This Podcast Will Kill You - Ep 34 Cystic Fibrosis: Complete Somatic Rebellion

Episode Date: August 20, 2019

Despite being one of the most common genetic disorders, affecting millions of people worldwide, cystic fibrosis evaded medical description for thousands of years after its first appearance. But the last century has led to a revolution in diagnosis, treatment, and our understanding of the disease. This week we talk all things cystic fibrosis, from salty sweaty tests to European folklore, from Bell Beaker culture to gene therapy. And we are honored to be joined by Jay Gironimi, author of “Can’t Eat, Can’t Breathe, and Other Ways Cystic Fibrosis Has F#$%*d Me”, who chats candidly about his experience with CF. Oh, and the best part? Jay, also the talented musician behind All Hallow‘s Evil, wrote a custom song specifically for this episode! We loved it so much we named this ep after it, and we know you’re gonna love it too.  You can find Jay’s book on amazon in both paperback and digital versions, find the audiobook version on audible and more of his writing at canteatcantbreathe.com. You can also find his music at allhallowsevil.bandcamp.com and follow him on twitter @allhallowsevil. See omnystudio.com/listener for privacy information.

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Val, bad pun. Outdo it with Intuit QuickBooks. Feature availability varies by product. Well, my name is Jason Geronomy. I usually go by Jax. It's half the syllables. I was diagnosed with cystic fibrosis when I was nine months old because I was a very lethargic baby.

There are pictures of me from that time where you can see like, oh, that kid ain't right. And I think I am alive today through a very specific set of circumstances in that when my parents went to the doctors and were like, hey, this baby sucks. The doctor that they went to happened to work with a CF doctor in Yale, like they were partners on cystic fibrosis. So whereas I was a failure to thrive baby, he knew exactly why I was failure to thrive. and we were able to address that right away.

So since then, there has been a long journey, and it hasn't been fun, but I have been very lucky in most of my circumstances, in that there's new medicines, which aren't always easy to take, but sometimes they work. I'm able to get insurance, which is a real big thing, and was a real problem for me for a lot of years. And I'm actually doing okay now. I'm doing better now at 30.

then I was at 26, which is not how this used to go. I was one of the first people to go into an adult CF clinic because there weren't adults for a while. And so that was weird. I kind of missed the slide from the children's clinic, but what are you going to do? I feel like everything about successful people with CF and I'm successful in the fact that I'm not dead yet, I feel like it's really important to mention how they got insurance. And once again, it's very specific circumstances for me. and that I got very lucky in that there's two very large employers in my area who happen to

offer insurance for entry-level positions. And had that not existed at the time, I wouldn't exist now. And I'm also lucky in the fact that my job is a nine-to-five job, and I do not wake up that early. So everyone was very nice when I was like, hey, I'm coming in at noon and didn't question me because it takes me a long time to get ready. it takes a it's a large production keeping the show on the road when I wake up I don't feel great I don't think anyone feels great when they wake up but I'm extremely aware of my lungs when I wake up like I can feel them

and you kind of do like a diagnostic check of the body see see what you've got going on and then I have a vest that I wear and there's been a recent technological advance in that and that it used to be a vest that sort of it was like a giant blood pressure cuff that that you put around your chest. And it would push air through and make a whole lot of noise, kind of like a, which now it's like this, it looks like a jet pack. And you wear it and it's got little pods that,

I think they're essentially speakers. They're not really allowed to tell me that. But they kind of shake your chest. So they make more of like a, hmm, hmm, hmm. And while that's happening, I also have a nebulizer with which I inhale salt water at first to salt up the mucus and encourage water to go to it. And then the next step is a drug called pulmozyme,

which actually it snips out parts of the DNA of your mucus somehow and thins it out. So trying to force water into it, trying to force it thin. The vest runs for three 10-minute sessions, and in between each session you're supposed to cough and see if you can actually cough anything out. Last week, I actually had the occasion to cough out a large piece of sort of dry mucus that was like I could feel my bronchial tree imprint in it, which is a strange feeling. So I do that. I have some extra pills. I have to take, I have to take pills to eat

that have, I believe they're freeze-dried pig pancreas. They actually digest the food for me, but if my acid, my stomach acid is too acidic, they can't do it. I just tear up the pills, so I take ameprosol. I actually take pills for my pills to work, that's fun, Claritin, which is an easy one. I got to make sure you get enough vitamin D because I also have osteopenia, which is not osteoporosis, but almost. And then I go to work. And I've got this all down into about an hour. And then I do some work. I go home eventually. And I have to do the vest again when I get home, which another 30 minutes. I don't do the pulmozyme again, but I do the salt on top of that. And then I have to take a long-acting insulin before I go to bed because CF has done such

damage to my pancreas that it gave me diabetes as well, which is fun because people know what diabetes is. And they will talk about that with you all the time where CF scares them, I think. Something I learned in an old swamp thing comic is there's some guy can see the future. So I actually don't remember the context of it. But I don't think you're supposed to to know the way you're going to die. And, like, that was a very comic booky thing. Like, oh, I can't tell you how you're going to die. That will change your whole life.

But that made me think for a long time because for years, I was sure I knew how I was going to die. And it's become blurrier now. Like, there's, I'll give it, like, an 80% chance that CF kills me. There's a chance that something else could really come in and take the victory from it. But it made me incredibly more. forbid for so long. Because if I did, if I do have a gift or a superpower, mine is, for most people, comedy is tragedy plus time. I require very little time. I think most things are very funny.

When they happen to me, obviously, I think most things are very funny right immediately. And I think I made my family really uncomfortable with that. My grandmother, who was wonderful to me for so many years, was also one of those grandmothers. It was like, no, you're going to be fine. Everything's going to be fine. Like, you don't know that. Anything could happen tomorrow, and she'd be like, no, you're going to live so much longer than me. Like, you don't know that. She was right. But for me, CF is a thing that I know, and it is the thing that I do. It requires little to no bravery on my part. I just have to keep waking up and doing that. I have no other choice. But I think some people don't like to be confronted with the idea that, like,

their body could go into total rebellion at any point, as mine constantly is. It's shocking for them that I have a job, and again, it's not easy, and there's no shame and not having that if you're dealing with CF, but it's shocking for them to see someone doing quote unquote normal stuff while, again, body in total rebellion at any given point. And I just think most people don't like to grapple with that when it's literally the only thing I want to grapple with is how I'm going to die when it's going to happen. What's wrong with me? I don't know. You just heard from Jay Geronimo, who we had the most fun talking to this week. The most fun. He is an amazing author, musician, and just all around

hilarious person. And we have more of his interview later in the episode. So do keep your ears out for that one. Yeah, it was really thrilling to get to talk to him, and we can't wait for you to hear even more of his story. And there's one more thing that you should keep your ears out for at the end of the episode, and that's a special song written by Jay specifically for this episode. It's called Complete Sematic Rebellion, and we'll provide the link for download in our show notes. I think it seriously might be the coolest thing to happen on this podcast. Anyway, I'm I'm Erin Welsh. And I'm Aaron Elman Updike.

And this is, this podcast will kill you. And today we're talking about cystic fibrosis. That's right. Yes, this is our first genetic one. Is that right? I'm pretty sure. I'm pretty sure that it is, yeah. Yeah.

Okay. So what are we drinking this week? Our quarantini this week is the Dorothy H. Anderson. Yes. Thus named because there was an amazing researcher named Dorothy H. Anderson who described, I think, was one of the first people to describe cystic fibrosis and did tremendous amounts of research in her life on the condition. What is in the Dorothy H. Anderson? Well, there is pomegranate soda, lime juice, a splash of ginger ale, tequila. Always good. And you've got to have it with a salted rim.

and we'll talk about why throughout this episode. Perfect. Perfect. We'll post the recipe for our quarantini as well as the placebo rita, which is our non-alcoholic version, on our website and all of our social media channels. And let's see. I think we do have a couple bits of business.

Do we? Yeah. So one thing that I wanted to mention is that, hey, we have merch. We have t-shirts. Oh, we do. Mugs, pins. And guess what? We have soap.

