If you’re reading this, there’s a good chance you have been on the receiving end of a product that is the culmination of decades of research: an RNA therapeutic. Having recently entered popular knowledge thanks to the mRNA COVID-19 vaccine, the earliest research into the use of RNA as a way to deliver medical treatments can be traced back to the 1960s.
However, while technological advancements and research breakthroughs have since made mRNA vaccines possible, there remains much more to discover about RNA and its other potential therapeutic uses.
RNA is a uniquely fascinating molecule. If the double-stranded DNA helix serves as the genetic blueprint that outlines the protein to be made, then the single-stranded RNA can be thought of as the construction crew needed to build that protein from the blueprint. RNA can fold into different forms which allow it to carry out a vast array of functions, ranging from reading the DNA blueprint to transporting and assembling the amino acids needed to make up a particular protein.
At A*STAR’s Genome Institute of Singapore (GIS), Yue Wan is the Principal Investigator of a laboratory that focuses on developing technologies to capture accurate snapshots of RNA’s many forms and structures. Wan and her team also aim to better understand the mechanism behind RNA folding and how RNA structure affects health and disease, to harness its potential as a targeted therapy against disease.
In this interview with A*STAR Research, Wan and her graduate student Ashley Aw talk about their research on RNA and its therapeutic potential, along with the importance of mentorship in advancing science.
1. What made you focus on RNA structure?
The past decades have been dedicated to understanding protein structures and how they can be targeted by small-molecule drugs. However, it has become clearer in recent years that only a small fraction of these proteins can be targeted. As such, we need to identify new drug targets in different diseases. RNA makes for a good candidate here because it can fold into complex secondary and tertiary structures.
That said, we must acknowledge that the field of RNA structure is about 20 years behind that of protein structure. Much remains to be learnt about the structure and function of RNAs in diseases.
The COVID-19 pandemic has further highlighted how important it is for us to understand RNA structure and folding. Like all viruses, SARS-CoV-2 uses RNA as its genetic material. We already know that some structures along the SARS-CoV-2 genome are important for virus translation, but much of it is still unexplored. The more we know about this viral genome, how it folds and what it interacts with, the better we can disrupt these interactions to prevent its spread and infection.
2. What makes RNA-based therapies so promising?
The world got a glimpse of RNA’s therapeutic potential with the mRNA COVID-19 vaccines. We can now quickly order genes of interest, make RNA out of them and deliver it into the body to generate vaccines. This system is highly flexible, allowing us to change sequences to quickly adapt to variants and respond rapidly to new infectious agents. Nonetheless, we are barely scratching the surface of this intriguing RNA realm—I believe we can take RNA therapeutics to new heights.
3. How would you develop your research going forward?
We want to continue pushing the frontier of RNA structure research to effectively target RNA structures. We are also aiming to expand the utility of our research beyond RNA vaccines.
4. As a group leader, how do you balance mentoring young scientists with your self-development?
I established my lab straight out of my PhD. I didn’t have a lot of experience mentoring students to start with. However, two things have worked for me. First, I always try to solve my students’ problems before working on things such as grants, because this helps guide them in the right direction as early career scientists.
Second, as a best friend of mine once advised me, a defining feature of a great leader is how they keep their supervisees’ best interests at the forefront rather than their own. I believe that this sense of magnanimity is very important. These two beliefs have helped me to become not only a better mentor but also a better researcher.
1. What inspired you to pursue a career in science?
At a young age, I was curious about how things worked. It was sometime during secondary school when I became entranced by how cells function, which led to my interest in the greater world of biological sciences.
After completing my undergraduate studies, I accepted the position of a Research Officer at A*STAR and worked on projects involving viruses. This experience cemented my desire to pursue a career in scientific research. I was also certain that I wanted to pursue my PhD studies locally. The A*STAR Graduate Scholarship appealed to me the most as it allowed me to continue my passion for research without leaving Singapore or A*STAR.
2. Can you tell us about your PhD project and why you chose to focus on RNA?
The focus of my project is to develop a method that uses direct RNA sequencing to look at the many different structures of RNA—the Wan Lab of RNA Structuromics led by Yue Wan allows me to do just that.
Before the development of our method, which we have named PORE-cupine, there was no easy way to determine the RNA structures of isoforms extracted from cells. Existing methods largely use short-read sequencing, which requires the amplification of RNA for reading and detection. This may, however, increase the complexity of the analysis.
In contrast, PORE-cupine can directly probe for the RNA structural information without the need for any amplification, which simplifies the process.
RNA is a valuable biomolecule to study as it is versatile in its functions, ranging from being a bridge between DNA and protein to having catalytic or recognition functions. By using PORE-cupine, we hope to identify the structures that are important for RNA’s many functions.
3. What key problems do you hope to address with your research?
If we can identify the RNA structures that are important for the replication of RNA viruses, we might be able to develop anti-viral drugs that eliminate a particular virus from its host. Although the development of drugs that target RNA structures is still in its early stages, we are well aware of its vast potential.
4. How has your time as a graduate student in the Wan Lab shaped your career?
My time in this lab has been really fulfilling. I was given the rare opportunity to develop my skills in both molecular biology and bioinformatics. My colleagues have also been very supportive and generous in sharing their knowledge. Above all, under the guidance and mentorship of Yue Wan, I have developed a solid mindset and am now more confident in every aspect of my work.