Speaker 1: Well, my name is Jason Geronomy. I usually go by
Speaker 1: Jake because it's half the syllables. I was diagnosed with
Speaker 1: cistic fibrosis when I was nine months old because I
Speaker 1: was a very lethargic baby. I just there are pictures
Speaker 1: of me from that time where you can see like
Speaker 1: a kid ain't right. And I think I am alive
Speaker 1: today through a very specific set of circumstances in that
Speaker 1: when my parents went to the doctors and were like, hey,
Speaker 1: this baby sucks. The doctor that they went to happened
Speaker 1: to work with a CF doctor in Yale, like they
Speaker 1: were partners on cystic fibrosis. So whereas I was a
Speaker 1: failure to thrive baby, he knew exactly why I was
Speaker 1: failure to thrive and we were able to address that
Speaker 1: right away. So since then, there has been a long
Speaker 1: journey and it hasn't been fun, but I have been
Speaker 1: very lucky in most of my circumstances in that there's
Speaker 1: new medicines which aren't always easy to take, but sometimes
Speaker 1: they work. I'm able to get insurance, which is a
Speaker 1: real big thing and was a real problem for me
Speaker 1: for a lot of years, and I'm actually doing okay now.
Speaker 1: I'm doing better now at thirty six than I was
Speaker 1: at twenty six, which is not how this used to go.
Speaker 1: I was one of the first people to go into
Speaker 1: an adult CF clinic because there weren't adults for a while,
Speaker 1: and so that was weird. I kind of missed the
Speaker 1: slide from the children's clinic. But what are you gonna do?
Speaker 1: I feel like everything about like successful people with CF,
Speaker 1: and I'm successful in the fact that I'm not dead yet.
Speaker 1: I feel like it's really important to mention how they
Speaker 1: got insurance, and once again, it's very specific circumstances for me,
Speaker 1: and that I got very lucky in that there's two
Speaker 1: very large employers in my area who happened to offer
Speaker 1: insurance for entry level positions, and had that not existed
Speaker 1: at the time, I wouldn't exist now. And I'm also
Speaker 1: lucky the fact that my job is a nine to
Speaker 1: five job and I do not wake up that early.
Speaker 1: So everyone was very nice when I was like, hey,
Speaker 1: I'm coming in at noon and didn't question me because
Speaker 1: it takes me a long time to get ready as
Speaker 1: a large production keeping the show on the road. When
Speaker 1: I wake up, I don't feel great. I don't think
Speaker 1: anyone feels great when they wake up. But I'm extremely
Speaker 1: aware of my lungs when I wake up, like I
Speaker 1: can feel them, and you kind of do like a
Speaker 1: diagnostic check of the body, see what you've got going on.
Speaker 1: And then I have a vest that I wear, and
Speaker 1: there's been a recent technological advance in that, and that
Speaker 1: it used to be a vest that sort of it
Speaker 1: was like a giant blood pressure cuff that you put
Speaker 1: around your chest and it would push air through and
Speaker 1: make a whole lot of noise kind of like a
Speaker 1: which now it's like this. It looks like a jet
Speaker 1: pack and you wear it and it's got little pods
Speaker 1: that I think they're essentially speakers. They're not really allowed
Speaker 1: to tell me that, but they kind of shake your
Speaker 1: chest so they make more of like a And while
Speaker 1: that's happening, I also have a nebulizer with which I
Speaker 1: inhale salt water at first to salt up the mucus
Speaker 1: and encourage water to go to it. And then the
Speaker 1: next step is a drug called polmozyme, which actually it
Speaker 1: snips out parts of the DNA of your mucus somehow
Speaker 1: and thins it out, so trying to force water into
Speaker 1: it trying to force it thin. The vest runs for
Speaker 1: three ten minute sessions, and in between each session you're
Speaker 1: supposed to cough and see if you can actually cough
Speaker 1: anything out. Last week, I actually had the occasion to
Speaker 1: cough out a large piece of sort of dry mucus
Speaker 1: that was like I could feel my baranchial tree imprint
Speaker 1: in it, which is a strange feeling. So I do that.
Speaker 1: I have some extra pills I have to take. I
Speaker 1: have to take pills to eat that have I believe
Speaker 1: they're freeze dried pig pancreas. They actually digest the food
Speaker 1: for me. But if my acid, my stomach acid is
Speaker 1: too acidic, they can't do it. I just tear up
Speaker 1: the pills, so I take amephersol. I actually take pills
Speaker 1: for my pills to work. That's fun. Clarendon, which is
Speaker 1: an easy one. I got to make sure I get
Speaker 1: enough vitamin D because I also have osteopenia, which is
Speaker 1: not osteoporosis but almost. And then I go to work
Speaker 1: and I've got this all down into about an hour,
Speaker 1: and then I do some work. I go home eventually,
Speaker 1: and I have to do the best again when I
Speaker 1: get home, which another thirty minutes. I don't do the
Speaker 1: pulmozyme again, but I do the salt on top of that,
Speaker 1: and then I have to take a long acting insulin
Speaker 1: before I go to bed because CF has done such
Speaker 1: damage to my pancreas that it gave me diabetes as well,
Speaker 1: which is fun because people know what diabetes is and
Speaker 1: they will talk about that with you all the time,
Speaker 1: where CF scares them. I think something I earned in
Speaker 1: an old swamp thing comic is there's there's some guy
Speaker 1: can see the future. So I actually don't remember the
Speaker 1: context of it, but I don't think you're supposed to
Speaker 1: know the way you're gonna die. And I like that
Speaker 1: was a very comic booky thing, like, oh I can't
Speaker 1: tell you how you're gonna die, that will change your
Speaker 1: whole life. But that made me think for a long time,
Speaker 1: because for years I was sure I knew how I
Speaker 1: was going to die. And it's become blurrier now, like
Speaker 1: there's i'll give it like an eighty percent chance that
Speaker 1: CF kills me. There's a chance that something else could
Speaker 1: really come in and take the victory from it. But
Speaker 1: it made me incredibly morbid for so long because if
Speaker 1: I did. If I do have a gift or a superpower,
Speaker 1: mine is. For most people, comedy is tragedy plus time.
Speaker 1: I require very little time. I think most things are
Speaker 1: very funny when they happened to me. Obviously, I think
Speaker 1: most things are very funny right immediately, and I think
Speaker 1: I made my family really uncomfortable with that. My grandmother,
Speaker 1: who was wonderful to me for so many years, was
Speaker 1: also one of those grandmothers like, no, you're going to
Speaker 1: be fine, Everything's going to be fine, Like you don't
Speaker 1: know that anything could happen tomorrow. And she'd be like, no,
Speaker 1: you're going to live so much longer than me, Like
Speaker 1: you don't know that. She was right. But for me,
Speaker 1: CF is a thing that I know, and it is
Speaker 1: the thing that I do. It requires little to no
Speaker 1: bravery on my part. I just have to keep waking
Speaker 1: up and doing that. I have no other choice. But
Speaker 1: I think some people don't like to be confronted with
Speaker 1: the idea that, like their body could go into total
Speaker 1: rebellion at any point, as mine constantly is. It's shocking
Speaker 1: for them that I have a job. And again, it's
Speaker 1: not easy, and there's no shame in not having that.
Speaker 1: If you're dealing with CF, but it's shocking for them
Speaker 1: to see someone doing quote unquote normal stuff while again
Speaker 1: body and total rebellion at any given part point. And
Speaker 1: I just think most people don't like to grapple with
Speaker 1: that when it's literally the only thing I want to
Speaker 1: grapple with is how I'm going to die when it's
Speaker 1: going to happen. What's wrong with me?
Speaker 2: Uh?
Speaker 3: I don't know.
Speaker 2: You just heard from Jay Geronomy, who we had the
Speaker 2: most fun talking to this.
Speaker 4: Week, the most fun.
Speaker 2: He is an amazing author, musician, and just all around
Speaker 2: hilarious person, and we have more of his interview later
Speaker 2: in the episode, so do keep your ears out for
Speaker 2: that one.
Speaker 5: Yeah, it was really thrilling to get to talk to him,
Speaker 5: and we can't wait for you to hear even more
Speaker 5: of his story.
Speaker 2: And there's one more thing that you should keep your
Speaker 2: ears out for at the end of the episode, and
Speaker 2: that's a special song written by Jay specifically for this episode.
Speaker 2: It's called Complete Somatic Rebellion, and we'll provide the link
Speaker 2: for download in our show notes. I think it seriously
Speaker 2: might be the coolest thing to happen on this podcast anyway.
Speaker 2: I'm Aaron Welsh.
Speaker 4: And I'm erin allman Updyke.
Speaker 2: And this is this podcast Will Kill You.
Speaker 5: And today we're talking about cystic fibrosis.
Speaker 2: That's right, Yes, this is our first genetic one. Is
Speaker 2: that right?
Speaker 4: Pretty sure?
Speaker 5: I'm pretty sure that it is.
Speaker 2: Yeah, yeah, okay, So what are we drinking this week?
Speaker 5: Our quarantini this week is the Dorothy h Anderson.
Speaker 2: Yes, thus named because there was an amazing researcher named
Speaker 2: Dorothy h Anderson who described I think was one of
Speaker 2: the first people to describe cystic fibrosis and did tremendous
Speaker 2: amounts of research in her life on the condition. What
Speaker 2: is in the Dorothy h Anderson?
Speaker 5: Well, there is pomegranate soda, lime.
Speaker 2: Juice, a splash of ginger ale.
Speaker 5: Tequila always good, and you've got to have it with
Speaker 5: a salted rim And we'll talk about why throughout this episode.
Speaker 2: Perfect Perfect.
Speaker 5: We'll post the recipe for our quarantini as well as
Speaker 5: the placeba Rita, which is our non alcoholic version, on
Speaker 5: our website and all of our social media channels.
Speaker 2: And see, I think we do have a couple of
Speaker 2: bits of business. Yeah, So one thing that I wanted
Speaker 2: to mention is that, hey, we have merch, we have
Speaker 2: T shirts, we do mugs, pins, and guess what we
Speaker 2: have soap.
Speaker 5: We do have soap. I think we did a bad
Speaker 5: job at telling you guys this, but we have soap
Speaker 5: so you can wash your filthy little animal hands.
Speaker 2: Also, the label is the cutest thing you've ever seen.
Speaker 2: It's adorable.
Speaker 5: You can find all of our merch at this podcast
Speaker 5: will kill You dot com if you just click on merch.
Speaker 2: And the other thing is that I saw this on
Speaker 2: Reddit and I just wanted to share this because I
Speaker 2: was I was lurking briefly, even though I haven't been.
Speaker 4: On very much.
Speaker 2: So on the tpwk y subreddity, there was a recent
Speaker 2: post or a post a while back about what people
Speaker 2: wanted to call fans themselves. What do they wanted to
Speaker 2: call themselves? Let me let me pull up some of
Speaker 2: these things. Actually, one of the top ones was filthy
Speaker 2: animals of course perfect. Another one was Vector's Amazing Air
Speaker 2: and Demiologists, Oh my god, air infected.
Speaker 5: Oh I like that.
Speaker 2: I love that extremophiles podcast, Phages, Quarantine Fiends, respiratory Droplets.
Speaker 2: I loved that one that I want.
Speaker 4: A T shirt that says that.
Speaker 2: The Herd, just that the herd is also amazing. So anyway,
Speaker 2: I just wanted to tell you that recently amazing.
Speaker 5: Yeah, this is very fun, but it's really funny. Okay,
Speaker 5: any other business.
Speaker 2: Actually there is one more thing. Oh yeah, this is
Speaker 2: our second to last episode of this season.
Speaker 5: Oh my gosh, it happened so quickly.