We do have soap. I think we did a bad job at telling you guys this, but we have soap so you can wash your filthy little animal hands. Also, the label is the cutest thing you've ever seen. It's amazing. You can find all of our merch at this podcast will kill you.com if you just click on merch. And the other thing is that I saw this on Reddit and I just wanted to share this because I was lurking briefly, even though I haven't been on very much. So on the TPWKY subreddit, there was a recent post or a post a while back about what people wanted to call fans themselves. What do they wanted to call themselves? Oh dear.

Let me pull up some of these things, actually. One of the top ones was filthy animals. Of course. Perfect. Another one was vectors, which is amazing. Um, arindemiologists. Oh my God. Air infected.

Oh, I like that. I love that. Um, extremophiles, podcast phages, quarantine feigns, respiratory droplets. I loved that one. Oh, my God. That's, I want a T-shirt that says that. The herd. Just that. The herd is also amazing.

So anyway, I just wanted to tell you that. Oh, that's. Amazing. Yeah. This is very fun. That's really funny. Okay. Any other business?

Actually, there is one more thing. Oh, yeah. This is our second to last episode of this season. Oh, my gosh. It happened so quickly. It happens so fast. And before you get alarmed by that news, we're only taking a relatively short break. We are coming back on October 29th for the premiere of,

our season three. And so subscribe to all of our social media, subscribe to our podcast so that you see when the new episode drops. Yes. And this is second to last. We're not leaving you high and dry. We've got another excellent episode coming out in two weeks. Yes. Okay. That's everything now? I think so. Well then. Let's get started. Tell me about the biology of cystic fibrosis. I can't wait. Okay, good. We'll take one quick break. Cistic fibrosis. This is going to be a fun one because we haven't done a genetic disorder before. So we're going to talk a little bit about genetics before we get started on anything. And on top of that, we get to talk about biochem, which just for some reason is one of my favorite things to do on this podcast. I guess so, yeah. It's one of my least favorite subjects. Okay.

Cystic fibrosis is an autosomal recessive genetic disorder, and it can be caused by actually a number of different mutations in a single gene. So it's always the same gene that gets messed up somehow, but there's a lot of different ways in which the gene can be mutated that end up resulting in slightly different presentations. of this disease or disorder. So first, let's define the words autosomal recessive, because some people might have never heard that. That basically means that you have to have two copies of this gene that are mutated in some way in order to actually have symptoms of this disease. So if you have just one mutation, you're what's called a carrier, but you pretty much

won't have any symptoms or be sick or have cystic fibroids. You have to have two copies of the gene, and so that's what autosomal recessive means in this case. Cool. Cool. And autosomal just means that it's not in the X or Y chromosome. It's in any of the other chromosomes. Right. Okay.

So the gene that is mutated in cystic fibrosis is called the CFTR, very creative, cystic fibrosis, transmembrane, conductance regulator gene. Okay. It's the cystic fibrosis gene. Right. This is a gene that codes for proteins that form channels through which ions pass. So this is where we're going to go a little bit biochem. Genetics course over biochem course beginning. Okay.

Here we go. I'm not going to get super into detail. I never do because it's not my strong suit and because we'd be here all day. And there's a lot more interesting things than just the biochemistry of this disorder. So what you need to know to understand why cystic fibrosis is such a big deal is that your body is made up of cells. Cells are just bags of water and electrolytes, which are floating in a matrix of water and electrolytes. Okay? Mm-hmm.

Cool. We're bags of water, tiny little bags of water, floating in water. And the linings of our cells are called plasma membranes. They're like the plastic of the water balloon that holds the water inside the cells. And these membranes only let certain things pass through them. Okay. They're selectively permeable. And a lot of the ways in which things pass through this water balloon membrane is through channels and pores.

And it's proteins that make up these channels and pores in the membrane. Cool. Yeah. Okay. So the CFTR gene codes for a protein that forms a channel that when it is normal sits in this membrane, across the membrane, and allows for ions to pass across it. Right. Okay. Okay. That's your, that's your biochem course.

Okay. Okay. So if you have a messed up version of this protein in some way, then you're not going to be able to properly control what is going in and coming out of cells. Okay. Okay. So the cystic fibrosis protein normally allows for the passage of chloride. That's the other half of sodium chloride. And also bicarbonate, HCO3 minus.

And by allowing these ions to pass through, it also indirectly regulates other ions like sodium. Right. So because once you change the balance of one ion, you affect a whole bunch of other ions as well, essentially. if that makes sense. So what ends up happening is just dysregulation. You get messed up movement of sodium, chloride, and bicarbonate, all three of those across the membrane. Okay. And that's how you end up with all of the problems that we see in cystic fibrosis. So can you elaborate a bit on what it means by messed up movement or dysregulation of those ions? Let's do that by talking about some of the different mutations that you can have.

And that will, I think, answer that question a little bit. So there's a number of different genotypes or different mutations that can lead to cystic fibrosis. They all result in this protein being messed up in some way. In one, you have a mutation that leads to defective protein production. So your protein is either too short or too long or got cut off. So basically, you don't have an actual protein being. placed in this membrane. So that means... The one that's making up the pore or the channel. Exactly. So you

don't have a pore or a channel being formed at all, which means you don't have any movement of chloride or bicarb across that membrane. Nothing goes in, nothing comes out. Exactly. Okay. So that's one potential mutation, class one mutation. Another one is a defect in processing of the protein. So you're making this protein, which is supposed to form a channel. But for some reason, it gets stuck inside of the cell and it can't actually make it to the plasma membrane. So you make the protein, but it doesn't actually make the channel. Does that make sense? Okay. Yeah. So it ends up looking pretty much the same as the first mutation, right? No pore in the membrane for ions to pass through. So that's a class two mutation. Then there are a number of other mutations that can result

in a protein that is made. So you make the protein. The protein forms a chance. and makes it to the cell surface, but it doesn't respond the way that it is supposed to to certain stimuli. So these are class three and class four mutations. And we're not going to get into the nitty-gritty of them, but it basically just means that you have an ion channel that's there, but it doesn't open when it's supposed to, to say, let chloride ions out, or it doesn't close when it's supposed to to stop chloride ions from leaving. So you have movement of ions. but not at the right time or at the right rate. Does that make sense? Yeah. And so there's an association with these types of mutations or these classes of mutations and the severity of symptoms?

Absolutely. You can imagine that if you're not making any of this protein, you're probably going to have more severe manifestations of disease than if you make some of this protein, it just doesn't quite work properly. Okay. That makes sense. And then, right. And then there's another a couple classes of mutation, class five and six mutations where you make the protein, it mostly functions normally, you just don't make quite enough of it. And so those might be the least sort of severe manifestations. And so I remember reading that there are around 1,000 different mutations that I guess are grouped into these different classes. Do you happen to know the distribution of, I know that there's one that's very, that's like the most common,

but what is the class distribution, I guess? So the most common is a class two mutation. Okay. That's the F508 mutation is a class two mutation. So that's a problem where you make the protein, but it doesn't get trafficked to the surface properly. So it's not actually doing its function. Okay.

Other than that, I'm not sure how common the other classes are. There are, I think, multiple thousands of mutations. It's bananas, how many different mutations there are. in this gene. Okay. So, you can imagine that with all of these different ranges of mutations, all affecting the same protein, you can end up with a pretty wide range of manifestations. So let's talk about some of the symptoms. Okay. Yeah. Yeah. Okay. So as a recap, you have a malfunctioning protein in some way that leads to abnormal movement of sodium, chloride and bicarbonate across cell membranes. Okay. So this channel protein, the CFTR protein,

is found in a whole bunch of different organs and tissues. It's not just in one place in your body. It's most highly expressed in glandular epithelia, fun way. Okay. Tell me what that is. It means in a few specific organs that have glands. So your lungs, your pancreas, your intestine, your sweat, and your reproductive tract. Okay. So you tell me where do you think we're going to see symptoms of this disorder? I'm guessing it's in all of those places that you just listed. Oh my gosh.

You're so correct about that. Okay. So yeah, lungs, pancreas, intestines, those are the biggest ones, reproductive tract as well. Sweat glands, we don't have to talk about it unless you want to later. Okay. I kind of do, but whatever. We'll get to it. Okay. The truth is, despite all that we know about how these mutations affect the CFTR proteins,

we don't fully understand how this leads to the specific disease manifestations that we see. There's a lot of different theories, and we'll talk about some of the possibilities. But the main cause of morbidity and mortality, so the main cause of illness and sort of suffering in people with cystic fibrosis, is airway symptoms. So when cystic fibrosis affects your lungs. Right. Okay. So we'll start with the lungs then,

and then we'll go kind of organ by organ. Okay. In your lungs, if you have a messed up CF protein, then you're going to have less chloride and bicarb being secreted out of your cells and into the space in between. your cells. The negatively charged ions. This leads to less water being secreted onto the surface of your airway. So that means that your airway ends up not being very well hydrated. Okay. So this can lead to difficulties in the transport and defense mechanisms that your

lungs normally have. So it can lead to super thick mucus being produced, less watery mucus, that's more viscous, that can lead to obstructive airways. So if you have, if you do not have one of these mutations, how does that ion transport prevent the adherence of pathogens or why is watery mucus more important? Yeah, so watery mucus is important because it first of all just protects the lining of your cells to begin with so that they don't get dried out or anything by the air and things like that. But it also, you have something in your lungs called the mucociliary escalator, which I think is an adorable name.

Escalator, that's very cool. Yes. It's a combination of the mucus that your cells produce and cilia, which are those little hair-like protusions that we've talked about before. And the combination of this mucous and the cilia helps to sweep anything that you inhale into the bottom of your lungs up and out of your lungs. Mm-hmm. Okay. So if you've got a bunch of thick, non-watery mucus, then it really impairs this mucosiliary transport, and it leads to obstruction of airways. Okay. So it doesn't just slow down

the escalator. It like turns it into a stairway and says... Yeah, not even a stairway. It's just like a flat. Yeah. Okay. Just a straight up cliff. Right. So this can directly obstruct the airways, but on top of that, it can also lead to chronic infections. You're at much higher risk. for bacterial infections because you can't clear anything that comes into your lungs out. Right. So it's a two-fold process where you have thick mucus that you're producing directly blocking your airways. And on top of that, you have infections that come in that you're unable to fight off.

Mm-hmm. Okay. On top of that, the cystic fibrosis protein has a role in helping to regulate inflammation through some other effects that it has on electrolyte transport. So you can end up with excess inflammation coming into your lungs to try and help fight off infection, which can actually further block your airways. So it's just basically kind of a mess in the lungs when you have this protein not working properly. Yeah.

And honestly, it's kind of the same thing that happens in other organs. So in your gut, in your intestines, you secrete a lot of mucus in your intestines as well. And it's the same thing. If you end up secreting really thick mucus instead of nice, clean, watery mucus, you can block ducks in the same way that you block the airways in your lungs. But in your gut, in your intestine, that's going to impair the cilia that are also there from absorbing a lot of nutrients.

So you can actually end up getting malnutrition and things like that. Mm-hmm. On top of that, it can lead to things like gastroesophageal reflux, acid reflx essentially, and impaired bowel transit. So things aren't moving along your gut the way that they're supposed to because ducks are blocked kind of the whole way along. Mm-hmm. So in really small babies, especially, this can end up leading to intestinal obstruction on top of the malabsorption that you might be having. Okay. So that's in your lungs and then in your guts.

And then we have your pancreas, which for those who might not remember, is a very important organ that secretes a whole bunch of enzymes that are important in digestion. And it's a very glandular organ. What does that mean? It's very glandy. It's very glandy. Yeah, it's made of a whole bunch of glands. What's an example of a non-glandy organ? Your heart.

Okay. It's a muscle, your heart. Okay. Not doing a lot of secreting. No, no. Okay. Okay, so if you can't secrete these enzymes that normally do digestion, then you're not going to be able to digest your food properly, essentially.

And so that's exactly what happens in cystic fibrosis. Instead of being able to properly secrete these enzymes, your pancreas is secreting thick, gunky stuff because the electrolytes and water are not balanced correctly. And this means that not only can you not properly digest foods, you end up not being able to absorb really important things like fat soluble vitamins because the pancreatic enzymes are really, really important in fat digestion especially. And fat digestion is important in being able to absorb fat soluble vitamins. Right. So it's not just that your intestines aren't able to absorb. It's also that the pancreas is not even able to help you break down what you need to in the first place. Exactly. Right. And you might also remember that your pancreas secretes other important things like insulin. Yeah. So if the ducks in your pancreas get plugged up and aren't able to

secrete insulin, then you can end up getting diabetes. And that's actually a really important aspect of cystic fibrosis that I feel like is maybe sometimes overlooked, at least just in common parlance. I think most people think about the lungs when they think about cystic fibrosis. But the development of diabetes is a really serious complication as well. Diabetes basically is just not enough insulin in your body. And if you don't have enough insulin, then you can't properly regulate glucose or sugar. So then you could end up having really, really high blood sugars and then that can kill you. Okay. So in cystic fibrosis, what diabetes looks like is a lack of insulin because you're not able to secrete it. So there's a number of different ways that you can get diabetes.

Similar things, blocking ducks, etc. can happen in your liver getting plugged up with mucus. This can end up leading to things like gallstones or stenosis. It can lead to cirrhosis, which is liver failure essentially. In people with uteruses and ovaries, you can end up getting delayed menarch, which is your first period. And in people with testicles, it's really common actually to have an absence of the vast deference. And that's the duct that normally carries sperm away from the testes. So that means infertility. So that's a lot. And honestly, that's not even all of it because while this protein is most highly expressed in those type of glandular tissues, It's expressed in a lot of other tissues as well.

And so cystic fibrosis can end up affecting your bones, which can increase the risk of fractures. It can increase your risk for anemia, kidney stones, chronic kidney disease. The list kind of goes on. It's pretty serious and it kind of, it's a whole body situation. So because this is a genetic disorder, the onset of symptoms is, very, very early. So what would that typically look like in an infant, I assume? I just love when you ask questions that are the thing I want to answer next. We do not. We did not rehearse this, I swear. No, we did not. Okay. So the next thing I want to talk

about is how we diagnose, how we recognize cystic fibrosis. Okay. Snap. Excellent. So with cystic fibrosis overall, you have thickened secretions in a bunch of your organs, lung, pancreas liver, blah, blah, blah. One of the ways that we actually can diagnose it is that you also end up with increased amount of salt in your sweat. Right. Okay. I know this.

Right. So that's one of the ways that we can actually diagnose cystic fibrosis. And nowadays, in the United States, in much of Europe, Australia, Canada, we actually do a newborn screen to test for cystic fibrosis. Because it is such a serious disease, such a serious disorder, we test for it pretty much every single newborn that is born in a hospital gets a little heel prick and we can test for cystic fibrosis gene mutations. You also could do it by testing sweat conductance essentially. You test to see how salty their sweat is, which I think It's just so interesting and cool that we can do that.

Well, it's ingenious. Yeah. Yeah. And what's really great is that if you detect it in a newborn, then you don't have to wait until these symptoms manifest to be able to start potentially treatment or at least preventative measures and things like that. Right. But if cystic fibrosis is not diagnosed by the newborn heel stick, then it's often diagnosed in childhood either because someone, keeps coming down with recurrent respiratory infections or just has chronic respiratory symptoms. So we're talking chronic cough, signs of obstructive disease that we can see when we do x-rays.

