Ep 223 ALS: Unraveling the mystery

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, has long mystified the medical community and brought tremendous sorrow to those impacted by the condition. But to tell the story of ALS as one solely of tragedy would do a disservice to those who have long fought to develop an effective treatment or raise awareness. Because it is through their tireless efforts that those with ALS will eventually be able to rewrite their own ending. In today’s episode, we attempt to convey the full picture of ALS: from what we know about its causes to the earliest medical descriptions, from the baseball player whose impassioned speech captured the public’s hearts to the promising research on the horizon. Tune in for all this and more. Support this podcast by shopping our latest sponsor deals and promotions at this link: https://bit.ly/3WwtIAu See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

• 0:01Speaker 00

  This is exactly right.

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• 1:42Speaker 04

  Hi, I'm Mark Hopkins. My great uncle, my uncle, and my dad all died of amyotrophic lateral sclerosis, or ALS, and I probably will too. ALS is a terminal neurodegenerative disease that causes the death of motor neurons, which control voluntary muscle movement. As the neurons die, people with ALS gradually lose the ability to move their limbs, talk, chew, and breathe. And sure enough, that's what happened. Uncle Bob was a big guy with a deep belly laugh. After his diagnosis in 1999, every time I saw him, he was skinnier, with less muscle mass, less ability to move, and increased difficulty speaking.

• 2:27Speaker 04

  Uncle Bob died in August 2001. Most cases of ALS are sporadic, with no known cause, but because my great uncle also died of ALS, we suspected that we were carriers of familial ALS. My uncle, and later my dad, were tested for the SOD1 gene mutation, which at the time was the only gene known to be associated with ALS, but the test was negative for both of them. So we were left not knowing whether our family simply had bad luck, or if we were carriers. That is, until July 2006, when my dad was diagnosed. This news was shattering on two levels.

• 3:11Speaker 04

  I knew that my dad was going to die, and despite not having any test results to prove it, I figured that three cases of ALS in one family was too many to be a coincidence. This was familial ALS, and I had a 50% chance of inheriting the disease-causing mutation. My dad's disease progression was similar to my uncle's. My mom became his full-time caregiver, and with the help of friends and the local ALS society, they did renovations to make their house more accessible. He died at home 11 months after his diagnosis, on June 3, 2007.

• 3:52Speaker 04

  For the next 16 years, the specter of ALS was always distantly hovering. I had a 50% chance of inheriting the disease, but with no way of knowing which side of the coin flip I was on. Then, in 2023, I attended a webinar about recent advances in ALS research, particularly since the fundraising boost from the Ice Bucket Challenge. I learned that in addition to SOD1, several other gene mutations associated with ALS had been identified. This piqued my interest, and I asked my doctor for a referral to the local genetics clinic. There, they retested a DNA sample from my dad and identified the cause of his ALS,

• 4:34Speaker 04

  a mutation in the C9orf72 gene. This discovery made me eligible for predictive testing, to see if I had inherited his mutated gene. Predictive testing is guided by international protocols. For example, everything is recorded on paper, keeping details out of my digital medical file to mitigate any discrimination based on genetic results. And over the course of four visits, I met with a genetic counselor, a psychiatrist, and a medical geneticist. I felt incredibly well-supported through the whole process. At the final visit, no one, not even the medical geneticist, knew my results.

• 5:16Speaker 04

  They were sealed in an envelope, so that right up until the envelope was opened, I could change my mind and not proceed. While there were good reasons for it, the envelope made the whole thing feel a bit like a twisted game show. Until it was opened, it was like a genetic version of Schrodinger's cat. I both did and did not have the mutation. When the envelope did open, though, it turned out that I was positive for the C9orf72 gene mutation. I did inherit it from my dad. What does that mean? As I understand it, 50% of folks with this genetic change become symptomatic by age 58, going up to over 90% by age 83.

• 6:01Speaker 04

  I'm currently 43 years old. My dad died at 55. And I'm not only at risk for ALS, but also for frontal temporal dementia, or FTD, which is a possibility I didn't know about before the predictive testing process. This knowledge puts me in a weird place. I'm not sick or dying, not yet, and not even showing symptoms. It's like I have a foggy crystal ball. It predicts the future, but doesn't tell me when or even if I'll get sick with ALS or FTD. After all, something else could take me out first. Getting this news has been a roller coaster of emotions, but ultimately, I'm glad that I know.

• 6:44Speaker 04

  It helps me make more informed choices for the future, and helps me to appreciate what I have now. My mentor used to say before he died, "We're not going to live forever. We have this precious, precious time to use in whatever way we choose." I will probably die of ALS, but for now, I'm alive, and I'm healthy, and that's pretty amazing.

• 7:55Speaker 05

  Thank you so, so much for sharing your story with us. I mean, it means, it means everything. It really is so important and impactful to hear these stories, and we just really appreciate you taking the time and being willing to share your story on this podcast.

• 8:11Speaker 06

  Yeah, it really means everything to us, so thank you.

• 8:15Speaker 05

  Truly. Hi, I'm Erin Welsh.

• 8:17Speaker 06

  And I'm Erin Allman Updike.

• 8:19Speaker 05

  And this is This Podcast Will Kill You.

• 8:21Speaker 06

  Today, we're talking about ALS.

• 8:24Speaker 05

  ALS, amyotrophic lateral sclerosis.

• 8:28Speaker 06

  Nice job, Erin.

• 8:29Speaker 05

  Also known as Lou Gehrig's disease, in some places known as Charcot's disease.

• 8:33Speaker 06

  Yeah, and in some places, maybe motor neuron disease.

• 8:37Speaker 05

  Motor neuron disease. There's a lot of distinctions between these two, or between all of these, apparently. And so, we'll get into all of that. There's a lot to cover today, and so, let's, first things first, it's quarantine time. Today, we are drinking the Iron Horse, which, if you did not know, is Lou Gehrig's nickname, or one of Lou Gehrig's nicknames.

• 8:59Speaker 06

  And it's fine if you didn't know, because I certainly didn't know.

• 9:02Speaker 05

  I grew up enmeshed in baseball lore, so...

• 9:07Speaker 06

  You've got the baseball references on Pat.

• 9:09Speaker 05

  You know, this season especially, it's been a little bit baseball-heavy, so I apologize.

• 9:14Speaker 06

  I really got the bug.

• 9:15Speaker 05

  I'm going to eat to Rockies games, worst team in baseball, still love them, dinner's the best.

• 9:21Speaker 06

  Cute merch, though.

• 9:22Speaker 05

  Very cute merch, very cute mascot. I'm there for it. Anyway, the Iron Horse Quarantini contains peach juice and thyme and lemon lime soda.

• 9:32Speaker 06

  Delicious, refreshing. You can make it at home by following along with the recipe, which you'll find on our website, thispodcastwillkillyou.com, and on all of our social media channels. So please make sure that you're following us over there if you're not already.

• 9:44Speaker 05

  Yes, yes, yes. And website stuff, you know, you know the spiel, the drill. We've got, oh, gosh, links to...

• 9:53Speaker 06

  That was a heavy sigh, just to have to talk about our website, Erin.

• 9:58Speaker 05

  I forgot that we have to do this. Yeah, okay, we've got, you know, links to things like merch, bookshop.org affiliate page, our Blood Mobile music, other things, sources for all of our episodes, firsthand account form. I mean, there's a lot of stuff. If you've not checked it out yet, might as well, just if you've got a free afternoon, three minutes, 30 seconds. That's all you need.

• 10:22Speaker 06

  Thank you all for being here with us today. If you haven't already rated or left us a quick review, or made sure that you're subscribed on your podcatcher or your YouTube channel, if you're watching it over there, we'd love it if you did that. But, you know, we love it that you're here regardless, so thanks.

• 10:41Speaker 05

  Thanks, thanks for tuning in.

• 10:42Speaker 06

  We've got a lot to cover today, Erin, like a lot. So should we just get straight to the point?

• 10:48Speaker 05

  I think that we should.

• 10:49Speaker 06

  Okay.

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• 13:30Speaker 06

  ALS, which as you said, Erin, stands for Amyotrophic Lateral Sclerosis, or in some places is grouped under the term motor neuron disease, or MND, is kind of an interesting thing because it is a disease, like a condition, but it's also something where the more that we have learned about it, the more that we realize maybe some of the things that we classify as ALS might actually be many diseases. So are they all the same thing, or are they not? It's still kind of an open question. Is there one underlying pathology that covers everything that ends up grouped as ALS or not?

• 14:12Speaker 05

  Right, because currently it is a, like, okay, that's jumping ahead. Currently it is diagnosed via symptoms, or are there other diagnostic techniques?

• 14:21Speaker 06

  Great question. It is a clinical diagnosis. So it is mostly based on symptoms. Usually you have to do, this is jumping way ahead, but I love it. Usually you do have to do additional imaging and things like EMG, which is like a nerve conduction test, or things like that. But it's mostly to exclude other conditions, or what are considered like ALS mimics. We want to make sure we're not missing a tumor in your brain. We want to make sure we're not missing some other, maybe a demyelinating disorder, or something like that. But in general, yeah, it is still a clinical diagnosis. We don't have any specific biomarkers, or any like one test that can say this is ALS for sure.