Speaker 2: It happens so fast. And before you get alarmed by
Speaker 2: that news, we're only taking a relatively short break. We
Speaker 2: are coming back on October twenty ninth for the premiere
Speaker 2: of our season three, and so subscribe to all of
Speaker 2: our social media, subscribe to our podcast so that you
Speaker 2: see when the new episode drops.
Speaker 5: Yes, and this is second to last. We're not leaving
Speaker 5: you high and dry. We've got another excellent episode coming
Speaker 5: out in two weeks. Yes, okay, that's everything now, I think, so.
Speaker 4: Well, then let's get started.
Speaker 2: Tell me about the biology of cystic fibrosis.
Speaker 5: I can't wait too.
Speaker 2: Okay, good, we'll take one quick break.
Speaker 5: Cystic fibrosis. This is gonna be a fun one because
Speaker 5: we haven't done a genetic disorder before, so we're gonna
Speaker 5: talk a little bit about genetics before we get started
Speaker 5: on anything. And on top of that we get to
Speaker 5: talk about biokim which just for some reason is one
Speaker 5: of my favorite things to do on this.
Speaker 2: Podcast, I guess, so, yeah.
Speaker 4: It's one of my least favorite subjects, okay.
Speaker 5: Cystic fibrosis is an autosomal recessive genetic disorder, and it
Speaker 5: can be caused by actually a number of different mutations
Speaker 5: in a single gene. So it's always the same gene
Speaker 5: that gets messed up somehow, but there's a lot of
Speaker 5: different ways in which the gene can be mutated that
Speaker 5: end up resulting in slightly different presentations of this disease
Speaker 5: or disorder. So first let's define the words autosomal recessive,
Speaker 5: because some people might have never heard that. That basically
Speaker 5: means that you have to have two copies of this
Speaker 5: gene that are mutated in some way in order to
Speaker 5: actually have symptoms of this disease. So if you have
Speaker 5: just one mutation, you're what's called a carrier, but you
Speaker 5: pretty much won't have any symptoms or be sick or
Speaker 5: have cystic fibrosis. You have to have two copies of
Speaker 5: the gene, and so that's what autosomal recessive means in
Speaker 5: this case. Cool cool, and autosomal just means that it's
Speaker 5: not in the X or Y chromosome. It's in any
Speaker 5: of the other chromosomes, right. Okay, So the gene that
Speaker 5: is mutated in cystic fibrosis is called the CFTR very
Speaker 5: creative cystic fibrosis transmembrane conductance regulator gene. Okay, it's the
Speaker 5: cystic fibrosis gene.
Speaker 1: Right.
Speaker 5: This is a gene that codes for proteins that form
Speaker 5: channels through which ions pass. So this is where we're
Speaker 5: going to go a little bit biokim genetics course over
Speaker 5: biokim course beginning.
Speaker 2: Okay, here we go.
Speaker 5: I'm not gonna get super into detail. I never do
Speaker 5: because it's not my strong suit, and because we'd be
Speaker 5: here all day and there's a lot more interesting things
Speaker 5: than just the biochemistry of this disorder. So what you
Speaker 5: need to know to understand why cystic fibrosis is such
Speaker 5: a big deal is that your body is made up
Speaker 5: of cells. Cells are just bags of water and electrolytes
Speaker 5: which are floating in a matrix of water and electrolytes.
Speaker 4: Okay, mm hm cool.
Speaker 5: We're bags of water, tiny little bags of water floating
Speaker 5: in water, and the linings of our cells are called
Speaker 5: plasma membranes. They're like the plastic of the water balloon
Speaker 5: that holds the water inside the cells. And these membranes
Speaker 5: only let certain things pass through them. Okay, they're selectively permeable,
Speaker 5: and a lot of the ways in which things pass
Speaker 5: through this water balloon membrane is through channels and pores,
Speaker 5: and it's proteins that make up these channels and pores
Speaker 5: in the membrane.
Speaker 2: Cool.
Speaker 5: Yeah, Okay. So the CFTR gene codes for a protein
Speaker 5: that forms a channel that, when it is normal, sits
Speaker 5: in this membrane across the membrane and allows four ions
Speaker 5: to pass across it.
Speaker 4: Right.
Speaker 5: Okay, that's your biocm course. Okay, Okay, So if you
Speaker 5: have a messed up version of this protein in some way,
Speaker 5: then you're not going to be able to properly control
Speaker 5: what is going in and coming out of cells. Okay, okay.
Speaker 5: So the cystic fibrosis protein normally allows for the passage
Speaker 5: of chloride that's the other half of sodium chloride, and
Speaker 5: also bicarbonate HC three minus, and by allowing these ions
Speaker 5: to pass through, it also indirectly regulates other ions like sodium.
Speaker 2: Right.
Speaker 5: So because once you change the balance of one ion,
Speaker 5: you affect a whole bunch of other ions as well, essentially,
Speaker 5: if that makes sense. So what ends up happening is
Speaker 5: just dysregulation. You get messed up movement of sodium, chloride,
Speaker 5: and bicarbonate, all three of those across the membrane, Okay,
Speaker 5: and that's how you end up with all of the
Speaker 5: problems that we see in cystic fibrosis.
Speaker 2: So can you elaborate a bit on what it means
Speaker 2: by messed up movement or dysregulation of those ions.
Speaker 5: Let's do that by talking about some of the different
Speaker 5: mutations that you can have, and that will I think
Speaker 5: answer that question a little bit. So there's a number
Speaker 5: of different genotypes or different mutations that can lead to
Speaker 5: cystic fibrosis. They all result in this protein being messed
Speaker 5: up in some way. In one, you have a mutation
Speaker 5: that leads to defective protein production, so your protein is
Speaker 5: either too short or too long or got cut off.
Speaker 5: So basically you don't have an actual protein being placed
Speaker 5: in this membrane, so that.
Speaker 2: It's the one that's making up the poor or the
Speaker 2: channel exactly.
Speaker 5: So you don't have a poor or a channel being
Speaker 5: formed at all, which means you don't have any movement
Speaker 5: of chloride or bicarb across that membrane.
Speaker 2: Nothing goes in, nothing comes out exactly.
Speaker 5: Okay, So that's one potential mutation Class one mutation. Another
Speaker 5: one is a defect in processing of the protein. So
Speaker 5: you're making this protein which is supposed to form a channel,
Speaker 5: but for some reason it gets stuck inside of the
Speaker 5: cell and it can't actually make it to the plasma membrane.
Speaker 5: So you make the protein, but it doesn't actually make
Speaker 5: the channel. Does that make sense? Okay, Yeah, So it
Speaker 5: ends up looking pretty much the same as the first mutation, right,
Speaker 5: no pore in the membrane for ions to pass through.
Speaker 5: So that's a class two mutation. Then there are a
Speaker 5: number of other mutations that can result in a protein
Speaker 5: that is made. So you make the protein, the protein
Speaker 5: forms a channel and makes it to the cell surface,
Speaker 5: but it doesn't respond the way that it is supposed
Speaker 5: to to certain stimuli. So these are class three and
Speaker 5: class four mutations, and we're not going to get into
Speaker 5: the nitty gritty of them, but it basically just means
Speaker 5: that you have an ion channel that's there, but it
Speaker 5: doesn't open when it's supposed to say, let chloride ions out,
Speaker 5: or it doesn't close when it's supposed to stop chloride
Speaker 5: ions from leaving. So you have movement of ions, but
Speaker 5: not at the right time or at the right rate.
Speaker 5: Does that make sense?
Speaker 2: Yeah, And so there's an association with these types of
Speaker 2: mutations or these classes of mutations and the severity of symptoms.
Speaker 5: Absolutely, you can imagine that if you're not making any
Speaker 5: of this protein, you're probably going to have more severe
Speaker 5: manifestations of disease than if you make some of this protein.
Speaker 5: It just doesn't quite work properly.
Speaker 4: M Okay, that makes sense.
Speaker 5: And then right, and then there's another a couple classes
Speaker 5: of mutation, class five and six mutations where you make
Speaker 5: the protein it mostly functions normally, you just don't make
Speaker 5: quite enough of it, and so those might be the
Speaker 5: least sort of severe manifestations.
Speaker 2: And so I remember reading that there are around one
Speaker 2: thousand different mutations that I guess are grouped into these
Speaker 2: different classes. Do you happen to know the distribution of
Speaker 2: I know that there's one that's very that's like the
Speaker 2: most common, but what is the class distribution?
Speaker 5: I guess, so the most common is a class two mutation.
Speaker 2: Okay, that's the The.
Speaker 5: F five to oh eight mutation is class two mutation.
Speaker 5: So that's a problem where you make the protein, but
Speaker 5: it doesn't get trafficked to the surface properly, so it's
Speaker 5: not actually.
Speaker 4: Doing its function.
Speaker 5: Other than that, I'm not sure how common the other
Speaker 5: classes are. There are I think multiple thousands of mutations.
Speaker 5: It's it's bananas how many different mutations there are in
Speaker 5: this gene. Okay, So you can imagine that with all
Speaker 5: of these different ranges of mutations all affecting the same protein,
Speaker 5: you can end up with a pretty wide range of manifestations.
Speaker 5: So let's talk about some of the symptoms.
Speaker 4: Okay, yeah, okay, So.
Speaker 5: As a recap, you have a malfunctioning protein in some
Speaker 5: way that leads to abnormal movement of sodium chloride and
Speaker 5: bicarbonate across cell membranes.
Speaker 4: Okay.
Speaker 5: So this channel protein, the CFTR protein, is found in
Speaker 5: a whole bunch of different organs and tissues. It's not
Speaker 5: just in one place in your body. It's most highly
Speaker 5: expressed in glandular epithelia.
Speaker 4: Fun Okay, tell me what that is.
Speaker 5: It means in a few specific organs that have glands.
Speaker 5: So your lungs, you're pancreous, you're intestine, your sweat glands,
Speaker 5: and your reproductive tract. Okay, so you tell me where
Speaker 5: do you think we're going to see symptoms of this disorder.
Speaker 2: I'm guessing it's in all of those places that you're listed.
Speaker 5: Oh my gosh, you're so correct about that. Okay, So yeah, lungs, pancreous, intestines,
Speaker 5: those are the biggest ones. Reproductive tract as well, sweat glands.
Speaker 5: We don't have to talk about it unless you want
Speaker 5: to you later, ok kind of do but okay, whatever,
Speaker 5: we'll get in to it, Okay, Okay. The truth is,
Speaker 5: despite all that we know about how these mutations affect
Speaker 5: the CFTR proteins, we don't fully understand how this leads
Speaker 5: to the specific disease manifestations that we see. There's a
Speaker 5: lot of different theories, and we'll talk about some of
Speaker 5: the possibilities, but the main cause of morbidity and mortality. So,
Speaker 5: the main cause of illness and sort of suffering in
Speaker 5: people with cystic fibrosis is airway symptoms. So when cystic
Speaker 5: fibrosis affects your lungs, right, Okay, So we'll start with
Speaker 5: the lungs then, and then we'll go kind of organ
Speaker 5: by organ. Okay, in your lungs, if you have a
Speaker 5: messed up CF protein, then you're gonna have less chloride
Speaker 5: and bicarb being secreted out of your cells and into
Speaker 5: the space in between.
Speaker 2: Your cells, the negatively charged ions.
Speaker 5: The negatively charged ions. This leads to less water being
Speaker 5: secreted onto the surface of your airway, so that means
Speaker 5: that your airway ends up not being very well hydrated. Okay,
Speaker 5: So this can lead to difficulties in the transport and
Speaker 5: defense mechanisms that your lungs normally have. So it can
Speaker 5: lead to super thick mucus being produced less watery mucus
Speaker 5: that's more viscous. That can lead to obstructive airways.
