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The Science of Food & Inflammation - Semir Beyaz PhD

The Science of Food & Inflammation - Semir Beyaz PhD
Endometriosis 2023:
Global Patient Symposium
Together for Tomorrow
March 18-19, 2023 - Einhorn Auditorium, Lenox Hill Hospital, NYC

Great. Thank you so much, um, for the invitation, and thank you all for, um, you know, coming here today, I believe, uh, patient, clinician and, uh, scientist. Partnerships are very important for us to understand diseases and then treat the diseases. And today I'll give you a, um, you know, few vignettes of, uh, my journey and how I ended up, uh, trying to figure out what endometriosis is and how we can, how we can potentially one day cure it. And the main focus today is not endometriosis. It's about how we can understand a bigger problem, nutrition. And so there is a lot of buzz about nutrition, but we know very little about it. And I will show you how we can really now make progress in understanding the nutrients that we introduce to our body, go into our tissues, go into our cells, and affect who we really are.

So, um, I will tell you that what you will get from the seminar may not be what you have anticipated when you read the title. You'll get the significance, the challenges, and the value of mechanism based nutrition. And by mechanism based nutrition, what I mean is that you truly understand from the minute you eat something, what happens to your body. Where does this nutrient, let's say it's fat, get digested. And then when it get digested, how does it get incorporated into your bloodstream? How does it go to the cells, which cells like to feed on that nutrient? And then what happens to you overall? And then the second part is, you know, fitting to this group is that why you should support and advocate for mechanism based nutrition research, because there is a lot of resources in our community in the world that are wasted, and we still cannot understand what we should eat.

What you are not gonna get from this seminar is a magic recipe that will cure all your melodies. I wish I could give that to you, but I'm not gonna be able to do that. So this is just upfront. However, if you continue supporting mechanism based nutrition, uh, I love cooking, I love, I love food. I like, uh, I'm from a southeastern Mediterranean part of Turkey, so food is an essential part of our daily lives. And so, you know, if you continue support, uh, endometriosis Foundation of America, maybe we will meet again in a, a patient day and I'll, I'll bring some of those, uh, uh, magic recipes with me. Um, so the one thing that I wanna highlight is why the problem of nutrition is really difficult is because it's, it constantly evolves and we are part of a rev evolution right now. So the way that we evolved our own food choice started million years ago.

So here I try to highlight it, um, you know, from fruits to, uh, start eating vegetables and meat, uh, we come here to homo sapiens, which is, uh, uh, coinciding to around between 800,000 years ago to 50,000 years ago, we started experimenting with, uh, meat fire and cooking. And then civilization started around Eastern Mediterranean, middle East 10,000 years ago. And then we introduced grains and agriculture, and we settled, and we started cooking and generating all these great grandma recipes that I hope some of you still have and not consuming fast food. But look where we are at now. Half of human population is undergoing a problem called overnutrition. We have very easy access to food. You know, you can order it, it can come, it has processed food, it has simple nutrients that your gut doesn't easily, um, uh, uh, does, does easily digest, and, uh, uh, doesn't do its proper job.

And half of our population is going under something called undernutrition. So undernutrition is not just about not eating food, it's also not eating quality food. So those two problems actually underlie almost every single disease that we facing human population. And these are some numbers for you that I don't think, you know, you should remember just to pinpoint billions of people total in the world right now have malnutrition. Many of us in this room are gonna undergo a malnutrition period in our lifetime. So it is increasing and contributing to the rates or, and worse outcomes of many diseases. So these diseases include cancer, cardiovascular disease. We know very little about actually how nutrition affects endometriosis. And I will highlight some of the work that I'm trying to dig in right now, understanding how nutrients affect endometrial biology. So, but we know what your grandma said to you is true, you are what you eat.

So I will highlight some of these examples too, but we don't know how, like what makes you what you eat. This is still an open question. So in my lab at Coldspring Harbor Laboratory, which is in Long Island, um, on a beautiful campus right by the water. So hopefully we, we will invite you guys to have a, uh, a patient day over there. And, um, you know, we can talk about the updates of, of the research there. We try to understand this in a, a holistic manner because, you know, nutrition needs to be understood both at the cellular and molecular level, but also at at the whole organism level. And so we know that nutrients are used in your body for three things. Now, one, your cells require energy to survive, so nutrients can be metabolized and can generate energy. The other thing is, it can make up the building blocks of your cells.

So your cells are composed of membranes, DNA, organelles, all these things are building blocks so nutrients can provide those essential units. And then the, the, the more recent things that is becoming really exciting about nutrition research, it also influences the identity, the function of yourselves. So like all of us in that room ourselves, ourselves have different personalities, different identities, different functions that carry out, you know, the, the, the function of the organs that they are part of. So then this becomes a big challenge to understand from the minute that you ate that bagel or the cream cheese or that, uh, uh, donut, what is going on? What's going on in your immune cells? What's going on in your, uh, endometrial epithelial cells? Then how the tissue that com is composed of multiple cells is adapting to that alteration, how different organs that are, uh, part of systems and, uh, uh, multi, uh, multisystem partnership that's making this whole organism work properly are affected by it.

And then the most challenging aspect is that I can do all these three things in a mouse and controlled manner and little bit in a human. But humans and organismal states are complex, right? What are we talking about when we talk about organismal states? We have different body mass indexes, we have different age range, we have different genetic ancestry. We are coming, uh, from different parts of the world that have accumulated different genetic, uh, makeups. And we may be at different stages of what we call the health and disease spectrum. So these are very complicated, but we know that there is something about metabolism that affects who we are. And those come from two paradigms so far. So the first paradigm is what the grandmother told us, right? So you are what you eat. Uh, so from, for thousands of years, humans experimented with food as medicine.

So far we don't have a medicine as a food or food as medicine yet, but we are going in that direction. I'll highlight three interventions that have shown some association. Number one is ketogenic diet. It's a very popular these days. Every a hundred years it becomes popular. Last time it was popular in 1920s, people have observed that, uh, you know, ketogenic diet feeding, which means that very high amount of fat and very low amount of carbohydrate can help mitigate epilepsy seizures. And now we are also trying to experiment how does it affect cancer? So I'll tell you, I study this every day. The, the, the, the association is not one-to-one. So there are a lot of variables. The other concerning effect is the association between western diet and obesity and overall mortality and cancer. And there is a puzzle between obesity and endometriosis that we also don't understand.

And, you know, I would love to, uh, you know, continue talking to clinicians to understand that puzzle better. And the, the last one I wanna highlight is there is thousands of years of narrative that fasting in many civilizations have been associated with longevity and health span. And we don't know actually how that this, how does it happen? We know that if you fast warms, they live a little bit longer, but it's not clear if that's the case in humans. We know at the cellular level, yourselves like yourself, choose certain food when they are, uh, acquiring specific set of functions. So I'll give you three examples from your body. Number one is your tissues, especially tissues like endometrium, they regenerate, endometrium, regenerates every month during the due to shedding of the epithelial layer. And the re regeneration is facilitated by, by the stem cells of the endometrium.

So what does the, those stem cells do? They replenish themselves and they give rise to those specialized cell types of the endometrium. I call them progenitor and differentiated cells. And there are theories about the initiation of the endometrium due to some problems of that harmony, of that process that takes place between the decision of a stem cell to become a progenitor differentiated cell. And we know that these cells have a choice of a metabolic state. We don't know precisely yet how it is in endometrium. I know it little bit in, uh, the intestine, but this is where we are going towards. We also know that immune cells have the same similar pattern of, uh, uh, choice of metabolism. So, uh, you can have resting immune cells, you ha you can have actively fighting immune cells a against a pathogen. Uh, and then you can have some memory cells that are, you know, after vaccination or exposing to a pathogen, they are waiting to respond again.

And they also have different metabolic programs. And lastly, I will highlight there is a lot of lessons that we learned from cancer biology, which is this abnormal transformation of a regular, uh, stem cell or a cell in a tissue to the cell that takes over the entire body. So this malignant transformation of cancer also has some metabolic requirements. And so the analogy of this normal to tumor transformation for endometriosis is quite remarkable. And, you know, uh, because another cell type in the body without cancer that can do that type of transformation and then can go at distant site and create its own home, is only happening in a disease like endometriosis. So I wasn't trained as an endometrial biologist, or, uh, I didn't think about endometriosis unfortunately until like few years ago. And luckily now I met Dr. Sk. And we are gonna go and apply all these knowledge that we have learned so far to endometriosis.

But the problem is, you know, beyond my ability to ask those questions or my colleagues' ability to ask those questions, in general, there is very little known about endometrial biology. So because we know that these two parts interact, I will say that we have an opportunity to use nutrients or as medicine, and we also have a larger opportunity to define those targets of mechanistic targets that can become therapeutics. So, you know, maybe in a year, maybe in three years, maybe in five years, I don't know when, but hope, I'm hoping that we will apply that knowledge to endometriosis so that I can definitively tell you when you eat something, how does, how does that affect, uh, disease outcome in, in endometriosis? So there are some challenges that are not visible, so it fits the title. But, uh, I wanna tell you basically, uh, you know, a philosophical aspect.

Where are we? Why are we cannot, why are we not making important progress for discovering nutrients as therapeutics? And this fits everything that we go through in our lives. So in our lives, if we wanna reach a wisdom, if we wanna accumulate knowledge, we go through this cycle between our competence and confidence. And so there are, you know, psychological theories about that. And I teach that to my students in the lab who are aspired to become scientists. So when you have very low competence of a, uh, of a subject, you think that you can do it, you think that you can answer it. So people who don't know anything about something, they can easily talk about that topic. And, you know, pretend they are experts. And in America, we are seeing that problem. In my home country, Turkey, we have that problem. And in the lab we have that problem.

When, you know, you start working on a topic, then your confidence drops because then it, you see the challenge, you see the, the the problem. So in order to make a discovery, you need to go through that constant struggle between thinking that you learned something and then thinking that you're so stupid and you have no idea what you're dealing with. And so as a scientist, the biggest thing that we do every day in our lab is to reset that mindset and not to give up every day. You are gonna learn something new about what you are working on, not by thinking how smart you are is by failing. When you fail, it shows you the way. And good scientists are the ones that can go through that zone and then do nothing that, you know, they know everything. The good scientists are the ones that wanna go out of that comfort zone and figure out what they don't know.

So the main problem is that we don't know what we don't know when it comes to nutrition. So how can we figure that out? I will give you an example by looking at fat. So, you know, my lab studies biology of fatty acids and fat, you know, we study other things as well. So I'm happy to answer some questions about fibers and vitamins and something like that. But I just wanna use fat as an example, how complicated the problem is, look how many different fat sources you can choose from for breakfast or lunch or dinner. This is, say, a fitting topic before lunch, I guess. Uh, so you know, large coconut, uh, milk, cheese, dairy products, uh, olive fish, so many things that can generate some sources for the fat intake that you have. So these fats in your food source are composed of these things we call fatty acids.

Okay? So they, when you eat them, they're in the form of triglyceride means that three fatty acids are attached to the sta head. And then when you go to the intestine, they get digested. But look, what are the differences? You have different chain length, different saturation, different double bond position. Don't ask me why, because some chemists back in the days chose to label them with omega-3, omega six and omega nine, depending on where the double bond in that molecule is. And then you have the configuration. I bet you heard of this, trans fat is bad for you, CI fat is good for you. So it, I, I'll get into that later. But this is one part, one layer of that complexity. The other complexity is how do you consume that fat? Is it you are consuming low fat, considering the total intake or percent of the calories?

Is it high fat? Is it high fat, low carb ketogenic? Is it, are you constantly eating it? Are you time-restricted eating it? Are you eating it little bit and then reverting it to like plant-based diet? Are you doing the cyclic regimen? Are you a already lean person? Are you an obese person and you are trying to not eat fat or eat fat? I mean, it's crazy. So like the op the the possibilities are insane. So that's why I cannot answer your specific question about what you eat, because you are very unique, and I haven't done the experiment yet, but I, I'll give you some, and this is, I'm not gonna give that in a scientific session, but for here, because I, I get those questions all the time, this is my personal advice for a general human being, otherwise not having a significant disease, uh, you know, follow a balanced diet, get electrolytes, preferably from vegetable sources.

Uh, uh, fiber is very important for GI health and variety of fat sources and types. So I'm Mediterranean, we eat fish, we eat lamb, we eat everything. So, but you know, your grandmother was right, moderation and moderation and moderation even itself. And so embrace life, you know, like this is a, you know, patient day. I wanna tell you that, um, uh, you know, I didn't understand and know how horrible, uh, the situation is when it comes to, uh, women health. I take the blame for it. When I was doing my PhD, I was studying colon cancer, which hits mostly men and some women. Uh, but when I realized that how, how much we need to do for reproductive health, especially in women, I devoted around 50% of my lab to the study of ovary, endometrium, and its diseases. So we need to embrace life and we will solve these problems day by day together.

Um, if you can do that, if you have a balanced diet and embrace life and you know, uh, uh ha have a balanced life, I think this is a good lifestyle recommendation that you can get from a basic scientist like me. The other thing that I can tell you as a friend to avoid is trans fat, highly processed, uh, food, uh, excess simple sugar, uh, sedentary lifestyle, stress, sleep deprivation. So you live in New York City. If you can do those things, good for you. If you can't, it's fine. Yes, <laugh>. So I will, you know, tell you that again, we don't know how diverse dietary fat sources definitively affect health and disease in real humans. But I'll take you through a journey how I'm in my lab trying to unpack this. So bear with me. There are some technical aspects, but I will go through it in a, a very non-technical term.

So in my lab, we really zoom into individual cell types in your body. So yours, uh, uh, the cells that we study in your body are called epithelial cells, which is the lining of endometrium for the people who are curious of, uh, what endometrium looks like at the cellular level. And then there are some immune cells. And so as an immunologist, I was taught to think only about immune cells. This is what science disciplines do to you. And then I was like, this is ridiculous. There are other cells that immune cells are constantly talking. So I was lucky in my PhD to start studying the communication between epithelial cells and immune cells. And that led me to ask a different, uh, member of that puzzle is what the microbes are doing. So I will show li little bit about that. There is a constant communication between microbes and host cells, including immune cells and epithelial cells.

And so these affect, uh, regeneration, which we studied in the context of physiology and diseases like cancer, endometriosis, infection, inflammation, you know, you can apply that knowledge to everything. You can study this as a, as I said, at cellular level and organismal level. We use different methods that I'm not gonna bore you with, but we basically design experimental frameworks to definitively understand how a nutrient affect physiology or disease. And so the simple journey of food, you eat the food, where does it go? You chew it, hopefully you're chewing the food before you eat it. It goes to your stomach. Proteins get digested there. And then if you're talking about fat, the digestion starts around the other, which is the small intestine. And then let's take a closer look to it so that you appreciate what I'm talking about when we are trying to link that.

You know, like when a surgeon looks at the, uh, intestine versus a cell, biologist looks at the intestine. So, uh, your intestine is a, a tube and it's composed of these finger-like structures that absorb those nutrients and facilitate the digestion. And at that interface, as you can see here, there are so many different things. There are veins, there are these micro structures that are called intestinal glands. So endometrium has a similar structure of gland. So look at that crypt. At the bottom of that crypt, there is a stem cell. The stem cell sits and then give rise to these cells for the intestine. We know a lot about what the factors in that microenvironment that regulate that. And for that reason, we can recreate those structures on a dish. So we can take those structures, we can add those, uh, goodies that this, the cells like, and then we can regrow the, uh, the, the gland on a dish to study its biology.

And so we know very little about the same process for endometrium. And so, uh, this is just highlighting the main, uh, concerns that we need to address to understand endometrial biology. There are so many diseases that are hitting, you know, like almost everyone in that room, probably with very high prevalence, including endometriosis, ayos, fibroids, fertility, and endometrial cancer coupled together, I mean, majority of our population are struggling from those diseases. Yet, as a biologist, I can tell you it's crazy that we know so little about it. And so as a biologist in the lab, you can study things in a mouse model or in a dish or you know, in a tube. But you cannot understand a disease like endometriosis, like that. You need human systems. You need to understand the biology of the human to understand the disease and then to treat the disease.

So that gap needs to be closed. And these events like that are, are giving me hope because this is how we can close it. And you know, I met Dr. Kin not too long ago. I wish I had met him, uh, long, longer time ago. But now we are gonna dive deeper into closing that gap. How do we do that by developing a better understanding? So this is the human salla project that my lab is leading. It's a collaborative project across several investigators in greater New York area. We wanna understand cell by cell, how does an endometrial epithelium looks like? What are the immune cells? What are the fibroblasts? What are, you know, these specialized cell types? And so this is not something that I can do alone. I need co computational support. I need, uh, patient recruitment efforts. It's not easy to, uh, convince a patient to enroll in a study.

