The discovery of a new type of cell could fundamentally alter how cystic fibrosis researchers seek a cure for the often-fatal hereditary disease. A paper published Wednesday in Nature describes how an ongoing cellular mapping project helped scientists identify this rare cell type, which appears to play a key role in managing rehydration and pH balance—huge issues for cystic fibrosis patients. A second paper in the same journal offers a similar finding.
Scientists have long known mucus proteins do not form properly in cystic fibrosis patients, and that these structural irregularities cause salt–water imbalances and dehydration. This leads to a buildup in the lungs of thick, sticky mucus that can trigger breathing problems and potentially life-threatening infections. But until now researchers had thought a different cell was involved in the disease, and they lacked the technological capability to discern exactly which cells harbor the mutated proteins.
The newly identified cells have been dubbed “pulmonary ionocytes” because they seem to be involved in transporting ions—electrically charged particles like those in table salt—across lung tissue. In cystic fibrosis patients these cells also appear to produce vast quantities of mutated mucus proteins, which are called cystic fibrosis transmembrane conductance regulators (CFTR).
How could such a fundamental thing have been missed for so long? “I think it just speaks to the complexity of the disease and the fact that we really just didn't understand the cellular basis of the lung,” says Jayaraj Rajagopal, a pulmonologist and developmental biologist at Massachusetts General Hospital who co-authored one of the new papers.
More than 70,000 people worldwide are currently living with cystic fibrosis. Patients typically get frequent lung infections and can sometimes suffer from malnutrition because their abnormally thick mucus can also block nutrient absorption in the pancreas. This can cause patients to die young. But new drugs have helped lengthen life expectancy, and today the median predicted survival age is close to 40—but the condition has remained incurable.
The identification of the new cell type will not quickly change current therapy, which has become dramatically better in recent years, thanks to new treatments such as Symdeko and Kalydeco (both from Boston-based Vertex Pharmaceuticals). These drugs help improve the function of the mutated gene associated with CFTR production, so that mucus will be thinner and less viscous. Still, Rajagopal says the new research is very likely to transform the ongoing pursuit of a gene therapy or stem cell treatment that might someday cure the disease. “It’s as though you’re fundamentally reframing a problem so you can attack it anew,” says Rajagopal, who is also an associate member at the Broad Institute of MIT and Harvard, and a Howard Hughes Medical Institute faculty scholar. He and the other researchers had not originally set out to change the understanding of cystic fibrosis. Instead, their goal was to analyze all the cells lining the trachea (windpipe).
When they carefully sorted all the cell types found in that part of the body using cellular-tagging techniques and computer algorithms—an approach which has only been technologically feasible for the last few years—they found there were seven cell types in the lining instead of the six that had previously been counted. And that seventh type—the pulmonary ionocytes—were churning out CFTR. “This was definitely a surprise,” Rajagopal says. “It took a long time to convince ourselves it was true.”
The researchers, from Mass General and Broad, initially studied both healthy and CFTR–mutated mice. Then they confirmed the presence of pulmonary ionocytes in healthy human lungs. A team from Novartis and Harvard Medical School reports a very similar finding in the other paper published Wednesday in Nature.
The Broad Institute research is part of a project called the Human Cell Atlas—an international effort begun in 2016 with the goal of mapping every cell type in the body. Participants envision it as something like the Human Genome Project, and all the data it nets will be made publicly available. Massachusetts Institute of Technology biology professor Aviv Regev, who co-authored one of the new studies and is the founding co-chair of the project, says technological advances have made the multistep process of identifying and analyzing each cell feasible on a large scale, although the atlas will still take years to complete.
To map the windpipe’s lining, Regev and her team sequenced the genes of a single cell and then grouped cells based on their similarities and differences, with the help of a computer sorting system. That’s when they saw that there were seven types of cells in that part of the body rather than six. The process is not perfect, says Regev, who is a core member of the Broad Institute. “But if you look at very large numbers of cells and you use the right computational approaches,” she says, “you can ignore these little imprecisions and noise and errors, and you can see the commonalities.”
After working with mice the researchers tested healthy lungs in human cadavers to confirm people also have pulmonary ionocytes. The scientists have not yet looked for the cells in cystic fibrosis patients—or in other organs it can affect, such as the pancreas. The findings also still need to be explored by researchers specializing in cystic fibrosis, says Eric Sorscher, a professor of pediatrics at Emory University and a member of the board of the Cystic Fibrosis Foundation, an advocacy group. But Sorscher, who was not involved in the new research, praises it as impressive and important. “It’s a real tour de force,” he says.
Rajagopal thinks this work will lead to many more surprises, and to a far deeper understanding of both healthy and diseased cells. In the meantime he says he has been struck by the power of even incomplete information about a disease like cystic fibrosis. “One of the things I'm amazed about is that we could have made so much progress in cystic fibrosis research without knowing this piece of information,” he says. “That actually creates a huge amount of optimism in me, because it means that we can create a huge amount of progress without knowing everything.”