This Podcast Will Kill You - Ep 56 Sickle Cell Disease: Invisible Illness, Enduring Strength

Episode Date: August 18, 2020

Neglected and ignored by the medical establishment throughout most of its history, sickle cell disease remains one of the most common (and commonly misunderstood) genetic conditions in the world. In this episode, we break down the myriad effects that one nucleotide substitution can have on the human body and discuss the basics of what it means when blood cells sickle. Continuing with the theme of the seen and unseen, we then turn to the history of sickle cell disease, a history of long-standing injustice and the unending fight to raise awareness and provide support for those impacted by the condition. And as always, we wrap up with a discussion on the current global status of sickle cell disease and some exciting new treatment options on the horizon. We are so honored and thrilled to be joined this episode by not one, not two, but three incredible guests! You’ll hear first from Marsha Howe and Sharif Tusuubira, who share with us some of their firsthand experiences living with sickle cell disease. And then in our current status section, Dr. Megan Hochstrasser from the Innovative Genomics Institute walks us through the mind-blowing genome editing approaches being used to treat genetic conditions such as sickle cell disease.You can follow Marsha on her website for her non-profit organization and blog “My Life With Sickle Cell” as well as through her social media channels: Twitter: @MarshaMLWSC, Instagram: @marsha_h181, Facebook: Marsha Howe. And make sure to check out B Positive Choir too! Twitter: @bpositivechoir and Instagram: @bpositivechoir.Learn more about Sharif Tusuubira’s amazing advocacy efforts on his website and through his social media channels: Twitter: @tkksharif, Instagram: @tkksharif, Facebook: Sharif Kiragga Tusuubira. You can also watch his 2017 talk in Washington, DC as a Mandela Washington Fellow.And to learn more about the futuristic-sounding research being done at the Innovative Genomics Institute (including using CRISPR to develop a faster, cheaper coronavirus test!), you can follow Megan (@thecrispress) and IGI (@igisci) on Twitter, or head to their website. See omnystudio.com/listener for privacy information.

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podcasts. My name's Marcia. I live in the UK, as you can tell by my accent. And I've had sick yourself for the longest time I can remember. My parents found out when I was about six years old. my mum knew she had the trait but my dad didn't know that he carried the trait and obviously my

older sister was born and she just had a trait so my mum was like okay fine she had got that for me but when I came about I was born with another sort of illness on top of sickle cell which is called B6 deficiency so it kind of must

be sickle cell So over the many years growing up, I was becoming sick. They couldn't quite work out. And then it was when my younger sister was born, they said, you know, let's be tested for sick or self. And that's when they found out that I had the full-blown disease. I kind of understood I had an illness much later on. I would say when I was about nine, eight or nine, yes, I went to a hospital. prior to that, but it just didn't really sunk. I kind of let my parents deal with it all,

like, okay, well, you manage my health. I managed being a child and playing with my friends and stuff like that. I didn't really understand it to, I think as I went later on in my teenage years, when I started going to secondary school, that's when I started taking more control over my illness and saying, okay, well, you know, I have to eat right. I have to dress right. I have to make sure I get enough rest and, you know, not overstress myself because I know if I don't, these things can trigger off a crisis and I can be left out of school for like weeks on end. And it was only when I joined sort of like a be positive choir that I actually came out and a lot of my school friends, it was like, do you know what? I did not know you had sleeper-selt.

I didn't know how to explain it to them in a way and I didn't know how they would receive me I always think like if I said it I would lose friends which I remember having a friend who said they didn't want to be my friend because they thought they could catch sick of salt if they held my hand and I was like it doesn't work that way

unless you're born with the disease it does not work that way so it was very um I shield myself just so I wouldn't have to face that negativity and that hurt later on my adult years, I was like, no, you know what, if you don't like me the way I am, then that's fine. Somebody else will, there's many people in this world that will. And I grew that confidence and was able to mentor

or talk to other teenagers, girls and boys who were in my situation to say, you know, don't let supercell stop you from doing what you want to do. when I do get in a crisis and I'm in pain, the best way to describe it, it has to be like when you get a really bad cold and you have aches and pains. And all of your body hurts on 10 times worse a skill than aches and pains when you got a cold.

And you just want it to stop. And it's brought me to tears before many a times. And it's brought me to the parts where I'm like, do you know what, I don't want to be here on this earth because I don't want to experience this pain. Why do I have to go for it? You know, why was I the unlucky one? And I did kind of go for the phase of blaming my parents, so to speak, him, you know, you should have checked each other before you had me. Why didn't you do this? And, you know, your mind starts thinking loads of things of, you know, if I, if I wasn't here, would I be in a better place?

Or if I was born before my sister, would I be in a better place? You just think many things. Every day you wake up, you don't know if it's going to be a good day, if it's going to be a bad day. And I think that affects your social life as well because you're forever canceling on your friends. and it's the same with relationships. I've broken up with a lot of partners because they don't understand the extent of sick or going into hospital. That's our last result on our mind.

We tend to not quite going into hospital, but we want to try and treat it the best we can at home. Sometimes we don't like them hospitals because of the stigma that we get. we get looked upon as, oh, we're drug addicts, or, you know, we're not really in pain, we're just here because we need a fix. And it's like, I don't want to be in hospital. This is the last place I want to be. Luckily enough, my family are amazing, blessed out. I have snapped up them many times.

But it's not a case that I mean to. It's just a case of all I can feel is this pain. I don't want to feel the pain anymore. And I have apologised to them afterwards, but now they kind of know my routine. You know, when I say I'm in a crisis, they don't answer silly questions. They're just like like pain meds, a heat pad or hot bath,

or if it's that bad, do you need to go to the hospital? And obviously, I've got a son who is fantastic. He, I call him a little Dr. Quinn. The minute, you know, I say, Mommy's not feeling very well. He's on it with the pain meds, the hot cups of tea, the hot water bottle, everything he can think of to make, to cheer me up. He'll put my favourite movie on and cuddles and just sit there with me. So he is literally amazing. But because it's just me and him that live together, I feel like that sometimes he feels his childhood

got robbed. And sometimes he feels that he can't be a child because he has to look after the mummy and also be himself, which I knew was quite hard. And I think that was the same thing when I knew when I was going to have children, you know, what impact would my health have on him? And for me, when I fell pregnant, after my pregnancy, that's when my sickle cell got worse. I had a minor stroke. More things were happening to my body where I felt like it was deteriorating.

and I felt that that was not made aware to me when I was thinking about starting a family. So I'm now going over that hurdle of experience and things where I feel that maybe I could have been made more aware of and given that option of what to do. But nevertheless, he's still a blessing and I love them to pieces. And I think wow That where I

joined B Positive Choir It's a journey that You don't want to end Singing for Britain's got talent Singing for the Queen Megan, Prince Harry Prince William

Everyone It was amazing It was like I was living a dream I had to keep saying Pinch me somebody pinch me Is that Megan over there? No So it was actually amazing

and the way since we've come on that platform, it's gone viral. I think it's got more awareness. Everybody's starting to get involved and starting to be more clued up and taking notice of what sick or cell is and how they can go around helping to spread the awareness. And I feel that it's a way that brings the community together as well because in the choir there are many people who have the illness and we share our stories we've got you know everybody experiences sick or cell differently so it's nice and where we become like a big

unit and we get to share it around the world which is amazing and we have a laugh we have a love and that's the main thing yes you have your down days but also you have your good days and but everyone always says, you know, how is it? You're always smiling. And I think I look at the positive that now I don't see sick or cell as a burden as I did before. I actually see it as a gift and a blessing to have because I can go out and spread the word about sickle and make friends. Yeah, I'm happy. Literally, I feel like I couldn't be any more happier. So my name is Sharif, Toosvida. I was born in Kampala, Uganda, a small East African country. and I have sick or cell disease.

So when I was born, my mom and dad had a very sweet love story. They gave about to their baby boy. Like all parents are very excited that they have a baby boy. I think after about four or five months after that, I started to show up with, I was very irritated. I was always crying and they told me I had all the social in hands. And they didn't know what was really going on. And my mom kept on going to different health centers.

And until the time, one doctor did suggest, you know what, we need to do a sickle cell test to be able to find out if this child doctor has sickle cell. And so that was the change of their story. Because once she told my dad, they actually broke up and my dad left her because he's like, no, I've not had any child or a sickle cell, and in my family, we don't have sickle cell disease.

So my mom ended up having to raise me as a single mother because my dad had left. During that time, she was pretty scared about what's going on. She didn't know what was going on because at that time, early 90s, sickle wasn't really a very big thing. Most people have SQL to date in Uganda. We find that over 90% of the babies who were born in

Secaulte cell died before their fifth party. So this is mostly because we don't have a comprehensive follow program that you're going to be diagnosed and go to a Secausal Center and be followed up to see the people of the care. All that has not been there. If it has started to come up, I think, in the last one or two, three years,

we're starting to see Seekosovo, the centers across the country in Uganda. So during that time when she was pretty long, pretty scared, she named me Tussubira. So my second name is Sharia. Tosu Bida means we hope. So her introduction with the name of her dosovida was mostly because of the fact that she wanted to have a way to always have some hope in her heart. Because if everyone around you is trying to say, your baby is going to die, every mom would be scared. But as a child growing up, I didn't know what was going on.

Yes, I would have pain and cry and ask what's going on. My mom did not really have a will of explaining it to me until I think to my child. my six or seven years, when I go out to play and kids have come to play, they would say, they would say Temuzania, which means in my local language do not play with him. He's sick. So that's where I start to realize that there's something different about me. So that was my kind of childhood experience. And this was the case whereby I'll be on the pitch, trying to kick the ball, and I feel pain in my leg, feel pain in my hand, and sometimes I just couldn't walk. My friends would have to carry me home. I'd always ask my mom, what's

going on? Why me? Why am I feeling like this? Why? I remember that at the time of growing up, I asked how for a knife, so I said I could cut off my hand and cut off my leg because it was bringing too much pain for me. And they're like, no, we can't do that. You can't just, you can't just cut off the leg because you're in too much pain. But even then, yes, I would feel very stigmatized and feel very bad about it. And when he went to school, it was actually very different as well at school because at school, in the rainy seasons, extreme seasons, or been pain and they couldn't go to school. So you miss like two weeks or three weeks of school

and the teachers would say, where has he been? And so often my mom would have to explain, you know what? He has sick or cell? If he has missed, if he tells you, it's hands are sick, he can't write, it's fine. You have to understand. But it was really hard for the teachers to understand because, like I said,

this is the diseases most people they not know about. Like, even the teachers are like, this kid has just, just has an excuse. Every time I want him to come and draw on the blackboard, he's saying his hand is hurting. You want him to be part of the class activity. he's saying he feels pain in his leg and feels painy and there.

