Journal Club with Dr. Peter Attia | Effects of Light & Dark on Mental Health & Treatments for Cancer
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Welcome to the huberman lab podcast, where we discuss science and science space tools for everyday life. I made you huberman and am a professor of neurobiology and opened logy at stanford school of medicine. Today Marks the second episode in our journal club series with myself in doctor Peter attia.

Doctor Peter atia, 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 nine. 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 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. Now 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 as safely possible throughout the entire day, and a separate additive effect of being in as much darkness at night as possible. I described 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 dark knight exposure at night.

In other words, light and dark have independent and additive effects on mental health, and during today's discussion, you will learn exactly how to apply light exposure and dark exposure in order to get those benefits. Then Peter presents a paper about novel treatment for cancer. I must say, it's an extremely important conversation that everybody, regardless of whether or not you may have had cancer or know somebody has had cancer, ought to listen to.

He highlights the current technology of cancer treatment as well as the future technology of cancer treatments and the key role that the immune system and the auto immune system play in treatment 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 researchers at stanford.

IT is, however, part of my desired 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 eight sleep. Eight sleep makes smart matters covers with cooling, heating and sleep tracking capacity. Now spoken many times before in this podcast about the fact that sleep is the foundation of mental health, physical health and performance.

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Select countries in the eu and australia. Again, that eight sleep, that com slash huberman. Today's episode is also brought to us by Better help. Better help offers professional therapy with a license therapies Carried out online. I've been going to therapy for well over thirty years.

Initially, I didn't have a choice that was a condition of being allowed to stay in school, but pretty soon I realized that therapy is extremely valuable. In fact, I consider doing regular therapy just as important as getting regular exercise in cardiff. Asked lar exercises and resistance training, which of course, I also do every week.

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Again, that's a Better help out com slash huberman. Today's episode is also brought to us by due juve makes medical grade red light therapy devices. Now there's one thing of consistently emphasize on this podcast the incredible role that light can have on our biology. And of course, I 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 circuit, ad them daytime mood, focus on alertness and improve sleep.

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And again, that's jove dot com slash huberman for this month only january twenty twenty four, driver is offering exclusive discounts to huberman levEllier ers with up to five hundred dollars off select view products. Again, that you spell J O O V V dot com slash huberman to get up to five hundred dollars of selective products. And now for my discussion with doctor Peter attia.

great to have you here for journal club. Number two, i'm already confident this is going to become irregular 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 um sharing our skills at reading and sharing data and people listening can do that as well.

So last time I went first, so I think i'm going to put you in the hot seat first and have have you go first and i'll follow you.

okay. I'm really excited about this paper um for a number of reasons. First of all, 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 gonna an important point in more than eighty five thousand people as part of this cohort in the U. K. I'll just mention a couple of things to give people background, and I keep this relatively brief.

First of all, there is 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 daylight and mood in 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 they are shorter, significantly more people report feeling lower mood and affect, okay.

So there's a long standing treatment for a seasonal effective disorder, which is to give people exposure to very bright light, especially in the morning, the way that that Normally accomplished this with these sad lamps, seasonal effective disorder lamps, those lamps are basically bright, meaning more than ten thousand locks, lights that they place on their kitchen counter, at their table, in the morning or in the office. So they are 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. Now a couple of other key points. The biological mechanisms for all this are really well established.

There's a set of cells in the neural retina to Lance the backy. There's sometimes called intrinsically photosensitive red. No gangling cells are sometimes called melon ops and retinal al gangland cells. I'll talk about those in a bit of detail a moment. It's well known that those cells are the ones that respond to two different types of light input, not one, but two different types of light input.

Intent information to the hypothesis where your masters caching clock resides, then your master circadian clock sends out secretary signals, so peptides, hormones, but also neural signals, to the brain and body and say, hey, now it's day time. Now at tonight time, be awake, be asleep. But IT goes way beyond that.

These melon ops trying sicily photo sensitive retina gang lin sells, we know, also projected areas of the brain, like the habana, which can triggered next native effect, negative mood. They can trigger the release of dopamine, or the suppression of dopamine, the release of satan in the suppression of. Of serotonin.

And so they're not just cells for setting your circadian clock. They also have a direct line literally once in apps away into the structures of the brain that we know powerfully control mood. So 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 stimulation these cells respond to. One is very bright light, as we just talked about. That's why getting a lot of daytime suddenly is correlated with elevated mood. That's why looking at a ten thousand looks artifical lamp can offset seasonal effective disorder.

By the way, just take couple of questions on that. Um how many lucks 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 hundred thousand locks. On a really bright day could be three hundred thousand locks. okay?

Most indoor environments, even though they might seem very bright, I like think of you're kind of like a department store with a bright light, believe or not, that's probably only closer to six thousand locks maximum, and probably more like four thousand locks. 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 or an average of hundred thousand locks. But IT won't seem that bright because you don't cold see the sun. But it's also because when there's cloud cover, a lot of those long wavelength light such as orange and red light aren't coming through, however, and this is so important, the circadian clock, the supermarket is matic nucleus IT sums full times.

It's a full times summing system. So basically if you're outside in eight thousand, looks very overcast, U K. Winter day, and you're walking around hopefully without sunglasses because some classes are gonna filter a lot of those photons out your circuit clock is summing the photons.

So it's an integration mechanism. It's not triggered in a moment. And actually that the experiments of recording from these cells, first done by David burns in IT Brown, were, you know, historic in the field of visual neuroscience.

When shown, bright light on these intrinsically photosensitive ells get trank up the intensity, the light, and the neurons would ramp up their membership potential and then start spiking firing action, but tell or long trains of action potentials that have been shown to go on for hours. And so that's this signal is a propagating into the whole brain and body OK. So the the important understands this is not a quick switch.

That's why I suggest, on non cloudy days will call them that people get ten minutes or so of sunlight in the rise in the early part of the day, another ten minimum in the later part of the day, as much sunlight in their eyes as they safely can throughout the day. But since you're physician, I should just, and you had a guest on talking about this recently, when the sun is low in the sky, low solar eringer sunlight, that's really the key time for a reason, will talk about in a moment. And when the sun is low in the sky, you run very, very little risk of inducing cat act.

By looking in the general direction of the sun, you should still blank as needed to protect the eyes. It's when the sun is overhead, and there's all those photos is coming in quickly, in one, in a short period of time that you do have to be concerned about car act and macuto generation if you're getting too much daytime sunlight. So the idea is sudden glasses in the middle 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 for safety reasons.

But another question answer, yeah, if person is indoors, but they have large windows, so there they're getting tons of sunlight into their space. They don't even need ambient indoor light. How much the photos 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 wavelength are filtered out.

In other words, if you can't see the sun through the window, even if sufficient light is being provided that insufficient to trigger this phenomenon.

that's right. However, if you have, you know, 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 centres 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 a very low resolution. Think of them as big pixel.

They're not interested in patterns and edges in movement. They're interested in how much ambient light that happens to be. Now keep in mind that this mechanism is perhaps the most well conserved mechanism in cellular organisms. So i'll use as a way to frame up the four types of light that one needs to see every twenty four hours for optimal health. And when I say optio health, I really mean mental health and physical health.

But we're gona 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 condos ons, one that responds to short wavelength A K blue light, and another one that responds a longer way link like orange and red. So your dogs have this, we have this. And it's a comparison mechanism in the cells of the eye, these neurons of the eyes, they compare contrast between blue and orange, or sometimes blues and reds and pinks, which are also a long wave in light.

There are two times of day when the sky is enriched with blues, oranges, pink and reds, and that low solar ring of 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. So these cells have these two can photo pignone, and they say, how much blue light is there? How much red light is there or orange light and the subtraction between those two trigger the signal for them to fire the signal off to the circuit ting clock to the brain.

And that's why I say, look at low solar angle sunlight early in the day. What that does is IT. What called is phase advanced the clock.

This can get a little technical. 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 twelve hours. okay.

So when you stand closer to the kids so your kid swings back and you give me an a push, you're shortening the period, right? You're are not allowing the swing to come all the way up. That's what happens.

When you look at morning sunlight, you're advancing your circuit, an clock, translate to english or non nd 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, solemn of sunlight. So in the the afternoon setting, sun or evening setting, you do the exact opposite.

Your face delaying in the clock is the equivalent of your kid being at the very top of the of the arc. And so it's gone, you know, maybe twelve a half hour, twelve less twelve and a half hours as the duration of that swing. And you run up and you push them from behind, 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 important to view loser angle sunlight in the morning and again in the evening as often as possible.

And it's done by that. Read out of those two photo pigments now, midday son, which contains its bright light, but you see, as White light contains all of those wavelength that equal intensity. So the middle the day is the so called circuiting dead zone.

In the middle of the day, bright light triggers the activation of the of the other ops in the millin ops in which increases mood, increases feelings of well being, has some other consequences, but you can't shift your circuit I and clock by viewing the sun in the middle the day because it's in the circuit and dead zone. It's the equivalent of pushing your kids 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 sunlike the midst 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 beautiful, or paintings, or things that sort, but rather for setting the circadian clock.

Now, what if you only do one of these ends? So what if you've got contain 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 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 lighting your eyes that next morning. The reason is Better to do in the morning as opposed to the evening, although both would be to do the 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, retina sensitivity increases and IT takes a very little light to shift your circuiting 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 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 is your netflix and occupation. The a mount of military and suppression from nightmare exposure is having by viewing evening setting son.

Now keeping in mind you don't need to see the sun cross the horizon IT can just be when is low solar angle so you're looking for those yellow, blue or blue, pink, blue, red contrast. And on cloudy days, believe they are not they're still there, just you don't perceive as much of IT coming through. So there 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, get perhaps invest in one of these satellites so that they can be a bit expensive there. Couple of companies are starting to design sunrise simulators and evening simulators that are actually good, that actually work um 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 o light T U O.

And that light ball was developed by the biologist of the university washington, who basically discovered these color opponent mechanisms. Um those lights are not particularly expensive but they're um they do seem to work. In fact, they the the study that is emerging again, unpublish 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 the morning, they're getting nineteen reversals of blue, orange per second. So when you look at this light IT looks like A A barely flashing White light but it's reversals of orange and blue orange and um a red and blue and at so is the .

person looking at at perceive what i've used one .

of these um you just looks like a flickering light. And of course is the always the potential of a placement effect.

But lots not going to say, is there 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 they have done with the ten thousand locks, sad lamps, and in which most people use to try into sunrise simulation in their home. But keeping in mind that sunrise is gives you this comparison of short in long wave length light, just a bright ten thousand lock slide triggers one of the absence 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 the excels that's relevant and not the one that's most relevant. So i'm excited about what two o is doing. I think that um and again, I have no relation to them except that I know the biologists who do the work that that provide the mechanistic logic for that engineering.

I still think um we're the like the really like early days of this stuff. What should be done is to have this stuff built into your laptop, right? You should be built into your phone.

And hopefully he will be. No, I mentioned this color contrast thing in sunrise and sunset. I mentioned the bright light throughout today.

But there's a fourth light stimulus that turns out to be really important in this will provide the segway into the paper. Turns out the 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 is dark.

Absence of is the absence of light. But what this paper really drives home is that people who make IT a point to get dark exposure, night A K. The absence of light at night actually benefit, even if they're not getting in a 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 of accurately timed light exposure to the eyes in the context of mental health. I think, you know, 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, you know, also don't suffered from jet lag too much. Some people can stay up late, get a lot of bright light explosion, the midnight and during the day. They've got their sun classes on all day, and they're a great mood all the time.

Other people are more suspect ble these sorts of things and we don't know whether not polymorphism underly 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 um 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 arouse on alertness which correlates with all sorts of you know neo modulator and hormonal outputs. And um so none of this should come as any surprise. A woman in one last thing, there was a study published gosh, over ten years ago now from chucks iser lb bit.

Harvard medical school is a phenomenal lab expLoring circadian human health behavior. He is just consider no on illumination in the field, but there wasn't a study that was in error where they had publishing science magazine that light shown behind the need could shift circuit dian rythm, 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 relevant here. And as far as we know, the color of one's eyes, the darkness or lightness of one's eyes, bears onal relevance on their sensitivity to these types of mechanisms.

and on and on. So, 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, my hobby, right? I'm always doing artery in the morning and rocking in the afternoon.

