Meet the Expert

Learn what Dr. Andrew Halayko, a scientist at the forefront of preclinical asthma research, has to say about his research and the current state and future of the field.

Dr. Andrew Halayko is a Principal Investigator in the Departments of Internal Medicine & Physiology and Pathophysiology at the University of Manitoba. The Halayko lab focuses on the pathogenesis of bronchial asthma and is at the forefront of preclinical asthma research. We sat down with Dr. Halayko to learn more about his work and get his thoughts on the current state and future of asthma research.

Interview:

 

Q: What led you into asthma, airway smooth muscle research and what interests you the most about it?

A: I came into Asthma research without a plan, it wasn’t something on my radar. I started as a grad student in the department of agriculture studying barley germination.

When I finished my Masters, I was not prepared to do a Ph.D., but I was lucky enough to get a summer position working with Dr. Newman Stephens in the Physiology Department at the University of Manitoba, and this led to me getting a full time job as a lab technician with him. Dr. Stephens was a world-renowned expert in airway smooth muscle physiology. What he liked about me was that I was a biochemist and he wasn’t doing biochemistry when I started working with him. I knew virtually nothing about the lungs and airway biology. I just grew into it, and before I knew it, I was assisting Ph.D. students in his lab in a very real way. It dawned on me that for much of the work they were presenting as their own, I had developed or suggested it, right down to the experiments. My colleagues were all prompting me to do a Ph.D., so I did. After almost 5 years of being a research tech, I did my Ph.D. That is how I grew into understanding and appreciating asthma and the role of airway biology.

The most interesting thing for me about asthma was that on the surface is a pretty simple disease; airways constrict, and in some people they don’t relax well, but beyond that it’s a life-threatening disease. It affects many people so that is important in my eyes, that I’m not dealing with a niche disease. We seem very close to achieving the knowledge we need to have a bit of a breakthrough in the therapeutics of asthma and understanding why some people are asthmatic and others are not.  I think that’s the carrot I always come back to, that we always seem like we could be one study away from a breakthrough that can make a difference.

 

Q: What is the general landscape of asthma looking like in terms of asthma research? You said we are very close to a breakthrough. Are there key topics or questions that are being asked or need to be asked to get there? What do you think is missing?

A: I think the areas that are right at the forefront and need to be pushed upon, but not necessarily in this order are: the origins of the disease, how certain environmental triggers exacerbate the disease, what is severe and steroid-refractory asthma, and infectious disease in asthma.

When looking at the origins of the disease, what are the triggers and exposures? Genetics and epigenetics are part of this as well, but what predispose somebody to become asthmatic? How can one kid who develops asthma or shows asthmatic symptoms be exposed to virtually the same conditions prenatally and postnatally as another kid who does not exhibit disease? This makes the developmental origins of the disease, is an important area. In our work with some of the SCIREQ infrastructure we have will be looking at maternal exposure and we would like to look at paternal exposure as well and how that increases the risk of asthma developing in the child. This would not be genetic based, but rather environmental based.

I think the other area that is important is environmental exposures of how certain environmental triggers exacerbate the disease perhaps because of factors if early life exposures are involved.

A third one that I think is really important, and it’s been an area of interest for us for many years, is “what is severe asthma?”. “What is steroid refractory asthma?”, and what breakthrough in understanding in pathophysiology do we need to develop a therapy that might work beyond the ones we’ve got now, which work pretty well in 80% of the asthma population if they take the drugs.

The final area that has emerged is infectious disease in asthma and lung health; are asthmatics at a higher risk for severe disease when it comes to Covid-19?. Covid-19 is the current pandemic but there will be others. What is it about the asthmatic airway that predisposes more severe responses or disease in individuals with those infections?

To me those are the four areas of the biggest impact or most importance right now. There are others however, those are not the only four.

 

Q: The vast majority of groups that work with asthma tend to be targeting therapeutics, recoveries or treatments and it sounds like you’re more looking at the pathogenesis or trying to stop it before it even develops.  Do you see that in a difference in approach?

A: It is certainly one of the approaches we use, we also do the preclinical testing you’re talking about and that is kind of the bread and butter part of the program. These types of projects are easy to give to graduate students, you know they are going to get something and as a supervisor it’s great to give students projects that will work.

The developmental origin really isn’t an emerging concept in the respiratory field; if you look for instance at the ATS meeting, you see all sorts of abstracts about the origin of the disease and not just asthma, but other chronic lung diseases but there isn’t a consolidated group or group of people saying “we study the origins of lung disease”, so that makes it attractive to me. I always like to be doing something that is a bit unique. I recognize that the mainstream topics are where you can make your money in terms of grants and papers, but I have always been pushed to do unique things and perhaps look at things a little differently than other people in the field.