Speaker 2: So if you have if you do not have one
Speaker 2: of these mutations, how does that ion transport prevent the
Speaker 2: adherence of pathogens or why is watery mucus more important?
Speaker 4: Yeah?
Speaker 5: So watery mucus is important because it first of all,
Speaker 5: just protects the lining of your cells to begin with,
Speaker 5: so that they don't get dried out or anything by
Speaker 5: the air and things like that. But it also you
Speaker 5: have something in your lungs called the mucociliary escalator, which
Speaker 5: I think is an adorable.
Speaker 4: Name, escalator, that's very cool.
Speaker 5: Yes, it's a combination of the mucus that your cells
Speaker 5: produce and ccilia, which are those little hair like protrusions
Speaker 5: that we've talked about before. And the combination of this
Speaker 5: mucus and the ccilia helps to sweep anything that you
Speaker 5: inhale into the bottom of your lungs up and out
Speaker 5: of your lungs. Okay, So if you've got a bunch
Speaker 5: of thick, non watery mucus, then it really impairs this
Speaker 5: mucosciliary transport and it leads to obstruction of airways.
Speaker 2: Okay, So it doesn't just slow down the escalator, it
Speaker 2: like it turns it into a stairway.
Speaker 5: And says, yeah, not even a stairway, it's.
Speaker 4: Just a gate in front of it.
Speaker 2: Yeah, okay, just a straight up cliff. Right.
Speaker 5: So this can directly obstruct the airways, but on top
Speaker 5: of that, it can also lead to chronic infections. You're
Speaker 5: at much higher risk for bacterial infections because you can't
Speaker 5: clear anything that comes into your lungs out right. So
Speaker 5: it's a twofold process where you have thick mucus that
Speaker 5: you're producing directly blocking your airways, and on top of that,
Speaker 5: you have infections that come in that you're unable to
Speaker 5: fight off. Okay, on top of that, the cystic fibrosis
Speaker 5: protein has a role in helping to regulate inflammation through
Speaker 5: some other effects that it has on electrolyte transport, So
Speaker 5: you can end up with excess inflammation coming into your
Speaker 5: lungs to try and help fight off infection, which can
Speaker 5: actually further block your airways. So it's just basically kind
Speaker 5: of a mess in the lungs when you have this
Speaker 5: protein not working properly. Yeah, And honestly, it's kind of
Speaker 5: the same thing that happens in other organs. So in
Speaker 5: your gut, in your intestines, you secrete a lot of
Speaker 5: mucus in your intestines as well, and it's the same thing.
Speaker 5: If you end up secreting really thick mucus instead of nice, clean,
Speaker 5: watery mucus, you can blocked ducts in the same way
Speaker 5: that you block the airways in your lungs, but in
Speaker 5: your guts in your intestine, that's gonna impair the cilia
Speaker 5: that are also there from absorbing a lot of nutrients,
Speaker 5: so you can actually end up getting malnutrition and things
Speaker 5: like that. On top of that, it can lead to
Speaker 5: things like gastro esophageal reflux, acid reflux essentially, and impaired
Speaker 5: bowel transit. So things aren't moving along your gut the
Speaker 5: way that they're supposed to because ducts are blocked kind
Speaker 5: of the whole way along. So in really small babies especially,
Speaker 5: this can end up leading to intestinal obstruction on top
Speaker 5: of the malabsorption that you might be having. Okay, so
Speaker 5: that's in your lungs and then in your guts, and
Speaker 5: then we have your pancreas, which, for those who might
Speaker 5: not remember, is a very important organ that secretes a
Speaker 5: whole bunch of enzymes that are important in digestion. And
Speaker 5: it's a very glandular organ.
Speaker 2: It's verylandy.
Speaker 5: It's very glandy. Yeah, it's made of a bunch of glands.
Speaker 2: What's an example of a non glandy organ.
Speaker 4: Your heart?
Speaker 2: Okay, it's a muscle, your heart, Okay, not doing a
Speaker 2: lot of secreting.
Speaker 5: No, no, okay, okay, So if you can't secrete these
Speaker 5: these enzymes that normally do digestion, then you're not going
Speaker 5: to be able to digest your food properly, essentially, and
Speaker 5: so that's exactly what happens in cystic fibrosis. Instead of
Speaker 5: being able to properly secrete these enzymes, your pancreas is
Speaker 5: secreting thick, gunky stuff because the electrolytes and water are
Speaker 5: not balanced correctly. And this means that not only can
Speaker 5: you not properly digest foods, you end up not being
Speaker 5: able to absorb really important things like fat soluble vitamins,
Speaker 5: because the pancreatic enzymes are really really important in fat
Speaker 5: digestion especially, and fat digestion is important in being able
Speaker 5: to absorb fat soluble vitamins.
Speaker 2: Right, So it's not just that your intestines aren't able
Speaker 2: to absorb, it's also that the pancreas is not even
Speaker 2: able to help you break down what you need to
Speaker 2: in the first place, exactly right.
Speaker 5: And you might also remember that your pancreas secretes other
Speaker 5: important things like insulin.
Speaker 4: Yeah, so if the ducts in your.
Speaker 5: Pancreas get plugged up and aren't able to secrete insulin,
Speaker 5: then you can end up getting diabetes. And that's actually
Speaker 5: a really important aspect of cystic fibrosis that I feel
Speaker 5: like is maybe sometimes overlooked, at least just in common parlance.
Speaker 5: I think most people think about the lungs when they
Speaker 5: think about cystic fibrosis, But the development of diabetes is
Speaker 5: a really serious complication as well. Diabetes basically is just
Speaker 5: not enough insulin in your body, and if you don't
Speaker 5: have enough insulin, then you can't properly regulate glucose or sugar,
Speaker 5: so then you could end up having really really high
Speaker 5: blood sugars and then that.
Speaker 2: Can kill you.
Speaker 5: Okay, So in cystic fibrosis, what diabetes look like is
Speaker 5: a lack of insulin because you're not able to secrete it.
Speaker 5: So there's a number of different ways that you can
Speaker 5: get diabetes. Similar things blocking ducts, et cetera can happen
Speaker 5: in your liver getting plugged up with mucus. This can
Speaker 5: end up leading to things like gallstones or stenosis. It
Speaker 5: can lead to cirrhosis, which is liver failure essentially. In
Speaker 5: people with uteruses and ovaries, you can end up getting
Speaker 5: delayed menarch which is your first period. And in people
Speaker 5: with testicles, it's really common actually to have an absence
Speaker 5: of the vast deference and that's the duct that normally
Speaker 5: carries sperm away from the testes, so that means infertility.
Speaker 5: So that's a lot, and honestly, that's not even all
Speaker 5: of it. Because while this protein is most highly expressed
Speaker 5: in those type of glandular tissues, it's expressed in a
Speaker 5: lot of other tissues as well. And so cystic fibrosis
Speaker 5: can end up affecting your bones, which can increase the
Speaker 5: risk of fractures, It can increase your risk for anemia,
Speaker 5: kidney stones, chronic kidney disease. The list kind of goes on.
Speaker 5: It's pretty serious, and it kind of it's a whole
Speaker 5: body situation.
Speaker 2: So, because this is a genetic disorder, the onset of
Speaker 2: symptoms is very very early. So what would that typically
Speaker 2: look like in an infant? I assume I.
Speaker 5: Just love when you ask questions. That are the thing
Speaker 5: I want to answer.
Speaker 1: Next.
Speaker 2: We did not rehearse this, No, we did not.
Speaker 5: Okay, So the next thing I want to talk about
Speaker 5: is how we diagnose, how we recognize cystic fibrosis.
Speaker 2: Okay, snap, excellent.
Speaker 5: So with cystic fibrosis, overall, you have thickened secretions and
Speaker 5: a bunch of your organs, lung pink or silver blah
Speaker 5: blah blah. One of the ways that we actually can
Speaker 5: diagnose it is that you also end up with increased
Speaker 5: amount of salt in your sweat, right, okay, Right, So
Speaker 5: that's one of the ways that we can actually diagnose
Speaker 5: cystic fibrosis. And nowadays in the United States, in much
Speaker 5: of Europe, Australia, Canada, we actually do a newborn screen
Speaker 5: to test for cystic fibrosis. Because it is such a
Speaker 5: serious disease, such a serious disorder, we test for it.
Speaker 5: Pretty much every single newborn that is born in a
Speaker 5: hospital gets a little heel prick and we can test
Speaker 5: for cystic fibrosis gene mutations. You also could do it
Speaker 5: by testing sweat conductance. Essentially need test to see how
Speaker 5: salty their sweat is, which I think is just so
Speaker 5: interesting and cool that.
Speaker 4: We can do that.
Speaker 2: Well, it's it's ingenious, yeah, yeah.
Speaker 5: And what's really great is that if you detect it
Speaker 5: in newborn, then you don't have to wait until these
Speaker 5: symptoms manifest to be able to start potentially treatment or
Speaker 5: at least preventative measures and things like that. Right, But
Speaker 5: if cystic fibrosis is not diagnosed by the newborn helstick.
Speaker 5: Then it's often diagnosed in childhood, either because someone keeps
Speaker 5: coming down with recurrent respiratory infections or just has chronic
Speaker 5: respiratory symptoms, so we're talking chronic cough signs of obstructive
Speaker 5: disease that we can see when we do X rays,
Speaker 5: so their lungs will look like they're obstructed when we
Speaker 5: look at an X ray, Or you can do pulmonary
Speaker 5: function tests, but on a baby that's pretty difficult because
Speaker 5: you have to be like now inhale and exhale, and
Speaker 5: babies don't know those words.
Speaker 2: Then it would it also be seen in like nutritional
Speaker 2: like would it be obvious in terms of malnutrition?
Speaker 5: Yeah, so on if you on top of the respiratory
Speaker 5: and sinus symptoms, you can also sometimes get very commonly,
Speaker 5: or used to be more common in very young infants,
Speaker 5: something called maconium ilius, which is obstruction of the bowels
Speaker 5: by a mucus plug. Or it can manifest at first
Speaker 5: with pancreatic disease, which is basically what you said, where
Speaker 5: you have malnutrition and malabsorption, and then the child would
Speaker 5: present with what they call failure to thrive, so they're
Speaker 5: not growing properly, etc. Because they're not able to absorb
Speaker 5: the nutrients that they're eating.
Speaker 2: And so is this something where again, if you're in
Speaker 2: a place where it is not standard to do the
Speaker 2: heel prick test, that again the type of mutation you
Speaker 2: have might influence when those symptoms emerge.
Speaker 5: Absolutely, because it's also very possible that someone isn't diagnosed
Speaker 5: until adulthood, especially if they have a mutation that doesn't
Speaker 5: result in a complete lack of the protein but is
Speaker 5: just one of these disregulated proteins or a lowered amount
Speaker 5: of a relatively normal protein. So in those people in
Speaker 5: adults who are diagnosed with cystic fibrosis, they're more likely
Speaker 5: to present with GI symptoms, so just general like GI distress,
Speaker 5: maybe diarrhea, maybe really smelly or fatty stools. Diabetes is
Speaker 5: a common presentation of cystic fibrosis in adults because of
Speaker 5: that pancreatic dysfunction, or they might not even be diagnosed
Speaker 5: until they try to have a baby and they're found
Speaker 5: to have infertility or lowered fertility, especially for people with
Speaker 5: testes that would normally be making sperm, and they're found
Speaker 5: to have what's called azospermia, which means no sperm. Yeah,
Speaker 5: So if a person has these kinds of symptoms, maybe
Speaker 5: these GI symptoms, maybe new onset diabetes or chronic respiratory illness,
Speaker 5: then you might start to suspect maybe this person has
Speaker 5: a cystic fibrosis mutation. So that's when you get to
Speaker 5: do the sweat test.
Speaker 2: Aha.
Speaker 5: You also, if that test is negative or for some reason,
Speaker 5: if you can't do it, you can do what's called
Speaker 5: a trans epithelial nasal potential test, oh, which means sticking
Speaker 5: to probes in your nose and testing for the electrical
Speaker 5: potential because yeah, yeah, right, that's so cool. Yeah, And
Speaker 5: then you especially if those tests are positive. But even
Speaker 5: if they're not, and you still suspect maybe there's something
Speaker 5: going on here, then you would do genetic screening mm hmm.
Speaker 5: And one of the reasons that newborn screening and genetic
Speaker 5: screening in general is really common these days is that
Speaker 5: there are a lot of new treatments available that we'll
Speaker 5: talk about in the current events section that are specific
Speaker 5: to the types of mutations that we see in cystic fibrosis.
Speaker 5: So that means that they'll work for people with certain mutations,
Speaker 5: but they won't work for people with other mutations. So
Speaker 5: knowing exactly what cystic fibrosis mutation you have is important
Speaker 5: in determining the course of treatment.
Speaker 4: That makes sense.
Speaker 5: So yeah, that's it. Oh, that's the biology of cystic fibrosis. Okay,
Speaker 5: So tell me erin. What do we know about cystic
Speaker 5: fibrosis and how did it come to be?
Speaker 2: Oh? Well, okay, big question here, here we go.
Speaker 5: Let's take one quick break first.
Speaker 2: Cystic fibrosis is an ancient disease, which you might have guessed.
Speaker 2: But how do we know this? Okay, Well, we know
Speaker 2: this for a couple different reasons. One is that it
Speaker 2: has left traces in old European folklore. So there's this old,
Speaker 2: commonly quoted prophecy of quote, woe to the child who
Speaker 2: tastes salty from a kiss on the brow, for he
Speaker 2: is cursed and soon must die.
Speaker 5: No way, yes, are you serious?
Speaker 2: Yeah? So that's like an old prophecy that's been found
Speaker 2: in several different old several different things, like an old
Speaker 2: Swiss German dictionary. It was in an old Swiss almanac
Speaker 2: of children's songs and games.
Speaker 5: That is so interesting.
Speaker 2: Yeah, and we also know that cystic fibrosis is old
Speaker 2: because there was this description of an autopsy of a
Speaker 2: quote bewitched eleven year old girl done in fifteen ninety five,
Speaker 2: and her pancreas was described to be swollen, hardened, gleaming.
Speaker 4: And white.
Speaker 2: Ooh, so that's a pretty telltale sign of cystic fibrosis
Speaker 2: as well. Okay, so those are traces, those are written traces, right.
Speaker 2: The real smoking gun of cystic fibrosis is ancient origins.
Speaker 2: I don't know. There are lots of how it lies
Speaker 2: in our genes. Okay. So, as you mentioned, this condition
Speaker 2: is caused by having a mutation on the CFTR gene,
Speaker 2: and tracing the geographic patterns of that mutation and of
Speaker 2: variations in that mutation or the types of mutations can
Speaker 2: tell us a lot about where and when the mutation
Speaker 2: probably first appeared. I love it. Yes, it was an
Speaker 2: interesting opportunity to dive into some of the evolutionary genetics,
Speaker 2: which I don't not in my wheelhouse whatsoever, but very fun,
Speaker 2: very interesting. Bear with me here we go. For a
Speaker 2: long time, despite the widespread prevalence of this mutation, researchers
Speaker 2: had a really tough time pinning down exactly where it
Speaker 2: began and how it spread. So if you look at
Speaker 2: research from the early two thousands, they're like, Okay, so
Speaker 2: the mutation probably originated anywhere between three thousand years ago
Speaker 2: to fifty two thousand years ago. It's a you know,
Speaker 2: pretty big range. Yeah, and the geographic origin was even
Speaker 2: trickier to nail down. Ancient DNA analysis of skeletons from
Speaker 2: as early as seven hundred BCE did find the presence
Speaker 2: of the mutation in some samples, which is amazing. It's
Speaker 2: I can't yeah, very fascinating, but that still left so
Speaker 2: many questions unanswered until last year. I found a recent
Speaker 2: study published in twenty eighteen that claims to have resolved
Speaker 2: some of these long standing controversies about the origin of
Speaker 2: cystic fibrosis. Okay, so these what these researchers did is
Speaker 2: that they took DNA samples from people of European ancestry
Speaker 2: with cystic fibrosis, and then they tried to get a
Speaker 2: wide geographic range of people spanning from all over Europe.
Speaker 2: Then they could compare their DNA sequences to see when
Speaker 2: the mutation is likely emerged, overlay that with geographic information
Speaker 2: that they had collected, and basically they could make this
Speaker 2: geographic timeline of the origin and spread of the CF mutation.
Speaker 5: Just one of the mutations or multiples.
Speaker 2: So this is just the most common one, Okay, so
Speaker 2: this is let me find out what the number is.
Speaker 2: Delta F five oh eight is the one, yeah, so yeah,
Speaker 2: and so this is the one that's that's the most
Speaker 2: the most prevalent, yeah, in the population. So it turns
Speaker 2: out that after they did this, their most likely scenario
Speaker 2: is that the mutation, this delta F five oh eight
Speaker 2: first emerged around twenty seven hundred BCE, which is apparently
Speaker 2: the Bronze Age. Haven't really learned what that is yet.
Speaker 4: How am I to do this age?
Speaker 2: Yes, I imagine the jewelry is fantastic in small settlements
Speaker 2: living along the Atlantic and western Europe, probably France or Portugal.
Speaker 4: Huh okay.
Speaker 2: But then what they did was they teamed up with
Speaker 2: some archaeologists to look at human movement patterns during that
Speaker 2: time to see if they could find anything that would
Speaker 2: account for the relatively rapid spread of the mutation throughout
Speaker 2: Europe following this early first appearance, and they found that
Speaker 2: there was a group called the bell Beaker people that
Speaker 2: were known for their extensive migrations and cultural exchanges. Basically,
Speaker 2: what they would do is move throughout the entirety of
Speaker 2: Western Europe over a thousand years and mary or have
Speaker 2: children with the people that they like as as they travel.
Speaker 4: They traveled, Yeah, just like leaving babies in their wake.
Speaker 2: Well, I don't know how many generations, or maybe it
Speaker 2: was like, yeah, maybe we'll be like, Okay, this time,
Speaker 2: we'll stay here, and then the next our kids will
Speaker 2: move to the next village and the next village and
Speaker 2: someone and someone fascinating. Yeah, So I think it's really
Speaker 2: cool that these geneticists teamed up with these archaeologists and
Speaker 2: anthropologists to say, Okay, what's what's happening here? Yeah? Okay,
Speaker 2: but why is it important to understand where and when
Speaker 2: the cystic fibrosis mutation comes from?
Speaker 1: Yeah?
Speaker 4: Why should we care?
Speaker 2: Why should we care? That's always a good question to
Speaker 2: ask about anything that you're learning. Right. The first reason
Speaker 2: why we should care it can This can be applied
Speaker 2: to any disease. So the more we know about a
Speaker 2: disease and how it spreads in a population or where
Speaker 2: it comes from, the better chance we have of controlling
Speaker 2: or curing it. And the second reason is that in
Speaker 2: the case of cystic fibrosis. Understanding where the mutation came
Speaker 2: from can give us clues as to why it exists
Speaker 2: at such high frequencies, because, as we know, when you
Speaker 2: have two copies of this mutation, it is often sadly fatal,
Speaker 2: and it would have been especially more so in the
Speaker 2: time before modern medicine. Right, But this is one of
Speaker 2: the most, if not the most common mutations of people
Speaker 2: of European descent, with about one in twenty five people
Speaker 2: carrying one copy of the mutation of any of these mutations.
Speaker 2: So why was it not selected out of the population?
Speaker 2: Why does it still exist? Basically because usually when we
Speaker 2: see a lethal mutation with a high frequency, it's a
Speaker 2: clue that it's doing something beneficial as well, like as
Speaker 2: we saw in the case with sickle cell anemia protecting
Speaker 2: against malaria.
Speaker 5: Heterozygote advantage.
Speaker 2: There we go, Yeah, so this heads I get advantage. Basically,
Speaker 2: people who carry one copy of the mutation would benefit
Speaker 2: from the protection that that mutation offers while not being
Speaker 2: negatively affected by the presence of two copies of the mutation.
Speaker 2: And so that's what researchers think might be going on
Speaker 2: with the cystic fibrosis mutation. So what are some of
Speaker 2: these hypotheses, right?
Speaker 5: I love it.
Speaker 2: Typically a lot of people immediately go to infectious diseases
Speaker 2: because that was such an important thing to protect against
Speaker 2: in times before modern medicine, antibiotics, et cetera, et cetera.
Speaker 2: So some of these things hypotheses include cholera, typhoid, diarrhea
Speaker 2: with associated with lactose consumption, or tuberculosis. So the idea
Speaker 2: is that one copy of this CFTR mutation would protect
Speaker 2: against those diseases. And there seems to be some physiological
Speaker 2: support for this or for at least some of these diseases,
Speaker 2: like the choleratoxin requires normal CFTR proteins to cause disease,
Speaker 2: for example, but it's still not it's a little bit
Speaker 2: hand wavy, so other things don't quite add up. So
Speaker 2: in the case of cholera, cholera has occurred at much
Speaker 2: higher frequencies in tropical areas compared to Europe, but the
Speaker 2: rate of the cystic fibrosis mutation is not correspondingly high there. Yeah,
Speaker 2: and same goes for typhoid, and no studies have confirmed
Speaker 2: that people with assistic fibrosis mutation are more resistant to
Speaker 2: any of these diseases, because that would be a horribly
Speaker 2: unethical study.
Speaker 5: Yeah, it's just theoretically based on the channels and in
Speaker 5: some mouse models it's right too cold water, get it?
Speaker 2: Yeah yeah, huh wow, that.
Speaker 4: Was funny actually, And.
Speaker 2: So it could be that the mutation has a benefit
Speaker 2: other than protecting against an infectious disease, or could be
Speaker 2: that it protected against the disease that is no longer
Speaker 2: known to us. Oh, I mean, we don't know. In
Speaker 2: any case, this part of the story of cystic fibrosis
Speaker 2: is still seems like it's still being written. Yeah, okay,
Speaker 2: quick recap. So the cistic fibrosis mutation probably originated around
Speaker 2: twenty seven hundred BCE in Portugal or France and rapidly
Speaker 2: spread throughout the rest of Europe. Okay, okay. We have
Speaker 2: these mentions in folklore and a few little anecdotal reports
Speaker 2: throughout the seventeen hundreds and eighteen hundreds, but it's not
Speaker 2: until the late nineteen thirties that we get an official
Speaker 2: description of cystic fibrosis.
Speaker 5: Nineteen thirties, even though way back in the forever they
Speaker 5: were talking about salty kids.
Speaker 2: Salty kids. Yeah wow, Yeah, And I mean, I think
Speaker 2: part of this is because it does affect people differently
Speaker 2: and a lot of different organs in very different ways,
Speaker 2: and it's hard to it's hard to tie the things together,
Speaker 2: I think. Yeah, until so then we have this the
Speaker 2: namesake of our quarantine, this episode, Dorothy Anderson. All right,
Speaker 2: so let me tell you a little bit about doctor Anderson.
Speaker 4: Tell me all about her, because I did.
