Speaker 1: So the day I was born had some quirks. First,
Speaker 1: it was the most beloved of national holidays, Groundhog Day.
Speaker 1: It was an Appalachian February full of blustery snow. And
Speaker 1: this is my favorite part. My dad's truck broke down
Speaker 1: on the way to meet my mom at the hospital,
Speaker 1: so he caught a ride with my uncle Tommy and
Speaker 1: their good buddy Peanut. That's all fun, not atypical, but
Speaker 1: there was one specific quirk about that day that's important.
Speaker 1: I was born with a broken collar phone. At the time,
Speaker 1: this was not super concerning. The concerning part happened ten
Speaker 1: weeks later when I was kicking around in my crib,
Speaker 1: just doing my baby thing, and my mom heard a
Speaker 1: snap and a screen. She rushed me to the er
Speaker 1: and the X ray showed a broken femur. To make
Speaker 1: a long story short way shorter, because you can imagine
Speaker 1: the questions my parents had to answer about that. I
Speaker 1: was eventually diagnosed with a rare bone disease called osteogenesis imperfecta,
Speaker 1: which we call OH or brittlebones for short, because osteogenesis
Speaker 1: and perfecta is a mouthful. I was born in nineteen
Speaker 1: eighty one, and I think at the time, there were
Speaker 1: just a few types. Now there are even more, ranging
Speaker 1: from incredibly severe to very mild. Mine is a mild form.
Speaker 1: Mostly my OI seems to affect the long bones of
Speaker 1: my legs. I've broken my femurs numerous times, which is
Speaker 1: not a bone that typically breaks without major efforts. And
Speaker 1: even though my bones are the most obvious part of
Speaker 1: my body affected by OI, it evidences in other ways
Speaker 1: in my body too. It affects my teeth, which isn't
Speaker 1: common for every person with OI, but mine have always
Speaker 1: broken very easily. I have some intense sculliosis, which again
Speaker 1: not everybody has, but it's not uncommon. As an adult,
Speaker 1: I am a tower in four foot nine. I work
Speaker 1: with kids a lot, and they always think it's awesome
Speaker 1: that I'm usually smaller than they are. The whites of
Speaker 1: my eyes are a little bit blue. That's a common
Speaker 1: part of OI called blue scin. So it definitely shows
Speaker 1: up in my body in all kinds of ways, and obviously,
Speaker 1: because my body is the vehicle through which I experienced life,
Speaker 1: it shows up in my life in.
Speaker 2: All kinds of ways.
Speaker 1: Somebody recently asked me if growing up was hard because
Speaker 1: of my bones and my first thought, honestly, is that
Speaker 1: my childhood was really great. I have the coolest, funniest
Speaker 1: and most genuinely kind parents. They already had my older sister,
Speaker 1: Bridget when I came along, and of course the three
Speaker 1: of them weren't expecting to have a baby with a disability.
Speaker 1: But I never felt anything but loved as an adult.
Speaker 1: I'm especially amazed that they didn't have a Google to
Speaker 1: read about OI. They didn't have anything like WebMD to
Speaker 1: freak out overall the what it is together. There was
Speaker 1: no support group on Facebook they could use for questions.
Speaker 1: The three of them just had each other, and somehow
Speaker 1: they helped me learn to move through the world, a
Speaker 1: world that's definitely not made for all bodies, with some
Speaker 1: independence and with a whole lot of joy. My brother
Speaker 1: came along five years later, and he also has OI.
Speaker 1: We both used a wheelchair and a walker most of
Speaker 1: the time when we were kids because our bones were weak,
Speaker 1: but our parents would just load them up and we
Speaker 1: would still go on family vacations or go hang out
Speaker 1: with family. My mom would pull me through her garden
Speaker 1: and a wagon. My dad would back the wheelchair up
Speaker 1: into my grandparents' house every weekend, so I could hang
Speaker 1: out with them. My big sister, who was always so
Speaker 1: much cooler and more fun and more awesome, would still
Speaker 1: take me out and do things with me. So with
Speaker 1: my family, I never felt left out. School was a
Speaker 1: little bit different, and of course it would be The
Speaker 1: word I usually heard people describe me with was fragile,
Speaker 1: and for a good reason. Any adult at a school
Speaker 1: would want kids to be extra careful around you. Sports
Speaker 1: were huge in my small town, and naturally any kind
Speaker 1: of contact sport was a heck no for me. But
Speaker 1: as my friends got more and more into sports, I
Speaker 1: full on embraced my nerd self and I got into books.
Speaker 1: I love to read, and I realized pretty soon I
Speaker 1: love to write, and even if I weren't disabled, I
Speaker 1: would have loved writing. But I think my disability was
Speaker 1: a conduit to the early realization that my imagination is limitless.
Speaker 1: In the actual physical world, my body has limits, sometimes
Speaker 1: a lot of them, but my imagination doesn't and it
Speaker 1: never has, and I learned how to flex my imagination
Speaker 1: like a muscle. It's another way I got through the
Speaker 1: trauma that can come with OHI A specific memory I
Speaker 1: have of that would be when I would break my
Speaker 1: leg and I would be at the hospital waiting to
Speaker 1: get it set, which is a very painful process, And
Speaker 1: as that was happening, I would close my.
Speaker 3: Eyes and I would imagine Narnia.
Speaker 1: I would think about as Land from the Lion, the
Speaker 1: witch in the wardrobe right, and what his fur would
Speaker 1: feel like between my fingers, or I would imagine what
Speaker 1: his roar sounded like, and if I could feel it
Speaker 1: inside my chest. And that made me feel brave. And
Speaker 1: I think that's where I realized fiction has the very
Speaker 1: real benefit of helping me realize how brave I can be.
Speaker 1: So it got me through some of that. Because of
Speaker 1: the type of OI I have, my bones did get
Speaker 1: a little stronger as I got older. There's no cure
Speaker 1: for OI, so my bones are always going to be fragile.
Speaker 1: But around the time I started high school, I was
Speaker 1: able to walk independently without a walker or a wheelchair
Speaker 1: as long as I was careful, And I realized then,
Speaker 1: for me at least, sometimes it's just as hard, if
Speaker 1: not harder, to advocate for your body and your health
Speaker 1: when your disability seems invisible, even though it isn't, even
Speaker 1: though it's something that still dictates everything you do in
Speaker 1: a day as an adult, especially lately, OI has affected
Speaker 1: my career, but not in a way I thought it would.
Speaker 1: I actually get to write for a living, which has
Speaker 1: been my dream job since I was in third grade. Specifically,
Speaker 1: I get to write novels for kids. To me, those
Speaker 1: novels that we read as kids are at the best books.
Speaker 1: Those are the books that help me trudge through the dark,
Speaker 1: that helped me realize how brave I could be. My
Speaker 1: first novel for kids was published in twenty fourteenth Scholastic.
Speaker 1: My first novel was a contemporary fantasy called a Snicker
Speaker 1: of Magic, and I got to keep writing more and
Speaker 1: more after that, and I love it. But I had
Speaker 1: never written a character like me who had OI until now.
Speaker 1: My most recent novel, Hummingbird, came out in August of
Speaker 1: twenty twenty two, and this one is about a girl
Speaker 1: named Olive who is homeschooled because she also has osteogenesis
Speaker 1: and perfecta, and her parents are kind of nervous about
Speaker 1: all of attending the public school, but she talks them
Speaker 1: into it. She goes, and the first day of sixth
Speaker 1: grade is a disaster, as sixth grade often is, until
Speaker 1: she hears a story about an enchanted creature in the
Speaker 1: woods that Grant's wishes, and she decides she is going
Speaker 1: to find it now. Obviously, Olive, like I said, has
Speaker 1: brutal bones, HERI is mildlike mind, and at first this
Speaker 1: wasn't going to be a big part of her story
Speaker 1: because honestly, I didn't know if people wanted to really
Speaker 1: read about how I felt about my disability. The most
Speaker 1: common line I see in books when a character is
Speaker 1: disabled is something like, my disability is my superpower, which
Speaker 1: is awesome, but it's not always how I feel. Most days,
Speaker 1: I love my life and I'm grateful for my body.
Speaker 1: I'm grateful I get experienced life inside it, but my
Speaker 1: body also breaks for seemingly no reason sometimes, and that
Speaker 1: can be frustrating and painful. I always say my relationship
Speaker 1: with my body will be the most complicated I have
Speaker 1: in my life, and that's true, but who would want
Speaker 1: to read that? So at first, when I was writing
Speaker 1: about Olive, I just wanted her to be fully, completely
Speaker 1: confident in herself, figuring out her own way to move
Speaker 1: through the world. Magic Adventure First crushures all of that
Speaker 1: good stuff, but it's like I couldn't find the heart
Speaker 1: of her story. And then in twenty nineteen, I was
Speaker 1: walking through the kitchen one night to check the doorlocks
Speaker 1: and I slipped and dog droll and as I was falling,
Speaker 1: I heard the snap that water is sickening, terrible sound,
Speaker 1: and then came this flood of pain, because breaking the
Speaker 1: femur is no joke. And in the months after that,
Speaker 1: I remembered what it feels like to be in that
Speaker 1: specific place again, to be in physical therapy again, nervous
Speaker 1: every time something hurts, to not be able to get
Speaker 1: in some buildings again because there's no access to them.
Speaker 1: And one night I was playing Mario on the couch
Speaker 1: beside my husband, having an intense pity party for myself,
Speaker 1: and I said, I'm broken and I hate my body
Speaker 1: and I'm frustrated, and he very gently said, hey, your
Speaker 1: leg's broken, you aren't broken. And that's what gave me
Speaker 1: the clarity I needed to write a Hummingbird in a
Speaker 1: way that was absolutely true to me. All of and
Speaker 1: I both love our families, we both love Dolly Parton,
Speaker 1: we both romanticize life and we see the magic in it,
Speaker 1: and we both have this disability that is sometimes really
Speaker 1: frustrating especially all of age. She's twelve. In the story,
Speaker 1: she is seeing how bodies are changing all around her
Speaker 1: and how hers isn't, or how it is changing but
Speaker 1: not quite the same way, and that can be tough.
Speaker 1: It was tough for me at least. I remembered what
Speaker 1: it was like to feel left out, to be called fragile.
Speaker 1: But I also remember the people in my life who
Speaker 1: loved me and who called out every good thing instead.
Speaker 1: My parents, my siblings, now justin my husband, my friends.
Speaker 1: They've all helped me find these doorways into my imagination,
Speaker 1: and they've helped me make the life I love that
Speaker 1: I'm really proud of. So in the story, all of
Speaker 1: actually sets out thinking she is going to wish away
Speaker 1: her OI. And I won't spoil it and tell you
Speaker 1: what happens, but I will say that, like all of
Speaker 1: I still believe a person's body is the least interesting
Speaker 1: thing about them. But having said that, I'm more passionate
Speaker 1: than ever about writing books where every kind of kid
Speaker 1: and everybody feels accepted and loved and knows they have
Speaker 1: a place to belong. No matter how old we are,
Speaker 1: I think we all just want to know somebody's staving
Speaker 1: a seat for us in the cafeteria. And because of
Speaker 1: that book, I am talking a lot about OI now
Speaker 1: and how it looks in my life, and specifically when
Speaker 1: I talk to kids. There is one scene I bring up.
Speaker 1: There is a scene where all of wonders if she's
Speaker 1: ever going to have a big life because of her body.
Speaker 1: She's experiencing gym class for the first time, and that's
Speaker 1: when her self esteem really starts to tank because she
Speaker 1: sees how different bodies looks, and she starts asking the
Speaker 1: big questions, what if nobody ever wants to go out
Speaker 1: with me because my body doesn't look like other people's bodies?
Speaker 1: What if I can't have the career I want to
Speaker 1: have because of how I look? All of the big
Speaker 1: hard stuff and the answer to that question, This is
Speaker 1: what I tell kids, even though it's kind of corny. Yes,
Speaker 1: you get to have a big, amazing life in the
Speaker 1: body you are in. You get to fall in love,
Speaker 1: you get to have adventures and experience so much joy.
Speaker 1: This is all one small part of a really big story.
Speaker 1: And I hope other kids with OOUGHI have never ever
Speaker 1: doubted that maybe they haven't, and that would be awesome,
Speaker 1: But just in case, there's somebody out there wondering like
Speaker 1: I did, if the body therein will hinder them from
Speaker 1: living the life if they want to have it, won't.
Speaker 1: I hope kids who read the book, No, there's magic
Speaker 1: out there waiting for them. They get to experience it
Speaker 1: in the body therein, and they deserve every good thing
Speaker 1: to end. I'll say that in the story, there is
Speaker 1: a line when Olive says, my bones are fragile, but
Speaker 1: I am not, and that is how I feel about
Speaker 1: my body too.
Speaker 2: Oh my gosh, Natalie, thank you so so much for
Speaker 2: sharing your story like that was absolutely amazing.
Speaker 3: Yeah, thank you for sharing it with us and all
Speaker 3: of our listeners and so many more with your book.
Speaker 2: Yes, oh my gosh. Okay, everyone right now, go out
Speaker 2: pick up a copy of Hummingbird by Natalie Lloyd. It
Speaker 2: is amazing. I cannot recommend it highly enough. I laughed,
Speaker 2: I cried like I could not put it down. And
Speaker 2: Natalie has so many other books, so you can find
Speaker 2: them all on her website Natalie Lloyd dot com. And
Speaker 2: we will also post a link to where you can
Speaker 2: find all of Natalie's books on our show notes for
Speaker 2: this episode, as well as on our website for this episode.
Speaker 2: We sure will Hi, I'm erin.
Speaker 3: Welsh and I'm erin alman Updyke.
Speaker 2: And this is this podcast will kill you.
Speaker 3: And today we're talking about osteogenesis imperfecta. We certainly are.
Speaker 2: This is a really interesting one because I know we've
Speaker 2: been doing more non infectious diseases like as the seasons
Speaker 2: have gone on, but it's just amazing how each one
Speaker 2: of them sort of gives us this opportunity to look
Speaker 2: at something totally different that we never really get to
Speaker 2: think about, like collagen. I know, what the heck.
Speaker 3: It's been since season two that we've talked about collagen.
Speaker 2: I know, I kept thinking collagen is the pull and
Speaker 2: peel Twizzlers?
Speaker 3: Is that? Yes? Oh my gosh, Aaron, you basically took
Speaker 3: my whole biology section done.
Speaker 2: Done, onto the history. Just kidding, just kidding. We do
Speaker 2: have a lot to cover today, and so maybe we
Speaker 2: should start by getting into quarantine any time.
Speaker 3: Absolutely, what are we drinking this week? Aaron?
Speaker 2: This week?
Speaker 3: Aaron?
Speaker 2: I love this me too. We're drinking the collagen fizz.
Speaker 3: It's just feels good that I can't believe that we've
Speaker 3: never done it before.
Speaker 2: I know, we both scrolled through are like our entire
Speaker 2: page of quarantinies looking for it. Their collagen doesn't appear
Speaker 2: in the title, right.
Speaker 3: Yeah, which I mean clearly we need to do more
Speaker 3: collagen based diseases, for sure. There's so many other options,
Speaker 3: for sure. In any case, what's in a collagen fizz?
Speaker 2: A collagen fizz is just a simple twist variant on
Speaker 2: your standard gin fizz. It has gin naturally, it has
Speaker 2: collagens collagen it actually kind of does. It has passion
Speaker 2: fruit juice, it has lime juice, simple syrup, club soda,
Speaker 2: and of course for the collagen part, egg white foam.
Speaker 3: Gotta love that.
Speaker 2: Yeah.
Speaker 3: We'll post the full recipe that quarantine as well as
Speaker 3: our non alcoholic plusy barreta on our website This Podcast
Speaker 3: will Kill You dot Com and our social media. Do
Speaker 3: you follow us yet? You should follow us?
Speaker 2: There website stuff on our website This Podcast will Kill
Speaker 2: You dot Com. There's no end to what you can find.
Speaker 2: There's transcripts, there's sources for each and every one of
Speaker 2: our episodes. There's music by Bloodmobile check it out. There
Speaker 2: are links to bookshop dot org, affiliate account, and our
Speaker 2: Goodreads list. There's links to merch, which is pretty sweet
Speaker 2: if you ask me. There's links to Patreon. There's a
Speaker 2: little about us section that is woefully outdated.
Speaker 3: Woefully I just looked at it and I was like, oof, Yep,
Speaker 3: we updated it since we graduated, but it's been a minute.
Speaker 2: I've avoided looking at it because I'm like, this is
Speaker 2: it's gonna make me want to do something, and I
Speaker 2: don't want to do something about it right now. Anyway,
Speaker 2: lots of stuff on our website.
Speaker 3: Check it out. Mm hmmmm hm. Well with that, should
Speaker 3: we get into the biology of this disorder?
Speaker 4: We absolutely should right after this break.
Speaker 3: Osteogenesis imperfecta is also called brittle bone disease, and that
Speaker 3: Moniker exists because the main symptom or consequence rather of
Speaker 3: osteogenesis imperfecta is in fact, bones that are very prone
Speaker 3: to fracture, bones that break easily and are brittle. But
Speaker 3: of course it's a bit more complicated than that. And
Speaker 3: in fact, osteogenesis imperfecta is a lot more complicated than
Speaker 3: I realized when we decided to do this episode.
Speaker 2: I had no idea.
Speaker 3: It's classic, classic, right, yeah, so historically speaking, and I
Speaker 3: promise I'm not stepping on your toes arin.
Speaker 2: How dare you?
Speaker 3: Mm hmm, I say the word history, and then I
Speaker 3: have to qualify it. But historically speaking, osteogenesis imperfecta had
Speaker 3: been classified into like four different subgroups, types one through four.
Speaker 3: Type one was considered relatively mild and by far considered
Speaker 3: the most common type of osteogenesis imperfecta. Type two was
Speaker 3: the most severe and actually lethal perinatally, so either shortly
Speaker 3: before birth or after birth. Type three was considered relatively
Speaker 3: severe and progressive, and then type four was considered the
Speaker 3: most moderate, so somewhere in between types one and type three. Nowadays, though,
Speaker 3: this classification system does not hold up because we have
Speaker 3: now identified dozens of potential mutations that are involved and
Speaker 3: a very wide range of clinical phenotypes or the way
Speaker 3: that osteogenesis imperfecta presents. And so what we know now
Speaker 3: is that at its core, no matter what the mutation
Speaker 3: or mutations are that are involved, and we'll get there,
Speaker 3: we'll talk about all of that. But osteogenesis imperfecta is
Speaker 3: broadly speaking, a disorder of collagen formation. So to understand it,
Speaker 3: let's start first with collagen yay, good, And for this
Speaker 3: we can harken back to our Scurvy episode all the
Speaker 3: way back in season two, still one of my all
Speaker 3: time phaves. I think same same, such a great episode,
Speaker 3: it's super fun. If you haven't listened, check it out.
Speaker 3: But collagen is integral to the story of scurvy, just
Speaker 3: as it's integral to the story of osteogenesis imperfecta. So
Speaker 3: collagen is a protein, it's a whole bunch of proteins,
Speaker 3: structural proteins that happen to be one of, if not
Speaker 3: the most common proteins in our human bodies. And proteins
Speaker 3: are simply chains of amino acids. That's really all they are.
