Welcome to the huberman Lab podcast where we discuss science and science based tools for everyday life. I'm Andrew huberman, and I'm a professor of neurobiology and Ophthalmology at Stanford school of medicine today marks the second episode in our Journal Club series with myself. And dr. Peter Atia. Dr. 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
Other of the best-selling book out live as well as the host of his own terrific podcast the drive for today's episode Peter and I each select a different paper to share with you. We selected these papers because we feel they are both extremely interesting and extremely actionable first. I present a paper that is about how light exposure during the morning and daytime as well as dark exposure at night each have independent and positive effects on Mental Health as well as the ability to reduce.
The symptoms of many different mental health disorders. I've talked before on this podcast and elsewhere about the key importance of seeing morning sunlight as well as trying to be in dim light at night. However, the data presented in the paper today really expands on that by identifying the key importance of not just morning sunlight, but getting bright light in one's eyes as much as safely possible throughout the entire day and a separate additive effect of being in as much Darkness at night as
As possible. I describe the data in a lot of detail. Although you do not need a background in biology in order to understand that discussion and there's a key takeaway, which is that if you can't get enough light in your eyes during the daytime you would be well advised to get as much Darkness exposure at night in other words light and dark have independent and additive effects on mental health during today's discussion. You'll learn exactly how to apply light exposure and dark exposure in order to get those benefits.
Peter presents a paper about novel treatments for cancer. I must say it's an extremely important conversation that everybody regardless of whether or not you may have had cancer or know somebody who's had cancer ought to listen to he highlights the current technology of cancer treatments as well as the future technology of cancer treatments and the key role that the immune system and the auto immune system play in treatments for cancer. I assure you that by the end of today's Journal Club episode you will have learned.
And a ton of new information about light and dark and mental health as well as cancer and the immune system and treatments for curing cancer before we begin. I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme. I'd like to thank the sponsors of today's podcast. Our first sponsor is eight sleep eight sleep makes Smart.
Coverage with cooling Heating and sleep tracking capacity spoken many times before in this podcast about the fact that sleep is the foundation of mental health physical health and performance. Now a key component of getting a great night's sleep is that in order to fall and stay deeply asleep your body temperature actually has to drop by about 1 to 3 degrees. And in order to wake up feeling refreshed and energized your body temperature actually has to increase by about 1 to 3 degrees one of the best ways to make sure that those temperature changes occur at the appropriate times at the beginning.
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Well over 30 years initially. I didn't have a choice. It was a condition of being allowed to stay in school. But pretty soon. I realized that therapy is extremely valuable. In fact, I consider doing regular therapy just as important as getting regular exercise, including cardiovascular exercise and resistance training, which of course I also do every week. The reason I know therapy is so valuable is that if you can find a therapist with whom you can develop a really good rapport, you not only get terrific support for some of the challenges in your life, but you also can derive
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Atiya and Earth great to have you here for Journal Club number two. I'm already confident. This is going to become a regular for
us. I'm excited. I really enjoy this because I get to pick papers. I'm really excited about I get to hear papers that you're excited about and
We get to sharpen our skills at reading and sharing data and people listening can do that as well.
So last time I went first, so I think I'm going to put you on the hot seat first and have a view go first and I'll follow you. Okay?
Well, I'm really excited about this paper for a number of reasons. First of all it at least by my read is a very powerful paper in the sense that it examined light exposure Behavior as
Well as dark exposure behavior and that's going to be an important point in more than 85,000 people as part of this cohort in the UK. I'll just mention a couple of things to give people background. I'll keep this relatively brief. First of all, there's a long-standing interest in the relationship between light and mental health and physical health and we can throw up some very well agreed upon bullet points. First of all, there is such a thing as seasonal affective disorder.
Order it doesn't just impact people living it really Northern locations. But basically there's a correlation between day length and mood and mental health such that for many people not all but for many people when days are longer in the spring and summer, they feel better. They report fewer depressive symptoms and conversely when days are shorter significantly more people report feeling lower mood and affect. Okay, so there's a
Long-standing treatment for seasonal affective disorder which is to give people exposure to very bright light, especially in the morning the way that that's normally accomplished as with these sad lamps seasonal affective disorder lamps and those lamps are basically bright meaning more than 10,000 Lux lights that they place on their kitchen counter or at their table in the morning or in their office. So they're getting a lot of bright light that is proven to be
Fairly effective for the treatment of seasonal affective disorder what's less understood is how light exposure in the middle of the night can negatively impact mood and health. And so where were 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
Them's for all this or really well-established. There's a set of cells in the neural retina, which aligns the back of your eye. They're sometimes called intrinsically photosensitive retinal ganglion cells are sometimes called melanopsin retinal ganglion cells will talk about those in a bit of detail in 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 and send information to the hypothalamus where your master circadian clock resides and then
Our Master circadian clock sends out secretory signal so peptides hormones, but also neural signals to the brain and body and say hey now it's daytime now. It's night time be awake be asleep, but it goes way beyond that these melanopsin intrinsically photosensitive retinal ganglion cells. We know also project areas of the brain like the habenula which can trigger negative affect - mood they can trigger the release of dopamine or the suppression of dopamine the release of Serotonin the suppression.
Do of Serotonin and so they're not just sells for setting your circadian clock. They also have a direct line literally one synapse away into the structures of the brain that we know powerfully control mood. So the mechanistic basis for all this is there so there's just a couple of other key points to understand for people to really be able to digest that data in this paper fully. There are basically two types of stimuli that these cells respond to one is very bright.
Light as we just talked about that's why getting a lot of daytime sunlight is correlated with elevated mood. That's why looking at a 10,000 looks artificial lamp can offset seasonal affective disorder.
By the way, just a couple questions on that. How many Lux does the sun provide on a sunny day at noon?
Okay great question. So if you're out in the sun with no cloud cover or minimal cloud cover in the middle of the day at noon chances are it's over 100,000 law.
On a really bright day could be 300,000 looks okay, most indoor environments, even though they might seem very bright. I like to think of your kind of like department store with a bright light believe it or not. That's probably only closer to 6,000 looks maximum and probably more like 4,000 looks most brightly lit. Indoor environments are not that bright when it comes down to toad.
The 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 100 thousand looks but it won't seem that bright because you don't quote unquote see the Sun but it's also because when there's cloud cover a lot of those long wavelength of light such as orange and red light aren't coming through. However, and this is so important the circadian clock.
The suprachiasmatic nucleus, it sums photons. It's a photon summing system. So basically if you're outside in 8,000 looks very overcast UK winter day and you're walking around hopefully without sunglasses because sunglasses are going to filter a lot of those photons out. Your circadian clock is summing the photons. So it's an integration mechanism. It's not triggered in a moment.
And actually that the experiments of recording from these cells first done by David Burson at Brown were you know historic in the field of visual Neuroscience when he Shone bright light on these intrinsically photosensitive cells get crank up the intensity of the light and the neurons would ramp up their membrane potential and then start spiking firing Action potentials work long trains of action potentials that have been shown to go on for hours. And so that's this signal that's a propagating into the whole brain and body Okay, so
The important thing to understand is this is not a quick switch. That's why I suggest on non cloudy days. We'll call them that people get ten minutes or so of sunlight in their eyes in the early part of the day another 10 minimum in the later part of the day as much sunlight in their eyes as they safely can throughout the day. But since you're a physician I should just and you had a guest on talking about this recently when the sun is low in the Sky low solar angle sunlight. That's really the key time for reasons. We'll talk about in a moment.
Went and when the sun is low in the sky you run very very little risk of inducing cataract by looking in the general direction of the sun. You should still blink as needed to protect the eyes. It's when the sun is overhead and there's all those photons coming in quickly in one in a short period of time that you do have to be concerned about cataract and macular degeneration. If you're getting too much daytime sunlight, so the idea is sunglasses in the middle of the day or fine, but you really should avoid using them in the early and later part of the day unless you're driving into the sun.
And you know for safety
reasons another question Andrew. Yeah, if if a person is indoors, but they have large windows. So there's they're getting tons of sunlight into their space their don't even need ambient indoor light how much of the photons are making it through the glass and how does that compare to this
effect? Yeah in general unless the light is coming directly through the window. Most of the relevant wavelengths are filtered
out in other words if you can't see the sun.
Through the window even if sufficient light is being provided that's insufficient to trigger this 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 centers in the brain reside mainly in the bottom two thirds of the neural retina and are responsible for looking up. Basically, they're Gathering light from above these cells.
Also very low resolution. So think of them as big pixels, they're not interested in patterns and edges and movement. They're interested in how much ambient light there happens to be now. Keep in mind that this mechanism is perhaps the most well conserved mechanism in cellular organisms. So there and I'll use that as a way to frame up the four types of light that one needs to see every 24 hours for Optimal Health. And and when I say Optimal Health, I really mean mental health and physical health, but we're going to talk about mental health mainly today.
In this paper, there's an absolutely beautiful evolutionary story where by single-cell organisms all the way to humans dogs rabbits and everything in between have at least two cone opsins one that responds to short wavelength light AK blue light and another one that responds a longer wavelength light orange and red. So your dogs have this
We have this and it's a comparison mechanism in these cells of the eye these neurons of the eye. They compare contrast between blues and orange or sometimes blues and reds and pinks which are also all long wavelength light.
There are two times of day when the sky is enriched with Blues oranges pinks and reds and that's low solar angle sunlight at Sunrise and in the evening these cells are uniquely available to trigger the existence of those wavelengths of light early in the day and in the evening not in the middle of the day. So these cells have these two cone photopigments and they say how much blue light is there. How much red light is there orange light?
And the subtraction between those two triggers the signal for them to fire the signal off to the circadian clock of the brain and that's why I say look at low solar angles sunlight early in the day. What that does is it what call it as phase advances the clock this can get a little Technical and we don't want to get too technical here, but think about pushing your kid on a swing the period of That Swing the duration of That Swing is a little bit longer than 12 hours. Okay, so
When you stand closer to the kids so your kids swings back and you give it a push you're shortening the period right now allowing the swing to come all the way up. That's what happens when you look at morning sunlight, you're advancing your circadian clock translated to English or non nerd speak. You're making it such that you will want to go to bed a little bit earlier and wake up a little bit earlier the next day.
In the evening when you view low solar angle sunlight. So in the after the afternoon Setting Sun or evening Setting Sun you do the exact opposite your face is delaying in the clock. It's the equivalent of your kid being at the very top of the of the arc. And so it's gone, you know, maybe 12 and a half hour 12. Let's say 12 and a half hours is the duration of that swing and you run up and you push them from behind and give them a little more push. That's the equivalent of making yourself. Stay up a little later and wake up a little later these
These two signals average so that your clock stays stable You Don't Drift meaning you're not waking up earlier every single day or going to sleep later every single day. This is why it's important to view low. So low angle sunlight in the morning and again in the evening as often as possible and it's done by that readout of those two photopigments now midday Sun.
Which contains it's bright light, but you see it as white light contains all of those wavelengths that equal intensity. So the middle of the day is the so called circadian Dead Zone in the middle of the day bright light triggers the activation of the of the other apis in the melanopsin which increases mood increases feelings of well-being has some other consequences, but you can't shift your circadian clock by viewing the sun in the middle of the day because it's in the Circadian Dead Zone. It's the equivalent of pushing your kid on the swing when they're at the
Bottom of the arc, you can get a little bit more but not much and in biological terms you get nothing. So this is why looking at sunlight in the middle of the day is great, but it's not going to help anchor your sleep-wake cycle. And if you think about this is incredible, right every organism from single cells to us has this mechanism to know when the sun is rising and when the Sun is setting and it's a color comparison mechanism which tells us that actually color vision Evolved first, not for pattern vision.
Not for seeing beautiful sunsets and recognizing that's beautiful or paintings or things of that sort. But rather for setting the circadian
clock now what if you only do one of these enters so what if you've got constant exposure to low Morning Light, but your job prevents you from doing the same in the evening or vice
versa? Yeah a great question better to get the Morning Light because if you have to pick between low solar angle light earlier later in the day and keep in mind if you miss a day no big deal. It's a slow integrative mechanisms.
I'm averaging across the previous two or three days. But if you miss a day you want to get twice as much light in your eyes that next morning. The reason it's better to do in the morning as opposed to the evening. Although both would be to do best would be to do both. Excuse me, is that most people are getting some artificial light exposure in the evening anyway, and here's the Diabolical thing. Your retina is very insensitive to light early in the day. You need a lot of photons to trigger this mechanism early in the day as the
They goes on retinol sensitivity increases and it takes very little light to shift your circadian clock late in the day. Keep in mind also that if you do see afternoon and evening sunlight, there's a beautiful study published in signed science reports. Yes science reports two years ago showing that that can partially offset the negative effects of artificial light exposure at night. I think of this as your Netflix inoculation in the amount of melatonin suppression from Nighttime light exposure is halved by
Doing evening Setting Sun now. Keep in mind. You don't need to see The Sun Cross The Horizon it can just be when it's low solar angle. So you're looking for those yellow blue or blue pink blue red contrast and on cloudy days, believe it or not. They're still there. Just you don't perceive as much of it coming through. So they're really so that's three things that we should all strive to do view low solar angles on literally in the Dave you solar angle sunlight later in the day and get as much bright light in our eyes as we safely can ideally from sunlight throughout
out the day and if you can't do that, perhaps invest in one of these sad light so they can be a bit expensive there a couple companies that are starting to design Sunrise simulators and evening simulators that are actually good that actually work but right now my read is that aside from one company out there which by the way, I have no relationship to it's called the 20 light tu0, and that light bulb was developed by the biologist at the University of Washington who
He discovered these color opponent mechanisms. Those lights are not particularly expensive. But there they do seem to work. In fact, they they're the study that is emerging again unpublished data seems to indicate that if you look at it for more than five or six minutes, it can induce a mild Euphoria. That's how powerful this contrast is and what they did there in that light. I'll just tell you the mechanism is they figured out then when most people look at low solar angle sunlight in the morning. They're getting 19 reviews.
Reversals of blue orange per second. So when you look at this light, it looks like a barely flashing white light, but it's reversals of orange and blue orange and you know, red and blue and it's
happened. So what is the what is the person looking at it
perceive? Well, I've used one of these you just looks like a flickering light and of course, there's always the potential of a placebo effect,
but was going to say, is there a way to control for that by having something that looks the same to the user, but of course is not
Producing the same photo effect.
Yeah. Well, they've done that with the 10,000 Lux sad lamps and you would and which most people use to try and induce Sunrise simulation in their home. But keeping in mind that Sunrise is gives you this comparison of short and long wavelength light just a bright 10,000 Lux light triggers one of the options that but it won't set your circadian clock. So most of the sad lamps that are out there are activating only one of the mechanisms in
these cells that's relevant and not the one that's most relevant. So I'm excited about what 20 is doing. I think that and again I have no relation to them except. I know the biologists who did the work that provide the mechanistic logic for that engineering I still think we're in the like really like early days of this stuff. What should be done is to have this stuff built into your laptop, right? It should be built into your phone and hopefully it will be now. I mentioned this color contrast thing.