Speaker 2: A little deep dive into her biography and it was
Speaker 2: it's just cool, all right. So she was born in
Speaker 2: nineteen oh one in Asheville, North Carolina, which is an
Speaker 2: amazing place. Yep, I love it. Dorothy was fascinated by
Speaker 2: science and medicine, and she went to get her bachelor's
Speaker 2: in zoology and chemistry and then her MD, and she
Speaker 2: did all this by the time she was twenty five.
Speaker 5: What Dorothy killing me?
Speaker 2: She worked incredibly hard to support herself, having lost both
Speaker 2: of her parents before starting college, and it seemed like
Speaker 2: she was well on her way to becoming a surgeon.
Speaker 2: She was doing an internship and everything, and then she
Speaker 2: tried to do her residency at this particular hospital and
Speaker 2: was denied because she was a woman. That was the reason. Yeah,
Speaker 2: very frustrating.
Speaker 5: Was she like, mm, watch me go.
Speaker 2: She was like, all right, fine, I'll do research. And
Speaker 2: she got her PhD in ender chronology, like you do.
Speaker 2: It was just no problem.
Speaker 4: So, oh my gosh.
Speaker 2: She did eventually work as a pathologist and pediatrician at
Speaker 2: the baby's hospital at the Columbia Presbyterian Medical Center. Wow.
Speaker 2: So and it was there that she noticed in one
Speaker 2: child that had died of Celiac disease, that there was
Speaker 2: this fibrosis of the pancreas, which was not something that
Speaker 2: she had seen in other babies with Celiac. So she
Speaker 2: wrote up her finding with this full description of the condition,
Speaker 2: and she named this disorder cystic fibrosis of the pancreas. Oh,
Speaker 2: that's how it got its name.
Speaker 4: Wow.
Speaker 2: And so that happened in nineteen thirty eight. And that's
Speaker 2: that naming of it, that description, even though it had
Speaker 2: been mentioned in medical texts earlier in that century, that
Speaker 2: was the description that put it on the map, that
Speaker 2: started people to do research on it. And also a
Speaker 2: big reason is because this is what she did. For
Speaker 2: the rest of her career. She worked on cystic fibrosis.
Speaker 2: She made these amazing observations that led to the development
Speaker 2: of the diagnostic sweat test. Wow. And she also hypothesized
Speaker 2: that it was an autosomal recessive disorder.
Speaker 4: Wow.
Speaker 2: Yeah.
Speaker 5: I never thought about where it got the name cystic
Speaker 5: fibrosis specifically, And it's so interesting that it's from that
Speaker 5: she saw someone and it was a pancreatic disease, Like
Speaker 5: that's where she saw it and that's where she diagnosed it,
Speaker 5: when today we mostly think about lung issues.
Speaker 4: That's so interesting.
Speaker 2: Well, it's really interesting, and I think a lot of
Speaker 2: people felt later on that it was a misnomer and
Speaker 2: there was like a question of should we change this name,
Speaker 2: should we call it something else? And I mean, at
Speaker 2: a certain point changing the name is just going to
Speaker 2: lead to more confusion. So but it's yeah, so that's
Speaker 2: that's the origin of the name.
Speaker 4: Oh wow.
Speaker 2: Yeah. And so okay, before I move on to the
Speaker 2: rest of the history of this fibrosis, I just want
Speaker 2: to tell you a little bit more about how awesome
Speaker 2: doctor Anderson was because I again my deep dive, so
Speaker 2: she was incredibly meticulous and insightful in her research, and
Speaker 2: she contributed so much to the field of medicine. Besides
Speaker 2: the work that she did on cystic fibrosis, especially in
Speaker 2: things like cardiac medicine, and throughout her entire she's just
Speaker 2: a huge inspiration because throughout her entire career she faced
Speaker 2: a ton of resistance getting criticized or ridiculed by her
Speaker 2: colleagues because of her unkempt appearance or her unladylike hobbies.
Speaker 2: Because she loved to woodwork and hike and live in
Speaker 2: the woods and have these amazing parties. She was a Stonemason,
Speaker 2: she championed women's rights. She's so cool.
Speaker 4: Yeah, how ba.
Speaker 2: But she also had a ton of loyal supporters and
Speaker 2: friends who who just loved her and would always talk
Speaker 2: about how generous and kind she was.
Speaker 5: So and now she has a quarantine named after her.
Speaker 2: Yes, thank you, doctor Anderson. Okay, So back to cystic fibrosis. So,
Speaker 2: research advancements didn't start immediately after doctor Anderson's publication in
Speaker 2: nineteen thirty eight. And that's a big part of that
Speaker 2: is because of World War Two, a lot of medical
Speaker 2: research started to focus on not focus on war wounds, bioweapons.
Speaker 2: Now who knows, I don't know. Yeah, And during this
Speaker 2: time also, case descriptions were the most common reported thing.
Speaker 2: It was just building this recognition of this is what
Speaker 2: this person had, this is their case history, et cetera.
Speaker 2: And it was during these writing up these case descriptions
Speaker 2: that people started to recognize the familial nature of the disease,
Speaker 2: but researchers still didn't know how like the exact mechanism
Speaker 2: of autosomal recessive disorders.
Speaker 4: Question.
Speaker 2: Yeah, when was Mendel doing his thing with peas eighteen sixties?
Speaker 5: Okay, so people knew, like a little bit knew.
Speaker 2: Yeah, So, like the concept of trait dominance had existed
Speaker 2: for a very long time, but it was figuring out
Speaker 2: the location of the mutation that was a long ways away,
Speaker 2: and understanding the role of this gene versus that gene
Speaker 2: and how all those things functioned. It was, Yeah, it
Speaker 2: was much more like it. I think it needed the
Speaker 2: understanding of how DNA worked before we could make those
Speaker 2: those leaps. Yeah, and so as we know, figuring out
Speaker 2: the mutation was still a long way away, but there
Speaker 2: was a lot that could be done in the meantime. So,
Speaker 2: for instance, the discovery of antibiotics greatly improved quality of
Speaker 2: life and the longevity of people who were diagnosed specistic fibrosis.
Speaker 2: Because you were you could then prevent lung infections or
Speaker 2: cure lung infections that could cause irreparable damage to the tissue,
Speaker 2: and then also recognizing how important diet was, having you know,
Speaker 2: the proper amount of fat and nutrient absorption. All of
Speaker 2: these things were starting to get recognized, but many doctors
Speaker 2: around the world were still unaware of this disorder or
Speaker 2: helpless against it, and most children didn't survive to the
Speaker 2: age of seven during this time, and part of the
Speaker 2: problem was in correctly diagnosing the condition. So some of
Speaker 2: these procedures could be horribly invasive and others were kind
Speaker 2: of subjective, and so when the sweat test was developed
Speaker 2: in the mid nineteen fifties, it really helped to both
Speaker 2: start supportive therapy early for someone who had cystic fibrosis
Speaker 2: and to also give epidemiologists a handle on the widespread
Speaker 2: prevalence of the condition. Physiotherapy also started to be used
Speaker 2: around the same time, and then doctors started to recognize
Speaker 2: the threat that chronic pseudomonous infections caused, and then they
Speaker 2: started to recognize how harmful chronic antibiotic use could be.
Speaker 2: So it's kind of a lot of it was a
Speaker 2: learning curve or if this wasn't an easy thing to
Speaker 2: figure out. There was a lot of trial and error,
Speaker 2: a lot of you know, how do we do this?
Speaker 2: Is this the right? Is this the best way to
Speaker 2: provide supportive therapy for someone with cystic fibrosis?
Speaker 5: Right?
Speaker 2: And I think that the increased recognition also led to
Speaker 2: the formation of a lot of cystic fibrosis organizations. So
Speaker 2: in the nineteen sixties is when a lot of these
Speaker 2: organizations kind of got up and running. And this allowed
Speaker 2: parents of children with cystic fibrosis or partners of people
Speaker 2: with cystic fibrosis to connect and form supportive groups. And
Speaker 2: it also promoted the exchange of information among researchers once
Speaker 2: you have kind of a group of people together saying
Speaker 2: this is these are my experiences, or this is the
Speaker 2: research that I found. And also this international collaborations were formed,
Speaker 2: and that meant a lot of steady progress being made
Speaker 2: on treatment or at least supportive therapy. And you can
Speaker 2: see the progress in the numbers in terms of the
Speaker 2: life expectancy. So between the ages between the years of
Speaker 2: nineteen sixty eight to nineteen seventy seven, the median age
Speaker 2: of survival rose from fourteen years to twenty years, wow,
Speaker 2: which is in less than ten years. And this increase
Speaker 2: wasn't consistent geographically or even across hospitals within the same country,
Speaker 2: because many people could not afford around the clock care
Speaker 2: for their child. I mean, can you imagine the hospital
Speaker 2: bills in the US for all the hospital stays that
Speaker 2: you would need, all of the treatment, all of the care. Yeah.
Speaker 2: And so despite the incremental improvements and therapy that helped
Speaker 2: extend the lifespan of children or people with cystic vibrosis,
Speaker 2: many researchers felt as in the dark about the condition
Speaker 2: as they did in the beginning of their career thirty
Speaker 2: years earlier. By the nineteen eighties, the gene that held
Speaker 2: the mutation that causistic vibrosis was still unknown, Like no
Speaker 2: one knew what that gene.
Speaker 5: Was in the nineteen eighties, the nineteen.
Speaker 2: Eighties, But during that time some progress had been made
Speaker 2: in understanding the biochemistry, and so that was helpful, and
Speaker 2: it was it was finally in nineteen eighty nine when
Speaker 2: the link was made between cystic fibrosis and a mutation
Speaker 2: in a gene on chromosome seven. So the CFTR gene.
Speaker 5: Wow, that's in our lifetime.
Speaker 2: In our lifetime. Yeah. Cool, And this was a big
Speaker 2: deal because once the location of that gene was identified,
Speaker 2: this meant that people could be tested for it, to say,
Speaker 2: are you a carrier? Do you have the condition? Et cetera.
Speaker 2: And I keep saying mutation, but what I really mean
Speaker 2: is mutations plural, because there are thousands of different types
Speaker 2: of mutations. Okay, so this that's and that's basically all
Speaker 2: that I have for the history. But I kind of
Speaker 2: wanted to like end cap this a little bit in
Speaker 2: a way because in doing the research for this episode,
Speaker 2: I did something that I haven't done as mut and
Speaker 2: that is read memoirs of people. And what it did
Speaker 2: was really remind me served as a great reminder how
Speaker 2: just how important it is to read about an experience
Speaker 2: from someone else's perspective. And so reading these memoirs really
Speaker 2: hit home to me how difficult it is to talk
Speaker 2: about disease or wellness with our limited vocabulary. And I
Speaker 2: don't just mean you and my limited vocabulary, but how
Speaker 2: do we know, like when we say words like this
Speaker 2: hurts well, how much does it hurt a lot? Okay? Yeah,
Speaker 2: we can use more descriptive language. We can use a
Speaker 2: scale from one to ten, But like, how do you
Speaker 2: how can you understand a scale if you don't know
Speaker 2: what someone's baseline is. Yeah, one person who's like, oh,
Speaker 2: I'm feeling a bit crezzy. Another person might be like,
Speaker 2: oh my god, I'm in agony. I'm dying right now.
Speaker 2: This is extremely painful. And I feel like our own
Speaker 2: baselines change over time. A hangover at thirty two is
Speaker 2: a lot different than a hangover at twenty two personal experience.
Speaker 4: And is there such a thing as a hangover at
Speaker 4: twenty two? I don't.
