Anyone setting out to explore a new holiday locale would likely turn to a map application on their smartphone for their navigational needs. Whether in quaint towns or bustling cities with elaborate railways, digital maps today serve as trusty sidekicks to visualise and pinpoint the best routes to reach one’s destination.
Similarly, the human brain carries a rich and complicated topography. Across its convoluted landscape, ‘highways’ and ‘towns’ of neurons and their supporting cells endlessly convey and process information. The networks of pathways between these cells give rise to the complex functions of our minds, such as vision, memory and behavioral control.
However, this labyrinth of cellular connections can be confusing to navigate even to trained eyes. Much of this complexity boils down to how cells activate their genes differently across developmental periods and brain regions. These variations not only influence individual functions, but also govern the connections that the cells make to form brain circuits.
Jinyue Liu, a Principal Investigator at A*STAR’s Genome Institute of Singapore (GIS), is on a mission to make sense of the intricacies of these brain networks and decipher how various disorders alter their connections. But doing so will require having a map of the underlying gene activation patterns.
As the Head of the Laboratory of Single-Cell Spatial Neuromics at GIS, Liu works with her team to build comprehensive maps of the brain by harnessing spatial transcriptomics approaches. This emerging class of molecular techniques involves charting gene expression patterns and their relative locations in a given tissue. Molecular ‘guidebooks’ based on these could help scientists precisely trace the brain’s circuits on a molecular level, helping them develop new treatments that target disrupted connections in neuropsychiatric disorders.
1. What drives your interest in neurobiology?
All of us are unique on so many levels, whether in the ways we think and act, the circumstances that affect our health, or the DNA that makes us. I’m particularly interested in how individual brain circuits are assembled. The process of brain wiring is governed by some common rules. However, the brain cells that participate in each circuit and their levels of activity distinguish each one of us. Brain disorders often arise when these circuits malfunction, though their severity may vary from person to person.
My research aims to understand both the individuality and the commonalities between different people and translate them into something purposeful in the clinic. For example, in personalised psychiatry, doctors could select the most appropriate treatment strategies based on the unique neural circuitry underlying each person’s condition. By investigating unique and common features among patients, we can better tackle different neurological disorders and start to find new and more targeted treatments.
2. How did the A*Star Scholarship shape you as a researcher?
During my PhD training at Harvard University under A*STAR’s National Science Scholarship, I got to witness first-hand the rise of the genomics revolution. My colleagues and I were adopting newly emerging technologies—from microarrays to bulk RNA sequencing and single-cell RNA sequencing—to examine the role of our genes in building the nervous system. These efforts led to the discovery of many new types of cells that differ in the genes they express.
It dawned on me that the next big gap in knowledge is how these diverse cells converse with one another to give rise to higher-order functions. I thus sought ways to understand how cells are organised in space within tissues and arrived at spatial transcriptomics for the next phase of my research.
We were fearless and tactful in embracing new technologies to break new frontiers and the experience proved incredibly valuable in setting me up to become an independent researcher. Moreover, I saw how my mentors and seniors were able to anticipate the next ‘big thing’ in the field. That kind of insight is a soft skill that can’t be learned from textbooks, yet it was critical in my development as a scientist.
3. Why does spatial transcriptomics matter in studying brain development and disorders?
As the saying goes, “no man is an island”. Similarly, no cell is an island. The interactions between cells determine the functions of the tissues they belong to, and may contribute to how diseases occur. To study these interactions, it’s important to look at where and how individual cells express their genes. Spatial transcriptomics allows us to do just that.
This class of molecular profiling techniques involves quantifying and locating the expression of numerous genes within an area of intact tissue. Preserving tissue context enables us to see how our brain is organised and how it becomes disorganised in diseases. In recent years, spatial transcriptomics has been used to address important biological questions about brain development, ageing and neurodegeneration.
4. How might your team’s work translate to new clinical applications?
Our research focuses on identifying the key cell-to-cell interactions that underlie various brain disorders by using patient-derived stem cells and other model systems.
In studying autism spectrum disorder (ASD), for example, we used three-dimensional tissue structures called organoids to emulate the developing brain. We found that some cells were misplaced in the autism organoid model compared to those seen in normal brain development. These misplaced cells may go on to make abnormal connections later in life, potentially accounting for the behavioral symptoms seen in individuals with autism.
While we’re still a long way off from fully understanding ASD, applying spatial transcriptomics is already helping us to start uncovering its roots. From there, we hope to find more effective ways to manage the condition.
5. How has A*STAR supported your development as a Principal Investigator?
A*STAR has equipped us with the resources and a talented team to make exciting research happen. At GIS, we have a strong core of diverse scientists who are investigating DNA and RNA to address human diseases. Such an environment truly facilitates interdisciplinary and impactful research. Moreover, A*STAR has provided a home for building my laboratory. Pursuing research is no doubt challenging, but I feel very fortunate to have the space to develop my lab, pursue my scientific interests and nurture my team.
6. What advice would you share with younger colleagues on pursuing research?
Be clear about your motivations for pursuing research. It is a long journey, and you will need a lot of perseverance. Science is constantly evolving, so it’s important to keep up with the latest discoveries to stay inspired and relevant. Invest in teamwork, as research is a collaborative activity. Learn to see the big picture, and stay open-minded and curious. That way, we’ll be able to see the next step before it unfolds, and be the ones to drive science forward.
