Episode 9: Taking a Breath
Welcome
This episode hosted by Olivia Moir with guest Dr. Jens Madsen dives into the field of immunology, specifically in our very early life, where we will focuse our attention to a group of proteins called collectins, and their importance when it comes to the proper functioning of our lungs.
If you don’t know very much about airways, don't worry, because this episode dives into the basics of what is so important about them and their development for our early life, and throughout our life course. In addition to this, we discuss Dr. Madsens current work, and the clinical applications of his research.
About the Guest
Dr Madsen completed his undergraduate studies at Odense University, Denmark with a Bachelor Degree in Molecular Biology followed by a Master of Science degree in Biomedicine. His PhD degree in Immunology was gained from University of Southern Denmark in 2002 followed by a postdoctoral position at the same institution. His second postdoctoral position was at University of California San Francisco from 2004 until 2007 investigating the importance of innate immunity against influenza A virus infections. Dr. Madsen was a Lecturer in Child Health at the Faculty of Medicine, University of Southampton from 2007 -2015 before he was promoted to Associate Professor from 2015. He changed institution to UCL in 2019, to take the recombinant fragment of human surfactant protein D (rfhSP-D) into a first in man clinical phase I safety trail in preterm infants.
You can find more on Dr. Jens Madsen's work here.
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Transcript
Speakers:
Host - Olivia
Guest – Dr. Jens Madsen
00:00:03 Olivia Moir
Hello, everyone, welcome back to it all starts here I am your host, Olivia Moir, and we are back here today at the Institute for Women's Health at UCL here in London. And today we are going to be dipping our toes into the field of immunology relating to the lungs, specifically in our very early life, and when I say early life, I'm talking right as newborn. And we are going to be talking about a group of proteins that are called collections and their importance when it comes to the proper functioning of our lungs. So to do this, I have with me doctor Jens Matson, who is an associate professor at the Institute for Women's Health here at UCL, with his research focusing on airways and the importance of innate immunity for the maintenance of a normal, healthy lung and during infection, inflammation and repair processes.
So as per usual, if you don't know very much about the lungs or airways, don't worry, because today we will dive into the basics of what is so important about them and their development for our early life and throughout our life course.
It is such a pleasure to have you here with me today. And why don't we just jump right into things and hear firstly a little bit of background on how you got into this field.
00:01:32 Dr. Jens Madsen
Thank you Olivia. Thank you. And it's thank you for having me. It's a pleasure being here and yeah, so it all started a long time ago. So I'm Danish. I'm from Denmark. I did my masters there. And I started around, I must have been 19.
And that's where I dwelled into this area just by coincidence actually. So I was applying for one type of project and the supervisor didn't have any room left. So he's like, why don't you go and talk to the guy over next door? So I did. And that's how I ended up here so. So that was very interesting. So we did the masters together and then he said, oh, we should apply for a PhD, and then we did in the kind of same subject area, And that led to a postdoc, and that led to a fellowship in the states. And during my postdoc in Denmark, I met a clinical fellow called Howard Clark and we stayed in the same field and via EU frame program which is now called horizon programs. We met twice a year for a couple of years and then when he became Professor, we teamed up to try and do what we do and take it into clinical trials and that's how that's how we ended up here, the rest is history.
00:02:41 Olivia Moir
You make it sound so easy. I wish everything was just that. Go with the flow. I mean, I guess it can be sometimes.
00:02:47 Dr. Jens Madsen
Well, and never had a plan as a five year plan as such, but you have to grab opportunities when they come along. So that's what I'm trying.
00:02:49
Absolutely. I keep learning that, OK, so a little bit about, you know, we've heard about your how you got into the field, but then maybe you can tell us about why you're so interested in studying within this sort of niche particularly.
00:03:08 Dr. Jens Madsen
Yes. So lungs are very unique. It's one of the last organs to fully develop during pregnancy because there's really no use for them until you're born. And I am in the field of neonatology, which is newborn babies and particularly ill borns and a lot of pre term babies and a normal pregnancy is 40 weeks. So around 10 months.
And if you're born earlier than 32 weeks, then your lungs are not fully developed. They cannot sustain themselves and therefore you need help.
So if you are born earlier than 32 weeks, you can develop something called respiratory distress syndrome (RDS), which is kinda inflammation of the lungs and nowadays you can treat it by giving some treatment with the lung lavages or extracts from long lavages from cows or from pigs. But they're not complete, they're missing some components and we want to add those components back to help the babies.
00:03:59 Olivia Moir
Very cool. So are these components the collections?
