Taking a deep breath can seem like a simple process; however, for millions of people with asthma, inflammation of the airways could make it difficult to breathe. While current treatments help manage symptoms, scientists are working to develop new therapies that target the underlying causes of the condition. Co-host Maria Wilson speaks to Jane Kenny, Senior Director and Senior Principal Scientist, Drug Metabolism & Pharmacokinetics, and Mark Wilson, Principal Scientist, Immunology Discovery, to learn more about the biology of asthma, the complexities behind inhaled drug delivery and how current research is informing the future of asthma care.
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Transcript of Two Scientists Walk Into A Bar: “Take A Deep Breath: Treating Asthma” with Jane Kenny and Mark Wilson
Maria: I'm Maria Wilson.
Danielle: I'm Danielle Mandikian.
Maria: And we are scientists. We. Love. Science.
Danielle: Yeah, we do. So, when we aren't doing it, the next best thing is to talk about science! What's really awesome is we are surrounded by some of the most brilliant minds in research!
Maria: So there is always someone interesting to talk to. But there's never much time to just chat at work. That's why we are so excited to be hosting this podcast. We are going to step away from the labs today to talk to other scientists about the cool stuff they are thinking about, working on and imagining...
Danielle: as well as how some of these discoveries just might lead to new medicines. So, grab your favorite drink, get ready to unlock your science brain and join us for Two Scientists Walk into a Bar...
Maria: The show for scientists, science geeks and the people who love them!
Maria: Hello, everybody! I'm here today with two great scientists and great friends, Jane Kenny and Mark Wilson. Jane is an expert in drug metabolism and pharmacokinetics. Mark is a research biologist. So, both of my guests today are also British transplants like I am, so I am thinking we temporarily, for today, rename the podcast, "Two Scientists Walk Into The Pub!" Although, of course, I'm in the pub by myself, thanks to the Delta wave, and my guests are video conferencing in. But we're delighted to be here to talk about asthma. Asthma is a disease area close to my heart. I've worked on this disease area myself, and I'm very, very interested in the way the immune system and the cells of the airway interplay to cause this very challenging disease. Now, we tend to think of asthma as something debilitating and unpleasant, but not necessarily life-threatening. And while that's true for many people, it's not always the case.
I did want to start off the podcast by dedicating the episode today to the memory of Farida Kohgadai, who was only 35 years old when she died from a severe asthma attack just a few months ago, leaving behind her husband and her baby daughter. This tragedy really brought home to all of us how serious a disease asthma still is. So, guys, welcome! Let's start off talking about the biology of asthma. Mark, walk us through the basics.
Mark: So, asthma is clinically defined as reversible airway obstruction, and there are two main areas that I think really capture the compromised lung function. It can be measured quite nicely with forced expiratory volume in one second, or FEV1. And this declines over time in subjects with asthma. And the second aspect is the episodic flares or exacerbations of disease and often referred to as "asthma attacks." Together, these can both impact the quality of life, the ability to work or study and really compromise your lung function and everything downstream of just simple oxygen in your circulation and your blood. And, so really, the two main outstanding questions from the biological perspective of what really contributes to that lung function decline, and what are those triggers of the exacerbations or those asthma attacks? And, biologically, what actually happens in the lung that compromises gas exchange and the ability to breathe?
Jane: I would add to that and Maria, you highlighted, the tragedy that can occur with severe asthma. But it's not only a very severe disease, but it can also be very prevalent. The World Health Organization did find that in 2019 over 260 million people were suffering with asthma. And within the U.S. here, the CDC defines eight percent of adults have asthma, and it's one of the most prevalent, severe diseases in children. And so, one in 13 people then are suffering from asthma. You think of most social gatherings -- well, that we used to be in -- you have several folks dealing with this in just about any environment that you're in. So it really is something that needs our attention, and medicine advances are required.
Maria: And I think one of the things it might be helpful to understand a bit more about is why in some people is it a relatively benign condition, and in some people, it becomes very severe? Do we understand that at all?
Mark: I think that's a fascinating question. What really leaves us susceptible to responding to the same air that we breathe sitting right next to each other: one person responds in a certain way and another person responds in another way? So, underlying all of that, there's multiple layers to this. First, is the genetic susceptibility. What has become clear over decades of work now is there are certain risk factors, genetically, that leave people hyper-responsive -- or their response to otherwise innocuous antigens and allergens in the air is just a bit too much. Equally, a lack of a regulatory response: so, some people are tolerant to these things, and other people react overtly and unnecessarily.
