WEBVTT - Ep 34 Cystic Fibrosis: Complete Somatic Rebellion 0:00:00.280 --> 0:00:03.640 Well, my name is Jason Geronomy. I usually go by 0:00:03.720 --> 0:00:06.360 Jake because it's half the syllables. I was diagnosed with 0:00:06.400 --> 0:00:11.320 cistic fibrosis when I was nine months old because I 0:00:11.440 --> 0:00:15.680 was a very lethargic baby. I just there are pictures 0:00:15.720 --> 0:00:18.040 of me from that time where you can see like 0:00:18.160 --> 0:00:21.560 a kid ain't right. And I think I am alive 0:00:21.600 --> 0:00:24.440 today through a very specific set of circumstances in that 0:00:24.520 --> 0:00:27.240 when my parents went to the doctors and were like, hey, 0:00:27.240 --> 0:00:32.040 this baby sucks. The doctor that they went to happened 0:00:32.040 --> 0:00:36.760 to work with a CF doctor in Yale, like they 0:00:36.800 --> 0:00:40.839 were partners on cystic fibrosis. So whereas I was a 0:00:40.960 --> 0:00:43.960 failure to thrive baby, he knew exactly why I was 0:00:44.040 --> 0:00:46.320 failure to thrive and we were able to address that 0:00:46.440 --> 0:00:52.160 right away. So since then, there has been a long 0:00:52.240 --> 0:00:54.840 journey and it hasn't been fun, but I have been 0:00:55.120 --> 0:00:59.760 very lucky in most of my circumstances in that there's 0:00:59.840 --> 0:01:04.120 new medicines which aren't always easy to take, but sometimes 0:01:04.120 --> 0:01:06.840 they work. I'm able to get insurance, which is a 0:01:06.880 --> 0:01:09.360 real big thing and was a real problem for me 0:01:09.400 --> 0:01:13.319 for a lot of years, and I'm actually doing okay now. 0:01:13.360 --> 0:01:16.000 I'm doing better now at thirty six than I was 0:01:16.040 --> 0:01:18.400 at twenty six, which is not how this used to go. 0:01:18.680 --> 0:01:20.160 I was one of the first people to go into 0:01:20.200 --> 0:01:24.039 an adult CF clinic because there weren't adults for a while, 0:01:24.840 --> 0:01:26.679 and so that was weird. I kind of missed the 0:01:26.720 --> 0:01:29.520 slide from the children's clinic. But what are you gonna do? 0:01:29.920 --> 0:01:35.720 I feel like everything about like successful people with CF, 0:01:35.720 --> 0:01:38.319 and I'm successful in the fact that I'm not dead yet. 0:01:38.440 --> 0:01:40.560 I feel like it's really important to mention how they 0:01:40.600 --> 0:01:44.920 got insurance, and once again, it's very specific circumstances for me, 0:01:45.040 --> 0:01:46.839 and that I got very lucky in that there's two 0:01:47.040 --> 0:01:50.680 very large employers in my area who happened to offer 0:01:50.760 --> 0:01:54.920 insurance for entry level positions, and had that not existed 0:01:54.960 --> 0:01:59.640 at the time, I wouldn't exist now. And I'm also 0:01:59.720 --> 0:02:02.520 lucky the fact that my job is a nine to 0:02:02.640 --> 0:02:05.520 five job and I do not wake up that early. 0:02:05.600 --> 0:02:08.120 So everyone was very nice when I was like, hey, 0:02:08.120 --> 0:02:11.280 I'm coming in at noon and didn't question me because 0:02:11.280 --> 0:02:15.079 it takes me a long time to get ready as 0:02:15.080 --> 0:02:17.560 a large production keeping the show on the road. When 0:02:17.600 --> 0:02:19.600 I wake up, I don't feel great. I don't think 0:02:19.600 --> 0:02:22.840 anyone feels great when they wake up. But I'm extremely 0:02:22.919 --> 0:02:25.320 aware of my lungs when I wake up, like I 0:02:25.360 --> 0:02:27.280 can feel them, and you kind of do like a 0:02:27.400 --> 0:02:31.040 diagnostic check of the body, see what you've got going on. 0:02:31.160 --> 0:02:35.280 And then I have a vest that I wear, and 0:02:35.360 --> 0:02:38.120 there's been a recent technological advance in that, and that 0:02:38.160 --> 0:02:41.240 it used to be a vest that sort of it 0:02:41.320 --> 0:02:43.760 was like a giant blood pressure cuff that you put 0:02:43.800 --> 0:02:47.120 around your chest and it would push air through and 0:02:47.320 --> 0:02:48.880 make a whole lot of noise kind of like a 0:02:50.760 --> 0:02:53.400 which now it's like this. It looks like a jet 0:02:53.480 --> 0:02:56.919 pack and you wear it and it's got little pods 0:02:57.040 --> 0:03:00.640 that I think they're essentially speakers. They're not really allowed 0:03:00.639 --> 0:03:02.440 to tell me that, but they kind of shake your 0:03:02.480 --> 0:03:06.520 chest so they make more of like a And while 0:03:06.520 --> 0:03:11.079 that's happening, I also have a nebulizer with which I 0:03:11.120 --> 0:03:15.480 inhale salt water at first to salt up the mucus 0:03:15.560 --> 0:03:18.160 and encourage water to go to it. And then the 0:03:18.200 --> 0:03:21.680 next step is a drug called polmozyme, which actually it 0:03:21.760 --> 0:03:24.360 snips out parts of the DNA of your mucus somehow 0:03:24.400 --> 0:03:28.040 and thins it out, so trying to force water into 0:03:28.080 --> 0:03:30.880 it trying to force it thin. The vest runs for 0:03:31.120 --> 0:03:33.680 three ten minute sessions, and in between each session you're 0:03:33.680 --> 0:03:36.240 supposed to cough and see if you can actually cough 0:03:36.240 --> 0:03:40.120 anything out. Last week, I actually had the occasion to 0:03:40.240 --> 0:03:44.120 cough out a large piece of sort of dry mucus 0:03:44.160 --> 0:03:47.360 that was like I could feel my baranchial tree imprint 0:03:47.400 --> 0:03:51.240 in it, which is a strange feeling. So I do that. 0:03:51.560 --> 0:03:53.720 I have some extra pills I have to take. I 0:03:53.800 --> 0:03:56.920 have to take pills to eat that have I believe 0:03:56.920 --> 0:03:59.560 they're freeze dried pig pancreas. They actually digest the food 0:03:59.640 --> 0:04:02.280 for me. But if my acid, my stomach acid is 0:04:02.320 --> 0:04:04.800 too acidic, they can't do it. I just tear up 0:04:04.840 --> 0:04:09.080 the pills, so I take amephersol. I actually take pills 0:04:09.120 --> 0:04:11.840 for my pills to work. That's fun. Clarendon, which is 0:04:11.840 --> 0:04:13.240 an easy one. I got to make sure I get 0:04:13.320 --> 0:04:16.440 enough vitamin D because I also have osteopenia, which is 0:04:16.440 --> 0:04:20.440 not osteoporosis but almost. And then I go to work 0:04:20.839 --> 0:04:24.280 and I've got this all down into about an hour, 0:04:25.080 --> 0:04:30.080 and then I do some work. I go home eventually, 0:04:30.640 --> 0:04:32.719 and I have to do the best again when I 0:04:32.760 --> 0:04:36.120 get home, which another thirty minutes. I don't do the 0:04:36.160 --> 0:04:38.720 pulmozyme again, but I do the salt on top of that, 0:04:39.440 --> 0:04:43.120 and then I have to take a long acting insulin 0:04:43.160 --> 0:04:46.080 before I go to bed because CF has done such 0:04:46.160 --> 0:04:49.520 damage to my pancreas that it gave me diabetes as well, 0:04:50.279 --> 0:04:52.960 which is fun because people know what diabetes is and 0:04:53.400 --> 0:04:55.880 they will talk about that with you all the time, 0:04:55.920 --> 0:05:00.479 where CF scares them. I think something I earned in 0:05:00.560 --> 0:05:03.960 an old swamp thing comic is there's there's some guy 0:05:04.000 --> 0:05:05.720 can see the future. So I actually don't remember the 0:05:05.720 --> 0:05:08.760 context of it, but I don't think you're supposed to 0:05:08.800 --> 0:05:12.159 know the way you're gonna die. And I like that 0:05:12.320 --> 0:05:15.000 was a very comic booky thing, like, oh I can't 0:05:15.040 --> 0:05:16.560 tell you how you're gonna die, that will change your 0:05:16.560 --> 0:05:19.279 whole life. But that made me think for a long time, 0:05:19.440 --> 0:05:22.640 because for years I was sure I knew how I 0:05:22.680 --> 0:05:27.400 was going to die. And it's become blurrier now, like 0:05:27.839 --> 0:05:30.359 there's i'll give it like an eighty percent chance that 0:05:30.400 --> 0:05:32.880 CF kills me. There's a chance that something else could 0:05:32.880 --> 0:05:36.120 really come in and take the victory from it. But 0:05:36.240 --> 0:05:41.200 it made me incredibly morbid for so long because if 0:05:41.240 --> 0:05:44.360 I did. If I do have a gift or a superpower, 0:05:44.480 --> 0:05:49.160 mine is. For most people, comedy is tragedy plus time. 0:05:49.520 --> 0:05:52.200 I require very little time. I think most things are 0:05:52.279 --> 0:05:54.560 very funny when they happened to me. Obviously, I think 0:05:54.560 --> 0:05:58.160 most things are very funny right immediately, and I think 0:05:58.200 --> 0:06:02.440 I made my family really uncomfortable with that. My grandmother, 0:06:02.600 --> 0:06:06.240 who was wonderful to me for so many years, was 0:06:06.279 --> 0:06:08.360 also one of those grandmothers like, no, you're going to 0:06:08.400 --> 0:06:10.360 be fine, Everything's going to be fine, Like you don't 0:06:10.440 --> 0:06:13.520 know that anything could happen tomorrow. And she'd be like, no, 0:06:13.560 --> 0:06:15.359 you're going to live so much longer than me, Like 0:06:15.440 --> 0:06:20.560 you don't know that. She was right. But for me, 0:06:20.760 --> 0:06:22.919 CF is a thing that I know, and it is 0:06:22.960 --> 0:06:25.200 the thing that I do. It requires little to no 0:06:25.279 --> 0:06:27.880 bravery on my part. I just have to keep waking 0:06:27.960 --> 0:06:32.279 up and doing that. I have no other choice. But 0:06:32.360 --> 0:06:36.560 I think some people don't like to be confronted with 0:06:36.760 --> 0:06:41.000 the idea that, like their body could go into total 0:06:41.040 --> 0:06:45.560 rebellion at any point, as mine constantly is. It's shocking 0:06:45.600 --> 0:06:47.520 for them that I have a job. And again, it's 0:06:47.520 --> 0:06:50.160 not easy, and there's no shame in not having that. 0:06:50.200 --> 0:06:52.720 If you're dealing with CF, but it's shocking for them 0:06:52.760 --> 0:06:57.440 to see someone doing quote unquote normal stuff while again 0:06:57.640 --> 0:07:00.560 body and total rebellion at any given part point. And 0:07:01.400 --> 0:07:03.240 I just think most people don't like to grapple with 0:07:03.279 --> 0:07:05.080 that when it's literally the only thing I want to 0:07:05.120 --> 0:07:08.120 grapple with is how I'm going to die when it's 0:07:08.160 --> 0:07:09.560 going to happen. What's wrong with me? 0:07:09.960 --> 0:07:10.520 Uh? 0:07:11.120 --> 0:07:47.680 I don't know. 0:07:46.080 --> 0:08:00.720 You just heard from Jay Geronomy, who we had the 0:08:00.800 --> 0:08:02.640 most fun talking to this. 0:08:02.680 --> 0:08:04.080 Week, the most fun. 0:08:04.640 --> 0:08:09.920 He is an amazing author, musician, and just all around 0:08:09.960 --> 0:08:16.000 hilarious person, and we have more of his interview later 0:08:16.040 --> 0:08:18.920 in the episode, so do keep your ears out for 0:08:19.000 --> 0:08:19.600 that one. 0:08:19.920 --> 0:08:22.320 Yeah, it was really thrilling to get to talk to him, 0:08:22.480 --> 0:08:24.560 and we can't wait for you to hear even more 0:08:24.600 --> 0:08:25.240 of his story. 0:08:25.920 --> 0:08:28.240 And there's one more thing that you should keep your 0:08:28.240 --> 0:08:31.000 ears out for at the end of the episode, and 0:08:31.040 --> 0:08:35.559 that's a special song written by Jay specifically for this episode. 0:08:36.400 --> 0:08:39.560 It's called Complete Somatic Rebellion, and we'll provide the link 0:08:39.600 --> 0:08:42.960 for download in our show notes. I think it seriously 0:08:43.080 --> 0:08:47.640 might be the coolest thing to happen on this podcast anyway. 0:08:47.920 --> 0:08:50.600 I'm Aaron Welsh. 0:08:49.600 --> 0:08:51.479 And I'm erin allman Updyke. 0:08:51.440 --> 0:08:53.760 And this is this podcast Will Kill You. 0:08:54.280 --> 0:08:57.920 And today we're talking about cystic fibrosis. 0:08:58.520 --> 0:09:03.560 That's right, Yes, this is our first genetic one. Is 0:09:03.600 --> 0:09:03.880 that right? 0:09:03.880 --> 0:09:04.440 Pretty sure? 0:09:04.520 --> 0:09:05.600 I'm pretty sure that it is. 0:09:05.760 --> 0:09:11.800 Yeah, yeah, okay, So what are we drinking this week? 0:09:12.240 --> 0:09:15.880 Our quarantini this week is the Dorothy h Anderson. 0:09:16.440 --> 0:09:21.000 Yes, thus named because there was an amazing researcher named 0:09:21.000 --> 0:09:24.960 Dorothy h Anderson who described I think was one of 0:09:24.960 --> 0:09:28.480 the first people to describe cystic fibrosis and did tremendous 0:09:28.520 --> 0:09:33.199 amounts of research in her life on the condition. What 0:09:33.360 --> 0:09:34.800 is in the Dorothy h Anderson? 0:09:35.320 --> 0:09:38.760 Well, there is pomegranate soda, lime. 0:09:38.559 --> 0:09:40.880 Juice, a splash of ginger ale. 0:09:41.000 --> 0:09:44.440 Tequila always good, and you've got to have it with 0:09:44.640 --> 0:09:48.720 a salted rim And we'll talk about why throughout this episode. 0:09:49.080 --> 0:09:50.559 Perfect Perfect. 0:09:51.000 --> 0:09:53.680 We'll post the recipe for our quarantini as well as 0:09:53.679 --> 0:09:56.480 the placeba Rita, which is our non alcoholic version, on 0:09:56.640 --> 0:09:59.160 our website and all of our social media channels. 0:09:59.480 --> 0:10:01.679 And see, I think we do have a couple of 0:10:01.760 --> 0:10:07.760 bits of business. Yeah, So one thing that I wanted 0:10:07.800 --> 0:10:10.280 to mention is that, hey, we have merch, we have 0:10:10.360 --> 0:10:13.360 T shirts, we do mugs, pins, and guess what we 0:10:13.440 --> 0:10:14.280 have soap. 0:10:14.720 --> 0:10:16.760 We do have soap. I think we did a bad 0:10:16.840 --> 0:10:20.480 job at telling you guys this, but we have soap 0:10:20.760 --> 0:10:23.320 so you can wash your filthy little animal hands. 0:10:23.520 --> 0:10:26.959 Also, the label is the cutest thing you've ever seen. 0:10:27.280 --> 0:10:28.040 It's adorable. 0:10:28.880 --> 0:10:31.600 You can find all of our merch at this podcast 0:10:31.679 --> 0:10:34.720 will kill You dot com if you just click on merch. 0:10:36.280 --> 0:10:39.280 And the other thing is that I saw this on 0:10:39.360 --> 0:10:41.480 Reddit and I just wanted to share this because I 0:10:41.640 --> 0:10:44.000 was I was lurking briefly, even though I haven't been. 0:10:43.920 --> 0:10:44.520 On very much. 0:10:45.480 --> 0:10:50.040 So on the tpwk y subreddity, there was a recent 0:10:50.160 --> 0:10:54.840 post or a post a while back about what people 0:10:54.920 --> 0:10:58.040 wanted to call fans themselves. What do they wanted to 0:10:58.080 --> 0:11:01.800 call themselves? Let me let me pull up some of 0:11:01.840 --> 0:11:05.680 these things. Actually, one of the top ones was filthy 0:11:05.720 --> 0:11:12.960 animals of course perfect. Another one was Vector's Amazing Air 0:11:13.080 --> 0:11:18.640 and Demiologists, Oh my god, air infected. 0:11:19.280 --> 0:11:20.199 Oh I like that. 0:11:20.320 --> 0:11:27.839 I love that extremophiles podcast, Phages, Quarantine Fiends, respiratory Droplets. 0:11:27.880 --> 0:11:30.600 I loved that one that I want. 0:11:30.520 --> 0:11:31.880 A T shirt that says that. 0:11:32.160 --> 0:11:37.720 The Herd, just that the herd is also amazing. So anyway, 0:11:37.840 --> 0:11:41.360 I just wanted to tell you that recently amazing. 0:11:41.679 --> 0:11:44.880 Yeah, this is very fun, but it's really funny. Okay, 0:11:44.920 --> 0:11:46.559 any other business. 0:11:47.240 --> 0:11:52.439 Actually there is one more thing. Oh yeah, this is 0:11:52.679 --> 0:11:55.600 our second to last episode of this season. 0:11:56.040 --> 0:11:58.720 Oh my gosh, it happened so quickly. 0:11:59.000 --> 0:12:03.120 It happens so fast. And before you get alarmed by 0:12:03.120 --> 0:12:06.720 that news, we're only taking a relatively short break. We 0:12:06.800 --> 0:12:10.720 are coming back on October twenty ninth for the premiere 0:12:10.760 --> 0:12:15.040 of our season three, and so subscribe to all of 0:12:15.040 --> 0:12:18.640 our social media, subscribe to our podcast so that you 0:12:19.000 --> 0:12:20.720 see when the new episode drops. 0:12:21.040 --> 0:12:23.880 Yes, and this is second to last. We're not leaving 0:12:23.880 --> 0:12:26.720 you high and dry. We've got another excellent episode coming 0:12:26.720 --> 0:12:32.120 out in two weeks. Yes, okay, that's everything now, I think, so. 0:12:34.640 --> 0:12:36.679 Well, then let's get started. 0:12:37.120 --> 0:12:39.760 Tell me about the biology of cystic fibrosis. 0:12:40.280 --> 0:12:41.080 I can't wait too. 0:12:41.400 --> 0:12:44.280 Okay, good, we'll take one quick break. 0:13:12.679 --> 0:13:15.960 Cystic fibrosis. This is gonna be a fun one because 0:13:15.960 --> 0:13:20.840 we haven't done a genetic disorder before, so we're gonna 0:13:20.840 --> 0:13:23.319 talk a little bit about genetics before we get started 0:13:23.360 --> 0:13:26.439 on anything. And on top of that we get to 0:13:26.440 --> 0:13:29.920 talk about biokim which just for some reason is one 0:13:29.960 --> 0:13:31.440 of my favorite things to do on this. 0:13:31.320 --> 0:13:34.080 Podcast, I guess, so, yeah. 0:13:33.520 --> 0:13:37.000 It's one of my least favorite subjects, okay. 0:13:37.520 --> 0:13:42.960 Cystic fibrosis is an autosomal recessive genetic disorder, and it 0:13:43.000 --> 0:13:47.200 can be caused by actually a number of different mutations 0:13:47.600 --> 0:13:51.439 in a single gene. So it's always the same gene 0:13:51.679 --> 0:13:54.720 that gets messed up somehow, but there's a lot of 0:13:54.760 --> 0:13:58.120 different ways in which the gene can be mutated that 0:13:58.320 --> 0:14:03.800 end up resulting in slightly different presentations of this disease 0:14:03.960 --> 0:14:08.920 or disorder. So first let's define the words autosomal recessive, 0:14:09.080 --> 0:14:12.400 because some people might have never heard that. That basically 0:14:12.480 --> 0:14:15.760 means that you have to have two copies of this 0:14:15.880 --> 0:14:19.440 gene that are mutated in some way in order to 0:14:19.480 --> 0:14:23.560 actually have symptoms of this disease. So if you have 0:14:23.760 --> 0:14:27.240 just one mutation, you're what's called a carrier, but you 0:14:27.640 --> 0:14:30.560 pretty much won't have any symptoms or be sick or 0:14:30.680 --> 0:14:33.680 have cystic fibrosis. You have to have two copies of 0:14:33.680 --> 0:14:36.440 the gene, and so that's what autosomal recessive means in 0:14:36.480 --> 0:14:40.760 this case. Cool cool, and autosomal just means that it's 0:14:40.840 --> 0:14:43.240 not in the X or Y chromosome. It's in any 0:14:43.280 --> 0:14:47.760 of the other chromosomes, right. Okay, So the gene that 0:14:47.920 --> 0:14:52.600 is mutated in cystic fibrosis is called the CFTR very 0:14:52.640 --> 0:14:59.600 creative cystic fibrosis transmembrane conductance regulator gene. Okay, it's the 0:14:59.640 --> 0:15:01.640 cystic fibrosis gene. 0:15:01.240 --> 0:15:01.360 Right. 0:15:02.040 --> 0:15:05.800 This is a gene that codes for proteins that form 0:15:06.280 --> 0:15:11.280 channels through which ions pass. So this is where we're 0:15:11.320 --> 0:15:14.520 going to go a little bit biokim genetics course over 0:15:15.360 --> 0:15:16.880 biokim course beginning. 