So it's not uncommon that i'm seeing both of those. How relevant is that that the sun be above the horizon? So for example, um IT begins to get light about in thirty minutes before sunrise and then you know right it's so of sunrise at seven thirty first light is seven and then you know sort of seven fifteen to seven a thirty is actually quite bright.

I mean, you can see anything and everything in the same is true at sunset. So does does that thirty minutes or when son is beneath the horizon? Can't the two part of that .

ten minutes IT does I mean, in an ideal circumstance, you'd get outside and see the sunrise every day, and you'd see the sun set 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 sun rise 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 mellon ops and mechanism. If you want to be awake, if you want to stay a sleep 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 ten 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 trying 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 in its dark when you're walk into your car, is a kind of ery feeling. That sort of ery feeling may corporate with the fact that you miss a signal, your brain is trying to order your brain and body in time.

And that's what that all of this is, right, trying to orient in time. And again, some people are more acceptable to that. The other, some people might like that feeling of, oh, I went in when I was bright and I come out when I start.

But the vast majority of people feel Better when they're getting this morning and evening sunlight exposure. And this is especially important kids, right? This is one of the things that, you know, this paper points out in their good data, that people are spending approximately ninety percent of their time indoors, daytime time indoors.

And those indoor environments are simply not bright enough. You think others, all these bright lights and some people are putting bu blockers on in the middle day, which is the worst thing you could possibly do if you're gna wear a 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 blockers. You just simply should dim the lites and ideally have lights that are set a little bit lower in your environment, which the skinning avian had been doing for a long time. So you kill the overhead lights and don't obsess about right light exposure in the middle night. In fact, for a long time, irons and other people were saying, oh, you know, even just a brief flash of light and milk the night can get quash militant onand, that's true. But the other time in which you're in the circuit I and dead zone is in the middle of the night.

You can't shift your circuit ti and clock in the middle night but you know all of this gets down to interweaving rythm of light sensitivity, temperature, hormonal output court is all I mean there's a whole landscape of circuiting biology this paper um which he was published in a new journal i'm really excited about nature mental health this journal is just launched to recently is entitled day and night light exposure are associated with psychiatric disorders and objective light studying in more than eighty five thousand 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 nightlight exposure associated psychiatric disorders this if this a newspaper headline you like, oh my god is what what are 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 going to bring up another paper unannounced, but I will say that this paper built off a previous study entitled time spent in outdoor lighters associated with mood, sleep and circadian rythm related outcomes. And that was a cross action launch unal study in four hundred thousand biobank participants. So this U.

K. Biobank is incredibly valuable resource, and there are now multiple studies establishing. That once pattern of light exposure is extremely important.

Now, the previous study in four hundred thousand participants basically nailed home the idea that the more time you spend outdoors, the Better is your mood, the Better is your sleep, the Better is the ethnicity 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 at measured depressive disorder, generalized and anxious polar.

Here's the the basic take away and i'll i'll quote them here and then i'll tell you my interpretation that here I am coding, avoiding night light and seeking light during the day. I love that word, seeking maybe a simple and effective non formal logic 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 that needs to be a practice, much like them, to cardio or resistance training.

Okay, so, so what do they do in this study? So basically they gathered up. One hundred thousand people are so IT eventually was pared down to about eighty six thousand participants, because some just didn't qualify, didn't report their data back.

They equipped them with accelerators on their risk. And those rist vices also could measure ambient light. Now that's not a perfect tool, is what you'd love to do is measure ambient light at the level, 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 and then at night is a different color. And then if you're getting too much light exposure, we'll go to a different color frame. This has to be possible. You don't have to wonder if you're got enough lighter in 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 I mean, that was going to ask you about that to these risks based devices potentially get covered by clothing and some turn over. You have your sleeves down. I have my sleeves.

They had IT on the outside the sleep, but they asked that you will 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 advantage by thinking, you know, when the person is out and about, they're not often looking right at the sun. You're talking to a colleague under an overhanging, for instance. So it's it's not it's direction, right? okay.

And then they had two hypotheses, two primary hypotheses, one, that greater light exposure on the day is with lower risk for psychiatric disorders. And two second hypotheses, 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 tablet TTS and mild night, okay, then they collected information about how much light exposure people were getting, as well as they're sleep in their activity, and so on.

I should mention this was done in males and females. IT was a slightly older cohort than one is used to seeing people in their fifties and sixties. They had psychiatric diagnosis information, and then they divided people into especially two groups.

But they had a lower so A Q one in A Q to a lower cortile. That meant people that we're getting less daytime light as opposed to the third and fourth quartile more daytime light. They also had a nighttime light exposure evaluation and they had people with the low q one in q two.

So these people are getting less nighttime light versus q 3， q four, more nighttime light nicely. 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, ten hours a day, fourteen hours a day.

Because the more active you are, the more opportunity for light exposure you have during the day, all night, for instance. okay. So IT, they had, I would say, fairly complete data sets then, and i'm just going to hit the top counter of what they did in any and sleep .

during sleep efficiency at a was determined of the cells. Ete.

that's right as self report. Yeah not not ideal. right? You d love to for people be wearing a wooden or or or a ring or something in that sort. But this was initiated some time ago.

So they either didn't have access to that technology or for whatever reason, didn't select IT. I'd like to take a brief moment and think one of our sponsors in that, A G one. A G one is a vitamin, mineral, probiotic c drink that also contains adaptations.

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Then what they did is they got, they have information on who has major depressive disorder, who has P, T, S, D, generalized anxiety, bipolar psychosis, IT said a 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 of 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 nigh time, light exposure and psychiatric outcomes. So basically asking is the relationship between how much light you get IT during the day and how much like you get at night and how bad your or your depression is.

Orange ideas, etta, looking at, you know, just a standard ratio of the probability that you have a certain symptoms or set of symptoms versus you don't given a certain amount of light exposure model too, adjusted for the age of the person, their sex and ethnicity in 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.

All these people were all in the U. K.

Where they were. They were all in the, okay, as far as I know, and the model three adjusted for employment.

So employed the versus unemployed, which if you think about is pretty important, like you say, when an unemployed son has a lot more time to control these variables, but an employed person who is 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 at sara.

And so this, we can say very safely, is that the outcomes with each of these models 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 of the paper, IT doesn't seem like model one, two or three gifts from one another in terms of total outcome.

Yeah, that's an unusual aspect of this paper. So these adjustments are very standard, right? So that this is a classical c tool that used in most epidemiology because you don't have a anonymizing.

So once your anim ization is out the window, you know you you're like so much. For example, the paper i'm gna present is based on R, C, T. There will be no models. It's just here, the data.

Yes, here they're asking people, what? What do you do? Report back to us.

We're onna. Measure your light exposure. But known was assigned. Denny groups are swapped that whatever content controls are there are there are really not there just comparisons between groups.

So what is interesting to me um is that is exactly as you said, and we will make all these figures available in addition to the papers. But um I mean, there is 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 cortile comparisons where you might creep from you 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 ninety five percent of the information, which is, you know I I mean, I think in one way that suggests that there's less dependency on those variables. Of course, its still doesn't address probably the greatest question I have here, which i'm sure we'll get to at some point as as you continue.

yeah. So i'm very curous what that question is, but i'll i'll suppress my curiosity for the moment. If we look at figure two of this paper and I realized a lot of people are listening and 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 are listening. Essentially, what they're looking at is but they call the odd's ratio, which is the probability of something happening in one group version IT by the probability of something happening another group. I guess that would IT by way of example, be you're going to look at the odds ratio of, you know the probability of somebody getting lung cancer if they smoke versus probably somebody getting lung cancer if they don't smoke.

So odds ratio IOS and hazard ratios are often confused. They're very similar. And odds ratio OS generally referred to a lifetime exposure where as a hazards ratio is um 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 ods ration of um you know death so let's talk all cause mortality for a smoker versus on smoker. And the answer where one point seven eight i'm making that up but that's directionally correct.

One point seven eight as an odds ratio means there's a seventy eight percent chance greater of the outcome of interest, in this case, death by any cause in the affected group, which be the smokers. So automatic o of two is one hundred percent. In other show of three is two hundred percent. So the math has take the number, subtract one, and that's the percent.

You know, figure two of this paper is one of the key take comes they they essentially look at the odds ratio, uh, people who are in the let's say that let's just look at the nighttime light exposure and .

just remind me, ander cousin and everybody else watching every one of these is showing second, third forth as your ax access, right, meaning they're all being compared to the first cortile. That's right in the first cortile is lowest light exposure or higher light explores.

Well, well, we have to between .

day and night, that's right. So we stated.

sure. So a if we look at, you know, what is your risk of a psychiatric chAllenge? Broadly speaking, what panel is, is major depressive disorder if you are in the second cortile, third cortile or fourth cortile of nightlight exposure. So second being the least amount of nightlight exposure, third being more nightlight exposure, and fourth, the most nightlight exposure relative to the first cortile.

This is just a stupid thing. Like if I were doing this figure, if you were doing this in 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. understand? absolutely. But and maybe the teaching point, I think, is for people when they review articles like don't be afraid to do that, just kind .

of like I like.

yeah exactly it's like I draw the era that's increasing light, that's decrease light and that's how I can pay attention and what's actually happening.

And i'm actually in touch with the editorial staff at nature mental health. Don't know that I covering this paper until after this comes out. You know, I think one thing that science fernal really, really need to do is start making the read ability of the articles Better for non experts.

I mean, chances are, if you can 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 pass IT because um 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 in a second quarter's low amounts of nightlight exposure to define what that is, you know, third cortile is more light exposure and the fourth maxi amount of light exposure at night. And basically what you see is that the probability of having worse major depressive symptoms generally increases as you go from the second to third to fourth quartile. So more nightlight exposure, worse for you.

And there's a dose response, if you will, of the effect. Now we can march through or describe figure to pretty quickly by saying the same thing is true. Now we're just talking about nightlight exposure for generalizing xii d disorder.

So that's panel sea by polar disorder. Although the difference between the second and third cortile bipolar disorder isn't a dramatic, once you get up to the fourth cortile 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 of this paper to reemphasize that point several times.

In fact, they say that while light exposure during the day, of course, we will go into the data is show 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 by polar um in the person with bipolar disorder who's struggling with either a man or or depressive episode, 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 necessary mean that the person sleeping less, although in a about man, a manic episode presumable, they are, is independent of exercise, is independent of a bunch of other things, because any any logical person will hear this and say, okay, well, they are the game were lie at night, because they're doing a bunch of other, other things, but is largely independent of those other things. Likewise, the symptom logy of P T S D gets far worse with increasing light exposure at night. Self harm really takes A A leap from being fairly.

I don't want a minimal at the second and third courteous of low and less, say, medium amusing, some of taking some liberties here, but low in medium amounts of a artifical light exposure night. Then for people who get quite a lot of nighttime light exposure, self harm goes up and probability of psychotic episodes goes up or psychotic symptoms. No, what's nice is that the what's nice about the data is that the exact verses basically true for daytime light exposure, although not across the board, we can generally say that for major depressive disorder, generalized xiety, bipolar symptoms, there is a little more scattered P, T, S, D 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 literally drop the probability or the severity of the symptoms.

and we can just explain again that the odds tio now seem to be going down. So an odd show of point seven now refers to a thirty percent reduction in the variable of .

interest here. exactly. Now, the psychosis, a panel left which focuses on psychosis, I think, is also worth mentioning in 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 I C U.

Psychosis, which is that people come into the hospital for a broken leg or a car accident, maybe they were getting surgery from from Peter back when, for something totally independent, their house in the hospital. And as anyone who's ever been in a hospital as a patient or visitor knows, the light, 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 environments in hospitals is absolutely .

counter to help, especially in the intensive care unit. Yeah, right? So I think the intense care unit up kins, the main one, the main C U didn't have windows.

People who who go into the hospital with with a brain injury or or with a stroke and the I get contacted all the time, even though i'm not clinch. What should I do for my kid, my parent, I would say, get them near a window and start to the best of your abilities controlling their sleep wake cycle. Now, often times there there, you know, nurses coming in and taking blood tests and measuring pulses in the mill the night.

