• njikomes

Shruti Naik: Inflammation, Memory, Epigenetics, Skin Health, Stem Cells, Tissue Repair & Cancer

Updated: Aug 4

Full episode transcript below. Beware of typos!

Nick Jikomes

But especially after reading your review paper, I'm not sure I've ever this excited To learn about skin before.


Shruti Naik 5:03

Well, I think people really underestimate our skin. They think it's sort of this like, flimsy barrier, you know. And it's actually really remarkable. There's a lot of really interesting biology there that you can learn from not only just to understand skin health, but to understand how our tissues work across the body.


Nick Jikomes 5:22

Yeah, absolutely. Can you just start off by telling everyone a little bit about who you are? And what what your lab studies?


Shruti Naik 5:28

Sure. Hi, my name is Dr. Shruti Naik. I am an assistant professor at NYU and My lab studies how immune cells talk to non immune cells in our bodies, Ferrier tissues, like the skin in the gut, and what those conversations mean for maintaining health and driving disease.


Nick Jikomes 5:49

Yeah, and a lot of what we'll talk about today has to do with inflammation and how our body instigates inflammatory events. And why does that and how that can go well, and how that can go awry? Can you just start off by just having, let's have a broad discussion about inflammation and what it is and what it's supposed to be doing? I think we all have an intuitive sense of what inflammation is. But when you think at the level of cells and stuff, what is inflammation?


Shruti Naik 6:15

Yeah, it's sort of interesting, right? Because people throw this word inflammation around a lot like you see all of these like herbal supplements that can curb inflammation, or, you know, your probiotics that are anti inflammatory. So I think scientists are still trying to figure out exactly what inflammation is. But the textbook definition is sort of redness, swelling, heat, the kind of visible thing that you get when you have for instance, a cut an infection, you know, pain that you feel, and those are all sort of canonical definitions of acute inflammation. And then there's a second type of inflammation called chronic inflammation, which is a little bit stealthier and a little bit harder to detect. And this type of inflammation is just like a very low grade production of mediators, from immune cells that interact with other cell types. And sometimes these mediators can be really damaging, like, they can be reactive oxygen species, types of chemicals that can damage other cells, or that can, that can, essentially evolutionally They're meant to kill bad guys pathogens, but producing low levels can hurt our own body and cause pathology. So those are the two broad types of inflammation that we talk about. But I think there's still, it's very, it's surprising that this is an age old concept, and yet, we're still learning about what it is and what it does. Yeah,


Nick Jikomes 7:45

ya know, a good distinction that I think we'll come back to many times is the distinction between acute inflammation and chronic inflammation. Inflammation is, I think, generally something our bodies, we want our bodies to turn on and turn off at the appropriate time. But sometimes that doesn't happen, it becomes chronic, and it becomes a problem. The other thing I want to ask you about here, just on inflammation generally is, is inflammation, something that we can think about very generically, or is the nature of inflammation different depending on what's driving it. So if you get a cut, or a bruise is the is what's happening under the hood going to be completely and utterly different from the inflammation you get from an infection, or are there commonalities that that sort of cut across all of those, all of the things that can drive an inflammatory event?


Shruti Naik 8:33

Yeah, I mean, I think the the answer is both right. That's, that may sound like a cop out. But I think that one, biology is redundant. So oftentimes, many features that are involved in a cut may also be involved in an infection. And that's some of the things that we're realizing we actually recently had a study in our lab, from our lab that showed that, you know, certain immune derived factors that are really critical for killing bugs are also really critical for signaling into your skin cells, your epithelial cells, and helping them adapt to low oxygen environment and helping them heal after a cut. So we're realizing that our body has repurposed a lot of immunological signals that are involved in like pathogen response dealing with pathogens for other purposes. I think again, you're raising the question that needs to be needs more attention and needs to be answered, which is, how, how are the rules set for inflammation? What happens when you have a cut versus when there's an infection versus versus an autoimmune response, right, where inflammation has really just gotten out of control. And it seems as though the same players show up again and again, and in some contexts are doing good things. And in some contexts, they are really out of control. The checks and balances have been taken away and they're just, they've kind of amplified to a point where your body doesn't know how to do with it, and that's when disease ensues.


Nick Jikomes 10:03

You know, one thing that's just occurring to me is, how does one know in their everyday life, whether inflammation is operating within the normal regime that makes it adaptive. And when it gets out of control, a simple example, that, you know, we see all the time in our lives is, you know, you get like a bad bruise or something. And presumably, you want that inflammation to happen to some extent, to handle the tissue damage that's going on there. One of the first things people in our culture do is they immediately put ice on it or something to try and quell the inflammation. Is that inappropriate way to handle that? And we're generally, you know, how do we think about whether or not we want to sort of let our body do its thing? Versus try and mitigate the inflammation acutely in some way?


Shruti Naik 10:51

Yeah, I mean, for cutters, scrape your body's just doing its, you know, its due diligence and like, pain is, in many ways, a mechanism for the body to say, Oh, my God, something bad is happening here, right, your nervous system is informing your brain, and then your brain is reacting and saying something bad is happening here. So first of all, I'm not willing to give medical advice. I'm not a clinician. So I want to make that very clear. But I think in acute inflammation, all of those things are normal. And we've kind of the modern Modern medicine has allowed for a lot of the conveniences like painkillers that allow us to sort of dampen those responses, right? Well, when when inflammation clearly goes awry, is in context of if you have an autoimmune condition, you have psoriasis, if you are, you know, 30% of kids in in the western world have eczema, which is an which is an inflammatory condition. If you have inflammatory bowel disease, these are all sort of examples where your immune system has just gotten out of control. And in fact, even you know, a lot of the damage caused by COVID-19. We've realized that in fact, it's our immune system when it's unchecked. And so those are situations in which you really do want to dampen the immune system. And in fact, frontline therapies, for instance, that's why this is frontline biologics, in inflammatory bowel disease, frontline biologics, in rheumatoid arthritis. Frontline biologics are all immune dampening. Right. So that's a situation where it's very clear, this is a bad response.


