Where chemistry meets biology
At the intersection of chemistry and biology, Clive Chung (Croucher Fellow 2015) is exploring the development of chemical compounds for the diagnosis of cancer and a better understanding of neuron cells.
While it may seem like cancer cells don’t have much in common with healthy neuronal cells, reactive oxygen species (ROS) are found to play important roles in both cells for signaling proliferation and communication.
These reactive oxygen species make up a family of compounds including hydrogen peroxide, superoxide, and hypochlorous acid, some of which are found in the body.
While it was once thought that ROS simply aided the immune system by killing bacteria, advances in our chemical toolbox and improvements made in imaging techniques have revealed that these reactive species are actually very important for cell communication.
“Neuronal cells can talk to one another using these reactive species as signaling messengers,” says Chung. One example is learning and memory.
NADPH oxidases (Nox) are enzymes expressed throughout the central nervous system (CNS) and are major sources of ROS production in our brain. It's been found that both mice and humans lacking functional Nox have cognitive deficiencies, suggesting that ROS signaling is essential for normal brain function and development.
“Our body is very smart,” he goes on, “it keeps a very tight regulation on the concentrations of these reactive species. If a signaling event occurs, there will be a burst increase in the concentration of the reactive species, followed by a quick decrease back to normal levels in most cases.”
Regulating the balance of ROS is critical as overproduction of ROS can cause oxidative damage and lead to cell death. Interestingly, cancer cells show higher ROS levels than normal cells, probably owing to aberrant cell metabolism and the activation of oncogenes (cancer causing genes).
The cells adapt to survive under this oxidative stress and utilize this high level of ROS to transduce signals that can promote uncontrolled tumor growth, proliferation, and metastasis, which is the spreading of cancer from one organ to another.
As far as cancer prognosis goes, this is one of the worst things that can happen. Prostate cancer, for example, often metastasizes to the bones, and once cancer has metastasized, current treatments are rarely able to kill it, leading to a dramatic increase in the likelihood of death.
In view of the significant impact of ROS on the physiology of cancer and neuronal cells, it's believed that selective and sensitive detection of ROS can lead to better diagnosis of cancer and neuronal diseases, which, in turn, will lead to the development of more effective therapies as well.
Greater imaging ability
Luminescence imaging is a powerful technique that shows good spatial and temporal resolution; and while it does have its drawbacks, it's demonstrated great success in understanding molecular signaling.
Right now, some luminescent probes for ROS have already been developed. But while they are useful at the cellular level, in larger masses of cells they are far less effective.
As studying ROS levels in these larger, more complex biological samples is believed to provide valuable information on cell-cell communication, Chung is working on developing new chemical modalities for imaging ROS not only at the cellular level, but also in tissue and small animals.
With careful design of the chemical structures of ROS probes, the probes will be able to stain ROS in biological samples permanently. Therefore, unlike current luminescence probes that leak out from samples readily upon fixation, new probes developed by Chung will be able to work effectively in larger tissue sections of organs and tumors.
Together, the high selectivity and sensitivity of the probes enable better imaging of the ROS. With a more accurate image, it's easier to differentiate between which cells are metastatic cancer cells, which are non-invasive cancer cells, and which are harmless, non-cancerous cells.
Going forward, Chung hopes to use this new ROS imaging tool to better tame and control the spread of cancer; and more importantly, to determine the metastatic power of cancer in patients. With a better understanding of the threat, doctors will be able to put together a treatment plan to more effectively curb the risk of metastasis.
Chung has also utilized the probes for studying neurons, as they are the main communicators in the body. Currently, ROS signaling in neurons is still not fully understood; it's still unknown from how far away a neuron is able to talk to another using ROS as a messenger. With these newly developed probes, Chung hopes to answer this question and unravel even more mysteries related to ROS signaling in neurons.
In addition to the new probes that can permanently stain ROS in biological samples, Chung is interested in investigating ROS signaling across different organs and tissues in small animals.
As current luminescent probes rely on two passes of light through the sample (inbound light for excitation and the outbound light that is observed) larger masses of cells like organs or entire animals are an obstacle in getting a clear view of the sample.
To remedy this, Chung is working on new classes of bioluminescent probes for ROS. Bioluminescent probes would excite and release light in the presence of certain substrates, offering a clearer signal, with the light unobstructed by an additional pass through tissue. Subtle engineering of the photophysical properties and functionalities of these new bioluminescent probes will hopefully result in superior ROS imaging in small animals.
A first taste of Science
Since secondary school, Chung has had a strong interest in chemistry. After participating in a chemistry competition, the Hong Kong Chemistry Olympiad for Secondary Schools, Chung knew he wanted to pursue a career in science.
The contest consisted of attacking a problem by putting together an experiment and reporting the findings, the essence of the scientific method.
Chung’s experiment sought to find foods that when eaten together, weren’t good for our health. For example, vegetables containing oxalic acid combined with a food like bean curd, containing calcium, could result in the formation of calcium oxalate, a component in kidney stones.
“This competition really gave me the first taste of experimentation and designing a project,” says Chung, and while now he calls the hypothesis crazy, this competition certainly set him on the path for a life in science.
Though he majored in Chemistry in his undergrad, he fortified his chemical knowledge with biology, picking up a lot of biochemistry courses.
Chung believes that science should be viewed holistically, without the sharp dividers between disciplines that have existed for centuries. His research just goes to show how much more can be accomplished when one is willing to dip their toes in the knowledge on the other side of the barrier.
Years later, with tools and materials far more complicated than test tubes, orange juice, and bean curd, Chung is still walking the same path between disciplines, building bridges that may one day save lives.
Clive obtained his BSc (Chemistry) at the University of Hong Kong in 2008. With strong interest in the development of new chemical tools for biological and biomedical applications, he worked under the supervision of Prof. Vivian Wing-Wah Yam in the University of Hong Kong, focusing on luminescence imaging of DNAs, proteins and cancer cells based on supramolecular interactions of platinum(II) complexes. He received his PhD in 2013, and worked as a postdoctoral fellow of Prof. Chi-Ming Che in the University of Hong Kong, in which he investigated anti-cancer properties and nano-formulations of metal complexes. He is now studying at the University of California, Berkeley.
To view Chung’s personal Croucher profile, please click here.