So that was another issue. Because of my sicker cell, I had complications like Johnny's in my eyes and had a disbanded pretty pretty. So all those things made me look more of an outlier. Like, you don't, yes, you look like everyone else, but your eyes are pretty yellow. So that's a thing that you have to explain everyone. Why are your eyes yellow? I didn't know how much to break it down, but all I would say, yes, I have sick or say

it's a blood disease, that's all I'll say, and when I'll get sick, and we had a school nurse, I'll go and get care from the nurse. So the high school was a bit, was a much bad experience. So during my second day in the university, I did get sick, and I got sick, and I think I missed almost three or four weeks of school. So when everyone was asking where Sharif, and I mean, and I didn't really do my disclosure, and that's the time I had started to date, I was dating a very beautiful woman. And when I got sick, I was in hospital, and she tells me, you know what, I can't do with you because of your sick or cell. I mean, I've never seen, myself with someone with SecoSel.

That was a turning point for me. So that that was my driving factor now to make a change in not only my life, but in the life of all those people living in SecoSals, such that they don't have to go through what had gone through. So it was me, myself, Ashraf, and two other people, Evelyn and another guy Salim, we agreed to create an organization called Seagosol Network, Uganda. It was the first SecoSel nonprofit that we did register.

Because of my background and stigma and experience I had, one of the first projects actually implemented was having Seagosal cancer training. When I looked at my background of laboratory science and the fact that in our market you could have people test for HIV, I thought to myself and said, I think we should be able to test for sickle cell. We started out at all our community events, we would have a team of laboratory people to do the sickle cell screening. Our counselors to do the general type council, such that people could understand what it means if you're a trait, what it means if you're a trait, what it means if we're a lot of people. if you have sickle cell, and all those things. And after two years of this, our local means of health actually did accept and adopt this program.

It's now been rolled out and several health centers have these rapid sickle cell testing kits. People now can be able to access the sickle cell screening test, whatever they are. So in Uganda, we have a tribe called the Baganda tribe makes up the biggest proportion of the population. But we did have a local name for sickle. And this is not only the Baganda,

but most tribes in Uganda, that you don't actually have a local name for SecoSel. And the indicator for this means that if you don't have a local name for something, it means you're not talking about it. If you're not talking about it, then that explains all the stigma. So because people don't talk about it, there's no name. But the biggest win for me as the advocate is the fact that the kingdom gave us a local name for SecoSel. They did say now we pronounce that sickle in our language is called Nambi.

At least now, somebody who's uneducated, somebody who has never been to school, can have a word that they can know to mean sick or cell, and that in a way helps us beat the stigma because then people can be able to talk about in their mother town. Looking back on how the journey has come from the time when we introduced committee's causal screening, from the time when we have a local name, to the fact that we have not been able to support the emergence of so many sickle non-profits. For example, the time when we started, there was only one non-profit in Uganda working on sickle cell called Sikhistration of Uganda. Today, as I speak, seven years later, we have over 25 CBOs, committee-based, organization, all working for SecoSel in local communities. I think in 2019, I decided,

know what, I've been, I've been an advocate for the past few years. I think I need to think of something more challenging. That's how I found out. I thought of coming back to grad school, and I decided to come back to the U.S. for my grad school. So I came back, I went to the University of Kansas as a PhD student. When I came to the U.S., I was hearing a lot of this thing of the racial, the racial bias in terms of psychocer. And it had actually never happened to me until one time, I think in May, I go to the ER. I had a lot of pain in my, I was actually very sick. I had a lot of pain.

I spent the whole thing in the ER. They give me all the pain made. I was still in pain. But guess what happened to me? The ER doctor says, you're fine. We have checked everything very normal. So we can't admit you. One of the key driving factors in terms of why, even as advocates living in the US,

we need to come out and promote more awareness about sick or so such that the doctors would have more understanding. I think one of the key important aspects may not be so much. much of a big deal in the US, but it's a big deal is where in the world, whereby people not understanding and accepting sick or cell, having all these myths and beliefs. So it still goes back to awareness. People have to understand that this is like

any other blood disease. If you can take good care of yourself, if you can have a comprehensive follow-up, if you can do whatever we can do to stay healthy, then I can live like anybody else. I shouldn't worry about death. I shouldn't worry that would not be able to meet my dreams. My story started out because

of a heartbreak, because of a lab, sad love story, I ended up being a sicker's advocate. Today I was able to find love, I'm married to Sophia and have two kids, Niemansheath, and they're part of my support system to keep me healthy and strong and going. So I appreciate them and everyone who's supporting me. Thank you. Thank you so much, Marcia and Cherie, for sharing your stories with us. We really, really appreciate it. And we want to tell you a bit more about our amazing guests. Marcia started her blog, My Life with Sickle Cell in 2016, and has since been recognized for her awareness-raising efforts by appearing on TV programs, radio shows,

newspapers, you name it. And in her firsthand, she mentioned being a member of the B-Positive Choir, which is a choir made up of people with sickle-cell disease or those who have friends or family members affected. And the B-Positive Choir has made amazing strides in raising awareness of sickle-cell disease as well as encouraging blood donations. And also, as you heard, they were on Britain's got talent and performed in front of the royal family, which is pretty dang cool. That's amazing. Our other incredible guest, Sharif, has been instrumental in a number of different advocacy and outreach efforts, which you heard a bit about in his firsthand, including launching the East

Africa Sickle Cell Alliance, working with the Pan-African Sickle Cell Federation International, and serving as the first executive director of the Uganda Sickle Cell Rescue Foundation. That's incredible. So amazing. Sharif's amazing advocacy and outreach efforts have been recognized by many organizations. In 2017, he was named a Mandela Washington Fellow through the Young African Leaders Initiative. In 2018, he became a telemachus fellow under the Global Thinkers Forum. And this year, 2020, he was named the International Sickle Cell Advocate of the Year. No big deal. No big deal. Oh, and he's just casually also getting his PhD studying quantitative genetics at the University of Kansas. Just casually getting a major degree. Right? Oh, my goodness. That's amazing. We will provide links to both Marcia and Sharif's websites and social media handles on our website.

This podcast will kill you.com and in our show notes, if you'd like to learn more about these awesome humans and their work. Yeah. Hi, I'm Aaron Welsh. And I'm Erin Elman Updike. And this is, this podcast will kill you. This week, we are, as you may have guessed, you might have figured it out by now. Covering sickle cell disease. Yeah. This is a big one, obviously. This is a huge one. And we've been wanting to do this one for a while. And I'm very excited now that we're finally doing it because there's so much, there's so much to it. Yeah, absolutely. There's such fascinating. biology. I can't wait to learn about the history. I have a feeling it's going to be equal parts,

fascinating, and infuriating. That's my guess. Oh, I would say maybe not even equal parts. I would say mostly infuriating. Great. Yeah, awesome. Okay. There are some like, you know, shining moments, but yeah. Oh, but I can tell you that there are some very exciting things to talk about in the current event section for which we had the pleasure of speaking with a very special guest, Dr. Megan Hochstrazer, whose education programs manager at Innovative Genomics Institute in Berkeley. It's incredible. I'm sure that you may have heard the word CRISPR or genome editing at some point and been like, what the heck is that? Don't worry, we're going to get into it, at least a little bit. And it's going to make you so thrilled and make you feel like you're living in the future.

It's thrilling. But before we get into all of the thrilling, things that we're going to talk about today. Aaron, what time is it? I believe, Erin, that it is quarantini time. You would be correct about that. What are we drinking today? We are drinking the Witten. Oh, lovely. Oh, yes. And the Witten is named for Dr. Charles Witten, who, among many other amazing accomplishments, was the co-founder of the Sickle Cell Disease Association of America. And he made amazing strides in raising awareness of sickle cell throughout the 70s and 80s and into the 90s as well. And he also initiated a lot of programs that were designed to provide more opportunities for those underrepresented in medical fields to actually have medical school as an opportunity.

So we wanted to name our quarantini to honor this amazing human in the tiniest possible way. And to do so, what is in this quarantini exactly? The Whitten is strawberry infused tequila, which is so good. So good. Just really easy to do. It just takes patience. And lime juice and agave syrup. Fabulous.

We'll post the full recipe for that quarantini, as well as our non-alcoholic placebo rita on our website. This podcast will kill you.com and all of our social media channels. so make sure you're following us. And we have one more piece of business before we get into the business of sickle cell. Just a little one, which is a big news, actually. We have new merch. New merch.

We've been waiting. We're so excited. We have some really fun, cool things. Like, we'll just drop a few little hints. You want a hoodie? We got a hoodie. You want some socks? Oh, you need some socks to keep your things.

toe is warm. Big shout out to Abigail Irvin Penner, who's always incredible artwork, is featured on so many of these. Honestly, like, I'm, I'm in love. I can't wait to be TPWKY, head to toe, baby. I mean, literally. Head to toe and for my sips. Yeah. Okay. If you would like to see this new merch, you can head to this podcast Will Kill You.com and click on the merch tab at the top of the screen. All right. Is that all of our business, Erin? I believe. so. Well then, let's take a quick break and dive straight into the biology of Sickle Cell. Let's do it. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrived with pre-portioned ingredients so there's no meal planning and no extra grocery trip.

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This is a story of the inner workings of the MSS and how one man's ambition and mistakes opened its vault of secrets. Listen to the sixth bureau on the I-Heart radio app, Apple Podcasts, or wherever you get your podcasts. So sickle cell disease, or SCD, I think it's often taught as sickle cell anemia, right? This like one particular illness. But in fact, sickle cell disease is a group of disorders of red blood cells. and it's a genetic disease, which means it's inherited, so it's caused by a mutation. But as we'll see, it's not just one single mutation and there's not just one single manifestation.

So we're going to start from the very beginning before we even get into sickle cell disease itself and talk about blood. Cool. Yes. Okay. We've talked about blood before a little bit. We have, but we've never talked about this. We have talked about, when have we talked about blood? Hepatitis C.

