Jonathan Wolf (3:17)

I mean, one thing I heard really clearly was that not only does it have to be incredibly good at attacking sort of these bad things outside, but it needs to be really smart at recognizing whether this is actually part of my body, so it mustn't be attacked. I'm interested that you mentioned that just in this summary. Is that a very important part of what it needs to do in order to be healthy?

Daniel Davies (3:37)

Absolutely, because you will know that there are any number of products and ideas telling you how to boost your immune system. And on the face of it, that sounds quite a simple thing that we want to be doing. But having just told you the complexity of what the immune system has to do, a layer of depth in the idea of boosting the immune system is immediately in paramount. What does that actually mean? If you just somehow boost the ability of your immune system to be very active and start fighting things, then you don't want to do that because it would inadvertently start attacking things that are part of the normal healthy body, and that would then cause you problems in itself. So it's important that we understand the complexity and the nuance in what the immune system has to be able to achieve. Because already we're at the point where some of the sound bites and clickbait you might come across for do this one thing to boost your immune system already now we could be questioning what does that actually mean? I don't want to just boost my immune system in a very general way to make it more active. I need it to be restrained in some situations because I don't want the immune system to react against my own body or things that are not particularly harmful to me. Like would happen if your immune system started reacting against food or something and gave you an allergic reaction.

Jonathan Wolf (4:57)

One of the things I thought of as you were describing this, like not reacting to things that are normal in the environment is seasonal allergies or hay fever. And I'm probably thinking about that because I get this now regularly, which I never did as a kid. Is that an example of like my immune system?

Daniel Davies (5:13)

You know, I mean, sometimes we belittle allergies because they're not spoken about in the same way that cancer is, because allergies are not really a top 10 cause of death. But the number of people who get allergies you just mentioned, you get allergy, I get allergies, hay fever as well. It's 2 billion people. So allergies are incredibly important. And by and large, they are the outcome of our immune system reacting against something that is not particularly harmful, like it could be pollen, as an example. But there are many different types of allergies, of course. So just even that knowledge in itself hopefully means that thinking about the complexity of the immune system means it's all about having the immune system react to things that are truly dangerous, but not overreact against things that are not really a problem for the body. There's another side to that as well, which is that when you do get a genuine infection, a virus infection, let's say, and your immune system has to deal with that. So that involves a heightened state of our immune system. The particular cells in your body that are good at fighting that virus have to multiply in number. You might experience a fever, depending on what type of infection it is. But then again, you don't want your body in that heightened state of immune activity because that would put it at risk of overreacting against something that's not harmful. So a lot of what we're talking about in good immune health is keeping the immune system balanced rather than, you know, utterly boosted in some way.

Jonathan Wolf (6:40)

And I get the impression that maybe we don't come back to balance as much as perhaps we're designed to. I mean, you talked about the allergies. Two billion people with allergies. I just remember my grandparents sort of telling me that almost nobody had allergies when they were growing up. I don't know if that's true. Are we, like, coming back to normal in the same way that we are meant to?

Daniel Davies (7:01)

It's a very hard question to answer. I mean, the number of people diagnosed with allergies has been increasing. And some of that could be that we're better at recognising allergies than we used to be. It could be true that we are more susceptible to certain kinds of illnesses we used to be. And again, another reason for that might be that we're living longer on average. As we age, our immune system changes. Some autoimmune diseases do tend to arise more as we age. So there are many factors in the increasing prevalence of an immune system problem. In terms of allergies. One of the things that you might be thinking about is the effect of our microbiome. And there's this general idea that perhaps being exposed to something like a less hygienic environment or to microbes when we're younger trains our immune system to be better at dealing with allergies. So that comes from wonderful and pioneering research by Gordon Strachan at St. George's Hospital in South London. We're not too far from where we're speaking right now. And he made the observation that large families, the younger siblings, tend to develop less allergies or less hay fever. And he had the idea that perhaps in a larger family, especially, a younger sibling was more exposed to infections when they were younger because the older, the other people in the family might get infections. So you had this idea of that perhaps an exposure to germs when you're younger somehow protects you against allergies. And he called that the hygiene hypothesis, which probably many of their listeners will be somewhat familiar with, that does also correlate with studies of children growing up on farms. One particularly careful study, or a group of studies, if you like, has looked at different communities in the usa. And one group essentially lives nearer to where animals live and the environment where animals are. And they are less likely to develop. Develop allergies than another farming community that tends to use mechanical farming tools and live further away from where the animals live. So that, again, fits with this idea of the hygiene hypothesis, that more of an exposure to germs does somehow train your immune system to protect you against allergies when you're older. But as we've said right at the outset of this podcast, everything is very nuanced and complicated. And there could be other explanations to those farming data. For example, unprocessed milk also is used in farms, which may also have some protective benefit. We understand very little about what that is. From my perspective as a scientist, I've kind of been trained to kind of hear something and then think of, like, 10 other explanations of why that might be true rather than the one that I've just been told. And it's exactly the case in this that there's lots of possible explanations for how growing up on a farm may influence the onset of allergies. And the bottom line is we don't know enough about the details of how that works to give us an actionable outcome. And it's particularly difficult because I couldn't take dust from an animal house on a farm and somehow expose children to that to see what happens, because you would be exposing healthy children to something that we understand very little about and is even potentially dangerous, and that just isn't ethically possible to do. So it's very hard to do the experiments to find out what is it. Is there some important ingredient to the environment of growing up in a farm that helps train our immune system? And right this very minute, we don't know enough detail to make this an actionable thing that leads to any advice. So we have to be very careful about explaining what the results are, what the experiment is.

