Grains of salt explain cystic fibrosis.

For decades, scientists have searched for a thread that could unravel the deadly mystery of cystic fibrosis, a genetic ailment that kills 1 in 2,400 whites and 1 in 17,000 blacks worldwide during what might have been the most productive years of their lives.

Now, researchers may have found just such a thread. Reporting in the April 19 Cell, investigators at the University of Iowa College of Medicine in Iowa City say that their work promises to clear up many stubborn questions about the disease-and that it may ultimately lead to newer, more effective treatments.

The investigators began their work by trying to answer perhaps the most perplexing question about cystic fibrosis: How does a genetic defect turn ordinarily sterile lungs into mucus-clogged breeding grounds for harmful bacteria? They knew that the defect in the cftr gene prevents the channel that normally carries chloride ions into cells from forming.

Although the research was remarkably complex-it used lung tissue grown in the laboratory from cells of people with cystic fibrosis and from cells of healthy people-the answer appears to be simple. Cells lining the inner surface of the lung produce a natural antibiotic that works only in a low-salt environment.

In cystic fibrosis, the lack of a working chloride gateway results in airway surface fluid that is loaded with salt.

"It's a paradigm shift in our understanding of cystic fibrosis," asserts team member Jeffrey J. Smith. "Now that we have a clear understanding of what the problem is, we can begin asking how we fix the problem and come up with solutions that begin to make sense."

How the water-salt imbalance occurs is a matter of elementary biochemistry.

Sodium and chloride, the two components of salt, travel in lockstep. When chloride is unable to enter lung cells, salt accumulates in the airway surface fluid. The natural antibiotic appears unable to combat infection in this brine.

The Iowa researchers placed bacteria on the lung tissues grown in the lab.

They found that normal tissue killed the bacteria and that cystic-fibrosis-afflicted tissue did not-until they reduced the amount of salt in the surface fluid.

"My reading of the paper is that this is pretty solid," says Jeffrey J. Wine of Stanford University. "The next thing they'll do is try to identify what the lung secretes that has this antibiotic property, isolate it, modify it so that it is not susceptible to salt, and then give it to people."

Smith agrees. "If we could correct the natural mechanism for killing bacteria, it would lessen the inflammatory process and ultimately lessen damage to the lung."

The action of the natural antibiotic is similar to that of compounds that have been found in insects, frog skin, cow lungs, and human intestines. In the lung fluid, it appears to be effective against several microorganisms and is hardy enough to withstand boiling for 10 minutes, Smith and his colleagues report.

Using a synthetic version of the substance found in frogs, Magainin Pharmaceuticals of Plymouth Meeting, Pa., has already begun to make a natural antibiotic intended for the treatment of cystic fibrosis.

Smith plans to look in the human lung and perhaps further afield. "Could there be animals living in the sea that make natural antibiotics that aren't sensitive to salt?" he asks.