B-ing Part of the Solution

Building pathways for progress

Dr Ng Shi Yan (Science ’08) is an Adjunct Assistant Professor at NUS Department of Physiology and a rising force in the area of stem cell research, particularly in the realm of motor neuron diseases. Dr Ng has received a number of awards, including the National Research Foundation Fellowship (2018), A*STAR International Fellowship (2012) and Merck Millipore Young Scientist Award (2011).
    
   

In 2014, few people were aware of the ice bucket challenge. It had been around for a few years, and involved people dumping ice water on themselves. But it then blew up on the Internet when it took on a different purpose: raising funds for the treatment of amyotrophic lateral sclerosis or ALS. In a way, the ice bucket challenge was perfectly suited to ALS, as Dr Ng Shi Yan (Science ’08) notes — pouring ice water on oneself mimics the sensation that ALS sufferers feel.

At her Neurotherapeutics Laboratory at the Institute of Molecular and Cell Biology, Dr Ng investigates ALS and other motor neuron diseases, using human-induced pluripotent stem cells (iPSCs) to model the diseases and do incredible things such as build spinal organoids. More impressive still is her discovery of the potential of a form of vitamin B3 called nicotinamide in treating ALS. “My interest has always been in using stem cells to understand how our body functions,” she explains. “In the later part of my research, we’re looking into the context of disease, and the rationale was to be more relevant to the kind of work we are doing in Singapore, where we are trying to solve problems.” Dr Ng notes that Singapore’s ageing population poses the biggest risk factor for neurodegenerative diseases, such as ALS. “I wanted to work on a simple enough problem to address, because with complex problems, we would only be advancing the field forward just a little bit at a time,” she adds. By focusing on a simple project, Dr Ng hopes to make a bigger impact. 

Motoring On

To understand all this a little better, here is a working definition of ALS. It is a progressive neurodegenerative disease that affects nerve cells called motor neurons in the brain and the spinal cord, resulting in the brain losing control of voluntary muscles. The Greek word ‘amyotrophic’ literally means no muscle nourishment. According to the published literature on ALS, it is the most common type of motor neuron disease. There are two types of ALS, sporadic and familial — sporadic ALS has no known cause and is the version where age is the decisive factor, while familial ALS arises in individuals with ALS running in the family. ALS is almost always fatal within five years of diagnosis, although many of us may be familiar with a man who lived with ALS for many decades — the late physicist Dr Stephen Hawking. Needless to say, Dr Hawking’s case is exceptional.

Motor neurons are nerve cells that connect the brain and the spinal cord with the skeletomuscular system, and Dr Ng’s work focuses on these types of cells. In a 2020 study, she and other researchers found that all forms of ALS motor neurons exhibited similar defective metabolic profiles, which they attributed to issues in the mitochondria of cells. In the mitochondria, a type of protein called Sirtuin-3 (SIRT3) maintains mitochondrial function and integrity. Activating SIRT3 using nicotinamide reversed the defective metabolic profiles in the team’s ALS motor neurons, as well as correcting a constellation of ALS-associated phenotypes (characteristics which are observable). Dr Ng notes that this work was done in the lab on iPSCs from healthy controls, those with familial ALS, and sporadic ALS patients. While she hopes to partner with clinicians for trials outside the lab, with real patients, the work has not progressed to that stage yet. 

As noted earlier, nicotinamide is a vitamin B derivative and its usefulness with regard to affecting SIRT3 was “serendipitous,” says Dr Ng, as her team did not set out with this result in mind. “This was what our research showed, and we changed our thinking accordingly.” What they were doing was investigating if defective mitochondrial respiration could be the common pathway implicated in both sporadic and familial ALS, and they discovered that it was. In fact, the respiration issue was caused by reduced SIRT3, which they resolved with nicotinamide. Dr Ng stresses that while the idea of popping a vitamin to treat ALS is exciting, it is meant to complement existing pharmaceutical therapies. “We hope that combining nicotinamide with the existing drugs will improve health spans and longevity for ALS patients,” she says. Of course, this will all depend on the aforementioned clinical trials.

Making Mini Spinal Cords

Dr Ng’s expertise is not specifically related to ALS but to motor neurons in general, and she came to this area due to her exceptional skills with this type of cell in the lab. “The lab I was in while I was doing my post-doctoral work was very good at making motor neurons. Obviously, if you want to have a wider impact on diseases of the central nervous system, you’d look specifically into Alzheimer’s or Parkinson’s, but it turned out that I was not very good at that time at making those cells in the lab. So the reason I work on motor neurons is because I’m good at making the cells!” Prior to setting up her lab here in 2015, Dr Ng was looking into spinal muscular atrophy (SMA), but since a promising treatment was already in the works, she turned her focus to ALS and other matters of the spinal cord. 

On that note, the Neurotherapeutics Laboratory is working on another project that involves growing spinal organoids, intentionally damaging them and then injecting stem cells into these structures to try and heal them. This work is most relevant to people with spinal cord injuries due to accidents and the like, rather than diseases. “Spinal organoids are like mini spinal cords that are supposed to mimic spinal cord development. We’re trying to see what happens if we cut these mini spinal cords...does it resemble the effect of actual spinal cord injury? We’re still trying to figure this out.” 

Dr Ng explains further that she and her team believe that the spinal cord retains its expertise in doing its normal work, and that what is needed to return more or full functionality in cases where the spinal cord is severed or injured, is to heal the damage by injecting specific stem cells. Creating spinal organoids in the lab also has potential as a platform for therapeutic discovery, which Dr Ng and her team highlighted in another earlier project to do with SMA. The project demonstrated overt motor neuron degeneration in SMA spinal organoids (created from SMA patient-derived iPSCs), and showed how such degeneration could be prevented. 

Slowing Down Ageing

Another more recent project from 2020 also showed promise in reversing defects in spinal organoids grown from mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) patient-derived iPSCs. This project was the first to look into motor neurons or neuromuscular junctions in MELAS, and it revealed that excessive Notch signalling (a type of communication between neighbouring cells) underlies a variety of defects. The study also demonstrated how to reverse these defects in the organoid cultures. MELAS is both an adult-onset disease and one that develops in foetuses, which is a reminder that motor neuron diseases are not just a threat to older people.

Of course, many types of neurodegenerative diseases are related to ageing, and it seems that there might be general benefits to Dr Ng’s research. “One of the things we had in mind when we started the ALS project was that what we found might have wider implications for other ageing conditions as well. Diseases like ALS are like an exaggerated form of ageing because they share some commonalities at the molecular level. So in one sense, we are saying that if we can slow down ageing (at the level of the cell), we can prevent neurodegenerative diseases (like ALS).”