A totally lethal gene mutation, so the theory goes, would disappear from the population fairly soon, having killed off all the individuals harboring the mutant in their genome. Aberrant genes survive, in theory, because they confer an advantage on individuals who carry them that makes up for their pathogenicity. A well-known example is sickle-cell anemia, caused by a mutant hemoglobin gene. It produces misshapen red blood cells, which jam up the capillaries in the circulation. The sickling gene occurs mainly in people of West African ethnic origin, where it protects carriers of the mutant against malaria. If only one parent carries the sickling trait, he or she may pass it on harmlessly to the couple's offspring. But if both mother and father have the mutation, their children are born with a one-in-four chance of inheriting the life-threatening anemia, by being homozygous. Just as the sickle-cell gene predominates in black people (about 9 percent of African-Americans carry it), so the mutant gene for cystic fibrosis (CF) is the most common, fatal, homozygous recessive disorder of the Caucasian population. Now it turns out that CF has persisted down through the ages because it protects against cholera, a worldwide scourge throughout human history. How CF Works Against Cholera This week's issue of Science (Oct. 7) tells the story, titled "Cystic Fibrosis Heterozygote Resistance to Cholera Toxin in the Cystic Fibrosis Mouse Model." The mutated gene product in CF is called the cystic fibrosis transmembrane conductance regulator (CFTR). This protein reduces the flow of chloride ions (Cl-) across the membranes of many epithelial tissues, notably those of the intestinal tract. Thus, many infants born with the mutant gene from both parents die quickly of meconium ileus, an obstruction of their small bowel. Children who survive this neonatal threat to life have usually died young of blockages to pancreas, airways and other organs by thick mucus deposits. In recent years, improved medical care has somewhat lengthened CF life expectancy. Cholera, on the other hand, kills by opening cell membranes to the uncontrolled discharge of water and its dissolved electrolytes. This efflux swiftly and fatally dehydrates its victims. (Two-thirds of the body consists of water.) In this lethal secretory diarrhea, as in CF, the chloride-channel is implicated. As the principal author of the Science paper, Sherif Gabriel, an electrophysiologist at the University of North Carolina, points out: "These two diseases are connected by the cAMP-regulated, Cl- channel CFTR." Gabriel noted that cAMP, cyclic adenosine monophosphate, is ubiquitous in intestinal epithelium, where it regulates chloride-ion (Cl-) channels and fluid secretion that ensues. "This chloride permeability," he wrote, "is mediated entirely through CFTR." The long-held hypothesis that CF endows its carriers with a selective advantage against cholera (as sickle cells do against malaria) has remained a hypothesis, Gabriel told BioWorld Today, for lack of an animal model to test it. His co-authors created such a surrogate in mice by successively cross-breeding normal mice with rodents in which they had knocked out the CFTR gene. Eventually, they had three model strains: u knockout animals lacking the mutant gene entirely _ CFTR-/-, u heterozygotes carrying only one mutant gene, _ CFTR+/-, and u homozygous mice, i.e., with genes mutated in both chromosomal arms _ CFTR+/+. (The CFTR gene resides on the long arm of human chromosome 7.) First, Gabriel's group administered 10 micrograms of cholera toxin to normal homozygotes. Six hours later, the animals' intestines were full of water. In cystic fibrosis homozygotes, the same cholera toxin dose produced no fluid outpouring whatever. "Intestinal fluid secretion," the Science paper reported, "was highest in the CFTR+/+ mice, intermediate in the CFTR+/- mice, and lowest in the CFTR-/- mice." Gabriel suggests that "a plausible explanation of our results is that fluid and Cl- secretion are proportional to the amount of CFTR protein expressed in the intestinal epithelium." Hypothesis Is Proven The fact that one in 20 Caucasians harbors one copy of the mutant gene," Gabriel said, which is "higher than expected, supports the hypothesis that this trait protects its carriers against cholera." He cited a historical study, which calculated that "a mere two percent increase in the number of CFTR carriers some 23 human generations ago, when cholera ravaged the population of medieval Europe, would cause the carrier frequency we see today, specifically because of the cAMP and CFTR connections between the two diseases." Beyond at last bolstering the hypothesis, Gabriel sees clinical utility in the CF-cholera connection. "It's of clinical interest to the secretory diarrhea of cholera, which remains one of the leading causes of infant mortality around the world." He added, "That's certainly one of the main aspects we'll be looking at. If we could potentially utilize some of the agents we know of that inhibit CFTR, we have a chance at pharmacological intervention against secretory diarrhea." He concluded, "I guess the biotechnology field is probably the best place to go with it." n
-- David N. Leff Science Editor
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