This Podcast Will Kill You - Ep 115 Altitude Sickness: Balloons though?

Episode Date: March 21, 2023

In our episode on the bends, you joined us as we explored how low we can go. Now we’re back with a similar invitation: come along to learn how high we can fly (and what happens to our bodies when we get up there). In this very special episode, we examine the short-term effects and potentially deadly consequences of life at great heights and ask how we came to understand the relationship between altitude, oxygen, and health. This journey begins earlier than you may have guessed, back to a time before oxygen was discovered, and winds through unexpected avenues, including misadventures in hot air balloons and early experiments demonstrating the vitality of air, as we trace how the pieces of high altitude physiology were put together. A big part of what makes this episode so very special is our guest, Dr. Jonathan Velotta, Assistant Professor of Evolutionary Biology at the University of Denver, who joins us to chat about some of the incredible ways that humans and other animals have adapted to live at high altitude. Tune in for a bird’s-eye view of what it’s like to have a high life. See omnystudio.com/listener for privacy information.

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Terms and Conditions Apply. Visit blueapron.com slash terms for more information. This is Bethany Frankel from Just Be with Bethany Frankel. Listen, I have a bone to pick with these dog food brands calling themselves fresh, natural, healthy. Sounds great, but a lot of these quote-unquote fresh dog foods in your fridge are not even 100% human grade, which is why feed your babies, just food for dogs. It's good enough for big and smalls, my precious babies, so it's good enough for your babies. 100% human grade, real ingredients, beef, sweet potatoes, green beans, delicious.

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Santana won this tour 2026, the power, the energy. Come celebrate your favorite hits from Woodstock to Supernatural and Beyond with very special guest, the Doobie Brothers. Get tickets now at LiveNation.com. Santana and Doobie Brothers won this tour, 2026. I come to the fatal hour when we were about to be seized by the terrible influence of the atmospheric decompression. At 7,000 meters, we were all standing in the basket. Civil, numbed for a moment, has revived. Crochet Spinelli is motionless in front of me.

Look, he says to me, how beautiful those cirrus clouds are. The sublime spectacle before our eyes was. indeed beautiful. Towards 7,500 meters, the numbness one experiences is extraordinary. The body and the mind weaken little by little, gradually, unconsciously, without one's knowledge. One does not suffer at all. On the contrary, one experiences inner joy, as if it were an effect of the inundating flood of light. One becomes indifferent. One no longer thinks of the perilous situation or of the danger. one rises and is happy to rise. Vertigo of lofty regions is not a vain word.

But as far as I can judge by my personal impressions, this vertigo appears at the last moment. It immediately precedes annihilation. Sudden, unexpected, irresistible. Soon I wanted to seize the oxygen tube, but could not raise my arm. My mind, however, was still very lucid. I was still looking at the barometer.

My eyes were fixed on the needle, which soon reached the pressure number of 290, then 280, beyond which it passed. I wanted to cry out, we are at 8,000 meters, but my tongue was paralyzed. Suddenly I closed my eyes and fell inert, entirely losing consciousness. It was about 1.30. At about 3.30, I opened my eyes again. I felt numb, weak, but my mind was active. The balloon was descending with terrifying speed. Civil's face was black, his eyes eyes dull, his mouth open and full of blood. Crochet's eyes were half shut and his mouth bloody. The shock as we struck the ground was extremely violent. It was four o'clock. As I set foot on the

ground, I was seized by a feverish excitement and fainted, growing livid. I thought I was going to join my friends in the other world. However, I recovered little by little. I went to my unhappy companions, who were already cold and rigid. I had their bodies sheltered in a neighboring barn. Sobs choked me. What? Yeah. A fatal balloon flight. Wow.

Yeah. Aaron, you have to tell me what that's from. Okay. So that was an account by Tassandier of the fatal balloon ride of 1875. He and his two companions went up to past 8,000 meters, which, by the way, is like over 26,000 feet. and they all lost consciousness, and then their balloon went out. They crashed, and two of the three died. That is horrific.

And also makes me so intrigued in what the history of today's episode is going to be, because it is nothing like what I expected. And wow. Yeah. I didn't even, like it didn't even realize that the balloon thing would be kind of a left turn or seem like a left turn. But it is surprisingly relevant. I cannot wait to hear all about it. Hi, I'm Aaron Welsh.

And I'm Aaron Alman Updike. And this is, this podcast will kill you. And today we're taking a few left turns or a sense and decent. I don't know, I tried. I appreciate the effort. To talk about altitude and altitude sickness. Yeah. Yeah.

I am really excited for this, especially because before starting this, I had no idea what the history was going to be. And it turned out to be, I think, one of my favorite episodes to put together. Ooh. Also, do you remember our very first episode this season, RSV, and I told the history of ventilators? And I said at some point in that episode, gosh, I would love to tell the story of oxygen someday. Do we get to? A little teaser, maybe. Can't wait.

Very excited. Yeah, it's going to be really fun. I know nothing about the history of this and only really knew prior to this what I learned in like various physiology classes. So it was really fun to research. And it's just going to be a fun episode. It is, and it's going to be made extra fun by the presence of a very special guest who is near and dear to our hearts. Especially yours. Especially mine.

And that's just another little teaser, and you'll hear more about this very special guest later in the episode when they will come on to discuss some of the evolutionary aspects and current research going into altitude sickness and high altitude. adaptation. Ooh, I can't wait. I'm really excited about it. Me too. Okay, but before that, it is definitely quarantining time. It is. What are we drinking this week? We're drinking high and dry. We are. You know, it was really difficult to come up with a quarantini recipe, everyone. It really was. We are struggling. This is not, this is one of the hardest parts of this job. It honestly, it is. It is. It used to be one of the easiest, and now it's like just scrolling through pages and pages of our past quarantini's. Right. Like how many different times can we use this one item?

A lot. Yeah. So we wanted to make this a dry cocktail as possible. So that means as little sugar as possible. And so in this, which is essentially a modified poloma, we have tequila, we have grapefruit juice. We have a little bit of blood orange juice. And we're topping it with an egg white foam. You know, for that aeration.

Get it? So funny. We will post the full recipe for the quarantini as well as the non-alcoholic placebo on our website, this podcast will kill you.com, as well as on all of our social media channels. Our website, this podcast will kill you.com. It's a really great website that has. It has a lot of stuff on it, so you should go there and check it out. You should.

You should. The end. That's all that needs to be said. Any other business, Erin? You know, I don't think so. Okay. Well, I have lots of questions about the history of this. So let's start with, you know, the biology.

Come on. I want to hear about the biology. Yeah. We'll take a quick break. And then you can answer all my thousands of questions about the biology of altitude sickness. We'll try. We'll try. Dinner shows up every night, whether you're prepared for it or not.

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different washes, so I'm about to go order some more. Refresh your wardrobe with Quince. Go to quince.com to get free shipping on your order and 365-day returns, now available in Canada, too. That's Q-U-I-N-C-E dot com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. So to understand the kind of disordered states that can result from ascending to or existing at high altitudes, we first have to understand what the heck actually changes at high altitude and what our normal physiologic response is to these changes. So that's how we're going to kind of divide up this section of the episode. First, we're going to talk about the environmental variables that actually

change when we go to altitude. And then we'll talk about what our typical physiological response is to those environmental changes, both in like the short term and the medium to long term. And then we'll talk about what happens when these changes maybe don't work that well or don't go as planned or something along those lines. And that's when we'll get into both acute as well as a little bit of detail on chronic mountain sickness in their various forms. Sounds excellent. And one thing I will say for those who are really into the physiology part of this is I am. I'm going to do this with like a minimum of math. Okay.

Math formulas turns out don't really translate well to like podcast audio format. Okay. Oh, really? Yeah. P1s and V's. Okay. Let's get into it. By far, the single greatest environmental change that we see with respect to increasing altitude is a decrease in the partial pressure of oxygen.

What is this? actually mean. So when we ascend, either up a mountain or perhaps a balloon, the barometric pressure, that is, the pressure that the atmosphere exerts on our bodies, declines because the mass of atmosphere above us is literally less mass. Right. And this decline in barometric pressure leads to a decline in the partial pressure that oxygen exerts. So the air at high altitude, is the same percentage of oxygen, 21% oxygen, as we talked about in our Ben's episode last season. That's right. But what you can think of it as is the density of those oxygen molecules is less.

So per breath, you're getting less dense oxygen molecules. And as we talked about in our Ben's episode, when we inhale air, which is 21% oxygen, some amount of that oxygen in that breath travels down our lungs into our alveoli and has to diffuse across our alveoli into our bloodstream, into our capillaries. And the transfer of this oxygen into our bloodstream is determined in part by its partial pressure gradient, by how much pressure it's exerting in our alveoli relative to our capillaries. So if this partial pressure declined, which we know it does as we ascend in altitude, that means that we are transferring less oxygen into our bloodstream.

So in short, what we see is less density, less pressure of oxygen in the air, which leads directly to less oxygen making it into our bloodstream, which is called hypoxemia. Then what we see is less oxygen in our tissues, which is called hypoxia. Sometimes people use the terms hypoxemia and hypoxia interchangeably. They're technically different things. Anyways. I see you nerds will love that little tidbit. Okay.

But obviously, in any case, this is not great because our cells and our tissues do rely on oxygen to make energy and to function. So, luckily, our body has a lot of compensatory mechanisms that. that it uses when we ascend to altitude, or in other words, when we are faced with what's often called hyperic hypoxemic or hyperic hypoxic situations. That means low pressure, low oxygen situations. This process is known as a climatization, and it has several steps that occur both in like a very short term and a longer period, like days to weeks' time frame. Let's get into it.