Sunrise and sunset I mentioned the bright light throughout the day but there's a fourth light stimulus that turns out to be really important and this will provide the segue into the paper turns out that dark exposure at night independent of light exposure during the day is important for mental health outcomes. Now, most people think dark exposure. How do I think about that? Well, it is dark. Yes since of light is the absence of light but what this paper really drives home is that people who make it a point to
to get dark exposure at night aka the absence of light at night actually benefit, even if they're not getting enough sunlight during the day and this is especially true for people with certain mental health issues. So I don't think we can overstate the value of pretty 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
But you know also don't suffer from jet lag too much. Some people can stay up late get a lot of bright light exposure in the middle the night and during the day they're got their sunglasses on all day and they're in a great mood all the time other people are more susceptible to these sorts of things and we don't know whether or not genetic polymorphisms underlie that I personally am very sensitive to sunlight in the sense that if I don't get enough sunlight, I don't feel well after a couple of days, but I'm less sensitive to light exposure at night for instance, but I think
It is perhaps is a big statement but is perhaps the most fundamental environmental stimulus for levels of arousal and alertness which correlate with all sorts of, you know, neuromodulator and hormone outputs. And so it none of this should come as any surprise. I will mention one last thing there was a study published gosh over 10 years ago now from Chuck's icers Lab at Harvard Medical School is phenomenal lab exploring circadian human health behavior. He's just considered a
Nopony luminary in the field but there wasn't a study that was in error where they had published in Science magazine that light shown behind the knee could shift circadian rhythms. And that paper was retracted and a lot of people don't know that it was retracted light exposure to the eyes as 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 no relevance on their sensitivity to these types of mechanisms and on and on
so one question one comment the question again.
When is going back to the morning evening light and I spend a lot of time looking at those types of skies, for example, just because of the nature of my hobbies great, right because I'm always doing archery in the morning and rocking in the afternoon. So it's not uncommon that I'm seeing both of those. How relevant is it that the Sun be above the Horizon. So for example, it begins to get light about an 30 minutes before sunrise and then you know, right it's so sun rises at 7:30 first.
Is 7 and then you know sort of 7:15 to 7:30 is actually quite bright. I mean you can see anything and everything and the same is true at Sunset. So does does that 30 minutes pre or when sun is Beneath The Horizon constitute part of that 10
minutes. It does. I mean in an ideal circumstance you'd get outside and see the sunrise every day and you'd see the sunset every day even on cloudy days. Some people like myself wake up before the sun comes up in which can I get this question all the time?
Well in the absence of powers to make the sunrise faster, which I'm not aware. Anyone has certainly not me. I think the best thing to do is simply to turn on as many Bright Lights as you can indoors to trigger that melanopsin mechanism. If you want to be awake if you want to stay asleep or sleepy then keep them dim and then get outside once the sun is starting to come out some people wake up after the sun has risen right in which case get what you can and some people wake up 10 a.m. Or noon in which case you can still get the bright light exposure.
But you won't shift your circadian clock now in the evening, especially in the winter months. It's important to look West and try and get some sunlight in your eyes in the evening. If you've ever gone into the clinic for instance at 2:00 in the afternoon after lunch, you know, and then in the winter and then come out and it's dark when you're walking to your car. It's a kind of eerie feeling that sort of eerie feeling May correlate with the fact that you missed a signal your brain is trying to orient your brain and body.
In time and that's what all of this is right trying to orient in time. And again, some people are more susceptible to that than others. Some people might like that feeling of oh I went in when it was bright and I come out when it's dark but the vast majority of people feel better when they're getting this morning and evening sunlight exposure and this is especially important in kids. All right. This is one of the things that you know, this paper points out in their good data that people are spending approximately 90% of their time indoors nowadays daytime.
Indoors and those indoor environments are simply not bright enough. You think others all these bright lights and some people are putting blue blockers on in the middle of the day, which is the worst thing you could possibly do if you're going to wear blue blockers and I don't think they're necessary. But if you're going to wear them you'd want to wear them at night. And in the evening, you don't need to wear blue blockers. You just simply should dim the lights and ideally have lights that are set a little bit lower in your environment, which the Scandinavians have been doing for a long time. So, you know kill the overhead lights.
And don't obsess about bright light exposure in the middle of the night. In fact for a long time. I and some other people were saying, oh, you know even just a brief flash of light in the middle of the night can quash your melatonin, that's true. But the other time in which you're in this quote-unquote circadian dead zone is in the middle of the night. You can't shift your circadian clock in the middle of the night, but you know, all of this gets down to enter weaving rhythms of light sensitivity temperature hormone output.
I saw it. I mean there's a whole landscape of circadian biology this paper, which was published in a new Journal. I'm really excited about called nature mental health. This journal was just launched recently is entitled day and night light exposure are associated with psychiatric disorders and objective light study and more than 85,000 people. Now, I have to say that I think the title of this paper is terrible. Sorry folks at nature mental health because if one just read the title, it sounds like
Day and night light exposure associated with psychiatric disorders in right if this were If This Were a newspaper headline and be like, oh my goodness, what do you supposed to do? Right, but that's not the conclusion the conclusion is that getting a lot of sunlight exposure during the day and getting a lot of dark exposure at night is immensely beneficial for psychiatric health and in a number of ways now, I'm not one to bring up a another paper unannounced but I will say that this paper built off a previous study.
Entitled time spent in outdoor light is associated with mood sleep and circadian rhythm related outcomes. And that was a cross-sectional longitudinal study in 400,000 bio Bank participants. So there's UK biobank is an incredibly valuable resource and there are now multiple studies establishing that one's pattern of light exposure is extremely important. Now the previous study in four hundred thousand participants basically nailed home the idea that the more time you spend Outdoors.
The better your is your mood the better is your sleep the better is the rhythmicity of your sleep-wake cycles and on and on something that I think even though people say we've known that for thousands of years needed scientific substantiation. This new study essentially looked at the relative contributions of daytime light exposure and nighttime dark exposure and they did that on a background of a looking in particular people had major depressive disorder generalized anxiety PTSD.
Bipolar disorder here's the basic takeaway and I'll quote them here and then I'll I'll tell you my interpretation that here. I'm quoting avoiding night at light and seeking light during the day. I love that word seeking may be a simple and effective nonpharmacologic means for broadly improving mental health. So it'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 it needs to be a
as much like Zone to cardio or resistance training. Okay. So what do they do in this study? So basically they gathered up 100,000 people are so it eventually was paired down to about eighty six thousand participants because some just didn't qualify or didn't report their data back. They equipped them with accelerometers on their wrists and those
Wrist device is also could measure ambient light now. That's not a perfect tool because what you'd love to do is measure ambient light at the level of the Eyes by the way, will somebody design an eyeglass frame that changes color when you've gotten sufficient light from sunlight during the day and then and then at night is a different color and then if you're getting too much light exposure will go to a different color frame. This has to be possible so that you don't have to wonder if you got enough light during the day and of course if it's at the level of the eyes then you know,
that's what's landing at the eyes.
Um, it's let me know that's was going to ask you about that it do these wrist based devices potentially get covered by clothing and some learned over have your sleeves down. I have my sleeves
up. They had it on the outside the sleeve but they ask that people just keep it on their dominant hand. It's not perfect. But in some ways it's kind of nice that it's not perfect. We could turn that disadvantage into an advantage by thinking, you know, when the person is out and about they're not often looking right at the sun, you know, if you're talking to a colleague under an overhang for
Students so it's not Perfection Ali it's directionally, right? Okay, and then they had two hypotheses to primary hypotheses one that greater light exposure in the day is associated with lower risk for psychiatric disorders and to Second hypotheses greater light exposure at night is associated with higher risk for psychiatric disorders in poor mood. This is 0 so relevant for the way we live now people on screens and tablets in the middle of the night. Okay, then they collected information about how much light exposure people were getting as
well as their sleep and their activity and so on I should mention this was done in males and females. It was a slightly older cohort than one is used to seeing people in their 50s and 60s. They had psychiatric diagnosis information and then they divided people into essentially two groups, but they had a lower so a q1 and Q2 a lower quartile that meant people that were 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 in the low Q 1 and Q 2. So these people are getting less nighttime light versus Q 3 q 4 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 like 10 hours a day 14 hours a day because the more active you are the more opportunity for light exposure you have during the day or night for instance, okay.
So they had I would say fairly complete data sets then and I'm just going to kind of Hit the top Contour what they did in
each and sorry sleep duration sleep efficiency Etc was determined off the
accelerometer. That's right as well as self-report. Yeah, not not ideal. Right you'd love to for people to be wearing a whoop bander or a ring or something of 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.
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Then what they did is they got they have information on who has major depressive disorder who has PTSD generalized anxiety bipolar psychosis Etc. And then they ran three models and you can tell me what you think about the power of these models, but you know somebody who thinks about the mechanistic aspect of all 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 night time.
Light exposure and psychiatric outcomes. So just basically asking is there a relationship between how much light you get it during the day and how much light you get it night and how bad your or your depression is or anxiety is ETC looking at, you know, just a standard ratio of the probability that you have a certain symptom or set of symptoms versus you don't given a certain amount of light exposure model to adjusted for the age of the person.
Their sex and ethnicity and photo period so they looked at you know, how long the days were in that given person's region of the world and then model 3 will see
these people were all in the UK where
they were and they were all in the UK as far as I know and then model 3 adjusted for employment. So employed versus unemployed, which if you think about it is pretty important like you say, well an unemployed person has a lot more time to control these variables but an employed person who's doing shift work does not right?
And they they Incorporated information about employed versus unemployed physical activity which turns out to be very important and then things like shift work etc. And so these we can say very safely is that the outcomes with each of these models the results were very similar. So we don't want to discard the differences between those models entirely but in my read is in every figure the paper, it doesn't seem like model 1 2 or 3.
Differ from one another in terms of total income. Yeah,
that's an unusual aspect of this paper. So these adjustments are very standard, right? So that's this is a classic tool that's used in most epidemiology because you don't have randomization. So once randomization is out the window, you know, you you're like, so for example, the paper I'm going to present is based on an RCT. There will be no models. It's just hear the database.
Yeah. So you're they're asking people what what do you do report back to us? We're going to measure your light exposure, but
One was assigned any groups or swap their the whatever can quote unquote controls are there they're really not there. It's just comparisons between
groups. So what is interesting to me? Is that as it's exactly as you said and will make all these figures available in addition to the papers. But I mean, they're it's very unusual that there's no difference between the unadjusted and the adjusted models. And as you say, there's probably two
Two places out of you know 30 when you look at all the different quartile comparisons where you might Creep from, you know, statistically significant just out of it or just into it. But yeah, you could simplify this figure to completely by just showing one of the models and you would be you know, getting 95% of the information which is you know, I mean, I think in one way that suggests
That there's less dependency on those variables. Of course. It's still doesn't address probably the greatest question I have here which I'm sure we'll get to at some point as you continue.
Yes. Oh, I'm very curious what that question is, but I'll hold I'll I'll suppress my curiosity and the moment so if we look at figure to of this paper, and I realize a lot of people are listening and they're not able to look at this. Although we have posted the figures on the YouTube versions of this just
A clear what's going on just for those that are listening essentially what they're looking at is what they call the odds ratio, which is the probability of something happening in one group versus divided by the probability of something happening another group. I guess would by way of example would be you know, if you're going to look at the odds ratio of you know, the probability of somebody getting lung cancer if they smoke versus probability somebody getting lung cancer if they don't smoke
so odds ratios and Hazard ratios are often confused.
They're very similar and odds ratio is generally referred to a lifetime exposure. Whereas a hazard ratio is defined over a specific period of time, but the math is still effectively the same and using the example you gave if you took the odds ratio of you know death, so let's talk all-cause mortality for a smoker versus a non smoker and the answer. We're 1.78. I'm making that up at that's directionally correct. 1.78 is an odds ratio means there's a 78
Percent chance greater of the outcome of interest in this case death by any cause in the affected Group which be the smokers. So odds ratio of 2 is 100% an odds ratio of three is two hundred percent. So the math is take the number subtract one and that's the percent,
you know figure to of this paper is one of the key take homes. They essentially look at the odds ratio of people who are in the let's say that let's just look at the nighttime light.
Exposure
and just remind me Andrew because and everybody else watching every one of these is showing second third fourth as your x-axis right meaning they're all being compared to the first quartile. That's right in the first quartile is lowest light exposure or its highest light exposure lowest
well, or will we have to
differentiate between day and night. That's right. Okay, so restate it
sure. So if we look at you know, what is your risk of a psychiatric challenge brought?
Speaking what penile a is is major depressive disorder. If you are in the second quartile third quartile or fourth quartile of nighttime light exposure. So second being the least amount of nighttime light exposure third being more nighttime light exposure and forth the most nighttime light exposure relative to the first quartile.
This is just a stupid thing. Like if I were doing this figure if you were doing this in a lecture, you know, what you would do to make it so easy you would draw arrows on it. That's a
thing light exposure at night. Yep, decreasing light exposure in the day. It's the same information. It just makes it easier for the reader to understand absolutely but and I maybe the teaching point I think is for people when they review articles, like don't be afraid to do that and just kind of like,
oh, I wouldn't
exactly so it's like I draw the arrow that's increasing light that's decreasing light and that's how I can pay attention to what's actually happening.
Right and I'm actually in touch with the editorial staff at Matrix at nature mental health of the they don't know that I'm covering this paper until
For this comes out, you know, I think one thing that scientific journals really really need to do is start making the readability of the Articles better for non-experts. I mean chances are if you can't understand a graph and this is true for everybody chances are there's a problem with the way it's presented. Yep. Put it on them. But then of course try and parse it because you know rarely if ever is it all spelled out clearly. But anyway, that's what we're trying to do here. So yeah, the way I would have done is say s quartiles low.
It's of nighttime light exposure to find what that is, you know third quartile is more light exposure and then fourth maximum amount of light exposure at night and basically what you see is that the probability of having worse major depressive symptoms linearly increases as you go from the second to third to Fourth quartile, so more nighttime light exposure worse for you and there's a dose response.
If you will of the effect now, we can March through or describe figure to pretty quickly by saying the same thing is true. Now. We're just talking about nighttime light exposure for generalized anxiety disorder. So that's panel C bipolar disorder. Although the difference between the second and third quartile and bipolar disorder isn't as dramatic. Once you get up to the fourth quartile bipolar symptoms get much worse when people are getting nighttime light exposure. I really want to emphasize
a size that point because they go on in the discussion of this paper to re-emphasize that point several times. In fact, they say that while light exposure during the day, of course, we will go into the data is beneficial for mental health for people with bipolar disorder. It seems that light exposure at night is especially problematic independent of how much sunlight they're getting during the day. So you're bipolar in the person with bipolar disorder who's struggling with either a manic or depressive 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 couldn't completely control this but this is largely independent of things like sleep duration. So that doesn't necessarily mean that the person sleeping less although in about being a manic episode presumably they are it's independent of exercise. It's independent of a bunch of other things because any any logical person will hear this and say, okay. Well, they're the game more light at night because they're doing a bunch of other things.
Things but it's largely independent of those other things likewise the symptomology of PTSD gets far worse with increasing light exposure at night self-harm really takes a leap from being fairly. I don't want to say minimal at the second and third quartile solo and let's say medium. I'm using some taking some Liberties here, but low and medium amounts of artificial light exposure at night then for people who get quite a lot of nighttime light exposure self-harm goes
And probability of psychotic episodes goes up or psychotic symptoms. Now, what's nice? Is that the what's nice about the data is that the exact inverse is basically true for daytime light exposure. Although not across the board. We can generally say that for major depressive disorder generalized anxiety bipolar symptoms there. It's a little more scattered PTSD and self-harm the more daytime light exposure.
Ideally from sunlight because that's actually what's being measured in most cases we can talk about how we know that is going to approximately linearly drop the probability or the severity of the
symptoms and we could just explain again that the odds ratio is now seemed to be going down. So an odds ratio of .7 now refers to a 30% reduction in the variable of interest
here exactly. Now that the psychosis panel laughs which focuses on psychosis.
