Semir Beyaz, PhD - The Nature and Nurture of Endometriosis: Defining Genetic and Environmental Underpinnings

All right. Thank you, Caroline, for putting together this awesome program. And as Caroline mentioned, Katie Burns is not just an awesome person. She's an awesome scientist. She's a great friend. And I'm fortunate to have met her at this conference and we are working together to make an impact for many women struggling from endometriosis. So today I'm going to tell you the nature and the nurture of endometriosis. Nature is where genes that you inherit or variants that can arise during your development. And the nurture is the environment, the exposures that you have that makes you who you are. And so as we mentioned, we embarked on this new journey around like eight months ago now with the foundation started Setchkin Endometriosis Research Center for Women's Health, dedicated our efforts towards first understanding endometrium and potentially developing new diagnostics and therapeutics tools. And so I'll give you a little bit of overview on these research initiatives and we'll be very happy to discuss with you if you have any questions.

So this is a cartoon. I try to instruct this new AI modality by telling what to plot. Did a very good job, but it wasn't too my greatest liking. So I'll walk you through this process one by one. So as I told you, and I have a mic, so I don't need to lean. That's great. So as I told you, the nature is the genes. So you can have genetic differences based on what you inherit from your parents. So those are usually called germline variants. So you get one copy of your DNA from your mother, one copy of your DNA from your father, and then you make up your unique genomic landscape. And then during the development, since you are a zygote and then you develop an early fetus, you can acquire some genetic changes that also can define your genetic makeup. And then those then become somatic variants as you are developed and formed real human body.

And then different parts of your bodies, depending the exposures that they get and sometimes just luck during cell division, you can acquire some mutations, some variants. So when we think about endometriosis, all of these concepts are equally important. And why are we talking about genes? Can anyone tell me why genetics is important when it comes to endometriosis? Any thoughts from the audience? Do you think genes are important when it comes to endometriosis? Yes. Okay. So can you tell me why it is important, you think? Because I learned it from Dr. Roberta Klein at a past patient day. Perfect. Good. All right. So the answer is we understand that certain endometriosis patients may involve genetic penetration. In some families, even twins or sisters, you see like this disease implicating that there may be some inheritance pattern. In some other cases, that's not the case. When you do a collective study, when you look at all of the endometriosis patients and try to look at different gene variants that may associate with the disease compared to like general population or people who don't have it, there is some signal.

However, we don't know the specific genes that may be driving that process. There is no single gene that we can attribute to the development of endometriosis. But the deficit in the field is that there are different ways that you can look at genes. So you can look at it based on variants identified in population. And so this is how you, when you do ancestry.com or 23andMe, they tell you where you're coming from by just looking very tiny snippets of the information in your millions and millions of base pair of genetic information in your DNA. And so one thing that we are hoping to do is that from one telomere to another, for every single chromosome, look at the DNA, look at the genetic information at the highest possible resolution, and then figure out with people who have familiar history of endometriosis and people who do not have, and some people who never had or are at risk of endometriosis to pinpoint specific genetic lesions that may help us explain the pathophysiology, the pathology of the disease, and potentially can also aid with diagnostic tools because those are also largely lacking.

And so when you understand the genetics, you understand only one component of that disease. And this part is particularly important because when you look at endometriosis lesions, and some people who did those studies are in the audience, Dr. Stechkin, Dr. Ihan, and many others have looked at specific lesions and found that endometriosis can contain some oncogenic mutations that are found in cancer cells, but endometriosis itself doesn't fully behave like cancer or considered cancer clinically, but it behave in that clonal somatic mutation pattern, suggesting that we can understand more and more about that disease if you look at the genes and figure out why they are showing that pattern. This part is the most complicated part. And I'm fortunate because in the previous session, it was mentioned that how much important that the food and our lifestyle affects endometriosis. And a major part of my research in my lab is focused on environmental regulation of endometriosis through interaction, gene and environment interaction that can influence the initiation and progression of that disease.

And so food is an integral part of our lives. In the past patient day meetings, I showed you how our research is now highlighting the food that you eat is not just about like energy and calories. It is really defining how your cells work in your body and depending on what kind of food you eat, you can skew your body towards healing or towards scarring. And so we did most of that work in model systems like mice and model systems like stem cells or tissue cells on a dish, but now we are also taking some of those discoveries into real humans in clinical trials. And then the other component that we are really excited and exploring is gut biology, gut health, and then systemic metabolism. These are very important, highly complex processes that are very difficult to untangle in a heterogeneous patient population, but there is enough signal that's available telling us that microbiome, systemic metabolism, microbial metabolism, either due to exposures that we get through the food or our other exposures such as sleep and stress can influence endometriosis.

And then there are additional factors, physical activity, sedentary behavior or exercise and very overlooked concept of pollution. We live in cities. Cities are not clean. You are every single day exposed to a lot of toxins and politans and one of those things are microplastics. We drink from plastic bottles. We have very heavy exposure to those non-natural things that our body did not evolve for the past million years to cope with. So like how do they influence? This is an important area of investigation. So together those create this multidimensional puzzle in which in human body, you can see here that endometriosis not only is a disease of these endometriotic cells, but it affects the whole body from the brain to cardiovascular system, to gastrointestinal system, immune system, endocrine system, metabolism. There is not one single piece that doesn't interact with one another in your body. So you need to be holistic in that setting.

