By Kimberley Wang, Manager, Media and Publications, Communications and Outreach
In the wake of COVID-19, scientists are asking, what is the next pandemic and when will it come? LKCMedicine Associate Professor of Infection and Immunity Luo Dahai, who is also the Provost’s Chair in Medicine, shares his passion for research on viruses that are causing public health issues and what keeps him going.
Having won the Dean’s Award for Research 2021 for excellent research performance and contribution to LKCMedicine, A/Prof Luo continues to lead his team in preclinical studies of antiviral drug discovery targeting viruses such as Chikungunya, Zika and dengue. In this interview with The LKCMedicine, he talks about how their discoveries could help researchers find different ways to improve drugs and therapies for these diseases and more.
Q: What motivated you to pursue a career in research?
The SARS outbreak happened around 2003, when I was finishing my undergraduate studies. With my biology background, I had a basic knowledge of pathogens. But SARS was a real-life example and I realised that there is so much unknown about these viruses and different pathogens that can cause diseases. As an undergraduate, there was a gap between the information in the textbooks and what I wanted to learn. That was when I decided that I want to continue a lot of these queries and the best way would be graduate studies.
I applied for graduate studies and chose a subject that is related to molecular biology – dengue. In Singapore, it is one of the viruses that keep coming back and cause social and economic burden. I learnt that what you read and understand from lectures is different from the real everyday research. It is much tougher trying to generate new knowledge than to learn existing knowledge. In graduate studies, you get a chance to fill up the gaps that people have not been able to. In these moments, where you have a discovery and you are the first person on this planet to find and observe it – it is a kind of joy that keeps you going.
Q: Why did you decide to specialise in infection and immunity?
To better understand a virus, you have to study the host. Our host response to virus infection is immunity – the protection against the virus. These are two pillars of the same research subject. You have the virus trying to attack and make use of the host’s resources and to propagate itself. On the other hand, the host doesn't want this burden and has all sorts of protective mechanisms, either immunity or adaptive immunity. The history of human beings has always been about trying to improve our health through different means of medicine.
Q: Your lab studies the molecular events involved in the battle between host and pathogens, in particular, between RNA viruses and humankind. What are the main challenges in this research area?
Traditionally, basic research related to some of these viruses is not taken so seriously compared to cancer or cardiovascular disease – diseases that seemingly cause more impact on human society. Sometimes, viruses come and go so most people don't feel it is a big deal. It is also a challenge when you are trying to recruit research staff or students.
In a way, it is about how much public attention is drawn to it. If there is no epidemic or pandemic that happened in your own society, you might not realise the social public health impact at all. For example, we may talk about Ebola, but Singapore has never experienced it so it doesn’t cause any deep impact to individuals in this society. Among viruses, there also some that draw more significant attention than others. It also depends on the country or region. If it happens in a developed country, then there might be more attention and resources for increasing public health awareness, and for prevention and treatment.
The big question with viruses is, you never know what the next pandemic could be and when it will come. COVID-19 is a good example. There was no single country that was really prepared for it and in a sense, there was no way to be sufficiently well-prepared. It is more difficult to study and there are a lot of questions which are hard to address scientifically within the lab, especially for viruses that are less well-known. If it is not a pandemic, you may not get all this attention and then there will be consequences. In summary, the challenge is getting consistent support that will gather momentum and last for a longer period of time so that the research can progress continuously.
Q: Could you share a key research project that you are currently working on?
Chikungunya virus research is a programme that I initiated after I started my lab. It is a virus that increasingly causes public health issues across the world. Not so much in Singapore, probably because dengue is more dominant and the virus hasn't spread as broadly. But if you look around across the globe, in southern Europe, Southern Asia and the Americas, it is getting worse, because of climate change and increased human activities. There has been growing interest and attention among many European labs compared to say 5 or 10 years ago.
When we started the Chikungunya virus research back in 2015, I was very happy as it was my first Tier 1 grant and my first as a young Principal Investigator. To kickstart the research, I read about the virus and found that there were good questions to ask and to perform experiments, compared to a well-studied virus like HIV. We quickly set up experiments, generated interesting data and managed to publish our work. Given the amount of resources, it was not a super big paper but it was well-received – one of the first studies on the enzyme that is responsible for the virus RNA replication. Before us, there were fewer than 10 research articles about it. We proved that even as a small lab, we could do some novel research.
