The root problem, and even its immediate physiological consequences, are crystal clear in cystic fibrosis. A mutation leads to a nonfunctional chloride channel.

But despite the fact the defective gene was identified in the 1980s, and that its discovery improved cystic fibrosis therapeutics, there is still no cure, and the median life expectancy for cystic fibrosis patients is a much-improved, but still much too brief, 36.5 years.

Though the defective channels are not limited to the lungs, cystic fibrosis patients most often succumb to lung disease.

Because of the defective channel, the mucus coating the lungs cannot be kept moist by normal osmotic processes, and as a result, patients are prone to bacterial infections.

Part of the problem in bringing cystic fibrosis therapeutics to market is the usual one for rare diseases, despite the fact that the Cystic Fibrosis Foundation has been a prime mover in venture philanthropy. (See BioWorld Today, May 9, 2007.)

But even at the most basic science level, new discoveries continue to be made about the mechanisms of cystic fibrosis. Two recent papers explore the relationship between the channel and the cellular protein processing machinery - both investigate how the mutant channel is processed differently in the endoplasmic reticulum, and how its absence affects the processing of other proteins in the golgi network.

The trans golgi network is an intracellular organelle that processes proteins. Among other things, proteins are glycosylated, which means they have sugars added to them, in the trans golgi network. In cystic fibrosis patients, the trans golgi network is more acidic than usual, because the inability to transport chloride leads to an accumulation of positively charged protons. In the first paper, published in the Oct. 18, 2007, issue of the Journal of Clinical Investigation, researchers from the University of New Mexico reported on how the increased acidity alters the activity of furin, an enzyme that glycosylates proteins in the trans golgi network.

In the JCI paper, the researchers compared cultures of cystic fibrosis cells to cultures of airway epithelial cells where the defect had been genetically corrected. They found that furin was more active in the acidic trans golgi network of the cystic fibrosis cells. That activity in turn makes the cells more sensitive to P. aeruginosa via two separate mechanisms.

The active furin leads to an increased release of the cytokine TGF-beta from the trans golgi network; that in turn down-regulates macrophages, making them less effective in fighting P. aeruginosa.

In addition, the active furin appears to directly help P. aeruginosa become more infective. The bacterium is among the pathogens that co-opt the network for their own processing, and the more active furin leads to higher levels of the P. aeruginosa's main toxin, ExoA, which in turn led to higher levels of apoptosis in cystic fibrosis than normal cells, an effect that could be reversed by adding furin inhibitors to the culture.

The researchers concluded that in cystic fibrosis patients, the effects synergize and cause "irreversible pathology in the CF lung, which leads to respiratory failure and premature death. . . . The beneficial effects of furin inhibitors described here strongly suggest that furin is a suitable pharmacological target and that provides new opportunities for therapeutic intervention in correcting a set of linked abnormalities in CF."

Working on a different protein processing organelle - the endoplasmic reticulum, where proteins are synthesized and folded prior to getting the finishing touches in the golgi network - a paper in the Sept. 25, 2007 issue of the Proceedings of the National Academy of Sciences shows that the mutant channel is itself processed differently in different species.

The researchers, from the University of Iowa, focused on the most common mutation in cystic fibrosis: a channel that lacks phenylalanine-508. The mutation accounts for the majority of cystic fibrosis cases in humans.

They found that in human cells, almost all of the mutant channel is degraded in the endoplasmic reticulum and never makes it to the membrane - leading to a reduction of chloride currents by 95 percent. "The protein essentially gets stuck in the endoplasmic reticulum," first author Lynda Ostedgaard told BioWorld Today, "because it doesn't pass quality control."

In both pigs and mice, the mutant channels were processed more like the wild-type ones, and the reduction in chloride current was less severe than in humans. The authors concluded that "there is a gradient in the severity of the [mutant protein] processing defect, with human worse than pig and pig somewhat worse than mouse."

The mechanisms behind the difference are unclear, but Ostedgaard said that while pig and human sequences for the channel are 93 percent identical, the mouse is only about 80 percent identical to the human, which probably leads to folding differences.

In the meantime, the finding helps explain why a mouse model for cystic fibrosis has been hard to come by. Knockout mice typically do not develop the lung problems that are the main enemy of cystic fibrosis patients. Indeed, Ostedgaard said, that failure is the reason the scientists are working on a pig model for cystic fibrosis in the first place.