• 15:00Speaker 05

  Okay.

• 15:01Speaker 06

  And even more interestingly, there's so much that's really fascinating and horrifying about ALS. It used to be considered a purely neuromuscular disease, meaning a disease of the nerves that are affecting our muscles, or our motor neuron system. However, the more that we know, the more that we know, and now we know that ALS actually affects more than just our motor system. So ALS is a progressive neurodegenerative disorder that primarily is affecting our motor neurons. So what I want to do in this part of the episode to understand ALS and how it causes the symptoms that it does, is I first want

• 15:45Speaker 06

  to do a little bit of nervous system anatomy, because I think that that will help us to explain a lot of the symptoms that we see in ALS and how it progresses. And then we can talk about the why. Like, what do we think is the cause of ALS, the TLDR being that we still don't really know? And then we can talk about how we treat it, which, again, spoilers, we don't really have a lot of treatments, and certainly nothing that constitutes a cure. So that's the Cliff Notes version. Let's get into the details, shall we?

• 16:17Speaker 05

  Yeah, yeah, yep.

• 16:19Speaker 06

  Most of us understand that our muscles, all of our voluntary muscles in our body, are controlled by nerves. And our brain, along with our brainstem and our spinal cord, are the central connectors of our nervous system. So pretty much all of our nerves in our body come in two sets. There's the nerves that travel from our brain to our spinal cord, or our brainstem, in the case of our cranial nerves. And then there's a second set of nerves that travel from our spinal cord or brainstem to whatever the target organ is. So when it comes to our motor nerves, meaning the ones that are controlling the movement of our hands, our arms, all of our muscle movements, we have a motor cortex

• 16:59Speaker 06

  in our brain. I brought a brain, but I don't know if this is a little too much. If you're only listening, you can just use your hand to pretend that it's a brain. You tuck your thumb into your palm, and then wrap your fingers around your thumb, and this is kind of the shape of your brain. The outside is the cortex, the inside's your inner brain. Your wrist would be your brainstem, that's here on this brain. And then your wrist, or your forearm would be like your spinal cord, okay?

• 17:27Speaker 05

  Okay.

• 17:27Speaker 06

  So along the cortex, kind of maybe where, I don't know, your middle finger is, if you're using your hand, this is what we call the motor cortex, here. Free motor and motor cortex.

• 17:40Speaker 05

  Free motor and motor.

• 17:41Speaker 06

  This is where all the nerves that will control our muscles originate.

• 17:45Speaker 05

  Wow.

• 17:46Speaker 06

  They send a signal that will travel through the inner part

• 17:51Speaker 05

  Oh my gosh, this is very exciting.

• 17:53Speaker 06

  Sorry, this is too much, but I had it here, so.

• 17:55Speaker 05

  I love this.

• 17:56Speaker 06

  They will send a signal that will travel through the inner part of our brain, and then down to either the brainstem, if we're talking about our cranial nerves, like the ones that innervate our face, or to whatever level in our spinal cord they need to travel to. So let's say we want to control the movement of our thumb.

• 18:13Speaker 05

  Yep.

• 18:14Speaker 06

  So we'll have a nerve that starts here in our motor cortex. It will send a signal that travels all the way down to like the spinal cord in our neck, and then it will synapse, meaning there will be a break in that nerve, and it will connect to another nerve, a whole new neuron, that sends a signal that will travel all the way down our arm to our thumb and say flex, or extend.

• 18:38Speaker 05

  Yes, okay.

• 18:39Speaker 06

  Okay?

• 18:39Speaker 05

  Yes.

• 18:40Speaker 06

  So two separate sets of nerves.

• 18:43Speaker 05

  So all the messages are originating in our motor cortex?

• 18:47Speaker 06

  Motor cortex.

• 18:47Speaker 05

  And then they're traveling to one certain point, at which point then it's like, okay, now here's the central hub, then final destination.

• 18:56Speaker 06

  Exactly. It's like a layover station, okay, like a relay station in your spinal cord.

• 19:01Speaker 05

  Okay.

• 19:02Speaker 06

  And then that signal has to travel along another set of neurons, right? The nerves that go from our motor cortex to our spinal cord are called the upper motor neurons. And then the nerves that go from our spinal cord to the destination, to our muscle, are called the lower motor neurons.

• 19:19Speaker 05

  Okay, I have like a question that's very, I think, very basic anatomy. But like, so you have these nerves that originate in your motor cortex, they, and then like, let's say that it's your big toe instead of your thumb. Is that, like, where is that nerve located along your spinal cord?

• 19:35Speaker 06

  Yeah, your big toe would be all the way down in like your lumbar spine.

• 19:38Speaker 05

  Okay, okay, okay. And that's like, so it's like one, so then that's a very long nerve, and then another very long nerve?

• 19:45Speaker 06

  Yes, correct. Two really long axons on those nerves, 100%.

• 19:50Speaker 05

  Can you imagine giraffes? Yeah, anyway, that's another story.

• 19:53Speaker 06

  I wonder if they have multiple synapses. I actually don't know anything about giraffe nerves.

• 19:57Speaker 05

  Giraffe neurology, yeah.

• 20:00Speaker 06

  Someone who's a large animal vet, let us know.

• 20:01Speaker 05

  Yes.

• 20:03Speaker 06

  But nerves are really incredible, Erin. But, but the important part for us today is that there's these two different sets. There's upper motor neurons, brain to spinal cord, and then lower motor neurons from spinal cord to our muscles. Our sensory nervous system, by the way, does the exact same thing in the opposite direction. So we also have two sets of those. They just send signals the other way.

• 20:22Speaker 05

  The nervous system is very, very interesting.

• 20:25Speaker 06

  It's a lot, which is why I get nervous every time we do one of these diseases, Erin. So in ALS, what we see is we see degeneration of the nerves in both parts of this neuromuscular system, in our upper motor neurons and in our lower motor neurons. And it turns out that this results in a combination of two different kinds of symptoms. So very often in ALS, one of the first symptoms might be something like muscular weakness. And a lot of times it'll start in just one area, maybe in the hands or the feet, where it just feels like I'm dropping things, I can't grip them as easily. So maybe just weakness. Now, weakness alone is an upper motor neuron signal.

• 21:10Speaker 06

  This is telling us that there's a lack of signal from the brain to the spinal cord. But at the same time, we might see symptoms like atrophy, that is, muscles that are actually starting to decrease in size. And sometimes with this atrophy, we might see fasciculations, which means little muscle twitches or cramping. Now, these are lower motor neuron signs, because what this means is that the muscle itself is no longer being innervated at all. And so it is, it is wasting away without any signal to it at all. Does that make sense?

• 21:46Speaker 05

  So the brain, like if you have the upper motor neuron degeneration with the weakness, it's just your brain is not sufficiently delivering the signal saying, grab that spoon or whatever it is.

• 21:59Speaker 06

  Yeah, and we can see more than just weakness. So what we also see with upper motor neuron signs is we actually see hyperreflexia. So you know, like when the doctor checks your knee reflexes and they want to see that your knee moves a little bit, but not too much? If your knee moves quite a lot, that's what we call hyperreflexia, meaning that there's no inhibition on that reflex loop because the upper motor neuron is damaged. We also can actually see increased tone and muscle spasms. And that's again, because we've lost some of the inhibitory features that our motor cortex of our brain is usually sending to our spinal cord.

• 22:40Speaker 06

  So it's all lower motor neurons that are still trying to do a thing, but they're not getting the coordinating signal from our brain. Those are all upper motor neuron signs. But then at the same time, we'll see atrophy of the muscles, we'll see fasciculations, which again are those little twitches that result from the loss of a signal and your nerves trying to compensate by like sending other signals from closely related axons that haven't yet been affected.

• 23:08Speaker 05

  Oh, okay.

• 23:09Speaker 06

  And we can see actually the opposite in tone, meaning reduced tone. So more of like a flaccid paralysis, almost.

• 23:17Speaker 05

  Yes.

• 23:18Speaker 06

  Those are lower motor neuron signs, signs of damage to the lower motor neurons.

• 23:23Speaker 05

  Okay, and this degeneration is happening simultaneously, or it starts with one or then the other?

• 23:29Speaker 06

  Yes, and. So it is happening in multiple areas, but it usually starts with a focal, like you notice a focal symptom first, right? You'll notice it in one place and then it will spread. And it will spread to multiple body areas. And it will spread in terms of, it might start with only lower motor neuron signs and then involve upper motor neuron signs. Or you might not see those upper motor neuron signs unless you look for them on a neurologic exam and things like that.

• 24:00Speaker 05

  Okay.

