings to Singapore’s low COVID-19 rates and resulting low mortality, “which was likely due to efficient national responses and high-quality medical care”, they noted in the paper.

“Specifically, since the start of the outbreak, the Singapore government had proactively established official COVID-19 resources and subscription services, as well as frequent briefings and press conferences by the Prime Minister and other officials, to keep the public informed of the latest COVID-19 situation in Singapore,” the authors added.

They also pointed to robust contact-tracing, mask-wearing, social distancing, financial aid schemes and the nationwide distribution of free masks and sanitisers as specific factors which helped alleviate psychological distress.

Where distress was associated with personal and social factors, the researchers recommended implementing proactive health education policies: “Focused health education targeting younger adults, unmarried individuals, non-Singapore citizens, and those with worse health conditions could potentially prevent psychological distress in high-risk kidney transplant recipients and the donor population.”

▸11 March 2022

The pandemic rages on

Today marked the second anniversary of the World Health Organisation’s declaration of COVID-19 as a pandemic. By this time, an estimated six million people had died from the virus worldwide.

On the same day in Singapore, the multi-ministry taskforce announced that from 15 March 2022, safe management measures would be streamlined to ease the nation’s transition to becoming COVID-19 resilient and resuming more social and economic activities. The decision came in the wake of Singapore’s first Omicron wave, which had not led to large increases in hospitalisations.

▸18 March 2022

Kamini Kunasegaran among five lab techs honoured with special COVID-19 Hero Award

Ms Kamini Kunasegaran had made the Bertoletti lab’s pivot from studying the hepatitis B virus to SARS-CoV-2 a practical reality. She had achieved this by reorganising reagents and adapting what the lab had learnt about studying T cells in hepatitis B-infected patients to work for SARS-CoV-2-infected and vaccinated people. And all that in a matter of weeks.

“Kamini was the figure who made our ‘lab transformation’ a reality,” says Professor Antonio Bertoletti from Duke-NUS’ Emerging Infectious Diseases Programme.

“She did this not only by working alone but by involving and motivating young research technicians and PhD students, creating a dedicated laboratory team that produced extremely high-quality results in a new area of research in a very short time,” he added.

The results of those efforts speak for themselves: by July 2020, the team had published a paper in Nature despite having had to conduct their experiments under the tightest COVID-19 restrictions imposed by the Singapore government, working all hours as samples came in.

In recognition of these stellar accomplishments, Kamini today received the Asian Scientist Lab Tech of the Year 2021 MiRXES COVID-19 Hero Award from MiRXES CEO Dr Zhou Lihan at a ceremony held in Gardens by the Bay’s Flower Dome.

Speaking about her reaction to the news, Kamini said, “I was pleasantly surprised and delighted to have received this award. More importantly, I am thankful for being part of a wonderful team for giving me the opportunity to contribute to the fight against COVID-19.”

▸24 March 2022

PM announces easing of Singapore’s COVID-19 safety measures

Prime Minister Mr Lee Hsien Loong announced that Singapore would ease its safe distancing measures come 29 March 2022. This was a significant milestone in the nation’s fight against SARS-CoV-2 and a decisive move towards living with COVID-19—just short of a complete opening up.

Most significantly, wearing masks outdoors would become optional, though it would remain mandatory indoors.

▸26 April 2022

Singapore’s national alert level downgraded to DORSCON Yellow

As Singapore emerged from its first Omicron wave without seeing a spike in COVID-19 hospitalisations, the national risk framework for disease outbreaks, commonly referred to by its acronym DORSCON, was lowered from orange to yellow. It had been at orange since 7 February 2020.

This change also heralded the end of a raft of restrictions, including safe distancing between people, as well as groups and Health Risk Notices for close contacts of COVID-19 patients. Fully vaccinated, healthy travellers could now enter Singapore without taking a pre-departure COVID-19 test.

While this ended COVID-19’s pandemic phase in Singapore, living with the virus continues to throw up new challenges that require answers and solutions from scientists at Duke-NUS and our partners.

To follow the Duke-NUS COVID story into the endemic phase, we invite you to head to our virtual timeline, accessed via the QR code: