Why do our body’s defenses sometimes turn against us? What would store enough energy to power our cities? How does the same genetic code make a diverse world of cells? Can we make carbon-based chemicals part of a sustainable future?
These questions, and their potentially impactful answers, are among several that will be investigated by eight exceptional A*STAR researchers with the support of the Singapore National Research Foundation (NRF)’s 2024 Fellowship and Investigatorship awards.
Each year, the NRF provides opportunities for researchers of all nationalities to explore new frontiers in science through these two schemes. Now in its 16th year, the NRF Fellowship supports early-career scientists as they conduct independent projects with high odds of research breakthroughs, while the NRF Investigatorship supports principal investigators with an established record of leadership in their fields as they pursue high-risk, groundbreaking discoveries.
The NRF class of 2024 includes three NRF Investigators and five NRF Fellows from a range of A*STAR’s research institutes. In this issue of A*STAR Research, we speak to the A*STAR researchers in NRF’s class of 2024 about the scientific questions they hope to answer, and the impacts that their answers might have on our world.
9th NRF Investigatorship (NRFI)
For research leaders in pursuit of high-risk, groundbreaking work
Qi-Jing LI
Research Director, Institute of Molecular and Cell Biology (IMCB)
One of the human body’s many defence mechanisms, T cells protect the body against cancer cells and cells infected by pathogens. A key part of the T cell toolbox is a group of proteins called T cell receptors (TCR)—found on each T cell’s surface, they help detect alarming antigens and trigger an immune response.
Early in his career, Qi-Jing Li’s work focused on identifying how T cells distinguish between cells that belong (self) and cells that don’t (non-self), and how this mechanism was built during T cells’ development. Li’s team discovered a rheostat, microRNA miR-181a, that modulates T cell sensitivity and drives self-versus-non-self recognition. Li would bring this expertise forward into immuno-oncological trials; while he initially focused on analysing data from other trials, he moved on to conducting trials and generating new human data.
In 2021, Li and colleagues discovered a novel subset of effector T cells that appear in several tumour types and present as exhausted T cells. They found that the descendants of these cells appeared in distant healthy tissue before cancer cells migrated there. Liberating the seemingly ‘exhausted’ cells to healthy tissues led to the formation of long-standing memory cells that could defend against potential cancer metastasis.
Li and his team intend to further explore the mechanisms behind generating distant resident memory T cells and how they can be harnessed, through cellular engineering, to prevent breast cancer metastasis. With the support of the NRFI, Li aims to establish a research programme at A*STAR dedicated to developing patient-centric therapies.
“I aim to explore and validate clinically viable, immediately actionable methods to halt metastasis before it begins. My ultimate ambition is to harness the full therapeutic potential of these preventive strategies, significantly advancing immune-oncology and improving patients’ lives.”
Niranjan NAGARAJAN
Associate Director, Genome Institute of Singapore (GIS)
The development of antibiotics in the early 1900s was a cornerstone of modern medicine. Today, we face the growing problem of antimicrobial resistance where many of our existing treatments are no longer effective.
To give us an edge in the race against evolving pathogens, Niranjan Nagarajan and his team work to understand and remodel the genetics of microbial communities to enlist them as allies in combatting colonisation by pathogens.
But first, the team has to accomplish the challenging task of analysing large amounts of DNA and RNA sequencing data. One problem the team is working on is genome assembly, where fragmentary ‘reads’ are obtained from DNA and pieced together to obtain the genomes of target microbes. Nagarajan compares the process to solving a large puzzle with millions of pieces to find an answer that has never been found before.
Over time, he hopes to expand the lab’s work beyond metagenomics and computational biology towards culturomics and metabolic modelling. Ultimately, Nagarajan’s team aims to build a collection of strains, genomic information and modelling capabilities that can harness microbial communities to solve challenges across infectious diseases, food production and sustainability.