So their lungs will look like they're obstructed when we look at an x-ray. Or you can do pulmonary function tests. But on a baby, that's pretty difficult because you have to be like, now inhale and exhale. And babies don't know those words. And would it also be seen in like, nutrition? nutritional, like, would it be obvious in terms of malnutrition? Yeah. So if you, on top of the respiratory and sinus symptoms, you can also sometimes get very commonly,

or used to be more common in very young infants, something called maconium ilis, which is obstruction of the bowels by a mucous plug. Mm. Or it can manifest at first with pancreatic disease, which is basically what you said, where you have malnutrition and malabsorption, and then the, you know, you know, you, you child would present with what they call failure to thrive. So they're not growing properly, etc., because they're not able to absorb the nutrients that they're eating. And so is this something where, again, if you're in a place where it is not standard to do the heel prick test, that,

again, the type of mutation you have might influence when those symptoms emerge? Absolutely, because it's also very possible that someone isn't diagnosed until adult. especially if they have a mutation that doesn't result in a complete lack of the protein, but is just one of these dysregulated proteins or a lowered amount of a relatively normal protein. So in those people, in adults who are diagnosed with cystic fibrosis, they're more likely to present with GI symptoms. So just general like GI distress, maybe diarrhea, maybe really smelly or fatty stools. diabetes is a common presentation of cystic fibrosis in adults because of that pancreatic dysfunction

or they might not even be diagnosed until they try to have a baby and they're found to have infertility or lowered fertility, especially for people with testes that would normally be making sperm and they're found to have what's called aesospermia, which means no sperm. Yeah. So if a person has these kinds of symptoms, maybe these GI symptoms, maybe new onset diabetes or chronic respiratory illness, then you might start to suspect maybe this person has a cystic fibrosis mutation. So that's when you get to do the sweat test. Aha. You also, if that test is negative or for some reason if you can't do it, you can do what's called a transepathelial. nasal potential test. Oh. Which means sticking two probes in your nose and testing for the electrical potential.

Yeah. Yeah. Right? That's so cool. Yeah. And then you, especially if those tests are positive, but even if they're not and you still suspect maybe there's something going on here, then you would do genetic screening. Mm-hmm.

And one of the reasons that newborn screening and genetic screening in general is, is really common these days is that there are a lot of new treatments available that we'll talk about in the current event section that are specific to the types of mutations that we see in cystic fibrosis. So that means that they'll work for people with certain mutations, but they won't work for people with other mutations. So knowing exactly what cystic fibrosis mutation you have is important in determining the course of treatment. That makes sense. So, yeah, that's it. Oh.

That's the biology of cystic fibrosis. Okay. So tell me, Erin, what do we know about cystic fibrosis? And how did it come to be? Oh, well, okay. Big question here. Here we go. Let's take one quick break first.

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They are so comfortable. The fit is amazing, and they come in a bunch of different washes, so I'm about to go order some more. Refresh your wardrobe with Quince. Go to quince.com slash this podcast to get free shipping on your order and 365-day returns, now available in Canada, too. That's Q-U-I-N-C-E.com slash this podcast to get free shipping and 365-day returns, quince.com slash this podcast. Cistic fibrosis is an ancient disease, which you might have guessed. But how do we know this? Okay, well, we know this for a couple different reasons. One is that it has left traces in old European folklore. So there's this old commonly quoted prophecy of, quote,

wo to the child who tastes salty from a kiss on the brow, for he is cursed and soon must die. No way. Yes. Are you serious? Yeah. So that's like an old prophecy that's been found in several different old, several different things like an old Swiss German dictionary.

It was in an old Swiss almanac of children's songs and games. So interesting. Yeah. And we also know that cystic fibrosis is old because there was this description of an autopsy of a, quote, bewitched 11-year-old girl done in 1595. And her pancreas was described to be swollen, hardened, gleaming, and white. Ooh. So that's a pretty telltale sign of cystic fibrosis as well.

Okay, so those are traces, those are written traces, right? The real smoking gun of cystic fibrosis ancient origins. I don't know, there are lots of S's in that. I don't know how you pluralize that. Yeah. It lies in our genes. Okay, so as you mentioned, this condition is caused by having a mutation on the CFTR gene and tracing the geographic patterns of that mutation and of variations in that mutation or the types of mutations can tell us a lot about where and when the mutation probably first appeared. I love it. Yes. It was an interesting opportunity to dive into some of the evolutionary genetics, which I don't,

not in my wheelhouse whatsoever. Very fun. Yes. Very interesting. Bear with me. Here we go. For a long time, despite the widespread prevalence of this mutation, researchers had a really tough time pinning down exactly where it began and how.

how it spread. So if you look at research from the early 2000s, they're like, okay, so the mutation probably originated anywhere between 3,000 years ago to 52,000 years ago. It's a pretty big range. Yeah. And the geographic origin was even trickier to nail down. Ancient DNA analysis of skeletons from as early as 700 BCE did find the presence of the mutation in some samples, which is amazing.

It's, I can't, yeah, very fascinating, but that still left so many questions unanswered until last year. I found a recent study published in 2018 that claims to have resolved some of these longstanding controversies about the origin of cystic fibrosis. Okay, so what these researchers did is that they took DNA samples from people of European ancestry with cystic fibrosis, and then they tried to get a, wide geographic range of people spanning from all over Europe. Then they could compare their DNA sequences to see when the mutations likely emerged, overlay that with geographic information that they had collected, and basically they could make this geographic timeline of the origin and spread of the CF mutation. Just one of the mutations or multiples?

So this is just the most common one. Okay, okay. So this is, let me find out what the number is. is delta f 508 is the one yeah so yeah and so this is the one that's that's the most the most prevalent in the population so it turns out that after they did this their most likely scenario is that the mutation this delta f 508 first emerged around 2 700 bc e which is apparently the bronze age okay haven't really learned what that is yet i to do this age of bronze is the age of bronze yes i imagine the jewelry is fantastic. In small settlements, living along the Atlantic in Western Europe, probably France or Portugal.

Huh. Okay. But then what they did was they teamed up with some archaeologists to look at human movement patterns during that time to see if they could find anything that would account for the relatively rapid spread of the mutation throughout Europe following this early first appearance. and they found that there was a group called the Bell Beaker people that were known for their extensive migrations and cultural exchanges. Basically, what they would do is move throughout the entirety of Western Europe over a thousand years and marry or have children with the people that they, like, as they traveled.

Yeah. Just like leaving babies in their wake. Well, I don't know how many generations. Or maybe it was like, yeah. And they'd be able to like, okay, this time we'll stay here. And then the next, our kids will move to the next village and the next village and so on and so on. Fascinating. Yeah.

So I think it's really cool that these geneticists teamed up with these archaeologists and anthropologists to say, okay, what's happening here? Yeah. Okay, but why is it important to understand where and when the cystic fibrosis mutation comes from? Yeah, why should we care? Why should we care? That's always a good question to ask about anything that you're learning, right? The first reason why we should care, this can be applied to any disease. So the more we know about a disease and how it spreads in a population or where it comes from,

the better chance we have of controlling or curing it. And the second reason is that in the case of cystic fibrosis, understanding where the mutation came from can give us clues as to why it exists at such high frequencies. because as we know, when you have two copies of this mutation, it is often sadly fatal. And it would have been especially more so in the time before modern medicine. But this is one of the most, if not the most common mutations of people of European descent with about one in 25 people carrying one copy of the mutation of any of these mutations. of any of these mutations.

So why was it not selected out of the population? Why does it still exist, basically? Because usually when we see a lethal mutation with a high frequency, it's a clue that it's doing something beneficial as well, like as we saw in the case with sickle cell anemia protecting against malaria. Heterozygot advantage. There we go. Yeah, so this heterozygote advantage, basically, people who carry one copy of the mutation

would benefit from the protection that that means. mutation offers while not being negatively affected by the presence of two copies of the mutation. And so that's what researchers think might be going on with the cystic fibrosis mutation. So what are some of these hypotheses, right? I love it. Typically, a lot of people immediately go to infectious diseases because that was such an important thing to protect against in times before modern medicine, antibiotics, et cetera, et cetera. So some of these things, hypotheses include cholera, type.

diphoid, diarrhea, associated with lactose consumption, or tuberculosis. So the idea is that one copy of this CFTR mutation would protect against those diseases. There seems to be some physiological support for this or for at least some of these diseases, like the cholera toxin requires normal CFTR proteins to cause disease, for example, but it's still not, it's a little bit hand-wavy, so other things don't quite, add up. So in the case of cholera, cholera has occurred at much higher frequencies in tropical areas compared to Europe. But the rate of the cystic fibrosis mutation is not correspondingly high there. Yeah. And same goes for typhoid. And no studies have confirmed that people with

a cystic fibrosis mutation are more resistant to any of these diseases. Because that would be a horribly unethical study. Yeah. It's just theoretically based on the channels and in some mouse models. It seems to hold water. Get it? Yeah. Wow, that was funny, actually. And so it could be that the mutation has a benefit other than protecting against an infectious disease, or could be that it protected against a disease that is no longer known to us.