Ink is also worth mentioning in a bit more detail. There's a fairly dramatic reduction in psychotic symptoms as one gets more daytime light exposure independent of nighttime light exposure. There's a well-known phenomenon called ICU psychosis, which is that people come into the hospital for a broken leg or car accident. Maybe they were getting surgery from from Peter back when for something totally independent. They're they're housed in the hospital and as anyone who's ever
ever been in a hospital as a patient or visitor knows the light in the lighting environment. The hospital is absolutely dreadful for health. Just Dreadful. I mean people often complain about the food in the cafeteria is being unhealthy that's often not always true not always true. But the lighting environments in hospitals is
absolutely just a special especially in the Intensive Care Unit. Yeah, right. So I think the the Intensive Care Unit at Hopkins the main one the main sick you didn't have
Windows.
People who go into the hospital with with the brain injury or or with a stroke or something. I get contacted all the time, even though I'm not a clinician. What should I do for my kid my parent my always say get them near a window and start to the best of your abilities controlling their sleep-wake cycle now oftentimes, there's there, you know nurses coming in and taking blood test and measuring pulses in the middle of the night. That's disruptive there. There's bright light not just blue light that's disruptive. It's noisy. That's disruptive. ICU psychosis is when non-psychotic individual start having sex
Psychotic episodes in the hospital because of nighttime light exposure and in some cases lack of daytime sunlight we can say that with some degree of confidence because when those people go home, even though sometimes their symptoms for what brought them to the hospital in the first place get worse their psychosis goes away now, and it's independent of medication. So let's just be really Direct.
There is a possibility that we are all socially jet-lagged that we are all disrupting these mood regulation symptoms. The system's scuse me by not getting enough daytime light and by getting too much nighttime light if we want to look at just some of the bullet points of the takeaways and Peter. Thank you you highlighted a few of these
but can we just go back to this? Figure 24? So yeah sure. There's a handful of things that I really
enjoy is don't want I want to dig in the deer. Yeah,
and again, I normally wouldn't
Make so much. Hay out of this except for the fact that they're so tight. But the there are a few that really stand out. And again, I love this figure. I would have labeled it a little differently to make it completely user friendly, but nevertheless the increasing light at night and the impact on depression where the let's let me be really Technical and when I say and the relationship or correlation to depression is very strong the relationship to light and sound.
Of harm in the upper quartile. So when you take those 25 percent of people with the most nighttime light that relationship to self-harm is interesting and completely uncoupled from the other 75% That's interesting
undo by uncoupled you mean that at the lower levels of light exposure at night. You're not seeing an increase in self-harm not what's and then once you get to that fourth quartile, it's a big step. It's a like a thirty percent greater risk of a sorry.
Yeah, so it's totally flat the first second third quartile. No different and then
Fourth big jump and then the the the inverse relationship right as light increases during the daytime you see this reduction in self-harm interesting the PTSD relationship based on nighttime light and The psychosis relationship based on daytime light. Those are the ones that really jumped out to me. I think anxiety relatively the you no less impressive here and and bipolar disorder didn't seem as strong right as well. So I think
Those are the big ones that aggregate that jumped out to me.
Yeah, I agree. There's a there's a bit more scatter on generalized anxiety and the degree of the significant degree of significant change is not as not as robust. In other words getting a lot of daytime light ideally from sunlight is not necessarily going to reduce your levels of anxiety getting a lot of nighttime light exposure is not increasing nighttime anxiety that much although 20% you know is not nothing for now.
Nighttime light exposure. But yeah, we're The psychosis major major depression and self harm a really, you know, they leap out. Actually we maybe we even just drill a little bit deeper on major depression. And basically when you go from the 2nd to 3rd quartile of nighttime light exposure somewhere nighttime light exposure you basically go from no significant increase to almost almost a 20 percent increase and then as you get up to the fourth quartile, so the most nighttime light exposure at about 25%
increase in major depressive symptoms not that's no joke and you know and I think that I think that we you know, we were to I mean, we don't have the data right here, but if we were to look at what standard SSRI treatment for major depression, you know people debate this pretty actively but light is is a very potent stimulus and the timing of light is critical because on the the inverse is also true as you get to the fourth quartile of daytime light exposure you get
Out a 20% reduction in major depressive
disorder what I like about a study like this is that it puts the error bars so easy to see on the data and why is that interesting? Well, there's
there's there's a there's a belief that bigger is always better in sample size and we often talk about that through the lens of power analysis, right? So how many subjects do we need to to reach a conclusion that is powered to you know this level and that's that's true. But what I don't think that's discussed as often is the opposite of that which is what if you overpower a study in other words, what if the power analysis says to be
To have a level of power at 90% you need 1000 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 could be a bad thing because it means you are very likely to reach the testicle 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
really not overpowered is that you have varying lengths of error bars and what that tells me is that and again, this is not like a formal statistical analysis. It's just kind of like a back-of-the-envelope statistical analysis. If you look for example at self-harm in the top quartile, you actually have pretty big error bars. In fact, all the self-harm have sort of slightly bigger error bars and yet when you look at for example the depression, even though the error bars aren't all the same size. They're tighter. In fact when you look at the relationship between
Depression and daytime light the error bars are really really small. So that just gives me confidence that there is variability in this which paradoxically you kind of want to see because it tells me that this wasn't just done. You know, there was I think you said eight thousand subjects were in this and I
realized 80 more than
86,000 $86 or yeah, you realize that it wasn't that this should have been done with a tenth of that or a half of that and we're picking up a signal that is statistically relevant, but clinically
Relevant.
Yeah, thanks for for that point that I didn't pay attention to that. I mean I paid attention to the error bars, but I didn't know that so thank you. I'm learning to and I suppose for people that are listening we can just give them a sense of what the error bar ranges are for self harm. They're running, you know as much as 20% either side of the mean the average and for major depression. It looks like it's more like let's say 8 to
10% if that yeah.
Right. So yeah, I see what you're saying with. So when you get a very large sample size, you're going to have some outliers in there and you can mask those outliers just by having so many data points, right?
Yeah, because these error bars directly tell you whether or not you're statistically significant. So what's really nice about this type of graph and you see these in there's going to be a graph in my paper where you see the same analysis. They're always drawing the 95.
Five percent confidence interval on the on the data point and if the 95% confidence interval does not touch the the line of unity which in this case is the the Hogs ratio of 1.0 or the x axis then you know, it's statistically significant to the confidence interval. They've defined which is almost assuredly 95% Sometimes they'll make it tighter at 99. And so that's why you can just look right at these and go. Oh look, you know in depression the second quartile didn't reach the testicle significance because the error bars
Touching the line just as the case for the second and third quartile for self harm. But when you look at the fourth quartile, you can see that the lower tip of the error bars isn't anywhere near Unity. And so we know without having to look up the p-value that it's smaller than either .05 4.1. However, they've defined it and it's really amazing. When you see these, you know, overpowered studies which are easier to do epidemiologically where you know, the P value ends up being microscopic, you know,
they can they can drive their p-values down to anything low because sample size can be infinite but you know, you can see that it's just like the the error bar is just skimming above the the unity line but it's so so so
tight one. I'd like to take a quick break to acknowledge. Our sponsor element element is an electrolyte drink that has everything you need and nothing you don't that means zero sugar and the appropriate ratios of the electrolyte sodium magnesium and potassium and that correct ratio.
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Can go to drink element spelled LMN t.com huberman to try a free sample pack again. That's drink element.com huberman. One thing that I hope people are taking away from this study. Is that imagine? You're somebody who has a very sensitive circadian mood system. Well, that would mean you need less daytime light exposure to feel good or less bad, but it also means that you might need
Very little light at night in order to negatively impact your mood systems. And in fact, they make this argument in the discussion as an interesting point that I think is worth mentioning the what because here what I again what I like about this study is that they've separated day and nighttime light exposure turns out that many of the drugs that are used to treat bipolar disorder reduce the sense our are effective.
Perhaps in part because they reduce the sensitivity of the light sensing circadian apparatus. I now that's interesting right if you think about this. Okay. So these are drugs that can ameliorate some of the symptoms of bipolar perhaps in part by reducing the extent to which nighttime light exposure can relieve bipolar symptoms Kitt, excuse me can exacerbate bipolar symptoms conversely. There's evidence that people who take certain antidepressants may surprise.
Press 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, you know talk to your psychiatrist. But if we know one thing for sure it's 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 eye movement sleep or the Circadian cycle.
much any drug alter circadian rhythm
For better or worse but if we start to think about which medications might adjust our overall sensitivity to light sometimes this could be a good thing you think less sensitivity to light. Well for people who have bipolar disorder the amount of daytime light exposure isn't that important for their overall mood regulation, but the amount of nighttime light exposure really is in other words Darkness for eight hours every night should be viewed in my opinion as a treatment for bipolar disorder not the only treatment but it's also clear that we should all be avoided.
Eating really bright extensive really bright nighttime light exposure. I mean if anything, you know, my takeaway from this study is that Darkness at night is the fourth key light stimulus now what a couple of things very bright moon light very bright candle light is probably only like
Gosh, 3250 Lux what when you go outside on a brightly lit full moon night. I encourage people to download this free app. I have no relationship to it called light meter and it gives you a pretty good read of what the locks are in that barn. By the way. A lot of people don't realize this they think you just tap the button and then it tells you how many luxury hold it down. Its 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 moonlit night.
I mean we should have a full moon
tonight. Yeah, let's do it. You're not going to get above 100 looks that's incredible. You're sitting at a candlelight dinner with your spouse or with friends and it's clearly bright enough to see them put that lux meter right up not too close to the flame 50 to 200 Lux
forcing experience a couple of months ago on an elk hunt where it was a full moon which actually makes the hunting not so great, but it was the first time I've ever known.
Noticed my shadow in relation to the Moon. That's how bright it seemed. The light was
this is Halloween appropriate. Yeah coming up. We're getting this close to Halloween.
So so it's remarkable for interesting to think it could be that dim
campfire, you know and firelight you think okay gathering around a campfire with then? Okay, you know everyone circadian rhythm must have been disrupted for ages before the development of electric electricity. No know that those campfires are extremely bright, but they're there they're not there.
Not that bright compared to a very densely overcast day.
And what is your phone? If you don't use any sort of light mitigating Tech on
it, well distance matters, but at the distance were holding it. Yeah with so with all the the wavelengths cranked up. So no, there is a nice feature intrinsic to the phone. We can eliminate the blues at night or you know this kind of thing, but if you crank it up to maximum light intensity probably something like, you know 500 to 1000 lat.
Looks now keep in mind though. It's additive right so it's over time. So Lux is a measure of I think it relates back to CD as the amount of light Shone and I think it's like the one meter away and there's a squaring and a falling off of distance. We can look it up. These are old measurement old-school measurements converted to Lux, but keep in mind if you're looking at your phone or tablet at 800 locks or 500 Lux in the evening you do that for two hours. Well, you're summing quite a
Photons now it is true and I do want to be fair to the biology and would be dishonest to say anything different. We hammered on people about not shifting their circadian rhythm with light at night, but we know that the middle of the day in the middle of the night our circadian dead zones, you can't shift your circadian rhythm that well in the middle of the day in the middle of the night, but you can provide a wake-up signal for your body and brain it's really that sunrise and sunset that are critical. That's why I said therefore things see sunrise or
sun rising. You don't need to see across the Horizon Sunset bright light during the day minimize light exposure at night and you don't need Pitch Black. In fact pitch-black probably just increases the frequency of injury, you know, I get up in the middle of the night to use the bathroom. Probably once I think it's normal I go back to sleep, you know, if it were pitch-black, I probably enjoy myself. So just did just dim it down some people use red lights, you know, our friend Ricardo mental friend. Yeah, Rick Rubin is
a funny story about Rick. Yeah, of course, of course, you know this
Sorry, but just the I just in case where X listening he'll appreciate this. You know, when Rick was here staying last summer. He's up in our guest house and he came down after the first night and he was like unacceptable. You know what I'm talking about acceptable accommodations. What did he do?
He removed all the lighting that existed in that room and replaced it with red light bulbs, which I later used when I stayed here and then later stole laughed the teenage me I took them.
Took him. That's why Derek when he stayed here and laying or anyone else has stayed here Conte or anyone else didn't have those. I took them. I love them.
So funny Joe is like, you know Rick changed every light in the Guesthouse to read. I'm like, yeah. I know. I didn't know that but I'm not
surprised. Yeah, well in his place he has mostly either no lighting or red lighting so during the day just goes by ambient light and then red light in the evening and or candle light and it's great and you know people here red lights and they think they have to buy these
Expensive red light units, 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 well, can I just use a red film or can I put a t-shirt over the lamp? I worry about people putting t-shirts over lamps because of the fire hazard, but I'll be honest I dim the lights in my home at night. When I travel sometimes I will bring one of the the stolen from Rick Rubin red
lights the red the Rick Rubin staff. Here's something where I've sort of soften my tune. So I used to be kind of a hardliner. No blue.
Ooh light in the evening guy, you know had the you know, everything was red light at night as far as my phone using flux on the computer, you know, whatever it was.
I suspect that that matter is 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 it probably is true in others as well. And at least some others. Is that what I'm doing on my phone matters more than how bright my phone is in other words if I've got the best blue light filter in the world on my phone, but I'm doomed scrolling social media.
And getting lit up on email. That's way worse for me than if I've got my phone on maximum light and I'm like watching YouTube videos of F1 cars and driving around having fun like yeah until totally different experience. So so so the context matters and I think I think for that reason I would want people to be mindful of the whole picture, you know going to bed under a period of you know, intense duress.
Brought on by something, you know, that's an equally dangerous component to all of this. That's that's distinct from what we're talking about. But you know you just want to I'd like I want people to be able to think of this in the context of
everything. Yeah. I it's a really important point. One thing. I'll say is that if you're going to stay up past your normal bedtime, if you're going to get a lot of light in your eyes, I would hope they will be for fun reasons and three reasons you enjoy you should definitely spend some nights out. You should definitely do some all-nighters studying if you really, you know, if you
If it's going to help you get the grade, that's permanent. Right? I'd certainly have done all nighters studying and grant writing for years. You know, there are going to be the inevitable all-nighters do to God forbid a hostage trip to the hospital or you heard something on the news that really amped you up or you just simply can't sleep that stuff is going to happen. So I think the goal should be to minimize light exposure at night and I think what you just said is especially true because we don't know for instance people talk about the negative impact of social media is it the fact that people are looking at
This little box for so many hours per day. Is it all the things they're not doing is it what they're looking at per se all of those things interact and are really important. We know based on studies from the Stanford sleep lab that if you wake up in the middle of the night looking at what time it is can be very disruptive to your ability to fall back asleep and to your sense the next day. It's a placebo effect, but it's a powerful one of how tired you are the next day. They've done this where they wake people up in the middle the night and then they say it's
it's you know for am versus to am versus 6 a.m. And people's perceived levels of energy during the day in some ways correlate with what they think how much sleep they think they got likewise in this is one of the concerns potential concerns with sleep trackers. Yep. Ali crumb talked about this when she came on our podcast, you know, if people see a poor sleep score they often feel worse than if they see a good sleep score now, of course physiology matters, you can't lie to yourself and say, you know got a great night's sleep simply by virtue of
Score, but I worry more about the false. Well, I won't if it's false negative at that. We don't want to put valence on this seeing a bad sleep score and then deciding that you're going to have a terrible day. You know, I think about sleep scores an indication that you might need to dial some things in a bit better getting a great sleep score is an indication that you might be doing a number of things right and start looking at these things as average as wouldn't would you
agree? Yeah completely. I don't think it's that different from CGM. Right? Like I think that CGM is an amazing tool to provide insight.
