This Podcast Will Kill You - Ep 69 Huntington’s disease: Let’s talk frankly

Episode Date: March 23, 2021

Despite being one of the earliest recognized genetic diseases, many aspects of Huntington’s disease remain shrouded in mystery. This stems in part from our limited grasp on how our own minds work but also from the dark history of Huntington’s disease and the shame and silence that accompanied it for so long. In this episode, we attempt to bring what we know about Huntington’s disease into the light, to talk frankly about the characteristics and progression of this hereditary disease, the role of eugenics in creating and promoting the stigma surrounding it, the ethical considerations surrounding genetic testing, and the medical and scientific advancements that give us reason to hope. And we are so grateful to the provider of our firsthand account for sharing their perspective on what it’s like to be diagnosed with this disease. Tune in for all this and more. See omnystudio.com/listener for privacy information.

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My name is Jay, and I am 34 years old, and I was recently diagnosed with Huntington's disease. My grandfather was diagnosed with Huntington's and his. 80s. But I don't think he and my grandmother really understood this, you know, severity of the illness and its implications for their children and grandchildren. So they never really told us until my father started seeing some symptoms in his 50s. So that's when I found out, I guess I was 28. I had just been married. You know, there's so much optimism.

And then I find out from my parents that there's this terrible shadow, you know, that's going to be potentially hanging over my life. And it was definitely really, really hard. I'm not going to lie. Your priorities sort of shift. just trying to maximize the years that you might have with a good quality of life, you know. So I didn't get tested right away. I really wasn't ready.

But over the years, I started to, I guess, come to a point of acceptance. And I also started to see symptoms starting to appear. things like coordination issues, balance issues, also difficulty swallowing and drinking. So that's how it's starting to affect me and it got to a point where I was ready to be tested. And so I did that, I guess, a few months ago, actually. And now I have the official results that I am positive for Huntington's disease. at that point, I guess it wasn't as bad as I thought, actually, to get those words. For me, it was, I guess, a little bit freeing to finally have some solid answers and to know what my reality would be.

You know, I'm really lucky to have a really supportive husband with me. he's been a rock for every step of the way being understanding for all my decisions one in particular is that I feel really strongly that I don't want to pass this on to my children I know that's maybe a controversial opinion but I just can't imagine

potentially burgeoning them with this same difficulties that I'm experiencing. So we'll be using IVF. They have this cool technology where they can test the MVOs, and that's the route we'll be taking. But obviously it's also time-consuming and expensive and not a guarantee. So it's one of the most disappointing things about this diagnosis

This is one of the few things I really knew I wanted was a baby. And now we can't just conceive the natural way. We've got to go through all these hurdles. Another aspect about it that's really difficult is because it's a family disease. You see, I saw my grandfather suffer from it, and now my father is suffering from it. and now I'm going to have the same symptoms and my aunt, also and possibly my brothers. So it's really difficult to not feel like you're being a burden

if you want to, you know, share your feelings with your family members and reach out to them without being potentially a burden to them when they are also dealing with this kind of stress and also being a burden to my husband, of course. Eventually, he'll be caring for me more and more. So, yeah, it's really, really hard. Hi, this is Jay's husband. Some of the difficult things are trying to explain

to say my side of the family, what's going on, my sisters, have their families going along and things like that. And at this point, we've had your diagnosis, I guess, for more than a month. But we still haven't found the right time or place or way to even tell our extended families or my family even. I think basically for you, it's just your. immediate family on one side that we've really talked to about it, but we don't even know how to tell our friends about this because we just don't have, we don't have the words, and we don't know how to,

I guess, like, we're not looking for sympathy, but we also don't, we don't want to keep it a secret. And given that it's not something that can be cured like cancer or COVID, this is something that is something that is not going away. And I think that has been one of the really stressful parts that we haven't really figured out a good way to share with those that are even closest to us. I think that has definitely weighed on me at least to have this information and not be able to really talk to people about it yet because we don't know how. I think another thing that we've kind of been thinking a lot about is just, you know, like, what do we do? unlike some diseases, again, that do have cures, when do we need to tell our insurance? Because we definitely will want some of, you know, all as much of the care to be covered by insurance. But that's not something that a lot of people have been able to give us advice on or there's not a good rule book or a guidebook out there.

and because everybody's path with hunting teams is different than the solutions and how they resolve it is all different. I think one of the really difficult part is that Jay's grandfather showed symptoms in his 80s and his path and how he dealt with it was very different than her father, who was in his 50s when he was diagnosed. and that's very different from Jay, who started displaying symptoms in her 30s. And so there's even when we look for comparisons to how to manage and how to deal with it, we don't have a particularly good role model or something to compare to. and we're kind of going at our own pace and in our own direction and hoping that we get it right, but also being really aware that we don't have a lot of flexibility that we have to get it right the first time because all these days are precious.

Yeah, I guess that's definitely a downside of it being a relatively very disease unlike something like breast cancer. there's just not as much resources. There's not like, you know, the kind of community that you get when you're diagnosed with cancer. Let's say there's not as much research, not as much funding. So, yeah, I guess overall I've been trying to just, you know, do it day by day, little by little. some days are good, some days are bad, but it's my reality now, and you don't really have a choice anymore, right? You just have to, you're on the train, so you kind of have to deal with it. And I guess that's been how I'm trying to look at it. And hopefully I can just keep some

optimism as things progress, you know, despite what might come. Thank you so, so much for sharing your story with us. We really appreciate it. Yeah, thank you. Hi, I'm Erin Welsh. And I'm Erin Alman Updike. And this is, this podcast will kill you. And today we're talking about Huntington's disease. Yes, we are. This is just one of a handful of the genetic diseases that we have covered, Aaron, right? Yes, it is. And it's very different than the other genetic disorders that we've covered so far. Yeah. I mean, this is a big topic to cover. So yeah. So let's like maybe get right down to business with business we should cover. Yeah, the first business, as always is quarantini time.

It's quarantini time. And this week, we are drinking the Marjorie. The Marjorie. Named for Marjorie Guthrie, who was the founder of one of the biggest Huntington's Disease Advocacy groups in the U.S., now called the Huntington's Disease Society of America, I believe. Excellent. And what is in the Marjorie? The Marjorie is vodka, orange juice, unsweetened cranberry juice, and a little bit of Amaretto. Excellent. 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.

As always. And the usual business, I guess. You know, we have transcripts, which is thrilling. Thrilling. You can find those on the transcripts tab of our website. And on our website, you can also find all kinds of other fun things like a Goodreads list or a link to a Goodreads list, a link to our bookshop. affiliate page, any of the sources that we use in all of our episodes, link to Bloodmobiles' music page on Bandcamp.

I mean, it's all there. Just check it out. You'll have a fun time. It's a very fun time on the website. All right. Well, this is, as you said, Erin, it's a very big topic. So shall we take a quick break and then dive right in? Let's do it.