So first, involuntarily, all of these are involuntary. We're not conscious of these things happening. But most quickly, the change that we see as we ascend in altitude is that we see an increase in ventilation. So basically, because of this drop in partial pressure, you have less oxygen diffusing into our capillaries and arteries. What happens then is that this decrease in oxygen leads to the stimulation of chemoreceptors in our aorta, which comes off of our heart, as well as our carotid arteries that go up to our brain. There are receptors in these vessels whose job it is is to sense how much oxygen there is in our blood and then stimulate our brain to fluctuate the depth and the rate of our breathing. That is so cool. It's so cool because it is entirely involuntary.

It's not like if you go up to altitude, you'll sit there feeling like you need to take deep breaths. This is an involuntary response that's just happening. Yeah. It's called the hypoxic ventilatory response. And we'll get into that a little bit more later. But let's keep going because that's just the first of like a cascade of changes. So first, we start breathing deeper and faster. What that does is it ends up lowering the amount of carbon dioxide in our alveoli.

You can essentially think of it as we're breathing off extra carbon dioxide as we breathe like this. And that helps to increase the partial pressure of oxygen because they are inversely related in our alveoli. How are we doing that? That's just like a matter, again, of mathematics. Okay, just like properties of gases and behaviors of gases. Yeah. So it's not like changing the concentrations. It's just changing the partial pressures by blowing off more CO2.

You have an increased pressure of oxygen. So what that does is allow our capillaries to continue extracting, to maintain a steeper gradient for the diffusion of oxygen into our capillaries, which is what we need because there's less pressure of oxygen from the atmosphere itself. It's so cool. I know, I know. It keeps going. It keeps going. At the same time, this reduction in carbon dioxide that we see also leads to what we know of as a respiratory alkalosis.

Because carbon dioxide, as I'm pretty sure we talked a lot about in our Ben's episode, in our bloodstream results in acidification. So you can think of it as an acid. So if we're blowing off carbon dioxide, now we have an increase in the pH of our blood, which is alkalosis. If this happens at sea level, like when we hyperventilate at sea level, our brain would try to compensate for this change in pH that we see to actually inhibit our respiration. But at altitude, this process is maintained by this hypoxic ventilatory response. by those chemoreceptors, we already mentioned, and additional chemoreceptors in our brain to continue these high levels of ventilation because we're specifically facing lower partial pressure of oxygen in this setting.

So hyperventilation at sea level is different than the hypoxic ventilatory response? It sure is, Erin. What? How? So is this those specific chemoreceptors that are? only activated at altitude? So no, it's not that they're only activated at altitude, but they're being activated in part by this lowered partial pressure of oxygen, and then in combination with this response, the changes in alkalosis. So it's more like a

combination of all of these factors rather than a pure hyperventilation that you see at sea level without all of the additional factors, if that makes sense. Yes, okay. Altitude is not necessarily the only place that you would see this happen, but this is what happens at altitude. So, Erin, where else would we see this happen? So there have been other studies that look, we'll get into it a little bit more later, but at like, is it the pressure changes or is it just the hypoxia? But so really it's, it seems that a lot of it is driven by the hypoxia initially. Yeah. Yeah. So the next part of what we see, because of this respiratory alkalosis, is that this naturally triggers our kidneys to try and compensate by peeing off more base in the form of bicarbonate.

So we resort less bicarbonate. And that is actually just a normal physiologic response to a respiratory alkalosis. That's how we compensate. Okay. And that happens kind of a slightly longer time frame than the respiration part of it. So that I know was like a lot of different. I loved it. I'm thrilled. But basically, to sum it up in short, we have a decrease in the partial pressure of oxygen, which is less oxygen in our arteries that triggers our brain to breathe deeper and faster, to then breathe off more carbon dioxide and allow more oxygen to diffuse into our arteries so that we maintain good oxygen concentration. But that's not all. Of course not.

Because oxygen in our bloodstream is not just dissolved in our bloodstream. like a gas. In fact, nearly all of the oxygen in our bloodstream is bound to a pretty important protein that everyone's probably heard of on our red blood cells, aka hemoglobin. So the next bit of the acclimatization process involves hemoglobin. And this part takes a little bit more time. So the respiratory response is starting immediately as we ascend. But within one to two days of ascent to altitude, what we see is.

is a rise in the concentration of hemoglobin. Hemoglobin is the protein that's binding and carrying oxygen and then delivering it to our tissues. And that's important. Binding oxygen and then releasing it and delivering it. Oh, huh. Okay. I could tell that's like sort of a remember this because it's going to come back later.

Is that like, this is on the test. It's exactly how it felt. So within one to two days, we see a rise in the concentration of hemoglobin. And this happens because the volume of our plasma in our blood actually falls up to 15 to 25 percent, which is a phenomenal amount. Yeah. And this happens primarily via like a gentle diureasus. We start peeing off more fluid to decrease the plasma volume and then increase the concentration. of hemoglobin. Okay. A question here about altitude. Yeah? At what point do these things happen?

This is such a good question. There's no threshold. There's gradients. Because as you ascend, the partial pressure falls, right? Just no matter what. But when we look at, for example, dysfunction in this process, we don't tend to see altitude sickness until we're, getting pretty high, like 2,500 meters or about 8,000 feet. Sometimes we can see it at slightly lower altitudes. But I don't think, from what I have read, there's not like an altitude at which you see respiratory compensation starts versus stops. Like, it's just a kind of gradual process. But is there a proportional response to altitude? Like, do you lose less plasma if you go up only 2,500 meters compared to 5,000 meters?

Yeah, that's a good question. I don't know. I didn't see that in the studies that I read. We can ask our guests. Okay. I'll note it down. Yeah. Because I think that would be really interesting, especially I think we'd have more data on that in animals than we do in humans. Because what I will say about this whole process that we've learned about the acclimatization process is that it tends to be studied once we get to an animalization process. is that it tends to be studied once we get to an altitude at which you're at risk for acute mountain sickness, so above that 2,500 meters usually, and then studied in people depending on how quickly they go up versus how slowly they continue to ascend, if that makes sense. Yeah. Okay. But that's the first step of this next process.

Reduction in plasma volume, increase in concentration of hemoglobin. This is actually a relatively short-lived phenomenon that we see because then what happens over the next period of days to weeks is that this triggers erythropoietin, which is one of the major things that we make to stimulate red blood cell production. So what we see is an increase in red blood cell production. and then over the course of days to weeks to a month or two, our total red blood cell mass will actually increase overall. So if you're at altitude for less than a week, you're not going to see all of this play out. This is something that happens over the course of time.

But here's why this gets to be so important. Because there's also this thing in physiology, called the oxygen dissociation curve that people might have heard of. This is a measure of both how tightly our hemoglobin binds this oxygen, like how much of an affinity it has for grabbing and becoming fully saturated with oxygen, which it has to do in our lungs, and also how readily it gives up its oxygen at the level of our tissues. Because both of these parts of hemoglobin are really important.

There has to be a balance between grabbing and holding all that oxygen and then letting it go when we need to let it go. So what's really cool about this acclimatization process is that we see effects on both levels of this oxygen dissociation curve. What we see is that the increase in blood pH that I mentioned from that respiratory alkalosis shifts this oxygen curve such that hemoglobin has a greater affinity for oxygen. So under alkalotic conditions, a greater pH, hemoglobin's like, ah, I need that oxygen, give it to me.

I'm going to grab it and hold it. And it gets really efficient at that. But in addition to what I mentioned about just increasing overall hemoglobin mass, the other thing that we see our red blood cells making more of as we acclimatize is a substance. called 2-3 BPG or 2-3 bisphosphoglyceric acid. No one cares. This is something that helps our hemoglobin actually have a decreased affinity for oxygen or an increase in the ability of our hemoglobin to offload oxygen at the level of our tissues. And these two processes work together rather than canceling each other out, right? So that we have hemoglobin. We have hemoglobin that becomes more efficient at grabbing oxygen under conditions which it needs to,

which is in our lungs when that partial pressure dictates that it needs to grab oxygen, and better at offloading it at the level of our tissues when the gradients are dictating, we need to offload this oxygen. Very cool. Those are the major processes of acclimatization. We see them in the short term, mostly with respiration. We see them in the long term with these changes in hemoglobin. We do also see, especially in the very short term, like within 24 hours of ascending to

altitudes above 2,500 meters is most of our data, we see an increase in cardiac output and heart rate, which is thought to be related to increases in our sympathetic nervous system activity because of this initial hypoxia. This part, the like increase in cardiac output, tends to normal. over a period of days. And then what we actually can see is a decrease in stroke volume or the amount of blood that each heartbeat pushes out because of that decrease in plasma volume, which is really interesting. And then we also see changes that happen at the level of our vascular, so like our blood vessels, in some cases might vasodilate to allow blood to push more oxygen

to our tissues. But in our pulmonary vascular, so the blood vessels in our lungs, we often can see a vasoconstriction that happens because of the decrease in the concentration of oxygen. And so this is kind of like a balance that our body has to do. And we'll get into what can happen when maybe that doesn't go so well, shall we? So I know that that's a lot. And that's just what's happening in our bodies in general when we go up a mountain or a balloon. Yeah, that is physiologic acclimatization. You can think of it really as our body doing the best that it possibly can to try and deal with the fact that we just rapidly decrease the amount of oxygen surrounding us. But as I described, that process itself is not instant. It takes time. It takes hours to days to weeks. Parts of it are

relatively rapid, but that full process of acclimatization really can take quite a long time. So what we can see is that in the time period between ascent to altitude and full acclimatization, we are at risk for illness if this process doesn't go according to plan, I guess. And this illness can take three major forms. Acute mountain sickness or AMS. high-altitude cerebral edema, or haste, and high-altitude pulmonary edema or hape. And these are the three major forms that are often lumped under altitude sickness, for example. Question about acclimatization when it comes to humans, because there are elevations or altitudes at which we simply can't acclimatize enough where, symptoms of acute mountain sickness could occur or probably will occur. There's a limit, right?

