How Cystic Fibrosis Went From Fatal to Treatable

Jennifer Abbasi¹

When physician-scientist Michael J. Welsh, MD, was starting out as a medical student in the 1970s, cystic fibrosis (CF) was a terminal disease. Inspired by pediatric patients who wouldn’t make it past their teens and by a newfound love for scientific discovery, Welsh made CF the focus of his benchwork. Over the following decades, his research would contribute to the understanding of the genetic condition—with its “confusing mix of lung, pancreatic, liver, and intestinal disease”—and how to treat it.

Michael J. Welsh, MD, in his laboratory. University of Iowa

After Lap-Chee Tsui, Francis Collins, and collaborators identified the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, Welsh and his colleagues and then others deduced its function, classified its disease-causing variants, and demonstrated that their activity could be restored. Based on this and other foundational work, the first disease-modifying medication, ivacaftor, was introduced in 2012. Seven years later came the highly effective elexacaftor-tezacaftor-ivacaftor combination drug (Trikafta), which the Cystic Fibrosis Foundation called “the single greatest therapeutic advancement in the history of CF.”

Thanks to work by Welsh and many others, it’s now generally understood that the CFTR protein is a channel through which chloride or bicarbonate flow through the membrane of epithelial cells in the lungs and other organs, including the liver, gastrointestinal tract, and pancreas. When the protein’s function is disrupted in the lungs, mucus becomes thick and sticky, obstructing the airways and leaving patients prone to chronic bacterial infections and inflammation. This ultimately leads to a decline in lung function and to the lung condition bronchiectasis, in which the airways are permanently widened and inflamed. But today, people with CF who are treated with the triple-combination therapy can expect a far longer and healthier lifespan.

In recognition of these achievements, Welsh, who is a professor of internal medicine and a pulmonologist at the University of Iowa, has been chosen as corecipient of the 2025 Lasker-DeBakey Clinical Medical Research Award. He recently sat down with JAMA Medical News to discuss his life’s work and the future of CF treatment.

This interview has been edited for clarity and length.

JAMA:Can you start by telling us about your earliest experience with cystic fibrosis?

Dr Welsh:This journey really began for me when I was a junior medical student on my pediatrics rotation. I’m walking down the hall, and before I get to the room where I’m supposed to see a patient, I can hear harsh coughing. I go in the room, and there’s a 7- or 8-year-old little girl. It’s obvious she’s breathing hard. I can see her using her accessory muscles of ventilation. I hear her coughing and then I smell for the first time the odor of Pseudomonas aeruginosa, a common organism that affects the lungs of people with CF. I hear from her and her parents about all the things she can’t do and how much of her day is spent with a variety of different therapies.The sobering part was when we left the room because then my attending told me that she wouldn’t make it to her teens. If she did make it to her teens, she almost certainly would never make it out of her teens. There are certain patients that are burned into your memory. That little girl is burned into my memory.

JAMA:I’d love to hear how things have evolved for patients with cystic fibrosis since then.

Dr Welsh:As I advanced through my internal medicine and pulmonary training, and then became a faculty member in the pulmonary division here at the University of Iowa, I remember we’d work really hard for these patients. We’d be treating them with antibiotics. They’d be doing postural drainage. We put them in vests to try and shake loose the thick, sticky mucus that they had. Sometimes they’d be on steroids. But we were not fundamentally changing the course of the disease. The lung disease continued to get worse. As a physician, one always wants to do something for your patients. And as my research evolved, I realized that I might have the opportunity to at least better understand the disease.

JAMA:Fast forward to today. How is life different now?

Dr Welsh:It’s amazing. As I worked on this disease, my hope was that maybe we could stop the progression. That if we started an effective therapy, maybe people would stop getting worse. But it’s beyond what I could have hoped for—people actually get better now. When the new medications became available, our rate of lung transplants here at the University of Iowa plummeted by 75%. I could give you a lot of statistics, but even more important than that, at least as a physician, is the individual stories.I remember a pediatric pulmonologist colleague told me about a patient he had. This patient had been hospitalized twice already, which means they had significant, significant disease. This person was [now] running competitively. It’s beyond belief, as somebody who’s taken care of people with CF, to see them improve. It’s unfathomable. Now people are getting on with their lives. Our patients are getting married, having children, planning for the future. Now it’s estimated that a person with CF who starts the medication at a fairly young age will live a normal duration of life. And it’s not just the duration, it’s the quality of life they live. It’s completely changed.

JAMA:When you made the transition from physician to physician-scientist, why did you choose cystic fibrosis?