Jane: And there's also a factor of, as the disease progresses within an individual, medications that were effective start to lose their ability to deal with the symptoms. You keep increasing your doses; you then start to lose the effect. And that's why, in the most severe populations, we need alternatives to help address the underlying causes of the disease, not just the symptoms, the inflammation, the airway constriction.
Mark: Allergic asthma that we can pick up and read in textbooks and is often referred to in common discussions is classically considered to be driven by exposure to airborne allergens -- house dust mite allergens, cockroach, grasses and pollens and things like that.
Maria: Cats, right? I have a friend who literally can't breathe if a cat has ever lived in a house.
Mark: Increased exposure to cat allergen can actually tolerize you to it. So, there's some really interesting immunology behind that: should you avoid the cat or should you slowly have exposure to the cat? That's not advice by any means, but an interesting immunological conundrum there.
Maria: I'm glad my kids are not here because this is my argument against having a cat.
Mark: The response -- that immune response to, let's say, your cat allergen here -- why do some people respond to that and others don't? If we take those individuals that do respond: when we inhale those allergens, and they travel down the main connecting airways past those airway epithelial cells -- so these are cells that line your airways -- they're responsible for cleaning the air, for humidifying the air, and for warming it. And these are all features that allow optimal gas exchange in the lower airways. But really, those connecting airways and those epithelial cells, when they encounter some of that cat allergen, for some people, they react to that allergen immunologically when they otherwise shouldn't. I can sit next to a cat all day long and not have a reaction to it. Other people, unfortunately, one little glance at a cat crossing the road, crossing that path, and they may have a mild asthma attack. And so immunologically, those epithelial cells, they respond to that cat allergen when they otherwise shouldn't. They recognize it as something foreign and potentially dangerous. And we can get into the evolution of why and what is it about the cat allergen itself that makes that potentially immunogenic and reactive. And some earlier work that we did many years ago looked at the similarity between cat allergens and allergens in general and their ancient ancestors as parasitic worms.
The allergens themselves are very similar to antigens from parasitic worms. And the allergic response has very well evolved to expel parasites. And so, we can see how the similarities of our immunological past -- that we used to live and cohabitate with parasites for millennia -- we've eradicated those parasites now, in most parts of the developed world, at least. And yet the immune response to those allergens has remained. And so, we react in a very pro-parasite expulsion-like manner to those allergens that we encounter in the airways, or in the intestines to parasites.
Maria: That's so interesting. It evolved as a survival response. So that's possibly why there are so many people who have retained this responsiveness to this allergen, even though now it's maladaptive -- you really don't want to have asthma.
Mark: That's absolutely right. I think we should think about our immune system in that way, but it has evolved to protect us from things. And, unfortunately, sometimes it gets carried away, or reacts to things that it shouldn't, including foreign antigens like allergens, and even self-allergens causing autoimmune diseases, too. So, that immune response that's triggered by those epithelial cells that produce a variety of factors, and they're being nicely coined as alarmins because they've literally raised the alarm to the immune system. And that triggers an innate inflammatory response, an adaptive inflammatory response, with a whole variety of immune cells recruited into those spaces where the allergens are encountered. And so that immune reaction at sites where really, it's not needed and shouldn't respond, can cause that narrowing of the airways, that thickening of the tissue, mucus production. Again, responses that would be wonderful if there was a parasite there, but it's not. It's just an innocuous allergen.
Stephanie: Hi Maria!
Wellington: Hi Maria!
Maria: That's Wellington and Stephanie, my producers. Hi guys!
Stephanie: I think it's surprising to learn that we have some of these processes that persist in our body but are not actually helping us. How do we think about this? And why are they still there?
Maria: That's a great question. I think it's because of the slow process of evolution, and evolution being driven by reproductive fitness. And so, you can imagine that, while sure, having some genetics that predispose you to asthma is not particularly useful to you, it's also not really impacting reproductive fitness all that much. So, there's nothing that's driving those genes out of the population, although they're probably not being selected for as strongly as they were back in the past when we were parasite-ridden.
Wellington: So then, are there other examples of this?
Maria: Wellington, yes, there are, like the one most people have heard of is sickle cell anemia, where the sickle cell defect is potentially protective against malaria. So, it was selected for in populations of African and southern European descent.