Nick Jikomes 12:27

I see. I see. Yeah, and I definitely want to get into later in the discussion, the the causes and the modern, the variables of the modern world that are driving up a lot of these chronic inflammatory conditions. Before we do that, I want to sort of build up some concepts and some facts for people. A lot of what we're going to talk about is based on a review paper that you wrote recently about inflammatory memory, how our bodies remember inflammatory events, and why that's a good thing and why it can also be a bad thing. I think an interesting place to start here is you mentioned a story that was really interesting in that paper, and it's about the famine that happened in the Netherlands in 1944. Can you just briefly describe what happened there and how this sorts of tie into this concept of inflammatory memory that we'll talk about?


Shruti Naik 13:13

Yeah. So it doesn't necessarily try to tie into inflammatory memory, per se, but you're just trying to this time to this idea that our bodies have remarkable ability to remember our experiences. And that is true of inflammatory experiences, but realizing that's also true nutritional experiences. So this was sort of the, you know, the exemplar of public health studies, to sort of exemplify this, which is, in the 1940s, there was a famine, the Dutch famine, you know, attributed to World War Two and events around it, were children that were born to mothers during that period of famine in this community really had long term consequences for their metabolic health. So they had a higher risk of, you know, weight gain of diabetes, shorter lifespan, things like that. Whereas in that same community, if children are born before or after they were didn't have any of these sorts of adverse symptoms. So what that said was that if you're developing in utero, in a mountain nutritional situation, your body is now fundamentally altered. And that has nothing to do with genetics because if it was genetics, and you would have you know, the kids that were born before and after having the same issues, developing the same issues late in life, but really environments impact how you develop and and those impacts are long lasting. And so we now know that they happen through phenomenon called epigenetics or things that are beyond just the DNA code in your genes, but how that DNA is arranged how that DNA is actualized or made into proteins, and those are the things that are unfolding. Of course, the example I gave you as a nutritional example. But we now also understand that if you have, for instance, maternal infection, it's a very similar thing. So, ultimately, you know, this idea of inflammatory memory or tissue memory is about how our body adapts to the environment. And, you know, as you sort of touched upon or suggested, like, why is the incidence of inflammatory disease going up in the Western world, our genes have not changed that much in the last 30 or 40 years, or at least not that I know of, right? evolution takes a very, very long time. And yet the incidence of inflammatory diseases going up, we wonder if this could be environmental exposures.


Nick Jikomes 15:53

Interesting. So So basically, one of the things that you just said is, if a woman is pregnant, the developing fetus within her can listen to what's going on in terms of her nutrition profile, and her calorie consumption and what's going on in that in uterine in utero environment. And the body of the developing baby can effectively remember what was going on in that environment such that it has long term consequences for the health of the adult that will develop.


Shruti Naik 16:25

Exactly I mean, that's what the Dutch famine cohort study really tells us. And that's what experimental studies have shown. And certainly we know from a lot of clinical observations, that's true, I think this is why we pay so much attention to maternal nutrition, maternal infection, maternal health, but I must emphasize that there's still a lot of work being done in the space. And so those are early examples of, you know, public health studies that have supported these notions. And we're now starting to unfold exactly how these things happen in various contexts.


Nick Jikomes 17:01

Yeah, and one of the things, when we think about the concept of memory, I think, when you define it phenomenologically, everyone's got a really good intuition for memory, like we remember things we all we all know what that means. We store information that we can use later on. And by default, I think most people naturally think about memory in the context of neurons and the brain, our brains can remember things. Typically, people will think about that as being stored in the strength of synapses, the connections between neurons. But of course, what you've already started tell us is that a lot of other cells in our bodies, and a lot of other tissues outside the brain are capable of memory. So at a cellular level, how do you think about what memory actually is?


Shruti Naik 17:47

Yeah, so the immune system encodes memories in two different ways. The way that it's most famous for encoding memory is what is the basis of vaccination, which is, you have B cells that make antibodies and T cells that have receptors that are similar to antibodies that they don't secrete. And these are really remarkable at looking at different shapes on bad guys, and pathogens, like cancers. And you know, and identifying these shapes, and they get selected based on how well they identify the shapes. And then they basically form into memory cells. And this is the basis of why you know, your COVID-19 vaccination works so well, and you're not forming, you know, you're not people aren't getting so severely sick when they're vaccinated. Because they have these memory cells that can make antibodies and quench the pathogen rapidly. So that's what we call cellular memory. And that's sort of been the hallmark of the immune system, and the basis of almost every vaccination that we know right? Rotavirus, smallpox, HPV, what have you. But there's another form of memory that we are that, you know, really has come to light in the last, I would say 15 years. And we think of it as as sort of more nonspecific memory. So instead of specifically seeing a certain shape on a bacteria and remembering it, this kind of memory is remembering when you have an inflammatory encounter, like if you have a cut or scrape. And this time, it's any cell that is in the immune system that is potentially long lived, that remembers this at the level of the DNA as a little chromatin and was talking about epigenetics. So if you think about it, as you know, as a human being, I have a memory of my previous encounters and I encode it in my brain and my neurons, a cell encodes its fears encountered as image brain, which we think is the nucleus. And the way it does it is by essentially changing It's accessibility. So genes are usually part of your DNA, they're maintained and chromatin chromatin is, is intertwined into different states. And when these are not being used chromatin is usually close, because it costs the cell a lot of energy to keep it open. But once a cell experiences an inflammatory encounter, we realized that they not only do they open up their stress response genes, but they never close them to keep them open. And what that allows the cell to do is if it ever encountered a stress response, again, it is now able to respond much more faster, because it doesn't need to open chromatin, it doesn't need to do all of these other things that a naive or previously never encountered cell has done. And so sorry, go ahead.


