Welcome to the Huberman Lab Podcast where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today marks the second episode in our journal club series with myself and Dr. Peter Attia. Dr. Peter Attia, as many of you know, is a medical doctor who is a world expert in all things health span and lifespan.
He is the author of the best-selling book Outlive as well as the host of his own terrific podcast, The Drive. For today's episode, Peter and I each select a different paper to share with you. We selected these papers because we feel they are both extremely interesting and extremely actionable. First, I present a paper that is about how light exposure during the morning and daytime as well as dark exposure at night.
Each have independent and positive effects on mental health, as well as the ability to reduce the symptoms of many different mental health disorders. I've talked before on this podcast and elsewhere about the key importance of seeing morning sunlight as well as trying to be in dim light at night.
However, the data presented in the paper today really expands on that by identifying the key importance of not just morning sunlight, but getting bright light in one's eyes as much as is safely possible throughout the entire day and a separate additive effect of being in as much darkness at night as possible. I describe the data in a lot of detail, although you do not need a background in biology in order to understand that discussion.
And there's a key takeaway, which is that if you can't get enough light in your eyes during the daytime, you would be well advised to get as much darkness exposure at night. In other words, light and dark have independent and additive effects on mental health. And during today's discussion, you'll learn exactly how to apply light exposure and dark exposure in order to get those benefits. Then Peter presents a paper about novel treatments for cancer.
I must say it's an extremely important conversation that everybody, regardless of whether or not you may have had cancer or no somebody who's had cancer, ought to listen to. He highlights the current technology of cancer treatments, as well as the future technology of cancer treatments and the key role that the immune system and the auto immune system play in treatments for cancer.
I assure you that by the end of today's journal club episode, you will have learned a ton of new information about light and dark and mental health, as well as cancer and the immune system and treatments for curing cancer. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public.
In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is 8 Sleep. 8 Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. I've spoken many times before on this podcast about the fact that sleep is the foundation of mental health, physical health, and performance.
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8 Sleep currently ships in the USA, Canada, UK, select countries in the EU, and Australia. Again, that's 8Sleep.com slash Huberman. This episode is also brought to us by BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out online. I've been going to therapy for well over 30 years. Initially, I didn't have a choice. It was a condition of being allowed to stay in school. But pretty soon I realized that therapy is extremely valuable.
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Again, that's BetterHelp.com slash Huberman. Today's episode is also brought to us by Juve. Juve makes medical grade red light therapy devices. Now, if there's one thing I've consistently emphasized on this podcast, it's the incredible role that light can have on our biology.
Of course, I'm always telling people that they should get sunlight in their eyes as soon as possible after waking on as many days of their life as possible for sake of setting circadian rhythm, daytime mood focus and alertness, and improve sleep.
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Personally, I use the handheld Juve every day. The handheld Juve is about the size of a thick piece of toast, and I also own a Juve panel that allows for full body exposure, and I use that one approximately five times per week for about 10 to 15 minutes per session. If you'd like to try Juve, you can go to Juve spelled J-O-O-V-V dot com slash Huberman.
Again, that's Juve dot com slash Huberman. For this month only, January 2024, Juve is offering exclusive discounts to Huberman Lab listeners with up to $500 off select Juve products. Again, that's Juve spelled J-O-O-V-V dot com slash Huberman to get up to $500 off select Juve products. And now for my discussion with Dr. Peter Atia. Andrew, great to have you here for Journal Club number two. I'm already confident this is going to become a regular for us.
I'm excited. I really enjoy this because I get to pick papers. I'm really excited about. I get to hear papers that you're excited about, and we get to sharpen our skills at reading and sharing data, and people who listen and can do that as well. So last time I went first, so I think I'm going to put you on the hot seat first and have you go first, and I'll follow you.
Okay. Well, I'm really excited about this paper for a number of reasons. First of all, it, at least by my read, is a very powerful paper in the sense that it examined light exposure behavior, as well as dark exposure behavior. And that's going to be an important point in more than 85,000 people as part of this cohort in the UK. I'll just mention a couple of things to give people background, and I'll keep this relatively brief.
First of all, there's a long standing interest in the relationship between light and mental health and physical health, and we can throw up some very well agreed upon bullet points.
First of all, there is such a thing as seasonal effective disorder. It doesn't just impact people living at really northern locations, but basically there's a correlation between day length and mood and mental health such that for many people, not all, but for many people, when days are longer in the spring and summer, they feel better. They report fewer depressive symptoms, and conversely, when days are shorter, significantly more people report feeling lower mood and affect.
Okay. So there's a long standing treatment for seasonal effective disorder, which is to give people exposure to very bright light, especially in the morning. The way that that's normally accomplished is with these sad lamps, seasonal effective disorder lamps, and those lamps are basically bright, meaning more than 10,000 lux lights that they place on their kitchen counter or at their table in the morning or in their office.
So they're getting a lot of bright light. That is proven to be fairly effective for the treatment of seasonal effective disorder. What's less understood is how light exposure in the middle of the night can negatively impact mood and health. And so where we are headed with this is that there seems to be, based on the conclusions of this new study, a powerful and independent role of both daytime light exposure and nighttime dark exposure for mental health.
So all of other key points, the biological mechanisms for all this are really well established. There's a set of cells in the neural retina, which aligns the back of your eye. There's sometimes called intrinsically photosensitive retinal ganglion cells, or sometimes called melanobs and retinal ganglion cells. We'll talk about those in a bit of detail in a moment.
One of those cells are the ones that respond to two different types of light input, not one, but two different types of light input and send information to the hypothalamus where your master circadian clock resides, and then your master circadian clock sends out secretory signals, so peptides, hormones, but also neural signals to the brain and body and say, hey, now it's daytime, now it's nighttime.
So if you're awake, be asleep, but it goes away beyond that. These melanobs and intrinsically photosensitive retinal ganglion cells, we know also projected areas of the brain, like the hebenula, which can trigger negative affect negative mood. They can trigger the release of dopamine or the suppression of dopamine, the release of serotonin, the suppression of serotonin.
They're not just cells for setting your circadian clock. They also have a direct line, literally one synapse away into the structures of the brain that we know, powerfully control mood. So the mechanistic basis for all this is there. So there's just a couple of other key points to understand for people to really be able to digest the data in this paper fully.
There are basically two types of stimuli that these cells respond to. One is very bright light as we just talked about. That's why getting a lot of daytime sunlight is correlated with elevated mood. That's why looking at a 10,000 lux artificial lamp can offset seasonal effective disorder. By the way, just take a couple questions on that. How many lux does the sun provide on a sunny day at noon?
Okay, great question. So if you're out in the sun with no cloud cover or minimal cloud cover in the middle of the day at noon, chances are it's over a hundred thousand lux. On a really bright day could be 300,000 lux. Okay, most indoor environments, even though they might seem very bright, I like to think of your kind of like department store with the bright lights. Believe it or not, that's probably only closer to 6,000 lux maximum and probably more like 4,000 lux.
Most brightly lit indoor environments are not that bright when it comes down to total photon energy. Now, here's the interesting thing on a cloudy day. When you're outside, it can be as bright as an average of 100,000 lux. But it won't seem that bright because you don't quote unquote see the sun. But it's also because when there's cloud cover, a lot of those long wavelength of light, such as orange and red light aren't coming through.
However, and this is so important, the circadian clock, the superchismatic nucleus, it sums photons. It's a photon summing system. So basically if you're outside in 8,000 lux very overcast UK winter day and you're walking around, hopefully without sunglasses because sunglasses are going to filter a lot of those photons out. Your circadian clock is summing the photons. So it's an integration mechanism. It's not triggered in a moment.
And actually the experiments of recording from these cells first done by David Berson at Brown were, you know, historic in the field of visual neuroscience when shown bright light on these intrinsically photosensive cells, crank up the intensity of the light and the neurons would ramp up their membrane potential and then start spiking firing action potentials or long trains of action potentials that have been shown to go on for hours.
And so that's the signal that's propagating into the whole brain and body. Okay, so the the important thing to understand is this is not a quick switch. That's why I suggest on non cloudy days, we'll call them that people get 10 minutes or so of sunlight in their eyes in the early part of the day. Another 10 minimum in the later part of the day as much sunlight in their eyes as they safely can throughout the day.
But since your physician, I should just and you had a guest on talking about this recently when the sun is low in the sky low solar angle sunlight. That's really the key time for reasons we'll talk about in a moment. And when the sun is low in the sky, you run very, very little risk of inducing cataract by looking in the general direction of the sun.
You should still blink as needed to protect the eyes. It's when the sun is overhead and if there's all those photons coming in quickly in one in a short period of time that you do have to be concerned about cataract and
macular degeneration if you're getting too much daytime sunlight. So the idea is sunglasses in the middle of the day are fine, but you really should avoid using them in the early and later part of the day unless you're driving into the sun and you need you know for safety reasons. Another question I understand if if the person is indoors, but they have large windows. So they're getting tons of sunlight into their space.
They don't even need ambient indoor light. How much of the photons are making it through the glass and how does that compare to this effect? Yeah, in general, unless the light is coming directly through the window. Most of the relevant wavelengths are filtered out. In other words, if you can't see the sun through the window, even if sufficient light is being provided, that's insufficient to trigger this phenomena.
That's right. However, if you have windows on your roof, which some people do skylights, that makes the situation much, much better. In fact, the neurons that in the eye that signal to the circadian clock and these mood centers in the brain reside mainly in the bottom two thirds of the neural retina and are responsible for looking up basically. They're gathering light from above.
These cells are also very low resolution. So think of them as big pixels. They're not interested in patterns and edges and movement. They're interested in how much ambient light there happens to be. Now, keep in mind that this mechanism is perhaps the most well-conserved mechanism in cellular organisms. So they're and I'll use as a way to frame up the four types of light that one needs to see every 24 hours for optimal health.
And when I say optimal health, I really mean mental health and physical health, but we're going to talk about mental health mainly today in this paper. There's an absolutely beautiful evolutionary story whereby single cell organisms all the way to humans, dogs, rabbits and everything in between have at least two conopsens, one that responds to short wavelength light, aka blue light, and another one that responds to longer wavelength light, orange and red.
So your dogs have this, we have this, and it's a comparison mechanism in these cells of the eye, these neurons of the eye. They compare contrast between blues and orange or sometimes blues and reds and pinks, which are also all long wavelength light. There are two times of day when the sky is enriched with blues, oranges, pinks and reds and that's low solar angle sunlight at sunrise and in the evening.
These cells are uniquely available to trigger the existence of those wavelengths of light early in the day and in the evening, not in the middle of the day. These cells have these two cone photo pigments and they say how much blue light is there, how much red light is there, or orange light. And the subtraction between those two triggers the signal for them to fire the signal off to the circadian clock of the brain. And that's why I say look at low solar angles sunlight early in the day.
What that does is it, what we call it, is phase advances the clock. This can get a little technical and we don't want to get too technical here, but think about pushing your kid on a swing. The period of that swing, the duration of that swing is a little bit longer than 12 hours. So when you stand closer to the kid, so your kid swings back and you give it a push, you're shortening the period.
You're not allowing the swing to come all the way up. That's what happens when you look at morning sunlight. So you're dancing your circadian clock, translate to English or non nerd speak, you're making it such that you will want to go to bed a little bit earlier and wake up a little bit earlier the next day. In the evening, when you view low solar angle sunlight, so in the afternoon setting sun or evening setting sun, you do the exact opposite.
You're phased the lane in the clock. It's the equivalent of your kid being at the very top of the of the arc. And so it's gone, you know, maybe 12 and a half hour, 12 let's say 12 and a half hours is the duration of that swing and you run up and you push them from behind and give them a little more push. That's the equivalent of making yourself stay up a little later and wake up a little later.
These two signals average so that your clock stays stable. You don't drift, meaning you're not waking up earlier every single day or going to sleep later every single day. This is why it's important to view low solar angle sunlight in the morning and again in the evening as often as possible. And it's done by that readout of those two photo pigments. Now mid day sun, which contains its bright light, but you see it as white light contains all of those wavelengths that equal intensity.
So the middle of the day is the so called circadian dead zone in the middle of the day bright light triggers the activation of the of the other ops and the melancholy which increases mood increases feelings of well being has some other consequences. But you can't shift your circadian clock by viewing the sun in the middle of the day because it's in the circadian dead zone. It's the equivalent of pushing your kid on the swing when they're at the bottom of the arc.
You can get a little bit more but not much. And in biological terms, you get nothing. So this is why looking at sunlight in the middle of the day is great, but it's not going to help anchor your sleep wake cycle.
And if you think about this is incredible, right every organism from single cells to us has this mechanism to know when the sun is rising and when the sun is setting and it's a color comparison mechanism, which tells us that actually color vision evolved first, not for pattern vision, not for seeing beautiful sunsets and recognizing that's beautiful or paintings or things of that sort, but rather for setting the circadian clock.
Now what if you only do one of these and so what if you've got constant exposure to low morning light, but your job prevents you from doing the same in the evening or vice versa. Yeah, a great question. Better to get the morning light because if you have to pick between low solar angle light earlier later in the day and keep in mind if you miss a day, no big deal.
It's a slow integrative mechanism averaging across the previous two or three days, but if you miss a day, you want to get twice as much light in your eyes that next morning. The reason it's better to do in the morning as opposed to the evening, although both would be to do best would be to do both, excuse me, is that most people are getting some artificial light exposure in the evening anyway.
And here's the diabolical thing. Your retina is very insensitive to light early in the day. You need a lot of photons to trigger this mechanism early in the day as the day goes on retinal sensitivity increases and it takes very little light to shift your circadian clock late in the day. Keep in mind also that if you do see afternoon and evening sunlight, there's a beautiful study published in science, science reports.
Yes, science reports two years ago showing that that can partially offset the negative effects of artificial light exposure at night. I think of this as your Netflix inoculation. And the amount of melatonin suppression from nighttime light exposure is halved by viewing evening setting sun. Now keep in mind you don't need to see the sun cross the horizon. It can just be when it's low solar angle.
So you're looking for those yellow blue or blue pink blue red contrast and on cloudy days believe it or not, they're still there just you don't perceive as much of it coming through. So they're really so that's three things that we should all strive to do. View low solar angle sunlight early in the day view solar angle sunlight later in the day and get as much bright light in our eyes as we safely can ideally from sunlight throughout the day.
And if you can't do that, perhaps invest in one of these sad lights so that they can be a bit expensive. There are a couple companies that are starting to design sunrise simulators and evening simulators that are actually good that actually work. But right now my read is that aside from one company out there which by the way have no relationship to it's called the two oh light to you.
And that light bulb was developed by the biologists of the University of Washington who basically discovered these color opponent mechanisms. Those lights are not particularly expensive but they're they do seem to work. In fact, they they're the study that is emerging again unpublished data seems to indicate that if you look at it for more than five or six minutes, it can induce a mild euphoria.
That's how powerful this contrast is and what they did there in that light. I'll just tell you the mechanism is they figured out that when most people look at low solar angle sunlight in the morning, they're getting 19 reversals of blue orange per second. So when you look at this light, it looks like a barely flashing white light but it's reversals of orange and blue orange and you know red and blue and it's happening.
What is the person looking at it perceive? Well, I've used one of these you just looks like a flickering light and of course there's always the potential of a placebo effect but lots of us going to say is there a way to control for that by having something that looks the same to the user but of course is not producing the same photo effect.
You know, they've done that with the 10,000 lux sad lamps and you would and which most people use to try and induce sunrise simulation in their home but keep in your mind that sunrise is gives you this comparison of short and long wavelength light.