And another sort of speculative thought is that a disease like cystic fibrosis, which is one of the more common genetic diseases, maybe being heterozygous for that was protective in the past, perhaps against some other disease that our ancestors had to handle. And that's why that gene has persisted in the population.
Maria: Jane, can you tell us a little bit about how the medicines that we take address those responses, and how we think about treating asthma?
Jane: Yeah. One of the mainstays of asthma treatment has been the bronchodilators, the beta agonists. These are designed to relax the airways, open them up, and allow you to breathe again. The challenge with those is that as these sorts of steroids, the doses increase, you start to then have the balance of lack of efficacy and then onset of side effects that we don't want. One of the things that's a mainstay of asthma treatment, of course, is inhaled drug delivery. It's an amazingly simple concept, right? Put the medicine exactly where it needs to go into the lungs. But for something that is so simple, it's incredibly complex to achieve -- and to achieve well and to achieve reproducibly across a whole population of people who take an inhaler in a different way, hold it in a slightly different orientation, need slightly different breathing inhalation-exhalations to activate. It's an incredibly complex science that until we started digging into it, I actually had no real understanding of. And we spent a lot of time learning about what makes a good inhaler and how to get the medicine to the right part of the lung in the right concentrations at the right time. Really, it's physics. It's [laughs] kind of flow dynamics and particle physics. It's quite fascinating.
Maria: So when you think of the classic asthma inhaler, you have the blue puffer and the brown puffer, right? My mom had asthma. And so we always had those all over the house in everybody's pockets. And you really take them for granted. And they've been around, I think -- I just looked this up -- about 65 years now, those were first invented, right? And they're wonderful because one of the things you can do by inhaling a drug is that you can actually make it sort of pretty much only go in your lungs and avoid side effects of the drug in other parts of your body. And then what Mark was talking about, as you can imagine, your immune system is extremely important. And while there's lots of different medicines you can use to dampen down your immune system, you may not want to completely dampen down your immune system, you know, every day for a chronic disease like asthma, right? So, this balance between, treating the airway inflammation that he was talking about, but not completely obliterating your whole immune system so that you still can fight off infections. So inhaled drug delivery is really compelling as a way to get drugs into the airway, but it's super hard.
Jane: It is super hard. I think that's it in a nutshell. So, it's a simple concept that's incredibly complex. Not only have you got the device to design, how am I getting a particle airborne? How am I getting it into the lung? And we all remember our lung stats, right? The lung has a surface area of approaching a tennis court. It actually has, you know, 1500 meters of airway pathways to get that. You've got to get at your molecule, your particle into the right place in the lung. But then you've got to get it to stay there, acting in the lung. But then when it's absorbed through the lung, you don't want it to hang around in the bloodstream. You want that to be cleared or metabolized rapidly so that your pharmacological activities retain just in the lung. And so then how do we do that from a design perspective if we are starting to make a new medicine for asthma?
This series of different levers that we can pull within drug discovery and development around the balance of particle size, for one -- just how big or small you make your particles, can target where you get down into the depths of the lung. We don't want to be all the way down in the alveolar bed, which is where the real oxygen transfer happens. We want to be a little bit higher up in these epithelial cells, the conducting zone, where the inflammation and the mucus secretion occurs during asthma attacks. We also want to be able to pull levers about how fast then the molecule will dissolve and get inside the cell if you've got a target that's actually inside the lung cells.
Once it's inside the lung cell, how do you get it to stay there and not pass all the way through? You then have to anchor that maybe through affinity to proteins in the tissue, through looking at physicochemical properties like lipophilicity or basicity. And then how quickly, once it does make it to the bloodstream, it's metabolized or cleared by our wonderful liver so that you actually don't have a large circulating amount. And let's not forget, when you take an inhaled medicine, a large portion of that is swallowed. It actually doesn't even get to the lung because we're swallowing a big chunk of what we actually put in our mouths. So, anything that is swallowed, we don't want that to be getting through our absorption in the intestine into the body as well.
Maria: How do we know where the drug is? Because when we typically develop drugs, we take some blood, and we measure the drug in the bloodstream. I don't think anyone's going to volunteer for a clinical study where we're going to go in and take a, you know, a piece of your lung and try and measure how much drug is in the lungs. How do we figure out where the drug has gone when we inhale it?
Jane: That's the million-dollar question for this, right? And we've employed all sorts of different techniques to try and do that, because how do you measure this, right? As you said, the way that we normally measure drug concentration is by actually taking a blood sample and detecting it there.
