Speaker 1: I come to the fatal hour, when we were about
Speaker 1: to be seized by the terrible influence of the atmospheric decompression.
Speaker 1: At seven thousand meters, we were all standing in the basket,
Speaker 1: civil numbed for a moment, has revived. Crochet Spinelli is
Speaker 1: motionless in front of me. Look, he says to me,
Speaker 1: how beautiful those serous clouds are. The sublime spectacle before
Speaker 1: our eyes was indeed beautiful. Towards seven thy five hundred meters,
Speaker 1: the numbness one experiences is extraordinary. The body and the
Speaker 1: mind weaken little by little, gradually, unconsciously, without one's knowledge.
Speaker 1: One does not suffer at all. On the contrary, one
Speaker 1: experiences inner joy, as if it were an effect of
Speaker 1: the inundating flood of light. One becomes indifferent. One no
Speaker 1: longer thinks of the perilous situation or of the danger.
Speaker 1: One rises and is happy to rise. Vertigo of lofty
Speaker 1: regions is not a vain word, but as far as
Speaker 1: I can judge by my personal impress rushians this vertigo
Speaker 1: appears at the last moment. It immediately precedes annihilation, sudden, unexpected, irresistible.
Speaker 2: Soon.
Speaker 1: I wanted to seize the oxygen tube, but could not
Speaker 1: raise my arm. My mind, however, was still very lucid.
Speaker 1: I was still looking at the barometer. My eyes were
Speaker 1: fixed on the needle, which soon reached the pressure number
Speaker 1: of two ninety, then two eighty, beyond which it passed.
Speaker 1: I wanted to cry out, we are at eight thousand meters,
Speaker 1: but my tongue was paralyzed. Suddenly I closed my eyes
Speaker 1: and fell inert, entirely losing consciousness. It was about one thirty.
Speaker 1: At about three thirty, I opened my eyes again. I
Speaker 1: felt numb, weak, but my mind was active. The balloon
Speaker 1: was descending with terrifying speed. Syville's face was black, his
Speaker 1: eyes dull, his mouth open and full of blood. Crochet's
Speaker 1: eyes were half shut and his mouth bloody. The shock
Speaker 1: as we struck the ground was extremely violent. It was
Speaker 1: four clock. As I set foot on the ground, I
Speaker 1: was seized by a feverish excitement and fainted. Growing livid,
Speaker 1: I thought I was going to join my friends in
Speaker 1: the other world. However, I recovered little by little. I
Speaker 1: went to my unhappy companions, who were already cold and rigid.
Speaker 1: I had their bodies sheltered in a neighboring barn. Sobs
Speaker 1: choked me.
Speaker 3: Uh what.
Speaker 1: Yeah, a fatal balloon flight.
Speaker 3: Wow, yeah, Aaron, what will you have to tell me
Speaker 3: what that's from?
Speaker 1: Okay, So that was an account by Tissandier of the
Speaker 1: fatal balloon ride of eighteen seventy five. He and his
Speaker 1: two companions went up to past eight thousand meters, which,
Speaker 1: by the way is like over twenty six thousand feet,
Speaker 1: and they all like lost consciousness, and then their balloon
Speaker 1: went out, they crashed, and two of the three died.
Speaker 3: That is horrific mm hmmm, and also makes me so
Speaker 3: intrigued in what the history of today's episode is going
Speaker 3: to be because it is nothing like what I expected.
Speaker 1: And wow, yeah, I didn't even like it. Didn't even
Speaker 1: realize that the balloon thing would be kind of a
Speaker 1: left turn or seem like a left turn. But it
Speaker 1: is surprisingly relevant.
Speaker 3: I cannot wait to hear all about it.
Speaker 1: Hi, I'm Aaron Welsh.
Speaker 3: And I'm Erin Almon Updyke, and.
Speaker 1: This is this podcast will kill You.
Speaker 3: And today we're taking a few left turns or a
Speaker 3: sense and decense. I don't know, I tried.
Speaker 1: I appreciate the effort.
Speaker 3: To talk about altitude and altitude sickness.
Speaker 1: Yeah, yeah, I am really excited for this, especially because
Speaker 1: before starting this I had no idea what the history
Speaker 1: was going to be, and it turned out to be
Speaker 1: I think one of my favorite episodes to put together.
Speaker 3: Ooh.
Speaker 1: Also, do you remember our very first episode this season
Speaker 1: are As and I told the history of ventilators. I
Speaker 1: said at some point in that episode, gosh, I would
Speaker 1: love to tell the story of oxygen someday. Get a
Speaker 1: little teaser, maybe.
Speaker 3: Can't wait.
Speaker 1: Very excited.
Speaker 3: Yeah, it's gonna be It's gonna be really fun. I
Speaker 3: know nothing about the history of this and only really
Speaker 3: knew prior to this what I learned in like various
Speaker 3: physiology classes, so it was really fun to research. And
Speaker 3: I'm it's just going to be a fun episode.
Speaker 1: It is, and it's going to be made extra fun
Speaker 1: by the presence of a very special guest who is
Speaker 1: near and dear to our hearts, especially yours, especially mine.
Speaker 1: And that's just another little teaser. And you'll hear more
Speaker 1: about this very special guest later in the episode when
Speaker 1: they will come on to discuss some of the evolutionary
Speaker 1: aspects and current research going into altitude sickness and high
Speaker 1: altitude adaptation.
Speaker 3: Oh, I can't wait. I'm really excited about it. We do, okay,
Speaker 3: but before that, it is definitely quarantining time.
Speaker 1: Is what are we drinking this week?
Speaker 3: We're drinking high and dry.
Speaker 1: We are. You know, it was really difficult to come
Speaker 1: up with a quarantini recipe. Everyone really was. We are struggling.
Speaker 3: This is not This is one of the hardest parts
Speaker 3: of this job. Honestly it is.
Speaker 1: It used to be one of the easiest, and now
Speaker 1: it's like just scrolling through pages and pages of our
Speaker 1: past quarantinies, like.
Speaker 3: How many different times can we use this one item?
Speaker 3: A lot?
Speaker 1: Yeah, So we wanted to make this a dry a
Speaker 1: cocktail as possible, so that means as little sugar as possible,
Speaker 1: and so in this which is essentially a modified Paloma,
Speaker 1: we have tequila, we have grapefruit juice, we have a
Speaker 1: little bit of blood orange juice, and we're topping it
Speaker 1: with an egg white foam, you know, for that aeration.
Speaker 1: Get it.
Speaker 3: That's so funny.
Speaker 1: We We will post the full recipe for the quarantiney
Speaker 1: as well as the non alcoholic plus see Burta on
Speaker 1: our website This podcast will Kill You dot com as
Speaker 1: well as on all of our social media channels.
Speaker 3: Our website, this podcast will kill You dot com. It's
Speaker 3: a really great website that has a lot of stuff
Speaker 3: on it, So you should go there and check it out.
Speaker 1: You should, you shouldn't. That's all that needs to be said.
Speaker 3: Any other business, Eric, you know, I don't think so okay, Well,
Speaker 3: I have lots of questions about the history of this,
Speaker 3: so let's start with, you know, the biology.
Speaker 1: Come on, I want to hear about the biology. Yeah,
Speaker 1: we'll take a quick break, and then you can answer
Speaker 1: all my thousands of questions about the biology of altitude sickness.
Speaker 4: We'll try we'll try.
Speaker 3: So to understand the kind of disordered states that can
Speaker 3: result from ascending to or existing at high altitudes, we
Speaker 3: first have to understand what the heck actually changes at
Speaker 3: high altitude and what our normal physiologic response is to
Speaker 3: these changes. So that's how we're going to kind of
Speaker 3: divide up this section of the episode. First, we're going
Speaker 3: to talk about the environmental variables that actually change when
Speaker 3: we go to out theode, and then we'll talk about
Speaker 3: what our typical physiologic response is to those environmental changes,
Speaker 3: both in like the short term and the medium to
Speaker 3: long term, and then.
Speaker 4: We'll talk about what happens when these changes maybe.
Speaker 3: Don't work that well or don't go as planned or
Speaker 3: something along those lines. And that's when we'll get into
Speaker 3: both acute as well as a little bit of detail
Speaker 3: on chronic mountain sickness in their various forms. Sounds excellent,
Speaker 3: And one thing I will say for those who are
Speaker 3: really into the physiology part of this is, I am
Speaker 3: going to do this with like a minimum of math. Okay,
Speaker 3: the math formulas turns out don't really translate well to
Speaker 3: like podcast audio format. Okay, so really yeah, p ones
Speaker 3: and vs. Okay, let's get into it. By far, the
Speaker 3: single greatest environmental change that we see with respect to
Speaker 3: increasing altitude is a decrease in the partial pressure of oxygen.
Speaker 3: What does this actually mean? So when we ascend either
Speaker 3: up a mountain or perhaps a balloon, the barometric pressure,
Speaker 3: that is the pressure that the atmosphere exerts on our
Speaker 3: bodies declines because the mass of atmosphere above us is
Speaker 3: literally less mass, and this decline in barometric pressure leads
Speaker 3: to a decline in the partial pressure that oxygen exerts,
Speaker 3: So the air at high altitudes is the same percentage
Speaker 3: of oxygen twenty one percent oxygen, as we talked about
Speaker 3: in our Benz episode last season.
Speaker 1: That's right, But.
Speaker 3: What you can think of it as is the density
Speaker 3: of those oxygen molecules is less, so per breath you're
Speaker 3: getting less dense oxygen molecules. And as we talked about
Speaker 3: in our Ben's episode, when we inhale air, which is
Speaker 3: twenty one percent oxygen, some amount of that oxygen in
Speaker 3: that breath travels down our lungs into our alveoli and
Speaker 3: has to diffuse across our alvoli into our bloodstream, into
Speaker 3: our capillaries. And the transfer of this oxygen into our
Speaker 3: blood stream is determined in part by its partial pressure gradient,
Speaker 3: by how much pressure it's exerting in our alveoli relative
Speaker 3: to our capillaries. So if this partial pressure declines, which
Speaker 3: we know it does as we ascend in altitude, that
Speaker 3: means that we are transferring less oxygen into our bloodstream.
Speaker 3: So in short, what we see is less density, less
Speaker 3: pressure of oxygen in the air, which leads directly to
Speaker 3: less oxygen making it into our bloodstream, which is called hypoxemia.
Speaker 3: Then what we see is less oxygen in our tissue choose,
Speaker 3: which is called hypoxia. Sometimes people use the terms hypoxemia
Speaker 3: and hypoxia interchangeably, they're technically different things. Anyways, icy you
Speaker 3: nerds will love that little titbit. Okay, But obviously in
Speaker 3: any case, this is not great because our cells and
Speaker 3: our tissues do rely on oxygen to make energy and
Speaker 3: to function. So luckily, our body has a lot of
Speaker 3: compensatory mechanisms that it uses when we ascend to altitude
Speaker 3: or in other words, when we are faced with what's
Speaker 3: often called hyperbaric hypoxymic or hyperbaric hypoxic situations that means
Speaker 3: low pressure, low oxygen situations. This process is known as acclimatization,
Speaker 3: and it has several steps that occur both in like
Speaker 3: a very short term and a longer period like days
Speaker 3: to week timeframe. Let's get into it so first, involuntarily,
Speaker 3: All of these are involuntary. We're not conscious of these
Speaker 3: things happening. But most quickly, the change that we see
Speaker 3: as we ascend an altitude is that we see an
Speaker 3: increase in ventilation. So basically, because of this drop in
Speaker 3: partial pressure, you have less oxygen diffusing into our capillaries
Speaker 3: and arteries. What happens then, is that this decrease in
Speaker 3: oxygen leads to the stimulation of chema receptors in our aorda,
Speaker 3: which comes off of our heart, as well as our
Speaker 3: carotid arteries that go up to our brain. There are
Speaker 3: receptors in these vessels whose job it is is to
Speaker 3: sense how much oxygen there is in our blood and
Speaker 3: then stimulate our brain to fluctuate the depth and the
Speaker 3: rate of our breathing.
Speaker 1: That is so cool.
Speaker 3: It's so cool because it is entirely involuntary. It's not
Speaker 3: like if you go up to altitude you'll sit there
Speaker 3: feeling like you need to take deep breaths. This is
Speaker 3: an involuntary response that's just happening. Yeah, it's called the
Speaker 3: hypoxic ventilatory response, and we'll get into that a little
Speaker 3: bit more later, but let's keep going because that's just
Speaker 3: the first of like a cascade of changes. So first
Speaker 3: we start breathing deeper and faster. What that does is
Speaker 3: it ends up lowering the amount of carbon dioxide in
Speaker 3: our alveoli. You can essentially think of it as we're
Speaker 3: breathing off extra carbon dioxide as we breathe like this,
Speaker 3: and that helps to increase the partial pressure of oxygen
Speaker 3: because they are inversely related in our ALVOLI.
Speaker 1: How are we doing that.
Speaker 3: That's just like a matter again of mathematics.
Speaker 1: Okay, just like properties of gases and behaviors of gases.
Speaker 3: Okay, yeah, So it's not like changing the concentrations, it's
Speaker 3: just changing the partial pressures. By blowing off more CO two,
Speaker 3: you have an increased pressure of oxygen. So what that
Speaker 3: does is allow our capillaries to continue extracting to maintain
Speaker 3: a steeper gradient for the diffusion of oxygen into our capillaries,
Speaker 3: which is what we need because there's less pressure of
Speaker 3: oxygen from the atmosphere itself. It's so cool, I know,
Speaker 3: I know, it keeps going, It keeps going. At the
Speaker 3: same time, this reduction in carbon dioxide that we see
Speaker 3: also leads to what we know of as a respiratory alkalosis,
Speaker 3: because carbon dioxide, as I'm pretty sure we talked a
Speaker 3: lot about in our Benz episode, in our bloodstream results
Speaker 3: in acidification, so's you can think of it as an acid.
Speaker 3: So if we're blowing off carbon dioxide now we have
Speaker 3: an increase in the pH of our blood, which is alkalosis.
