Stephen Schworer is searching for the origins of asthma

The NC TraCS K Scholar wants to know how lung tissue becomes asthmatic, in the hope of preventing the disease from developing.

Maybe it starts with an infection, like a cold or the flu, or is triggered by something in the air, like smoke from a nearby wildfire. Maybe it begins after exercising a little too vigorously. But no matter the cause, a severe asthma attack is frightening once it gets going.

Breathing trouble can quickly lead to coughing, wheezing, and chest tightness. As oxygen levels drop, a person may start gasping for air and feeling lightheaded. In a severe asthma attack, inhalers may offer little relief, and a trip to the emergency room becomes critical. In some cases, even emergency care can't stop the symptoms in time, and the attack can be fatal.

For the roughly 25 million Americans with asthma, this is the nightmare scenario. Luckily, most people with the disease only ever experience mild symptoms. But despite asthma's ubiquity, researchers still don't fully understand it—including the most fundamental question: What causes these symptoms?

Stephen Schworer, an assistant professor of rheumatology, allergy, and immunology and the UNC School of Medicine and a current K12 scholar with the North Carolina Translational and Clinical Sciences (NC TraCS) Institute, is trying to find answers. His research is attempting to discover why certain people develop the disease by investigating the complex cellular biology that causes a healthy lung to become asthmatic. Along the way, he's also developing new tools to better understand asthma's origins and uncover new treatments for this widespread disease.

...in the people who are more prone to developing severe asthma, if we can stop or change that process at an earlier stage, that would be great.

"Not everyone with asthma is going to develop severe disease," Schworer says. "But in the people who are more prone to developing severe asthma, if we can stop or change that process at an earlier stage, that would be great."

When we breathe in, air flows into our lungs and through a branching network of airways that get narrower and narrower until it reaches the alveoli, the tiny sacs where oxygen can enter the bloodstream. Each of us repeats this process countless times per day, without thinking about it. But for people with asthma, it's not always so simple.

In asthmatic lungs, a trigger—such as smoke, viruses, or dust—can set off an attack, which causes the airways to become inflamed, tightened, and filled with mucus. This makes those airways a lot narrower, or even blocked completely, preventing oxygen from reaching the blood. But we still don't know why some people develop asthma in the first place. It's also unclear why some people have mild symptoms while other people go on to develop severe, even life-threatening asthma.

Schworer thinks that some answers to these questions may be found at the very tips of the lung's airways. These small airways, which are less than two millimeters in diameter, make up most of the lung's airway network—yet because of their small size, they've been harder to study than the larger airways. But recent research involving lung biopsies of people with severe asthma has found a buildup of mucus blocking these tiny airways, Schworer says. It's now clear that this mucus plugging is often the main cause of death in people who die from asthma.

That begs the question: Where does all this mucus come from?

At a basic level, mucus comes from the cells lining the interior of the lung's airways, also known as the airway epithelium. There are a few different kinds of epithelial cells, but the most important, arguably, are the basal cells, which Schworer calls the "stem cells of the airway." These basal cells act as a blank canvas, capable of developing into all the other cell types lining the airway epithelium. Most of the time, they develop into ciliated cells, which are covered in tiny hairs called cilia that help move mucus and other substances around the airways. Other times, those basal cells become club cells, which secrete various proteins. And sometimes, the basal cells develop into goblet cells, which produce mucus.

Goblet cells aren't particularly common in the small airways. Yet one of Schworer's studies, conducted under the mentorship of Richard Boucher, found that people with severe asthma had an abundance of goblet cells in their diseased small airways, along with large amounts of a protein called MUC5AC, the main ingredient in lung mucus. That's to be expected—if you've got a lot of mucus, it stands to reason that you'd have a lot of cells that make mucus. Perhaps more surprisingly, Schworer also found that diseased lung sections also contained more basal cells than expected.

While we aren't sure why there are more basal cells in diseased tissue, this finding could offer a clue into how asthma develops. One of the major theories behind asthma's origins is that something (like a virus, for example) damages the lung. For some reason, the body doesn't repair this damage correctly. As a result, Schworer explains, certain areas of the lung might become more likely to produce goblet cells, which create mucus, leading to mucus buildup in those areas.

This is still just a theory. To help unravel what's happening in these airways, Schworer wants to figure out what causes basal cells to turn into goblet cells. His theory revolves around epigenetics, or how different genes in our DNA can be activated or deactivated. It's possible that some sort of epigenetic modification of the DNA inside the basal cells can turn various genes "on" or "off"—making them more likely to turn into goblet cells.

Schworer is taking a multi-pronged approach to test this. To start, he's using RNA sequencing technology to see which genes are active in the cells. He's also running ATAC sequencing to determine which parts of the DNA are open, or turned on, due to epigenetic modifications. In addition, he's looking for specific epigenetic markers that might be turning key genes on or off.

Some people with severe asthma seem to produce mucus in their lungs that just stays there...it would be great if clinicians could put the brakes on that process.

If certain epigenetic modifications are prompting basal cells to become goblet cells, that could be a huge opportunity for potential therapies. Medications could calibrate those epigenetic modifications, Schworer notes, allowing clinicians to turn different genes back on or off, which could possibly help prevent basal cells from turning into goblet cells. Some people with severe asthma seem to produce mucus in their lungs that just stays there, he adds—so, theoretically, it would be great if clinicians could put the brakes on that process.

Through his K project at NC TraCS, Schworer is also testing out some new methods of studying what happens in the lung's airways, building off existing research from some of his UNC colleagues. Typically, when researchers want to study the lung airway's epithelial cells in a lab setting, they scrape some of these cells out of a lung sample and grow them in a dish, Schworer says. But Scott Randell and Kenichi Okuda, lung researchers at the UNC School of Medicine, have developed a method for dissecting individual airways out of a lung and keeping those airways alive in a dish. This approach enables researchers to observe the airways in detail, with all their cells arrayed in the same structure, and possibly the same signals being sent back and forth, as would be found inside a living, breathing lung.

"These airways have the epithelial cells, and then underneath, all the other types of cells that are normally in the airway environment," Schworer says. "At least in theory, we can keep the relationships between these cells working."

Schworer is now studying how these airways-in-a-dish could be used for studying asthma, in part by taking advantage of a surprising phenomenon. After those airways have been dissected out of a lung, they can be frozen. Then, when thawed, the epithelium shifts into a neutral state composed entirely of basal cells. It's possible that, with the right time and conditions, those basal cells could be prompted to differentiate into other types of cells, including goblet cells, for further study.

This line of research could help answer some of the long-standing questions about where asthma comes from and how the disease may be exacerbated by cellular-level changes to the lungs. And Schworer points out that for many people, these questions—and the biology of these tiny airways—can have life-or-death consequences.

"People with asthma can die from having too much mucus plugging up their airways. Even if somebody doesn't die from mucus plugging, it can still contribute to asthma exacerbations and symptoms," he says. "So, if we understand why these diseased regions develop to begin with, perhaps we can prevent this disease, prevent the mucus plugging from happening."