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It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is outside. We're offering our listeners 15% off their first order of O'Keefs. just visit o'Keefscompan.com slash this podcast and code this podcast at checkout. In 2023, a story gripped the UK, evoking horror and disbelief. The nurse who should have been in charge of caring for tiny babies is now the most prolific child killer in modern British history.

Everyone thought they knew how it ended. A verdict, a villain, a nurse named Lucy Leppie. Lucy Lepe has been found guilty. But what if we didn't get the whole story? The moment you look at the whole picture, the case collapses. I'm Amanda Knox, and in the new podcast, Doubt the case of Lucy Lettby, we follow the evidence and hear from the people that lived it, to ask what really happened when the world decided who Lucy Lettby was.

No voicing of any skepticism or doubt. It'll cause so much harm at every single level of the British establishment of this is wrong. Listen to Doubt, the case of Lucy Lettby. Lettby on the IHeartRadio app, Apple Podcasts, or wherever you get your podcasts. So right up front, Huntington's is a neurodegenerative genetic disorder that is inherited in an autosomal dominant fashion. So what does that mean? It means that this is a disorder that's affecting the brain and the nervous system. And you only need one copy of the mutated gene in order to have disease.

So that's already different from the other two genetic disorders that we've covered in the past, namely sickle cell and cystic fibrosis, which are both autosomal recessive. So you have to have two copies of a mutated gene in order to have disease. But before we can actually talk about Huntington's disease, I think we need to step back and talk about our genes in more detail than I think we have on this podcast. at least recently. So here's where we'll begin. Our DNA is made up of little building blocks, like Legos, called nucleotides, which we give letters, A, T, C, and G. So three of these nucleotides grouped together form what's called a codon, because that is what codes for an amino acid. Well,

it codes for RNA, which codes for amino acids, but we'll ignore that. Okay. Right. Right. When you string a bunch of amino acids together, you get essentially a protein. Scattered throughout our genome, throughout not just human genomes, but like every genome, animals, plants, bacteria, we have these short, repeat sequences of nucleotides that are called microsatellites. They're like one to six nucleotide sequences that are repeated like T-A, T-T-A, all in a row. So that's some basic definitions. Now, on this podcast, we talk a lot usually in the context of viruses or bacteria, but this is true for human cells too, how every time our cells or any cell replicates,

it sometimes makes mistakes. And we call these mistakes mutations. Most of the time, these mutations result in like a single or small, base pair change, like one addition or a deletion or a substitution like a T for an A or something like that. But within these repeat regions, these microsatellite regions, a single mistake can lead to very big changes because what it often leads to is the gain or the loss of an entire repeat sequence. Right. So how does that happen? We don't fully know, but we think that what happens is that as our DNA polymerase that's

helping to replicate our DNA is chugging along, copying T-A, T-A, T-A, all in a row, it kind of slips out of position, and then it loses its place, and when it picks it back up, it does so earlier along that DNA chain. So if you have a region that's like T-A-T-A four times in a row, and it gets a little bit wonky during replication, the next cell, as after it replicates, would end up with T-A-T-A, like six times in a row or eight times in a row. So that's microsatellites. They exist throughout our genome, and the mutation rate tends to be higher in these repeat regions than in other parts of our genome. And the longer a microsatellite region is, the more likely it is that this type of slippage and

mutation can happen, and the more likely that the mutation results in large changes, especially expansion or growing of those regions and getting longer. So let's talk about how that relates to Huntington's disease. Yeah. Huntington's disease is a disorder that's known as a trinucleotide repeat disorder. So that means it's caused by an abnormal number of trinucleotide, three nucleotides, in a row, C, A, and G, that repeat a whole bunch of times, aka this is a microsatellite. And there are other diseases that are this trinucleotide repeat diseases, right? Absolutely, yes.

So fragile X is another example of a trinucleotide repeat disorder, where you have a repeat at the end of the X chromosome. You also have Friedrichs ataxia, there's muscular dystrophy, there's a whole host of trinucleotide repeat disorders. This is one. And this happens in a gene that we all have on chromosome four that's called the Huntington gene, where on chromosome four there's a series in everyone where we have this microsatellite. We have these C-A-G repeats.

But in the vast majority of the population, we have anywhere from five to like 28 copies of C-A-G all in a row. And another thing that's important about this repeat on chromosome four is that it's located in what's called an Exxon or a coding region, which means that our body, every human body and other animals too, we make a protein from this region that's called Huntington. It's a really clever name. But now we know that these microsatellite regions can sometimes be unstable and expand. And it turns out that once you get to above 28 repeats, that is when this region becomes

unstable. And that means that when those cells replicate, that particular region is likely to expand. It could contract, but it's more likely to expand. And once it expands above 40 repeats, that is when a person will develop Huntington's disease. Why 40, what happens at that point? Okay, great question. So the Y40 is an interesting question because it could be a little bit earlier than 40. It really doesn't ever happen any earlier than 36, but especially that high 30 region, you can have what's called incomplete penetrants where some people with that number of repeats might have disease and others might not. So that's kind of like a gray zone.

But essentially, the reason why, once you have a certain number of repeats, you end up with disease, is because that trinucleotide repeat is located in an exon, in a coding region. So that abnormally long set of repeats causes the production of an abnormal Huntington protein. And the more this repeat expands, the more abhorably long set of repeats, the more abnormal. abnormal this protein is. Mm-hmm. And probably the more abnormal protein you are producing as well. Okay.

So what does this protein do? Okay. Very good question. I'm not going to answer this satisfactorily because the answer is normally we don't know. So we know that this Huntington protein is essential to development because if you knock it out completely in mice, they don't live. Like they don't develop in utero and they die. So we know that this protein does something that's very important.

We think that it's involved with like trafficking of stuff inside of the cell, like moving things from one place to another within the cell. Within a cell, okay. Within a cell. But we don't know that for sure. We don't know the real function of normal, typical, what they call wild type huntington protein. but that still doesn't answer the question of like how does this actually cause disease like okay we have an abnormal

protein um so what yeah the short answer i'm going to try and give the shorter answer even though i think it's going to be less satisfying um we don't we don't really know Erin come on that's not satisfying give me the longer answer i warned you we don't fully know No, there's a lot of hypotheses about the like specific cellular mechanisms that are involved with this abnormal protein. We have a lot of evidence that it's what's called a gain of function. So in, for example, our cystic fibrosis episode, we talked about how when you have a mutation in the cystic fibrosis protein, you lose the function of that protein.

