Almost all of us know someone with asthma, perhaps many. It’s a ubiquitous condition that affects one in 13 people in the U.S. and more than 300 million worldwide. Asthma can be life-changing and in some cases life-threatening. But what if you could stop asthma in its tracks, rather than wait till the wheezing or coughing sets in? What if you could halt the progression before it damages the lungs? That’s the hope behind a 2021 KL2/Catalyst Medical Research Investigator Training (CMeRIT) award to pulmonologist Jehan Alladina, MD, an instructor in medicine at Massachusetts General Hospital (MGH) and graduate of our Clinical and Translational Research Academy.
You received the KL2/CMeRIT award in 2021 for research in translational immunology. How did you get interested in this particular area of research?
I did most of my training–from medical residency to pulmonary fellowship–at MGH, and I started off not being particularly interested in research. That wasn’t on my radar. But as I got deeper into this specialized field of pulmonary medicine, I realized there were so many unanswered questions. It struck me that other fields, such as oncology and cardiology, had precision therapies that could target specific pathways to help patients, but there seemed to be a gap in that kind of personalized medicine in pulmonology. It felt like there was an opportunity and a need to make progress there.
Chronic pulmonary diseases affect so many people, yet we’re mostly still using the same therapies that we used 50 years ago. Many of these agents suppress general inflammation and are not targeted at all. Steroids, for example, have been the mainstay of asthma therapy for decades. They block many inflammatory pathways, and therefore can lead to widespread side effects including increased susceptibility to infections. While newer agents target specific pathways of a subtype of inflammation, it’s unclear if they are changing the course of the disease or still blocking inflammation more generally.
What are the public health implications of this work?
Right now, all our asthma therapies treat symptoms. No therapy has been shown to be disease-modifying, meaning preventing the progression of disease. Pulmonary research has been somewhat behind the eight-ball compared to other disciplines in making advances towards disease-modifying therapies. The overall goal of our research program is to do just that. We’re trying to really drill down on the key pathways that underly asthma. Our ultimate goal is to modify the disease itself–even prevent its development altogether–rather than just treat the symptoms.
“Pulmonary research has been somewhat behind the eight-ball compared to other disciplines in making advances towards disease-modifying therapies. The overall goal of our research program is to do just that.”
By identifying specific pathways that drive asthma pathogenesis, we could not only achieve disease remission, but may also avoid the many side effects of drugs such as steroids that globally suppress normal immune function. We would then have the potential both to improve outcomes and prevent the off-target effects of these non-selective therapies.
What is the research question your KL2/CMeRIT award is examining, and why?
Our main research question is simple: why do some people get asthma and others don’t? We compare people who have allergic asthma, which is the most common type of asthma, to other people who have allergies but don’t develop asthma. We think there’s an opportunity to uncover the pathways that are the key drivers of asthma by comparing those two groups.
One unique aspect of our research is that we can directly examine the lung response to allergens, important triggers of asthma symptoms, by performing a segmental allergen challenge. We use bronchoscopy, a thin flexible camera inserted into the lung, to administer a mild allergen directly into one airway segment of the lung of study participants. Twenty-four hours later, we take samples of the airway fluid and tissue from the lungs. This study design enables us to examine what happens in the lung during an asthma exacerbation in a controlled manner. For example, we can study the cells that move into the airways after an allergic insult, which isn’t possible without the challenge experiment. This is a technically complex study design that is only done at a few centers worldwide.
Experimentally, I’ve coupled our study design with single-cell RNA sequencing, a relatively new technique that’s well suited for human translational research where samples are scarce and can be difficult to come by. This technique allows us to look at all the genes expressed by each single cell in the tissue, and to understand how the gene programs of cell types and disease conditions differ from one another. What we see in our challenge experiments is a big influx of immune cells, especially mononuclear phagocytes, in both allergic asthmatics and controls. These cells have been implicated in animal models of asthma, but it’s been difficult to sort out their role in human disease, in part because they’re a heterogeneous class of cells with many different subtypes. Using single-cell RNA sequencing, we’ve identified an immature, inflammatory subtype of mononuclear phagocytes that is enriched in the asthmatics but not the controls. We believe that this cell type and the factors that program its inflammatory state likely play an important role in driving the persistent inflammation and structural remodeling that define asthma.
What do you see as the value of research mentorship programs like these?
Without mentorship we simply couldn’t perform this kind of research as junior investigators. It provides both the opportunities and the necessary infrastructure to do meaningful research. My mentor, Benjamin Medoff, MD, MGH assistant professor of medicine, built this research bronchoscopy program from scratch over 10 years ago along with Andrew Luster, MD, PhD, MGH Harrison Professor of Medicine. Because of this program, I was able to come in and almost immediately test interesting questions and perform translational research that truly feels relevant to human disease. The ability of mentors to lay that historical groundwork is essential for successful future research endeavors.
“Without mentorship we simply couldn’t perform this kind of research as junior investigators. It provides both the opportunities and the necessary infrastructure to do meaningful research.”
In my case, Ben’s unique expertise not only in translational research, but also in immunology, was vital. When I started in his lab, I didn’t have any formal immunology training. He has guided me through the intricacies of this complex field. He’s also been extremely supportive of the vision I have for my career path. I was clear from our earliest conversations that I wanted to do human-based translational studies because it’s important to me as a physician-scientist to continue to have that connection to patients. Even though his lab has a large animal-research component, he has been very supportive in my commitment to human translational work.
Harvard Catalyst in general has been extremely helpful for my early career. When I was a pulmonary fellow, I was a trainee in the two-year Clinical and Translational Research Academy. I feel like we can get a little siloed in our own work, so being able to have a community of people across divisions to share ideas and struggles with has been really invaluable. I’ve had many opportunities to engage with people doing similar work at early stages in their careers, and the main benefit has been the opportunity to be continually inspired by the impressive work of my peers and colleagues. I continue to recommend Harvard Catalyst’s programs and resources to trainees contemplating research.
What do you do for fun outside of work?
In the fall of 2020 we rescued a pandemic puppy, Juniper, and [my partner] David, Juniper, and I just love to get outside whenever we can. Maine is probably our favorite place to go, but we often just head generally north to get out of town. We also live right next to the Arnold Arboretum, so that’s our local space where we go practically every day to just reset and unwind.