Posts Tagged ‘cystic fibrosis’

Ionocytes (orange) extend through neighboring epithelial cells (nuclei, cyan) to the surface of the respiratory epithelial lining. This newly identified cell type expresses high levels of CFTR, a gene that is associated with cystic fibrosis when mutated.


Two independent research teams have used single-cell RNA sequencing to generate detailed molecular atlases of mouse and human airway cells. The findings, reported in two studies today (August 1) in Nature, reveal the gene-expression patterns of thousands of lung cells, as well as the existence of a previously unknown cell type that expresses high levels of the gene mutated in cystic fibrosis, the cystic fibrosis transmembrane conductance regulator (CFTR).

“These papers are extremely exciting,” says Amy Ryan, a lung biologist at the University of Southern California who was not involved in either study. “They’ve interrogated the cellular composition and the cellular hierarchy of the airways by using a single-cell RNA-sequencing technique. That kind of information is going to have a significant impact on advancing the research that we can do, and hopefully the derivation of new therapeutic approaches for any number of airway diseases.”

Jayaraj Rajagopal, a pulmonary physician at Massachusetts General Hospital and Harvard University and coauthor of one of the studies, had been studying lung regeneration and wanted to use single-cell sequencing to look at differences in the lungs’ stem-cell populations. He and his colleagues teamed up with Aviv Regev, a computational biologist at the Broad Institute of MIT and Harvard University, and together, the two groups characterized the transcriptomes of thousands of epithelial cells from the adult mouse trachea.

Rajagopal, Regev, and colleagues uncovered previously unknown differences in gene expression in several groups of airway cells; identified novel structures in the lung; and found new paths of cellular differentiation. They also described several new cell types, including one that the team has named the pulmonary ionocyte, after salt-regulating cells in fish and amphibian skin. These lung cells express similar genes as fish and amphibian ionocytes, the team found, including a gene coding for the transcription factor Foxi1, which regulates genes that play a role in ion transport.

The team also showed that pulmonary ionocytes highly express CFTR, and are in fact the primary source of its product, CFTR—a membrane protein that helps regulate fluid transport and the consistency of mucus—in both mouse and human lungs, suggesting that the cells might play a role in cystic fibrosis.

“So much that we found rewrites the way we think about lung biology and lung cells,” says Rajagopal. “I think the entire community of pulmonologists and lung biologists will have to take a step back and think about their problems with respect to all these new cell types.”

For the other study, Aron Jaffe, a biologist at Novartis who studies how different airway cell types are made, combined forces with Harvard systems biologist Allon Klein and his team. Klein’s group had previously developed a single-cell RNA-sequencing method that Jaffe describes as “the perfect technology to take a big picture view and really define the full repertoire of epithelial cell types in the airway.”

Jaffe, Klein, and colleagues sequenced RNA from thousands of single human bronchial epithelial and mouse tracheal epithelial cells. The atlas generated by their sequencing analysis revealed pulmonary ionocytes, as well as new gene-expression patterns in familiar cells. The team examined the expression of CFTR in human and mouse ionocytes in order to better understand the possible role for the cells in cystic fibrosis. Consistent with the findings of the other study, the researchers showed that pulmonary ionocytes make the majority of CFTR protein in the airways of humans and mice.

“Finding this new rare cell type that accounts for the majority of CFTR activity in the airway epithelium was really the biggest surprise,” Jaffe tells The Scientist. “CFTR has been studied for a long time, and it was thought that the gene was broadly expressed in many cells in the airway. It turns out that the epithelium is more complicated than previously appreciated.”

These studies are “very exciting work [and] a wonderful example of how new technologies that have come online in the last few years—in this case single-cell RNA sequencing—have made a very dramatic advance in our understanding of aspects of biology,” says Ann Harris, a geneticist at Case Western Reserve University who did not participate in either study.

In terms of future directions, the authors “have shown that transcription factor [Foxi1] is central to the transcriptional program of these ionocytes,” says Harris. One of the next questions is, “does it directly interact with the CFTR gene or is it working through other transcription factors or other proteins that regulate CFTR gene expression?”

According to Jennifer Alexander-Brett, a pulmonary physician and researcher at Washington University School of Medicine in St. Louis who was not involved in the studies, the possibility that a rare cell type could be playing a part in regulating airway physiology is “captivating.”