Absolutely, there is a limit to this process. A climatization can only do so much. And just for reference, so that people can understand, like, when we say the partial pressure decreases, how much are we actually talking? Everest Base Camp is at 5,300 meters. And at that point, the partial pressure of oxygen is about half what it is at sea level. So already you've reduced it by half. And then at the summit, which is over 8,000 meters, the partial pressure of oxygen is a third of what we see at sea level. So these are extreme conditions that we're talking.

about, we cannot acclimatize to that point for the long term. Right. I mean, obviously people have climbed it without supplemental oxygen, but... Right. We can't hang out up there. No. Let's get into these three forms of altitude sickness. Acute mountain sickness, haze, or high altitude cerebral edema, and then we'll talk about high altitude pulmonary edema. or hape. So acute mountain sickness, this is the most benign, the most common, and the most rapid onset. Usually we see the symptoms of acute mountain sickness within four to 12 hours, though it could be within a day or so, of ascent to altitude. And again, at this, we're usually

talking about altitudes greater than 2,500 meters or about 8,000 feet, although it can happen in some instances at lower than 2,500 meters at lower altitudes. And there are a few different scoring systems that you can use to diagnose this. But in general, we look at a constellation of symptoms that include a headache. And in a lot of scoring systems, a headache actually has to be present to diagnose acute mountain sickness. So like headache is a defining feature. And simultaneously, you might.

might see GI symptoms, like a loss of appetite, maybe some nausea, vomiting. You might have some dizziness. Fatigue is a really common symptom that progresses to lassitude, which I love as a word. But that is just a complete lack of energy, lack of motivation to do anything like you can't even kind of get up. and very, very commonly we also see insomnia or sleep disturbances despite the fatigue. Mm-hmm, yeah. And then we also can often see a decrease in urine output. Those are the constellation of symptoms that encompass acute mountain sickness.

In terms of if we look at labs or imaging findings, which become important in some of the other forms of altitude sickness, lab values tend to actually. be pretty normal. You can see a slightly lower than average blood oxygen level if you're testing people's blood oxygen, but there's a large amount of variation in that number when it comes to just acute mountain sickness itself. Most of the time, this can be self-limited and can resolve even without necessarily descending to a lower altitude. This can resolve with just time or sometimes with the assistance of various medications that I'll talk about a little bit later on. But then there is haste. Quick question, though.

Yeah. I know you could ask a question. Before we go on to haste and hape, why do we see those symptoms of acute mountain sickness? I'm not going to answer that question right now. Okay. Because there's still a lot of debate on this, but a lot of papers consider acute mountain sickness. sickness and haste or high altitude cerebral edema as ends of a spectrum. Okay.

So that's why I want to talk about that before I let you ask those questions, Erin. Sorry. Because I knew. Sorry, sorry. That was your question. I'm always getting ahead of things. You're like, no, but I have to ask it. I have to know right now, right now.

I know. I demand it. But let's talk about haste first, and then we can try and understand acute mountain sickness and haste simultaneously. Hase is characterized predominantly by exactly what the name says, swelling or edema of the brain itself. Hase is terrifying. It is extremely life-threatening. And the symptoms that we see in many cases are considered a progression of what we saw in acute mountain sickness.

So if you think of lassitude and fatigue, this then progresses to altered consciousness, to mental status changes. One big thing that we see is what's called truncle ataxia. So ataxia is not being able to walk in a typical fashion, like having a lot of instability and irregular gait all of a sudden. You can still see the headache, but a lot of it really is this altered consciousness. And it's terrifying because haste can progress to coma and death in as little as 24 hours. Okay. And it's scary because if you are having mental status changes and that may make you less likely to recognize that you need help? Absolutely. Yeah. And again, just the rapidity of this progression, right? The need for very, very urgent treatment. So even if you have people that are there with you that recognize

that something is not right, being able to access treatment really quickly is important. And you asked Erin, why? Like, why do we see this? What's? happening here. The truth is, and I found this really fascinating, given how much we know about the physiology of the acclimatization process, is that when it comes to the pathophysiology of these disorders, we don't understand them, like, at all? Very little. Like, very little. So first of all, there's still some debate as to whether AMS and Hase are really, you know, these ends. And of a spectrum or not. There's a lot of thought that it is purely this hypoxia that is driving this process.

But why are we seeing this hypoxia? What parts of this acclimatization process are failing us? Is it poor ventilatory response that we're just not seeing? And that leads to hypoxia that leads to all these other things? We don't necessarily have super strong data to say that, yes, that's true. There is some data that suggests that this is driven by fluid shifts. So I mentioned that we have this sympathetic stimulation, which can cause vasoconstriction. We also are having vasodilation, and we can see increases in, like, cerebral blood flow.

There's also suggestion that we have an increase in vascular permeability. because of oxidative stressors that are happening at the level of our blood vessels. So there might be low-grade inflammation that is going on in the process of AMS and progression to cerebral edema. But truly, that is kind of the extent of what we really know about AMS and HACE, which is really interesting to me. Okay, two questions. Number one, I know you can get hape without AMS. Can you get HACE without AMS? It's a really good question. Like I said, one of the defining features of AMS is a headache. And by some scoring systems, you can't call it AMS unless there's a headache. You can have haste without a headache. But does that really mean that someone didn't. have AMS previously or not? I don't know. So to answer your question, I don't know. And I think that that's part, that's kind of part of this debate. And there is a lot of study to try and look at,

do we see any signs of a little bit of cerebral edema, a little bit of increased cerebral blood flow, a little bit of the things that make us so worried about haste, do we see those signs starting in AMS. And we just don't have a ton of answers. And we really don't know why things like nausea or a lack of appetite or a headache are all somehow connected. So we have some data on that. Okay. So with AMS, there are some studies that suggest we do have a little bit of intracellular adema, if not full-on cerebral edema. Like our cells are at least getting a little swollen. Okay. And while we think that this likely doesn't irritate our cerebral pain receptors, what does make sense is the nausea vomiting because there's nerve fibers that connect to certain

centers in our brain that our sensory nerves travel through, that if these areas are a little bit swollen and irritated, that might result in nausea and vomiting. Okay. But yeah, that's kind of like the most specific thing that I found. Wow. Okay. I'm so surprised. I'm so surprised too, honestly. But it's really, really interesting. And it's not the end because we still have high altitude pulmonary edema or hape. This is different because it's our lungs and not our brain. but otherwise I think of it as kind of similar. The onset of this is slower and tends to happen one to five days after a cent

and is rare after a week or so. We often, like you mentioned, Aaron, we often can see acute mountain sickness AMS first but not always in the case of hate. And the symptoms here are again what you'd expect based on the name. We have edema in our lungs. fluid shifting into our lungs. So the symptoms that we see are dyspnea, difficulty breathing, shortness of breath. And a lot of it starts as severe exertional dyspnea or exertional

shortness of breath. Now, everyone who exercises is going to get breathless or feel short of breath. But what this is characterized as is excessive shortness of breath compared to everyone else that you came up the mountain with or other people around you on the mountain. so like an excessive amount of shortness of breath, along with cough, a feeling of chest tightness. And then this can progress to a more severe cough, shortness of breath that makes it difficult to even lie down flat. If you listen to someone's chest, you would hear crackles or maybe even gurgling sounds. And eventually this can progress to the production of like a pink frothy sputum. which would mean that things are getting pretty severe.

And when we look at things like labs, we would see pretty severe hypoxia. So we have pretty low levels of blood oxygen in these people, which then is going to result in really fast breathing, that tachypnea, breathing really fast, and a faster heart rate. And on x-rays, we see a lot of evidence of fluid throughout the lungs in this very patchy distribution usually. And again here, Aaron, we do not fully understand this pathophysiology. But what we do know is that there's at least some component driven by this hypoxic pulmonary vasoconstriction that we see as part of this acclimatization process. So what this then can lead to is an increase in pressure in the pulmonary arteries. Mm-hmm. And then there's a few different thoughts on how this then leads to the edema that we see.

It could be that then these arteries become a little bit leaky because of this increased pressure. It could be that this vasoconstriction is happening just in certain places, like in patchy distribution, both in our arteries and or maybe in our veins even, in our lungs, which can then lead to increases in pressure just in small areas that then might lead to. fluid being able to leak out of just those small areas, which would explain the patchiness that we tend to see on X-ray. Honestly, it didn't seem very, like, well-fleshed out in terms of, like, the real drivers. Yeah.

It used to be thought that it was really more heart failure that was driving it, but now it's really thought that it's probably more a pulmonary process that then can lead to dysfunction in the heart as well, rather than heart failure that's the initial driver of this process. Okay. That's interesting because that is in contradiction with some of the historical text that I read. But that makes sense that you learn more. Because historically, like this looks like a heart failure response. Yeah. Absolutely. Then there's also a big thought that inflammation plays a role because in some people with hape, if you look at the fluid that you collect from this edema, it has a lot of inflammatory markers. But not all. of them and usually not until later in the disease process. So it's really unclear how big of a role inflammation really plays in this disease. So I really want to talk about treatment, but first I want to ask about risk factors. So these things can happen to anyone who goes up to altitude. Are there certain risk factors associated with either haste or hape or even AMS?

Honestly, no. Okay. Which is fascinating. Yeah. The major determinants of risk are altitude, how high are you actually going, the rate of assent, the degree to which someone is pre-acclamatized. Like, have you ever been to altitude? Have you been going to altitude over the course of the last few weeks? And now you're going a little higher than before and that kind of a thing. And then the rest of it is literally individual susceptibility.

Weird. And that we just don't know. Okay. There's no differences in like terms of other disease states, like even when it comes to like lung disease. With hate, the one exception is that someone with a history of hate has like an over 60% chance of getting hate again if they go to that same altitude. But not things like chronic lung conditions or age? Not even age. Older individuals seem slightly more susceptible.

than younger adults and children, but not even, like, dramatically so. Things like smoking and alcohol use do not increase the risk of AMS. This is... This is... Wild. Yeah, this is not what I expected. I know. It's really, really interesting. Having a history of migraines may be very minor risk factor. Very minor. That's it. That's it. That's it.