After two years into the research, we applied for more grants. Although the virus is less severe than dengue, it is still relevant both in Singapore and globally. We received a Tier 2 grant that is close to $1 million, which puts us in a position to achieve more ambitious goals and not just focus on a single small protein in the virus. We can look at different aspects of the virus. We also have the chance to develop a more integrated understanding of the virus. Last year, we managed to publish a paper in Cell Host & Microbe, along with a few other research findings which are both interesting and surprising because you can’t really predict how the virus enzymes look like and behave.
Good results and published papers help to draw attention from the international research community. We presented our work at conferences and to collaborators who are studying the same viruses from different angles using different expertise. We started to establish international collaborations which are mostly stimulating and productive. We managed to get another Tier 2 grant to go deeper into the virus replication systems and new collaborators to join in the effort with us. We also found industry collaborators who are interested in developing antivirals for Chikungunya and other related viruses.
I also want to emphasise that my lab is lucky enough to get continuous support over at least six years. Because of that, my team could continuously invest in this research topic. Without a foundation, without the years of accumulation of knowledge and expertise in specific subjects, we would not be able to reach this level of research breakthrough.
Q: How do you see this research making an impact on the lives of patients and the population in general?
During the COVID-19 pandemic, along come these innovative mRNA vaccines. People tried to make use of the Chikungunya virus and related alphavirus replication system and developed so-called self-amplifying mRNA vaccines. This kind of vaccine candidate has some advantages in efficiently expressing the antigen that triggers the specific immune response and generates protective antibodies.
The kind of research we do may not be directly related to vaccines but there is still potential to improve vaccine candidates. Our basic research indirectly helps improve the vaccine’s performance, efficacy and safety. In a broader sense, it is not limited to COVID vaccines. It can be therapeutic candidates for other diseases. Our findings will help in future vaccine development. Overall, studying viruses generate other benefits as well, such as cancer immune therapies and gene therapies. These virus properties will at some stage be of very valuable use for researchers to find different ways to improve therapies or drugs for various diseases.
Q: What advice would you give our MBBS students who are interested to get involved in research?
I teach our Year 1 and 2 students biology subjects, which are more focused on the basic understanding of virus properties combined with immunology. Overall, they are very intrigued especially given the context of COVID-19. It is very timely that they have first-hand experience of how a virus can cause so much damage. The response from our students was generally positive when we introduced a short introductory session on COVID-19. These are additional materials on top of their regular curriculum, but it was well-received.
During the class, I introduce the latest research and update them on the understanding of COVID-19, including the progress in vaccine development. We can see that they ask a lot of questions during the lessons. Through this, we planted seeds which meant propagating their minds, and they may come back to it. Even after graduating, if they have this idea in mind, they may indicate interest in working in an infectious disease department and pick up from where they left off. They can then continue their interest in clinical research related to viruses and vaccines.
Q: Even as we move towards living with COVID-19, there are questions about whether current vaccines will protect us against new viral variants. What are your thoughts on how the future will look like?
From a scientific point of view, SARS-COV-2 is an amazing virus. I remember reading the news about the virus outbreak in 2019. Back then, many of us were guessing that it was probably like a seasonal flu and by next summer, it would be gone. We were wrong. When the first vaccines were developed, showing good results in clinical trials, we thought that it was the end of the pandemic, but it didn't happen. The virus just mutates again, finding different ways of overcoming our immune system’s defence. Every day, you see news of countries that had good protection in the past starting to see breakthrough infections. We are still actively trying to understand the virus.
During the pandemic stage, vaccines and antivirals were developed very quickly, compared to other kinds of drugs developed in the past years. Still, everybody recognises that it’s not good enough – one or two drugs is not going to end it. After antiviral therapy with a coronavirus protease inhibitor drug for five days, some patients still tested positive for COVID after finishing the treatment. After they stopped the treatment, the virus may not be eliminated from the patients completely.
To me, this is very surprising. If there are patients who become resistant to drugs, this will cause future difficulties for any new drugs too. A lot of questions need to be answered. We are already three years into the pandemic and there is still so much to be studied. We really need to be patient for the long-term research into antiviral development.
Q: I’m sure your work keeps you very busy! What do you like to do to relax and unwind?
Whenever I have time, I spend it with my family at home. It is indeed very demanding if you want to be a good researcher, colleague, mentor, and teacher at work. At the end of the day, I want to reserve some energy for the family because my children are always energetic. Later this year, we are going overseas and I’m very much looking forward to it.
A/Prof Luo with his team and family during a recent lab retreat