Though the esophagus is a vertical tube that connects the mouth and stomach, food doesn’t simply fall down the tube, propelled by gravity. Instead, the esophagus is lined with powerful muscles that pump food to the stomach with waves of rhythmic contractions.
John Pandolfino, MD, ’94 ’96 ’01 GME, chief of Gastroenterology and Hepatologyin the Department of Medicine, has spent much of his career investigating the pipes and valves of the esophagus — a natural fit for somebody who comes from a family of plumbers. “It’s probably in my blood,” he said.
However, anatomical mechanisms are just one of a triad of factors that can affect swallowing; brain-gut interactions and psychological stressors can also contribute to swallowing disorders. These cross-disciplinary causes have led Pandolfino to reach across institutional lines, collaborating with faculty in a range of departments and Feinberg and the McCormick School of Engineering.
What are your research interests?
My research interests focus on bolus transport through the esophagus as it pertains to swallowing issues, inflammation of the esophageal wall and gastroesophageal reflux. The core components of the work center around an interplay between clinical observation and developing physiologic and biomechanical models to explain those observations.
This translational science allows us to better phenotype patients and develop relevant biomarkers and targets to improve function and reduce symptoms. This work also requires an understanding of the brain-gut interaction that drives symptom severity, so understanding the role that psychological stressors and central nervous system modulation play in this relationship is a crucial part of our model and research program.
What is the ultimate goal of your research?
We have two specific aims. The first focuses on using physiology, principles of biomechanics, mathematical modeling and in-silico simulations to define normal and abnormal esophageal function. This requires expertise in engineering, physiology and clinical research, and our ultimate goal is to develop new tools to better understand esophageal diseases and to develop better biomarkers of disease severity and discover new targets for therapy. This part of our research requires collaboration with engineers and experts in tissue material properties at the McCormick School of Engineering, basic scientists focused on inflammation and fibrosis, and skilled data scientists.
Our second aim focuses on symptom expression of these abnormalities in bolus transport and how we can better quantify the severity and brain-gut interactions that modulate this output. This component requires collaboration with psychologists and experts in psychometrics, as well as clinicians focused on specific esophageal diseases, such as eosinophilic esophagitis, achalasia, scleroderma esophagus and gastroesophageal reflux disease. Our ultimate goal is to develop a universal model that connects the molecular perturbations that lead to abnormal esophageal bolus transport and describe how these mechanical changes lead to symptoms and reduced quality of life. We theorize that mathematical and in-silico models developed in our lab can be used to define better treatments and personalize the approach to these heterogeneous disorders.
How did you become interested in this field of research?
I became interested in this work during my gastroenterology fellowship when I had the opportunity to work with my mentor, Peter Kahrilas, MD, '84 GME, here at Northwestern. Peter combined astute clinical observation with an in-depth understanding of physiology to explain disease pathogenesis. This form of research was very exciting because it had immediate impacts on patient outcomes. We were able to describe markers of severity in GERD that could be targeted for therapy. Over the years I extended this model to dysphagia and developed strong collaborations with my engineering colleagues, Neelesh Patankar, PhD, and Walter Kou, PhD, to incorporate in-silico models to better understand the “plumbing” of the esophagus.
I have also been fascinated by what drives symptom severity as I realized early on that even if I fixed the plumbing, some patients would not get better. Since then, I’ve worked with my colleagues in psychology to better understand how stress and anxiety can modify symptoms and how cognitive flexibility and function alter how the patient interacts with that symptom. Laurie Keefer Levine, PhD, and Tiffany Taft, PsyD, were very generous in helping me better understand these interactions and eventually became very important collaborators. These interactions have made me a much better scientist and also changed the way I practice medicine.
Lastly, I have developed a new-found interest in the molecular underpinnings of why the esophageal wall loses its ability to accommodate and propel a bolus, and new collaborations with basic scientists, like Marie-Pier Tetreault, PhD, have taught me how these fundamental cellular changes can be linked and explained by our current models. This is the best part of my job as I constantly get to learn and incorporate new ideas to improve my work.
How is your research funded?
Fortunately, our work has been funded by many sources. The National Institutes of Health has been a major supporter of our work, and we currently have a new P01 grant funding three unique projects and two specific cores focused on bio-physiologic modeling and tissue material properties within the grant.
Additionally, the Digestive Health Foundation (DHF) has provided much-needed infrastructure to support a biorepository and the components that allow us to connect tissue and blood to state-of-the-art physiologic models and psychometrics. The DHF has also funded multiple pilot studies that support some of the hypotheses of the P01, and this has been a great platform for young investigators.
What resources at Northwestern have been helpful?
Feinberg has been a major resource and provided funds to further augment the work of the P01 and the cores that we developed for that application. The Department of Medicine was equally supportive and also helped in our ability to recruit junior faculty and support trainees involved in our research. Of course, Northwestern University Clinical and Translational Sciences Institute (NUCATS) and the Biostatistics Collaboration Center (BCC) were crucial for the success of our grant and our current work. NUCATS provided a unique opportunity to present our proposal to a panel of experts and their input was crucial in modifying our proposal and organizing our admin core. The BCC has been a standard component of our work as we have relied on their team for proposal preparation and ongoing data analysis.