Nick Jikomes 20:52

No, I just didn't say so. So what you're saying is, it's really expensive to turn to keep all of the genes on inside every given cell, there's a lot of work and metabolic energy that needs to go into that. So the genes are literally wound up, most of them are wound up and inaccessible, because if you don't need to use them, you don't want to waste energy using them. So if something happens, you get injured, or you get an infection, you want to unwind some of the inflammation related genes and turn them on. But what you're saying is that the cells can then sort of keep those genes in in an open or accessible state so that if you encounter that thing, again, they can sort of turn on right away.


Shruti Naik 21:31

Exactly. And so it's a way it's in many ways a cost saving measure on the cells part, right? I'm just ready to go. And if you think about it, it's sort of like, well, if I've encountered this pathogen before, then I'm likely to encounter it again. So why don't I just stay ready? And why don't I just be alert?


Nick Jikomes 21:51

I see. And that that makes perfect sense. So it's adaptive, because it allows you to respond more quickly, the second time you encounter that stimulus that instigated inflammation the first time. But of course, this brings us right to right to the flip side of this, which is it can presumably become problematic if those genes stay on. And the inflammatory response just becomes constitutive, and you start taking on collateral damage. So how do we start to think about that?


Shruti Naik 22:21

Yeah, I mean, this is a really challenging concept, right? Because then your urges, as a scientist say, well, let's just turn on all the genes and like, get people ready. For, you know, the bad guys like, what if we could be ready for the next pandemic, but hold on, you know, too much of a good thing. It's not always good. And this is what we think underlies a lot of autoimmune conditions when things are unchecked. And so you just have sort of an out of control response. And I think this is the challenge that we're facing now, as immunologist is defining how do you activate a cell enough to let it function at its optimal state, but not hyper activate it to the point where it's going to be going to cause disease? Or how do you change a cell's disease state, and stop it from being hyper activated and bringing it back into sort of a healthy zone of activation? And I think this is a major challenge that we're gonna have to face and address in the next five to 10 years.


Nick Jikomes 23:31

And so do we know so when you have one of these inflammatory events, that causes the chromatin in a cell to unwind so that the inflammation genes can be turned on? Does it typically stay on wind? So that there those inflammation genes are accessible in the future? Or are there cells where the cell is very good at winding and unwinding and winding and unwinding those genes? Is that a common thing that you see?


Shruti Naik 23:56

You know, we don't know fully, and then it's an A large part because it's been hard to look at the chromatin it at a cellular resolution level. So that's something that we're doing now. The other thing that we don't fully understand is, how is this accessibility inherited from one cell to its donor, because those don't live for, you know, years. And yet, we know the accessibility, keeping this open is if I divide, my daughters are going to have that same imprint. We also don't know how the decision gets made for which genes say open, which seems close. So what I mean by that is, if I'm, you know, if I'm a stem cell, and I encounter some kind of inflammatory signal, I'm going to open up a ton of genes. And yet consistently, only a subset of them stay open in the memory for so how does the cell decide if these are the most important ones to keep them these are the ones that are going to help safeguard me from future threats? These are all questions that we really need answers to because they'll help us do Ella mechanisms to manipulate that cell state to that prime response state and not hyper responsive state.


Nick Jikomes 25:08

Yeah, and it's super interesting to think about the epigenetics here, when when, as you mentioned, you think about a cell dividing and giving birth to a new cell. Because I think what you're hinting at is, when a cell divides, the new cell doesn't just sort of start completely reset and start over with a clean slate, it can, at least in some cases, inherit what the other cell learned, I've learned effectively, in in its previous cell cycle. So I think this gets us into the area of, you know, one thing it makes me think of is the area of, you know, stem cells and new cells being used to repair tissue damage and stuff. So can you start to talk to people a little bit about, about skin and tissue damage, so when when you get a cut, or a scrape or something, and then your body physically repairs that skin? What's going on there in terms of cell division and stem cells and all those things?


Shruti Naik 26:02

Yeah, so So tissues, like the skin and the gut, and lungs, their barrier tissue, so they have evolved really sophisticated repair mechanisms, right, because they have to cope with this stuff every day. And when you have damage, essentially, the job of your tissue is to make more tissue to expand. And that task is assigned to stem or progenitor cells. So these are cells that are I don't mean embryonic stem cells, these are tissue stem cells. So these are really relegated to that individual tissue. They live there, they have the identity of the tissue, but they also have the ability to become other things within the confines of that tissue. So my skin stem cell is not going to suddenly become a kidney. In its in the skin, right, it's going to give rise to other skin cells, other epithelial cells, other keratinocytes your outer layer of skin, as needed. So when you have a cut, at the edge of the wound, the progenitor cells multiply, they make more of themselves because you have to generate more cells to make tissue mass, right. And then they migrate to seal the tissue. And so this is what's really interesting about memory is one thing that we don't fully understand is, is is it entirely contained within the cell or do other cells contribute to it as well, and how we know that other you know, you do have you can isolate the effects to individual cells themselves. But tissues are really cooperative, you know, multi system, multi organs are really multi tissue units, right? They're not just one cell type. And so how all of these things cooperate to make this process happen, is still very much an active area of investigation. But then as the sun migrates and seals the breach, and that's how you have your sort of epithelial layer healed, and underneath, there's a layer of your skin called the dermis, which essentially heals by forming a scar. And this is why when you have a major wound, you you in fact end up forming a scar and you have scar tissue at least granulation tissue your fibroblasts, progenitors or dermal progenitors, multiply, they make scar tissue paper collagen down. And, and so that's how they potentially the job is to seal the breech as fast as possible and not let any sort of harmful agent.