And you pretty much know the insights after a relatively short period of time 30 days maybe at the outside 94 a really prefer a person with a very complicated life and you know, all you need to know about how the inputs affect the output thereafter if you choose to use it. It's a behavioral tool in other words, you're using this to build in a Hawthorne effect. I think the same is largely true with sleep trackers. Most people have this profound sense of learning when they first encounter one of these things and
It's again. You've heard it a hundred times. Oh my God, I can't believe what alcohol does to my sleep or
caloric tracker? Exactly. I think Elaine Norton. Zap carbon. I have no Financial relationship to it. I use it or and it's taught me. Wow, like I consume a lot of calories in the form of certain things at certain times of day and there's just a lot of good learning in
that but the act of tracking that helps you manage it and similarly. I think it's the act of knowing you're going to be looking at that score that gamify zit that kind of helps.
People do the right things and you know what? I'm not going to have that drink tonight or I'm not going to eat that snack before bed because I've now been conditioned to see how that impact score that said. I think that, you know recovery scores and things like that are just notoriously poor at predicting performance. And I think there's a reason that serious athletes would never use things like that. They would tend to rely on them more tried-and-true methods of predicting Behavior such as heart rate may be heart rate variability.
But morning resting heart rate probably more predictive than anything else and then you know in work out things such as heart rate heart rate recovery lactate threshold things like that. So yeah, I agree. I think we have to and I say this as a guy who's generally perceived to be the most Pro device guy in the world people would be surprised how sparingly I use things like that.
I mean, I do some Tracking not as much as you I love things that seem to work the
first time in every time in terms of our natural biology based on a couple of criteria. There's an established mechanism. It's been explored in the context of pathology like mental health disorders as well as ProHealth in healthy individuals that it make really good sense at the level of kind of wellness and let's just say ancient Health, you know, when you talk about getting a lot of sunlight during the day a lot of people say well, of course get outside and play.
Not getting too much light at night. Of course, is it just good old quote unquote good old fashion advice people spend 90% of their time indoors. Now, their daytime environments are too dim. Their nighttime environments are too bright and this kind of misleading aspect of artificial light that when you see a bright bulb you think I'm getting a lot of photons is part of the problem and the fact that when you're out on an overcast day and it you know, you think there's sun quote-unquote isn't
Out well, it's hidden by cloud cover. But just think about how well you can navigate that environment without a flashlight and verses at night where you would require a flashlight we evolved under this traumatic difference in De night availability of photons independent whether or not you can quote see the Sun and it's just very clear that are the all the mechanisms in our brain and body that regulate mood are just powerfully regulated by this stuff. So,
I've made it a point to really reduce the amount of nighttime light that I'm getting but I am less concerned about flipping on the light switch to use the bathroom as I used to be a used to think. I'm like washing all my melatonin. This is terrible. I know I can't shift my circadian clock then. I know that that light yes while it's bright if it's brief. I'm not going to worry about it too much. Would it be better to have a you know dim light on as opposed to write like sure but I'm not going to stress it in a hotel bathroom or so. I'm not going to walk around, you know shielding my eyes people sometimes ask me by
The way is it different to look at the phone directly versus if you tilt the phone away. Well, it absolutely is. I mean think about a flash light Shone on the ground in front of you very few photons getting in your eyes versus shown directly into your eyes. Think about ambient light from the Sun going everywhere versus looking in the general direction of the Sun so East in the morning West in the afternoon, of course the directionality of the light matters, so I'm not saying it you know that you need to like peek at your phone as if you're looking, you know over the edge.
Double bowl or something into it, but my friend Sam her taro's head of the chronobiology unit at the National Institutes of mental health. We used to room together at meetings. We stopped because he's a terrible snorer. So I just could either a few times when I considered suffocating him in the middle of the night since he was already suffocating himself now, we just we don't stay in the same rooms anymore were no longer postdocs, but I caught him looking at his phone in the middle of the night and he would tilt it like away like he's holding a platter for those that are just listening and kind.
Like looking over at the screen there only. What are you doing? This is ridiculous. He's I'm trying not to get so much light in my eyes. That's a little extreme. But I think it illustrates the point which is how much direct light exposure you get it night matters how much direct sunlight exposure you get especially early and late early morning late afternoon and throughout the day. It really matters
now remind me Andrew. What is the wavelength of sunlight?
Great. So sunlight is going to include all visible
visible. Which runs from how many? Yeah,
so well, let's let's we can answer two questions there.
This wrist sensor detected 470 degree as 70 nanometer to 650 NM light. So that's going to be blue and UltraViolet UltraViolets kind
of its kind of like a blue to
Orange. Yeah blue blue to Orange. That's what this was measuring. So red light is going to be more like 680 far red is getting out to 7720 and up upwards of that blue light is going to fall somewhere in the low fours ultraviolet is getting down into the high threes and and
Lower and so these Spectra of light so during the day, you know midday light you're getting what looks like white light. You'll see how the skies blue in 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 of the day, you're getting all visible Spectra. So you getting everything from UV all the way out to red light is just coming in at equal
intensities. So is that a potential limitation of this study in that? It didn't have a sensor that could pick up the full spectrum of light.
Potentially especially since they're you know, we don't think of humans as UV capable. Like we can't perceive UV light like a ground squirrel for instance can has UV sensors in it sighs turns out you know, why they use this it's crazy. They actually, you know, when the ground squirrels sit up on their haunches, they're actually signaling one another they rub your and on their belly and it reflects UV that the New York Times for some reason has been running a series of papers or articles rather about
out naturally occurring fluorescence at night and all sorts of to be scorpions and monotremes like the Platypus. No one really knows the reason for these odd odd wavelength of light emissions for all these animals, but you know, we view things in the blue violet and up to read and you know, we're not pit vipers we can't see far red, but we can see lower than 470 nanometers and we can see higher than 700
650. Is there a technology reason why?
Had such a narrow band in these sensors is it not possible that they could have used a wrist sensor that was wider.
This study was initiated in 2013. The tech was probably far worse than it is now again, I would love for somebody to design an eyeglass where it's measuring how many photons you're getting across the day. I'm not a big fan of having everything be a path I'd so I would love it if the frame would just shift color across the morning you go outside on a cloudy day, you know, you wear these glasses and and by
The way it's fine to wear eye glasses or contacts for sunlight viewing for setting your circadian rhythm. People always say well, why is it that okay in a window 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 our sunglasses filtering this
out way too much. We can safely say way too much probably causing it tenfold decrement in the total flux count that's landing on your retina. But of course, uh, you know sunglasses are important driving in this
Into sun and and some people are very sensitive eyes. I can't sit at a cafe with a bright brightly reflective table in the afternoon. I just I just squint like crazy. I can't do it my dad who's you know darker I'd and you know it South South American descent. He you know, he can just sit there just fine. My mom who's got light eyes like me and you know, we're like it's really tough. You just have a terrible time, you know people differ in their light
sensitivity.
So there's one other macro question I have here and it's not answerable because without randomization we can't know it but it's the question of how much reverse causality can exist in these observations. So again, these observations demonstrate very tight correlations, very strong associations, especially in the five areas that we highlighted but
It's possible that part of what we're seeing is reverse causality brought on by both the treatments which you've already kind of alluded to and also the condition itself.
You want to explain reverse causality for people and maybe could you mention for those that missed the Hawthorne effect? Just yeah.
Yeah. The Hawthorne effect is as in effect that is named after an observation of what took place in a factory where they were actually studying.
Worker productivity with light of all things but it what it refers to is the idea that people will change their behavior when they are observed. So if if I said well, I really want to know what a day in the life is like for Andrew huberman. I'm going to follow him around for a day. It's very unlikely that his behavior that day will be exactly as it was if I wasn't there
and so the right you probably will never see a day in the life of Andrew huberman, although it's pretty it's pretty scripted.
Traveling it's a it's a you know, it's morning sunlight hydration and you know some cardio or weight training and then a lot of time reading papers it be the most boring video in the world because mostly me reading and underlining
things but it's why gamifying things can be beneficial right? It's why a CGM can can be beneficial because it's sort of like somebody's watching you and you're going to modify what you eat 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 it in other words, you can set up an accountability partner where your health coach or someone is actually seeing the data. So that's what it is. Now as far as reverse causality when you look at variables, so let's just pick a common one that's unrelated to this. So there's an association that more diet soda consumption is associated with greater obesity.
Bit paradoxical right that sure it is. Yeah. It's been demonstrated in many series that the greater the consumption of diet soda the greater the prevalence of obesity and that has been postulated by some to suggest that non-nutritive sweeteners such as aspartame or sucralose or things like that are actually part of what's causing obesity. And while there are probably some arguments you could make around the impact that those things might have.
On the gut microbiome and maybe there's some way and that's happening. It's also equally likely if not, probably more likely that there's reverse causality there that a person who is obese is therefore contemplating how much they're eating or thinking. Hey, what's an easy way that I can reduce calories. How about instead of drinking a Coke? I drink a Diet Coke and so there the causality which you would impute to mean. The drink is causing the Obesity. It might be no. The Obesity is causing the choice of drink.
So here the question is how much of the effect we're seeing is a result of the condition that's being studied. Right how much of the disruption in both day and night except light exposure is the result of the depression. It's dis 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.
Ermine this and sadly these questions can only be answered through either direct randomization or mendelian randomization, which by the way, I was going to also ask you do you know if anyone has examined this from 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 study able but that would be interesting
what Peter is saying is, you know, if you knew something about the genomes of these people you would be in a great position to perhaps even link up light susceptibility genes or light light sensitivity right jeans with jeans for you know Pathways and wall to major depression bipolar, but getting to this issue of reverse causality. I mean, I think it's very
Or to imagine that the person who is experiencing a manic episode is going to be up for two weeks at a time sadly and getting a lot of nighttime light exposure. You know now Dart nighttime dark exposure is a treatment for bipolar is something that people are starting to talk about so making sure that you have those people are awake that there at least blue blocking at night reducing their online activities, but people with severe manic episodes have a hard time regulating their own behavior, of course,
and it's not one or the
the other like I don't want the question to come across to the listener that it has to be one or the other. It's only a can cause b or B can cause a no it's actually a lot of times these things feed off each other going back to the soda example. I actually think there's a bit of both right? I actually think there's a real clear body habitus dictates beverage choice, but I also am starting to think that in susceptible individuals non-nutritive sweeteners will alter the gut biome and that
Ters metabolism. What
about just hunger? Remember Lane telling me and I've seen at least one of the studies that you know water is probably better for us than diet soda, but that for some people diet soda is a great tool for reducing caloric intake. I also know some individuals not me who drink diet soda. I drink diet soda from time to time mainly stevia-sweetened sodas, but but what I'm referring to here people
As myself who drink diet soda and it seems to stimulate their appetite. There's something about the the sense that perception of sweet as driving hunger. Whereas not eating or drinking anything with Cal with any sweetness doesn't seem to this is one of the things I wonder if impacts why some people like intermittent fasting because for some people, you know, just even the perception. I wonder if the perception of sweetness or even just the smell of food. We know can stimulate
Appetite so you can imagine that the perception of Sweetness in the mouth. Even if there's no calories there. I don't think it necessarily makes people hypoglycemic but perhaps it makes them think about like sweet means food for instance for years. I love the combination of a Diet Coke and a slice of pizza whenever I was in New York, ideally two slices of pizza. So now every time I have a Diet Coke which isn't that often but I like Diet Coke, especially a little bit of lemon in it. I just think about a slice of cheese or mushroom or pepperoni pizza.
Yeah, it's like I want I crave it more. So there's a parrot Association there that I think is real and we know based on Dana Smalls Lab at Yale that there's this paired association between the sweetness from sucralose and there's an insulin response. They actually had to Cease the study in kids because they were they were becoming pre-diabetic, you know, which unfortunately meant the study was never published. Have you talked to Dana on this
podcast know we wrote a premium newsletter on this several months ago it it's got to be
Like I don't know 10 to 20 thousand words on all things related to sugar
substitutes. I'll read
that so the so yeah folks are interested in this topic. I would refer them to the premium newsletter on sugar substitutes. I think it was our September Edition the short of it is the data are a little bit noisy, but but there is indeed some some sweeteners in some studies do result in that phenomenon. You describe the cephalic insulin response.
And I came away from the research that went into that which was a Herculean effort on the part of the team a little bit more confused than when I went in but being even more cautious around artificial sweeteners than I was going in so and not for the reasons that I don't necessarily I don't I didn't find any evidence that these things are cancer-causing right? So that's the headline stuff people worry
about. Oh that's weird ass like like 10
Like crazy. I came away more confident that from us from a long-term safety perspective in terms of matter in terms of you know, cancer and catastrophic outcomes like that. That was an 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 may therefore my takeaway was buyer beware use limited amounts only.
The one by the way, that's still emerge to me is a reasonable one. It's the only one that I use and I've talked about a lot is Xylitol.
Xylitol is the pardon me. I should say Xylitol for chewing so for gum and a Leo louse as an additive. So those were the safer. Yes. Those were those are basically the only two I will consume
y'all. I'll drink a Diet Coke every now and again if I'm on a plane or yeah, you know this law that got past few years ago. You can't bring liquids in of your own into the airport and on the plane like what a great you years ago. What a great scheme. What a great scheme to get
People to buy overpriced 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 use a little bit I drink things with a little bit of stevia and the occasional Diet Coke and I generally avoid sucralose. I don't like the way it tastes monk fruits too sweet. But yeah, we could we maybe we'll do a podcast on then the Future Okay, so I think we can wrap this paper because I
really will but tell me what you think about that point Andrew like
All I mean, you know, you know more about this stuff than I do. But if you had to just lay on your judgment, right, so if it were if it were a hundred 20, you would say the light is 100% causal in the effects were seeing if it were 0 to 100 you'd say nope. The behavior is 100% causal of the exposure to light. Where do you again? Can't know it. Yeah, what does your intuition tell
you?
Okay, there's my intuition and then there's my recognition of my own bias because you know, I started working on these circadian Pathways originated in the eye back in your in 98 as a graduate student at Berkeley the cells these melanopsin intrinsically sensitive retinal ganglion cells were discovered in the early 2000s by guy named McGee prevents. Yo Dave Burson samraat are Sachin pant and others but and it was one of the most important discoveries in all of biology clearly, so I've been very
Excited about these systems, but if I set that aside, so bias disclosure made.
I think 65 to 75% of the effects are likely due to light directly now. It's impossible to tease those apart as you mentioned, but to play Devil's Advocate against myself, you know, you could imagine that the depressed individual is laying around indoors with the curtains drawn. They didn't sleep. Well the night before which gives you a photo sensitivity that isn't Pleasant like it sucks that bright light in your eyes first thing in the morning if you especially if especially if you didn't sleep well,
And then there are you know, making their coffee in a dimly lit what they think is brightly lit environment. And then there you look at their phone and the state of the world Sox and their state of their internal landscape is rough and there maybe they're dealing with a pain or you know injury or something and their likelihood of getting outside is low and when they do get outside they're going to shuffle and you know, so I could see how the behaviors could really limit the amount of light exposure and then evening rolls around
They've been tired all day and a common symptom of depression. He fall asleep and then two or three in the morning, they're wide awake. What are you gonna do it two or three when you're Wide Awake sit in the dark? No, you're gonna get online. You're going to listen to things you might have I'm not recommending this but alcoholic drink in order to try and fall asleep. I mean, this is the pattern and so, you know shaking up that pattern is really what so much of my public health work these days is about and trying to get people onto a more natural daylight night.