Just a bright 10,000 lux light triggers one of the options that that but it won't set your circadian clock so most of the sad lamps that are out there are activating only one of the mechanisms in these cells that's relevant and not the one that's most relevant.
I'm excited about what 2o is doing. I think that and again, I have no relation to them except I know the biologists who do the work that provide the mechanistic logic for that engineering. I still think we're in the like really like early days of this stuff. What should be done is to have this stuff built into your laptop. It should be built into your phone and hopefully it will be now.
I mentioned this color contrast thing in sunrise and sunset I mentioned the bright light throughout the day but there's a fourth light stimulus that turns out to be really important and this will provide the segue into the paper. Turns out that dark exposure at night independent of light exposure during the day is important for mental health outcomes now most people think dark exposure how do I think about that well it's dark.
It's the absence of light but what this paper really drives home is that people who make it a point to get dark exposure at night aka the absence of light at night actually benefit even if they're not getting enough sunlight during the day and this is especially true for people with certain mental health issues. So I don't think we can overstate the value of accurately timed light exposure to the eyes in the context of mental health. I think there's so much data by now.
I will say however that some people seem more resilient to these light effects than others meaning some people also don't suffer from jet lag too much.
Some people can stay up late get a lot of bright light exposure in the middle of the night and during the day they got their sunglasses on all day and they're in a great mood all the time other people are more susceptible these sorts of things and we don't know whether or not Pauli morphisms underlie that I personally am very sensitive to sunlight in the sense that if I don't get enough sunlight I don't feel well after a couple of days.
But I'm less sensitive to light exposure at night for instance but I think it is perhaps is a big statement but is perhaps the most fundamental environmental stimulus for levels of arousal and alertness which correlate with all sorts of you know neuromodulator and hormone outputs and so it none of this should come as any surprise.
I mentioned one last thing there was a study published gosh over 10 years ago now from Chuck's isers lab at Harvard Medical School is a phenomenal lab exploring circadian human health behavior he's just considered a no pun luminary in the field but there wasn't a study that was in error where they had published in science magazine that light shown behind the knee could shift circadian rhythms and that paper was retracted and a lot of people don't know that it was retracted light exposure to the eyes is what's really good.
And as far as we know the color of one's eyes like darkness or lightness of one's eyes bears no relevance on their sensitivity to these types of mechanisms and on and on. So one question one comment the question again is going back to the morning evening light and I spend a lot of time looking at those types of skies for example just because of the nature of my hobbies right because I'm always doing archery in the morning and rocking in the afternoon.
So it's not uncommon that I'm seeing both of those how relevant is it that the sun be above the horizon so for example it begins to get light about in 30 minutes before sunrise and then you know right it's so sun rises at 7 30 first light is seven and then you know sort of 7 15 to 7 30 is actually quite bright I mean you can see anything and everything in the same is true at sunset.
So does does that 30 minutes pre or when Sun is beneath the horizon constitute part of that 10 minutes it does I mean in an ideal circumstance you get outside and see the sunrise every day and you see the sunset every day even on cloudy days. Some people like myself wake up before the sun comes up in which and I get this question all the time well in the absence of powers to make the sunrise faster which I'm not aware anyone has certainly not me.
I think the best thing to do is simply to turn on as many bright lights as you can indoors to trigger that melanops and mechanism if you want to be awake if you want to stay asleep or sleepy then keep them dim and then get outside once the sun is starting to come out some people wake up after the sun has risen right in which case get what you can and some people wake up 10 a.m. or noon in which case you can still get the bright light exposure but you won't shift your circadian clock.
Now in the evening especially in the winter months it's important to look west and try and get some sunlight in your eyes in the evening if you've ever gone into the clinic for instance at two o'clock in the afternoon after lunch you know and then in the winter and then come out and it's dark when you're walk into your car.
It's a kind of eerie feeling that sort of eerie feeling may correlate with the fact that you missed a signal your brain is trying to orient your brain and body in time and that's what all of this is right trying to orient in time and again some people are more susceptible to that than other some people might like that feeling of oh I went in it when it was bright and I come out when it's dark but the vast majority of people feel better when they're getting this morning and evening sunlight exposure and this is especially important in kids.
Alright this is one of the things that you know this paper points out and their good data that people are spending approximately 90% of their time indoors nowadays daytime time indoors and those indoor environments are simply not bright enough you think oh there's all these bright lights and some people are putting blue blockers on in the middle of the day which is the worst thing you could possibly do if you're going to wear blue blockers and I don't think they're necessary but if you're going to wear them you'd want to wear them at night and in the evening you don't need to wear blue.
You don't need to wear blue blockers you just simply should dim the lights and ideally have lights that are set a little bit lower in your environment which the Scandinavians have been doing for a long time so you know kill the overhead lights and don't obsess about bright light exposure in the middle of the night in fact for a long time I and some other people were saying oh you know even just a brief flash of light in the middle of the night can you wash your melatonin that's true but the other time in which you're in this quote unquote circadian dead zone is in the middle of the night.
You can't shift your circadian clock in the middle of the night but you know all of this gets down to inter weaving rhythms of light sensitivity temperature hormone output cortisol it I mean there's a whole landscape of circadian biology this paper which was published in a new journal I'm really excited about called nature mental health this journal was just launched recently is entitled day and night light exposure are associated with the same kind of energy that is in the middle of the night and I'm going to say that this is a very important thing.
Light exposure are associated with psychiatric disorders and objective light study in more than 85,000 people now I have to say that I think the title of this paper is terrible sorry folks at nature mental health because if one just read the title it sounds like day and night light exposure associated with psychiatric disorders right if this or if this or a newspaper headline you like oh my goodness what do you supposed to do right but that's not the conclusion the conclusion is that getting a lot of.
Sunlight exposure during the day and getting a lot of dark exposure at night is immensely beneficial for psychiatric health and in a number of ways now I'm not one to bring up another paper on announce but I will say that this paper built off a previous study entitled time spent in outdoor light is associated with mood sleep and circadian rhythm related outcomes and that was a cross sectional longitudinal study in 400,000.
Biobank participants so this UK biobank is an incredibly valuable resource and there are now multiple studies establishing that one's pattern of light exposure is extremely important now the previous study in 400,000. Participants basically nailed home the idea that the more time you spend outdoors the better your is your mood the better is your sleep the better is the rhythmicity of your sleep wake cycles and on and on something that I think
even though people say we've known that for thousands of years needed scientific substantiation this new study essentially looked at the relative contributions of daytime light exposure and nighttime dark exposure and they did that on a background of looking in particular people who had major impressive disorder generalizing anxiety PTSD bipolar disorder.
Here's the basic takeaway and I'll quote them here and then I'll tell you my interpretation that here I'm quoting avoiding night at light and seeking light during the day I love that word seeking maybe a simple and effective non pharmacologic means for broadly improving mental health so that's a pretty bold statement right and I love that they say seeking because it implies that people aren't reflexively getting the light exposure that they need that this needs to be a practice much like zone to cardio or
resistance training. Okay, so what do they do in this study? So basically they gathered up 100,000 people or so it eventually was paired down to about 86,000 participants because some just in qualified didn't report their data back.
They equipped them with accelerometers on their wrist and those wrist devices also could measure ambient light now that's not a perfect tool because what you'd love to do is measure ambient light at the level of the eyes by the way will somebody design an eyeglass frame that changes color when you've gotten sufficient light from sunlight during the day and then
at night is a different color and then if you're getting too much light exposure will go to a different color frame this has to be possible so that you don't have to wonder if you got enough light during the day.
And of course if it's at the level of the eyes then you know that's what's landing at the eyes and it's let I mean I was going to ask you about that it to these wrist based devices potentially get covered by clothing in some like turn over you have your sleeves down I have my sleeves up they had it on the outside of the sleep but they ask that people just keep it on their dominant hand it's not perfect
but in some ways it's kind of nice that it's not perfect we could turn that disadvantage into a advantage by thinking you know when the person is out and about they're not often looking right at the sun you know if you're talking to a colleague under an overhang for instance so it's it's not
it's not it's not it's directly right okay and then they had two hypotheses to primary hypotheses one that greater light exposure in the day is associated with lower risk for psychiatric disorders and two second hypothesis greater light exposure at night is associated with higher risk for psychiatric disorders in poor mood this is also relevant for the way we live now people on screens and tablets in the middle of the night.
Okay then they collected information about how much light exposure people were getting as well as their sleep and their activity and so on I should mention this was done in males and females it was a slightly older cohort then one is used to seeing people in their 50s and 60s they had psychiatric diagnosis information and then they divided people into essentially two groups but they had a lower so a q1 and a q2 a lower quartile that meant people that were getting less daytime light
and they had a lower risk for the third and fourth quartile more daytime light they also had a nighttime light exposure evaluation and they had people were in the low q1 and q2 so these people are getting less nighttime light versus q3 q4 more nighttime light.
So they also looked at sleep duration and they looked at photo period meaning how long the days were for those individuals how active they were look 10 hours a day 14 hours a day because the more active you are the more opportunity for light exposure you have during the day or night for instance.
Okay so they had I would say fairly complete data sets then and I'm just going to kind of hit the top contour of what they did in each and sorry sleep duration sleep efficiency etc was determined off the accelerometer that's right as well as self report yeah not not ideal right you'd love for people to be wearing a woot band or or ring or something that sort but this was initiate some time ago so they either didn't have access to that technology or for whatever reason didn't have access to that technology.
So I'm just going to take a brief moment and think one of our sponsors and that's a G1 a G1 is a vitamin mineral probiotic drink that also contains adaptogens I started taking a G1 way back in 2012 the reason I started taking it and the reason I still take it every day is that it ensures that I meet all of my quotas for vitamins and minerals and it ensures that they get enough prebiotic and probiotic to support gut health.
So I think that's something that over the last 10 years we realized is not just important for the health of our gut but also for our immune system and for the production of neurotransmitters and neuromodulators things like dopamine and serotonin in other words gut health is critical for proper brain functioning.
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So a G1 allows me to get the vitamins and minerals that I need probiotics prebiotics the adaptogens and critical micronutrients so anytime somebody asks me if they were to take just one supplement what that supplement should be I tell them a G1 because a G1 supports so many different systems within the body that are involved in mental health physical health and performance to try a G1 go to drink a G1 dot com slash human and you'll get a year supply of vitamin D3 K2 and 5 free travel packs of a G1 again.
That's a drink a G1 dot com slash human. Then what they did is they got they have information on who has major depressive disorder who has PTSD generalized anxiety bipolar psychosis etc. And then they ran three models and you can tell me what you think about the power of these models but you know somebody who thinks about the mechanistic aspect of all this a lot but not somebody who's ever run this type of study I'd be really curious.
Model one examined the unadjusted association between day and night time light exposure and psychiatric outcome so just basically asking is there a relationship between how much light you get it during the day and how much light you get it night and how bad your or your depression is or anxiety is etc.
Looking at you know just a standard ratio of the probability that you have a certain symptom or set of symptoms versus you don't given a certain amount of light exposure model to adjusted for the age of the person their sex and ethnicity and photo period so they looked at you know how long the days were in that given person's region of the world. And then model three people were all in the UK where they were all in the UK as far as I know.
And then model three adjusted for employment so employed versus unemployed which if you think about is pretty important like you say well an unemployed person has a lot more time to control these variables but an employed person who's doing shift work does not right and they they incorporated information about employed versus unemployed physical activity which turns out to be very important.
And then things like shift work etc. And so these what we can say very safely is that the outcomes with each of these models the results were very similar so we don't want to discard the differences between those models entirely but in my read is in every figure the paper it doesn't seem like model one two or three.
Different from one another in terms of total income yeah that's an unusual aspect of this paper so these adjustments are very standard right so that's this is a classic tool that's used in most epidemiology because you don't have randomization so once randomization is out the window you know you like so for example the paper I'm going to present is based on an RCT there will be no models it's just here the data right you're asking people what what do you do report back to us we're going to measure your life.
exposure but no one was assigned any groups swap there the whatever can quote unquote controls are there. They're really not there it's just comparisons between groups so what is interesting to me. Is that as it's exactly as you said and will make all these figures available in addition to the papers but. I mean there it's very unusual that there's no difference between the unadjusted and the adjusted models and as you say there's.
Probably two places out of you know thirty when you look at all the different quartile comparisons where you might creep from you know statistically significant just out of it or just into it but. Yeah you could simplify this figure to completely by just showing one of the models and you would be you know getting 95% of the information which is. You know I mean I think in one way that suggests.
That there's less dependency on those variables of course it still doesn't address probably the greatest question I have here which i'm sure will get to at some point as you continue. So I'm very curious what that question is but I'll I'll I'll suppress my curiosity for the moment you know so if we look at figure two of this paper and I realize a lot of people are listening and they're not able to look at this although we have posted the figures on the YouTube versions of this.
Just want to make clear what's going on just for those that are listening essentially what they're looking at is what they call the odds ratio which is the probability of. Something happening in one group versus divided by the probability of something happening another group I guess it would it by way of example be you know if you're going to look at the.
odds ratio of you know the probability of somebody getting lung cancer if they smoke versus probability somebody getting lung cancer if they don't smoke so odds ratios and hazard ratios are often confused they're very similar and odds ratios generally refer to a lifetime exposure whereas a hazard ratio.
Defined over a specific period of time but the math is still effectively the same and using the example you gave if you took the odds ratio of you know death so let's talk all cause mortality for a smoker versus a non smoker and the answer were 1.78 i'm making that up but that's
actually correct 1.78 as an odds ratio means there's a 78% chance greater of the outcome of interest in this case death by any cause in the affected group which be the smokers so odds ratio of 2 is 100% and odds ratio of 3 is 200% so the math is take the number subtract 1 and that's the percent.