Speaker 3: If this happens at sea level. Like when we hyperventilate
Speaker 3: at sea level, our brain would try to compensate for
Speaker 3: this change in pH that we see to actually inhibit
Speaker 3: our respiration. But at altitude, this process is maintained by
Speaker 3: this hypoxic ventilatory response by those chemo receptors we already mentioned,
Speaker 3: and additional chemo receptors in our brain to continue these
Speaker 3: high levels of ventilation because we're specifically facing lower partial
Speaker 3: pressure of oxygen in this setting.
Speaker 1: So hyperventilation at sea level is different than the hypoxic
Speaker 1: ventilatory response, it sure is, arin what how like? So
Speaker 1: is this those specific chemoreceptors that are only activated at altitude?
Speaker 3: So no, it's not that they're only activated altitude, but
Speaker 3: they're being activated in part by this lowered partial pressure
Speaker 3: of oxygen and then in combination with this response, the
Speaker 3: changes in alkalosis. So it's more like a combination of
Speaker 3: all of these factors rather than a pure hyperventilation that
Speaker 3: you see at sea level without all of the additional factors.
Speaker 3: If that makes sense. Yes, Okay, altitude is not necessarily
Speaker 3: the only place that you would see this happen, but
Speaker 3: this is what happens at altitude.
Speaker 1: So Aaron. Where else would we see this happen.
Speaker 3: So there have been other studies that, look, we'll get
Speaker 3: into it a little bit more later, but at like
Speaker 3: is it the pressure changes or is it just the hypoxia,
Speaker 3: But so really it's it seems that a lot of
Speaker 3: it is driven by the hypoxia initially.
Speaker 4: Yeah.
Speaker 1: Yeah.
Speaker 3: So the next part of what we see because of
Speaker 3: this respiratory alkalosis is that this naturally triggers our kidneys
Speaker 3: to try and compensate by peeing off more base in
Speaker 3: the form of bicarbonate, so we resorb less by carbonate
Speaker 3: and that is actually just a normal physiologic response to
Speaker 3: a respiratory alkalosis. That's how we compensate, okay, And that
Speaker 3: happens kind of a slightly longer time frame than the
Speaker 3: respiration part of it, So that I know, was like
Speaker 3: a lot of different I loved it.
Speaker 1: I'm thrilled.
Speaker 3: But basically, to sum it up, in short, we have
Speaker 3: a decrease in the partial pressure of oxygen, which is
Speaker 3: less oxygen in our arteries. That triggers our brain to
Speaker 3: breathe deeper and faster to then breathe off more carbon
Speaker 3: dioxide and allow more oxygen to diffuse into our arteries
Speaker 3: so that we maintain good oxygen concentration. But that's not all,
Speaker 3: of course, not because oxygen in our bloodstream is not
Speaker 3: just dissolved in our bloodstream like a gas. In fact,
Speaker 3: nearly all of the oxygen in our bloodstream is bound
Speaker 3: to a pretty important protein that everyone's probably heard of
Speaker 3: on our red blood cells, aka hemoglobin. So the next
Speaker 3: bit of the acclimatization process involves hemoglobin, and this part
Speaker 3: takes a little bit more time. So the respiratory response
Speaker 3: is starting immediately as we ascend, but within one to
Speaker 3: two days of ascent to altitude, what we see is
Speaker 3: a rise in the concentration of hemoglobin. Hemoglobin is the
Speaker 3: protein that's binding and carrying oxygen and then delivering it
Speaker 3: to our tissues. And that's important, binding oxygen and then
Speaker 3: releasing it and delivering it.
Speaker 1: Oh okay, I could tell that's like sort of a
Speaker 1: remember this because it's going to come back later.
Speaker 3: Is that like this is on the test.
Speaker 1: It's exactly on the test camelt.
Speaker 3: So within one to two days we see a rise
Speaker 3: in the concentration of hemoglobin. And this happens because the
Speaker 3: volume of our plasma in our blood actually falls up
Speaker 3: to fifteen to twenty five percent, which is a phenomenon
Speaker 3: out And this happens primarily via like a gentle diarysis.
Speaker 3: We start peeing off more fluid to decrease the plasma
Speaker 3: volume and then increase the concentration of hemoglobin.
Speaker 1: Okay, a question here about altitude. Yeah, at what point
Speaker 1: do these things happen?
Speaker 3: This is such a good question. There's no threshold, there's
Speaker 3: gradients because as you ascend, the partial pressure falls, right,
Speaker 3: just no matter what. But when we look at, for example,
Speaker 3: dysfunction in this process, we don't tend to see altitude
Speaker 3: sickness until we're getting pretty high, like twenty five hundred
Speaker 3: meters or about eight thousand feet. Sometimes we can see
Speaker 3: it at slightly lower altitudes, but I don't think from
Speaker 3: what I have read, there's not like an altitude at
Speaker 3: which you see respiratory compensation starts versus stops. It's just
Speaker 3: a kind of gradual process.
Speaker 1: But is there a proportional response to altitude, Like do
Speaker 1: you lose less plasma if you go up only twenty
Speaker 1: five hundred meters compared to five thousand meters.
Speaker 3: Yeah, that's a good question. I don't know. I didn't
Speaker 3: see that in the studies that I read. We can
Speaker 3: ask our guests.
Speaker 1: Okay, I'll note it down, Yeah.
Speaker 3: Because I think that would be really interesting, especially I
Speaker 3: think we'd have more data on that in animals than
Speaker 3: we do in humans. Because what I will say about
Speaker 3: this whole process that we've learned about the acclimtization process
Speaker 3: is that it tends to be studied once we get
Speaker 3: to an altitude at which you're at risk for acute
Speaker 3: mountain sickness, so above that twenty five hundred meters usually,
Speaker 3: and then studied in people depending on how quickly they
Speaker 3: go up versus how slowly they continue to ascend, if
Speaker 3: that makes sense. Yeah, okay, But that's the first step
Speaker 3: of this next process. Reduction in plasma volume, increase in
Speaker 3: concentration of hemoglobin. This is actually a relatively short lived
Speaker 3: phenomenon that we see because then what happens over the
Speaker 3: next period of days two weeks is that this triggers erythropotin,
Speaker 3: which is one of the major things that we make
Speaker 3: to stimulate red blood cell production. So what we see
Speaker 3: is an increase in red blood cell production, and then
Speaker 3: over the course of days two weeks, to a month
Speaker 3: or two, our total red blood cell mass will actually
Speaker 3: increase overall. So if you're at altitude for less than
Speaker 3: a week, you're not going to see all of this
Speaker 3: play out. This is something that happens over the course
Speaker 3: of time. But here's why this gets to be so important,
Speaker 3: because there's also this thing in physiology called the oxygen
Speaker 3: dissociation curve that people might have heard of. This is
Speaker 3: a measure of both how tightly our hemoglobin binds this oxygen,
Speaker 3: like how much of an affinity it has for grabbing
Speaker 3: and becoming fully saturated with oxygen, which it has to
Speaker 3: do in our lungs, and also how readily it gives
Speaker 3: up its oxygen at the level of our tissues. Ah,
Speaker 3: because both of these parts of hemoglobin are really important,
Speaker 3: there has to be a balance between grabbing and holding
Speaker 3: all that oxygen and then letting it go when we
Speaker 3: need to let it go. So what's really cool about
Speaker 3: this acclimatization process is that we see effects on both
Speaker 3: levels of this oxygen dissociation curve. What we see is
Speaker 3: that the increase in blood pH that I mentioned from
Speaker 3: that respiratory alkalosis shifts this oxygen curve such that hemoglobin
Speaker 3: has a greater affinity for oxygen, so under alcoholic conditions,
Speaker 3: a greater pH hemoglobin's like, ah, I need that oxygen.
Speaker 3: Give it to me. I'm gonna grab it and hold it.
Speaker 3: And it gets really efficient at that. But in addition
Speaker 3: to what I mentioned about just increasing overall hemoglobin mass,
Speaker 3: the other thing that we see our red blood cells
Speaker 3: making more of as we acclimatize is a substance called
Speaker 3: two three bpg okay or two three biz phosphogelyceiric acid.
Speaker 3: No one cares. This is something that helps our hemoglobin
Speaker 3: actually have a decreased affinity for oxygen or an increase
Speaker 3: in the ability of our hemoglobin to offload oxygen at
Speaker 3: the level of our tissues. And these two processes work
Speaker 3: together rather than canceling each other out right, so that
Speaker 3: we have hemoglobin that becomes more efficient at grabbing oxygen
Speaker 3: under conditions which it needs to, which is in our
Speaker 3: lungs when that partial pressure dictates that it needs to
Speaker 3: grab oxygen, and better at offloading it at the level
Speaker 3: of our tissues when the gradients are dictating we need
Speaker 3: to offload this oxygen very cool. Those are the major
Speaker 3: processes of acclimatization. We see them in the short term,
Speaker 3: mostly with respiration. We see them in the long term
Speaker 3: with these changes in hemoglobin. We do also see, especially
Speaker 3: in the very short term, like within twenty four hours
Speaker 3: of ascending two altitudes above twenty five hundred meters. As
Speaker 3: most of our data, we see an increase in cardiac
Speaker 3: output and heart rate, which is thought to be related
Speaker 3: to increases in our sympathetic nervous system activity. Because of
Speaker 3: this initial hypoxia, this part the increase in cardiac output
Speaker 3: tends to normalize over a period of days, and then
Speaker 3: what we actually can see is a decrease in stroke volume,
Speaker 3: or the amount of blood that each heartbeat pushes out,
Speaker 3: because of that decrease in plasma volume, which is really interesting, huh.
Speaker 3: And then we also see changes that happen at the
Speaker 3: level of our vasculature. So like our blood vessels in
Speaker 3: some cases might vasodilate to allow blood to push more
Speaker 3: oxygen to our tissues, but in our pulmonary vasculature, so
Speaker 3: the blood vessels in our lungs, we often can see
Speaker 3: a vasoconstriction that happens because of the decrease in the
Speaker 3: concentration of oxygen, and so this is kind of like
Speaker 3: a balance that our body has to do. And we'll
Speaker 3: get into what can happen when maybe that doesn't go
Speaker 3: so well, shall we? So I know that that's a lot,
Speaker 3: and that's just what's happening in our bodies in general
Speaker 3: when we go up mountain or a balloon. Yeah, that
Speaker 3: is physiologic acclimatization. You can think of it really as
Speaker 3: our body doing the best that it possibly can to
Speaker 3: try and deal with the fact that we just rapidly
Speaker 3: decrease the amount of oxygen surrounding us. But as I described,
Speaker 3: that process itself is not instant. It takes time. It
Speaker 3: takes hours to days to weeks. Parts of it are
Speaker 3: relatively rapid, but that full process of acclimatization really can
Speaker 3: take quite a long time. So what we can see
Speaker 3: is that in the time period between ascent to altitude
Speaker 3: and full acclimatization, we are at risk for illness if
Speaker 3: this process doesn't go according to plan I guess, and
Speaker 3: this illness can take three major forms. Acute mountain sickness
Speaker 3: or AMS, high altitude cerebral edema or HACE, and high
Speaker 3: altitude pulmonary edema or hape, and these are the three
Speaker 3: major forms that are often lumped under altitude sickness.
Speaker 1: For example, question about acclimatization when it comes to humans,
Speaker 1: because there are elevations or altitudes at which we simply
Speaker 1: can't acclimatize enough where symptoms of acute mountain sickness could
Speaker 1: occur or probably will occur. There's a limit, right.
Speaker 3: Absolutely, there is a limit to this process. Acclimatization can
Speaker 3: only do so much. And just for reference so that
Speaker 3: people can understand, like when we say the partial pressure decreases,
Speaker 3: how much are we actually talking. Everest Base camp is
Speaker 3: at five thousand, three hundred meters and at that point
Speaker 3: the partial pressure of oxen is about half what it
Speaker 3: is at sea level, so already you've reduced it by half.
Speaker 3: And then at the summit, which is over eight thousand meters,
Speaker 3: the partial pressure of oxygen is a third of what
Speaker 3: we see at sea level. So these are extreme conditions
Speaker 3: that we're talking about. We cannot acclimatize to that point
Speaker 3: for the long term.
Speaker 1: Right, I mean, obviously people have climbed it without supplemental oxygen,
Speaker 1: but right, you can't hang.
Speaker 3: Out up there. You let's get into these three forms
Speaker 3: of altitude sickness acute mountain sickness HACE, or high altitude
Speaker 3: cerebral edema, and then we'll talk about high altitude pulmonary
Speaker 3: edema or HATE. So acute mountain sickness this is the
Speaker 3: most benign, the most common, and the most rapid onset.
Speaker 3: Usually we see the symptoms of acute mountain sickness within
Speaker 3: four to twelve hours, though it could be within a
Speaker 3: day or so of ascent to altitude. And again, at
Speaker 3: this we're usually talking about altitudes greater than twenty five
Speaker 3: hundred meters or about eight thousand feet, although it can
Speaker 3: happen in some instances at lower than twenty five hundred
Speaker 3: meters at lower altitudes, and there are a few different
Speaker 3: scoring systems that you can use to diagnose this, but
Speaker 3: in general we look at a constellation of symptoms that
Speaker 3: include a headache, and in a lot of scoring systems,
Speaker 3: a headache actually has to be present to diagnose acute
Speaker 3: mountain sickness, so like headache is a defining feature. And
Speaker 3: simultaneously you might see GI symptoms like a loss of appetite,
Speaker 3: maybe some nausea, vomiting, You might have some dizziness, fatigue
Speaker 3: is a really common symptom that progresses to lassitude, which
Speaker 3: I love as a word, but that is just a
Speaker 3: complete lack of energy, lack of motivation to do anything
Speaker 3: like you can even kind of get up, and very
Speaker 3: very commonly we also see insomnia or sleep disturbances despite
Speaker 3: the fatigue. Yeah, and then we also can often see
Speaker 3: a decrease in urine output. Those are the constellation of
Speaker 3: symptoms that encompass acute mountain sickness. In terms of if
Speaker 3: we look at labs or imaging findings, which become important
Speaker 3: in some of the other forms of altitude sickness, lab
Speaker 3: values tend to actually be pretty normal. You can see
Speaker 3: a slightly lower than average blood oxygen level if you're
Speaker 3: testing people's blood oxygen, but there's a large amount of
Speaker 3: variation in that number when it comes to just acute
Speaker 3: mountain sickness itself. Most of the time this can be
Speaker 3: self limited and can resolve even without necessarily descending to
Speaker 3: a lower altitude. This can resolve with just time or
Speaker 3: sometimes with the assistance of various medications that I'll talk
Speaker 3: about a little bit later on. But then there is
Speaker 3: hase quick question though, Yeah, I know you can ask
Speaker 3: a question before, Okay, before we go on to HASE
Speaker 3: and hate. Why do we see those symptoms of acute
Speaker 3: mountain sickness. I'm not going to answer that question right now, okay,
Speaker 3: because there's still a lot of debate on this, but
Speaker 3: a lot of papers consider acute mountain sickness and hate
Speaker 3: or high altitude cerebral edema as ends of a spectrum. Okay,
Speaker 3: So that's why I want to talk about that before
Speaker 3: I let you ask those questions.