And we are doing this not just in woman who can go to Memorial or Lenox Hill in the city. We are also trying to go to community hospitals so that we can diversify our patient pool. Ethnic, uh, disparities are very, uh, concerning about diseases. And there are some disparities are exist. We know in endometriosis, people with different ancestries exhibit different risk and different outcome for the disease. So this is what we are doing. We are generating these maps. It's like, it's similar to the human genome project, but more difficult because in human genome project, one person was sequenced and he was a male in his late, uh, fifties. And now we are trying to sequence, uh, close to a hundred women, uh, from diverse a trees. So it is challenging, but we are taking upon that challenge. So in addition, we are developing these a avatars called organoids that I showed you.

We grow that tissue on a dish, and then we then study how the behavior of the tissue happens. So we developed this biobank at Cold Spring Harbor Laboratory in partnership with Northwell. Uh, um, and so mostly so far we have collected either benign endometrium from like fertility, uh, clinics or endometrial cancer from, uh, oncology services. And, uh, uh, we are hoping to set up a partnership with, uh, Dr. Kin's clinic to do the same thing for endometriosis. So this is what an organoid looks like. These are like little ball structures that are composed of cells. These are the cells of the endometrium. And so you can see if fluorescence picture here, the blue denotes the dna, which is in the nucleus, and the magenta is the cell body, which is the cytoskeleton. So you can see that there are balls of cells hanging around together.

And then right around the corner, there are some rogue cells that are trying to push from that ball like structure. So this is a model we are developing to study the initiation of a, of an endometriosis. Like what makes a cell that's sitting on that endometrium one day to decide and go to the abdomen or to the lung or somewhere distant in the body and sets sharp and pretend that it's, it's in the uterus. So we don't know that. And, you know, we can answer that question if we apply those tools of molecular biology and genetics and cell biology to that particular problem. So I know I can do that because we made that progress for intestinal stem cell biology, and we will make the same progress for endometrial biology. So I'll give you some vignettes in the last few minutes. Did I get the last five minutes sign there yet?

No. Did I? No, I didn't get it yet. Right. Okay, cool. Do I have it yet? I I can't see the time. Okay. Yeah. Anyway, I mean, if you are bored, you just yell at me, I'll stop. But the first example I wanna show you is how can we understand the mechanism of disease and impact patient life? So during my PhD at Harvard, as I told you, I tackle the question, how does nutrition and overnutrition like obesity can affect tissue regeneration and cancer outcomes? Specifically, we focused on the, on the gut, uh, and we defined exactly what happens when you eat a lot of fat. So this fat diet that we used was lard based diet. So lard has a lot of saturated fat and little bit monounsaturated fat. And so if you consume that for a lot as a mouse or as a human, you end up becoming little bit obese.

That elevates fatty acids. It activates some factors, some genes in your, in your cells, and that makes those cells little bit proteinogenic. So it confuses those cells. And so we, we published series of like landmark papers demonstrating molecule by molecule, cell by cell, gene by gene. How does that affect? So that has some relevance for cancer, but it also has some fundamental knowledge that can be applied to any stem cell biology. And so this is what we develop now at, at my lab, uh, across different tissue types. We understand that there is some regenerative fitness of a tissue, and this regenerative fitness is defined by the cells of the tissue like stem cells. So if you have a lot of uncontrolled abnormal regenerative capacity that can lead to cancer. So cancer is this uncontrolled growth, and some theories are suggesting that maybe endometriosis is also due to that, I don't know.

And then if you have less regenerative fitness, then you get degeneration. So somewhere in between you need to have health that's defined by, by those resilient cells that are upon damage, they will recover. Okay? So if they don't recover and if the damage is constantly happening, you get degeneration or scarring afterwards if you cannot recover that. So we found some regenerative diet regimens that can address that. But this is just telling you how much we now know about what a nutrient does to your tissue. I can link up one specific fatty acid type by looking at all of the fatty acids that are commonly used in your diet. So this is some data slide that I'm not gonna hopefully lose you. So we can, we can look at these cells individually and check different fatty acids and how they affect the growth of a stem cell.

And so look in control, this is a self-explanatory. The, the size of that organ, like structure is small. When you treat it with omega six fatty acid, it's big. So that means omega six fatty acid is promoting the regenerative capacity of the tissue. We showed the same thing using a mouse model and human uh, model. So we developed this regenerative regimen of a low fat diet, elevated level of this omega six fatty acid called arachidonic acid. And we use the fungus derived oil to elevate the levels because, uh, you know, as I told you, like the abundance of the fat in the diet is essential. So to reach the therapeutic dose, we had to use a fat source that had 40% of its triglyceride in the form of omega six. So then what we did is we recapitulated that organismal alteration of that metabolism also increases regeneration by elevating stem cell activity.

So that has some, uh, uh, controversial, uh, outcomes. Why? Because if you now Google Omega six fatty acids and ask about its health benefits, you're gonna see hundreds of publications from the past 30 years saying that omega six is bad for you and omega-3 is good for you. So while there is some mechanistic understanding of those observations, they are not properly done. What we are showing here is the fundamental aspect of what omega six is actually doing in your body. So when you have a damage to yourselves, the first thing that your cells do, they flip some fatty acids from their membranes. This is the most ancient way of your body to tell itself that there is damage that it needs to act on. So the first cell that was created in the ocean billion years ago used that strategy to repair itself. So arachidonic acid is one of those fatty acid that is very abundant in your membranes.