Speaker 2: Oh god, I don't think so. And I think part
Speaker 2: of this issue with communicating effectively how we feel or
Speaker 2: what we're feeling is not just with this limited language,
Speaker 2: but also it has to do with the difficulty in
Speaker 2: relating to someone what it's like to be you, to
Speaker 2: have your experiences and your memories and the way you
Speaker 2: see the world, because that forms so much of how
Speaker 2: we perceive our own selves and also how we interpret
Speaker 2: other people's feelings or words. And that's something that I
Speaker 2: came across many times in some of these that I
Speaker 2: read for the episode, that for people born with cystic fibrosis,
Speaker 2: they have not known a life without it, so they
Speaker 2: so you can't ask them, hey, what's it like to
Speaker 2: have cystic fibrosis, because it's like, well, it's this is
Speaker 2: what I know, this is how I have lived.
Speaker 6: You know.
Speaker 2: Yeah. And also like it would be like if they
Speaker 2: asked you what's it like to not have cystic fibrosis,
Speaker 2: it would be the same sort of thing, Well, this
Speaker 2: is what I know, you know. And so for that reason,
Speaker 2: we can't. I don't know what I'm trying to say exactly,
Speaker 2: so we can't. I think it's it's very difficult to
Speaker 2: ever or impossible to ever truly understand what someone else
Speaker 2: is going through or what their experiences are. But I
Speaker 2: think the most important thing is that we need to try.
Speaker 2: We should try, because it builds empathy. Another thing that
Speaker 2: kept popping up in these memoirs was that other people
Speaker 2: use the cistic fibrosis as an identifier. For those people,
Speaker 2: it's one of the their identity is cystic fibrosis, and
Speaker 2: that's not what it is. That's not the case, that's
Speaker 2: not what it should be. And Jay, whom you heard
Speaker 2: from in the first hand, sheds a little bit more
Speaker 2: light on what this is like for him and more
Speaker 2: about who he is.
Speaker 5: So let's hear what Jay has to say in his
Speaker 5: own words.
Speaker 1: I growing up never enjoyed the tone of cystic fibrosis
Speaker 1: stuff like. I never felt like there was something for me,
Speaker 1: and I wondered if there were other people like me
Speaker 1: out there. I figured there had to be, and this
Speaker 1: writing the book was an easy way to find them.
Speaker 1: Because I grew up on the internet, so I've seen
Speaker 1: support groups and things like that, but they are not
Speaker 1: for people like me. Cystic fibrosis is also called, well
Speaker 1: sometimes called by people sixty five roses because there was
Speaker 1: a child who couldn't say cystic fibrosis, and so they
Speaker 1: always called it sixty five roses. I was not that kid.
Speaker 1: I knew exactly what it was at a very young age.
Speaker 1: I knew how to take my own pills at a
Speaker 1: young age, which upset babysitters sometimes because you know, when
Speaker 1: you have a little six year old kid and he's
Speaker 1: about to swallow six giant pills by himself, that's a
Speaker 1: real nerve wracking moment. But to see like all the
Speaker 1: like the inspirational quotes and everything not, like, you know,
Speaker 1: I'm glad I have it. It's such a gift, like
Speaker 1: I do not consider a gift in any way. But
Speaker 1: I also not that I don't enjoy talking about it
Speaker 1: when people ask about it, But it's my CF is
Speaker 1: like a vampire, and that you have to invite it
Speaker 1: into the conversation. I usually won't just bring it up
Speaker 1: myself because I like to think that there's so much
Speaker 1: more about me than just CF, which may or may
Speaker 1: not be true. But that's actually why about half the
Speaker 1: chapters of the book don't involve CF, because I think
Speaker 1: it's very important to note that people get the disease,
Speaker 1: the disease doesn't get people. I hoped that there was
Speaker 1: a group of people where CF was a problem they had,
Speaker 1: but not a defining portion of their personality. And it
Speaker 1: has certainly changed my personality in ways that I don't know.
Speaker 1: I like to talk about swamp thing more than CF
Speaker 1: most times, or like you can get me started on
Speaker 1: Iron Man or Amorphous, the Kings of Finished Metal. Those
Speaker 1: things are very important to me. Music is very important
Speaker 1: to me. CF is not important to me, and that
Speaker 1: if it went away, I'm sure it would be an
Speaker 1: adjustment for me, but I'd be fine. I would just
Speaker 1: stop taking pills. It's not like I would lose a
Speaker 1: portion of myself. I think my favorite thing to do
Speaker 1: in the world is record music. All Hallows Evil is
Speaker 1: the name of the project I do it. It's usually
Speaker 1: just me. There were some other people in it for
Speaker 1: some time, but I play all the instruments and everything.
Speaker 1: So I have started that in two. Two thousand and
Speaker 1: two is the first official album. So I have seventeen
Speaker 1: years of albums where I recently went through and remastered
Speaker 1: them and remix them and everything for public consumption again.
Speaker 1: And it is painful to listen to because I remember
Speaker 1: that feeling like I didn't have anything to lose and
Speaker 1: there is nothing to hold back, and I at the time,
Speaker 1: I would have been very offended if someone was like, hey,
Speaker 1: are you okay? Yeah, no, man, this is just what
Speaker 1: I do. And it's funny because I went back and
Speaker 1: tried to I was remastering all the albums and I
Speaker 1: dug up some things that I had written the first
Speaker 1: time we reissued the catalog, and I wrote that stuff
Speaker 1: when I thought I was okay back in like two
Speaker 1: thousand and five, and looking at it now, I'm like, wow,
Speaker 1: I feel like I need to go back and apologize
Speaker 1: to everyone I interacted with at that time because I
Speaker 1: was just I had lost insurance a couple times, which
Speaker 1: is terrifying to know that you are one decision away
Speaker 1: from dying. I lost insurance, started coughing at blood, charged
Speaker 1: two thousand dollars in drugs to my credit card fix
Speaker 1: that problem, but it took a long time to fix
Speaker 1: the mental problems there. And I realized while I was
Speaker 1: making music easily now that it is one of the
Speaker 1: only times that I don't think about anything else, Like
Speaker 1: I'm completely focused on what I'm doing while I'm recording instruments,
Speaker 1: while while I do the vocals. Then I'm right back
Speaker 1: to thinking about cf because it's tough to breathe sometimes.
Speaker 1: But I think that's what I enjoy about it is
Speaker 1: it's one of the few things that I can just
Speaker 1: really focus on and it can be really good at
Speaker 1: without worrying about like like I can't. I probably could
Speaker 1: be decent at running if I tried, but it's difficult.
Speaker 1: Like music, the barrier to entry was very low. My
Speaker 1: entire life, I felt like I've had something to prove,
Speaker 1: and I realized that I've always been trying to prove
Speaker 1: myself as someone who's disabled but able to do this stuff,
Speaker 1: and so I always thought when people are like, oh, wow,
Speaker 1: you're really good at this, what I always heard was
Speaker 1: you're really good at this for someone with cystic fibrosis.
Speaker 1: And it was shocking the day I realized that there
Speaker 1: were maybe two people out of sixty at work that realized.
Speaker 3: I had something wrong with me.
Speaker 1: The thing that people need to I'd like people to
Speaker 1: understand is that I got very good at a lot
Speaker 1: of things because I have a chip on my shoulder
Speaker 1: and it is still there and it will never leave
Speaker 1: me because I know that I always started from way
Speaker 1: behind the starting line on most things. And the reason
Speaker 1: that I have been relatively successful, like I make like
Speaker 1: a living at this point, has almost nothing to do
Speaker 1: with me and the fact that I'm good at those things,
Speaker 1: because being good at those things means nothing if you
Speaker 1: don't have the right opportunity for it. So if I
Speaker 1: were born five years earlier, or like I don't know,
Speaker 1: seventy miles to the west of where I was born,
Speaker 1: I'd be dead. I can't quit my job. I do
Speaker 1: not know how to quit my job, because that is
Speaker 1: how that's literally keeping me alive. More so than the money,
Speaker 1: it's the insurance my drugs cost three hundred thousand dollars
Speaker 1: a year. There's no way, there's no amount of money
Speaker 1: I could make. And the thing is, even if I
Speaker 1: did make that amount of money, they won't sell.
Speaker 3: Them to you.
Speaker 1: It was so difficult to get someone to sell me
Speaker 1: a drug. And then that's when I found out that
Speaker 1: they wouldn't give me the insurance discount. I was paying
Speaker 1: cash and had to pay four hundred dollars more than
Speaker 1: an insurance company would have made. There is such a
Speaker 1: specific set of circumstances, and it kind of irks me
Speaker 1: when people are presented as like, yeah, this battler is
Speaker 1: battling this disease and making it happen, and it's like,
Speaker 1: you don't realize. I hate to use luck, but there is.
Speaker 1: You have to be offered the opportunity to take it,
Speaker 1: and those opportunities aren't open for a lot of people.
Speaker 1: And I'm lucky in that. Again, I'm very good at
Speaker 1: a lot of different technical things which happen to be
Speaker 1: the thing that people want right now. If it turned
Speaker 1: out that like our entire economy changed now, like woodworking
Speaker 1: was the most valued skill, I'm out. I've got nothing
Speaker 1: for you because I Can't Breathe in the sawdust. To
Speaker 1: have those opportunities and be able to take advantage of
Speaker 1: them is kind of lucky. I not only have been
Speaker 1: given the opportunities, but I have skills to take advantage
Speaker 1: of these opportunities and the best way possible. And it
Speaker 1: is the only reason that I'm still alive, and I
Speaker 1: wish it were easier for everyone to be alive.
Speaker 5: If you loved Jay as much as we did, you
Speaker 5: can find more of his writing at Can't Eat, Can't
Speaker 5: Breathe dot com.
Speaker 2: And you can find his book Can't Eat, Can't Breathe
Speaker 2: and other ways cystic Fibrosis has f't me on Amazon
Speaker 2: and any other place where you want to get your
Speaker 2: books where Definitely, seriously go check out his book.
Speaker 5: It's incredible, highly recommend it. It's really great. Yes, and
Speaker 5: you can also find more of his music at Allhollows
Speaker 5: Evil dot bandcamp dot com.
Speaker 2: And that's also where you can find his latest album
Speaker 2: titled No God's Only Monsters, So go check it.
Speaker 5: Out, and you can find him tweeting at All Hollows Evil.
Speaker 2: Okay, so the last eighty years of cystic fibrosis have
Speaker 2: been big. Yeah, since its first description eighty years ago.
Speaker 2: Cystic fibrosis has gone from a disease of relative obscurity
Speaker 2: to one of the most research genetic diseases out there.
Speaker 2: The expected lifespan has gone from six months to over
Speaker 2: thirty years, and so much progress has been made in
Speaker 2: treatments and potential cures. So I'm hoping, Aaron, that you'll
Speaker 2: tell me some good things about cystic fibrosis and gene
Speaker 2: therapies and other great things on the horizon.
Speaker 5: I can't wait too. We'll take one more short break.
Speaker 5: So overall, it's estimated that the incidents of cystic fibrosis
Speaker 5: is about one in three thousand among people of Northern
Speaker 5: European descent. It's a very high incidence, yeah, especially for
Speaker 5: an autosomal recessive disorder. The highest incidence is actually in Ireland,
Speaker 5: which for some reason is not what I was expecting,
Speaker 5: but there it's about one in fourteen hundred. Wow.
Speaker 4: Yeah.
Speaker 5: So, and it's very different in people of different descent.
Speaker 5: So in people of like Latin American descent, the incidence
Speaker 5: ranges from about one in four thousand to one in
Speaker 5: ten thousand. In African Americans it's between one and fifteen
Speaker 5: to one in twenty thousand, and even lower in people
Speaker 5: of Asian backgrounds. And what I think is really important
Speaker 5: is that it's not to say that it's impossible. And
Speaker 5: one of the biggest gaps that we have in looking
Speaker 5: at all of the numbers is that these numbers all
Speaker 5: come from the US, Canada, Europe, Australia, So there's a
Speaker 5: lot of countries and entire regions of the globe from
Speaker 5: which we don't really have a handle on what the
Speaker 5: incidence of cystic fibrosis actually is.