2 of this paper is one of the key take homes they essentially look at the odds ratio of people who are in the let's say that let's just look at the nighttime light exposure and just remind me Andrew because and everybody else watching that every one of these is showing second 3rd 4th as your x axis right meaning they're all being compared to the first quartile that's right in the first quartile is lowest light exposure or highest light exposed
well or what we have to night time between day and night that's right because we restate it sure so if we look at you know what is your risk of a psychiatric challenge broadly speaking what panel a is is major depressive disorder if you are in the second quartile 4th quartile or 4th quartile of night time light exposure so second being the least amount of nighttime light exposure 3rd being more nighttime light exposure and 4th the most nighttime light exposure relative to the first quartile
this is just a stupid thing like if I were doing this figure if you were doing this in a lecture you know what you would do to make it so easy you would draw arrows on it that say increasing light exposure at night decreasing light exposure in the day it's the same information it just makes it easier for the reader to understand
but that's but maybe the teaching point I think is for people when they review articles like don't be afraid to do that and just kind of like what is this exactly so it's like I draw the arrow that's increasing light that's decreasing light and that's how I can pay attention to what's actually happening right and I'm actually in touch with the editorial staff at nature at a nature
mental health although they don't know that I'm covering this paper until after this comes out you know I think one thing that scientific journals really really need to do is start making the readability of the articles better for non experts I mean chances are if you can't understand a graph and this is true for everybody
chances are there's a problem with the way it's presented you put it on them but then of course try and parse it because you know rarely if ever is it all spelled out clearly but anyway that's what we're trying to do here
so yeah the way I would have done is say second quartiles low amounts of nighttime light exposure and define what that is you know third quartile is more light exposure and then fourth maximum amount of light exposure at night and basically what you see is that the probability of having worse major depressive symptoms
linearly increases as you go from the second to third to fourth quartile so more nighttime light exposure worse for you and there's a dose response if you will of the effect now we can march through or describe figure two pretty quickly by saying the same thing is true now we're just talking about nighttime light exposure for generalized anxiety disorder so that's panel C bipolar disorder although the difference between the second and third quartile and bipolar disorder is an
important thing is that the first quartile is a very dramatic one you get up to the fourth quartile bipolar symptoms get much worse when people are getting nighttime light exposure I really want to emphasize that point because they go on in the discussion this paper to the other time in fact they say that while light exposure during the day of course we will go into the data is beneficial for mental health for people with bipolar disorder it seems that light exposure at night is especially
problematic independent of how much sunlight they're getting during the day so you're bipolar in the person with bipolar disorder who's struggling with either a manic or depressive or who's making a point to get sunlight during the day who's also getting light exposure at night is making their symptoms worse and keep in mind they they couldn't
completely control this but this is largely independent of things like sleep duration so that doesn't necessarily mean that the person sleeping less although in a manic episode presumably they are it's independent of exercise it's independent of a bunch of other things because any any psychological person will hear this and say okay well they're they're game more light at night because they're doing a bunch of other things but it's
largely independent of those other things likewise the symptomology of PTSD gets far worse with increasing light exposure at night self harm really takes a leap from being fairly I don't want to say minimal at the second and third quartile so low and let's say medium I'm using some I've taken some of these here but low and medium amounts of of artificial light exposure at night then for people who get quite a lot of nighttime light exposure self harm goes up
and probability of psych psychotic episodes goes up or psychotic symptoms now what's nice is that the what's nice about the data is that the exact is basically true for daytime light exposure although not across the board we can generally say that for major depressive disorder generalize anxiety bipolar symptoms there it's a
little more scattered PTSD and self harm the more daytime light exposure ideally from sunlight because that's actually what's being measured in most cases we can talk about how we know that is going to approximately linearly drop the probability or the severity of these symptoms and we could just explain again that the odds ratios now seem to be going down so an odds ratio of 0.7 now refers to a 30%
reduction in the variable of interest here exactly now the psychosis a panel of which focuses on psychosis I think is also worth mentioning in a bit more detail there's a fairly dramatic reduction in psychotic symptoms as one gets more daytime light exposure independent of nighttime light exposure there's a well known phenomenon called ICU psychosis which is that people come into the hospital for a broken leg or car accident maybe they were getting surgery from from Peter back when for
something totally independent their their housed in the hospital and as anyone who's ever been in a hospital as a patient or visitor knows the light in the lighting environment the hospital is absolutely dreadful for health just dreadful I mean people often complain about the food in the cafeteria is being unhealthy that's often not always true not always true but the lighting
difference in hospitals is absolutely especially in the intensive care unit right so I think the intensive care unit Hopkins the main one the main sick you didn't have windows people who go into the hospital with with a brain injury or or with a stroke or something I get contacted all the time even though I'm not a clinician what should I do for my
kid my parent might always say get them near a window and start to the best of your abilities controlling their sleep wake cycle now oftentimes there's you know nurses coming in and taking blood tests and measuring pulses in the middle of the night that's disruptive there there's bright light not just blue light that's disruptive it's noisy that's
disruptive ICU psychosis is when non-psychotic individuals start having psychotic episodes in the hospital because of nighttime light exposure and in some cases lack of daytime sunlight we can say that with some degree of confidence because when those people go home even though sometimes their symptoms for what brought them to the hospital in the first place get worse their psychosis goes away now and it's independent of
medication so let's just be really direct there is a possibility that we are all socially jet lagged that we are all disrupting these mood regulation symptoms systems excuse me by not getting enough daytime light and by getting too much nighttime light if we want to look at just a moment of the bullet points of the takeaways and Peter thank you highlighted a few of the use but can we just go back to this figure to for a second full of things that really
was going on I want to dig in the day yeah yeah I just and again I normally wouldn't make so much hay out of this except for the fact that I was a little tight but the there are a few that really stand out and again I love this figure I would have labeled it a little differently to make it completely user friendly but nevertheless the increasing light at
night and the impact on depression or the let's maybe really technical and when I say and the relationship or correlation to depression is very strong the relationship to light and self harm in the upper quartile so when you take those 25% of people with the most nighttime light that relationship to self harm is interesting and completely uncoupled from the other 75% that's
interesting on your back uncoupled you mean that at the lower levels of light exposure at night you're not seeing an increase in self harm not what's the first one you get to that fourth quartile it's a big step it's like a 30% greater risk of so yeah so it's totally flat the first second third quartile no different and then fourth big jump and then the the inverse relationship right as light increases during the daytime you see this reduction in self harm interesting the PTSD
and the relationship based on nighttime light and the psychosis relationship based on daytime light those are the ones that really jumped out to me I think anxiety relatively the you know less impressive here and bipolar disorder didn't seem as strong as well so I think those those are the big ones that that jumped out to me yeah I agree there's a bit more scatter on generalizing anxiety and the degree of the
the degree of significant change is not as not as robust in other words getting a lot of daytime light ideally from sunlight is not necessarily going to reduce your levels of anxiety getting a lot of nighttime light exposure is not increasing nighttime anxiety that much although 20% you know is is not nothing for nighttime light exposure but yeah where the psychosis major major depression and self harm are really you know they leap out actually
we maybe we can just drill a little bit deeper on major depression and basically when you go from the second to third quartile of nighttime light exposure some more nighttime light exposure you basically go from no significant increase to almost almost a 20% increase and then as you get up to the fourth quartile so the most nighttime light exposure you're at about 25% increase in major depressive symptoms that's no joke and you know and I think that I think that we you
know we were to I mean we don't have the data right here but if we were to look at like standard SSRI treatment for major depression you know people debate this pretty actively but light is is a very potent stimulus and the timing of light is critical because on the the inverse is also true as you get to the fourth quartile of daytime light exposure you get about a 20% reduction in major depressive disorder
what I like about a study like this is that it puts the error bars so easy to see on the data and why is that interesting well there's there's a there's a there's a belief that bigger is always better in sample size and we often talk about that through the lens of power analysis right so how many subjects do we need to
to reach a conclusion that is powered to you know this level and that's that's true but what I don't think gets discussed as often is the opposite of that which is what if you overpower a study in other words what if the power analysis says to be to to have a level of power at 90% you need a thousand subjects and you say great we're going to do 10,000 subjects well you're
clearly powered for it but you might be overpowered and people might say well why would that be a bad thing it could be a bad thing because it means you are very likely to reach statistical significance in things that might not be actually significant and so one thing about this study that is just a quick back like kind of a quick and dirty way to tell that it's probably not overpowered is that you have varying lengths of
error bars and what that tells me is that and again this is not like a formal statistical analysis it's just kind of like a back of the envelope statistical analysis if you look for example itself harm in the top quartile you actually have pretty big error bars in fact all the self harm have sort of slightly bigger error bars and yet when you look at for example the depression even though the
error bars are all the same size they're tighter in fact when you look at the relationship between depression and daytime light the air bars are really really small so that just gives me confidence that there is variability in this which paradoxically you kind of want to see because it tells me that this wasn't just
done you know there is I think you said 8,000 subjects were in this and I realize 80 more than 86,000 yeah you realize that it wasn't that oh this should have been done with a tenth of that or a half of that and we're picking up signal that is statistically relevant but clinically irrelevant yeah thanks for for that point that I didn't pay attention to that I mean I paid attention to the air bars but I didn't know that so thank you I'm learning to and I
suppose for people that are listening we just give them a sense of what the error bar ranges are for self harm you're running you know as much as 20% either side of the mean the average and for major depression it looks like it's more like let's say 8 to 10% if that yeah yeah 5 right so yeah I see where you're saying was so when you get a very large sample size you're going to have some outliers in there and you
can mask those outliers just by having so many data points right yeah because these error bars directly tell you whether or not you're statistically significant so what's really nice about this type of graph and you see these in there's going to be a graph in my paper where you see the same analysis they're always drawing the 95% confidence interval on the on the data point and if the 95% confidence interval does not touch the the line of unity which in this case is the the the
the odds ratio of 1.0 or the x axis then you know it's statistically significant to the confidence interval they've defined which is almost assuredly 95% sometimes they'll make it tighter at 99 and so that's why you can just look right at these and go oh look you know in depression the second quartile didn't reach statistical significance because the error bars are touching the line just as the case for the second and third quartile for self harm but when you look at the
fourth quartile you can see that the lower tip of the error bars isn't anywhere near unity and so we know without having to look up the p value that it's smaller than either 0.05 or 0.1 however they've defined it and it's really amazing when you see these you know overpowered studies which are easier to do epidemiologically where you know the p value ends up being microscopic you know they can they can drive their p values down to anything low because sample size can be
infinite but you know you can see that it's just like the the error bar is just skimming above the the unity line but it's so so so tight one I'd like to take a quick break to acknowledge our sponsor element elements is an electrolyte drink that has everything you need and nothing you don't that means zero sugar and the appropriate ratios of the electrolyte sodium magnesium and potassium and that correct ratio of electrolytes is extremely important
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I like the citrus I like the watermelon I like the raspberry frankly I can't pick just one it also comes in chocolate and chocolate mint which I find tastes best if they are put into water dissolved and then heated up I tend to do that in the winter months because of course you don't just need hydration on hot days and in the summer and spring months but also in the winter when the temperatures are cold and the environment tends to be dry
if you'd like to try element you can go to drink elements spelled element E dot com slash human to try a free sample pack again that's drink element dot com slash human one thing that I hope people are taking away from this study is that imagine you're somebody who has a very sensitive circadian mood system
well that would mean you need less daytime light exposure to feel good or less bad but it also means that you might need very little light at night in order to negatively impact your mood systems and in fact they make this argument in the discussion as an interesting point that I think is worth mentioning the way because here what I again
when I like about the study is that they've separated day and nighttime light exposure turns out that many of the drugs that are used to treat bipolar disorder reduce the sense are are effective perhaps in part because they reduce the sensitivity of the light sensing circadian apparatus
now that's interesting right if you think about this okay so these are drugs that can ameliorate some of the symptoms of bipolar perhaps in part by reducing the extent to which nighttime light exposure can relieve bipolar symptoms could excuse me can exacerbate bipolar symptoms conversely there's evidence that people who take certain antidepressants may suppress the ability for daytime light to positively impact the mood systems of the brain
now of course we don't want people halting their medication on the basis of that statement alone please don't talk to your psychiatrist if we know one thing for sure it's that if you want a significant outcome and a paper as a scientist give a drug any drug and look at the amount of rapid eye movement sleep or the circadian cycle pretty much any drug alter circadian rhythm for better or worse but if we start to think about which medications might adjust our overall sensitivity to light
sometimes this could be a good thing you think less sensitive to the light well for people who have bipolar disorder the amount of daytime light exposure isn't that important for their overall mood regulation but the amount of nighttime light exposure really is in other words darkness for eight hours every night
should be viewed in my opinion as a treatment for bipolar disorder not the only treatment but it's also clear that we should all be avoiding really bright extensive really bright nighttime light exposure I mean if anything you know my takeaway from the study is that darkness at night is the fourth key light stimulus now a couple of things very bright moonlight very bright candle light is probably only like
gosh three to fifty locks what when you go outside on a bright brightly lit full moon night I encourage people to download this free app I have no relationship to it called light meter
it gives you a pretty good read of what the looks are in the environment by the way a lot of people don't realize is that think you just tap the button and then it tells you how many looks you hold it down it's kind of fun you can scan around the room and see how many looks are on average coming from that location or outside
go out on a really bright moonlit night I mean we should have a full moon tonight yeah let's do it yeah you're not going to get above 100 looks that's incredible you're sitting at a candle light dinner with your spouser with friends and it's clearly bright enough to see them
put that looks me to write up not too close to the flame 50 to 200 locks I had a lot of interesting experience a couple of months ago on an elk hunt where it was a full moon which actually makes the hunting not so great but it was the first time I've ever noticed my shadow in relation to the moon that's how bright it seemed the light was this is Halloween appropriate yeah coming up we're recording this close to Halloween so it's remarkable
interesting to think it could be that dim campfire you know and fire light you think okay gathering around a campfire within okay you know everyone circadian rhythm must have been disrupted for ages before the development of electric electricity no no those campfires are extremely bright but they're they're not they're not that bright compared to a very densely overcast day
and what is your phone if you don't use any sort of light mitigating tack on it well distance matters but at the distance we're holding it yeah yeah with so with all the the wavelengths cranked up so no there is a nice feature intrinsic to the phone where you can eliminate the blues at night or you know this kind of thing but if you crank it up to maximum light intensity probably something like you know 500 to 1000 locks now keep in mind though it's at the end of the day
it's now keep in mind though it's additive right so it's over time so lux is a measure of I think it relates back to kendelas is the amount of light shown and I think it's like the one meter away and there's a squaring and a falling off of distance we can look it up these are old measurement old school measurements
convert to lux but keep in mind that if you're looking at your phone or tablet at 800 lux or 500 lux in the evening you do that for two hours what you're summing quite a lot of photons now it is true and I I I do want to be fair to the biology and it'd be dishonest to say
anything different you know we hammered on people about not shifting their circadian rhythm with light at night but we know that the middle of the day in the middle of the night are circadian dead zones you can't shift your circadian rhythm that well
in the middle of the day in the middle of the night but you can provide a wake up signal for for your body and brain it's really that sunrise and sunset that are critical that's why I said there four things see sunrise or sun rising you don't need to see it cross the rise and sunset bright light during the day minimize light exposure at night and you don't need pitch black in fact pitch black probably just increases the frequency of injury you know I get up in the middle of the night
to use the bathroom probably once I think it's normal I go back to sleep you know if it were pitch black I'd probably injure myself just just dim it down some people use red lights you know our friend Rick or friend yeah Rick Ruben is a funny story about Rick yeah of course of course you know this story but just the I just in case Rick's listening he'll appreciate this you know when Rick was here staying last summer he's up in our guesthouse and he came down after the first night and he was like
acceptable you know what I'm talking about except a little accommodations what did he do he removed all the lighting that existed in that room and replaced it with red light bulbs which I later used when I stayed here and then later stole what I left
the teenage me I took them I took them that's why Derek when he stayed here Lane or anyone else is stayed here can't hear anyone else didn't have as I took them I love them so funny Jill is like you know Rick changed every light in the guesthouse to red I'm like yeah I'm no I didn't know that
but I'm not surprised yeah well in his place he has mostly either no lighting or red lighting so during the day just goes by ambient light and then red light in the evening and or candle light and it's great and you know people here red lights and they think they have to buy these expensive red light units that's not what we're talking about that you can literally buy red party lights are just a red bulb some people say well can I just use a
red film or can I put a t-shirt over the lamp I worry about people putting t-shirts or a lamp because of the fire hazard but I'll be honest I dim the lights in my home at night when I travel sometimes I will bring one of the stolen from Rick Rubin red lights
the Rick Rubin stat here's something where I've sort of softened my tune so I used to be kind of a hard liner no blue light in the evening guy you know had the you know everything was red light at night as far as my phone using flux on the computer you know whatever it was I suspect that that matters somewhat but I think what matters more is the stimulation that may come from those things
what I've come to realize at least in me which means it probably is true in others as well and at least some others is that what I'm doing on my phone matters more than how bright my phone is in other words if I've got the best blue light filter in the world on my phone but I'm doom scrolling social media and getting lit up on email that's way worse for me than if I've got my phone on
my phone and I'm like watching YouTube videos of f1 cars and driving around having fun like it's a totally different experience so so the context matters and I think I think for that reason I would want people to be mindful of the whole picture
and I think that's a really bad under a period of you know intense duress brought on by something you know that's an equally dangerous component to all of this that's distinct from what we're talking about but you know you just want to I like I want people to be
all thinking of this in the context of everything yeah I it's a really important point that you one thing I'll say is that if you're going to stay up past your normal bedtime if you're going to get a lot of light in your eyes I would hope that it will be for fun reasons and for reasons you enjoy you should definitely spend some nights out you should definitely do some
all nighters studying if you really you know if you if it's going to help you get the grade that's permanent right I'd certainly have done all nighters studying and grant writing for years you know there are going to be the inevitable all nighters due to
God forbid a hospital or you heard something on the news that really am too up or you just simply can't sleep that stuff is going to happen so I think the goal should be to minimize light exposure at night and I think what you just said is especially true
because we don't know for instance people talk about the negative impact of social media is it the fact that people are looking at this little box for so many hours per day is it all the things they're not doing is it what they're looking at per se all those things interact and are really important I we know based on studies from the Stanford sleep lab that if you wake up in the middle of the night looking at what time it is can be very disruptive to your ability of fall back asleep and to your sense the next day it's a placebo effect but it's not going to be a good thing to do.
