JANILEE: Welcome, friends. You found just Janilee at the corner of “Am I crazy?” and “No, you're not. Here's the science to prove it.” This is VILIFIED. These Just Janilee episodes are little miniature episodes that occur in between the main episodes. And in these mini episodes, we dive into more of the research specific elements of topics that have been brought up and discussed in our main episodes. Today we are talking about Epigenetics. Now, in the last episode, I nerded out a little bit about Epigenetics with Larissa and I explained how Epigenetics express themselves kind of like a seesaw. And that was a really simplified version and it is still true. And I still default to that explanation when people ask me, “Why do you like Epigenetics so much?” But today I wanted to go into a couple different little  aspects of Epigenetics and just see what we find.

So for starters, I just want to say at the beginning and the onset here, show Notes. Show Notes. Show Notes. Show Notes. I mentioned them in main episodes, but I really push them in the Just Janilee because every single document, every single journal, everything that I'm referencing is found in the Show Notes. Show notes. Show notes, show notes okay, if you don't know how to get to the Show Notes, you just go to Vilifiedpod.com. And at the top of the right-hand corner of the website you're going to click on JJ episodes. You're going to select this episode, which is 3.5 Epigenetics. You're going to scroll down to the bottom blue part of the screen there's, the blue part at the top. We don't want that one. Skip all the way down to the blue part at the bottom and you will have a list of links. You click on it, boom. Document opens. That simple. I try and usually put them in the order that I will reference them. So that should also help you if you want to follow along. When I have just one document that I'm referencing only from, I will put in parentheses, this is the one you want. But today we're just going to be bouncing around between a couple of different papers.  

All right, Epigenetics, what is it?  I actually spent a little bit of time earlier today a little worried about how I was going to explain this because in order for Epigenetics to be cool and in order to explain why Epigenetics is so fascinating, there has to be a somewhat basic understanding of genetics. And I started writing down words and definitions, which I do at the beginning of certain episodes so that we can go through some terminology to preface us for the conversation we'll have today. And I did that and I felt like I was back in high school writing out flashcards for biology class.  And that just seemed really boring. And I try and make these Just Janilee episodes not only accessible to anyone and everyone who wants to participate, but also to simplify things to a level where they are understandable. So I kept thinking about it and I landed on a really weird analogy. So bear with me and hopefully this will help us understand genetics on a basic level.

So, bunch of words we have to throw out. The first one is somatic. Now we mentioned somatic in the last JJ just generally episode, and it refers to any experience that we have internally, like that we feel in our bodies. That is true in the fields of psychology. In epigenetics, it's more to the field of biology. And in biology it has a slightly more specific definition. So when we refer to somatic, if you see that in any of the papers or if it's mentioned in the podcast today, somatic refers to parts of organisms that contain the reproductive cells.  That part of organisms is called the soma. So when we say somatic, we're referring to things from the soma. Simply put. Simple enough, right?

Okay, so then we start getting into a little bit of a trickier thing to explain. So this is the analogy I came up with, and bear with me here. So if you have a bowl in the kitchen and you want to make cookies, you have to put ingredients in the bowl, right? And as you add ingredients, the name of what you have in the bowl changes. First, you have a single ingredient, say butter. And then you add some sugar and you cream them together. It's not really butter, it's not really sugar, even though those are two things that go into it. But it's kind of a separate paste type thing. And then if you add wet ingredients and dry ingredients, then you have a dough, right? And then if you add chocolate chips, you have cookie dough. It's just a more broad way of explaining it. So keep that kind of “building on” in mind. We're going to be defining things at different steps along the way with different names. But that doesn't mean that we haven't talked about it before. Just like you have cookie dough and you don't call it butter because there's more added, but butter is still a part of it. You with me? Okay. I hope that helps.