Speaker 2: Hmm.
Speaker 5: Yeah, So we know that it's more common in people
Speaker 5: of Northern European descent, but that doesn't mean that it
Speaker 5: doesn't exist across the globe, because it does. It's just
Speaker 5: a lower yeah, And a lot of the places that
Speaker 5: we do have a really good idea of the incidents
Speaker 5: are places where these newborn screening programs have been initiated.
Speaker 5: And I want to talk about them for a minute
Speaker 5: because I think this is pretty incredible. These newborn screening
Speaker 5: programs have been shown to reduce mortality, like decrease the
Speaker 5: death rate, improve growth and neurocognitive outcomes, so that because
Speaker 5: babies who are diagnosed early can get treatment early, they
Speaker 5: have better like brain outcomes, which cystic fibrosis we didn't
Speaker 5: even talk about it being able to affect your brain.
Speaker 5: And they've also been shown for those people who are
Speaker 5: keeping tally on these numbers to be very cost effective.
Speaker 2: There we go.
Speaker 5: So, you know, so newborn screening is routine in a
Speaker 5: number of different countries, and it basically just is a
Speaker 5: heal prick and they actually test for the blood level
Speaker 5: of a protein that's higher in most infants with cystic fibrosis.
Speaker 5: So it's a it's not a straight genetic screen right
Speaker 5: off the bat. It's just a test for this specific protein, right, which.
Speaker 2: Is I imagine it's pretty rapid results.
Speaker 5: Yeah, I think you get them back here. I think
Speaker 5: you get them back within a week or two.
Speaker 2: Okay.
Speaker 5: So overall, when we look at cystic fibrosis, even with
Speaker 5: these newborn screening programs, the prevalence of cystic fibrosis in
Speaker 5: the population is actually increasing. But it's for a very
Speaker 5: good reason, and that's because major developments in treatment have
Speaker 5: improved survival. So more people are living with cystic fibrosis. Gotcha, Okay, Yeah,
Speaker 5: so it's a happy increase.
Speaker 2: That's great.
Speaker 5: So, yeah, in the US, between two thousand and twenty ten,
Speaker 5: survival improved by one point eight percent per year.
Speaker 2: That's amazing, it's incredible.
Speaker 5: And today the median survival of children that are born
Speaker 5: today with cystic fibrosis is fifty six years, which is
Speaker 5: still it's still so young, like fifty six is so young, but.
Speaker 2: It's so young. But when you look back at the
Speaker 2: history of the past years, to go from six months
Speaker 2: to fifty six years.
Speaker 5: And that's today, and it's improving every year because we're
Speaker 5: getting better at treating it every year, which is yeah, amazing. Yeah, However,
Speaker 5: a small caveat, not a small caveat, a big caveat.
Speaker 5: Is that overall when we look across the globe, median
Speaker 5: survival is still in the mid twenties to early thirties.
Speaker 5: So we're not better everywhere, but in places like in
Speaker 5: the US, where we have access to treatment, it is
Speaker 5: getting better. And a lot of it does have to
Speaker 5: do with this early detection. In the US and twenty ten,
Speaker 5: almost sixty percent of people that were diagnosed with cystic
Speaker 5: fibrosis were diagnosed by that newborn screen, compared with only
Speaker 5: eight percent of people in the year two thousand were
Speaker 5: diagnosed as newborns.
Speaker 2: Hmmm. Yeah, interesting.
Speaker 5: So overall prevalence is increasing, but it's because we're getting
Speaker 5: better at treating it, and so that's what I want
Speaker 5: to talk about next.
Speaker 2: Yeah, tell me about the treatments.
Speaker 5: Let's talk all about it. It's a really happy, fun,
Speaker 5: good stories.
Speaker 4: Okay.
Speaker 5: So there is so much recent that is going into
Speaker 5: actual treatments. And for a long time, all we could
Speaker 5: do to treat cystic fibrosis was treat the symptoms. So
Speaker 5: if you got recurrent respiratory infections, you would treat the infection.
Speaker 5: If you were having pancreatic insufficiency, then you could give
Speaker 5: them maybe pancreatic enzymes. Okay, it's not going to fix
Speaker 5: your pancreas, but at least you can digest your food.
Speaker 5: But now there's all of these new drugs being developed
Speaker 5: and tested to target the cause of the disease, to
Speaker 5: target the messed up protein itself, so that we can
Speaker 5: fix this disorder from the start rather than just treating
Speaker 5: the symptoms. Wow. The biggest difficulty is that, because there
Speaker 5: are so many different mutations, there hasn't yet been a
Speaker 5: single drug or a single intervention that can work for
Speaker 5: all of the different types of cystic fibrosis, if that
Speaker 5: makes sense.
Speaker 2: Yeah, So have there been any that work for at
Speaker 2: least one?
Speaker 5: Oh, there's been multiple.
Speaker 2: Oh good.
Speaker 5: And I do want to say that I am not
Speaker 5: assisting fibrosis researcher or expert, and so I know that
Speaker 5: there's so much going on that I know I haven't
Speaker 5: covered at all, and so for that, especially if you
Speaker 5: researched this, I apologize if I don't mention your current research,
Speaker 5: but I want to talk about some of the things
Speaker 5: that have had the biggest impacts and some of what
Speaker 5: I think is the coolest. And I'm biased because my
Speaker 5: friend actually did some of this.
Speaker 4: Research, which is very cool. It's really cool research. Okay.
Speaker 5: So one new drug that has been developed and works
Speaker 5: really great for some people and doesn't work at all
Speaker 5: for others is called if a cafter.
Speaker 4: Have you heard of it? No, I've a cafter.
Speaker 5: It's such a weird name for a drug. This drug
Speaker 5: works for people with a mutation, not the most common mutation,
Speaker 5: but a mutation that affects about four people living with
Speaker 5: cystic fibrosis, that one of those class three or four
Speaker 5: mutations that affects the way the protein works, the mechanism
Speaker 5: of the protein. So you have the protein, it's not misformed,
Speaker 5: it makes it all the way to the surface, but
Speaker 5: it's not working properly. Okay. It's called a gating mutation.
Speaker 5: So if a cafter can essentially improve the movement of
Speaker 5: electrolytes across this protein, it targets this bad gating protein directly,
Speaker 5: and it's really really effective. It essentially just allows for
Speaker 5: the movement of electrolytes. How I don't know that details
Speaker 5: of it erin.
Speaker 4: That's it.
Speaker 2: That's just I don't understand.
Speaker 5: How that's when we get too deep into pharmacology that
Speaker 5: I can't handle.
Speaker 2: I'm unsatisfied.
Speaker 5: Well, you're going to be more unsatisfied, okay, Okay, but
Speaker 5: it works. The point is that it works if you
Speaker 5: have very a protein, but it's just not functioning correctly.
Speaker 5: It's not gating correctly. If a cafter essentially combined to
Speaker 5: that protein in a certain way, that allows for proteins
Speaker 5: to allows for ions to move properly across that protein. Okay,
Speaker 5: But obviously that's not going to be effective for people
Speaker 5: who maybe don't make any cystic fibrosis protein, right, yeah, okay,
Speaker 5: So there are some other options. There's two other drugs
Speaker 5: tes aicafter I think that's how you say it, and
Speaker 5: luma caafter tease cafter tesaicafter and luma caft. These both
Speaker 5: are beneficial for the most common mutation of cystic fibrosis,
Speaker 5: that's the delta F.
Speaker 4: Five O eight.
Speaker 5: So that mutation is a mutation in the processing of
Speaker 5: the protein. So you make the protein in your cells,
Speaker 5: but then you can't get it shuttled to the surface
Speaker 5: to actually insert in the membrane. So these two drugs
Speaker 5: help in the processing and trafficking of that protein to
Speaker 5: get it to the cellser Does that make.
Speaker 2: Sense, I'm just kidding. That's cool, very yes, it's very cool.
Speaker 5: So if you have a mutation where your body is
Speaker 5: still making the protein but it's not being trafficked properly,
Speaker 5: these two drugs can help with that. However, what is
Speaker 5: even more interesting to me is that they've actually only
Speaker 5: been shown to be helpful when you give them in
Speaker 5: combination with I A cafter.
Speaker 3: Huh.
Speaker 5: So I a cafter helps the functionality of that protein,
Speaker 5: which I would guess essentially just means that, yeah, you're
Speaker 5: making it and the problem is that you're not trafficking it,
Speaker 5: but there must be something else going on with that
Speaker 5: protein too, that it's just gating properly as well.
Speaker 2: It's not the maybe as slightly misfolded or something like.
Speaker 5: That exactly right, But a combination of either tes a
Speaker 5: caafter or lumicafter and if a cafter.
Speaker 2: Also these cafter can we talk about cafter?
Speaker 5: I don't know, but it kills me cafterh okay. But
Speaker 5: these drugs in combination are four are people with this
Speaker 5: specific mutation hugely beneficial, like incredibly so. But even with
Speaker 5: these three drug options and their combinations, there's still going
Speaker 5: to be a lot of people who straight up don't
Speaker 5: make the protein, right, because that's a whole class of mutation,
Speaker 5: don't make any protein, or others who just don't make
Speaker 5: enough of it. So helping to traffic it or helping
Speaker 5: it to gate, that's not going to help. There's not
Speaker 5: enough of the protein, and so these drugs aren't going
Speaker 5: to be helpful at all if that's the type of
Speaker 5: mutation that you have. So this is where I'm going
Speaker 5: to brag, Oh about a friend of mine, not about myself.
Speaker 5: A shout out to my friend Kat who did her
Speaker 5: PhD and worked on the development of a new drug.
Speaker 5: This brand spanking new came out in twenty nineteen, not
Speaker 5: yet doing human trials, but there was trials in cell
Speaker 5: culture and in pigs, and it's.
Speaker 4: This is so cool.
Speaker 5: This drug that she helped develop for her PhD straight
Speaker 5: up functions as a CFTR protein channel. Whoa, So she
Speaker 5: found a small molecule that's actually amphotericin b, which is
Speaker 5: an anti fungal medication that we already use, which means
Speaker 5: that it's already been tested in humans, which is going
Speaker 5: to help down the road in terms of getting it
Speaker 5: through like process of testing.
Speaker 4: Et cetera.
Speaker 5: You know what I'm saying, Yeah, I got charity, No, yeah, okay.
Speaker 2: I read it.
Speaker 5: Functions as a small molecule that inserts itself into the
Speaker 5: cell membrane and allows for the transport of bicarbonate across
Speaker 5: this cell membrane.
Speaker 2: Okay.
Speaker 5: Bicarbonate is one of the things that is normally transported
Speaker 5: in the CFTR protein.
Speaker 1: Cool.
Speaker 2: It's so cool.
Speaker 5: And they found that when they gave this amphoterrasin b,
Speaker 5: which again it's a drug that we use as an
Speaker 5: antifungal that's actually pretty gnarly when you give it at
Speaker 5: high concentrations. At really low concentrations, it's highly selective to
Speaker 5: only allow these anions, this bicarb to pass across the membrane.
Speaker 5: So it's not going to further mess up any electrolytes
Speaker 5: because it's not allowing just anything to pass through. And
Speaker 5: they compared the efficacy in changing the phs of the
Speaker 5: airway surface between this molecule so amphoterracin and ivicafter, which
Speaker 5: again is one of those big drugs that they use,
Speaker 5: and they found that it had similar effects. So we
Speaker 5: know that because if a caafter is working for people
Speaker 5: with cystic fibrosis with these certain mutations, it changes the
Speaker 5: airway surface pH in this way amphoteras and be changes
Speaker 5: it in the same way. But by actually acting as
Speaker 5: a protein, you don't have to have a protein there
Speaker 5: already for it to happen.