• 24:01Speaker 06

  In most people who are diagnosed with ALS, about 60% of them, this is how their symptoms will progress. They'll start with, you know, signs in their hands or their feet or their legs, and these are what are called spinal symptoms, meaning those first symptoms are happening from nerves that are exiting via the spinal cord, whether it's upper or lower motor neuron, but it's happening in your body, okay?

• 24:24Speaker 05

  Okay.

• 24:25Speaker 06

  Neck down.

• 24:26Speaker 05

  Neck down.

• 24:26Speaker 06

  30% of people, on the other hand, have what are called bull bar symptoms first. Why do they call it bull bar? I don't know. What this means is that it's the nerves in our cranial nerve system that affect our head and neck that are affected first.

• 24:43Speaker 05

  Okay, and so these are, these are not really like upper or lower motor neurons?

• 24:49Speaker 06

  No, they're exactly the same, upper and lower. It's just that instead of the lower motor neurons leaving from the spinal cord, they leave from our brain stem.

• 24:56Speaker 05

  These are from our brain stem. So, yeah. How, how does, how do symptoms manifest in those 30%?

• 25:02Speaker 06

  So in those people, we tend to see things like difficulties in speech, difficulty swallowing. We might see atrophy of the muscle of the tongue, rather than say, the muscle of your calf. We might see fasciculations in the tongue, rather than fasciculations or those muscle twitches in something like your hand. So it's really the same exact types of symptoms, but it's affecting the nerves of your face, which means the nerves that are involved in chewing, in speaking, in swallowing, in eating. And because of that, this tends to be a more severe presentation and it tends to be more rapidly progressive.

• 25:42Speaker 06

  Almost everyone with ALS will end up having both spinal and bull bar, so both spinal cord and brain stem symptoms. But depending on which is the first presenting symptom, that's one of the things that can help us know how rapidly this disease might progress.

• 26:00Speaker 05

  Does that also, is, does that rule also follow where like the lower in your body, the symptoms first show, this, you know, or like the higher, if it's like your shoulder versus your feet?

• 26:12Speaker 06

  That's a good question. I don't have a perfect answer to that. It's not sort of as straightforward as that.

• 26:18Speaker 05

  Okay.

• 26:19Speaker 06

  But it's a good question. But if it is bull bar symptoms, so if it is like kind of facial neck muscle symptoms first, then it does tend to be more rapidly progressive. Similarly, eventually ALS, because it is by definition a progressive disease where it is spreading over time, both in severity of symptoms and in location of symptoms, over time, people will develop more and more of both these upper and lower motor symptoms. We'll see severe muscle wasting, we'll see spasticity that develops, which can really affect dexterity. Eventually, regardless of where symptoms start, we'll see difficulties in speech, chewing

• 27:01Speaker 06

  and swallowing, which can make it really difficult to eat, which then leads to weight loss. Weight loss can also occur independently of the, the difficulties with kind of coordinating those muscles, which we don't fully understand.

• 27:13Speaker 05

  Okay.

• 27:14Speaker 06

  And then ultimately, the muscles of respiration are almost always affected. And respiratory failure is the most common cause of death in ALS.

• 27:24Speaker 05

  Okay.

• 27:27Speaker 05

  I know that we don't exactly know the mechanism, but what do we know? And how does degeneration spread?

• 27:37Speaker 06

  This is a great question, Erin, and we, we don't fully know. What we do know is that the nerves, so the axons, you said, oh my gosh, that's a really long nerve that has to go all the way to your foot.

• 27:48Speaker 05

  Yes.

• 27:48Speaker 06

  So what we see in ALS is that the nerve axons actually do start to degenerate themselves. So the nerves sort of retract from wherever they're supposed to be going and they start to degenerate. And then eventually, the nerve cell itself actually dies. And that is why we then see, the name is amyotrophic lateral sclerosis. Sclerosis is scarring, and we see evidence on autopsy of scarring in the areas where these nerve cells are, right? In the brain and in the spinal cord. So we know that that is happening. We also know that, and I said this at the beginning, we used to consider this just a neuromuscular disorder, but it isn't only a neuromuscular disorder.

• 28:31Speaker 06

  About 13% of people with ALS actually have pretty substantial memory and cognitive symptoms, meaning that even though we think of this as affecting only the motor cortex in our brain, so only if you're looking at your fingers, like this maybe middle finger or so, it's actually affecting other parts of our brain as well, especially the frontal lobes and the temporal lobes. Some people think that frontotemporal dementia, which is a type of dementia associated with things like behavioral change and speech difficulties, might actually be a spectrum of disease with ALS on the opposite end.

• 29:08Speaker 05

  Yeah, especially with like genomic studies looking at familial cases of FTD and ALS and stuff like that.

• 29:18Speaker 06

  Families, families where you have someone with no history of ALS in the family, but they do have a family history of frontotemporal dementia. Over the course of their disease, anywhere from 30 to 50% of people with ALS will have some type of symptoms that could fall under the umbrella of frontotemporal dementia type of symptoms, or some kind of cognitive symptoms that are a part of their ALS picture. And we didn't used to think that that was the case. It used to be that we just thought this was only a muscular condition, but it's more than that. And at the end of the day, none of that actually explains why, like, how is this happening? And that's because we don't really know. About 5 to 15% of cases of ALS are considered genetic.

• 30:01Speaker 06

  They're considered familial ALS. But there's not one gene that is causative.

• 30:08Speaker 05

  Right.

• 30:08Speaker 06

  There's at least 20, although some newer papers said up to 40 genes that we have found associated with ALS. Many of these, if we can see them clustering in families, are, we think, inherited in an autosomal dominant fashion, meaning you only need one copy of this mutated gene to put you at risk of having the disease.

• 30:28Speaker 05

  Which is like Huntington's and like frontotemporal dementia.

• 30:31Speaker 06

  Exactly. However, they don't have 100% penetrance, which means that even though you have a copy of this gene, it doesn't mean 100% for sure that you will develop ALS. So it makes genetic counseling really important and really complicated because it's not black and white. And 85 to 90% of people with ALS have no family history, and this is considered sporadic ALS. Some of these people, if we do, like, look at their genetics, we might find some of these same genes that we see in familial ALS, but not always.

• 31:07Speaker 05

  Right.

• 31:07Speaker 06

  So what we know about what causes ALS, there's a few things. One is that we see a buildup of proteins, abnormally folded and abnormally aggregated proteins in the neurons of people with ALS.

• 31:23Speaker 05

  What kind of proteins?

• 31:25Speaker 06

  Specifically, 95% of people have this one called TDP43, which is a protein that's normally only found in the nucleus of our cells. But in ALS, we see it in the cytoplasm, forming these aggregates.

• 31:38Speaker 05

  Huh.

• 31:39Speaker 06

  Why exactly? We don't know. There are a bunch of different genes that are associated with ALS risk, and a lot of them have to do with, like, either RNA or DNA and membrane trafficking, so like, moving things across membranes. Some of them, though, have to do with oxidative stress, or mitochondrial dysfunction, or inflammation, or just protein aggregation in general. So the short answer is, we don't know. We know that this protein is there and is abnormally built up in about 95% of people with ALS. But why is that happening? In most cases, we don't know. And while we know that there are a lot of genetics that

• 32:23Speaker 06

  are a part of this, it's not all genetics. And there are definitely huge environmental exposures, as well as aging itself, that probably contribute to ALS. And there's been, I think, a lot of, like, it's this environmental exposure, or it's that environmental exposure that causes ALS. We absolutely do not have a cause.

• 32:42Speaker 05

  Yeah. Or, or maybe there are multiple causes, like, you know, and, and the proteins and some of these other things, are they cause or consequence? Like, what, you know?

• 32:51Speaker 06

  That's a great question, Erin. Yes.

• 32:54Speaker 05

  Okay. How, how predictable is ALS?

• 32:58Speaker 06

  Oof.

• 32:59Speaker 05

  Which is a big question. So I can be more specific.

• 33:01Speaker 06

  Yeah. Do you mean how predictable that someone's going to get it, or how predictable is the course of disease?

• 33:07Speaker 05

  Two, well, two kind of separate questions. One is how predictable is the course of disease? And maybe specifically in, like, sporadic cases. And then, within familial cases, how predictable does that clinical picture, or the, the age of onset and stuff like that, does that more predictable? Or where it's, it's the symptoms start?

• 33:26Speaker 06

  Yeah. This is, that's such a good question, Erin. You always ask really hard questions.

• 33:31Speaker 05

  Sorry.

• 33:31Speaker 06

  No, that's okay. I like it. It's a really important question. The average lifespan of someone with ALS is only about two to five years after symptoms start. Usually, it's a bit shorter, like, median survival is about two to three years for bulbar onset, and three to five years for, if you have that spinal onset.

• 33:57Speaker 05

  Okay.

• 33:58Speaker 06

  And the biggest difference, one of the biggest differences between familial and sporadic is that the average age of diagnosis or age of symptom onset is older for sporadic. So late 50s, early 60s for sporadic disease, late 40s, early 50s for familial disease.