Speaker 1: Darren, I knew was your question. I'm always getting ahead
Speaker 1: of things. Yeah, you're like, no, but I have to ask.
Speaker 1: I have to know right now, right now, I know,
Speaker 1: I demand.
Speaker 3: But let's talk about HASE first, and then we can
Speaker 3: try and understand acute mountain sickness and HACE simultaneously. HACE
Speaker 3: is characterized predominantly by exactly what the name says, swelling
Speaker 3: or edema of the brain itself. HACE is terrifying. It
Speaker 3: is extremely life threatening, and the symptoms that we see
Speaker 3: in many cases are considered a progression of what we
Speaker 3: saw in acute mountain sickness. So if you think of
Speaker 3: lassitude and fatigue, this then progresses to altered consciousness, to
Speaker 3: mental status changes. One big thing that we see is
Speaker 3: what's called trunkle ataxia, So ataxia is not being able
Speaker 3: to walk in a typical fashion, like having a lot
Speaker 3: of instability and irregular gait all of a sudden. You
Speaker 3: can still see the headache, but a lot of it
Speaker 3: really is this altered consciousness. And it's terrifying because haste
Speaker 3: can progress to coma and death in as little as
Speaker 3: twenty four.
Speaker 1: Hours, Okay, And it's scary because if you are having
Speaker 1: mental status changes and that may make you less likely
Speaker 1: to recognize that you need help.
Speaker 3: Absolutely, yeah, And again, just the rapidity of this progression right,
Speaker 3: the need for very very urgent treatment. So even if
Speaker 3: you have people that are there with you that recognize
Speaker 3: that something is not right, being able to access treatment
Speaker 3: really quickly is important. And you asked, Aaron, why, like,
Speaker 3: why do we see this? What's happening here? The truth is,
Speaker 3: and I found this really fascinating, given how much we
Speaker 3: know about the physiology of the acclimatization process, is that
Speaker 3: when it comes to the path of physiology of these disorders,
Speaker 3: we don't understand them like at all, very little, very little.
Speaker 3: So first of all, there's still some debate as to
Speaker 3: whether AMS and HACE are really, you know, these ends
Speaker 3: of a spectrum or not. There's a lot of thought
Speaker 3: that it is purely this hypoxia that is driving this process.
Speaker 3: But why are we seeing this hypoxia? What parts of
Speaker 3: this acclimatization process are failing us? Is it poor ventilatory
Speaker 3: response that we're just not seeing and that leads to
Speaker 3: hypoxia that leads to all these other things. We don't
Speaker 3: necessarily have super strong data to say that, yes, that's true.
Speaker 3: There is some data that suggests that this is driven
Speaker 3: by fluid shifts. So I mentioned that we have this
Speaker 3: sympathetic stimulation which can cause vasoconstriction. We also are having
Speaker 3: vasodil and we can see increases in like cerebral blood flow.
Speaker 3: There's also suggestion that we have an increase in vascular
Speaker 3: permeability because of oxidative stressors.
Speaker 4: That are happening at the level of our blood vessels.
Speaker 4: So there might be low grade inflammation that is going
Speaker 4: on in the process of AMS and progression to cerebral edema.
Speaker 3: But truly, that is kind of the extent of what
Speaker 3: we really know about AMS and HACE, which is really
Speaker 3: interesting to me.
Speaker 1: Okay, two questions. Number one, I know you can get
Speaker 1: HEPE without AMS. Can you get HACE without AMS?
Speaker 3: It's a really good question. Like I said, one of
Speaker 3: the defining features of AMS is a headache, and by
Speaker 3: some scoring systems, you can't call it AMS unless there's
Speaker 3: a headache. You can have HASE without a headache. But
Speaker 3: does that really mean that someone didn't have AMS previously
Speaker 3: or not? I don't know. So to answer your question,
Speaker 3: I don't know. And I think that that's that's kind
Speaker 3: of part of this debate. And there is a lot
Speaker 3: of study to try and look at. Do we see
Speaker 3: any signs of a little bit of cerebral edema, a
Speaker 3: little bit of increased cerebral blood flow, a little bit
Speaker 3: of the things that make us so worried about HASEE.
Speaker 3: Do we see those signs starting in AMS? And we
Speaker 3: just don't have a ton of answers.
Speaker 1: And we really don't know why things like nausea or
Speaker 1: a lack of appetite or a headache or all somehow connected.
Speaker 3: So we have some data on that. Okay, So with AMS,
Speaker 3: there are some studies that suggest we do have a
Speaker 3: little bit of intracell edema. If not full on cerebral edema,
Speaker 3: like our cells are at least getting a little swollen.
Speaker 3: And while we think that this likely doesn't irritate our
Speaker 3: cerebral pain receptors, what does make sense is the nausea
Speaker 3: vomiting because there's nerve fibers that connect to certain centers
Speaker 3: in our brain that our sensory nerves travel through. That
Speaker 3: if these areas are a little bit swollen and irritated,
Speaker 3: that might result in nausea and vomiting. Okay, but yeah,
Speaker 3: that's kind of like the most specific thing that I found. Wow, Okay,
Speaker 3: I know for us, I'm so surprised too, honestly, but
Speaker 3: it's really really interesting, and it's not the end, because
Speaker 3: we still have high altitude pulmonary edema or HAPE. This
Speaker 3: is different because it's our lungs and not our brain,
Speaker 3: but otherwise I think of it as kind of similar.
Speaker 3: The onset of this is slower and tends to happen
Speaker 3: one to five days after ascent and is rare after
Speaker 3: a week or so. We often, like you mentioned, Aaron,
Speaker 3: we often can see acute mountain sickness AMS first, but
Speaker 3: not always in the case of HAPE, and the symptoms
Speaker 3: here are again, what you'd expect based on the name.
Speaker 3: We have edema in our lungs, fluid shifting into our lungs.
Speaker 3: So the symptoms that we see are dyspnea, difficulty breathing,
Speaker 3: shortness of breath, and a lot of it is starts
Speaker 3: as severe exertional dyspnea or exertional shortness of breath. Now,
Speaker 3: everyone who exercises is going to get breathless or feel
Speaker 3: short of breath, but what this is characterized as is
Speaker 3: excessive shortness of breath compared to everyone else that you
Speaker 3: came up the mountain with, or other people around you
Speaker 3: on the mountain, So like an excessive amount of shortness
Speaker 3: of breath along with cough a feeling of chest tightness,
Speaker 3: and then this can progress to a more severe cough
Speaker 3: shortness of breast that makes it difficult to even lie
Speaker 3: down flat. If you listened to someone's chest, you would
Speaker 3: hear crackles or maybe even gurgling sounds. And eventually this
Speaker 3: can progress to the production of like a pink, frothy sputum,
Speaker 3: which would mean that things are getting pretty severe. And
Speaker 3: when we look at things like labs, we would see
Speaker 3: pretty severe hypoxia. So we have pretty low levels of
Speaker 3: blood oxygen in these people, which then is going to
Speaker 3: result in really fast breathing that to kipnea, breathing really
Speaker 3: fast and a faster heart rate. And on X rays
Speaker 3: we see a lot of evidence of fluid throughout the
Speaker 3: lungs in this very patchy distribution. Usually, and again here
Speaker 3: erin we do not fully understand this pathophysiology, but what
Speaker 3: we do know is that there's at least some component
Speaker 3: driven by this hypoxic pulmonary vasoconstriction that we see as
Speaker 3: part of this acclimatization process. So what this then can
Speaker 3: lead to is an increase in pressure in the pulmonary arteries.
Speaker 3: And then there's a few different thoughts on how this
Speaker 3: then leads to the edema that we see. It could
Speaker 3: be that then these arteries become a little bit leaky
Speaker 3: because of this increased pressure. It could be that this
Speaker 3: vasoconstriction is happening just in certain places, like in patchy distribution,
Speaker 3: both in our arteries and or maybe in our veins,
Speaker 3: even in our lungs, which can then lead to increases
Speaker 3: in pressure just in small areas that then might lead
Speaker 3: to fluid being able to leak out of just those
Speaker 3: small areas, which would explain the patchiness that we tend
Speaker 3: to see on X ray. Honestly, it didn't seem very
Speaker 3: like well fleshed out in terms of like the real drivers.
Speaker 3: It used to be thought that it was really more
Speaker 3: heart failure that was driving it, but now it's really
Speaker 3: thought that it's probably more a pulmonary process that then
Speaker 3: can lead to dysfunction in the heart as well, rather
Speaker 3: than heart failure that's the initial driver of this process.
Speaker 1: Okay, that's interesting because that is in contradiction with some
Speaker 1: of the historical texts that I read, but that makes sense.
Speaker 3: But yeah, yeah it can work because historically like this
Speaker 3: looks like a heart failure response. Absolutely. Then there's also
Speaker 3: a big thought that inflammation plays a role because in
Speaker 3: some people with hape, if you look at the fluid
Speaker 3: that you collect from the edema, it has a lot
Speaker 3: of inflammatory markers, but not all of them, and usually
Speaker 3: not until later in the disease process. So it's really
Speaker 3: unclear how big of a role inflammation really plays in
Speaker 3: this disease.
Speaker 1: So I really want to talk about treatment, but first
Speaker 1: I want to ask about risk factors. So these things
Speaker 1: can happen to anyone who goes up to altitude. Are
Speaker 1: there certain risk factors associated with either HACE or HAPE
Speaker 1: or even AMS?
Speaker 3: Honestly, no, okay, which is fascinating.
Speaker 1: Ye.
Speaker 3: The major determinants of risk are altitude, how high are
Speaker 3: you actually going, the rate of assent, the degree to
Speaker 3: which someone is pre acclimatized, like have you ever been
Speaker 3: to altitude? Have you been going to altitude over the
Speaker 3: course of the last few weeks and now you're going
Speaker 3: a little higher than before in that kind of thing,
Speaker 3: And then the rest of it is literally individual susceptibility
Speaker 3: weird in that we just don't know, okay. There's no
Speaker 3: differences in like terms of other disease states like even
Speaker 3: and when it comes to like lung disease with hape.
Speaker 3: The one exception is that someone with a history of
Speaker 3: HAPE has like an over sixty percent chance of getting
Speaker 3: HAPE again if they go to that same altitude, but.
Speaker 1: Not things like chronic lung conditions or age.
Speaker 3: Not even age. Older individuals seem slightly more susceptible than
Speaker 3: younger adults and children, but not even like dramatically. So
Speaker 3: things like smoking and alcohol use do not increase the
Speaker 3: risk of AMS.
Speaker 4: This is Aaron, I can see your face wild.
Speaker 1: Yeah, this is not what I expected.
Speaker 3: I know, it's really really interesting having a history of migraines.
Speaker 3: Maybe very minor risk factor, very minor.
Speaker 2: Huh.
Speaker 3: That's it. That's it. That's the only that's the only thing. Wow, Okay,
Speaker 3: I know. Treatment which you ask about. Yes, an ounce
Speaker 3: of prevention is leth a pound of cure love the accent,
Speaker 3: thank you, magnificent nineteen forties. I don't know. So really,
Speaker 3: the major way to prevent this is to ascend slowly.
Speaker 3: That's it. That's the number one thing. And I'm not
Speaker 3: going to tell you exact numbers on this because even
Speaker 3: all of the recommendations on the slowness or quickness of
Speaker 3: your ascent and how many rest days are based purely
Speaker 3: on observational studies. There's no like randomized control trials. It's
Speaker 3: not like real data that we can base it on.
Speaker 3: And every individual has different tolerances, et cetera. So anyways,
Speaker 3: but there are also medicines that we can use to
Speaker 3: reduce the risk of AMS and or help treat AMS.
Speaker 3: And because hace and to a lesser extent, hate are
Speaker 3: thought to be all reflective of this impaired acclimatization process.
Speaker 3: In theory, these medicines might also reduce your risk of
Speaker 3: those as well, rather than just AMS. Okay, so there's
Speaker 3: a couple different things that we can use. The main
Speaker 3: one that's often used is acetazolamide, which acts both to
Speaker 3: stimulate respiration at least a little bit, and then is
Speaker 3: also a mild diuretic. So this helps to increase our
Speaker 3: plasma volume and increase hemoglobin concentration to basically just jumpstart
Speaker 3: or boost our normal acclimatization process. Deximethizone or steroids is
Speaker 3: the other thing that we use to do similarly. Okay,
Speaker 3: there's some limited evidence for things like iyboprofin, but I
Speaker 3: don't know that there's super great evidence for any of
Speaker 3: those other things. And beyond that, for anything severe, it's
Speaker 3: access to increased oxygen, so pure oxygen on the face
Speaker 3: and descent immediately to lower altitudes.
Speaker 1: It is I guess, maybe not easy, but.
