A channel opens and a breakthrough lets cystic fibrosis patients breathe

Part III of IV

Office was a generous word for the room in which Dr. Mike Welsh did lots of his research.

Large closet fits better.

Welsh was mostly alone, hunched over specialized microscopic equipment on a sabbatical from rounds at the University of Iowa, where he was a physician-scientist.

And he worked predominantly in the pitch-dark in order to see the fluorescent molecule attached to the protein he was studying, a necessity to make its movements visible within the cell.

Figuring out the structure and the function of this particular protein could be the key to solving the medical mystery of cystic fibrosis, the cause to which he'd dedicated his early career.

He hoped it would be, at least.  

By now, as 1990 dawned a new decade, Welsh had studied cystic fibrosis for nearly 20 years, ever since medical school, when a pivotal patient screening pushed him to specialize in pulmonary medicine. He'd examined a young girl, 7 or 8, with the disease and learned not just that she would die before seeing her teens, but the life she would lead until then would be filled with invasive therapies and harsh treatments that only marginally eased her pain.

Altruism had drawn Welsh to medicine, but research, searching for a cure, had been the only salve that cauterized his bleeding heart.

In the almost two decades since that girl's critical checkup, Welsh focused his experiments on salt and water balance, which was long thought to hold the answer to the enigmatic, confusing mix of CF symptoms.

Ranging from sticky mucus in the lungs to cysts in the pancreas to distressed bowels and intense fatigue, the physical manifestations of cystic fibrosis seemed so disparate, like clues pinned neatly to a case wall without any bold strings or furious circles to show a unifying connection. It was a syndrome, really, a collection of ailments rather than a disease with a specific course.

Soon after cystic fibrosis' official discovery and naming in 1938, parents — whose children were then dying before their fifth birthdays — allied to establish a foundation that incentivized physicians to tackle this fairly rare disease.  

Welsh was one of those scientists, and years and years of his research into the inner workings of defective CF cells pinpointed one of the main issues: chloride wasn't flowing freely in the bronchi. Instead, chloride seemed to get stuck inside the cells, which was drawing water out of the airways and out of the natural mucus. Hence the dehydrated, gunky variety of mucus in CF lungs. 

In the 1980s, the foundation began aggressively funding the search for the gene that caused CF. There had been success for other conditions in the new field of gene therapy, and the aspiration was to replicate that path in cystic fibrosis: Discover the altered gene, place healthy versions of the gene into innocuous viruses, give those to patients, hope that kickstarts their system.

Indeed, when the gene was identified in 1989, the optimism was galvanic, like how the electricity in the air shifts just before a summer thunderstorm.

There had been moderate gains since then, but gene therapy hadn't been the panacea everyone wanted. Delivering viruses to the lungs was tricky — considering they'd evolved to defend against just such attacks.   

Scientists thought they'd found a map out of the CF maze with the gene, but unscalable hedges kept popping up every time they turned toward what was marked as the exit.

Welsh worked on some gene therapy studies, even had some big findings, but focused again on cellular mechanics when those wins didn't translate to the body. While lots of others continued to try to fix the gene throughout the early 90s, Welsh decided to try to fix what the gene made – a protein.

He knew the altered gene somehow bungled the production of a protein: But what did that protein make within a cell? And what did it do?    

In the wake of the gene's identification, Welsh and his team spent a year making tiny adjustments to its DNA until they could correctly reproduce the protein in the lab, a complicated process for some scientifically complex reasons. But now, finally , Welsh and his team were able to study its structure and function.

So, there he was. In the dark. Watching fluorescent molecules.

The protein he focused on was named CFTR, a merciful shorthand for cystic fibrosis transmembrane conductance regulator. It belonged to a family of proteins, researchers learned, all of which were pumps. So most scientists assumed CFTR pushed something inside of a cell out, or vice versa.

