By William J. Cromie
Millions of people in the United States, Canada, and Europe carry a ticking time bomb in their cells -- a mutated copy of a gene known as CFTR. If both mother and father possess the mutation, each of their children has a one in four chance of dying before age 30.
A single copy of the mutated CFTR gene is present in one out of every 20 people of European origin. The 25 percent of those children who inherit two mutant copies get cystic fibrosis, a lethal disease that attacks the lungs. Until the 1950s, almost all such newborns died in early childhood.
Cystic fibrosis sufferers produce unusually salty sweat, a trait used to detect the disease. In the past, if a baby tasted salty when kissed, people knew the infant would die before its second birthday. Even today, when lung infections can be controlled with antibiotics, most victims of cystic fibrosis, 30,000 people in the United States, die before age 30.
Men with cystic fibrosis are usually sterile, and only recently have women with the disease been able to become pregnant.
This lethality and sterility present medical scientists with a mystery. Why does the mutation persist when, until quite recently, those who got the disease perished before passing it on? To survive the ruthless culling of evolution, the mutation must provide some advantage. But what is it?
Researchers at Harvard University and their colleagues at the universities of Bristol and Cambridge in England have found a likely answer.
"People with only one copy of the mutated gene apparently gain protection from infection by the bacterium that causes typhoid," says Gerald Pier, professor of medicine at Harvard Medical School.
Typhoid comes from eating food or drinking water contaminated with Salmonella typhi, a bacterium common in places with poor sanitation. Carried into the gut with corrupted water or food, the bug gets into the intestinal wall, then moves into the bloodstream. People with one copy of the mutated CFTR gene gain protection against such infection.
In lungs, a protein produced by the CFTR gene binds to another bacterium, usually Pseudomonas aeruginosa, and causes the germ to be expelled by coughing, sneezing, or expectoration. But cystic fibrosis patients lack this protein and thus suffer infections that clog airways and destroy lung tissue.
The Good and Bad
The same type of benefit occurs in people of African descent who carry mutations in the gene responsible for making hemoglobin, a vital blood protein that carries oxygen. If genes from both parents are mutated, each offspring has a 25 percent chance of getting sickle-cell anemia, a painful, disabling disease that affects approximately 4,000 African-American babies born every year in the United States.
Those with only one mutated gene, however, gain resistance to the parasite that carries malaria. Such resistance gives blacks a big advantage in Africa, where malaria kills about one million children a year. However, this resistance is not so advantageous in this country, where the mosquito-borne disease is well controlled.
In another example, scientists at the National Cancer Institute suggest that a gene mutation, which provides resistance against the AIDS virus, may be linked with past resistance to Black Death, a plague that killed a quarter of the population of Europe roughly 650 years ago.
"The origin of the mutation is coincident with the appearance of bubonic plague in the 14th century," notes Pier. "No clear cellular and molecule evidence exists for a connection with AIDS protection, as it does in sickle-cell anemia and cystic fibrosis. Nonetheless, it could be another potent example of how infectious organisms and genes shape our history and evolution."
Pier and his colleagues focus their research on different types of lung infections involved in cystic fibrosis. They found that Pseudomonas aeruginosa causes 80-90 percent of these infections. They also discovered that CFTR protein binds to this bacterium and promotes its clearance from the lungs.
If the CFTR gene has a certain kind of mutation, however, the protein it produces does not do the job properly, resulting in a progressively deadly infection.
Cystic fibrosis also affects the gastrointestinal tract, so Pier's group looked for connections between CFTR and gut bacteria. First, they found that cells from the intestinal walls of people with cystic fibrosis don't bind to typhoid bacteria as well as cells from those people without the disease. Next, working with cells in laboratory dishes, they converted those from cystic fibrosis patients to cells containing normal CFTR genes.
These engineered cells bind tightly to the typhoid bacterium, enabling the germs to infect the blood, something they could not do before they were "fixed." This finding is sound cellular proof of the advantage carried by the genetic mutation.
Pier says the discovery has "very important medical applications for development of vaccines against both typhoid and cystic fibrosis."
The oral typhoid vaccine now available requires four separate doses. "In poor countries where sanitation is most compromised, that's a serious limitation," Pier notes. "We want to make a vaccine that needs to be given only once."
Such a vaccine might also be used to stimulate the body to mount defenses against a variety of organisms that cause infections by penetrating the gut wall. These invaders include other types of salmonella, and bacteria such as shigella which causes diarrhea and abdominal pain.
It also may be possible, Pier believes, to weaken the pseudomonas bacterium most responsible for cystic fibrosis and use it as a vaccine. The weakened bug would not be potent enough to cause the disease, but it would stimulate the body's immune system to fight infections from bacteria in contaminated food or water.
"We definitely plan to pursue the development of such vaccines," Pier says. "We also need to obtain better understanding of how organisms like the typhoid bacterium cause human infections, and why genes work the way they do to make it easier or more difficult to get a disease."
Copyright 1998 President and Fellows of Harvard College