I have frequently looked at using methods and techniques from other disciplines and other diseases. Early in my career I noted that in pulmonary hypertension research they looked at vascular smooth muscle, and since I was really focused on smooth muscle biology, I would look to that literature and see what are they doing, and how that would be unique in the airway field.

I find the disease origins part fascinating because it’s so broad and it encompasses a lot of territory in terms of biology but also the approaches you can use. It’s hard work, and I think that’s why people don’t generally gravitate there. If you’re going to do a study with mice you’re talking about investing a ton of time, the pregnant mom and then the infants and you’re waiting at least 12 weeks before you make your first measurement and maybe there’s nothing there. That’s a lot of time to invest to come up with a null answer.

 

Q: Most common therapeutic development of asthma, the real-world implications are an inhaler, it’s a treatment, it’s a way to suppress the response that you’re having. What do you think the real-world implication or potential treatments can be, when you’re looking at the origins of the disease, or shunting that initial development?

preclinical asthma research

 

A: I think it could be educational and lifestyle-associated. Regulatory bodies could take notice. We’re talking about understanding what we are doing and exposing ourselves to that may be in our control, but that we didn’t know is contributing to the disease. I think the literature is growing, for example showing that any kind of solvent or volatile chemical that has a scent associated with it – whether it be laundry detergent, air freshener you plug in the wall at home, or the flavouring in e-cigarettes – are linked with lung pathobiology. What we’re talking about then is getting evidence that either confirms or denies a cause and effect relationship. With that solid evidence you can start making decisions about regulations for these kinds of compounds. I look at e-cigarettes, vaping, and cannabis as the current ones that we need evidence for governments to make decisions on control because there is real-world evidence that there’s damage.

The other one is that we are repurposing drugs for inhaled use for asthma therapy and its easy to see how really good preclinical data can pretty rapidly be turned into an early trial in humans. So, I think that’s another thing with asthma research, that there is a route to people at the bedside for trial. We live with the understanding we can have a real-world impact on the management of the disease in our lifetime.

 

Q: You see the majority of this as being more policy, education awareness kind of limiting that early life exposure to compounds that could be a risk, potentially, even just urban particulates filtering the air in your home would be bad for a newborn?

A: I think that’s one part of where we can make an impact. For example, we have a collaborator with the Workers Compensation Board of Manitoba and some of the work we are doing now is leading a project where they are monitoring occupational air quality. These are individuals working in all aspects of society, like in a nail or hair salon right through to the sites in Manitoba where they are building dams. The equipment on these construction sites is diesel engine driven and has a lot of diesel fumes, so understanding how those exposures are affecting health is where we can make an impact.

Not a driving force, but to give a personal touch, my father was a welder and a smoker and he died of lung cancer. I often wonder if the air quality he was exposed to daily in a welding shop contributed to his disease. That is not to lay blame on anyone, it is simply our lack of knowledge and that’s part of this project. That is a satisfying role to have on my radar, that we might be able to interface with people that can make the decision and put in measures to control the quality of air in, say, a welding shop. As I have gotten more mature as a researcher and professional, I recognize now how I can interface with the people who can regulate air quality, and as a scientist and not overwhelm them and beat them over the head with data, but instead tell them a story and work with them, not just “talk at them”.

 

Q: What made you initially choose SCIREQ equipment for your studies?

A: I believe it was around 2005 when we got our first flexiVent. We had been using another method of measuring breathing, something called Penh. By using Penh, we recognized the shortcomings and the field as a whole was coming to realize that it is not a reliable way to measure airway reactivity. Thus, we started looking for a better method, and flexiVent was the one that was quite obvious to us. I had met and chatted with Drs. Jason Bates and Charlie Irvine, so I was familiar with them and had heard them speak many times about the early versions of what would become the flexiVent. It was a natural choice for me and move forward with the flexiVent.

I should add that one of the things that have allowed us to work with SCIREQ is our research institute, the Children’s Research Institute of Manitoba (CHRIM), which has always been very supportive of pediatric research and has financially supported our acquisition of all of the SCIREQ equipment that we’ve purchased over the years. We’ve always positioned this equipment within a core facility, and this has been used by many users collaborating with us. I can think of at least 10 investigators from diverse fields, such as genetics, endocrinology, cardiology and rheumatology, where the flexiVent work we did with them has made a big impact on their work, and even brought them fully into the lung research field.