Speaker 3: Straightforward, straightforward and logical, just like in our Bens episode.
Speaker 1: Yeah, precisely.
Speaker 3: Yeah, AMS, which is by far the most common form
Speaker 3: that we see, can often be treated conservatively, so without
Speaker 3: having to descend to a lower altitude with just rests, rehydration,
Speaker 3: treating the headache, and then just waiting it out before
Speaker 3: ascending to further altitudes. But again we.
Speaker 4: Worry about pregression to hate. So that's terrifying.
Speaker 1: Yeah.
Speaker 3: Yeah. A quick side note. When I said that alcohol use,
Speaker 3: for example, doesn't increase your risk of AMS or hase,
Speaker 3: this is true. But alcohol and other medications like sleeping medications,
Speaker 3: et cetera, can depress the high poxic drive to breathe,
Speaker 3: so might worsen hypoxemia, might worsen any hypoxymia that does exist,
Speaker 3: but there have been no trials that show that conclusively. Huh,
Speaker 3: just so you know.
Speaker 1: Wow.
Speaker 3: So that is all acute mountain sickness altitude sickness. But
Speaker 3: that's not the end quite aarin. There's also chronic mountain sickness.
Speaker 3: And this is what can happen when someone lives at altitude,
Speaker 3: for we're talking like their whole entire life and continues
Speaker 3: to grow an age at altitude. What we see in
Speaker 3: chronic mountain sickness is what's called a polypythemia, or an
Speaker 3: increased overall red blood cell mass to an extent that
Speaker 3: is problematic, coupled with a decreased ventilatory drive, which we
Speaker 3: think maybe in part just happens with age, but this
Speaker 3: leads essentially to chronic hypoxia. So what we see is
Speaker 3: very very high hemoglobin levels, very high hematocrites, along with
Speaker 3: chronic hypoxia, which the symptoms of that might mean dilated
Speaker 3: blood vessels because again your blood vessels are trying to
Speaker 3: get this oxygen to our tissues. We can see cyanosis,
Speaker 3: so skin turning blue, and then a host of complications
Speaker 3: that can arise from just how high these hemoglobin levels
Speaker 3: can get. And again here we don't fully understand this process.
Speaker 3: But what I really didn't realize is that it's estimated
Speaker 3: to affect like five to ten percent of people potentially
Speaker 3: that live at very high altitudes for the entirety of
Speaker 3: their lives.
Speaker 1: It's really interesting.
Speaker 3: Yeah, yeah, it's really interesting. There's a lot, Aaron, I
Speaker 3: don't even know how to ask, like, we how did
Speaker 3: we get here?
Speaker 1: I guess well, I'll take us on some kind of journey,
Speaker 1: so and I'll get started right after this break. The
Speaker 1: history of altitude sickness can be framed around a single word, hypoxia.
Speaker 1: Oh yeah, we learned in the biology section that hypoxia
Speaker 1: means that there are low levels of oxygen in your tissues.
Speaker 1: Take a step back and consider all of the layers
Speaker 1: of knowledge that go into that word. What are all
Speaker 1: the things we have to know in order to understand
Speaker 1: hypoxia in the context of altitude sickness. Well, we have
Speaker 1: to know what are considered normal levels of oxygen in
Speaker 1: our tissues and how a decrease can be detrimental to
Speaker 1: our health, which means we have to know how to
Speaker 1: measure oxygen concentration in tissues. We have to know how
Speaker 1: oxygen gets into our tissues and the role that it
Speaker 1: plays in our bodies, which means understanding cellular respiration as
Speaker 1: well as how our lungs function with our circulatory system.
Speaker 1: We have to know what things can cause oxygen levels
Speaker 1: to drop and why. In the context of altitude sickness,
Speaker 1: this means that we have to know the relationship between
Speaker 1: altitude and oxygen, which requires knowing about how atmospheric pressure
Speaker 1: behaves under certain conditions and the composition of air, which
Speaker 1: means we have to know what oxygen is. So in
Speaker 1: this one word hypoxia, there are crammed hundreds of years
Speaker 1: of scientific investigations and observations integrating knowledge from disparate fields,
Speaker 1: from anatomy and physiology to chemistry and the properties of gases.
Speaker 3: I love this already, Aaron, You've hooked me good.
Speaker 1: That was my goal, But I just felt like it's
Speaker 1: so easy for us today to take this word for granted,
Speaker 1: along with the knowledge that goes into it, which is
Speaker 1: why my goal for this history section is to take
Speaker 1: us through how we fit those puzzle pieces together to
Speaker 1: gain a big picture understanding of why high altitudes affect
Speaker 1: us the way they do. Kind of like with our
Speaker 1: bends or decompression sickness episode where I barely talk about scuba.
Speaker 1: The history of altitude sickness as I am choosing to
Speaker 1: tell it, you could tell it a number of different ways,
Speaker 1: is not one filled with the daring exploits of a
Speaker 1: bunch of dudes attempting to climb the world's tallest mountain
Speaker 1: and learning that life at altitude is very dangerous.
Speaker 4: Honestly, Thank goodness, there.
Speaker 1: Are many books out there if that's what you're interested in.
Speaker 1: But instead, this is going to be a history of
Speaker 1: scientific discovery of the big moments in physiology and chemistry
Speaker 1: that brought us from not knowing that air exerts pressure
Speaker 1: or that oxygen existed, having no idea what the lungs
Speaker 1: actually do or why high altitude makes you sick all
Speaker 1: the way to breezely using the word hypoxia, dropping it
Speaker 1: in a sentence.
Speaker 3: I love it, thrilled.
Speaker 1: Now that I've said what this history does include, let
Speaker 1: me tell you what it doesn't, namely the evolutionary aspects
Speaker 1: of life at high altitude. For that piece of the puzzle,
Speaker 1: we're going to be chatting with, as we mentioned a
Speaker 1: very special guest later in this episode who is going
Speaker 1: to share some fascinating information on how certain animal and
Speaker 1: human populations have adapted to living at high altitudes, how
Speaker 1: varied those adaptations can be, and what high altitude adaptation
Speaker 1: can tell us about human health.
Speaker 3: I cannot wait.
Speaker 1: I know, I am really excited, But first we've got
Speaker 1: a whole history to get through. As we'll learn more
Speaker 1: about humans have been living at high altitudes for tens
Speaker 1: or even hundreds of thousands of years, as well as
Speaker 1: just traveling through certain areas that are at high altitude.
Speaker 1: So we as humans have likely noticed the effects of
Speaker 1: high altitude on our health for a very long time.
Speaker 1: Observations of high altitude are scarce or close to non
Speaker 1: existent in ancient Greek and Roman medical texts, although scientists
Speaker 1: in the seventeenth century believed that Greek and Roman physicians
Speaker 1: were well aware of the dangers of high altitude. From
Speaker 1: an English translation of Francis Bacon quote, the ancients also
Speaker 1: observed that the rarity of the air on the summit
Speaker 1: of Olympus was such that those who ascended it were
Speaker 1: obliged to carry sponges moistened with vinegar and water, and
Speaker 1: to apply them now and then to their nostrils, as
Speaker 1: the air was not dense enough for their respiration. Oh
Speaker 1: and so the sponge part shows that people believed that
Speaker 1: it was the lack of water vapor in the air
Speaker 1: at high altitude that made it difficult to breathe. Interesting
Speaker 1: because they didn't know what oxygen was yet. I Okay,
Speaker 1: it's possible that we simply haven't found the ancient Greek
Speaker 1: and Roman references to altitude sickness, but there are certainly
Speaker 1: descriptions of the negative effects of high altitude in ancient
Speaker 1: Chinese texts. In a classical history text from the first
Speaker 1: century CE, there is a description of an envoy traveling
Speaker 1: over mountainous terrain around thirty seven to thirty two BCE,
Speaker 1: and this envoy was warned of the danger along the route,
Speaker 1: not just in terms of the robbers known to frequent
Speaker 1: the area, but also because of the terrain. Quote again,
Speaker 1: on passing the Great Headache Mountain, the Little Headache Mountain,
Speaker 1: the Red Land, and the Fever Slope, men's bodies became feverish,
Speaker 1: they lose color and are attacked with headache and vomiting,
Speaker 1: the asses and cattle being all in like condition.
Speaker 3: Ooh, Green Headache Head Mountain.
Speaker 1: And four hundred years later, also from ancient Chinese texts,
Speaker 1: is where we find what is likely the first description
Speaker 1: of high altitude pulmonary edema hate quote. Having stayed there
Speaker 1: till the third month of winter, Fa Hien and the
Speaker 1: two others, proceeding southwards, crossed the little Snowy Mountains on
Speaker 1: them the snow lies accumulated both winter and summer. On
Speaker 1: the north side of the mountains. In the shade, they
Speaker 1: suddenly encountered a cold wind, which made them shiver and
Speaker 1: become unable to speak. Huai King could not go any farther.
Speaker 1: A white froth came from his mouth, and he said
Speaker 1: to fa hien, I cannot live any longer. Do you
Speaker 1: immediately go away? That we do not all die here?
Speaker 1: And with these words he died end quote gosh, yeah,
Speaker 1: but the frothy, frothy mountain could be can't breathe? Yeah.
Speaker 1: We have to jump ahead quite a bit in time
Speaker 1: to about the fifteen hundreds before we find more mentions
Speaker 1: of altitude sickness, beginning with those given by the Jesuit
Speaker 1: priest Father Joseph Deacosta, who described the headache, nausea, and
Speaker 1: difficulty breathing that appeared. And he was at high altitudes
Speaker 1: in the Peruvian Andes. And he wasn't the only Jesuit
Speaker 1: priest who noticed these effects. Shortly after, father Alonzo de
Speaker 1: Ovali wrote in the early sixteen hundreds that quote, when
Speaker 1: we come to ascend the highest point of the mountain,
Speaker 1: we feel an air so piercing and subtle that it
Speaker 1: is with much difficulty we can breathe, which obliges us
Speaker 1: to fetch our breath quick and strong, and to open
Speaker 1: our mouths wider than necessary. I mean, yeah, love it.
Speaker 1: These various descriptions of altitude sickness clearly demonstrate that, yes,
Speaker 1: people noticed the effects of altitude, and some even went
Speaker 1: as far as to explain, in vague terms, anyway, why
Speaker 1: this thin air or subtle air made you feel this way?
Speaker 1: But to them, the air was thin because it didn't
Speaker 1: have much moisture. It was dry. When did thin air
Speaker 1: come to mean what it does today? In other words,
Speaker 1: when did people discover atmospheric pressure and oxygen? As it
Speaker 1: turns out, at very different times. Let's start with the
Speaker 1: discovery of atmospheric pressure, because if you want to know
Speaker 1: what's in the atmosphere, like oxygen, you first have to
Speaker 1: know that the atmosphere exists, and you have to understand
Speaker 1: how it behaves. Like today, if you tune into a
Speaker 1: weather forecast, you may hear something about a low pressure
Speaker 1: or a high pressure system, like a low pressure system
Speaker 1: is moving into the Four Corners region today, bringing with
Speaker 1: it gusty winds, hail, frequent lightning, and heavy rainfall. And
Speaker 1: that forecast probably wouldn't even register or make you do
Speaker 1: a double take unless your car was like out in
Speaker 1: the open and you're like, oh my god, Hale, what
Speaker 1: am I going to do? But it would make Galileo,
Speaker 1: for instance, do a double take, as well as many
Speaker 1: other scientists of the early seventeenth century because they did
Speaker 1: not believe that air weighed anything or exerted any pressure.
Speaker 1: We know today, of course, that it does. That atmospheric
Speaker 1: pressure can be thought of as how much the air
Speaker 1: weighs or is pressing down on you, and that things
Speaker 1: like temperature and weather an altitude can affect this pressure.
Speaker 1: For instance, when you go closer to sea level, that
Speaker 1: air presses down on you more and more, and as
Speaker 1: you ascend, it presses down less and less. And we
Speaker 1: know these things today about atmospheric pressure in large part
Speaker 1: thanks to one of Galileo's students, Evangelista Torricelli, who invented
Speaker 1: the first barometer, which is a tool, of course, to
Speaker 1: measure the level of atmospheric pressure.
Speaker 3: I love this.
Speaker 1: I am going to attempt to explain what Torricelli's barometer
Speaker 1: looked like and how it worked, so that we can
Speaker 1: picture how air pressure changes, like how you can see
Speaker 1: that happening.
Speaker 3: Okay, okay.
Speaker 1: Imagine a test tube, right, a long test tube, one
Speaker 1: end is open. Fill it with a liquid. Let's go
Speaker 1: with mercury, okay, and then imagine a little dish that
Speaker 1: you also fill with mercury. You're gonna plug the open
Speaker 1: end of that test tube with your thumb, right, okay,
Speaker 1: and then you're gonna flip it over so that the
Speaker 1: plugged end is in the dish of mercury. By the way,
Speaker 1: don't try this at home. This is don't do this.
Speaker 1: And it's standing upright, okay, Then you're gonna quickly remove
Speaker 1: your thumb plug trying to let like no air in, right,
Speaker 1: So it's already under the mercury level. And when that happens,
Speaker 1: a little headspace will appear at the top of the
Speaker 1: test tube as the atmospheric pressure outside of the tube
Speaker 1: equalizes with the pressure inside.
Speaker 2: Right.
Speaker 1: So now you have this upside down test tube that
Speaker 1: contains mercury with a little bit of headspace in this
Speaker 1: dish that also has mercury level. Right.
Speaker 3: Did I sorry? Did I fill the test tube like
Speaker 3: completely or was I half full or completely completely full? Okay?
Speaker 2: Okay? Cool?
Speaker 3: Coo cool?
Speaker 1: And so right now everything all the pressures have equalized.