You can't do that in the lung. And even if you did, when you measure that, you'd have to grind it up. How much was actually sitting there as a solid particle versus how much is absorbed into the lung cell versus how much was actually in the plasma proteins? So just by even taking a sample, you're not getting a real measurement. And so, one of the things that we were employing was: Let's try and model out and predict where we think these molecules will get.
And there's a lot of different techniques we can employ there, the first being computational fluid dynamics on the particle engineering side of things just to model where we think, based on flow and particle size, we can get the particle into the lung. And then once we're in the lung, we can then build physiological-based pharmacokinetic models to try and make essentially a mathematical model of the lung with the different compartments of -- here's my extracellular fluid, here's my lung cell. Here's how quickly I get through these different membranes, here's how I partition once I'm in -- I, being the drug. If I'm a drug, here's how I partition from intracellular target to bound within proteins but retained in the tissue. And then once I'm absorbed into the systemic circulation, how quickly it's then metabolized. We can model those different parameters, and that then allows us to predict what shows up in plasma, and we can measure plasma. It's an indirect measurement.
Maria: What are these different particles?
Jane: Oh yeah. This is really cool science. And I'll hold my hand up by straight away saying that this is not my area of expertise. But I'll share what I have learned by working with our wonderful formulators. And so, the first thing is when we make -- let's take a small molecule, dry powder as an example. We make it a crystalline material.
The molecule itself has its own natural crystal form. It could be spikey. It could be hexagonal. It could be jagged edges. The actual shape of the particle is really important for the lungs. If it's the needle-like crystals, they tend to align and fly like arrows and cause irritancy. And so, we actually are very intentional about how we shape our particles. And you can do that through micronization and milling.
That's just the first step that we would take. We also know how big those particles need to be or how small -- really in reality -- they need to be to get to the right part of the lung. Somewhere between, you know, two to four microns being the sweet spot for the average particle size.
We then can do some very cool kind of more complex thing where we make kind of an aggregated particle spheroids where you blend different types of supportive polymers to create like a lattice of perfectly round beads that you can then target which different size -- by spray dried dispersion or the very complex outside of my understanding methodologies. They really can then engineer these particles so that you can really place them at where we think they need to be in the lung. And then, we've got our indirect measures of efficacy or blood concentrations to tell us whether we managed to get them where we want them to go.
There's also a really cool device that allows us to measure which segments of the lung we think we might get it to. So, this is called the cascade impactor that has a mechanical throat on the front, and you pass the pressure down. And you essentially create a breath or an inspiration. And you can measure where the particle gets through a series of very different filter sizes and gates. And that can tell you how deep your molecule might be able to make it into the lung. And from this, we put this together, with our modeling and simulation, with our clinical observations, to try and understand have we achieved what we set out to do?
Maria: I remember looking at some electron microscopy pictures of some of these particles. We called them the whiffle balls, didn't we? Because that's what they looked like. It looked like a ball that was like a mesh. And you can imagine that that's very light, and it would fly very easily. Now these are, of course, absolutely microscopic.
Wellington: Maria, talking about particles and modeling, this is really cool. I didn't know this stuff existed in research biology. What's this called?
Maria: So, Wellington, what this really is, is the science of drug metabolism and pharmacokinetics, which is a really important discipline in developing a drug. And it's basically what happens to the drug when you put it into your body. Either you're injecting it, or you're eating it, or you're inhaling it, as we're talking about here. And then it's going to be distributed by the bloodstream through the various organs of the body and then metabolized, usually by the liver, sometimes in other parts of the body and ultimately excreted. So, understanding what your body is doing to that molecule is really, really important. And it's also one of the hardest things about drug development because you can throw something onto a bunch of cells in a dish and say, ”Hey, yes, this is doing exactly what I wanted to do”, but then you swallow it, and it just gets destroyed by your stomach. It doesn't ever get to the cells that it needs to get to in the body to do its job. So that's essentially the discipline, and it's an incredibly important part of the work that we do in drug development.
Maria: One of the ways you alluded to that we do know whether the drug got to the lung is can we measure some kind of activity? So, I wanted to punt it back over to Mark there to talk about the different ways we can potentially measure whether we've got any activity, whether we can look at different cytokines or different biomarkers and things that might help us understand whether our drug is engaged in the lung.