Dr Welsh:I was trained in internal medicine, and then in pulmonary disease. The little girl I told you about had been on my mind, but I wasn’t thinking about trying to develop a new treatment. I was studying how chloride moves across epithelia. I was studying intestine at that time, because by studying intestine, I could learn some of the tools and techniques that people used. But at the end of the day, I would go and get lungs and trachea from other labs that were doing animal experiments, and I’d study them.And I remember one night, I did some electrophysiologic experiments, and I saw this surprising result. That night I went home at 3 or 4 in the morning. I couldn’t sleep, and I became completely obsessed with trying to figure out what was going on. I would think about my experiments when I was eating. I’d think about my experiments when I was at the grocery store. I’d think about my experiments when I was at the movies. And then when I discovered the answer, I was overcome with a sense of peace. It was like all the endorphins in my brain let loose, and it was then that I decided that a physician-scientist would be my life’s work.As I went back to the University of Iowa and I started taking care of people with CF, I thought maybe I can apply some of my work to at least beginning to understand the disease.

JAMA:What was known about the disease when you were a young physician, and how has our understanding of it improved in that time?

Dr Welsh:It’s really an interesting arc. This arc started with Dorothy Andersen, a pathologist at Columbia University in New York. She was doing autopsies on kids who were thought to have died from a primary intestinal disease, and she found that that was not the case. She started to see these changes in the pancreas, changes in the lungs. She gave the disease its name, cystic fibrosis of the pancreas. Then Paul di Sant’Agnese, also at Columbia University, was taking care of patients during the [1948] heat wave in New York City, and he found that the patients that were coming in with heat stroke or dehydration were often his cystic fibrosis patients. And so he put two kids with CF and two kids that didn’t have CF in blankets so they heated them up, and he saw that the sweat in people with CF had more chloride.That was really an important discovery, because what that ultimately led to was the sweat test. For years and years and years, if you thought somebody might have cystic fibrosis, you’d measure the amount of salt chloride in their sweat. People with CF had more chloride. Then for a significant period of time, there was a tremendous effort to try and understand what’s going on. How do you put together the sweat, the lung disease, the pancreatic disease, the intestinal disease, the liver disease? It was a confusing mix.A man named Paul Quinton at UC [University of California] Riverside made an important discovery. He actually has CF, and often was studying his own sweat glands. The way the gland works is that you make sweat down in the coil, and it’s a sodium chloride–rich solution, sort of like saline. As it moves up the duct to the surface, where we just want water to evaporate to cool [us down], the salt gets absorbed out. He discovered that in cystic fibrosis the problem was the chloride did not get reabsorbed. You can’t just absorb the chloride, the negatively charged ion, and not the positively charged ion, the sodium, so both were blocked. That was really an important discovery.At that point, I collaborated with a colleague, Jonathan Widdicombe at UCSF [San Francisco], and we discovered that the problem lay in the apical membrane of airway epithelia. Airway disease was the primary cause of morbidity and mortality, and we discovered that the chloride could not move across the apical membrane.

JAMA:What is the apical membrane?

Dr Welsh:In the epithelia are sheets of cells that line the airways—the bronchi, the bronchioles, trachea, etc—and the apical membrane is the side of the cell that faces the air. Chloride could get into the cell, but it couldn’t get out across the apical membrane, and that pinpointed the defect. That was important also, because it began to suggest a unifying hypothesis: chloride movement across the apical membrane of airway epithelia. And then with time, you begin to understand that this was a common problem in the pancreas, in the intestine, lungs, sweat gland, and so on.So that’s where we were in 1989. And in 1989, Lap-Chee Tsui at Toronto, Francis Collins in Michigan, Jack Riordan at SickKids in Toronto, discovered the gene that’s mutated in people with CF. They called it cystic fibrosis transmembrane conductance regulator, or CFTR for short.

JAMA:A lot of discoveries have happened since then, including many that you’ve been a part of. How did we get to the medications that we have today?

Dr Welsh:The first question after the CFTR gene was discovered was if you take a normal CFTR gene that doesn’t have variants in it, can that correct the defect? That was the first experiment we did in collaboration with Alan Smith and his colleagues at Genzyme, and we said, “Yes, we can put a CFTR gene into a CF cell and now it has chloride transport.” That was a particularly exciting experiment for me because I was still doing the experiments myself.The next real issue was that you’ve got these instructions, this DNA, but what is it doing? What is it making? There was lots speculation that it must be a pump. That it must be moving something into or out of the cell, and that something then maybe regulates chloride channels. We took the simplest hypothesis: it’s a chloride channel. That was so exciting because that opened up subsequent studies. It also said, “If you’re going to go hunting for a new medicine for CF to treat people, your target would be that channel.” You’d try and develop an assay that could measure channel function. After that, we spent a lot of time trying to understand how this channel works and how it’s broken. How do these [gene] variants break the channel?The common variant that causes most CF, particularly in people with Northern European ancestry, is called ΔF508. We looked at that and a lot of different ones, and we were able to put them into categories. Though some variants caused the instructions to be so bad that you never make the channel at all, with some variants, like ΔF508, [the channels] are made, but they don’t progress through the biosynthetic pathway. They never get to the apical membrane where they can do their work. Some variants are produced but they don’t open. And finally, some are made, get to the cell surface, and open, but the channel doesn’t let enough chloride go through.If you want to develop a new medicine to treat cystic fibrosis, you need to know what kind of variant they have, and then you would target toward either something that increases the opening—we might call that a potentiator—or something that fixes the transport, that we would call a corrector.The last thing I’d mention along the way would be the ΔF508 variant. That’s the variant that doesn’t traffic to the cell surface. We took cells expressing the variant with CFTR ΔF508 and cooled them down. When we did that, there it was—there’s the [CFTR] protein. It had matured and gotten to the cell surface. And we were exceptionally excited when we used electrophysiologic techniques and we could see the channels open. With that, we begin to appreciate that CFTR is not totally trashed [in this disease]. You cool it down 6 degrees centigrade, from 37 down to 31 or 30 degrees, and it works.The fact that we could do these fairly innocuous kind of things and get CFTR to work says it’s not completely broken. We can’t put people in the refrigerator to treat their CF, but maybe one could develop a medicine to do that. It gave you confidence that carrying this on to develop a medicine might be possible.