It's a placebo effect but it's a powerful one of how tired you are the next day they've done this where they weigh people open the middle of the night and then they say it's you know 4 am versus 2 am versus 6 am and people's perceived levels of energy during the day in some ways correlate with what they think how much sleep they think they got likewise and this is one of the concerns potential concerns with sleep trackers
Ali come talk about this when she came on our podcast you know if people see a poor sleep score they often feel worse than if they see a good sleep score now of course physiology matters you can't lie to yourself and say you know got a great nice sleep simply by virtue of sleep score but I worry more about the the false well if it's a false negative that we don't want to put valence on this seeing a bad sleep score and then deciding that you're going to have a terrible day
you know I think about sleep scores and indication that you might need to dial some things in a bit better getting a great sleep score is an indication that you might be doing a number of things right and start looking at these things as averages wouldn't you agree yeah completely I don't think it's that different from CGM right like I think that CGM is an amazing tool to provide insight
and you pretty much know the insights after relatively short period of time 30 days maybe at the outside 90 for a really for a person with a very complicated life and you know all you need to know about how the inputs affect the output thereafter if you choose to use it it's a behavioral tool in other words you're using this to build in a hot horn effect
I think the same is largely true with sleep trackers most people have this profound sense of learning when they first encounter one of these things and it's again you've heard it all hundred times oh my god I can't believe what alcohol does to my sleep right or caloric trackers exactly like I think a lane Norton's app carbon I have no financial relationship to it I use it or and it's taught me wow like I consume a lot of calories in the form of certain things at certain times of day and there's just a lot of good learning in that but it's the only thing that I can do is I can do it
learning in that but it's the act of tracking that helps you manage it and similarly I think it's the act of knowing you're going to be looking at that score that gamifies it that kind of helps people do the right things you know what I'm not going to have that drink tonight or I'm not going to eat that snack before bed because I've now been conditioned to see how that impact score that said I think that
you know recovery scores and things like that are just notoriously poor at predicting performance and I think there's a reason that serious athletes would never use things like that they would tend to rely on the more tried and true methods of predicting behavior such as heart rate maybe heart rate variability but morning resting heart rate probably more predictive than anything else and then you know in workout things such as heart rate heart rate recovery lactate threshold things like that so
yeah I agree I think we have to and I say this as a guy who's generally perceived to be the most pro device guy in the world people would be surprised how sparingly I use things like that I mean I do some tracking not as much as you I love things that seem to work the first time and every time in terms of our natural biology based on
a couple criteria there's an established mechanism it's been explored in the context of pathology like mental health disorders as well as pro health in healthy individuals that it make really good sense at the level of kind of wellness and let's just say ancient health you know when you start getting a lot sunlight during the day like a lot of people say well of course get outside and play not getting too much light at night of course is just good old quote and
quote good old fashioned advice people spend 90% of their time indoors now their daytime environments are too dim their nighttime environments are too bright and this kind of misleading aspect of artificial light that when you see a bright bulb you see a lot of photons is part of the problem and the fact that when you're out on a overcast day and it you know you think their son quote and quote isn't out well it's hidden by cloud cover but just think about how well you can
navigate that environment without a flashlight versus that night where you would require a flashlight we evolved under this traumatic difference in day availability of photons independent whether or not you can quote see the sun and it's just very clear that are the all the mechanisms in our brain and body that regulate mood are just
powerfully regulated by this stuff so I've made it a point to really reduce the amount of nighttime light that I'm getting but I am less concerned about flipping on the light switch to use the bathroom as I used to be I used to think I'm like
washing all my melatonin this is terrible I know I can't shift my circadian clock then I know that that light yes while it's bright if it's brief I'm not going to worry about it too much would it be better to have a you know dim light on as opposed to bright light sure but I'm not going to stress it in a hotel bathroom or
so I'm not going to walk around you shielding my eyes people sometimes ask me by the way is it different to look at the phone directly versus if you tilt the phone away well it absolutely is I mean think about a flashlight shown on the ground in front of you very few photons getting in your eyes versus shown directly in your eyes think about ambient light from the sun going everywhere versus looking in the general direction of the sun so east in the morning west in the afternoon of course the directionality of the light matters so I'm not saying it you know
that you need to like peak at your phone as if you're looking you know over the edge of a bowl or something into it but my friend Sam or her Taro's head of the chronobiology unit the national institutes of mental health we used to room together at meetings we stop because he's a terrible snorer so I just could either a few times when I considered suffocating him in the middle of the night since he was already suffocating himself now we just we don't stay in the same rooms anymore we're no longer postdocs but I caught him looking at his phone in the middle of the night
and he would tilt it like away like he's holding a platter for those that are just listening and kind of like looking over at the screen they're like, what are you doing this is ridiculous thanks I'm trying not to get so much light in my eyes that's a lot always stream but I think it illustrates the point which is how much direct light exposure you get at night matters how much direct sunlight exposure you get especially early and late, early morning late afternoon and throughout the day it really matters now remind me Andrew what is the wavelength of sunlight great so sunlight is going to include all of them
visible visible. Which runs from how many? Yeah, so well let's let's we can answer two questions there. This wrist sensor detected 470 degree is 70 nanometer to 650 nanometer light. So that's going to be blue and ultraviolet ultraviolet kind of like blue to orange. Yeah blue to orange. That's what this was
measuring. So red light is going to be more like 680. Far red is getting out to 7 720 and up upwards of that blue light is going to fall somewhere in the you know low force ultraviolet is getting down into the high threes and and lower. And so these these spectra of light. So during the day you know mid day light you're getting what looks like white light. You'll see oh the sky is blue and the sun is bright white light. It's not even yellow to your eye. And of course
don't stare at especially in the middle of the day. You're getting all visible spectra. So you're getting everything from UV all the way out to red light. It's just coming in at equal intensities. So is that a potential limitation of this study in that it didn't have a sensor that could pick up the full spectrum of
light? Potentially especially since they're you know we don't think of humans as UV capable like we can't perceive UV light like a a ground squirrel for instance can has UV sensors in its eyes turns out you know why they use this it's crazy. They actually you know when the ground squirrel sit up on their haunches they're actually signaling one another they rub your and on their belly
and it reflects UV. The the New York Times for some reason has been running a series of papers or articles rather about naturally occurring fluorescence at night and all sorts of these scorpions and monotremes like the platypus. No one really knows the reason for these odd odd wavelength of light emissions
for for all these animals. But you know we view things in the blue violet and up to red and you know we're not pitvipers we can't see far red but we can see lower than 470 nanometers and we can see higher than seven six hundred and fifty. Is there a technology reason why they had such a narrow band in these sensors is it not possible that they could have used a wrist sensor that was wider? This study was initiated in 2013 the tech was probably far worse than it is now.
Again I would love for somebody designed an eyeglass where it's measuring how many photons you're getting across the day. I'm not a big fan of having everything be amplified so I would love it if the frame would just shift color across the morning like you go outside on a cloudy day you know you wear these glasses and and by the way it's fine to wear eyeglasses or contacts for sunlight viewing for setting your circadian rhythm. People always say well why is it that
okay in a windows not well. Corrective lenses are actually focusing the light on your retina the windows and and windshields are scattering the light and filtering. And how much are sunglasses filtering this out? Way too much. We can safely say way too much probably causing a 10 fold decrement in the total lux count that's landing on your retina but of course I you know sunglasses are important driving into in to sun and and some people have
very sensitive eyes I can't sit at a cafe with a bright brightly reflective table in the afternoon I just I just squint like crazy I can't do it my dad who's you know darker eyed and you know South South American descent he you know he can just sit there just fine my mom who's got light eyes like me and you know we're like it's really tough just have a terrible time you know people different
their light sensitivity. So there's one other macro question I have here and it's not answerable because without randomization we can't know it but it's the
question of how much reverse causality can exist in these observations. So again these observations demonstrate very tight correlations very strong associations especially in the five areas that we highlighted but it's possible that part of what we're seeing is reverse causality brought on by both the treatments which you've already kind of alluded to and also the condition
itself. Do you want to explain reverse causality for people and maybe could you mention for those that missed the Hawthorne effect just yeah yeah the Hawthorne effect is is an effect that is named after an observation of what took place in a factory where they were actually studying worker productivity with light of all things but what it would refer us to is the idea that people will change their behavior when they are observed so if if I said well I really want to
know what a day in the life is like for Andrew Huberman I'm going to follow him around for a day it's very unlikely that his behavior that day will be
exactly as it was if I wasn't there. And so the reason why you probably will never see a day in the life of Andrew Huberman although it's pretty it's pretty scripted unless I'm traveling it's a you know it's morning sunlight hydration and you know some cardio or weight training and then a lot of time reading papers it'd be the most boring video in the world because it's mostly me reading and underlining things but it's why um game of flying things can be beneficial
right it's why a CGM can can be beneficial because it's sort of like somebody's watching you and you're going to modify what you eat and responds to it or why tracking can really be an effective way to reduce input because you there's a
sense of being monitored by doing that especially if someone literally monitors it in other words you can set up an accountability partner where your health coach or someone is actually seeing the data so that's what it is now as far as reverse causality when you look at variables so
um let's just pick a common one that's unrelated to this so there's an association that more diet soda consumption is associated with greater obesity it's a bit paradoxical right um is that true it is yeah it's it's been demonstrated in many series that the the greater the consumption of diet
soda the greater the prevalence of obesity and that has been postulated by some to suggest that non-neutritive sweeteners such as aspartame or sucralose or things like that are actually part of what's causing obesity um and while there are probably some arguments you could make around the
impact that those things might have on the gut microbiome and maybe there's some way and that's happening it's also equally likely if not probably more likely that there's reverse causality there that a person who is obese is therefore contemplating how much they're eating or thinking hey what's an
easy way that I can reduce calories how about instead of drinking a coke I drink a diet coke and so there the causality which you would impute to mean the drink is causing the obesity it might be no the obesity is causing the choice of drink so here the question is
how much of the effect we're seeing is a result of the condition that's being studied right how much of the disruption in both day and night light exposure is the result of the depression it's regulating the sleep maybe they're sleeping more during the day and more awake
at night because of depression again these are you can't know this this is where epidemiology never allows us to determine this and sadly these questions can only be answered through either direct randomization or Mendelian randomization which by the way I was going to
also ask you do you know if anyone has examined this from a Mendelian standpoint that would be that would be very interesting because I have to believe well it would be interesting I don't know enough about the biology to know what snips would be
studyable but that would be interesting what Peter is saying is you know if you knew something about the genomes of these people you would be in a great position to perhaps even link up light susceptibility genes or light like sensitivity genes with genes for
you know pathways involved in major depression bipolar I mean get it gained to this issue of reverse causality I mean I think it's very straightforward to imagine that the person who's experiencing a manic episode is going to be up for two weeks at a time
sadly and getting a lot of nighttime light exposure you know now dark nighttime dark exposure as a treatment for bipolar is something that people are starting to talk about so making sure that you with those people are awake that they're at least blue blocking at night
reducing their online activities but people with severe manic episodes have a hard time regulating their own behavior of course and it's not one or the other like I don't want the question to come across to the listener that it has to be one or the other it's
only a can cause b or b can cause a no it's actually a lot of times these things feed off each other going back to the soda example I actually think there's a bit of both right I actually think there's a real clear body habitus dictates beverage choice but I also am starting to think that
ins susceptible individuals non-neutrative sweeteners will alter the gut biome and that alters metabolism what about just hunger I remember Lane telling me and I've seen at least one of the studies that you know water is probably better for us than diet soda but that
for some people diet soda is a great tool for reducing caloric intake I also know some individuals not me who drink diet soda I drink diet soda from time to time mainly stevia sweeten sodas but but what I'm referring to here are people besides myself who
drink diet soda and it seems to stimulate their appetite there's something about the this and the perception of sweet as driving hunger whereas not eating or drinking anything with calorie with any sweetness doesn't seem to this is one of the things I wonder if it impacts why
some people like intermittent fasting because for some people you know just even the perception I wonder if the perception of sweetness or the even just the smell of food we know can stimulate appetite so you can imagine the the perception of sweetness in the mouth even if there's no calories there
I don't think it necessarily makes people hype a guy seem like but perhaps it makes them think about mmm like sweet means food for instance for years I love the combination of a diet coke and a slice of pizza whenever I was in New York ideally two slices of pizza
so now every time I have a diet coke which isn't that often but I like diet coke especially a little bit of lemon in it I just think about a slice of cheese or mushroom or pepperoni pizza it's like I want I crave it more so there's a paired association there that I think is real and we know based on
Dana Small's lab at Yale that there's this paired association between the sweetness from sucralose and that there's an insulin response they actually had to cease the study in kids because they were they were becoming pre-diabetic you know which unfortunately meant the study was never
published have you talked to Dana on this podcast no we we wrote a premium newsletter on this several months ago it it's got to be like I don't know 10 to 20 thousand words on all things related to sugar substitutes so yeah folks are interested in this topic I would refer them to the premium newsletter on sugar substitutes I think it was our September edition the short of it is the data are a little bit noisy but but there is indeed some some sweeteners
in some studies do do result in that phenomenon you describe the cephalic insulin response and I came away from the research that went into that which was herculean effort on the part of the team a little bit more confused than when I went in but being even more cautious around artificial sweeteners
than I was going in so and not for the reasons that I don't necessarily I don't I didn't find any evidence that these things are cancer causing right so that's the headline stuff people worry about I think I was like 10 grand yeah yeah yeah like crazy that I came away more confident that from us from a long-term safety perspective in terms of met up in terms of you know cancer and catastrophic outcomes like that that wasn't the issue but I came away much more
cautious around these things can really be mucking around with both your brain chemistry and your gut chemistry which can pertain to your metabolism and therefore my takeaway was buyer beware use limited amounts only the one by the way that still emerged to me as a reasonable one it's the only one that I use and I've talked about a lot is xylitol xylitol is the apart me I shouldn't say it xylitol for chewing so for gum and alulose as an additive so those are the safer yes those are
those are basically the only two I will consume now I'll drink a diet coke every now and again if I'm on a plane or something yeah you know this law that got past few years ago you couldn't bring liquids in of your own into the airport and on the plane like what a few years ago what a great scheme what a great scheme to get people to buy over priced fluids in the airport like I mean they're more important issues in the world but like this one really gets me but yeah I use a
little bit I drink things a little bit of stevia in it the occasional diet coke and I generally avoid sucralose I don't like the way it tastes monk fruits too sweet but yeah we get we get we get maybe we'll do a podcast on then the future okay so I think we can wrap
this paper because I really well but tell me what you think about that point Andrew like how I mean you know you know more about this stuff than I do but if you had to just lay on your judgment right so if it were if it were a hundred to zero you would say the light is 100% causal in the effects
we're seeing if it were zero to a hundred you'd say nope the behavior is 100% causal of the exposure to light where do you again you can't know it yeah what is your intuition tell you okay there's my intuition and then there's my recognition of my own bias because you know I started
working on these circadian pathways originally in the eye back in year in 98 as a graduate student Berkeley that the cells these melmopsin intrinsically sensitive retinal ganglion cells were discovered in the early 2000s by a guy named Igy Provencio Dave Berson San Maratar Sachin Pantan others but
that and it was like one of the most important discoveries in all of biology clearly so I've been very excited about these systems but if I set that aside so bias disclosure made I think 65 to 75% of the effects are likely due to light directly now it's impossible to tease those apart as