Night dark Rhythm. But yeah, it's impossible that he's part. We do know this and this is really serious. We know that in almost every instance every almost every Psychopathology report of suicide in the weeks, but especially in the days preceding suicide that person's circadian rhythms looked almost inverted from their normal patterns.
And that's true of non bipolar individuals as well, you know, circadian disruption and disruption in psychiatric Health are inextricable conversely positive mood and affect and and circadian Behavior seemed very correlated. I mean, I think it's clear that if you want to become an early riser get light in your eyes and get activity in your body early in the day you built the UN train to those rhythms so that you start to anticipate that morning.
Out you start to anticipate the morning sunlight. Just one more scientific point we know that when you view bright bright sunlight in the morning or just sunlight that's illuminating your environment. As you said, you don't even have to see the sun itself that there's a 50 50 percent increase in the amplitude of the morning cortisol Spike, which is a good thing, right? That's where you want it because it's inversely real the amplitude of the morning quarters. All spike is inversely related to the amplitude of the evening cortisol Spike and high evening cortisol is associated with middle.
Night waking and on and on so, you know, I'm very bullish on these mechanisms. I also love that they're so deeply woven into our evolutionary history, you know that we share with single cell organisms and so wild but of course, there's going to be a bidirectionality there and it's impossible to see where one thing starts in the other one stops.
I mean, here's my take Andrew. First of all, I actually with far less Authority than you agree with your assessment.
Assessment and might even be a little bit more bullish might even put it at 80/20 and here I'll give you my explanations which stem more from my fastidious battles with epidemiology in general right? Like because so much of the world that I live in still has to rely on epidemiologic data. And so how do you make sense of it? And the truth of it is most of it is really pretty bad, but I tend to find myself looking at the Austin Bradford Hill criteria.
Area all the time and for folks who don't know he was a statistician who basically proposed a set of criteria believe there are eight of them and I can't believe I don't know every one of them off by Heart by certainly used to but the more of these criteria to there that are met within your correlations the more likelihood you will find causality. So when I think of your data here the data in this paper, I'll tell you what makes these correlations.
Seem to have causality within them in the direction that's being proposed. Look at the dose effect. So dose effect matters and this is done in quartiles. And that's a very elegant thing if they just did it as on off it would be harder hi-low. That's right. But the fact that he didn't quartiles allows you to see that every example in figure 2. I don't believe there is an exception to this,
you know, and I think also in the in the others
only there's only one exception to what I'm about to say. Sorry to out of like
God knows how many they're all monotonically increasing and decreasing in other words. The dose effect is always present. Another thing is biologic plausibility. You've spoken at length about that today. So in other words, sometimes you have to look at abedini ology and ask is there a biologic explanation and here there is you've added another one which is evolutionary conservation to the biologic plausibility. Then you can talk about animal models or experiments in humans over short durations that generally support these
These findings and so those are just a couple of the the Bradford Hill criteria that that lead to you know, my belief that yeah, there's reverse causality here, but it's not the full explanation. And that more of the explanation is probably the direction that's being proposed. And if that's true because then at the end of the day, like what's the purpose of the discussion the purpose of the discussion is if you are under the influence of any of these psychiatric
Missions in addition to the treatments you're doing now. What else can you do and to me the takeaway is follow these light behaviors. I mean, it's a relatively low lift and you consider some of the things like I'm over here asking people to do Zone 2 for 3 hours a week and vo2max workouts and all this other stuff and like I think all those things matter for mental health as much as physical health, but this strikes me as on the spectrum of low asks if it
It shows if it's only even 30% causality 70% reverse causality. Like I'll take those I would still in state that
yeah, and it's you know, it's taking your coffee on the balcony. It's and people will often say well, how do you do this with kids? The kids should be doing it too, right? You know, it means popping your sunglasses off. It means getting out for just a few minutes and the fact that it's additive that these you know, these Photon mechanism Photon counting mechanisms. They some is great and looky
This paper also says and I should have stayed this earlier. If you missed your daytime light ration, get your nighttime dark ration, they are independent and additive. So that's I mean that's a really something but of course ideally you get both by appreciate your take on it and you know, and thanks for for your expertise in parsing epidemiology. I look at fewer studies of that of that sort, but I learned from you and that's one of the reasons I love doing these Journal clubs is I learn so
So along those lines tell us about the paper you selected. I'm really eager to learn more.
Well, I wanted to pick a paper that was you know, kind of interesting is a paper and and this this paper I think is interesting in that it is kind of the landmark study of a class of drugs, but in the same way that you kind of picked a paper that I think has a much broader overarching importance. The reason I picked
This paper which is from New England Journal of Medicine. It's about 10 years old. No correction 13 years old is because it is kind of the landmark study and a class of drugs that I believe are the most relevant class of drugs. We've seen so far in cancer therapy. And even though the net effect of these drugs has only served to reduce mortality by maybe eight to ten percent which is not a huge amount.
Aunt it's the manner in which they've done it that gives me great. Hope for the future even if it's through other means so I'll take a step back before we go into the paper for again just the context and background so the human immune system is kind of a remarkable thing. It's hard when you're sort of trying to imagine. What's the most amazing part of the human system and maybe it's my bias as well because just as you
Spent you know your time in the in the light system and the photo sensing system. I spent my time in the Immunology world, but it is remarkable to me how our immune systems evolved and they have this really brutal task, which is how can they be tuned to
detect any
foreign pathogen that is harmful without knowing a priori what that could be while at the same. So in other words, how can you
You tune a system
to be so
aggressive that it can eradicate any virus or bacteria billions of years into the future without knowing what it's going to be. But at the same time it has to be so forgiving of the self that it doesn't turn around and attack the self. It's remarkable. And of course we can always think of the Exceptions. There are things called autoimmune conditions. So clearly the system fails fails and the immune system turns around and attacks.
Self if you see a person with Vitiligo, I have a little bit of Vitiligo on my back a couple of spots clearly the immune system is attacking something there and destroying some of the pigment
I didn't realize Vitiligo is
autoimmune. Yeah, if you know, they're so there are lots of you know, more serious autoimmune conditions, of course, you know, somebody that has lupus or you know, where the immune system can be attacking the kidney the immune system can be attacking any autoimmune conditions can be deadly, but fortunately they were very rare and for the most part this immune
Um Works remarkably well, so how does it work? And why is it that cancer seems to evade it virtually all of the time. This is the question. Now, let's first of all talk about how it works. And then when I tell you how it works, you'll say that sounds amazing clearly. It should be able to destroy cancer going to simplify it by only talking about one system, which is how T cells
Cognise and get activated how to T cells recognize antigens. So we have something called an antigen. So an antigen is an antibody generating peptide. So it's a it's a it's a protein almost always a protein they can be carbohydrates, but they're almost always proteins and they're very very small peptides. Like we're talking as little as nine amino acids, maybe up to 20 amino acids. So teeny tiny little peptides, but
it's
Raising that in
such a short peptide the body can recognize if that's Andrew or not Andrew. I mean when you again think about like weird we talk about proteins in Kill adult ins right? We're talking about proteins in terms of thousands of amino acids that make up every protein in your body and yet if it's samples a protein and sees that hey this little 9 10 15 peptide amino acid is not part of you. I know it's bad and therefore I'm going to
Irate an immune response to it. So we have what are called antigen presenting cells you have cells that go around sampling peptides and they will on these things called MHC class receptors bring the peptide up to the surface and serve it up to the T Cell. There are two types of these there's MHC class 1 and MHC Class 2. I only braces major histocompatibility complex. That's correct.
And we refer to them that way because they did because of the context in which they were discovered which was for organ rejection. So not surprisingly when you need to put a kidney into another person if that kidney is deemed foreign. It will not last long and the early days of organ transplantation were Rife with immediate rejections and by not not in a mean the immediate Tsar the ABO incompatibilities, but you know the sort of next layer of incompatibility.
He was MHC incompatibility which would lead to you know, within within weeks. The organ is gone as opposed to within hours. So you have these two classes of MHC you class 1 and Class 2 class one is what we call endogenous. So this is basically what happens when a protein or an antigen is coming from inside the cell. So let's consider the flu. So if you get the flu the influenza virus infects the respiratory
helium of your, you know, your larynx and that virus as you know, folks listening might remember from our days of talking about covid viruses can't replicate on their own. What they do is they hijack the replication Machinery of the host and they use that either to insert their RNA or DNA to replicate and in the process proteins are being made while those proteins are the proteins of the virus not of us so some of those peptides get launched.
These MHC class II MHC class 1 glove basically the glove comes up to the surface and a T-cell comes along and in the case of MHC class 1. It's a cd8 T-cell. These are what are called the killer T cells, right? And so this cell comes along and with its T Cell receptor. The T Cell receptor meets the MHC class 1 receptor with the antigen in it. And if that's a lock it realizes that's my Target and it
Begins to replicate and proliferate and Target those and that creates the immune response. And by the way, that's how it works. When you vaccinate somebody you're basically pre building that thing up.
So it would this fall under the Adaptive immune response or the innate immune
response. So this is adaptive. Yep. Innate is just these pure antibody response in the on the b-cell side. I won't get into that for the for the purpose of this discussion. The other example is MHC Class 2, and that's also part.
The Adaptive system or the innate system, which is more what we call the exogenous form. So these are peptides that are usually coming from outside the cell. So we're going to focus more on the MHC class 1 because this is peptides that come from inside the cell. Okay, so just keep in the back of your mind. If a foreign protein gets presented from inside a cell to outside a cell the T cells recognize that and they will mount a foreign response. And by the way, that's why we basically can beat
Any virus like if you consider how many viruses are around us the fact that we almost never die from a viral infection is a remarkable achievement of how well this immune system works.
We're constantly combating these virus
constantly. And by the way, we don't really have very effective antiviral agents but not like antibiotics like we have antibiotics up the Wazoo. I mean we're way better at fighting viruses and
bacteria. Can I just ask one question? I've always wondered about this to what extent is our ability to ward off virus.
On a day-to-day basis as an adult reliant on us having been exposed to that virus during development like like as I walk around today. Maybe I'll be exposed to 100,000 different viruses. Would you say that half of those I've already got antibodies to because I was exposed to them at some prior portion of my life. Yeah hard hard work with and the other ones. I'm just building up antibodies. Like I was on I was on a plane last night. Someone was coughing. So I was hiding and I'd covid awhile ago, so I wasn't too worried about that and I feel
great today, but you know, I just assumed that on that plane. I'm in a swamp of viruses no matter what and that most of them have already been exposed to since I was a little kid. So I've got all the antibodies and they're just fighting it back binding up those viruses and
destroying. Yeah. I think it's part that and I also think it's part of them that our body can destroy without mounting much of an immune response. So therefore your immune system is doing the work and it's yet. It's not mounting a systemic inflammatory response.
Response that you're not
sensing. So is it also a physical trapping in you know in my nasal epithelium?
Yeah virus. Yeah. So yeah, let like there you have huge barriers, right? So the skin, you know the hairs in your nose, all of these things are huge barriers, but assuming that still a bunch of them are getting in at least the respiratory ones. That's the other thing to keep in mind right there were certain viruses that are totally useless floating around the air right? There are certain viruses, you know, the virus is that most people are really afraid of you know, hep C Hep B HIV well,
You know if they're sitting on a table or floating around the air, they're of no threat to you. They have to be you know, sort of transmitted through the barrier. But again some of these viruses you're going to defeat without an enormous response and then some of them, you know, why is influenza quote-unquote such a bad virus, whereas the common respiratory cold kind of Sidelines you for a day. It's the immune response that you're feeling the worst the bigger the immune response to the virus the more you're feeling that you feel
Immune system going crazy, right, you know the interleukins that are spiking the third spacing that occurs to get more and more of the immune cells there that Spike of your temperature as your body basically tries to cook the virus. All of that stuff is your body if you doing. Yep, yeah, you're being drained and all this happening. So
one more point I'll mention just but just to close the loop on the autoimmunity. How is it that we learn not to attack ourselves? That's something called thymic selection that occurs in infancy. So you and I have a no good for nothing tiny little thymus that would be it's almost impossible to see these things. You know, when we used to operate on people, you know, the thymus is barely visible in an adult in a healthy adult outside of thymic tumors, but as a child and a child the thymus is
Large and the purpose of the thymus is to educate T cells and basically show the T-cells what self is an any T cell that doesn't immediately recognized it gets killed. So it's it's a really clever system where we basically teach you to recognize self very very early age. And if you can't do that you're weeded out and then the thymus in volutes thereafter because it's sort of served its purpose. Okay. Now let's talk about cancer.
So what do we know about cancer? So we know that again, you know cancer is a genetic disease in the sense that every cancer has genetic mutations. Most of those mutations are somatic which means most of those mutations are mutations that occur during the course of our life. They're not germline mutations
the germline being the eggs and sperm right? So it's all other cells and I love that you pointed out that, you know, there can be
The cancer can be genetic but isn't necessarily inherited right? In fact, it's really an addict and they think inherited right? Yes inherited as always genetic to some extent but genetic isn't always
inherited. Yeah. So there are a handful of cancers that are derived from inherited mutations. So Lynch syndrome is an example of that hereditary polyposis is an example of that where you have a gene that gets passed.
Through the germline and that Gene codes for a protein like all genes do and it's either you have too much of a gene or too little of the gene. So it's either a gene that promotes cancer and you have too much of that or it's a gene that prevents cancer and you have too little of it or a dysfunctional version of it. Right? So braca is an example that bracket is hereditary braca codes for a protein and the women and men but mostly the women that we think about who have a braca mutation that all
Some cases almost guarantees breast cancer. It's because of a defective copy. So it's like they don't get the protein that they need to protect them from breast cancer. So what do we know? Well, we know that and this is probably one of the most remarkable things I've ever learned and it still blows my mind every time well actually before I get to that point I want to make I want to make my point. Okay, so so you might think so cancer. We you know ourselves.
Um cancerous but they're clearly hijacked because they have these mutations and as a result of these mutations, they make proteins that allow cancers to behave differently and Cancers behave differently from non cancers into very critical ways. The first way is that they do not respond to cell cycle signaling. So if you cut your skin it heals, but how does it know to heal just right and not to keep growing and growing and growing
And growing and growing well 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 my when you don't need to give you meant that we could keep doing these. Yeah, that's right, um within months
you would regenerate a full liver. That's so
isn't that amazing. So while it's like a salamander you cut off a salamander Limb and please don't do that experiment because other people are doing
it anyway and it grows back as a status of knows how much to grow back.
So so so when the cell is perfectly functioning it knows how much to grow and it simple cancer losses that ability that is one of the Hallmarks of cancer. It just keeps growing doesn't grow faster. By the way. That's a misnomer people think cancers grow faster than on cancers. There's no real evidence that that's the case. They just don't stop growing. The second property of cancer is the capacity to leave the site of origin.
Go someplace else and take up residence. So that's metastasis the metastasis component. So if you think about it for a minute
a cell that never stops
replicating and has the capacity to up and leave and move and take up residence is clearly different from the cell itself. Right? So if I have a cell of colonic epithelium the cell that lines the inside of my colon. It's clearly got a set of proteins in it. But if all of a sudden that thing can grow grow grow grow grow not stop not stop not
not listen to the signal and then somehow wind its way into the liver and just keep growing and growing and growing. It must have different proteins. So the question then becomes why does cancer even exist how has our immune system not figured out a way to just silence this and eradicated the way it does to virtually every virus you encounter and to me this is one of the most interesting questions in all of biology and it really comes down to how clever cancer is unfortunately how
Generally clever it is it basically does a lot of things to trick the immune system. So it has its own secretor e factors that Tamp down the immune system it grows in an environment because of its nature. So one of the things that's long understood about cancer is it's heavily glycolytic and when something is heavily glycolytic it's going glucose to pyruvate to lactate non-stop. There are lots of reasons for that.