Speaker 3: And in the case of collagen, collagen is made of
Speaker 3: a few different specific amino acids glycine, prolene, hydroxyproleine, hydroxy lysine,
Speaker 3: and probably some others, but glycine is an important one.
Speaker 3: And in a collagen protein, here is the way that
Speaker 3: it forms. Amino Acids make chains link together to form chains.
Speaker 3: These chains are called pro collagens. Three of these chains
Speaker 3: have to then twist together in a certain way in
Speaker 3: what's called a triple helix. So if you think of
Speaker 3: our DNA as being a double helix, this is a
Speaker 3: triple helix and this triple helix is what you mentioned, Aaron.
Speaker 3: You can think of it like a pull and peel twizzlers.
Speaker 2: Right exactly what is I'm picturing in my head right now?
Speaker 3: Yes, that is what you should be picturing. But then
Speaker 3: multiple of these twizzlers, multiple of these triple helices have
Speaker 3: to then come together in a fairly complex way to
Speaker 3: form the larger scale fibers and networks that make up
Speaker 3: collagen as a whole. Protein and collagen or collagens happen
Speaker 3: to be pretty important proteins. Like I said, some papers
Speaker 3: will tell you that thirty percent of the dry weight
Speaker 3: of our body is collagen.
Speaker 1: I saw that.
Speaker 3: Yeah, it's massive. I had no idea like me either.
Speaker 3: I knew collagen was a big deal, but I didn't
Speaker 3: know it was that big of a deal. And it's
Speaker 3: not just collagen, as I've alluded to. There are in
Speaker 3: fact five different types of collagen, types one through five,
Speaker 3: that make up literally so many parts of our body.
Speaker 3: These are structural proteins. Collagen makes up our blood, vessels,
Speaker 3: our muscles, our skin, our cartilage, our connective tissue, the
Speaker 3: basement membranes, which is like where one layer of cells
Speaker 3: might change to a different type of cells. They make
Speaker 3: up our hair, and of course, our bones. Integral to
Speaker 3: today's episode of these five different types of collagen, our
Speaker 3: bones are primarily made up of type one collagen, which
Speaker 3: then becomes mineralized to form our hard bones. But type
Speaker 3: one collagen is not only found in our bones. It's
Speaker 3: also an important component of our skin, of our tendons,
Speaker 3: of our blood vessels, and even the structure of a
Speaker 3: lot of our organs. Can I just throw out the
Speaker 3: etymology of collagen real quick, because I.
Speaker 2: Don't have it in my history, please. It basically means
Speaker 2: like glue generating.
Speaker 3: I love that. Yeah that's very accurate, Like collagen holds
Speaker 3: us together?
Speaker 2: Yeah, exactly.
Speaker 3: Beautiful. So collagen, it's a complex protein. I just keep
Speaker 3: saying collagen as if it's singular. It's many collagen.
Speaker 2: I mean, we also talk about osteogenesis imperfecta as a disorder,
Speaker 2: and it's certainly not a dissember.
Speaker 3: So forgive us for the grammatical errors here. But because
Speaker 3: these are complex proteins, it is then understandable that there
Speaker 3: are a lot of places where things could get a
Speaker 3: little wonky, and we talked about some of that in
Speaker 3: our scurvy episode. There is some like deep biochemistry that
Speaker 3: we could get into about, like the triplet complexes and
Speaker 3: how they have to form with every third amino acid
Speaker 3: being glycine and et cetera, et cetera. But if we
Speaker 3: just think of making a protein as starting with a
Speaker 3: set of building blocks like connects, those are the best
Speaker 3: ones I can think of. You know those toys.
Speaker 1: Yeah, yeah.
Speaker 3: So if each of these blocks are our amino acids,
Speaker 3: these have to fit together to make a specific type
Speaker 3: of strand, and then each of these strands have to
Speaker 3: fit together in this precise way for this triple helix
Speaker 3: to be formed in the correct way so that it's
Speaker 3: strong enough and able to then fold and twist together
Speaker 3: to build larger structures. At any and all of these levels,
Speaker 3: at the amino acid level, or at the triple helix level,
Speaker 3: or at the larger structural level, there could be things
Speaker 3: that get a little bit messed up and therefore cause
Speaker 3: issues with the strength of that collagen. Osteogenesis imperfecta is
Speaker 3: a group of genetic based disorders of collagen production, either
Speaker 3: affecting the quantity of collagen that's produced or the quality
Speaker 3: of that collagen. That's what it is at its core,
Speaker 3: so older textbooks, like I mentioned, older papers will describe
Speaker 3: it specifically as an autosomal dominant disorder, meaning that it's
Speaker 3: coming from a mutation in a gene on not our
Speaker 3: sex chromosomes, but our autosomes, and that will cause disease
Speaker 3: even with just one copy present, as opposed to lots
Speaker 3: of the other genetic diseases that we've covered on the podcast,
Speaker 3: where you have to have two copies of a mutated
Speaker 3: gene to be able to have disease like cystic fibro
Speaker 3: or sickle cell. And that's because that in the past,
Speaker 3: osteogenesis imperfecta was considered to be caused by mutations specifically
Speaker 3: in one of two genes, col ONEA one and col
Speaker 3: one A two, And these are two genes that encode
Speaker 3: for our type one collagen, the most abundant form of
Speaker 3: collagen in our bones and our skin and tendons and
Speaker 3: lots of other things. And it is still true that
Speaker 3: the vast majority of cases of osteogenesis imperfecta, about eighty
Speaker 3: five to ninety percent of cases, are caused in this
Speaker 3: way by autosomal dominant mutations in these two genes, or
Speaker 3: at least one of these two genes, the genes that
Speaker 3: are encoding for type one collagen. But not every case
Speaker 3: of osteogenesis imperfecta fits that description, and even within that,
Speaker 3: there are so many different specific mutations that can occur
Speaker 3: in that.
Speaker 2: I mean, it kind of reminds me to some degree
Speaker 2: of cystic fibrosis, where there's like a whole different array
Speaker 2: yeah mutations and downstream effects and where it happens and
Speaker 2: when it happens and what the results are and stuff
Speaker 2: like that.
Speaker 3: Yes, one hundred percent in our cystic fibrosis episode. We
Speaker 3: talked a lot about that, and to reflect that there
Speaker 3: are no longer considered only four classes of osteogenesis imperfecta.
Speaker 3: Most papers that I read said there's about nineteen or twenty,
Speaker 3: depending on the phenotype or clinical presentation. At least one
Speaker 3: paper that I read proposed an entirely different classification system
Speaker 3: that grouped osteogenesis imperfecta by like metabolism and phenotype into
Speaker 3: like A through E, and then subgroupings within each of
Speaker 3: those obligated. But the point is we now know there
Speaker 3: are dozens of different specific genetic mutations in a whole
Speaker 3: bunch of different genes and locations on different genes on
Speaker 3: various chromosomes at this point, but they all end up
Speaker 3: affecting either the production of type one collagen or the
Speaker 3: formation or the folding or the mechanics of type one collagen.
Speaker 2: Can I ask a question about the typing system?
Speaker 3: Sure?
Speaker 2: Are the types more about the end result? Are they
Speaker 2: more about the mutation itself leading to the end result?
Speaker 2: Or are does there exist like a functional typing system
Speaker 2: with different treatment protocols or diagnostic criteria or something like that.
Speaker 3: Yeah, great question. So when it comes to the typing
Speaker 3: of ostrogenesism perfecta, from what I can tell, it's still
Speaker 3: a little bit messy and maybe like in the process
Speaker 3: of undergoing revision, because there are different papers that proposed
Speaker 3: different ideas on how to classify it. Okay, but a
Speaker 3: lot of effort has been made to try and link
Speaker 3: known genotypes, so like known and found specific mutations to
Speaker 3: people to individuals that are living with osteogenesis and perfecta
Speaker 3: regardless of the symptoms. If that makes sense, Okay, because
Speaker 3: as we all talk about, one hope is for things
Speaker 3: like gene therapy or targeted therapy, and so knowing what
Speaker 3: the mutations are help in that respect. But as we'll
Speaker 3: also talk about in some ways you can also treat
Speaker 3: more broadly, if that makes sense. Yeah, yeah, yeah, so
Speaker 3: kind of both. And but it is true that these
Speaker 3: different mutations can lead to really variable degrees of disruption
Speaker 3: to the structure of collagen and therefore really huge variation
Speaker 3: in terms of symptoms and clinical findings. The way that
Speaker 3: I think of it is, depending on what the mutation is,
Speaker 3: you can think of replacing that sturdy twizzler rope that
Speaker 3: you could use to build stuff, or like the connects
Speaker 3: rope with like cooked spaghetti noodles or uncooked spaghetti noodles,
Speaker 3: or like a nylon rope that's like slipperar. Right, Like,
Speaker 3: just a lot of different ways that things could change
Speaker 3: that all lead to bones that are more easily fractured,
Speaker 3: but not necessarily all in the same way.
Speaker 1: Yeah.
Speaker 3: Now, another important part of the story of osteogenesis in
Speaker 3: perfecta is that not all mutations involve the formation of collagen.
Speaker 3: One of the most common mutations is in fact a
Speaker 3: null mutation that causes normal collagen production, but at half
Speaker 3: the amount that is typical. Okay, so you can imagine
Speaker 3: that collagen that is formed the way that it should
Speaker 3: be has the same strength, but because you just have
Speaker 3: less of it, the overall symptoms tend to be a
Speaker 3: lot less severe. Okay, So this is often associated with
Speaker 3: that old school classification of type one ostrogenesis imperfecta.