And then what we do to untangle that, now this is going into the weeds in the lab, is that we look at the genetics and how environment interact with genetics, and then we try to understand how our body works. If you don't understand how endometrium works to begin with, how menstruation leads to this regenerative process that every month it creates itself from the ground, you are not going to understand how endometriosis work or how other diseases that impact endometriosis such as endometrial cancer and infertility. So we are very good at looking at the genetics and how genetics interact with the environment, which is called epigenetics. It's beyond genetics. And then look at stem cells. Those are the mother cells that sustain the development of the tissue in every regenerative tissue. You have those, and then you have immune cells that can survey those stem cells.

And if there is a bad behaving cell, immune system is very good at surveying and eliminating. And for some reason, when it comes to these rogue cells that initiate or trigger endometriosis in your pelvis or in your colon or in your thorax, for some reason, immune cells are not eliminating them. Instead, they are becoming part of the problem, causing inflammation, causing scarring, and we are trying to figure out how these processes can be reversed. So healing versus scarring is a big paradigm. And the microbes are here. We know from our previous work that microbes are altered by the environment, most importantly, less likely by the genetics, but then can also influence the physiology and the disease processes. And so this healing and scarring is one of our major focus to figure out at the molecular level and at the cellular level and at the genetic level.

And this, we hope that will give us the toolkit to diagnose endometriosis better, to treat endometriosis better. And one day, possibly, we can prevent it from happening at a risk population. So you don't have to deal with that pain, with that scarring. If we can identify the risk population with a genetic tool or with some molecular tool, then you can potentially prevent it. I don't know how we will do that, but that's my dream because a hundred years ago, as I mentioned to you earlier, cancer prevention was a dream. Cancer treatment beyond surgery was a dream. Now we have targeted therapies, now we can screen, now we can prevent. And so the same methods can be deployed for endometriosis, and that's one of our major vision. And so how can we do that? I can show you just a vignette in our lab. As I mentioned to you, your body regenerates in multiple organs, but endometrium is very unique.

In endometrium, you do that once a month, you purge those cells and then you remake that. And so this process is inflammatory, as Katie said, but that inflammation is not bad. Your body needs that inflammatory signal to heal, to heal homoesthetically. But what happens, let's say, when damage happens too much, you have a choice. You can either heal or you can have scarring. So if you look at little worms like plonarius, they can regenerate no matter how many times you injure them, no matter how, from wherever you injure, they can rebuild their body. Same thing with celemander. But us humans, if you damage too much or if the damage is not resolved and inflammation is persistent, you get this thing called fibrosis. It's scarring. It forms a scar tissue. It's like little mushy meshy acellular material that acts like a glue. And in many advanced endometriosis cases, that's a very major problem.

And even after surgery, that becomes a problem. And so we are trying to develop human-based systems. This is showing endometriosis on a lab dish. This is like a regular well behaving endometrium on a dish that we developed by getting a specimen from a human patient. And then this is by changing the environment of those cells, we can skew their behavior towards invasive and migratory and endometriosis like inflammatory state. So that tells you environment can change a lot when it comes to endometrial biology. And so we are now testing this context, sorry, testing this to define the genetic and environmental factors. So we can delete genes, we can activate genes on a lab dish. This is what we are very good at. We can add some environmental factors like we are good at dissecting nutrients and metabolism, and then we can measure how this can impact the processes of healing and scarring time.

Perfect. That's the last slide. So I just want to tell you, as a scientist, how important it is to come to these patient day events, because you guys inspire us, right? We learn from your stories, you guys inspire us. And same thing with talking to the clinicians and surgeons, because you are at the front of that battle. And then we are in the lab trying to figure out how those processes are emerging, looking at the genes and the molecules. So two years ago, I was talking to a couple of patients, then I discussed with Dr. Seshkin and I realized some of the basic science questions that we ask in the lab are highly relevant to endometriosis. So we know that when your cells are exposed to something like an inflammatory marker or a dietary factor, they remember that exposure. It's encoded in their DNA. So it's not inherited, it's learned behavior.

So we think that cells and tissues retain memories of past exposure. So we have some work on looking at the diet and toxin, other people have shown stressors and pollutants and inflammation can evoke epigenetic and cellular changes within the tissue. So this is now a vision that I'm setting for myself for the next 10 years is to figure out even after you do the excision surgery, what remains in the tissue, what remains in your other systems like cardiovascular system, GI tract, your brain, your other parts of your body, what are the changes that persist? How we can mitigate those, how we can prevent those or how we can erase those, how we can get rid of those bad memories and give new memories. So that's not something that we can resolve in one day, but I just want to tell you, this is what I learned from you guys.

You inspired me to do that work and now we are going to return back to you in the subsequent patient day meetings. So thank you so much for being here. Thank you so much for inspiring us and thank you so much for keeping the fight