you mentioned but to play devil's advocate against myself you know you could imagine that the depressed individual is laying around indoors with the curtains drawn they didn't sleep well the night before which gives you a photosensitivity that isn't pleasant like it sucks to have bright light
in your eyes first thing in the morning if you especially if you especially if you didn't sleep well and then they're you know making their coffee in a dimly lit what they think is brightly lit environment and then they're you look at their phone and the the state of the world sucks and
their state of their internal landscape is rough and they're maybe they're dealing with a pain or you know injury or something and they're likely to get outside is low and when they do get outside they're going to shuffle and you know so I could see how the behaviors could really
limit the amount of light exposure and then evening rolls around they've been tired all day and a common symptom of depression you fall asleep and then two or three in the morning they're wide awake what are you gonna do it two or three when you're wide awake sitting the dark no you're
gonna get online you're gonna listen to things you might have I'm not recommending this but alcohol drink in order to try and fall asleep I mean this is the pattern and so you know shaking up that pattern is really what so much of my public health work these days is about and trying to get people
onto a more natural daylight night night dark rhythm but yeah it's impossible to tease apart we do know this and this is really serious we know that in almost every instance every almost every psychopathology report of suicide in the weeks but especially in the days preceding suicide
that person circadian rhythms looked almost inverted from their normal patterns and that's true of non bipolar individuals as well you know circadian disruption and disruption and psychiatric health are inextricable conversely positive mood and affect and circadian behavior seem
very correlated I mean I think it's clear that if you want to become an early riser get light in your eyes and get activity in your body early in the day you you built the you in train to those rhythms so that you start to anticipate that morning workout you start to anticipate the morning
sunlight just one more scientific point we know that when you view bright bright sunlight in the morning or just sunlight that's illuminating your environment as you said you don't even have to see the sun itself that there's a 50 50 percent increase in the amplitude of the morning cortisol
spike which is a good thing right that's when you want it because it's inversely the amplitude of the morning quarters all spike is inversely related to the amplitude the evening cortisol spike in high evening cortisol is associated with middle of the night waking and on and on so you know
I'm very bullish on these mechanisms I also love that they're so deeply woven into our evolutionary history you know that we share with single cell organisms it's so wild but of course there's going to be a bi-directionality there and it's it's impossible to see where one thing starts and the other one stops I mean here's my take Andrew first of all I actually with far less authority than you agree with your assessment and might even be a little bit more bullish might even put it at 80
20 and here I'll give you my explanations which stem more from my fisterious battles with epidemiology in general right like because so much of the world that I live in still has to rely on epidemiologic data and so how do you make sense of it and the truth of it is most of it is really pretty bad
but I tend to find myself looking at the Austin Bradford Hill criteria all the time and for folks who don't know he was a statistician who basically proposed a set of criteria believe there are eight of them and I can't believe I don't know every one of them off by heart I certainly used to
but the more of these criteria that are met within your correlations the more likelihood you will find causality so when I think of your data here the data in this paper I'll tell you what makes these correlations seem to have causality within them in the direction that's being proposed look at the dose effect so dose effect matters and this is done in quartiles and that's a very elegant thing if they just did it as on off it would be harder that's right but the fact that they didn't
quartiles allows you to see that every example in figure two I don't believe there is an exception to this you know and I think also in the in the there's only one exception to what I'm about to say sorry two out of like god knows how many they're all monotonically increasing and decreasing in other
words the dose effect is always present another thing is biologic plausibility you spoken at length about that today so in other words sometimes you have to look at epidemiology and ask is there a biologic explanation and here there is you've added another one which is evolutionary conservation
to the biologic plausibility then you can talk about animal models or experiments in humans over short durations that generally support these findings and and so those are just a couple of the the Bradford Hill criteria that that lead to you know my belief that yeah there's reverse causality
here but it's not the full explanation and that more of the explanation is probably the direction that's being proposed and if that's true because then at the end of the day like what's the purpose of the discussion the purpose of the discussion is if you are under the influence of any of
these psychiatric conditions in addition to the treatments you're doing now what else can you do and to me the takeaway is follow these light behaviors I mean it's it's it's a it's a relatively low lift yeah and you consider some of the things like I'm over here asking people to do zone two
for three hours a week and VO two max workouts and all this other stuff and like I think all those things matter for mental health as much as physical health but this strikes me as on the spectrum of low asks if it shows if it's only even 30% causality 70% reverse causality like I'll take those I
would still instate that yeah and it's you know it's taking your coffee on the balcony it's and people will often say well how do you do this with kids the kids should be doing it too right you know it means popping your sunglasses off it means getting out for just a few minutes and the fact
that's additive that these you know these photon mechanized photon counting mechanisms they some is great and look you this paper also says and I showed stated this earlier if you missed your day time light ration get your nighttime dark ration they are independent and additive so that's I mean
that's a really something but of course ideally you get both but I appreciate your take on it and you know and thanks for your expertise in parsing epidemiology I look at fewer studies of that of that sort but I learned from you and that's one of the reasons I love doing these journal clubs
is I learn so along those lines tell us about the paper you selected I'm really eager to learn more well I wanted to pick a paper that was you know kind of interesting as a paper and and this this paper I think is interesting in that it is kind of the landmark study of a class of drugs but
in the same way that you kind of picked a paper that I think has a much broader overarching importance the reason I picked this paper which is from New England Journal of Medicine it's about 10 years old no correction 13 years old is because it is kind of the landmark study in a
class of drugs that I believe are the most relevant class of drugs we've seen so far in cancer therapy and even though the net effect of these drugs has only served to reduce mortality by maybe 8 to 10 percent which is not a huge amount it's the manner in which they've done it that gives me great
hope for the future even if it's through other means so I'll take a step back before we go into the paper for again just the context and background so the human immune system is kind of a remarkable thing it's it's hard when you're sort of trying to imagine what's the most amazing part of the
human system and maybe it's my bias as well because just as you spent you know your time in the in the light system and the in the photosensing system I spent my time in the immunology world but it is remarkable to me how our immune systems evolved and they have this really brutal task
which is how can they be tuned to detect any foreign pathogen that is harmful without knowing a priori what that could be while at the same so in other words how can you tune a system to be so aggressive that it can eradicate any virus or bacteria billions of years into the future without
knowing what it's going to be but at the same time it has to be so forgiving of the self that it doesn't turn around and attack the self it's remarkable and of course we can always think of the exceptions there are things called autoimmune conditions so clearly the system fails fails
and the immune system turns around and attacks the self if you see a person with vitiligo I have a little bit of a vitiligo on my back couple of spots clearly the immune system is attacking something there and destroying some of the pigment I didn't realize that the LIGO is autoimmune
yeah if you know there's so there are lots of you know more serious autoimmune conditions of course you know somebody that has lupus or you know where the immune system can be attacking the kidney the immune system can be attacking any autoimmune conditions can be deadly but fortunately they are
very rare and for the most part this immune system works remarkably well so how does it work and why is it that cancer seems to evade it virtually all of the time this is the question now let's first of all talk about how it works and then when I tell you how it works you'll say that sounds
amazing clearly it should be able to destroy cancer um when I simplify it by only talking about one system which is how T cells recognize and get activated how T cells recognize antigens so we have something called an antigen so an antigen is an antibody generating peptide so it's a
it's a it's a protein almost always a protein they can be carbohydrates but they're almost always proteins and they're very very small peptides like we're talking as little as nine amino acids maybe up to 20 amino acids so teeny tiny little peptides but it's amazing that in such a short peptide the
body can recognize if that's Andrew or not Andrew I mean when you're getting think about like we talk about proteins in kill adultons right we're talking about proteins in terms of thousands of amino acids that make up every protein in your body and yet if it samples a protein and sees that
hey this little 9 10 15 peptide amino acid is not part of you I know it's bad and therefore I'm going to generate an immune response to it so we have what are called antigen presenting cells you have cells that go around sampling peptides and they will on these things called MHC class
receptors bring the peptide up to the surface and serve it up to the T cell there are two types of these there's MHC class one and MHC class two I only versus a major histic compatibility complex that's correct and we refer to them that way because they did because of the context in
which they were discovered which was for organ rejection so not surprisingly when you need to put a kidney into another person if that kidney is deemed foreign it will not last long and the early days of organ transplantation were rife with immediate rejections and by not not I mean
the immediate are the ABO incompatibilities but you know the the sort of next layer of incompatibility was MHC incompatibility which would lead to you know within within weeks the organ is gone as opposed to within hours so you have these two classes of MHC you've class one and class two
class one is what we call endogenous so this is basically what happens when a protein or an antigen is coming from inside the cell so let's consider the flu so if you get the flu the influenza virus infects the respiratory epithelium of your you know your larynx and that virus
as you know folks listening might remember from our days of talking about covid viruses can't replicate on their own what they do is they hijack the replication machinery of the host and they use that either to insert their RNA or DNA to replicate and in the process proteins are being made while
those proteins are the proteins of the virus not of us so some of those peptides get launched onto these MH class MHC class one glove basically the glove comes up to the surface and a T cell comes along in the case of MHC class one it's a CD8 T cell these are what are called the killer T cells
right and so this cell comes along and with its T cell receptor the T cell receptor meets the MHC class one receptor with the antigen in it and if that's a lock it realizes that's my target and it begins to replicate and proliferate and target those and that creates the immune response
and by the way that's how it works when you vaccinate somebody you're basically pre-building that thing up with this fall under the adaptive immune response or the innate immune response though this is adaptive yep innate is just the pure antibody response in the on the B cell side I won't
get into that for for the purpose of this discussion the other example is MHC class two and that's also part of the adaptive system or the innate system which is more what we call the exogenous form so these are peptides that are usually coming from outside the cell so we're going to focus
more on the MHC class one because this is peptides that come from inside the cell okay so just keeping the back of your mind if a foreign protein gets presented from inside a cell to outside a cell the T cells recognize that and they will mount a foreign response and by the way that's why
we basically can beat any virus like if you consider how many viruses are around us the fact that we almost never die from a viral infection is a remarkable achievement of how well this immune system works we're constantly combating these virus constantly and by the way we don't really
have very effective antiviral agents it's not like antibiotics like we have antibiotics up the wazoo I mean we're way better at fighting viruses than bacteria can I just one question I've always wondered about this to what extent is our ability to ward off viruses on a dated basis as an adult
reliant on us having been exposed to that virus during development like like as I walk around today maybe I'll be exposed to a hundred thousand different viruses would you say that half of those I already got antibodies to because I was exposed to them at some prior portion of my life
yeah hard work and the other ones I'm just building up antibodies like it was on I was on a plane last night someone was coughing so I was hiding and I had COVID a little while ago so I wasn't too worried about that and I feel great today but you know I just assume that on that plane I'm in a swamp
of viruses no matter what and that most of them I've already been exposed to since I was a little kid so I've got all the antibodies and they're just fighting it back binding up those viruses and destroying them yeah I think it's part that and I also think it's part of them that our body can
destroy without mounting much of an immune response so therefore your immune system is doing the work and it's yet it's not mounting a systemic inflammatory response that you're not sensing so is it also a physical trapping in you know in my nasal epithelium yeah so yeah like they're you
have huge barriers right so the skin you know the hairs in your nose all of these things are huge barriers but assuming that still a bunch of them are getting in at least the respiratory ones that's the other thing to keep in mind right there are certain viruses that are totally
useless floating around the air right there are certain viruses you know the viruses that most people are really afraid of you know hep C hep B HIV well you know if they're sitting on a table or floating around the air there are no threat to you they have to be you know sort of transmitted
through the barrier but again some of these viruses you're going to defeat without an enormous response and then some of them you know like why is influenza quote-unquote such a bad virus whereas the common respiratory cold kind of sidelines you for a day it's the immune response
that you're feeling the worst the bigger the immune response to the virus the more you're feeling that you feel your immune system going crazy right you know the inner lukins that are spiking the third spacing that occurs to get more and more of the immune cells there the spike of your
temperature as your body basically tries to cook the virus all that stuff is your body the fatigue yeah yeah you're being drained and all this happening so one more point I'll mention just but just to close the loop on the autoimmunity
how is it that we learn not to attack ourselves that's something called thymix selection that occurs in infancy so you and I have a no good for nothing tiny little thymus that would be it's almost impossible to see these things you know when we used to operate on people you know the thymus is
barely visible in an adult in a healthy adult outside of thymic tumors but as a child in a child the thymus is quite large and the purpose of the thymus is to educate t cells and basically show the t cells what self is and any t cell that doesn't immediately recognize it gets killed so it's a
really clever system where we basically teach you to recognize self they're at a very early age and if you can't do that you're weeded out and then the thymus invulutes thereafter because it's sort of served its purpose okay now let's talk about cancer so what do we know about cancer so we
know that again you know cancer is a genetic disease in the sense that every cancer has genetic mutations most of those mutations are somatic which means most of those mutations are mutations that occur during the course of our life they're not germline mutations the germline being the
eggs and sperm right so it's all other cells and I love that you pointed out that you know there can be genetic that cancer can be genetic but isn't necessarily inherited right in fact it's really genetic and they think inherited right yes inherited is always genetic to some extent but
genetic isn't always inherited yeah so there are a handful of cancers that are derived from inherited mutations so Lynch syndrome is an example of that hereditary polyposis is an example of that where you have a gene that gets passed through the germline and that gene
codes for a protein like all genes do and it's either you have too much of a gene or too little of a gene so it's either a gene that promotes cancer and you have too much of that or it's a gene that prevents cancer and you have too little of it or a dysfunctional version of it right so
braca is an example of that braca is hereditary braca codes for a protein and the the women and men but mostly the women that we think about who have a braca mutation that all in some cases almost guarantees breast cancer it's because of a defective copy so it's like they don't get the protein that
they need to protect them from breast cancer so what do we know well we know that and this is probably one of the most remarkable things I've ever learned and it still blows my mind every time well actually before I get to that point I want to make I want to make another point okay so
so you might think so cancer we you know ourselves become cancerous but they're clearly hijacked because they have these mutations and as a result of these mutations they make proteins that allow cancers to behave differently and cancers behave differently from non-cancers in two very critical
ways the first way is that they do not respond to cell cycle signaling so if you cut your skin it heals but how does it know to heal just right and not to keep growing and growing and growing and growing and growing well it knows that because there are cell cycle signals that tell it time to
grow time to stop if believe it or not this is an extreme example if you donated to me half of your liver which I know you would absolutely I give you more than half a month well you don't need to give me that we could keep doing these general clubs right within months you would regenerate a full
liver that's so isn't that amazing so well it's like a salamander you cut off a salamander limb and please don't do that experiment because other people are doing it anyway and it grows back and it knows how much to grow back so so when the cell is perfectly functioning it knows how much
to grow and it's well cancer loses that ability that is one of the hallmarks of cancer it just keeps growing doesn't grow faster by the way that's a misnomer people think cancers grow faster than non-cancers there's no real evidence that that's the case they just don't stop growing the second
