Looking for treatments in the gene: Dr Alan Wong decodes disease genetics
Dr Alan Wong Siu-lun is an Assistant Professor of the School of Biomedical Sciences at the University of Hong Kong (HKU) and employs both synthetic biology and combinatorial genetics to decode the complex genetic basis of diseases including cancers and neurodegenerative disorders.
Always fascinated by the treatment human disease, Wong studied biochemistry at CUHK after originally opting for pharmacy.
“Doctors are on the frontline of patient care but someone needs to help design the drugs and treatments,” he says, “that is what interested me.”
As an undergraduate he was recruited for a research project undertaken by Professor Edwin Chan into fruit fly genetics. Using the fruit fly as a genetic disease model, the team was able to examine how genes impact neurodegeneration.
It was Wong’s first taste of looking at genetics as a means to create a disease model. As an undergraduate in 2003, he was involved in the same team looking at the SARS virus and successfully identified the function of a SARS protein by putting the gene into a fly to demonstrate cell death.
“It was a small contribution to solving the SARS puzzle,” says Wong and these early experiences inside a research laboratory, looking at the genetic code of the SARS virus using the fruit fly model inspired him to become more immersed in this area of science.
“Genetics is an interesting topic,” he says explaining that it is possible to have hundreds of different fly strains with different genetic characteristics and look at how individual genes impact on disease phenotypes by removing individual genes and examining how it impacts the disorder.
Human brains with neurodegeneration typically have aggregates where proteins form clumps. These structures are found on brain slices but researchers could not be sure if they were toxic or beneficial. Could this clustering be a defence mechanism of the brain and therefore an outcome rather than a cause of neurodegeneration?
While at CUHK, Wong also worked on characterising a form of oligomeric aggregates that appear to be more toxic for polyglutamine-induced neurodegeneration. He continued in a similar field of study for his PhD study at HKUST supervised by Professor Nancy Ip.
Wong looked at cell death pathways with specific reference to another neurodegenerative disease (Parkinson’s disease) using cultured neurons as a model. He found a mechanism to switch on and switch off cell death, which opened up the possibility of targeting drug design to turn off that switch, even while the disease was still in place.
A big change
Wong was offered a post doctorate position at the Synthetic Biology Group, led by Professor Timothy Lu, at Massachusetts Institute of Technology (MIT) which was something of a departure from his established areas of expertise. MIT has a reputation for excellence in engineering and synthetic biology and he found himself one of the few on the MIT team at that time with specialist knowledge of mammalian cells. This allowed him to integrate synthetic biology with mammalian cell biology.
“It was an uncertain move away from neurodegeneration to such an unfamiliar field but I wanted to learn about synthetic engineering,” says Wong who found his colleagues were treating genetics like electronic components, seeking to engineer the biological equivalent of a circuit board.
“It’s weird but it’s very interesting because the MIT team wanted to engineer cells that could have new behaviours but their experience was more suited to bacterial cells rather than mammalian cells,” explains Wong.
It was very challenging at the start because there was so much for Wong to learn and it proved to be a very different experimental strategy which remains a novel way to devise new therapeutic strategies.
“We were using DNA code to programme a cell to make it exhibit new behaviour. It’s like using DNA code like Lego blocks,” he explains.
Engineering the gene
They devised a platform using bar coding strategies so that they could examine the barcode and see which barcode impacts cell behaviour. The team could then use that model to identify the best combination of microRNAs or genes that could, for example, inhibit cancer growth.
“We could identify different combinations of genetic interaction that allow cancer cells to be sensitised to chemotherapy and inhibit cancer cell growth,” he says. This is the field of combinatorial genetics that he is now focused on at HKU and it is still a very unexplored area of research. Ultimately, it could lead to the development of multiple drug treatments or a cocktail drug attacking multiple targets simultaneously.
After three and a half years of post-doctoral work at MIT, Wong was keen to return to his home city where he had received a great deal of support for his career, including that from the Croucher Foundation. He became the first recruit at the newly merged School of Biomedical Sciences at HKU and focused on the development of combination therapy which he could progress in the short term.
“What I learned at MIT is to explore all possibilities, even those we had not previously considered. To think differently and to be creative. Of course you need to know the basics to form a solid foundation but I want to use those MIT principles to nurture the next generation of scientists in Hong Kong,” he says.
Dr Alan Wong Siu-lun obtained his B.Sc. and M.Phil. degrees in Biochemistry and Molecular Biotechnology from the Chinese University of Hong Kong in 2005 and 2007 respectively, and completed his Ph.D. in Biochemistry at the Hong Kong University of Science and Technology in 2011. He joined the Synthetic Biology Group at Massachusetts Institute of Technology from 2012-2016 for postdoctoral training. Dr Wong was awarded the Croucher Foundation Studentship (2008), the Butterfield-Croucher Award (2008), the Croucher Foundation Fellowship (2012), and the Hong Kong Institution of Science Young Scientist Award in life science (2011). He was appointed as Assistant Professor at the HKU School of Biomedical Science in 2016 and focuses on synthetic engineering and combinatorial genetics to decode the complex genetic bases of human diseases, as well as the design and engineering of genetic circuits for providing new biomedical solutions.
To view Dr Wong’s personal Croucher profile, please click here.