0:15:17.400 --> 0:15:18.680 Okay, here we go. 0:15:19.120 --> 0:15:21.880 I'm not gonna get super into detail. I never do 0:15:23.040 --> 0:15:25.680 because it's not my strong suit, and because we'd be 0:15:25.720 --> 0:15:27.640 here all day and there's a lot more interesting things 0:15:27.680 --> 0:15:31.640 than just the biochemistry of this disorder. So what you 0:15:31.720 --> 0:15:34.960 need to know to understand why cystic fibrosis is such 0:15:34.960 --> 0:15:38.520 a big deal is that your body is made up 0:15:38.520 --> 0:15:43.440 of cells. Cells are just bags of water and electrolytes 0:15:44.360 --> 0:15:48.400 which are floating in a matrix of water and electrolytes. 0:15:48.840 --> 0:15:50.800 Okay, mm hm cool. 0:15:51.160 --> 0:15:54.320 We're bags of water, tiny little bags of water floating 0:15:54.680 --> 0:15:58.760 in water, and the linings of our cells are called 0:15:58.880 --> 0:16:02.720 plasma membranes. They're like the plastic of the water balloon 0:16:02.800 --> 0:16:07.480 that holds the water inside the cells. And these membranes 0:16:07.560 --> 0:16:13.560 only let certain things pass through them. Okay, they're selectively permeable, 0:16:14.720 --> 0:16:17.920 and a lot of the ways in which things pass 0:16:18.080 --> 0:16:22.240 through this water balloon membrane is through channels and pores, 0:16:23.000 --> 0:16:26.440 and it's proteins that make up these channels and pores 0:16:26.520 --> 0:16:27.400 in the membrane. 0:16:27.600 --> 0:16:27.920 Cool. 0:16:28.120 --> 0:16:31.680 Yeah, Okay. So the CFTR gene codes for a protein 0:16:31.840 --> 0:16:35.240 that forms a channel that, when it is normal, sits 0:16:35.320 --> 0:16:39.080 in this membrane across the membrane and allows four ions 0:16:39.600 --> 0:16:40.800 to pass across it. 0:16:41.240 --> 0:16:41.480 Right. 0:16:41.880 --> 0:16:47.560 Okay, that's your biocm course. Okay, Okay, So if you 0:16:47.600 --> 0:16:49.960 have a messed up version of this protein in some way, 0:16:50.360 --> 0:16:52.520 then you're not going to be able to properly control 0:16:52.960 --> 0:16:57.200 what is going in and coming out of cells. Okay, okay. 0:16:57.480 --> 0:17:02.360 So the cystic fibrosis protein normally allows for the passage 0:17:02.360 --> 0:17:06.040 of chloride that's the other half of sodium chloride, and 0:17:06.119 --> 0:17:12.920 also bicarbonate HC three minus, and by allowing these ions 0:17:12.920 --> 0:17:19.560 to pass through, it also indirectly regulates other ions like sodium. 0:17:19.840 --> 0:17:20.040 Right. 0:17:20.119 --> 0:17:23.400 So because once you change the balance of one ion, 0:17:23.640 --> 0:17:26.640 you affect a whole bunch of other ions as well, essentially, 0:17:27.000 --> 0:17:29.760 if that makes sense. So what ends up happening is 0:17:29.840 --> 0:17:34.280 just dysregulation. You get messed up movement of sodium, chloride, 0:17:34.320 --> 0:17:38.359 and bicarbonate, all three of those across the membrane, Okay, 0:17:39.040 --> 0:17:40.600 and that's how you end up with all of the 0:17:40.640 --> 0:17:42.800 problems that we see in cystic fibrosis. 0:17:43.160 --> 0:17:46.359 So can you elaborate a bit on what it means 0:17:46.359 --> 0:17:51.720 by messed up movement or dysregulation of those ions. 0:17:51.960 --> 0:17:54.359 Let's do that by talking about some of the different 0:17:54.440 --> 0:17:56.880 mutations that you can have, and that will I think 0:17:57.280 --> 0:17:59.840 answer that question a little bit. So there's a number 0:17:59.840 --> 0:18:02.919 of different genotypes or different mutations that can lead to 0:18:03.040 --> 0:18:07.840 cystic fibrosis. They all result in this protein being messed 0:18:07.920 --> 0:18:11.480 up in some way. In one, you have a mutation 0:18:11.640 --> 0:18:16.119 that leads to defective protein production, so your protein is 0:18:16.160 --> 0:18:19.480 either too short or too long or got cut off. 0:18:19.800 --> 0:18:24.120 So basically you don't have an actual protein being placed 0:18:24.160 --> 0:18:25.520 in this membrane, so that. 0:18:25.600 --> 0:18:27.480 It's the one that's making up the poor or the 0:18:27.560 --> 0:18:28.760 channel exactly. 