“I am passionate about my field because it is one of humanity’s grand challenges. We hope that our work will not only contribute to meaningful solutions, but also recalibrate our relationship with the microbial world that we live in.”
Zhi Wei SEH
Principal Scientist, Institute of Materials Research and Engineering (IMRE)
Decades ago, batteries kept car radios going; today, batteries keep cars on the go. Thanks to lithium-ion (Li-ion) technologies, batteries now power smartphones and city buses. However, even Li-ion batteries have their shortfalls: they rely on costly rare metals, are less energy-dense than liquid fuels, and are generally impractical for energy storage at a home- or city-wide scale.
Zhi Wei Seh’s investigations revolve around new battery chemistries that overcome Li-ion’s current theoretical energy limits. To Seh, multivalent-ion batteries–which use more common metals–are promising candidates for high-energy, low-cost Li-ion alternatives. However, many gaps remain in our fundamental understanding of how to design around them, as they lack the decades of research experience that informs Li-ion development.
By exploring structure-property relationships and constructing prototypes, Seh aims to uncover universal design principles for multivalent-ion batteries based on magnesium, zinc and aluminium, with the goal of creating a unified framework to guide their general development. Through theory computations and machine learning, they are accelerating the development of practical batteries for portable electronics, electric vehicles, grid energy storage and other applications.
“I hope to build better batteries to support humanity’s sustainability efforts. I believe the true measure of success is not the number of papers or citations to your name, but rather whether your work will make a real impact on future generations.”
16th NRF Fellowship (NRFF)
For early career scientists in pursuit of independent research
Leslie BEH
Principal Investigator, Institute of Molecular and Cell Biology (IMCB)
As the driving force behind most biological functions, RNA acts as a blueprint for the synthesis of proteins. However, this blueprint can be modified through molecular and cellular processes that later impact the instructions that are passed along. While such modifications have been identified, their significance and functions remain largely unknown.
Leslie Beh—whose previous research includes identifying and engineering new DNA-modifying enzymes—now works to accomplish a similar goal with RNA. Beh and his team at IMCB hope to illuminate the roles RNA modification plays in human health and disease.
To do this, Beh’s lab will harness synthetic messenger RNA (mRNA) harbouring different modifications at specific positions. These site-specifically modified mRNAs will be used in quantitative assays to determine how the position, number and type of modifications influence biological functions.
Looking ahead, Beh’s team hopes to publish their findings from mechanistic studies of RNA modifications and CRISPR-Cas systems.
“The NRF Fellowship has enabled me to undertake high-risk, high-impact research in epitranscriptomics. I’m excited to dive into this field with fresh experimental approaches and perspectives.”
Kenneth LAY
Principal Investigator, A*STAR Skin Research Labs (A*SRL)
Our skin is a fortress that protects our delicate organs from a harsh environment. Within that fortress, stem cells act not only as bricklayers, but also watchmen: in addition to replacing the millions of skin cells we shed each day, they also work closely with our immune cells to ward off microbes, toxins, radiation and other external dangers around the clock.
Kenneth Lay aims to build a research programme that will shed more light into the biology of skin stem cells, as many mysteries remain over how these cells respond to signals from both the outside world and the microenvironment around them. How these skin stem cells respond can mean the difference between stem cells that help or hurt; in particular, their working relationship with immune cells can determine whether they maintain a healthy skin barrier or trigger inflammatory skin diseases such as atopic dermatitis and psoriasis.
Lay hopes to unearth new insights into how skin stem cells function in healthy and diseased skin, which would pave the way towards harnessing their remarkable regenerative capacity and modulating them for better patient outcomes.
“I see the NRF Fellowship as a vote of confidence and an empowerment to realise my vision of improving lives through scientific discoveries; mentor and train new generations of scientists; and drive Singapore’s growth as a world-leading biomedical research hub.”