Podcast Host / Advertiser (10:39)

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Jonathan Wolf (12:31)

I'm listening to this and thinking that much of the world has sort of gone through an unintended experiment about this sort of hygiene hypothesis. And so many of us lived through Covid. There was sort of social distancing we were definitely much more conscious. Many of us about wash our hands. We weren't with other people. I know from speaking to doctors that there was like this really big fall of many other infectious diseases through this period. And then obviously we've all gone back into life. So I imagine that you're going to tell me, like over the next decade or something, there's this sort of fascinating almost worldwide intervention to see whether or not this has had any impact on our immune systems.

Daniel Davies (13:07)

Yeah, so that's a very interesting point, and that's exactly true. The pandemic has opened up a lot of what our immune system is, does, how it changes. Obviously, everyone experienced different symptoms and outcomes from being infected with COVID 19 and that correlated very precisely with things happening in their immune system. So we did learn a lot about that and the learning is continuing.

Jonathan Wolf (13:28)

You talked about cancer, and I guess when I was thinking about immune health, it's like it's all fighting off viruses and infections. How does cancer fit into this?

Daniel Davies (13:40)

Many decades ago, people did think that cancer wasn't really anything to do with the immune system because, I mean, there are some rare occasions when cancer can be caused by a virus. But most of the time, cancer is just your own cells that are dividing in an out of control way. And so it's your own body cells gone wrong. And so your immune system doesn't have anything as obvious to look at as, you know, the spike protein of the COVID virus. That is definitely alien to the body, but we have dramatically changed our view of that. The immune system can definitely see cancer developing in many ways. In fact, two big ways for a cell to turn cancerous. Mutations arise that make the cell start to divide, multiply in an uncontrolled way, and then that leads to some changes in the protein molecules that that cell makes. And your immune system can directly detect those changes in protein molecules. That's one way. Another way is that when a cell becomes cancerous, very often that cell itself has an ability to know that it's dividing in an uncontrolled way. For example, its DNA might be damaged in some way, or if it was exposed to UV light, for example, and that cell itself can start to display molecules at its surface that tell the immune system, look, I'm damaged, kill me. So cancer can be seen by the immune system. It couldn't be more important because this does lead to all kinds of new medicines. One of the major new ways of us treating cancer in some patients is to use immune therapies that are called checkpoint inhibitors. We spoke earlier in the podcast of the importance of the immune system coming back down to its normal resting state after it's fought off a virus, for example, that's a very important process. The immune system has to be able to bring your body back down to its normal state once you've cleared out a virus. But if that process happens while your immune system is trying to fight off something like cancer, that would inevitably be bad. So in a long term situation where the immune system is fighting off a cancer developing, you don't want the immune system to put the brakes on and come back down to its normal resting state. But that does happen. And so checkpoint inhibitors are a type of therapy where you block the brakes on the immune system from coming on and you keep up the immune cells being able to fight off a particular type of cancer. And for some patients, I mean, it doesn't work for all patients, doesn't work for all types of cancer. But for some patients who have been told they have a short time to live now, live for a much, much longer time on account of these types of therapies, checkpoint inhibitors. So we go from basic science of what is the immune system. You just asked me, does it fight cancer? Yes, there was a revelation in understanding the immune system can fight cancer. And then not only is that important in its own right, but that kind of insight very directly leads to developing new medicines that allow the immune system to fight off cancer.