0:18:28.960 --> 0:18:31.160 So you don't have a poor or a channel being 0:18:31.200 --> 0:18:34.600 formed at all, which means you don't have any movement 0:18:34.680 --> 0:18:37.000 of chloride or bicarb across that membrane. 0:18:37.040 --> 0:18:39.240 Nothing goes in, nothing comes out exactly. 0:18:39.320 --> 0:18:45.000 Okay, So that's one potential mutation Class one mutation. Another 0:18:45.080 --> 0:18:48.679 one is a defect in processing of the protein. So 0:18:48.880 --> 0:18:52.000 you're making this protein which is supposed to form a channel, 0:18:52.400 --> 0:18:54.800 but for some reason it gets stuck inside of the 0:18:54.840 --> 0:18:57.640 cell and it can't actually make it to the plasma membrane. 0:18:57.920 --> 0:19:00.400 So you make the protein, but it doesn't actually make 0:19:00.440 --> 0:19:03.960 the channel. Does that make sense? Okay, Yeah, So it 0:19:04.160 --> 0:19:07.800 ends up looking pretty much the same as the first mutation, right, 0:19:07.920 --> 0:19:11.080 no pore in the membrane for ions to pass through. 0:19:12.160 --> 0:19:14.960 So that's a class two mutation. Then there are a 0:19:15.080 --> 0:19:18.440 number of other mutations that can result in a protein 0:19:18.880 --> 0:19:22.680 that is made. So you make the protein, the protein 0:19:23.000 --> 0:19:25.760 forms a channel and makes it to the cell surface, 0:19:26.320 --> 0:19:29.000 but it doesn't respond the way that it is supposed 0:19:29.040 --> 0:19:32.800 to to certain stimuli. So these are class three and 0:19:32.880 --> 0:19:34.920 class four mutations, and we're not going to get into 0:19:34.920 --> 0:19:37.600 the nitty gritty of them, but it basically just means 0:19:37.640 --> 0:19:42.280 that you have an ion channel that's there, but it 0:19:42.320 --> 0:19:46.160 doesn't open when it's supposed to say, let chloride ions out, 0:19:46.359 --> 0:19:49.240 or it doesn't close when it's supposed to stop chloride 0:19:49.240 --> 0:19:53.840 ions from leaving. So you have movement of ions, but 0:19:53.960 --> 0:19:56.440 not at the right time or at the right rate. 0:19:56.720 --> 0:19:57.520 Does that make sense? 0:19:57.840 --> 0:20:01.119 Yeah, And so there's an association with these types of 0:20:01.240 --> 0:20:06.399 mutations or these classes of mutations and the severity of symptoms. 0:20:06.760 --> 0:20:09.440 Absolutely, you can imagine that if you're not making any 0:20:09.560 --> 0:20:12.320 of this protein, you're probably going to have more severe 0:20:12.359 --> 0:20:15.880 manifestations of disease than if you make some of this protein. 0:20:15.960 --> 0:20:17.560 It just doesn't quite work properly. 0:20:17.840 --> 0:20:19.760 M Okay, that makes sense. 0:20:19.800 --> 0:20:23.080 And then right, and then there's another a couple classes 0:20:23.080 --> 0:20:26.560 of mutation, class five and six mutations where you make 0:20:26.640 --> 0:20:29.680 the protein it mostly functions normally, you just don't make 0:20:29.720 --> 0:20:31.760 quite enough of it, and so those might be the 0:20:31.840 --> 0:20:34.320 least sort of severe manifestations. 0:20:35.320 --> 0:20:40.120 And so I remember reading that there are around one 0:20:40.200 --> 0:20:43.480 thousand different mutations that I guess are grouped into these 0:20:43.480 --> 0:20:46.479 different classes. Do you happen to know the distribution of 0:20:47.080 --> 0:20:49.600 I know that there's one that's very that's like the 0:20:49.600 --> 0:20:52.840 most common, but what is the class distribution? 