And that's what causes disease. Here we have the opposite, where the production of this abnormal protein, is what's involved. It's not that the Huntington protein is no longer doing whatever Huntington protein is supposed to do. It's that it's doing something new and different and bad. Right. Okay. So we know that the accumulation of this abnormal protein, it forms aggregates, it forms these beta pleated sheets, they aggregate into cells. And then also possibly the mRNA itself that codes for this protein is somehow toxic to our cells and it causes cell death. So that's the end result is what happens is cells die because of this abnormal protein. And while Huntington protein is

found kind of throughout our body, like this gene is expressed in a lot of different tissues, for whatever reason, this abnormal protein causes damage primarily to the central nervous system. So that's why we see this as a neurodegenerative disease because it's causing cell death in neurons. Is it expressed more highly there or what's happening? Good question. Don't fully know. Okay. At least I don't fully know.

We can get even more specific and getting more specific will help us to understand the symptoms of Huntington's disease itself. Because we know the cells in our brain that are the most affected. One of the main areas that we see the loss of neurons and damage to neurons is in the striatum of the basal ganglia. So while we do see eventually the entire brain becoming involved and like widespread atrophy, this striatum of the basal ganglia is the first and hardest hit area. So what is the basal ganglia? We actually talked about this way back in our encephalitis lethargica episode. a million years ago.

Do you remember that? Yeah. No, I don't. I don't remember. Okay. Well, let me tell you then. The basal ganglia, it's a set of brain structures that are deep in our forebrain that essentially help to control movement.

So the basal ganglia helps to coordinate inputs from the motor cortex of our brain. They process them. and then they put outputs out to the thalamus and other places that go to our muscles and actually initiate smooth muscle movement. Well, skeletal muscle, but I mean like smooth coordinated movement. Okay. It's also, the basal ganglia is involved in a lot of other things like cognition and emotion. Like this is our brain. It's all very integrated. But one of the major functions is in this coordination of movement. And a lot of what the basal ganglia does specifically is actually to inhibit movements. So that when this basal ganglia is damaged, we lose that ability to inhibit

movement. So movement becomes uncontrolled or uncoordinated. Okay. And is this a common structure that is damaged in other movement disorders like Parkinson's or something? Precisely. So in Parkinson's, it's a different. set of neurons and they're more specific. And so that's why we actually have better treatments. We still don't have treatments to like treat Parkinson's, but to treat the symptoms, we're better at Parkinson's that we are at Huntington's because of what is being damaged. But this region has more varied functions and so it's harder to target to fix. Okay. Gotcha. Yeah. So that finally brings us to the symptoms of Huntington's disease. The characteristic symptoms, which gave Huntington's

disease an earlier name that I'm sure you'll talk about, Aaron. The characteristic symptoms are Korea or Korea form movements. These are involuntary motor movements, especially in the extremities, so like arms and legs, fingers and toes. The involuntary movements, they're kind of like muscle twitches essentially that usually start out early in the course of disease in smaller muscles. So like fingers, face twitches, that especially early in disease might not be noticeable to anyone other than the person who's experiencing them, like you wouldn't even notice them. And they might not interfere very much at all with daily life. But eventually they spread to affect essentially any or every voluntary muscle, which includes the muscles of the face and the throat that are involved

in talking, chewing, swallowing. And so then dysarthria, which is difficulty speaking, can become a problem, as well as dysphasia or difficulty swallowing and eating, which is very problematic. Yeah. And then eventually, as this disease progresses, this increase that we see in muscle movement actually transitions to what's called hypokinesia and Brady kinnesia, which means slowing of muscle movement and less muscle movement. And this causes like a difficulty in initiating voluntary movement. So muscles become very rigid. And this is actually not unlike what we see in Parkinson's disease as well. You have a lot of rigidity in Parkinson's disease. Right. Yeah. So of course, all of these symptoms can have huge effects on a person's activities of daily living.

Things like walking become very difficult and can result in frequent falls, which can be very dangerous. But even activities like getting out of bed, showering, getting dressed, all of these can become difficult because you don't have control over the movements of your muscles. And then dysphasia, so difficulty swallowing, is particularly problematic because that can result in aspiration of food into the lungs, which can result in pneumonia. But Huntington's disease is not just a motor disorder, which is why the old name is no longer the name. Huntington's causes a range of neurocognitive and psychiatric changes as well. So first, not first in terms of the course of disease, but just first of what I'm going to talk about, is depression, which is far more common in people with Huntington's disease than in the general population.

And I think what's important is that it might be easy if you just aren't thinking to dismiss this as the result of being diagnosed with an incurable fatal disease. But it's not just that. even though we don't fully understand depression in general and the effects of depression on the brain or every single change that happens in Huntington's disease in the brain, we do have a lot of evidence that the effects of Huntington's on the structure of the brain itself is what makes people more at risk for depression and other psychiatric illnesses like anxiety, psychosis, mania, etc. It's like actual physical changes.

Exactly, right. And then the other hallmark of Huntington's disease is dementia, which is cognitive decline. So unlike Alzheimer's, so I think Parkinson's, Huntington's, and Alzheimer's often get talked about in relation to each other for different reasons. But unlike Alzheimer's dementia, which tends to affect memory first, especially short-term memory, the dementia and cognitive decline with Huntington's disease tends to affect what we call executive functions first. So that's things like decision making, planning, kind of like mental flexibility to new scenarios and reaction. And so this can result in behavioral changes. And this is something that friends and family can sometimes notice, even sometimes before a person experiencing these

changes might notice anything. But they can be very subtle and often can happen before any of these motor signs and can stay very mild for a long, long time throughout the course of disease. Okay. And this is likely because the basal ganglia is involved with a lot more than just motor coordination. Right. So these kind of small changes and small amounts of neuronal death scattered throughout can result in these changes. And because Huntington's does eventually affect the entire brain, eventually memory becomes impaired as well. And so in terms of the progression and like, first of all, how predictable is it?

Are there, you know, stages that, you know, you could say, well, this is the typical stage one, stage two, et cetera. And if it is predictable, why do we see, like, why does that happen? and why does it progress in that order? Yeah, great question. There are stages in that there is pre-symptomatic and then what we call clinical disease, which is after a person becomes symptomatic. And most of the time we consider symptomatic to be symptomatic with motor symptoms.

Okay. But then a lot of times, you know, if you are talking with someone and they think about it, they're like, yeah, well, maybe I have noticed like a little bit of a personality change or I was having difficulties at work before that. But they wouldn't have attributed it because they didn't know that they had Huntington's, right, until the motor symptoms happened. But to answer your question, no, there isn't a sequence to this. Okay. And it can be very, very variable from person to person. and the sequence does not depend on the number of repeats. So the vast majority of people with Huntington's disease will have onset sometime

between their 30s and 50s. And everyone that has more than 40 of these CIG repeats will have symptoms by age 65, pretty much. But while the length of repeats doesn't correlate to like, what symptom is going to be first or even how quickly the symptoms are going to progress or anything like that, what it does correlate to is the early onset of symptoms. Right. So the longer this CAG repeat, the earlier you're likely to see symptoms onset. And then that happens in successive generations, right? Exactly. Yeah. So something called anticipation happens where because this microsatellite region is so unstable, which with each generation, that length is likely to become

longer. It doesn't necessarily, but essentially 75% of the time when that cell replicates, when any cell replicates that has that unstable repeat, it will expand. And so that means that a child with a longer repeat could have earlier onset of disease. Once you get to above, of like 60 repeats, you can have what's actually called juvenile onset Huntington's, which happens if someone has symptoms before age 20. And that does tend to look a little bit different than Huntington's that has a normal onset of 30 to 50, where you have more of that slow, rigid movement early on in the disease rather than the Korea form involuntary movement. But what is kind of universal is that once symptoms begin, then this disease does progress, and it continues to progress.