Now, we're going to jump into some definitions about genetics in general.  First definition, DNA.  If you're like me, you know what DNA stands for. I'm not going to say it here because I want to keep things simple and not confusing. But what we need to know about DNA for this definition, DNA is self-replicating material. Boom. That's it. So if you have multiple DNAs together, you have a gene. What is a gene? This is spelled G-E-N-E by the way. Not those things that we wear as pants that I definitely took off before I settled in to record this. Genes are sections of DNA. That's it. So what happens if you have multiple genes together or a long chain of DNA that's called a chromosome. Summing that up again just to make sense. DNA is self-replicating material. Genes are multiple DNA [strands]. Chromosomes are multiple genes (or a long chain of DNA).  And if we're talking about chromosomes, but we want to talk about the individual elements that make up the chromosome. We call those chromatin. {Editor’s Note: this includes: DNA, RNA & binding proteins.}

All right. A couple of other words here genotype and phenotype. It's interesting because sometimes you have, like, prefixes and suffixes, and you see them on words and you're like, “Oh, I know what that word means because I recognize that prefix.” But then you have words that are very similar, and it gets really confusing, like genotype and phenotype. Genotype is the set of genes that are responsible for characteristics. There's a lot of different genotypes, but if we take one genotype, it's a bunch of genes grouped together that create a characteristic of the organism. And humans are organisms, so we're talking about ourselves in this case, too. And then phenotype is how that characteristic actually expresses itself. Now, if you have any recollection of biology class, this is pretty common in you have brown eyes. So that means that you have a genotype, you have a group of genes in your DNA, right? Like your DNA, which is made up of genes that says “This characteristic of this organism is going to be brown eyes.” And then the phenotype is it expresses as brown eyes. But we also know from basic biology that that doesn't always happen because there are these things called recessive genes, right? Where you can have a whole bunch of genes that get together, create a genotype that says, “Well, we should have brown, and we have brown.” But the genotype shifts just a little bit. And so the phenotype, the expression is blue eyes.  Right, the whole dominant versus recessive genes. So that is a very brief, very quick summary of genetics. I'm not going to get into it at all. I'm not going to get into it much more because it's not that important [for this episode]. But that's enough basic understanding for me to explain epigenetics, okay?

So, every paper that you read on Epigenetics usually has, like, an introduction section where it explains what epigenetics are and how epigenetics are manipulated and changed and how scientists run their experiments on them. And that's all cool and whatnot, but I started to try to explain it, and I just got really hung up on the details, and I felt like I wasn't able to accurately express just how cool epigenetics is. So I decided to roll it back just a little and to talk about the history of epigenetics in a more broad term.  So here's a quote from one of the papers.  

“Our present definitions of epigenetics reflect our understanding that although the complement of DNA is essentially the same in all of an organism's somatic cells, patterns of gene expression differ greatly among different cell types, and these patterns can be clonally inherited.”

Okay, so what does that mean? Our present definitions of epigenetics reflect on blah blah, blah complement of DNA. And that's complement L-E-M-E-N-T. So not like “Oh, you have nice DNA.” That's a compliment. Complement means they work well together. English is great.  So it's essentially the same in all of the organisms. Somatic cells remember somatic referring to reproductive cells, those traits, those genes that are passed on. So basically all of the organisms, somatic cells have essentially the same DNA, but the patterns of the gene expression - remember that genes are multiple genes together makes up DNA. The genes themselves, the way they express, can differ greatly among different cell types. And they can be clonally inherited. So you can have the DNA is pretty much the same in all of the somatic, the reproductive cells of an organism. But that doesn't mean that the gene expression, that phenotype, the way that it shows up on the surface, can't be altered. And once it is altered, that last part of that quote, “these patterns can be clonally inherited”. That just means that once altered, the somatic cells will then reproduce with the clonally altered with that altered gene expression.  This is when I mentioned the seesaw. Once the seesaw is switched to the other way, then the next biological child will inherit that gene expression. Right?

So I'm looking right now at the paper that is called A Brief History of Epigenetics. Now, in this paper, they go through three different ways to alter genes, and I'll explain a summary of them at the end. But what they learn from these three different methods is well, the second method specifically mentions that

“Heritable genes in the phenotype could occur without corresponding changes in the genes.”

So heritable just means it shows up in those somatic cells and it can be passed on to the next organism. And but changes in the phenotype could occur without changing the genes. So that genotype, right? So the way that the gene is expressed can be changed without the genes having to rearrange themselves to create a completely different strand of DNA. It's just saying that gene expression can be changed even if the genes that wrote the code didn't say to express that way.