That's the only thing. Wow. Okay. I know. Treatment, which you ask it about. Yes. An ounce of prevention is worth a pound of cure. Love the accent.

Thank you. Magnificent. 1940s? I don't know. So really the major way to prevent this is to ascend slowly. That's it. That's the number one thing. And I'm not going to tell you exact numbers on this because even all of the recommendations on the slowness or quickness of your assent and how many rest days are based purely on observational studies.

There's no like randomized control trials. It's not like real data that I can base it on. Right. And every individual has different tolerances, et cetera. So anyways. But there are also medicines that we can use to reduce the risk of AMS and or. help treat AMS, and because haste and to a lesser extent hate, are thought to be all reflective of this impaired acclimatization process,

in theory these medicines might also reduce your risk of those as well, rather than just AMS. Okay. So there's a couple different things that we can use. The main one that's often used is acetyzolamide, which acts both to stimulate respiration at least a little bit, and then is also a mild diuretic. So this helps to increase our plasma volume and increase hemoglobin concentration to basically just jumpstart or boost our normal acclimatization process. Dexamethazone or steroids is the other thing that we use to do similarly.

Okay. There's some limited evidence for things like ibuprofen. But I don't know that there's super great evidence for any of those other things. And beyond that, for anything severe, it's access to increased oxygen, so pure oxygen on the face, and descent immediately to lower altitudes. It is, I guess, maybe not easy, but straightforward. Straightforward and logical, just like in our Ben's episode. Yep, precisely. Yeah. AMS, which is by far the most common form that we see, can often be treated conservatively.

So without having to descend to a lower altitude with just rest, rehydration, treating the headache, and then just wading it out before ascending to further altitudes. But again, we worry about progression to haste. So that's terrifying. Yeah. Yeah. A quick side note. When I said that alcohol use, for example, doesn't increase your risk of AMS or haste, this is true. But alcohol and other medications like sleeping medications, etc., can depress the hypoxic drive to breathe. So might worsen hypoxemia. Might worsen any hypoxemia that does exist. But there have been no trials that show that conclusively. Huh. Just so you know. Wow. So that is all acute mountain sickness, altitude sickness, but that's not the end, quite, Erin.

There's also chronic mountain sickness. And this is what can happen when someone lives at altitude for, we're talking like, their whole entire life and continues to grow an age at altitude. What we see in chronic mountain sickness is what's called a polycythemia or an increase. overall red blood cell mass to an extent that is problematic, coupled with a decreased ventilatory drive, which we think maybe in part just happens with age, but this leads essentially to chronic hypoxia. So what we see is very, very high hemoglobin levels, very high hematic crates, along with chronic hypoxia, which the symptoms of that might. mean dilated blood vessels because again your blood vessels are trying to get this oxygen to

our tissues we can see cyanosis so skin turning blue and then a host of complications that can arise from just how high these hemoglobin levels can get and again here we don't fully understand this process but what I really didn't realize is that it's estimated to affect like five to 10% of people potentially that live at very high altitudes for the entirety of their lives. It's really interesting. Yeah. Yeah, it's really interesting. There's a lot. Aaron, I don't even know how to ask. Like, we, how did we get here? I guess. Well, take us on some kind of journey. So, and I'll get started right after this break. Anyone who works long hours knows the routine.

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The history of altitude sickness can be framed around a single word, hypoxia. Oh, yeah. We learned in the biology section that hypoxia means that there are low levels of oxygen in your tissues. Now let's take a step back and consider all of the layers of knowledge that go into that word. What are all the things we have to know in order to understand hypoxia in the context of altitude sickness? Well, we have to know what are considered normal levels of oxygen in our tissues and how a decrease can be detrimental to our health, which means we have to know how to measure oxygen concentration in tissues.

We have to know how oxygen gets into our tissues and the role that it plays in our bodies, which means understanding cellular respiration, as well as how our lungs function with our circulatory system. We have to know what things can cause oxygen levels to drop and why. In the context of altitude sickness, this means that we have to know the relationship between altitude and oxygen, which requires knowing about how atmospheric pressure behaves under certain conditions and the composition of air, which means we have to know what oxygen is. So in this one word, hypoxia, there are crammed hundreds of years of scientific investigations and observations, integrating knowledge from disparate fields, from anatomy and physiology to chemistry in the

properties of gases. I love this already, Erin, you've hooked me. Good. That was my goal. But I just felt like it's so easy for us today to take this word for granted, along with the knowledge that goes into it, which is why my goal for this history section is to take us through how we fit those puzzle pieces together to gain a big picture understanding of why, how we high altitudes affect us the way they do. Kind of like with our bends or decompression sickness episode, where I barely talked about scuba, the history of altitude sickness, as I am choosing to tell it, you could tell it a number of different ways, is not one filled with the daring exploits of a bunch of dudes attempting to

climb the world's tallest mountain and learning that life at altitude is very dangerous. Honestly, thank goodness. There are many books out there, if that's what you're. interested in. But instead, this is going to be a history of scientific discovery of the big moments in physiology and chemistry that brought us from not knowing that air exerts pressure or that oxygen existed, having no idea what the lungs actually do or why high altitude makes you sick, all the way to breezily using the word hypoxia, dropping it in a sentence. I love it. He's thrilled.

Now that I've said what this history does include, let me tell you what it doesn't, namely, the evolutionary aspects of life at high altitude. For that piece of the puzzle, we're going to be chatting with, as we mentioned, a very special guest later in this episode, who is going to share some fascinating information on how certain animal and human populations have adapted to living at high altitudes, how varied those adaptations can be, and what high-altitude adaptation can tell us about human health. I cannot wait. I know. I am really excited. But first, we've got a whole history to get through.

As we'll learn more about, humans have been living at high altitudes for tens or even hundreds of thousands of years, as well as just traveling through certain areas that are at high altitude. So we as humans have likely noticed the effects of high altitude on our health for a very long time. Observations of high altitude are scarce or close to non-existent in ancient Greek and Roman medical texts, although scientists in the 17th century believed that Greek and Roman physicians were well aware of the dangers of high altitude. From an English translation of Francis Bacon, quote, The ancients also observed that the rarity of the air on the summit of Olympus was such that those who ascended it were obliged to carry sponges moistened with vinegar and water and to apply them now and then to their nostrils as the air was not dense enough for their respiration. Oh.

And so the sponge part shows that people believed that it was the lack of water vapor in the air at high altitude that made it difficult to breathe. Interesting. Because they didn't know what oxygen was yet. I... Okay. It's possible that we simply haven't found the ancient Greek and Roman references to altitude sickness, but there are certainly descriptions of the negative effects of high altitude in ancient Chinese texts. In a classical history text from the first century CE,

there is a description of an envoy traveling over mountainous terrain around 37, to 32 BCE, and this envoy was warned of the danger along the route, not just in terms of the robbers known to frequent the area, but also because of the terrain. Quote, again, on passing the Great Headache Mountain, the Little Headache Mountain, the Redland, and the fever slope, men's bodies became feverish, they lose color and are attacked with headache and vomiting. the asses and cattle being all in like condition. Ooh, green headache mountain and little headache mountain. And 400 years later, also from ancient Chinese texts, is where we find what is likely the first description of high-altitude pulmonary edema, hape. Quote, having stayed there till the third month of winter,

Fa Hien and the two others, preceding southwards, cross the little snowy mountains. On them the snow lies accumulated both winter and summer. On the north side of the mountains, in the shade, they suddenly encountered a cold wind, which made them shiver and become unable to speak. Huai King could not go any farther. A white froth came from his mouth, and he said to Fa Hien,

I cannot live any longer. Do you immediately go away that we do not all die here? And with these words, he died. End quote. Gosh. Yeah. But the frothy mouth could be. Can't breathe.

Yeah. We have to jump ahead quite a bit in time to about the 1500s before we find more mentions of altitude sickness, beginning with those given by the Jesuit priest, Father Joseph de Acosta, who described the headache, nausea, and difficulty breathing that appeared when he was at high altitudes in the Peruvian Andes. And he wasn't the only Jesuit priest who noticed these effects. Shortly after, Father Alonzo de Ovali wrote in the early 1600s that, quote, When we come to ascend the highest point of the mountain, we feel an air so piercing and subtle that it is with much difficulty we can breathe, which obliges us to fetch our breath quick and strong and to open our mouths wider than necessary. I mean, yeah. These various descriptions of altitude sickness clearly demonstrate.

that yes, people noticed the effects of altitude, and some even went as far as to explain, in vague terms anyway, why this thin air or subtle air made you feel this way. But to them, the air was thin because it didn't have much moisture. It was dry. When did thin air come to mean what it does today? In other words, when did people discover atmospheric pressure and oxygen? As it turns out at very different times. Let's start with the discovery of atmospheric pressure, because if you want to know what's in the atmosphere, like oxygen, you first have to know that the atmosphere exists, and you have to understand how it behaves. Like today, if you tune into a weather forecast, you may hear something about a low pressure or a high pressure system, like a low

pressure system is moving into the four corners region today, bringing with it gusty winds, hail frequent lightning and heavy rainfall. And that forecast probably wouldn't even register or make you do a double take unless your car was out in the open and you're like, oh my God, hail, what am I going to do? But it would make Galileo, for instance, do a double take as well as many other scientists of the early 17th century because they did not believe that air weighed anything or exerted any pressure. We know today, of course, that it does, that atmospheric pressure can be thought of as how much the air weighs or is pressing down on you, and that things like temperature and weather and altitude can affect this pressure. For instance, when you go closer to sea level, that air presses

down on you more and more, and as you ascend, it presses down less and less. And we know these things today about atmospheric pressure in large part thanks to one of Galileo's students, Evangelista Torricelli, who invented the first barometer, which is a tool, of course, to measure the level of atmospheric pressure. I love this. I am going to attempt to explain what Torricelli's barometer looked like and how it worked so that we can picture how air pressure changes, like how you can see that happening. Okay. Okay. Imagine a test tube, right? A long test tube. One end is open.

