Assoc Prof Low Boon Chuan: Unravelling the chemistry of life

Associate Professor Low Boon Chuan has always been fascinated by how life is formed. When he was young, he would dig up earthworms from the garden and watch as they wriggled back into the soil. “Why does this animal need to live underground? Why does it thrive in such dark, damp conditions?” he would wonder.

From these early observations, his passion for experimentation grew when he made hydrogen gas from electrolysed saltwater, and studied how yeast cells divide under his school’s microscope. Assoc Prof Low explained, “Around this time, I started to think about the difference between living and non-living things. That was when I started to fall in love with biochemistry – the chemistry of life!”

It was this love of biochemistry, and his curiosity for how life works, that made Assoc Prof Low pick up a microbiology textbook one day during his school holidays. While skimming the pages, he came across a phrase he had never seen before: genetic engineering. “I just remember thinking ‘wow!’ with genetic engineering you can splice and clone genes. That was amazing to me!” he recalled.

Discovering this new world of genetic engineering was the trigger that accelerated Assoc Prof Low’s career, and he went on to pursue his dream of becoming a scientist.

Entering the world of mechanobiology

After spending his undergraduate and postgraduate years at the Department of Biochemistry in the University of Otago, New Zealand, he joined the Institute of Molecular and Cell Biology in 1995 as a postdoctoral fellow. In 2000, he joined theNUS Department of Biological Sciencesas an Assistant Professor and delved deeper into genetic engineering and cell biology. Later, in 2009, Assoc Prof Low became one of the founding scientists who helped establish theMechanobiology Institute (MBI) in NUS.

Mechanobiology is an emerging field of science focusing on the physical and mechanical aspects of biological functions. “My research is focussed on how cells signal – the way they communicate with one another and within themselves. These signals form the basis for all cellular events, such as how they grow and differentiate themselves, and how they develop into either healthy or diseased organs and tissues,” shared Assoc Prof Low.

Assoc Prof Low leads a dynamic team at MBI to investigate these mechanobiological mysteries and more. With his multidisciplinary team, Assoc Prof Low emphasises education as a key pillar of research. “Mentoring and educating my team is an important part of what I do. I learn from them too,” he said.

Together, the team integrates biophysics and mathematical modelling to understand the chemical processes of cells and examine the structure of proteins.

Assoc Prof Low (back row, second from left) and some members of his research team in May 2019

Proudest research breakthrough

Recently, Assoc Prof Low achieved one of his ultimate research goals. In a paper published inPNASon 25 May 2021, he and his collaborators outlined the structure of the ‘RhoGAP BCH domain’ in proteins.

In cell biology, domains are the distinct functional or structural units in a protein. They are responsible for how a protein functions or interacts in a cell. In this case, the BCH domain is a regulator for ‘Rho GTPases’ – a class of molecular switches that regulate the cell’s morphology as it migrates, divides, dies, and forms tissues and organs.

Assoc Prof Low first discovered the BCH domain in 1999 at the end of his postdoctoral term, and his latest achievement of solving the structure of the ‘RhoGAP BCH domain’ has been 10 years in the making. The breakthrough finally came when he went back to what had first fascinated him as a child: yeast.

“The yeast gene had a similar BCH domain to the human gene. We managed to grow and crystallise the protein incredibly well using yeast. This was the moment of truth!” he said. The team then managed to solve the yeast’s RhoGAP BCH structure and used mathematical and molecular modelling to define the structure in humans that helped delineate how the BCH domain controls Rho signalling at the molecular level.

“Unravelling this structure has been one of my dreams for a very long time. I told my students that I won’t retire until I solve the structure. Now that I’ve accomplished this, I can go on to achieve other goals!” Assoc Prof Low added.

The structure of the RhoGAP BCH domain

Interdisciplinary impact

The BCH domain has far-reaching impacts in many areas of disease. In October 2020, Assoc Prof Low’s group showedhow another BCH domain-containing protein orchestrates the force exertion as a brake to modulate cell motility, the failing of which could drive cancer cell metastasis.

In 2015, his group solved the mystery of a motor coordination disorder that made it difficult for patients to coordinate complex movements. This mystery was revealed by linking functions of abrain-specific BCH domain protein to acetylcholine signalling.

Assoc Prof Low currently collaborates with colleagues fromNUS Medicineto further examine the role that the BCH domain plays in brain cells and neuronal activity, and also the development of healthy and ageing hearts. “We will work together to learn exactly how the human heart develops and how it changes with heart disease,” he elaborated.

“From a humble discovery, the BCH domain has become a versatile, pluripotent, functional scaffold domain that controls heart cells, cancer cells, and neurons. That was completely unexpected when I first discovered it,” he said. But this is a happy coincidence as Assoc Prof Low enjoys collaborating with a wide variety of scientists from different disciplines. “Interdisciplinary research is the way forward. The ability to interact with my colleagues from different walks of life is so important,” he added.

It is this passion for interdisciplinary education and research that spurred Assoc Prof Low to help run theNUS University Scholars Programme (USP) where he is both the Deputy Director and a Residential Fellow. The USP focuses on strengthening undergraduates’ core academic and professional skills which enable them to make connections across fields, an area close to Assoc Prof Low’s heart.

Now that he has solved the RhoGAP BCH structure with many years left until he retires, Assoc Prof Low wants to unravel the structures of various BCH domain proteins, and also discover how BCH domains could be modified in cells to achieve versatile functions. But he also has more humble goals of imparting his knowledge to the next generation of biochemists and cell biologists. “Before I retire, I want to produce even more scientists who can serve society better. That is what I want for my legacy,” he said.