0:20:52.960 --> 0:20:56.200 I guess, so the most common is a class two mutation. 0:20:56.720 --> 0:20:59.080 Okay, that's the The. 0:20:58.440 --> 0:21:01.040 F five to oh eight mutation is class two mutation. 0:21:01.480 --> 0:21:04.040 So that's a problem where you make the protein, but 0:21:04.080 --> 0:21:08.040 it doesn't get trafficked to the surface properly, so it's 0:21:08.080 --> 0:21:09.480 not actually. 0:21:09.280 --> 0:21:10.119 Doing its function. 0:21:10.600 --> 0:21:13.000 Other than that, I'm not sure how common the other 0:21:13.040 --> 0:21:17.000 classes are. There are I think multiple thousands of mutations. 0:21:16.720 --> 0:21:20.760 It's it's bananas how many different mutations there are in 0:21:20.800 --> 0:21:26.440 this gene. Okay, So you can imagine that with all 0:21:26.480 --> 0:21:30.680 of these different ranges of mutations all affecting the same protein, 0:21:31.160 --> 0:21:34.520 you can end up with a pretty wide range of manifestations. 0:21:34.920 --> 0:21:36.920 So let's talk about some of the symptoms. 0:21:37.320 --> 0:21:40.000 Okay, yeah, okay, So. 0:21:40.080 --> 0:21:43.440 As a recap, you have a malfunctioning protein in some 0:21:43.480 --> 0:21:49.159 way that leads to abnormal movement of sodium chloride and 0:21:49.240 --> 0:21:51.879 bicarbonate across cell membranes. 0:21:52.240 --> 0:21:52.600 Okay. 0:21:53.920 --> 0:21:57.679 So this channel protein, the CFTR protein, is found in 0:21:57.720 --> 0:22:00.080 a whole bunch of different organs and tissues. It's not 0:22:00.160 --> 0:22:03.320 just in one place in your body. It's most highly 0:22:03.359 --> 0:22:06.399 expressed in glandular epithelia. 0:22:06.760 --> 0:22:08.440 Fun Okay, tell me what that is. 0:22:08.800 --> 0:22:12.520 It means in a few specific organs that have glands. 0:22:12.960 --> 0:22:18.560 So your lungs, you're pancreous, you're intestine, your sweat glands, 0:22:18.680 --> 0:22:23.400 and your reproductive tract. Okay, so you tell me where 0:22:23.400 --> 0:22:26.480 do you think we're going to see symptoms of this disorder. 0:22:26.720 --> 0:22:29.920 I'm guessing it's in all of those places that you're listed. 0:22:30.280 --> 0:22:37.320 Oh my gosh, you're so correct about that. Okay, So yeah, lungs, pancreous, intestines, 0:22:37.359 --> 0:22:41.520 those are the biggest ones. Reproductive tract as well, sweat glands. 0:22:42.119 --> 0:22:43.960 We don't have to talk about it unless you want 0:22:44.000 --> 0:22:46.760 to you later, ok kind of do but okay, whatever, 0:22:46.920 --> 0:22:51.840 we'll get in to it, Okay, Okay. The truth is, 0:22:51.960 --> 0:22:55.240 despite all that we know about how these mutations affect 0:22:55.560 --> 0:23:00.760 the CFTR proteins, we don't fully understand how this leads 0:23:00.760 --> 0:23:04.480 to the specific disease manifestations that we see. There's a 0:23:04.480 --> 0:23:07.680 lot of different theories, and we'll talk about some of 0:23:07.720 --> 0:23:13.760 the possibilities, but the main cause of morbidity and mortality. So, 0:23:13.840 --> 0:23:16.280 the main cause of illness and sort of suffering in 0:23:16.320 --> 0:23:23.040 people with cystic fibrosis is airway symptoms. So when cystic 0:23:23.080 --> 0:23:27.639 fibrosis affects your lungs, right, Okay, So we'll start with 0:23:27.680 --> 0:23:29.600 the lungs then, and then we'll go kind of organ 0:23:29.600 --> 0:23:34.800 by organ. Okay, in your lungs, if you have a 0:23:34.960 --> 0:23:40.520 messed up CF protein, then you're gonna have less chloride 0:23:40.840 --> 0:23:46.000 and bicarb being secreted out of your cells and into 0:23:46.160 --> 0:23:48.000 the space in between. 0:23:47.720 --> 0:23:49.840 Your cells, the negatively charged ions. 0:23:49.920 --> 0:23:54.119