I think there's more than one.
What is that afford it? Does that well, so it's interesting is that for did a migratory potential know so
it's super interesting. So that's the effect that what I just described is called the Warburg effect and when Warburg proposed this which God was probably in the 1920s. It was before World War one before World War Two he proposed it because he thought the mitochondria of cancer cells were defective. So he proposed that the, you know cancer cells mitochondria.
Don't work, hence. They have to undergo glycolysis. They can undergo aerobic metabolism. We now know that that's not the case. So, we now know that the the Warburg effect or the varberg effect of referred to him correctly by his name almost assuredly does not have to do with defective mitochondria, others have proposed several mechanisms. I think there's probably more than one thing going on. So so so a paper that came out in 2009 very influential paper.
By a guy named Matt vanderheiden and Craig Thompson and Luke antley proposed that the reason that cancer cells do the Warburg effect is that they're not optimizing for energy. They're optimizing for cellular building blocks. And if you do the mass balance, it completely makes sense, like dividing cells need building blocks more than energy and glycolysis while very inefficient for generating ATP is much more efficient at generating substrate to make more cells, but another
Mechanism is exactly at this one glycolysis lowers the surrounding pH because of lactate lactate attracts hydrogen pH goes down and guess what that does to the immune system to tracks the immune system. So it's also a way to hide from the immune
system. So there's a like a pH cloaking. Yes leveraging pH to cloak. That's right a signal that the immune system would otherwise
see. Yep. And then when you layer on top of that that it knows how to secrete things like il-10 tgf-beta all of these other secretory factors,
That also inhibit the immune system. Basically, it's figured out a way to kind of hide itself from the immune system
the way you described it cancer. Sounds like a virus. Yeah. I mean, it sounds a lot like a virus and that leads me to ask are there any examples of contagious cancers? I recall seeing some studies about these little critters down in Australia Tasmanian devils that like they would they scratch each other and fight as Tasmanian devils do actually quite cute and they get
Cancers and tumors growing on
their face. Yes, so
and so it was it was this like 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 Hep B hep C, but they're even cancers like cutaneous cancers that arise from viruses, but
I don't know if that's quite the same as what you're
saying. Like no. No, it's in there both it what you're saying is an important point. I mean, we don't want to go down the rabbit hole of HPV, but right that's increasing susceptibility to cervical cancer. Now, there's a vaccine against HPV. Yeah, there wasn't when we were in college as we all knew. There was no vaccine, but the okay so but yeah direct transmission of cancers from one one organism to the next more rare. Yes. Okay. So
now here a moment ago I said there's
Really incredible thing about cancer that blows my mind and about our immune 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 50 years where his oncology made huge progress, it's made great progress in blood tumors leukemias and some kinds of lymphomas. In fact, there's two kinds of lymphomas where the progress has been remarkable.
One has been in Hodgkin's lymphoma. And the other has also been an immunotherapy has been in a type of b-cell lymphoma where that b-cell demonstrates or present something called a cd19 receptor. So in b-cell lymphomas with cd19 and you don't think there's a very unique Niche immunotherapy won't talk about that today called car T therapy that has got rid of those guys and then leukemias of also been pretty good but in solid organ tumors there have been
Only two real breakthroughs in the last 50 years one has been the therapy for a certain type of testicular cancer and it's really just a chemotherapy cocktail that has been found to work really well and the other has been in this really rare kind of gastric cancer called the GI stromal tumor which happens to result from one mutation in a kinase pathway and there's one drug that can now Target that and it works. It's kind of amazing cures that cancer. Is that what I'm talking about are they?
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 its lung. It's then breast and prostate in men and women. It's colorectal. It's pancreas. Those are the big five they kill more than 50% of Americans. It cancer was not certain. Let me restate that more than 50 percent of cancer deaths in Americans come from those five. These are what we call the solid epithelial tumors and you can March down the list.
Stand most cancers that most people are thinking of are those cancers. Well, here's the thing more than eighty percent of those cancers.
Have antigens that are recognized by the hosts immune system. I will state it again because it is so profound 80% at least of those cancers
actually generate an antigen
meaning a little peptide
in that cell gets presented to the T cell and it is recognizable. And now the question is why is
that not sufficient to induce remission and
The short answer is there are not enough T cells that are able to act and or they are being sufficiently inhibited from acting which gets me to the point of this paper one of the ways in which the body inhibits the immune system, which we should remind ourselves is an important thing right is something called the checkpoint inhibitor. Okay, so go back to that idea that I talked about before you have a nanny
In presenting cell it brings up an MHC receptor with a peptide on it. And there is a T-cell that is coming and I actually brought a diagram which we're going to I'm going to link to this but I don't want to make this too complicated but I really think that this figure is helpful to understand how these papers how these drugs work. So the MHC receptor with the peptide is sitting there and it binds to the TC T Cell receptor on the T Cell, but there is another receptor on the
The T-cell a ctla-4 receptor and that binds to a receptor that I won't bother naming now because it's the names don't matter but there's another receptor on the antigen presenting cell that binds to that and that acts as the brakes in the reaction. So ctla-4, which is on the T Cell binds to another CD receptor on the antigen presenting cell and it says Tamp down the response.
And the reason for that is we want to keep our immune system and check this basically is a way of asking the immune system system because remember when the immune system sees that antigen it wants to go nuts. It wants to start replicating and killing that this is a cd8 T-cell it is a targeted killer T Cell. The checkpoint says let's double-check that let's be sure. Let's Tamp down the response and as a result of that a thought experiment.
Urged, which was what if we block ctla-4? What if we block the checkpoint? Could we unleash the immune system a little bit more and
I will say this at the time
it was proposed. It seemed a bit far-fetched because of the complexity of the immune system. It seemed a little far-fetched that simply blocking the checkpoint would have any effect.
It's also worth noting that prior to this one immunotherapy had found some efficacy, which was trying the exact opposite strategy rather than blocking the inhibitor. It was throwing more accelerant at the fire which was giving something called interleukin 2. So interleukin-2 is for lack of a better word candy and fuel for T cells. So the idea was if we have T cells that in
lately recognize a cancer antigen. Can we just give high doses of interleukin-2 and have them undergo proliferation and response and the answer turned out to be yes, but only in two Cancer's melanoma and kidney cancer and only at very small levels about 10% of the population would respond to these things. Now look that's 10% of people who were going to be dead within six months because these are devastating Cancers and once they spread there are no treatments that have any
Efficacy whatsoever. In fact I think median survival for metastatic melanoma at the time was probably 4 months. So this was a very Grim death sentence,
but the idea now
was what about doing the exact opposite approach instead of trying to throw more fire at the T-cell. What if we can take its breaks down less gas? Pardon me instead of giving more gas. Let's give less brakes and there were some phase to some phase one studies that demonstrate efficacy face.
To and the paper I'm going to talk about today is the is the phase 3 study that compared the first version of these so so the drug we're going to talk about today is an antique ctla-4 drug called epilim AB, there is another drug out there that came along shortly thereafter. That is an anti pd-1 drug. So PD One turns out to be another
They're one of these checkpoints on T cells and the Nobel Prize. By the way, I think it was 2018 or 2019 in medicine or physiology was actually awarded to The two scientists who discovered ctla-4 and pd1 so you know this I believe this is the only Nobel Prize in medicine for immunotherapy. It's a very big deal. So this study sought to compare the
act of anti ctla-4 to a placebo and the placebo in this case was not a real Placebo. It was a peptide vaccine called GP 100 to ask the question in patients with metastatic melanoma. What would be the impact on median survival and overall survival? So let's talk a little bit about the paper. So again, one of the funny things about this is
I used to read these papers a lot Andrew these used to be this is me my bread and butter paper. So I mean, you know be you know reading these like I'm you know, it's a my hobby and and I don't read them that much anymore. So it was kind of amazing how long it took me to remind myself of stuff. I used to remember but you do have to kind of go back and read the methods and figure out
who were the patients in this. What was the eligibility criteria? Why did they do it this way?
And of course it all kind of came back to
to me, but it took a minute. So so the first thing is these are all patients who had progressed through every standard therapy. So these are patients for whom there were no other options these patients either had very Advanced stage three melanoma, which means it was local Regional melanoma, but it couldn't be resected. So an example of that would be a cancer that was
You know completely engulfing like where let's say the primary site was the cheek and it had completely grown into all of the surrounding soft tissue. It hasn't spread anywhere, but it was you know, all the lymph nodes of the neck and I've seen patients like this and it's you know, it's just completely disfiguring and they'd already been through the standard chemotherapy and nothing was working in the thing was growing and then it was mostly made up of patients with stage four cancer. Now melanoma has a very
funny staging system. So in cancer, we typically talk about something called the tnm staging system. It is the standard way that cancers are staged T refers to the tumor size n refers to the lymph node status and M refers to the presence or absence of metastasis. And for most cancers. It is a very simple system it is, you know, T is typically a number 12 sometimes up to three and four and is typically 0 1 or 2 and M is
0 or 1 either there's no Mets or there are mats. So for example in colorectal cancer, the T staging determines the depth in the colon wall that it went n is did it go to Matt's and I think in: I may be a little rusty on this I think: has n 0 1 or 2 depending on how many lymph nodes and then m0 did it go to anything beyond that like to the liver lungs Etc or not. Melanoma is a bit more complicated. It has M 0 meaning no Mets, but it also has a
m 1 a.m. 1 BM 1 C and M 1 D and within each of those it has a threshold for high and low lactate dehydrogenase or LDH. So it's both a staging based on Imaging and biochemical and the reason for that is LDH level is such a strong prognostic indicator of survival in addition to M staging higher LDH levels tend to reflect more acidity which we talked about why that's problematic tends to reflect faster-growing.
Tumors higher turnover higher metabolic activity M1A. Let me see if I can remember this M1 A's are Cancers that have metastasized to surrounding soft tissue or soft tissue or anywhere in the body. So anywhere else on the skin and you might think well, that's kind of crazy. Like how does that happen? And it's really bizarre. You can have a patient who had a melanoma that showed up in one part of their body and then they have metastasis on other parts of their
our skin m1b is I always get B and C confused. I think B is the lung so m 1 B is to the lung m1c is to any internal organs so liver Etc and m1d is to the CNS and as those numbers increase as those letters increase the prognosis gets lower and lower and lower. So one of the first things I always look at when I look at a paper like this is tell me about the patient population. Like what what was the you know, what?
A breakdown of patience and in table 1 so that's again in clinical paper's like this table 1 is always always always Baseline characteristics. Oh, I should mention one other thing Andrew this was done as a three two, one two, one randomization.
So again in the simplest form a study would have two groups, right you would have we're going to just have a treatment group and a placebo group. But in this arm you had three groups with one of them being the placebo the placebo got just GP 100, which is just a cancer vaccine. By the way. This is a cancer vaccine that never showed any efficacy. So it was a cancer vaccine that had been tested both with interleukin-2 directly.
And as an adjuvant for patients who had metastatic melanoma risks or had sorry, not metastatic. Melanoma had melanoma respected who were tumor-free and then given the vaccine as adjuvants to see did that have an effect on outcomes and it didn't so it's kind of a known Placebo. So you had that group then you had the anti ctla-4 group and then you had anti ctla-4 + GP 100
as rationale
for the three two, one two one. It's
Basically, it increases statistical power, right? So, you know, this total study was a little under 700 people they put 400 in the anti ctla-4 + GP 100 group and then, you know a little over 130 in each of the other two groups. So you're always going to be able to make these two comparisons, right what you can check by doing. This is is there any effective GP 100 in this setting which had never been done before so again,
Is a known protein expressed by melanoma and all of these people were haplotype to make sure that their immune system would recognize it and the question was would giving people anti ctla-4 i.e. Taking the breaks off their immune system with or without GP 100 make a difference. So kind of going through this you can see it sort of skews about 60% to 40% male-to-female. They talk about something called the ACOG performance status that
It refers to how healthy a patient is coming in. So e Cog 0 is no limitations whatsoever, which is kind of amazing when you really consider something. I think this speaks to just how devastating this diseases. These are patients who all have like six months to live, right, you know a year Max and yet look at this 58 to 60 percent of them have no limitation on their quality of life at this very moment that's going to change dramatically, you know absent a cure here.
Many Cog one has some limitation and you can see that ACOG 1 plus e cos 0 is basically 98% of the population. You can see the staging their so again, very very few of these patients are the m0 category M. Zeros are people who have stage 3 disease that is so aggressive. It can't be respected. That's about 1% But the majority of these people are the M1. Asm1 bees em, once he's so these are people with very aggressive cancers. You can also see that
That about 10 to 15 percent of these people also have CNS metastasis. He's again the poorest prognosis of the poor and then you can see the about 40% of them have the LDH level above cut off. All of this is to say we're talking about a group of patients who have a very high likelihood of not surviving more than you know a year it would be very, you know,
It that many of these patients would survive more than a year. So so basically more than 70 percent of these people have visceral metastases. He's a third have high LDH and 10 more than 10% have brain Mets. They've also all progressed through standard therapy. So
radiation chemo.
Yeah and the chemo for for for melanoma can be, you know, kind of toxic chemo that 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,
you know, it's interesting. I think you're referring to the GP 100 and I think the thinking was okay. It hasn't been effective in other treatments. For example, when combined with il-2 or as an adjuvant, but never before has it been tried with a checkpoint inhibitor, which is the technical term for this.
Type of drug. I think there was also some belief that it would be easier to enroll patients. I don't think they stated this but that's often the case. It would be easier to enroll patients. If they would know that even in the placebo arm. They're still getting an active agent
got it and I suppose there's always the possibility that the combination of the failed drug with a new drug would work and then so you're increasing the probability for novel Discovery
for sure. And again, if you go back to the
Randomization of three two, one two one. It's really only one-fifth or 20 percent of the participants that would get just the GP 100. So in other words, you're basically telling people when they come into this study, there's an 80% chance you're going to get anti ctla-4. That's a much better set of odds than you know, your typical study where you're going to be fifty percent likely to get the agent of
Interest right in people who are literally
Dying of cancer that they they don't want to be in the control group,
right? That's right. So the primary outcome for this study actually changed in the study now they have to get permission to do that. But the so the original primary endpoint was the best overall response rate. So I have to explain how response rates are measured. This is this is a bit complicated remember all of these patients by definition have measurable.
Able cancer by visible either on the surface of their body but more likely on an MRI or CT scan. So all of these patients had to be scanned head-to-toe within 12 weeks of enrollment again, there's another thing I should point out here, which I know you understand but it's always worth reminding people when a study like this takes place. It usually takes place over many years and so it's not the case that all 700 of these patients were enrolled on the same day and finished, you know, we finished observing them on the same day. No. No this took place for a very long period of time.