It is essentially universally fatal within about 10 to 30 years of initial onset of symptoms. Most of the time, death is not from the disease itself, but from complications associated with falls or more commonly with pneumonia. due to aspiration because of that dysphasia and difficulty swallowing. Right. So we talk about this as a genetic inheritable disease, but can it occur randomly? Yes. So it can certainly occur where there is no family history. Right.

And that's because if you have a CAG repeat length of anywhere from like 26 to 35 or 28 to 35. That is an unstable length, but you yourself and anyone in your family wouldn't have disease from that. But that microsatellite could mutate in your eggs or your sperm, and then your children could have Huntington's disease. So we do see it happen. Absolutely. I think I read, I should double check this number, but I think I read about 8% of the time. Okay. Yeah. So not super common, but absolutely possible. So that's the biology of Huntington's disease. I guess one question I didn't ask was why, why is it a later in life onset? Yeah, it's a good question. It's likely related to that it takes that much time for this abnormal protein to accumulate.

So remember that because this is an autosomal dominant disorder, you only need to have one. copy of this gene. So how often is your cell copying, making a protein based on that half, based on that mutated gene versus based on your normal copy? So like what's the ratio of normal Huntington in your cells to abnormal Huntington in your cells? And how long does it then take to accumulate this toxic protein? It's also interesting that there's not like a check system for abnormal proteins? So it's very interesting and it's something that people are working on in terms of treatment like can we change how cells process protein and deal with it so that we don't have this accumulation of these abnormal protein sheets. Right. Yeah. What I think is very interesting about

the biology of Huntington's Aaron is that we know so much like I just gave you so much detail, right? Like a lot of detail. And yet, we also know so little at the same time. Yeah. Yeah. And I think a lot of that, too, has to do with just that we know so little about our brain. You know, our brain is still neurocognitive disorders in general are not well understood. The mechanisms, the specific nitty-gritties of it. Right. We just don't have the answers yet. Well, and then that, of course, course, like, prohibits any, like, good treatments from being developed quickly. So what I'm curious about Aaron is how we got to this point. Like, what is Huntington's like in history? Because it's been around forever. This protein is in us. So how did we get to this point?

Yeah. I will try to answer those questions. Right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keeffe's Working Hands hand cream is such a relief. 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, and absorbs quickly. A little goes a long way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works.

O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is, outside. We're offering our listeners 15% off their first order of O'Keefs. Just visit o'Keefscompan.com slash this podcast and code this podcast at checkout. In 2023, a story gripped the UK, evoking horror and disbelief. The nurse who should have been in charge of caring for tiny babies is now the most prolific child killer in modern British history. Everyone thought they knew how it ended. A verdict,

a villain, a nurse named Lucy Letby. Lucy Lettby has been found guilty. But what if we didn't get the whole story? The moment you look at the whole picture, the case collapses. I'm Amanda Knox, and in the new podcast, doubt the case of Lucy Letby, we follow the evidence and hear from the people that lived in, to ask what really happened when the world decided who Lucy Lettby was.

No voicing of any skepticism or doubt. It'll cause so much harm at every single level of the British establishment of this is wrong. Listen to Doubt, the case of Lucy Lettby on the IHeartRadio app, Apple Podcasts, or wherever you get your podcasts. I'm Clayton Eckerd, and in 2022, I was the lead of ABC's The Bachelor. Unfortunately, it didn't go according to plan. He became the first Bachelor to ever have his final rose rejected. The internet turned on him. If I could press a button and rewind it,

I would. But what happened to Clayton after the show made even bigger headlines. It began as a one-night stand and ended in a courtroom with Clayton at the center of a very strange paternity scandal. The media is here. This case has gone viral. The dating contract. Agree to date me, but I'm also suing you.

Please search warrant. This is unlike anything I've ever seen before. I'm Stephanie Young. This is Love Trapped. This season, an epic battle of He Said She Said, and the search for accountability in a sea of lies. Listen to Love Trapped on the Iheart Radio app, Apple Podcasts, or wherever you get your podcasts. In the June 30th, 1806 edition of the Suffolk Gazette, there's a brief news communication from East Hampton, describing the tragic death of a woman named Phoebe Hedges, who was believed to have walked into the sea and

not look back. Quote, this extraordinary step is attributed to her extreme dread of the disorder called St. Vitus's Dance, with which she began to be affected and which her mother now has to a great degree. This is one of the earliest reports of what would later be described as Huntington's disease. And I apologize for starting off in such a dark way, but I think that there's a lot that we can tell from this really short description in this. newspaper. First, it shows us that St. Vitus' dance still seem to be widely known. If you remember

from our dancing plague episode, I'm going to go over that briefly again later. Anyway, the point is it was still widely known. Also, that the disease can be extremely emotionally traumatic, especially due to its familial nature, like you talked about, Aaron. And also that the exclusion or stigmatization of families where Huntington's was known to occur wasn't the rule that in some communities, like apparently in East Hampton, these families or individuals that had Huntington's were highly respected and very much integrated into and accommodated by the community. And I mentioned this last point because it serves as a sharp contrast for a good chunk of the social history of Huntington's, and especially some of the prejudices that were created shortly

after the disease was first described, and that persisted long after that. So let's begin. Most histories of Huntington's disease start off with the man for whom the disease is named, George Huntington. But I wanted to go back a little further than that. Of course you did, Erin. Of course. Context, contact. Context. In case you haven't listened to our Dancing Plague episode, which I think it's a pretty fun episode, so I recommend it, right? Yeah, definitely. Essentially, what happened was that in 1518, there were also other small outbreaks, but the big one happened in 1518 in Strasbourg. There was this outbreak of contagious and unstoppable dancing.