And when you hit that cell or when you damage it, or when you infect it, it is released. When it's released, there are two options in your tissue. You can either regenerate, you heal, you can close that scar, uh, uh, uh, problem, and then move on. Or for some reason, we as mammals, we get scarring. We cannot fully regenerate. If you are a plenary, if you're a little warm, if I cut you just from the middle or from your head, you can regrow everything. If you're a salamander, if I chopped the leg, it grows. But mammals, they don't do that. So we are trying to understand that this fundamental fatty acid we have shown across life kingdoms to be very important to mediate that regenerative process. So what does this dietary or achio acid mean to us? And why did you know large body of literature said omega six is bad for you?

It's inflammatory? Well, there is some reality to it. If you are obese, if you have chronic inflammation, if you have cancer, you see a lot of damage in your cells and that releases omega six from your cells. And then if you eat a lot of red meat, if you eat a lot of, uh, uh, you know, uh, processed food and other things, that can also elicit this chronic conditions, which can elevate that marker of damage, which is omega six. But the cause and effect relationship needs to be properly addressed. So this is now our model. When you give dietary fatty acid, which is this damage molecule, in the absence of damage, it can make those resilient cells by reprogramming them. And when you give the damage, then it can make the regeneration process much effective. It reduces the scarring. And so we have an unproven theory yet maybe the reason that you are getting this bad effects of the omega six is because you are depleting the of omega, of omega six in cell membranes and therefore creating this unhealthy environment for the cells.

As I told you, everything is a balance, is a balance also in the cell membrane. Saturated fat and unsaturated fat. As you, if you break that balance, you break the health of your cell. So we are trying to explore that hypothesis right now, and we are trying to posit that idea that with, in the absence of a damage, if you provide that signal, you can rejuvenate your cell. It's kind of a vaccination, right? In the absence of an act to infection, by showing a snippet of the microbe, you can boost your immune system. So we do the same thing to the tissue stem cells. We give, we give like a marker of that, uh, uh, uh, uh, damage in the absence of a damage using diet. And it's digested and incorporated into your system, and then it promotes regeneration. This is wonderful. We don't know the significance of that to endometriosis, although I discussed with Dr.

Sk some hypothesis and there is relevance. Two things are relevant. Endometriosis is also kind of a scar, right? And then endometriosis at the late stages, I, I saw some amazing pictures from Dr. Sk, it looks like, like a scar that didn't heal. And so there is some pathway, there is a path for us to understand in that process, how does that fundamental biology can be applied to our ability to understand endometriosis better? And hopefully one day treat it. So the other thing that I will highlight, uh, with the few time, uh, few minutes that I have is how do nutrients directly affect immune system? So the, the, the lessons we learned came from cancer. So, uh, we study how does immune system and cancer fight with each other? They're in constant fight. They have similar metabolic demands, it looks like. And then this metabolic T of war enables cancer to grow and win in your body.

If your immune cell is resilient, it can win that battle. Every day, every one of us here will have one cell that will go rogue and will become cancer. What happens? Immune system sees it and clears, clears it. When that fails, then you get the clinically observable cancer, and then you go to an oncologist and get the therapy. What we found, I will show you this metabolic fitness concept applies to immune cells as well. We see that in most tumors that have been showing that growth, immune cells are excluded. Tumor creates its own kingdom. And this correlates with reduced metabolic fitness. So we engineered the immune cells to have enhanced metabolic fitness. And boom, what we saw is like it doesn't, immune system doesn't care anymore. It goes into the tumor, kills the tumor cells, and then tumor is cleared away. So you have heard of a concept called immunotherapy, which wasn't a thing 20 years ago.

It became a thing around 12, 13 years ago. And so now with that notion, we are understanding better ways of reprogramming of our immune system to make it more fit. So in endometriosis, there is an immune component. There is inflammation that is heavily driven by those crazy rogue immune cells. How do we control that? How do we bring that fitness to a balance? So this is gonna be very important. And the other important aspect, how can we tune that up and down using nutritional interventions? So your immune cells are what you eat. I will pass through this. Your microbiome is what you eat. We have a michel entry star restaurant to test nutritional interventions in mice by using different types of diets and look at microbes, immune cells and stem cells, how they communicate with, uh, with, with each other. And then I wanna just tell you at the end how much we still need to learn to address mal nutrition and what are the potentials that we have as opportunity to, uh, uh, uh, uh, develop strategies of mechanism based nutrition to address, uh, uh, uh, the diseases that are, uh, mentioned up.

And to really create a healthy society. Our society needs mechanism based nutrition. And so we are trying to put a lot of effort in that direction. It's not easy. It requires a lot of actual work in the lab and outside of the lab. And so, uh, your future is what you eat and what you can do about it is come to those patient scientists, clinician advocacy events, you know, understand our problems. Let us understand your problems so that we can strengthen that bond. And this is very important because I need to make a discovery to treat a disease, right? Like everyone is asking, I have, I have pain. Like what do I do? So the clinician operates and then we ask the clinician what's the problem? And then we go to the lab and try to make a discovery. It's not an easy process. It requires learning.

We need to learn. We need to critically think intellectual aptitude and critical thinking. I need to read a lot of papers to understand that. And then I need to go to the lab and do the experiment. These are very critical, but requires support from who from the society. We, I, I'm a scientist, I cannot do that alone. How did science evolve to that level with the renaissance humanity? Through the Renaissance created a systemic way that we do science. This is how we started proper universities and so on. And where we are at today, we are consuming our society without knowing what we are eating and expecting to get answers on demand. Whenever I present some lecture like that, I always get the question, so what should I eat? So what should I eat? You should support research. You should go out and become an advocate to support research.