00:04:02 Dr. Jens Madsen
Yes, that's correct and so the component is called surfactant and it stands for surface active agent so the the lungs are made of tiny little air sacs or balloons. They're so tiny that that say if you have an inch, you can stack 100 and 2025 next to each other. Very tiny little air sacs and they have to they expand when you breathe in like this? And then they come close together. When you exhale. Like an empty balloon, Almost. And you can, you know, probably if if you're trying to blow a balloon by yourself, it's very hard in the beginning it takes a lot of effort and it's the same for the lungs if the air sacs are empty. It's very hard, but if they're kind of blown up a little bit, they're easier to keep them open. And for this we have this protein called surfactant, which is mainly lipids or oil. And then there's some proteins in them. And there are 4 proteins, they're called surfactant protein A, B, C, D.
We refer to them as SP-A, SP-B, SP-C and SP-D. The preparation we give babies contains SP-B and SP-C, but they do not contain SP-A or SP-D. They are purified out during their purification.
00:05:13 Olivia Moir
Right, I remember learning about this really briefly. I mean, I've done research with the lungs, so I know a bit about surfactants and really just that they are crucial to survival and proper functioning lungs. But I remember learning about this in one of my courses where we talked about the surfactants that are administered, and the fact that A&D were kind of filtered out in the process and I think that's relating to the fact that they're hydrophobic?
00:05:41 Dr. Jens Madsen
Yes, so lipids, you know oil and and water does not mix, and SP-B and SPC really likes oil, they are what we call hydrophobic, whereas the proteins my team is working with, SP-A and SP-D are hydrophilic – they like water. During the purification process that goes into making surfactant to be administered to the fetal lungs, water is used to purify the proteins and the hydrophilic molecules (SP-A and SP-D) bind to the water and are purified out unfourtunately.
You mentioned collectins in the beginning of this episode, there are collagenous-lectins, which means they bind sugar molecules, that’s the lectin bit, and they contain a collagen region, giving them their name of “collectins”.
00:06:11 Olivia Moir
Very cool. So then. OK, so we got a little bit about the basics. So then with your research currently, are you focusing on surfactant in early life or what is your kind of research around?
00:06:24 Dr. Jens Madsen
Yes. So we mainly because surfactant is mainly given to preterm babies. So that's what we're looking at for now and the proteins we work with is part of the immune system. So they are very good at stopping virus infections and bacterial infections and clearing particles, pollution from the lungs and because the preterm babies don't have that, they're very vulnerable for viral infections and inflammatory events, they are very vulnerable already, and this only makes them increasignly vulnerable. So we would like to give it back.
So there's a surfactant treatment they give them helps them breathe, but they are still very prone to virus infections. And with that, there's also all the comorbidities, their lungs never develop normally or they have a high chance of not developing normal lungs and they could also have learning disabilities. So there's a neurological component as well. So if we can help them early on, it's really impactful life.
00:07:16 Olivia Moir
It's crazy how? I mean, I think when we think of early life and the crucial organs that are involved in that, I don't. I mean I don't I could be wrong, but I feel like a lot of people don't automatically think of the lungs and how this can impact the onset of other conditions. But I guess it makes sense because that's where you know the transition when you're first born, you're breathing and then your breath is what keeps you alive. So then if you have lungs that aren't functioning. And stop me at anytime if I'm saying something wrong.
00:07:47 Dr. Jens Madsen
Yeah, no, it's it's absolutely right. You're correct. So yeah, no, no, it is correct. Yes. And you have. So you if you take all your little air balloons and your lungs and you unfold them, they cover an area similar to half the size of a tennis court that you have inside. You're right. And if you're pre, if you're pre term and you have this inflammatory disease, you don't develop as many air balloons as you need and therefore your air will be smaller, so you will always don't have a normal lung development.
00:08:13 Olivia Moir
Right.
00:08:14 Dr. Jens Madsen
So, and therefore it's have an impact for life, yeah.
00:08:18 Olivia Moir
Crazy. And then you sort of touched on there about the fact or we just talked about that surfact in A&D are not administered. But I mean surely if that is what's produced in a normal, I say normal with air quotes healthy lung, when you, if you are born preterm and then you aren't, you know developing all types of surfactant properly, but then you're administered B&C. Is it not? Kind of bad that you don't have the remaining two other surfactant proteins [SP-A and SP-D].
