October 1994

The cystic fibrosis gene may have survived through hundreds of human generations because it gives protection against cholera.

Studies at the University of North Carolina School of Medicine at Chapel Hill have found that laboratory mice carrying cystic fibrosis genes did not suffer the deadly diarrhea that is typically caused by cholera.

This, said a researcher who conducted the study, Dr. Sherif E. Gabriel, may explain why cystic fibrosis is one of the most common gene defects.

"The frequency of the CF gene has caused people to speculate for many years why it was at such a high level," Dr. Gabriel said. "When you have a gene that codes for a fatal disorder, you expect the numbers in the popula-tion to continually be decreasing. But this has not happened with CF."

A report on the research is being published on Friday in the journal Sci-ence.

A basic belief in evolutionary biology holds that genes survive over thou-sands of generations only if they confer some advantage to the species. If a gene confers a disadvantage, like a lethal disorder, the theory is that it will eventually disappear from the gene pool because carriers of the gene would not have the opportunity to reproduce as frequently as those who did not carry the flawed gene. But the CF gene has not obeyed this rule. About 1 in every 20 Caucasians carries a CF gene. A single copy of the gene does not cause the disorder.

When two carriers become parents, however, their children have a 1-in-4 chance of inheriting two CF genes. This would cause cystic fibrosis, a dis-order that until recent decades was nearly always lethal at a young age.

Cystic fibrosis kills because it prevents the normal flow of salts out of the gut and lungs. This leads to formation of a thick mucus that can obstruct the intestine and block breathing in the lungs.

Dr. Gabriel said the CF gene protected carriers against cholera because it blocked the same molecular pathway used by the disease toxin to cause diarrhea.

Cholera kills by causing a severe and unrelenting loss of fluid. Most of the disease victims die from dehydration. Some victims can lose up to a pint of fluid an hour from uncontrolled diarrhea.

Clue to Why Cystic Fibrosis Has Survived

New York Times 1

October 1994

Dr. Gabriel said cholera did not have this effect on mice that carried the CF gene.

In his study, Dr. Gabriel said, he used 60 mice divided into three groups. A third had a normal gene complement. A third carried one CF gene, and the final group carried both of the CF genes. The mice were then injected with cholera toxin.

Mice with the normal gene complement died from a typical cholera diar-rhea. But those with one CF gene suffered from a diarrhea that was only half as severe. And mice with both CF genes did not suffer the cholera symptom at all, Dr. Gabriel said.

Cholera has historically killed millions of humans and is currently epidemic in parts of India and Peru. The disease is usually spread through contami-nated food or water. Most people recover only if they get pure water, salts and sugars to replace that lost to diarrhea.

Dr. Gabriel suggested that in the great cholera epidemics that have struck humanity over the centuries, carriers of the CF gene would have had a better chance of surviving than would people who had the normal gene complement. In this way, the CF gene would have been carried forward, from generation to generation, in sufficient numbers to remain a part of the human gene pool.

Clue to Why Cystic Fibrosis Has Survived

New York Times 2