DNA is often portrayed as a neat double helix in popular media, but in reality, it’s more like a tangled mess of telephone wires crammed into each of our cells. As these intricate bundles of DNA contain instructions for everything our bodies do—from how we grow to how we heal—even a tiny modification can disrupt our cells’ proper functions, causing issues ranging from birth defects to cancers.
That’s where cutting-edge tools like CRISPR come in. Imagine having the power to precisely switch a gene ‘on’ or ’off’ at will, or correct mistakes in the messages DNA sends to our cells. CRISPR has revolutionised our ability to do just that, offering new ways to study genes, develop treatments and even tackle diseases once thought incurable.
For A*STAR National Science Scholar Chen Gang Goh, CRISPR technology represents the ultimate toolbox for understanding and repairing our DNA. Now a PhD candidate at the Cancer Research UK (CRUK) Cambridge Institute, Goh’s work in genome engineering focuses on DNA damage repair (DDR): how our cells try to fix mistakes in their genetic code. Using genome-wide CRISPR screens, Goh probes the interactions between genes to shed light on DDR and uncover new strategies for cancer treatment.
In this interview with A*STAR Research, Goh shares his fascination with CRISPR technology, its impact on his scientific journey, and the future he envisions for such genetic tools in healthcare.
1. How did your fascination with biology and genetics begin?
It started with the first research proposal I wrote during my A-levels. Based purely on a literature search, it explored how sorbitol, an artificial sweetener, might be repurposed for alternative treatments. Though daunting at the time, piecing together a logical and coherent explanation for how things work left me with a feeling of lasting satisfaction.
I've always been curious about how the human body works at the cellular level; in particular, the genetic code amazes me. It’s mind-blowing how just four DNA bases—A, T, C and G—can encode our entire biological blueprint.
During my undergraduate studies in biochemistry and biotechnology at Imperial College London in the UK, I realised my true passion lay with DNA. It was fuelled by the advent of CRISPR-Cas9 into the field. Its ability to manipulate the genome with ease was revolutionary, allowing us to figure out what genes did simply by switching them on and off.
After graduation, I joined Wei Leong Chew at the A*STAR Genome Institute of Singapore (A*STAR GIS), where I spearheaded a project on CRISPR-Cas13, an alternative to CRISPR-Cas9 that edits RNA instead of DNA. RNA translates DNA’s instructions into proteins that do biological tasks; modifying RNA instead of DNA generally reduces unintended effects.
This experience shaped my decision to pursue DDR research, leading me to Professor Stephen Jackson’s lab at Cambridge for my ongoing PhD studies. Here, genome-wise CRISPR screens are the quintessential method to probe what genes do in specific contexts.
2. Tell us about your current work at CRUK Cambridge Institute.
My work revolves around topoisomerases: the enzymes that help untangle DNA during crucial cellular processes like replication and transcription. They act as molecular scissors that cut DNA to relieve tension generated from the said cellular processes, then cling on until the break is resealed.
However, these enzymes can sometimes get stuck on DNA strands, creating toxic lesions known as trapped topoisomerase cleavage complexes (TOPccs). These lesions are harmful to cells, but can also be exploited for cancer therapy. For example, topoisomerase inhibitors—a common class of chemotherapy drugs—deliberately trap these enzymes to target rapidly-dividing cancer cells, which need the enzymes more than benign cells.
My research aims to better understand DDR pathways that fix these lesions. Using base-editing CRISPR screens, I generate thousands of protein variants with single amino acid residue changes to identify regions critical for resolving trapped TOPccs. As we could pinpoint the modification that disrupts the outcome, such insights could help in designing more potent small molecule drugs with fewer side effects.
While I can’t share further details on this work, I recently published a complementary study on TDP1, a protein that normally helps resolve trapped TOPccs. What’s interesting is that in HAP1, a model human cancer cell line widely used in CRISPR research, TDP1 doesn’t function—which suggests HAP1 cells rely on alternative repair mechanisms. This highlights the risk of making generalisations about biological pathways based on genetic studies on a single model.
3. You worked on COVID-19 test development at A*STAR GIS during the pandemic’s height. What was that experience like?
When I joined A*STAR GIS, it felt as if everyone wanted to contribute in whatever way they could to combat COVID-19. Being part of a biological research institute felt like a call to action.
At A*STAR GIS, I was privileged to be on the team developing a testing kit based on loop-mediated isothermal amplification (LAMP). LAMP rapidly makes copies of trace amounts of DNA or RNA at a steady temperature; it was a faster, yet equally sensitive alternative to conventional polymerase chain reaction methods—which need precise heating/cooling cycles—for detecting SARS-CoV-2 infection.
I vividly remember an extended period of time where we worked in shifts under strict protocols. I didn’t meet some of my colleagues in person for months, relying instead on shared Google documents for daily updates and discussions, which often meant feedback and actions were more delayed than if we’d met physically.
We fought an uphill battle against time, resources and logistical issues but there were incredibly rewarding moments, such as when we discovered compounds that greatly improved the kit’s performance. Overall, it was a unique experience where I felt “we’re all in this together”.
4. What are some big questions in science you hope to answer in future?
One of my dreams is to witness a future where we almost fully understand the human genome and gene therapies are commonplace, not just for single-gene disorders but for more complex conditions. To achieve this, we need to address several challenges in gene therapy today, including immune rejection, delivery systems, target specificity and long-term efficacy.
I believe that everyone should have the chance to take control of their health and future, regardless of their genetic makeup and predisposition. Advancing gene therapies is crucial to levelling that playing field for everyone to lead a life of their choosing.
5. What advice do you have for your peers and juniors in science?
In science, things can easily get overwhelming. The trick is to focus on one step at a time. When you feel like you need a break, take one without guilt; those moments of rest have often turned out unexpectedly productive for me. Prioritise quality over quantity in your work hours.
As science can also be isolating, especially when you work long hours at the bench or keyboard, it’s important to stay sociable. Conversations with colleagues, friends or even strangers may seem like distractions, but trust me when I say a brief chat can spark the best ideas or solutions.
Finally, don’t let imposter syndrome hold you back. Share your thoughts, seek feedback and stay optimistic. Amid the setbacks, good things will come through.