And side note, 1518 happened to be the year after a big sweating sickness outbreak. in the area. Oh, it's all coming together. All coming together. Okay. And so this dancing outbreak came to be called St. Vitus's dance or St. Vitus's Korea, Korea from the Greek for dance, like choreography, etc. Because people would go to the shrine of St. Vitus to be cured. And although the 1518 outbreak was the largest, it was not the only one, and there were smaller outbreaks in the following years. And by the 1800s, these epidemics had stopped happening pretty much entirely, but the name of the condition or the condition itself didn't fade from public memory because other people still experienced these similar movement disorders, like, for instance, Phoebe Hedges, who I just

mentioned earlier. But what Phoebe was experiencing in 1806 was not an outbreak of dancing plague, of course. There was just no other name for it at the time. And St. Vitus' dance, or just Korea, was a sort of catch-all term for any kind of movement disorder at that time. Really, only starting in the 1800s is when clinicians started paying closer attention to these Koreas, especially those that happened in children, possibly because of the rise in rheumatic fever due to like population growth, cities, growth, et cetera. Yeah. And so when physicians started describing these cases,

they may have also noticed another kind of Korea, one that was different from this childhood or Siddentham's Korea. By the time that George Huntington's description of the disease was published in 1872, there were at least five other previous descriptions of the disease going back to like the 1840s. Huh. Interesting. But we call it Huntington's, not Waters disease or Lunds disease. Why? Yeah.

Well, it might just be a matter of timing, invisibility, and chance. Okay. But another thing that made Huntington stand out was his description, which the famous Dr. William Osler said, quote, There are few instances in the history of medicine in which a disease has been more accurately, more graphically or more briefly described. Huh. So there's just like a very, very good description.

Yeah. So he won the best description award. He won the best description award. Okay. And at the tail end of Huntington's publication, which largely focused on other forms of Korea, Huntington added a few paragraphs on what he called hereditary Korea,

noting its inherited nature, particularly that it didn't skip a generation. mental decline as a common occurrence, and it's typically adult onset. It was descriptive yet to the point, and in the decade after it was published, the disease that would later be called Huntington's Korea for this amazing description would get a whole lot more researchers interested in it, and not always for good reason. But before we get to that, I want to talk a bit about why the disease might have only been described in the late 1800s, which seems kind of late to me.

Yeah. Like, you know, St. Vitus's dance had been around for a long time. Three hundred years between. Yeah. Yeah. And so it might just be that like there are accounts that people can't distinguish between St. Vitus's dance and what might have been Huntington's, I'm not sure. But one of the things that people have suggested is that low life expectancy,

may have contributed to the apparent invisibility of the disease. So people were more likely to die of something else before developing any symptoms. Right, that makes sense. Which would, yeah, which would also then sort of like obscure the inheritability aspect of it. Right. But having said that, it's not like the 1800s. Like it's not like the year from like 1799 to 1800s came with this huge boost in life expectancy. For example, if you were born in 1601, your life expectancy was 38 years.

Oh, no. Whereas if you were born in 1831, life expectancy was 41 years, like from birth. Wow. So, and there are problems with life expectancy from birth because infant mortality was so high, et cetera. But anyway. So other people argue that it actually wasn't the slight increase in life expectancy, but rather the reframing of heredity overall and how we thought about the inheritance of traits.

What? Yeah. So there was this boom around this time in natural history research and experimentation and livestock in plant breeding that had led to people thinking critically and publishing widely about the inheritability of traits. Like Mendel. Like Mendel. Like Darwin. Like, if you remember. back to our preons episode, like all of the people who were doing sheep breeding at that time to try to

find the best marino wool. Right. Yeah. And also in medicine, there was still no germ theory in the early 1800s. And so Heredity joined my asthma as this way to explain why certain diseases occurred. Right. So there's that. And finally, there's the matter of George Huntington and East Hampton, so the man and the place. George's grandfather, A. who was also a doctor, moved to this area of Long Island, New York in the late 1700s, where he set up a medical practice. And shortly after he arrived, he learned of a few families in the area who were affected by something that people generally referred to as, quote, that disease.

Oh. The people who had that disease and their unaffected family members were not shunned or stigmatized. They held public office. They seemed to be supported by their families and by the rest of the community. It was just sort of like the way it is. It was like, this is how we are here. And George's father also became a doctor. And some of his patients were also people with what would later be called Huntington's disease.

And sometimes George would go on rounds with his dad. And so when George finished medical training, he not only was equipped with the ability to observe and describe certain conditions. he had the generational knowledge of his father and grandfather. And he also happened to live in a town which had a higher prevalence than in surrounding areas. Okay. And so this set him up to write his On Korea in 1872. It was the only article he ever published, apparently. Wow. Yeah. When his paper came out, other reports of Huntington started to trickle in, and not just from the U.S., Germany, France, Italy, France, Italy, Italy, Italy, Britain, Austria, Cuba, Poland, Russia, and many other places reported case descriptions of what had started in 1887 to be called Huntington's Korea. And this research in the late 1800s filled in the details of the clinical picture that Huntington

had painted. So, for instance, insanity was mentioned as a defining feature in George Huntington's description of the disease, but later physicians noted that the mental impairment, due to the disorder was not always severe or it was variable or it onset differently. And it was essentially their understanding of how cognitive function worked became more nuanced. Yeah. Yeah. And then the average age of onset was studied.

Autopsies were performed on people who had died from Huntington's and these showed these physical changes in the brain. And there was a whole lot of compare and contrast with the other. highly studied form of Korea from this time. So Sidenham's Korea. William Osler, who was super interested in all types of Korea, got in touch with Huntington to ask whether he could arrange a meeting with some people who were affected by the disease in the town. And Huntington said, no, I don't think that's a good idea. I want to respect these people of privacy and you shouldn't bother them. Wow. Which like in the late 1800s, I'm shocked by. I'm totally shocked. But I know.

Way to go. Yeah. I'm guessing Osler didn't listen? Actually, he did, yeah. He was like, okay. And then Huntington moved away to a different town, and another doctor took over the practice, and Osler asked him. And at first, this new doctor, Osborne, said the same thing that Huntington had said.

No, it's best if you don't come here. But then he changed his mind. And it seems that he thought that maybe by having Osler, come there to do more research on the disease, it could increase awareness that could lead to more support and medical treatment and cures. But on the other hand, it could bring increased scrutiny and unwanted attention to these people without their consent. Osler never did end up visiting East Hampton. He did conduct research on Huntington's disease on other families and other places. But in the last few years of the 19th century and in the first several decades of the 20th,

Huntington's and Osborne's initial fears were realized as the focus on Huntington's turned to one of the defining characteristics of the disease. It's heritability. So like I mentioned, general patterns of inheritance had been figured out for a while by the end of like the 1800s, thanks to livestock breeders who really could be considered like the first geneticists, even more so, I would argue, than Mendel. By the time Mendel was playing with his peas in the 1860s, these breeders already knew about dominant and recessive forms of inheritance, like maybe not in that formal language, but like they were incredibly knowledgeable.

But interest in the field of heritability grew throughout the late 1800s and into the 1900s, especially when Mendel's work, which was published in 1866, but was sort of like lost, like no one talked about it. And it was rediscovered in like 1900. Yeah. And Mendel's work gave this like form and calculation and structure to these patterns. And the interest grew even more broadly beyond that. It wasn't just plant or livestock breeders or natural historians that had an interest in which traits were passed down, but also so-called social thinkers, quote-unquote, who began to take these biological concepts and apply them to what they saw as social problems. So begins the story of eugenics.