Nick Jikomes 28:32

I see so so when we think about the skin, there's a bunch of different cell types that compose the skin tissue. And basically, there's, there's effectively always stem cells, they're sort of sitting and waiting for the appropriate signal, like getting a cut or physical injury. And when they get that signal, they start to divide and differentiate and turn into the new cells that will plug the whole basically.


Shruti Naik 28:55

Well, so this is a this is a really interesting point, because actually, there's some cells there all the time, and they're actively dividing all the time. So you know, all your dead skin, but floss off. Every time anyone exfoliate from the shower, like you know, all your exfoliating face washes, that's all depth can that come out of your body that needs to be replaced. And so this is what we call baseline or homeostatic regeneration. And that can that those new cells are generated by the stem cells that are living in your skin. What happens after injury is it really just kicks it up a notch because now it's not just replenishing the basal level of cells dying as their slots office of their skin. Now, it's about making the hole making new tissue plugging a big hole. And so that's when, you know, the program really amplifies. But there is this baseline function that your tissue stem cells that's


Nick Jikomes 29:53

interesting so that there's always stem cells there. They're always dividing just to replace the normal turnover of cells in our skin. that that just happens naturally. Is there like, is there there must be sort of like a baseline rate, the body's expecting that to happen on what happens if Can you wash your skin too much or too little in terms of how it impacts this, this constant cycling of those stem cells?


Shruti Naik 30:20

Yeah, I mean, you know, no one's done these kinds of studies where they've looked at what happens to your stem cells, if you're just like going crazy with showers or exfoliating? I suspect it probably does. Because I think we sort of understand that the stem cells are really sensitive to their environment. And so they're going to respond to what's needed, right? Because they don't want to, if they stop functioning, there's going to be a big hole in your skin. So I suspect they do. But no one I haven't seen that study. I see.


Nick Jikomes 30:52

Yeah, and I suppose that this whole process all of the mechanisms that regulate how and when the stem cells are regenerating our tissues, presumably, that just starts to break down over time as we age. And that's why as you get older, your skin just starts to heal more slowly and look, the way it used to.


Shruti Naik 31:10

Well, what's really interesting is not only to the stem cells, their functionality goes away, but you also have chronic inflammation. And that relationship between chronic inflammation and how your stem cells age is really starting to come together. So there's an and again, part of that is inflammatory memory, because there have been some really interesting studies done actually in fruit flies, where people give recurrent inflammation. So recurrent infections, recurrent, you know, inflammatory signals. And what you see is you see a phenomenon that's very similar to aging, your stem cells aren't behaving and the way a young stem cell would, and so it's this idea that it's exhausted or it's senescent, or it's, it's just not functioning as youth. And yet, in timescales, it's not an age stem cell, it's just been through that many experiences.


Nick Jikomes 32:09

Interesting, interesting. And so skincare for most of my life is not something I really cared about. But more recently, I do, because skin is super important. It's super important from the perspective of all the things that you've been telling us and you can tell us about what skin does and why it's crucial for health. It's all just important from the fact that people are spending billions of dollars every year on a multitude of skincare products, and it's always difficult to parse. You know, the the sense from the nonsense there. I didn't really plan to ask you this, but as as a scientist with your expertise, what how do you think about your own skin health? Do you what what act? What things do you actually do that you think actually help maximize the integrity of your skin?


Shruti Naik 32:59

Yeah, again, I'm not a medical doctor, this is not medical advice. This is an opinion, I have to say that, like getting a lot of trouble. You actually, I don't usually do this. But I really think there's a recent book by James Hamblin that addresses this topic. What it's called, I can look it up quickly. It's called like the science of skin, I think. But there's two things that have been proven to work in the skin. And that is, yeah, the new signs of skin, clean, the new signs of skin are the two things that have worked and the reason I'll explain why I brought up James's book are retinols and sunscreen, I use sunscreen, religiously, it's really, really critical. UV damage is real. And I collaborate a lot of folks who study melanoma and I just I even in the winter, if the sun is out, put on some sunscreen. I cannot emphasize that enough. So


Nick Jikomes 34:08

we take these one at a time. So what what is retinol?


Shruti Naik 34:12

Retinol is like a vitamin A derivative, and it's thought to help your skin essentially with that turnover process. And then and potentially with collagen production. And sunscreen essentially just blocks out UV damage, right? So it's going to block out the mutagenic effects of UV and it's also going to block out the other damage because UV does other things other than just cause DNA mutations that causes like physical damage to the skin. Sunburn is not great for the skin, it's actually really, really harmful. And so those are the two things that that absolutely well I don't like retinol, I think that's everyone should talk to their dermatologist. But sunscreen is available over the counter. And I highly, highly, highly, highly recommended.


Nick Jikomes 35:09

And now, when when we think about like UV light, so UV light, super interesting in terms of its effects on physiology, there's the bad side of it, you know, it's mutagenic, it will cause DNA mutations, it will cause other forms of physical damage. As you mentioned, the other thing that most people have heard about is that it's related to vitamin D production, it actually modulates various aspects of metabolism and behavior. Believe it or not, that's something I've been learning about recently. And, you know, with all of that stuff in mind, you know, that it does good things. And it also does bad things. Basically, the two poles of opinion, I'll just say that I hear with respect to like, the question of sunscreen and UV radiation and some exposure are, you know, on the one hand, you, you have some people who tell you always put on sunscreen, anytime you're exposed to the sun for any length of time, no matter what. And then you have other people that will say, avoid sun burns, but make sure you're exposed to sunlight, so long as it's not giving you sun burns. Because if you follow the first piece of advice, you're missing out on the benefits of UV radiation. So what are your thoughts there generally? And how do you think about that?