That's disruptive. There's bright light, not just blue light. That's disruptive. It's noisy. That's disruptive. I see you 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 is independent of medication. So let's just be really direct. There is a possibility that we are all socially jet lag, that we are all disrupting these mood regulation symptoms as system. Excuse me, by not getting enough daytime light and by getting too much nightlight, if we want to look at just the bullet points of the takeaway and and Peter.

thank you highlighted, if you will use. But can we just .

go back to this figure .

to for us so I just again, I norm wouldn't much hay out of this except for the fact that they're so tight um but there are a few that really stand out and going 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 in the impact on depression only be really technical when I say in the relationship or correlation to depression is very strong um the relationship to light in self harm in the upper cortile. So when you take those twenty five percent of people with the most nighttime light, that relationship to self harm is interesting and completely uncoupled from the other seventy five percent. That's interesting.

Aren't you buy uncoupled? You mean that at the lower levels of light exposure, you're not seeing an increase in cell form? And then once you get to that fourth cortile, it's a big step. It's like a thirty percent greater risk .

of it's totally flat. The first, second, third quartile, no different fourth big jump um and the the inverse relationship, right as light increases during the daytime, you see this reduction in self harm. Interesting the P T S D relationship based on nighttime light and the psychosis relationship based on daytime, like those are the ones that really jumped out to me. I think anxiety relatively you less impressive here and and bipolar disorder didn't seem as strong right as well. So I think those those are the big ones that that jumped out to me.

Yeah, I agree. There's a there's a bit more scatter on generalized xef and the degree of the the degree of significant change is not is not as robust. In other words, getting a lot of day time light, ideally from sunlight is not necessarily going to reduce your levels of anxiety.

Getting a lot of nightlight exposure is not increasing nighttime anxiety that much, although twenty percent you know is not nothing um for a nightlight exposure. But yeah, where the psychosis, major major depression and cell hama 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, the third cortile of nightlight exposure and more of nightlight exposure, you basically go from no significant increase to almost almost a twenty percent increase.

And then as you get up to the fourth cortile, so the most nightlight exposure, you're at about twenty five percent increase in major depressive symptoms. That's no joke. Um and you know and I think that I think that we we were to I mean, we don't have the data right here, but if we were to look at like standard as R I treatment for major depression. Um people debate this pretty actively, but um light is is a very potent stimulus and the timing of light is critical because on the the universe also true as you get to the fourth cortile of daytime meet exposure, you get about a twenty percent 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, um there's there's there's 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 um to reach A A conclusion that is powered to you know this level and that's that's true.

But what I don't think it's discussed as often is the opposite of that, which is what if you overpower a study in other is what if the power analysis says to be uh to to have a level of power ninety percent, you need a thousand subjects and you say, great, we're going to do ten thousand 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 be a bad thing because that 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 length of arrow bars. And what that tells me is that, and again, this is not like a formal statistic analysis. It's just kind of like a back of the envelope statistical analysis.

If you look, for example, at self harm in the top cortile, you actually have pretty big area bars. In fact, all the self harm have sort of slightly bigger area bars. And yet when you look at, for example, the depression, even though the area bars aren't all the same size, they're tighter.

In fact, when you look at the relationship between depression and daytime, like the 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 I think you said eight thousand subjects were in this.

and I realized eight.

more than eighty six thousand. You realized 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 um signal that is statistically relevant but clinically.

And yeah, thanks for for that point that I didn't pay attention to that. I mean, I pay attention to the area bars, but I didn't know that. So thank you. I'm learning to and I suppose for people they are listening, we can just give them a sense of what the area bar ranges are for self harm. You they're running you as much as twenty percent either side of the mean, the average.

And for major depression, that looks like it's more like but like eight to ten percent down five, right? So um yeah I see we are seeing so when you get A A A very large sample size, you're gonna some outliers in there and you can mask those outliers just by having so many data points, right? Yeah because .

these era 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 others going to be a graph in my paper where you see the same analysis. Um they're always drawing the ninety five percent confidence interval on the on the data point and if the ninety five percent confidence interval does not touch the the line of unity, which in this case is the the hot ratio of one point zero the exec is then you know it's statistically significant to the confidence of role they've defined, which is almost assuredly ninety five percent.

Sometimes they will make IT tighter at ninety nine and so that's why you can just look right at these and go, oh look, you know in depression, the second cortile didn't reach statistical significance because the arrow bars are touching the line just as the case for the second and third cortile for self harm. But when you look at the fourth cortile, you can see that the lower tip of the era bars isn't anywhere near unity. And so we know, without having to look up the p value, that is a smaller than either point or five for point one, however, they've defined IT.

And it's really amazing when you see these over powered studies, which are easier to do epidemiologic ally, 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 swimming above the um the the unity line but it's so so so type. I'd like to take .

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If you'd like to try element, you can go to drink spelt elem t dot com slash huberman to try a free sample pack again. That's drink element dot com slash huberman. One thing that I hope people are taking away from the 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 wit. Because here what I again, what I like about the study is that you've separated day in that time, like power IT.

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 reduced the sensitivity of the light sensing circuit dian upper ee. Now that's interesting, right? If if you think about this, okay, these are drugs that can imitate some of the symptoms of bipolar, perhaps in part by reducing the extent to which nighttime meite exposure can relieve by polar symptoms, can, excuse me, can exacerbate by polar symptoms.

Conversely, there is evidence that people who take certain entire depression 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 psychiatry, but if we know, one thing for sure is that if you want to significant outcome and a paper as a scientist, give a drug and me drug and look at the amount of rapid i've moving sleep or the shakti an cycle, pretty much any drug alter rythm for Better or worse.

But if we started to think about which medications might adjust our overall sensitivity to light, sometimes this could be a good thing. You think less sensitive, be light. Well, for people who are bipolar disorder, the amount of daytime light exposure isn't that important for their overall mood regulation, but the amount of nightlight exposure really is.

In other words, darkness ss, 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 nightlight exposure. I mean, if, if anything, my take away from the study is that dark kiner seat night is the fourth key lights 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 brightly let full moon night? Encourage people to download this free APP.

I have no relationship to IT called light meter and IT IT gives you a pretty good read of what the locks are in the environs, by the way, like people don't realize that they think you just tap the button and then IT tells you how many lukes you hold IT down. It's kind of fun. You can scan around the room and see how many locks are, on average, coming from that location or outside. Go out on a really bright moon night.

I mean, we we should have a full moon tonight.

Yeah, I want to do IT. You're not gonna above hundred locks or you're sitting at a candlelight dinner with your spouse ser with friends and clearly bright enough to see them put that looks me to right not too close to the flame, fifty to two hundred locks.

And I had I had interesting experience a couple of months ago on an l cn. 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 HEllen appropriate. Yes, report this halloween.

So it's very interesting to think that could be that dim fire.

you know, in fire light, you think, okay, gathering around a cm fire with then, okay, you know, everyone, circuiting rythm must have been disrupted for ages before the development of the electric electricity. No, no, that those cm fires are extremely bright. But there are there they're they're not that right compared to a very densely overcast day.

And what is your phone if you don't use any sort of light mitigating a tack on IT?

Well distance matters um but the distance were yes yeah with so with all the the wavelength racked up so no there is a nice feature in transit to the phone. We can eliminate the blues at night this kind of thing. But if you crank up to maximum light intensity, probably something like you know five hundred to one thousand locks.

Now keep in mind now. It's additive, right? So it's over time. So looks as a measure of I think IT relates back to candelas as 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 at up. These are old measure, old school measurements. Convert to locks.

But keep in mind that you're looking at your phone or tablet at eight hundred locks or five hundred locks in the evening. You do that for two hours. What you're sum quite a lot of photos now IT is true.

And I, I, I do want to be fair to the biology and itd be dishonest to say anything different. We've hammed on people about not shifting their circle dian rythm with light at night. But we know that the middle day in the midnight are circuitry that zones.

You can't shift your circadian rythm that well in the middle the day, in middle 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 they're fourth.

See sunrise or sunrising. You don't need to see across the rising sunset bright lighter in the day, minimize light exposure at night, and you don't need pitch black. In fact, pitch black colleagues increases the frequency of injury.

I get up in the middle is the bathroom probably once I think it's Normal, I go back to sleep. And if I were pitch black, i'd probably injured myself. So just dimmed down. Some people use red lights. Our friend.

yeah, Richard, is unna story about rick.

Yeah.

of course.

of course you know this story.

but just in case works listings, you'll appreciate this you know when rick was a here staying last summer um he's up in our guest house and he came down after the first night and he was like, unacceptable i'm talking unacceptable .

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, still, when I left the teenage me, I took them, I took them. That's why Derek, when he stayed here, lane, or anyone else, he stayed here, can't anyone else didn't have as I took up, I love .

them so funny. Jell is like, you know, rick changed every light in the guest house to read. I'm like, yeah, I know I didn't know that, but i'm not surprised.

yeah. In his place, he has most either no lighting or red lighting so during the day just goes by ambient light um and then red light in the evening and or candle light and it's great. And you know people hear red lights and they think they have to buy these expensive red light units, but that's not what we're talking about, that you can literally buy red party lights or just a red bulb.

Some people say, what can I just use a red film? Or can I put A T shirt over the lab? I worry about people putting t shirt over the lab because of the fire hazard but i'll be I didn't the light to my home at night. Um when I travel, sometimes I will bring one of the the stolen from rick rubin red lights.

the rick rubin stuff. Here's something where i've sort of soft and in my tune. So I used to be kind of a hard liner no blue light in the evening guy um you know had the you know everything was red light at night as far as my phone using flocks on the computer know whatever IT was.

Um I suspect that that matters somewhat but I think what matters more is the stimulation that may come from those things. And what i've come to realize, at least in me, which means that probably is true and 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 domes throwing social media and getting lit up on email, that's way worse for me.

Then if i've got my phone on maximum late and i'm like watching youtube videos of f one cars and driving around having fun, like ah it's a totally different experience. So so the context matters. And um I think I think for that reason I would want people to be mindful of the whole picture. Um you know going to bed under a period of you know intense dres 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 know just what i'd like want people to people think of this in the context .

of everything yeah it's a really important point. One thing i'll say is that if you're going to stay up, pass your Normal bedtime, if you're gonna lot of light in your eyes, I would hope there will be for fun reasons and reasons you enjoy. You should definitely spend some nights.

You definitely some all nighters if you really know you, if it's going to help you get the grade, that's permanent. Where i'd i'd certainly ve done all nighters studying and grant writing for years. You know there are going to be the inevitable all nighters due to go a bit trip to the hospital, or you heard something on the news that really empty you up.

You just simply can't see that stuff is gna 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, princess, people talk about the negative impact of social media as the fact that people are looking at this little box for so many hours per day.

Is that all the things they're not doing? Is that what they're looking at per say, all those things interact and are really important. We know based on studies from the stanford sleep lab that if you wake up in mild night, looking at what time IT is can be very disruptive to your ability to fall back to sleep.

And to your sense, the next day, it's a placement effect, but it's a powerful one of how tired you are. The next day they've done this where they wait people in the midnight and then they say it's, you know four m versus two A M versus six m and people's perceived levels of energy during the day in some ways, correlated with what they think, how much sleep they think they got. likewise.

And this is when the concerns, potential concerns, or sleep tracking ers ali kum talk about this when he came on our podcast, you know, if people see a poor sleeping score, they often feel worse than if they see a good sleep score. Now, of course, physiology matters. You can lie yourself and say, you know, great night sleeps simply by virtue of sleeping ore. But I worry more about the the false. I if it's false negative that we don't want to put violence on this, seeing a bad sleep score and then deciding that you're gonna a terrible day, you know, I think a bad sleep score in indication that you might need to dial some things in a bit Better, getting a great sleep scope is an indication that you might be doing a number of things right and start looking at these things as averages.

Would you agree? Yeah, completely. I don't think it's that different from C. G M, right. Like I think that C G M is using tool to provide insight.

And you pretty much know the insights after a relatively appear to time thirty days, maybe at the outside ninety for a really for a person of a very complicated life. Um 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.