Fill it with a liquid. Let's go with mercury. Okay. And then imagine a little dish that you also fill with mercury. You're going to plug the open end of that test tube with your thumb, right? Okay. And then you're going to flip it over so that the plugged end is in the dish of mercury. By the way, don't try this at home. This is, don't do this. and it's standing upright. Okay. Then you're going to quickly remove your thumb plug, trying to let like no air in, right? So it's already under the mercury level.

Right. And when that happens, a little headspace will appear at the top of the test tube as the atmospheric pressure outside of the tube equalizes with the pressure inside. Right? So now you have this upside down test tube that contains mercury with a little bit of headspace in this dish that also has mercury level, right?

Did I, sorry, did I fill the test tube, like completely, or was like half full or like? Completely. Completely full. Okay, okay, cool, cool. And so right now, everything, all the pressures have equalized. The air is pressing down on the mercury in that dish to keep it at that level. If the air pressure increases, like let's say you go below sea level, the air will press down more on the in the dish, forcing the level in the tube to climb a bit higher. And if air pressure decreases,

maybe because you went up in altitude, then air will press down on the mercury in the dish less, allowing the outside level of mercury to rise and the level of mercury in the test tube to drop. So there's more headspace. Okay. I think I think I'm there. Okay. Okay. Because you're pushing down on the dish if you're going down if your pressure's increasing you're pushing more on that so that's going to push up on the mercury in the tube because it's they're connected in there and then the opposite's going to happen if you release that pressure then that's going to drop because then yeah i got it yeah isn't that cool yeah yeah so that was torricelli's barometer okay and this is a really remarkable device because with it, he showed that the air around us does exert pressure and that that pressure can change.

What may, the part that gets me is like, I can follow your logic of how he got there, but like, why did he do that? Why did he do in the first place? What made him think of doing that thing in the first place? And was he trying, was that what he was trying to show? Yes. Okay. Yeah. So he was trying to show that I think it was sort of like Galileo and others believed that the air exerted no pressure. But I think it was kind of beginning to be more of a contentious issue. Okay. And I can't remember the exact sequence of events or how I read it. But yeah, he just decided to test this out. How what an, like, how does your brain think of that before it's ever been done? I just love that. This is why I, loved this history so much because there's so much more of that in here. Torricelli also went so far as to suggest that the air on top of a

mountain weighed less and thus exerted less pressure than air at sea level. But he didn't demonstrate it with his barometer. That honor would fall to Blaze Pascal, Child Prodigy, philosopher, mathematician,

all around pretty famous dude. You've probably heard his name before. He's a year. He's a unit of measure. Uh-huh. There you go. So is Toricelli. Tor.

Oh. Yeah. Tor. Oh, Tor. Oh. But it wasn't actually blazed Pascal that would do it. It was his brother-in-law that would physically carry the barometer up the hill because Pascal was not in great health and he asked him to do it and report back. Oh, cute.

Well, when brother-in-law came back down the hill, he was super pumped to tell Pascal that, yes, indeed, the liquid dropped. And while this result was somewhat expected, this ground-truthing of the concept was a really exciting development, and it allowed Pascal to extend the logic about altitude and atmospheric pressure to suggest that the human body and pressure throughout the body in blood, tissues, etc., is also subject to atmospheric pressure changes, such as those you may experience if you go up in altitude. I love it. But just like Torricelli, Pascal left the experimental demonstration of this concept to others. Okay. At this point in the story, the mid-1600s or so, we're slowly building our understanding of how the atmosphere works, how it exerts pressure, and how that pressure changes based on things like temperature or altitude. But how do we relate this to the human body in like a demonstrable way? or any vertebrates body, really.

For that, we'll need a couple of Roberts, Boyle and Hook. Oh, mm-hmm. You may remember me mentioning some of Robert Boyle's experiments with air pressure and vacuums on animals in the 1670s, during our Ben's episode. Yeah, Boil's Law. Like, remember the bubble in the viper's eye? Mm-hmm.

It's like the first observation of decompression sickness. Well, it turns out that Boyle and Hook, they worked together a lot, so a belated apology to Hook for leaving him out of the Ben's episode. This pair did many more experiments using an air pump to investigate animals' responses to air pressure, such as testing how long animals could survive at different pressures, clearly demonstrating that at lower pressures, survival was shortened. Hook didn't stop with animal experimentation, however. He also devised a decompression chamber that humans could sit in to experience,

the effects of low pressure, testing it out, of course, on himself. He sat in his chamber for about 15 minutes at a pressure of about 570 tour or the equivalent of 2,400 meters, 7,800 feet, experienced a little bit of hearing loss and the candle he brought in with him extinguished long before time was up. No fresh air was being pumped in, by the way. The why of this, why survival was shorter at lower air pressures, why a candle would extinguish, why low air pressure led to certain symptoms, this why was still a big unanswered question, one that hook and boil would begin to scratch the surface of with their experiments on animal respiration. Because remember, at this point, no one knew what precisely the lungs did or what oxygen was.

Right, right. And I just want to pause and say how amazing it is that so many things are fitting together in terms of other topics we've talked about on the podcast before. Like I also mentioned Hook during our RSV episode when I talked about the development of artificial respiration. Oh, yeah. And his experiments on this subject would prove to be key to getting at this question of why. This period, during which Hook and Boyle were active in their research, followed close on the heels of a time when anatomical dissections of both animals and humans had greatly increased in popularity, being seen as not as sacrilegious as they had been in the past. These dissections and the beautifully illustrated anatomy books that were created by people like Andreas Fasilius encouraged physicians and scientists to link form.

form with function. We can draw the circulatory system, the major arteries and veins, the ventricles of the heart, but how did the heart pump blood? What role did the lungs play in the circulation of blood? Obviously, animals needed to breathe air using their lungs to stay alive, which Hook demonstrated with his dog experiment that I mentioned in the RSV episode, where he used those bellows through a cut in the dog's lungs, yeah. But how did the lungs do this? And why did all the blood pass through the lungs? Was it to cool the blood down, which was Galen's thought that still predominated during this time?

Or was it something else in the air that was essential for survival? Clearly, the lungs did something. Hook's colleague Richard Lower performed an experiment in 1669, where he compared the blood that had passed through the lungs with fresh air. It's like the lungs had just had fresh air. Okay. With venous blood. And noticed a stark difference in color. With the freshly ventilated blood being bright red and the venous blood a much darker red. What this color difference meant wasn't clear, but it did show that when blood came into contact with fresh air in the lungs, something changed.

And around the same time, Malpigy shed light on that lung blood interface through his descriptions, the first, of the alveoli and the pulmonary capillaries that linked the arteries and veins, descriptions that were made possible due to the increasing popularity, availability, and technological advancements of the microscope. Oh my gosh, it all comes full circle. It all comes full of circle. So now people were able to make the connection that fresh air inhaled through the lungs changes the blood through these structures that Mao Piggy described. Wow. But what about that fresh air was so important? Was it the air as a whole?

Or was it a particular component of that fresh air? John Mayow, a contemporary of hook and boil, began to suspect that it was the latter. that air was not uniform but made up of at least two distinct substances, one that was involved in combustion and respiration, and one that was not. He set out to test his hypothesis with a pretty cool experiment in my opinion, so I want to describe it here. First, he filled a shallow dish with water. Okay. Think of like a dog water bowl. Okay. Then he put a taper candle standing upright in that water, lit it, and then put a glass bell over it. Okay. Yep.

With the open end extending down into the water and resting on the bottom of the dish, effectively sealing the bell off along with the candle inside of it. Right. He observed that as the candle burned, the water level inside the bell rose, which suggested to him that the flame was consuming some part of the air, which the water came in to fill. and when that portion of air was used up, the flame went out, which it did. Oh, my goodness.

Very cool. He then replicated this experiment, but instead of a candle, he put a little mouse alive on a stool and covered it with a glass bell. Again, he saw that the water level inside the bell rose as the animal breathed. Stop it. And that as a certain point, all of the respiration. an air component was used up and the animal died. I, I, this is very cool. I mean, not for the mouse.

No, I know, I know. But just to think of the, these things, these are like principles, major principles. Right. That are being uncovered through like beautiful experiments that. I feel like this is something that maybe they like offhandedly mentioned during like a chemistry or a physics class at some point, but it was like in the middle of 16 different equations. And I was like, why do I have to learn this? But now it's like, without the equations, it's so cool. And that's a lesson for life, everyone.

These simple experiments by Mayo were groundbreaking for a couple of reasons. One was that they showed that air was made up of at least two different components. And that the second was that one of those components was crucial for both combustion as well as animal respiration. And like, did he assume that this must be the same component? Because that's also an interesting conclusion, right? Why combustion and respiration? Right. So he thought that there were two components of air, like only two components, one that was involved in, like one that was usable and one that was more inert, I guess. Okay. Yeah. And that was something that hook and boil hadn't picked up on. But I want to read this quote from Levoisier from about 100 years later.

Oh, okay. Quote, respiration is nothing but a slow combustion of carbon and hydrogen, similar in all respects to that of a lamp or a lighted candle. And from this point of view, animals which breathe are really combustible substances burning and consuming themselves. I love it. It's beautiful. Yeah. Okay. And we'll get back to LaVoisia in a second.

But also, Mayo didn't stop there with these experiments. He went on to suggest that this component of air, the one that's involved in respiration and combustion, is taken up by the lungs and passed into blood, where it is involved in heat production and muscle movement, which he pointed out was why breathing increases during exercise. since you need more of this substance in the air to move. Amazing. All right, so we've covered a lot of ground. So let's take stock briefly of what we've learned so far.

Yeah. We learned that the atmosphere exerts pressure, pressure that can be measured and that can change based on several different factors, including altitude. Okay. We've learned that air is not just one homogenous substance, that it is actually made up of several different components, at least one of which is necessary to sustain life and a candle flame, through some process involving respiration via lungs and the exchange of Venus and arterial blood in the lungs.