I mean, we don't know. In any case, this part of the story of cystic fibrosis is still, seems like it's still being written. Yeah. Okay. Quick recap. So, the cystic fibrosis mutation probably originated around 2,700 BCE in Portugal or France. Okay. And it rapidly spread throughout the rest of Europe. Okay.

Okay. We have these mentions in folklore and a few little anecdotal reports throughout the 1700s and 1800s. But it's not until the late 1930s that we get an official description of cystic fibrosis. 1930s, even though way back in the forever, they were talking about salty kids. Salty kids, yeah. Wow. Yeah. And I mean, I think part of this is because it does affect people differently and a lot of different organs in very different ways. And it's hard to tie all the things together, I think.

Yeah. Until, so then we have this, the namesake of our quarantini. this episode. Dr. Dorothy Anderson. All right, so let me tell you a little bit about Dr. Anderson. Tell me all about her. Because I did a little deep dive into her biography, and it was, it's just cool. All right. So she was born in 1901 in Asheville, North Carolina, which is an amazing place. Yep, I love it. Dorothy was fascinated by science and medicine, and she went to get her bachelor's in zoology and chemistry, and then her MD. And she did all this by the time she was 25. What? Dorothy, killing me.

She worked incredibly hard to support herself, having lost both of her parents before starting college. And it seemed like she was well on her way to becoming a surgeon. She was doing an internship and everything. And then she tried to do her residency at this particular hospital and was denied because she was a woman. That was the reason. Yeah, very frustrating. Was she like, mm-mm, watch me go? She was like, all right, fine, I'll do research.

And she got her Ph.D. in endocrinology. Like you do. What? Just no problem. So. Oh, my gosh. She did eventually work as a pathologist and pediatrician at the babies hospital at the Columbia Presbyterian Medical Center.

Wow. So, and it was there that she noticed in one child that had died of celiac disease that there was this fibrosis of the pancreas, which was not something that she had seen in other babies. with celiac. So she wrote up her finding with this full description of the condition, and she named this disorder cystic fibrosis of the pancreas. Oh. That's how it got its name. Wow. And so that happened in 1938. And that's what, that naming of it, that description, even though it had been mentioned in medical texts earlier in that century, that was the description that put it on the map that started people to do research

on it. And also a big reason is because this is what she did for the rest of her career. She worked on cystic fibrosis. She made these amazing observations that led to the development of the diagnostic sweat test. And she also hypothesized that it was an autosomal recessive disorder. Wow. I never thought about where it got the name cystic fibrosis specifically. And it's so interesting that it's from that she saw someone and it was a pancreatic disease. Like that's where she saw it and that's where she diagnosed it. When today we mostly think about lung issues, that's so interesting. Well, it's really interesting.

I think a lot of people felt later on that it was a misnomer and there was like a question of should we change this name? Should we call it something else? And I mean, at a certain point, changing the name is just going to lead to more confusion. Right. But it's, yeah, so that's the origin of that. the name. Oh, wow. Yeah. And so, okay, before I move on to the rest of the history of cystic fibrosis, I just want to tell you a little bit more about how awesome Dr. Anderson was, because I, again,

my deep dive. So she was incredibly meticulous and insightful in her research, and she contributed so much to the field of medicine besides the work that she did on cystic fibrosis, especially in things like cardiac medicine. And throughout her entire, she's just a huge inspiration because Throughout her entire career, she faced a ton of resistance getting criticized or ridiculed by her colleagues because of her unkempt appearance or her unladylike hobbies because she loved to woodwork and hike and live in the woods and have these amazing parties. She was a stonemason. She championed women's rights.

What? What? She was so cool. Yeah. How BA. But she also had a ton of loyal supporters and friends who just loved her and would always talk about how generous and kind she was. And now she has a quarantini named after her.

Yes. Thank you, Dr. Anderson. Okay, so back to cystic fibrosis. So research advancements didn't start immediately after Dr. Anderson's publication in 1938. And that's a big part of that is because of World War II. A lot of medical research started to focus on not, focus on war wounds, bio-weapons. no, who knows, I don't know.

Yeah. And during this time, also case descriptions were the most common reported thing. It was just building this recognition of this is what this person had. This is their case history, et cetera. And it was during these writing up these case descriptions that people started to recognize the familial nature of the disease. But researchers still didn't know how, like the exact mechanism of autosomal recessive disorders. Question.

Yeah. When was Mendel doing his thing with peas? 1860s. Okay. So people knew like a little bit about. People knew. Yeah. So like the concept of trait dominance had existed for a very long time.

But it was figuring out the location of the mutation. Right. That was a long ways away. And understanding the role of this gene versus that gene and how all those things functioned. That would sense. Yeah. It was much more like it, I think it needed.

understanding of how DNA worked before we could make those leaps. Yeah. And so, as we know, figuring out the mutation was still a long way away, but there was a lot that could be done in the meantime. So, for instance, the discovery of antibiotics greatly improved quality of life and the longevity of people who were diagnosed with cystic fibrosis because you could then prevent lung infections or cure lung infections that could cause irreparable damage to the teeth. tissue and then also recognizing how important diet was, having the proper amount of fat and

nutrient absorption. All of these things were starting to get recognized. But many doctors around the world were still unaware of this disorder or helpless against it. And most children didn't survive to the age of seven during this time. And part of the problem was in correctly diagnoses. the condition. So some of these procedures could be horribly invasive and others were kind of subjective. And so when the sweat test was developed in the mid-1950s, it really helped to both start supportive therapy early for someone who had cystic fibrosis and to also give epidemiologists a handle

on the widespread prevalence of the condition. Physiotherapy also started to be used around the same time. And then doctors started to recognize the threat that chronic pseudomonas infections caused, and then they started to recognize how harmful chronic antibiotic use could be. So it's kind of a lot of, it was a learning curve. This wasn't an easy thing to figure out. There was a lot of trial and error, a lot of, you know, how do we do this? Is this the right? Is this the best way to, to provide supportive therapy for someone with cystic fibrosis? Right. And I think that the increased recognition also led to the formation of a lot of cystic fibrosis organizations. So in the 1960s is when a lot of these organizations kind of got up and running.

And this allowed parents of children with cystic fibrosis or partners of people with cystic fibrosis to connect and form supportive groups. And it also promoted the exchange of information among researchers. Once you have kind of a group of people together saying these are my experiences, or this is the research that I found. Yeah. And also this international collaborations were formed, and that meant a lot of steady progress being made on treatment or at least supportive therapy.

And you can see the progress in the numbers in terms of the life expectancy. So between the years of 1968 to 1977, the median age of survival rose from 14 years to 20 years. Wow. in less than 10 years. In less than 10 years. And this increase wasn't consistent geographically or even across hospitals within the same country because many people could not afford around the clock care for their child.

I mean, can you imagine the hospital bills in the U.S. for all the hospital stays that you would need, all of the treatment, all of the care? Yeah. Yeah. And so despite the incremental improvements in therapy that helped extend the lifespan of children or people with cystic fibrosis, many researchers felt as in the dark about the condition as they did in the beginning of their career 30 years earlier. By the 1980s, the gene that held the mutation that caused cystic fibrosis was still unknown.

Like, no one knew what that gene was. In the 1980s, wow. The 1980s. But during that time, some progress had been made in understanding the biochemistry, and so that was helpful. Okay. And it was finally in 1989 when the link was made between cystic fibrosis and a mutation in a gene on chromosome 7, so the CFTR gene. Wow.