Research and science needs to be part of the society. When you excluded from the society, then you get all these nonsense, the fugazi, the uh, non-scientific things that are putting you as patients at risk. So I will end with that statement. We need a new renaissance to bring science and society together. And I thank Dr. SK and all the physicians in his foundation for bringing patients and physicians and scientists and policy makers together. And together we will make an impact. We need to speak louder about those problems. We need to, uh, go to the policy makers and tell them that, hey, this disease is understudied. We know very little about woman, uh, health in general. We don't understand what cells of endometrium are doing that disease. So they need to know, they need to increase the budget of National Institute of Health. You know, it's ridiculous.

We have to spend three months, uh, to nine months to write one proposal to study that. And I will be triaged by reviewers telling me that, oh, I haven't published about endometriosis, so that I shouldn't be given the opportunity to study that. It's ridiculous. Leonardo DaVinci would not be able to do what he did in this age, in this country, 500 almost years ago. So we need a new renaissance. We need your support and we will make a difference. Hopefully next time we meet, I will tell you more stories of positive impact that we made.

Thank you so much. And so we have, we are, we're pivoting our schedule just a bit so that we can get lunch. You guys will not have to wait another hour for lunch. Yeah, <laugh>. Um, but

I was on time, right time.

You were fantastic. Perfect. We, and we have five minutes for q and a if you're willing to take some questions. Perfect. So any questions in the audience? Great. What should we

Eat for lunch? <laugh>?

Hi, um, my name is Simran. I'm a patient and I'm hoping to become a provider someday too. One thing that I hear a lot about is gluten and endometriosis. So the first time that I saw functional medicine practitioner, they told me a lot about how gluten has been studied. But if there hasn't been like so much research the way that you're saying, is it something that you would recommend or you would recommend, uh, really partaking in?

The short answer is, I don't know the most of the gluten research mechanistically and, you know, evidence based focused on the intestine. So, you know, the gluten intolerance hits some cells of the, of the GI tract and creates, you know, like the, uh, the, the, the syndromes. I haven't done any experiments and seen any proper experiment that associate gluten insensitivity to a situation like endometriosis.


You. Thank you.

All our sandwiches. They are blue for you by the way.

<laugh>? Yes.

Thank you for the presentation. I just had a quick question, Amanda, here in the middle there is Oh yes, right here. All of that. Okay. Um, and I don't know if you have the answer, but I'm just really curious and I'm sure a lot of my endo warriors have similar symptoms three days before my menstrual cycle and three days after I always get extra swollen. Sometimes I can't fit in my pants or there's just a variety of symptoms that come with it. So I always feel like at the most general terms, that I have extra inflammation in me at that time. How quickly do the cells turn over? Like if I need a plan? Cuz sometimes I all drink like three or four days of green juices straight. Yeah. Um, but like, how quickly do the cells turn over? So if we're planning on a monthly basis for this, like how do we, I guess, decrease the inflammation, especially during this time?

Yeah, I mean, that's a great question. So we, we know little bit about the kinetic of endometrial regeneration. So there is a phase in which the stem cells that regenerate, post menstruation does that healing process. And then right after they have this proliferative phase in which they make the endometrium ready to accept the, uh, you know, if there is a fertilized act for the implantation. So the, uh, the, the window of opportunity for the healing process is before that proliferative phase because technically your cells should be ready to go into the next, next stage if they are healed. If they are not healed, then that means there is a problem. So, you know, the healing process and the, the link between these different stages of the stem cells are still not understood. So part of our human cello loss project, we are actually trying to do that, but it's not gonna give a full answer.

We will try to get, uh, you know, endometrial samples from women at different stages of their menstrual cycle and also compare it to premenopausal and post-menopausal woman to figure out what is the real cell that is regenerating looks like, and you know, what kind of needs that cell that may have to like ameliorate, uh, situations like, you know, you, you are asking about. And, um, I hope, you know, like down the road we will have that answer. But this is a great question. I mean, I, I always thought about questions like that because the system is so complicated, right? So like, you know, menstruation is, you know, taking out of the previous layer. So if you are discarding like you are breaking the walls, discarding and then making a new, new system, new wall, and then, you know, during that time you change up and down how many cells that you are gonna make. And so, look, I studied intestinal epithelium, but I'm amazed by endometrial epithelium. So that's the reason that like, for the past two years, putting so much effort to study and understand that process better and we will get there. So I, I don't have a real answer today, but maybe in a year, maybe in two years, if you meet again, I may give you an answer.

Thank you Dr. Bees, for all your effort and we're really glad for you to be here. And it's a very informative, um, things that you have shared on us today. So with regards to the gluten, um, thank you for asking that. There is a book on that, it's like brain grain drain or something that, uh, gluten has been, uh, or, or wheat has been, um, altered because of during those times that there's a famine or something and it's been altered. The ancient grain are very good for our health, but the altered grain is affecting our health in a very bad way. That's why we have i b s and all these things that we are not able to really digest. It takes a metal, metal kind of digestive system to digest that gluten. So anyway, doc, doctor, um, we as an endometriosis patients, we always hear about inflammatory and non-inflammatory kind of diet. So sometimes it's not clear, but this is, has been studied an anti-inflammatory diet I think is really essential. Can you talk more a little bit on that? Yeah, thank you.

So the, so that concept of inflammatory versus non-inflammatory diet suffers from the complications that I just mentioned to you. So let's say if you consume red meat every day without any fiber, that is an inflammatory diet, not just because of the components of a red meat in it, but it is just, it's not a good diet for your digestive system. And overall your entire organismal physiology, that doesn't mean that meat is good for you or bad for you. Those shallow approximations are not good for us in general to understand how nutrients affect us. So the reason I wanted to give you the example of the omega six diet, because omega six dietary intake is often associated with this inflammatory diet patterns in epidemiological studies. And I give credit to those studies because it's very difficult to do those studies. However, you know, we cannot call omega six inflammatory and omega-3 non-inflammatory.