Speaker 1: The air is pressing down on the mercury in that
Speaker 1: dish to keep it at that level. If the air
Speaker 1: pressure increases, like let's say you go below sea level,
Speaker 1: the air will press down more on the mercury. In
Speaker 1: the dish, forcing the level in the tube to climb
Speaker 1: a bit higher. And if air pressure decreases, maybe because
Speaker 1: you went up in altitude, then air will press down
Speaker 1: on the mercury in the dish, less allowing the outside
Speaker 1: level of mercury to rise and the level of mercury
Speaker 1: in the test tube to drop. So there's more headspace.
Speaker 3: Okay, I think I'm there, Okay, okay, because you're pushing
Speaker 3: down on the dish, if you're going down, if your
Speaker 3: pressure's increasing, you're pushing more on that. So that's going
Speaker 3: to push up on the mercury in the tube because
Speaker 3: it's they're connected in there. And then the opposite it's
Speaker 3: going to happen if you release that pressure, then that's
Speaker 3: going to drop because then yeah, I got it.
Speaker 1: Yeah, isn't that cool?
Speaker 3: Yeah?
Speaker 1: Yeah. So that was Tori Chlly's barometer, Okay, And this
Speaker 1: is a really remarkable device because with it he showed
Speaker 1: that the air around us does exert pressure and that
Speaker 1: that pressure can change.
Speaker 3: What may the part that gets me, it's like, I
Speaker 3: can follow your logic of how he got there, but like,
Speaker 3: why did he do that? What made him think of
Speaker 3: doing that thing in the first place, and was he
Speaker 3: trying was that what he was trying to show or Okay.
Speaker 1: Yeah, so he was trying to show that. I think
Speaker 1: it was sort of like Galileo and others believed that
Speaker 1: the air exerted no pressure. But I think it was
Speaker 1: kind of beginning to be more of a contentious issue.
Speaker 3: Okay, And I.
Speaker 1: Can't remember the exact sequence of events or how I
Speaker 1: read it, but yeah, he just decided to test this out.
Speaker 3: What an like, how does your brain think of that
Speaker 3: before it's ever been done?
Speaker 1: I just know that this is why I loved this
Speaker 1: history so much, because there's so much more of that
Speaker 1: in here.
Speaker 4: Yeah.
Speaker 1: Torricelli also went so far as to suggest that the
Speaker 1: air on top of a mountain weighed less and thus
Speaker 1: exerted less pressure than air at sea level, but he
Speaker 1: didn't demonstrate it with his barometer. That honor would fall
Speaker 1: to Blaze Pascal. Child prodigy, philosopher, mathematician, all around pretty
Speaker 1: famous dude. You've probably heard his name before.
Speaker 3: He's a unit of measure.
Speaker 1: There you go, So is Torricelli tour? Oh yeah, tour,
Speaker 1: oh tour. But it wasn't actually Blazed Pascal that would
Speaker 1: do it. It was his brother in law that would physically
Speaker 1: carry the barometer up the hill because Pascal was not
Speaker 1: in great health, and he asked him to do it
Speaker 1: and report back cute. Well, when brother in law came
Speaker 1: back down the hill, he was super pumped to tell
Speaker 1: Pascal that yes, indeed the liquid dropped. And while this
Speaker 1: result was somewhat expected, this ground truthing of the concept
Speaker 1: was a really exciting development, and it allowed Pascal to
Speaker 1: extend the logic about altitude and atmospheric pressure to suggest
Speaker 1: that the human body and pressure throughout the body in blood, tissues,
Speaker 1: et cetera, is also subject to atmospheric pressure changes, such
Speaker 1: as those you may experience if you go up in altitude.
Speaker 3: I love it, but just.
Speaker 1: Like Toricelli, Pascal left the experimental demonstration of this concept
Speaker 1: to others. Okay, at this point in the story, the
Speaker 1: mid sixteen hundreds or so, we're slowly building our understanding
Speaker 1: of how the atmosphere works, how it exerts pressure, and
Speaker 1: how that pressure changes based on things like temperature or altitude.
Speaker 1: But how do we relate this to the human body
Speaker 1: in like a demonstrable way, or any vertebrate's body. Really,
Speaker 1: For that, we'll need a couple of Roberts Boil and Hook.
Speaker 1: Oh you may remember me mentioning some of Robert Boyle's
Speaker 1: experiments with air pressure and vacuums on animals in the
Speaker 1: sixteen seventies sixteen eighties during our Benz episode, Like remember
Speaker 1: the bubble in the viper's eye, It's like the first
Speaker 1: observation of decompression sickness. Well, it turns out that Boil
Speaker 1: and Hook they work together a lot. So related apology
Speaker 1: to Hook for leaving him out of the Benz episode
Speaker 1: that this pair did many more experiments using an air
Speaker 1: pump to investigate animal's responses to air pressure, such as
Speaker 1: testing how long animals could survive at different pressures, clearly
Speaker 1: demonstrating that at lower pressures survival was shortened. Hook didn't
Speaker 1: stop with animal experimentation, however, He also devised a decompression
Speaker 1: chamber that humans could sit in to experience the effects
Speaker 1: of low pressure, testing it out, of course, on himself.
Speaker 1: He sat in his chamber for about fifteen minutes at
Speaker 1: a pressure of about five hundred and seventy tour or
Speaker 1: the equivalent of twenty four hundred meters seventy eight hundred feet,
Speaker 1: experienced a little bit of hearing loss, and the candle
Speaker 1: he brought in with him extinguished long before time was up.
Speaker 1: No fresh air was being pumped in. By the way,
Speaker 1: The why of this, Why survival was shorter at lower
Speaker 1: air press pressures, Why a candle would extinguish, Why low
Speaker 1: air pressure led to certain symptoms? This why was still
Speaker 1: a big unanswered question, one that Hook and Boil would
Speaker 1: begin to scratch the surface of with their experiments on
Speaker 1: animal respiration. Because remember, at this point, no one knew
Speaker 1: what precisely the lungs did or what oxygen was right, right,
Speaker 1: And I just want to pause and say how amazing
Speaker 1: it is that so many things are fitting together in
Speaker 1: terms of other topics we've talked about on the podcast before.
Speaker 1: Like I also mentioned Hook during our RSV episode when
Speaker 1: I talked about the development of artificial respiration. Oh yeah,
Speaker 1: and his experiments on this subject would prove to be
Speaker 1: key to getting at this question of why. This period
Speaker 1: during which Hook and Boil were active in their research
Speaker 1: followed close on the heels of a time when anatomical
Speaker 1: dissections of both animals and humans had greatly increased in popularity,
Speaker 1: being seen as not as sacrilegious as they had been
Speaker 1: in the past. These dissections and the beautifully illustrated anatomy
Speaker 1: books that were created by people like Andreas Vesalius encouraged
Speaker 1: physicians and scientists to link form with function. We can
Speaker 1: draw the circulatory system, the major arteries, in veins, the
Speaker 1: ventricles of the heart. But how did the heart pump blood?
Speaker 1: What role did the lungs play in the circulation of blood. Obviously,
Speaker 1: animals needed to breathe air using their lungs to stay alive,
Speaker 1: which Hook demonstrated with his dog experiment that I mentioned
Speaker 1: in the RSV episode where he uses bellows through a
Speaker 1: cut in the dog's lungs. Yeah, but how did the
Speaker 1: lungs do this? And why did all the blood pass
Speaker 1: through the lungs? Was it to cool the blood down,
Speaker 1: which was Galen's thought that still predominated during this time,
Speaker 1: or was it something else in the air that was
Speaker 1: essential for survival. Clearly the lungs did something. Hook's colleague
Speaker 1: Richard Lower, performed an experiment in sixteen sixty nine where
Speaker 1: he compared the blood that had passed through the lungs
Speaker 1: with fresh air. It's like the lungs had just had
Speaker 1: fresh air with venus blood and noticed a stark difference
Speaker 1: in color, with the freshly ventilated blood being bright red
Speaker 1: and the venus blood a much darker red. What this
Speaker 1: color difference meant wasn't clear, but it did show that
Speaker 1: when blood came into contact with fresh air in the lungs,
Speaker 1: something changed. And around the same time, Malpiggy shed light
Speaker 1: on that lung blood interface through his descriptions the first
Speaker 1: of the alveoli and the pulmonary capitalation that linked the
Speaker 1: arteries and veins, descriptions that were made possible due to
Speaker 1: the increasing popularity, availability, and technological advancements of the microscope.
Speaker 3: Oh my gosh, it all comes full circle.
Speaker 1: It all comes full circle. So now people were able
Speaker 1: to make the connection that fresh air inhaled through the
Speaker 1: lungs changes the blood through these structures that Malpiggy described.
Speaker 3: Wow, but what about that fresh.
Speaker 1: Air was so important? Was it the air as a
Speaker 1: whole or was it a particular component.
Speaker 3: Of that fresh air?
Speaker 1: John Mayow, a contemporary of Hook and Boil, began to
Speaker 1: suspect that it was the latter. That air was not uniform,
Speaker 1: but made up of at least two distinct substances, one
Speaker 1: that was involved in combustion and respiration, and one that
Speaker 1: was not. He set out to test his hypothesis with
Speaker 1: a pretty cool experiment in my opinion, so I want
Speaker 1: to describe it here. First, he filled a shallow dish
Speaker 1: with water, think of like a dog water bowl. Then
Speaker 1: he put a taper candle standing upright in that water,
Speaker 1: lit it, and then put a glass bell over it yep,
Speaker 1: with the open end extending down into the water and
Speaker 1: resting on the bottom of the dish, effectively sealing the
Speaker 1: bell off along with the candle inside of it. Right.
Speaker 1: He observed that as the candle burned, the water level
Speaker 1: inside the bell rose, which suggested to him that the
Speaker 1: flame was consuming some part of the air which the
Speaker 1: water came in to fill, and when that portion of
Speaker 1: air was used up, the flame went out, which it did.
Speaker 3: Oh my goodness, very cool.
Speaker 1: He then replicated this experiment, but instead of a candle,
Speaker 1: he put a little mouse alive on a stool and
Speaker 1: covered it with a glass bell. Again, he saw that
Speaker 1: the water level inside the bell rose as the animal breathed,
Speaker 1: and that at a certain point all of the respiration
Speaker 1: air component was used up and the animal died.
Speaker 3: I I this is very cool. I mean not for
Speaker 3: the mouse.
Speaker 1: No, I know, I know, but just to think of
Speaker 1: these things, these are like principles, major principles, right, that
Speaker 1: are being uncovered through like beautiful experiments that I feel
Speaker 1: like this.
Speaker 3: Is something that maybe they like offhandedly mentioned during like
Speaker 3: a chemistry or a physics class at some point. But
Speaker 3: it was like in the middle of sixteen different equations,
Speaker 3: and I was like, why do I have to learn this?
Speaker 5: But now it's like without the equations, it's so cool,
Speaker 5: and that's a lesson for life everyone.
Speaker 1: These simple experiments by Mayou were groundbreaking for a couple
Speaker 1: of reasons. One was that they showed that air was
Speaker 1: made up of at least two different components, and that
Speaker 1: the second was that one of those components was crucial
Speaker 1: for both combustion as well as animal respiration, and.
Speaker 3: Like, did he assume that this must be the same component,
Speaker 3: because that's also an interesting conclusion, right, yes, why combustion
Speaker 3: and respiration?
Speaker 2: Right?
Speaker 1: So he thought that there were two components of air,
Speaker 1: like only two components, one that was involved in like
Speaker 1: one that was usable and one that was more inert.
Speaker 1: I guess, okay, yeah, And that was something that hook
Speaker 1: and boil hadn't picked up on. But I want to
Speaker 1: read this quote from Lavoisier from about one hundred years later. Okay, quote,
Speaker 1: respiration is nothing but a slow combustion of carbon and hydrogen,
Speaker 1: similar in all respects to that of a lamp or
Speaker 1: a lighted candle. And from this point of view, animals
Speaker 1: which breathe are really combustible substances, burning and consuming themselves.
Speaker 3: I love it, It's beautiful.
Speaker 1: I yeah, okay, we'll get back to Lavasia in a second.
Speaker 1: But also mayou didn't stop there with these experiments. He
Speaker 1: went on to suggest that this component of air, the
Speaker 1: one that's involved in respiration and combustion, is taken up
Speaker 1: by the lungs and passed into blood, where it is
Speaker 1: involved in heat production and muscle movement, which he pointed
Speaker 1: out was why breathing increases during exercise, since you need
Speaker 1: more of this substance in the air to move. Amazing.
Speaker 1: All right, So let's we've covered a lot of ground.
Speaker 1: Let's take stock briefly of what we've learned so far.
Speaker 1: We learned that the atmosphere exerts pressure, pressure that can
Speaker 1: be measured and that can change based on several different factors,
Speaker 1: including altitude. We've learned that air is not just one
Speaker 1: homogeneous substance, that it is actually made up of several
Speaker 1: different components, at least one of which is necessary to
Speaker 1: sustain life and a candle flame through some process involving
Speaker 1: respiration via lungs and the exchange of venus and arterial
Speaker 1: blood in the lungs. Okay, And we learned all of
Speaker 1: that over the course of just a few decades in
Speaker 1: the seventeenth century.
Speaker 3: So now we're still in the late sixteen hundred.
Speaker 1: Still roughly now, we're probably going mostly into the early
Speaker 1: to mid eighteenth century. Seventeens.
Speaker 6: Yeah, seventeen hundreds, Okay, cool, cool, cool, And I really
Speaker 6: kind of feel that like, at this point, the discovery
Speaker 6: of oxygen itself as one of those components, or the
Speaker 6: naming of it, seems almost anti climactic.
Speaker 1: What doesn't help is that there seems to be a
Speaker 1: good deal of contention over who gets priority for the discovery.
Speaker 1: As far as I could gather, there are four contenders
Speaker 1: for the title, Joseph Priestley, Carl Shiel, Henry Cavendish, and
Speaker 1: Antoine Lavoisier. And I'm not going to go into how
Speaker 1: each of them quote unquote discovered oxygen or the contribution
Speaker 1: they made, But in general, all of these discoveries involved
Speaker 1: the burning of an oxide of some sort in a
Speaker 1: sealed chamber and the realization that the released gas from
Speaker 1: that burning oxide could sustain life longer than ordinary air
Speaker 1: in the same type of chamber.