Oh yeah, this is a totally different blood discussion. Okay. Okay. So what we're going to talk specifically about is in our red blood cells, the protein that is actually responsible for carrying oxygen. And that protein is hemoglobin. Okay. So hemoglobin is a protein that's made up of four polypeptides, two pairs of polypeptides, two pairs of polypylopen. peptides, and these four polypeptides or strings of amino acids form the protein that's in our red blood

cells that actually carries oxygen, which obviously our tissues need in order to survive. So in most adult red blood cells, hemoglobin is made up of two alpha chains, alphas, and two beta chains. So alpha, alpha, alpha, beta, okay? Sounds good. Now, we also have some other forms of hemoglobin, like you can have two alpha chains and two delta chains. That's another kind of adult hemoglobin. And then in a fetus, before we are born, the majority of our hemoglobin is actually two alpha chains and two gamma chains. And that's called fetal hemoglobin.

Why? Great question. So glad you asked. So you know how fetuses are grown inside and all of their blood comes from mom, right? So that means that all of the blood that a fetus is getting is already partially deoxygenated. It doesn't have as much oxygen as the blood in our bloodstream because we're breathing in air. So because of that, fetal hemoglobin has to actually bind oxygen more tightly than adult hemoglobin. because it has to be able to get all of that oxygen out of mom's blood.

Does that make sense? Mm-hmm. Okay. Now, remember that because it's going to become very important in our discussion of sickle cell later. Okay? Okay. So, now we understand hemoglobin inside normal adult red blood cells. So what does that mean for sickle cell disease?

Why did I tell you all that? Turns out that sickle cell disease is produced by a. single amino acid change, if anyone cares, it's a glutamic acid to a valine, that in that beta hemoglobin chain. Okay. So it's a single mutation in beta hemoglobin that results in what's called sickled beta hemoglobin. So HBSS instead of HBA for adult. That is the change that if you have two copies of that mutated beta-globin gene, you have sickle cell anemia, the disease caused by two copies of these sickle-cell genes. So what happens if you have these sickle-cell versions of beta hemoglobin? Well, what happens is that in your red blood cells, at low oxygen concentrations,

like low overall oxygen concentrations in your blood, the hemoglobin forms a polymer. So multiple subunits, like multiple little globules of hemoglobin protein, will link together inside the red blood cell and form a linear chain. Like a little string of beads? Like a little string of beads, exactly. And this becomes rigid and causes a deformation in the whole red blood cell so that it kind of sucks in on itself and becomes sickle-shaped or like a crescent moon shaped.

So a normal adult red blood cell, even a fetal red blood cell, is shaped kind of like a donut. Like the, you know the things you go down the lazy river in, those like inflatable tubes with like the mesh in the middle so your butt doesn't fall through? Oh, I've never had one that had the mesh, but sure. The fancy version. Okay. So that's kind of what a normal red blood cell looks like. So when you have two copies of this sickle cell beta hemoglobin gene, all of your hemoglobin's line up in the red blood cell and sickle it. So instead of that nice donut, you have a C-shaped red blood cell. And that is kind of the core problem that results from two copies of this sickle cell gene. But how is that like, okay, it's just a different shape of your red blood cell. Why is that so bad? So these sickled cells are very rigid, okay?

Normal red blood cells are kind of like an inflatable donut. They're kind of squishy and squashy. So as they move through your blood vessels, from larger vessels to smaller vessels like your capillaries, they can squash and deform and scoge through small vessels and then pop back out on the other side. Sickled cells are more rigid, so they can't do that as well.

So what happens is these cells can start to get stuck, especially in small vessels. Okay. But it's not just the rigidness of the sickled red blood cells. So it turns out that once a red blood cell sickles like this, they're also literally stickier. Like proteins on the outside of them become more sticky so that they get stuck to the walls of your vessels and they get stuck to other like white blood cells and things that are rolling along in your vessels. Okay. And imagine what happens if you have a bunch of cells starting to stick to one another inside of your blood vessels. Well, you get a blood clot. You're going to get a blood clot. Exactly.

And so kind of the hallmark of sickle cell disease that we'll talk a little bit more about in a minute when we talk about the symptoms are what's called vasoeclusive crises. So you've literally have occlusion or blockage of your vessels. Small vessels like capillaries, but even larger vessels like in your brain leading to stroke. That sounds terrible. It's not great. That's for sure. And there's more. Okay. So now we know that these sickled cells, they get more sticky. They can get stuck in places. But on top of that, so red blood cells only sickle at lower oxygen concentrations. Okay. So for the most part in your arteries, even if you have sickle cell disease, your red blood cells are going to be in normal shape. It's not until you reach the

capillaries or the veins where oxygen concentration is lower, that the hemoglobin will form those chains and then cause the red blood cell to sickle. But this is reversible. But there's two problems with it. First of all, this tends to happen in microvessels, like your capy capillaries and small veins because that's where both oxygen concentration is low and you have slow flow. So the red blood cells in there for a long time comparatively. And so those two things combined lead to sickling. And in small vessels, if you sickle and you get stuck, then you can block those small vessels directly. Gotcha. Now another thing happens. Over time, this constant sickling and unsickling, sickling and unsickling, causes damage to the red blood cell membrane itself,

so like the outer shell of the red blood cell. And this can cause an irreversible sickling. So now it's just stuck sickled all the time. And those sickled cells in particular are very, very sticky. So that can cause sticking on the inside of vessel walls and to white blood cells in larger vessels, which could eventually lead to blockage of even larger vessels, not just small ones. Right. And it seems like the white blood cell thing then will play a role in immune system function. Oh, you're so accurate, Aaron. Here's a question. Yeah. And maybe it's jumping the gun. But your body, as we talked about in the hepatitis C episode, your body makes a lot, like makes new red blood cells very frequently. And so what does it do, like, does it attack the sickled

cells in any way or like what is their lifespan? I'm so glad that you asked, Aaron, it's totally jumping the gun, but it's the perfect question. I love it. So yeah, okay, I'm going to answer that question in a couple parts, okay? So first of all, you're right that white blood cells and things play a big role. And overall, even though this is technically a disease of just red blood cells, right, it's just hemoglobin being messed up. It's not just a disease that affects your red blood cells. overall there's an increase in inflammation and inflammatory state in sickle cell disease. And the more inflammation, so the higher people's leukocyte counts or white blood cell counts, the worse off their disease tends to be.

And as we'll see, there's huge variation in disease severity, and that's one factor that plays a role. Now, in terms of how long these blood cells last, that's a perfect question to ask. A normal healthy red blood cell has a lifespan of about 120. days. In someone with sickle cell disease, that lifespan is reduced by over 75%. So some estimates that I saw were the lifespan of a red blood cell in a person with sickle cell disease. So that's two copies of that sickle cell gene is about 16 days. Oh, wow. And so even if you, even if your body is producing blood, it's not enough to make up for the loss. Oh, you're getting the perfect. Yes, 100%. So there's two ways that you get anemia. One, like you said, you just can't make enough because you

need to constantly make more red blood cells and more red blood cells. But on top of that, as those cells sickle and unsickle and become damaged, that leads to hemolysis. So red blood cells actually breaking open within your vascular. So not only can you have anemia from lack of production, you can also have a hemolytic anemia. So breaking open those red blood cells. Now, that leads to even more problems because when you burst open red blood cells, all that hemoglobin that's inside those red blood cells is now released into the bloodstream. And this causes like a whole host of biochemistry reactions I'm not going to get into. But one thing that it does is it scavenges up all of the nitric oxide,

which is an important molecule that helps with things like vasodilation. So as your hemoglobin sucks up all that nitric oxide, now you have increased vasoconstriction, as well as damage to like the epithelium of the lining of your blood vessels, which causes even more stickiness. Okay. So it's like these horrible feedback loop, if that makes sense, where you have smaller vessels because you have less nitric oxide. You have damage to the inner layer, which increased. the stickiness, you have inflammation, so there's white blood cells rolling around, picking things up, and it's bad. It's a mess, okay? Yeah, that's like a, from one amino acid substitution,

this systemic, these systemic problems. Isn't that, it's fascinating that you can have so many effects from one single, and I mean, it's a single nucleotide, it's a single base pair change. Right, right. Wow. Yeah. Man. Okay, so let's talk about what these symptoms then look like. So now we know, like, what's happening in your blood vessels, and it kind of all boils down to, like, increased inflammation and blocking your vessels.

Okay. So I said this already, but the main complication are these vasoeclusive crises. And so these can manifest, as you can probably imagine, in so many different ways, depending on what vessels are getting blocked up. Okay. Mm-hmm. So in small child. children, especially tiny babies, like under the age of two, the most common presentation is when the

small blood vessels in their hands and feet get clogged up, this causes swelling of the hands and the feet. And this is really, really painful as well, because you're literally blocking blood flow to your hands and feet. And so in small babies that, for example, didn't have a newborn screen done, so they didn't know their parents maybe didn't know that they had sickle cell anemia. This is a really common way that they would come into the emergency room and be identified as having sickle cell anemia. Okay. Is there a treatment for that aspect of it or is it? So we'll talk about treatment more later, but for the most part, not really. Okay. Yeah. God. Yeah. Okay. So then as you can imagine, as you get older, these pain crises, these vaso-oclusive crises, just kind of keep happening.

And they can happen almost anywhere. So it's very common for people to come in with massive, massive amounts of pain without any kind of, you can't see anything wrong with them because it's these tiny blood vessels in your abdomen or your legs, in your arms, anywhere that get clogged up. This causes a huge amount of pain. If you imagine, like, a heart attack happens when you have a blockage of blood flow to your heart. Heart attacks are extremely painful. This is happening in small vessels throughout somebody's body during a sickle cell crisis.

This is a disease that is, I think, often very misunderstood. And the pain, I think, can be minimized by people because it's not visible. It's another kind of disease like we've talked about before where you don't look sick necessarily. And so I think it's really important to get across just how debilitating the pain associated with these can be. It's funny that you're using the phrases invisible and invisible because that's like, that's my theme. And when I talk about the history of it. Yeah, yeah. It's really, it's bad.

Mm-hmm. Okay. So then you also can have additional sim. symptoms are sort of more specific symptoms depending on where you have these blockages. It can happen in people that have a penis that can happen and you can get what's called priapism, which is a long-lasting and very painful erection. If it happens in the blood vessels under your skin, especially in your legs, which is really common, it can cause chronic ulcers, so open wounds on your legs, that are unable to heal because

they're not getting good blood flow over time. If it happens in your eyes, it can lead to blindness because the vessels in your retina become blocked. It can happen in your bones. And this is very serious because your bones are also alive. They need blood flow. So when you block off the vessels to your bones, you get what's called avascular necrosis. So that means tissue death because of lack of blood flow.