Speaker 2: Right, right, And so just like going with the poll
Speaker 2: and peel, because that is my framework for this, that
Speaker 2: might be like a poll and peel in half, uh
Speaker 2: huh essentially, or like half of the strands.
Speaker 1: Right.
Speaker 3: So, speaking of which, shall we talk about what the
Speaker 3: symptoms are?
Speaker 1: Right?
Speaker 3: So I said already there's a really wide range of phenotypes,
Speaker 3: but they all share a lot of things in common,
Speaker 3: most notably fractures. Bones that break easily result in many
Speaker 3: often fracture. In more severe cases, we can be talking
Speaker 3: about dozens to even hundreds of fractures, even early in childhood.
Speaker 3: Other really common findings are things like short stature, varying
Speaker 3: degrees of bony deformity. So this could be things like
Speaker 3: boeing of the bones of the legs, or curvatures in
Speaker 3: the spine like scoliosis, or even curvatures in the bones
Speaker 3: of the hand. And these types of changes can happen
Speaker 3: both as a result of the bones themselves just not
Speaker 3: being as structurally sound like not able to support the
Speaker 3: weight of the body and from the fractures themselves and
Speaker 3: the remodeling thereafter, especially when it comes to fractures in
Speaker 3: the spine that can end up leading to scoliosis for example.
Speaker 2: Okay, yeah.
Speaker 3: Another really common fine in osteogenesis imperfecta is blue sclera,
Speaker 3: so the whites of the eyes appearing blue, and this
Speaker 3: is kind of described in a lot of medical textbooks
Speaker 3: as one of those very classic osteogenesis imperfective findings. Importantly,
Speaker 3: it can also sometimes be a normal finding in newborns,
Speaker 3: but this is caused by thin scleral collagen, so the
Speaker 3: collagen in the eye is just not as thick, so
Speaker 3: then the underlying vasculature in our eyes is more prominent
Speaker 3: because of that, so they appear blue like the whites
Speaker 3: of the eyes. Hearing loss is another really common symptom.
Speaker 3: It's not always present, and it's not always severe hearing
Speaker 3: loss or complete hearing loss, but it often happens, especially
Speaker 3: with time and by the time people reach adulthood, and
Speaker 3: this can result either from damage to or disruption of
Speaker 3: the bones in the middle ear and can result in
Speaker 3: like really wide variation in degree of hearing loss, and
Speaker 3: then dentinogenesis imperfecta, which dentin is your teeth. This is
Speaker 3: something that can be found more commonly in the more
Speaker 3: severe forms of ostrogenesis imperfecta. But it essentially is when teeth,
Speaker 3: especially baby teeth, much more than adult teeth, which I
Speaker 3: find very interesting and I don't have a great explanation for,
Speaker 3: are not fully formed. They're small, and they often appear
Speaker 3: either like yellow brown or gray blue, and they are
Speaker 3: a lot weaker than a typical tooth or a typical
Speaker 3: baby tooth even is so those are kind of the
Speaker 3: main symptoms of all of the various forms of ostrogenesis imperfecta.
Speaker 3: The degree to which this causes impairment either physical disability,
Speaker 3: or leads to chronic illness really can vary. Some people
Speaker 3: might not ever be diagnosed until adulthood, if at all,
Speaker 3: where some people might be diagnosed in utero, and some
Speaker 3: may not survive childhood because of how many problems they
Speaker 3: end up having because of this, and there's everything in between.
Speaker 3: And so can you give me some sort of example
Speaker 3: for like the three points along the spectrum that you
Speaker 3: just described, Yeah, in terms of like what the like,
Speaker 3: what the mutation in the collagen is or how that
Speaker 3: collagen is different or what is that collagen not doing,
Speaker 3: So it really can depend. One of the papers that
Speaker 3: I read that tried to propose a newer classification system
Speaker 3: tried to break these down by the types of mutations,
Speaker 3: and like the biochemistry, I guess of these mutations. I'll
Speaker 3: be honest that I don't know how much traction this
Speaker 3: classifiction system has gotten, because like on the NIH website,
Speaker 3: for example, it still just says like nineteen different types
Speaker 3: and so grains of salt and all. But it really
Speaker 3: can vary. Some of the less severe phenotypes might just
Speaker 3: be impairments in either the amount of collagen that's produced,
Speaker 3: so like a null mutation where you're making half the
Speaker 3: amount of collagen, but it's normal collagen otherwise, or mutations
Speaker 3: that impair the ability of a normally formed collagen like
Speaker 3: monomer to assemble down the line, so like just the
Speaker 3: assembly part of it. Other more severe mutations might be
Speaker 3: from genes that are involved in modifications of collagen more
Speaker 3: down the line, like after the collagen is formed, now
Speaker 3: it gets modified in a way that makes it really
Speaker 3: structurally unsound. Okay, These tend to be less common and
Speaker 3: are recessively inherited, so they're not autosomal dominant. There are
Speaker 3: other mutations that could also be more severe that are
Speaker 3: involved in the way that collagen folds and cross links.
Speaker 3: Again like down the line, so like you have a
Speaker 3: normal twizzler rope, but when you're trying to link a
Speaker 3: whole bunch of those twizzler ropes together, it just doesn't
Speaker 3: work correctly. So there's a huge variety.
Speaker 2: And in terms of heritability, it's interesting to me that
Speaker 2: most types seem to be autosomal dominant, but there are
Speaker 2: a handful that are autosomal recessive. Which ones are which.
Speaker 3: Yeah, that's a great question. So it is really interesting.
Speaker 3: The autosomal dominant types, again are the ones that we
Speaker 3: probably knew a lot more about and are historically the
Speaker 3: ones most considered osteogenesis imperfecta. And those type one through fours,
Speaker 3: those are the null mutations, and those are mutations that
Speaker 3: can be in the collagen genes themselves, and so they
Speaker 3: are impairing the assembly of those collagen fibrils and those
Speaker 3: collagen strands. Even within that, there's huge amounts of variation
Speaker 3: in terms of what the phenotype could be right, because
Speaker 3: again that was like what we thought of when it
Speaker 3: was just types one through four, which is anything from
Speaker 3: relatively mild to perinatally lethal. But then there are so
Speaker 3: many other recessive types that are more about mutations not
Speaker 3: in the collagen genes themselves, but in the modifications of collagen,
Speaker 3: in the cross linking of collagen, in the things that
Speaker 3: happened down the line, where you would need to have
Speaker 3: two of the mutator allele to actually have that phenotype right,
Speaker 3: Whereas with the others, if there's a mutine in the
Speaker 3: collagen gene itself, even if you make some typical collagen,
Speaker 3: some proportion of your collagen is either abnormal or missing,
Speaker 3: and therefore you have some symptoms of disease.
Speaker 2: This might be an epidemiology question, okay, but what proportion
Speaker 2: of cases of osteogenesis imperfecta are inherited versus which are
Speaker 2: spontaneous mutation?
Speaker 3: Oh, that is such a good question. I don't actually know.
Speaker 3: I didn't really see that number anywhere, and I think
Speaker 3: part of the reason is that most of the numbers
Speaker 3: that I have are really just that eighty five to
Speaker 3: ninety percent of cases are mutations in those two genes
Speaker 3: that encode for type one collagen col one A one
Speaker 3: and col one A two. Eighty five to ninety percent
Speaker 3: of osteogenesis imperfecta is that that is autosomal dominant. The
Speaker 3: rest are so variable that I don't know. I don't
Speaker 3: know how many of them are denovo mutations versus genetic
Speaker 3: within families. It's also so many of them, many have
Speaker 3: been found in only one or a handful of patients,
Speaker 3: and so they're so rare that it's really hard to
Speaker 3: even know, especially with something that's autoso more recessive.
Speaker 2: Right, Yeah, Okay, So we've talked about like the mutations,
Speaker 2: We've talked about some of the different structures and disruptions
Speaker 2: in collagen function or quantity or whatever, and we've talked
Speaker 2: about some of the end results of that. What does
Speaker 2: that mean for a lifetime, and also what does that
Speaker 2: mean for the most severe type that you discussed, like
Speaker 2: how why is it fatal?
Speaker 3: Yeah? Yeah, So in terms of what does it mean
Speaker 3: for a lifetime, it can vary hugely, But in terms
Speaker 3: of when it is either lethal or results in severe disease,
Speaker 3: some of the most severe manifestations come from its effects
Speaker 3: on the bones in our torso and on our heart
Speaker 3: and lungs itself or themselves In the cases of these
Speaker 3: more severe disease manifestations, it's cardial pulmonary issues, heart and
Speaker 3: lung issues that lead to the most severe morbidity and mortality.
Speaker 3: So what we can see is recurrent lung infections like
Speaker 3: pneumonia and eventual heart failure as a result of lung disease,
Speaker 3: which is called core pulmoneal and this is very often
Speaker 3: due not to problems in the lungs themselves, but skeletal
Speaker 3: issues rib fractures, recurrent rib fractures, severe scoliosis, things that
Speaker 3: eventually lead to dysfunction or the inbit to inspire appropriately
Speaker 3: and to breathe enough so that then there is damage
Speaker 3: to the lungs over time because of that, or in
Speaker 3: some very severe cases it's respiratory failure in that perinatal
Speaker 3: period because there's not enough structure to be able to
Speaker 3: keep the lungs open, and because collagen also makes up
Speaker 3: our vasculature. There can be independent issues that arise with
Speaker 3: the cardiovascular system our heart, including like aortic root dilation,
Speaker 3: so the part of your aorta that attaches to the
Speaker 3: left ventricle of your heart getting a little bit dilated,
Speaker 3: which leads to regurgitation or backflow of blood back into
Speaker 3: our heart instead of making it out into the rest
Speaker 3: of our body, which then leads to increased pressure in
Speaker 3: the heart, which can also lead to heart failure down
Speaker 3: the line. So those are some of the more severe
Speaker 3: things that can happen as a result of this collagen issue,
Speaker 3: both in our vasculature but also just in the bones
Speaker 3: that make up our whole body. Yeah yeah, treatment, yeah,
Speaker 3: across the board. The most important component of treatment is
Speaker 3: actually physical therapy, so it's a lot about strengthening muscles
Speaker 3: to protect these bones. The other component of treatment is
Speaker 3: with medications, and we don't have great options yet, but
Speaker 3: one really common group of medicines are called bisphosphonates. These
Speaker 3: are the same medicines that we use to treat osteoporosis,
Speaker 3: and what they do is help with bone deposition like mineralization,
Speaker 3: and they decrease bone turnover. It's not fixing the problem,
Speaker 3: especially if the problem is the way that the collagen
Speaker 3: is formed, But the theory is that it helps strengthen
Speaker 3: the bones, like put a cast kind of around your
Speaker 3: noodle rope.
