The coughing neuroscientist
Neuroscientist Thomas Taylor-Clark is unravelling the mystery behind your lingering cough. Why does your asthma persist when our treatments are so effective and targeted? And why do you continue to cough after your cold is gone? Listen in and learn why neuroscientists are so interested in your lungs.
Many thanks to New World Brewery in Ybor for their hospitality. Music on this podcast was graciously donated by King of Spain; you can download the album here.
Episode transcript
Parmvir: Hey folks, welcome back to our podcast. And if you haven't already done so you can download it from iTunes. my name is Parmvir. And today we're here with a good friend of mine who is working as an assistant professor at the University of South Florida. His name is Thomas Taylor Clark. How you doing Tom?
Tom: Very well Parmvir. Thank you for inviting me.
Parmvir: So I should explain to people that we're actually very good friends and we've effectively grown up together as scientists having started our PhDs at the same time at UCL, University College London. And he now has the dubious pleasure of also being my boss
Tom: For long, for a long time,
Parmvir: For a long time.
Yeah. So can you tell the folks at home how one goes along a career path from London and ends up in Tampa.
Tom: When I was at school, I wanted to go to medical school. and so I applied to go to University College London, to apply to the medical school. But during that time, I took a couple of years off.
And realized that, medical school career wasn't for me. So my friend took a, a catalog of a University College London courses and threw a dart at it. And, and it landed on, pharmacology, which, is really the study of. How the body works and how various drugs can interact with the body. And I thought that sounded quite interesting.
So I decided to join the pharmacology department, which is a three year undergraduate course, and I did pretty well in that. And, during that time, my supervisor said, I should do a PhD. And since I didn't really want to get a proper job, I decided to, do a PhD in that department. And that is when I met you.
And, that was 2000. 2000. Yeah, it was 2000 and I did a four year PhD in a rather esoteric subject, which was the mechanisms involved in human nasal blockage. So when you have hay fever and your nose closes up, we wanted to know the mechanisms involved in that. And I did this with human subjects and I did a series of, pharmacological experiments and determined that what we kind of knew all along, which was, histamine worked through, which is, an inflammatory mediator worked through a number of different ways.
So then, when I got my PhD, my boss at the time said that I should find a job. And that seemed quite daunting. So, naively, I just wrote emails to a whole bunch of scientists, in America. And said, can I have a job as a postdoctoral fellow? About four of them replied saying yes, which I regard as pretty good, like odds.
And, and one of them was at Johns Hopkins, which is a really fantastic university in Baltimore. And so in 2004, me and my wife moved over to Baltimore for me to start my postdoctoral career. So I started learning about nerves, in the human body. And during that time, I published a lot of papers and I managed to secure some scientific reputation that when I wrote a grant to the federal agencies, which support science, that they then supported my science in a more grand fashion by giving me a big grant so that I could set up my own lab.
As is always the case with science, you have to move. So I moved down to the University of South Florida, which is when I phoned you up and said, do you want a job? And you said, yes, it's four years later and we are doing pretty well.
Parmvir: Can you explain to the audience a little bit about what our lab is doing right now?
Tom: In the lab. We have, obviously you Parmvir. I run the lab, but Parmvir is the chief of the lab. We also have technician Steve and two graduate students. We have about four or five projects, which are loosely connected to the understanding of how the body interprets danger signals to the airways. The airways are incredibly important for us to exchange oxygen with carbon dioxide.
And it's a very delicate area. These, this is not tough. Like the skin, it's a very soft, what we call a mucosal layer, which means that it is very susceptible to infection and disease and damage. And so evolution has developed a system which. Serves as a warning and defense mechanism for the airways, much like we have defense mechanisms throughout our body to tell us when bad things are happening.
And this could be anything from physical damage. Like when you stub your toe and it hurts to a cut or even a disease state where the body. Needs to know that something's wrong with that part of the body so that it can ostensibly protect it from future damage to allow it to repair itself. So we're interested in specifically how the lungs are protected and there's two general mechanisms by which the lungs are protected.
One through immune cells, like white blood cells, which come along and they chew up. The microbes, which get into the airways. And then secondly, a quicker response, which is a kind of nervous response. So when you walk past a, a bus and it churns all this ozone and pollution out at your face and you breathe it in, you want to get rid of that pollution before it does any lasting damage.