Another you're using this to build in a hathorn effect. I think the same is largely true with sleep tracking ers. Most people have this profound sense of learning when they first encounter one of these things. And and it's again, you've heard at all hundred times, oh my god, I can't believe what alcohol does to my sleep tracker.

exactly. I think a lane nord's APP carbon. I have no financial relationship to IT. I use IT or and it's taught me well. I 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 the active 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 game, a fies IT that kind of helps people do the right things. You know what? I'm not going to have that drink tonight. 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 um you know recovery scores is and things like that are just notorious ously poor at predicting performance and I think there's a reason that serious athletes would never use things like that um they would tend to rely on the more tried and true methods of predicting behavior such as hearts rate um maybe hearts rate variability, but morning resting heart rate probably more predictive than anything else and then you in workout things such as heart rate, hard rate, recovery related threshold, things like that. So yeah, I agree. I think we have to.

And I say this is a guy who's generally perceived to be the most pro device guy in the world. People would be surprised how sparring. Ly, 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 catcher, there's an established mechanism um it's been explored in the context of pathology like mental health reporter as well as pro health in healthy individuals um that IT make really good sense at the level of kind of um wellness and let just say ancient health.

You know, when you think about getting a last sunlight during the day love, you will say, of course, get outside and play, not getting too much light at night. Of course, this is just good coding or girl fashion advice. People spend ninety percent of their time indoors, smell.

Their daytime environments are too dim, their nights environments are too bright. And this can misleading aspect of artificial light that when you see a bright bulb, you think i'm getting a lot of photons is part of the problem in the fact that when you're out on an overcast day and IT you think the sun cortical isn't. Doubt it's hidden by cloud cover, but just think about how well you can navigate that environment without a flashlight verses at night where you would require a flashlight.

We have walked under this dramatic difference in the night, availability of photons independent, whether 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 regulate 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 used to think. I'm like quashing all my military. And this is terrible.

I know I can't shift my circle dian clock, then I know that that light, yes, well, it's bright. If it's a brief, i'm not to worry about IT too much. Would I be Better to have dim light on? Is a positive bright light? sure.

But i'm not gonna stress IT in a hotel bathroom, I am not going to walk around you shielding my people, who sometimes asked me, by the way, is IT different to look at the phone directly, verses if you till the phone away? Well, IT absolutely is. I mean, think about a flashlight shown on the ground in front of you, very few photos 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, western in the afternoon, of course, the directionality of the light matters. So i'm not saying that you know that you need to like peak at your phone as if you're looking you over the edge of a ball or something into IT.

But my friend Simon haiti is head of the chongqing logy, the national institute of mental health. We used to room together at meetings. We stopped because is a terrible snore. So I just out there a few times when I considered suffocating him in the middle night, since he was already suffocating himself. Now we just we don't stay in the same room anymore or no longer post dogs.

But I caught him looking at his phone in middle of the night and he would tilt IT like a way like he's holding a platter for those who are just listening. And I can't like looking over at the screen then only what are you doing? This is ridiculous. I'm trying not to get so much lighter mise. That's a look extreme, but I think that illustrates the point, which is how much direct light exposure you get at night matters, how much direct sunlight exposure you get, especially early in late, early morning, late afternoon and throughout the day, IT really matters.

Now remind me, under what is the wavelength th of sunlight?

great. So sunlight is going to include all visible, visible.

which runs from how many? Yeah, so, well.

let IT look. We can answer two questions there. This race sensor a detected four hundred and seventy degree is seventy nanometer to six hundred and fifty anoma ter lights. So that's gonna blue and ultraViolet.

UltraViolet kind of like blue, orange.

yeah, blue, blue to orange. That's what this was measuring. So red light is gonna be more like sixty um far red is getting out to seven, seven, twenty and up. Reports of that blue lie is gona fall somewhere in the low force. UltraViolet is getting down the high trees and and lower.

And so these these spectre of lights are during the day, you know, midday light, you what looks like White light youll see the skies blue and the sun is bright White light. It's not even yellow to your eye. And of course, don't stare IT. Especially in the middle the day you're getting all visible spectres, you're getting everything from U V. All the way out to red lights just coming in at equal intensities.

So is that a potential limitation of this study and that IT didn't have a sensor that could pick up the full spectrum of light potentially.

especially since there you we don't think of humans as U V A capable like we can't perceive U V like um like A A ground squirrel for instance, can has uv sensors in its ice. Turns out you know why they use this is crazy. They actually you know when the grounds girls sit up on their launch, they actually signal one another.

They rubb you in on their belly and IT reflects uv. Um the york times for some reason has been running a series of papers, uh or articles rather about a naturally occuring flu essence at night and all sorts of to be scorpions and monotremes s like the platypus. No one really knows the reason for these odd, odd engine of light emissions for all these animals.

But you know, we view things in the blue Violet end up to red. And you know we're not pit vipers. We can see far red, but we can see lower than four hundred and seventy animates, 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 real sense that was wider?

This study was initiated in two thousand and thirteen. The tech was probably far worse than IT is. Now again, I would love for somebody designed an eye glass where it's measuring how many photos you're getting across the day. I'm not a big fan of having everything be API fied, so I would love IT if IT the frame with your shift color accent. Ss, the morning you go outside on a cloudy day, you know you wear these glasses and and by the way, to find where eyeglasses or contacts for sunlight viewing for setting your rythm um people always say, well, why is IT that okay in the windows is not well, corrective lenses are actually focusing the light onto your retina. The windows and windshields are scattering the light and filtering.

And how much are sun glasses filtering this out?

Way too much? We can safely say way too much, probably causing a ten fold department in the total locks count that's landing on your retina. But of course, I you know, sing glasses are important driving in the into sun and and some people have very sensitive device.

I can't see IT a cafe with a brightly reflective table in the afternoon. I I just squint like crazy. I can do with my dad, who's you darker IDE and you know, south american dissent. He just sit there just fine my mom, who's got light eyes like me and the word like to really tough, just have a terrible time. Um you know people difference in their light sensitivity.

So there's one other group question I have here and it's not answerable because without random zone, we can't know IT, but it's the question of how much reverse cassity can exist in these observations. So again, these observations demonstrate very tight correlations, very strong associations, especially in the five areas that we highlighted. Um but it's possible that part of what .

we're seeing .

um is reverse casuality brought on by both the treatments which you've already kind of eluted to and also the condition itself you want to explain reverse .

casuality for people and maybe could you mention um for those that missed the heart thorn effect .

just yeah yeah the hathorn effect um is is an effect that is named after no an observation of what took place in a factory where they were actually studying worker productivity with light of all things um but what would refers to is the idea that people will change their behavior when they are observed so if um 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 I was if I wasn't there and so what .

you probably will never see a day in the life of ander huberman, although it's pretty it's pretty scripted unless i'm travelling. It's a it's know it's morning sunlight, hydrogen and you some cardio or weight training and then a lot of time reading papers to be the most boring video on the work is mostly me reading and underlining things.

But it's why um game flying things can be beneficial, right? It's why A C G M can can be beneficial because it's sort of like somebody y's watching you and you're going to modify what you eat in response 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 at 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 let's just pick a common one that's unrelated to there. So there's an association that more diet soda consumption is associated with greater obesity a bit paradoxically, right? Echo IT is yeah it's it's been demonstrated in many series. The the the greater the consumption of diet soda, the greater the prevalence of obesity. And that has been populated by some to suggest that non nutritive tive sweater's such as aspartame or suite loser 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 microbial and maybe there's some way and that's happening, it's also equally likely, if not probably more likely, that there's reverse sociality there that a person who is obese is therefore contemplating how much they are reading 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 they are the caselty which you would compute to mean the drink is causing obesity IT might be no, the obesity is causing the choice of drink. So here the question is um 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 just 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 random zone or mendelian random zone, which, by the way, I was going to also ask you, do you know if anyone has examine 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 studied, but that would be interesting.

What Peter saying is, you know, you knew something about the genome of these people. You would be in a great position to perhaps even link up light acceptability genes, but like light sensitivity right genes with genes for pathways involved in major depression by polar and getting to this issue of reverse caught.

I mean, I think it's very straight forward to imagine that the person whose experiences a manic episode is going to be up for two weeks at a time, sadly. And getting a lot of nightlight exposure now dark nighttime dark exposure is a treatment for bipolar is something that people are starting to talk about. So making sure that if those people are awake, that there at least bu blocking at night, reducing their online activities. But people with severe romantic 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 sota example, I actually think there's a bit about right? I actually think there's a real clear body habitat dictate tes beverage choice. But I also am starting to think that um insult ble individuals non nutritive tive sweeteners will alter the gut biome and that alters metabolise.

What about just hunger? I I remember red 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 cLorindy. I also know some individuals, not me, who drink diet soda. I I drink diet soda from time to time, mainly stevia sweden sodas. But but what i'm referred to hear people besides myself who drink so to and IT seems to stimulate their appetite.

There's something about the perception of sweet as driving hunger, whether not eating or drinking anything with color, with any sweetness doesn't seem to this one of the things that I wonder um if the impacts why some people like in a MIT and fasting because for some people you know just even the perception I wonder if the perception of sweetness or even just the smell of food we know can stimulate appetite. So you can mention the perception of sweetness in the mouth, even if there's no calories there. I don't think IT necessarily makes people hybrid guys seem, but perhaps IT makes them think about like sweet means food prances.

For years I love the combination of a diet code in a slice of pizza. When I was, I was in new york, ideally two slicing of pizza. So now every time I have a diet coke, which isn't that often, but I like diet coke, live lemon in IT, I just think about a slice of cheese or mushroom or pepe oni pizza, it's like I want I cay IT more.

So there's a pair association there that I think is real. And we know, based on dana smes lab at yell, that there is a pair association between the sweetness from super s and that there is an insulin response. They actually had to seize the study in kids because they were they were becoming prediabetic, you know, which unfortunately meant the study was never published.

Have you talked today on this podcast? No, we we wrote a premium news letter on this several months ago IT. It's gotta like I don't know, ten to twenty thousand words on all things related to sugar substitute rest in this topic. I would refer them to the premium move letter on sugar. 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 sweaters in some studies do do result in that if phenomenon you described the safe alick's sloan response um and I came away from the research that went into that which was herculean effort um on the part of the team a little bit more confused than when I went in but um being even more cautious around artificial sweeteners than I was going in and not for the reasons that I don't necessary I don't I didn't find any evidence that these things are cancer causing. right. So that's .

the headline stuff.

People worried that I came away more confident that from us, from a long term safety perspective, in terms of matter, in terms of the cancer in catastrophic outcomes like that, that wasn't 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 might take away with biremes, where use limited amount only.

The one, by the way, that still emerge to me, is a reasonable one, is the only one that I use. And affleck about a lot is yi at all. Pilot all is the apartment and said, zilog all for chewing so for gum um and ale los as an additive. So those are safer yes, those those are basically only too. I will consider altering .

could I coke every now again, if i'm on a plane or yeah, now this law I got past few years ago, you can bring liquids of your own into the airport, on the plane. Like what? A years ago? What a great scheme. What a great scheme to get people to buy over Priced fluids in the airport like I mean there are more important issues in the world but like this one really gets me but yeah I I use a little but I drink things a little bit of stevia, the occasional diet coke um and I I generally avoid the ciller I don't like to IT takes month fruits to sweet but there maybe will 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 more about this stuff than I do but if if you had to just lay on your judgment, right? So so if you if I were a hundred to zero, you would say the light is one hundred percent caught in the effects we're seeing. If they were zero to one hundred, you'd say, nope, the behavior is one hundred percent caul of the exposure onal light.

Where do you? Again, you can't know IT. Yeah, what does your intuition tell you?

Okay, there's my intuition. And then there is my recognition of my own bias because, you know, i'd start working on these circadian pathways origin in the eye. E back in year in ninety eight, as a graduate unit burly, the sells these male options in terms sick sense.

Retinal gangling cells were discovered in the early two thousands by guinness. Ae prevents o dave person, sam hazar, such a pant and others. But and he 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 sixty five to seventy five percent of the effects are likely due to light directly. Now it's impossible that is as apart as you mention. But to play devils advocate against myself, you know, you could imagine that the depressed individual is lying around indoors with the curtains drawn.

They didn't sleep well the night before, which gives you a photo sensitivity that isn't pleasant, like a sucks up bright light in your eyes first thing in the morning, if you, especially if you didn't sleep well. And then there, you know, making their coffee in a dimly lit, what they think is brightly, the environment. And then there you locate their phone in the the state of the world, socks and their stated, their internal landscape is rough.