Speaker 2: Okay.
Speaker 3: The idea behind this is that it would then prevent fractures.
Speaker 3: But apparently if you can't tell by how much I'm hedging,
Speaker 3: the data is a little bit equivocal so far on
Speaker 3: whether or not it actually prevents fractures.
Speaker 2: Yeah, well, and I mean, honestly, like that kind of
Speaker 2: makes sense given a huge variation in right different you
Speaker 2: know ways that collagen can I don't know, not work
Speaker 2: quite as well.
Speaker 3: And so yeah, it's like, yeah, it's so it's just
Speaker 3: such a huge array of possible symptoms and consequences resulting
Speaker 3: from a huge array of mutations. So I won't be
Speaker 3: surprised if someday all of these various classifications end up
Speaker 3: being considered different diseases in some respects quite honestly.
Speaker 2: Yeah, yeah, Aaron, I can't not ask, just I know
Speaker 2: that we should do a whole episode on this someday.
Speaker 2: But like, there are so many products out there with collagen.
Speaker 2: Do you have like a TLDR that you can give me?
Speaker 3: Oh, the easiest TLDR is that like you actually can't
Speaker 3: absorb collagen through your GI tract, like it's too big.
Speaker 3: So it's only like the either amino acids that make
Speaker 3: up collagen or like I think it's like hydrolyzed collagen,
Speaker 3: which is like what you probably take into powder. That's
Speaker 3: like little teeny tiny bits of collagen in your collagen
Speaker 3: powder that you might drink. There's like very mixed data
Speaker 3: on whether or not it does anything to drink your collagen.
Speaker 2: Okay, okay, but I would love.
Speaker 3: To do a whole episode on it.
Speaker 2: Let's do that, Let's do that and other supplements.
Speaker 3: There's we could do it again, a whole mini series.
Speaker 3: YEP added to the list.
Speaker 2: Okay, interesting.
Speaker 3: So speaking of interesting, Aaron, I don't think that I
Speaker 3: can ask where did this come from? But like, how
Speaker 3: did we get here when it comes to austun genesis?
Speaker 3: Im perfect that.
Speaker 2: Yeah, let's get into it right after this break. I
Speaker 2: want to start off the history section with a quote.
Speaker 2: Love that quote. One of the more frustrating endeavors for
Speaker 2: those interested in the history of medicine can be the
Speaker 2: desire to discover the first published description of a disease, operation,
Speaker 2: or procedure. Having attempted this on several occasions, I have
Speaker 2: concluded that it requires more than a large medical library,
Speaker 2: a good memory, luck, perseverance, or a high degree of
Speaker 2: suspicion for quoted sources, I am always left with the
Speaker 2: uneasy feeling that only the personal perusal of the original
Speaker 2: publication will convey the author's true thoughts. Meanings seem to
Speaker 2: change in quoted sources and often contain errors in regard
Speaker 2: to context, interpretation, translation, and bibliographic data. Osteogenesis Imperfecta is
Speaker 2: a case in point.
Speaker 3: So what you're saying is we don't know.
Speaker 2: Yeah, that was the paragraph to say three words we
Speaker 2: don't know. So that was from a paper titled Osteogenesis
Speaker 2: Imperfecta Historical back by Ulric Hweel, MD, published in nineteen
Speaker 2: eighty And when I read it, first of all, I
Speaker 2: was like, this is an amazing quote. Also, I love
Speaker 2: that this author devoted so much space to this sentiment.
Speaker 2: That's great. But it's a great quote I thought to
Speaker 2: begin the history of Osteogenesis imperfecta, And honestly, like many
Speaker 2: it's applicable to many other topics that we've covered, because
Speaker 2: I think it does sort of force us to think
Speaker 2: about what is important when tracing the history of a
Speaker 2: disease and why is it important? You know, is it
Speaker 2: that doctor so and so was the first to name something? Maybe,
Speaker 2: especially if you're that doctor so and so or related
Speaker 2: to that doctor so and so, or is it the
Speaker 2: order that things were discovered about a condition, or how
Speaker 2: the timing of discoveries influence the perception of a disease
Speaker 2: because of the current social or political climate, or how
Speaker 2: the discovery of a condition altered the experience of those
Speaker 2: who had it, or how the discovery changed medicine itself,
Speaker 2: or maybe it's like a combination of all those things,
Speaker 2: and it can be. And don't worry, this is not
Speaker 2: going to be just a giant philosophical discussion or lecture
Speaker 2: on how to construct a narrative on the history of medicine.
Speaker 2: I just thought that this quote kind of served as
Speaker 2: a good reminder that the stories that we tell are
Speaker 2: exactly that their stories, and the storytellers themselves choose what
Speaker 2: does or doesn't go into a story, and they're human.
Speaker 2: We're human with biases and flaws and sometimes typos, oftentimes typos.
Speaker 2: So what does that mean for osteogenesis imperfecta. It means
Speaker 2: that what I want to focus mostly on today is
Speaker 2: not who gets priority for the first description of this disorder,
Speaker 2: but how our understanding of it has grown over time
Speaker 2: and what that is meant for the people living with
Speaker 2: this disease, especially as the divide between knowledge and application
Speaker 2: has shrunk, but like not entirely at all. Okay, so
Speaker 2: let's get started with this history by heading back, as
Speaker 2: we often do, to ancient Egypt. Since osteogenesis imperfecta is associated,
Speaker 2: of course with skeletal changes, we can make fairly confident
Speaker 2: diagnoses in skeletal remains that have evidence of the disease,
Speaker 2: and the earliest of these that I came across is
Speaker 2: from an ancient Egyptian mummy, an infant from around one
Speaker 2: thousand BCE. The infant's skull and bones were consistent with
Speaker 2: osteogenesis imperfecta, specifically types three and four. I think there
Speaker 2: couldn't distinguish between those two. But from what I can tell,
Speaker 2: there aren't references to osteogenesis imperfecta in any ancient texts,
Speaker 2: or at least any that aren't like incredibly vague, and
Speaker 2: which I thought was kind of interesting.
Speaker 3: That is because it's, yeah, I mean, bones are often
Speaker 3: what we look to to see about so many other diseases,
Speaker 3: and so it's it is interesting.
Speaker 2: It is it is, And also like what proportion of
Speaker 2: medical writings from ancient from the ancient world remains today?
Speaker 2: What is still waiting to be translated et cetera. Like
Speaker 2: you know, it's I'm not saying that they don't exist.
Speaker 2: It's just that a I didn't read about them, be
Speaker 2: no one's read about them yet.
Speaker 3: I don't know.
Speaker 2: It could be both. But there is a legendary figure
Speaker 2: from the ninth century CE that has been said to
Speaker 2: have osteogenesis imperfecta Ivar the Boneless, who sometimes translated as Ivar.
Speaker 2: I hope it's Ivar or not Evar. Ivar the Legless.
Speaker 2: Ivar the Boneless was a Viking king slash leader slash
Speaker 2: person of importance who I couldn't get a handle on
Speaker 2: what position he held, but in any case, he makes
Speaker 2: an appearance in the thirteenth century epic poem The Tale
Speaker 2: of Ragnar Lodbrook. He was the son of Ragnar, and
Speaker 2: in this poem is the story of how Ivar travels
Speaker 2: to East Anglia and Northumbria to avenge his father, who
Speaker 2: was murdered by the King of Northumberland. He was successful,
Speaker 2: allegedly killing the king a Ella in a horrible way
Speaker 2: the Blood Eagle.
Speaker 3: Maybe read about it, maybe don't.
Speaker 2: Ultimately, Ivar dies in Dublin peacefully in the year eight
Speaker 2: seventy three before he died, he instructed that his body
Speaker 2: should be buried in a mound on the east coast
Speaker 2: of England, saying that as long as his grave was undisturbed,
Speaker 2: no invasion of England would be successful, and that apparently
Speaker 2: held true until William the Conqueror landed there in ten
Speaker 2: sixty six and burned Ivar's remains. Just a fun little
Speaker 2: story that has nothing to do. That's just mostly backstory
Speaker 2: on this guy Ivar, Okay, And because we don't know
Speaker 2: where Ivar was buried or if he existed at all
Speaker 2: or was just like a composite figure in this poem.
Speaker 2: But if he did exist, his body was possibly burned,
Speaker 2: So like we can't make a, you know, a diagnosis
Speaker 2: based on his remains. We can't know whether or not
Speaker 2: he had osteogenesis imperfecta. Ivar's mother was said to be
Speaker 2: cursed while she was pregnant with him, and he was
Speaker 2: unable to walk and was carried on a shield into
Speaker 2: battle where he would use a long bow, So maybe
Speaker 2: he had OI.