But Welsh had been researching chloride transport since long before the gene was discovered, and some of those early results suggested the problem may have been in a channel, which is more like a little pipe through a cell membrane.

Channels weren't understood well then, but a pore, Welsh thought, would let chloride flow through, not necessarily pump it. And part of that pipe's job would be to gate-keep: letting chloride, specifically, a negatively charged ion, pass while batting away potassium, say, or other electrolytes.

Welsh and his team didn't know for sure that the protein folded into a pore, but they offered an educated guess and started to make models of what CFTR would look like and what it would do if it was a pore.

Slowly, they made incremental changes to the protein, shifting its amino acids one at a time, to test their hypothesis. A grinding process, the team used electrophysical methods — including a technique originally invented to study snails — to measure ionic currents.

Day after day after day. After day.   

"It's like Sisyphus trying to push that rock up the damn hill," Welsh says. "And it keeps going back and forth, and that's the way of research back and forth and back and forth."

Mania, in some form, may be a core personality trait of Welsh and many researchers of his ilk, says Dr.  Paul McCray , chief scientific officer in Iowa's pediatrics department and a Welsh mentee. The indefatigable ability to get back in the blocks, knowing that 99 times out of 100 failure is almost certain.

"You can't do this kind of work unless you're kind of crazily obsessed," he says.

"There's a very high tolerance of frustration, starting it over again, retooling. The amount of creative problem-solving that it takes to make these things move forward is profound and probably underappreciated."

But, he says, the one time the experiment works is worth every false start. Discovery can be as rare as a Stradivarius — but it's also as euphoric as a Bach fugue played across its strings.  

And so it was when, one morning, a scream breaks the lab's serenity.

A graduate student comes running out of the side room where they'd taken up residence measuring and measuring. He heads toward Welsh like a heat-seeking missile, bellowing: I can't believe it worked . I can't believe it worked . I can't believe it worked .

I can't believe it worked!!!

Their educated guess had been right. CFTR was a chloride channel — and just the sort that would be needed in organs all throughout the body.

The red string began to appear before Welsh, connecting the push pins of CF clues that had felt disconnected for so long. 

"This channel is in the lung, it's in the pancreas, in the sweat gland, it's in the intestine. All these places have this channel. All these places have problems with chloride movement," Welsh says.

"All these places have disease that people with CF are suffering from."

But as it is with nesting dolls, there was another mystery right under this discovery.

Finding the gene revealed a faulty protein in people with CF, and studying the faulty protein revealed an abnormal chloride channel. But how, exactly, was it broken? Why was chloride not getting through this little channel?

And was it broken beyond repair?

"We learned there's lot of different mutations that can break CFTR," Welsh says. "It's a complex thing to make, but, just like many complex things, it's easy to smash."

So scientists all over the world started methodically inventorying the mutations they found while Welsh and his team focused on trying to fix the most common mutation. More mania.

Thousands of mutations were eventually identified with each one being separated into one of six distinct classes and then catalogued by severity. 

"If you want to fix something, you need to know why it's broken or how it's broken," says Dr. David Stoltz, chief of the university's pulmonary division and one of Welsh's mentees. "And so those initial understandings were critical to set the stage for what was to come."

"I think it also started to offer hope for people with cystic fibrosis."

People like Kay VanThornout , one of Welsh's patients and a ringleader in his lab, always signing up for trials and offering support to young people navigating a scary diagnosis.

She'd been trained in science and advocacy by her father, who, upon learning four of six children had CF, became a respiratory therapist and began fashioning his own homemade breathing masks.

Two of the VanThornout children died young, but two, including Kay, had milder mutations that blunted their symptoms and allowed them to live longer.

After various tests or exams, Welsh and VanThornout, who was in her 40s, elderly by CF standards, would sit on wooden benches outside the lab and chat. And one day he asked her: Why Kay? Why are you doing this?