That's in our lifetime, Erin. In our lifetime, yeah. How cool. And this was a big deal because once the location of that gene was identified, this meant that people could be tested for it to say, are you a carrier? Do you have the condition, et cetera? And I keep saying mutation, but what I really mean is. is mutations plural.

Yeah. Because there are thousands of different types of mutations. Okay. So this, that's, and that's basically all that I have for the history, but I kind of wanted to like end cap this a little bit in a way because in doing the research for this episode, I did something that I haven't done as much. And that is read memoirs of people. And what it did was really remind me, served as a great reminder,

just how important it is to read about an experience from someone else's perspective. And so reading these memoirs really hit home to me how difficult it is to talk about disease or wellness with our limited vocabulary. And I don't just mean you and my limited vocabulary. But how do we know, like when we say words like this hurts, well, how much does it hurt? A lot. Okay. Yeah, we can use more descriptive language. We can use a scale from one to ten.

But like, how can you understand a scale if you don't know what someone's baseline is? One person who's like, oh, I'm feeling a bit cruddy. Another person might be like, oh, my God, I'm in agony. I'm dying right now. This is extremely painful. And I feel like our own baselines change. time. A hangover at 32 is a lot different than a hangover at 22. Yes. Personal experience. Is there such a thing as a hangover at 22? I don't. Oh, God. I don't think so.

No. And I think part of this issue with communicating effectively how we feel or what we're feeling is not just with this limited language, but also it has to do with the difficulty in relating to someone what it's like to be you, to have your experiences and your memories and the way you see the world, because that forms so much of how we perceive our own selves. And also how we interpret other people's feelings or words. And that's something that I came across many times in some of these memoirs that I read for the episode, that for people born with cystic fibrosis, they have not known a life without it. So you can't. ask them, hey, what's it like to have cystic fibrosis? Because it's like, well, it's, this is what I know.

This is how I have lived, you know? And, and also, like, it would be like, if they asked you, what's it like to not have cystic fibrosis, it would be the same sort of thing. Well, this is what I know, you know. And so for that reason, we can't, I don't know what I'm trying to say exactly. So we can't, I think it's, it's very difficult to ever, or impossible to ever truly understand what someone else is going through or what their experiences are. But I think the most important thing is that we need to try. We should try because it builds empathy. Another thing that kept popping up in these memoirs was that other people use cystic fibrosis

as an identifier for those people. It's one and the same. Their identity is cystic fibrosis. And that's not what it is. That's not the case. That's not what it should be. and Jay, whom you heard from in the first hand, sheds a little bit more light on what this is like for him and more about who he is. So let's hear what Jay has to say in his own words.

I growing up never enjoyed the tone of cystic fibrosis stuff. Like I never felt like there was something for me. And I wondered if there were other people like me out there. I figured there had to be, and this writing the book was an easy way to find them. Because I grew up on the Internet, so I've seen support groups and things like that, but they are not for people like me. Cystic fibrosis is also called, well, sometimes called by people 65 roses because there was a child who couldn't say cystic fibrosis. And so they always called it 65 roses. I was not that kid.

I knew exactly what it was at a very, very. young age. I knew how to take my own pills at a young age, which upset babysitters sometimes, because, you know, when you have a little six-year-old kid and he's about to swallow six giant pills by himself, that's a real nerve-wracking moment. But to see, like, all the, like, the inspirational quotes and everything about, like, you know, I'm glad I have it. It's such a gift. Like, I do not consider a gift in any way. But I also, not that I don't enjoy talking about it when people ask about it, but it's my, my CF is like a vampire and that you have to invite it into the conversation. I usually won't just bring it up myself because I like to think that

there's so much more about me than just CF, which may or may not be true, but this is actually why about half the chapters of the book don't involve CF, because I think it's very important to note that people get the disease. The disease doesn't get people. I hoped that there was a group of people where CF was a problem they had, but not a defining portion of their personality. And it has certainly changed my personality in ways that I don't know. I like to talk about Swamp Thing more than CF most times. Or like, you know, you can get me started on Iron Maiden or amorphous, the Kings of Finish Metal. Those things are very important to me.

Music is very important to me. CF is not important to me in that if it went away, I'm sure it would be an adjustment for me, but I'd be fine. I would just stop taking pills. It's not like I would lose a portion of myself, I think. My favorite thing to do in the world is record music. All Hollow's Evil is the name of the project I do it. It's usually just me.

There were some other people in it for some time, but I play all the instruments and everything. So I have, I started that in 2002 is the first official album. 17 years of albums where I recently went through and remaster them and remix them and everything for public consumption again. And it is painful to listen to because I remember that feeling like I didn't have anything to lose and there is nothing to hold back. And at the time, I would have been very offended if someone was like, hey, are you okay? Like, yeah, no, man, this is just what I do. And it's funny because I went back and tried to,

to remastering all the albums and I dug up some things that I had written the first time we reissued the catalog and I wrote that stuff when I thought I was okay back in like 2005 and looking at it now I'm like wow I feel like I need to go back and apologize to everyone I interacted with at that time because I was just I had lost insurance a couple times which is terrifying to know that you are one decision away from dying. I lost insurance, started coughing up blood, charged $2,000 in drugs to my credit card, fix that problem. But it took a long time to fix the mental problems there.

And I realized while I was making music easily now, that it is one of the only times that I don't think about anything else. Like, I'm completely focused on what I'm doing. doing while I'm recording instruments. While I do the vocals, then I'm right back to thinking about CF because it's tough to breathe sometimes. But I think that's what I enjoy about it, is it's one of the few things that I can just really focus on.

And they can be really good at without worrying about, like, I can't, I probably could be decent at running if I tried, but it's difficult. Like music, the barrier to entry was very low. my entire life I felt like I've had something to prove. And I realized that I've always been trying to prove myself as someone who's disabled but able to do this stuff. And so I always thought when people are like, oh, wow, you're really good at this. What I always heard was you're really good at this for someone with cystic fibrosis. And it was shocking the day I realized that there were maybe two people out of six.

at work that realized I had something wrong with me. The thing that people need to, I'd like people to understand is that I got very good at a lot of things because I have a chip on my shoulder and it is still there and it will never leave me because I know that I always started from way behind the starting line on most things. and the reason that I have been relatively successful, like I make like a living at this point, has almost nothing to do with me and the fact that I'm good at those things.

Because being good at those things means nothing if you don't have the right opportunity for it. So if I were born five years earlier or like, I don't know, 70 miles to the west of where I was born, I'd be dead. I can't quit my job. I do not know how to quit my job, because that is how, that's literally keeping me alive. More so than the money, it's the insurance. My drugs cost $300,000 a year. There's no way, there's no amount of money I could make. And the thing is, even if I did make that amount of money, they won't sell them to you.

It was so difficult to get someone to sell me a drug. And then that's when I found, out that they wouldn't give me the insurance discount. I was paying cash and had to pay $400 more than an insurance company would have made. There is such a specific set of circumstances, and it kind of irks me when people are presented as like, yeah, this battler is battling this disease and making it happen, and it's like you don't realize, I hate to use luck, but there is, You have to be offered the opportunity to take it, and those opportunities aren't open for a lot of people. And I'm lucky in that, again, I'm very good at a lot of different technical things, which happened to be the thing that people want right now. If it turned out that our entire economy changed and now, like, woodworking was the most valued skill, I'm out.

I've got nothing for you because I can't breathe in the sawdust. To have those opportunities and be able to take advantage of it. of them is kind of luck. I not only have been given the opportunities, but I have skills to take advantage of these opportunities in the best way possible. And it is the only reason that I'm still alive and I wish it were easier for everyone to be alive. If you loved Jay as much as we did, you can find more of his writing at can't eat, can't breathe.com. And you can find his book, can't eat, can't breathe, and other ways cystic fibrosis has effed me on Amazon and any other place where you want to get your books where definitely, seriously, go check out his book. It's incredible.

Highly recommend it. It's really great. Yes. And you can also find more of his music at all hollows evil. Bancamp.com. And that's also where you can find his latest album titled No Gods Only Monsters. go check it out. And you can find him tweeting at All Hollow's Evil. Okay, so the last 80 years of cystic fibrosis have been big. Yeah. Since its first description, 80 years ago, cystic fibrosis has gone from a disease of relative obscurity to one of the most research genetic diseases out there.