And their baby, they are dealing with a painter, or, you know, a injury or something, and they are likely to of getting outside. This is low. And when they do get outside, they're onna shuffle.

And so I could see how the behaviors could really limit the amount of light exposure and then evening roles around. They've been tired all day in a common symptom of depression. You fall asleep.

And in two or three in the morning there right awake, what are you going to do IT two or three when you're going to except in the dark? No, you're going to get online and you're going to listen things you might have. I'm not recommending this, but at alcohol, drink in order to try and falls sly.

I think this is the pattern. And so shaking up that pattern is really so much of my public health work these days is about and trying to get people onto a more natural daylight, nigh dark rythm. But yet it's impossible that he's, but we do know this, and this is a really serious.

We know that in almost every instance, almost every psychopathology report of suicide in the weeks, but especially in the days preceeding suicide, that person circon rythm looked almost inverted from their Normal patterns. And that's true of non bipolar individuals as well. Satan, disruption and disruption in psychiatric health are inextricable. Conversely, positive mood and affections in circling behaviour seem very correlated.

I mean, I think um it's clear that if you want to become an early rise or get light in your eyes and get activity in your body early in the day, you built that you in trained to those rythm so that you start to anticipate that morning workout, you start to anticipate the mornings sunlight. Just one more scientific point. We know that when you view the bright sunlight in the morning, or just sunlight that's illuminating your environment, as you said, you only have to see the sun itself, that there is a fifty five, zero percent increase in the amplico of the morning cordial Spike, which is a good thing because it's inversely the amplitude.

The morning quarles bike is inversely related to the amplitude of the evening quarter biking. High evening quarters was associated with middle the night waking and on and on. So um you know i'm very bullish, ed, on these mechanisms.

I also love that there so deeply woven into our evolutionary history, you know, that we share our single health organisms and so wild. But of course, there's going to be a bite 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. And the first, though I actually with far less authority than you um agree with your assessment and might even be a little bit more bullish, might even put IT at eighty twenty and and here or i'll give you my explanations which um stem more from my factitious battles with epidemiology and 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 um but I I tend to find myself looking at the Austin bradford hill criteria all the time.

And for folks who don't know um 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 my heart I certainly used to um but the more of these criteria that are met within your correlations, the more likelihood um you'll find casuality. So when I think of your data here, the data in this paper, i'll tell you what makes these correlations seem to have casuality within them in the direction is being proposed. Um look at the dose of so those effect matters and this has done in cortile and that's a very elegant thing.

If they just did IT as on off IT would be harder. That's right. If if they didn't cortile allows you to see that every example in figure too, I don't believe there is an exception to this.

no. And I think also in in .

the there's only one exception to what i'm about to say sorry to out of like god knows how many they're all monotonic ally increasing and decreasing. In other words, the dose effect is always present. Another thing is biologic plausibility.

You spoke at length about that today. So another 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 to the biologic plausible bit, 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 hilo criteria that that lead to you know my belief that others reverse causality here。 But um it's not the full explanation and that more of the explanation is probably the direction that being proposed.

Um and if that's true, because then at the end of the day, like what's the purpose of the discussion? The ppos 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 for me, the takeaway is follow these light behaviors.

I mean, it's it's it's a relatively low lift. And you consider some of the things like i'm over here asking people to do zone two for three hours a week and view two max workouts and all the 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 thirty percent causality, seventy percent reverse calls like i'll take those I I will instate that .

yeah it's you know it's taking your coffee on the balcony is and 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 sunglass off.

IT means getting out for just a few minutes in. The fact is additive that these these photo mechanical hoon counting mechanisms, they some is great and luck. This paper also says, and I should stay at this earlier, if you missed your daytime light russian, get your nights dark rasha.

They are independent and additive so that I mean that's really something, but of course ideal if you get both. But I appreciate your take on IT and you know and thanks for for your your expertise in passing epidemiology. I'd 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 I learned. So along those lines, tell us about the paper you selected. I'm really eager to learn more.

Well, I I wanted to pick a paper that was, you know, kind of interesting as a paper. And this this paper, I think is interesting in that IT is kind of the landmark study of a classic drugs. But in the same way that you kind of picked the paper that I think has a much broader overarching um importance, the reason I picked this paper, which is um from the england journal medicine, it's about ten years old.

Note correction, thirteen years old is because IT is kind of the landmark study in a classic drugs that I believe are the most relevant classic 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 eight to ten percent, which is not a huge amount, um it's the man in which they would ve done IT that gives me great hope for the future even if it's through other means. So um i'll take a step back before we're going to the paper for again just the context and background. Um so the human immune system is kind of a remarkable thing.

Um 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're time in in the light system, in the photo sensor system, I spent my time in the immunology world. But IT is remarkable to meet 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 priority, what that could be? Well at the same.

So 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 an attack. The self.

It's remarkable. And of course, we can always think of the exceptions. There are things called ottawa mune conditions. So clearly, the system failures, 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 what you like. Go was auto a um if you know .

there are lots of more serious autoimmune conditions, of course, you know somebody that has loops or you know where the immune system can be attacking the kidney, the immunity stem can be attacking, automatic 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 evaded virtually all of the time? This is the question now. But 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 simplified by only talking about one system, which is how tea cells recognize and get activated, how t cells recognize intel gent, so we have something called an ant gen. So an ant gen is an anti body generating peptide. So it's it's a it's a protein, almost always a protein.

They can be carbohydrate but almost always proteins and they're very, very small peptides like we're talking. As little as nine amino acids may be up to twenty amino acid ti tiny little peptides. But it's amazing that in such a short peptide.

The body can recognize if that's Andrew or not. Andrew. And again, think think about like we talk about proteins and killed dolt ins, right? We're talking about proteins in terms of thousands of a mino assets that make up every protein in your body.

And yet if it's samples of protein and seize that, hey, this little nine, ten, fifteen peptide mino acid is not part of you. I know it's bad and therefore i'm going to generate immune response to IT. So we have where called into gen presenting cells.

You have cells that go around sampling peptides, and they will, on these things called M H C class receptors, bring the peptide up to the surface and serve IT up to the TCL. There are two types of these. There's M H C class one and M H C class two.

I this is a major history ability complex that's correct.

And um we referred 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. In the early days of organ transplantation were rife with immediate rejections.

And but not not in immediate immediately are the abo in compatibility ties. But you know the sort of next layer of in compatibility with M, H, C, in compatibility, which would lead to within within weeks the organ has gone, as opposed to within hours. So you have these two classes of M H C, if class one in class two, class one is what we call this.

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 influence of virus infects the respiratory epithelium of your, you know, your and that virus.

As you 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 R N A 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 on to these M H class. M H C class one, a glove, basically, the glove comes up to the surface and A T cell comes along. In the case of M H C class one, it's A C D eight t cl.

These are what are called the killer t cells, right? And so this cell comes along, and with its tea sel receptor, the tec l recept tor meets the M H C. Class one reception with the ant gen 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 that works. You've accent ate somebody. You're basically pre building .

that thing up set up with this fall under the adaptive immune sponsor, the innate mind response.

But this is adaptive up, nate is just these pure antibody response in the on the b outside. I won't get into that for for for the purpose of this discussion. The other example is M H C class two and that's also part of the adaptive system.

而 the innate system， which uh is more what we call the um exogenous form. So these are peptides that are usually coming from outside the cell. So we're going to focus more on the M H C class one because this is peptides that come from inside the cell. Okay, so just keeping the back your mind. If a foreign protein gets presented from inside a cell, outside a cell, the tea cells recognize that and they will mount a foreign sponsored, by the way, that's why we basically can beat any like if you consider how many viruses are around us, the fact that we almost never die from a viral effect is a remarkable achievement of how well this immune system works.

State biting, these are constantly.

And by the way, we don't really have very effective antiviral agents. It's not like anti biotics, like we have anti biotics up the water zoo. I mean, we're way Better at fighting viruses and bacteria. Can I one question.

I always wondered about this. To what extent is our ability to ward off viruses on a daily basis as an adult reliant on us having been exposed to that virus during development as I walk around today, maybe i'll be exposed to one hundred thousand different viruses. Would you say that half of those, I worry, got any bodies too because I I was exposed to them at some prior portion of my life.

Yeah, work. And the other ones i'm just building up and bodies. I was I was on a plane last night, so I was coffee s so I was had covered all a while ago, so I wasn't 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 always been exposed to since I was a little kid. So i've got all the other bodies, and they're just fighting IT back by ending up those viruses and destroying that.

You, 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 a unresponding. So therefore your neon system is doing the work and yet it's not mounting a systemic inflammatory .

response that you're not not sensing. So is there also a physical .

trapping in my nail? Um there you have huge barriers, right? So the skin, the hair 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 are 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, the viruses that most people are really afraid of. You see hep b HIV. Well, if they're sitting on a table or floating around the air, there are no threat to you.

They have to be you sort of transmitted through the here um but again, some of these viruses you're going to defeat without an enormous response and then some of them, you know why is influenza quote quote such a bad virus, whether the common respiratory called kind of sidelines you for a day, it's the immune response that you're feeling, the worse the bigger the immune a response to the virus, the more you're feeling that you feel your immune system going crazy, right? You know the inner lucan that are spiking the third spacing that occurs to get more and more of the immune cells there. The Spike of your temperature is your body basically tries to cook the virus.

All of that stuff is your body doing. Yep, you're being drained in all this happening. So one more point I mentioned just but just to close the loop on the otto community um how is IT that we learn not to attack ourselves that something called thyme c selection that occurs in infancy so you and I have a no good for nothing in tiny little famous that would be its almost in possible to see these things, you know, when we used to Operate on people in the themis is barely visible in an adult, in a healthy adult outside of thyme c tumors.

But as a in a child, the thymus is quite large. And the purpose of the Thomas is to educate tea cells and basically show the tea cells what self is. And any tea cell that doesn't immediately recognize IT gets killed.

So it's it's a really clever system where we basically teach you to recognize self. There are a very early age, and if you can't do that, you're weight IT out. And then did the Thomas s evolution there after, 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. Um most of those mutations are some matic, which means most of those mutations are mutations that occur during, of course, of our life. They're not .

germline mutations. The germ line being the are eggs and spur, right? So it's all other cells and I love that you pointed out that you there can be the cancer can be genetic but isn't necessarily inherited gene and they think inherit right yes, inherited is always genetic to some extent but um genetic isn't always .

inherit yeah so there are a handful of cancers that are derived from inherit mutations. So linch syndrome is an example of that hereditary polypods is is an example of that where you have a gene that gets passed through the germ line 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 or and you have too much of that or it's a gene that prevents cancer and you have too little of IT or a diffunce tional version of IT. It's so bra isn't example. That bracket is hereditary raca codes for a protein.

And the the women and men, but mostly the women that we think about who have a brack commutation that all in some cases almost guarantees breast cancer is 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 what 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.

Um well, actually before I get to that point, I want to I want to make point. Okay so so you might think so. Cancer we eat, you know ourselves become cancer is 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 signals.

So if you cut your skin IT heels, but how does IT know to heal just right and not to keep growing and growing and growing and growing and growing? Well 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 we could keep doing these days.

within months, you would regenerate a full .

liver that so is not amazing. So well, it's like a salmon entree cut off a salome's a limit. Please don't do that experiment because other people are doing IT anyway. And IT grows back. The company .

knows how much to grow back.

So so when .

the cell is perfectly functioning, IT knows how much to grow. And 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 missing where people. Cancers grow faster than non cancer. 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 sight of origin, go some place else and .

take up residents.

Meta is 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, the cell that lines the inside of my collen clearly got a set of proteins in IT.

But if all of a sudden that thing can grow, grow, grow, grow, grow, not stop, not stop, not not listen to the signal, and then somehow wind its way in to 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 away 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 biology.

And IT really comes down to how clever cancer is, unfortunately, how evolutionary clever IT is. IT basically does a lot of things to trick the immune system. So IT has its own secretary factors, the tamp down the immune system.

IT grows in an environment because of its nature so one of the things that long understood about cancer is its heavily like colitis. And when something is heavily gyuia dic, it's going glucose to peru vate to locate non stop. There are lots of reasons for that. Um I think there's more than one that afford IT.