"She said, 'I know this isn't going to help me, but maybe it'll help somebody else,'" Welsh says. "She's not unique, either. There are others who say, 'I'm participating in this study even though I know it won't help me.'"

One community. Built on endurance, but more so longanimity — the ability to not only tolerate the wait but to hold the pain of that burden with fortitude and serenity while you wait. In religious texts, longanimity means something like waiting on God's providence.

Or, in this case, on science.

Welsh just had to crack open the next nesting doll. 

The poet: Silence like a loaded gun

Lung. Transplant.

The words feel heavy and unnatural when William O'Neal II repeats them back to the doctor standing over his bed, like trying to blow a bubble and spitting out rocks instead.

For a year and a half, O'Neal had been studying film at Florida State, the next step in the education he began in hospital rooms as a kid.

After a childhood of never-ending cystic fibrosis treatments — tethered to his house for multiple nebulizer aerosol therapies and hours strapped into a vest that shook his chest violently in hopes of loosening the mucus that blanketed his lungs — O'Neal was enjoying the freedom of college with the abandon of young adulthood. Misty nights made clear in sunrise. Mistakes learned from and laughed off in equal measure. 

It's a common trope for kids with CF to Google their life expectancy. By the late 2010s, cystic fibrosis patient lifespans had grown to about 40, O'Neal learned, which was the best case scenario his parents were given when he was born right before the turn of the new millennium.

He wore that knowledge like a spur on his flank: If 40 is death, then 20 is midlife crisis, so all the experiences he wants have to fit into half a life. They have to happen now, the 20-year-old thinks. Right now .

"Everyone knows they will die," he says. "Not everyone thinks about it that much."

But then, in April 2019, his illness flares. His inhales are so wading-pool shallow that he can't speak full sentences, gagging for breath mid-way like he'd run a marathon between the subject and verb.

Time for the go-bag.

Extended stays at the hospital are routine for CF patients, "tune-ups," some in the community call these two-week sojourns, a necessity when symptoms begin to overpower at-home therapies.

O'Neal checks into the hospital, but this visit feels different. They give him an IV. Treatments around the clock. Two weeks pass.

Then another two. A parade of doctors and nurses and respiratory therapists. All the interventions that had worked before were failing.

At six weeks, doctors order a bronchoscopy, a procedure that vacuumed out his lungs. But nothing seemed to be changing his prognosis.  

We've tried everything we can, the doctor says. We don't know what else to do for you.

The only prescription they had now was to go home and wait.

For what? Silence marked their bloated pause like a loaded gun.

"Lung transplant," the doctors said.

Death was the other option, of course, the one they didn't want to acknowledge. His parents began to stifle sobs.

"Then I really saw the fear on their faces for the first time in my life," O'Neal says. "They were facing the fear that they had when I was first diagnosed. It's come already. So, death was just staring us all in the face." 

The rapier of CF had finally found his soft underbelly. An inevitability he'd prepared for, but, still, its slice stung. 

"I had made my, you know, my peace with dying," O'Neal speaks these words like he's chiseling them into a table. "Even my parents, they were like. … We had conversations about, you know, I love you. I love you."

At his childhood home outside Atlanta, O'Neal's parents set up the basement for him. Some semblance of independence as they all, well, waited.

The ochre-walled bedroom was toward the back of the house, behind two doors separated by a small hallway. The layout reminded him of the Holiest of Holies, the inner sanctum of the old Temple in Jerusalem where he'd learned that scripture says God's presence manifested.

Where, also, no one is supposed to roam, and those with unrepented sin faced death upon entry.

That God's dwelling could also be a sepulcher seems cosmically right to O'Neal in that moment.

This windowless room, his Holiest of Holies in small-town Georgia, is a mausoleum of sorts, dark and quiet. No clear marking of passing time, just each day perpetually collapsing into the next.

His dad tried to gussy up the ceiling with stars that glowed in the dark, but they just made everything green.