Speaker 3: But another explanation for his name that some authors suggest
Speaker 3: was that it was an insult, suggesting that he wasn't
Speaker 3: really up to the task.
Speaker 2: In certain ways.
Speaker 3: But it was just that he couldn't walk, that's the
Speaker 3: only Yeah, oh interesting.
Speaker 1: I know.
Speaker 2: So this is what, like, the amount of conjecture that
Speaker 2: comes out of some of these early histories of.
Speaker 3: Diseases is simply staggering. Yeah, yeah, and we're.
Speaker 2: Never gonna know. Yeah, but I did want to mention
Speaker 2: him because his name comes up in like every history
Speaker 2: of osteogenesis imperfecta more or less. And there are a
Speaker 2: few other possible references to what could be osteogenesis imperfecta
Speaker 2: in like ancient and medieval times, but very much in
Speaker 2: theme with the quote at the beginning. The original ancient
Speaker 2: source can't be found, or it's been mistranslated or whatever,
Speaker 2: so let's move on to the seventeenth century. That is
Speaker 2: where we have to go from here, and that's when
Speaker 2: the next possible reference to ostrogenesis improvecta shows up in
Speaker 2: France in sixteen seventy five, from the philosopher Nicholas D. Malibranche,
Speaker 2: who wrote that quote. About seven or eight years ago.
Speaker 2: A young man could be seen at the Incurable's hospital
Speaker 2: who was born mad and whose body was broken in
Speaker 2: the same places as murderer's bones are broken. He lived
Speaker 2: for about twenty years in this condition. Several people saw him,
Speaker 2: and the late queen mother, when paying a visit to
Speaker 2: this hospital, was curious to see him and even to
Speaker 2: touch the arms and legs of that young man where
Speaker 2: his limbs were broken.
Speaker 1: End quote.
Speaker 2: Des Malabranche then provided his reasoning for why this man
Speaker 2: had this condition.
Speaker 3: Quote.
Speaker 2: The cause of this terrible accident was the fact that
Speaker 2: the mother, having heard that a criminal was to be
Speaker 2: put on the wheel, went to see the execution. All
Speaker 2: the blows that were given to that wretch struck the
Speaker 2: imagination of that mother forcefully, and as an indirect consequence,
Speaker 2: the tender and delicate brain of her child.
Speaker 1: End quote.
Speaker 2: Sorry, what so, Yeah, he is not even like suggesting,
Speaker 2: but just like stating very firmly that this guy's mother,
Speaker 2: who when pregnant with him, saw this public execution, and
Speaker 2: that every blow that landed on the guy who was
Speaker 2: on the wheel that the person put to death. Then
Speaker 2: when he was born he later had breaks in all
Speaker 2: the same It sounds it not.
Speaker 3: Only makes no sense, it also why does it sound
Speaker 3: weirdly familiar? Oh? I think epilepsy was a lot about
Speaker 3: when someone was pregnant and they witnessed something thing, and
Speaker 3: then I think it was epilepsy and that sounds familiar.
Speaker 2: I mean to be honest, Aaron, we know that it's
Speaker 2: going to be a thousand different things, right, like, yeah,
Speaker 2: anything that you can blame a woman for.
Speaker 3: Yeah, yeah, it's always mom's fault.
Speaker 1: Yeah.
Speaker 2: Yeah, it doesn't make any sense. The next reference to
Speaker 2: what is likely osteogenesis imperfecta was written with slightly less
Speaker 2: conviction about what caused it. Okay, This is from a
Speaker 2: medical report from France in sixteen ninety quote. On March eighth,
Speaker 2: sixteen ninety, a woman in her late twenties was admitted
Speaker 2: to the Hotel Due in Paris. She complained that over
Speaker 2: the past four months she had suffered extreme and diffuse
Speaker 2: pain all over the body, with no apparent feverish episode.
Speaker 2: Although she could walk and move without restriction, she suffered
Speaker 2: unbearable pain anyone touched her. After three months of forced
Speaker 2: bed rest, she could no longer walk, All bones fragmented
Speaker 2: and it was impossible to touch her without causing new fractures.
Speaker 2: The pain increased progressively until she died. On dissection, we
Speaker 2: found that the upper and lower limb bones, clavicles, ribs,
Speaker 2: vertebrae and the pelvis were broken. Not a single unbroken
Speaker 2: bone was found. The bones were thin, tender, and full
Speaker 2: of red marrow. Upon manipulation, they pulverized and dissolved like
Speaker 2: a rotten, wet tree bark. We could sink our fingers
Speaker 2: into her skull bones, the consistency of which was similar
Speaker 2: to that found in a fifteen day old neonate. Cartilages
Speaker 2: and articulations showed no sign of alteration. The internal organs
Speaker 2: were healthy, and no other signs of her pathological condition
Speaker 2: were found. It is known that smallpox can cause bony erosion,
Speaker 2: but in this case, the bones were melted and softened.
Speaker 2: What was the cause and nature of their dissolution?
Speaker 3: End quote? Wow, Yeah, that's it's a pretty it's a
Speaker 3: pretty gnarly description. Yeah. Yeah, that is a sounds like
Speaker 3: a very severe form.
Speaker 2: What struck me about this was the mention of pain,
Speaker 2: because you didn't really talk about pain very much. But
Speaker 2: is pain a major feature of some of these different
Speaker 2: types of ostrogenesism perfecta?
Speaker 3: I mean certainly yes, especially because these fractures are painful,
Speaker 3: like breaking a bone is incredibly painful. So it's not
Speaker 3: that this disruption in collagen disrupts in any way all
Speaker 3: of the nerves and everything else that's involved. So the
Speaker 3: fractures themselves are going to be painful. The way that
Speaker 3: bones heel might lead to additional kind of damage down
Speaker 3: the line, like we talked with the school osis and
Speaker 3: things like that, which can be painful. So certainly pain
Speaker 3: can be a component of osteogenesis imperfect at Okay.
Speaker 2: Yeah, okay, Well anyway, so still traveling through these early mentions,
Speaker 2: there is sometimes people mentioned someone named Armand as providing
Speaker 2: the next description of OI in seventeen sixteen, but I
Speaker 2: didn't really find any more about that, Like that was it.
Speaker 2: Then we have the dissertation of Swedish surgeon Olaus jakab Eckmann,
Speaker 2: published in seventeen eighty eight, which had previously been considered
Speaker 2: the first scientific description of the disease, even though he
Speaker 2: considered them to be cases of osteomalaysia that ran in families.
Speaker 2: So he described four generations living in a mining district
Speaker 2: with bony disorders resulting in disability, but he just thought
Speaker 2: that it was Osteomalaysia.
Speaker 3: Yeah, yeah, that is interesting because ricketts, which we already
Speaker 3: did this sees it and scurvy are all definitely on
Speaker 3: the differential, that is, when it comes to osteogenesis imperfected.
Speaker 2: Yeah, yeah, But are you seeing how the quote at
Speaker 2: the beginning is like so relevant because and then and
Speaker 2: then there's this, and then like there are so many
Speaker 2: different instances of the first description of this and that. Anyway, personally,
Speaker 2: what I think is that the first description that really
Speaker 2: matters is the one from Edmund AxMan in eighteen thirty one,
Speaker 2: where he describes for the first time the four major
Speaker 2: characteristics of osteogenesis imperfecta bone fragility, joint hypermobility with easy dislocation,
Speaker 2: blue sclera, and a frail body. A couple of years later,
Speaker 2: Lobstein described a condition he called osteosatherosis idiopathica, an abnormal
Speaker 2: brittleness of bones, particularly afflicting children and the elderly, also
Speaker 2: mentioning that it can run in family. It's unclear whether
Speaker 2: he was actually talking about like a combination of osteoporosis
Speaker 2: and rickets or actually OI. And so at this point
Speaker 2: we have okay, we don't have a complete clinical clear picture,
Speaker 2: but we have now gotten like a distinct condition. So
Speaker 2: this is not just like a symptom that people are
Speaker 2: talking about this is a collection of symptoms, there are
Speaker 2: recognizable features, and that makes diagnosis a possibility by around
Speaker 2: like the first half of the nineteenth century, but like
Speaker 2: a diagnosis of what, because what we now know is
Speaker 2: osteogenesis imperfecta didn't yet have that name, right, So how
Speaker 2: did that happen? Gerardis Vrolik was a professor of anatomy
Speaker 2: and physiology and of theoretical and clinical obstetrics at the
Speaker 2: University of Amsterdam in the early nineteenth century.
Speaker 3: What is theoretical obstetrics?
Speaker 2: It's just imagining how everything happens.
Speaker 3: Okay, cool, Yeah, Okay.
Speaker 2: Malpractice insurance is very low. That's my dorkiest joke yet.
Speaker 3: I really liked it, thank you.
Speaker 2: As if anyone needed malpractice insurance in the nineteenth century.
Speaker 1: Yeah.
Speaker 2: One of Rolick's special interests was congenital disorders, and that
Speaker 2: was a topic that was very popular at the time.
Speaker 2: I saw it described in one paper as the golden
Speaker 2: era of descriptive territology. Anyway, Rolick, in addition to publishing
Speaker 2: case studies of some of the congenital disorders that he
Speaker 2: treated or came across, he also began a private collection
Speaker 2: of specimens humans and other animals.
Speaker 3: That sounds witionable.