So you evoke a reflex, which we all know as cough and you cough it out. Well, that's the idea, at least. And that's great. We want a cough reflex. That's really important when you're eating a cookie and the crumb breaks off and it goes down your trachea. That's going to be really bad news for your windpipe, your trachea, and if it gets into your lung, that's really, really bad news.
So we want to be able to cough that out. Unfortunately, there's a number of different diseases or disease states where the cough reflex is excessively activated. So instead of coughing, once to a reasonable cookie crumb stimulus, we cough a thousand times a day to no stimulus whatsoever. Our aim is to understand why these reflexes are behave inappropriately in certain states.
And then if we know that then maybe even we'll be able to prevent that with future pharmacological treatment. So that's the that's, that's what we do in the lab.
Parmvir: And so this also goes partway to explaining why neuroscientists are studying respiratory disorders, with everybody thinking of asthma as being an immune disease.
And most of the treatments targeting those immune cells.
Tom: The majority of the treatments are antiinflammatories. Yeah, that's absolutely true. asthma was a very, very serious disease for a lot of people up until the development of corticosteroid antiinflammatories and they did a great deal to treat asthma.
So deaths from asthma collapsed, even though the number of people experiencing asthma, like symptoms has increased in the last 50 years. And this is fantastic. And it's due to the use of antiinflammatories the way they work is that drugs prevent the development of inflammation in the lungs so that you have less broncospasm, which is the closing of the airways.
The, the problem that we face today is that people still are suffering a great deal from asthma. It's no longer for the vast majority of people, a life threatening disease. It's still continues to dramatically affect people's work lives. it costs billions and billions of dollars a year in terms of, lost wages, lost work days, in particular, in fact, lost school days for children.
And the question is why these antiinflammatory drugs are one of the most fantastic therapies ever developed. They are utterly wipe out inflammation. They are incredible. And yet we still have the disease. So that led a bunch of scientists, maybe 30 years ago to start questioning well, why do we still have disease even when, these antiinflammatories are so fantastic at doing what they need to do, which is reduce inflammation.
And it seems like. Now we're getting into rather controversial evidence, but it seems like there is a neuronal component to the airway. So if you actually look in the lungs, you see a whole bunch of air sacs. That's easy to see. You can see that when you just take a bunch of lungs and you cut them open, you can see these air sacs and they're connected by these tubes to your, your windpipe, your trachea.
But infiltrating all these air sacs are these tiny nerves. That's probably about 25,000 of these nerves. And the vast majority of these nerves, 90% of these nerves are sensory. And what I mean by sensory is they detect the environment in the lung. And when they detect the environment, the lung, they send signals up into the brain and those signals can then initiate various defensive reflexes.
What we think is happening is when these nerves are stimulated, they initiate a reflex. So our reflexes, when one nerve talks to another and then causes an output, and that output is also in the lung and that causes the lung to close to constrict. There seems to be a lot of evidence to suggest that the nerves are all working in concert to make the lung close again.
Much like the inflammation was making the lung close. The nerves are also contributing to that. So although we have diminished the disease of asthma, there's still such a substantial portion, which is insensitive to antiinflammatories. It seemed logical to then look at the nerves. That's why the neuroscientists look in the airways.
And in fact, neuroscientists look not just in the airways, but also in the stomach and the esophagus in the lower intestine, because the nerves are the rapid response of the body. And if you have a disease which affects one part of the body, it's likely that that causes problems with the nerves as well.
So irritable bowel syndrome is, a problem of the bowels, but it also creates inappropriate behavior in the nerves, which exacerbates that problem. So if you just treat the local tissue and you don't treat the nerves, then you're not solving the entire problem.
Parmvir: And so this is why cough is kind of an interesting case because a lot of people will find that as part of the whole kind of range of symptoms of a cold they'll have this miserable cough.
The cold will eventually go away, but the cough doesn't the cough pesters you for a very long time afterwards.
Tom: Yes, that's right. So obviously this is when we get into human disease, we're dealing with a real variation in how people react, but also in an individual, a given, respiratory tract infection, like a viral infection that you get every single year, a cold, you will respond differently from year to year to year.