His circadian rhythm lost beat and he slept. And slept. And slept. He'd always been Pre-Raphaelite slender, but he lost more weight. Became waiflike, wearing sickness like face paint.

His only appointment was rehab once a week. When he walked in, 15 gray heads turned. Average age 80. He told them his story as they all mounted their treadmills, more dragging than walking.

"They were just so shocked that me, at 20, could be suffering in the way that they, at 80, were," he says.

He wasn't shocked. Not really. He'd wanted more time, undoubtedly, but the cage had always been closing around him, space constricting with each breath.  

"I had acceptance in this quiet, cool, calm way where it's like this thing inside my body that's been chasing me since I was young, it's finally caught up to me," he says.

"I was living the nightmare that I had always thought about. And I wasn't afraid. I was just really sad that it had come so early, you know?"

His parents urged him to go back to school. They were still hoping. Pushing him out was there was their way of not accepting that they'd all only made it halfway, by Google's standards at least, for how long his life should last.

But O'Neal stopped planning once he heard the word transplant .

Books and movies had always soothed O'Neal, a nascent writer and poet, helping him break free, creatively, of the illness that took up residence inside his organs. Soon those stories stopped providing the same level of comfort. He heard one of his favorite poets had a stroke. He couldn't focus. He couldn't retain.

It was like when a film reel ends and the projector is still on, that loose last frame flapping with each rotation.

One night, when he hadn't left his room for something like three days, his father descended the stairs and followed the carpeted hallways back to his living sepulcher. He picked O'Neal up like a bundle of wood and carried him to the car.

In the back, next to him, sat his sister. Mom in the front. Dad drove. Thirty minutes to downtown Atlanta.

O'Neal watched the streetlights pass, their cadence like a tide of sorts, pooling off-yellow light like waves.

"I think it was the one time in my life that I have sincerely been blissfully at peace," he says. "And that sounds dark, but it's like, I had nothing to hope for. I was just in this quiet silence."

His sister, barely 18 then, cried because she was preparing for what would happen next. His mom didn't because she wasn't.

No one spoke. And then they drove back. And his dad placed him back in bed.

"It's like you're back in the womb. It felt like that," O'Neal says. "I was waiting to be born into something else, whether that was the heaven my parents were talking about, or it was another life."

"Something crazy was gonna happen."

Two weeks later, his phone rang.

The eureka moment: FROG EGGS

A few days before Christmas, the December 1991 issue of Science magazine hit newsstands — and Welsh's desk. He reads Science , Nature and Cell basically cover to cover, has for many years.  

Inside this edition were stories on the new field of forensic DNA fingerprinting, on the plight of Soviet scientists after the collapse of the USSR and on the "Molecule of the Year," which was bestowed upon the " buckyball ," a new form of carbon that, at the time, held promise for chemists studying interstellar matter, superconductivity and targeted medicines.

But Welsh was looking for the paper from the lab of Francis Collins, who had, a few years earlier, identified the CF gene. Now doing research on the most common genetic mutation for CF patients, Collins wrote that his lab was seeing some chloride movement in the experiments they were conducting on the broken protein.

Welsh had been surprised to hear of the paper's publication and, now, even more surprised to read its findings .Chloride movement would mean there was hope yet for the protein, that there was a possibility it could be fixed.

Welsh hadn't seen anything of the sort, and, while others had been furiously attempting early gene therapy, he'd been one of the leaders in trying to figure out the mechanics of the malfunctioning protein.

Still, Collins' data all looked good. How could that be?

Welsh went back through the figures and thumbed toward the "Methods" heading.

"Then, as I studied their paper, I realized they had done this in frog eggs," he says.

If sentences could scream, this one howled: FROG EGGS.

Welsh had worked with those before. They're kept incubated at a lower temperature than human cells — 18 degrees Celsius (64.4 degrees Fahrenheit) versus 37 degrees Celsius (98.6 degrees Fahrenheit).