Jonathan Wolf (16:42)

So sort of right now and all the time, one of the important jobs that my immune system is doing is effectively sort of scanning my body for like new cancer and like hitting it before it becomes some sort of like bigger cancer that I might end up being aware of and a doctor been aware of.

Daniel Davies (17:00)

Absolutely true. So all the time your cells are becoming damaged through exposure, for example, to UV light, sunlight or other things are going on in the body. And one of the jobs of your immune system is to kill off cells where cancer might be developing. And a lot of the time you would not be aware of that. In fact, it's quite hard to know how often in your body is a cel, kind of on the way to turning cancerous and your immune system has killed it off again. The experiments are actually really hard to do. How would you know that if you're not aware of it? So the immune system is, one of its jobs is to stop cancer developing in the body. And how often that happens, how important that is, it's quite hard to know. But it's definitely happening in your body and mind all the time. I'M sure.

Jonathan Wolf (17:42)

So there's probably something right now. There's like a cell in my body that might be going wrong, and my immune system is zapping that, absolutely killing it off.

Daniel Davies (17:49)

And this is the kind of research that my own lab does, actually. So we are watching these process happen down a microscope to understand the details of what's happening.

Jonathan Wolf (17:59)

I invite you back probably, to go deep into that. I actually wanted to ask another question, though. Cause you mentioned before, which I'm fascinated by this idea that my immune system is completely different from my wife's immune system and your immune system. Why?

Daniel Davies (18:13)

One reason why your immune system is different to mine is simply because of the genes we have. You and I have the same set of genes, the sort of 22,000 genes that make up the human genome, but we all have slightly different versions of some of those genes. A small fraction of all the genome is a bit different between you and me. So that gives us our differences. And so people might think that the genes that are most different between people, the genes that vary the most between me, you, and everyone listening to this podcast, would be genes that control things that are just obviously different, like our hair color, our eye color, our skin color, but actually the genes that vary the most between every person listening to this podcast, our genes in our immune system. So right off the bat, at that level of how our genes vary, your immune system is pretty much the most unique thing about you. This couldn't be more important. So if you got infected with a virus and you said your wife got infected with the same virus and she recovered quicker than you, that might well be one reason for that would be that she might have a different version of immune system genesis.

Jonathan Wolf (19:23)

I feel like she would argue it's just because of, like, my moral failings and, like, just complaining too much and not getting on with life.

Daniel Davies (19:30)

Jonathan. Right. That flippant, jokey comment couldn't be more important to me because one of the things that I personally take away from the fact that we all have different immune system genes is that if you get a virus and I get a virus and you recover in two days and I'm flat out ill for a week because we're bombarded with a lot of messaging about health, exercise, you know, do this stuff, I'll be thinking, oh, no, Jonathan's probably going to the gym every day and he's not stressed. And look, his whole life is wonderful, and look at my life and I'm ill for a week. But that is not true. It could just be that by chance, you've inherited genes that I'll make you better at detecting that type of virus. So we mustn't blame ourselves. There's another really important take home message from that, which is that this is a fundamental story about human diversity. There's no inherent hierarchy to our immune system genes. No one has a better or worse set of genes. Really our diversity in immune system genes is what makes all of us stronger. And there are very clear examples of this. So if you have a particular immune system gene called HLA B27, you are more likely to develop a particular type of autoimmune disease and closing spondylitis. It doesn't mean that if you inherit that gene you're likely to get that autoimmune disease, but it means that people with that autoimmune disease are more likely to have that gene. On the face of it, then that means that that particular immune system gene would be bad to inherit. But actually, if you're infected with hiv, there's a big difference amongst people of how long it takes to develop aids. And people with that particular immune system genetic inheritance are more likely to spend a longer, much longer time from infected with HIV to when they would develop AIDS if they weren't treated. So it means that that particular immune system gene correlates with them being better at fighting off the virus hiv. So immune system gene, but on the one hand seems to have a negative consequence. It's more likely correlated with some autoimmune disease. Developing is good for you in another sense that it correlates with you helping fighting off hiv. So this is really important because it means that the worst things that have ever happened to humanity have happened because of our misunderstanding of what our diversity is. It is fundamentally important to how we live and how we survive different kinds of diseases.

Jonathan Wolf (22:00)

I'd love to switch on to talk about some of these myths that we understand about the immune system. And you've already talked about about the idea that boosting it is bad. I'd love to talk about vitamin C because I wasn't feeling very well last week and my daughter's babysitter immediately said, oh, you should go and take lots of vitamin C. And I was like, I'm pretty sure I've heard from people that maybe this doesn't really work anymore. What are the facts?

