Dr Man-yan Wong: molecular pharmacologist and neuroscientist

28 April 2018

Dr Man-yan Wong is currently an investigator at the Novartis Institutes for Biomedical Research conducting drug discovery research. Prior to joining Novartis, she was trained at Harvard Medical School, University of Pittsburgh, and Genentech, with a focus in neurobiology.

While Dr Man-yan Wong (Croucher Fellowship 2014) was an undergraduate student at the University of Hong Kong, she had never thought of pursuing graduate research and a PhD, but a year of study abroad changed her mind. 

Fascinated by the microscopy tools used by Professor Edwin Levitan’s lab to monitor the dynamic processes of neurons in live animals, Wong decided to pursue her PhD training under Professor Levitan’s mentorship at the University of Pittsburgh, with a focus on neuropeptides transport and release. Neuropeptides are a class of protein-like neurotransmitters released from neurons to modulate the function of other cells, hence regulating a wide range of important neurophysiological processes such as behaviour, learning and memory.

Dr Man-yan Wong, Croucher Fellowship 2014

Because neurons are highly extended and differentiated, with the neurotransmitter release site, the synapse, located at distant nerve terminals, neuropeptides produced at the cell body have to be delivered efficiently to the synapse in order to replenish their constant depletion at the synapse. Wong was particularly interested in delineating the logistics underlying neuropeptides transport. Specifically, how individual neuropeptide-containing cargo, the dense-core vesicle, is routed along the axon to reach the destination synapse. By genetically adding fluorescent tags to neuropeptides, Wong labelled the vesicles in fruit flies and monitored the movement of these vesicles in neurons.

The study would improve our understanding of the pathology of various neurodegenerative diseases, as growing evidence has shown that deficits of axonal transport are associated with neurodegeneration. Nevertheless, the research question Wong chose turned out to be quite challenging and would require good doses of creativity and determination to overcome. “The neurons were filled with tens of thousands of labelled vesicles all moving in different directions. Even after photobleaching all the vesicles at the synaptic terminal, large amount of unbleached vesicles would refill the bleached area quickly, making it impossible to track the movement of each and every vesicle.”

To overcome this, Wong thought of a clever trick to deplete the fluorescent signal from all but one vesicle, thus making the vesicle much more tractable. “Think of it as tracking thousands of children in a busy airport terminal,” Wong said. “Say if all these children are each carrying a green balloon. In order to isolate the trajectory of one particular child within a section of the terminal, you not only have to pop all the pre-existing balloons within the section, but all the subsequent balloons from other children after the first child enters the section.”

This analogy explains the principle of the simultaneous photobleaching and imaging technique Wong developed. Wong imaged and monitored the movement of the first unbleached vesicle that entered the photobleached region, while using additional laser to continuously photobleach the entrance of the nerve terminal, thus preventing contaminating signals from other unbleached vesicles and allowed for the tracking on single vesicle easily. Using this novel imaging technique, Wong was able to show that instead of having many “one-to-one highways” between the cell body and each synaptic terminal, neuropeptide vesicles appeared to circulate within the neuron. During delivery, vesicles enter the nerve terminal and pass through multiple synapses, only sporadically would they be captured at specific synapses. Upon arrival at the most distal synapse, vesicles would return and continue their journey back to the cell body, meanwhile still be sporadically captured at synapses that are in need. This elegant cellular delivery system works similarly to the conveyor belt in sushi restaurants, where sushi dishes are continuously supplied and circulating for instant consumption by patron on-demand. The finding was published in Cell.

Towards the end of her PhD training, Wong got an opportunity to intern at Genentech, a biotech company based in the San Francisco area, with a focus in studying the mechanism of axon degeneration using biomedical imaging techniques. The internship experience has made Wong realized the potential of her basic research background in contributing to translational research and drug development. She has also found it satisfactory to work on research projects that could more directly impact patients. With that in mind, after completing her postdoctoral training at Harvard Medical School, Wong joined Novartis Institutes of Biomedical Research to continue her research career, leveraging her skills and knowledge in neuroscience on drug development.

Dr Man-yan Wong is currently an Investigator at Novartis Institutes. Previously, she received her PhD in Molecular Pharmacology from the University of Pittsburgh and post-doctoral training at the Harvard Medical School. She is the recipient of the Croucher fellowship and the Edward R and Anne G Lefler fellowship, and was selected as one of the top young scientists to participate the 65th Lindau Nobel Laureate Meeting in summer 2015. 

To view Dr Wong’s Croucher profile, please click here