Shruti Naik 36:18

Yeah, I mean, I'm definitely in the like, put on sunscreen at all times category, because, again, I think, you know, there's different forms of UV radiation, and we can kind of get into the details of that. But by and large, every colleague I've spoken to who works in melanoma, just, you know, or squamous cell carcinoma, these are like really devastating cancers. Or just aging, because the damage that's caused to your skin, I highly recommended. So that's kind of where I land. Um, and, and, and that's worked for me. This is why I like to emphasize I'm not a physician, but I have never heard a physician say don't use sunscreen. So that's kind of my opinion on the matter.


Nick Jikomes 37:09

Got it. Got it. So when we think about, you know, the skin and what it does, and the sort of amazing mechanisms for how it can remember what's happened to it, and and follow up on that with with faster action in the future? Can you start to talk a little bit more about ways that that goes awry things that happen where you get these chronic inflammatory states? I mean, I'm sure there's any number of examples we can talk about. I have psoriasis myself, I know that there's other examples you could give. But what are some concrete examples of when the sort of inflammatory memory that our cells are capable of becomes maladaptive and turns into one of these chronic inflammatory states of the skin? Yeah, I


Shruti Naik 37:49

mean, I think there's a lot of examples of that psoriasis being one of them, because, you know, I think, by and large psoriasis shows up in the same place over and over again. And that is one of the big examples of tissue memory because it doesn't, you know, it can exacerbate it can cover larger body areas, but very often, folks, it's crisis or atopic dermatitis, find this recurrence in the same location. All right. So that's always kind of historically been an example of, of memory in that same site where the disease will go away and come back and go away and come back. What was your other question? Oh, my God, my brain? No,


Nick Jikomes 38:30

I'm just asking it. Yeah. Talk about examples where you get these chronic inflammatory.


Shruti Naik 38:34

Other, you know, there was this really interesting study recently. So again, I must emphasize, this is a relatively new area that was started, you know, we started understanding of nonspecific inflammatory memory in immune cells in the late aughts. And then five years ago, I made this discovery that this also happens in non immune cells like stem cells. And so it's a really new relatively recent field. And so we're just starting to understand this. And there's also been links to cancer with inflammatory memory. So one of the you know, for a very long time, people have appreciated the inflammation and cancer are sort of go hand in hand. People often call cancers wounds that do not heal. This was a really famous statement made by a Harold Dirac in the I want to say the 70s or 80s. But but there was a really remarkable study done in mice in which inflammatory memory was linked to pancreatic cancer. So what they did was they inflamed the pancreas and then they let the pancreas go back and become healthy. And what they saw was that this that when you gave these sort of post inflamed pancreas carcinogens, they develop cancer much, much faster and the cancer was much worse than healthy. You know, that pancreas that had never seen inflammation before, despite the fact that When you just looked at the post inflamed or naive, quote unquote, pancreas, they look exactly the same. Again, this was something that was happening at an epigenetic level where there was a memory in the cells, and that was leveraged inappropriately, to drive cancer in this case, and this case, inflammatory mediators drove cancer inappropriately. So this is another situation where you know, you had and what's what the sort of the good part of that was that those pancreas also healed better. So if you cause the post inflamed pancreas damage, they heal better, they didn't let any of the enzymes leak into your body cavity, things like that. So on the one side, you're getting more containment, more healing, but in their site, that same facet is now being hijacked in in cancers.


Nick Jikomes 40:51

I see. Yeah, this, this was something that jumped out to me in the review paper that you wrote that I read recently. And I never even really thought about this, the idea that physical like tissue damage can be tied to the subsequent probability that you're gonna develop something like cancer or other diseases. You mentioned, you mentioned this observation that you know, mutant mice that actually are good at wound healing that heal wounds faster, tend to display increased sensitization to oncogenic stimulator, they're more sensitive to things that can cause cancer. Do we know much more about the mechanisms that connect those dots there? Or is that just sort of the the observation that we have?


Shruti Naik 41:31

Yeah, I mean, I think this so one thing that we see a lot is the same players that are involved in wound healing, I described this process, right, we're like your progenitors need to multiply, and they need to migrate the same sort of things happen in cancer, the same cellular processes, your tumors are just cells that are multiplying out of control, in a large part, because they have a check on their multiplication and a proliferation has been removed, right, or their cell death has been removed. Because in a healthy tissue, once you reach a certain critical mass, you stop dividing, or when you divide too much, you die, right. And so when those checks are removed, you become a tumor. A lot of because a lot of the same processes are engaged in wounds and tumors, and also those are mirrored in the immune system, and wound and tumor. So a lot of the same features that are critical for wound healing, also go right in tumors. You know, one factor that we found interleukin 17, is this inflammatory factor that helps your epithelium adapt to hypoxia. But it's also really bad. And it's associated with really bad prognosis in different kinds of cancer, including colon cancer. And so is it helping those cancer cells adapt in ways that it helps the wound progenitors adapt? Right. And this, again, comes back to this challenge that, in fact scientists have is you can't take something away that or give too much of something and just assume it's gonna be fine biology is a really fine balance. And this is where it becomes important to remember that developing therapies is about navigating that balance. So you're not sort of going in and saying, Oh, just just add as much as possible. And I'll take care of the problem.