Daniel Davies (22:26)

So vitamin C is actually a really fascinating story. I mean, vitamin C is important for health, no question. But the thing that we're talking about here is about her immune health. I've been brought up thinking if I have a Cold, right. Drink some orange juice and you'll be fine. And that somehow made sense to me. But it's really just a prejudice. It's really just something I've been brought up with. And now I'm trained to be more skeptical about these things and think about what is the actual evidence, what are the experiments. I started to look into that more and actually it turns out that the way we think about vitamin C has been hugely influenced by one individual, Linus Pauling, who won two Nobel Prizes. He wrote a scientific paper on the nature of chemical bonds. And the journal it was published in the scientific magazine, if you like, that published. It said, normally we send this to be looked at by other scientists, but in this case there's no one in the world that is good enough to judge this particular piece of work. We'll publish it anyway. It was that level of scientist. Later in life he campaigned against, against nuclear bombs and he won a second Nobel Prize, this time for peace. So he was someone that we are listening to and he was very easily seen on the TV and radio. In 1970 he published a book on vitamin C and the common cold. And boom. New factories had to be built to keep up with demand. Everyone is listening to him. We need higher doses of vitamin C. His argument was that the level of vitamin C that we were told to have comes from a level that was known to stop you getting scurvy, which is something that happens if you're very deficient in vitamin C. And his argument was that, well, that's not the same as knowing how much is actually healthy for you to have, just that it avoids a particular illness. He cherry picked the data that was out there and basically through anecdotes came to conclusion that we need more vitamin C and it would help us fight off colds. Him and his wife Eva Helen, they Both took about 10 times the amount of vitamin C that's recommended and felt it gave them a lot more energy, fought off colds. He actually also said that high doses of vitamin C will stop you getting cancer, all sorts of other things. Now the truth is vitamin C will not stop you catching a cold. That is unequivocally proven in clinical trials and tests. The people who have a regular supplementation of a high dose of vitamin C on average get over a cold about 8% quicker, which would mean that if you're ill for a few days, you might get better a few hours earlier. If you supplement with a high dose of vitamin C. Even that information alone is very difficult to act on because people that take a high dose of vitamin C are probably doing other things in their lives as well, which might make them get over a cold a bit quicker. So it's very hard to know. But by and large, vitamin C is not going to help you with a cold. So for me, the take home message is not only that orange juice isn't going to help me with my cold, it's also that we need to be very, very careful about any one person's opinion.

Jonathan Wolf (25:39)

Well, I think you've just demolished taking vitamin C in order to stop getting a cold. I'd love to come on to one other myth, and we got this a lot, but it made me actually think of my grandmother who used to always say, now we're getting into the wind to wrap up warm because otherwise you're going to catch a cold. Is that true?

Daniel Davies (25:56)

Wrapping up warm won't stop you catching a cold. But it is true that there is a seasonal variation to the types of viruses that are multiplying well in a particular season, and it does make us more susceptible to the cold in a certain time of year.

Jonathan Wolf (26:13)

Help me to unpack that. So you're saying that I'm more likely to catch flu and a cold in the winter?

Daniel Davies (26:18)

Yes.

Jonathan Wolf (26:19)

But it's not because I am physically exposed to the cold.

Daniel Davies (26:22)

Yes, there's some limit to that, because if you were so cold that your health was affected in a general way, then you would maybe succumb to the symptoms of the cold more. If you looked after yourself in a general way and kept warm, your body would be in a stronger position to be able to deal with an infection.

Jonathan Wolf (26:39)

Dan, I'd love to switch to links between immune health and mental health because we've talked a lot about protection against diseases and against cancer. But I know in your book you also discussed that it's not just physical health that the immune system is somehow engaged with. Is that right?

Daniel Davies (26:58)

When your immune system is fighting off a virus infection, you might experience a fever. You know that a fever is affecting you mentally as well as physically. Obviously your temperature is raised.

Jonathan Wolf (27:07)

I mean, I feel rubbish whenever I'm sick. I complain all the time. Everyone at Zoe knows that. Everyone at home is like, I'm like a terrible invalid. I'm incredibly frustrated because I want to be doing all this stuff, but I just feel tired and I feel like my brain is like somehow everything is like cotton wool.

Daniel Davies (27:24)

In hindsight, it feels obvious that our mental health is somehow connected to our immune health. Perhaps some of that has evolved deliberately. Like if you have an infection Then you feeling weaker, tireder, staying in bed is good for you in terms of helping your healing process, but also it's good for humanity because you're not wandering around affecting everyone else. So some of that process is very likely to have evolved in a very deliberate way. Now, there are some very interesting experiments looking at whether, more generally than that, our immune health is connected to our mental health. It's very hard to assess anybody's immune health in any way because it's so complicated.