And this is a story that I've touched on so many times in this podcast. If you remember back in any of the episodes where I talk about eugenics, especially I think the birth control episode, you may remember how the term race suicide, quote unquote, really gained traction in the early 20th century in the U.S. It was one of Teddy Roosevelt's favorite terms. Basically, white middle class Americans began to be fearful of the influx of immigrants, the growth of the lower class, their own declining birth rate, etc. Essentially, they were worried that they were going to become outnumbered by those they deemed to be unfit or less than. The word degeneration itself began to take on multiple meanings.

It could be used medically to describe how someone's ability to walk and talk and function normally, slowly deteriorated. And to the eugenesis, it could be used to vaguely describe the gradual decline of society, whatever that meant, however they wanted it to mean. Eugenics and this concept of race suicide focused particularly on who was procreating and how to control it. They wanted to encourage certain people to procreate more and prevent others from procreating at all by force if necessary. The first few decades of the 20th century saw the rise of eugenics from this niche theoretical biology concept to a widespread public movement, with state laws legitimizing this way of thinking and genetic research providing a scientific basis for it. marriage prohibition, involuntary sterilization, racist immigration laws, those were all like the order of the day. And I think I'm probably repeating myself from past episodes when I say

that Hitler and the Nazi party got many of their ideas from, like directly from the eugenics movement in the United States. It's hard to overstate how just how pervasive eugenics became and in some ways still is today. Anyway, as eugenics gained traction, it began to hone in on certain groups of people or individual traits or conditions that they felt were, quote, unfit. One of these was Huntington's disease. Huntington's disease was actually one of the first genetic diseases to be described as dominant by William Bateson and Reginald Punnett of like Punnett Square fame in 1907.

And, you know, this is something that, like, I think I have to relearn every so often, but just as the 20th century birth control movement in the U.S. has its roots in eugenics, so does the study of genetics. Yeah, I always have to relearn that as well. If someone was a geneticist in the early 1900s, they were very likely also eugenicist. Since George Huntington first described the condition in 1872, there had been no substantial developments in terms of treatment of the disease. And because of this, eugenesis then increasingly turned towards emphasizing prevention, either through sterilization, restricting immigration, or outlawing marriage. Enter Charles Davenport. Charles Davenport may not have started the eugenics movement in the U.S., but he was friends with Francis Galton, who was the father of

Eugenics, and he also founded the Eugenics Record Office in 1910, where field workers and scientists were trained in how to collect and analyze data to push their eugenic propaganda. Osborne's fears about the increased attention to the residents of East Hampton and elsewhere with Huntington's disease were about to come true. after Davenport read about the genetic basis of Huntington's and its patterns of inheritance, he viewed it as a perfect subject for a large-scale project in which he would identify the source of the disease in the U.S., as well as shed more light generally on heritable disease. The person responsible for carrying out much of this study was the eugenics field worker,

which like, I can't believe is an actual phrase, a job title. eugenics field worker. In the 1900s. Yes. Yeah. Named Elizabeth Muncie. Muncie would go around to towns in different states where families with Huntington's had been identified, both to interview them as well as construct a family tree.

Over her years as a field worker, she created pedigrees with over 5,000 people and identified nearly a thousand people with Huntington's, about 250,000. of which we're still living at the time of her survey. And while I was reading about this, I just could not stop thinking about how horrifying it is that there was a eugenics records office collecting the names and locations of people with certain diseases. And we can get a taste as to what could have happened with this info in the U.S. hypothetically by looking at what did happen in Germany. In the Years leading up to World War II, people with Huntington's were among the hundreds of thousands of people forcibly sterilized in Germany. Of the 350,000 to 400,000 people sterilized in Germany during

1933 to 1939, around 3,000 to 3,500 of those people were people that had Huntington's. And then when the war started, so did the exterminations. And we don't really have good numbers for that with regards to people with Huntington's. Anyway, back to Muncie and her fieldwork. Rather inconveniently for Charles Davenport, who held these prejudicial views that people with diseases of any kind were degenerate or feeble-minded,

Muncie actually gained a great deal of admiration and respect for many of the people that she interviewed. I mean, she was still eugenicist, let's not forget that. Yeah. But what she found was that there was no hard and fast rule as to who developed Korea and who didn't in terms of like, oh, this person is a scoundrel. Oh, this person is like really well respected in the community.

Right. It has nothing to do with who you are or what you do for a job or anything like that. Yeah. And this went against the prevailing thought of the day, at least for the eugenicist, that the disease was specific to lower classes. And that was a notion that persisted well. to the 1960s in terms of Huntington's. Charles Davenport and Elizabeth Muncie published the data that Muncie collected in 1916.

In the, get this, this is an actual journal, American Journal of Insanity. What? Yes. I wonder when it stopped being a journal or what it turned into. I know. You probably just turned into something. Can we Googling it? It lasted until 1921, I think.

Oh, American Journal of Psychiatry. I'm pretty sure. Yeah. So what they showed in this article was a much more varied picture than the one that George Huntington had painted in nearly 40 years prior. In it, they discussed the variability of the disease, both in symptom severity and age of onset. In general, though, the paper was terrible, statistically, and broad claims were made about the unfitness of these families and the bad characters at the top of the family tree. This article was essentially used as this platform for his eugenic propaganda. And this way of thinking about Huntington's didn't die out with Davenport, unfortunately.

If anything, this article and that research, quote-unquote research, added fuel to the fire. based in part on Davenport and Muncie's publication, there was a Connecticut psychiatrist named Percy Vessie who created an origin story of Huntington's in the U.S. as one in which witchcraft and scoundrels featured prominently from the very beginning. Oh, come on. I mean, this account was based on like horrible research and just an absence of facts. Everyone in his story was either, you know, described as a criminal or a low life of some kind of. and he smeared the name of every person he listed. He then blamed Huntington's disease for their behavior.

And in 1932, he used this article to urge sterilization. His fiction of witchcraft and criminality associated with a disease was thoroughly, entirely, completely disproven, but only in the 1960s. Wow. Yeah. So it was repeated and repeated and repeated. and still I saw it in some papers from like the 80s. Oh, no.

Yeah. This story, which also I will note has been reclaimed by some people with Huntington's as a way to sort of like show the enormous prejudice and exclusion and faced by people with the disease and the difficulties in overcoming that. Yeah. But this story created this set of stigmatizing associations that persisted in Huntington's literature for decades. I was shocked but also not shocked to find out that in 1951, there was an article published in the journal Science, like this extremely prestigious journal, in which the authors claimed that there was enormously higher fertility in men with Huntington's compared to their siblings that did not have the disease.

They used a sample size of two. Two brothers. That's it. What? 1951, science magazine. These claims were refuted eight years later. Eight years later. Eight years?

