The mechanics of cancer: Joseph Ng begins his PhD at King’s College London

12 August 2016

Ng Chi Fung Joseph is a brand new Croucher Scholar, who will begin his program of PhD study at King’s College London this October. The next few years will provide an opportunity to develop his interest in the field of cancer research, analysing the mechanistic aspect of a significant yet overlooked group of proteins in generating mutations that bring about cancer.

Ng’s PhD research will focus on the APOBEC family of proteins, crucial mutators that alter DNA sequences. While both the sequence context which these proteins infer and the DNA changes they make have been identified, the structure of APOBEC proteins is still unknown and their mechanism not fully understood. Typically, APOBEC proteins are involved in antibody production, and the family has previously been investigated in relation to the inhibition of HIV replication in host cells.

However, it was recently discovered that these proteins are linked to the development of cancer cells. Exactly how the proteins contribute to cancers is currently unclear, one possibility being misregulation which induces APOBEC proteins to enter the nucleus and mutate genomic DNA.

Joseph Ng

Mutation consequences

Ng will join two laboratories once he arrives at KCL, directed by Professors Franca Fraternali and Michael Malim. This collaborative project allows him to continue to weave together his various passions into one research project, as one of the laboratories focuses on computations predictions, and the other on experimental science. Not only do these two laboratories have a history of collaboration, both have previously worked with APOBEC proteins in the context of HIV replication.

Discoveries are frequently being made in relation to the APOBEC family of proteins, and the cutting-edge nature of the research drew Ng to this area. For instance, teams recently discovered that APOBEC mutations not only initiate cancer development, but also aid its progression, colonising other areas of the body and allowing cancers to spread. 

Furthermore, APOBEC proteins are implicated in various cancer types, including lung and breast cancer, as opposed to one single organ, meaning that breakthroughs in this research could greatly impact cancer diagnosis and treatment in general.

Structure of the APOBEC3A protein solved as a dimer (shown green and blue) using X-ray crystallisation. APOBEC3A, like other members of its family, is a “zinc-coordinated” enzyme with a zinc atom (grey dot) bound at its active site.

The direct benefits of the research would be knowledge of how the APOBEC mutators perform their jobs, which would have implications for drug development, allowing drugs to structurally target the key sections of these proteins in order to stop their function. Another potential outcome is that, if the cause of the cancer-specific activation of these proteins is discovered, a drug could be developed to prevent the expression and activation of the proteins before they could adversely impact the body.

Ng imagines that he will continue working with cancers, particularly since, although detection techniques and treatments are advancing, many aspects of cancers remain enigmatic. 

He aims to investigate how critical proteins in cancers not only initiate the development of cancers, but also help them progress, and hopes that one day he could utilise computational data analysis to create predictions which would inform laboratory research, aiming to develop clinically applicable strategies to treat cancer.

The structural detail of the binding of nucleotides to the active site the APOBEC proteins is unresolved.

Computational data and -omics

The final year project of Ng’s undergraduate degree at Hong Kong University (HKU) also tackled cancer, so he has some experience of working with the disease. He focused on gastric cancer, a type prevalent in Asia. 

The project explored various mutations in different tumours of the same disease, addressing the hypotheses that mutations in a tumour arise at different time points, and the more heterogenous the mutations within tumour, the more difficult it would be to treat. Using computational data, Ng examined which mutations appeared early and which did not, exploring how their temporality shaped cancers. 

He studied this using DNA sequences from tumours of gastric cancer patients, which were compared to their healthy template, allowing any mutations to be identified. At the same time, the tumour DNA was also profiled for any copy number changes, because such gains or losses of sections of chromosomes are also crucial in initiating cancers. 

Combining this data then allowed him to make predictions via computational algorithms as to how different forms of this cancer might progress. Although each tumour has a unique evolutionary trajectory, the heterogeneity of mutations intertwine with the importance of an unstable genome in shaping cancer and the impact of mutations in attracting immune cells that attack the tumour. These topics remain relevant in current cancer research.

Ng is also interested in the ‘-omics’, encompassing genomics and proteomics, which he describes as the “recurring theme in all my projects”. 

This suffix refers to exploring a large volume of biological data which requires a computational approach to be fully understood. In addition to this, he considers medical ethics important, and recently published a paper on debate about genomic testing being made available to the public (Chung & Ng, 2016, Journal of Medical Ethics). 

Ng stresses the importance of personal, as well as biological, implications in research, saying that one of the most important tasks a scientist face, “is that if specific technologies interest you, and these technologies are developing, you have a responsibility to put forward how these technologies might be used in daily life.”

Ng Chi Fung Joseph recently completed his undergraduate degree at Hong Kong University (HKU), which included a year studying abroad at King’s College London (KCL). In October, he will return to KCL to begin his PhD program, supported by the Croucher Foundation. His PhD research will focus on APOBEC proteins, a critical protein family which have recently been identified as involved in DNA mutations which can trigger the growth of cancer.

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