November is COPD Awareness Month in the US. Chronic Obstructive Pulmonary Disease (COPD) is a serious lung disease that makes it hard to breathe. It is caused by long-term exposure to irritating gases or particulate matter, most often from cigarette smoke. People with COPD are at increased risk of developing heart disease, lung cancer and a variety of other conditions. According to the American Lung Association, COPD is the third leading cause of death by disease in the United States. More than 15.3 million people have been diagnosed with COPD, but millions more may have the disease without even knowing it.
We recently spoke with Douglas N. Robinson, Corrine R. Kliment, Jennifer Nguyen, and Ramana Sidhaye of the Johns Hopkins University School of Medicine about the Robinson lab's research on COPD.
What is the connection between your research and COPD?
Our research has been focused on understanding how cells form and maintain their necessary shapes (i.e. cell morphogenesis). Tissues then depend on the ability of cells to assume the crucial shapes so that they can connect and maintain tissue integrity. While we started out by trying to understand the fundamental underpinnings of cell shape control, we now know that these concepts, and even the specific proteins, carryover to larger tissue structures.
Importantly in COPD, the disease stems from a loss of tissue integrity of the airways, which are the tubes through which air enters the lung. The cells that line the airways have a specific shape, and they make connections so that they create a barrier that prevents particles, including bacteria, from entering the surrounding lung tissue. Not only do they maintain a barrier, they have specialized structures on their surfaces called cilia, which flutter like boat oars thereby helping to move particles out of the lung. For these to work properly, the airways maintain an optimally hydrated mucus layer that helps protect the airway from the particles and creates an environment in which cilia can move the particles out of the lung. During the development of COPD, there is a failure of the airways to maintain this tissue barrier, including the properly hydrated layer that allows the mucus to flow easily.
Why is your research important to those concerned about COPD?
Currently, about 10-15% of the world’s population (15% in the U.S.) is affected by COPD. Yet, the major treatment strategies focus on symptoms, not root causes of the disease, and these strategies have not really progressed in the past 40 years. We hope to have an impact on this.
How did you get into this area of research?
Initially, my pulmonary physician scientist colleague Ramana Sidhaye, Associate Professor of Medicine at Johns Hopkins, who knew about our interest in the fundamentals of cell shape control reached out to start having conversations about what might be underlying the loss of airway tissue integrity in COPD. After a series of lunch conversations, we recognized many points where our concepts and strategies could be utilized to help uncover new biology related to COPD. We then had a terrific opportunity when then pulmonary fellow Corrine Kliment, now Assistant Professor at University of Pittsburgh Medical Center, joined our team. We have since recruited Jenny Nguyen, a pharmacology doctoral student, and are likely to recruit more students in the next year or so. We think this speaks to the importance of having sufficient green space in the university science enterprise to allow for idea sharing.
How long have you been working on it?
Ramana and I started working together around 2011, but then we had a little layoff until Corrine, and then Jenny, joined our group. Now, our projects in COPD have expanded dramatically.
Do you receive public funding for this work? If so, from what agency?
Yes, Ramana and I have an R01 through NHLBI. Corrine recently received a K08 award from NHLBI, a Burroughs Wellcome Careers Award in the Medical Sciences, and a Parker B. Francis Fellowship Award. During her Post-doctoral work, Corrine was also able to secure support through an NIH F32 Award from NHLBI and a Baurenschmidt Award from the Eudowood Board at Johns Hopkins. Jenny also received an NIH F31 award.
Have you had any surprise findings thus far?
We have had a number of exciting findings. First, we have found that cigarette smoke dramatically shifts the organization of actin and myosin II, two key proteins involved in cell and tissue integrity. Further, another major protein, E-cadherin, which functions like cellular glue, helping hold the cells together in the tissue, is strongly ablated by cigarette smoke.
Perhaps even more surprising findings come from a study that is currently ongoing. We recognized that big breakthroughs were slow to come by given the complexity of the airway tissues and the relative difficulty in studying them. We hypothesized a few years ago that core biology that is fundamental to cells in general would be impacted by cigarette smoke, the major environmental toxin that leads to COPD in the U.S. Therefore, we decided to leverage one of our favorite model systems in Dictyostelium discoideum (Dicty for short) and performed a genetic selection for genes that could protect from cigarette smoke extract; in effect, we made Dicty smoke cigarettes! We found several genes that could protect Dicty cell viability and then tested the human counterparts in immortalized human airway cells and primary airway cells. The genes were also protective there as well. This story has many essential threads that we are pursuing, but the point is that new unexpected cell and tissue biology, and even some pathways to new therapeutic strategies, are now available to be explored. We are excited to be doing that.
What is particularly interesting about the work from the perspective of other researchers?
We hope that this work underscores the importance of team-based science where researchers from different fields come together to identify and pursue important questions related to human health. Moreover, basic model organisms and systems are powerful for studying complex human biology. We should not forget that these powerful systems continue to provide invaluable opportunity for uncovering key mechanisms of disease.
What is particularly interesting about the work from the perspective of the public?
Fundamental research is the key to unlocking the basis of disease. Once we do this, we can develop the information we need to seek strategies to treat, and ultimately, we hope, reverse and even cure the disease. Researchers from a range of disciplines are needed to build strong teams with all the requisite skills and insight to make these leaps. We are committed to these goals.