Well, this is afforded a migratory that is so interesting.

So that's the effect that what I just describe called the perfect. And when war berg proposed this ah which god was probably in the nineteen twenty is was before world war one, before world war two um he proposed that because he thought that might a cona of cancer cells were defective. So he proposed that the, you know cancer cells might a country that don't work.

Hence they have to undergo like colosse they can undergo uh a robic um uh metabolic um we now know that's not the case. So we now know that the the war bg effect or the varberg effect i'll refer to him correctly by his name um almost assuredly does not have to do with effective medical ria. 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 two thousand nine very influential paper um by getting a map vender hide and um crag thomson and Lucy proposed that the reason that cancer cells do the warming effect is that they're not optimizing for energy. They are optimizing for solution building box and if you do the mass baLance IT completely makes sense like cells need building blocks more than energy and click losses, 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. GLK holism lowers the surrounding ph because of the late tracks. Hydrogen PH goes down.

And guess what that does to the immune system? The tracks the immune system. So it's also a way to hide from the immune system.

So there's like A P H clock, use IT leveraging PH to cloak that's right to signal that the immune system would otherwise say.

yep. And then when you layer on top of that, that IT knows how to secrete things like I ten, T G F beta, all of these other secretary factors that also inhibit the immune system, basically, it's figured out a way to have hide itself from the immunity stem.

The way you describe that cancer sounds like a virus. You, I mean, IT sounds a lot like of virus. And that leads me to ask, are there any examples of contagious cancers reusing some studies about these critters down in australia, tasmanian devils that like they would, they scratch each other and fight as tasmanian devils do actually quite cute um and they will get cancer and tumors growing on their .

so and I got 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 HPV sure yeah HPV be uh hepsy uh but but there are even cancers like cutaneous cancers that arise from viruses. But um I don't know that's quite the same as what you're saying. Like no.

no, no, if they're what you're saying is an important point. I mean, we don't want to go down the the rapper hole of A H P V but right that increasing sustainable to serval cancer um now there's a vaccine against H P V. Yeah there wasn't when we were in college as we all knew um there was no vaccine but the okay so but yet a direct transmission of cancers from one one organism to the next more .

rare yes okay. So now here a moment of guy I said there's this really incredible thing about cancer that blows my mind and about our mon system, which is that at least eighty percent 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 fifty years where his oncology made huge progress, it's made great progress in a blood tumors lukie as and some kinds of lifers. In fact, there's two kinds of linthorpe where the progress has been remarkable. One has been in hodgen slm foa and the other has also been an immoral therapy has been in a type of B L limo a um where that bcl demonstrates uh or present something called A C D nineteen reception.

So in in, in b cell informers with city nineteen that there's a very unique niche immo therapy won't talk about that today called car tea therapy that has got rid those guys. And then luke mias, i've also been prety good, but in solid organ tumors, they've been only two real breakthroughs the last fifty years. One has been the therapy for a certain type of testicular cancer um and 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 gastro cancer called the gastro tumor, which happens to result from one mutation in a kin's pathway.

And there's one drug that can now target that and IT works. It's kind of amazing. curious. Here's 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 long.

It's then breast and prostate. In men and women, it's color, rectal. It's pancreas. Those are the big five. They kill more than fifty percent of americans IT cancer wise.

Not sorry to let me be restate that more than fifty percent of cancer depth and 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 eighty percent of those cancers have and genes that are recognized by the host immune system. I will take IT again, because IT is so profound, eighty percent, at least of those cancers actually generate an indigent, meaning a little peptide in that cell gets presented to the TCL, and IT is recognizable.

And now the question is, why is that not sufficient to induce remission? And the short answer is they are not enough tea 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 energy presenting cell. IT brings up an mhc recept 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 in a link to this good. 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 M H C receptor with the peptide is sitting there and IT bins to the TCT cl receptor on the TCL, but there is receptor on the TCL A C T L A four receptor and that bind to a receptor that I won't bother naming now because it's the names don't matter, but there's another reception on the presenting cell that binds to that and that acts as the breaks in the reaction. So C, T, L, A four, which is on the t cell, bines to another C, D receptor on the agent percent cell and IT says, tamp down the response. And the reason for that is we want to keep our union system and 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 C D A T cl IT is a targeted killer t cell. The checking 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 C T L A four? What if we block the checkpoint? Could we unleash the immune system a little bit more? And I will say .

this at the .

time I was proposed IT seemed a bit far fetched um because of the complexity of the immune system IT seemed a little far fetched that simply blocking the check check point 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 interlude. So overlook into is, for lack of a Better word, Candy and fuel for tea cells. So the idea was, if we have t cells that innately recognize a cancer and gen, can we just give high doses of interaction to and have them undergo proliferation and response? And the answer turned out to be yes, but only in two cancers, melanoma and kidney cancer.

And only at very small levels, about ten percent of the population would respond to these things. Now look at ten percent of people who were gonna dead within six months because these are devastating cancers and once they spread, there are no treatments that have any efficacy what's ever infect. I think median survival for medical atic melanoma the time was probably four months.

So this was a very grim death um but the idea now was, what about doing the exact opposite approach? Instead of trying to throw more a fire at the T, C, L, what if we can take its brakes down? Let's gas a put.

Instead of giving more gas, let's give less breaks. And um there were some face to some face one studies that demonstrate africa y face to and the paper went to talk about today is the is the phase three a study that compared the first version of these. So so the drug we're going to talk about today is an N T C T L A four drug called um ipl mab.

Um there is another drug out there that came came along shortly there after that is um an antip d one drug. So P D one h turns out to be another one of these checkpoints on t cells. And the nobel prize, by the way, I think that was two thousand nineteen or two thousand and nineteen in medicine or physiology, was actually awarded to the two scientists who discovered C, L, A four N, P, D one.

So you this I believe this is the only nobel prize in medicine for immunity. Erp y the very big deal. So this study um sought to compare the effect of N T C T A four to a placebo.

And the placebo in this case was not a real placebo. IT was a peptide vaccine called G P one hundred. Um to ask the question in patients with meta static melanoma, what would be the impact on median survival and overall survival?

So um let's talk a little bit about the paper. So again, one of the funny thing about this is I used to read these papers a lot under these these these should be, this will be my bread butter paper. So I I mean, you know be you know reading these like i'm you know it's of my hobby and and I don't read them that much anymore.

So I 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 to 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 um IT IT took a minute.

So so the first thing is these all patients who had progressed through every standard therapy, so these patients for whom there were no other options, 嗯， these patients either had very advanced stage three melanoma, which means IT was local regional melanoma, but IT couldn't be receptive. So an example of that would be um a cancer that was you completely engulfing, like where IT looks like the primary site was the cheek. And I had completely grown into all of the surrounding soft tissue.

IT hadn't spread anywhere, but that was all the limped nodes of the neck. And and i've seen patients like this and it's it's just completely disfiguring um 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 alanna has a very funny staging system. So in cancer we typically talk about something called the T N M staging system. In is the standard way that cancers are staged.

T refers to the tumor size, n refers to the lift node status, and m refers to the presence or absence of meta is 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, and is typically zero, one or two. And m is zero or one either there's no mets or there r mets.

So for example, color rectal cancer um the tea staging determines the depth in the colon wall that IT went and is did you go to match? And I think in collen, i'm libruls y on this. I think collen has n zero, one or two, depending on how many limp nodes.

And then m zero, did IT go to anything beyond that like to deliver long inside of IT or not melanomas, a bit more complicated. IT has m zero, meaning no match, but IT also has m one A, M one B, M one c and m one d. And within each of those, IT has a thresh hold for high and low, lacked dehydrogenation ines or L D H.

So it's both a staging based on ing and biochemical. And the reason for that is L D H level is such a strong praga stic indicator of survival. In addition to m staging, uh, higher L D H levels tend to reflect more acidity, which we talked about.

Why that's problematic tends to reflect faster growing tumors, higher turn over, higher metabolite activity. M one a you see if I can remember this, m one a are cancers that have metasomatic ed to um surrounding soft tissue or soft timer e anywhere in the body so anywhere else on the skin. And you might think 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 metastable on other parts of their skin. M one. B is I always get b and c confused.

I think b is the log. So m one b is to the long, m one c is to any internal organs, so liver eeta. And m one d is to the C N S. And as those numbers increase, as those letters increase, the prognosis gets lower and lower and lower.

So one of the first things I was look at when I look at a paper like this is tell me about the patient population like what what was the um 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. I should mention one other thing, Andrew, this was done as a three to one to one randomizing. So again, in the simpler st form of a study would have two groups right? You would have um we're going to just have a treatment group in a plus bo group, but in this ARM you had three groups with one of them being the placebo.

The places o got just G P one hundred, which is just a cancer vaccines. By the way, this is a cancer vaccine that never showed any efficacy so IT was a cancer vaccine that been tested both with interlude directly and um as an adjacent ent for patients who had metastatic milano a or had sorry, not metastatic million oma who had milano a receptive, 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 policy boat. So you had that group, then you had the N T C T L A four group and then you had N T C T L A four plus G P one hundred .

as right for the .

thread one to one. It's basically IT increases statistical power, right? So you this total study was a little under seven hundred people.

They put four hundred in the ntc T A four plus G P one hundred group, and then you know, a little over one hundred and thirty in each of the other two groups. So you're always going to able to make these two comparisons right. What you can check by doing this is, is there any effective G P.

One hundred in this setting, which has had never been done before. So again, G P one hundred is unknown protein expressed by milano a and all of these people were help typed to make sure that their immune system would recognize IT. And the question was, would giving people N T C T L four I E, taking the breaks off the immune system, whether without G P one hundred, make a difference?

So kind of going through this, you can see its sort of skills, about sixty percent to forty percent mail 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 zero is no limitations whatsoever, which is kind of amazing when you really consider something. I think this speaks to just how devastating this diseases. Um these are patients who all have like six months to live, right you a year max.

And yet look at this, fifty eight to sixty percent of them have no limitation on their quality of life at this very moment that's going to change dramatically um you know absent to cure here and then e cog one has some limitation and you can see that e cog one plus e cog zero is basically ninety eight percent of the population. You can see the staging there. So again, very, very few of these patients are the m zero category.

M zeros are people who have stage three disease that is so aggressive that can be receptive. That's about one percent. But the majority of these people are.

The m one is m one bees. M one sees. So these are people with very aggressive cancers. You can also see that about ten to fifteen percent of these people also have cns metastatic, again, the poorer prognosis of the poor.

And then you can see the about forty percent of them have the L D H level above cut off. All of this is to say we're talking about a group of patients who have um you a very high likelihood of not surviving more than you know a year. IT would be very unlikely that that many these patient would survive more than a year.

So so basically more than seventy percent of these people have visceral metasomatic. Uh, a third have higher the age and ten more than ten percent have brain mets. They've also all progressed through standard therapy. So um radiation .

chemo yeah and .

the chemo for for million oma can be you know kind of a toxic chemo that really just doesn't really do anything.

So is IT common place to use a treatment that failed in clinical trials as a placebo in these sorts of studies? Yeah, it's interesting.

I I think you are an obvious to the gp one hundred and I think the thinking was okay. IT hasn't been effective in other treatments, for example, when combined with I L two or as an advent. But never before has IT been tried with a checkpoint inhibitor, which is the technical term for this type of drug.

Um I think there was also some belief that, that would be easier to enroll patients. I don't think they stayed this, but that's often in the case that would be easier to enroll patients if they would know that even in the policy. But warm, 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 increase in the probability for novel discovery.

for sure. And again, if you go back to the analyzation of three to one to one, it's really only one fifth or twenty percent of the participants that would get just the G P. One hundred.

So another is you basically telling people when they come in to this study, there's an eighty percent chance you're going to get ntc ta 4。 That's a much Better set of odds than you. You're typical study where you're going to be fifty percent likely to get the uh, agent of interest.

Writing 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.

Um but so the original primary end point 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 visible either on the surface of their body but more likely on a MRI C T. scan. So all of these patients had to be scanned head to to within twelve 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 seven hundred to these patients were enrolled on the same day and finished, you know, we finished observing them on the same day. You know, know this took place for a very long create time.

This took place across tens of centers. I came over if this was just globally across the world, IT might have been across the world. Um and so every center really needs to IT here to a very strict protocol.