So your bone marrow will literally die. Oh my God. Yep. So that's pretty bad, as you can imagine. That can also lead you susceptible to like osteomyelitis, which is infection of your bone, like a bacterial infection of your bone because you don't have good blood flow to that bone. It can happen in your spleen, which is very common. And with your spleen, kind of two different things, kind of. can happen. So you can have like an, what's called an acute splenic crisis. So all of a sudden,

your spleen, like blood flow to your spleen gets blocked. This can cause your spleen to enlarge very rapidly. And that can kill you. Like that alone can kill you. Your spleen is an organ where a ton of blood flows through it because it's a lymphatic organ. So all of your white blood cells kind of hang out in your spleen and are responsible for like gobbling up bacteria and cleaning your bloodstream of infection. Okay. So because it has such huge volumes of blood flow, if you block that blood flow, then you can die just from that alone. But it can also happen and it commonly does happen where over time, small vessels get blocked little by little in your spleen, leading to long-term death of your spleen, what's called auto infarction.

Right. So that a person, even though they have a spleen in their body, it's essentially non-functional. It's like you removed it. So that leaves you very susceptible to infection, especially bacterial infections, because you don't have a spleen to take care of all those bacteria. So it's very common for people, especially young children, to die not from sickle cell anemia or sickle cell disease itself, but from an overwhelming bacterial infection because their spleen is non-functional.

God. Another really horrible outcome would be stroke. And this is especially what is so tragic is that stroke is very common in young kids with sickle cell anemia. And so that's essentially not just from small vessels being blocked, but from larger blood vessels in your brain that get blocked. And then overall, the most common cause of death and the second most common cause of emergency room visit for someone with sickle cell anemia, at least in this country, is what's called acute chest syndrome, or ACS. And this is when you essentially get those crises in your

lungs. Oh my God. Yeah. And what is awful and also very interesting about ACEs. is that the trigger for that can be almost anything. So it doesn't necessarily start with just these sickled cells blocking blood vessels. It can be a viral infection that causes inflammation that then triggers all these events. It could be an asthma attack because you can have asthma and sickle cell that triggers all of these events. It can be fat embolism because if you have, for example, necrosis of your bones, your bone marrow is full of fat. Little pieces of that fat can break off and travel to your lungs, and then those little emboli, they're called, can cause a blockage that can then trigger all these

downstream effects. So acute chest syndrome, ACS, is, it's basically a triad of extreme chest pain, infiltrates, so fluid and junk all over your lungs, and then what's called arterial hypoxemia. So not able to get oxygen in your arteries because of all this fluid and junk in your lungs. This is horrible. It's really, really awful. So, yeah, that's kind of the overall symptom picture of what happens with sickle cell anemia or sickle cell disease. And so these happen, like you talked about, these tend to happen at different stages of someone's life. So what, like, why is that? Is it just a matter of, of, like, your body growing and, like, certain things growing at certain times more? Like, yeah. Yeah, it's a, it's a really good question. It's not, I don't fully know, but it is the case that people tend to present differently at different ages. So, like, in very young kids, the first presentation might be that hand and foot swelling, right, in like a very young baby. As they get older, especially under five,

it's very common to have bacterial infections that can end up becoming very serious. Then at a certain age, stroke is a common manifestation. And then after that, these pain crises and acute chest syndrome. Right. Oh, my gosh. Yeah. And then on top of that, like we said kind of already, you have kind of chronic anemia. So not enough red blood cells, this homolysis, which leads to fatigue. It leads to jaundice. You can have gallstones very commonly because of all this hemoglobin in your bloodstream. It can cause the formation of gallstones. So you can have huge pain from that. It's very bad. Kidney failure is really common. If you block the kidneys, the bloodstream to your kidneys, you can have kidney failure. That's really common.

I mean, it's everything. I mean, anywhere that your blood flows. Yeah. Exactly. Jeez. And what I also want to mention that I think is often glossed over is the, huge amount of mental and behavioral health complications from this. Depression and anxiety are very, very high among people living with sickle cell because they have chronic pain. Not only are they living

with chronic pain, not only do they have a reduced life expectancy, they're frequently in the emergency room, they're frequently being hospitalized. That's a massive amount of financial cost that's incurred. And on top of that, there's a longstanding history of medical professionals not believing or not taking seriously the pain that you're in. So, yeah, this is a very, it's a single mutation that leads to so very many complications. Oh, yeah. Oh, yeah. Yeah. Well, is it a single mutation?

I don't, there's my transition. Okay. So all of that is kind of the description of. sickle cell anemia, which is when you have two copies of that mutated beta-globin genes so that you have messed up hemoglobin. That's not the only way that you can have sickle-cell disease. There are a number of other mutations that can result in sickle-cell disease that is usually less severe than sickle-cell anemia, although in some cases it's almost as severe. So if you have one copy of the sickle, like HBS, that sickle cell allele, and then you have one copy of a beta thalassemia allele. So

beta thalassemia is something most people might have heard of, or thalassemia maybe you've heard of. This is another entirely separate mutation of your beta-globine gene. Right. You can have one copy of HBS and one copy of beta thalassemia, then you kind of have thalassemia and you kind of have sickle cell disease. You have like a combination of both. So typically your symptoms aren't going to be as severe as someone with two copies of sickle cell, but you're still going to have some of that. You can still have some cells that sickle essentially. Okay. Gotcha. Yeah. There's another gene called HBC. That's like another form of sickle cell. So you can be HBS, H. H.S. B. C. That's a whole other one. There's another type of thalassemia called alpha thalassemia. So that's where

those alpha polypeptides are messed up rather than the betas in your hemoglobin. And that typically leads to actually like a less severe form of sickle cell anemia or of sickle cell disease. Why? Like what's the difference between the alpha and the beta that it would be a different severity? So it's actually, this is very complicated, but it's actually because instead of only two copies of alpha, we have four copies of alpha. So if you have just one mutation, you still have three good copies. Gotcha. So what's I think really important to kind of, it's a good question. I'm glad you asked that, Erin, because what's important about this is that if you have one copy of this HBS, this sickle cell allele, you're still going to make that kind of messed up beta hemoglobin.

But you'll make enough normal that you won't have these sickling events. Okay? Mm-hmm. You make enough normal hemoglobin that they can't form those chains and sickle unless you have, like, extremely low oxygen concentrations, okay? So in rare instances, you can still get sickling. But in general, it's going to be a lot less. It's not going to be nearly as many of your red blood cells.

If you have two copies, all you make is a messed up beta hemoglobin. Okay? So all of your red blood cells have. this messed up hemoglobin, okay? Right. And this is where, like, the language around it is so important to remember, like, the difference between sickle cell disease, sickle cell trait and sickle cell anemia. Exactly.

And that's led to a lot of confusion in the history of it, as I'll talk about. Yeah. And so sickle cell trait would be if you have one copy of HBS and one copy of a normal HBA, or normal adult hemoglobin. Right, right. Oh gosh. So yeah, okay. I think that's all about those types of things.

What else do you want to know about the biology? I've got more for you. Well, I want to know about treatments. Okay, let's talk about it. It's not great. Okay. There are some good things. So remember how, especially for young kids,

most common cause of, like, death is overwhelming bacterial infect. So in many countries in the world, we now screen for sickle cell disease in newborns. And if you identify somebody with sickle cell disease, you can start treating them prophylactically. So before they ever get sick with penicillin. So these kids get penicillin just every day for like the first five years of their life. So that has reduced the death rate to like less than 3% compared to over 25%. That's great. So that's great. Vaccinating babies is massively helpful in preventing overwhelming infection

because we have vaccines for a lot of the things that commonly cause infection in these kids. But beyond that, so that's kind of like we can prevent kids from dying at a very young age from sickle cell. But beyond that, we really have cruddy treatment for sickle cell disease and sickle cell anemia. if somebody comes in with one of these acute crises of pain, there's not much more to do besides pain control, which I'm sure you'll talk more about later is like, yeah, the problems, so many problems. You can give transfusions, so you can do an exchange transfusion

where you take out their blood and give them new blood, essentially, so that can decrease the amount of sickled cells in their blood, which can be very helpful. but the only actual treatment like drug that we have is hydroxy urea, which this is so fascinating. We have no idea how it does this, but what it does is it increases the amount of that fetal hemoglobin, that gamma hemoglobin. I see your confused face, Aaron. Yeah.

How, why is, how? Okay, how I can't answer. normal amount. Do we have like any amount of gamma hemoglobin just circulating at any given time? Yes. So and great question. Potentially yes. And there's massive amounts of variation in how much fetal hemoglobin a non-sicle cell disease person produces. And even within someone with sickle cell disease, how much fetal hemoglobin they have correlates to how severe their disease is. So the more fetal hemoglobin, the less severe their disease tends to be. So giving somebody hydroxyurea increases the production of fetal hemoglobin

decreases the severity of disease. That's fascinating. Fascinating. And I have a question. Okay. Do you know, is there any sort of elevational or altitudinal gradient in terms of like, let's say if populations whose ancestral history has been mostly like high, elevation, do they produce more gamma hemoglobin than those at lower elevations?

That's such a good question. And I can't remember. That is such a good question, Aaron. I can't remember. I don't know if people tend to have higher fetal hemoglobin, but there are certainly adaptations in populations that have lived for a long time at high altitudes where their hemoglobin has a higher affinity. So it binds tighter to oxygen the way that fetal hemoglobin does the same way. Interesting. Yeah. There's so much more to that whole, like the whole oxygen thing and altitude. We can't get into it. But I know. I mean, there's, we really should do like an episode on blood. Ooh. Because I also want to talk about blood groups at some point. Oh, I know. We've never done that. That would be super fun. I'd love to talk about blood even more. Okay. People will be experts by then because we did it in hepatitis and now we're doing hemathealine. It's cool. Okay, so that's hydroxyurea.

So that is considered a disease-modifying agent. It's the only one we have because it actually improves your functioning, essentially, by increasing the amount of fetal hemoglobin. But the only cure, and I'm going to put that in air quotes, is bone marrow transplant. But that has its own suite of problems. Absolutely. Always does. Yeah. So it has to be, you know, a perfectly, you know, a perfectly,

or very well-matched donor, which is very difficult to find. It requires that you wipe out somebody's entire bone marrow first, which leads them very susceptible to infection. Then once you put in the new bone marrow, you can have auto-rejection, et cetera. And so because the severity of sickle cell disease and sickle cell anemia is so, it ranges so much, transplants are not generally done except in very severe cases and even then only in high income countries like the US or the UK. So it's very rare essentially, which is problematic since that's the only curative treatment that we have. Right. And it's like curative as in like it's done forever. Like you're... Yeah, as long as your body doesn't reject it, then yes. You have you have brand new bone marrow so you

no longer make these sickled cells. You could still pass that on, right? You would still be able to if you had a kid, they could have either sickle cell trait or sickle cell anemia. But yeah, you would be cured. Yeah, I think that's all the major things I wanted to talk about for the biology. Okay. Gosh, this is a big one. It's a big one. Erin, where did this come from?

