A chance encounter leads to groundbreaking bladder exstrophy research

Professor Wei Cheng recalls the path that led to the discovery of the gene and mechanism responsible for bladder exstrophy in humans

During a recent conversation with the Association for the Bladder Exstrophy Community, Dr. Wei Cheng (郑伟) recounted his chance encounter with bladder malformation in a mouse. This encounter ultimately led an international research team to identify the gene and mechanism that causes bladder exstrophy in humans. Dr. Cheng recalls this journey and the worldwide collaboration that made it possible. 

Professor Wei Cheng (郑伟) is both a paediatric surgeon and a molecular genetics scientist. He is currently Chair of Paediatric Surgery, United Family Hospital, Beijing and Adjunct Professor at Monash University, Melbourne, Australia. He is also a Visiting Professor at PLA General Hospital, Beijing and Capital Institute of Pediatrics, Beijing.

“The strange appearance of something in the mouse’s abdomen”

It was at Sick Kids Toronto that my involvement with bladder exstrophy took an extraordinary turn. I’m a pediatric surgeon who has always maintained a passionate interest in research and I’m forever searching for answers as to why some children are born with congenital anomalies. Back in 2002, I was at the University of Toronto studying for a PhD in Developmental Biology. I chose Toronto specifically to pursue research into anal-rectal malformation, as the team at Sick Kids Research Institute had already developed a genetic mouse model for that condition.

By chance, another research group at the Institute was working on a neurological disease using a different mouse model. They were puzzled by the strange appearance of something in the mouse’s abdomen and presented it for discussion at a regular research meeting. Staring at the slide, my boss (also a pediatric surgeon) speculated that we were looking at a malformation of the bladder. I was fascinated, and decided to dissect the mouse to investigate further. In so doing, I was able to confirm that the mouse had developed bladder exstrophy. This finding was exciting because with a mouse model, we had a chance to understand more about the condition. So at that moment, I decided to change my entire PhD research project and focus on bladder exstrophy.

A groundbreaking research discovery for bladder exstrophy 

The research took almost 5 years to complete, but using the model we were able to identify both the gene and the mechanism that causes bladder exstrophy…in a mouse. When gene p63 mutates, it leads to an unstoppable process of programmed cell death, or apoptosis, in the front wall of the bladder and this results in bladder exstrophy. These results were published in the influential scientific journal, “Development.”
However, my ultimate goal was always a clinical one. As a doctor, I believe the real power in medical research comes when we translate findings for clinical application. We call this “translational research.” I was determined to prove whether the findings from this mouse model were equally applicable to the human condition.

Bladder exstrophy community collaborates in global research effort

In 2008 I relocated to Australia to take up a position as Professor of Paediatric Surgery at Monash University in Melbourne. There, I immediately focused the efforts of my research laboratory to study gene p63 and bladder exstrophy in humans. Because bladder exstrophy is a rare disease, occurring in just 1 in 40,000 newborns, I knew this would require an international collaboration effort. To ensure our results were statistically significant, we set about the difficult task of collecting DNA from many countries around the globe, including medical centers in USA, Canada, Spain, China, India, Bangladesh, Malaysia and Australia. Civil Hospital in Ahmedabad was one of the first centers to be involved and DNA was collected during the 1st Annual Workshop for Exstrophy-Epispadias Complex. This Workshop is now in it’s 9th year. At that time, I also reached out to BE support groups like BEECHAC Australia and A-BE-C in the USA. Families and patients willingly came forward to participate in the study, and I am forever grateful for the enthusiastic support of the BE community to the research project.

The future of bladder exstrophy research 

At Monash University, I led a small team of post-doctorate fellows and PhD students to ultimately prove that a mutation in p63 is indeed associated with bladder exstrophy in humans, solving a mystery that has long confounded doctors and affected families alike. The research findings also shed light on associated anomalies, like spina bifida and cleft palate that sometimes occur in bladder exstrophy patients. The findings were published in the leading journal, “PLOS Genetics.”
I am now based at United Family Hospital Beijing, having returned to my hometown after almost 40 years outside China. I believe that for our understanding and treatment of these rare diseases to progress, we need to concentrate the treatment of patients in a limited number of centers. In India, Civil Hospital in Ahmedabad is already leading the way in this regard, and I am hopeful that China will adopt the same approach. What is impressive is that Civil Hospital has rapidly amassed the skills and experience, and with their commitment the team is able to undertake the most complicated cases. In addition, the transfer of knowledge and skills through the participation of some of the world’s leading BE surgeons, represents a remarkable collaborative effort which I’m proud to be involved with.
As a surgeon-scientist with an active interest in genetic research, I believe that further advances in bladder exstrophy will come only from a concerted collaborative effort between both clinical study and basic science research and I remain fully committed to my endeavors in both these disciplines.

Professor Wei Cheng (郑伟), Chair of Paediatric Surgery, United Family Hospital, Beijing and Adjunct Professor at Monash University, Melbourne, Australia, and Visiting Professor at PLA General Hospital, Beijing and Capital Institute of Pediatrics, Beijing.