Mark: Yeah, that's a good question. And just to get back to Jane's work there, I mean, this is a great example using models as a predictive science in there. And Aviv touched on that in the previous podcast about how we can use predictive science in the future. Going back to those epithelial cells that line the airways, there's some of the cells that'll encounter the drug if we can get it to the right place at the right time. And so, understanding how those cells would respond to the drug is pretty important so we can assess the biomarkers. There's a PD biomarker, pharmacodynamic biomarker, that would read out: Did the drug actually get to the right place at the right time to have the desired effect?
One pathway that we know relatively well is the role of a certain cytokine, interleukin-13. And it activates these epithelial cells in patients with asthma. And those cells will produce nitric oxide. And part of that is released as a gas. And we can measure that in exhaled breath as a fraction of exhaled nitric oxide. And that's a very sensitive biomarker to tell us: Did the drug get to the right place, and did it block and prevent IL-13 activity? And if it did, then we'd expect, if the models are correct, that the FENO, or the Fraction of Exhaled Nitric Oxide, would be reduced. And so, we can use that as one example of a relatively sensitive biological pathway that we would predict we could inhibit if the drug got to the right place at the right time. And so, we can use -- that's one example -- use many others as readouts of potential activity of our drug in the lung at the right place at the right time.
We could also go systemic to see whether there were any effects in the circulation that we can read out if the drug got to the place at the right time, using other kinds of biological pathways.
Maria: I think it might be helpful to talk a little bit about the current treatment landscape for asthma, which has evolved quite a lot recently. There have been some quite good targeted medicines developed that hit both that sort of allergic side of things, which you talked about, Mark, and then that slightly more mysterious, nonallergic asthma. Jane, did you want to talk a little bit about the latest and greatest in asthma therapies and how they target the disease?
Jane: I've seen and I'm following all the different cytokine kind of modulators that are addressing these underlying causes. And I think that's really what's differentiating the new medicines that are coming now versus what has been the mainstay -- the steroids that have been the mainstay of asthma treatment for so long. It's really targeting the underlying inflammation rather than just treating the symptoms that present.
Maria: Yeah, Mark, maybe tell us about eosinophils because you can't talk about asthma without talking about eosinophils, can you?
Mark: Yeah, you know, that standard of care that Jane nicely covered before of inhaled corticosteroids and that those increasing doses almost defining the severity of disease. I'm starting to think whether that's the best course of management -- are those inhaled corticosteroids doing what we think they're doing or are they doing more? And it's very well described of the side effects of steroids. But what about the side effects of steroids in the lung? We know the mechanism of action: primarily to switch off gene expression in a variety of ways.
But what about their effects on the stromal cells in the lung, the epithelial cells that line the airways, the fibroblasts that sit beneath them in the smooth muscle cells? Do they have any impact on those? And if they do, can they actually be contributing to a different phenotype of the disease or not? That's an area that I'm starting to get more and more interested in because those subjects with severe disease are on the highest dose of inhaled corticosteroids, and yet, it's still not controlling their disease. Is that actually contributing to their disease or not?
Maria: Right. Right.
Mark: There's some interesting questions that we're starting to kind of play with.
Maria: Yeah.
Mark: As Jane mentioned, you know, targeting the cytokines -- those alarmins that I mentioned earlier on that have released from those epithelial cells, which really ring the alarm to the immune system -- can we target those alarmins and prevent that initial alarm from ringing? That's an area that's getting a lot of attention. And then the cytokines and these small protein mediators that essentially pull in those other immune cells, cytokines and chemokines.
We're targeting them and picking them off one by one like a sniper from a distance, and asking if we block one or the other, can we prevent the recruitment of different immune cells into the lung, and particularly those eosinophils? Incredibly well-studied in the context of intestinal parasite infections where those parasites that infect the intestine are surrounded by eosinophils, which we think release a whole host of toxic mediators that kill those parasites.
They're recruited to the lung, as well, in equal numbers. Their purpose and their recruitment to the lung -- we have no idea why they go there or what they do -- but we know they can reach those toxic mediators and cause damage to the local tissue in smooth muscle cells. And so really, getting rid of those eosinophils in the lung seems like a good idea, and there are a variety of therapies tied to those. And then the cytokines and other mediators that those immune cells actually produce that have effects on the local stroma, particularly on the smooth muscle cells, causing bronchoconstriction.
The triptans, the prostaglandins, the leukotrienes and the histamines release there, targeting each one of those either separately or even together. And then some relatively blunt but somewhat effective treatments of bronchial thermoplasty.
Maria: Yes. That's fascinating. Yeah, yeah.