And we don't understand why there's variations between people and why there's variations within a certain person. But nevertheless, sometimes when you get a cold and don't forget, this is infection mainly in your nose actually, but it causes an inflammation in down your entire airway. And then you start coughing.
Well, why are you coughing? Well, you're probably coughing for a really good reason. You're coughing cause you're producing mucus and you want to get rid of that mucus. That serves two purposes. It's kind of a symbiotic relationship. It's quite cunning. It serves the purpose of the human that you want to get that gunk out of your lungs.
That's great. But it also serves the purpose of the infective agent as well. It wants to get out of your lungs after it's replicated a million times. It replicated, it wants to get out. And in fact, other people. So the cough is, is, is kind of, mutually beneficial for the individual, not necessarily for the human population, but nevertheless, we want to get rid of this mucous.
Okay. That's great. That's what we want the body to do. But unfortunately, what can happen is that the inflammation caused by the infection changes, how the nerves behave to the point at which then when the inf infection goes away because your immune system, kills all the virally infected cells, the nerves maintain this inappropriately changed, uh, state.
So now the nerves think that something's wrong and they continue to initiate this cough. When actually nothing else is wrong, but your nerves are this hypersensitive watch guard. Who's just saying something's really bad. We've gotta cough. We've gotta cough and, and nothing's bad. And so that's when you start getting a dry cough and a dry cough can be very debilitating for people.
I think people naturally feel that when they cough, they want to cough something up. They want to, they want to feel cough satisfaction when they don't cough anything up. There's a tendency just to keep going. Now we don't know if that keeps going, like I'm going to cough 10 times. Cause nothing happens.
We don't know if that's because the nerves are triggering a cough 10 times or there's something inside the brain, which is saying, well, that didn't work. Keep going. So you have a system where the nerves are inappropriately active and this can be very serious in people with underlying airway disease. So being a healthy individual that you are.
You get a cough for two weeks and it's really not a problem, but if you have asthma, you can then, and I have a very mild form of asthma. I don't feel asthma at any point until I get a respiratory tract infection and then I can cough for about four or five weeks. And you've heard me it's really bad. Hundreds of times a day.
Now what's the difference between an individual who gets a respiratory tract infection and someone who has asthma and gets a respiratory tract infection. Why is one way worse than the other? And this is a part of a science that is continually progressing. We know that there are similar things, substances, which are produced by the viral infection.
Which are the same as those substances produced by inflammatory asthma. And we think that those synergize together to make the nerves overly excitable, what do we want to do about this? Well, there are three kind of general things that we want to do about this. We can stop the nerves being activated directly at the source.
And in fact, the vast amount of our research goes towards identifying the ways that the nerves are directly activated. We can say, okay, I'm going to stop that. And hopefully we'll stop the disease. But frankly, I don't think that will solve the problem. Although we will stop specific substances activating the nerve, the nerves are just generally excitable they're cranky, you know, anything's gonna annoy them.
And so perhaps we need to change their excitability and prevent them being cranky. And there's kind of two ways to do this: one, the nerves themselves their processes can be acutely changed on a short term basis by inflammatory mediators. So. That's a whole bunch of special words to say that on a short term basis, that nerves can be excitable and maybe we can target that.
But maybe the most critical thing is these nerves actually change their longterm behavior. So at a certain period in an animal's life, if you give them a viral infection, then you will change that nerve's behavior for the rest of its life. So when a nerve used to be perfectly normal and you give it a viral infection now for the rest of its life, it is a cranky hyperexcitable nerve.
You can see how, if that happened in humans, that that could represent a plausible reason why you get these continued episodes constantly. Interestingly enough. That's actually been shown for a whole bunch of nerves can happen, not just nerves in the airways, but nerves throughout the body. They can have these triggers.
And it's actually really very interesting because if you do the viral infection at one part of its life, the excitability will change just for two weeks. But another part of his life it's critical period. When you give it the infection, it will change forever. And the processes by which this occur. Are only beginning to be understood and we certainly have no way of treating those issues right now.
But once we understand the mechanisms, yeah, maybe we can.
Parmvir: So, we actually have some questions for you from the big wide world outside. And one that's been emailed in from Praveen is why does alcohol make my asthma worse? And are there some types of alcoholic drinks, more likely to trigger it? So should she stick to beer or whiskey?