Jonathan Wolf (28:03)

So, Dan, there's not just like a simple blood test that just gives me a scale on my immune health in the way that I might get a sort of cholesterol check.

Daniel Davies (28:12)

I think the answer has to be no for the moment. But one of the ways we can get some sense of what's happening inside a person is to look at the particular types of molecules that immune cells use to communicate with each other. So during an immune response, as we've mentioned, there are lots of different kinds of immune cells in the body and they have to communicate with each other. And one of the ways they do that is that an individual cell will produce a protein molecule that comes out and then goes and touches another immune cell. And those kinds of molecules are called cytokines. And there are over 100 different types of cytokines, and they do all kinds of things in the body. In fact, it's a bit unfortunate to me that cytokines aren't more famous. They deserve more public recognition. They're easily as important as antibodies, which people have probably heard of. I would predict, over the next decade. Cytokines are something that everyone listening to the Zoe podcast is going to have heard more about. Cytokines. There are over 100 of them. They're how immune cells communicate with each other. Now, cytokine levels flux up and down in the body, in your blood anyway, during the day, different ones are rising in the morning, in the evening, etc. But you can measure cytokine levels to give some proxy of how much the immune system is in a state of activation in a person. Studies have shown that if you measure the levels of one particular cytokine that happens to be called IL6 in children age 9, those who have a higher than average level of cytokine are more likely to develop depression when they're age 18, which isn't entirely proof of anything in itself, but is in line with the idea that a higher activation of the immune system at some age correlated with the later development of some mental condition later in life, it's quite powerful Although it's only a correlation. And so again, with any correlation, there could be any number of other things. It could be that the higher cytokine level is an outcome of something else that then linked to mental health later. And it's certainly not true that all cases of depression are linked to higher levels of cytokines. But there is something in that, another version of that type of experiment that's more reductionist, requires scientists to use animals. And of course, you know, the mental health of a mouse is an impossible thing to fathom. But it turns out that if you inject a mouse with a cytokine like IL6 that mimics some sense of inflammation or some level of an immune response happening, that mouse is more likely to then not explore their cage, go into a darker part, not be in the light, not interact with other mice, which is somehow reminiscent of behaviors that could relate to depression. So again, it's another level of evidence that an immune molecule used by immune cells to communicate each other can elicit behaviors that look a bit like what might happen in a mental health condition.

Jonathan Wolf (31:19)

It's really interesting. I know that, you know, from myself as an individual that my mental health is definitely affected when I'm unwell. Like, I very rapidly go from being sick to then like feeling quite low about it, feeling like I'm going to be sick for ages. You know, again, there's a certain suggestion I might be a bit of a hypochondriac. Maybe that's part of why I co founded Zoe. So it's really interesting that you're saying there is some evidence that this sort of immune system being on for too long or too much, could have some effect in a way that's measurable about how you feel in this sort of more mental health way.

Daniel Davies (31:56)

Another very important line of evidence comes from when people are taking a particular medicine that blocks the action of a cytokine. So stopping immune cells communicate with each other. And one of those is called anti tnf. Anti tnf. TNF being a particular cytokine. That means that immune cells communicate with each other. And that's often taken by people with rheumatoid arthritis, for example, because it dampens the inflammation that they have. And there is evidence that people on an anti TNF medicine very quickly feel in some way rejuvenated, even before that type of medicine has had a clear physical impact on their actual autoimmune problem that they were taking that kind of medicine for. So there's several lines of evidence that our immune health and mental health are connected. There are some correlations between cytokine levels and mental health developing. There are examples where people are taking medicines that are in the immune system, but it seems to also affect their mental health. And there are experiments in animals where eliciting immune reactions seems to affect the behaviors of mice. That would be normally thought of as a mental condition. But like a lot of the things that we're discussing today, it's fascinating. It's extremely important. It might make some people think about their mental health in a different way. Every time you get a new window into how the, how the body works, it might make you think about where some mental health condition might be originating from. But what's really important is, firstly, this wouldn't apply to all mental health conditions, but paramount is that this cannot be taken yet to indicate what you do about it. There are hints of something really important happening between our immune system and our mental health, but it isn't yet at the point where there's an actionable thing for you to do.

Jonathan Wolf (33:50)

And, Dan, a lot of scientists that I've interviewed on this podcast over the last few years are looking at interventions with food or the microbiome and talking about impacts on inflammation as one of the things that they are measuring and believe is involved. We've been mainly talking about immune system, but I've heard you use the word inflammation once or twice. Is inflammation linked to what you're describing?