• 34:16Speaker 05

  Okay.

• 34:17Speaker 06

  But there is a lot of variation within that. So it's not necessarily super predictive, this is exactly how your course is going to go, or how quickly things are going to progress. There are factors that affect it, like, how old you are when you first start to show symptoms, with the exception of people who are very, very young, who have even more rare forms of ALS, which tend to be quite rapidly progressive. Usually, it's the older that you are when you start to show symptoms, the shorter survival times are. A shorter time to diagnosis is actually associated with the shorter survival, which we think maybe is because it shows that it's a more aggressive or more rapid disease that's more

• 35:00Speaker 06

  easily recognizable. But there's not, like, clear-cut, there's not clear-cut answers. It's not, it is not a super predictable disease, other than that, it is progressive, if that answers your question.

• 35:13Speaker 05

  Yeah. I mean, there are many famous people who have developed ALS, and, like, I think Stephen Hawking comes to mind for a lot of people, for motor neuron disease.

• 35:24Speaker 06

  Yeah.

• 35:25Speaker 05

  And so he was, he was an extreme outlier in this, because he was very young when he was diagnosed, and it progressed over decades.

• 35:31Speaker 06

  Right.

• 35:32Speaker 05

  And we, like, I guess, I mean, there is no, I don't know what the question is here, but like, there, we may be grouping all of these things into one disease with a different, that might have different cause, or different mechanism, or different initiation that just sort of follows the same pathway. And so, are there differences between ALS, motor neuron disease? What are the subtypes? Like, how, how can you determine rate of progression? And of course, like, familial versus sporadic is, you know, self-explanatory, but the rest of these things.

• 36:07Speaker 06

  Yeah, there are a lot of, sort of, subtypes of ALS that sometimes get their own names. So there's things like what are called pseudo-bulbar palsy. There's respiratory ALS, meaning that your respiratory muscles are one of the first that are affected. This is very severe and tends to be much more rapidly progressive. There's also two other conditions that sometimes get grouped and sometimes don't get grouped. One is called primary lateral sclerosis, and this is something that we actually only see degeneration of the upper motor neurons. So no lower motor neuron symptoms, meaning no atrophy, no fasciculations.

• 36:48Speaker 06

  And then on the flip side, we have progressive muscular atrophy, which is exclusively lower motor neuron symptoms. So then, we have muscle atrophy, but we don't have the spasticity, we don't have the increase in tone. And these actually share overlapping genetic risk factors, and very often, on autopsy, we see signs of both upper and lower motor neuron involvement. But some of these, especially like primary lateral sclerosis, is not as progressive as ALS. So I, I don't, I don't have great answers for you, Erin, because there is, I think, a lot of open questions. And that's just some, there, there, I have so many papers with, like, so much detail on many other specific variants that might

• 37:31Speaker 06

  have a slightly better prognosis, maybe a slightly less rapid, you know, prognosis, or slightly less rapid progression of this disease, whereas others might have a more rapid progression of disease. But it's not, it is not very clear-cut, because there's, there's so many different things. But there's just still so many open questions as to, like, ultimately, what is the cause? And there's still so many open questions into, like, how do we then go about treating ALS?

• 38:03Speaker 05

  Right. How, how do we go about treating ALS?

• 38:06Speaker 06

  Right now, there are two drugs that are available specifically for the treatment of ALS. One is called Rylozole, I think I'm pronouncing that right. It has been shown to increase survival by about three months, on average. And this one is probably the most widely approved drug across the globe.

• 38:27Speaker 05

  Okay.

• 38:27Speaker 06

  There's another one called edavaron, that can slow disease progression, but only in a pretty small subset of people. And it tends to be those who have more rapidly progressive disease. And it's not approved in a lot of places. It is approved in the US, but it's not approved in most of Europe, for example. In 2023, there was a very novel therapy approved, a drug called Toferson, which is actually a type of gene therapy that targets just one gene that is associated with familial and some cases of sporadic ALS. And it was approved under a special pathway, but it's still also in the middle of clinical trials, because it hasn't shown clearly that there's improvement in, like,

• 39:09Speaker 06

  the rate of progression or improvements in survival. But the data is, like, promising, so it was approved as, like, an accelerated approval process. There's so many people doing work on this and we'll talk a little bit more about it, but in truth, the most important thing to improve the quality of life and to prolong survival in people living with ALS is access to a multidisciplinary care team. Time and time again, that's actually the thing that improves quality of life and longevity. That means coordination with physical therapy, occupational therapy, speech therapy, dieticians, GI, your primary care, of course, neurology, respiratory therapy, social workers, palliative

• 39:48Speaker 06

  care, to treat spasticity and sci-leria, or excessive salivation, to treat the pain that's associated, to treat the malnutrition that we see, to treat the respiratory failure when that starts to arise. So it really does require access to a wide range of specialists. And that is one of the big problems, is that not everybody has access to that.

• 40:11Speaker 05

  Gosh, and it, I mean, I think it just like, this is where the role of caregiver is also so important to not overlook and the challenges of being a caregiver. And it's just, yeah, it is because it is so multifaceted, because it is so, I mean, it is, it is, it is so heartbreaking.

• 40:32Speaker 06

  It is.

• 40:33Speaker 05

  It is really heartbreaking.

• 40:34Speaker 06

  It really is. Because we don't have a lot to sort of change the course of the disease by any means right now.

• 40:38Speaker 05

  So these drugs, do they all act in similar ways?

• 40:42Speaker 06

  No, they all act in different ways and we don't really understand why they work.

• 40:46Speaker 05

  Yeah.

• 40:46Speaker 06

  In all honesty, because we, again, don't really understand the pathophysiology of ALS. But I have lots of papers that people want to read more about this and so many other gene therapies that people are working on that are very exciting. But I've talked for a long time, Erin.

• 40:58Speaker 05

  Well, I have one more question, though. Mouse models, like, do we have good animal models or, or anything for?

• 41:07Speaker 06

  Historically, all of the models relied on one specific gene mutation, a mouse model with one specific gene mutation. And not everyone with ALS has that gene mutation. So we were limited for a really long time. Now there are newer mouse models that focus on that protein, that TDP43 protein.

• 41:26Speaker 05

  Okay.

• 41:26Speaker 06

  Which is, again, present in almost everyone with ALS. And so those models, we, like, people are very excited about now having access to animal models that are that, rather than just this other gene that not everyone with ALS has. But it has been a problem historically, is just not having perfect animal models. And even still, our animal models are not perfect, which is why there will be so many gene therapies especially that have been trialed in preclinical trials in animal studies, and that end up just not showing any efficacy once they get to human trials, which is really disappointing.

• 42:02Speaker 05

  Yes.

• 42:04Speaker 06

  So Erin, can you tell me about the history of ALS?

• 42:08Speaker 05

  I can do that, yes.

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• 45:19Speaker 05

  The early history of the science of ALS, it kind of reads like a who's who of 19th century neurologists. Like, you'll recognize many of these names, maybe not for the person themselves, but for many of the diseases for which they're, yeah. So there's Charles Bell, who's considered the father of modern neurology and the namesake for Bell's palsy. He's often credited with describing what is thought to be the first case of ALS, or, yeah, it's kind of hard to do retrospective diagnosis, but he's credited with, you know, describing the first case of ALS in 1824.

• 45:53Speaker 06

  Okay.

• 45:54Speaker 05

  Francois Erin wrote about progressive muscular atrophy in the 1850s, which turned out to be an umbrella term under which certain cases of ALS fell.

• 46:05Speaker 06

  Okay.

• 46:05Speaker 05

  There's Duchenne, who's a major French neurologist, who also gave his name to multiple conditions like Duchenne, much so dystrophy. And he also described it as what was likely a case of ALS around the same time as Erin, but at the same time, or, but he, he was like, this is a muscular disorder. He didn't think about the neurons.

• 46:25Speaker 06

  The nerves. Yeah, that's so interesting.

• 46:27Speaker 05

  Yeah. And then Crevalier, I don't know how you say his name. Among the first to describe the lesions in multiple sclerosis, he played a big role in MS, he suggested nerve involvement in some cases of progressive muscular atrophy.

• 46:43Speaker 06

  Okay.

• 46:43Speaker 05

  So those are all some of the who's who's. But the history of ALS, or neurology itself, would be incomplete without mentioning Jean-Martin Charcot's contributions to the field.

• 46:57Speaker 06

  Charcot?

