PEMM Research Identifies Possible Breakthrough Treatment for Cystic Fibrosis

Sladjana Skopelja-Gardner, a fifth-year PhD student in Dartmouth’s Program in Experimental and Molecular Medicine (PEMM), recently published the first article from the United States to address a role for autoantibodies in cystic fibrosis (CF). “People don’t think of cystic fibrosis as an autoimmunity disorder and most of the research in favor of that perspective was done 20 years ago without much recent progress,” she explains.

Her first-author paper, The role for neutrophil extracellular traps in cystic fibrosis autoimmunity, was published in the Journal of Clinical Investigation Insight (JCI) in November, 2016 under the direction of her principal investigator (PI), Dr. William Rigby. This research was funded by a pilot grant from the Dartmouth Lung Biology Center of Biomedical Research Excellence (COBRE), headed by Bruce Stanton.

CF is a genetic disease caused by a mutation in a protein that regulates the movement of salt in and out of cells. The mutation thickens mucus, which builds up in the lungs. The thickened mucus in the lungs creates a favorable environment for infection, which leads to inflammation and loss of lung function. Respiratory failure resulting from decreased lung function is the leading cause of death in CF patients. However, research has yet to identify the exact cause of decreased lung function. Skopelja-Gardner has found that infection by a specific species of bacteria strongly associates with an autoimmune reaction that correlates with lung function.

Skopelja-Gardner has demonstrated that bactericidal permeability-increasing protein (BPI) is the main autoimmune target in CF. This protein normally kills harmful bacteria in the body. She explains how an autoimmune reaction to BPI may happen:

“Autoimmunity is when your body thinks part of itself is a foreign invader, i.e. bacteria or viruses, and attacks. We have found that the ‘foreign’ target in CF is BPI. Autoimmunity to BPI is mainly found in patients with a history of Pseudomonas aeruginosa infection, which is the most common infection in CF patients.  We speculate this reaction against BPI could happen two ways. BPI could be inactivated by the bacteria, which would save the bacteria, but it would also make a new version of BPI that the body does not recognize as its own. Another possibility is that human BPI could look like a bacterial protein. This could confuse our immune system into thinking that our protein is actually from the bacteria.”

Their next steps will investigate these mechanisms to identify proteins involved in the development of autoimmunity and the subsequent loss of lung function. In the future, the proteins they identify could be used as therapeutic targets for CF with the potential to significantly decrease mortality.

Sladjana Skopelja-Gardner attended Dartmouth as an undergraduate student before beginning her career as a PhD student. In her first year as an undergraduate student she began research with Dr. Nicholas Shworak studying a model of septic shock. Sladjana credits much of her scientific expertise to Dr. Shworak saying, “He taught me everything: from how to use a pipette to planning out my own experiments.” Although new to research, she excelled in the lab environment and was awarded the James O. Freedman Presidential Scholar Award, allowing her to complete a fully funded senior thesis which opened doors for her to obtain a position in industry. At Celdara Medical, she advanced the production side of a protein involved in the septic shock model she studied with Dr. Shworak. After her year in industry, she was inspired to apply for a PhD program and further her involvement in the research process, which brought her back to Dartmouth.

When asked about her methods to achieve success in publication, she advised students to think of their experiments and research in terms of a paper. “Start outlining what each figure is going to be based on your data, then make a story that connects those figures to make a succinct point,” she elaborates. Although she admits that the review process for publication was long and, at times, frustrating, she believes it was one of her most valuable experiences: “I feel like I have contributed something to the scientific world. Someone is going to read this paper and it will inspire them to make their own hypotheses and try their own ideas in the field. It fuels me to work harder and produce even more data.”

She also encourages students to stay excited and motivated to learn from their research. “I have trained myself to find a silver lining and not get disillusioned. There are weeks where you won’t get any good data and experiments won’t work. But, I ask myself every week, what have I learned? That way, even if everything goes wrong, I have benefited from all of my time and effort that week.”

In the future, she will complete a post-doctoral position in the state of Washington. She hopes her post-doctoral experience will launch her into a career as a principal investigator and professor. Skopelja-Gardner wants to have a first-hand role in keeping graduate students ecstatic about their work from the moment they arrive until the moment they graduate: a way of life she embraces both in her research and in her role as a teaching assistant for Dartmouth’s undergraduate immunology course. Without a doubt, many great things can be expected from this soon-to-be two-time Dartmouth alumna.