Why does anyone have to live with sickle cell disease? and what the heck is up with this mutation? Tell me about it. Okay. As soon as we take a short break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented,

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for this I'm going to concentrate primarily on the HBSS. form, not talk about thalosemia, this is just about sickle cell anemia and sickle cell trait, I think that the best place to start is in the name itself. Because, you know, aside from being one of my favorite things to learn about and talk about for any disease, it can also be incredibly revealing, especially in the case of sickle cell. Because the name tells us not only what those who named it saw and what was important to them in describing this disease, but it also makes us kind of. consider what discovery is. Like, what does discovery mean and how often that term is misapplied

to something that could more accurately be called a development. Oh. So when the term sickle cell anemia was first used by Western medicine in 1922, named by Dr. Verna Reim Mason, the medical field was still in the midst of this big rush of new technology and new theories. and new hypotheses that led to enormous leaps forward in the understanding of disease, both infectious and non-infectious. And with huge improvements in, you know, microscopic, surgical, and other medical tools, physicians could now get a much more detailed look at what was going on inside the human body. And among other things, this led to a shift in how diagnoses were made.

So previously, doctors may have had to a real. rely solely on symptoms of disease as described by the patient. But with these new tools, it allowed for measurements and observation. So the art of medicine was becoming a science. And this is something that we've kind of talked about before. Yeah. And the vast increase in knowledge of medicine and the human body also changed the medical field in terms of specialization. Because with the volume of information that was growing day by day, it was nearly impossible for one person to learn it all and retain it all. And so there was not only the capacity, but also the need for specialists in certain fields. Okay. Interesting. And so both of these shifts were enormously beneficial to the people

being treated, because with an accurate diagnosis, you had a greater chance of getting appropriate treatment and care. But there were also some unintended consequences. But there were also some unintended consequences. So in some ways, medicine became more about the body and less about the person. And the heightened attention paid to measurements or direct observation could sometimes take away from the experience of the person receiving treatment. And this is reflected in the naming of sickle cell anemia. As you mentioned, the term sickle cell describes the shape of the affected cells, which is a direct result of the mutated allele. And it was given that name by the physicians who first observed these types of cells under a microscope. But the condition, the experience

of sickle cell anemia had been known long before the 1900s, thousands of years before, and people who lived in areas of high prevalence, notably in parts of Africa, had names for the disease as well. And I have a list of these names. but I don't want to butcher them entirely. But one of the commonalities of these names is that they have sort of this onomatopoeia, this onomatopoetic, like, rhythm to them. And that's because it represented the repetitive gnawing pain of sickle cell anemia rather than the cellular morphology.

Right. So it's like a description of what people were going through, not just of this, what the cell looks like. Exactly. Fascinating. And there was also another name. that was reported in the African medical literature in the late 1800s. It was a term Agbongis, meaning children who come and go, which is in reference to the high childhood mortality. Yeah. And so, yeah, these names describe someone's experience with the disease and perhaps

how they would define it rather than a cellular observation, which was completely removed from the experience. I mean, if you think about it, if you have sickle cell anemia, you are probably familiar with these extremely painful episodes characteristic of the disease, but you may have never seen your own sickle-shaped cells under a microscope. Right. So I just think that was a very, yeah. Oh, I love that, Erin. That's so, so interesting and important.

And I don't think I ever would have thought about it, quite honestly. And this is not my observation. This is something I've read in a book. But I think it also, it did make me think about other diseases that we have talked about. And, you know, there is a lot of meaning and a name, whether it's specific to a location. And we've talked about the issues with that. And or whether it's this very clinical, detached way, objective way of looking at a condition. And I think, I mean, there are some other ones that have, that are more about the experience itself like dengue.

I remember may have some link to the painful bone breaking sensation. But, yeah, it's a. That's very interesting. It was interesting. It was interesting. Yeah. And also, as the author of one of the books I read pointed out, the sharp contrast between the visible, the sickle-shaped cells and the invisible, the excruciating pain endured

in the various names of sickle cell anemia in many ways it mirrors the history of the disease, particularly throughout the 20th and 21st centuries in the U.S. Ooh. Okay. So, though there were some brief descriptions of what was likely sickle cell anemia since the 1800s, the mid-1800s, the first clinical description of the disease was made in 1904 by the University of Chicago physician James Herrick, who reported, quote, peculiar, elongated and sickle-shaped red blood corpuscles in a 20-year-old patient of his named Walter Clement Knoll, who was originally from Grenada, and the only one.

person of African descent to be accepted into the Chicago College of Dental Surgery that year. Wow. Yeah. So, Noll had some, I don't know if it's Noelle or Noll, so I'm just saying Noll. Noel had some ulcers on his leg and described painful episodes and other symptoms of anemia. And so Herrick drew some blood and gave it to his intern named Ernest Irons to check it out. And Irons made the actual observation, like that description, but.

Herrick reported his findings at a conference in 1910, and then Irons was given no credit. As per yuge. As per huge. And although Walter Clement Knoll recovered from his illness after his visit to Herrick, he did die at a young age at 32 of pneumonia, 12 years after that visit. And this first description of sickle cell anemia was closely followed by many others, who noted that it primarily affected black Americans of African descent. These are all American physicians.

And that complications arising from the condition often led to death at an early age. And despite these warning bells going, hey, we have a serious disease here on our hands. Maybe we should learn more about it and how to treat it. Sickle cell anemia remained largely invisible for a couple of decades before finally gaining some recognition in the 1930s. Wow. Okay. So why was sickle cell anemia obscured for so long? I can guess.

There are many reasons. Part of it was the pre-antibiotic high prevalence of acute infectious diseases and also pre-vaccine, some of which mimicked the symptoms of sickle cell anemia, such as malaria, and made it more difficult to see this disease underneath. And when antibiotics, vaccines, and antibiotics, vaccines, and individuals. infectious disease control policies were implemented in the, you know, early decades of the 20th century, other chronic diseases became much more visible. So it was like kids were just getting sick and dying from sickle cell anemia before they knew that it was because of sickle cell anemia.

Exactly. Okay. That makes sense. Exactly. But of course, the other enormous component was the inherent racism in medicine. Yep. Higher rates of disease, higher infant mortality, and lower life expectancies overall in black Americans compared to white Americans was dismissed by the vast majority of those in the medical field, which of course were primarily white, as either evidence for a biological basis of race, or they said, oh, that this is just indicating that, you know, there's large, widespread ignorance of medical practices. Oh, geez. And essentially, the fact that black Americans faced worse health outcomes was seen as

normal as an inevitability. I would say, unfortunately, that still is... The bias in medicine? Oh, yeah. Oh, yeah. Yeah. And this false concept of racial superiority in biology is so longstanding and insidious and is still, like we talked about, very present today in medicine.

So following the American Civil War, some opponents of emancipation claimed that the black race would die out and that the high rates of disease and poverty, um, that the white race among black people were evidence that enslavement was a good thing. And these paternalistic beliefs bled into policy, policies which were designed to uphold these divisions of class and privilege and prevent any movements across those invisible but very real lines. In addition, there was the bigger issue of how risks of disease overall were perceived. So in much of the American South, for instance, discussions about disease were framed as the dangers posed by black people rather than the dangers the diseases posed to black people.

So this is something that like I've talked about before in the context of syphilis, tuberculosis, hookworm, and so on. So high rates of disease among black people were not seen as worrisome because they were directly damaging the health and, you know, shortening life expectancy of black people. It was more, oh, well, we don't want white people to get sick from black people. Right. So that is where the focus primarily was. How can we prevent white people from getting sick with what the black people have?

Exactly. Yeah, exactly. Yeah. And this shaped policy and attitudes toward public health and access to health care. Basically, the only way a public health policy was going to be enacted or research funds awarded was if the disease affected or threatened to affect white Americans in some way. Okay. And so when antibiotics and vaccines became more widely available throughout the 1930s and 40s, the widespread prevalence of chronic diseases such as sickle cell anemia was revealed.

At the same time, the commodification of health and people's bodies had really ramped up. And what I mean by that is that basically alongside the medical developments of the late 19th century and early 20th century, people's health and bodies began to be assigned a monetary value. How much did this procedure cost? How much did that medicine cost? How much did someone's poor health limit their productive output? Right. Disability-adjusted life years and...

Yep, right. The medical profession contributed to this not just through the exchange of money for treatment, but also by assigning intrinsic values to certain conditions. People with rarer diseases were seen as value. to the medical profession. Hospitals in poverty-stricken, densely populated urban areas were considered to be great places to get experience in training as a medical student. And the term clinical material was frequently used as a way to even further remove the person from the medical experience, as in whatever general hospital supplied an adequate amount of clinical

material to train students at not one but two medical schools. I'm sorry. So that means clinical material meaning sick humans. Yeah. Humans or like different cases or like different surgeries. I mean, and this is like this is still today. Oh, it really is. It's very much like, oh, you should do, you should, you know, get experience there because you're likely to see more of these diseases. The amount of times I heard, oh, we've got really interesting pathology at this residency program. I'm like, wow, that's horrible for the people in that area. But yeah. Yeah.

And employers also played a large role and continued to play a large role in the commodification of health, maximize profits and productivity by ensuring that your employees are well enough to work. And of course, if your health can't be improved, consider dropping them. Against this backdrop of this enormous growth of medical knowledge, reduction of infectious disease, and commodification of health and disease, awareness of sickle cell anemia rose greatly. And in the coming decades, this fame would grow to become in some ways a double-edged sword.

So on the one hand, the adoption of sickle cell anemia throughout the 1950s, 60s, 70s as a cause by many social groups and the increase in research funding for it led to a great deal of important knowledge being gained and in raising awareness overall. researchers fascinated by the puzzle that the disease posed, not necessarily by the people experiencing the disease. They had uncovered that certain conditions like low oxygen and high acidity could induce

sickling of cells, and they had also observed that sickling could also result in people who did not have the disease but were relatives of those that did. In 1949, two papers published nearly simultaneously by Dr. James Neal and Colonel E.A. B. beat presented the hypothesis that the disease was an autosomal recessive trait, meaning that it was inherited. And like you said, the two copies were required for disease to be present. I also want to note that, once again, discovery versus development, that the inheritability of sickle cell anemia had long been recognized in some groups where the disease was especially prevalent, such as among certain populations in Ghana.