Nick Jikomes 43:22

I see. I see. So basically, cancer is runaway cell division, it's when cells escaped the normal checks and balances that that regulate the process of division in a way that's that that's healthy. And so if we think about regeneration, and stem cells and stuff, every time those stem cells are meant, in some sense to divide and differentiate, so every time that there's damage, and they do that, each one of those events is just another chance for the checks and balances to break down somewhere. And for that to turn into a cancer.


Shruti Naik 43:54

Right? I mean, and then you have mitogens, right, for instance, up with that, that cause damage in cells. So this again, is comes back to a big question, which is, you know, doesn't matter if the damage is in a stem cell? Or does it matter if it's in the daughter cell? And how to cells deal with that damage? And if they're not dealing with it properly? Are they going to go multiply out of control? The, again, you're asking excellent questions. I don't, or maybe the field doesn't really have answers to that we're all trying to get to the bottom of because they're so fundamental to eradicating these conditions.


Nick Jikomes 44:33

Yeah, and then like, the other thing that's interesting about all of this is, you know, when we think about an inflammatory event being instigated at a barrier tissue, like the skin or in our intestines or something, what we've been talking about are sort of local memory, local mechanisms of fairly nonspecific memory. So cells in the skin or in the intestine, that sort of lived down there can remember and subsequently respond to some inflamm toward the stimulus better. But then also, there's recent observations that I think you mentioned in your paper about how the, those mechanisms in the body and the peripheral tissues can also interface with the brain. So places like the insula, and the brain can hook up to neurons that physically reached down to the gut. And your brain can keep track of and remember, you know, gut inflammation and things like this. So So what are we learning there about how the brain and the gut say, are interacting and how memory is stored at the level of the brain for something that's happening in the periphery?


Shruti Naik 45:31

Yeah, this is actually a really, really exciting area. So for a very long time, scientists have known that there is a connection between our mental health and manifestations of inflammatory diseases. And and we also know that immune cells respond to inflammatory mediators, we know neurons respond to immune mediators. So ever since beautiful study, recently, by Alicia Royals, in I think she's at the Technion, where she actually found that if you have a peripheral infection in the gut, it's, it's encoded at certain parts of your brain. And when even when the inflammation goes away, when the infection results, if you just stimulate that part of the brain, you're able to re bring bring that infection or that inflammatory response back. And so the implications are that if we understand the brain more, and we understand this access more, maybe shutting off autoimmune diseases could be entirely based on just treating parts of the brain. Right? If I could shut off your psoriasis by figuring out which part of the brain is encoded in, that will be remarkable. We don't know yet if that's possible, but that's certainly the implication of the study.


Nick Jikomes 46:47

Interesting. So yeah, the the brain can literally reach down and touch the gut and touch the you know, the other parts of our body. And it can remember inflammatory events that happened that were localized and contained in the gut or in the skin, or somewhere that never got into the brain. And then at least in this one example that you gave, the brain can actually turn on that inflammation again, if it I mean, the implication here is that to turn on that inflammation, again, you don't necessarily need the physical stimulus in your gut to happen, you might be able to learn to say like, Oh, I saw this thing over there that came in through my eyeballs and my, my sensory perception that was associated with that. And you could you could have something sort of driven top down like that?


Shruti Naik 47:29

Well, presumably, yes, in the study, they in fact, has stimulated the specific parts of brain. So it wasn't, they didn't show that there was a connection between visual stimuli and inflammation, I'm not saying there may, there may be that yet to be determined, but they physically stimulated the locus of the brain that was encoding that sort of memory. And so the idea may be that, you know, you stimulate that locus, and so you activate in the peripheral neurons, the secretion of XYZ factors that then trigger the local immune compartment that trigger the disease. And so it's this sort of communication between the brain and the peripheral system that's, that simulates what the brain feels when you have disease.


Nick Jikomes 48:15

Yeah, and, you know, one of the things I want to circle back to is this idea that, you know, we can, you know, our likelihood of developing certain metabolic disorders or certain chronic diseases, inflammatory diseases, can be connected to stuff that we're exposed to in utero or in early life in our body remembers something about the things that happened to us at those times. And that can have implications in adulthood. So if we circle back to the Dutch famine example, that was super interesting, for the following reason. So basically, Dutch famine happens, children that were developing at that time, are presumably in some kind of caloric and or nutritional deficit, their bodies remember this, and this is making them more likely to have certain metabolic diseases in the future. That's pretty intuitive. I think, you know, if there's some kind of calorie or nutrient that deficit, then that causes problems down the road from metabolism makes a lot of sense. What's interesting is that, in the so called Western world, today, we're seeing this rise in chronic inflammation, chronic diseases, this rise in metabolic disorders. And yet, we at least ostensibly, don't have a deficit of calories and nutrition, right? You know, we can all go to the store and get whatever we want. And yet we're seeing a rise in these things. So how do you start to think about things like diet, and how the current diet we have, even though you know, we're not most of us most of the time, are getting all the calories and more that we need. We're getting all the nutrition and more than we need, at least we think we are. Why are these things rising in a state of surplus rather than a state of deficit?


Shruti Naik 49:55

Well, I think again, we go back to this idea of too much of a good thing, right? Because you said we're getting all the calories you Need and more. That's the ad wars where the problem arises. So for instance, just the opposite of the Dutch famine example, maternal obesity is associated with increased risk of early onset codal, cancer, increased risk of asthma and allergies gets tons of increased risks and offspring, right? So it's not sort of there, I think we have to realize that biology happens at an optimal state, you know, it's not too little or too much, it's not good. And what the optimal state is, depends on who you are, you know, but I think that now we have the problem of over nutrition, and obesity. And that's becoming a global pandemic, that's, you know, that's the next global pandemic, in my opinion. And those are situations where you do see increased onset of disease, and transmission, I think there are studies that are currently ongoing, that are starting to examine how maternal obesity impacts offspring, because that's something that's really, really critical today. You know, the the other area where people are starting to realize that that sort of, you know, maternal exposures may be playing a role is infections and getting not getting the right signals during development. So there have also been a lot of sort of incredible studies that are starting to link certain cytokines, certain inflammatory factors being present at the wrong time during development, with things like autism, and it's, again, it's still early days, but their viral infections are are linked to developmental disorder. So So seeing the wrong signal during development can have really lasting consequences. And that, you know, it doesn't mean under nutritionally over nutrition or not, you know, the wrong inflammatory cue at the wrong time.