Mark: It seems kind of medieval.
Maria: Mm-hmm.
Mark: But it seems to work in some patients.
Maria: And this is where you actually burn a piece of the lung away. Is that a crude way of thinking about it?
Mark: Yeah, I don't know if it burns the lung...
Maria:[Laughs]
Mark: But that radiofrequency energy is applied to the airway, and that heat that's caused leads to a reduction in smooth muscle cell mass around the airways.
Maria: Okay.
Mark: And if those smooth muscle cells are the cells that really constrict the airways, then reducing that mass has some benefit to patients and can lead to bronchodilation of the airways. It seems crude, but it seems to be effective. And I think it highlights if we can understand the structural cells of the lung a bit better, where these immune reactions are having their effect, then maybe we can understand different biologies in there, too.
Stephanie: Maria, remind me what an eosinophil is and how do they relate to the stromal cells that Mark is talking about?
Maria: Eosinophils are white blood cells, which are made in the bone marrow, and then they migrate to the tissues where they're needed or where they think they are needed because what they're trying to do is fight infection. But what they're doing in asthma is inflaming the lung tissue, and they secrete all these cytokines and factors that influence the stromal cells that Mark was talking about. So the eosinophils are not lung cells, they're cells that have come from the bone marrow to try and protect the lung. But in fact, they're actually damaging the lung.
Maria: Something we also wanted to talk about was something which, as you know, is near and dear to my heart, is targeting kinases that mediate the cytokine signals in the lung. Kinases make great targets for drugs. Many drugs hit this type of molecule. Could you speak a little bit, Jane, about how we might target kinases, intracellular targets in the lung?
Jane: Yeah, I think this is a really hot field right now. And as Mark already mentioned, the IL-13, there are multiple other cytokines that play a role in asthma. And if you could then target one of the cytokines, after the kinase proteins that actually the cytokines signal through, you could potentially actually have a multiplicative effect on multiple different ways that the disease is manifesting in patients. And so that's one of the areas that is really, really exciting.
There's several kinase inhibitors or many kinase inhibitors already in active therapy in other indications. The challenge here is that they do a lot in the body, and you don't want to mess with that in a chronic indication if it's only in the lung. You need these pathways active and signaling. If you inhibit them in an area that you don't need to, you end up with side effects that are going to cause problems. And so, this then brings us back to why the inhaled delivery for some of these kinase inhibitors might be such a beautiful way of solving this problem: because you can get the topical exposure in exactly the organ you want to address -- in our case the lung. And you can minimize the exposure for the rest of the body, side-cutting or short-circuiting all those potential side effects by keeping these things topically in the lung. And that's really one of the goals of research right now is can we do this? There's early proof that these sorts of mechanisms are going to have an impact in asthma. And then it's fine-tuning like, how do we get the right balance of properties in molecules that allow us to do this so that maybe the next generation of asthma medications are going to be inhaled delivery for some of these topical cytokines.
Maria: Yeah. That sounds very promising and fascinating. And you alluded to the future. What do you guys think? What is the future of asthma care? Can we cure it? Will it go away? What about technology?
Jane: Well, let me come from the technology angle, and then I'll kick it to you, Mark, for kind of the more biology angle. I am really excited about what smart devices can do in the asthma space. If you think of what we can do, not just on a societal tracking of where we're seeing pollution or outbreaks of rhinovirus, for example, then we know we're going to get an uptick in asthma exacerbations in that area. Or just the smart devices as the inhaler development. How is that molecule being delivered? Are they remembering to take their inhaler every day? Are they taking it in the right way to get the best use out of that molecule in their lungs? Just these sorts of tweaks that a smart device with real-time feedback for the user, prompts like, "Hey, smartphone, have you taken your inhaler today?" You've heard, "Yes, you've taken this dose correctly. You need to do it again in eight hours." These little things actually make a really big difference for disease management And so I think that smart technology of, not just predicting where outbreaks might be, so that maybe we can take some preventative measures that we're learning from our current situation.
Maria: Right, so your phone might say to you, ”The pollen count is high today in your area. Please don't forget your inhaler,”or something like that, right?
Jane: That's right, right.
Maria: Yeah.
Mark: Yeah, and I guess with respect to the biology the new areas that I'm particularly thinking about are non-immunological aspects --
Maria: Yeah.
Mark:-- of lung function particularly in asthma.