Yeah. That makes sense. Yeah. And also in 1949, Dr. Harvey Itano and Dr. Linus Pauling demonstrated that the sickling was caused by an abnormality in a hemoglobin molecule, prompting them to call it a molecular disease. I think it might actually be the first disease described as a molecular disease. A few years later, the individual amino acid substitution leading to the structural change in hemoglobin was identified, teaching researchers that single mutation could be responsible for this whole suite of systemic effects on the body. Yeah, which is pretty incredible.

Oh, yeah. But a huge shift in the notion or representation of sickle cell trait or that sickle cell that mutated allele as a disease condition came about with the hypothesis, first floated in like the mid-1940s, that the sickle cell trait, so again, one copy of that mutated allele, actually provided a level of protection against the falcipera malaria parasite. Mm-hmm. Giving insight into why the allele was present at relatively high rates despite its deleterious effects.

Right. And so this is an example of what is called a balanced polymorphism. And this turned the dichotomy or this long-standing dogma of normal equals good and abnormal equals bad on its head. Yeah. It's why the term normal is stupid. Yeah. Yeah. It's inadequate. It doesn't. It doesn't. I mean, what is normal? Like, it's not, and sometimes it's hard. Like, I'm like, I don't, I don't know another word to use, but that it's not a good word in medicine. I know. Because we need to improve our vocabulary. Yeah. For that. So, but these, these scientific breakthroughs,

particularly in its labeling as a molecular disease and all the hype that that generally, generated, it got a lot of researchers super excited to jump on the sickle cell train, which was also pulled forward by the increasing interconnectedness of hospitals, research institutions, public health departments, and outreach groups. And this wealth of new information about the nature of sickle cell trait and sickle cell anemia did not, though, necessarily translate directly into lives saved. Because in much of the South, racial segregation still prohibited black Americans from seeking care at the highest funded hospitals, which were, of course, white only.

Yeah. Wow. In addition, and here comes the other side of that, you know, double-edged sword, despite these advancements in the understanding of the disease, outside of academia, such as in political discussions or debates, clear knowledge about the exact nature of sickle cell anemia lagged far behind, especially in understanding the difference between sickle cell trait and sickle cell anemia. For instance, during World War II, a controversial debate arose about whether sickle cell

trait, so having the one copy, posed a threat to the health of soldiers who had the trait. In other words, posed a threat to war efforts. Oh, gosh. Suddenly, this disease that had been invisible for so long was now visible and could be used to discriminate against those with the disease or even just the trait. After four people in the Marine Corps with sickle cell trait died after a training exercise at a high elevation, strict limits were placed on whether those with sickle cell trait could become pilots, either in the armed forces or commercial airlines or hold other positions.

So not just in armed forces. like a huge, huge restrictions placed on that, but also in other parts of the workforce. So like flight attendants, there was a lot of issues with health insurance carriers dropping people who were found to have sickle cell trait or sickle cell anemia. Oh, my God. And so these restrictions were instances of racial discrimination. Yeah. Since the overwhelming majority of those forbidden from entering the armed forces, for instance,

due to sickle cell trait, were black. And class action lawsuits led to the removal of some of these restrictions, but only decades after they were first put in place. Oh, my God. But of course, just because restrictions are gone does not mean that racial discrimination in the workplace was gone. And whether it was because the parent of a child was sickle cell anemia was more likely to miswork or if they themselves were affected, there was simply no shortage of ways for people to be discriminated against. into the 1960s and 1970s, sickle cell trait and sickle cell anemia moved or was pulled even further into the spotlight. In academic circles, sickle cell became the focus of narratives that interwove biology, anthropology, and history to explain whatever story was the goal of the author. And these narratives were sometimes criticized for their tendency to make sweeping generalizations about entire groups of people or entire.

higher places, or for forcing the facts to fit the story, making it sort of a just-so story. Other researchers finally began talking about how sickle cell disease and inadequate medical care may lead to poverty rather than poverty being the cause of disease and ill health, and understanding the more of the cycle of poverty and access to health care. And in the sociopolitical sphere, sickle cell disease took on new meaning during the civil rights movement of the 1960s. It was held by some civil rights groups to be symbolic of the long-standing, invisible or ignored pain and suffering experienced by so many who had long been racially discriminated against and whose access to health care had always been restricted. Despite the increased awareness

of sickle cell, it still lagged behind other genetic diseases in terms of funding, particularly those that disproportionately affected white people, such as cystic fibrosis. Oh, yeah. So, for example, in 1967, there were roughly the same new number of cases of cystic fibrosis and sickle cell anemia, but the difference in funding from volunteer organizations was staggering. For cystic fibrosis, these organizations raised $1.9 million. And for sickle cell, that number was $50,000. Do you want some current numbers or do you want me to tell you those later?

Tell me those later, but I'm, yeah, I'm sure that they're not any better at all. Yep. Yep. But there was a lot of charitable work being done and awareness efforts that were made. So the Black Panther Party, among other groups, organized and created a massive network of healthcare centers across the country where one of the goals was to raise sickle cell awareness and funding. Dr. Charles Witten, for whom our drink is named, started the sickle cell detection and information center in Detroit in 1971, and also helped found the Sickle Cell Disease Association of America, which has been instrumental not only in their educational efforts, but also in assisting families

who have been impacted by sickle cell disease. And also he did a lot of work in terms of lowering barriers for people who are underrepresented in medicine to be able to get to. go to medical school and have that as an option. Federal funds also poured in as Nixon signed into law the Sickle Cell Anemia Control Act in 1972. And so this act included increased funds for research, as well as health care for those impacted. It also required genetic screening to be voluntary rather than mandatory, which had been a huge issue previously because that just like paved the way for discrimination.

Yeah. And it also included support for reproductive counseling. And during the 70s, our understanding of the disease itself became more nuanced as well. So first, new research about the possible origins of the allele showed that it likely emerged in four different mutational events between 70,000 and 150,000 years ago, three events that took place in Africa and a fourth that took place in either Saudi Arabia or Central India. This allele emerged in different places around the world. It's not just from one origin event. Secondly, there was the growing awareness of other human gloomal disorders and the fact that sickle cell trait was found in non-black people as well,

which threw some complexity into the discussion in the 70s. representation of sickle cell anemia and popular media also increased as characters with the disease were featured in a couple of movies or TV episodes and magazines featured articles about the condition. But once again, here comes the other side of that double-edged sword. The prominence of sickle cell anemia and political discussions of this time meant that some politicians felt as though they could use the disease to symbolize whatever they wanted. to in order to drive their own narrative about race relations in the U.S. And sometimes it was used, sometimes that was used to bring about real positive change, but other times it was twisted to halt forward progress. Let's take genetic screening and reproductive counseling as an example.

Okay. The push for genetic screening for sickle cell anemia and sickle cell trait came at a time when genetic screening in general had greatly increased, and when discussion of reproductive rights was at the fore. forefront, especially issues of birth control and abortion. Genetic screening to look for sickle cell trait or sickle cell anemia, although it was helpful in terms of getting people the medical attention that they may need, it often did an inadequate job of explaining what exactly the difference between sickle cell trait and sickle cell anemia was. And this inadequate explanation

may have been unintentional or intentional at times, it appears. So, So people who had the trait, just one copy of the allele, were often openly discouraged from having children and urged to have abortions or undergo sterilization, procedures that were sometimes made free as an incentive. Ugh. Yeah. And then the concept of mandatory screening for this and other genetic disorders was floated. And Linus Pauling, the Nobel Prize winner and whose name I mentioned earlier as being the scientist,

Yep. He suggested that everyone who had the sickle cell trait should have it tattooed on their forehead so that when they see another person with a tattoo, they can avoid falling in love and wanting to have children with them. What? Mm-hmm. Mm-hmm. Oh. And these acts, these discussions, of course, resulted in accusations of course resulted in accusations of restricting black fertility, racial genocide and new eugenics, and rightfully so.

Yeah, that's what sounds like to me. Oh, yeah. And this misleading reproductive counseling for sickle cell was just one way that reproductive restrictions were intentionally or forcefully placed upon black people. I really recommend killing the black body by Dorothy Roberts to read more about that topic. And so before wrapping up with the history of sickle cell

in the 1980s and 1990s, I want to read a quote by the author of Dying in the City of the Blues that I think does a really good job of summing up the 1970s and sickle cell perfectly. The story of sickle cell disease in the early 1970s also revealed the ways in which the political process both channeled and deflected the popular activism of the time. It was a time of grudging recognition of the Black experience, but it proved difficult to translate that awareness directly into health policy without creating enormous this new, stigmatizing burdens for black Americans and without fostering growing cynicism about

racial politics. Yep. Yep. And so that brings us to the 1980s and 1990s. I don't want to step on your toes too much, Aaron, about whatever you're going to talk about. So I'm just going to go over a few big developments or patterns that emerge during this time with regard to sickle cell that I have a feeling you'll talk more about.

Okay. Let's see. Yeah. So as you mentioned, pain management is a huge component of sickle cell anemia. And the sympathy for people with sickle cell that seemed characteristic of the 1960s and 1970s kind of gave way to this disturbing trend of cynicism and stigma. More and more health care providers seem to simply not believe that people with sickle cell anemia were experiencing a true painful episode.

And there were increasing reports. of healthcare providers accusing their sickle cell anemia patients of faking it, of exhibiting drug-seeking behavior, and correspondingly limiting the pain medication prescribed. And earlier when you talked about the different timeline of when at different ages you experience, you're more likely to experience one symptom over another, that the increase in painful episodes in late adolescence and early adulthood is something that also like made this whole, made this whole thing worse, they were like, oh, well, you're a young adult, you're just seeking drugs, so I'm not going to give you any. Oh, my God. And this is, you know, this is despite the

fact that there was research indicating that this wasn't going on, that people with sickle cell anemia were just as worried about their own, you know, narcotic consumption or pain medication consumption as, as anyone else. And it was, it's just like, it didn't seem to make a difference. Yeah. It's, like, it seemed to be like this, this belief that became so embraced and, like, so difficult to get rid of. It's so frustrating that in so many papers that you read, it's still something that is mentioned, like, oh, you often have to use opioids to treat pain, which can lead to addiction. It's like, that's true in anyone, and there's no higher rates of opioid addiction in people with sickle cell anemia than in the general population. Like, there just isn't. So it's, it's infuriating that you'd be

like withholding treatment that is necessary. Oh, uh-huh. Yeah. Well, and there's also, there was also something that was mentioned in this book about how there was research indicating that opioid addiction starting from hospital treatments or medical treatments is extraordinarily low. That is not the way that the vast majority of opioid addictions begin. And so, but despite all this, this enormous bias still remains.