In this paper one of the experiments mentioned is called Drosophila. There's a quote, and I won't read it, but essentially what it's saying is, when all of the chromatin - remember those things that make up the chromosomes - all of the chromatin is here. It's all representative. It's all balanced, and everything is here.  But the phenotype, that expression is not normal. Everything under the surface is normal. Everything under the surface is normal, but on the surface, it's not normal. Also when we talk about generational trauma, this is also where epigenetics shows up because previous ancestors, the way that they lived their life created certain gene expressions, those phenotypes, those on the surface changes and then they were clonally, passed down through biological ancestors, down to us now. And so we're simultaneously… epigenetics is…  I don't know how to phrase this, but it's a fun dichotomy for me to sit and think about and explorer about the fact that we're simultaneously kind of screwed because of certain propensities that we have from past generations because of their ability to use epigenetics to change gene expression and gene phenotypes.  But then also we live now when there's enough science about epigenetics that we live in a time when we understand how much power we have over genes, expressions, over those phenotypes, and we can actively change them. It's such a fascinating concept for me to just sit and think about out. We have all this generational trauma. We have all of these propensities from past generations.

But I mean, science of epigenetics didn't really start until the 1910s is when it kind of started to be a thing. And then more deep research of it happened around the 1930s. I actually found and I referenced it in the show notes. There is NIH. Remember I said in the first JJ, it's a great place for resources. NIH has a human genome project and I launched it in Hoof. I didn't launch it and I linked it in the show notes, but it has this really cool kind of history timeline of gene research history throughout time. Two things I wrote down that I thought was cool is in 1987, the first human genetic map was made. It wasn't complete. It still isn't complete today. But that was the first time that there was a genetic map. And so because of that, fueled by that discovery, in 1990, the human genome project launched. And if you're at all interested in any of this, definitely check out that page.  

Okay. Going on with this epigenetics, right. This first paper, it goes into a lot of the science of, like, how these people did this and it talks about methylation. We will actually talk about methylation a little bit more in reference to cancer, which we'll get to in just a moment. But it talks about methylation. It talks about chromatin. It mentions at the end of the article here, we now know of countless examples of epigenetic mechanisms. Right? It walked us through how people came to even have the idea that epigenetics could be a thing.  And it lists down here the three methods that they used to do their research in the early days of epigenetics being a concept. And these are actually research methods that are still used today. So let's not discount them just because they happened a while ago.

So the first thing they used was DNA methylation. The second thing was histone modification, and the third thing was having a presence of a histone variant. So that last one is not something that the scientists were able to control or change, but it is something that they were aware of and able to document. So a couple of definitions here as we move into the second paper, which is about cancer and how cancer and epigenetics relate, which is very fascinating. Histone is a group of basic proteins. So, remember, genes are made up of proteins. DNA is made up of proteins. Protein is the very smallest part of those definitions we went over earlier. A histone is a group of basic proteins. So in cancer cells, there are well, in all cells, there are groups of CpG is what they're called, which they're just a specific combination of proteins that are common and that are found in about 40% of all organism cells. And the C and the G stand for different nucleotides. So cytosine and guanine. And the P refers to the phosphodiester bond that keeps those two nucleotides connected. In case you were curious what the CpG stood for, there you have it. Not important for what we're talking about here and now. So if we were to have those CpG parts of  cells, and they're common,  then maybe we could manipulate those to get certain results. Spoiler alert: YUP. That's what happened.

So in order to understand how epigenetics relates to cancer, very simple explanation of how cancer occurs. Our body is always replicating genes. It's just part of life, and that's why we shed our skin, et cetera, et cetera. And so when our body is replicating these genes, if it replicates a gene that's wonky… The body is [in] homeostasis. So the whole organism as a whole just wants to stay level. It wants to stay the same. And so it will try and be like, “Yo, wonky cell. Don't make more of you.” And if that's successful, then we're good. But if the body and the organism is not successful, that wonky cell can become cancer. It occurs in stages. First, it's malignant, which is medical terminology for invading normal tissue, right? The non wonky cells. And then it becomes a neoplasm, which is like a pre-cancer abnormal growth. When I was double checking that I was understanding this correctly, I was like, “So if a neoplasm is just an abnormal growth, does that mean that a goiter is a neoplasm?” Why did I think of goiter? I don't know. Probably because Tangled was in my head. Goiters - and this is according to NIH, as well, by the way.

