Unravelling mysteries: a love affair with CFTR

20 July 2017

Professor Chan Hsiao Chang has spent her research career looking at the role of cystic fibrosis transmembrane conductance regulator (CFTR) in a variety of issues and its defects associated or specific to people with cystic fibrosis (CF).

Professor Chan Hsiao Chang (Croucher Senior Research Fellowship 2007) was recently awarded the status of Emeritus Professor when she retired from the Chinese University of Hong Kong on 1st August this year. Chan was Professor of Physiology and Director of the Epithelial Cell Biology Research Centre, a centre that she helped establish. Chan spent almost 30 years delving into the mysteries of CFTR while also inspiring a new generation of CFTR researchers.

Chan was influenced in the classroom, “I was inspired by a teacher who said the next century would be biology,” she explains. It took some time to discover her true passion, following various streams of biology until finding the right fit. “I really wanted to do something original, so I moved to the University of Chicago and found my interest in CFTR,” she says.

Chan describes her relationship with CFTR research a ‘half-life love'. Her passion can be evidenced by the impressive range and depth of her research. Her specific focus has allowed her to follow up on various issues arise from a CFTR defect. “CFTR is everywhere in the body. So its mutations would present a lot of physiological problems,” she points out.

Patients with cystic fibrosis present a number of clinical manifestations that affect various tissues and organs, but many research in the West are focusing on CF lung disease, the major cause of death. “My understanding is that people actually overlooked the importance of CFTR in basic physiology,” she states.

Her work has led her to a variety of research collaborations, including understanding why CFTR defect leads to infertility. “I was not trained as a reproductive biologist,” Chan points out the need for collaboration. “The first thing I tried to understand was how CFTR works in reproductive function, which might provide some clues as to how a CF defect could lead to infertility,” she says. “So I needed to collaborate with people who are experts in reproduction or reproductive biology.”

Following her idea of the importance of CFTR’s role in the whole body, Chan continued her research. “I know that CFTR causes a lot of problems, like diabetes. There is no clear answer as to why a CF patient would develop diabetes,” she explains. “So I am actually moving around the pathological phenotypes of CF, trying to give answers to all different diseases.”

When it came to diabetes in people with cystic fibrosis, Chan found that CFTR had a role in pancreatic ß-cells, which no one had previously looked at. “A lot of people did not recognise CFTR is expressed in ß-cells,” she says.

“The thing is CFTR is strongly expressed in ductal cells. That is why a lot of studies focused on pancreatic ducts,” Chan explains. “We started looking into CFTR in pancreatic ducts and we initially hypothesised that the defect in the bicarbonate secreted from the duct would affect ß-cell function.” However, what they saw didn’t support this idea, so Chan and her team tried putting a CFTR inhibitor in the ß-cell, “all of a sudden, we found wow - it has an effect on insulin secretion, so we had to completely change our thinking,” Chan exclaims. Chan uses this as a good way to teach her students about making incorrect assumptions, “even a weak signal, we have to confirm whether that is real or not, otherwise we miss a lot.”

She also tried to understand the role of CFTR in development. The first thing Chan and her team recognised when using CF mice was that they could not get enough mutant mice. “We were getting way below the mendelian ratio. Supposedly we should be getting the homozygous ratio of 1 out of 4,” she says. This result piqued her curiosity and caused her to posture there may be a severe defect in the early stages of development of CF mice.

This led to a study published on CFTR and embryo development. “We found, for the first time, CFTR in embryonic stem cells,” Chan says, explaining that they were trying to understand how it works.

“The team found that the ESCs of the knock-out mice have defects in mesoderm/endoderm differentiation,” Chan says. “It is known that mesoderm/endoderm differentiation would be important for the development of bone, heart, intestine and pancreas, so that actually explains a lot in terms of developmental defects that nobody has ever explained.”

Chan also found more answers in this research. "We also discovered that CFTR is interacting with an important signalling pathway, the ß-catenin pathway which is vital for embryo development. That actually links to why defects in CFTR could lead to developmental defects."

Chan explains that her publications and awards pale in comparison to the enjoyment she gets from her daily work. "Every day is a highlight because I am excited by so many ideas and CFTR interests me every day," she explains.

While she doesn't know the future of the research centre she established at CUHK, Chan does know she has inspired a new generation of CFTR researchers. "I have lots of students who have graduated and work in China, I can see a lot of CFTR research coming out of China, and I am glad. I know, at least, I'm partly, if not mostly, responsible for the increased interest in CFTR in China, and I am quite pleased with that," she says happily. So while Chan has retired from science this will not be the end of her work, "I am quite positive that my students in other institutes will be doing a lot of things on CFTR."

"Lucky me, I found a real love in CFTR research," she says.

Professor Chan is a leading authority in epithelial cell-related research with broad interests in a number of related fields, including reproductive tract functional genomics, epithelial transport and signaling mechanisms, epithelial-derived cancer metastasis, epithelial differentiation of stem cells as well as epithelial-mediated mucosal immune defense mechanisms. She was the founding Director of the Epithelial Cell Biology Research Center, first of its kind ever found in China. She has contributed significantly to a number of important discoveries, including a cell shrinkage-activated cation channel (Science 1992), a novel defensin molecule in the epididymis and its role in sperm maturation (Science 2001, Nature Cell Biology 2004), the role of CFTR in male and female fertility and infertility (Nature Cell Biology 2003, PNAS 2007), and signaling mechanism underlying embryo implantation (Nature Medicine 2012).

In 2017, she was awarded the title Emeritus Professor by The Chinese University of Hong Kong.