Daniel Davies (34:14)

Okay, yes, that's a good point. So we should just unpack what these terms mean. So inflammation is essentially, Yes, a sort of level of activation of immune system. So the most acute example of inflammation would be if you get a cut and the cells are swarming in to that place where you've experienced a cut and it goes red, it gets bigger, it gets slightly hot. And that's. So their immune system is there to fight off any opportunistic germs that might enter the body through that cut. That's a kind of localized inflammation. But equally rheumatoid arthritis, where you have a sore joint is also due to inflammation in the sense that the immune system is active and it started to attack parts of the body or become overactive in a joint where it shouldn't be and it's causing you a problem. That is also inflammation, in a sense. It's any state of the immune system that is active is essentially what inflammation is. But that can also be on a whole body level. You can have a sort of higher level of background inflammation. And that tends to be the idea that many of your immune Cells are sort of slightly being tickled in some way, so they're producing, for example, more cytokines that would be inflammatory, causing immune cells to be slightly active. And that would be a sort of background level of whole body inflammation, which can happen, for example, as we age. And that's one reason why it's thought that older people are more susceptible to autoimmune diseases because they have a higher level of this background inflammation in their body.

Jonathan Wolf (35:48)

Fascinating. And so if we can sort of what I think what you're saying is great to have this turned on when I'm sick and I want to deal with it. But if this is sort of higher than sort of normal for long periods of time, and you can potentially measure that through these cytokines you're talking about that may be having some of the negative impacts. And here you're saying one of the potential impacts that it might have is actually on your mental health over time.

Daniel Davies (36:10)

Yes, that is all possible, but it's also quite speculative. Every part of what you said is the best sort of scientific consensus opinion of how we're thinking about things, but a lot of it isn't really proven. Yes, there's this idea that as we age, there's a more of a background inflammation going on in the body and that might link to one of the reasons why problems might arise and could also affect our mental health. But equally, we don't really know if that's actually totally true. It's like that's where our thinking is. We haven't really proven that. Yes, now we can measure five cytokines in your blood and tell you you are more likely to get depression. We need to counteract that immediately. We're not at that level. We're on a path to understanding. And so the answer is yes, you and I are talking about things that are sort of known but not entirely clearly established. And science is always on a trajectory. Hopefully we saw that during the pandemic. Do you remember, early on we would be talking about what we need to do to counteract the COVID virus. Should we all be wearing masks? If an envelope comes in your door, should you not be touching it for a week? And the science evolved and told you that as we went along, we did start to learn more about it. And that is true of all of these big issues.

Podcast Host / Advertiser (37:28)

If you want to help your friends.

Jonathan Wolf (37:29)

And family support their immune system and stay healthy this winter, why not share this episode with them now? I'm sure they'll thank you. One thing that I know, my colleagues, Professor Tim Spector and Sarah Berry have talked about quite a lot as we've been doing these, like, really big nutrition and microbiome studies here at Zoe is how little scientists have tended to measure anything about how people feel. And so sleep, energy, mood, all of these sorts of things that historically they've said, well, if you can't measure it with like something in your blood or something like that, then it's almost sort of been discounted. So it's sort of somehow not sufficiently scientific. And so one of the things we've done with a lot of these studies at very large scales, right, hundreds of thousands of people is look at what happens to things like energy and mood. And I think in a number of these interviews, intervention seen amazing shifts. And what they've said is just basically this hasn't tended to be measured before. And so I'm just listening to what you're describing about not knowing the impact on your mental health and you talk about depression, but obviously for many of us it's more just sort of how do I feel each day. And part of what I understood is just hasn't really been measured very much. So of course, you can't know what happens until you start to measure it.

Daniel Davies (38:46)