Could it be the temperature? he thought. Something so simple?

Raising temperature breaks bonds, bindings melt and connections fracture. It's why his mom washed really dirty farm clothes in high heat.

But at low temperatures, chemical reactions take place slower. The energy levels are lower. The cold strengthens, reinforces — like water into ice.

Maybe at the higher heat, the protein folds too quickly and makes a mess of itself. "Like globbing a bunch of spaghetti together," says Bijal Trivedi, whose book " Breath from Salt " traces the rise of cystic fibrosis' treatments. 

So Welsh and his team made the cells like they always did, but they put them into a colder incubator: 30 degrees. 26. 23. Colder and colder.

And they saw that as they lowered the temperature, the protein matured. It folded better. It made it to the cell's surface where the channel could work. It opened.

"And we could see chloride movement," Welsh says.

"It didn't work normally, but it worked reasonably well, about a third as well as the normal CFTR protein."

"Reasonably well," however, could be the difference between living and dying for CF patients. Welsh had proven that through cooling the cells, the protein could be rescued and the chloride channel restored. In the lab, at least.

His further research would demonstrate more about the protein's characteristics and operations, "incredibly innovative" work that revealed fundamental truths about "what made the CFTR protein tick," says Dr.  JP Clancy , senior vice president of clinical research for the  Cystic Fibrosis Foundation  and a former Welsh colleague.

"It was an observation that could easily have been overlooked: 'It works in frog eggs,'" says Trivedi. "But he was the one that questioned why it worked there, and if he hadn't recognized that this protein isn't totally trashed, that the mutation isn't destroying this protein completely, that there is still a glimmer of hope, then there wouldn't have been an incentive to try and get that protein to function.

"It was that eureka moment that let others know, OK, maybe there is a way to fix this protein," she says. "And that basically opened up the playing field for drug discovery."

Since refrigerating people wasn't a viable treatment, Welsh and the CF Foundation would need chemists and pharmacologists to create a small molecule that could replicate or strengthen what happened in the cold. 

No one had ever, in the entire history of drug development, fixed a protein. The chances they'd be able to find a molecule that would, essentially, shove into this deformed protein and force it to twist and turn in just the right way so that it was functional again was — putting it mildly — remote, Trivedi says.

But there was one pharmaceutical company interested in just this type of precision medicine.

And they had technology on their side.

Drugs like 'duct tape': Transformative innovations — and Bill Gates' checkbook — offer hope

In the 1990s, the revolution that had rocked personal computing was coming for the pharmaceutical industry.

Rapid advancements in chemistry allowed scientists to create millions of small molecules themselves instead of having to license collections of chemicals from large companies and build compounds atom by atom.

Similar improvements in robotics allowed researchers to miniaturize and automate. Previously, drug compounds were placed by hand one at a time in single test tubes.

Now, through high-throughput screening, chemical reactions are tested in tiny trays and monitored by computers, allowing for tens of thousands of possible molecules to be screened in rapid succession.

At Aurora Biosciences (which was later purchased by a company called Vertex Pharmaceuticals), researchers turbocharged high-throughput screening, tweaking the process to be faster and even more accurate.

"They were building these instruments themselves. You know those startups that started in a garage in Silicon Valley and became monoliths? This was very much the same thing," Trivedi says.

"Because no one had ever built these machines where you could have 10,000 tiny little test tubes, put cells in all of them, put different chemicals in all of them and then see what the chemical did to the cell. That wasn't possible before."

Without this convergence of emerging technologies — plus enhanced data processing tools — there wouldn't have been a way forward for CF patients or their families.

But using this technology on the CFTR protein would cost millions. Way more than the normal channels for fundraising.  

A CF Foundation board member whose two sons had the disease suggested asking his boss, who'd just started a philanthropic foundation. Bill Gates' dad — yes, the board member worked at Microsoft — heard their pitch and sent them a check for $20 million. Through the mail. The seed money to start this gamble. 