• 46:58Speaker 05

  Charcot, who was a very famous French neurologist, he looms large in the history of neurology and psychology more broadly, having made important contributions to the study not just of ALS, but also multiple sclerosis, Parkinson's disease, hysteria, whoops, epilepsy, Tourette's Syndrome, and Charcot-Marie Tooth Disease, among others. And he spent his career at the Sao Pierre Traire Hospital, which was a charity hospital that became famous thanks to Charcot for the study of neurological and psychological conditions, which it was not yet a divided field necessarily. Thousands of patients passed through these hospital doors, giving Charcot ample opportunity to observe and take

• 47:41Speaker 05

  note of patterns that could signify a new, undescribed disease. And his approach was kind of revolutionary for the time, right? It involved linking symptoms to pathology. How did a person act during life? You know, where did they experience muscle weakness or pain? And then after they died, were there any noticeable lesions or anomalies in any part of their anatomy? And so this is how, this, this process is how he recognized what became known as ALS. In 1869, with observations from just a handful of patients, really, Charcot presented the first description of ALS. It included, you know, early symptoms,

• 48:24Speaker 05

  progression, prognosis, and he gave it the name that we still use today, amyotrophic lateral sclerosis.

• 48:30Speaker 06

  Wow.

• 48:31Speaker 05

  And so he did this because, as you said, amyotrophic, meaning no muscle nourishment, lateral, meaning the location in the spinal cord with the degenerating motor neurons, and sclerosis, meaning the hardening or scarring. And in the US, we also use the name Lou Gehrig's disease. More on that in a bit. But elsewhere around the world, it's occasionally still referred to as Charcot's disease, which I did not know. He also linked the symptoms of the disease to its pathology, namely the deterioration of lower motor neurons. And he based his observation, like I said, on just like, I think, 20 patients and five autopsies.

• 49:06Speaker 06

  Wow.

• 49:07Speaker 05

  But his description, it's very similar to the one that we use today. It would at least be quite recognizable to modern neurologists. They would take one look and go, oh, yeah, that's, that's ALS.

• 49:16Speaker 06

  ALS. How interesting.

• 49:18Speaker 05

  How interesting. Yeah. And his conclusion is also sadly mostly unchanged from then to today. So, quote, "At present, the prognosis is grave. As far as I know, there is no case in which all the symptoms occurred and a cure followed. Is this an absolute block? Only the future will tell." End quote. And so far, the future has continued to say that it is mostly an absolute block. We, I mean, the fact that we have made some progress with drugs is really encouraging, but it is also difficult when you read, when you read that in his observations.

• 49:55Speaker 06

  Yeah.

• 49:56Speaker 05

  And so from this period of time, from Charcot's time, over the next 50 or so years, what the future brought was not a cure, but it did bring an expansion in the clinical picture of ALS. Researchers sought to categorize it among other types of degenerative diseases, and they colored in details about, you know, things like different stages, the patient population, familial patterns that they were observing, and the timeline of progression. By and large, though, it remained in the shadows. The phrase amyotrophic lateral sclerosis recognizable only to those few doctors with a special interest in neurology.

• 50:35Speaker 06

  Interesting.

• 50:36Speaker 05

  But in the last years of the 1930s and the early 1940s, one person would turn ALS into a household name, and his name would forever be linked to this tragic disease. And of course, I'm talking about Lou Gehrig. So here in the US, Lou Gehrig's disease is often used interchangeably with ALS, which is an unexpected legacy for the star first baseman of the New York Yankees. Lou Gehrig was not the first famous person, quote, unquote, celebrity, to be diagnosed with this disease, nor was he the last. Yet, his is the name that many of us most associate with this disease. Today, when people hear the name Lou Gehrig, they're, I think, they're more likely to think not of his, like, you know,

• 51:20Speaker 05

  slugging powers or his skilled fielding abilities, you know, the things that landed him in the baseball Hall of Fame, but of his strength and resilience when faced with a devastating diagnosis. I mean, and many people may not even know that he was a baseball player.

• 51:34Speaker 06

  Right. They just have heard of Lou Gehrig's disease.

• 51:37Speaker 05

  Lou Gehrig's disease. Yeah, some guy. So I kind of wanted to understand more, like, I knew a little bit more about Lou Gehrig. I knew that he was the iron horse, et cetera. But I was like, I want to know this full story. Why is it Lou Gehrig's disease?

• 51:51Speaker 06

  Right.

• 51:52Speaker 05

  So I want to tell you a little bit of the story of Lou Gehrig.

• 51:55Speaker 06

  Okay.

• 51:55Speaker 05

  So Henry Louis Gehrig was born on June 19th, 1903.

• 52:00Speaker 06

  Oh, my God, that's my birthday!

• 52:02Speaker 05

  I know.

• 52:02Speaker 06

  I didn't know we were birthday twins!

• 52:05Speaker 05

  Birthday twins.

• 52:06Speaker 06

  Wow, I don't know why that makes you feel like really something.

• 52:11Speaker 05

  Isn't that fun when you find a birthday twin?

• 52:16Speaker 06

  Yes, I don't know why that, every time. You're birthday twins!

• 52:20Speaker 05

  Birthday twins!

• 52:21Speaker 06

  Okay, wow, me and Lou Gehrig, I never knew that.

• 52:23Speaker 05

  You and Lou Gehrig, so now you're on special ties.

• 52:25Speaker 06

  June 18th.

• 52:26Speaker 05

  Yep, there you go. Yep. Okay, so 1903, in East Harlem, two German immigrants, Anna and Heinrich, and he was the only one of his parents' four children to survive childhood.

• 52:37Speaker 06

  Wow.

• 52:38Speaker 05

  One brother died in infancy, and his two sisters died in childhood from measles and whooping cough. And perhaps because of this, Lou was the apple of his mom's eye. He was devoted to her, like, almost to the point where it was like, this guy, like, he was really just, he was a mama's boy.

• 52:55Speaker 06

  Who's mama's boy.

• 52:56Speaker 05

  For sure. Super, super. And he was also devoted to the sport of baseball, which he discovered as a boy. And at that time, baseball was very much a working-class sport. It was not yet America's pastime. It was kind of played in, like, the alleys, and it was something that you did, like, it wasn't a fancy sport in any, in any regard. And so when Lou expressed interest in playing professionally, his mom was like, that's not a real job. You can't, no, you're going to become an engineer.

• 53:24Speaker 06

  Not an option.

• 53:25Speaker 05

  Yeah. But it was becoming a real job, and it was growing rapidly in popularity, thanks especially to players like Babe Ruth, whose home runs on the field and antics off the field bridged sports and entertainment. It, like, turned, celebrity, like, celebrity is where it started to come into play.

• 53:44Speaker 06

  Okay.

• 53:45Speaker 05

  Hitting overall, uh, used to be much scrappier and strategic, like, a lot of bunts, a lot of stealing, a lot of, like, you know, trying to get in between the, the fielders. And home runs were mostly, like, inside the park.

• 53:59Speaker 06

  Okay.

• 53:59Speaker 05

  Before Babe Ruth.

• 54:00Speaker 06

  Okay.

• 54:01Speaker 05

  And also before a change in, like, the way that baseballs were constructed and rules banning certain practices, especially when it comes to pitching. There's, like, a lot of fun thing about the history of baseball.

• 54:11Speaker 06

  Baseball history, I love it.

• 54:12Speaker 05

  You know, it's, it's, it is really, I, yeah, I have a soft spot. But fans loved these new heavy hitters, like Babe Ruth, as did the team owners, who were like, okay, everyone's coming to the stadium now, we're making money, let's start selling hot dogs, you know, like, that kind of thing. And, um, and so Gehrig, while he was playing high school baseball and also college ball, and I think he also played football at Columbia, he had shown that he was an incredibly powerful hitter, hitting the ball not just over the fence, but like, out of the park entirely, into the streets behind.

• 54:45Speaker 06

  Wow.

• 54:46Speaker 05

  And baseball scouts were like, is this the next Babe Ruth? So he signed with the Yankees in 1923, so he was, you know, uh, just 20 years old.

• 54:57Speaker 06

  Yeah.

• 54:58Speaker 05

  Mostly pinch hitting until 1925. And that was when he, the first baseman, had a headache, wasn't feeling well, and he was like, I'm going to sit out this game. So Lou Gehrig stood on first.

• 55:09Speaker 06

  Popped in.

• 55:10Speaker 05

  Popped in. And from that date, June 2nd, 1925, he played in every single Yankees game until April 30th, 1939.

• 55:18Speaker 06

  What?

• 55:20Speaker 05

  Uh-huh.

• 55:21Speaker 06

  Every single game?

• 55:22Speaker 05

  Every single game.

• 55:23Speaker 06

  He never missed a game?

• 55:24Speaker 05

  Never missed a game. That's the iron horse nickname.

• 55:26Speaker 06

  That's the iron horse.

• 55:28Speaker 05

  Yeah. That's 2,130 consecutive game streak. And it wasn't broken until, uh, the 1990s, maybe 1995, by Cal Ripken Jr.

• 55:37Speaker 06

  Wow.

• 55:39Speaker 05

  Yeah.

• 55:39Speaker 06

  That is impressive.

• 55:41Speaker 05

  It's impressive, yeah.

• 55:42Speaker 06

  He's never had a cold, or just, like, played through it?

• 55:44Speaker 05

  Oh, no, he definitely, he had the flu once, and his manager, I think, somehow got it to be called, uh, like, got it to be rained out, and there was no rain, or something like that. So there's, like, a little bit of trickery going on here and there.