My own personal view, to add to what you just said is it's not so much that we haven't tried or thought about measuring things, it's actually that it's really, really hard. Let's take sleep. Immune health, as we've already said, is actually quite a hard thing to do any measurement about. When you look at cytokine levels, you could look at antibodies produced in response to a vaccine, but there's not an easy way of saying, how was anyone's immune health doing? There's an easier way of looking at how well people do in a cognitive test. So a very obvious thing is you just look at how much people are sleeping for and then see how they perform in some kind of cognitive test afterwards. And the bottom line from that kind of experiment is that sleeping seven hours is best. If you sleep less than that, you perform less well on average in a cognitive test, if you sleep more than that, which is a bit more surprising, you also do less when the cognitive test. Okay, great. So now we know seven hours is the amount of sleep, but let's take another view of that. Seven hours might be true on average. I have no idea what's best for you or me individually. Some of us are going to sleep later, some of us are waking up earlier, some of us are napping in the daytime. Some of us are sleeping with lights on, lights off. Some of us are sleeping in a noisy environment, a quiet environment. So you start off with something very simple. But once you think, hold on a minute, what was the experiment? And now you start to think, okay, I've already told you, things are very different individually. For all these things, there's a nuance in seven hours sleep isn't enough information. Would it matter if I did three hours sleep and then four hours sleep later? What about the different phases of sleep, the depth of sleep, the environment I'm sleeping in? Are other people in the room? All kinds of nuances relate to sleep. So I think it's not that these things haven't been measured, it's that it's really, really hard. So in that example of sleep, we are also on a trajectory of improving these measurements. I'm sure that many commercial companies are thinking about ways to monitor your sleep in a more complicated way. A wearable device, something in your mattress. More and more and more, we will get more and more complicated measurements that do help us navigate things. That then leads us to a whole nother issue. As all of these things become more and more possible for you to understand your own body individually with more and more measurements, more and more metrics, Sleep, the levels of a thousand billion things in your blood, how much of that do you really want to know? How exactly is that going to help you live happier? These are very difficult issues to navigate already. Now you can have a genetic test that says might say you've got a 1 in 10 chance of developing a certain type of cancer in the next 10 years. And what if that was a one in five chance? What if that was in five years? These are very, very hard things to think about personally. So we're entering a world where first of all, these measurements are hard. Interpreting what they mean for you individually is extremely hard as well. What does it mean for you personally when you get this information? All of these things are very, very difficult to deal with.

Jonathan Wolf (41:59)

So, Dan, I think you've drawn a picture for me of just how important my immune system is, my immune health, how much it's affecting everything from fighting cancer to my mental health potentially. I'm pretty confident I speak for myself, but also for most of our listeners who say, okay, I'd like to talk about some practical advice, therefore, about what I could do to set myself up as well as possible. I'm going into the winter, you know, I know that I've got more risk of getting cold and flu and all of these sorts of things like what actually might I be able to do to set myself up as well as possible. Could we maybe start with whether there are any immune boosting supplements that would really support my immune health?

Daniel Davies (42:46)

The consensus view probably best comes from, as obvious as it sounds, the sort of basic guidelines that you would get from, you know, medical establishment. As kind of unsatisfying as that sounds, that's probably the where the consensus is. The best established example, or one of the good examples would be vitamin D supplements during the winter for people living in the uk, where it's certainly not as sunny as it might be in other parts of the world. That's the recommendation of the UK government, for example. And it is true that in a clinical trial, vitamin D supplements did reduce the chance that people with an average age of 67 were susceptible to autoimmune disease. That reduced the chance they get an autoimmune disease by 22%. So vitamin D levels are important. So that would be an example of a, of a supplement that is recommended, for example, by the UK government.

Jonathan Wolf (43:42)

And are there any others that you would be recommending or are you, this is back to you, like you don't want to really boost it and you've already thrown vitamin C out the window.

Daniel Davies (43:51)

There are established cases of vitamins being important. Vitamin A is very important, for example, but most people would be getting that level of vitamin A they need, for example, through a normal varied diet. And so it wouldn't be the case that you need to supplement. So the one thing where I would say will affect your immune health and you can do something about it perhaps is long term stress. A lot of the data that we've talked about, a lot of the experience we've talked about, are things coming from correlations between things. But with stress we've taken that to another level. We've taken it to a kind of molecular level understanding of what happens so that we do understand in detail how stress very directly affects your immune health. When your body senses some threat, it goes into this fight or flight response. So a signal, your hypothalamus will react to this perception of an issue and send the message to pituitary gland. Send a message to adrenal gland produces adrenaline and cortisol stress hormones. Those stress hormones get your body ready in a state of action to deal with the threat. And as part of that they quieten down other body systems that aren't so important for dealing with that moment. And that includes your immune system. So when cortisol levels are high, your immune system is quiet and down. So for a short period of time, this is entirely fine in a fight or flight response.

Jonathan Wolf (45:24)

So your example here is like, I've seen a lion, I need to run away. It's like, forget about fighting a cold, all you need to do is escape this lion. So it's all focused.

Daniel Davies (45:34)

We'll deal with the cold later. Let's run now. But if that persists, stress, of course, can be long term. If you're changing job, getting divorced, any number of reasons.