This took place across tens of centers. I can't remember if this was just globally or across the world. It might have been across the world. And so every Center really needs to adhere to a very strict protocol and you have a central organization that is running this so you have a drug company. I think this is Bruce term Bristol-Myers Squibb that makes the drug they provide the drug and then you have a cro or clinical research organization. That is basically managing the trial and the trial is being
Being done at Cancer Centers all over the world are all over the country and you know enrollment I think began in 2008 for this no. No, I think it completed in 2008. It probably started in about 2004 2005. And therefore you had to kind of have real clear protocols around the so a complete response is the easier of these to understand a complete response is everything vanishes completely that's very rare in cancer therapy. So
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 50% reduction by diameter because remember in this type of Imaging you're looking at 2 D versus 3D. So if you're looking at a lung lesion and it's this big it had you know, if it's 2 cm long it has to go to at least one centimeter in diameter.
Amateur so it's a 50% reduction at least of every single lesion with no new lesions appearing and no lesions growing. So it's very strict criteria right against ER means everything vanishes Pyaar means at least a 50% by diameter which by the way is a much bigger diameter much bigger reduction terms of tumor volume. When you consider the linear versus the third power relationship of length and volume of every single lesion.
Nothing new appearing regardless of how small and no lesion growing. So that's a PR. So you basically have no response progression your we talk about those together and then partial response and complete response. So initially the the authors of this study we're going to change the primary endpoint of this was going to be the best overall response rate. So what was the proportion of patients that hit PR? What was the proportion that hit a CR? That's very
Common in this type of paper where the outcomes are typically so dire. However, oh, I think I said, I think I said that the study was I don't remember when the study ended but the amendment was made to change the primary endpoint to overall survival at some point during the study. So and by the way that tends to be the metric everybody cares most about so the overall survival
or metastatic melanoma is 0 with the exception of people who respond to interleukin-2 high-dose interleukin-2 and that will boost the overall survival rate to somewhere between eight and ten percent very very low these patients many of whom had already taken and progressed through interleukin-2 Let me refresh my memory on what percentage of those
as patients about a quarter of these patients had already taken high dose interleukin-2 and by definition the fact that they're in this study means they had already progressed through that that treatment had failed just reiterate just kind of the state these patients are in. So now let's look at Figure 1. So again, I'll describe it because I realized many people are just listening to us. All of this will be available both in the video and then we'll link to the paper.
So figure 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 kaplan-meier survival curve. So on the x-axis for this curve is time and time here is shown in months. And on the y-axis is the overall survival the very top 100 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 GP 100 the anti ctla-4 Group by itself and the anti ctla-4 + GP 101 of the characteristics of a kaplan-meier curve is by definition. They have to be decreasing in a monotonic fashion because it's cumulative overall survival. That just means it can't like come down and go back up. Nobody comes back to life. So once a person dies, they are censored from the study.
And the curve drops and drops and drops and you can see that they kind of highlight and I actually think it makes the graph a little harder to read when they when they put some of those marks on there. But what really becomes clear when you look at this is that there's a key. There's a clear distinction between the curve for the placebo group the GP 100 group and the other two the two treatment groups now you'll note at the very end that the to
eat meat groups appear to separate a little bit. I'll talk about that in a second. So when I look at these Andrew, I'm the first thing I always turn my attention to I can't resist. I have to look at the right-hand side of the graph because what does that really telling me? Right the tail of this is showing me the true overall survival and I want to sort of figure out what is going on. So in the GP 100 Group, which is the placebo group it is kind of amazing to think that there is still one person who is alive at Forty Four.
It's amazing. I mean it's both sobering and amazing that like one person made it to 44 months. The next thing I ask myself is well how long did half of the people make it that's called median survival and to do that you go up to the y axis and you draw a little line from the 50 over and then you bring that down and that's you know, that's that's that's awfully low. It's about yeah, in fact the table will tell us
exactly what that is because I think it's really hard to eyeball that stuff. So let's go to so there's always a table that will accompany these things and let's pull up that table. I've got this paper spread out over so many things that's Adverse Events. Whereas our survival table here your to
subgroup analysis of overall survival.
It would probably be helpful if I stapled these things together because it would
be well. This is always a trade-off actually for since this is a journal Club episode. I will say that stapling helps but it also prevents one from separating things out writing in the margins. I like these little mini clips. Yeah, no Financial relationship to the mini clips either just out to state that because I always get if you don't say that people go you must have a stake in these mini clips. I like these little mini clips. In fact, I'm such a nerd. I always have one of these pilot.
V 7s in my Pock on my pocket of my hip and then on my pockets are always filled with with these little mini clips. And but then again, I have a friend who's a musician he's and he's always raining guitar picks. So, you know, it's a as far as occupational hazards go of being a nerd
then all I went to clubs are a big fan of the mini clips as well. But I went without a today. Alright, so thank you. Yes table to all right. So so let's look at table to while looking at the kaplan-meier curve because now this allows us to see a couple of things by the way.
Remember how I said there's like that one person who kind of is still alive in the treatment group. Well, you can tell that he's not a complete responder he or she is not a complete responder because under evaluation of therapy in table 2 it says best overall response and it says complete responders 0 so there is zero complete responders in the placebo. There were two partial responders again at partial responder is
Some lesions got smaller. Some got bigger stable disease is it didn't really change that much and Progressive disease is obviously it went beyond not
devalue say partial response. I could lesions got smart. They literally just tracing the the circumference of one of these, you know skin lesions and saying okay got bigger
special. We'd literally beat had rulers in claggy. Yep. Yep
Fisk this feels so crude in terms of like like, I mean it makes total sense.
Suns by like in terms of like modern medicine, oh like your lesion Grew From like 3 mm to 6 millimeters on it. We're literally like drawing little boundaries around little blotches on the
skin. Yeah, you're putting a little measuring tape on them. Now again, most of these are happening in the Radiology Suite because most of the disease for these patients is inside the body remember more than 70 percent of these patients had visceral metastasis. So liver soft tissue lung brain, you know, these are in fact if you include low
Liver brain and viscera. It's it's all pretty much all the patients. So most of this is looking at a CT scan or an MRI for the brain got it. Okay, so that's that's kind of the first thing that comes up the median response rate should be shown pretty prominently here. So I'm looking through this and that the where is median response. Maybe it's shown in a different table. Let's see.
see
. Disease Control rate time to progression
I remember it's about 10 months, but maybe that's just in the text. Yep. Here it is. So I thought this would be in a table, but it's it's on page seven fifteen of the paper. It just reports it. So, I'm sorry I misspoke the 10 months was for the anti ctla-4 + GP 106 point four months for the GP 100 alone. That's the control and then 10.14 the
Auntie ctla-4 alone. Okay. So again, I always and I get I'm just always doing this. I'm kind of going back to the paper to be like, does that make sense? And yeah, you kind of called it right? You said median survival was about eight. Well, it turns out it's actually like six and change because because it has that little ding in it and it's out to a little past ten on the two other. So the net takeaway here is again just to put that in English because it's so profound 50% of the patients in the control group were dead in
as months 50% of the patients in the treatment group. Both treatment groups were dead in 10 months. So what that means in cancer speak is these drugs extended median Survival by four months.
Now that's a that's an important concept. You know, when we think about how has cancer therapy changed over the past 50 years median survival for metastatic cancer has increased across the board. So a person today with metastatic colorectal cancer or a woman today with metastatic breast cancer or person with metastatic lung cancer. These people will live longer with those diseases today. Thanks.
It's mostly two treatments. This is not an early detection lead time bias issue. This is treatments are allowing people to live longer and that's an important part of the story but it's only half of the story yet. It often gets touted as the story the other half of the story and frankly the story that I think is more important is what is overall survival doing and if you go back to those cancers, the answer is zero.
So overall survival hasn't changed for solid epithelial tumors it is it was 0% in 1970 and it's zero percent today. Everyone dies. Everyone dies from metastatic solid organ tumors. Now again, there's those there's those Niche examples I gave you testicular cancer is now an exception GI stromal tumors would be an exception and I'm not including leukemias and lymphomas were now there are exceptions.
Okay Within
In not to try and be overly optimistic, but if I look at the graph in Figure 1 and I look out at the tail of the graph. That's right. And for those are just listening what I see and I'm far less far less familiar with this type of work and this analyzing these type of data. But what I see is that people in the placebo group They're All Dead except that one. Yep. They basically all dead at forty four months. Yep, but when I look at
Number how long it takes for everyone to be dead in the true treatment groups. It's like 50 looks like 53 54 months
or so and they're and they're not dead. That's the
point they're hanging in there. Right? So because you know an extra somebody who lost both of my scientific advisors two of the three the other one to Suicide we've talked about this before but the other two different cancers both had the bracket 2 mutation, by the way.
You know an extra eight to ten months with your kids or with your spouse or to quote unquote get your Affairs in order is is a big deal. I meant still depressing the sense that nobody survives long term, but you know an extra 10 months as long as one is not miserable in that time completely miserable. I mean that's extra 10 months of living. All
right. Well and what's interesting here is you know, the observation period stops and some of these patients are still.
Going so what you're highlighting is kind of the point. I want to make which is overall survival is the most important metric and it's the highest bar make no mistake about it and it's certainly not the bar any drug company is ever going to want to talk about for a cancer drug, but why not because because they don't none of them work, right? Like we don't have you know, like
draw only want to talk about cures. They don't want it. So they only let's talk about
median survival. They want they only want to talk about extending median survival.
And you know, there are you know, lots of people out there that are on this on this platform. I don't need to get on to it, but who will say like, look it's a real racket ink in oncology today where drugs that are extending median Survival by four weeks are being put on the market at a tune of you know, 50 to 100 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 40,000
dollars and
Advertised as significant
yes extent because it was that that was a statistical significant Improvement in median survival time. Just yeah, so it's a look it's really understandable why people are very skeptical of the Pharma industry and I think you know a much more nuanced view is necessary. Clearly. I don't think Pharma is all bad, but I really understand why people lose faith in Pharma when when you know, these types of products somehow make regulatory approval
does insurance cover these kinds of
drugs.
It can in fact it often does it depends on the FDA approval of course in the indication but a lot of times they do right? So yeah, there's a societal cost to these things. But but there's also a patient cost right? So a lot of times insurance doesn't fully cover it and a patient has to Bear the the cost difference and on top of that you alluded to this a second ago, which is what if your quality of life is dramatically compromised as a result of this treatment. And yes statistically you're going to live nine days longer or three weeks longer.
But at what cost to your health in those final remaining days and by the way, you're potentially straddling your loved ones with enormous debt in your absence. So it's a super complicated
topic. There's a dignity component to I may have seen this in people dying, you know at some point they become such a diminished version of their former selves that they don't want to be seen by people that
way. So what is exciting about this
This drug, although it's this paper is not the one that shows it. The reason I chose this paper Andrew is because it was the first approval a second drug came along. That is an anti pd-1 drug. That drug is called Kate Ruda that drug turned out to be even better and had it has even a greater response rate both in terms of median survival and overall survival, but this was the landmark paper. I also have a slight bias here with and I'll disclose
I was in a moment why but I think it just talks about very interesting biology. So let's talk about a couple things that stick stuck out to me in this paper the first thing that stuck out to me and the author's didn't comment on it unless they did and I missed it is look at figure to so figure 2 is the subgroup analyses where you're sort of showing a similar graph to the one you showed earlier.
Right where you you show the response rate or the change in response between the groups and then you put the error bars on it. And this is where we talk about how well it's a 95% confidence interval. So it does it touch the unity line. So these are called like tornado plots typically and what you'll notice is that in the top you're looking at sort of commits comparing the anti ctla-4 with
P 100 versus the GP 100 and in the bottom you're looking at the ante ctla-4 versus the GP 100. So at a glance you can see GP 100 is not doing anything. I mean that's that's the first takeaway of comparing a to be what I find. Most interesting is look at the subgroup analysis of females notice that in females while there's a trend towards risk reduction and this is risk reduction for overall mortality. So again, I just want to restate that the primary output
Come of this trial was changed to overall survival, which I think is the better outcome by the way, and overall for all patients in when you compare anti ctla-4 plus Placebo versus placebo. There was a 31 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 kaplan-meier
curve living longer living longer and it sounds like a big difference.
And in some sense big there's some sense. It is a big deal. It is for those people because you're
really looking at basically 0% surviving in the placebo group versus 20% of people are still alive at fifty six months in the treatment group, but look that means 80% have died, right but notice that and and sorry when you just look at the anti ctla-4 + GP 100 in the subgroup be that
Hazard ratios even showing more compression. It's a 36 percent reduction in risk of death. But notice that the females did not reach significance. So in the in the first group they barely do and you can see that because the confidence interval runs from point five five two point nine two and notice the error bar almost touches the line and in the second one, it does not reach significance at all. So I actually went and kind of did a little reading.
On this after and I said, hey, you know, how much did this study was this an outlier study and it turned out it wasn't and that about half the studies of anti ctla-4 did indeed find that the drug was less effective in women than men which I found interesting now. I couldn't find any great explanation for it. But the most plausible explanations fit into two categories. The first are maybe there are differences in the immune response to the
Rug, if you're a man or a woman the second comes down to dosing I should have said this at the outset, but of course these drugs are not like a pill where it's like everybody gets, you know, 50 milligrams of this. They're all dosed based on weight. So this study is dosed. I believe it three milligrams per kilogram and because most men are heavier than women men are getting a higher dose than women and weight and body surface area and immune system like these things are not all
Lee linear so I kind of wonder if this difference is simply explained by men on average getting a higher dose than women
interesting.
Last
thing I want to talk about here is in table three. So table 3 always an important table to look at in any paper is what are the adverse outcomes right where the adverse effects of the drug? Yeah.
I spend some spend a little bit of time with this and I confess it. Yeah. I definitely don't want cancer to the extent that I can avoid it, but this table made me wonder whether or not I would also want to just avoid cancer treatment given
The life extension provided I mean these Adverse Events are pretty uncomfortable.
The sound was just to put just to put in perspective and you always have to kind of, you know be mindful of how many of these adverse events are occurring in people just because their disease is progressing. So the first thing I always want to look at is total Adverse Events in all three groups. Not just great. So grade 3 in grade 4 are real toxicities right great for toxicity is life-threatening toxicity, by the way.
Grade 3 is pretty significant toxicity grade 1 and 2. We typically just you know, that's not that severe rent a little rash to put some corticosteroids on it. It went away kind of thing. Okay. So in the treatment + GP 100 group 98.4% of people reported some event so all but one point six percent in the NT ctla-4 group alone. It was 96.7% So only three point one percent did not but in the placebo group, it's 97 percent. So it's
Gonna Keep in mind like oh, 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 for toxicities. There were six point one percent of those in the placebo group 8.4% in the anti ctla-4 group and 6.8% in the combined group. So not a huge difference in grade 4 toxicity. Meaning that
whatever adverse events are occurring may not be
Later to
the may not be related to the treatment again. These are if you think about it, and it's a very awful sad morbid thought to imagine. These are you're looking at the adverse responses of people more than 80% of whom died during the course of a very very short study. And so, you know, it's very difficult to disentangle what effects or what side effects a person is having just from that process as they are from the actual treatment, but if there is an area where there's a really clear
We're difference. It's down in the autoimmune category. So if you look at any immune related events, you can see that in the anti ctla-4 + GP 100 group. It's about 60 percent in both of those treatment groups versus 30% And if you look at the grade 3 and 4 toxicities, it's 10% in the anti ctla-4 15% in the anti.
Alone group and only 3% in the treatment. So that's our real difference.