• 55:56Speaker 06

  Okay, okay.

• 55:57Speaker 05

  It was like, he'd go in for one inning or something like that.

• 55:59Speaker 06

  Right, right, just to keep the streak alive.

• 56:01Speaker 05

  Exactly, yeah. But, I mean, he also was, like, it wasn't, maybe there was a little bit of vanity there, but he really, I think, loved to play.

• 56:09Speaker 06

  Loved to play.

• 56:09Speaker 05

  And loved to work hard, and was like, there's no excuse not to hustle, and not to, like, run around, you know, I, I just, yeah. Um, and so that's, yeah, that's the iron horse nickname. Uh, and it was the one that stuck. Other nicknames had been tried out, like Buster Gehrig and Babe Ruth, you know, like, they were trying to make them a duo, because they were both on the Yankees. Or my personal favorite, Biscuit Pants, because apparently he had a big butt.

• 56:33Speaker 06

  Oh!

• 56:35Speaker 05

  And so they called him Biscuit Pants.

• 56:37Speaker 06

  Looks like two little biscuits.

• 56:39Speaker 05

  I guess so. Isn't that so cute? Yeah.

• 56:42Speaker 06

  That's hilarious.

• 56:43Speaker 05

  But I think that, like, it's, it's funny, he was not a nicknameable guy, right? Babe Ruth was out there, partying, womanizing, just like, smoking on field, you know, just like, a complete, all, all this chaos and all this, like, you, you, people loved, sports writers loved him, they loved to write about him. And Lou Gehrig was like, I'm going to turn in early.

• 57:05Speaker 06

  I'm going to go play baseball.

• 57:06Speaker 05

  I'm going to go play baseball. Yeah, and they were like, where, some guy was like, he, he lacked color, is what, is how he described him. He was, it was described as incredibly shy, like, he did not like to interact with, uh, sports writers or anything like that. He was very eager to please, afraid to impose, a near teetotaler. And, yeah, he tended to just turn in early. He used to just, like, oh, I'm going to go to the movies and then turn in for the night. And so, uh, yeah, they, the sports writers got kind of fed up with this, and they were like, okay, we're not going to be able to turn him into another celebrity like Babe Ruth. And so for the fans, he also just became kind of part of the scenery. Like, he was always there, he was an essential part of

• 57:49Speaker 05

  the scenery, he was an incredible hitter, but he was just kind of there. You know, he, he followed Ruth in the batting order, and, yeah. Um, he wasn't a fa, a fan favorite. But, and the stories about his frugality are legendary. He would chew exactly one stick of gum per game, no more. He would, like, yeah, he would instruct, like, some, somebody would be like, you know, okay, this is all my gum for the season, this is all I can chew. He would often opt out of, like, cab rides or free dinners if it meant that he had to tip someone. He sent basically all his money to his parents. His mom was primary breadwinner, his dad didn't seem to be able to really hold down a job. And

• 58:32Speaker 05

  he eventually bought them a house, where he lived with them for years. And he said that the day that he bought his parents the house, that was the proudest day of his life, which makes me like, oh.

• 58:43Speaker 06

  I know.

• 58:43Speaker 05

  I know. He did eventually move out when he got married at the age of 30, uh, but his mom was not happy. She had apparently ruined every single relationship that he had been in until then. And then he was like, I'm putting my foot down, this, I'm marrying her. But despite his frugality, Lou was extremely generous in other ways, like, with his thoughtfulness and with his time. He would buy candy for his teammates' moms on their birthdays. He would invite sick teammates over to his house so that his mom could take care of them for a few days as they recovered. He would spend time coaching the new guys, he would be like, well, let me just, let's work on your, on the way you hold the bat, or your stance, or whatever. And Babe Ruth loved Lou Gehrig's mom. He bought her a chihuahua,

• 59:27Speaker 05

  which she named Jidge, which is, I guess, one of his nicknames.

• 59:33Speaker 05

  I don't know. This is so much more lore than I was expecting, Erin. I know. I really fell in love. I really fell in love. And unfortunately, the good times between Lou Gehrig and Babe Ruth did not last. There was some falling out a few times, but that's a story for another day with a lot of gossip of the time. Drama. Yeah. Yeah. I think Lou Gehrig's mom said insulting things about Babe Ruth's wife or daughter or something like that. Anyway. Ooh. Yeah, yeah, yeah. But Lou was a true team player. He was helping to coach the new guys. He was terrified of disappointing his manager. And he never understood why anyone would try less than their hardest. And he might have been boring in his personal life, but on the field, he was anything but.

• 1:00:16Speaker 05

  He set so many records and he hit so many milestones during his baseball career, like the number of grand slams, 23, which was, I think, a record until maybe a couple decades ago. He hit four homers in a game. He led the league in home runs, RBIs, and batting average, which is the so-called baseball triple crown. And he hit 493 home runs in his career. I mean, he was exceptional. He was an exceptional player. And so when his hitting and his fielding started to falter in 1938, it was noticeable. Dropped balls, bruises on his hands, not hitting the ball as hard. He ordered lighter and lighter bats. You can see like the history of his,

• 1:00:59Speaker 05

  the bats that he ordered were just getting lighter by a few ounces every time. And for a while, it was explained away by a slump, by getting older. He was 35, which in professional baseball is like, you know, it's, it's up there. Right. In professional sports, yeah. Mm-hmm. And sportswriters noticed. Quote, "It is my conviction that Lou Gehrig is a very tired man," one wrote. And while he never got back the slugging of previous years, you know, it was kind of like what once would have been a homerun turned into a triple or what was once a double was now a single, that kind of thing. He did recover somewhat over the 1938 season. But when that season ended, things deteriorated much more quickly. He was tripping on curbs. He had a hard time gripping objects.

• 1:01:43Speaker 05

  And it was, it became enough of an issue that he saw a doctor who told him that it was gallbladder trouble and prescribed a diet rich in fruit. At the time, I will say, yeah, just in a little bit of defense here, ALS was not well-known outside of neurology. And there was like an under, I think the following year, 1938, there were under like nine papers published on ALS. So it was very, very unknown at the time. It was a very niche disease. But still gallbladder? Maybe he had a gallbladder. Maybe he had gallbladder trouble. I don't know. Okay, okay. But he was such a rule follower, so he'd followed that diet to a T and continually exercised, kept trying to build up his strength again because he couldn't.

• 1:02:26Speaker 05

  He was like, why, why aren't I as strong as I used to be? And nothing seemed to work. Nothing seemed to do any good. And if in 1938, there was a suspicion that something had changed with Lou Gehrig, in 1939, all doubt was removed. Swinging and missing at 19 batting practice pitches, the ball dropping out of his glove, stumbling over the bases, and his bulky, you know, biscuit pants frame began to shrink. He was shrunken. And the transformation was so startling that sportswriters and fans, instead of like jeering or criticizing or booing, they were supportive. They probably sensing that something major was wrong with this player

• 1:03:10Speaker 05

  that had, they had seen for, you know, 14 years. And so his long, over to, you know, 21, 30 game streak came to an end on April 30th, 1939. He had stood on first base since almost the stadium was built. And when the announcement was made, the fans were shocked and then they gave a standing ovation. And Lou Gehrig hit his face as he cried. This was like an incredibly, incredibly devastating moment, I think, for him. And I knew that, you know, he knew that it had to come. But I think it was just, it was never going to be easy. But I think with the knowledge that something else was going on that was preventing him was awful. And he, at this point, still didn't know what? He still didn't know.

• 1:03:53Speaker 05

  So he played his last game of Yankees baseball on, well, of any baseball, on June 12th, 1939. And the next day, he traveled to the Mayo Clinic in search of answers. The first doctor who saw him immediately recognized the signs of ALS because his, his own mother had actually died of the disease a few years before. Oh, wow. But he wasn't a neurologist and he was like, I need to consult with one because this diagnosis will be completely life-altering. This is one of the world's greatest living athletes, you know? I want to make sure that this is what this is. And in the 70 years since Charcot's description, doctors had gotten better at recognizing ALS but not treating it.

• 1:04:38Speaker 05

  And so that hesitation that he was feeling, that was understandable. And over that week, though, tests did confirm ALS. And they broke the news to Gehrig gradually. He wrote to his wife saying, you know, "I think I have a 50/50 chance of staying the same as I am right now and that I'll probably need a cane in about 10 to 15 years." And maybe the doctors weren't being entirely transparent. Maybe he was trying to shield his wife from the news. Maybe there was hope that, you know, there was progress in other arenas that would transfer here. But in any case, he did know that he would never play baseball again. And this news didn't stay private for long and, and intentionally so.

• 1:05:18Speaker 05

  It was like the doctors wrote a letter to, you know, announce to the public this diagnosis. And when it was announced, it was met with shock and heartache. Suddenly, it seemed that fans saw Lou Gehrig for what he had meant to baseball over the last decade and a half. Suddenly, it was this like, this person that they were like, oh, he has been here for so long. He finally became a fan favorite. You know, they were about to lose one of baseball's greatest players and this was absolutely front-page news. And, and it happened as his, like when his career was over, which is, is sad.