property of cancer is the capacity to leave the site of origin go someplace else and take up residence that's the metastasis component so if you think about it for a minute a cell that never stops replicating and has the capacity to up and leave and move and take up residence is clearly
different from the cell itself right so if I have a cell of colonic epithelium that cell that lines the inside of my colon it's clearly got a set of proteins in it but if all of a sudden that thing can grow grow grow grow grow grow not stop not not not listen to the signal and then somehow
wind its way into the liver and just keep growing and growing and growing it must have different proteins so the question then becomes why does cancer even exist how has our immune system not figured out a way to just silence this and eradicate it the way it does to virtually every virus
you encounter and to me this is one of the most interesting questions in all of biology and it really comes down to how clever cancer is unfortunately how evolutionarily clever it is it basically does a lot of things to trick the immune system so it has its own secretory factors that
tamp down the immune system it grows in an environment because of its nature so one of the things that's long understood about cancer is its heavily glycolytic and when something is heavily glycolytic it's going glucose to pyruvate to lactate nonstop there are lots of reasons for that
I think there's more than one what is that afford it does that well so it's interesting is that afforded a migratory potential no so it's super interesting so so that's the effect that what I just described is called the warberg effect and when warberg proposed this which God was probably
in the 1920s it was before world war one before world war two he proposed it because he thought the mitochondria of cancer cells were defective so he proposed that the you know cancer cells might a conduit don't work hence they have to undergo glycolysis they can't undergo aerobic metabolism
we now know that that's not the case so we now know that the the warberg effect or the warberg effect if I'll refer to him correctly by his name almost assuredly does not have to do with defective mitochondria others have proposed several mechanisms I think there's probably more
than one thing going on so so so a paper that came out in 2009 very influential paper by a guy named Matt Vanderhiden and Craig Thompson and Lou Cantley proposed that the reason that cancer cells do the warberg effect is that they're not optimizing for energy they're optimizing for
cellular building blocks and if you do the mass balance it completely makes sense like dividing cells need building blocks more than energy and glycolysis while very inefficient for generating ATP is much more efficient at generating substrate to make more cells but another proposed mechanism
is exactly at this one glycolysis lowers the surrounding pH because of lactate lactate attracts hydrogen pH goes down and guess what that does to the immune system detracts the immune system so it's also a way to hide from the immune system so there's a like a pH cloaking
use leveraging pH to cloak that's right the signal that the immune system would otherwise see yep and then when you layer on top of that that it knows how to secrete things like IL-10 TGF beta all of these other secretory factors that also inhibit the immune system basically it's figured
out a way to kind of hide itself from the immune system the way you describe it cancer sounds like a virus yes I mean it sounds a lot like a virus and that leads me to ask are there any examples of contagious cancers I recall seeing some studies about these little critters down in
Australia Tasmanian devils that like they would they scratch each other and fight as Tasmanian devils do actually quite cute and they get cancers and tumors growing on their faces yes so so and so it was it was it was like a literal physical interaction that could transmit cancer from one
animal to the next so it's less that there are viruses that cause cancer so in that sense you could argue yes there are contagious cancers well HPV sure yeah HPV hep B hep C but but there even cancers like cutaneous cancers that arise from viruses but I don't know if that's quite
the same as what you're saying like no no it's in there both it what you're saying is an important point I mean I mean we don't want to go down the rabbit hole of HPV but right that's increasing susceptibility to cervical cancer now there's a vaccine against HPV yeah there wasn't when we were
in college as we all knew there was no vaccine but the okay so but yeah direct transmission of cancers from one one organism to the next more rare yes okay so now here a moment ago I said there's this really incredible thing about cancer that blows my mind and about our immune system
which is that at least 80% of solid organ tumors and we're going to mostly talk about solid organ tumors because that's where the field of oncology has made very little progress so if you go back 50 years where his oncology made huge progress it's made great progress in blood tumors leukemias
and some kinds of lymphomas in fact there's two kinds of lymphomas where the progress has been remarkable one has been in Hodgkin's lymphoma and the other has also been an immunotherapy has been in a type of B cell lymphoma where that B cell demonstrates or presents something called a CD19
receptor so in in B cell lymphomas with CD19 immunotherapy there's a very unique niche immunotherapy we won't talk about that today called CAR-T therapy that has got rid of those guys and then leukemias have also been pretty good but in solid organ tumors there've been only two real breakthroughs
in the last 50 years one has been the therapy for a certain type of testicular cancer and it's really just a chemotherapy cocktail that has been found to work really well and the other has been in this really rare kind of gastric cancer called the GI stromal tumor
which happens to result from one mutation in a kinase pathway and there's one drug that can now target that and it works it's kind of amazing curious that cancer is that what I'm talking about are the cancers that kill virtually everybody else this is what when you sort of line up what are the
big causes of cancer death let's start at the top it's lung it's then breast and prostate and men and women it's colorectal it's pancreas those are the big five they kill more than 50% of Americans it cancer wise not sorry let me restate that more than 50% of cancer deaths in Americans
come from those five these are what we call the solid epithelial tumors and you can march down the list and most cancers that most people are thinking of are those cancers well here's the thing more than 80% of those cancers have antigens that are recognized by the hosts immune system
I will state it again because it is so profound 80% at least of those cancers actually generate an antigen meaning a little peptide in that cell gets presented to the T cell and it is recognizable and now the question is why is that not sufficient
to induce remission and the short answer is there are not enough T cells that are able to act and or they are being sufficiently inhibited from acting which gets me to the point of this paper one of the ways in which the body inhibits the immune system which we should remind ourselves
is an important thing right is something called the checkpoint inhibitor okay so go back to that idea that I talked about before you have an antigen presenting cell it brings up an MHC receptor with a peptide on it and there is a T cell that is coming and I actually brought a diagram
which we're going to I'm going to link to this because I don't want to make this too complicated but I really think that this figure is helpful to understand how these papers how these drugs work so the MHC receptor with the peptide is sitting there and it binds to the T cell receptor on the T cell
but there is another receptor on the T cell a CtLA4 receptor and that binds to a receptor that I won't bother naming now because it's the names don't matter but there's another receptor on the antigen presenting cell that binds to that and that acts as the breaks in the reaction so CtLA4
which is on the T cell binds to another Cd receptor on the antigen presenting cell and it says tamp down the response and the reason for that is we want to keep our immune system in check this basically is a way of asking the immune system because remember when the immune system sees that
antigen it wants to go nuts it wants to start replicating and killing that this is a Cd8 T cell it is a targeted killer T cell the checkpoint says let's double check that let's be sure let's tamp down the response and as a result of that a thought experiment emerged which was what if we block
CtLA4 what if we block the checkpoint could we unleash the immune system a little bit more and I will say this at the time it was proposed it seemed a bit farfetched because of the complexity of the immune system it seemed a little farfetched that simply blocking the checkpoint would have any
effect it's also worth noting that prior to this one immunotherapy had found some efficacy which was trying the exact opposite strategy rather than blocking the inhibitor it was throwing more accelerant at the fire which was giving something called interleukin 2 so interleukin 2 is
for lack of a better word candy and fuel for T cells so the idea was if we have T cells that innately recognize a cancer antigen can we just give high doses of interleukin 2 and have them undergo proliferation and response and the answer turned out to be yes but only in 2 cancers melanoma
and kidney cancer and only at very small levels about 10% of the population would respond to these things now look that's 10% of people who were going to be dead within six months because these are devastating cancers and once they spread there are no treatments that have any efficacy whatsoever
in fact I think median survival for metastatic melanoma at the time was probably four months so this was a very grim death sentence but the idea now was what about doing the exact opposite approach instead of trying to throw more fire at the T cell what if we can take its breaks down
less gas per mean instead of giving more gas let's give less breaks and there were some phase two some phase one studies that demonstrated efficacy phase two and the paper I'm going to talk about today is the phase three study that compared the first version of these so so the drug we're
going to talk about today is an anti CTA for drug called ipilimab there is another drug out there that came came along shortly thereafter that is an anti PD1 drug so PD1 turns out to be another one of these checkpoints on T cells and the Nobel Prize by the way I think it was 2018 or 2019 in
medicine or physiology was actually awarded to the two scientists who discovered CTLA for and PD1 so you know this I believe this is the only Nobel Prize in medicine for immunotherapy it's a very big deal so this study sought to compare the effect of anti CTA for
to a placebo and the placebo in this case was not a real placebo it was a peptide vaccine called GP100 to ask the question in patients with metastatic melanoma what would be the impact on median survival and overall survival so let's talk a little bit about the paper so again one
of the funny things about this is I used to read these papers a lot Andrew these these used to be these used to be my bread and butter papers so I mean you know be you know reading these like I'm you know it's a my hobby and and I don't read them that much anymore so it was kind of amazing
how long it took me to remind myself of stuff I used to remember but you do have to kind of go back and read the methods and figure out who were the patients in this what was the eligibility criteria why did they do it this way and of course it all kind of came back to me but it took a
minute so so the first thing is these are all patients who had progressed through every standard therapy so these are patients for whom there were no other options these patients either had very advanced stage three melanoma which means it was local regional melanoma but it couldn't be
resected so an example of that would be a cancer that was you know completely engulfing like where let's say the primary site was the cheek and it had completely grown into all of the surrounding soft tissue it hadn't spread anywhere but it was you know all the lymph nodes of the neck and I've
seen patients like this and it's you know it's just completely disfiguring and they'd already been through the standard chemotherapy and nothing was working and the thing was growing and then it was mostly made up of patients with stage four cancer now melanoma has a very funny staging system so
in cancer we typically talk about something called the TNM staging system it is the standard way that cancers are staged T refers to the tumor size N refers to the lymph node status and M refers to the presence or absence of metastases and for most cancers it is a very simple system it is you
know T is typically a number one two sometimes up to three and four N is typically zero one or two and M is zero or one either there's no metz or there are metz so for example in colorectal cancer the T staging determines the depth in the colon wall that it went N is did it go to metz and I think
in colon I'm gonna be a little rusty on this I think colon has N zero one or two depending on how many lymph nodes and then M zero did it go to anything beyond that like to the liver lung etc or not melanoma is a bit more complicated it has M zero meaning no metz but it also has M1A
M1B M1C and M1D and within each of those it has a threshold for high and low lactate dehydrogenase or LDH so it's both a staging based on imaging and biochemical and the reason for that is LDH level is such a strong prognostic indicator of survival in addition to M staging
higher LDH levels tend to reflect more acidity which we talked about why that's problematic tends to reflect faster growing tumors higher turnover higher metabolic activity M1A let me see if I can remember this M1A's are cancers that have metastasized to
surrounding soft tissue or soft tissue anywhere in the body so anywhere else on the skin and you might think well that's kind of crazy like how does that happen and it's really bizarre you can have a patient who had a melanoma that showed up in one part of their body and then they
have metastases on other parts of their skin M1B is and I always get B and C confused I think B is the lung so M1B is to the lung M1C is to any internal organ so liver etc and M1D is to the CNS and as those numbers increase as those letters increase the prognosis gets lower and lower
and lower so one of the first things I always look at when I look at a paper like this is tell me about the patient population like what was the you know what was the breakdown of patients and in table one so that's again in clinical papers like this table one is always always always
baseline characteristics oh I should mention one other thing Andrew this was done as a 3-1-1 randomization so again in the simplest form a study would have two groups right you would have we're gonna just have a treatment group and a placebo group but in this arm you had three groups
with one of them being the placebo the placebo got just GP 100 which is just a cancer vaccine by the way this is a cancer vaccine that never showed any efficacy so it was a cancer vaccine that had been tested both with interleukin 2 directly and as an adjuvant for patients who had metastatic
melanoma risk or had sorry not metastatic melanoma who had melanoma resected who were tumor-free and then given the vaccine as adjuvants to see did that have an effect on outcomes and it didn't so it's kind of a known placebo so you had that group then you had the anti-CTLA 4 group
and then you had anti-CTLA 4 plus GP 100 as for the 3-1-1 it's basically it increases statistical power right so you know this total study was a little under 700 people they put 400 in the anti-CTLA 4 plus GP 100 group and then you know a little over 130 in each of the other two groups
so you're always going to be able to make these two comparisons right what you can check by doing this is is there any effect of GP 100 in this setting which they've never been done before so again GP 100 is a known protein expressed by melanoma and all of these people were haplotype to
make sure that their immune system would recognize it and the question was would giving people anti-CTLA 4 i.e. taking the breaks off their immune system with or without GP 100 make a difference so kind of going through this you can see it sort of skews about 60% to 40% male to female
they talk about something called the e-cog performance status that refers to how healthy a patient is coming in so e-cog 0 is no limitations whatsoever which is kind of amazing when you really consider something i think this speaks to just how devastating this disease is these are patients
who all have like six months to live right you know a year max and yet look at this 58 to 60 percent of them have no limitation on their quality of life at this very moment that's going to change dramatically you know absent a cure here and then e-cog 1 has some limitation and you can
see that e-cog 1 plus e-cog 0 is basically 98 percent of the population you can see the staging there so again very very few of these patients are the M0 category M0's are people who have stage three disease that is so aggressive it can't be resected that's about 1 percent but the majority
of these people are the m1a's m1b's m1c's so these are people with very aggressive cancers you can also see that about 10 to 15 percent of these people also have cns metastases again the poorest prognosis of the poor and then you can see the about 40 percent of them have the LDH level above
cutoff all of this is to say we're talking about a group of patients who have you know a very high likelihood of not surviving more than you know a year it would be very you know unlikely that many of these patients would survive more than a year so so basically more than 70 percent of
these people have visceral metastases a third have high LDH and 10 more than 10 percent have brain meds they've also all progressed through standard therapy so radiation chemo yeah and the chemo for for melanova can be you know kind of a toxic chemo that that really just doesn't really
do anything so is it commonplace to use a treatment that failed in clinical trials as a placebo in these sorts of studies yeah it's interesting I think you're referring obviously to the GP 100 and I think the thinking was okay it hasn't been effective in other treatments for example when
combined with IL-2 or as an adjuvant but never before has it been tried with a checkpoint inhibitor which is the technical term for this type of drug I think there was also some belief that it would be easier to enroll patients I don't think they stated this but that's often the case it would be
easier to enroll patients if they would know that even in the placebo arm they're still getting an active agent got it and I suppose there's always the possibility that the combination of the failed drug with a new drug would work and then so you're increasing the probability for
novel discovery for sure and again if you go back to the randomization of three to one to one it's really only one fifth or 20% of the participants that would get just the GP 100 so in other words you're basically telling people when they come into this study there's an 80% chance you're going
to get anti-CTLA 4 that's a much better set of odds than you know your typical study where you're going to be 50% likely to get the agent of interest right in people who are literally dying of cancer that they don't want to be in the control group right that's right so the primary outcome for
this study actually changed in the study now they have to get permission to do that but the so the original primary endpoint was the best overall response rate so I have to explain how response rates are measured this is this is a bit complicated remember all of these patients by definition have
measurable visible cancer by visibly they're on the surface of their body but more likely on an MRI or CT scan so all of these patients had to be scanned head to toe within 12 weeks of enrollment again there's another thing I should point out here which I know you understand but
it's always worth reminding people when a study like this takes place it usually takes place over many years and so it's not the case that all 700 of these patients were enrolled on the same day and finished you know we finished observing them on the same day no no this took place for a very
long period of time this took place across tens of centers I can't remember if this was just globally or across the world it might have been across the world and so every center really needs to adhere to a very strict protocol and you have a central organization that is running this so you
have a drug company I think this is Bristol myrsquib that makes the drug they provide the drug and then you have a CRO a clinical research organization that that is basically managing the trial and the trial is being done at cancer centers all over the world or all over the country and
