The epigenetic pioneer, Dr. Randy Jirtle, returns to New Frontiers to share his latest groundbreaking work. And I really do mean groundbreaking. Dr. Jirtle’s work in mapping our “imprintome” is literally creating a brand new branch of scientific study that is expected to provide valuable insights and opportunities for epigenetially-targeted therapies, including nutrition and lifestyle. What I so appreciate about Dr. Jirtle’s work is that it clearly demonstrates how we are not inescapably at the mercy of our genes. Instead, Dr. Jirtle views disease-associated genes as a starting point for the environment to direct its expression. Join me on this episode of New Frontiers to find out what your imprintome actually is, why it is so important, and what you can expect from this area of scientific discovery in the near future. ~DrKF
Have You Met Your Imprintome Yet? Here’s Why You Should
Dr. Randy Jirtle has been mapping our “imprintome” – a set of almost 1,500 incredibly important genes that are epigenetically regulated in a different way to other genes. We have two copies of every gene in our DNA, both of which are usually expressed at least to some degree. However, imprinted genes work differently – for these genes we only express one of the gene pair and the other is permanently silenced (“imprinted”) during embryonic development through epigenetic mechanisms, primarily DNA methylation. Or at least that’s what should happen. What makes these genes so valuable to map out and study is that the dysfunction of epigenetic imprinting is associated with the development of disease. In addition, the malleability of DNA methylation, including via nutrition and other environmental factors, provides an opportunity to modify that disease trajectory. This work opens the door to a brand new field of scientific study that will include mapping the imprintome of specific diseases, and investigating interventions that target the epigenetics of those specific genes.
In this episode of New Frontiers, learn about:
- How our understanding of epigenetics has evolved in the last decade.
- What is the imprintome and what can it tell us about the pathophysiology of disease in humans?
- How does gene imprinting work?
- What is an imprint control region (ICR)?
- Why is understanding our imprintome potentially so useful to scientific study?
- Can the imprintome be used to predict diseases such as cancer, Alzheimer’s, autism, and obesity?
- The potential role of the imprintome in aging.
- How might imprinting help us target diseases more broadly- for example, target “cancer in general” rather than specifically breast or lung cancer?
- Can imprinted genes be altered epigenetically?
- How nutrition can potentially skew the imprintome.
Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine and, of course, today is no exception. I’m very honored, excited to be back with Dr. Randy Jirtle. We’re going to be doing a deep dive into epigenetics and his extraordinary work in mapping out the imprintome. You’ll learn what that is and why it’s incredibly important to us, to our health, to our health span, lifespan, et cetera, but first, let me tell you about him and then we’ll jump right into that work.
Professor Randy Jirtle was at Duke from ’77 to 2012. He’s now a Professor of Epigenetics at North Carolina State University. Dr. Jirtle’s research interests are in epigenetics, genomic imprinting, and the fetal origins of disease susceptibility. He’s known for his groundbreaking studies linking environmental exposures in early life to the development of adult diseases through changes to the epigenome and for determining the evolutionary origin of genomic imprinting in mammals and the human imprintome. He’s published over 200 peer-reviewed articles. He’s edited three books. He’s received numerous awards, including being nominated for Time’s Person of the Year Award in 2007, The Linus Pauling Award through the Institute for Functional Medicine, the Alexander Hollaender Award.
There’s also a really cool English documentary about his work titled Are You What Your Mother Ate? The Agouti Mouse Study, based on his 2003 very famous study that we’ll chat about later on. Welcome to New Frontiers, Dr. Jirtle. It’s really fabulous to have you back, and just let me just as you, there you are –
Dr. Randy Jirtle: Thank you very much. I always enjoy talking to you either at meetings or here, but…
Dr. Kara Fitzgerald: Well, let’s get to the heart of the matter. You’re sitting in front of a bunch of stuffed animals and I’m very familiar… I have a five-year-old at home now, and I know you have grandkids actually, so stuffed animals are everywhere, but tell me why these are relevant.