00:08:46 Dr. Jens Madsen
Yeah, it is, but it's because the lungs are not able to develop themselves in the beginning. So there's a window of opportunity if you don't have any SPD, it's because it resets the long, it keeps it long in a quiet state are non inflamed and we know from animal models in the literature if you don't have any SPD you get an inflamed lung. So it kind of puts the immune damp on the immune system.
It still promotes uptake and and clear viruses and bacteria, but it keeps all the immune system in a coincident state, so you don't have any inflammation and the lung probably needs that for normal function. So if you're missing out on that, you have a very high risk of having an inflammatory disease.
00:09:25 Olivia Moir
Right. And so then how does this carry on like later on in life? So let's say you were to have surfactant administered, you know, in the very early stages as the newborn. Do you need that still going forwards in your adult life?
00:09:37 Dr. Jens Madsen
Yeah, yeah, absolutely. You have, it continues through life. So we know that people with other chronic inflammatory diseases such as asthma.
Or chronic obstructive pulmonary disease COPD, or for instance, people who have severe corona over 19, which just had they all also have low levels of SPD and they could probably benefit from therapy as well.
00:09:57 Olivia Moir
Right.
Cool. And then in terms of the administration of that, is that like how was that given?
00:10:03 Dr. Jens Madsen
So at the moment it's it can be given as an intro. When you intubate it. So if you're on a ventilator, but we are trying to develop it long term, so you could have it as an inhaler, for instance, maybe even as a electronic cigarette or vapor, who knows.
00:10:20 Olivia Moir
Yeah, I mean, I guess it's kind of a stretch connecting the dots, but not really. I mean in terms of like vaping and cigarettes, obviously people who have deficiencies in surfactant like that isn't really something that you'd want. I mean, no one should be engaging in that really, but I guess that would put a lot of stress on your lungs.
00:10:41 Dr. Jens Madsen
Yeah. No, it does because there is a turnover and we know that if you have a traumatic event, the normal turnover time for SPD is around half, half, sorry, 12 hours. So if you lose the ability to produce SP-D, everything is gone pretty much within 24 hours.
00:11:00 Olivia Moir
OK. So then in terms of, I mean misconceptions that might exist in the field of research relating to surfactant as well as just to normal healthy lung development. Are there different things that you have encountered so far in your career, or you find miscommunication about a certain topic.
00:11:21 Dr. Jens Madsen
Well, we try to get funding for this. So we started Professor Howard Clark and I joined forces in 2007 to try the to raise the funding for this. And we thought it's going to take couple years. It's taking 12 years to get the funding in place for the clinical trial. And there is a kind of misconception in the field that because suffect and treatment have been so popular since the late 80s, that nothing is needed anymore.
But it is right because it's not the full full mixture they give, we're missing these components and we want to add them back, but it's not normal knowledge that these components are missing. So we've been struggling to get funding for it, but we're very happy that we have got the funding now.
00:11:58 Olivia Moir
Yeah. So then when you say the missing components, you mean all the surfactant types or?
00:12:04 Dr. Jens Madsen
No. Just just. Yeah. The two that we work with, so SP-A and SP-D, but they're missing from all theanimal-derived products on the market. So that's mainly from cow longs from pig lungs because they all follow the same purification procedure.
00:12:06 Olivia Moir
So then in terms of creating something that would have like diving really into that science cause that's so interesting to me, but in terms of creating sort of a compound that would include like all of the surfactants, it would have to be suitable for both the hydrophobic and hydrophilic molecules. So how does that work? I mean I'm sure it's complicated but.
00:12:40 Dr. Jens Madsen
It is complicated. It is a very unique mixture. And So what we do now is that we give them the surfactant first, then we administrate SP-A and SP-D hours after.
So it's a combination treatment.
00:12:50 Olivia Moir
OK, so different types of compounds given depending on the surfactant types?
00:12:55 Dr. Jens Madsen
Yes. So we give them a surfactant treatment first and this opens all the little air balloons in, in the airways and then we can give our SP-A and SP-D afterwards and then it will coat all the air balloons from the inside. That's what we hope.
00:13:15 Olivia Moir
And then in terms of measuring in an individual, the levels of surfactant like to know where you're at, is there a way to do that or you just kind of assume that they the dossage is sufficient based on previous experiments?
00:13:17 Dr. Jens Madsen
No, you can see it because if they are in general, it's a factor and they can't breathe, so their oxygen levels are very low the and they have all their markers as well. So if you give them a factor, the oxygen level will increase.