If you, if I have just 32nd, I wanna show you something about fish oil and, and brain, if you, if, can you put up that presentation? So how many people think that if you have a brain injury, you should take fish oil? I mean, how many, uh, how many, uh, ads you would see about how fish oil is good for your brain health a lot, right? So we have, uh, we have, we did a study thinking that was true. So we created this mouse model. We damaged, we gave a, a concussion to, to the mice and then, um, I mean we had to do that to study it <laugh>. So it basically, we have two options. Either we'll use some NFL players, which we are in process of doing it, or we'll use a mouse. So until we find the NFL players, we did it in a mouse and then we fed this mouse, not a regular fish oil dive.

We just gave the fish every uh, uh, after two days. Okay? So it's like what, uh, healthy American person should eat. But we gave a lot of fish in that one day. And so this puzzle is just telling you one thing at the end, we saw a big deficit and high levels of inflammation and tissue destruction in the brain six months after that concussion. So fish oil, yes, it is good for many things. I know that in the gut it does so many cool things, but for example, in the brain it doesn't do it. So why now we are trying to figure that mechanism. Because when you look at your brain, the distribution of omega-3 and omega six and saturated fat is really critical to be in a particular balance. If you tip that balance when you have a damage and then continue to get that fish oil, it just exacerbates it.

So these are two contrasting evidence to our public knowledge, right? Like if you read whatever, you know, like your favorite TV show or uh, uh, magazine, they say, oh, omega six is bad and omega-3 is good for you. But context matters, right? So context matters. You are what you eat, but it may be contrary to what you think you may know. And this is very important to understand. This is very important to advocate for that research. If I knew already everything, trust me, I will give you the best recipe and I will teach you how to make it here in the kitchen. And, uh, but we don't know. So, you know, this is really highlighting the severity of the situation. So many patients are taking these things without proper understanding of how that works. So if we are gonna incorporate food as medicine, we need to treat it and, and study it as medicine, right? So we need to understand the mechanism. So I will just end with that statement for the inflammatory, non-inflammatory diet. Every diet can be inflammatory and every diet can be non-inflammatory if you understand what that diet does. And so, yeah, so you know, <laugh>, I I told you in the beginning, that may not be the, that may not be the answer you wish to get, but it is, it is the state right now

Question. We tend, we, we have this tendency to tell patients not to eat red meat, not because of these things, not necessarily all these things. You wonderfully said, by the way, this is a great presentation anyways. But we tell them, look, there is high level of estrogen on these, uh, uh, meat products that you know, that they make them give them growth hormone, estrogen to make them taste better and high intensity of fat. What's your opinion on this? Yes. How can, how can this audience

Yeah, that's a great question. Not

Feel guilty. Yes. When they have this wonderful yeah, at times steak or meat.

So that's a great point. So that, that's the type of thing that I want. I encourage you to think. So like when you think about the red meat, don't just think it about, you know, red meat. Think about what inside that red meat and how can it affect. So yes, if you're eating five days a week, red meat that can elevate, uh, especially depending on the constituents within that meat and how you cook it. Certain factors that can trigger inflammation. And so like let's say if you do it for just one week and not do anything for nine months, I don't know what happens. We know some examples that diet exposures have memory in the body. So, uh, uh, in real human, it's very difficult to make that, uh, uh, you know, suggestion for me as a basic scientist. But in general, I can tell you, you know, like consuming a lot of red meat and not consuming enough fiber and vegetables, put you in a situation that your gut is not gonna be healthy.

Your microbes are gonna be, uh, you know, dysbiotic, which will in turn trigger, uh, uh, uh, inflammation and local and systemic inflammation. So, but you know, as a scientist, I cannot tell a group of patients that, you know, be vegan or vegetarian or, you know, eat this. We need to understand the mechanism. So in terms of the, a depo and the ability of these meats to contribute to, uh, you know, inflammatory processes and the hormone signaling, you need to be, uh, you know, careful, I would say, you know, like until we understand these properly, try to adapt a diet that makes you feel content and embrace life. So like, this is what I tell people who are forcing themselves to go into a ketogenic diet, which long term has health deficits. You, you didn't evolve to be on a ketogenic diet. If you, if ketogenic diet makes you feel happy for three, four days, maybe do it.

Whatever makes you feel content at that time except for pro processed food and, and simple sugars because they are like cocaine and they will make you feel great until they consume you. So avoid those. But you know, like my take on, you know, like red meats, if you properly cook your red meat and if it's not like containing hormones and additives and preservatives and you know, from craft family, hot pocket, readymade, uh, uh, uh, sliced steak, uh, it, it's probably fine to consume it because it has also good nutrients in it. There is a reason that we evolved as carnivores at some point because, you know, red meat can provide iron and other nutrients that you may not be able to get, uh, from, you know, like spinach, you need to eat, you know, one kilogram of spinach to get, you know, like the same amount of nutritional intake of a center cut file that's, you know, medium rare. Uh, so <laugh>, yeah.

One more question over

Here. Hi. Hi. Um, so my question is centered around the regrowth of endometriosis. So I'm recovering from stage four. I had the surgery about two years ago and my surgeon gave me a number of tools, like a toolkit to keep inflammation down, like meditation. Yeah, low stress, you know, anti-inflammatory diet. For me, the stress is not manageable. Like I'm just a stress ball. I will like make up stress of nowhere. So I feel like that's hard for me to manage, but what I do have discipline over is my diet. Yeah. So I've spent like the last two years researching on podcasts and Mediterranean diet and I've cut out dairy, gluten, alcohol, and I have to say I feel so much better, but there's definitely no balance. Like, I definitely have developed a fear of food, like a obsession because I'm so scared of it coming back. I've heard so many fellow patients say they've had six, seven surgeries, and I don't have time in my life to have another surgery. Like I need to go on and live it. So I've become, so I guess it's put a knife in my social life because yeah, I have friends that wanna go out and drink and eat pizza and, you know, I, I'm literally scared of the food. So am I on the right track or what exactly makes endo grow back?