“Pathological studies of thyroid nodules indicate that a definite percentage of nodule goiters are malignant and that an even higher percentage are true neoplasms.”

So, yes, goiters are neoplasms. When a neoplasm becomes cancerous, however, is when the cancer starts to replicate on its own, when it's not just a growth that invaded normal tissue, but when it starts to replicate on its own. And then if it gets even worse, you can have metastasis, which is when there's a second place far away from the first place that this cancer showed up, and it's replicating on its own there, too. So just different stages of cancer being more invasive.

So, using these stages of how invasive cancer can be, scientists actually noticed a pattern that when you have specific areas, specific tissue cells that are under methylated, it's basically a ripe, growing ground for cancer. So, what's methylated? So, fancy word, but essentially what it means is you have the chemical methyl that is put into a gene. And it helps control that gene reproduction, that gene splitting. It helps keep it normal. And so if you have Hypo and that prefix Hypo means not enough if you have Hypomethylation, you don't have enough of that methyl chemical going in and keeping things in place. And so cancer can come in and wreak havoc. And if you have hyper and that prefix hyper means more, I remember it because you can be hyper, and that's just excess energy. So hyper is too much. It's an excess. So if you have hypermethylation, then whatever cells have that hypermethylation, they'll grow a lot faster.

So in this paper, these scientists are like, “Okay, so we have this kind of structure of how genes work. And remember that CpG I mentioned earlier that's in most cells, this includes cancerous cells and cells before they become cancerous cells. And so what the scientists found and they tried it in multiple ways, is that if they could find areas that had Hypo, not enough methylation, then they could manually add in more methyl chemicals to that tissue, that cell, that part of the organism, and it would increase that cell's ability to replicate correctly. And if they were able to find cells that had hypermethylation and were able to reduce the amount of methyl that was in those cells, then they would slow down.  So, essentially, what they found is that the CpG part of cells is a really cool place and very effective to, say, “Make more methyl” or to say, “Stop making methyl.” And scientists have their scientific ways, and if you want to read about it, read the paper. But they have their scientific ways of saying, do this or don't do this. And they actually tested this. I remember I was reading this, and I said out loud at one point, I was like, “Why would you do that?” And it was here.  They were talking about…

“Such interactions can be seen when hypermethylation inactivates the CpG island of the promoter of the DNA repaired genes.”

And I read that and out loud I'm going, “Why would you do that?” And then I was like, oh, well, because we want to make sure that our hypothesis is correct and that it's consistent. But essentially what that's saying is when hypermethylation inactivates the CpG island of the promoter of the DNA repair genes. So it's a bunch of just… let's break that down.  You have the CpG island, which is what the scientists are targeting, and they pointed at it and they said, “Stop making methyl.” which inactivated the promoter of the genes that actually repaired the DNA. And so basically they just said, “Hey, cancer, come in and take over.” And so it's just this really fascinating paper, honestly, to read about it. And so you have like, hypermethylation of… here's a quote.

“Hypermethylation of CpG islands in the promoter regions of tumor suppressor genes is a major event in the origin of many cancers.”

So basically what I was saying before about you don't have enough methylation, cancer is going to come in and take root. So how does this all help? Well, essentially - there's even a table in here that talks about different types of cancers and how they will show up in specific genes. And there actually are some companies, if you look up, like genetic research companies. {Editor’s Note: Janilee didn’t list any specific companies to avoid any possibility of getting sued.} There are people and there's, like, active R&D [Research & Development] out there about, “Okay, we know that if this gene has this mutation, this type of cancer will show up or is more likely to show up.” And, I mean, kudos to the scientists. It's amazing and fascinating work.  But there's in this paper a table that goes into what those people, what those scientists and what those companies and organizations and labs have all been able to do is they've come together and they said, “Hey, look!” So, like, the very first one here, by the way, if you're following along, this is on page 1152, and it says, table one, epigenetic aberrations among different tumor types. So type of cancer, colon cancer. And it lists there it has MLH1, RARB2, SFRP1 and WRN. Those are gene abbreviations. And in those genes, if there's a mutation or an area - a CpG area - with hyper myelination.  There's more likely to be colon cancer.