Okay. And we learned all of that over the course of just a few decades in the 17th century. So now we're still in the late 1600s still? Roughly. Now we're probably going mostly into the early to mid-18th century. 17-Hundredths, yeah. 17-100s. Okay, cool, cool, cool.

And I really kind of feel that, like, at this point, the discovery of oxygen itself, as one of those components or the naming of it, seems almost anticlimactic. What doesn't help is that there seems to be a good deal of contention over who gets priority for the discovery. As far as I could gather, there are four contenders for the title. Joseph Priestley, Carl Schill, Henry Cavendish, and Antoine Lavoisier. And I'm not going to go into how each of them, quote-unquote, discovered oxygen or the contribution they made. But in general, all of these discoveries involved the burning of an oxide of some sort in a sealed chamber and the realization that the released gas from that burning oxide could sustain life longer than ordinary air in the same type of chamber. Okay. Yeah. These experiments also help to lay the groundwork for describing the properties of other components of air besides oxygen, including carbon dioxide and nitrogen. So Lavoisier, the person who gets credit not so much for the priority, but the most impactful early research done on oxygen, in 1771, described these gases role in respiration as such, quote, eminently respirable air, which he later called oxygen, that enters the lungs, leaves it in the form of chalky aeroform acids, carbon dioxide, in almost equal volume.

Respiration acts only on the portion of pure air that is eminently respirable. The excess, that is, its mephitic portion, nitrogen, is a purely passive medium, which enters and leaves the lung without change or alteration. The respirable portion of air has the property to combine with blood and its combination results in its red color. At this point, in the story, I wouldn't blame you if you asked, but what about altitude sickness? Isn't that what the episode is about? I honestly, I'm enjoying this so much that, like, good. Well, if you listeners out there have been waiting for some mention of altitude sickness, in the history section, your long weight is almost over, and I appreciate your patience.

I wanted to go into how these connections were made between the atmosphere and altitude and respiration and oxygen, because they are fundamental to understanding so many things, including the effects that altitude has on our bodies, something that people were about to experience in ways they never had before. Oh, because, because balloons. Balloons, though. I know. Well, think about it.

I would never have guessed balloons, even if I thought about it. I don't often think about balloons. Well, you're going up super high, super fast. I know, but like, I forget that balloons are a thing that people decided to jump in at some point. You know, like, who, why? I think they still do. I think there are many people that still do what I do. I would love actually to go and let a lot air balloon. It's on my list, but still.

I know, I know. I did not expect it either, but I was pleasantly surprised. So as Lavoisier was characterizing these gases that are involved in respiration, other scientists were seeing how they could turn this new information about these and other gases into application, especially in the context of controlled combustion. perhaps using combustion to power some sort of vehicle. Say a balloon that could travel long distances, both across the landscape as well as vertically. Say a balloon. Say a balloon.

People had for hundreds of years, like I've said now a thousand times, climbed mountains or crossed mountain passes or lived at high altitudes. And many people, most people who experience those things, or lived at altitude, recognized and noted the signs and symptoms of being at high altitude. But these, at least in the written literature, often tended to be isolated descriptions and didn't necessarily lend themselves to systematic study, which was the opportunity that hot air balloons provided, along with being able to see the effects of high altitude, namely acute and extreme hypoxia, separate from the physical exertion of climbing a mountain with no time for acclamation. Yeah, that's really interesting.

Yeah. These early hot air balloonists were reaching heights of 6,000, 7,000, even 9,000 meters. Oh, my. So that's 9,000 meters is 29,500 feet, which is taller than Everest. That's like, don't go there. Don't. No. Don't do it.

Yeah. And they were doing this within a matter of minutes. Yeah. And so of course they noticed that as they ascended, breathing became more and more difficult. Their heart beat faster and faster, and they became confused and tired, often hit with this massive headache. And even though they could recognize that altitude had this effect, they weren't sure how. And had yet to make the link that as air pressure changed, so did pressure in blood and tissues. Experiments in decompression chambers, mainly by Paul Bairt, who will meet in a bit, had shown that supplemental oxygen could be helpful for keeping symptoms at bay at higher altitudes, but only if you use it.

So in the first-hand account that I read, the people in that balloon were carrying oxygen, but not enough of it, and they didn't use it until it was too late. So he talked about how he was, like, grabbing for the oxygen but couldn't do it. Yeah. But while these balloon excursions demonstrated the potentially deadly effects of rapid ascent to extreme altitude, they're not quite the same as altitude sickness or acute mountain sickness. But don't fret. Because as balloons were getting more popular, so was mountaineering, which had been popular for hundreds of years. But the sport underwent a big boom during the period of widespread colonization by European nations, often pleasantly called something like. the golden age of exploration, particularly during the mid-1700s and into the 1800s. Naturalist with an interest in mountaineering, like Alexander von Humboldt, or mountaineers with an interest in science, like Edward Wimper, set their sights on various mountain peaks, the Matterhorn, Chimborazo, Mont Blanc, etc. And as they learned how to set a route or which gear was best,

they also learned to recognize the signs and symptoms of mountain sickness, and they wrote about their experiences. And so at this point in the story, I should probably introduce the quote-unquote father of modern high-altitude physiology and medicine, Paul Baird. When Baird enters the picture around the 1860s, 1870s or so, what we get is a switch from the largely anecdotal reports of the effects of altitude from mountaineers and balloonists, to a systematic study analyzing what was happening to your body physiologically when you go up in altitude. And with the patronage of a Parisian physician, Denise Giordine, who also had an interest in high altitude medicine, Barrett conducted a series of experiments where he put animals in hyperic chambers, which simulated the low pressure of high altitude. He then played around with pressure levels until the animals became sick or died.

And then he measured the amount of oxygen in their blood. What he found was that illness or death always occurred at a certain level of blood oxygen. But even more than that, he repeated this experiment where he kept the air pressure at sea level, but he lowered the overall oxygen concentration in the air. Again, he played around with oxygen concentrations in the air and watched for when the animals got sick or died, and then measured their blood oxygen. He found that regardless of whether he lowered the pressure or lowered the oxygen concentration, the animals got sick or died when their blood oxygen hit a certain point.

Basically, he showed that it mostly came down to oxygen. Yeah. He also plotted the first oxygen dissociation curves. Oh, that's cool. Yeah. Love those. This finding was important, both because it filled in a piece of the conceptual puzzle of high-altitude physiology, and also because it provided a relatively straightforward way to treat the negative health effects of high altitude,

more oxygen, whether by descending or through use of supplemental oxygen. Although whether supplemental oxygen was actually helpful was under debate for a surprising number of decades after this. This also raised the question of whether humans could get used to high altitudes and compensate for the lower oxygen in some way if they spent enough time up there. And like I said many times, people did and do live at a high altitude in cities such as La Paz in Bolivia, which is at a whopping 3,600 meters or nearly 12,000 feet in elevation. Wow. Yeah. Barrett speculated that people and other. animals who had sustained exposure to high altitude may produce more red blood cells for increased

oxygen absorption, which was later proven correct. And after Barrett's extensive research into high altitude physiology, the field really kind of opened up in the last couple of decades of the 1800s, with high altitude field stations established and expeditions organized to remote high altitude locations. These stations also served as home bases where people could study other disciplines such as astronomy, physics, and glaciology. And in some places, like Pikes Peak in Colorado, which is at 4,300 meters or 14,100 feet, or La Aroya in Peru, which reached an altitude of 4,800 meters or 15,700 feet, railways were constructed to these sites so that the general public could also see what things were like above the clouds or so people could mine. Side note, La Arroyo might sound vaguely familiar to you

because I've mentioned it on the podcast before. In our Bartonella episode, I talked about how at least, I know, cast your mind back. Right. But in that episode, I talked about how at least 4,000 people died while working on the railroad to connect Lima to La Arroya. Oh, yeah. This same railroad. And these 4,000 or so people died from Bartonella Basiliformis, aka Carion's disease. Wow. Isn't that connections?

There's so many, Aaron. I love that. By the early 20th century, scientists had made tremendous strides in understanding the relationship between altitude, oxygen, and health. But there was still a ton of details to be figured out, like how mechanistic. oxygen is used and how it acts in various tissues as well as the steps involved in cellular respiration. That, however, don't worry, is a topic for another day. I was like, oh gosh. And instead, I want to close out this history section by talking about how the clinical picture

of acute and chronic high altitude sickness and complications was filled in over the 20th century. This is the last time I'll say it, but it bears repeating that not only have people lived at high altitude for tens of hundreds of thousands of years, but they've also recognized the negative health consequences of high altitude. And that's evidenced by the fact that there are many different local and regional names for altitude sickness. One of these was picked up by researcher Thomas Holmes Ravenhill, who published a paper in 1913 titled, quote, some experiences of mountain sickness in the Andes. End quote. In this paper, he classified mountain sickness into three primary forms. Puna of a normal type.