you know enrollment I think began in 2008 for this no no I think it completed in 2008 it probably started in about 2004 2005 and therefore you had to kind of have real clear protocols around the so complete response is the easier of these to understand a complete response is everything
vanishes completely that's very rare in cancer therapy so instead what we kind of look for is a partial response a partial response and there are really different ways to define this there are different criteria but this is the most common way you define a partial response a partial response
is at least a 50% reduction by diameter because remember in this type of imaging you're looking at 2d versus 3d so if you're looking at a lung lesion and it's this big it had you know if it's two centimeters long it has to go to at least one centimeter in diameter so it's a 50% reduction at
least of every single lesion with no new lesions appearing and no lesions growing so it's very strict criteria right again CR means everything vanishes PR means at least a 50% by diameter which by the way is a much bigger diameter much bigger reduction in terms of tumor volume when you consider the
linear versus the third power relationship of length and volume of every single lesion with nothing new appearing regardless of how small and no lesion growing so that's a PR so you basically have no response progression you're right we talk about those together and then partial response and
complete response so initially the the authors of this study were going to the primary endpoint of this was going to be the best overall response rate so what was the proportion of patients that hit PR what was the proportion that hit a CR that's very common in this type of paper where the outcomes
are typically so dire however oh I think I said I think I said that the study was I don't remember when the study ended but the amendment was made to change the primary endpoint to overall survival at some point during the study so and by the way that tends to be the metric everybody cares
most about so the overall survival for metastatic melanoma is zero with the exception of people who respond to interleukin 2 high dose interleukin 2 and that will boost the overall survival rate to somewhere between 8 and 10% very very low these patients many of whom had already taken and progressed through interleukin 2 let me refresh my memory on what percentage of those patients about a quarter of these patients had already taken high dose interleukin 2 and by definition the fact that they're
in this study means they had already progressed through that that treatment had failed just reiterate just kind of the state these patients are in so now let's look at figure 1 so again I'll describe it because I realized many people are just listening to us all of this will be available both in the video and then we'll link to the paper so figure 1 is a figure that probably looks really familiar to
people who look at you know any data that deal with survival it's called a Kaplan Meyer survival curve so on the x-axis for this curve is time and time here is shown in months and on the y-axis is the overall survival at the very top 100% at the bottom 0% and it has three graphs or three curves
that are superimposed on one another for each of the three groups again the control group which is the GP 100 the anti-CTLA for group by itself and the anti-CTLA for plus GP 100 and one of the characteristics of a Kaplan Meyer curve is by definition they have to be decreasing in a monotonic
fashion because it's cumulative overall survival that just means it can't like come down and go back up nobody comes back to life so once a person dies they are censored from the study and the curve drops and drops and drops and you can see that they kind of highlight and I actually think
it makes the graph a little harder to read when they when they put some of those marks on there but what really becomes clear when you look at this is that there's a key that there's a clear distinction between the curve for the placebo group the GP 100 group and the other two the two
treatment groups now you'll note at the very end that the two treatment groups appear to separate a little bit I'll talk about that in a second so when I look at these Andrew I the first thing I always turn my attention to I can't resist I have to look at the right hand side of the graph
because what is that really telling me right the tail of this is showing me the true overall survival and I want to sort of figure out what is going on so in the GP 100 group which is the placebo group it is kind of amazing to think that there is still one person who is alive at 44 months
it's it's amazing I mean it's both sobering and amazing that like one person made it to 44 months the next thing I ask myself is well how long did half of the people make it that's called median survival and to do that you go up to the y-axis and you draw a little line from the 50
over and then you bring that down and and that's you know that's that's that's awfully low it's about yeah in fact the table will tell us exactly what that is because I think it's really hard to eyeball that stuff so let's go to so there's always a table that will accompany these things
and let's pull up that table I've got this paper spread out over so many things that's adverse events where is our survival table here you're two subgroup analysis of overall survival it would probably be helpful if I stapled these things together because it would be
well this is always a trade-off actually for since this is a journal club episode I will say that stapling helps but it also prevents one from separating things out writing in the margins I like these little mini clips yeah no financial relationship to the mini clips either just have to
stay back because I always get if you don't say that people go you must have a stake in these mini clips I like these little mini clips in fact I'm such a nerd I always have one of these pilot V5 V7s in my pocket on my pocket of my hip and then my pockets are always filled with with these little mini clips and then again I have a friend who's a musician he's and he's always raining guitar picks so you know it's as far as occupational hazards go of being a nerd no I like I like I'm a big fan
of the mini clips as well but I I went without it today all right so thank you yes table two all right so so let's look at table two while looking at the Kaplan Meyer curve because now this allows us to see a couple things by the way remember how I said there's like that one person who kind of is
still alive in the treatment group well you can tell that he's not a complete responder he or she is not a complete responder because under evaluation of therapy in table two it says best overall response and it says complete responders zero so there was zero complete responders in the placebo
there were two partial responders again a partial responder is some lesions got smaller some got bigger stable disease is didn't really change that much and progressive disease is obviously it it went beyond not even you say a partial response like it lesions got smaller they literally just
tracing the the circumference of one of these you know skin lesions and saying okay got bigger smaller yeah you literally we've had rulers in more phlegmology yep yep I feel like this feels so crude in terms of like like I mean it makes total sense but like in terms of like modern medicine
oh like your lesion grew from like three millimeters to six millimeters and they're literally like drawing little boundaries around little blotches on the skin yeah you're you're putting a little measuring tape on them now again most of these are happening in the radiology suite because
most of the disease for these patients is inside the body remember more than 70% of these patients had visceral metastases so liver soft tissue lung brain you know these are in fact if you include lung liver brain and viscera it's it's all pretty much all the patients so most of this is looking
at a CT scan or an MRI for the brain done it okay so that's that's kind of the first thing that comes up the median response rate should should be shown pretty prominently here so I'm looking through this and the the where is median response maybe it's shown in a different table let's see
not disease control rate time to progression I remember it's about 10 months but maybe that's just in the text yeah here it is so I thought this would be in a table but it's it's on page 715 of the paper it just reports it so I'm sorry
I misspoke the 10 months was for the anti CTLA 4 plus GP 100 and 6.4 months for the GP 100 alone that's the control and then 10.1 for the anti CTLA 4 alone okay so again I was and again I'm just always doing this I'm going back to the paper to be like does that make sense and yeah you kind of
called it right you said median survival was about eight well it turns out it's actually like six and change because because it has that little ding in it and it's out to a little past 10 on the two others so the net takeaway here is again just to put that in English as it's so profound
50% of the patients in the control group were dead in six months 50% of the patients in the treatment group both treatment groups were dead in 10 months so what that means in cancer speak is these drugs extended median survival by four months now that's that's an important concept
you know when we think about how has cancer therapy changed over the past 50 years median survival for metastatic cancer has increased across the board so a person today with metastatic colorectal cancer or a woman today with metastatic breast cancer or a person with metastatic lung cancer
these people will live longer with those diseases today thanks mostly to treatments this is not an early detection lead time bias issue this is treatments are allowing people to live longer and that's an important part of the story but it's only half of the story yet it often gets touted
as the story the other half of the story and frankly the story that I think is more important is what is overall survival doing and if you go back to those cancers the answer is zero so overall survival hasn't changed for solid epithelial tumors it is it was 0% in 1970 and it's 0% today
everyone dies everyone dies from metastatic solid organ tumors now again there's those there's those niche examples I gave you testicular cancer is now an exception GI stromal tumors would be an exception and I'm not including leukemia and in the end lymphomas where now there are exceptions
okay within not to try and be overly optimistic but if I look at the graph in figure one and I look out at the tail of the graph that's right and for those are just listening what I see and I'm far less far less familiar with this type of work and this analyzing these type of data but what I
see is that people in the placebo group they're all dead except that one yeah they're basically all dead at 44 months yep but when I look at the number how long it takes for everyone to be dead in the true treatment groups it's like 50 looks like 53 54 months or well and they're and they're not dead
that's the point they're hanging in there right so because you know an extra as somebody who lost both of my scientific advisors two of the three the other one the suicide we've talked about this before but the other two to different cancers both had the brachatum mutation by the way
you know an extra eight to ten months with your kids or with your spouse or to quote unquote get your affairs in order is is a big deal I mean it's still depressing in the sense that nobody survives long term but you know an extra ten months as long as one is not miserable in that time
completely miserable I mean that's extra ten months of living right well and what's interesting here is you know the observation period stops and some of these patients are still going so what you're highlighting is kind of the point I want to make which is overall survival is the most
important metric and it's the highest bar make no mistake about it and it's certainly not the bar any drug company is ever going to want to talk about for a cancer drug but why not because because they don't none of them work right like we don't have you know like they only want to talk about cures
they don't want to talk about median survival they want to they only want to talk about extending median survival and you know there are you know lots of people out there that are on this on this platform I don't need to get on to it but who will say like look it's a real
racketing in oncology today where drugs that are extending median survival by four weeks are being put on the market at a tune of you know 50 to a hundred thousand dollars per treatment that's not uncommon in oncology there was one drug that was approved for pancreatic cancer I believe it
extended median survival by nine days and it costs forty thousand dollars and it's being advertised as significant yes yes because it was that was a statistical significant improvement in median survival I'm just yeah so it's not I think it's really understandable why people are very skeptical
of the pharma industry and and I think you know a much more nuanced view is necessary clearly I don't think pharma is all bad but I really understand why people lose faith in pharma when when you know these types of products somehow make regulatory approval does insurance cover these kinds of drugs
it can in fact it often does it depends on the FDA approval of course in the indication but a lot of times they do right so yeah there's a societal cost to these things but but there's also a patient cost right so a lot of times insurance doesn't fully cover it and a patient has to bear
the cost difference and on top of that you alluded to this a second ago which is what if your quality of life is dramatically compromised as a result of this treatment and yes statistically you're going to live nine days longer or three weeks longer but at what cost to your health in those
final remaining days and by the way you're potentially straddling your loved ones with enormous debt in your absence so it's it's a super complicated topic yeah there's a dignity component too I may have seen this in people dying you know at some point they become such a diminished version
of their former cells that they don't want to be seen by people that way so what is exciting about this drug although it's this paper is not the one that shows it the reason I chose this paper Andrew is because it was the first approval a second drug came along that is an anti PD1 drug
that drug is called K Truda that drug turned out to be even better and had it has even a greater response rate both in terms of median survival and overall survival but this was the landmark paper I also have a slight bias here and I'll disclose in a moment why but I but I think it just
talks about very interesting biology so let's talk about a couple things that stuck stuck out to me in this paper the first thing that stuck out to me and the authors didn't comment on it unless they did and I missed it is look at figure two so figure two is the subgroup analyses where you're
sort of showing a similar graph to the one you showed earlier right where you you showed the response rate or the change in response between the groups and then you put the error bars on it and this is where we talk about how well it's a 95% confidence interval so does it touch the unity
line so these are called like tornado plots typically and what you'll notice is that in the top you're looking at sort of it's comparing the anti ctla for with GP 100 versus the GP 100 and in the bottom you're looking at the anti ctla for versus the GP 100 so at a glance you can see
GP 100 is not doing anything I mean that's the that's the first takeaway of comparing A to B what I find most interesting is look at the subgroup analysis of females notice that in females while there's a trend towards risk reduction and this is risk reduction for overall mortality so again
I just want to restate that the primary outcome of this trial was changed to overall survival which I think is the better outcome by the way and overall for all patients in when you compare anti ctla 4 plus placebo versus placebo there was a 31% risk reduction in overall mortality
that's what that's that's the mathematical interpretation of what you're seeing at the tail end of that Kaplan Meyer curve living longer living longer and it's it sounds like a big difference and it sounds like a big difference it is a big difference it is for those people because
you're really looking at basically 0% surviving in the placebo group versus 20% of people are still alive at 56 months in the treatment group but look that means 80% have died right but notice that and and and sorry when you just look at the anti ctla 4 plus GP 100 in the subgroup B that hazard
ratios even showing more compression it's a 36% reduction in risk of death but notice that the females did not reach significance so in the in the first group they barely do and you can see that because the confidence interval runs from 0.55 to 0.92 and notice the error bar almost touches the line
and in the second one it does not reach significance at all so I actually went and kind of did a little reading on this after and I said hey you know how much did this study was this an outlier study and it turned out it wasn't and that about half the studies of anti ctla 4 did indeed find
that the drug was less effective in women than men should I find interesting now I couldn't find any great explanation for it but the most plausible explanations fit into two categories the first are maybe there are differences in the immune response to the drug if you're a man or a woman
the second comes down to dosing I should have said this at the outset but of course these drugs are not like a pill where it's like everybody gets you know 50 milligrams of this they're all dose based on weight so this study is dosed I believe it 3 milligrams per kilogram and because
most men are heavier than women men are getting a higher dose than women and weight and body surface area and immune system like these things are not all perfectly linear so I I kind of wonder if this difference is simply explained by men on average getting a higher dose than women interesting.
Last thing I want to talk about here is in table 3 so table 3 always an important table to look at in any paper is what are the adverse outcomes right where the adverse effects of the drug yeah I spent some I spent a little bit of time with this and I confess it you know I definitely don't want
cancer to the extent that I can avoid it but this table made me wonder whether or not I would also want to just avoid cancer treatment given the life extension provided I mean these adverse events are pretty uncomfortable yeah so just to put just to put in perspective and you always have to kind
of you know be mindful of how many of these adverse events are occurring in people just because their disease is progressing so the first thing I always want to look at is total adverse events in all three groups not just great so grade 3 and grade 4 are real toxicities right grade 4
toxicity is life threatening toxicity by the way grade 3 is pretty significant toxicity grade 1 and 2 we typically just you know that's not that severe right a little rash to put some corticosteroids on it went away kind of thing okay so in the treatment plus GP 100 group 98.4% of people reported
some event so all but 1.6% in the anti-ctlA4 group alone it was 96.7% so only 3.1% did not but in the placebo group it's 97% so it's more to keep in mind like you know everybody's having some adverse effect okay well what if you say well let's just limit it to the most severe events
well let's just talk about grade 4 toxicities there were 6.1% of those in the placebo group 8.4% in the anti-ctlA4 group and 6.8% in the combined group so not a huge difference in grade 4 toxicity meaning that whatever adverse events are occurring may not be related to the treatment again these
are if you if you think about it and it's a very awful sad morbid thought to imagine these are you're looking at the adverse responses of people more than 80% of whom died during the course of a very very short study and so you know it's very difficult to disentangle what effects or what
side effects a person is having just from that process as they are from the actual treatment but if there is an area where there's a really clear difference it's down in the autoimmune category so if you look at any immune related events you can see that in the anti-ctlA4 plus
GP 100 group it's about 60% in both of those treatment groups versus 30% and if you look at the grade 3 and 4 toxicities it's 10% in the anti-ctlA4 15% in the anti-ctlA4 alone group and only 3% in the treatment so that's a real difference when it makes sense that people getting this drug plus placebo or just the drug would have autoimmune issues because this is an immunotheraic.
It's an immunomodulator in fact what is it doing it is taking the breaks off the immune system but then again the things that they list out per peritis is that a irritation of the skin? Yeah irritation of the skin. I'm not a physician but I know that anyitis is going to be like an inflammation and OMA unfortunately likely a cancer or cell replication. Look at the difference in vitiligo. I mean wow yeah so very good. Sorry look at the gastrointestinal differences.