It makes sense that people getting this drug plus Placebo or just the drug would have autoimmune issues because this is an
immunotherapy. It's an immunomodulator. In fact, what is it doing? It is taking the brakes off the immune
system. But then again the things that they list out pruritus, is that a
irritation. It's yeah irritation of the skin
Notch physician, but I know that any
this is going to be like an inflammation and Oma unfortunately likely a cancer cell replication. Look at the difference in Vitiligo I go. I mean wow. Yeah. So very very
sorry. Sorry. Look at the gastrointestinal differences. Yeah and the Vitiligo, right? So 3.7% 2.3 percent point eight percent. The GI stuff is the most common stuff. You're going to see there. Those are those are the really big
ones now, of course, there's diarrhea and there's diarrhea. Oh, yeah. I like those travelers diarrhea.
Ya know these Aiden overly. Yeah, and these people and I mean for diarrhea and then there's like can't really do anything besides make trips back and forth to the bathroom.
Well, there's there's there's put it this way. There's you know colitis here is diarrhea. So significant these patients require IV fluids. Now, what what you don't see here is how many of these patients actually required corticosteroids to reverse the autoimmunity. So a lot of times what will happen here in these studies or with these drugs is the autoimmunity becomes so significant that you have to stop the drug and give
Steroids do the exact opposite you now have to shut the immune system down. So you just took the brakes off it with the drug. And now you need to shut it down with corticosteroids when I was was I invented know when I was in my fellowship. I wrote a paper about autoimmunity correlating with response rate in NT ctla-4 early on this was during the phase to work.
So so the NCI was a very early adopter of participating in these trials and you know, it was observed that at least hypothesize. This is what the paper basically wrote about which was is there any correlation between autoimmunity and response and it turned out the answer was yes, there's a very strong correlation. So there was no difference in autoimmune.
Immunity between the doses and the sort of paper we wrote was to dosing schedules. So it was basically the full dose the three milligrams per kilogram versus a low dose 1 milligram per kilogram. This is a phase 2 trial. Those are your two arms. They're turned out to be no difference in autoimmunity between them but there was a big difference between the response rate that tied to autoimmunity in other words autoimmunity predicted response now, I think
Over time these investigators the doctors who administer these treatments are getting better and better at catching these things earlier because these autoimmune conditions can actually be devastating. So on a very personal note when kite Ruda came out. I want to say it was around 2000.
Eleven. Oh, no. Oh gosh. It must have been 2013-2014 thereabouts again. It was for treatment of metastatic melanoma. I want to come back and explain why melanoma gets all of the attention in autoimmune condition in immunotherapy conditions all state that but but anyway a friend of mine got pancreatic cancer and he got the bad type of pancreatic cancer. So this is and like the
No, carcinoma the pancreas. So this is a non-survivable type of cancer furthermore his was unresectable. So explain what that is. Yeah. So the own so about 20% of people who have pancreatic cancer technically have it in a way where you could still take out the head of the pancreas, right? The Whipple procedure Whipple procedure right now tragically, most of those patients will still
recur. My understanding is that pancreatic cancer progresses from
anterior to posterior in the pancreas and that the Whipple is a removal of the front and the anterior. That's the Whipple procedure. So if the cancer has progressed far enough caudle into the posterior pancreas, then there's nothing left to cut out basically. Well, we survived without a pancreas for any amount of time. Oh, yeah. Absolutely. Why don't they just remove the whole
pancreas? Oh, that's my point. It's already micro metastasized. So it's not the surgical procedure is not the challenge anymore. It used to be so.
You know Johns Hopkins, which is one of the hospitals where this was pioneered like the the 30-day mortality for a Whipple procedure was I don't know 80% and the reason was to figure out how to suture a pancreas to the bowel without the so the pancreas is such an awful organ to operate on because it's enzymes are designed to digest anything and everything. So imagine now you have to cut the pancreas.
In half take out the head of the pancreas with the duodenum and then somehow so that open half of a raw pancreas to the end of the jejunum and not let it digest itself
someone at Hopkins figure this out.
Now. The first one was actually done by a 0 Whipple but yes at Hopkins is where they figured out the way to put drains in the surgical technique how to do it in two layers what type of stitches to use like all of the new
Census of this were worked out in a few places, but I would say Hopkins more than anyplace
else in our their Physicians you like try this on non-human primates or something or is this always just done on patients and
it well nowadays. I mean put it this way even 25 years ago at a at a major Centre like Hopkins the the mortality of that procedure is less than 1% Amazing. Yeah, it's told them in some victories. Well, yes, but here's my point it that that's no longer the bottleneck right taking out the pancreas safely as
complicated and challenging is that it is and if you need a Whipple procedure, you only want to have it done by someone who just does that night and day because it's you don't want Weekend Warriors doing it. That's not why people are living or dying they're dying because the pant 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 pancreas or the head of the pancreas or the tail of the pancreas the location of the tumor is predictive of survival.
Only in the extent that it basically is a window into how soon did symptoms occur. So pancreatic cancers in the tail tend to be more fatal, even though their way easier surgically to take out because by the time you develop symptoms of a tail pancreas cancer, it's a big cancer.
So I was going to ask this question later, but I'll just ask it now given the link between the immune system and these cancers is there.
Are an idea in mind that people who are let's say 40 and older or 50 and older who don't yet. They're not diagnosed with any cancer would periodically just stimulate their immune system to wipe out whatever early cancers might be cropping up, you know, just take a drug to just ramped up the immune system even to the point where you start out a little diarrhea maybe a few skin rashes and then come off the drug, you know, just basically to
Fight back whatever little cell growths are starting to take place in skin or liver or you know, maybe for you know, three weeks out of each year. I mean why
not? That's an interesting question. I've never thought of it through that lens. I suppose the question is what can we do to keep our immune systems as healthy as possible as we age
because on a normal circadian schedule there's evidence for that
sure know there's evidence that certainly if it promotes sleep anything that promotes
oats better rest is going to promote immune health because if you ask the macro question, which is like, why does the prevalence of cancer increase so dramatically with age there are certain diseases where it's really obvious why the prevalence of the disease increases with
age? Yeah, like mac like age-related macular degeneration
sure or cardiovascular disease is by far the most obvious because it's an area under the curve exposure problem the more exposure to lipoproteins and more the endothelium gets
Edge the more likely you are to accumulate plaque and it get it totally makes sense. Why 10 year olds don't have heart attacks and 80 year olds do
but when you sort of acknowledge that well, hey, you know, you know anybody's acute accumulating genetic mutations were always surrounded and being bombarded by things that are altering the Genome of ourselves. Is it simply a stochastic process where the longer you live the more of these mutations you're going to occur until at some point. One of them just wins. I think that's got to be a big part of it, but I think another part of it and I clearly am not alone in thinking this is that our immune systems getting weaker and weaker.
We age right? I mean, you know, we people become more susceptible to infections as they get older and I think that that's equally playing a role in our susceptibility to cancer. So yeah, I think the question is how do you modulate immunity as you age? And to me that's one of the most interesting things about rapamycin potentially is that when taken the right way it seems to enhance cellular immunity which again that that's potentially a really big deal yet at least
in short term human experiments in response to vaccination. It's enhancing vaccine response. So the question is would that translate into cancer. Nobody knows could that be one of the reasons why animals treated with rapamycin live longer and get less cancer don't know, you know, it could also be that it's at a fundamental level that's targeting nutrient sensing where I was going with that story was that
Maybe I'll back up for a moment why melanoma so we didn't really know this like 30 40 years ago in the early days of immunotherapy. But what we know now is that most cancers probably have about 40 mutations in them. That's like ballpark 4050 mutations is standard fare for a cancer. But melanoma happens to be one of the cancers that has many many more mutations and
More mutations that cancer has the more likelihood that it will produce an antigen that's recognized as non-self and that's why in the early days of immunotherapy. The only things that worked were il-2 against metastatic melanoma and kidney cancer because kidney cancer turned out to also be one of those cancers that for reasons that are not clear produced hundreds of mutations. And so it's no surprise that the early studies of checkpoint Inhibitors were also done in
Metastatic melanoma where you basically have more shots on goal again. If I'm going to take the brakes off my immune system. I might as well do it in an environment where there are more chances for my T-cells to find something to go nuts against so it's 2013-2014 and this friend of mine who has something called Lynch syndrome, which is a one of those few hereditary or germline mutations that results in a huge increase.
The risk of cancer he had already had colon cancer at about the age of 40 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 they said yeah, we nothing we can do like it's too advanced. So that's you know to put that in perspective. That is a death sentence and that's not that's a that's a six-month survival.
Oil and at around that time there was a study that had come out in the New England Journal of Medicine that had talked about how patients with Lynch syndrome had lots of mutations. And so we you know talked with his doctors about the possibility of enrolling him in one of the kite Ruta trials. There is one going on I think at Stanford and be you know, the thinking being well, you know, you would want to Target a checkpoint inhibitor against somebody who has a lot of mutations and even
Typically, we don't see that in pancreatic cancer. His is a unique variant of it because it's based on this and so sure enough. He was tested for these mismatch repair genes. He had them enrolled in the trial and amazingly had not only a complete regression of his cancer and he's still alive and cancer-free today ten years later, but the 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 pancreatectomy based on his immune system. So now he actually has Type 1 diabetes is no pancreas projects insulin. Yeah or no. He's no no he has to use insulin just like something I
planned I had to pick being alive with type 1 diabetes and of
course the no comparison, but it's just an interesting example of how you know remarkable. This treatment was able to work when you were, you know, you could completely unleash the immune system of a
And you eradicate the cancer and the rest of the cells around it and you know, there are many organs we could live without you know, there are certain organs. You can't live without you. I can't live without your heart lungs liver kidneys, but but many things that kill people arise from organs the breast you could live without all breast tissue prostate prostate you can live without all the frosting
digit would choose to do to live without these but I'm
saying if you had metastatic cancer and you
Had a bullet that could selectively Target at issue you would take it. And right now the only tissue we can do that against is a cd19 b-cell and that's what those car T cells are. So right now these are not tissue specific treatments, but their mutations specific what the last thing I'll say about this paper that I found interesting and I was looking for it and I was surprised they didn't at all comment on if there is any correlation between autoimmunity and response. Hmm, so they obviously acknowledge the autoimmune.
City in in table three, but I would have loved to have seen a statistical analysis that said hey, is there any correlation between response rate and autoimmunity but they didn't comment to that effect. So we're left kind of wondering what the current state of that is and I guess in summary. I'll say that the reason I thought this was an interesting paper to present is that I still believe that immunotherapy is probably the most important hope
We have for treating cancer and while I think we're still only scratching the surface of it. So collectively the overall survival increase for patients with metastatic solid organ. Tumors is about eight percent better than it was 50 years ago in virtually all of that has come from some form of immunotherapy I think is promising and I think the Holy Grail is that it meaning the next step if you go back to where we started the discussion.
Sharon is coming up with ways to engineer T cells to be even better recognizers of antigens and there's many ways to do that one is to directly engineer them. Another is to find T cells that have already migrated into tumors. Those are called tumor infiltrating lymphocytes or till and expanding those and Engineering them to be better and younger.
Is it possible to engineered?
Our own T cells to be more pH very intolerant meaning since this, you know cloaking of the of a local area by changing the pH can could we you know, pull some T cells. I'm always saying about the inoculation stuff like pull some T cells as part of our standard exam when were 30 and you know and grow some up in an environment that the pH is is slightly more acidic than than normal and then reintroduce them to
Audio, I mean after all they are our T cells in other words give them a little opportunity to evolve that the conditions they can thrive in right or even just keep them in the freezer in
case we have some so the interesting thing is I don't know that if you just got them to be comfortable in a lower pH it would be sufficient because there are still so many other things that the cancer is doing as far as using other secreting factors.
It seems that by far the most potent thing comes down to expanding the number of T cells that recognize the antigen and making sure that you can get that number big enough without aging them too much. So in some senses, it has become a longevity problem of T cells the way to think about it is you want an army of soldiers who are wise enough to recognize the bad guys which comes with age
But young enough to go and kill and right now both extremes seem to be unhelpful right when you go and find tumor infiltrating lymphocytes in a tumor. They're very wise they know which one they've demonstrated that they can do everything. They can outmaneuver the cancer, but they're too old to do anything about it. And when you take them out to try to expand them by three logs, which is typically what you need to do expand them by a thousand fold the can't do anything about it.
And what about avoiding? Melanoma altogether, I
Obviously avoiding sunburn, you know, I somehow I got couched as anti sunscreen and that is absolutely not true. I I said some sunscreens contain things that are clearly immune disrupt endocrine scuse me disruptors and we're going to do a whole episode on sunscreen. Maybe we could do some
tricks for the I think I'm actually planning something on that as
well. I want yeah, I mean and some dermatologists reached out some very very skilled dermatologist reach out and said that indeed some sunscreens are downright dangerous, but of course melanoma is
Dangerous physical barrier no one disputes physical barriers for sunscreen, right everyone. Everyone agrees that that is unlikely to have endocrine disruption. So physical barriers are Undisputed but aside from limiting sunlight exposure to the skin. What are some other risks for
melanoma? I mean, I think that's the biggest one. I do not believe that smoking poses a risk for melanoma. And if it does it's going to be very small there are hereditary cases. So one needs to
be pretty mindful when taking a family history. And by the way, there are really weird genetic conditions that link melanoma to other cancers such as pancreatic cancer, by the way. So whatever I'm taking somebody's family history and I hear about somebody that had melanoma and some of that had pancreatic cancer. I'm there's a couple genetics genetic test will look at to see if that's a person that's particularly sensitive just and a from a genetic predisposition, but I do think that first and foremost it's and
The way I
think with melanoma that although it's not completely agreed upon. I think it's less about sun exposure and more about sunburn. Right. So and again, I'm sure there's somebody listening to this who will chime in and apply a more nuanced response to that. But I think there's a there's a fundamental difference between a mountain the sun getting Sun making some vitamin D versus I'm getting scorched and under you know, undergoing significant UV damage there.
Might also be something to be said for the time in one's life and I've certainly seen things that suggest that early, you know, early repeated sunburns would be more of a risk. So look, I think that's not a controversial point in the sense that like who wants to be sunburned, right? So it's like whatever one needs to do to be sunburned whether it's you know, you know being mindful of what the UV index is wearing the appropriate cover wearing the appropriate sunscreen. I also find the whole kind of
Auntie sunscreen establishment to be a little bit
odd, the anti sunscreen establishment is odd, you know, I'm trying to open the door for a nuanced discussion about you know, the fact that some sunscreens really do contain Ling's like oxide benzene's and things that are real. Yeah, but when you get here, you're spraying them on kids. Yeah,
but no, I'm just look at the straight of you know, the good old-fashioned mineral sunscreen. Yes, perfectly safe. Yeah. Yeah, it's far as
we know I also dare we cross the seed oil debate into this.
Some of the folks who are really anti seed oil also claimed that seed oils increased risk for sunscreen Peter and I are smiling because we have teed up a debate soon with some you know, anti seed oil and less anti seed oil experts. So that that's forthcoming. That's going to be a fun one. I will be doing all that with our shirts on. I really appreciate you walking us through this paper Peter. I have never looked at a paper on cancer.
And certainly not one like this. I learned a lot and it's such an interesting field obviously because of the importance of getting people with cancer to survive longer and Lead better lives, but also because of the the interaction with the immune system, so we learned some really important
Immunology. Yeah, and this was this was great. I feel much more confident now in the belief that the the exposure to light early and late in the day can actually have
Benefits and I said, I think that there's I think there's there's some causality here, and I think it shouldn't be ignored
cool. Well, this was our second Journal Club. I look forward to our third next time you'll go first. We'll just keep alternating and we've also switched venues, but we both wore that the correct shirt, and I hope people are learning and not just learning the information, but learning how to parse and think about papers and I certainly learned from you Peter. Thank you so much.
Thanks enter. This is
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