Puna was the word for mountain sickness that people in northern Chile used, where Ravenhill carried out his studies. And that is what we would call today acute mountain sickness. And then two divergent types. Puna of a cardiac type, high altitude pulmonary edema. And number two, Puna of a nervous. type, high-altitude cerebral edema. Yeah. Ravenhill's work was largely overlooked, though, until the 1960s when it was quote-unquote

rediscovered. But in the meantime, a good deal of research on altitude sickness and severe outcomes was conducted primarily by South American researchers, including Launcio, Le Zaraga, Morla, who described the first cases of Hape in Peru. In all of their publications, these researchers noted how quickly the affected person recovered after descending to a lower altitude, which is a useful thing to know. But their work was not really acknowledged, likely because of the bias against scientific publications, not written in English. And this is notable when high altitude pulmonary

edema was quote unquote rediscovered in the U.S. by Charles Houston in his 1960 New England Journal of Medicine paper, quote, acute pulmonary edema of high. altitude. In this paper, he described a 21-year-old skier in Colorado who developed, quote, severe dyspnea, weakness, and cough, and had to be evacuated. At the hospital, he was observed to have a bluish tint to his skin, difficulty breathing, and rattling in the lungs, but no evidence of heart disease. Houston suggested that, quote, both acute and chronic anoxia may cause striking elevation of the pulmonary artery pressure, failure of the left ventricle and pulmonary edema. Since exercise in severe cold, together with anoxia, may have cumulative effects, this

explanation appears to be the most probable. You may have caught that in that description, Houston also mentioned chronic anoxia, which had been an area of interest for several researchers for decades, and that is the physiological changes that occur when spending time at high altitude, as well as comparing populations of humans and other animals that had spent generations at high altitude with their lowland counterparts. One of the most prominent researchers in this area was Carlos Monge Madrano, who in the mid-1900s characterized chronic mountain sickness, sometimes called Monhe's disease. By this period, the field of high altitude physiology had grown immensely, helped along by

military investigations during World War II into how pilots performed at certain altitudes, when to deploy oxygen, etc. By veterinary studies, exploring how to breed cattle that thrived at altitude, and it was also helped along by medical researchers wanting to know how low oxygen levels from other things besides altitude, like decreased lung function, could be treated. And also by ecologists and evolutionary biologists who wanted to tease apart questions like, do all mammals acclimate to altitude in the same way? What is the genetic basis of high altitude adaptation in humans? Are there ways that mammals evolved to live at high altitude predictable? And so many more. So many. So many. And here today,

to answer some of these questions is a very special guest, Dr. Jonathan Vallata, assistant professor at the University of Denver and my partner. We'll take a quick break here and then hear what John has to say about the evolutionary basis of high altitude adaptation. Oh, it's going to be so good. I'm really excited. Hi, I'm John Vallata. I'm an assistant professor of biology at the University of Denver. My lab studies evolutionary biology and physiology of vertebrates. So we're interested in how animals have adapted to their environment at the physiological and genetic levels. One of the big things we're working on right now is adaptation to low oxygen and cold in a high-altitude rodent. That's the North American deer mouse.

But we also study the genetics and the physiology of ion and water balance evolution in species of fish. I love it. I'm so excited. It's really funny to say thank you so much for joining us today because we literally live together. I am looking at a Skype screen that's the two of them, but they're actually just sitting. right next to each other in the same room. It's fantastic. Also, I love that we are probably still two of the only people left in the world that use Skype. Yes.

I think we have a little bit of superstition in terms of like, let's not mess this up. We know that this works. There are Gen Ziers that don't know what Skype is. That's actually true. Well, then. All right. Well, let's actually get into why we have John. here today, not just to talk about the pros and cons of Skype. So, and that is evolutionary adaptation to high altitude. One of the aspects that I was thinking about, though, is just how difficult life at high altitude seems, right? Everything is cold. Everything is cold. There's no oxygen.

The sun is trying to kill you with high UV. You're dehydrated all the time. Why live at high altitude. Are there any benefits for animals living at high altitudes? That was a question for me? Yeah. Okay. Oh, you forgot one, which is that food is scarce, obviously. Oh, yeah. So, yeah, the challenges of high altitude, obviously are, you know, hyperic hypoxia, as Aaron mentioned. And so a few animals really can and do live there. And so that means that there's just fewer predators and competitors. So basically, if you can deal with the environmental challenges, and it's a fairly good place to live. So North American deer mice, for example, are really only rodent that lives at high altitude in the Rockies above tree line,

and there are very few larger predators there. At lower altitudes, in the forests where they also live, they're hunted by, you know, owls, foxes, pine martins. So lots of things like to eat them. And so at high altitude, they're probably relatively safe. They're also safe from other competitors, other rodents that, you know, live in very similar environments and eat similar food. So in terms of environmental conditions, though, it's really challenging. So, yeah, like you said, if you can evolve to deal with those environmental challenges, then you're relatively safe from other things in the world that are trying to kill you. And at high altitude, we do see some predators occasionally, like we've seen Pine Martins hunt deer mice at the summit of some of the mountains and the Rockies,

but that's probably relatively rare, and they're probably not there living there or there very often, but just coming up and then going back down. It's like a nice easy snack. A little day trip up to the summit for the view and a snack. So what is the highest altitude that a mammal has been found at? And also, what about birds? Like, do they still cruise around up there?

Yeah. Yeah, so recently, like in 2020, there was a new record of the highest dwelling mammal by J. Stores and colleagues, and it's a mouse called a yellow-rumped leaf-eared mouse. So this is philotis, Anthropagis,rupestris, is the scientific name. I had to practice that one. So actually, it was captured by hand on the summit of a volcano between Chile and Argentina. It's Jujiazaco is the name of the volcano. So that's 6,700 meters. So it's about 21,000 feet. So it's, you know, some of the highest peaks in the world do have animals. There are other high altitude dwelling mammals.

Like there's credible records of PICA, which are sort of like a rabbit, closely related to rabbits, at or around, I guess, 6,000 meters on Everest. And so, yeah, that's pretty much as high as we've ever found mammal. And again, the leaf-eared mouse at 6,700 meters is the record. So it's not like these mice are day visitors up to high altitude. Their home range is very small. So like for a North American deer mouse, the maximum home range is just like an acre or so. And so they're living up there, which is incredible because, again, there's not much to eat. Obviously, the oxygen is very low and it's very cold all the time.

So you mentioned birds. So birds are interesting because they can fly, obviously. And so birds can fly as high or higher than the tallest summits in the world. So there's a couple of birds that I think are good examples. So Nate Center and colleagues have tracked a migratory shorebird called the Bulls. black-tailed godwit at 5,000 to 6,000 meters. And the amazing thing about this is that they're not flying over anything in particular, like no land structures. They're just flying that high to take advantage of what they think are better air temperatures and solar radiation that make for more

efficient flying. There are animals, there are birds that fly over the Himalaya, so that have been seen flying at 7,000 meters. But they sort of hug the land. And so for them, They are more so flying over land structures, whereas the godwits are flying to take advantage of that better air. One of the last things I'll say is that they're exercising this whole time. Birds aren't just cruising in altitude, so they are flying, and flight is an incredibly energetic activity. And birds do have very efficient breathing, which is one of the things that helps them. That is amazing that they're flying that high and not just like holding their breath to go up for a little. little bit and then coming back down like what yeah that is really cool to think about that how much

work they're doing at that altitude one of the questions that i asked erin earlier in the biology section and she said i don't know but we should ask john this or maybe we both said that was about whether physiological responses to altitude are proportional to the altitude so like are you producing twice as many red blood cells as you are if you go up twice as high in altitude. So. Yeah. I mean, generally, I'd say yes. I don't think there seems to be really a threshold.

And the climatization changes are mostly linear. And I mean, at least the work that I'm familiar with is in deer mice. So there's been some work by colleagues of mine, Katie Ivy and Graham Scott that have shown that breathing, for example, increases pretty linearly with decreasing partial pressures of oxygen. And then we've shown that red blood cells and hemoglobin concentrations increase steadily with decreasing pressure as well. So there's not a lot of great data, I guess I would say. But in general, I think it's pretty clear that, yes, as you move up in altitude, the acclimatization responses are proportional to that decrease in partial pressure. Cool. There you go.

Oh, wow. I love that it was just like a yes. Yes. Moving on. I guess I could have just said yes. So we talked about during this episode that a lot of humans have lived at high altitudes, like maybe alongside these deer mice, for example, for hundreds of thousands of years. So do we see any genetic adaptations to this, both in humans and in these animals?

And what's the difference between a climatization when we talk about that and adaptation. Yeah, so I guess I do want to preface this by saying that human evolution is not my field, but I would like to summarize here some of the really cool work that's been done by biologists and anthropologists. A lot of the work that I think I can talk about knowledgeably is by Cynthia Bell, who's an anthropologist at Case Western Reserve. And you asked about acclimatization and adaptation. So acclimatization is like all of those changes that you talked about, Aaron, so red blood cell, production, changes in breathing, those things that happen in the short term or within the lifetime of an individual that sort of give us more oxygen when we need it. But adaptation, of course,

is an evolutionary process. It's where we see any change, but in this case, physiological change that occurs over generations because those changes have some sort of advantage. And so all those changes are based on changes in our genes. To answer your question, humans do show adaptation to high altitude, and it's really interesting. And so I think the best way to look at it is to take two examples of two mountainous regions in the world where people live and where adaptations to altitude have arisen. And so these regions are the Andes in South America and the Tibetan plateau in the Himalaya. And so there are establishments, towns and cities, in some cases, really big cities over 4,000 meters above sea level, so that's, you know, above 14,000 feet.

And we see that there are genetic adaptations to high altitude that we assume come from living there over many generations. And so, Aaron, you mentioned chronic mountain sickness, and that's the association of chronic mountain sickness with polysathemia, which is overproduction of red blood cells. And then I think you mentioned hypertension, which is high blood pressure. And so the incidence of chronic mountain sickness in some South American high altitude cities in Bolivia and Peru can be up to 15 plus percent in one estimate that I saw, whereas the incidence of chronic mountain sickness on the Tibetan Plateau is much lower, about 1% or less. And this is from one estimate from about 2016. And so on Tibetan Plateau is, I think, higher on average, but most of

the cities in which people live are probably similar. Some of the adaptations that we see in the Andes are really interesting, and they generally are larger chest circumference and a greater total lung volume. And so this is likely an adaptation to just simply get more air into the lungs. Other adaptations in the region include higher on average hemoglobin and red blood cell concentrations. And I think this is intuitive based on what you said, Aaron, about acclimatization, because more red blood cells improves oxygenation in the blood. And so sort of to that end, there has have been studies that have shown that increased hemoglobin and red blood cells is associated with higher arterial oxygen content. So they have more oxygen in their blood, actually more than when

compared to some people at sea level. And the thing about this is that it may have a cost. And this would be sort of consistent with higher rates of chronic mountain sickness because more red blood cells sort of changes the content of your blood. It makes it thicker. And that could put a strain on your heart, which is a muscle, as it's pumping a more viscous fluid. And so if you couple that with other changes that you mentioned, like pulmonary vasoconstriction, which again is just the constriction of the vessels in your lungs, that all puts a strain on the right part of the heart, especially, as it pumps a thick blood through a constricted pulmonary vasculature.