So already, Epigenetics has helped with so much cancer research. But with this experiment that's talked about in this paper, it actually is turning into a type of treatment as well for cancers, where you can say, all right, if we're able to control the methylation aspect of different cells, we can basically down the cancer and speed up the good cells.  So if you think about, the most common cancer treatments right now are chemotherapy and radiation, which basically just kills all of the fast reproducing cells in a human's body.  And that's cancer cells, right? It's those wonky cells because they have that hypermethylation. And so if you kill those cells, then we can kill the cells. But how do we kill all the bad cells without killing the good cells? This could be the answer! Literally Epigenetics is. And I… I'm not nearly educated enough to even start theorizing lab experiments. I'm going to leave that to the professionals and the people who have done, bless them countless years of school and study and research. But literally, epigenetics is helping to cure cancer. Or not cure, but at least treat. How can you not think epigenetics is cool? Okay, I get it. You're a hard sell. Let's keep going because there's more papers. And these papers are awesome.

So there is one that talks about developmental dynamics. I found a really good part to help explain what this paper is all about. On page 1148, and it is under the heading LINEAGE RESTRICTION. It talks about how when embryos develop, all of the cells are basically clamoring to be the winner, to be the one that's expressed, right?  And how in all of that, in addition to being loud and being expressed, they also have to repress other cells and other characteristics to be expressed. And so there's this quote.

“Because repression must be maintained throughout the life of the animal, epigenetic mechanisms are ideal for mediating such events.”

So essentially, “Okay, I got to keep these other people silent, so I'm going to use these epigenetic factors that are going to help for as long as this organism is alive.” And so they have these things that are called silencing transcription factors, or neuron restrictive silencing factors.  And it goes into the details, and if you want to read it - again, I recommend it, it's fascinating. But this quote here helps us explain what we want to know about it. So it talks about,

“therefore, these REST, or NRSF, [which are the acronyms for those silencing transcription factors and everything  or neuron restrictive silencing.] They must not simply be an off switch for neuronal genes. Rather, the degree of repression mediated by those [silencer factors] is tailored to the developmental stage of the cell.”

Now, this is really fascinating because it especially relates back to what we were talking about in the main episode. Okay? So you have from literally an organism's very beginning once the organism is formed, right? Once there is an organism that is starting to have characteristics, which is not I mean, it's got to have like a heart, it's got to have lungs, it's got to be able to function on its own, right? Genes aren't just there when you're born and that's it. No, they're changing forever and always. So it has nothing to do with the creation of the organism. But once the organism is created, these factors, right? “The degree of repression mediated by those [silencer factors] is tailored to the developmental stage of the cell.” That means it's tailored to you when you're a child, it's tailored to you when you're a teenager, it's tailored to you as an adult, it's tailored to you in old age. It's tailored to all organisms. Basically, as this organism grows, I got to maintain control. And it's not control so much as homeostasis. Control was a poor choice of word on my side, but every organism thrives and craves homeostasis. Homeostasis is essentially I don't want things to change.  So when we have this cognitive ability and actually make a choice to change, those factors are going to be something we have to take into account and they're going to try and gently push us back into the chair because homeostasis. But if we are persistent enough in making those changes, it’ll step aside and we can change the phenotype, we can change how those genes express. And as we've seen in these papers, that translates into generational change that literally changes the future generations.  Assuming you have biological children. But even if you don't have your own biological children, it's being able to help people overcome these types of silencing factors. I mean, think about it. They're tailored to your specific age because it's not going to come out and smack you in the chair like trauma responses do. It's just going to gently say, “Homeostasis? Homeostasis?” And we're going to say, “No, I don't want homeostasis. I want change. I want growth.” And then those restrictive factors will step back and say, “All right, change.” And that is so cool. I mean, it's on such a small level. And the science is interesting. And I will link all of the papers I've referenced, plus more in the show notes. Go check it out. For sure, if any of this interests you. But just to realize, it was so cool for me to realize. And I'm reexperiencing how cool it is to understand that on such a small level. Our bodies want homeostasis to keep us safe, right? Our bodies, they're designed to keep us safe. The end.  But they’re not opposed to growth. They just have factors in place to help us make sure that's what we want.

“You sure you want growth?”

“Yes, I'm sure I want growth.”

“All right, go for it.”

And we can grow, and we can change, and it's beautiful.