Apart from investigating the potential role for ionocytes in lung function, Alexander-Brett says that researchers can likely make broad use of the data from the studies—particularly details on the expression of genes coding for transcription factors and cell-surface markers. “One area that we really struggle with in airway biology . . . is [that] we just don’t have good markers” to differentiate cell types, she explains. But these papers are “very comprehensive. There’s a ton of data here.”

D.T. Montoro et al., “A revised airway epithelial hierarchy includes CFTR-expressing ionocytes,” Nature, doi:10.1038/s41586-018-0393-7, 2018.

L.W. Plasschaert et al., “A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte,” Nature, doi:10.1038/s41586-018-0394-6, 2018.


Ethan Dean has always dreamed of being a garbage man. He never tires of playing with toy garbage trucks and loves to watch the real ones drive past his house.

On Tuesday, the 6-year-old with cystic fibrosis got his wish, riding shotgun in a booster seat through Sacramento as an honest-to-goodness garbage truck driver with a set of wheels labeled “Ethan’s Garbage Truck.”

He donned a green cape that read “Hero Ethan” and a big smile as the truck stopped to pick up trash and recyclables. It wasn’t a chore for Ethan, who said his favorite part of the day put on by the Make-A-Wish Foundation was “cleaning up garbage.” Hundreds of people gathered to cheer him on.

After being surprised at his school, Ethan and the garbage truck made five stops.

am Thurman, the Waste Management employee who drove Ethan, said when he agreed to take part, he had no idea how big the day was going to be.

And as for Ethan?

“He can’t wipe that grin off his face,” Thurman said. “He looks like it’s Christmas morning and he’s unwrapping his first present.”

Ethan was diagnosed with cystic fibrosis as an infant and began treatment at eight weeks old. The genetic disorder is characterized by a buildup of thick mucus and frequent lung infections, and the median life expectancy is about 40 years old.

When Make-A-Wish Foundation agreed to grant his wish in February, there was little doubt what he wanted it to be.

“We pretty much knew it was going to be about garbage trucks,” said Ethan’s dad, Ken Dean, laughing.

He’s been watching them come down the street since he first learned how to crawl, Dean said. Ethan also has a garbage truck bedspread and pillow, garbage truck toys and has had a garbage truck birthday party.

Ethan’s big day comes three years after Make-A-Wish transformed San Francisco into Gotham for a 5-year-old boy who had battled leukemia for years and dreamed of being Batkid. Miles Scott traveled from one crime scene to another, rescuing a damsel in distress and thwarting the plans of The Riddler and The Penguin, as crowds of people cheered him on.

Ethan’s dream is being a less fantastic, more everyday superhero. When he visited Make-A-Wish and was asked about some of his dreams, almost all of his answers were garbage-truck related, said Jennifer Stolo, CEO of the local chapter of the Make-A-Wish Foundation.

Ethan’s uncle, Tim Dean, said it means a lot to the family to have people who don’t even know him come out to celebrate.

At least 500 people gathered at the Capitol for a press conference and VIP lunch at the end of Ethan’s day.

Erika Sizemore doesn’t know Ethan and said she learned about his special day on social media. It hit home for her, she said, because she has two boys, Kane and Benny, who also love garbage trucks.

“As soon as he got out of the truck I cried,” she said, tearing up. “It could happen to any of our kids. He is an amazing little kid and I just think that any of could be in the same boats as his parents are.”

New research from the University of Iowa answers a question that has vexed cystic fibrosis (CF) researchers for almost 25 years: Why don’t mice with CF gene mutations develop the life-threatening lung disease that affects most people with CF?

The research team, led by Michael Welsh, discovered an answer to this long-standing scientific puzzle, and in doing so, identified a proton pump that could be a target for new CF therapies. They published their results Jan. 29 in the journal Science.

“Since the first CF mouse was reported in 1992, I have been asked hundreds of times, ‘Why don’t CF mice have respiratory host-defense defects and develop lung infections?’” says Welsh, who is a professor of internal medicine, molecular physiology, and biophysics; a Howard Hughes Medical Institute Investigator; and director of the Pappajohn Biomedical Institute at the UI.