Yeah and the vitiligo right so 3.7% 2.3% 0.8% the GI stuff is the most common stuff you're going to see there. Those are the really big ones. Of course there's diarrhea and there's diarrhea. There's travelers diarrhea. There's these. And these people in the four diarrhea and then there's like can't really do anything besides to make trips back and forth to the bathroom. Well there's put it this way. There's colitis here is diarrhea so significant.
These patients require IV fluids. Now what you don't see here is how many of these patients actually required corticosteroids to reverse the autoimmunity. So a lot of times what will happen here in these studies or with these drugs is the autoimmunity becomes so significant that you have to stop the drug and give corticosteroids. Do the exact opposite. You now have to shut the immune system down. So you just took the brakes off it with the drug and now you need to shut it
down with corticosteroids. When I was, was I in mental? No. When I was in my fellowship I wrote a paper about autoimmunity correlating with response rate in anti-CTLA IV early on. This was during the phase two work. So the NCI was a very early adopter of participating in these trials. It was observed that at least hypothesized, this is what the paper basically wrote about, which was, is there any correlation between autoimmunity and response? It turned out the answer
was yes. There was a very strong correlation. So there was no difference in autoimmunity between the doses. So the paper we wrote was two dosing schedules. So it was basically the full dose, the three milligrams per kilogram versus a low dose, one milligram per kilogram. This is a phase two trial. Those are your two arms. There turned out to be no difference in autoimmunity between them. But there was a big difference between the response rate that tied to autoimmunity.
In other words, autoimmunity predicted response. Now I think over time these investigators, the doctors who administer these treatments are getting better and better at catching these things earlier because these autoimmune conditions can actually be devastating. So on a very personal note, when Kaitruda came out, I want to say it was around 2011, no, no, no, gosh, it must have been 2013, 2014. Thereabouts. Again, it was for treatment of metastatic melanoma.
I want to come back and explain why melanoma gets all of the attention in autoimmunity conditions. In immunotherapy conditions, I'll state that. Anyway, a friend of mine got pancreatic cancer. He got the bad type of pancreatic cancer. This is like the adenocarcinoma of the pancreas. So this is a non-survivable type of cancer. Furthermore, his was unresectable.
Can you explain what that is? Yeah. So about 20% of people who have pancreatic cancer technically have it in a way where you could still take out the head of the pancreas. Right. The Whipple procedure. The Whipple procedure. Now, tragically, most of those patients will still recur. My understanding is that pancreatic cancer progresses from anterior to posterior in the pancreas and that the Whipple is a removal of the front and the anterior. That's the Whipple procedure.
So if the cancer has progressed far enough, caudal into the posterior pancreas, then there's nothing left to cut out, basically. Well, can we survive without a pancreas for any amount of time? Oh, yeah. Absolutely. So why don't they just remove the whole pancreas? Oh, that's my point. It's already micrometasticized. So it's not. The surgical procedure is not
the challenge anymore. It used to be. So, you know, at Johns Hopkins, which is one of the hospitals where this was pioneered like the 30-day mortality for a Whipple procedure was, I don't know, 80%. And the reason was to figure out how to suture a pancreas to the bowel without the, so the pancreas is such an awful organ to operate on because its enzymes are designed to digest
anything and everything. So imagine now you have to cut the pancreas in half, take out the head of the pancreas with the duodenum, and then somehow sew that open half of a raw pancreas to the end of the jajunum and not let it digest itself. So when did Hopkins figure this out? Now, the first one was actually done by A.O Whipple, but yes, at Hopkins is where they figured out the way to put drains in the surgical technique, how to do it in two layers,
what type of stitches to use. Like all of the nuances of this were worked out in a few places, but I would say Hopkins more than any place else. And are there physicians who like try this on non-human primates or something? Or is this always just done on patients? Well, nowadays, I mean, put it this way, even 25 years ago, at a major center like Hopkins, the mortality of that procedure was less than 1%. Amazing. Yeah. So they have been some victories.
Well, yes, but here's my point. That's no longer the bottleneck, right? Taking out the pancreas safely, as complicated and challenging as that is, and if you need a Whipple procedure, you only want to have it done by someone who just does that night and day because you don't want weekend warriors doing it. That's not why people are living or dying. They're dying because the pancreas just comes back. It was already spread to the liver by the time you did it. You just
didn't realize it yet. So whether you took out the whole pancreas or the head of the pancreas or the tail of the pancreas, the location of the tumor is predictive of survival only in the extent that it basically is a window into how soon did symptoms occur. So pancreatic cancers in the tail tend to be more fatal, even though they're way easier surgically to take out because by the time you develop symptoms of a tail pancreas cancer, it's a big cancer. I was going to ask this question
later, but I'll just ask it now. Given the link between the immune system and these cancers, is there an idea in mind that people who are, let's say, 40 and older or 50 and older who don't yet, they're not diagnosed with any cancer, would periodically just stimulate their immune system to
wipe out whatever early cancers might be cropping up. Just take a drug to just ramp up the immune system, even to the point where you start out with a little diarrhea, maybe a few skin rashes, and then come off the drug, just basically to fight back whatever little cell growth is starting to take place in skin or liver, maybe for three weeks out of each year. I mean,
why not? Yeah, that's an interesting question. I've never thought of it through that lens. I suppose the question is, what can we do to keep our immune systems as healthy as possible as we age? Stay on a normal circadian schedule. There's evidence for that. Sure. No, there's evidence that certainly if it promotes sleep, anything that promotes better rest is going to promote immune health. Because if you ask the macro question, which is like, why does the prevalence of cancer increase
so dramatically with age? There are certain diseases where it's really obvious why the prevalence of the disease increases with age. Yeah, like age-related, macular degeneration. Sure. Or cardiovascular diseases by far the most obvious, because it's an area under the curve exposure problem. The more exposure to lipoproteins and the more the endothelium gets damaged, the more likely you are to accumulate plaque. It totally makes sense. Why 10-year-olds don't have
heart attacks and 80-year-olds do. But when you sort of acknowledge that, well, hey, anybody's accumulating genetic mutations. We're always surrounded and being bombarded by things that are altering the genome of ourselves. Is it simply a stochastic process where the longer you live, the more of these mutations you're going to occur until at some point one of them just wins?
I think that's got to be a big part of it. But I think another part of it, and I clearly amodeling thinking this, is that our immune system is getting weaker and weaker as we age. People become more susceptible to infections as they get older. I think that's equally playing a role in our susceptibility to cancer. I think the question is, how do you modulate immunity as you age? To me, that's one of the most interesting things about rapamycin potentially is that
when taken the right way, it seems to enhance cellular immunity. That's potentially a really big deal. I get at least in short-term human experiments in response to vaccination. It's enhancing vaccine response. The question is, would that translate into cancer? Nobody knows. Could that be one of the reasons why animals treated with rapamycin live longer and get less cancer? Don't know. It could also be that it's at a fundamental level that's targeting nutrient sensing. Where I was going with
that story was that maybe I'll back up for a moment. Why melanoma? We didn't really know this like 30, 40 years ago in the early days of immunotherapy. But what we know now is that most cancers probably have about 40 mutations in them. That's like ballpark 40, 50 mutations is standard fair for a cancer. But melanoma happens to be one of the cancers that has many, many more mutations. And the more mutations a cancer has, the more likelihood that it will produce an antigen that's
recognized as non-self. And that's why in the early days of immunotherapy, the only things that worked were IL2 against metastatic melanoma and kidney cancer. Because kidney cancer turned out to also be one of those cancers that for reasons that are not clear produced hundreds of mutations. And so it's no surprise that the early studies of checkpoint inhibitors were also done in
metastatic melanoma where you basically have more shots on goal. Again, if I'm going to take the breaks off my immune system, I might as well do it in an environment where there are more chances for my T cells to find something to go nuts against. So it's 2013, 2014 and this friend of mine who has something called Lynch syndrome, which is a one of those few hereditary or germline mutations that results in a huge increase in the risk of cancer. He had already had colon cancer at about
the age of 40 and had survived that. It was a stage three cancer, but he had survived it. Well, now five years later, he had developed pancreatic cancer. And when he went to see the surgeon, they said, yeah, we have something we can do. Like, it's too advanced. So to put that in perspective, that is a death sentence. And that's a six month survival. And at around that time, there was a study that had come out in the New England Journal of Medicine that had talked about how patients
with Lynch syndrome had lots of mutations. And so we talked with his doctors about the possibility of enrolling him in one of the Kaitruda trials. There was one going on, I think it's Stanford. The thinking being, well, you would want to target a checkpoint inhibitor against somebody who has a lot of mutations. And even though typically we don't see that in pancreatic cancer, his is a unique variant of it because it's based on this. And so sure enough, he was tested for these
mismatch repair genes. He had them enrolled in the trial and amazingly had not only a complete regression of his cancer. And he's still alive and cancer free today, 10 years later. But the treatment worked so well at activating his immune system that his immune system completely destroyed his pancreas. So now he is effectively had a pancreatectomy based on his immune system. So now he actually has type one diabetes is no pancreas. He injects insulin to the other.
No, he has to use insulin just like some type one diabetes. He had to pick being alive with type one diabetes. Of course, no comparison. But it's just an interesting example of how remarkable this treatment was able to work when you were, you could completely unleash the immune system of a person. And you eradicate the cancer and the rest of the cells around it. And you know, there are many organs we could live without. You know, there
are certain organs you can't live without. I can't live without your heart lungs, liver, kidneys. But many things that kill people arise from organs, the breast, you could live without all breast tissue. You could live without all plastic. You would choose to do to live without these. Right. But I'm saying if you if you had metastatic cancer and you had a bullet that could selectively target a tissue, you would take it. And right now the only tissue we can do that
against is a CD19 B cell. And that's what those CAR T cells are. So right now these are not tissue specific treatments, but their mutation specific. The last thing I'll say about this paper that I found interesting and I was looking for it and I was surprised they didn't at all comment on if there was any correlation between autoimmunity and response. So they obviously acknowledge the autoimmunity in table three. But I would have loved to have seen a statistical analysis that said, hey,
is there any correlation between response rate and autoimmunity? But they didn't comment to that effect. So we're left kind of wondering what the current state of that is. And I guess in summary, I'll say that the reason I thought this was an interesting paper to present is that I still believe that immunotherapy is probably the most important hope we have for treating cancer. And well,
I think we're still only scratching the surface of it. So collectively, the overall survival increase for patients with metastatic solid organ tumors is about 8% better than it was 50 years ago. And virtually all of that has come from some form of immunotherapy. I think is promising. And I think the holy grail is that meaning the next step, if you go back to where we started the discussion, is coming up with ways to engineer T cells to be even better recognizers of antigens.
And there's many ways to do that. One is to directly engineer them. Another is to find T cell that have already migrated into tumors. Those are called tumor infiltrating lymphocytes or TIL. And expanding those and engineering them to be better and younger. Is it possible to engineer our own T cells to be more pH variant tolerant? Meaning since this cloaking of a local area by changing the pH, could we pull some T cells?
I'm always thinking about the inoculation stuff. Like pull some T cells as part of our standard exam when we're 30 and you know, it grows some up in an environment that the pH is slightly more acidic than the normal and then reintroduce them to the body. I mean, after all they are our T cells. In other words, give them a little opportunity to evolve that the conditions they can thrive in. Or even just keep them in the freezer in case we
get them. So the interesting thing is I don't know that if you just got them to be comfortable in a lower pH, it would be sufficient because there are still so many other things that the cancer is doing as far as using other secreting factors. It seems that by far the most potent thing comes down to expanding the number of T cells that recognize the antigen and making sure that you can get that number big enough without aging them
too much. So in some senses, it has become a longevity problem of T cells. The way to think about it is you want an army of soldiers who are wise enough to recognize the bad guys which comes with age, but young enough to go and kill. And right now both extremes seem to be unhelpful, right? When you go and find tumor infiltrating lymphocytes in a tumor, they're very wise. They know which one they've demonstrated that they can do everything. They can outmaneuver the cancer,
but they're too old to do anything about it. And when you take them out to try to expand them by three logs, which is typically what you need to do, expand them by a thousand fold. They can't do anything about it. And what about avoiding melanoma altogether? I mean, obviously avoiding sunburn. You know, I somehow I got couched as anti-sund screen and that is absolutely not true. I said some sun screens contain things that are clearly immune to endocrine, excuse me,
disruptors. And we're going to do a whole episode on sunscreen. Maybe we could do some journal. I think I'm actually planning something on that as well. I want to do some. Yeah, I mean, and some dermatologists reached out. So very, very skilled dermatologist reached out and said that indeed some sun screens are downright dangerous. But of course melanoma is super dangerous. Physical barrier, no one disputes physical barriers for sunscreen. Everyone agrees that that
is unlikely to have endocrine disruption. So physical barriers are undisputed. But aside from limiting sunlight exposure to the skin, what are some other risks for melanoma? I mean, I think that's the biggest one. I do not believe that smoking poses a risk for melanoma. And if it does, it's going to be very small. There are hereditary cases. So one needs to be pretty mindful when taking a family history. And by the way, there are really weird genetic
conditions that link melanoma to other cancers, such as pancreatic cancer, by the way. So whenever I'm taking somebody's family history and I hear about somebody that had melanoma and someone that had pancreatic cancer, there's a couple genetics. Genetic tests will look at to see if that's a person that's particularly sensitive just from a genetic predisposition. But I do think that
first and foremost, it's... And by the way, I think with melanoma that, although it's not completely agreed upon, I think it's less about sun exposure and more about sun burn. So, and again, I'm sure there's somebody listening to this who will chime in and apply a more nuanced response to that. But I think there's a fundamental difference between a mountain the sun, getting sun, making some vitamin D versus I'm getting scorched and undergoing significant
UV damage. There might also be something to be said for the time in one's life. And I've certainly seen things that suggest that early repeated sunburns would be more of a risk. So look, I think that's not a controversial point in the sense that like who wants to be sunburned, right? So it's like whatever one needs to do to be sunburn, whether it's being mindful of what the UV
index is, wearing the appropriate cover, wearing the appropriate sunscreen. I also find the whole kind of anti-sunscreen establishment to be a little bit odd. Well, the anti-sunscreen establishment is odd. I'm trying to open the door for a new aunt's discussion about the fact that some sunscreens really do contain things like oxybenzines and things that are real. Yeah, but when you're spraying them on kids...
Yeah, but when you just look at the straight of the good old-fashioned mineral sunscreens, perfectly safe. Yeah, yeah. As far as we know, I mean, I also dare we cross the seed oil debate into this. Some of the folks who are really anti-seed oil also claim that seed oils increase risk for sunscreen. Peter and I are smiling because we have teed up a debate soon with some anti-seed oil and less anti-seed oil experts. So that's forthcoming. That's going to be a fun one. We'll be doing
all of that with our shirts on. I really appreciate you walking us through this paper, Peter. I've never looked at a paper on cancer and certainly not one like this. I learned a lot and it's such an interesting field, obviously because of the importance of getting people with cancer to survive, longer and lead better lives, but also because of the interaction with the immune system.
So we learned some really important immunology. Yeah, and this was great. I feel much more confident now in the belief that the exposure to light early and late in the day can actually have benefits. And as I said, I think there's some causality here and I think it shouldn't be ignored. Cool. Well, this was our second journal club. I look forward to our third. Next time you'll go first. We'll just keep alternating. We've also switched venues, but we both wore the correct shirt.
And I hope people are learning and not just learning the information, but learning how to parse and think about papers. And I certainly learned from you, Peter. Thank you so much. Yeah, thanks. I know this is great. Thank you for joining me for today's journal club discussion with Dr. Peter Atia. If you're learning from and you're enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us. In addition, please
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