Speaker 3: Okay, yeah.
Speaker 1: These experiments also helped to lay the groundwork for describing
Speaker 1: the properties of other components of air besides oxygen, including
Speaker 1: carbon dioxide and nitrogen. So Lavoisier the person who gets
Speaker 1: credit not so much for the priority but the most
Speaker 1: impactful early research done on oxygen in seventeen seventy one
Speaker 1: described these gases role in respiration as such quote eminently
Speaker 1: respirable air, which he later called oxygen that enters the
Speaker 1: lungs leaves it in the form of chalky airform acids
Speaker 1: carbon dioxide in almost equal volume. Respiration acts only on
Speaker 1: the portion of pure air that is eminently respirable, the
Speaker 1: excess that is its mephitic portion. Nitrogen is a purely
Speaker 1: passive medium which enters and leaves the lung without change
Speaker 1: or alteration. The respirable portion of air has the property
Speaker 1: to combine with blood, and its combination results in its
Speaker 1: red color at this point in the story. I wouldn't
Speaker 1: blame you if you asked, but what about altitude sickness?
Speaker 1: Isn't that what the episode is about?
Speaker 7: I honestly, I haven't enjoying this so much that like, good, Well,
Speaker 7: if you listeners out there have been waiting for some
Speaker 7: mention of altitude sickness in the history of section, your
Speaker 7: long wait is almost over, and I appreciate your patience.
Speaker 1: I wanted to go into how these connections were made
Speaker 1: between the atmosphere and altitude and respiration and oxygen, because
Speaker 1: they are fundamental to understanding so many things, including the
Speaker 1: effects that altitude has on our bodies, something that people
Speaker 1: were about to experience in ways they never had before. Ooh,
Speaker 1: because because balloons balloons, though I know, well think about it,
Speaker 1: I would never have guessed balloons even if I thought
Speaker 1: about it. I don't have to think about balloons. Well,
Speaker 1: you're going up super high, super fast.
Speaker 2: I know.
Speaker 3: But like, I forget that balloons are a thing that
Speaker 3: people decided to jump in at some point, you know,
Speaker 3: like why what.
Speaker 1: If they still do? I think there are many people
Speaker 1: that still do. Hotter though I would love actually to
Speaker 1: go and like a lot air balloon. It's on my list.
Speaker 1: But still, I know, I know, I did not expect
Speaker 1: it either, but I was pleasantly surprised. So as Lavoisier
Speaker 1: was characterizing these gases that are involved in respiration, other
Speaker 1: scientists were seeing how they could turn this new information
Speaker 1: about these and other gases into application, especially in the
Speaker 1: context of controlled combustion, perhaps using combustion to power some
Speaker 1: sort of vehicle, say a balloon, that could travel long distances,
Speaker 1: both across the landscape as well as vertically, say a balloon,
Speaker 1: say a balloon. People had for hundreds of years, like
Speaker 1: I've said now a thousand times, climbed mountains or crossed
Speaker 1: mountain passes, or lived at high altitudes, and many people,
Speaker 1: most people who experience the things or lived at altitude,
Speaker 1: recognized and noted the signs and symptoms of being at
Speaker 1: high altitude, but these, at least in the written literature,
Speaker 1: often tended to be isolated descriptions and didn't necessarily lend
Speaker 1: themselves to systematic study, which was the opportunity that hot
Speaker 1: air balloons provided. Along with being able to see the
Speaker 1: effects of high altitude, namely acute and extreme hypoxia, separate
Speaker 1: from the physical exertion of climbing a mountain with no
Speaker 1: time for acclimation.
Speaker 3: Yeah, that's really interesting.
Speaker 1: Yeah, these early hot air balloonists were reaching heights of
Speaker 1: six thousand, seven thousand, even nine thousand meters. Oh so
Speaker 1: that's nine thousand meters is twenty nine thousand, five hundred feet,
Speaker 1: which is taller than Everest.
Speaker 3: That's it. Don't go there, don't do it.
Speaker 1: Yeah, And they were doing this within a matter of minutes. Yeah,
Speaker 1: And so of course they noticed that as they ascend it,
Speaker 1: breathing became more and more difficult, their heart beat faster
Speaker 1: and faster, and they became confused and tired, often hit
Speaker 1: with this massive headache. And even though they could recognize
Speaker 1: that altitude had this effect, they weren't sure how, and
Speaker 1: had yet to make the link that as air pressure changed,
Speaker 1: so did pressure in blood and tissues. Experiments and decompression chambers,
Speaker 1: mainly by Paul Barrett, who will meet in a bit,
Speaker 1: had shown that supplemental oxygen could be helpful for keeping
Speaker 1: symptoms at bay at higher altitudes, but only if you
Speaker 1: use it. So in the first hand account that I read,
Speaker 1: these the people in that balloon were carrying oxygen, but
Speaker 1: not enough of it, and they didn't use it until
Speaker 1: it was too late. So we talked about how he
Speaker 1: was like grabbing for the oxygen but couldn't do it.
Speaker 3: Yeah.
Speaker 1: But while these balloon excursions demonstrated the potentially deadly effects
Speaker 1: of rapid ascent to extreme altitude, dude, they're not quite
Speaker 1: the same as altitude sickness or acute mountain sickness. But
Speaker 1: don't fret because as balloons were getting more popular, so
Speaker 1: was mountaineering, which had been popular for hundreds of years.
Speaker 1: But the sport underwent a big boom during the period
Speaker 1: of widespread colonization by European nations, often pleasantly called something
Speaker 1: like the Golden Age of Exploration, particularly during the mid
Speaker 1: seventeen hundreds and into the eighteen hundreds. Naturalists with an
Speaker 1: interest in mountaineering like Alexander von Humboldt or mountaineers with
Speaker 1: an interest in science like Edward Whimper set their sights
Speaker 1: on various mountain peaks the Matterhorn, Chimborazzo, mont Blanc, etc.
Speaker 1: And as they learned how to set a root or
Speaker 1: which gear was best, they also learned to recognize the
Speaker 1: signs and symptoms of mountain sickness, and they wrote about
Speaker 1: their experiences. And so at this point in the story,
Speaker 1: I should probably introduce the quote unquote father of modern
Speaker 1: high altitude physiology and medicine, Paul Bert. When Barrett enters
Speaker 1: the picture around the eighteen sixties eighteen seventies or so,
Speaker 1: what we get is a switch from the largely anecdotal
Speaker 1: reports of the effects of altitude from mountaineers and balloonists
Speaker 1: to a systematic study analyzing what was happening to your
Speaker 1: body physiologically when you go up in altitude. And with
Speaker 1: the patronage of a Parisian physician, Denise Jordinay, who also
Speaker 1: had an interest in high altitude medicine, Berrett conducted a
Speaker 1: series of experiments where he put animals in hypobaric chambers,
Speaker 1: which simulated the low pressure of high altitude. He then
Speaker 1: played around with pressure levels until the animals became sick
Speaker 1: or died, and then he measured the amount of oxygen
Speaker 1: in their blood. What he found was that illness or
Speaker 1: death always occurred at a certain level of blood oxygen,
Speaker 1: but even more than that. He repeated this experiment where
Speaker 1: he kept the air pressure at sea level, but he
Speaker 1: lowered the overall oxygen concentration in the air. Again, he
Speaker 1: played around with oxygen concentrations in the air and watched
Speaker 1: for when the animals got sick or died, and then
Speaker 1: measured their blood oxygen. He found that regardless of whether
Speaker 1: he lowered the pressure or lowered the oxygen concentration, the
Speaker 1: animals got sick or died when their blood oxygen hit
Speaker 1: a certain point. Basically, he showed that it mostly came
Speaker 1: down to oxygen.
Speaker 3: Yeah.
Speaker 1: He also plotted the first oxygen association curves.
Speaker 3: Oh that's cool, Yeah, I love those.
Speaker 1: This finding was important both because it filled in a
Speaker 1: piece of the conceptual puzzle of high altitude physiology, and
Speaker 1: also because it provided a relatively straightforward way to treat
Speaker 1: the negative health effects of high altitude more oxygen, whether
Speaker 1: by descending or through use of supplemental oxygen, although whether
Speaker 1: supplemental oxygen was actually helpful was under debate for a
Speaker 1: surprising number of decades after this. This also raised the
Speaker 1: question of whether humans could get use to high altitudes
Speaker 1: and compensate for the lower oxygen in some way if
Speaker 1: they spent enough time up there. And like I've said
Speaker 1: many times, people did and do live at a high
Speaker 1: altitude in cities such as Lapause in Bolivia, which is
Speaker 1: at a wapping thirty six hundred meters or nearly twelve
Speaker 1: thousand feet in elevation.
Speaker 3: Wow.
Speaker 1: Yeah. Barrett speculated that people and other animals who had
Speaker 1: sustained exposure to high altitude may produce more red blood
Speaker 1: cells for increased oxygen absorption, which was later proven correct,
Speaker 1: and after Barrett's extensive research into high altitude physiology, the
Speaker 1: field really kind of opened up in the last couple
Speaker 1: of decades of the eighteen hundreds, with high altitude field
Speaker 1: stations established and expeditions organized to remote high altitude locations.
Speaker 1: These stations also served as home bases where people could
Speaker 1: study other disciplines such as astronomy, physics, and glaciology, and
Speaker 1: in some places like Pike's Peak in Colorado, which is
Speaker 1: at forty three hundred meters or fourteen thy one hundred feet,
Speaker 1: or La Arroya in Peru, which reached an altitude of
Speaker 1: forty eight one hundred meters or fifteen thousand, seven hundred feet.
Speaker 1: Railways were constructed to these sites so that the general
Speaker 1: public could also see what things were like above the clouds,
Speaker 1: or so people could mine side note, la Arroya might
Speaker 1: sound vaguely familiar to you because I've mentioned it on
Speaker 1: the podcast before. In our Barnella episode, I talked about how,
Speaker 1: at least I know, cast your mind back right. But
Speaker 1: in that episode I talked about how at least four
Speaker 1: thousand people died while working on the railroad to connect
Speaker 1: Lima to la Arroya. Oh yeah, this same railroad, and
Speaker 1: these four thousand or so people died from Bartonella bacilliformis
Speaker 1: aka Carryon's disease. Wow, isn't that connections?
Speaker 3: There's so many, Aaron.
Speaker 1: I love that. By the early twentieth century, scientists had
Speaker 1: made tremendous strides in understanding the relationship between altitude, oxygen
Speaker 1: and health, but there were still a ton of details
Speaker 1: to be figured out, like how mechanistically oxygen is used
Speaker 1: and how it acts in various tissues, as well as
Speaker 1: the steps involved in cellular respiration. That, however, don't worry
Speaker 1: is a topic for another day.
Speaker 3: I was like, oh gosh.
Speaker 1: Yeah, and instead I want to close out this history
Speaker 1: by talking about how the clinical picture of acute and
Speaker 1: chronic high altitude sickness and complications was filled in over
Speaker 1: the twentieth century. This is the last time I'll say it,
Speaker 1: but it bears repeating that not only have people lived
Speaker 1: at high altitude for tens of hundreds of thousands of years,
Speaker 1: but they've also recognized the negative health consequences of high altitude.
Speaker 1: And that's evidenced by the fact that there are many
Speaker 1: different local and regional names for altitude sickness. One of
Speaker 1: these was picked up by researcher Thomas Holmes Ravenhill, who
Speaker 1: published a paper in nineteen thirteen titled quote Some Experiences
Speaker 1: of Mountain Sickness in the andes end quote. In this paper,
Speaker 1: he classified mountain sickness into three primary forms. POONA of
Speaker 1: a normal type PUNA was the word for mountain sickness
Speaker 1: that people in northern Chile used where Ravenhill carried out
Speaker 1: his studies, and that is what we would call today
Speaker 1: a cute mountain sickness. And then two divergent types POONA
Speaker 1: of a cardiac type high altitude pulmonary edema and number
Speaker 1: two PUNA of a nervous type high altitude cerebral edema. Yeah,
Speaker 1: Ravenhill's work was largely overlooked though until the nineteen sixties,
Speaker 1: when it was quote unquote rediscovered, but in the meantime
Speaker 1: a good deal of research on altitude sickness and severe
Speaker 1: outcomes was conducted, primarily by South American researchers, including Leoncio
Speaker 1: Lizardaga Morla, who described the first cases of hate in Peru.
Speaker 1: In all of their publications, these researchers noted how quickly
Speaker 1: the affected person recovered after descending to a lower altitude,
Speaker 1: which is a useful thing to know, but their work
Speaker 1: was not really acknowledged, likely because of the bias against
Speaker 1: scientific publications not written in English. And this is notable
Speaker 1: when high altitude pulmonary edema was quote unquote rediscos covered
Speaker 1: in the US by Charles Houston in his nineteen sixty
Speaker 1: New England Journal of Medicine paper quote Acute pulmonary edema
Speaker 1: of high altitude. In this paper, he described a twenty
Speaker 1: one year old skier in Colorado who developed quote severe dyspnea, weakness,
Speaker 1: and cough and had to be evacuated at the hospital.