In answering this question, Viral Shah, first author on the study and a student in the Medical Scientist Training Program at the UI Carver College of Medicine, homed in on the thin layer of liquid that covers the mice’s airways, i.e., the tracheal and bronchial passages. Shah and his colleagues studied the liquid’s acidity, the importance of which was revealed in earlier UI studies using pigs with CF. That work showed that the CF pigs had an abnormally acidic airway liquid, and that increased acidity impaired the ability of their airways to fight off infection.

Shah explains that, normally, two opposing processes control airway acidity. The cystic fibrosis transmembrane conductance regulator (CFTR) channel secretes bicarbonate, a base. That process is countered by the secretion of protons—an acid. The balance tightly controls the acidity of liquid in the airways.

In people, pigs, and mice with CF, the CFTR channel is lost, stopping the flow of bicarbonate into the airways. When that happens in people and pigs, their airway liquid becomes more acidic, reducing their ability to fight infection. But in mice, the airway liquid does not become more acidic, and they are not prone to infection. That fact led the scientists to ask what secretes acid into the airways of people and pigs that is missing in the mice. They discovered that a proton pump called ATP12A is responsible.

Shah and his colleagues made the discovery by comparing airway tissue from humans, pigs, and mice. The scientists showed that blocking ATP12A in airway tissue from pigs and humans with CF reduces the acidity of their airway liquid and restores their airways’ defenses against infection. Conversely, putting the ATP12A proton pump into the airways of CF mice increases the acidity of the liquid and predisposes the CF mice to bacterial infections.

“This discovery helps us understand the cause of lung disease in people with CF. It may also identify ATP12A as a new therapeutic target,” Shah says. “We wonder if blocking ATP12A in people with CF could halt the progression of lung disease.”

Shah adds that targeting ATP12A could potentially be helpful for all forms of CF, regardless of a patient’s CFTR mutation, because ATP12A is independent of CFTR.

The CF pig model was developed in 2008 by Welsh and his research team at the UI, with colleagues from the University of Missouri. The CF pig closely mimics human CF disease, including the lung problems absent from CF mice, and has proven very useful in advancing our understanding of CF lung problems.

In addition to Shah and Welsh, the research team on the Science study included David Meyerholz, Xiao-Xiao Tang, Leah Reznikov, Mahmoud Abou Alaiwa, Sarah Ernst, Philip Karp, Christine Wohlford-Lenane, Kristopher Heilmann, Mariah Leidinger, Patrick Allen, Joseph Zabner, Paul McCray, Lynda Ostedgaard, David Stoltz, and Christoph Randak.

The research was funded in part by grants from the National Institutes of Health, the Cystic Fibrosis Foundation, and the Roy J. Carver Charitable Trust.

A “perfectly spherical” chicken egg has sold for an “unbelievable” £480 on the internet auction site eBay.

Kim Broughton found one of her hens – now renamed Ping Pong – had laid the round egg in her garden in Latchingdon, Essex, on 17 February – Pancake Day.

She decided to auction the egg in aid of the Cystic Fibrosis Trust after a friend’s son died from the disease.

Ms Broughton, 44, said she imagined the buyer was interested in preserving, rather than eating, the unusual egg.

The item, laid by a Buff Orpington hen – described as the “Scarlett Johansson of the chicken world” – attracted 64 bids, but the identity of the winner is not yet known.

Ms Broughton said she had been tempted to cook and eat the egg before being told it was “one-in-a-billion”.

She said: “I was literally about to crack it open to make a pancake when a mate saw the photo I put on Facebook and messaged me to say ‘Don’t do it!’

“Apparently somebody had sold one before for more than £90 so I thought ‘Great if I can sell if for that’.

“When it was at £20 I thought ‘Who’d pay that for an egg?’ and then it went through the roof. It’s unbelievable”.

Ms Broughton, who said she was known as “the mad chicken woman”, said she was nervous about sending the egg through the post.

“At the moment it’s safely in my son’s lunchbox padded with kitchen roll – but if I send it in a hard box it should be quite safe,” she said.

Speaking to BBC Essex Ms Broughton said she would be keeping a close eye on future eggs in the hope of raising “a few more quid” for the charity.