Making molecules

13 April 2016

As a student, Dr Wai-Lung Ng enjoyed the challenge of chemistry, but never imagined that he could pursue it as a career. Since then, his passion for the subject has led him from Hong Kong to the United States to the UK, and his work has helped to develop small-molecule inhibitors that potentially offer a more effective treatment for diabetes. Now, his research explores both the fundamentals and applications of chemical protein modification, and could have could have a great impact on the development of new medicines.

Even in secondary school Ng was drawn to chemistry. He enjoyed the intellectual challenge, but as his studies progressed he realised the massive potential of synthetic chemistry. The ability to create new molecules and materials held such promise for improving living standards and saving lives. Following his passion, he majored in chemistry at the Chinese University of Hong Kong for both his undergraduate and PhD degrees.

In his PhD research, Ng studied the cancer and diabetes fighting capabilities of readily available carbohydrate molecules. By transforming these molecules to target certain proteins, their anti-diabetic potential could be realised.

Diabetes interferes with the body’s ability to regulate glucose in the blood, and since the kidneys act as a sort of filter for all the blood in our system, glucose regulating molecules in the kidneys make the perfect target. Alongside his mentor, Professor Tony K. M. Shing, Ng explored the physiology of diabetes, targeting the sodium-dependent glucose co-transporter 2 (SGLT2) protein, which is responsible for the reabsorption of glucose molecules in the kidneys.

The team proposed that carbohydrate-based small molecules could be synthesised to selectively inhibit the SGLT2 protein, which would promote urinary glucose excretion, lowering the levels of glucose found in the bloodstream. Ng was able to synthesise some novel small-molecule SGLT2 inhibitors using gluconolactone, and eventually created stable, potent, and selective inhibitors — anti-diabetic agents that could provide an alternate and potentially more effective way to treat diabetes.

A change of pace

During the final year of his PhD, Ng also received the chance to study at the Massachusetts Institute of Technology (MIT) in the US on a Fulbright scholarship, under the guidance of world-leading synthetic chemist, Professor Stephen L. Buchwald. The opportunity arose when he faced a bottleneck in his research, motivating him to reach out to a leading chemistry scholar. This provided him with the chance to work and study abroad in a culturally diverse environment, something Ng stresses is not only enjoyable but also important for personal growth.

The Buchwald group at MIT focuses on the development of a transitional metal-catalysed organic reaction and methodology, which helps streamline the synthesis of drug candidates and novel functional materials. At MIT, Ng learned a completely different skill set, which he believes complemented the skills he learned as a carbohydrate chemist at CUHK, and would be useful to him when developing his own research programs as an academic.

While at a chemical biology conference hosted by MIT, Ng met Professor Benjamin G. Davis of Oxford University, an expert in chemical biology and protein modification. Inspired and encouraged by Professor Davis, Ng decided to leave his comfort zone of organic chemistry and move into the field of chemical biology, despite having no research experience in this area.

Chemical biology appealed to Ng as he highly values interdisciplinary research because it provides a chance to tackle scientific problems from a different angle, offering answers to certain challenging and long-standing biological questions. Although the change of field would involve working with proteins, which are more difficult to work with than smaller molecules due to their larger size and complexity. Ng was fascinated by the possibilities this area of research held and, always keen for a new challenge, he moved to Oxford after completing his PhD.

Ng describes his current research as “a multidisciplinary project which lies on the interface of organic chemistry, biochemistry, and cell biology, aiming to enable in-depth studies of the unknown aspect of epigenetics.” The project intends to develop bond-forming strategies for protein modification, both in vitro and in vivo. One application of his research would be to improve the physical and biological properties of therapeutic proteins, such as increasing the protein’s resistance to degradation within the body. 

Epigenetics

Another important application of the development of these bond-forming strategies is to study the exact function of post-translational modifications (PTMs) of proteins. Post-translational modifications occur during or after protein biosynthesis, and common examples include phosphorylation and glycosylation.

The reactions developed by Ng will be employed to elucidate the unknown biological functions of certain PTMs on histone proteins. When compressed for storage within the nucleus, DNA is tightly wrapped around histone proteins, almost like a little wound up spool of DNA. These histones are in turn bundled together to form a nucleosome. PTMs on histone and nucleosome complexes are closely associated with the development of many diseases, including cancer. However, there are many different histone PTMs, and the biological significance of many of these modifications is not understood, due to a lack of existing tools to access and study histones with well-defined PTMs.

Misregulations of epigenetic mechanism often cause different diseases, and models of histone proteins with the associated PTMs are needed to better study and understand the effects these modifications have on disease progression. Although bioorthogonal reactions developed in recent years have greatly assisted in the study of proteins, many of these reactions create carbon-heteroatom bonds that are not naturally found in proteins, limiting their use in chemical biology. Therefore, developing new reactions that can construct natural carbon-carbon bonds is vital.

Ng’s research is aimed at tackling these challenges and is expected to have an impact in the field of epigenetics. He creates synthetic histones with PTMs installed post-expressionally, which will then be used as models to examine the interactions between histones and their regulating enzymes in order to elucidate the biological significance of these PTMs. Once the disease-causing mechanism in relation to a particular PTM is discovered, it can help scientists develop new drug candidates to interfere with this mechanism.

Out of the lab

While acknowledging the importance of fundamental research, Ng is also passionate about translational research, the bridge between the healthcare industry and academic research. He hopes to eventually move into this area as he enjoys seeing his research have a positive impact on the real world. In addition to research, he is passionate about teaching, considering it a responsibility to pass his knowledge onto the next generation of scientists, and to inspire them to participate in scientific research. Ultimately, Ng’s goal is to become an academic entrepreneur who can develop new treatments and diagnostic technologies for diseases while simultaneously making these technologies readily available.

Like many Croucher Fellows, Ng wishes to return to Hong Kong in the future to contribute to the scientific research community here. He hopes to have his own lab, which would allow him the freedom to control the direction of his research. Alongside this, he would work to raise the general public’s awareness of science, helping them to understand the purpose and implications of chemistry within society. Ultimately, he said, “I’ve been supported by different people and funding agencies in Hong Kong for many years, and I feel like I am in debt to them, so I will try my best to give back.”

Dr Wai-Lung Ng graduated from the Chinese University of Hong Kong (CUHK) with a First Class Honours B.Sc. degree in 2010. There, he completed his PhD in 2014 with support from the Hong Kong PhD Fellowship and the T C Cheng Postgraduate Scholarship. He undertook the final year of his PhD at Massachusetts Institute of Technology (MIT) as a Fulbright Scholar (2013-2014) with funding provided generously by the Lee Hysan Foundation and the Fulbright Program. His PhD focused on the creation of anti-diabetics agents, sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors, which could offer an alternative way of treating diabetes. Since then, he has worked at the University of Oxford as a Croucher Foundation Postdoctoral Fellow, where he is currently researching chemical biology and chemical protein modification.

To view Dr Ng’s personal Croucher profile, please click here.