As the foundation went looking for the money and internal priorities at the new company continually shifted, the pharmaceutical scientists would not let this project go, Trivedi says.

How other people kept photos of their families at their benches, these scientists' chemical hoods were plastered with images of molecules and accompanying scribbled notes, she says. The chemists and engineers brought in patients and families to ask questions and to update them on the research, an incredibly unusual model at the time.

"Their hearts became just as entwined as Mike's did," Trivedi says. "I think that's really important, too. Especially at a point when pharmaceutical companies are often the bad guys in the conversation, behind those facades, they're hard-working scientists, and they were very emotionally committed to this disease."

Even using high-throughput, the process was still iterative: looking through combinations to find a little benefit. Then having a chemist tweak those so they work better and better and sharper and sharper.

Honing and improving. Over and over and over.

Working through two decades, spending hundreds of millions of dollars, Vertex developed four drugs that function in part like "duct tape," says Welsh, "holding things together in the right shape." In the simplest terms, the drugs essentially turn on the chloride channel, allowing salt and water to move.

The university was an approved testing site when the first drug, Ivacaftor , which repaired the protein mutation for about 5% of CF patients, went to trials around 2010.

One of Welsh's research assistants, who also was a nurse, administered the double-blind study, interviewing and testing patients. The first day patients returned for evaluation after a course of the drugs, she came into Welsh's office.

What are we giving these people? she asked.

One patient had walked into the clinic and told her: I'm not on the placebo. I haven't felt this good for years .

"The change was that abrupt," Welsh says. "They can breathe again. It's like everything changes. It's like … like they're reborn."

Slowly, more drugs were approved to help more people: Orkambi in 2015, Symdeko in 2018 and Trikafta in 2019, which ultimately treats up to 90% of CF patients in the U.S.

"None of us would've ever imagined, would never have allowed ourselves to hope, that it could be this good," Welsh says. "I would never allow myself to hope that."

He pauses. A crinkly smile spreads as he adds, with a wry laugh: "And I have high expectations."

The research and drug discovery had been like Sisyphus, back and forth and back and forth. A series of daring explorations, to be sure.  

"But In this case," he says, "we got that boulder to the top of the hill."

Part IV: Post purge, he could finally finish a sentence. Up next, choosing life

Courtney Crowder is the Register's Iowa Columnist and a senior writer. Please share stories and tips at  ccrowder@dmreg.com  or 515-284-8360.

The Miracle of Breath series continues

This is Part 3 of a four-part series. The final part describes William O'Neal II's exorcism when a box of pills arrives on his parent's doorstep and follows Welsh as he explores the costs and rewards of forever changing the trajectory of science — and of people's lives. And we go back to the Iowa City dive bar where science met impact on one unbelievable, cathartic and intimate evening.

The Miracle of Breath series and "Giving Back Breath," its companion documentary, trace the story of how Dr. Mike Welsh's meticulous experimentation led to a breakthrough that transformed cystic fibrosis from a lethal diagnosis into a manageable condition.

Told through the night Welsh met one of the people his work saved in an Iowa City bar, the 20-minute documentary is a co-production of the science-focused production company HHMI Tangled Bank Studios , USA TODAY Co. and the Des Moines Register.

Watch the film online and then dive deeper into the series.

Watch the 'Giving Back Breath' documentary free on YouTube

Influential Iowans

This is the last of the Des Moines Register's series on Influential Iowans. Through the end of 2025 and the start of 2026, the Register has publish profiles of people who have shaped our state and the country beyond. These people influence our politics, food, sports, communities, music, city development and arts, and health. They were chosen by Register staff ― and each is fascinating on their own. Together, they show the rich fabric of Iowa's influence.

—  Rachel E. Stassen-Berger, Des Moines Register executive editor

This article originally appeared on Des Moines Register: How obsession finally unlocked a cystic fibrosis breakthrough