Yeah. After World War II, the U.S.'s infatuation with eugenics was mostly over, and research on Huntington's turned towards treatment and molecular diagnosis. And I just want to say that I feel like I spent a lot of time on eugenics, and I do all the time in these episodes. Yeah, it's like every time. other episode, I think, these days. Yeah.

It's a horrible and depressing topic. But I feel like it's not talked enough about in history or biology classes, at least in the ones that I took. Maybe that's different now. But I think it's really important to remember how people can misuse or misquote or straight up makeup information to push their own propaganda. By couching something in science or scientific language, you can really, like, cause a lot of harm if your claims are not supported or if you're pushing some sort of

propaganda. And I think in the U.S., we have this tendency to ignore the dark part of our history and pretend like we were the heroes, we were the saviors in like all of our stories. We have to acknowledge our past, our dark past so that we can be better. Yeah. It just, it has to happen. I think also a lot of the response that some people have about, you know, eugenics, is like, oh, well, it was another time. It was, you have to understand it in the context of that time. And it's like you can both understand why eugenics became popular in the context of the time and also be horrified that it became popular and that state laws existed.

Yeah. Like those two things are not mutually exclusive. Not in fact, they are both true. Right. It's just like this happened to people. This actually did happen to people. How do we not have this happen again? Yeah.

Let's just be better. Let's try. Anyway, speaking of better and better things, along with the renewed scientific interest in Huntington's, there was also the birth of several advocacy and support programs. The first was the committee to combat Huntington's disease, now called the Huntington's Disease Society of America, founded by Marjorie Guthrie in 1967, the same year that her husband, and this is what cracks me up, Aaron, because every time I said this to you, you were like, I don't know who that is. I don't know who that is. So I feel like you were talking about him in a completely different context recently, and I was

like, yeah, I don't know who that is, and I didn't even realize that it was Huntington's. Yeah. Woody Guthrie. Yeah, Woody Guthrie. I didn't know who that was. And then when I saw his name on the Wikipedia page, I was like, oh, I know who he is now. That's the guy that Aaron keeps talking about. Yeah. I thought you were just talking about him for other random reason.

He has, he's like music, right? Yeah. He's like music. Yeah. Woody Guthrie was an incredibly influential folk singer-songwriter. So he inspired the whole, you know, folk music generation. He wrote This Land as Your Land, for instance. I know that song.

A lot of other songs that you would recognize. His guitar said, this machine kills fascists, which is also another thing I was thinking for our quarantini name. Ooh, that would be good. Anyway, so Woody Guthrie started to develop symptoms of Huntington's in like the 1940s and finally was diagnosed in 1952. And Marjorie, when he got his diagnosis, she was asking the doctors all these questions and the doctors were just like, well, that's it, sorry, like there's nothing we can do.

There's no advice I can give you. That's it. And she was like, no, this, I'm not going to accept that. Like this isn't it. Like I want to talk to other people who've experienced this. I want to bring us all together so that we can get support, so we can get advice so we can raise awareness to get more information about this disease. And so in 1967, which was the same year that Woody Guthrie died of the disease, she founded

this organization where other people could find information and get support. And this organization, her mission, was instrumental in shedding light on this disease, getting people to talk about their experiences and how the medical establishment was frankly failing them. And later on in navigating the very complicated issues of testing, insurance, financials, genetic counseling, because of all of these years of prejudice surrounding Huntington's and stigma and shame, there was sort of this like culture of almost like silence around the disease. So like even within families, it wasn't necessarily acknowledged. And I think that in more recent years, due in part and large part to this organization and other organizations that were founded, there's been a push to like increase awareness and to stop talking about it in these like, you know, eggshell tiptoe terms.

Right, like hushed tones. Let's talk frankly about this disease and what we can do about it and what are the different options. What is the research telling us? What support can be provided? And on the other side of things, there was another organization that was founded more on the scientific angle, on the scientific research angle, called the Hereditary Disease Foundation, started by Dr. Milton Wexler, whose wife, Leonor, died of Huntington's. Also, two of their daughters, one named Alice, is a historian, I believe, and she wrote, like, one of the books I read. Oh, wow. And another of their daughters, Nancy, is a geneticist that helped to do, like, a ton of Huntington's disease research.

So, very cool. That's very cool. So this foundation had a different aim. They wanted to understand the mechanism of the disease. So in the early 1960s, researchers came across a large cluster of people with Huntington's disease in the Zulia region of Venezuela by the shores of Lake Maracaibo. In this group of people, Huntington's was at a particularly high prevalence. So there were even some people suspected of being homozygous for the trait, meaning they had two copies of the mutated allele. And this group of people was

studied by the foundation. And ultimately, just to sort of like long story short it, in 1983, a marker for the gene was found, and its location was identified as being on the fourth chromosome. And 10 years later, in 1993, the last big point in the timeline of Huntington's disease so far, the exact gene was found. And isolating the gene for Huntington's disease was huge. On the scientific front, it allowed for researchers to understand how this allele produced the effects that it did and to try to come up with potential therapies. And from the patient's point of view, it held answers. Because identifying this gene meant that you could be tested for the disease.

But it's not as simple as that, of course. Because with this new ability to test came a bag of ethical considerations since this was a heritable disease. So, for instance, if a parent did not want to get tested, but you did, and you found out that you were positive, how do you deal with that? And Erin, I know you're going to talk a bit more about this aspect. So I'm just going to kind of wrap it up here and say that we've come a long way in our understanding of Huntington's disease and how it works and in reducing some of the stigma and shame that used to be so prevalent. But just like you said, in many ways, we are kind of right where we were at the beginning. So, Aaron, I'm hoping that you'll tell me the ways

that we've gotten better and maybe some hope for the future. I'll try to. We'll take a quick break first. So before we talk a little more about the genetic testing bit, let's just quickly go over the numbers. Overall, the prevalence of Huntington's worldwide on average is somewhere between four and 10 per 100,000 people. Okay. It does vary quite a bit based on region, and we don't fully know why, like why this region is more prevalent than others. But in general, in Asia, the prevalence tends to be far lower.