Tom: I'm not a medical doctor, so you cannot take my advice as gospel. Well, there is data which suggests that alcohol can cause asthma exacerbations, but the mechanism isn't known, I would probably postulate three possibilities though. The first is chronic alcohol ingestion can cause systemic inflammation, probably because your liver can't cope with the amount of whiskey that you're drinking Praveen.
And so, an increase in systemic inflammation will kind of just boost up the amount of inflammation in your lung causing an asthma attack. I don't know if that's likely, we do know that alcohol can affect nerves, but not directly. Obviously alcohol has major effects on nearly all nerves, but that's a very high concentration.
It's usually a depressive effect. When you get drunk, the feelings of intoxication are due to a depressive effect on the central nervous system. So, if you would extrapolate that to the nerves in the airways, you'd say that you'd get less asthma cause you're knocking down the activity of the nerves. I don't think that happens.
I'm not, I'm not advising IV ethanol as a treatment for asthma. But, I think, my, my favorite idea about this is alcohol gets broken down into a number of, different metabolites, some of which can then activate the defensive sensory nerves. So who knows, maybe it's possible that, she's, causing all these things or, or none of them.
I certainly don't know. And what type is the best to drink? I don't know if you believe that stuff about tannins, you might be inclined to avoid red wine, but the only thing I can think of is the antioxidants in some alcohol may help your anti inflammatory protection, but I don't know, don't drink.
Parmvir: Probably the easiest
Tom: That's the best treatment, you know, if you can protect yourself by stopping doing something, you know, when someone says it hurts when I lift my elbow? Well don't lift your elbow, you know, it's pretty simple.
Parmvir: So via Caroline, from Twitter, with respect to the recent, very topical IPCC report on climate change, how do you think increasing pollution as a result of this climate change might affect asthma sufferers?
Tom: That's a great question. We know that the, meterological environment also is how much pollution that we have in the air. So, if I understand this correctly, when you have a hotter environment, the pollution increases from the car pollution and ozone pollution increases. So if you look at the smog and pollutant data from the EPA, you see it's centered around obviously urban areas, but it's centered around urban areas in a hot locations.
And potentially I could see how, an increase in the warming of the planet, if indeed, that occurs that you could have just simply a greater amount of pollutants in the airways. And we know that pollutants have a number of devastating effects, causing asthma exacerbations. So the answer is probably yes, it will get worse.
Parmvir: So one from the floor here from Arturo, how much control do we really have over coughing? And can we really stop mid cough if we train really, really hard,
Tom: this is also a fantastic question, which is going to get me into some really in depth neuroscience about the cough reflex. It actually turns out that you have two completely distinct coughs. And those two coughs are initiated by two completely distinct nerve populations in the lungs. So I'd like to separate these into two types of cough. The first cough is that explosive cough, that you get when you inhale something into your windpipe. So when you're say drinking and then someone tells a really good joke and then it goes up your nose and then down into your trachea and then you uncontrollably, cough.
You can't control this. And in fact, this cough is so powerful that it is not blocked by anesthesia. So when you go, when you're in the operating room and you're about to be intubated so that you can be safely ventilated when you're under anesthesia, when you put the intubation tube in, I've no idea what it's called.
Probably laryngoscope. I don't know. Something like that. When it goes into the, into the trachea, even though you're completely out, you cough and you cough once because those nerves sense that, and they cough, but then the nerves go, okay, I've stopped. Then when you pull out the tracheal tube, the nerves detect that change again, and you cough again.
That cough, you cannot control. No amount of control will stop that. I mean, you can't even control it when you're asleep. So. No. However, the other type of cough, which we're far more familiar with when, when you think about respiratory infections is a more lower airway cough. So this is in your lungs and it's kind of a scratchy urge to cough thing.
And you're like, uh, uh, ahem, ahem. And you can control that even though you can have these nerves be hyperexcitable. If you are, and particularly, if you take a deep breath in. Something about that deep breath can minimize the cough sensation reflex in your body. So my advice actually is that when you have that kind of viral infection of the cough, and this is through a totally different nerve to the kind of explosive cough, this scratchy cough, you will eventually cough but try instead of coughing 10 times, try and say, I don't need to cough that time.