The expected lifespan has gone from six months to over 30 years. and so much progress has been made in treatments and potential cures. So I'm hoping, Erin, that you'll tell me some good things about cystic fibrosis and gene therapies and other great things on the horizon. I can't wait, too. We'll take one more short break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keeffe's working hands hand cream is such a relief.

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Not all customers will qualify. Contact dealer for details. Offer ends 3-2. So overall, it's estimated that the incidence of cystic fibrosis is about one in 3,000 among people of northern European descent. It's a very high incidence. Yeah, especially for an autosomal recessive disorder. The highest incidence is actually in Ireland, which for some reason is not what I was expecting. But there it's about one in 1,400.

Wow. Yeah. So, and it's very different in people of different descent. So in people of like Latin American descent, the incidence ranges from about one in 4,000 to one in 10,000. In African Americans, it's between 1 in 15 to 1 in 20,000 and even lower in people of Asian backgrounds. And what I think is really important is that it's not to say that it's impossible. And one of the biggest gaps that we have in looking at all of these numbers is that these numbers all come from the U.S., Canada, Europe, Australia. So there's a lot of countries and entire regions of the globe from which we don't really have a handle on what the incidence of cystic fibrosis actually is.

Hmm. Yeah. So we know that it's more common in people of Northern European descent, but that doesn't mean that it doesn't exist. exist across the globe because it does. It's just at lower. Yeah. And a lot of the places that we do have a really good idea of the incidents are places where these newborn screening programs have been initiated. And I want to talk about them for a minute because I think this is pretty incredible. These newborn screening programs have been shown to reduce mortality, like decrease the death rate, improve growth and neurocognitive outcomes so that because babies who are diagnosed early can

get treatment early, they have better like brain outcomes, which cystic fibrosis, we didn't even talk about it being able to affect your brain. And they've also been shown for those people who are keeping tally on these numbers to be very cost effective. There we go. So, you know, so newborn screening is routine in. in a number of different countries. And it basically just is a heel prick. And they actually test for the blood level of a protein that's higher in most infants with cystic fibrosis. So it's not a straight genetic screen right off the bat.

It's just a test for this specific protein. Right. But I imagine it's pretty rapid results. Yeah. I think you get them back. Here I think you get them back within a week or two. Okay. So overall, when we look at cystic fibrosis, even with these newborn screening programs, the prevalence of cystic fibrosis in the population is actually increasing.

But it's for a very good reason. And that's because major developments in treatment have improved survival. So more people are living with cystic fibrosis. Gotcha. Okay. Yeah. So it's a happy increase. Yeah.

That's great. So, yeah, in the U.S., between 2000 and 2010, survival improved by 1.8% per year. That's amazing. It's incredible. And today, the median survival of children that are born today with cystic fibrosis is 56 years, which is still, it's still so young. Like, 56 is so young, but when you look back at the history of the past 80 years to go from six months. to 56 years. And that's today. And it's improving every year because we're getting better at treating it every year, which is amazing. Yeah. However, a small caveat, not a small caveat, a big caveat, is that overall, when we look across the globe, median survival is still in the mid-20s to early 30s. So we're not better everywhere. But in places like in the U.S. where we have access to treatment, it is getting better. And a lot of it does have to do with this early detection.

In the U.S. in 2010, almost 60% of people that were diagnosed with cystic fibrosis were diagnosed by that newborn screen, compared with only 8% of people in the year 2000 were diagnosed as newborns. Hmm. Yeah. Interesting. So overall, prevalence is increasing, but it's because we're getting better at treating it. And so that's what I want to talk about next. Yeah, tell me about the treatments.

Let's talk all about it. It's a really happy, fun, good stories. Okay. So there is so much research that is going into actual treatments. And for a long time, all we could do to treat cystic fibrosis was treat the symptoms. So if you got recurrent respiratory infections, you would treat the infection. If you were having pancreatic insufficiency, then you could give them maybe pancreatic enzymes. Okay.

It's not going to fix your pancreas, but at least you can. digest your food. But now there's all of these new drugs being developed and tested to target the cause of the disease, to target the messed up protein itself, so that we can fix this disorder from the start rather than just treating the symptoms. Wow. The biggest difficulty is that because there are so many different mutations, there hasn't yet been a single drug or a single intervention that can work for all of the different types of cystic fibrosis, if that makes sense. Yeah. But have there been any that work for at least one?

Oh, there's been multiple. Oh, good. And I do want to say that I am not a cystic fibrosis researcher or expert, and so I know that there's so much going on that I know I haven't covered at all. And so for that, especially if you research this, I apologize if I don't mention your current research. But I want to talk about some of the things that have had the biggest impacts and some of what I think is the coolest and I'm biased because my friend actually did some of this research, which is very cool. It's a really cool research. Okay, so one new drug that has been

developed and works really great for some people and doesn't work at all for others is called Ivacfter. Have you heard of it? Mm-mm. Ivakhafter. It's such a weird name for a drug. This drug works for people with a mutation, not the most common mutation, but a mutation that affects about four people living with cystic fibrosis, that one of those class three or four mutations that affects the way the protein works, the mechanism of the

protein. So you have the protein, it's not misformed, it makes it all the way to the surface, but it's not working properly, okay? it's called a gating mutation. So Ivecafter can essentially improve the movement of electrolytes across this protein. It targets this bad gating protein directly, and it's really, really effective. It essentially just allows for the movement of electrolytes. How?

I don't know the details of it. Erin, that's... That's just... I don't understand. How? How? That's when we get too deep into pharmacology that I can't handle. I'm unsatisfied.

Well, then you're going to be more unsatisfied, okay? Okay. But it works. The point is that it works. If you have a protein, but it's just not functioning correctly, it's not gating correctly, if a cafter essentially can bind to that protein in a certain way that allows for proteins to, or allows for ions to move properly across that protein. Okay?

But obviously that's not going to be effective for people who maybe don't make any cystic fibrosis protein, right? Yeah. Okay. So there are some other options. There's two other drugs, tezacfter, I think that's how you say it, and lumacafter. Tezacfter and lumacfter. These both are beneficial for the most common mutation of cystic fibrosis. That's the delta F508.

Uh-huh. So that mutation is a mutation in the processing of the protein. So you make the protein in your cells, but then you can't get it shuttled to the surface to actually insert in the membrane. So these two drugs help in the processing and trafficking of that protein to get it to the cell surface. Does that make sense? How? I'm just kidding. That's cool. That's very cool. Yes, it's very cool. So if you have a mutation where your body is still making the protein, it's not being trafficked properly, these two drugs can help with that. However, what is even more interesting to me is that they've actually only been shown to be helpful when you give them in combination with Ivecafter. So Ivecfter helps the functionality of that protein, which I would guess essentially just means that, yeah, you're making it and the problem is you're not trafficking it, but there must be something else going on with that protein too, that it's just not

gating properly as well. It's not the maybe as slightly misfolded or something like that. Exactly. Right. But a combination of either tezacfter or lumacfter and Ivafter, also these chafter, can we talk about cafter? What does that mean? Seriously. I don't know, but it kills me. Cafter. Hmm. Okay. But these drugs in combination are for people with this specific mutation, hugely beneficial. Like, incredibly so. But even with these three drug options and their combinations, there's still going to be a lot of people who straight up don't make the protein, right? Because that's a whole class of mutation. I don't make any protein.

Or others who just don't make enough of it. So helping to traffic it or helping it to gate, that's not going to help. There's not enough of the protein. And so these drugs aren't going to be helpful at all if that's the type of mutation that you have. So this is where I'm going to brag. Oh. about a friend of mine, not about myself. Shout out to my friend Kat, who did her PhD and worked on the development of a new drug.

This is brand spanking new. It came out in 2019, not yet doing human trials, but there was trials in cell culture and in pigs. And it's, this is so cool. This drug that she helped develop for her PhD straight up functions. as a CFTR protein channel. Whoa. So she found a small molecule that's actually amphotericin B, which is an antifungal medication that we already use. Uh-huh.