• 1:05:57Speaker 05

  But, and on July 4th, 1939, Lou Gehrig Appreciation Day was held at Yankee Stadium. The mayor of New York, LaGuardia, gave a speech, as did Lou's manager, Joe McCarthy. Former teammates flew in, including Babe Ruth. And nearly 62,000 fans honored this legend of baseball. Gehrig didn't want any part of it. He always hated being in the spotlight and he told his manager that he'd, quote, "Give a month's pay to get out of this." Makes me really sad. And during the speeches, Gehrig, he stood silently at home plate, head down, just like wringing his hat and crying the whole time.

• 1:06:41Speaker 05

  And his manager sobbed as he talked about their friendship. People laid gift at his feet. And when the speeches were nearing their end, you know, Lou turned to walk back to the dugout. The fans were like, no, no, no. We, they started to chant, "We want Lou, we want Lou." And his manager stopped Lou and was like, whispered a few words like, "Just say something, say something." And so reluctantly, he turned back to the microphone and he stood silently for a few minutes while gathering his thoughts. He hadn't practiced or drafted anything fully. He just had a rough idea of what he wanted to say. And then he started on what is probably the most famous speech in baseball. I think it's been called like Baseball's Gettysburg Address or something.

• 1:07:25Speaker 05

  I'm going to read the whole thing and there is no existing recording of the entirety of it, whether written or video or audio. But this is what has been pieced together from various accounts. So. Quote, "For the last two weeks, you've been reading about a bad break. Today, I consider myself the luckiest man on the face of the earth. I have been in ballparks for 17 years and have never received anything but kindness and encouragement from you fans. When you look around, wouldn't you consider it a privilege to associate yourself with such fine-looking men as are standing in uniform in the ballpark today? Sure, I'm lucky. Who wouldn't consider it an honor to have known Jacob Ruppert,

• 1:08:07Speaker 05

  also the builder of baseball's greatest empire, Ed Barrow? To have spent six years with such a grand little fellow as Miller Huggins? To have spent the next nine years with that smart student of psychology, the best manager in baseball today, Joe McCarthy? Who wouldn't feel honored to room with such a grand guy as Bill Dickey? When the New York Giants, a team you would give your right arm to beat and vice versa, sends you a gift? That's something. When you have a wonderful mother-in-law who takes sides with you and squabbles against her own daughter? That's something. When you have a father and mother who work all their lives so that you can have an education and build your body? It's a blessing. When you have a wife who has been a tower of strength and shown more courage than you dreamed existed?

• 1:08:52Speaker 05

  That's the finest I know. So I close in saying that I might have had a bad break, but I have an awful lot to live for. Thank you." Oh my God. Sorry, Erin. I'm losing it. Ah. Okay. It was very emotional to read this whole book. By the last, I read a book on Lou Gehrig's life and by like the last chunk of it, I was just like non-stop, like just heartbroken. Yeah. But with this speech that he gave, the luckiest man speech, he achieved something that he had never quite managed in his many, many years of playing professional baseball. He became a hero. For his incredible athletic ability, yes.

• 1:09:35Speaker 05

  But even more so for his gratitude, his resilience, his reliability, his courage. Lou Gehrig's name had become synonymous with ALS, not because of his diagnosis, but because of how he reacted to it. The luckiest man. And over the rest of 1939 and 1940, his health and his strength began to decline steadily. But he never gave up hope or lost faith in his team of doctors at the Mayo Clinic. He, his letters to them are so earnest, it is truly heartbreaking because he's, he asks for their honest opinion, saying, "I don't want you to think I'm a crybaby, but there's something going on with my body that I don't understand and I want your, I want the truth from you. What do you think is going to happen to me?"

• 1:10:20Speaker 05

  And in January 1941, he wrote, quote, "Don't think that I am depressed or pessimistic about my condition at present. I intend to hold on as long as possible. And then if the inevitable comes, I will accept it philosophically and hope for the best. That's all we can do," end quote. And over the next few months, I know, I'm sorry. It's really awful. I can't look at you because you're making me cry too.

• 1:10:48Speaker 05

  Oh, God. Okay. Yeah, we're a mess.

• 1:10:51Speaker 06

  Yeah, we are.

• 1:10:51Speaker 05

  We're a mess.

• 1:10:54Speaker 05

  And over the next few months, he continued to write or dictate letters because he couldn't really hold a pen anymore. But his letters no longer contained any questions about like, what are my chances? He didn't talk about his condition. I think that, deep down, he knew that this was, this was the end for him. And publicly, he still said, I have a 50/50 chance. But I think he knew that that wasn't what was going to happen. And on June 2, 1941, Lou Gehrig died, just shy of two years since his diagnosis. He was 37 years old. His widow, Eleanor, dedicated the rest of her life to ALS research. And when she died in 1984,

• 1:11:36Speaker 05

  she left her entire estate to the study of this disease. And, you know, I think, reading the story of Lou Gehrig, this is, I mean, his story is remarkable because of the time that he was in his, the fact that he was such a major public figure, and the way that it raised awareness of this disease, his experience with it, researching this episode, has really, I think, drove home for me how incredible it is that one person can have such an impact. And I'm not talking about just Lou Gehrig. I'm not talking about just, you know, Charcot. And it's every single person. You know, ALS is a relatively rare disease, yet most people know what it is because of these notable people who have been affected by it, like

• 1:12:21Speaker 05

  Lou Gehrig, like Stephen Hawking, and because of some wildly successful awareness and fundraising campaigns, like the Ice Bucket Challenge of 2014, which I wanted to mention because, again, it is, it is such an incredible example of how social media can be used for good in many ways. Yeah. So the origins of the Ice Bucket Challenge are like somewhat murky, but at least the former Boston College baseball player Pete Freitz is credited with really blowing it up and turning it viral. And he was diagnosed with ALS a couple of years earlier at the age of 27. And in case you don't remember, the Ice Bucket Challenge,

• 1:13:01Speaker 05

  it was the summer months of 2014, over 17 million people posted videos of themselves dumping buckets of water, ice water over their heads. And these videos were watched more than 10 billion times by nearly half a billion people around the world.

• 1:13:15Speaker 06

  Wow.

• 1:13:15Speaker 05

  And it's true, like, not all of the people who participated or scrolled past a video donated or even mentioned ALS in the video. And the trend was relatively short-lived. But by the end of the summer, more than 28 million people donated an estimated $220 million worldwide.

• 1:13:35Speaker 06

  Wow.

• 1:13:36Speaker 05

  Which went to research, patient and community services, and public and professional education, many times over the usual budget for ALS research. I mean, it was really impactful. And even if they, even if someone didn't donate, they were much more likely to know what ALS was, thanks to the challenge. And it really demonstrated the power of social media in raising awareness about conditions like ALS. And more than a decade later now, it's, it's difficult to quantify still the impact of the Ice Bucket Challenge on our understanding or treatment of ALS, just as it's hard to measure how Lou Gehrig changed the landscape of ALS by humanizing the disease, by putting a face to it, a name to it. And

• 1:14:20Speaker 05

  it's true that we can't yet point towards a transformative drug or a complete understanding of the drivers and the mechanism of ALS. But that doesn't mean that there's been no progress. And perhaps one of the biggest legacies of Lou Gehrig, of the Ice Bucket Challenge, has been hope. With community engagement and resources for research, a treatment for a cure, you know, it brings hope that that could be within reach. In 1889, Charcot, struggling with the feeling of helplessness in the face of this untreatable, inevitably fatal disease, he offered these words of hope, quote, "Let us keep looking in spite of everything. Let us keep searching. It is indeed the best method of finding. And

• 1:15:05Speaker 05

  perhaps, thanks to our efforts, the verdict we will give such a patient tomorrow will not be the same that we must give this man today." So with that, Erin, tell me where we are with ALS in our search, in our hope.

• 1:15:55Speaker 06

  Erin, I'm so glad that you included that quote from Charcot, because I saw that at the end of a paper that I read. And I was like, this is, it's incredible that this was written so long ago.

• 1:16:06Speaker 05

  Yeah.

• 1:16:07Speaker 06

  And is still so true and so impactful, like, the power of just not giving up. And I think that that's what's so incredible about the scientific community and about so many activists and, and people who have dedicated their lives to not giving up on research, on looking for a cure. So let me tell you about what's happening today, Erin.

• 1:16:30Speaker 05

  Yeah, please.