Yeah, so I mean, this is the reason that I refrain from, you know, saying, eat this, don't eat that. Because that is also a new disease in our society that people are, you know, getting obsessed with that particular diet pattern. And this is creating more problems, it's creating anxiety and eating disorders. So, you know, we, that's why I'm trying to be very careful in saying, you know, what's good for you and what's bad for you, because if I don't know it properly, I shouldn't say it. So in terms of inflammatory diets, I will give like a general view. Like if you drink alcohol every day, why is it inflammatory? Because it creates acid aldehyde, it's a reactive molecule, so that creates inflammation. If you, you know, like, uh, eat burnt meats every day, there are some compounds there that can create similar pathways if you don't have fiber, and if you don't take, you know, like enough, uh, if you don't have a balanced microbiota, and if you eat things that would create dysbiosis, they would also create inflammatory milu.

So I, I wish I can tell you like, I genuinely wish I can tell you something. All I can say that, you know, avoid processed food, avoid eating a single nutrient every day, diversify your diet, eat, uh, you know, vegetables, eat, uh, the things that have high electrolytes like cucumbers, you know, root vegetables, things like that. Those usually make your intestine happy. And then if your intestine happy, it can absorb those nutrients, it makes your microbiome happy, and then potentially it can make your endometriosis less severe by influencing the metabolic health in that tissue. So it's, you know, this is the best answer that I can give to you, but I have a lot of empathy for that situation that you are going through, because I had the same problem when I was a graduate student working 18 hours at Harvard, uh, living in a dorm.

I ate really bad. Then I had a, a colon polyp a year later and I had to force my gastroenterologist to do a colonoscopy because I was having bleeding. And then he was like, no, you are not gonna get a pope. You're just 25 years old. And I was like, but you know, like I really, I'm curious, I wanna know. And then I had the polyp, so like, I was at risk. And so then I became very obsessed with the way that I eat. You know, like I, I was just on a cucumber diet because I had obsession over cucumber. I still eat a lot of cucumber every day, <laugh>. Um, but, but you know, then I, when I started working on the problem scientifically, I realized that we sh we, we are really need to be careful what we tell patients, this is good for you and this is not good for you until we have mechanism based nutrition.

Until if I can tell you, hey, this is your regimen, this is gonna go into your gut, this is how your microbiome is gonna react to it. This is what's your endometrial inflammatory cells and stem cells are gonna behave like, then I will, I will sign on that and I will vouch and I will campaign. But now I don't have that knowledge yet, but we are going in that direction. So I wanna tell you that we, I'm working a lot on solving that problem. And you know, with, with you and your support and your advocacy, my goal is every year make, make more progress. Make more progress. So like next year, hopefully, I'll tell you better things and I'll be like, Hey, we learned a little bit more. And in, in four or five years, maybe we will be able to figure out a proper diet that will go hand in hand with an endometriosis management.

One, one final question. Okay. <laugh>, if you're willing to keep

Talking. Yeah, of course. I mean, I can do that

On some dinner. Our food is almost here, so, okay. Um, I get a this question a lot from patients. Yeah. Um, but do you, what are your thoughts on organic versus non-organic?

Yeah, I mean, that's a tough one. So, as a scientist, I, you know, I cannot tell you a definitive answer. As a person, I think there is value in organic agriculture and organic food and, uh, if it is not abusing the, uh, system, right? So like, now there is also like an organic industry that's abusing the, the agriculture and like not treating the land properly and you know, all this stuff. So, you know, organic food can be good for you because, you know, it has all the natural processes that, you know, capitalism hasn't destroyed yet, right? So from fertilizers to the way that you, uh, deal with, you know, pasts and stuff, you know, you eliminate all these nonsense that we are introducing to our body that we don't need. So think about, you know, what your ancestors were eating 500 years ago, they didn't have that much food that you have today.

Most of them were dying from infectious diseases. Okay? So today we are not dying from infectious diseases, we are dying from cancer, uh, we are dying from cardiovascular disease. Why is that? Because of the food that we are consuming. So if your food has all these unnecessary things, hormones, pesticides, you know, random things that your agriculture company decides to put on it that I don't even know when they're shipping it, they put these like shiny preservatives. I don't know what they do to it. So until we study it and show that, you know, like they are great for you, I cannot say eat it. But, you know, then there is the problem. Like, not many people can afford organic food, right? So, you know, like you cannot afford an organic avocado or banana. If you are, you know, like making a PhD stend or you know, a resident stipend, you may if you're a surgeon, but you know, for general population, I refrain from saying that, oh, you know, eat organic and not, I mean, you need to have a balanced diet first, and then if you have the option, yeah, maybe use organic, maybe use farm.

It's even better. You know, like, you know, find, find a local agriculture, go to the uh, uh, you know, uh, north Fork of Long Island. There are a bunch of, you know, um, uh, farms over there and, and get their produce if they are doing the organic, uh, procedures. So that's my nonscience answer. So the science answer is that I don't know. The nonscience answer is that if you can afford it, and if you know that it's doesn't have these like random preservatives, uh, then you can eat it.

Fantastic. Yeah. And on that note, we are gonna take a break for lunch. Great. You made everybody

So hungry. Oh, enjoy the food. Thank you.