Jonathan Wolf (45:45)

Running Zoe.

Daniel Davies (45:46)

Running Zoe. Yeah. Your immune system can be suppressed for a longer time and then that does correlate with more and more susceptibility to infections.

Jonathan Wolf (45:54)

So that's true. That's not just one of these myths, like if you're under stress for a long period of time, you are more susceptible to infection.

Daniel Davies (46:01)

Yes, that has been proven in multitudes of ways. And what makes us really know that that's not just a correlation is because we can do very precise experiments. For example, if I just add cortisol to immune cells in a lab dish, they will be less good at killing cancer cells. So that kind of molecular level analysis of how this plays out makes us confident that this is a process that is genuinely true and it's not a kind of something else going on that stress correlates with something else and immune system correlates. So that gives us confidence in that being an actual thing. Now here's the kicker in this though. Everything I'm coming at you with is always more complicated right this minute from everything we've said, stress, long term stress can affect your immune health. It seems like I should do things to relax. Tai chi, jigsaw, puzzle, coloring, whatever it is you might do to relax, to not be stressed in the long term. However, it hasn't actually been proven unequivocally that practices that reduce stress improve your immune health. Everything would point to that being true. And it is proven that, for example, practicing Tai Chi does lower your cortisol levels. That is proven. But what's not proven is that those practices will protect you against infectious diseases. And that again comes back to this really important message, that the experiments are really hard. On balance, it seems to me very clear that stress affects your long term health. And doing things to not get stressed if you can, is important.

Jonathan Wolf (47:39)

We had a lot of questions about exercise and I guess at both ends, like, does regular exercise help my immune system? But also what about, for example, when you're not feeling very well? Or what about if you're doing something really intense? Actually is that bad. And I feel it's funny. So often as populous, I sort of come back to like what my grandmother used to say and how often I feel like scientists say that something sort of sensible. It's like, oh, doing something regular is good, but like if you really push yourself, that might actually be bad. Like, yeah.

Daniel Davies (48:09)

So roughly speaking, there's a lot of truth. Obviously there's always going to be a lot of truth in whatever your grandmother said to you. Apart from maybe vitamin C. The best benefit for exercise always comes to people that are not doing much exercise and they start doing some exercise, they get a huge benefit from that.

Jonathan Wolf (48:22)

A benefit to their immune system.

Daniel Davies (48:24)

Yes, there is a benefit to our immune system and that comes from lots of different things happening in the body. Muscle, for example, produces the cytokines we spoke about in terms of immune cells. Communicate with each other.

Jonathan Wolf (48:38)

If you were going to give me and the listeners like a specific one or two things that we could just start doing straight after we stopped listening to this call, what would they be?

Daniel Davies (48:49)

One, try to avoid where you can long term chronic stress. Two, every time you see something that feels like you've just been let in on a new secret to what's going to improve your immune health, be a little bit skeptical and think about, well, what was the experiment they did?

Jonathan Wolf (49:10)

I love it, Dan. We've covered so many things on this show, so I always try and do a wrap up, but I feel more like it's a set of fascinating things I've learned. So I discovered that my immune system is fighting cancer inside me right now while I'm doing this show. The vitamin C is not going to stop me catching a cold. That the story I've been told about long term stress affecting my immune system and my risk of getting infections is actually true. But it's months, not hours. So it's okay to do something stressful like a podcast, but like constant anxiety and worry really can affect my health that we all have a completely different immune system. So it's not just that I'm feeble when I get sick and the rest of my family don't. It could just be it's that particular virus that there's some real evidence about this hygiene hypothesis that like living in like a completely hygienic environment when we're little might not actually be good for us. Exercise does help my immune system. And you said sort of wherever you are, like, particularly if you're not doing very much, like stepping up to more can really not only help with everything else that I'VE heard of on this show, but actually can literally improve my immune system. There seems like to be good reason to believe that my mental health can be linked to my immune system. And finally, I heard it here for the first time. Cytokines. I don't know what they are. Most people listening to the show don't know what they are. But in the next few years, they're going to be famous. You said there's about 100 of them. It's somehow how the immune system is communicating with, with each other. And it's great when it goes up when we're sick, but actually, generally we would like this to be low because we don't want our immune system boosted all the time. We want it actually to be like sort of low and sort of not doing too much most of the time and then able to sort of shoot in and fight something when required.

Daniel Davies (51:04)

Okay, that's a good summary. Everything we said was as truthful as we can make it. But when you go to university to study immunology, let's say the textbook is a thousand pages and even that is just the beginning.

Podcast Host / Advertiser (51:22)

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