That's where it's kind of the lowest worldwide. It's estimated there at about 0.5 per 100,000 people. In western, central, and eastern Europe, so all over Europe, as well as the UK, prevalence estimates have varied between two and seven per 100,000. In Africa, where we don't have as good of estimates, they've varied between 1 and 4 per 100,000. In Oceania, it's estimated at 5 per 100,000, and then in North America, 7 per 100,000. But this also varies a lot within North America. Okay. South America outside of that region in Venezuela that you mentioned, which is much higher,

we really don't have good numbers on like the rest of South America, very limited data. But so worldwide overall, like five to 10 per 100,000 people. And like I said, in the biology section, the mean age of onset is around 40 years, so 30 to 50 years. And then life expectancy tends to be about 10 to 20. maybe 30 years once symptoms appear. Okay. And that part doesn't vary based on income, based on country, based on anything. And that's largely because even though individual manifestations of this disease can vary,

like the overall course doesn't really vary. And the way that we deal with it in all these different countries, regardless of country's income, doesn't really vary either. So to kind of get into both what we can do for treatment and then also what you are mentioning, Aaron, about this ethical dilemmas when it comes to genetic testing. The bottom line is that right now, in terms of treatment, we have nothing that can change the course of disease. We don't have any medicines or treatments that can address. the underlying issues or the progression of disease. We have symptomatic treatments, especially for

the koreaform movements, those involuntary motor movements. We have drugs that affect like dopamine pathways and some other things that can help with those involuntary movements. We also have drugs that can treat things like depression and anxiety, antipsychotics if psychotic symptoms develop. So we have those kind of psychiatric drugs, but we don't have anything specific to Huntington's, and we don't have anything to address the underlying issue itself. And so in part because of that, this is not a genetic disorder like, for example, cystic fibrosis or sickle cell disease that we've talked about before, where early identification can lead to vastly improved outcomes because of the treatment options that we have available, right? This is not that.

And so genetic testing can tell a person that they have this gene and can tell them that they are going to develop Huntington's or not. But it has sparked quite a lot of debate about when and whether to do genetic testing, especially when it comes to children. Like at what age should someone be allowed to decide that they want to get tested. Yeah. But it also brings up ethics in regards to the idea that, of course, ethically, everyone has a right to know their own health status, right? I have a right to know what's going on in my body.

If there's a test that can tell me that I have a genetic disorder and I want to know it, I have a right to know that. But every person also has a right to not know. and I have a right to keep all of my information secret to me if that's what I want. Yeah. So like you mentioned, Aaron, a person getting genetic testing done for something like Huntington's that is autosomal dominant necessarily discloses information about the parents' health status. Right.

That they may or may not have wanted disclosed. It also could release information about, for example, an identical twin. Oh, yes. Right? And so there is a lot of kind of ethical issues surrounding this. So regarding all of these like ethical considerations and whatnot, do you know how much that happens to vary country to country? Very good question. I do not. I imagine it could vary quite a lot, especially because when it comes to disease and how much people want to know culturally, that varies hugely in different. countries. So in some places, like, people don't want to know necessarily, especially if the outcome is going to be bad, right? Right. And so, so I imagine that it varies quite,

quite a lot. Okay. Yeah. So there's not like, there's not an answer to this, right? It's a, it's a very person specific. And so this is the kind of thing that really has to be a discussion between an individual and their health care provider. Yes. And genetic counselors, especially. But, Aaron, I like to try to end these episodes on more hopeful notes. So let's talk about the future. Gene therapy.

Gene therapy. And really, I think that one of the things about how much we do know about hunting, is that even if we don't know every detail about the specific mechanisms, we know a lot and we know enough to know that gene therapy is a real possibility for treatment of this disease. Yeah. And that's, I think, really, really incredible. So there are a lot of different possibilities. And there are people working on kind of all of these different.

I have links to a number of papers that go in a lot of detail on all of the different research that's being done and the different kind of ways that you could target Huntington's disease from a variety of different angles with gene therapy. Okay. So a lot of it is maybe using something like RNAI, which are little small pieces of RNA that can go in and kind of make changes. I think that the most exciting prospect is CRISPR. Oh yeah. Which we talked about in a lot more detail in the sickle cell episode because there, I think we're a little bit further along than we are in Huntington's. But CRISPR, just for anyone who hasn't listened to that or who has forgotten, is a way by which you can go in to a cell and make very specific targeted changes one time that persist for the life of that cell. So you can actually change the DNA very specifically and cut out that mutant Huntington gene

and replace it with a non-mutated, like a normal type Huntington gene. And you can do so with one treatment, whereas most gene therapies that are in development would require a lot of infusions, which is especially difficult for neurodegenerative diseases where you have to be able to get that into the brain. So that requires like going directly into the brain, which is very problematic or very difficult. Yeah, sounds very risky. Yeah.

But there are a number of different strategies. Some gene therapies might try to reduce the expression of this mutant protein. So you might still make some of it, but you just wouldn't accumulate those toxic levels because you're making less of it. Okay. Others, like I mentioned, especially CRISPR, would just cut that mutated region out and replace it with a normal region. And then there are other therapies that are being developed, aside from just gene therapy, to try and address the downstream effects as well. Like, try and improve cognitive decline by addressing things like mitochondrial function, which we think is very involved in dementia and cognitive decline in general.

Oh, okay. So there is a lot of research being done. If you look at clinical trials.gov and you search for Huntingtons, you can find over 1,500 studies that are being done. Not all of those are drug studies or treatment studies. But that is a lot. It's like on par with cystic fibrosis and things like that when you kind of just search for those studies. Okay. If you check a link to a website where you can check specifically gene therapy studies, there are six studies currently listed.

on the gene therapy clinical trial database. Several of them are stem cell studies, because that's another possibility, is using stem cells to just like regrow the brain tissue that is damaged. Whoa. It's like a whole other mechanism. And some of those kind of address dementia in general, not just only Huntington's. Mm-hmm. But there are at least two gene therapy studies specifically that are in phase one and phase

two trials. So human trials for kind of safety and feasibility. That's cool. Yeah. So it is on the horizon. And I'll also link to another nature just sort of write-up article, not like a peer-reviewed publication, but an article about a group that's working on CRISPR specifically for Huntington's. So like there's a lot of hope, I think, and there's a lot on the horizon that could potentially come to fruition.

How quickly, how many people currently living with Huntington's will be able to see. those benefits. I don't know, but I believe it's possible. Yeah. Yeah. So that's Huntington's. Wow, that was a big one. It was, yeah. So sources? Sources. I want to shout out just a couple in particular. I have a bunch, but I want to shout out by Alice Wexler, the woman who walked into the sea. and also a textbook by Bates, Harper, and Jones called Huntington's Disease. Those had great history sections, and then I have a bunch of other additional papers. I also have a number of papers, especially interesting, I think, are the ones looking at the future, targets for future clinical trials in Huntington's disease,

and the slowing of neurodegeneration in Parkinson's disease and Huntington's disease, future therapeutic perspectives. You can find the list of all of our sources from every single episode on our website. This Podcast Will Kill You.com under the episodes tab. Thank you again so much to Jay for providing their firsthand account for this episode. We really, really appreciate it. Yeah, we do. Thank you. Thank you also to Bloodmobile for providing the music for this episode and all of our episodes. And thank you to the Exactly Right Network of whom we are a very proud member. And thank you to you listeners. We really appreciate you listening to this podcast.

We really like making it even when it's a tough topic to talk about. Yeah, we really do. And we appreciate you sticking with us all this time. All this time. Letting us make this podcast essentially. Yeah. Well, until next time, wash your hands. You filthy animals.

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