And you know, those structural cells I mentioned before, the epithelial cells that line the airways, that sit on the reticular basic membrane with underlying fibroblasts and smooth muscle cells and neurons and stem cells which feed all of these different populations. And don't forget, all the immune cells that are activated in amongst all of these structural cells in there. And this was highlighted in the last podcast of Two Scientists, that symphony of cells in there. But it's really -- it's a symphony of states of these cells.
They're all cells that have the potential to be activated or resting or senescent or tolerant. And so, we now have technologies to capture these states of all of these different cells at the same time, potentially during exacerbation. And that can really point towards what happens in the lung at the time of exacerbation in all of these different cell types, all structural cells as well as the immune cells. And what state are those cells in?
And I think that can really point towards whole new biologies that we haven't previously appreciated in the lung. And we can have this in the single-cell level where we dissociate tissues. We can even have expansion to see how cells are actually communicating with each other in these different states, both in two dimensions as well as in three-dimensional spatial resolution at the DNA and the RNA or the protein level, whatever is relevant and interesting. And I think this can help identify new pathways, new biologies and ultimately new targets that will allow us to get the right drug to the right cell in the right patient to meet that unmet need.
Maria: Really fascinating because when you think about it, going back to how I opened the podcast, something has gone terribly, terribly wrong when in an otherwise healthy person your lungs decide to close up and not let any oxygen into your body. And yet we still don't really understand exactly what that is, I think is what you're saying. And perhaps in a few more years, we'll start to have an even better understanding of the interplay of what's going on with all of those cells in your airway that causes this catastrophic effect of an asthma exacerbation.
Mark: That's right.
Maria: That's great. Thank you. I wanted to just segue a little bit because one of the overarching topics of this season is the impact of the COVID-19 pandemic both on us as scientists and researchers and also on the diseases that we treat. So, I think COVID-19, there's been some particularly interesting actual learnings about asthma from the behavioral changes that have happened during the COVID-19 pandemic. I wonder, Mark, could you talk a little bit about that, about the intersection between COVID-19 and asthma?
Mark: What we have observed is that the frequency of exacerbations of disease has dropped dramatically during COVID-19 times.
Maria: And that's surprising, right? I think some people might have thought it would have gotten worse, or that people -- asthma patients would have had more COVID. So, to me, that seemed non intuitive. But how did you react to that news?
Mark: I think this is a behavioral thing rather than a direct relationship between COVID-19 and asthma.
Maria: Okay.
Mark: There've been many studies and many reports of asking whether subjects with asthma are more or less susceptible to COVID-19. And there isn't really a clear picture that's coming out there. And it could really play in both ways, that those individuals that have those inflammatory responses in their lungs, you could imagine, could protect you from incoming viral infection. And equally, it could go the other way, too, that if you already had compromised lung function and possibly damaged airways, you could be more susceptible. So, it was an important question to ask. The data isn't really clear whether it's one way or the other, really increased or decreased the susceptibility.
Possibly, the explanation for the decreased frequency of exacerbations is that people have been inside more. People have been or should have been socially distancing. And therefore, there's been a relative reduction in the frequency of common colds and viral infections, not SARS-CoV-2 infections, but rhinoviruses and RSV infections that can often cause exacerbations. And so those triggers have really been significantly reduced. I know with a three-year-old, the frequency of colds in our household has been pretty low.
Jane: I can attest to that as well. Yeah, it's been quite phenomenal. Turns out when you wash your hands and wear a mask, we stop the spread of the common cold as well [laughs].
Mark: That's right. And so, if that's a trigger for your exacerbation, we've really reduced the number -- the frequency of those triggers. So, it's not a direct link between COVID, SARS-CoV-2, the virus and asthma, but rather the behavioral changes. So, if we socially distance, like Jane says, wash our hands and wear a face mask, we reduce the number of exposures we have to potential triggers that could cause those exacerbations.
Stephanie: Maria, we've heard about challenges with delivery and how complex the biology is. Asthma is really much more complex than I realized! It all sounds very exciting but also really challenging. So, Maria, can we turn the question back to you -- where do you think we'll be in the future with treating asthma?
Maria: So, I think there's lots of exciting things going on for the treatment of asthma, especially in the inhaled medicine space. The idea that you could have an inhaled, convenient medicine that was also very targeted towards the actual biology that's going wrong. I think we will see drugs like that in the next five to 10 years being available for asthma patients, for sure.
Maria: I should ask you both how you got into your career? How did you end up doing what you are doing?
