The gene that causes cystic fibrosis (CF) was discovered nearly 20 years ago, but since then progress toward conquering this devastating lung disease has been slow. Now researchers have a new tool: pigs engineered to develop CF. They’re considered a breakthrough because they are born with disease features much like those seen in newborn babies, whereas mouse models are not.
About one in 4000 babies in the United States is born with CF. It is caused by a defect in the gene CFTR, which generates an ion channel protein that moves salts and water across the cell membrane in certain tissues. The lungs of people with CF are normal at birth but over time get clogged with sticky mucus and become vulnerable to infections; despite new treatments, many patients die in their 20s or 30s. Mice created to have the CFTR defect are a far cry from the human reality of the disease: They don't develop lung ailments or damage to other organs, such as the pancreas. And this also means that they don’t provide much insight into how the disease progresses in children. So Michael Welsh, a physician and molecular physiologist at the University of Iowa in Iowa City, sought a better animal model "out of frustration," he says.
Five years ago, Welsh teamed up with animal scientist Randall Prather of the University of Missouri, Columbia, who develops transgenic pigs (ScienceNOW, 2 January 2002). They first disabled the existing CFTR gene in pig cells then cloned pigs from these cells, which wasn't easy because both steps have been perfected only in mice. Last April, the researchers reported those results in the Journal of Clinical Investigation, describing pigs with one silent copy of CFTR. Next, they mated these pigs to see if offspring with two bad copies of CFTR develop a CF-like disease. "We didn't know if we'd just end up with a big mouse," Welsh says.
Instead, they got something much closer to a human with CF, Welsh's team reports in this week's issue of Science. The newborn piglets have many of the same signs of CF seen in infants, including impaired salt transport, intestinal blockages, and pancreas and liver damage--but normal lungs.
One difference is that although only 15% of infants are born with an intestinal blockage, all the pigs were, and many had to be euthanized young. The team performed surgery to fix the blockage on some pigs and is now watching as they grow up for signs of lung problems. "We're excited but we're still holding our breath," Welsh says. He and several others have founded a company that will sell the pigs to drug companies and researchers studying CF.
Others in the CF field are heralding the pig's arrival. "It's a remarkable, seminal accomplishment," says Eric Sorscher of the University of Alabama, Birmingham. He and others say it should be useful not only for studying the natural history of the disease but also for improving gene therapy for CF, which has had limited success. "It's a lovely piece of work, and it's good to see it come to fruition," agrees Richard Boucher of the University of North Carolina, Chapel Hill.