10
Mar2015

by Avery Avrakotos, Education and Policy Manager

Veterinary pathologist and microbiologist David K. Meyerholz, DVM, PhD, DACVP, DACVM, will present a keynote address at PRIM&R's 2015 Institutional Animal Care and Use Committee (IACUC) Conference, which is being held March 17-20, in Boston, MA. Conference attendees can look forward to his address, titled Modeling the Origins and Mechanisms of Cystic Fibrosis, on Thursday, March 19.

Dr. Meyerholz is the director of the Division of Comparative Pathology and an associate professor of pathology at the University of Iowa Carver College of Medicine in Iowa City, Iowa. In preparation for the conference, I connected with Dr. Meyerholz to discuss his work and what prompted his interest in lung disease.

Avery Avrakotos (AA): At the conference, you will be speaking about your work modeling the origins and mechanisms of cystic fibrosis. What prompted your interest in the study of lung disease?
David Meyerholz (DM): My interest in lung disease started with my son who has reactive airway disease. Nearly every time he had a cold his airways would seize up; there were at least a couple times where his breathing became so labored that we had to rush him to the emergency room. Those experiences spurred my interest in lung disease, and when I started at the University of Iowa in 2006, I discovered that they had a really large cystic fibrosis (CF) program. I quickly became involved and started learning about the disorder.

AA: How has the use of animal models furthered what we know about cystic fibrosis?
DM: There wasn't an understanding of what CF was until 1938. At that time, children were dying from it, and a child was considered lucky to reach kindergarten age. Now, because of a lot of medical advances, people with CF have reached a median lifespan of about 37 years of age. Yet, we still don't understand the early changes that occur in CF. By the time many patients start presenting at the clinic—maybe six months or a year or two of age—they have already been experiencing lung disease sub-clinically. We don't have a clear understanding of the initial causes of the disorder, which would enable us to better treat infants born with CF.

In 1989, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which causes CF, was described for the first time. Within two years, we had mouse models for that, but mouse models don't recapitulate spontaneous lung disease in the same way that we see in humans. As a result, investigators started realizing that they needed to develop new animal models. Over the course of the last five years, we have been able to develop new models that have overcome the limitations seen in the mouse model. From those, we've been able to study and better understand what CF is doing to the lungs early on that makes them susceptible to infection and inflammation.

AA: What are some of the things that you've learned through your research?
DM: We've learned that CFTR, the gene again that causes CF, begins to cause damage in utero. As a result, CF neonates already have some damage to their airways at birth, which is a very important fact for furthering our understanding of the disorder.

We've also learned that CFTR is an anion channel, meaning that it transports chloride and bicarbonate across membranes regulating liquid secretion and pH of the airways. As a result of CF, the airway liquid is acidic and prevents the natural antibiotics of the lungs, which exist in the airway liquid, from working properly. It is sort of like we turn off our natural antibiotics, which makes our lungs more prone to infection. This knowledge has prompted the development of new therapies aimed at combating that issue.

We're also learning more about mucus; for example, we have known for years that CF mucus is "sticky" when secreted. So, instead of running out of our nose like it does with a cold, it gets stuck in individuals with CF. But, we're now learning that the mucus is sticky in part because it is often attached like an anchor to the submucosal gland ducts where it is produced. This "stuck" mucus holds all the bad things, such as bacteria, in the lungs and doesn't allow an individual to expel it, which further promotes lung disease.

It's sort of like putting a puzzle together; with all these little pieces of information, we're learning all the things that CF does early on, so that we can target therapies to each aspect and give CF patients and CF babies the best chance of having a prolonged and healthy life.

AA: What challenges have you encountered when translating the outcomes of your research to humans? How have you addressed those challenges?
DM: In some ways, we haven't faced many challenges with the animal model that we use—pigs—because, at least for CF, they have seemingly translated almost perfectly with what we see in humans. One interesting thing that has been a challenge is when we see something that we've never seen in humans. For instance, when the pigs were first born, we noticed that their tracheas looked abnormal. At the time, we thought, "Well, this is sure weird, because humans don't have this problem at birth." But, then we started reading and doing some studies in humans, and discovered that humans did have that issue. The pig model was actually able to show us a phenotype in humans that we hadn't recognized before. That is an example of a challenge that actually helped us to understand the human disease better.

AA: What advice do you have for members of the public who are interested in learning more about being a researcher? Are there any resources that you would recommend?
DM: Finding a personal connection to a disease or problem can help provide you with passion and a direction to pursue. For example, I had a student who went through my class last year whose grandmother had a certain type of cancer. Now, she's studying that type of cancer because she has a passion for it. Once you find what you're passionate about, you can seek out a researcher who is studying that problem, work in their lab, and gain an understanding of the situation and some of the challenges that have been encountered. Having someone with fresh eyes and who is able to think outside of the box can be helpful for stretching science and helping us to improve.

For more information about the 2015 IACUC Conference or to register, please visit our website. We hope to see you in Boston!

 

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