Mark: I've been incredibly fortunate to have some inspiring teachers along the way. And I think it was being in the right place at the right time or the wrong place at the wrong time, I'm not sure, that just inspired me in different ways. As an undergrad, describing how parasites infect cells just blew me away.
Maria: I love parasites. I worked in a parasite lab myself as a segue. And the guy next to me was working on trichinella, which is that thing that lives in pork. But what an amazing beast the trichinella is! Really, it's fascinating.
Mark: They're fascinating. I don't know if I love them, but they're fascinating to study.
Maria:[Laughs]
Mark: And so really, I just kind of pursued them and that took me into immune responses to parasites and into allergies and asthma. And then really just constantly asking questions and never being quite satisfied and surrounding myself with inspiring people. That's where I am now and hopefully will continue to be.
Maria: Jane, what about you?
Jane: I kind of backed into science through curiosity. I, like many girls growing up in the countryside, I was animal crazy. I actually wanted to be a vet or a veterinarian, as we call it in the U.S. And so I did a lot of work experience on dairy farms and in vet practices. And really, I found like once you'd seen your hundredth cat with the same thing, that it was quite boring and not for me. But what was fascinating was how you could give a tablet to the dog. The dog swallowed it, but it prevented the fleas from actually developing the mandibles that allowed them to nibble out of the eggs so you would kill fleas. And I was like how did they come up with that?
And that took me to pharmacology. And so I studied pharmacology as an undergraduate, and then quickly having worked in a lab through the summer, I got very curious about, well, then how do we develop more? How do we advance molecules? And I went back and studied drug metabolism and drug safety for my Ph.D. And it just has grown from there, that curiosity about how things work and what we can do to make them better that then ultimately deliver medicines to people that make a big difference. That's kind of how I got here.
Mark: So, fleas!
Jane: Fleas, yes. Fleas and parasites [laughs].
Maria: Exactly. It's all about the parasites, apparently. Yeah. I worked on lymphatic filariasis for my undergraduate project. So, another really interesting parasite.
Jane: I did malaria for my undergraduate. So, I have another bug to add to the mix.
Maria: Yeah.
Mark: Maybe the next podcast could be focused on parasites.
Maria: Oh, that would be so fun. We have to do that at some point maybe. But it was just -- thank you so much for sharing a little bit about your personal experiences there. It's really wonderful. And it's so wonderful that we've all come together to work on science and to do these really exciting projects. So how lucky are we. Fascinating conversation, both of you. Thank you so much for joining me in the pub.
Jane: Thank you. It's been a pleasure to be with you both this afternoon.
Mark: Thank you both very much. Cheers.
Wellington: Wow. Great conversation, Maria. Parasites and vet school. Doesn't that describe you?
Maria: So, yeah, I think that does! I think interest in animals and medicine and parasites can often lead to a broader interest in disease and a career in science.
Wellington: OK, so before we go, Maria, we have our first grab bag question. Ready?
Maria: I'm ready.
Wellington: So here it is: As a person who just got diagnosed with asthma, I'm discouraged to hear from my doctors that there is not much they can do to treat its root cause. There are multiple drugs that help manage my condition, but they all have long-term liabilities. Why is finding drugs to better control asthma without massive side effects, or better yet, treat the disease itself, so hard to achieve? And that's from Kate P.
Maria: That's a great question. And while there are some good treatments for asthma -- and I do hope you and your doctor can find a treatment plan that works well for you -- you're right, they all do require that you take the drugs regularly and that has an impact on your life. So, one of the challenges with a disease like asthma is that it is multifactorial -- like your specific asthma may not have the exact same underlying cause of someone else's, and without understanding the underlying cause to target, it's very difficult to come up with a true, curative treatment. But that doesn't mean that scientists are not trying to do that for exactly the reasons that you mentioned. And we touched earlier on what a future state of asthma treatment might be. And maybe one day we can understand an individual patient's disease much better: know that you have asthma type whatever, and it's caused by these specific factors, and this is how we cure your specific type of asthma. So we can only hope that we can develop something like that someday.
And that's our show! We are teeing up conversations about Alzheimer's disease, antibiotics, diversity in clinical trials and more. Danielle and I can't wait. Subscribe wherever you get your podcasts and leave us a rating. And if you have any questions about those topics or the science that we discuss today, go ahead and write to us for our grab bag segment. You can reach us at [email protected]. That's G-E-N-E dot com.
And now for me, it's back to puzzling over data!