You have a central organization that is running this, so you have a drug company, I think this is brito bristol marosin b that makes the drug, they provide the drug. And then you have a cro 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 two thousand eight for this. No, no, I think it's completed in two thousand eight eight, probably started about two thousand four, two thousand five. And therefore, you had to kind of have real clear protocols are on this.

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 is 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 fifty percent reduction by diameter. Because remember, in this imaging, you're looking at two d versus three d. So if you're looking at a long lesion and it's this big hit enough, it's two centimeters tres long IT has to go to at least one centimeter in diameter.

So it's a fifty percent 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. P, R means at least a fifty percent by diameter, which by the way, is a much bigger diameter, much bigger reduction.

Terms of tumor volume when you consider the lennar versus the third power relationship of lengths and volume of every single lesion with nothing new appearing regardless of how small and no legion growing. So that's A P. R.

So you basically have no response progression. We talk about those together and then partial response and complete response. So initially, the the authors of this study, we're going to the primary end point of this was going to be the best overall response rate.

So what was the proportion of patients that hit P R? What was the proportion that hit A C R? Um that's very common in this type of paper where the outcomes are typically so dire.

Um however, uh I think I said I think I said that the study was um I don't remember when the study ended but the amendment was made to change the primary and point to overall survival um at 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 mediatheque anoma is zero, with the exception of people who respond to inner look to hyde's inner lucan to.

And that will boost the overall survival rate to summer between eight and ten percent, very, very low. These patients, many of them had already taken and progressed through inner lucan. To let me refresh my memory on what percentage of those patients about a quarter of these patients had already taken hyde's in allusion to and by definition, the fact that there in the study means they had already progressed through that, that treatment had failed.

Just reiterate um just kind of the state these patients are in. So now let's look at figure one. So again, i'll describe IT because I realize many people are just listening to us.

All of this will be available both in the video and then will link to the paper. So figure one 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 caplin mire survival curve.

So on the x access for this curve is time, and time here is shown in months. And on the y access is the overall survival, the very top one hundred percent, at the bottom zero percent. 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 G P one hundred, the N T C T L A four group by itself, and the N T C T L A four plus G P one hundred. And one of the characteristics of a cabin mor curve is, by definition, they have to be decreasing in a monotonic fashion because it's cumulative overall survival. That just means I 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 that 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 there's a clear distinction between the curve for the placebo group, the G P one hundred group and the other two, the two treatment groups. Now you'll note at the very end that the two treatment groups appeared 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 turned 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 tale of this is showing me the true overall survival.

And I want to sort of figure out what is going on. So in the G P one hundred group, which is the placebo group, IT is kind of amazing to think that there is still one person who is alive at forty four months. It's it's amazing.

I mean, it's both sobbing and amazing that like one person made IT to forty four months um the next thing I asked 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 fifty over and then you bring that down and that's you know 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's our survival table here?

Your two subroutine analysis of overall survival.

We would pretty be helpful if I stay these things together .

because that would be, well, this is always a trade off actually, for since visit journal club episode, I will say that stapling helps, but IT also prevents one from separating things out. Writing in the march, I like these little mini clips, financial relationship to the mini clips either. Just have to state that because I always get, if you don't say that people go, you must have stake in these mini clubs. I like these little mini clubs. In fact, i'm such a nerd I always have one of these pilot v 5v seven in my on my pocket or my hip and then that my pockets are always filled with um with these little mini clipsed and then again I have a friend who is a musician is and he's always raining guitar pix so no it's as far as occupational hazards go of being a nerd。

The big end of the many car as well. I went without IT today. All right. So thank you. Yes, table too. right. So so let's look at table to while looking at the captain, mike curb, because now this allows us to see a couple of things, by the way, member, 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 is not a complete responder.

He or SHE is not a complete responder because um under evaluation of therapy in table too, it's has best overall response and IT says complete responders zero so there was zero complete responders in the policy boat. There were two partial responders. Again a partial responder is um some legions got smaller, some got bigger. Stable disease is IT didn't really change that much and progressive disease is obviously that went beyond not even when he says a partial .

response like a allegiance got smart and they literally just tracing the the circumference of one of the inner skin lesion and saying, okay, I got .

bigger litter. We had had rules. Logy feels .

so crude. I mean, make a sense. But like in terms of like modern medicine or like your leason grew from like three millimeters to six millimeters and are literally like growing low boundaries around low blockers on the skin.

Yeah, you you're putting a little measuring tape on them. Now again, most of these are happening in the radiology sweet, because most of the disease for these patients is inside the body. Remember, more than seventy percent of these patients had visual meta stasis.

So liver, soft tissue, long brain and these are right. In fact, if you include long liver, brain and VISA, it's it's all pretty much all the patients. So most of this is looking at A C T scan or an MRI for the brain.

Got IT. Um 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 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 ten months, but maybe that's just in the text.

Yeah here IT is so I thought this would be on a table, but it's it's on page seven, fifteen of the paper IT just reports IT. So i'm sorry, I miss spoke. The ten months was for the ntc T A four plus G P one hundred and six point four months for the G P one hundred alone.

That's the control. And then ten point one for the ntc t four alone. okay.

So again, again, and I can i'm just always doing this, i'm going to going back to the paper to be like this that makes sense. And yeah, you can call IT right? You said median survival was about eight.

Well, IT turns out it's actually like six and change because because that has that little thing in IT and it's out to a little past ten on the two other others. So the net take away here is, again, just to put that in english as IT so profound, fifty percent of the patients in the control group were dead in six months. Fifty percent of the patients in the treatment group, both treatment groups were dead in ten 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 his cancer therapy changed over the past fifty years, median survival for meta static cancer has increased to cross the board.

So a person today with meta static color rector cancer, or woman today with meta static breast cancer, or person with metastasis 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 aren't 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 empathise tumours, IT is IT was zero percent in one thousand nine seventy and it's zero percent today. Everyone dies. Everyone dies from meta static solid organ tumors.

And o there's is those niche examples I gave you. Particular cancer is now an exception. Um G I stronger tumors would be an exception and i'm not including lukie as in english famers were there are exceptions.

Okay with not to try be overly optimistic, but if I look at the graph in figure one and I look out at the tail of the graph, right, and for those are just listening what I see and and on far less, far less familiar with this type of work in this analysing these type of date. But what I see is that people in the placebo group, they're all dead, except that one, they're basically all dead at forty four months. But when I look at the number IT, how long IT takes for everyone to be dead in the true treatment groups like fifty looks like fifty three, fifty four months or there not debt.

That's the point they're hanging in there.

right? So because you know an extra somebody who lost both of my scientific advisers, two of the three, the other one, the suicide, we ve talked about this before, but the other, but two to different cancers, both at the black at two mutation, by the way. You know, an extra eight to ten months with your kids or with your spouse, or to quote, get your affairs in order is is a big deal. I mean it's still the pressing, 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 um 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 your 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 won 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 know, like only want to talk about cures. They don't want, they only want to talk about median survival. They 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 onto IT, but who will say, like, look, it's a real racket in oncology today where drugs that are extending median survival by four weeks are being put on the market at the tune of you fifty two 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 .

cost forty thousand dollars once being .

advertised as significant as a significant improvement .

in median survival.

So it's look, it's really understandable why people are very skeptical of the farmer industry and and I think you know a much more new ones to view is necessary. Clearly, I don't think farma is all bad um but I really understand why people lose faith in farma when you these types of products somehow make regulatory approval.

Does insurance cover these kinds of drugs?

Uh, I can infect IT often. Does IT depends on the F D A approval, of course, in the indication. Um but a lot of times they do, right. So yeah, there's a societal cost to these things um 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 time of that, you were looted 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 costs to your health in those final remaining days? And by the way, you're potentially struggling your loved ones with enormous debt in your family. So it's it's a super complicated topic.

There's a dignity component too. I may have ve seen this in people dying you at some point they become such A A diminished version of their form themselves 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 that. The reason that shows this paper, Andrew, is because IT was the first approval. A second drug came along, that is an anti P D one drug.

That drug is called k truda. That drug turned out to be even Better and had 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 with. I'll disclosed in a moment why I but I but I think IT just talks about very interesting biology. So let's talk about a couple things that are stuck out to me in this paper.

Um 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 to so figure to is the subgroup analysis where you are 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 ninety five percent confidence and also does IT touch the unity line.

So these are called like tornado plants typically and um which you notice is that in the top you are looking at um um sort of a IT gets comparing the N T C T L A four with gp one hundred verses the gp one hundred and in the bottom you're looking at the ntc tella four ver s the G P one hundred. So at a gLance you can see gp one hundred is not doing anything. I mean that's that's the first takeaway of comparing a to b.

Um 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 I gonna 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 n tc T A four plus plus eo versus policy o, there was a thirty one percent 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 .

capital mires living longer, living longer and IT IT sounds like a big difference and sense IT is .

a big well IT is for those people because you're really looking at basically zero percent surviving in the placebo group versus twenty percent of people are still alive at fifty six months in the treatment group.

But look, that means eighty percent have died, right? Um but notice that sorry, when you just look at the ntc T A four plus G P one hundred in the subgroup b that hazard ratio even showing more compression, it's a thirty six percent reduction in risk of death um but notice that the females did not significance so in the in the first group they barely do and you can see that because the confidence interval runs from point five five to point nine two. I noticed the era 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 um and that about half the studies of ntc T A.

For did indeed find that the drug was less effective than women than men. I found interesting. Now I couldn't find any great explanation for IT, but the most applausive 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, uh, comes down to doing, I should have set this at the outside but of course these drugs are not like a pill where it's like everybody gets you fifty milligrams of this for all dose based on weight. So this study is dose, I believe, at three million grim 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.

The last thing I want to talk about here is in table three. So table three, always an important table to look at in any paper, is what are the adverse outcomes, right? We're the adverse effects of the drug.

Yeah, I spent some I spent a little bit of time with this, and I I confess IT IT, yeah, I definitely don't want cancer to the extent I can avoid IT. But this table made me wonder whether not I would also want to just avoid cancer treatment, given the life extension provided. I mean, these adverse events are pretty uncomfortable yeah just just to .

put in perspective um and 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 progressive. So the first thing I was want to look at is total adverse events in all three groups, not just great. So great three and grade four are real toxicity, right? Great for toxic as life threatened toxicity, by the way, a great three is pretty significant toxicity.

Grade one, two. We typically just, no, that's not that severe, right? The little raps put some critical states on IT want a way to think OK. So in the a treatment plus G P one hundred group, ninety eight point four percent of people reported some event.

So all but one point six percent in the ntc T A four group alone, IT was ninety six point seven percent, so only three point one percent did not, but in the plus ebba group is ninety seven percent. That is more than to keep in mind. Like don't 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 four toxicity. There were six point one percent of those in the placebo group, eight point four percent in the N, T, C, T, A four group, and six point eight percent in the combined groups, so not a huge difference in grade four toxicity.

meaning that whatever adverse events are occurring may not be related to the, may not be .

related to the treatment. Again, these are if if you think about IT and and it's a very awful, sad more, but thought to imagine these are you're looking at the adverse responses of people, more than eighty percent of whom died during the course of a very, very short study. And so you know, it's very difficult to distant tangle 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 done in the ottawa mune category. So if you look at any immune related events, you can see that in the n tc T A four plus G P one hundred group, it's about sixty percent in both of those treatment groups versus thirty percent and if you look at the grade three and four toxicities, it's ten percent in the uh T C T A four, fifteen percent in the um ntc ta for a one group and only three percent in the treatment. So that's a real difference .

when IT make sense that people getting this drug plus or just the drug would have auto m issues because this is.

it's an immuno modulator. In fact, what is he doing? He is taking the brakes off the immune system.

But then again, the things that they listed out, prius, is that a irritation?

Skerritt.

I know that any ideas is going to be like an information. And oma, unfortunately likely a cancer or self replication.

Look at the difference .

in vital lider. I go, I mean, wow, yeah, so very sorry, sorry.

Look at the gaster and testing. No differences. Yeah, in the vitiligo, right? So three point seven percent, two point three percent point eight percent.

The G I stuff is the most common stuff. You're gna see there. Those, those are the really big ones.