Nick Jikomes 51:59

Yeah. I mean, one thing that I've been thinking about lately, to some extent, is, has to do with fasting, you know, intentionally fasting, it's sort of become trendy, again, in certain ways for, you know, health and health and wellness reasons. But I'm fascinated by the idea that, you know, historic, if you take the if you look at the long arc of history, virtually every culture in every major religion has incorporated some form of restriction of feeding some form of fasting in their cultural practices, right, Ramadan, Lent, you know, Eastern religions often incorporate a fasting in different ways. And, you know, I wonder if this is sort of, you know, none of the people that started all of these practices knew about chronic inflammation and cells in the body and all of the sciency mechanisms that were untangling today. And yet, somehow, they all converge convergently evolved to these practices where they're intentionally not eating things for some period of time. And to me, that's, that's super interesting, that this sort of cultural historical level, but you know, on the topic of fasting, in particular, you know, restricting how many calories and things that you're consuming intentionally? What do we what do we know there about the link between eating too much, on the one hand, and fasting, on the other hand, and the propensity to develop certain metabolic or inflammatory diseases?


Shruti Naik 53:23

Yeah, so I think there are, and this is, again, not my area of expertise. So I'm going to put that out there. But I know there are ongoing studies that that are, you know, really looking at like defined types of diets in controlled ways, right. So I take one person, and I put them on X define diet, and look to see how their immune system is responding, and then do a little wash out and then put them on another defined diet, and so you have the same person and how their immune system changes. And this the studies, I mean, really show that there are some profound diet specific changes. Beyond that, you know, this is again, really not my area of expertise. But I do agree with you that it's remarkable that so many cultures converge on the same sort of notion of not over nutrition. And the other thing to remember is, you know, when these notions of like controlling your food intake were put in place, they also didn't weren't faced with many of the things that we're faced with which are things like high fructose corn syrup, this sort of supplements and, and and the availability of all these like packaged foods, right. So I think that we kind of have a double whammy on our hands in many ways. Not only are we not only has our lifestyle changed so dramatically, and and but our access to the types of foods that are particularly harmful, may have changed as well.


Nick Jikomes 54:53

Yeah, and you know, on the subject of too much of a good thing, and thinking about diet and fasting, you know, I've had a number of this discussions with people about, you know, all sorts of different aspects of physiology, you know, mitochondrial energetic stuff, diet, nutrition stuff. And one thing that has come up at least a couple of times on the subject of, you know, too much of a good thing being a bad thing is, you know, whenever, many times at least when we're in deficit in some ways in our, in our body, whether it's in deficit of calories, or anything else, our bodies often have mechanisms that kick in to counteract those deficits, or even things like exposure to, you know, oxidative stress and making our own endogenous antioxidants and things like this. And, you know, the idea that's come up a couple of times is, if we are constantly ingesting, say, every antioxidant out there that we can get from our diet, we never actually allow our bodies to turn on their own anti oxidative stress mechanisms. And that could actually be a bad thing is that is that how we can start to think about things like this, that we that we don't always want to be in surplus, because it actually gives our body's endogenous mechanisms of repair and rejuvenation a chance to kick in and do their thing?


Shruti Naik 56:05

Yeah, I mean, that's part of it, right? I think that one, we're not giving our bodies the chance to have repaired regenerative mechanisms. It's the same with the immune system. So there's a sort of long standing hypothesis called the hygiene hypothesis, where people think that you're kind of too clean. And the evidence for this comes from like, for instance, farm children, children raised on farms have lower incidence of asthma, and, and expose, you know, the autoimmune exposure in westernized countries so much higher, but it's not going up in all non westernized countries. And then you look at countries where they've undergone westernization and exposure to sort of, you know, environmental pollutants or different dietary intakes, and you see that, that autoimmune exposure go up. And so it's one of those things where it's sort of like, your immune system has evolved an optimal state of functioning to clean is not great either. And so all the over antibiotic usage, and the and the sort of urban lifestyles have also contributed to this. increased incidence of of autoimmune onset.


Nick Jikomes 57:18

Interesting. The other thing I wanted to maybe ask you about was when we think about memory in general, and we think about how memories are instantiated at the level of cells doing stuff, you know, my background is in neuroscience. And, and I think the bias of most people when they think about memory is to think about neurons in the brain. And we touched on this before, but you know, I think if you ask the, if you pluck a random neuroscientists from their lab for a moment, you ask them how memories are stored, they'll say, Well, it probably has something to do with the strength of connections between synapses. And that at least has something to do with it. Although there is, you know, we still really don't know what a memory and gram in the brain is. And there is some debate of the extent to which it's, you know, connections between synapses between neurons, versus say, something happening in the nucleus to do with epigenetics and gene expression regulation. So, you know, given what you talked about before, for these peripheral forms of memory, that certain cells have been involved in arranging DNA in certain ways and keeping chromatin in certain configurations? When you think about memory at the cellular level? Do you think that different types of cells in different parts of the body brain versus immune system versus skin versus this versus that? Do they do you think they might all have distinct forms of cellular memory? or might there be a common core of cellular mechanisms to do with things like chromatin rearrangement? That is common to all forms of cellular memory?