And this is, I mean, this is a larger issue. Yeah. the invisibility of pain in medicine. We can't measure it. And I think that makes people trust it less, trust the person less. And it sort of goes back to what I was saying earlier about how medicine became more about the body and measurements and these things that you could, you know, you could put on a chart than it became about the person's experience itself. Yeah. Yeah.

Yeah. But, you know, in this context, what this meant, this increasing, you know, disbelief was that people with sickle cell anemia were at renewed risk for their pain, their experience to once again be neglected, ignored, and made invisible. And this persists today, this issue. Yeah. And these decades also brought the promise of many different therapies for sickle cell anemia. such as hydroxiauria, as you mentioned, and bone marrow transplantation,

which didn't necessarily uphold the shiny promises that had been made about them in their first introduction. But I'm really hopeful to hear more about new approaches. But I want to end now again with another quote, again from Keith Waylou, the author of Dying in the City of the Blues. For liberals, moderates, and conservatives alike, the history of neglect and the disease's chronic painful character seemed to reflect white America's neglect and misunderstanding of black health concerns

and demanded attention. The disease became a multi-purpose metaphor, a proxy in social, economic, and political debates about a wide range of seemingly unrelated issues. Okay, Erin, bring me up to speed on what's going on with sickle cell today. Okay, let's take a quick break first. All right. So we'll talk first about numbers, how many people are being affected by sickle cell in the U.S. and in the world today. And then we'll touch a little bit more on why that is and the malaria connection, because I do think that's a really interesting part of the story.

And then we'll talk about current research. Does that sound good? Sounds great. Okay. So we'll talk first about the U.S. and then globally. So in the U.S., newborn screening is conducted since 2006 or 2007 across the board in all states plus Puerto Rico in the U.S. Virgin Islands. So we know the rates of sickle cell allele in the population. So one copy, having one copy of sickle cell trait. Okay. So overall in the U.S., in 2010, the incidence was 15 per 1,000 babies born.

trait, trait, okay? But this is a huge range from 73 per 1,000 among black newborns to two per 1,000 in Asian, Native Hawaiian and Pacific Islander newborns, three in white babies, and seven per 1,000 in Hispanic newborns. And this is voluntary or mandatory screening? So newborn screening is generally, it's universal. I think it is possible to opt out of it, but in general, it's universal and kind of recommended. I think most of the time they don't want to let you leave the hospital without newborn screening. Because it doesn't only screen for sickle cell.

This screens for a whole bunch of different. We talked about this in this cystic fibrosis episode as well. Right, right. Because you're also identifying then those newborns with sickle cell anemia. But what's interesting is that it's actually hard to get a. number on the number of babies in the U.S. born with sickle cell anemia, which I think is interesting. So let's talk about the whole globe. How many people are born every year with sickle cell anemia? Globally estimates are about 300,000, just over 300,000 babies born every year with sickle cell

anemia. That's a huge number. It's a massive number. And I want to point out that that number is the number of babies born with sickle cell HBSS. But remember that there are other ways that you can have sickle cell anemia, right? You could have it with one copy of HBS and one copy of beta thalassemia. You could have it with one copy of HBS and one copy of HBC. Those aren't included in that estimate of 300,000. So it's thought that that total number accounts for about 70% of the total amount. of sickle cell disease, so that whole range of clinical disease worldwide.

And it's also estimated that about half of these babies worldwide are born in Nigeria, the Democratic Republic of Congo, and India. And that in many parts of sub-Saharan Africa, sickle cell anemia might be responsible for as much as 6% of all childhood mortality. 6%. Oh my God. Just from sickle cell anemia. Because in many places, in many parts of the world, under 5 mortality from sickle cell

anemia, so dying before your fifth birthday, can be as high as 50 to 90%, which is atrocious. Wow. Yeah. Wow. Yeah. Yeah. And that's because if baby. aren't identified by newborn screening, then they don't receive penicillin prophylaxis or they don't

receive adequate vaccinations, then it's very common than they will die from overwhelming infection before they turn five. So that's why newborn screening is so important and has been so helpful. Like, it's only worth screening if you can do something about it, right? So we screen for things that we can prevent death if we identify them early. And so that's what we can do with newborn screening. Yeah. I think it's just been, it's like, I mean, and this is in general, newborn screening or any kind of genetic screening is such a touchy issue because it can so easily lead to, you know, who has that information and how can they use it against you? Absolutely. I mean, plus it gets into so many things of, so if you identify a newborn with a genetic trait, that had to come from either mom or dad, right? So now you know that either mom or dad has this. Maybe they do. didn't want to know that. Like there's a whole, the ethics of all of that is wide ranging and more than we can talk about in this episode. But identifying babies with sickle cell anemia prevents

them from dying. So in that way, it's extremely important and helpful. But despite the fact that this is a very common disease and a very common trait among the population, like you said, funding discrepancies remain, which is why to date we have only one disease-modifying treatment, that is hydroxiaurea. So I want to talk, I want to give some more specific numbers. You mentioned them from, I think, the 60s and 70s. So let's talk about the last decade from 2008 to 2018. Good, I was hoping you would do this. This paper just came out in March of this year. So we'll compare federal funding per person between cystic fibrosis, which we did an episode on, and sickle cell disease. So cystic fibrosis is another genetic disorder. It's also identified on newborn screens.

It's also like the most common genetic disorder among white babies. So compared with cystic fibrosis per person with the disease in the U.S., cystic fibrosis received 2,800, in federal funding compared to $800 for sickle cell. Wow. That's $2,000 more. It gets even worse if you look at charitable foundation expenditures. Cistic fibrosis, $7,600 per person with cystic fibrosis compared to $100. Oh, my God.

Oh, my God. For sickle cell. Which, I mean, this directly leads to a, discrepancy in the number of new drug approvals. In that same time period, four new drugs were approved for cystic fibrosis, one for sickle cell. I mean, it just, it just trickles down and down and down. Like you have the research money, you have treatment accessibility, you have new treatments being developed, you have healthcare, access to health care, like all of these different components to it, which is, yeah. And so to put like a specific number two on the difference in terms of

overall prevalence of sickle cell versus cystic fibrosis in the U.S. This paper reported the U.S. birth rate of sickle cell disease is one in 365 black babies. For cystic fibrosis, it's one, it's very high. That's scary high. For cystic fibrosis, it's one in 2,500 white babies. Mm-hmm. Which is also, you could say, very high.

But one in 365 is a lot high. But yeah, when you put the numbers side by side, it is very, I mean, it's not surprising, but it is appalling that there's such unequal support in funds. And so I think it kind of leads to a really important question about why is it that this is such a prevalent disease? Because a lot of times when we have genetic diseases that are recessive, so you have to have two copies of that allele, in theory, evolutionarily, that. that allele, that mutation should die out, right?

If it's so bad that if you have two copies of it, you end up dying before the age of five, you're not going to be reproducing, so you're not going to be passing on that allele. So why is it at such high prevalence in the black population? Here's why, or at least what we think. It turns out that if you have one copy of this allele, it's very protective against dying from malaria.

it's very protective against infection, severe infection with plasmodium falciperum malaria. So in regions where plasmodium falciperum malaria, so that one species of malaria is very, very prevalent, the prevalence of this specific mutation is also very prevalent. What I think is so interesting is like this has been kind of an epidemiol, we've shown this epidemiologically in so many, many studies, just how massive the protection is, but there's still not a clear molecular answer as to how one copy of this allele protects you against dying from malaria. Overall, it seems like if you have some of that HBS beta hemoglobin, then your cells can eventually sickle, and then those cells that are infected with plasmodium, the plasmodium doesn't replicate. So essentially malaria can't

grow as well in those cells for like a number of different reasons that we still don't fully understand. Right, but it's it's only in the cells that have sickled. Yeah, and so it turns out that infected cells tend to sequester in certain organs that have low oxygen concentration. Right, so then those cells, yeah, spleen and liver. So then those cells end up sickling because of that. So whereas normally if you just have one copy, your cells wouldn't sickle very often, but these infected cells get sequestered under low oxygen concentration and then end up sickling, and then the plasmodium can't replicate. That's really interesting.

Yeah, it's pretty interesting. So I'll post a paper, one of the more recent papers I found going into more detail on that if you're interested. But yeah, so then I guess the question is where do we go from here? And even though we only get, what, 100 or 800 research dollars per 2,800 for cystic fibrosis, Is there research going on about more treatments? And the answer is yes. There's actually some pretty exciting in terms of technology treatments on the horizon.

So we have a very special guest on today to talk about the wonderful world of genome editing and specifically CRISPR as it relates to treatment options for sickle cell disease and other genetic disorders. So let me introduce Dr. Megan Hochstrazer, the education programs manager at Innovative Genomics Institute in Berkeley, who's here to tell us in much greater detail than I ever could, what CRISPR is, a little bit about genome editing and what that even means, how we can use it for diseases like sickle cell, what some of the drawbacks might be, and how far away we are from technology like this being in everyone's life. Excellent.

My name is Megan Hoxstrazer, and I work for the Innovative Genomics Institute or IGI at UC Berkeley. I am the education program manager, so I basically try to talk to people about all of the research that our Institute does and the science behind it and help them understand what it means and what it's all about. So the IGI or the Innovative Genomics Institute is a partnership between UC Berkeley and UC San Francisco. So we're a nonprofit research group doing academic research, trying to, to use genetic engineering tools like CRISPR to solve big world problems. So we work in biomedicine and human health. We work in sustainable agriculture. And we basically try to improve CRISPR based and other technologies that are used to manipulate DNA in different ways, improve the tools and then apply them to solve different problems. Oh my gosh. That's amazing. Good. Oh, that is so cool. So could you start off just by

telling us what exactly CRISPR is. I think that people have heard that term, but a lot of us don't know what it means. Sure. I mean, I got my PhD study in CRISPR, and I still am behind the times and understanding every little bit about it. It's really complicated. And actually, there's new CRISPR tools and CRISPR news like every other day. So it's hard to keep up with. But at the core, CRISPR, in the most basic terms, is a way of changing DNA. So it's a tool that scientists can use to make targeted precise changes in the sequence of DNA

that's in a living cell or organism. So this is really impactful because previously we were kind of limited to making synthetic DNA in a tube or something in the lab and kind of adding that to a cell or breeding two plants together to try to change the DNA in the plant,

the progeny plant, the child plant. But now we can take something that is alive, like a human being, make changes in their cells to change the DNA sequence, and they will continue to be alive. So that's a really amazing advancement, actually. So genome editing is actually the bigger category. So CRISPR is one type of genome editing tool. It is so, it's like I feel like I'm living in the future. It is. It's incredible. So specifically, you know, in this episode, we're focusing on sickle cell disease. And recently in the news there was, you know, stories about using genome editing to treat sickle cell disease. And could you maybe walk us through how that is done?