These and it's the same we saw with people who had COVID-19 that was in intensive care -
We did a couple of clinical trials during the pandemic where we repurposed the factor treatment from preterm babies to adults with with COVID-19. Sorry and they did improve after we gave it to them, so it could be a way of going forward. Hopefully it's not needed anymore, but it does show that we can apply this to adults.
And then of course, we would like to add our protein as well, but we were the pandemic was just a couple of years too early for us to try that.
We have to do a phase one safety trial first and that's what we're setting up to do now.
00:14:03 Olivia Moir
OK, cool. So then in terms of getting the surfactant proteins themselves, you said that they come from pigs and cows. Is that the only way that they can?
00:14:14 Dr. Jens Madsen
Yeah, currently it is because it's part of that treatment that is approved, a license to give. And so we produce them in, in cell lines like you also do with monoclonal antibodies for cancer treatment for instance. So we had to set up a new way of purifying them really.
So that's been part of the project as well.
00:14:34 Olivia Moir
OK. So then, OK, so we've covered the basics of surfactant and why they're important for the lungs. And then in terms of your research right now, you're working on the clinical applications including surfactant A&D into the administration.
Crazy. So then going forwards in this field, I mean, as you said, it's taken so much time to get here even you know how many years later.
00:15:00 Dr. Jens Madsen
Yes, it's taking over well, I guess 20 years almost.
00:15:04 Dr. Jens Madsen
And it's been good. And then going forward, we want to give it, as I said before, as you can self administer at home for instance, because often people with asthma who has exacerbations, there is certain components of that and often you see a virus like an airwave virus. And that's the same type of viruses that preterm babies are very vulnerable to, as well as susceptible to. And you see the same in people who has chronic obstructive pulmonary disease. They also have these exacerbations.
So our long term plans would be that if you are at home and you can feel like you're having attack coming on, If you can just take an inhaler and take a couple of puffs with, for instance, with SPD, meaning you can self medicate at home when you need it.
00:15:43 Olivia Moir
Right.
00:15:43 Dr. Jens Madsen
But it's a long procedure for us because we have to prove first that our protein is functional after you vaporize it and is still active on this kind of stuff. So it's something we would like to do of course.
00:15:56 Olivia Moir
Yeah, absolutely. I think that would be obviously really helpful. And I feel like you could tailor it to the person eventually too, like to create sort of like an individualized care.
00:16:03 Dr. Jens Madsen
Yeah. So we would love to do that.
00:16:07 Olivia Moir
That's so cool. So then in terms of like the field of the lungs, it feels like you sort of stumbled upon this field. Like you said, you didn't really have a plan going in and you just kind of said yes, where the opportunities arose. Is there anything crazy that you are not crazy even, but just things that you, you know, have learned that have stood out to you while you've been on this adventure and like going down this pathway of the lungs, I mean surely you've learned a lot more than just the surfactant relating to lung health, but are there different like tips or pieces of advice that you can give to the listeners about, you know maintaining healthy lungs or what you can do?
00:16:44 Dr. Jens Madsen
Yeah. No, I mean, stay healthy, of course always. So don't smoke. But just take good care of yourself as well, right? So make sure you have normal blood pressure. This kind of stuff. Sleep well. Yeah. Get treatment. Get your vaccinations if you can for flu. And this kind of stuff, particularly if you have a chronic airway disease.
Every time it gets cold, it's winter or the airway viruses survive really well. They like cold, humid weather and around 4 to 11° of Celsius, so that's why they're so popular in the winter. While you always see a surge of them coming up.
So if you're healthy and you don't have any side effects from vaccination, I would definitely recommend you to get vaccinated.
00:17:29 Olivia Moir
Agreed. Well, that was so, I mean, it's definitely more molecular, but I feel like, you know, having you talk through it helps us to see that it's maybe not as complex if you just sort of take the time to explain it. But it's been really cool to hear all about the surfactants. And yeah, I agree going forwards obviously be great to learn more about how this can be applied clinically.
00:17:45 Dr. Jens Madsen
Ohh thank you.
Yeah, I think what amazes me the most is as you said in the beginning, you have this if you can help babies in the beginning, you really have impact for life because it is so important for them that they have a normal lung function and then everything else. Not everything is simplified but develops better. If you have normal lungs, right, because all organs are dependent on sufficient oxygen supply.
00:18:18 Olivia Moir
Right.
00:18:19 Dr. Jens Madsen
So if you breathe well, you will do well.
00:18:23 Olivia Moir
Well, it’s been such a pleasure having you here on the podcast today. I really appreciate you coming in.
00:18:29 Dr. Jens Madsen
You're welcome. Thank you for having me.