Just wait every other and just calm yourself. And you can actually reduce the cough, breathing techniques and so forth. It can work, but you still need to like, you know, fund my research to help me totally cure it. But yeah. Yeah.
Parmvir: That's a question from Siobhan, given the number of people who die every year from asthma related symptoms, what changes would you recommend to education programs, everyday lifestyle, these kinds of things that you could change on a day to day basis without having to worry about what treatment you get.
Tom: Of course smoking is, is a big issue. It's a big issue for all respiratory disease, but asthma is, is one which is exacerbated by smoking.
But actually everyone knows that. I don't, I can't, I can't believe there's a single person, in the Western world who doesn't realize that smoking is bad for their lungs, probably the more important, and it's very mundane, but the, the mundane thing that we can do is improve compliance with taking of their corticosteroid treatment.
Corticosteroids, you have to just take them constantly. You have to take them every single day to reduce that inflammation. Cause if you stop taking them, the inflammation comes back. And then what we find is people say, well, I felt great for two months. Why do I need to continue to take this drug? And so they stop taking it and then they start having asthma again.
So if we can improve, the education of people, particularly those individuals who maybe can't afford to buy their corticosteroids, who don't have insurance, but nevertheless, if we could impress upon them the need to constantly take these drugs, then that will do a great deal for reducing asthma exacerbations and hospitalizations.
Parmvir: Okay. One final question from Dr. Basanta (David) who again is sitting here in the audience. One of the diseases that people know about with regards to the brain and neuronal damage is Alzheimer's. And so with Alzheimer's causing neuronal death, does this have any impact on the respiratory system?
Tom: I've no idea. I've no idea whatsoever.
Yeah. I, Alzheimer's specifically kills, we don't, we don't necessarily know why, but the plaque formation and the death of the cells is somewhat localized. And I'm not aware myself of outsiders affecting the peripheral nerves, the nerves in your lungs. I find that very unlikely. It may affect the brainstem where the nerves from the lungs communicate together and integrate that it's possible.
But I would have thought that it would be, if that was the case, then that would be a global change in all kinds of homeostatic control. So you'd have blood pressure changes, heart rate changes as well as breathing changes. And I'm not aware of any of that data.
Parmvir: Thank you very much for addressing our audience's questions.
And thank you so much for coming out and talking to us, Tom, and thank you to everyone for listening.
Tom: My pleasure.
[musical break]
Tom: This is a story of my utter, stupidity and utter dedication. My wife's 30th birthday is five days after mine and I love skiing. And I hadn't gone skiing in many years. And so my mother very kindly said that she would come over to the US and we'd go skiing together, which is brilliant. So we go all the way to Wyoming, to Jackson hole, which is pretty good skiing, I may add. My wife at the time is eight months pregnant. She's not skiing. She's just staying in the, rather lovely chalet that we rented. On the end of the first day, my ski boot becomes broken. Well, the way you fix a ski boot is you get the, the inner soft lining is molded to your foot and the way you mold it is you heat the boot up and the lining becomes malleable. And then you strap it onto the foot. Well, unfortunately the guy left the boot in the oven for too long and although I protested a lot, that it was too hot. He thought I was being rather soft. Maybe it was the [British] accent. I don't know. But in the end I got a third degree burn. On my foot, but because it was the first day of the holiday, what am I going to do?
Am I going to go up to the hospital? No, I'm going to go skiing for the rest of the week. On my third degree burn. During that week, I get cellulitis of the foot and necrosis of the area and it's looking pretty bad. And, we go back to Baltimore and the doctor said, can you feel that as he was poking my foot on the black bits of my foot?
And I said, no. And he said, that's really bad. You should go to the intensive care. The problem is I have to submit my grant application on Monday. And this is my last opportunity because our money had run out. The game was over. The dream was over. We couldn't live in the land of the free. He thought I was insane.
He let me go. The next day I submitted my grant. So you had to have like 20 copies. So I'm carrying this huge amount of paper, and I dump it on the administrator's desk and say, I'm done, I'm submitting, I'm off to ICU. And so I spent the next eight days in ICU with an IV drip of antibiotics and I had a rabies shot.
And let me tell you, rabies shots hurt like hell. And I kind of said to the doctor, will I lose my foot? And he said, no, but you're an idiot.
[musical break]
Tom: You've got, how many vertebrae do you have? 20 odd?