Like what in the case of sickle cell, how CRISPR was used to treat the disease? Sure. Yeah. So it's been a really exciting time to be in the CRISPR field because I was there kind of before it was used as a genome editing tool. And I was just interested in what it's normally doing, which I don't have to get into because it's a long story. But CRISPR actually comes from bacteria. And it's just this system that bacteria used to fend off viruses that infect them, which sounds so obscure and not interesting. But we were able to take this tool from bacteria and kind of steal it and use it for our own purposes.

So I've been watching the development of this field since the very beginning. And it's been amazing, actually, to see when patients like the person who's been covered, in NPR who has sickle cell talking about how they have been essentially cured. I mean, fingers crossed, it seems like she's really been cured of the disease. So it's been incredible to watch from the beginning. So it's very exciting. I guess I would say there are two general approaches to using CRISPR to treat sickle cell disease. And they're really different in a conceptual way.

So the most straightforward way you can imagine to fix a genetic disease would be to go in and change whatever the mutated letter is in the DNA to the correct letter, right? And that's what our institute is trying to do for sickle cell disease. That's our approach. It's kind of conceptually straightforward and understandable. The approach being used to treat the patients who are now in the news being treated for sickle cell disease with CRISPR is a little bit different. So instead of trying to fix the mutation in the hemoglobin gene that is causing their disease,

instead, those clinicians are editing cells to start producing something called fetal hemoglobin. So instead of fixing the broken hemoglobin, they actually turn back on this other hemoglobin that all of our cells have the instructions to make but is turned off. And that hemoglobin can compensate for the damaged one. That is so amazing. It's so incredible. Wow. And is this like a treatment like CRISPR? Does it fall under the category of treatment or cure?

Right. So in theory, CRISPR could be a one-time fix for something like sickle cell disease. I think we're not going to know how long things like this last until we actually try them in a person because we can test something in a mouse, but mice live for a couple of years. And then you don't know, right? So I think it remains to be seen how long-lasting the effects are. And it also remains to be seen whether or not there are side effects that will pop up later that we haven't been able to detect early on. But so far, it seems like things are going well. Again, this is only like two patients for which there are data, but I think it's really promising. And that's what's exciting about genome editing in general to me is that you could do a one-time treatment because you're not treating the symptoms of a disease. You're not doing some kind of lateral approach to kind of helping the person but not actually fixing the underlying cause. With genome editing, we can, in theory, correct the underlying mutations. we can change someone's DNA in their cells and keep them from having any kind of symptoms,

basically wiping out whatever the disease is. So it's super promising. I think one thing to note is that for some conditions, you've already done damage. Like just living with some of the genetic diseases that are out there like sickle cell, causes a lot of damage to your tissues. And there are things that you can't change once they've already happened. They're irreversible. But in theory, with sickle cell, you could say,

stop future crises, like pain crises, where the cells pile up and get stuck in a cell and cause really horrible pain and more damage. So you could kind of halt the progression of the disease permanently. But that still remains to be tested. So I guess that kind of leads into our next question, which is how close are we to this being something that, you know, is more commonly used beyond just a couple of patients? I think we're farther away than I would want to be. So I think it's going to be a slow process, and this is something I have to deal with all the time when I'm talking to people I know who have various diseases or I'm giving public talks, is that everyone wants their disease to be cured today or yesterday. And it's just a very slow process. So sickle

cell is one of the most mechanically treatable diseases. So there's just details about the way it works that make it treatable using genetic engineering or genome editing. And there are a couple of other conditions that are also possible to do with our current technologies. And so they're coming first. But there are thousands of genetic diseases out there and all of those deserve to have some sort of treatment. So I think it's going to be probably a couple decades before we start having really common treatments using genome editing. Right now we have, I guess, maybe three or four genetic diseases are in clinical trials using CRISPR and the clinical trial process takes years. But I think I would be shocked if you had told me when I was in graduate school that just, you know, six years later, basically, someone would be cured of a disease using CRISPR.

I would be stunned. I wouldn't have thought that was possible. So I think it is moving very fast in scientific terms, but it can be kind of slow in human terms. That makes sense. Yeah. Yeah. And so I guess speaking of clinical trials and, you know, why there might be potential for this to take a little bit longer than. than other traditional treatments, are there or have there been observed any downsides to CRISPR, either in the technology itself, whether it's like expensive or in sort of like the, you know, side effect kind of way? Yes. For sure.

So I think as fast as we can move scientifically, we're still a long way from figuring out a societal level solution to rolling out CRISPR-based therapies. There's a big gap between a scientific solution to a disease and a societal solution because we can make the greatest scientific tool we can come up with that works really efficiently and it's accurate and there's no side effects. But if we can't make that affordable or accessible to people, it's not going to have any impact. So the cost in particular of genetic therapies is a huge issue. And it's something we talk about all the time at our institute and are trying to strategize

and come up with ways to get around this. But it's enormously expensive. So there are, there's a similar technology called gene therapy that is a little bit different from CRISPR. You could kind of call CRISPR a gene therapy. But at its base, a gene therapy is using a virus to add in a gene. So instead of making a precise change in DNA like CRISPR, you're just throwing a gene in somewhere into the genome that will be helpful.

And actually you can, there is a gene therapy for sickle cell disease. You could throw in a copy, a healthy, copy of the beta-globin or hemoglobin gene to help people, and that's under development. But gene therapies are kind of an emerging approach to genetic disease that have only recently started being approved by the FDA. So they've been in development for a couple decades now and are finally starting to reach patients or real people, but their price tags have been swapping. So they've been a couple hundred thousand dollars to millions of dollars per treatment, which is more money than I have.

I don't know about you, but that's a lot of money. And I think on the one hand, we talked about how these approaches, since they're fixing the underlying cause of a disease, could be a single treatment. So if you compare the lifetime cost of treating something like sickle cell disease or beta thalcemia or these other blood disorders, that's going to be a lot of money. And then in theory, perhaps paying half a million dollars once is actually going to be cheaper than the long-term cost.

But if you can't afford that up front, it's a moot point. And I think right now we're kind of trying to figure out if this is something that's going to be covered by insurance companies. I think it's an issue in America that is kind of broader than the science. But we've been trying to think if there are scientific solutions. So hopefully someone will figure out some social solutions. to health care. But in the meantime, we're trying to figure out if there are ways that we can change the way we do the science that will actually change the outcome when things are priced eventually. So that's one thing that we're working on that I'm kind of hopeful about. One of the big

issues with sickle cell disease that's going to make this so expensive is that we're doing all of this gene editing I'm talking about inpatient cells that we've taken out of a patient. So we're not putting a shot in someone's arm or giving them a pill. We're taking their cells, extracting cells from their bone marrow, editing them in the lab, and then putting them back into the patient's body. And that's really complicated and expensive. It requires people with a lot of expertise to handle the cells, and it just jacks up the price by a lot. And there's also this requirement in a lot of these cases for using a virus to deliver the CRISPR tools. And manufacturing this virus is really expensive and difficult as well. So there are a lot of steps and compounding steps

potentially that add costs. So we've been trying to think, are there ways to do this in vivo? So instead of having to take cells out and put them back, can we just do the fix directly in a patient's body? So I think there are potential scientific solutions to some of these problems, but they're really, really hard problems, and they'll take a lot of investment. You said you've talked in this episode about kind of historic marginalization of people with siblings. cell and the way there's, you know, racism and medicine manifests in this disease. I think one of the promising things that's been happening lately is, one, this kind of reckoning amongst the white scientific community and others about how black communities have been affected by the practice of

science and government funding and medicine and all of that. And two, we were recently told that the NIH and Gates Foundation are now investing $100 million towards due to. doing in vivo therapies or potentially other therapies, but particularly in vivo therapies using genome editing for sickle cell. So that's a huge investment of money that I think could make a really big difference in how we're able to treat this disease and actually making it an affordable treatment for people. What an awesome interview. Thanks again so much, Megan, for taking the time to chat CRISPR and genome editing with us. We loved it. And Aaron, we should definitely do an entire episode on CRISPR someday. Oh, yeah. All right. Should we do sources? Yes, absolutely.

Okay. So for my sources, I read a few books. One is called Body and Soul, the Black Panther Party and the Fight Against Medical Discrimination by Alondra Nelson. Also, as I mentioned earlier, killing the Black Body by Dorothy Roberts, and Dying in the City of the Blues by Keith Waylou. And also I have a few other books and papers that I will link to. A couple of papers I want to shout out are by Steinsma at all, Walter Clement Knoll, first patient described with sickle cell disease, and by Barash in 1998, sickle cell trait policy and research paradigms. Awesome.

I read a few good book chapters that I will link to as well as there is a great sickle cell disease in nature review disease primers. that was from 2018 if you want just kind of a nice overview of the biology of sickle cell disease. And then if you want that paper on the comparison of funding between sickle cell and cystic fibrosis was by Fahim Farak at all, published in JAMA in 2020, just earlier this year. We post all of these sources as well as the sources from every one of our episodes on our website. This podcast will kill you.com. Just click on the episodes tab. Well, thank you again so much to the amazing Marsha and Cherie for sharing their experiences with us

and also to Megan for walking us through the incredibly cool world of CRISPR technology. Yeah, thank you all so much. And thank you to Bloodmobile for providing the music for this episode and all of our episodes. And thank you to you, listeners, for listening. We love you, we appreciate you. We hope you like this episode. Yeah, it was really fun. So we hope you had fun too. Until next time, wash your hands. You filthy animals. I'm Amanda Knox, and in the new podcast, Doubt, the case of Lucy Letby, we unpack the story of an unimaginable tragedy that gripped the UK in 2023.

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