Wan Ru LEOW
Scientist, Institute of Sustainability for Chemicals, Energy and Environment (ISCE2)
Petrochemicals are the lifeblood of modern society; everything we consume begins in some way from petrochemical refining. It’s an especially critical industry in Singapore, where 1.5 million barrels of crude oil are refined daily. However, current petrochemical refining processes not only need high temperatures, but often burn a large portion of their feedstocks. As a result, the industry generates large amounts of carbon dioxide, accounting for around half of Singapore’s carbon emissions profile.
To figure out how to cut the industry’s carbon emissions without compromising our modern quality of life, Wan Ru Leow aims to create novel technologies that transform how chemicals are made. At ISCE2, Leow and her colleagues are focusing on the dynamic reaction interfaces formed by electrocatalysts and their immediate vicinities.
By better manipulating such interfaces to achieve specific target reactions, Leow hopes to not only expand the repertoire of achievable electrochemical reactions for industrial processes, but also pave the way for cleaner, more benign chemical reactions powered by renewable energy. Building on these discoveries, Leow also intends to foster industrial partnerships to co-develop pilot-scale prototypes that can make real-world impacts on decarbonisation.
“My goal is to build niche technologies that eventually provide platforms for broader applications such as carbon capture or waste valorisation. The NRF Fellowship provides a great starting platform to establish photoelectrochemical capabilities new to ISCE2 and Singapore, and enables fundamental investigations into critical challenges in sustainability.”
Tim STUART
Senior Research Scientist, Genome Institute of Singapore (GIS)
In 2003, the Human Genome Sequencing Consortium announced it had decoded an essentially complete human genome, accounting for 92 percent of the full sequence. Nearly two decades later, the Telomere-to-Telomere (T2T) consortium announced they had filled the gaps in that code.
While researchers can now easily read DNA sequences, much remains unknown about how a single DNA sequence, when “read” by our cells, can lead to different biological functions, and even the formation of entirely different cells. To explore the relationship between sequence and function, and how it can be manipulated for precision gene therapy, Tim Stuart aims to engineer synthetic DNA regulatory elements that direct gene expression in specific cell types.
With colleagues at GIS, Stuart plans to expand on existing genomics methods, such as single-cell epigenomics, to develop expertise in building deep learning models for DNA sequences. The team’s work aims to advance capabilities in DNA sequence engineering and ultimately enable novel therapeutic applications that can target specific cell states in the human body—in what could be a gamechanger for precision healthcare.
“It’s an exciting time to be in genomics: DNA sequencing costs are falling fast, all kinds of new molecular methods are being developed rapidly, and all in parallel with massive improvements in AI and computation. I’m sure that many opportunities for interesting and exciting science will present themselves in the coming years.”
Yong Kiam TAN
Research Scientist, Institute for Infocomm Research (I2R)
Every system has its flaws: whether a factory, a hospital or a corporation, it’s always reassuring to know that a system is regularly audited for potentially harmful issues based on professional standards and best practices. Computer systems are no different; as we increasingly rely on them in many aspects of our lives, there’s a growing need for tools to confirm that they work as intended.
Yong Kiam Tan’s fascination with formal methods—the rigorous analyses of computer systems using mathematical tools and techniques—began during a summer research internship as an undergraduate at Cambridge University in the UK. For Tan, the field is entering an exciting era, as formal methods tools have become more widely adopted to verify the correctness of software and hardware in safety- and mission-critical settings.
Today, Tan’s research focuses on making formal methods produce more reliable verification results; as with any other software, formal methods tools are susceptible to bugs of their own. Tan aims to tackle this by “verifying the verifiers”; using formal methods to rigorously analyse formal methods tools. Working with collaborators at A*STAR and Nanyang Technological University, Singapore, Tan will also seek opportunities to apply formal methods in practice together with experts in adjacent areas, such as cybersecurity and AI.
“The NRFF is a preliminary endorsement of the value of formal methods research and my ability to pursue it. I hope to live up to that endorsement, and to introduce students to the fascinating world of formal methods through teaching and mentorship.”
