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Breathing Easier

Just over 20 years ago, a discovery was made that rocked the international medical research establishment: scientists at The Hospital for Sick Children had discovered the defective gene that causes cystic fibrosis.

No one was more excited than cystic fibrosis patients and their families. CF is a fatal disease affecting 1 in 2,000 to 3,000 Canadians.  It can cause gastrointestinal disease, liver disease, pancreatic disease, reproductive disorders and diabetes, and above all lung disease, the most common CF-related illness which is responsible for most CF-related deaths.

The discovery was led by former SickKids scientist, Dr. Lap-Chee Tsui, who became Vice-Chancellor and President of the University Hong Kong in 2002 and continues to serve as adjunct scientist at SickKids Research Institute.  He pioneered methods to identify the gene defect, and these methods have since been applied to the search for genes that cause other diseases.

It was no accident that the discovery happened at SickKids. With its long history of close interaction between basic research scientists and clinical scientists, and its critical mass of innovative thinkers, SickKids was – and is – poised for success. Scientists collaborate across disciplines, inside and outside SickKids, and contribute to the organization’s reputation as an international leader in research and patient care.

SickKids is home to a cluster of prominent CF researchers, including Christine Bear, who began investigating CF in 1989. A senior scientist in the Molecular Medicine Program and a professor of physiology and biochemistry at University of Toronto, Dr. Bear and Dr. Felix Ratjen – Division Chief for Respiratory Medicine, H.E. Seller’s Chair in Cystic Fibrosis at SickKids, a senior scientist in Translational Medicine and a professor of paediatrics at U of T – are co-leaders of the SickKids Centre for Cystic Fibrosis, established in 2007 to integrate care, research and learning and target new discoveries to the needs of patients.  

Dr. Christine Bear and Dr. Felix Ratjen


In 2004 Dr. Bear and her colleagues received funding from the Canadian Cystic Fibrosis Foundation and the Canadian Institutes for Health Research for an initiative called the BREATHE CF research program. By the time the program ended in 2009, her team had made considerable progress. For one thing, it had identified cellular pathways involved in correcting the defect caused by the major disease causing mutation- called deltaF.  Several proteins in these pathways are already in use in FDA-approved drugs; now the team hopes to move toward preclinical and clinical trials to prove their value in fighting CF. SickKids Corporate Ventures is pursuing commercialization of this discovery and others  made by the BREATHE program.

BREATHE researchers have also made great strides in developing methods for assessing drug efficacy in clinical trials, thereby improving the reliability of these trials and potentially shortening the time needed for bringing new therapies to the clinic.


Drs. Christine Bear and Felix Ratjen, co-leaders
of the SickKids Cystic Fibrosis Centre.

The key to preventing the disease in the first place is found in basic research – the kind of open-ended inquiry that doesn’t assume certain results – Dr. Bear says. At issue is the severity of CF, which varies greatly from one patient to another. As well, it is still unclear whether the chemical compounds that work in the lab will work in patients. The variability has been traced to secondary genes which influence the impact of CF mutations, and this is where the solution lies, she predicts.  

“Our goal at SickKids is to find how exactly these chemical compounds are working in the lab and in patients so we can inform our pharmaceutical partners about the necessary paths to discovery of drugs that are effective and safe for every CF patient. We envision a day when each CF patient will receive the best possible medication – early in life, to prevent the progression of disease.”


How the cystic fibrosis gene mutation can lead to cause and effects of CF


Mutations in the CF gene.

 SickKids is a leader in understanding how mutations in the cystic fibrosis gene can lead to the cause, development and effects of CF.

“We were the first to identify the mutation in the CF gene. Normally the CF gene leads to the production of the protein CFTR (the normal version of CFTR is shown in image at left), and this protein has a critical role in keeping a thin layer of fluid on the surface of cells, lining the airways and other affected organs,” says Christine Bear. “The thin layer of fluid helps to keep the airways clear of sticky mucus and bacteria.  

“The major mutation which causes disease in greater than 90 per cent of patients is called deltaF508. We know that this mutation causes the CFTR protein to become misfolded and trapped inside cells so that it cannot work on the surface to maintain a normal fluid layer. Our researchers, together with their international collaborators, showed that certain chemicals are capable of getting into cells and rescuing the mutant protein so that it escapes the intracellular trap to reach the surface and restore normal fluid.”