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About Sickkids
About SickKids

January 25, 2008

Commentary on Cystic Fibrosis research finding emphasizes the need for complimentary scientific approaches to solve complex disease problems

Toronto – Scientists at The Hospital for Sick Children (SickKids) have provided an important commentary on a research finding published in the January 25th edition of the scientific journal Chemistry and Biology . The commentary by Dr. Charles Deber, a Senior Scientist in the SickKid Research Institute's Molecular Structure & Function program, provides perspective and reflections on the results of a research study by Pissarra et al., focusing on the cystic fibrosis transmembrane conductance regulator (CFTR). The commentary is co-authored by Dr. Joanne Cheung and Dr. Arianna Rath, both post-doctoral research fellows in Dr. Deber's laboratory.

The primary gene mutation causing cystic fibrosis, F508del, was first identified by a team at SickKids in 1989. Since then, more than 1500 genetic mutations have been identified in the gene encoding CFTR. Each of these mutations can influence the way that the CFTR protein is biosynthesized, processed, folded, and transported in the cell. The challenge for scientists is to determine exactly how each of these mutations affects the function of CFTR and contributes to disease.

Scientists in several fields are now working to determine exactly how mutations in CFTR relate to structural and functional changes in the protein. Once this is understood, effective treatment strategies for cystic fibrosis (CF) may be developed. The strategy used by Dr. Deber is to study how the 3-D structure of membrane proteins relates to their function. In studying a highly complex protein such as CFTR, he employs genetic engineering to produce distinct segments or “domains” of the protein for research, specifically focusing on the domain which includes the chloride channel. In a series of publications from his laboratory, the segments from the normal protein are being compared to those containing CF-disease-producing mutations, and the structural alterations that may underlie CF disease are being characterized.

As a well-regarded expert in this area of research, Dr. Deber was asked to provide a commentary on the Pissarra paper. It has been speculated that the F508del mutation causes CFTR to misfold, but literature reports using another strategy – high-resolution X-ray crystallography – had indicated that the structures of the normal and the F508del CFTR nucleotide binding domain (NBD1) were very similar. Since several ‘background' mutations were introduced in the NBD1 domains to facilitate crystallization, Pissarra et al. used a biological approach in full-length CFTR proteins in cells to show that these mutations partially ‘corrected' CFTR function.

“The biological work described in the Pissarra paper nicely compliments the work of the chemists and biochemists working in this area,” states Deber. “Structure is the bridge between chemistry and biology, and together, they form a synergistic arsenal of techniques for finding the cause of complex diseases such as cystic fibrosis.”

This collaborative approach, of bringing different scientific disciplines together to find a treatment for diseases, is the strategy at the newly established Cystic Fibrosis Centre at SickKids. Dr. Deber is a contributing member of this new initiative.