Now of course, there's diary and there's diary. Oh yeah, there's travellers. The there yes, these people mean and there's like, can't really do anything besides to make trips back and .

forth to the bathroom. Well put of this way, collide us here is diaye so significant these patients require ivy flu. Is now what what you don't see here is how many these patients actually required critical steroid to reverse the auto community.

So a lot of times we'll happen here in these studies or with these drugs is the auto mundo becomes so significant, but you have to stop the drug and give cortical steroids, do the exact opposite. Do 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 cortical steroid? Um when I was was I am not know when I was in my fellowship um I wrote a paper about um auto community correlates with response rate in ntc T A for a early on.

This was during the phase two work. So so the N C I was a very early um uh uh adopter of participating in these trials and um you know IT was observed that at least hypothesize this is what the paper basically wrote about which was is there any correlation between otto community and response um and IT turned out the answer is yes. There was a very strong correlation, so there was no difference in ottawa.

Unity between the doses and the sort of paper we wrote was two dosing schedule. So IT was basically the folders, the three milligrams per kilogram versus low dose, one milligram per kilogram. This is a face to trial.

Those are two arms. There turned out to be no difference in otto, a unity between them. But there was a big difference between um uh the response rate that tied to auto community.

In other words, otto, a unity predicted response. Now I think over time these investigators, the doctors who administer these treatments s are getting Better and Better at catching these things earlier, because these ottawa mune conditions can actually be devastating. So on a very personal note, when katura, uh, came out, I want to say I was around two thousand, a leve known.

And no, gosh, IT must have been two thousand thirteen two thousand and fourteen thereabouts. Um again IT was for treatment of metastatic melanoma. I want to come back and explain why melanoma gets all of the attention in automobile condition in in therapy conditions i'll state but um but anyway a friend of mine got pancreatic cancer and he got the bad type pancreas cancer.

So this is like the add no personal of the pancreas. So this is A A non survivable type of cancer. Furthermore, his was unreachable.

So can you explain what that is? Yeah so the only so about twenty percent of people who have pancreatic cancer technically have IT in a way where you could still take out the head of the panky right the wipo procedure, a wipo procedure right. Um now tragically, most of those patients .

will still recur. My understanding is that pencarrow tic cancer progresses from enter to post terrier in the pancreas. The whipple is a removal of the front and the antero.

That's the whip procedure. So if the cancer has progressed far enough cordle into the post steria pancreas, then there's nothing left to cut out basically. Well, can we survive without a pancras for any amount of time? Oh yeah, absolutely. So why do they just remove the whole pancreatic?

Oh, that's my point. It's already micro, ma testified. So it's not the surgical procedure is not the chAllenge anymore. I used to be so, you know, john hopkins, which is one of the hospitals where this was pioneer, like the the thirty day mortality for a whip procedure was, I don't know, eighty percent, and the reason was to figure out how to suture a panel to the bowl without the of 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 and half, take out the head of the pancreas with the duodenum, and then somehow so that open half of a rap hanky's to the end of the june and not let IT digest itself.

Someone of hope can to figure this out.

Um now the first one was actually done by A O whipple. But yes, that 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 .

in other physicians who like try this on non human primates or something. Is this always just done on patients?

And well, nowadays, I mean, put of this way, even twenty five years ago, at at at a major center like hopkins, the the mortality of that procedure was less than one percent.

amazing. Yeah told some Victories. Well, yes, but here's my point.

That's no longer the bottles neck, right? Taking out the panky as safely as complicated and chAllenging as that IT isn't if you need a WIP procedure, you only want to have IT done by someone who just does that night day because it's you don't want weekend warriors doing IT. Um that's not why people are living or dying.

They're dying because the pants that the cancer 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 pank rist or the head of the pancreas or the tailor 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 panic, ana. Cancers in the tail tend to be more fatal, even though their 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 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, forty and older or fifty and older who don't yet they're not diagnosed with any cancer, would periodically to stimulate the immune system to wipe out whatever early cancers might be cropping up.

You know, just take a drug to just wrap p up the immune system, even to the point where you start out a little area, maybe a few skin rashes, and then come off the drug, you know, just basically do to fight back whatever the cell growth are starting to take place in skin or liver. Know baby, for, you know, three weeks out of each year. I mean, why not?

That's the same question. I never thought of IT through that lands. I suppose the question is, what can we do to keep our .

immunity stems as .

healthy as possible as we 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? Um there are certain diseases where it's really obvious why the prevalence of .

the disease increases with age. Yeah, age a generation.

sure. More cardio asal diseases by. Far the most obvious because it's an area under the curve exposure problem. The more exposure to like the proteins and the more the end of film gets damaged, the more likely you are to accumulate like. And again, IT totally makes sense.

Why ten year roads don't have heart attacks and eighty year odds do? But when you sort of acknowledge that, well, hey, you you know anybody's actually accumulating genetic mutations were always surrounded and being bombarded by things that are altering the genome of ourselves. Is IT simply a toaster process where the longer you live, the more of these mutations you're onna occur until at some point one of them just wins.

I I I think that's got to be a big part of IT, but I think another part of IT and I clearly a model and thinking this is that immune systems getting weaker and weaker as we age, right? I mean, you know you know, people become more acceptable to infections as they get older. And I think that that's equally playing a role in our suspects ability to cancer.

So yeah, I think the question is, how do you modulate immunity um as you age? And to me that's one of the most interesting things about rap micon potentially is that when take in the right way, IT seems to enhance um cellular community, which again that's potentially a really big deal again, at least in in short term human experiments in response to vaccination, it's enhancing vaccine response. So the question is what that translate into cancer? Nobody knows.

Could that be one of the reasons why animals treated with rapid islip longer and get less cancer? Don't know. You could also be that it's it's at a fundamental level, it's targeting nutrient sensing. Um where else going with that story .

was that maybe i'll .

back up for a moment why melanoma. So we didn't really know this like thirty, forty years ago in the early days of immunity erp y but what we know now is that most cancers probably have about forty mutations in them. That's like ballpark.

Forty fifty mutations is standard fair for a cancer. But melanoma happens to be one of the cancers that has many, many more mutations. In 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 a new therapy, the only things that worked were to against metastatic oma and kidney cancer, because kinney 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 of my immune system, I might as well do IT in an environment where there are more chances for my tea cells to find something to go nuts against.

So it's two thousand and thirteen, two thousand and fourteen. And this friend of mine who has something called linch syndrome um which is a one of those few herriton or german mutations that results in a huge increase in the risk of cancer. He had already had colon cancer about the age of forty um and had survived that was a stage three cancer but he had survived IT well now five years later had developed pancreatic cancer and when he went to see the surgeon um they said, yeah something we can do like it's too advanced so that's you to put that in perspective, that is a death sense and that's not that's a that's a six month survival.

And at around that time there was a study that had come out in the new england journal medicine that had talked about how patients with linch syndrome had lots of mutations. And so we, you know, talk with his doctors about the possibility of enrolling him in one of the cathode trials. There is one going on.

I think it's stanford and you the thinking being well, you you would want to target a checking inhibitor against somebody who has a lot of mutations. And even though typically we don't see that in pankratz cancer, his is a unique variant debt 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 still alive in cancer free today, ten years later, but the 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 panky attack to me based on his immune system. So now he actually has typed .

on diabetes is .

no pankau jacklin ah the yeah no he no he has to use just .

like some time alive type course .

no comparison. But it's just an interesting example of how you remarkable this treatment was able to work when you you you could completely unleash the immune system of a person and you eradicate the cancer and the rest of the cells around IT. And and you know there are many organs we could live without um you know there are certain organs you can't live without. You can't live without your heart, lungs, liver, kidneys um but but many things that kill people are ise from organs the breast. You could live without all breast tissue that would .

choose to do to live without this.

right? But I think if 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 C D nineteen b cell. 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 say about this paper that i've found interesting and I I was looking forward and I was surprised they didn't at all comment on if there was any correlation between the auto community and response hm, so they obviously acknowledged the auto community in in table three but I would have loved to have seen a statistical al analysis that said, hey, is there any correlation between response rate and auto community? But um 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 and tumors is about eight percent Better than he was fifty years ago in virtually all of that has come from some form of immunity.

Erp y um I think is promising. And I think the holy grail is the meaning. The next step, if you go back to where we started, the discussion is coming up with ways to engineer tea cells to be even Better recognizers of antigen.

And there's many ways to do that. One is to directly engineer them, another is to find tea cells that have already migrated into tumors. Those are called tumor. Infiltrating the emphasize or till, and expanding those and engineering them to be Better .

and Younger is IT possible to engineering our own t sales to be more P H very tolerant meaning um since this you know closing of the of the local area by changing the P H can could we paul M T cells, i'm always think about the inaccurate tion stuff like paul t cells as part of our standard exam when we're thirty and um you know and grow some up in an environment that the PH is is slightly more acik. Then um then Normal and then we introduced them to the body and after all they are our t cells um in other words, give them a little opportunity to evolve that the conditions they can thrive in, right? Or even just keep them in the freezer in case we yes.

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, um IT seems that by far the most potent thing comes down to expanding the number of t cells that recognize the world gen and making sure that you can get that number big enough without aging them too much.

So in some senses, IT has become a long gevalia of tea 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, emphasize in a tumor, they're very wise. They know which one theyve demonstrate that they can do everything they can out manually, 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 do anything.

And what about of waiting melanoma together? I mean, obviously, of waiting sun burn. You know, I somehow I got couch and sun screen and that is absolutely not true. Like I said, some sung screens contain things that are clearly immune rupal grant, excuse me, disrupters, and we're going to do whole episode on sun stream.

Maybe could do I really planning is yeah I think .

and some germanotta reached out a very, very skilled durmot gist reached out and said that indeed, some sung screen are are downright dangerous. But of course, melanoma is super dangerous. Physical bar known disputes physical barriers for sunscreen, right? Everyone, everyone agrees that, that is unlikely to have grant disruption. So physical areas are undisputed but aside from limiting sunlight exposure to the skin, um what are some other risks for milano A I mean.

I think that's the biggest one. I do not believe that smoking poses a risk for milano a and if he does, it's going to be very small. Um there are hereditary cases, so one needs to be pretty mindful when taking your family history. And by the way, they are really weird to conditions that link elantra to other cancer such as pancrates a cancer, by the way.

So whenever i'm taking somebody y's family history and I hear about somebody that had milano a and someone that had pancreatic cancer, um there's a couple genetics genetic test will look at to see if that's a person is particularly sensitive, just an a for a genetic previous position um but I do think that first and foremost, it's and by the way, I think with melanoma, although it's not completely agreed upon, I think it's less about sun exposure and more about sun burn, right? So so and again, i'm sure there's somebody listening this who will china and apply a more nuance response to that? Um but but I think there's there's a fundamental difference between a mountain, the sun getting on making some vitamin D E.

Versus i'm getting scorched and you undergoing significant U V damage. There might also be something to be said for the time in one's life and seen things that suggest that early, early, repeated sun burns 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 you being mindful of what the U V index is wearing the appropriate cover, wearing the appropriate sunscreen, I also find the whole a kind of anti sunscreen establishment to be a little bit odd.

But the enter sunscreen establishment is odd. You know, i'm trying to open the door for a nuances discussion about know the fact that some sung screens really due contain things like oxy, benzene and things that are real yeah but when you can, you're spring among kids yeah yeah you know.

you just look at the straight of you, the good old fashion mineral .

sunscreen yeah I I know I also there we cross the sea oil debate into this. Some of the folks who were really anticipated also claim ed, that c oil increased risk for some screen Peter are smiling because we we have teeth up A A debate soon with some you know anti oil and less anti oil um experts so that that's forthcoming that's to be a fun one will be doing all of that with our shirts on I really appreciate you um walking us through this paper Peter I have never looked a paper on cancer um and certainly not one like this. Um I learned a lot and um 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 the interaction with the immune system. So we learned some really .

important muno logy yeah and this this was great. I I feel much more confident now in the uh belief that the the exposure to light early and late in the day can actually have have benefits. And I analyst, I think that there's I think there's there's some cause 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 will just keep alternating. We've also switched venues but um we both wore the the correct short uh and um I hope people are learning my and not just learning the information but learning how to person think about papers and I certainly learn from you. Peter.

thank you so much. Yeah thank you.

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