Speaker 4: Does that make sense?
Speaker 2: I think so. And so this would apply to all
Speaker 2: different mutation groups.
Speaker 5: Exactly, you don't have to be able to make any
Speaker 5: of the cistic fibrosis protein in order for this to
Speaker 5: be beneficial.
Speaker 2: So would you have to take this antifungal medication for eternity.
Speaker 5: That's a good question that we don't know at this point,
Speaker 5: but they did test it in yeast, in human airway,
Speaker 5: epithelial tissue in culture, and then in pigs with cystic fibrosis,
Speaker 5: and in all of those it worked to Actually, in
Speaker 5: the pigs especially, it decrease the symptoms and prolonged these
Speaker 5: pigs living with cystic fibrosis.
Speaker 2: That's very cool.
Speaker 5: It is so cool. And again, this is a molecule
Speaker 5: amphatagre that's already a drug that we use to treat
Speaker 5: fungal infections. So in terms of basic safety testing, it's
Speaker 5: already gone through that. So now it just needs I mean,
Speaker 5: it still needs a ton of work in terms of
Speaker 5: clinical trials, but it makes it that much faster because
Speaker 5: it's not a completely new thing essentially.
Speaker 2: So can you explain the difference between bicarbonate and chloride
Speaker 2: and why, like, is one more important than the other
Speaker 2: in terms of ion transport or ion regulation.
Speaker 5: That's a great question. I'm glad that you asked it,
Speaker 5: because Kat was like, Aaron, don't forget to talk about
Speaker 5: bicarb when we do this episode. So for a long time,
Speaker 5: it was thought that the effects of the cystic fibrosis
Speaker 5: protein were mediated entirely through chloride, like this is a
Speaker 5: chloride channel, so chloride moving across is what's causing all
Speaker 5: of these symptoms. But it turns out it's not only
Speaker 5: chloride that moves through this channel. Bicarbonate also moves through
Speaker 5: and it might be even more important in some cases
Speaker 5: in actually causing and resulting in the symptoms that we see.
Speaker 5: So essentially both bicarb and chloride ions can move through
Speaker 5: this CFTR channel, and in this case, this amphoterisin drug
Speaker 5: is only working on the bicarb, but that alone is
Speaker 5: enough to actually benefit essentially without even touching the chloride.
Speaker 5: So it's likely that bicarb is a bigger player in
Speaker 5: the cystic fibrousis game than it has gotten credit for
Speaker 5: in the past.
Speaker 2: So are there other things in terms of gene therapy
Speaker 2: and there are medication, Yeah, yeah.
Speaker 5: So gene therapy has also mostly been studied in the
Speaker 5: young lungs.
Speaker 4: So using like a.
Speaker 5: Nasal spray that has a viral vector that has a
Speaker 5: functional CFTR gene in it, and then the idea is
Speaker 5: that that virus will then go and and infect your
Speaker 5: airway cells and put that functional CFTR gene into your
Speaker 5: airway cells, and then boom, Now you can make this
Speaker 5: functional cystic fibrosis protein. So there are definitely a number
Speaker 5: of different groups working on gene therapies. So far, they
Speaker 5: haven't been super effective in long term trials, but they
Speaker 5: are in trials. There's actually a huge group out of
Speaker 5: the UK called cfgene Therapy dot org and it's the
Speaker 5: UK Cystic Fibrosis Gene Therapy Consortium and they're doing a
Speaker 5: ton of work on gene therapy cool and that is
Speaker 5: probably a little further along in the process in terms
Speaker 5: of it has been tested on humans. It just hasn't
Speaker 5: been shown to be effective in long term so far.
Speaker 5: So I think one of the biggest issues with gene
Speaker 5: therapy in general is figuring out how to administer it
Speaker 5: and how to get this gene to actually work the
Speaker 5: way that we want it to once it's inside of
Speaker 5: human cells. We don't have a lot of control over
Speaker 5: that as of Yet another thing though that I think
Speaker 5: kind of harkens back to what you were talking about, Aaron,
Speaker 5: in terms of reading memoirs and understanding how cystic fibrosis
Speaker 5: people live with cystic fibrosis their entire life and so
Speaker 5: understanding that effect is another big area in cystic fibrosis
Speaker 5: research has been on understanding that quality of life is
Speaker 5: just as important in many ways as just longevity. So
Speaker 5: in a lot of medical studies you'll only see reported
Speaker 5: things like morbidity and mortality, and mortality is this one
Speaker 5: end point. But especially as we develop all of these
Speaker 5: new drugs that are allowing for people to live much
Speaker 5: longer lives living with cystic fibrosis, understanding how these drugs
Speaker 5: and these drug regimens affect your quality of life is
Speaker 5: being become really really important, and so a lot of
Speaker 5: recent search is taking this into account, and quality of
Speaker 5: life studies over the past ten years have really dug
Speaker 5: into this and trying to look at a few different issues.
Speaker 5: One is the importance of patient reported respiratory symptoms as
Speaker 5: one of the outcome measures, so not just maybe looking
Speaker 5: at like how many infections did you get or something
Speaker 5: very quantitative, but actually looking at the patient's reported symptoms.
Speaker 5: And then the growing perception that the prescribed treatments, even
Speaker 5: though we can say how incredible they are and how
Speaker 5: much they do, they're burdensome, Like we're talking about having
Speaker 5: to take pills for the rest of your entire life,
Speaker 5: multiple pills every single day.
Speaker 2: Well it's not just pills, but it's also these machines
Speaker 2: that people need to take time every single day often
Speaker 2: to break up the mucus to do this to Yeah,
Speaker 2: and it's yeah painful, yeah, yeah.
Speaker 5: And there's huge differences according to socioeconomic and racial and
Speaker 5: ethnic status in terms of who has access to these
Speaker 5: new developments and who's included in these research studies and
Speaker 5: all of that.
Speaker 2: So yeah, I think that that realm of research is
Speaker 2: really important. And I was doing a little bit of
Speaker 2: a dig into some of the psych I guess psychology
Speaker 2: papers around what teenagers sacistic fibrosis and what are some
Speaker 2: of the minimization of symptoms or just language choices and
Speaker 2: how they have taught how you talk about your physical
Speaker 2: feelings and also in terms of impact on family and
Speaker 2: you know, divorce rate, these sorts of things like how
Speaker 2: it's it's such a multifaceted thing where I feel like
Speaker 2: it's if we follow this formula every episode, right, we
Speaker 2: talk about the bio, the history and the epidemiology, and
Speaker 2: I feel like that there's so much more to every
Speaker 2: single disease that we talk about that we have talked about,
Speaker 2: and in this case, it was definitely tip of the
Speaker 2: iceberg in terms of feeling completely ill equipped to tell
Speaker 2: any version of a story of cystic fibrosis and saying like, well,
Speaker 2: there's also this aspect of it. There's this aspect of it,
Speaker 2: which is even more reason to talk about it, to say, hey,
Speaker 2: you know, share your experiences and so on. But yeah, yeah,
Speaker 2: there's there's a lot of really there's a lot of
Speaker 2: research and impact on aspects of cystic fibrosis that are
Speaker 2: maybe not immediately apparent or fall into the categories of medical.
Speaker 5: Or historical exactly. Yeah, so yeah, that's where we stand.
Speaker 2: It seems like it's a encouraging but yeah, overall encouraging.
Speaker 5: Still hard, still hard and heavy.
Speaker 2: Yeah. Sources, sources. I want to shout out a couple
Speaker 2: of papers. So one is Ramins at All from nineteen
Speaker 2: eighty nine, and that is the identification of the cystic
Speaker 2: fibrosis gene. And so this article is where they identified
Speaker 2: where the mutation is located on which gene, on which chromosome.
Speaker 2: And then there's a twenty eighteen paper by Farrell at
Speaker 2: all and so this is where I mentioned estimating the age.
Speaker 2: So the origin of this most common the delta f
Speaker 2: five eight mutation. And then there are three memoirs that
Speaker 2: I want to give a shout out to. One is
Speaker 2: called Alex The Life of a Child by Frank DeFord,
Speaker 2: and so this is a memoir written by a father
Speaker 2: about his daughter named Alex, who had cystic fibrosis. Another
Speaker 2: book is called My Foreign City by Elizabeth Scarborough, and
Speaker 2: so this is a book written by a woman whose
Speaker 2: husband had cystic fibrosis. And of course can't eat, can't breathe,
Speaker 2: and other ways cystic fibrosis has fed me by our
Speaker 2: very own jageronomy. All of these were incredible. I really
Speaker 2: highly recommend each one of these. I think it's it's
Speaker 2: just really valuable to read about someone's perspective, someone's experiences.
Speaker 5: Yeah. I had two really great reviews actually that are
Speaker 5: super comprehensive about cystic fibrosis biology and covers a lot
Speaker 5: of their epidemiology as well. So we, as always will
Speaker 5: post the links to all of our sources on our website,
Speaker 5: This podcast will Kill You dot Com under the episodes tab,
Speaker 5: and there you can find sources from every single one
Speaker 5: of our episodes.
Speaker 2: That's right, Jay, thanks again for everything.
Speaker 4: Thank you so much. It was so much fun. To
Speaker 4: talk to you. It was great.
Speaker 2: Yeah, and thank you to Bloodmobile for providing the music
Speaker 2: for this episode and all of our episodes. And again
Speaker 2: to Jay for sharing with us this brand new song
Speaker 2: that you guys are about to hear, so get excited.
Speaker 5: And thank you to all of you for listening. We
Speaker 5: really love making this podcast.
Speaker 2: This is great. Okay, Well, Jay has got one more
Speaker 2: nugget of advice for us all.
Speaker 1: The one other thing I need everyone to know is
Speaker 1: always wash your hands and never touch your face. That
Speaker 1: is the secret to everything.
Speaker 2: You heard them wash your hands.
Speaker 5: You filthy animals.
Speaker 4: Didn't know you're freaking much.
Speaker 2: Knows your failures too.
Speaker 1: It's no sound to break you down because it knows
Speaker 1: just what.
Speaker 3: You'll do.
Speaker 6: So much use how to destroy so much as out
Speaker 6: to kill.
Speaker 3: But if the world doesn't get you, bleed in.
Speaker 6: Baby, just know your body. Well, wait till your body
Speaker 6: to trans you, Wait till your body bring you nothing
Speaker 6: but than wait till your probably crewing.
Speaker 2: Not that daddy and you're freeing me took him up
Speaker 2: up to gather.
Speaker 3: If you think you Chian, it can make you, we
Speaker 3: would least expected. It can't kill you when you'll sleep
Speaker 3: If sare wheny you one morning, it'll.
Speaker 1: Be there when you die, you will take your final breath.
Speaker 6: Then it we'll say a last goodbye. Wait tell your
Speaker 6: body betrays you. Wait till your body brings you nothing
Speaker 6: for pain, Wait till you're probably prow what not that
Speaker 6: day and you stream and took your coming again.
Speaker 1: It follows your poor reper just.
Speaker 6: To fty, we not brave. It's always peny of print,
Speaker 6: and many'll always penny saying.
Speaker 4: Wait till your fondy betrays you.
Speaker 6: Wait till your body brings you nothing to pay, Wait
Speaker 6: till you're crawling.
Speaker 2: Through what's not that day?
Speaker 1: I just scream and took your comforts again.
Speaker 3: Wait, tell your body betrays you.
Speaker 2: Wait, tell your moty brings
Speaker 6: You nothing like hey, Wait till your line through whatnot
Speaker 6: that day and the scream just gonna be crawling again