Speaker 2: Yeah, I think it still exists. His son, who was
Speaker 2: also a physician with an interest in congenital disorders, inherited
Speaker 2: this collection after his father's death and studied it. One
Speaker 2: of the samples that he came across and found worthy
Speaker 2: of description was the skeleton of an infant that had
Speaker 2: died three days after birth with numerous fractures. Willem dissected
Speaker 2: the skeleton and found that there were fractures in every
Speaker 2: intact bone. The skull, large and with a high forehead,
Speaker 2: was fractured, the ribs were very thin, and development overall
Speaker 2: seemed incomplete. In eighteen forty nine, he published his description
Speaker 2: and his belief that the infant had a condition he
Speaker 2: termed osteogenesis imperfecta, stating that he believed, unlike most of
Speaker 2: his contemporaries, that it was a condition that the infant
Speaker 2: had been born with, rather than something they had acquired
Speaker 2: after birth, as in Rickets. Later re examination of the
Speaker 2: skeleton in the nineteen nineties led to the diagnosis of
Speaker 2: osteogenesis imperfecta type two. Over the second half of the
Speaker 2: eighteen hundreds and into the early nineteen hundreds, more observations
Speaker 2: trickled in some that seemed to be more or less
Speaker 2: a repetition of what had already been published, and others
Speaker 2: that added a bit more detail to the overall clinical picture,
Speaker 2: like Spurway in eighteen ninety six reporting on how bluish
Speaker 2: sclera sometimes happened in association with brittle bones, which was
Speaker 2: then repeated and elaborated on by Edo's in nineteen hundred,
Speaker 2: who hypothesized that quote, the transparency of the sclerotics indicates
Speaker 2: a want of the quality or quantity of the fibrous
Speaker 2: tissue forming the network of the various organs of the body,
Speaker 2: and probably explains the want of spring or toughness in
Speaker 2: the bones of these particular individuals.
Speaker 1: End quote.
Speaker 3: Great, great job led it.
Speaker 2: Honestly, pretty impressive.
Speaker 3: Solid.
Speaker 2: Yeah. Other researchers noted that coreticonus, like where the cornea
Speaker 2: gets thinner and kind of bulges out in the center
Speaker 2: like a cone, also sometimes occurred with bone fragility, with
Speaker 2: at least one researcher noting the hereditary nature of the condition.
Speaker 2: Hereditary hearing loss associated with brittle bones and blue sclera
Speaker 2: was described for possibly the first time in nineteen twelve
Speaker 2: in a paper titled four Generations of Blue Sclerotics by
Speaker 2: British ophthalmologists and Ian T. Charles Allen Adair Dighton, And
Speaker 2: this observation was repeated by others shortly after, and so
Speaker 2: like this is just I felt like a list a
Speaker 2: bunch of people who described a bunch of different things.
Speaker 2: And I feel like doing this episode right after Parkinson's
Speaker 2: made me realize how comparatively rare, or at the very
Speaker 2: least different the history of Parkinson's was, where there seemed
Speaker 2: to be like one landmark paper picked up by one
Speaker 2: landmark scientist, and then everything grew from there. Yeah, for
Speaker 2: osteogenesis imperfecta, it has seemed like centuries of incremental progress
Speaker 2: and repetition, you know, like dozens of people coming in
Speaker 2: and putting one piece of this thousand piece puzzle together
Speaker 2: time after time after time.
Speaker 3: Yeah. I mean I wonder if that reflects not only
Speaker 3: how variable osteogenesis imperfect it can be, but also how
Speaker 3: much more rare it is comparatively absolutely.
Speaker 2: And also like the way the story is told right,
Speaker 2: like maybe I could have been like and then in
Speaker 2: eighteen ninety six we had this example of whatever you know,
Speaker 2: and then everything came from there. But I think I
Speaker 2: think this is a good representation of how most science
Speaker 2: does actually happen right where it's not like it certainly
Speaker 2: can happen the way that Parkinson's, the history of Parkinson's did. Right,
Speaker 2: here's this one thing, WHOA that opened up this door
Speaker 2: to tons and tons of research. A lot of the
Speaker 2: time is it is this incremental progress. It is this
Speaker 2: like slight, you know, shedding a light and the light
Speaker 2: gets brighter and brighter and brighter and hits a wider
Speaker 2: and wider area.
Speaker 3: And sometimes the light doesn't change. But it's just I
Speaker 3: don't know. I thought that was interesting.
Speaker 2: Okay, Anyway, with osteogenesis imperfecta, we've made it into the
Speaker 2: twentieth century and we have a general clinical description of
Speaker 2: this disorder. We have a typing system, not the one
Speaker 2: we use today, not even the one that we used
Speaker 2: that you mentioned that was historical. We had one that
Speaker 2: was like, here's osteogenesis imperfecta inherited, and here's where it
Speaker 2: is acquired. Like it doesn't doesn't really track. But that
Speaker 2: system was based on severity and the age of presentation.
Speaker 2: We also had a growing recognition that many body systems
Speaker 2: were involved in the condition, like, not just bones, not
Speaker 2: just bones and eyes. There were many, many, many different
Speaker 2: organ systems and body systems involved, and we had some
Speaker 2: diagnostic criteria. But what we didn't have by the first
Speaker 2: half of the twentieth century is any real framework around
Speaker 2: why why are the bones prone to fracture? Why are
Speaker 2: the sclare of blue?
Speaker 1: Like?
Speaker 2: What is happening physiologically to cause the condition? There was
Speaker 2: a general notion that it was a congenital connective tissue disorder,
Speaker 2: a hypothesis supported by observations of dental cartilage, skin, and
Speaker 2: blood vessel involvement in addition to the familiar bone and
Speaker 2: eye and ear involvement. But what was happening at the
Speaker 2: cellular level in all of the various types of osteogenesis
Speaker 2: imperfecta I was still a mystery up into the nineteen seventies.
Speaker 3: Wow right.
Speaker 2: It was then that research on collagen had taken incredible
Speaker 2: steps forward, and also during the nineteen sixties, because even
Speaker 2: though collagen itself had been recognized since the nineteen thirties,
Speaker 2: I believe the technology and background knowledge needed to uncover
Speaker 2: the incredible importance and innumerable functions of this protein, like
Speaker 2: how it synthesized its assembly and structure, not to mention
Speaker 2: the many types of collagen. All of that background information
Speaker 2: and technology wasn't there until the nineteen sixties and seventies.
Speaker 2: But once these pieces came together, once collagen types one
Speaker 2: through four and all the major steps in biosynthesis had
Speaker 2: been identified, then finally people could start to get some
Speaker 2: clarity not only on how collagen worked, but what happened
Speaker 2: when it didn't work right. And just like what you said, Aaron,
Speaker 2: because collagen is so abundant in our bodies, literally the
Speaker 2: most abundant protein, and because it functions in so many
Speaker 2: different ways, it can go wrong in just an unbelievable
Speaker 2: number of ways.
Speaker 3: There are so many other diseases and disorders that we
Speaker 3: could cover that also have to do with collagen. I
Speaker 3: was like deep diving on earlier's Dan Lows while I
Speaker 3: was researching for this, So like, yeah.
Speaker 2: Gotta do that someday. We've gotten a lot of requests
Speaker 2: for sure. And as this research on collagen was happening,
Speaker 2: as this like literal opening up of the field of collagen,
Speaker 2: scientists were also busy tracking inheritance patterns in osteogenesis imperfecta,
Speaker 2: observing that both these autosomal dominant and autosomal recessive types
Speaker 2: were present, and also some of the ways that collagen
Speaker 2: could go wrong and become involved in these different types
Speaker 2: of ostrogenesis imperfecta. And so out of this, out of
Speaker 2: this kind of just whirlwind couple of decades of research,
Speaker 2: there was a great progress in genetic research in understanding
Speaker 2: the precise nature of those changes in collagen, and that
Speaker 2: has led to a greater understanding overall of the disorder
Speaker 2: as well as, like you said, Aaron hopes for treatment
Speaker 2: in the form of gene therapy. But like we talked
Speaker 2: about in our Parkinson's disease episode, all of that new information,
Speaker 2: while hugely important, doesn't necessarily translate into current application. With
Speaker 2: the introduction of physiotherapy, rehabilitation, and improvements in orthopedic surgery,
Speaker 2: we had come a long way in preventing and treating
Speaker 2: fractures in people with ostrogenesis imperfecta since those earliest descriptions.
Speaker 2: Until nineteen eighty seven, there was still no medication that
Speaker 2: could help with bone density, loss or pain, despite dozens
Speaker 2: of attempts. That year, a case study was published that
Speaker 2: described a twelve year old girl who was diagnosed with
Speaker 2: osteogenesis imperfecta after a spontaneous hip fracture. Her physicians prescribed bysphosphonate,
Speaker 2: or a type of bysphosphonate drug that had been used
Speaker 2: previously with some success in people with juvenile osteoporosis and
Speaker 2: other types of conditions where bone mass loss was a feature.
Speaker 2: Until this case, no one had apparently tried this drug
Speaker 2: on osteogenesis imperfecta, and over the course of a year,
Speaker 2: X rays and blood analysis showed increased bone mass, which
Speaker 2: was amazing. After years of no effect, no effect, no effect,
Speaker 2: finally there was a drug that showed some promise. A
Speaker 2: bunch of studies followed, and it seems like it does
Speaker 2: actually help with at the very least improving bone mass,
Speaker 2: if not necessarily pain or fracture risk or overall bone growth.
