First animal model for cystic fibrosis.

Scientists have developed the first animal model for cystic fibrosis (CF), a genetic disease that strikes one out of every 2,000 babies born in the United States. Two papers describing the research appear in the Aug. 21 SCIENCE.

Robert J. Beall, executive vice president for medical affairs at the Cystic Fibrosis Foundation, hails the new work as a major victory in the fight against this disease, which usually kills by age 30.

Two years ago, a U.S.-Canadian research team announced it had identified the defective CF gene on a specific human chromosome (SN: 9/2/89, p. 149). That report spurred John N. Snouwaert and his colleagues at the University of North Carolina at Chapel Hill to create a strain of mice carrying a genetic defect comparable to the one that causes CF in humans.

In a series of experiments, the North Carolina team disrupted the chromosome section containing the target gene. Next, the scientists mixed that defective DNA with cells taken from a developing mouse embryo. The DNA with the CF defect inserted itself into the mouse chromosomes. The researchers injected the altered cells into the mouse embryos.

They then implanted the eggs carrying the defective gene into the womb of a "foster mother" mouse. The pregnancies went to term. When the researchers examined the baby mice, they found that some had the CF genetic defect.

When carriers of the CF gene mated, some of their offspring were healthy. Others, however, inherited an illness that appeared similar to the CF that strikes human babies. For example, the diseased pups were smaller at birth and had problems with digestion, including a severe obstruction of the intestines caused by a difficulty moving sodium and chloride ions out of the epithelial cells lining the gut. Indeed, some of these pups died from the intestinal plugs.

That ion-transport defect also plagues epithelial cells lining the passages of the lungs, causing the thick mucus buildup that clogs the airways of children with CF. Further studies must determine whether the diseased mice will develop the abnormal mucus in the respiratory tract and suffer infections that typically strike people with CF, Beall says.

A second study, conducted by Lane L. Clarke and his coworkers at the University of North Carolina, adds to the evidence that the mouse model approximates the illness that strikes humans. Clarke's team demonstrated that intestinal and lung cells taken from CF mice show the abnormal ion transport that is characteristic of the human disease.

Like their human counterparts, mice with CF must inherit a defective gene from each parent. Those who inherit only one copy of the CF gene are called carriers. One in 20 Americans . carries this defect but shows no outward symptoms of the flaw, Earlier work at the University of North Carolina had demonstrated that an aerosol form of a diuretic drug slowed the pace of lung damage in young adults with the disease (SN: 4/28/90, p.260). The mouse model will accelerate the pace of such research by allowing scientists to test combinations of drugs a step that can be dangerous to take with human volunteers, says Richard C. Boucher, who took part in the drug study as well as the two new mouse studies.