And so this could lead to an increased incidence of hypertension. And not humans, but I could talk about deer mice a little bit, which is something I'm always finding myself talking about. They also have this increase in blood viscosity and vasoconstriction. And this leads to an increase in the actual size of the right ventricle of the heart. And it leads to an increase in the pressure in the right ventricle, which can contribute to things like heart failure. So yeah, that's some of the adaptations that are happening in the Andes. On the Tibetan plateau, we see slightly different adaptations. And this is really fascinating.

Instead of lots of red blood cells, which would increase oxygen-carrying capacity, studies find that the concentration of red blood cells are actually the same as someone who is living at sea level. And this is very different because if you or I were to go to the Tibetan Plateau, we would, as Aaron mentioned, really increase the number of red blood cells to get more hemoglobin. So this lower concentration of red blood cells should be disadvantageous in terms of blood oxygen level, but actually advantageous in terms of blood viscosity. Right? And so studies have shown that on average there is lower blood oxygen content. in this region compared to those that live at sea level. And so to make up for this possible cost, other studies have shown higher levels of nitrous oxide in the lungs. And so this is a chemical that is

produced by the body. It's a vasodilator. And so it keeps those lung vessels open. And that allows for better exchange of oxygen between lungs and blood. And this likely lowers the potential for hypertension. And so according to one study I read, the pressure in the arteries of the lungs is 28% lower in the Tibetan region compared to those in the Andes. That is so cool. So cool. So, so cool. It blows my mind, honestly. Yeah. Oh, man. So now that my mind is already blown about humans, I know that there's more to blow my mind about animals. So. That was my really terrible segue into this next question. No, it was good. I loved it.

Thank you. Which is, do we see these same adaptations to high altitude in other mammals besides humans? And I know you talked a little bit about deer mice. But I guess in general, do mammals evolve to live at high altitude in predictable ways? Yeah. I mean, yes and no. It all has to hinge on oxygen transport. where in terms of the physiology of an animal that happens does depend on the animal.

And so I can talk about a lot of examples of high-altitude deer mice, some of the similarities and some of the differences. So deer mice also reduce the amount of hemoglobin and red blood cell production when they're at altitude. So that's similar to the Tibetan story that I explained earlier. And they also have reduced pulmonary arterial pressure. So there have been studies by some colleagues that I've mentioned that have shown that Highland deer mice also have more capillaries. And those capillaries supply more oxygen to their muscles, which is really, really important for a deer mouse, especially, because they need those muscles to produce heat in a really cold environment.

And they do that by one of the ways is by shivering. And that requires oxygen. I'm just imagining these poor little deer mice just shivering. in order to stay alive for thousands of years. Like, I'm the best shiverer? That's so sad. Yeah, there's really strong selection on what we would call thermogenesis, the production of heat metabolically.

And so I should really preface this by saying that deer mice are winter active. They really need this oxygen and they really need this shivering because they're active pretty much all year long. going off of that, there have been some other studies, some by Zach Chevron and his colleagues that show that high altitude deer mice are more effective at using fat as a fuel source during this shivering. And this is because fats are way higher in energy, but they do take a lot more oxygen to burn. So if you can figure out, if you're a deer mouse, you can figure out how to get more oxygen, then you can burn fat and shiver better. And there's lots of other ones too.

I mean, yeah, how much do you want? So there's a lot of animal species, birds and mammals mostly, that have evolved a hemoglobin that has a higher affinity for oxygen. Some birds and mammals have an evolutionary adaptation to just have intrinsically higher oxygen affinity. So this means they can pick up more oxygen. So in many hummingbirds, the higher the elevation that these hummingbirds live, the greater the hemoglobin oxygen affinity on average. This is true of deer mice, too.

Deer mice that live at high altitude have a higher hemoglobin oxygen affinity and it is a genetic change. And this change in affinity is caused by mutations in the hemoglobin gene. If I could riff at the genetic level for a little while, one of the things that we see

is that there's a lot of mutations in animals and a lot of different animals in a gene called E-PAS-1. And so this is a gene that codes for a protein, that's what genes do, that initiates the body's response to hypoxia. So it's a really important gene, call it a regulator. And all the things we talked about, like red blood cell production, changes to the vascular, these things at the genetic level are controlled by EPAS1. And so there are adaptive mutations at this gene that we find in high altitude animals, including deer mice, also wolves, sheep,

humans, birds, dogs, and even a snake. Why, how are snakes up that high? I didn't know that like reptiles could survive at high altitude. That's amazing. I have no idea. I mean, some of the sheep and the dog thing is kind of interesting because those are animals generally that people have brought to high altitude. And so their evolution at high altitude.

is more recent. And I think the really fascinating thing about E-PAS-1 is that this is, you know, this is all happening independently, right? These are very distantly related species of mammals, birds, and reptiles. And so clearly E-PAS-1, the mutation at E-PAS-1 has some sort of beneficial effect. We don't really know what that is. We have found that in deer mice, the mutation in E-pass 1 is associated with having a higher heart rate when you're exposed to hypoxia. So that should mean better pumping of oxygenated blood to tissues, but that's probably just one effect. And a lot more research needs to be done. I'll leave you with one final cool thing about animals, deer mice again.

And that's that there are some really interesting studies showing that low altitude mice, so mice that live at sea level, produce low birth weight offspring when they're exposed to high altitude. So they have offspring that weigh less than they do if they were to breed at sea level. We would call this fetal growth restriction. And so there's some cool work going on by Kate Wilsterman and her colleagues that have been finding that in high altitude deer mice. So these are mice that are adapted to high altitude. They are protected from fetal growth restriction. And that in part has to do with adaptations in the placenta that improve gas and nutrient exchange from mom to fetus.

That is amazing. It's absolutely fascinating. So you discovered like a million amazing high-altitude adaptations in like the shortest amount of time it was amazing. And we already talked about how difficult it is to live at high altitude. So I guess my question is do these high-altitude adaptations themselves, as cool as they are, do they come with a cost? And do we know what that cost is? Yeah, so I think, I already mentioned blood viscosity in the association with hypertension. And so one of the other cool ones, at least that we've seen in deer mice, is that,

so there is this genetic variant for hemoglobin that I mentioned that's more prevalent at high altitude and it helps with picking up more oxygen in the lungs. And so one of the interesting things is that in mice with those genetic variants, when they exercise at low altitude, they tend to do worse than mice without that high altitude gene. And this is presumably because having that variant does help with picking up oxygen, but it also holds on to it more tightly, and so it has trouble giving it up at the tissues during exercise.

So if you just stay at high altitude, you're fine, but there is like a trade-off there, and that is a cost. You can never go back to the beach. Exactly. I'll pass. We have one last question for you, and it's designed to make you feel like you're back in grad school taking your prelims. Oh, great. Apologies.

I just had a flashback. What do you think is the biggest unanswered question in your field? Right. So, I mean, there are a lot of them, obviously. But I think really the biggest thing is how. genes, how changes to genes lead to adaptations of physiology, that is something that we know very, very little about. So aside from the work from J. Stores that I mentioned on hemoglobin and some others, we don't really know about how genetic changes lead to physiological adaptations.

We know there are genetic changes. We know there are physiological adaptations. We know there are genes that have mutations that are likely involved in adaptations, but we don't know how those mutations change, how the gene works and how the animal works and all of that. So I think that is really one of the frontiers, at least in sort of the evolutionary biology of high altitude. Awesome. Done. Well, thank you so much, Dr. Vallata for coming on to chat with us about high altitude adaptations.

And if any of you listeners out there are curious about. John's work and want to learn more, check out his website on d.edu.edu or whatever, we'll link to it on our website. I don't know the exact. We don't have to have it memorized. It's valatalab.com. Oh, yeah, that's right. You have an old, your own lab website. And you're welcome for making the long trek down to our basement. Thank you so much, John, for coming all the way down to chat with us. Anytime, anytime. Genuinely, it was really great to have you, so we really appreciate it.

Well, it was my pleasure. I've been a long-time listener, but first-time caller. How long have you been holding that one in? I practice that one. Is there anything else that we need to cover before we do sources? Just in case anyone was really dying for this information, we don't have numbers on the epidemiology of acute mountain sickness or chronic mountain sickness. Every study that you read on the incidence of acute mountain sickness has vastly different numbers.

So that's why we just kind of skipped over that part. And I will link to a couple of papers about high altitude training for those of you who are maybe really into it, because that was something we didn't touch on. That's all I've got. Okay. Well, with that, sources? Sources. I'm just going to shout out one, basically, and that was a book called High Life, a history of high altitude physiology and medicine by John West. Oh, and also there was a great TED-Ed talk about how barometers work that I'll link to. I had a whole number of papers

on the physiology of acclimatization and the pathophysiology of AMS. I think one of my favorites was by Murdoch in 2010 in BMJ clinical evidence just called altitude sickness. But I will list all of the rest of them. John, did you want to cite any of your sources? Yeah. Can I give you all of my – there's like probably 20, 25 papers in here that I summarized all for you guys. We will post all 25 of those and all of our. as well on our website, this podcast will kill you.com. We certainly will. Oh, thank you also to Bloodmobile,

who provides the music for this episode and all of our episodes. Thank you to Liana Squalachi for our excellent audio mixing. Love it. Thank you to the exactly right network. And thanks to you, listeners, so many thank you. We're not even done yet. But we really appreciate you listening, and we hope you liked this really deep dive, high climb into high altitude. physiology and history. No comment. And as always, an extra thank you to our patrons. We can't express enough how much we appreciate your support.

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