Which means that it's already been tested in humans, which is going to help down the road in terms of getting it through like process of testing, et cetera. You know what I'm saying? Yeah, I got you. We already know. Yeah, okay. I read your mind. It functions as a small molecule that inserts itself into the cell membrane and allows for the transport of bicarbonate across the cell membrane. Okay. Bicarbonate is one of the things that is normally transported in the CFTR protein. Cool. It's so cool.

And they found that when they gave this amphatercin-B, which again, it's a drug that we use as an antifungal that's actually pretty gnarly when you give it at high concentrations, at really low concentrations, it's highly selective to only allow these anions, this bicarb, to pass across the membrane. So it's not going to further mess up any electrolytes because it's not allowing just anything to pass through. And they compared the efficacy in changing the pHs of the airway surface between this molecule, so amphaterosin and Ivecfter, which again is one of those big drugs that they use. And they found that it had similar effects. So we know that because Ivecfter is working for people with cystic fibrosis, with these certain mutative,

It changes the airway surface pH in this way. Amphoterosene B changes it in the same way. But by actually acting as a protein, you don't have to have a protein there already for it to happen. Does that make sense? I think so. And so this would apply to all different mutation groups. Exactly. You don't have to be able to make any of the cystic fibrosis protein in order for this to be beneficial. So would you have to take this antifungal medication for eternity? That's a good question that we don't know at this point. But they did test it in yeast, in human airway epithelial tissue, in culture, and then in pigs with cystic fibrosis. And in all of those, it worked to actually, in the pigs especially, it decreased the symptoms and prolonged these pigs living with cystic

fibrosis. That's very cool. It is so cool. And again, this is a molecule, amphaterosin, that's already a drug that we use to treat fungal infections. So in terms of basic safety testing, it's already gone through that. So now it just needs, I mean, it still needs a ton of work in terms of clinical trials, but it makes it that much faster because it's not a completely new thing, essentially.

So can you explain the difference between bicarbonate and chloride? And why, like, is one more important than the other in terms of ion transport or ion regulation? This is a great question. I'm glad that you asked it because Kat was like, Aaron, don't forget to talk about bicarb when we do this episode. So for a long time, it was thought that the effects of the cystic fibrosis protein were mediated entirely through chloride. Like, this is a chloride channel. So chloride moving across is what's causing all of these symptoms. But it turns out it's not only chloride that moves through this channel. Bicarbonate also moves through. And it might be even more important in some cases in actually causing and resulting in the symptoms that we see.

So essentially both bicarb and chloride ions can move through this CFTR channel. And in this case, this amphaterosin drug is only working. on the bicarb, but that alone is enough to actually benefit, essentially, without even touching the chloride. So it's likely that bicarb is a bigger player in the cystic fibrosis game than it has gotten credit for it in the past. So are there other things in terms of gene therapy and not medication? Yeah. Yeah. So gene therapy has also mostly been studied in the lungs. So using like a nasal spray that has a viral vector that has a functional CFTR gene in it. And then the idea is that that virus will then go and infect your airway cells and put that functional CFTR gene

into your airway cells and then boom, now you can make this functional cystic fibrosis protein. So there are definitely a number of different groups working on gene therapies. So far, they haven't been super effective in long-term trials, but they are in trials. There's actually a huge group out of the UK called CFgientherapy.org. And it's the UK cystic fibrosis gene therapy, consortium. And they're doing a ton of work on gene therapy. Cool. So that, and that is probably a little further along in the process in terms of it has been tested on humans. It just hasn't been shown to be effective in long term so far. So I think one of the biggest issues with gene therapy in general is figuring out how to

administer it and how to get this gene to actually work the way that we want it to once it's inside of human cells. We don't have a lot of control over that as of yet. Another thing, though, that I think kind of harkens back to what you were talking about, Aaron, in terms of reading memoirs and understanding how cystic fibrosis, people live with cystic fibrosis their entire life. And so understanding that effect is another big area in cystic fibrosis research has been on understanding that quality of life is just as important in many ways as just longevity. So in a lot of medical studies, you'll only see reported things like morbidity and

mortality. And like mortality is this one endpoint. But especially as we develop all of these new drugs that are allowing for people to live much longer lives living with cystic fibrosis, understanding how these drugs and these drug regimens affect your quality of life is being become really, really important. And so a lot of research is taking this into account and quality of life studies over the past 10 years have really dug into this in trying to look at a few different issues. One is the importance of patient. reported respiratory symptoms as one of the outcome measures. So not just maybe looking at like how many infections did you get or something very quantitative, but actually looking at the patient's

reported symptoms. And then the growing perception that the prescribed treatments, even though we can say how incredible they are and how much they do, they're burdensome. Like we're talking about having to take pills for the rest of your entire life, multiple pills every single day. Well, it's not just pills, but it's also these machines that people need to take time every single day often to break up the mucus to do this. Yeah. And it's, yeah, painful. Yeah. Yeah.

And there's huge differences, according to socioeconomic and racial and ethnic status in terms of who has access to these new developments and who's included in these research studies. and who's included in these research studies and all of that. Yeah, I think that realm of research is really important, and I was doing a little bit of a dig into some of the, I guess, psychology papers around what teenagers with cystic fibrosis and what are some of the minimization of symptoms or just language choices and how you talk about your physical feelings. And also in terms of impact on family and divorce rate these sorts of things.

Like how it's such a multifaceted thing where I feel like it's we follow this formula every episode. Right. We talk about the biology, the history, and the epidemiology. And I feel like that there's so much more to every single disease that. that we talk about, that we have talked about. And in this case, it was definitely tip of the iceberg in terms of feeling completely ill-equipped to tell any version of a story of cystic fibrosis and saying, like, well, there's also this aspect of it, there's this aspect of it, which is even more reason

to talk about it, to say, hey, share your experiences and so on. But yeah. Yeah. There's a lot of really, there's a lot of research and impact on aspects of cystic fibrosis that are maybe not immediately apparent or fall into the categories of medical or historical. Exactly. Yeah. So yeah. That's where we stand. Seems like it's encouraging, but yeah. Overall encouraging. Still hard. Still hard and heavy. Yeah. Sources. Sources.

I want to shout out a couple of papers. One is Romans et al from 1989, and that is the identification of the cystic fibrosis gene. And so this article is where they identified where the mutation is located on which gene, on which chromosome. And then there's a 2018 paper by Farrell et al. And so this is where I mentioned estimating the age, so the origin. of this most common, the Delta F508 mutation. And then there are three memoirs that I want to give a shout out to. One is called Alex, The Life of a Child, by Frank DeFord.

And so this is a memoir written by a father about his daughter named Alex, who had cystic fibrosis. Another book is called My Foreign Cities by Elizabeth Scarborough. And so this is a book written by a woman who's, husband had cystic fibrosis, and of course, can't eat, can't breathe, and other ways cystic fibrosis has effed me by our very own J. Geronomy. All of these were incredible. I really highly recommend each one of these. I think it's just really valuable to read about someone's perspective, someone's experiences. Yeah. I had two really great reviews, actually, that are super comprehensive about cystic fibrosis biology

and covers a lot of their epidemiology as well. So we, as always, will post the links to all of our sources on our website. This podcast will kill you.com under the episodes tab. And there you can find sources from every single one of our episodes. That's right. Jay, thanks again for everything. Yeah. Thank you so much. It was so much fun to talk to you.

great. Yeah. And thank you to Bloodmobile for providing the music for this episode and all of our episodes. And again to Jay for sharing with us this brand new song that you guys are about to hear. So get excited. And thank you to all of you for listening. We really love making this podcast. This is great. Okay. Well, Jay has got one more nugget of advice for a song. all. The one other thing I need everyone to know is always wash your hands and never touch your face. That is the secret to everything. You heard him. Wash your hands. You filthy animals. What you'll do so much is out to kick. World doesn't get you bleeding. Know your body. You in your sleep. This is Bethany Frankel from Just Be with Bethany Frankel. Listen, I have a bone to

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