Speaker 2: But that alone is fantastic because there's really not been
Speaker 2: anything before then. And Aaron, I know you're about to
Speaker 2: tell me some more about like gene therapy and hopefully
Speaker 2: other potential medications. I only made it to the nineteen
Speaker 2: nineties with my research, but I think that one thing
Speaker 2: that's really crucial to talk about that kept coming up
Speaker 2: in some of these papers, although not enough is not
Speaker 2: just the potential health benefits of these medications, but also
Speaker 2: how they can improve quality of life. Fear of fractures,
Speaker 2: anxiety about going outside or being active, caution when it
Speaker 2: comes to everyday life and activity, isolation, or feelings of
Speaker 2: being different. These are all commonly reported themes in studies
Speaker 2: that try to examine the lived experience of people, both
Speaker 2: children and adults with osteogenesis imperfecta, And of course not
Speaker 2: every experience is the same, but I think that it's
Speaker 2: important to talk about and recognize the non physical effects
Speaker 2: that ostrogenesis imperfecta might have on someone. And certainly things
Speaker 2: like OI groups and awareness campaigns have been fantastic for
Speaker 2: building community and providing resources to people with osteogenesis imperfecta
Speaker 2: as well as their caregivers. But there's still a long
Speaker 2: way to go when it comes to treatment and access
Speaker 2: to that treatment, because we know it's got to be expensive,
Speaker 2: just has to be, so, Aaron, here's where I turn
Speaker 2: it over to you to tell me what those up
Speaker 2: and coming probably expensive treatments are, and you know everything
Speaker 2: else about where we stand with osteogenesis imperfecta today.
Speaker 3: I can't wait to try right after this break. So
Speaker 3: one of the first papers that I read for researching
Speaker 3: this episode described osteogenesis imperfecta as a quote fairly common
Speaker 3: rare disorder, which boxymoron. Yeah, I don't know what that means.
Speaker 3: But the stat that was quoted in that paper, as
Speaker 3: well as pretty much every paper that had statistics, was
Speaker 3: that osteogenesis imperfecta is found in one in fifteen to
Speaker 3: twenty thousand berths every year. Okay, so if we air
Speaker 3: in mathis, which you know I'm going to, According to Google,
Speaker 3: there are one hundred and forty million berths every year,
Speaker 3: and the CDC says that in the US there are
Speaker 3: over just a little over three point six million berths
Speaker 3: every year in the US. So if we assume on
Speaker 3: the low end, one in fifteen thousand people are born
Speaker 3: with osteogenesis imperfecta, that would be worldwide just over nine
Speaker 3: thousand people born with OI every year and two hundred
Speaker 3: and forty in the US each year. Okay, Now, since
Speaker 3: these are birth statistics, they are very likely underestimates because
Speaker 3: these are going to reflect relatively more severe forms of
Speaker 3: osteogenesis in perfecta, because there are always going to be
Speaker 3: people that don't end up getting diagnosed until later in
Speaker 3: their life because of less severe phenotypes or just not
Speaker 3: being diagnosed in infancy for one reason or another. A
Speaker 3: couple of papers that I read cited an estimated prevalence
Speaker 3: of twenty five to fifty thousand people in the United
Speaker 3: States living with OI, but it was very disappointingly difficult
Speaker 3: to get any additional data on prevalence worldwide.
Speaker 2: That surprises me.
Speaker 3: I know, and these are a whole variety of genetic disorders,
Speaker 3: but I couldn't find almost anything in terms of the
Speaker 3: estimates on like what is the variability geographically across the globe,
Speaker 3: because of course there's going to be some and there
Speaker 3: does seem to be some variability, but there was so
Speaker 3: little data, and the data that I found was like
Speaker 3: reported quite differently in the few countries that it was
Speaker 3: reported in like this many cases per one hundred thousand
Speaker 3: versus per ten thousand births in this kind, so like
Speaker 3: it was really hard to make any meaningful comparisons in
Speaker 3: other countries aside from the US. So I apologize, I
Speaker 3: just couldn't find it. But in any case, this is
Speaker 3: certainly a rare disorder. But as always, the more that
Speaker 3: we think about it and look for it and research
Speaker 3: it the more that we find. So in terms of
Speaker 3: where we stand with current research, again here I found
Speaker 3: less than I was hoping for, but not nothing. There
Speaker 3: is one new drug, very new drug making headlines big
Speaker 3: time that's in phase two and three clinical trials right now.
Speaker 3: This drug is a monoclonal antibody that specifically this is
Speaker 3: really interesting to me. It inhibits a small protein called sclerostin,
Speaker 3: which is a protein that is involved in the remodeling
Speaker 3: of bone. So the idea behind this is that by
Speaker 3: inhibiting the action of this protein, you end up having
Speaker 3: increased bone formation and decreased bone resorption that could lead
Speaker 3: to stronger bones and less fractures and increased quality of life.
Speaker 3: Can I ask a question about bone remodeling? Sure?
Speaker 1: Why?
Speaker 2: I feel like we talked about this in Ricketts, but
Speaker 2: I don't. Yeah.
Speaker 3: Yeah, So your bones are almost constantly, like your body
Speaker 3: is resorbing bone and then remodeling bone. And this process
Speaker 3: also happens a lot during the growth process. Like growth
Speaker 3: of bone is not just like this one off like
Speaker 3: your bone grows process. There's like the collagen parts of
Speaker 3: bone have to grow, the minimalization deposit has to happen like,
Speaker 3: it's a whole process, and there's this would be a
Speaker 3: fun whole episode honestly to do about like bones, osteoblasts
Speaker 3: and osteoclass and like. But in any case, it's a
Speaker 3: process that happens over time. Your bones are dynamic.
Speaker 2: Is that yeah? No, I mean that answers my question.
Speaker 2: But I guess my follow up question then, is is
Speaker 2: there a potential downside then to inhibiting the bone remodeling.
Speaker 3: I'm sure potentially, Okay, potentially, yes. I don't know any
Speaker 3: more details about it. I just know that the idea
Speaker 3: behind this is that if in the case that you
Speaker 3: have bones that are already more fragile, you want just
Speaker 3: an increase in bone formation, kind of in the same
Speaker 3: way that bisphosphonates are leading to more mineral deposition and
Speaker 3: less of the remodeling. If that makes sense.
Speaker 2: Yeah, yeah, yeah.
Speaker 3: The good thing about this particular treatment is that it
Speaker 3: is not mutation specific. This has the potential to help
Speaker 3: regardless of most of the underlying causes or mutations involved
Speaker 3: in osteogenesis in perfecta. It's still very much in clinical trials.
Speaker 3: I have no idea. Time will tell if it's effective
Speaker 3: or not. And I really expected to find a lot
Speaker 3: more because this is a genetic disorder, because many of
Speaker 3: the cases are autosomal dominant disorders, and we know the
Speaker 3: genes that are involved, a lot more information on where
Speaker 3: we stand with gene therapy. But I really didn't find much.
Speaker 3: And you know what else just occurred to me is
Speaker 3: that it seems like the very few treatments we have
Speaker 3: so far are mostly targeting bone, not any of the
Speaker 3: other organs or tissues affected by osteogenesis imperfecta. Yes, definitely, definitely,
Speaker 3: that's the vast majority of all treatments prior and current
Speaker 3: through that. Yeah. Yeah. The Osteogenesis Imperfective Foundation has some
Speaker 3: information on other trials that are ongoing, and there are
Speaker 3: a number of other additional targets that are being looked
Speaker 3: at in terms of other ways to try and treat mostly,
Speaker 3: like you said, Aaron, the bone components of osteogenesis imperfecta.
Speaker 3: There are also studies being done importantly by Baylor College
Speaker 3: of Medicine to look at mental health and quality of
Speaker 3: life overall in people living with osteogenesis imperfecta, which is
Speaker 3: always an overlooked part of any chronic disorder story quite honestly, Yeah,
Speaker 3: and a really important one at that. That's what I have,
Speaker 3: so it's not as much as I would have liked.
Speaker 3: Please let me know, listeners if I missed something major,
Speaker 3: because I'd like to know if there's more out there.
Speaker 3: But if you'd like to learn more, who have we
Speaker 3: got sources for you?
Speaker 4: Oh?
Speaker 2: We certainly do. I've got uh. I had more than
Speaker 2: a handful, but I'm only going to shout out too
Speaker 2: right now. One is by Wheel from nineteen eighty Osteogenesis
Speaker 2: Imperfecta Historical background, and then I read a book chapter
Speaker 2: from twenty fourteen by Silence and Lamonde titled Evolution of
Speaker 2: the present Understanding of the clinical and genetic heterogeneity and
Speaker 2: molecular and biochemical basis of Osteogenesis Imperfecta.
Speaker 3: Ooh, it's a mouthful. I have a number of papers.
Speaker 3: Some of my favorites were three different papers just titled
Speaker 3: Osteogenesis Imperfecta. Gotta love the simplicity of it. Two that
Speaker 3: were from the Lancet, one that was from Nature of You.
Speaker 3: Disease primers always a favorite. There are a whole bunch more.
Speaker 3: A paper about collagen if you want a deep dive
Speaker 3: on that, and papers about the current understanding the different
Speaker 3: classifications and of course investigations into treatments. You can find
Speaker 3: the list of sources from this episode and every single
Speaker 3: one of our episodes on our website, this podcast will
Speaker 3: Kill You dot Com under the episodes tab.
Speaker 2: Thank you Natalie again, so so much for sharing your
Speaker 2: story with us. Like, we just cannot express how much
Speaker 2: we appreciate you doing that.
Speaker 3: Yeah, thank you so much. Thank you also to Bloodmobile
Speaker 3: for providing the music for this episode and all of
Speaker 3: our episodes.
Speaker 2: And thank you to Tom Bryfogel for the audio mixing.
Speaker 2: We love it, we do.
Speaker 3: Thank you exactly right network, and.
Speaker 2: Thank you to you listeners.
Speaker 3: I hope you liked it.
Speaker 2: How do you feel about collagen.
Speaker 3: Collagen whole episode on it? Let us know. Yeah, And
Speaker 3: as always, a special thank you to our patrons. Thank
Speaker 3: you so much for your support. It means everything, it
Speaker 3: truly does.
Speaker 2: Okay, Well, until next time, wash your hands
Speaker 3: You fail the animals