Capitalizing on chance observations

Written by on November 1, 2011 in Research & Technology - No comments

By Marla Broadfoot

Though Richard Boucher, M.D., has viewed thousands of chest X-rays in his career, one stands out in his mind. Boucher (rhymes with touché) was doing a year of medical service in Eagle Butte, S.D., when an X-ray revealed dozens of opaque spherical objects lodged in the chest of one of his patients. At the time, tuberculosis was endemic among the Native Americans living in the area, and doctors would cut out lung tissue damaged by the disease and fill the space left behind with ping pong balls.

“I figured this field must be pretty interesting,” deadpanned Boucher, recounting the oddball moment that led him to become a pulmonologist.

Thirty-some years later, Boucher is a leader in the field, serving as a Kenan Professor of Medicine at UNC-Chapel Hill and helping to oversee the management of the NC Translational and Clinical Sciences (NC TraCS) Institute, UNC’s home of the Clinical and Translational Sciences Awards (CTSA), as a PI extender (a top-level position shared by four to assist the principal investigator in managing the institute). He also directs the Cystic Fibrosis Center, which in recent years has evolved into one of the largest CF research centers in the world.

Boucher’s first encounter with CF, one of the most common chronic lung diseases in children, was as a parent, not a clinician. One of his daughters had multiple pneumonias when she was just a baby, and was tested for CF. She did not have the disease, but Boucher says he didn’t realize how lucky he was then because he knew so little about the illness. He had never even seen a kid with CF when he was in medical school because those patients were kept in “mist tents” to maintain moisture in their lungs.

“There was always so much condensation on the plastic that you never saw the children inside,” explained Boucher. “It was almost like plants in there, it was so weird.”

Despite those early experiences, Boucher was still determined to study another illness, asthma, which affects a greater number of children and young adults. He developed a test to quantify the stickiness and dehydration of mucus secretions in his asthmatic patients. Then his colleague Michael Knowles, M.D., borrowed the technique for his CF patients. The results were so striking, so abnormal, that Boucher felt compelled to understand them.

“I found a new direction and I never went back,” recalls Boucher. “In this line of work, you have to take advantage of chance observations. It is a bit of luck, and a bit of just keeping your eyes open.”

Breathing treatment for CF

That ability to look at every anomaly with a curious mind has led Boucher to a number of discoveries revolutionizing the treatment of CF. Despite his singular accomplishments, he maintains that his greatest achievement is leading a multidisciplinary center that takes advantage of people’s collective knowledge, insight and hard work.

“We have essentially created a platform where we can begin to understand how the dominoes fall to produce lung disease in patients missing a functional CF protein,” Boucher said with pride.

CF is caused when patients have two defective copies of the gene coding for a protein called cystic fibrosis transmembrane conductance regulator, or CFTR. When the protein doesn’t work properly it affects the way chloride ions move across the surface of the lungs, making them clog up with sticky mucus that is prone to infection.

With the help of mouse-modeling gurus Oliver Smithies, Ph.D., and Beverly Koller, Ph.D., Boucher made a “knock-out” mouse with a defective CFTR gene. This small animal model of the disease mimicked many of the intestinal issues of human patients, but oddly enough possessed none of the lung problems. The finding pointed the researchers to factors that could offset the lung disease, and paved the way for new therapeutic options for CF. The CFTR protein mainly functions as a “chloride channel,” controlling the flow of ions that keep the mucus on the outside of the airways hydrated. But there are also other chloride channels that are quiescent, being called into action by hormones and other stimuli in the lung only when needed.

“The idea is that there is a local regulation system that serves as a sort of back-up, that we all need to flush out insults from the outside world, such as viruses or pollutants,” explained Boucher. “What we learned in the mouse has led us to ways to turn on this whole second set of chloride channels, picking up the slack for CF patients.”

One way to kick this back-up channel into gear is through exercise, which is why doctors recommend that their patients work out at least 30 minutes a day. As CF patients exercise, they breathe in a lot of dry air, forcing the body to come up with alternative ways to hydrate their airway surfaces. They can also add the use of devices such as “flutter vests” to their daily routine, which can trick their lungs into thinking they are exercising, again turning on these other chloride channels and helping to clear the chronically infected mucus secretions out of their lungs. Both approaches are decidedly low-tech, and are now part of the standard of care for CF patients.

The third piece of standard treatment came from another chance observation, initially made by Boucher’s colleagues Scott Donaldson, M.D., and William Bennett, Ph.D. Because the main manifestation of the disease is caused by a lack of salt and water in the lungs, the researchers wondered if they could simply add salt water to the airway surfaces by having patients inhale hypertonic saline. The saltwater solution would draw water from the tissues in the secretions and liquefy them, making it easier to clear mucus from the lungs. Boucher, who was brought in for some of the proof-of-concept studies and clinical trials, says the safe, effective and cheap approach went from an idea to a treatment in under five years.

Boucher holds 76 patents for such medical interventions and diagnostics, though he is too busy inventing to bother keeping a tally. The importance of patenting ideas was imparted on him long ago by the CEO of the CF foundation. Boucher was about to publish a paper on a potential therapy and had decided not to patent it so everyone could have access, but was quickly informed that unless the discovery was patented, no one would back it because there would be no return on their investment.

“You do think not to patent it, then it will be easier for everyone to get it, but it turns out that that is just not how the world works,” said Boucher. “Though patenting goes against one’s natural instinct, it is the best way to push it forward.”

In his role as PI extender at NC TraCS, Boucher is helping to accelerate the translation of similar discoveries, especially in terms of commercialization.

“Our number one challenge is changing the mindset on campus so faculty understand that commercializing our advances is actually something we ought to be doing,” said Boucher, who also helps lead NC TraCS’ Carolina Kickstart initiative, which guides scientists as they commercialize their drug compounds, therapies or devices. “Then we can show them that there are clear-cut rules for how to do it and that there are clear resources to help them along the way.”

Boucher, who through his own scientific contributions has helped to extend the life expectancy of CF patients from the age of 12 to 37, is optimistic that pushing academic research to the next level could one day make CF as easy to treat as asthma.

“Currently there are a lot of scientists investigating both low-tech approaches and high-tech biophysics and molecular biology approaches for CF,” stated Boucher. “Personally, I would be happy if we could put some drugs that would hydrate CF secretions in an aerosol vial. Then we could just tell our patients to take two puffs in the morning and two puffs in the evening and that they will be fine. I think that is very possible.”

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