• 1:16:32Speaker 06

  In terms of the kind of epidemiology of ALS, it's usually cited that the incidence every year is about two to three cases per 100,000 people. Most of the data that we have is from Europe or the US. And it's thought that the case numbers might be a bit lower, like, maybe one per 100,000 in places like South and Eastern Asia. But we don't really know if that is like a true difference, or if we're just not picking it up because there's not as much data in some other places. There also have been pockets of areas where we've seen really, really high incidence. For example, there's a condition, it actually has like

• 1:17:12Speaker 06

  a much longer name. It's like ALS and Parkinsonism type disease, or something like that, that we see in Guam. And then there have been other pockets. I think there's a pocket in France. There was a pocket in either Ireland or Scotland, where we've seen, like, small areas of higher incidence. We don't know, is that ALS? Is it something more specific? Is there something else going on? And what are the environmental factors that are playing in there? So in general, across the globe, it's about two to three cases per 100,000 people. In the US, the estimate in 2022 was that there were just under 33,000 people in the US living with ALS. And globally, it's thought that it's about 400,000 people

• 1:17:56Speaker 06

  that are living with ALS worldwide. So it's rare, but it's not that rare.

• 1:18:01Speaker 05

  It's not that rare.

• 1:18:02Speaker 06

  It's not that rare. And in many ways, it is thought that the incidence of this is going to continue to increase, not necessarily because of changes in exposures or things like that, but more just because we have an aging population. And because the mean age of onset is late 50s, early 60s, especially for sporadic disease, as our population increases in age, we think that the incidence of ALS is going to continue to increase. But it's not like there's a drastic increase or anything like that. And in terms of the future of, of ALS, there is so much work being done. And even though I don't have, you know, a

• 1:18:47Speaker 06

  world-changing drug to tell you about today, I don't want to give the impression that there hasn't been huge strides. There has been so much research, and there continues to be so much research, into better understanding the pathophysiology of this disease, into developing biomarkers, so that we can have better tests, not just for diagnosis, but also to monitor progression of this disease.

• 1:19:12Speaker 05

  Right. Which gives us a better sense of, is this medication effective?

• 1:19:16Speaker 06

  Yeah.

• 1:19:16Speaker 05

  Yep.

• 1:19:17Speaker 06

  Exactly. And in the development of treatments, there are so many really incredible things being done in still the research space, both the preclinical, so like, animal trials research, as well as early clinical trials, using things like microRNAs, using adeno-associated virus vectors to deliver gene therapies. Some of these are really incredible and have shown really great promise in animal models. And some have at least shown some promise in early clinical trials as well. So there is a lot of research that's going on that's incredibly important. But there's actually one thing in specific that I wanted to just give a shout out to.

• 1:20:00Speaker 06

  Because I came across this just by happenstance in like one line mention of a paper. And when I dug into it, it for me just highlights when people come together, they can do such incredible work. And that is a website, actually, called ALS Untangled. Did you come across this?

• 1:20:19Speaker 05

  Uh-uh.

• 1:20:20Speaker 06

  So this is a group that was founded in 2009 by the North American ALS Research Group. And what they do is they review and publish in peer reviewed journals their reviews of alternative and off label treatments for ALS. And the reason that I'm highlighting this, I talked already about the importance of a multidisciplinary team in the management of people living with ALS. Time and time again, in all the studies, that has been shown to improve quality of life, to improve survival. And at this point, ALS is still a progressive disease with no cure. And that news is devastating. Like devastating doesn't fully encompass what that entails.

• 1:21:03Speaker 05

  Yeah.

• 1:21:04Speaker 06

  And the lack of the medical establishment to have a concrete treatment plan, because we just don't have one for somebody when they're diagnosed with ALS, combined with the fact that this is considered a terminal disease, where we don't necessarily have an exact timeline of prognosis, but it's usually quite short, within a number of years, and that not everyone has access to these incredible multidisciplinary teams. What that means is that people very often will look elsewhere, outside of the traditional medical establishment for treatment options. And that makes total sense.

• 1:21:40Speaker 05

  Right.

• 1:21:40Speaker 06

  When you don't have a lot to offer. But that also means that people might be left susceptible to or exposed to therapies that might be harmful rather than helpful.

• 1:21:50Speaker 05

  Yeah.

• 1:21:51Speaker 06

  So this incredible organization researches and then publishes reviews of all of these alternative therapies that people might be hearing about online, so that they have a place to go to find organized, well documented information about almost any therapy that you can think of. And their website is incredible. They have a link to every single published review. You can suggest ideas. So if you or a family member has ALS or has heard about certain treatments that people are using for ALS, you can suggest that as a topic for a future review. You can go like treatment by treatment in alphabetical order. You can search for treatments. There is just so much potential for a tool like this for

• 1:22:35Speaker 06

  patients, for their families, for clinicians who are not experts in ALS.

• 1:22:40Speaker 05

  Right.

• 1:22:40Speaker 06

  When people come to you with questions, if you live in an area that doesn't have great specialty access, I just really wanted to give a shout out to this incredible organization and the work that they're doing, because it's really amazing. And it's like color coded. It's a really, really well done example of how to not dismiss patients' concerns, not to dismiss these ideas that, yeah, we might be missing something, but to bring this information together in a way that says, hey, these are also places where maybe we find something that says, let's do actual research on this. Let's look at this as a potential treatment. Here's what's been done so far. I just, I really loved it. And so I wanted to end with that, Erin. There's a lot of people out there doing incredible work.

• 1:23:20Speaker 05

  Ah, I love that. That is a very, that's a very cool, gosh, I wish we had that for everything.

• 1:23:26Speaker 06

  For so many different things. I know.

• 1:23:27Speaker 05

  Yes. Ah, this was a, this was a really emotional episode to do, Erin.

• 1:23:34Speaker 06

  Yeah, it was. And I am really glad that we did it.

• 1:23:38Speaker 05

  Me too.

• 1:23:39Speaker 06

  I feel like I learned a lot. I hope that, I hope that everybody learned a lot. I have so many places that people can learn more. There's so much, especially about the gene therapy research that's going on right now, that I just hope.

• 1:23:55Speaker 05

  Yes.

• 1:23:56Speaker 06

  That there is so much more that we can report in the next few years. You know what I mean?

• 1:24:00Speaker 05

  Totally. Should we tell the people where they can find sources?

• 1:24:04Speaker 06

  We should.

• 1:24:04Speaker 05

  Okay. I have, I have several, not as much as I normally do for this. If you want to learn more about Charcot's contributions, there's a paper from by Getz from 1999, Amyotrophic Lateral Sclerosis: Early Contributions of Jean-Martin Charcot. Then 2017, The Ice Bucket Challenge Delivers by Seun. But I will say that the source that I relied on the most for this and absolutely adored is a book called Luckiest Man: The Life and Death of Lou Gehrig by Jonathan Igg. And it is so well written. It really is. Like, I loved it. I mean, I think even if you don't care about baseball, watch baseball, anything like that, it is just a really great biography and it transports you to this time. And you feel like you get

• 1:24:49Speaker 05

  to know this person that was so, so important in the history of this disease.

• 1:24:54Speaker 06

  Yeah. I have a number of papers. There's actually probably at least a half a dozen, like large scale reviews, most of which are just titled Amyotrophic Lateral Sclerosis or something similar that were published everywhere from like 2001 until 2022. So I've got links to all of those. They're all good. They all say basically the same kind of thing over and over again, maybe with slightly different, you know, vibes here. But I will also shout out a few really good comprehensive reviews of where we are going to be going, going forward, if that makes sense. There was one from the Journal of Neurology in 2025 by Ruffo et al. called Advancements in Genetic Research and RNA Therapy Strategies for ALS: Current Progress and Future Prospects. That one was really good.

• 1:25:39Speaker 06

  There was a couple of other relatively recent ones, too, that just go like every single gene and what people have been doing to try and target those. There was a paper from 2024 that was a mouse model study, but looking at an RNAi delivery of a thing that could help everyone with ALS, not just people with certain genetic disorders. So that one was really great from Nature Communications 2025. And I also have a link to ALS Untangled, which is that website I mentioned. I think it's a really incredible resource. So check it out.

• 1:26:11Speaker 05

  Check it out. Thank you again to the provider of our firsthand account. I mean, yeah, we have no words. It means everything.

• 1:26:19Speaker 06

  It means, it means so much to, to have you share your story and your family's story. Thank you. Thank you. Thank you. Thank you.

• 1:26:27Speaker 05

  Thank you also to Blood Mobile for providing the music for this episode and all of our episodes.

• 1:26:32Speaker 06

  Thank you to Leanna and Tom and Mark and Pete and Jessica and Christina and everyone at Exactly Right for everything that you do to make this podcast possible.

• 1:26:42Speaker 05

  Thank you. Thank you. And thanks to you, listeners, for listening, watchers for watching. Let us know what you think.

• 1:26:49Speaker 06

  Yeah. Thank you for being here.

• 1:26:51Speaker 05

  Thank you.

• 1:26:51Speaker 06

  And as always, a special shout out to our patrons for your support over on Patreon. Thank you so much, so much for your support.

• 1:26:58Speaker 05

  Yes.

• 1:26:59Speaker 06

  It means a lot.

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  It means a lot. Until next time, wash your hands.

• 1:27:03Speaker 06

  You filthy animals.

• 1:27:31Speaker 10

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