Taking the lung apart cell by cell, to mend it

Friday, September 22, 2017
Christina Barkauskas, with painting by Kim Howard, PA-C

In 2016, the Duke School of Medicine selected 38 of its faculty for the new Duke Health Scholars and Duke Health Fellows Program. With funds from the Duke University Health System, the program supports the research efforts of early to mid-career clinician-scientists at Duke.

Among the faculty honored are 14 individuals from the Department of Medicine, including Christina Barkauskas, MD, assistant professor of medicine (Pulmonary, Allergy, and Critical Care Medicine).

The photograph of blue, pink and neon-green globes that Christina Barkauskas keeps on her desk inside the Nanaline Duke Research Building looks like a string of glowing holiday lights.

That is, until she decodes it.

Produced with a confocal microscope, the image is evidence of new insight into how some lung tissue repairs itself. It captures type 2 epithelial cells within alveoli functioning like stem or progenitor cells by giving rise to type 1 epithelial cells, which contribute to tissue repair.  

For Dr. Barkauskas, this is not knowledge for knowledge’s sake. It’s data needed to better serve  patients with often-lethal idiopathic pulmonary fibrosis. She is frustrated by how little she can offer most of them today.

Usually she is unable to identify the precise processes causing scarring an individual patient’s lungs. Nor can she predict how well each will respond to the best drugs so far available to her.

“I want to be able to tell them: ‘We think your disease is driven by this process and we’re going to target that process and hopefully give you a better outcome’,” Barkauskas said.

Many mysteries persist regarding fundamental mechanisms affecting normal repair of alveoli, the tens of millions of tiny sacs engaged in the life-sustaining gas exchange that admits oxygen to the human bloodstream and expels carbon dioxide.

On her own and working with others at Duke and elsewhere, Barkauskas has revealed multiple important processes in a string of high-profile publications that have captured other scientists’ attention.

“I am very familiar with the phenotype of people trying to solve fundamental problems in science at the highest level of scientific rigor. Christina has that phenotype,” said Nancy Andrews, MD, PhD, former dean of the School of Medicine.

Barkauskas decided that she would like to be a doctor during her childhood in northern New Jersey. She was inspired by a dedicated specialist who treated her multiple allergies and asthma so well that she wasn’t once admitted to the hospital.

“She made a really big difference in my life. I felt she really came to know me and what made me tick,” Barkauskas said.

Even during high school, Barkauskas was fascinated by biological systems and interactions. While an undergraduate at Princeton University, she dug deeper, exploring developmental genetics in fruit flies while earning a degree in molecular biology.

Medical school and internal medicine residency followed at Duke, where Barkauskas found herself drawn eventually to patients suffering from serious lung disease.

“This is not a silent disease. If your lungs aren’t working properly, you feel it. It’s more concrete for me and for my patients,” Barkauskas said.

Barkauskas by then wanted to mix research with medicine to “try to answer big questions.” So when Paul Noble, MD, then chief of the Division of Pulmonary, Allergy and Critical Care Medicine at Duke, asked her to consider spending two years in the lab of Brigid Hogan, PhD, FRS, Barkauskas jumped at the chance.

An elite developmental biologist with a long record of discovery, Dr. Hogan has long been interested in the identity and regulation of stem cells in the adult lung and their role in repair, scarring and cancer. Her laboratory was exactly the place for a young pulmonologist to learn to use sophisticated basic research tools, Barkauskas said.

It didn’t take that long for Barkauskas to apply those lessons.

“More than anyone else I have seen, Christina appears poised to identify the long-sought-after cellular interactions and signaling molecules that mediate alveolar repair,” said Michael Gunn, MD, chair of the Department of Medicine’s Research Development Council.

Studies Barkauskas pursued in mice revealed that one cell type assumed by many to be active in producing scar tissue in alveoli is not. She and collaborators also discovered that the mature alveolar cells in the photo are plastic enough to shift identity like stem cells might, which expands insight on their properties.

Barkausakas and collaborators have also uncovered that communication between different cell types — epithelial and mesenchymal — are required for alveolar repair. She invented an experimental model with three-dimensional alveolar organoids, rudimentary organs comprised of the interdependent cells, to expand laboratory studies of that relationship.

Her studies with genetically modified mice have shown that the presence of shortened telomeres in cells disrupts repair processes in mice alveoli, an intriguing finding because nearly 15 percent of patients with idiopathic pulmonary fibrosis (IPF) have telomere-related genetic mutations.

On her to-do list are gene-editing queries to better understand which DNA sequences promote or disrupt normal tissue repair, work that could turn up new biomarkers of disease and, possibly, new targets for better medicines for IPF.

That would serve her largest goal directly. “I would love to be able to find a way to personalize diagnoses and treatments,” Barkauskas said.

The series of profiles of our Duke Health Scholars were written by Catherine Clabby, freelance science journalist. Photos are by Ted Richardson.