 

Q: What led you to selecting the mouse as your animal model?

preclinical asthma research

A: Well, at first I think we just followed the crowd to be honest, the mouse has been the model of choice, you can make transgenics etcetera, but we’re also well aware of its limitations. We’ve always worked with mouse models. You can get the data you need and it is reliable. There was a point in my career that we did use rats, but we’ve not gone to develop a rat model. I often wonder if that’s been a wise choice or not, whether we should have been doing that simply because of structural similarities of the lungs of rats to a human. I wonder whether we missed things in using mice only that maybe we would have uncovered in our preclinical work with rats. I guess we’ll never know. You know you can only do so much in a day and I’ve had big groups of people in the lab over the years and we did what we could.

 

Q: What were some interesting insights that the flexiVent helped you obtain to answer your major research questions? 

A: We typically studied airway reactivity looking at Newtonian Resistance (RN) or total Respiratory System Resistance (RRS) changes to a methacholine challenge. On one occasion the tissue Hysteresisivity (η), Tissue Elastance (H) and Tissue Damping (G) led us to wonder about surfactant and whether it was affected, and it turned out that it was. Our current research focuses on oxidized phospholipids as a mediator of the oxidative stress response in airways. There’s a lot of phospholipid in surfactant and when we looked at that data from the flexiVent it was very clear that the airway wasn’t the only thing being affected in our asthma model. It turns out there is a substantial defect in surfactant quality. The flexiVent certainly provided the data that indicated we should also be looking at surfactant more closely. I would credit flexiVent data directly for making us realize that we needed to add it to our repertoire, and as a significant reason that we now study oxidized phospholipid biology rather intensely.

 

Q: What is next for the Halayko lab?

A: For me, the next aspect of our lab research that’s going to be new and is emerging, is the effect of the environmental exposures on lung health. We recently were able to establish the inExpose system for cigarette exposure and I’m lucky we’ve had new faculty recruits recently who are aligning with this interest, and making it blossom.

These new faculty researchers are working and using the lab that we’ve established as a core facility and they’re all interested in environmental exposures, We’ve put together a fairly large CFI proposal that has built a number of new SCIREQ pieces of equipment for exposure, monitoring lung function during development starting at a very early age, and for deeper understanding of airway reactivity by adding the Negative Pressure Forced Expirations (NPFE) extension measuring FEV0.1 in mice.

The next frontier is to move systematically to understand how specific environmental exposures directly affect airway function and airway biology, and contribute to the developmental origins of the disease through maternal and paternal, or early life experience. That’s not to say we’re going to leave behind what we’re doing now but what we’re looking for towards the future.

 

Q: What would be your main advice for someone starting a new lab or research in preclinical asthma?

A: The number one thing that comes to mind is that this is complicated work that requires commitment, time and a lot of strong preplanning to get reliable and insightful data. If you’re looking at asthma, like any chronic lung disease, they are multifactorial in their origin, pathogenesis and presentation. So the number one advice is to put yourself in the position that you’re working for a team of people that can enable you to get multifactorial data.

We’ve been lucky enough to be able to do that in our lung function lab. The lab now has a legacy flexiVent and brand new flexiVent FX. The legacy flexiVent was purchased 15 or 16 years ago and it’s seen thousands of mice. The flexiVent’s are enabling the new people that are starting out to do the work that they’re doing.

We also have three brand-new faculty members plus myself looking at the effects of cigarette smoking, maternal cigarette smoking and asthma risk in offspring. When I really think about it, it is a beautiful team. We have somebody who’s an expert in epigenetics (Dr. Meaghan Jones), and someone else who has a real keen interest in developing models for origins of disease asthma (Dr. Chris Pascoe); he happens to have been my former fellow who developed a mouse model that enables you to understand the risk of developing airway hyperresponsiveness in response to a metered allergen challenge. We also have another young faculty member and she has an interest in extracellular vesicles (Dr. Ayesha Saleem). She can take that capability in these mice and ask how is the signal getting from the smoking mom to the baby? Is it possible at the extracellular vesicles generated from the mom travel through the placenta to the child? I’m in the middle managing the core of the function lab, getting the money and the team together, and sitting back and watching things happen, led by the gifted young scientists.

It’s a nice place for me to be. Maybe I’m biased because of our own experience, but I would say that if you want to be successful this day and age in pre-clinical asthma research, put yourself in the position that you have lots of people that are invested in the same goals, but who have complementary capabilities to bring to the table, and then make use of them in the projects you want to do.

 

Thank you Dr. Halayko for this interview! Learn more about the Halayko Lab here.

If you have any questions about the flexiVent or inExpose for preclinical asthma research, please contact us!