Speaker 1: He was observed to have a bluish tint to his skin,
Speaker 1: difficulty breathing, and rattling in the lungs, but no evidence
Speaker 1: of heart disease. Houston suggested that quote, both acute and
Speaker 1: chronic anoxia may cause striking elevation of the pulmonary artery, pressure,
Speaker 1: failure of the left ventricle, and pulmonary edema. Since exercise
Speaker 1: and severe cold together with anoxia may have cumulative effects,
Speaker 1: this explanation appears to be the most probable, and you
Speaker 1: may have caught that in that description. Houston also mentioned
Speaker 1: chronic anoxia, which had been an area of interest for
Speaker 1: several researchers for decades, and that is the physiological changes
Speaker 1: that occur when spending time at high altitude, as well
Speaker 1: as comparing populations of humans and other animals that had
Speaker 1: spent generations at high altitude with their lowland counterparts. One
Speaker 1: of the most prominent researchers in this area was Carlos
Speaker 1: Monhe Medrano, who in the mid nineteen hundreds characterized chronic
Speaker 1: mountain sickness sometimes called Monhey's disease. By this period, the
Speaker 1: field of high altitude physiology had grown immensely, helped along
Speaker 1: by military investigations during World War Two into how pilots
Speaker 1: performed at certain altitudes, went to deploy oxygen, etc. By
Speaker 1: veterinary studies exploring how to breed cattle that thrived at altitude,
Speaker 1: and it was also helped along by medical researchers wanting
Speaker 1: to know how low oxygen levels from other things besides altitude,
Speaker 1: like decreased lung function could be treated, and also by
Speaker 1: ecology and evolutionary biologists who wanted to tease apart questions
Speaker 1: like do all mammals acclimate to altitude in the same way?
Speaker 1: What is the genetic basis of high altitude adaptation in humans?
Speaker 1: Are the ways that mammals evolved to live at high
Speaker 1: altitude predictable? And so many more, so many, so many,
Speaker 1: And here today to answer some of these questions is
Speaker 1: a very special guest, doctor Jonathan Vlada, assistant professor at
Speaker 1: the University of Denver, and my partner will take a
Speaker 1: quick break here and then hear what John has to
Speaker 1: say about the evolutionary basis of high altitude adaptation.
Speaker 3: Oh, it's going to be so good.
Speaker 1: I'm really excited.
Speaker 2: Hi. I'm John Volata. I'm an assistant professor of biology
Speaker 2: at the University of Denver. My lab studies evolutionary biology
Speaker 2: and physiology of vertebrates. So we're interested in how animals
Speaker 2: have adapted to their environment at the physiological and genetic levels.
Speaker 2: One of the big things we're working on right now
Speaker 2: is adaptation to low oxygen and cold in a high
Speaker 2: altitude rodent. That's the North American deer mouse. But we
Speaker 2: also study the genetics and the physiology of ion and
Speaker 2: water balance evolution in species of fish.
Speaker 1: I love it.
Speaker 4: I'm so excited.
Speaker 1: It's really funny to say thank you so much for
Speaker 1: joining us today because we literally live together.
Speaker 3: I am looking at a Skype screen that's the two
Speaker 3: of them, but they're actually just sitting right next to
Speaker 3: each other in the same room. It's fantastic.
Speaker 1: Also, I love that we are probably still two of
Speaker 1: the only people left in the world that use Skype. Yes, yeah,
Speaker 1: I think we have a little bit of superstition in
Speaker 1: terms of, like, let's not mess this up. We know
Speaker 1: that this works.
Speaker 2: There are gen zers that don't know what Skype is.
Speaker 1: That's oh, actually true.
Speaker 3: Well then.
Speaker 1: All right, well let's say let's actually get into why
Speaker 1: we have John here today, not just to talk about
Speaker 1: the pros and cons of Skype. So and that is
Speaker 1: evolutionary adaptation to high altitude. One of the aspects that
Speaker 1: I was thinking about though, is just how difficult life
Speaker 1: at high altitude seems right. Everything is cold, there's no oxygen,
Speaker 1: the sun is trying to kill you with high UV.
Speaker 1: You're dehydrated all the time. Why live at high altitude?
Speaker 1: Are there any benefits for animals living at high altitudes?
Speaker 2: That's a question for me. Okay, oh you forgot one,
Speaker 2: which is that food is scarce obviously. Oh yeah, So yeah.
Speaker 2: The challenges of high altitude obviously are you know, hyperbaric hypoxia,
Speaker 2: as Aaron mentioned, and so a few animals really can
Speaker 2: and do you live there? And so that means that
Speaker 2: there's just fewer predators and competitors. So basically, if you
Speaker 2: can deal with the environmental challenges, and it's a fairly
Speaker 2: good place to live. So North American deer mice, for example,
Speaker 2: are really only rodent that lives at high altitude in
Speaker 2: the rockies above tree line, and there are very few
Speaker 2: larger predators there. At lower altitudes in the forests where
Speaker 2: they also live, they're hunted by you know, owls, foxes,
Speaker 2: pine martins, so lots of things like to eat them,
Speaker 2: and so at high altitude they're probably relatively safe. They're
Speaker 2: also safe for other competitors, other rodents that you know,
Speaker 2: live in very similar environments and eat similar food. So
Speaker 2: in terms of environmental conditions though, it's really challenging. So yeah,
Speaker 2: like you said, if you can evolve to deal with
Speaker 2: those environmental challenges, then you're relatively safe from other things
Speaker 2: in the world that are trying to kill you. And
Speaker 2: at high altitude, we do see some predators occasionally, like
Speaker 2: we've seen pine martins hunt deer mice at the summit
Speaker 2: of some of the mountains and the rockies, but that's
Speaker 2: probably relatively rare, and they're probably not there living there
Speaker 2: or there very often, but just coming up and then
Speaker 2: going back down.
Speaker 1: It's like a nice easy snack.
Speaker 3: Little day trip up to the summit for the view
Speaker 3: and a snack. So what is the highest altitude that
Speaker 3: a mammal has been found at? And also what about birds,
Speaker 3: like do they still cruise around up there?
Speaker 1: Yeah?
Speaker 2: Yeah, so recently, like in twenty twenty, there is a
Speaker 2: new record of the highest dwelling mammal by Jay Stores
Speaker 2: and colleagues, and it's a mouse called the yellow rumped
Speaker 2: leaf eared mouse. So this is Philotus santhopygis rupestris is
Speaker 2: the scientific name I had to practice that one. So
Speaker 2: actually it was captured by hand on the summit of
Speaker 2: a volcano between Chile and Argentina. It's Jujah Jacko is
Speaker 2: the name of the volcano. So that's six seven hundred meters,
Speaker 2: so it's about twenty one thousand feet, so it's you know,
Speaker 2: some of the highest peaks in the world do have animals.
Speaker 2: There are other high altitude dwelling mammals, like there's credible
Speaker 2: records of pica, which are sort of like a rabbit
Speaker 2: closely related to rabbits add or around I guess six
Speaker 2: thousand meters on everest and so yeah, there's that's pretty
Speaker 2: much as high as we've ever found mammal. And again
Speaker 2: the leaf ared mouse at six thousand, seven hundred meters
Speaker 2: is the record. So it's not like these mice are
Speaker 2: day visitors up to high altitude. Their home range is
Speaker 2: very small, so like for a North American deer mouse,
Speaker 2: the maximum home range is just like an acre or so,
Speaker 2: and so they're living up there, which is incredible because
Speaker 2: again there's not much to eat, and obviously the oxygen
Speaker 2: is very low and it's very cold all the time.
Speaker 2: So you mentioned birds. So birds are interesting because they
Speaker 2: can fly, obviously, and so birds can fly as high
Speaker 2: or higher than the tallest summits in the world. So
Speaker 2: there's a couple of birds that I think are good examples.
Speaker 2: So Nate Center and colleagues have tracked a migratory shore
Speaker 2: bird called the black tailed godwit at five thousand to
Speaker 2: six thousand meters. And the amazing thing about this is
Speaker 2: that they're not flying over anything in particular, like no
Speaker 2: land structures. They're just flying that high to take advantage
Speaker 2: of what they think are better air temperatures in solar
Speaker 2: radiation that make for more efficient flying. There are animals,
Speaker 2: there are birds that fly over the Himalaya, so that
Speaker 2: have been seen flying at you know, seven thousand meters,
Speaker 2: but they sort of hug the land, and so for them,
Speaker 2: they are more so flying over land structure, whereas the
Speaker 2: godwits are flying to take advantage of that better air.
Speaker 2: One of the last things I'll say is that they're
Speaker 2: exercising this whole time. My birds aren't just cruising in altitude,
Speaker 2: so they are flying in Flight is an incredibly energetic activity,
Speaker 2: and birds do have very efficient breathing, which is one
Speaker 2: of the things that helps them.
Speaker 3: That is amazing that they're flying that high and not
Speaker 3: just like holding their breath to go up for a
Speaker 3: little bit and then coming back down.
Speaker 1: Like what, Yeah, that is really cool to think about
Speaker 1: that how much work they're doing at that altitude. One
Speaker 1: of the questions that I asked Aaron earlier in the
Speaker 1: biology section, and she said, I don't know, but we
Speaker 1: should ask John this, or maybe we both.
Speaker 3: Did, that.
Speaker 1: Was about whether physiological responses to altitude are proportional to
Speaker 1: the altitude, So like, are you producing twice as many
Speaker 1: red blood cells as you are go up twice as
Speaker 1: high in altitude?
Speaker 2: So yeah, I mean generally I would say yes. I
Speaker 2: don't think there seems to be really a threshold, and
Speaker 2: acclimatization changes are mostly linear, and I mean, at least
Speaker 2: the work that I'm familiar with is in dear mice.
Speaker 2: So there's been some work by colleagues of mine, Katie
Speaker 2: Ivy and Graham Scott that have shown that breathing, for example,
Speaker 2: increases pretty linearly with decreasing partial pressures of oxygen. And
Speaker 2: then we've shown that red blood cells and hemoglobin concentrations
Speaker 2: increase steadily with decreasing pressure as well. So there's not
Speaker 2: a lot of great data, I guess I would say,
Speaker 2: but in general, I think it's pretty clear that yes,
Speaker 2: as you move up in altitude, the acclimatization responses are
Speaker 2: proportional to that decrease in partial pressure.
Speaker 3: Cool.
Speaker 1: Oh there you go.
Speaker 3: Oh wow. I love that. It was just like a yes,
Speaker 3: yes moving.
Speaker 2: I guess I could have just said yes.
Speaker 3: So we talked about during this episode that a lot
Speaker 3: of humans have lived at high altitudes, like maybe alongside
Speaker 3: these dear mice, for example, for hundreds of thousands of years.
Speaker 3: So do we see any genetic adaptations to this, both
Speaker 3: in humans and in these animals? And what's the difference
Speaker 3: between acclimatization when we talk about that and adaptation.
Speaker 2: Yeah, So, I guess I do want to preface this
Speaker 2: by saying that human evolution is not my field, but
Speaker 2: I would like to summarize here some of the really
Speaker 2: cool work that's been done by biologists and anthropologists. A
Speaker 2: lot of the work that I think I can talk
Speaker 2: about knowledgeably is by Cynthia Bell, who's an anthropologist at
Speaker 2: Case Western Reserve. And you asked about acclimatization and adaptation.
Speaker 2: So acclimatization is like all of those changes that you
Speaker 2: talked about, Aaron, so red blood cell production, changes in breathing,
Speaker 2: those things that happen in the short term or within
Speaker 2: the lifetime of an individual that sort of give us
Speaker 2: more oxygen when we need it. But adaptation course is
Speaker 2: an evolutionary process. It's where we see any change, but
Speaker 2: in this case physiological change that occurs over generations because
Speaker 2: those changes have some sort of advantage, and so all
Speaker 2: those changes are based on changes in our genes. To
Speaker 2: answer your question, humans do show adaptation to high altitude
Speaker 2: and it's really interesting and so I think the best
Speaker 2: way to look at it is to take two examples
Speaker 2: of two mountainous regions in the world where people live
Speaker 2: and where adaptations to altitude have arisen. And so these
Speaker 2: regions are the Andes in South America and the Tibetan
Speaker 2: Plateau in the Himalaya. And so there are establishments, towns
Speaker 2: and cities, in some cases really big cities over four
Speaker 2: thousand meters above sea level, so that's above fourteen thousand feet,
Speaker 2: and we see that there are genetic adaptations to high
Speaker 2: altitude that we assume come from living there over many generations.
Speaker 2: And so Aarin, you mentioned chronic mountain sickness, and that's
Speaker 2: the association of chronic mountain sickness with polysthemia, which is
Speaker 2: overproduction of red blood cells. And then I think you
Speaker 2: mentioned hypertension, which is high blood pressure. And so the
Speaker 2: incidents of chronic mountain sickness in some South American high
Speaker 2: altitude cities in Bolivia and Peru can be up to
Speaker 2: fifteen plus percent in one estimate that I saw, whereas
Speaker 2: the incidence of chronic mountain sickness on the Tibetan plateau
Speaker 2: is much lower, about one percent or less, and this
Speaker 2: is from one estimate from about twenty sixteen, and so
Speaker 2: on Tibetan plateau is I think higher on average, but
Speaker 2: most of the cities in which people live are probably similar.
Speaker 2: Some of the adaptations that we see in the Andes
Speaker 2: are really interesting, and they generally are a larger chest
Speaker 2: circumference in a greater total lung volume, and so this
Speaker 2: is likely an adaptation to just simply get more air
Speaker 2: the lungs. Other adaptations in the region include higher on
Speaker 2: average hemoglobin and red blood cell concentrations. And I think
Speaker 2: this is intuitive based on what you said, Aaron about acclimatization,
Speaker 2: because more red blood cells improves oxygenation in the blood,
Speaker 2: and so sort of to that end, there have been
Speaker 2: studies that have shown that increased hemoglobin and red blood
Speaker 2: cells is associated with higher arterial oxygen content. So they
Speaker 2: have more oxygen in their blood, actually more than when
Speaker 2: compared to some people at sea level. And the thing
Speaker 2: about this is that it may have a cost, and
Speaker 2: this would be sort of consistent with higher rates of
Speaker 2: chronic mountain sickness because more red blood cells sort of
Speaker 2: changes the content of your blood. It makes it thicker,
Speaker 2: and that could put a strain on your heart, which
Speaker 2: is a muscle as it's pumping a more viscous fluid.
Speaker 2: And so if you couple that with other changes that
Speaker 2: you mentioned, like pulmonary vasoconstriction, which again is the con
Speaker 2: restriction of the vessels in your lungs, that all puts
Speaker 2: a strain on the right part of the heart, especially
Speaker 2: as it pumps a thick blood through a constricted pulmonary vasculature.