JAMA:How did all these discoveries culminate in the life-changing disease-modifying medications that we have today?

Dr Welsh:After CFTR was discovered and after we appreciated how variants cause disruptive CFTR, there was enormous activity. My corecipients of the Lasker Prize, Tito González and Paul Negulescu, tested multiple chemicals to see if they could fix CFTR. That was the start of a big drug discovery effort. And that led to a drug, ivacaftor, that would increase the percent of time the channel was open. And then they developed a 3-drug combination: 2 drugs to get the channel with the ΔF508 variant to the cell surface, plus ivacaftor to increase its open time there. That’s Trikafta. That’s a drug that has completely changed the story of cystic fibrosis.

JAMA:I imagine that now there have been advances based on structural biology and actually being able to visualize what these proteins look like. Is work in that area coming along?

Dr Welsh:Yes. I think the leader in that area would be Jue Chen at Rockefeller University in New York, and she’s just doing beautiful work. She’s studied structures of CFTR, and it’s just beautiful to see what this thing looks like. We were so far back in the dark ages when we were guessing what the structure might be, now we know exactly what it is, and that is driving development of new drugs for CFTR.

JAMA:That brings me to my next question. Where do you see the next big breakthroughs for treating the disease?

Dr Welsh:I’m not great at guessing the future, but what I can say is that there’s work along 3 main lines. The one that

has the most attention right now would be genetic therapies. Can we put in a new copy of the CFTR gene? That’d be gene therapy. The other is gene editing. Gene editing technology continues to get better and better and more and more exciting. A huge problem is delivery. You’d think, “Boy, a virus ought to be a great Trojan horse to deliver the gene,” but we evolved to keep viruses out of our lungs. So it’s a battle, and I’m hoping that there’ll be significant progress. There’s certainly a lot of effort there and a lot of smart people working on this.In the second area, we’re in the postmodulator era now. People who have disease and start on the highly effective modulators have improved a lot, but they still continue to have inflammation in their lung. Many of them still have infection in their lung. How can we develop treatments to further improve their lungs?The third thing would be: Can we understand the disease better? One area where we’re working is in models. We’ve developed a pig model of cystic fibrosis. When the pigs get disease, it looks very much like human CF. We’re using these models to ask what would happen if we developed successful gene therapy. What about the submucosal glands in the airway that produce a lot of the mucus? Do you have to fix just the surface cells that line the trachea, the bronchi, the bronchioles, or do you have to get down below the surface to fix the submucosal glands?The other thing to think about is that the modulators that we currently have, these highly effective medicines, are so great because they fix CFTR everywhere, in the intestine, the liver, the lung, the sweat gland. What happens if you only affect the epithelia in the lung? What are going to be the consequences for the pancreas? People with CF have CF-related diabetes; what will be the consequences there? What about the intestine? What about inflammation from those organs? What about inflammation from the lungs?I think we don’t understand that. We’re trying to understand the disease using this pig model, and it’s given us surprising results. We've found some really interesting things about the way kidney is affected by cystic fibrosis, by the way lung is affected by cystic fibrosis independent of some of the ways we usually think about.

JAMA:It feels like researchers will be going back a little bit to the start, in terms of applying gene therapies and how to get the systemic benefits. It sounds like there’s major questions around how that would work.

Dr Welsh:There are. Everybody has really good ideas of what'll happen if you fix the CFTR gene or put in a new copy. The question is how many cells, which cells? I think there’s a tremendous amount to learn here. Hopefully, it’ll be an exciting time. The delivery process—there’s a lot of progress there, and I hope that’ll be successful soon.

Article Information

Source: https://jamanetwork.com/journals/jama/fullarticle/2838865

Published Online: September 11, 2025. doi:10.1001/jama.2025.15328

Conflict of Interest Disclosures: None reported.