Shruti Naik 58:46

Yeah, I think that so. So I think how memory is established, the rules are probably going to be similar link is probably going to involve similar types of enzymes that open up chromatin, you know, parts of the chromatin that regulate other parts, like for instance, distal enhancers, I think what will be unique to cell types is and situations is what part of their DNA is accessible. So I what I mean by that is, if a cell sees a virus versus seeing another dying cell, it may likely remember different things. And then if that cell is a neuron versus versus a macrophage, it may likely remember different things. But these are all things that need to be worked out, you know, at what level is memory encoded? How cell specific is it? How to different if you have a tissue with many different cell types, or an organ with many different cell types, which of those encode how much memory and which cell matters? Or do they all matter together? Because if we're gonna reset your skin from forming psoriasis, we need to treat all the cells that matter, not just one filter, right? So those are the kinds of questions that we really need to start digging down into to understand how our tissues remember their encounters? And, importantly, how do we manipulate that to reset it, for instance, in aging, for instance, and disease.


Nick Jikomes 1:00:17

So given, you know, given how big of a problem, chronic inflammation is, given that it's on the rise, and that, on the one hand, we know that there's connections between things like diet and lifestyle, and in your in utero environment, all of these things with inflammation, but at the same time, on the other hand, we really don't know all the details, at least not at the level that allows us to control and fine tune these things. Are there any clear cut pieces of advice that are rooted in what we know scientifically that can help people minimize their odds of developing chronic inflammatory states? Or is the knowledge for that really not there yet?


Shruti Naik 1:00:58

Um, again, I always like to remind people, I'm not a clinician, but this is what I would do exercise and, you know, like, eat a balanced diet, and consult your physician. I think there's studies on the wait now that are ongoing, that are starting to look more precisely at how individual lifestyle factors impact onset of chronic disease, right. And I think that's going to require a level of personalized medication because it's not just one gene or one thing. There's families in which there's twins, where you know, identical twins, one will develop psoriasis, one will not. And, and so it's very hard to sort of give advice on like, if you do this, you're never going to develop a chronic disease because it is a multifactorial disease, it is so challenging to treat. And so, you know, I think diet. We know that, you know, obesity is associated with onset of many, many chronic diseases, we know lifestyle things, lifestyle choices, like smoking, not the greatest for many chronic diseases. And we know that exercise, which helps, I guess, goes back to sort of your, your obesity index, and your BMI, are the sort of key things that you can control and lifestyle choices that you can make that are associated with less onset of disease. But to say, if you take this magic pill, you're never going to get disease. I don't I don't think we're there.


Nick Jikomes 1:02:37

Yeah. So in some sense, the best pieces of advice are fairly common sensical. Exercise regularly is important. And not, there's a couple of things I want to ask about diet here. So not being in Super caloric surplus all the time, is good. And I guess there's many strategies one can take to do that one could be to develop your own fasting ritual, whatever that is. And not not overindulge too much. But that's very difficult for people. But you know, the other thing that you mentioned, which people always mention here, but I think is, it's really, it's really hard to act on this because there's some ambiguity, you know, eating a balanced diet. But how do you personally, I understand you're not a physician stuff? How do you start to think about what a balanced diet is, because for most of my life, the balanced diet, I was told by the Department of Health, the food pyramid, is clearly at the very least, I'm confident saying that's clearly not the best diet one can be on. So how does one even begin to think about what a balanced diet even should be?


Shruti Naik 1:03:41

Yeah, I agree with you. I think the I disagree with the food pyramid. Personally, I don't think you should be eating like loaves of bread. That makes it I do love carbs. So you know, it's always a challenge. But generally, I think like a medic, I've always read a Mediterranean diet, right, which in or food, lots of vegetables. Fermented foods. Don't have too much processed food. But I don't give up any aspect of like, I'm not big into ketosis or but yeah, I don't think cutting out any food group is necessary. I think it's just about sort of, not over indulging, and and being going for the fruits and vegetables. That's just my,


Nick Jikomes 1:04:35

ya know, and that makes perfect sense. I mean, the other thing that you mentioned that has come up a number of times in conversations I've had on the podcast is the gut microbiome and that basically, the two things that stuck in my mind are, you know, getting a good amount of fiber and getting a decent amount of fermented foods are generally going to be good for the gut microbiome.


Shruti Naik 1:04:53

Yeah, that's, yeah, that's 100%. I mean, all the data suggests that Christopher's Vegetables are fantastic for the gut microbiome. Yogurt. You know, the things that you don't want to eat as a kid are basically the things you should like if you're, if your kid is throwing his broccoli away, you should be eating that broccoli.


Nick Jikomes 1:05:16

Interesting, interesting. Well, we've we've covered a lot actually quite quite a diverse array of subjects that connected together here. Are there any things that you want to reiterate for people as takeaway points, or any final thoughts you want to leave people with on the general subject of inflammatory memory and related things?


Shruti Naik 1:05:35

I'm sure I mean, I think that, you know, there's this real desire in people, including myself, to have absolute answers, right isn't good or good thing or bad thing. And, and I don't think our body works that way. I think there's, it's really hard as a scientist to speak in absolutes. But what I think is remarkable is that everything you do your cells remember, and you know, whether they unleash that power to help you heal or help you fight pathogens, or whether it's sort of taken a bad turn and cause disease. I think the next decade or so or longer will be really focused on figuring out how that decision was made. And once we know that, it's going to really revolutionize how we treat diseases, how we prevent diseases, because that would be the ultimate goal.


Nick Jikomes 1:06:32

All right. Well, Dr. Sruthi nyac, thank you for your time.


Shruti Naik 1:06:35

Thanks so much. Thanks for having me.


Transcribed by https://otter.ai


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