A life-changing shift from neuroscience to cystic fibrosis research

Professor Jeff Wine (center) with his wife, Marlene Wine (right), and Chris Penland, the Cystic Fibrosis Foundation’s vice president of BioPharma Programs.
 

Sometimes a study sample size of one is an incredibly significant number.

For Jeff Wine, that one was his daughter Nina, who was diagnosed with cystic fibrosis as an infant in 1981. At that time, the potentially fatal lung disease had few good treatments, and Wine, who was then working on neuroscience experiments, decided to change his entire research program to focus on the disease.

“I made the foolhardy decision to start researching cystic fibrosis,” said Wine, an emeritus professor of psychology in Stanford’s School of Humanities and Sciences. “I read a paper with convincing evidence that the basic problem had to do with an ion channel. I knew about ion channels because nerve cells use them, so I thought maybe there was a role for somebody like me.”

That initial leap may have seemed risky but helped lead to significant advances in the understanding of the disease, and the Cystic Fibrosis Foundation recently recognized Wine’s contributions with the Dorothy Andersen and Paul di Sant’Agnese Distinguished Scientific Achievement Award. 

Wine, who is also the Benjamin Scott Crocker Professor of Human Biology, Emeritus, likes to say his career has had 44 milestones, one for each year his daughter has lived a healthy life, even running marathons. Wine credits her good health in part to taking preventative treatments of inhaled-antibiotics, and when she was 41, she further strengthened her health by starting to take the drug Trikafta, which is effective in helping 90% of cystic fibrosis patients live a normal life.

When Wine started in the field, cystic fibrosis was considered an “orphan” disease, meaning it was rare enough to discourage private companies from investing heavily in developing medications for it. About 30,000 people in the U.S. have cystic fibrosis, which involves defects to a gene called CFTR, or Cystic Fibrosis Transmembrane Conductance Regulator. This gene controls fluid transfer in and out of cells, including clearing mucus from the lungs. People with cystic fibrosis are more susceptible to lung infections, among other issues. 

From crayfish cells to human ones

Wine began his research career as a doctoral student at UCLA studying how crayfish escaped from predators through a response triggered and organized by a simple neural circuit. He continued this work at Stanford as a postdoctoral scholar and eventually a tenured professor. 

After more than a dozen years as a neuroscience researcher, Wine switched his focus to cystic fibrosis, shortly after his daughter was born. He brought the knowledge and techniques of studying nerve cells to epithelial cells, which form the protective linings throughout the body. Wine has since published more than a hundred scholarly papers on cystic fibrosis. 

Among his many contributions was the discovery that the sampling of sweat from a specific pathway could help measure how well CFTR was functioning—and what level of function would improve health. 

People with cystic fibrosis have abnormally high levels of salt in their sweat, a fact that was discovered in 1948 by Paul di Sant'Agnese, the namesake of the award Wine recently received. 

Almost 40 years later, researchers identified that CFTR ion channels controlled sweat production and the body’s reabsorption of salt by one of two pathways. They found that sweating by the secondary pathway was often absent in those with cystic fibrosis. 

To Wine, this meant that perhaps the function of CFTR could be measured. At the time, there was a treatment available called ivacaftor, a protein modulator that targets a specific CFTR protein defect carried by about 5% of people with cystic fibrosis. A research team led by Wine found that when ivacaftor restored even a small amount of that protein function, it produced large improvements in health. This allowed developers of other protein modulators to better target their treatments. 

The sample size of one

When Wine's daughter was diagnosed, these treatments were not available, and he knew that lung infections pose a big threat to people with cystic fibrosis. Physicians traditionally only treat these infections when symptoms appear for fear of creating antibiotic resistance, but by chance Wine was connected with Stanford pediatrician Birt Harvey, who developed his own approach of administering multiple inhaled antibiotics to cystic fibrosis patients before they became sick. 

Nina Wine became Harvey’s patient and has continued using inhaled antibiotics for more than 40 years without becoming resistant. Her father has since become an advocate for preventative antibiotic treatment for cystic fibrosis patients.

“The main success story is our daughter,” Wine said. “She never developed chronic lung infections. She never became a typical cystic fibrosis child, and now she is not a typical cystic fibrosis adult.”

This theory of preventative care has since been borne out by studies led by University of Iowa researchers, providing more evidence that this approach can work.

Wine is hopeful that it can be of use to other cystic fibrosis patients, especially the 10% who are still unable to benefit from protein modulators such as ivacaftor and Trikafta.  

“My argument is: If you have diabetes, you don't wait to take insulin; if you have cystic fibrosis, you shouldn’t have to wait to take inhaled antibiotics,” Wine said.