Purkinje cells in red. Courtesy of ZEISS Microscopy, https://creativecommons.org/licenses/by-nc-nd/2.0/

The role of secretin: how biological research is interrelated

17 February 2017

Professor Billy Kwok Chong Chow is one of Hong Kong’s most distinguished scientists, known for his expertise in molecular endocrinology and internationally recognised for his pioneer research into the novel functions of the human hormone, secretin.

Born and raised in Hong Kong, where he attended Diocesan Boys School, Chow developed an early interest in biology and when his family later emigrated to Canada, he completed a degree in physiology at the University of British Columbia (UBC).

“Ever since high school, at maybe 15 or 16 years of age, I’ve wanted to be a university professor,” said Chow. Outside work, Chow is also an accomplished Argentinian tango dancer and an avid collector of rare orchids.

Molecular biology was becoming established as an exciting new field while Chow was completing his undergraduate studies, so he chose this as a PhD subject within the department of biochemistry at UBC, while retaining an interest in neuroscience and physiology.

On completion of his PhD, he was offered post doctorate positions both at the University of Oxford and University of Kyoto but instead opted to return home and accepted a faculty position at the University of Hong Kong (HKU) in 1991. Initially, Chow looked for research areas that were achievable in Hong Kong, where funding for research was limited. Chow’s work focused on the functional characterisation of the secretin family of peptide hormone and receptor genes.

Professor Billy Chow

Secretin in the brain

Although secretin was the first hormone discovered in human history (by Starling and Baylis in 1902), knowledge of the hormone was limited to its gastro-intestinal functions. Before Chow and his team made significant breakthroughs into understanding the hormone, very little was known about the action of secretin on other parts of the human body.

To progress further into secretin research, Chow’s team made two transgenic mouse models. One with the secretin receptor gene deleted from the genome (secretin receptor knockout) and one with the secretin deleted from the genome (secretin knockout). These two animal models allowed Chow to ask specific questions about the actions of the hormone. The receptor knockout provided an animal model in which when secretin was added, there would be no response due to the lack of a receptor, providing the best control over the system.

“With the secretin knockout, if we put exogeneous secretin back into the system and if it gave rise to any physiological effect, we could draw conclusions,” explained Chow. The models were an expensive and time consuming investment that were to reap dividends over future years.

By using these models, Chow and his team discovered that secretin functions in the brain, particularly within the hypothalamic–pituitary-kidney axis, involve a complex set of direct influences and feedback interactions with higher brain centers, to regulate water and salt homeostasis. Together with his group’s effort in finding secretin’s direct neuroactive functions in the cerebellar Purkinje cells to control motor learning, secretin is now is re-classified as a neuroactive and neurosecretory hormone. These key discoveries represented a paradigm shift in endocrinology and the Croucher Senior Fellowship award in 2004 gave him more time and resources to pursue this line of research interest.

More recently, Chow’s team made further breakthroughs by demonstrating that secretin is related to heart disease. They discovered that secretin knockout mouse models developed pathological conditions similar to chronic heart failure problems and subsequently looked into the complex molecular mechanisms involved.

“I was not a neuroscientist before but because we found secretin in the brain, I had to learn about it. I was not a heart pathologist either but I have had to learn both disciplines because biological research is by its nature, interrelated,” Chow said.

Chow demonstrated that by removing the secretin gene, the mouse’s heart will undergo apoptosis and fibrosis. The mouse’s lungs suffer from perivascular (around a blood or lymph vessel) inflammation and edema, causing the animal to develop systemic and pulmonary arterial hypertensions. These are all pathological characteristics similar to chronic heart failure. By examining the associated molecular mechanisms, Chow believes this is related to nitrox-oxide and renin–angiotensin dysregulations. Renin-angiotensin is the hormone system involved in the regulation of the plasma sodium concentration and arterial blood pressure. When complications arise in the system, the heart can develop pathological conditions.

“It’s like writing a novel in that, once the principal characters have been formed they are in charge and it tends to write itself. We are not in control of where we might find the actions of secretin next,” Chow noted. 

In a later discovery, using the same models, Chow found that if he re-introduced secretin back into the system, it is possible to reverse these pathological conditions. This has potentially profound implications for the future treatment of some heart diseases but Chow also demonstrated the reverse was only observed in young animals (3-6 months). If the animal was older than 6 months old, it was not possible to reverse the symptoms.

“We hope that secretin could be potentially used as effective hormone replacement therapy (HRT) for certain chronic heart conditions but that is a long-term goal of my laboratory,” Chow said. 

On the basis of this discovery, his team is currently switching focus looking at the possibility of the development of an agonist and antagonist for secretin. Nevertheless, the role of secretin remains the core of his research efforts.

“That is the ultimate goal of all types of biological research- eventually we want to use our knowledge to help mankind,” he says.

Professor Billy Kwok Chong Chow graduated with a BSc and PhD from the University of British Columbia (UBC) before joining the University of Hong Kong in 1991. Currently, Chow is an Associate Dean (Development and External Relations) and Professor, Chair of Endocrinology in the Faculty of Science at the University of Hong Kong (HKU). He is a recipient of the Grace Pickford Award (2005), Outstanding Researcher Award (2005), the International Akira Arimura Young Investigator Award (2007), and the HKU Research Output Prize (2010). Chow was awarded a Senior Research Fellowship in 2004.

To view Dr Billy Kwok Chong Chow’s Croucher profile, please click here.