Speaker 2: And so this could lead to an increased incidence of
Speaker 2: hypertension and not humans. But I could talk about deer
Speaker 2: mice a little bit, just something I'm always finding myself
Speaker 2: talking about. They also have this increase in blood viscosity
Speaker 2: and vase of constriction, and this leads to an increase
Speaker 2: in the actual size of the right ventricle of the heart,
Speaker 2: and it leads to an increase in the pressure in
Speaker 2: the right ventricle, which can contribute to things like heart failure.
Speaker 2: So yeah, that's some of the adaptations that are happening
Speaker 2: in the Andes. On the Tibetan Plateau, we see slightly
Speaker 2: different adaptations and this is really fascinating. Instead of lots
Speaker 2: of red blood cells, which would increase oxygen carrying capacity,
Speaker 2: studies find that the concentration of red blood cells are
Speaker 2: actually the same as someone who is living at sea level.
Speaker 2: And this is very different because if you or I
Speaker 2: were to go to the Tibetan Plateau, we would, as
Speaker 2: Aaron mentioned, really increase the number of red blood cells
Speaker 2: to get more hemoglobin. So this lower concentration of red
Speaker 2: blood cells should be disadvantageous in terms of blood oxygen level,
Speaker 2: but actually advantageous in terms of blood viscosity, right, And
Speaker 2: so studies have shown that on average, there is lower
Speaker 2: blood oxygen content in this region compared to those that
Speaker 2: live at sea level, and so to make up for
Speaker 2: this possible cost. Other studies have shown higher levels of
Speaker 2: nitrous oxide in the lungs, and so this is a
Speaker 2: chemical that is produced by the body. It's a vasodilator,
Speaker 2: and so it keeps those lung vessels open and that
Speaker 2: allows for better exchange of oxygen between the lungs and blood,
Speaker 2: and this likely lowers the potential for hypertension. And so
Speaker 2: according to one study I read, the pressure and the
Speaker 2: arteries of the lungs is twenty eight percent lower in
Speaker 2: the Tibetan region compared to those in the Andes.
Speaker 7: Wow, it is so so cool, so so cool.
Speaker 1: It blows my mind, honestly. Yeah. Oh man, So now
Speaker 1: that my mind is already blown about humans, I know
Speaker 1: that there's more to blow my mind about animals. So
Speaker 1: that was my really terrible segue into this next question.
Speaker 2: That was good.
Speaker 3: I loved it, thank you.
Speaker 1: Which is do we see these same adaptations to high
Speaker 1: altitude in other mammals besides humans? And I know you
Speaker 1: talked a little bit about deer mice, but I guess
Speaker 1: in general, do mammals evolve to live at high altitude
Speaker 1: in predictable ways?
Speaker 2: Yeah? I mean yeah, and no, it all has to
Speaker 2: hinge on oxygen transport, where in terms of the physiology
Speaker 2: of an animal, that happens does depend on the animal,
Speaker 2: and so I can talk about a lot of examples
Speaker 2: of high altitude deer mice some of the similarities and
Speaker 2: some of the differences. So deer mice also reduce the
Speaker 2: amount of hemoglobin and red blood cell production when they're
Speaker 2: at altitude, so that's similar to the Tibetan story that
Speaker 2: I explained earlier. And they also have reduced pulmonary arterial pressure.
Speaker 2: So there have been studies by some colleagues that I've
Speaker 2: mentioned that have shown that highland deer mice also have
Speaker 2: more capillaries, and those capillaries supply more oxygen to their muscles,
Speaker 2: which is really really important for a deer mouse, especially
Speaker 2: because they need those muscles to produce heat in a
Speaker 2: really cold environment, and they do that by one of
Speaker 2: the ways is by shivering, and that requires oxygen.
Speaker 3: Just imagining these poor little deer mice just shivering in
Speaker 3: order to stay alive for thousands of years, like I'm
Speaker 3: the best shiverer. That's so sad.
Speaker 2: Yeah, there's really strong selection on what we would call thermogenesis,
Speaker 2: the production of heat metabolically, and so I should really
Speaker 2: preface this by saying that deer mice are winter active.
Speaker 2: They really need this oxygen and they really need this
Speaker 2: shivering because they're active pretty much all year long. Going
Speaker 2: off of that, there have been some other studies, some
Speaker 2: by Zach Chevron and his colleagues that show that high
Speaker 2: altitude deer mice are more effective at using fat as
Speaker 2: a fuel source during this shivering. And this is because
Speaker 2: fats are way higher in energy, but they do take
Speaker 2: a lot more oxygen to burn. So if you can
Speaker 2: figure out fear a dear mouse, you can figure out
Speaker 2: how to get more oxygen. Then you can burn fat
Speaker 2: and shiver better cool. And there are lots of other
Speaker 2: ones too, I mean, yeah, how much do you want?
Speaker 2: So there's a lot of animal species, birds and mammals
Speaker 2: mostly that have evolved a hemoglobin that has a higher
Speaker 2: affinity for oxygen. Some birds and mammals have an evolutionary
Speaker 2: adaptation to just have intrinsically higher oxygen affinity, so this
Speaker 2: means they can pick up more oxygen. So in many hummingbirds,
Speaker 2: the higher the elevation that these hummingbirds live, the greater
Speaker 2: the hemoglobin oxygen affinity on average. This is true of
Speaker 2: dear mice too. Dear mice that live at high altitude
Speaker 2: have a higher hemoglobin oxygen affinity and it is a
Speaker 2: genetic change. And this change in affinity is caused by
Speaker 2: mutations in the hemoglobin gene. If I could riff at
Speaker 2: the genetic level for a little while, one of the
Speaker 2: things that we see is that there's a lot of
Speaker 2: mutations in animals and a lot of different animals in
Speaker 2: a gene called ePass one. And so this is a
Speaker 2: gene that codes for a protein that's what genes do
Speaker 2: that initiates the body's response to hypoxia. So it's a
Speaker 2: really important gene called a regulator. And all the things
Speaker 2: we've talked about, like red blood cell production, changes to
Speaker 2: the vascularture, these things at the genetic level are controlled
Speaker 2: by epus one. And so there are adaptive mutations at
Speaker 2: this gene that we find in high altitude animals, including deer, mice,
Speaker 2: also wolves, sheep, humans, birds, dogs, and even a snake.
Speaker 1: Why how are snakes up that high? I didn't know that,
Speaker 1: like reptiles could survive at high altitude. That's amazing.
Speaker 2: I have no idea. I mean some of the sheep
Speaker 2: and the dog thing is kind of interesting because those
Speaker 2: are animals generally that people have brought to high altitude,
Speaker 2: and so their evolution at high altitude is more recent.
Speaker 2: And I think the really fascinating thing about ePass one
Speaker 2: is that this is all happening independently, right. These are
Speaker 2: very distantly related species of mammals, birds, and reptiles, and
Speaker 2: so clearly ePass one, the mutation at ePass one has
Speaker 2: some sort of beneficial effect. We don't really know what
Speaker 2: that is. We have found that in dear mice there
Speaker 2: is the mutation in ePass one is associated with having
Speaker 2: a higher heart rate when you're exposed to hypoxia, So
Speaker 2: that should mean better pumping of oxygenated blood to tissues.
Speaker 2: But that's probably just one effect and a lot more
Speaker 2: research needs to be done. I'll leave you with one
Speaker 2: final cool thing about animals deer mice again, and that's
Speaker 2: that there are some really interesting studies showing that low
Speaker 2: altitude mice, so mice that live at sea level, produce
Speaker 2: low birth weight offspring when they're exposed to high altitude,
Speaker 2: so they have offspring that weigh less than they do
Speaker 2: if they were to breed at sea level. We would
Speaker 2: call this fetal growth restriction. And so there's some cool
Speaker 2: work going on Kate Wilsterman and her colleagues that have
Speaker 2: been finding that in high altitude dear mice. So these
Speaker 2: are mice that are adapted to high altitude, they are
Speaker 2: protected from fetal growth restriction, and that in part has
Speaker 2: to do with adaptations in the placenta that improve gas
Speaker 2: and nutrient exchange from mom to fetus.
Speaker 3: That is amazing, It's absolutely fascinating. So you dis covered
Speaker 3: like a million amazing high altitude adaptations in like the
Speaker 3: shortest amount of time. It was amazing, And we already
Speaker 3: talked about how difficult it is to live at high altitude.
Speaker 3: So I guess my question is do these high altitude
Speaker 3: adaptations themselves as cool as they are, do they come
Speaker 3: with a cost? And do we know what that cost is?
Speaker 2: Yeah? So I think I's already mentioned blood viscosity and
Speaker 2: the association with hypertension, and so one of the other
Speaker 2: cool ones at least that we've seen in deer mice
Speaker 2: is the So there is this genetic variant for hemoglobin
Speaker 2: that I mentioned that's more prevalent at high altitude and
Speaker 2: it helps with picking up more oxygen and the lungs,
Speaker 2: and so one of the interesting things is that in
Speaker 2: mice with those genetic variants, when they exercise at low altitude,
Speaker 2: they tend to do worse than mice without that high
Speaker 2: altitude gene. And this is presumably because having that variant
Speaker 2: does help with picking up oxygen, but it also holds
Speaker 2: on to it more tightly and so it has trouble
Speaker 2: giving it up at the tissues during exercise. So if
Speaker 2: you just stay at high altitude, you're fine, but there
Speaker 2: is like a trade off there, and that is a cost.
Speaker 3: You can never go back to the beach exactly.
Speaker 2: We'll pass.
Speaker 1: We have one last question for you, and it's designed
Speaker 1: to make you feel like you're back in grad school
Speaker 1: taking your prelimbs.
Speaker 2: So great, apologies, I just had a flashback.
Speaker 1: What do you think is the biggest unanswered question in
Speaker 1: your field?
Speaker 2: Right? So, I mean there are a lot of them, obviously,
Speaker 2: but I think really the biggest thing is how genes,
Speaker 2: how changes to genes lead to adaptations of physiology. That
Speaker 2: is something that we know very very little about. So
Speaker 2: aside from the work from Jay Stores that I mentioned
Speaker 2: on hemoglobin and some others. We don't really know about
Speaker 2: how genetic changes lead to physiological adaptations. We know there
Speaker 2: are genetic changes, we know there are physiological adaptations. We
Speaker 2: know there are genes that have mutations that are likely
Speaker 2: involved in adaptations, but we don't know how those mutations change,
Speaker 2: how the gene works and how the animal works and
Speaker 2: all of that. So I think that is really one
Speaker 2: of the frontiers, at least in sort of the evolutionary
Speaker 2: biology of high altitude. Awesome done well.
Speaker 1: Thank you so much doctor Volata for coming on to
Speaker 1: chat with us about high altitude adaptations. And if any
Speaker 1: of you listeners out there are curious about John's work
Speaker 1: and want to learn more, check out his website on
Speaker 1: du dot edu or whatever. We'll link to it on
Speaker 1: our website.
Speaker 3: I don't know the exact we don't have to have
Speaker 3: it memories.
Speaker 2: It's lab dot com.
Speaker 1: Oh yeah, that's right. You haven't hear of your own
Speaker 1: lab website.
Speaker 2: And you're welcome for making the long track down to
Speaker 2: our basement.
Speaker 4: Thank you so much, John for coming coming all the
Speaker 4: way down to chat.
Speaker 2: With us anytime, anytime.
Speaker 3: A genuinely, it was really great to have you, so
Speaker 3: we really appreciate it.
Speaker 2: Well, it's it was my pleasure. I've been a long
Speaker 2: time listener, but first time caller.
Speaker 1: Eve been holding that one in.
Speaker 2: I practice that one.
Speaker 1: Is there anything else that we need to cover before
Speaker 1: we do sources?
Speaker 3: Just in case anyone was really dying for this information.
Speaker 3: We don't have numbers on the epitemology of acute mountain
Speaker 3: sickness or chronic mountain sickness. Every study that you read
Speaker 3: on the incidence of acute mountain sickness has vastly different numbers.
Speaker 3: So that's why we just kind of skipped over that part.
Speaker 3: And I will link to a couple of papers about
Speaker 3: high altitude training for those of you who are maybe
Speaker 3: really into it, because that was something we didn't touch on.
Speaker 3: That's all I've got. Okay, Well with.
Speaker 1: That sources sources, I'm just going to shout out one basically,
Speaker 1: and that was a book called High Life, A History
Speaker 1: of High Altitude Physiology and Medicine by John webs Oh.
Speaker 1: And also there was a great ted ed talk about
Speaker 1: how barometers work that I'll link to.
Speaker 3: I had a whole number of papers on the physiology
Speaker 3: of acclimatization and the path of physiology of ams. I
Speaker 3: think one of my favorites was by Murdoch in twenty
Speaker 3: ten in BMJ Clinical Evidence just called altitude sickness. But
Speaker 3: I will list all of the rest of them. John,
Speaker 3: did you want to cite any of your sources?
Speaker 2: Yeah, I can. I give you all of my There's
Speaker 2: like probably twenty twenty five papers in here that I
Speaker 2: summarized all for you guys.
Speaker 1: We will pullot all.
Speaker 3: We will post all twenty five of those and all
Speaker 3: of ours as well on our website. This podcast will
Speaker 3: kill you dot com.
Speaker 1: We certainly will. Oh.
Speaker 3: Thank you also to Bloodmobile, who provides the music for
Speaker 3: this episode and all of our episodes.
Speaker 1: Thank you to Leanna Squalacci for our excellent audio mixing
Speaker 1: love it.
Speaker 4: Thank you to the Exactly Right Network.
Speaker 1: And thanks to you listeners. So many thank yous, and
Speaker 1: we're not even done yet, but we really appreciate you listening,
Speaker 1: and we hope you liked this really deep dive, high climb,
Speaker 1: high to high altitude physiology and history no comment.
Speaker 3: And as always, an extra thank you to our patrons.
Speaker 3: We can't express enough how much we appreciate your support.
Speaker 1: It's true. Well, until next time, wash your hands, you
Speaker 1: filthy animals
Speaker 5: E.