Dr. Randy Jirtle: Well, everybody has different things. These actually are… They’re stuffed animals, but they’re stuffed animals, at least the one over here, this one, that’s a platypus, and the one right next to it, which you can see, that’s the echidna. Those are monotremes, and to determine, we’ll get into this, but to determine when the phenomena of genomic importing evolved, we had to get tissues, not only from marsupials, and eutherians are easy because they’re all over and we’re part of that group. But marsupials are primarily in Australia as you know except for the opossum, which is here in North America, but monotremes are only present in Australia. So to look at the evolution and to try to determine when the phenomena of genomic imprinting evolved, we had to get monotreme tissue. We did that, but once we got into it, then this is actually… I bought this for my daughter, but I never gave it back to her when she left home.
Dr. Kara Fitzgerald: That is so funny.
Dr. Randy Jirtle: I liked it so much, and my grandkids like it, too, because it’s a puppet, so that’s why the stuffed animals. I’ve got a whole array of different kind of animals because we used a lot of different animal species to look at the evolution of genomic imprinting.
Dr. Kara Fitzgerald: God, that’s so fascinating. You know, I want to just say random true fact. Isabella and I were looking at an echidna yesterday. We have this book on animals of Australia, so that was our bedtime reading.
Dr. Randy Jirtle: Yeah. They’re really cool animals. They’re like porcupines. I mean, you don’t want to mess with these things because they get down… I actually have seen them. They get down in the dirt and there’s these spike that come out and theirs are really sharp and you can’t get… The only soft part is their underbelly, and they protect that really well. The platypus I’ve seen, too, but they’re nasty, too. I mean, the males have poisonous claws on their back legs I think. I don’t know about the front, but that’s all for protection, right?
Dr. Kara Fitzgerald: Yeah, it’s fascinating. Yes, we have a little joke like we’ll touch the image of it on the screen and just go, “Ow, ow,” although now that’s she five, she was saying, “Mom, that’s just a picture, it doesn’t really hurt,” you know, because I still do it, “Mom.” Anyway-
Dr. Randy Jirtle: Well, when you take her down there and see one, she’ll see why.
Dr. Kara Fitzgerald: Yeah, yeah. Let’s talk about this, and we will circle back into the Agouti mouse study and kind of sort of where it all began, at least it all began for us and we started paying attention to your work so much. Talk about this genomic imprinting. Define it and your work around it. You’ve since just published; you and your team have mapped it out. I mean, it’s just a huge deal, and I know that you argue we’re going to be leaning heavy on evaluating our imprintome to identify disease risk. I think this will be information that will be front and center for us really very soon, so define it and walk us through what it is and really why we care about it.
Dr. Randy Jirtle: Yeah, I mean, I love this beginning because nobody’s ever asked me. I always have these animals behind. You’re the only one that actually ever… I don’t know if the only one that noticed it, but the only one that had enough nerve to ask me why I’m sitting in front of stuffed animals, but anyway, yeah, I got into the field of genomic imprinting… when I got in was the early ’90s. It’s incredible how it’s 30-some years ago now. In fact, we’ll talk about this is the 20th anniversary this year of the Agouti mouse study.
Dr. Kara Fitzgerald: It’s amazing.
Dr. Randy Jirtle: It was published in 2003 and that was published historically literally 50 years after the structure of DNA was identified, so we published our paper on the 50th anniversary of the identification of the structure of DNA. And the epigenome is basically the programs that lie on top of that structure of DNA, so it all ties together so incredibly, actually, I mean, almost beyond what you would think.
Dr. Kara Fitzgerald: Well, let me say this, though, to you, too. Not only is it 50 years post the establishment of DNA structure, concurrent to your publication was identifying the human genome, which was- and everybody was trained on that as the big deal, and your first paper didn’t make a ripple. You couldn’t even get it published. Now, of course, it’s the most cited paper in the history of science, so this about face from all things DNA to your work and thinking about the epigenome and the imprintome.
Dr. Randy Jirtle: The Agouti mouse study really in effect tied the programs, which were always there, but they were never appreciated and I think it’s because they couldn’t be studied readily. A lot of time and effort, and still, I mean, is put into looking at genomic changes, but it’s really only part of the story. I mean, I always use the analogy that the hardware of your computer is like the genome, and the epigenome is like the software that runs in these computers. We have 260 different cell types, so it’s like 260 different computers sitting there and running all different programs. That’s why you have different cell types because we all came from a single cell undifferentiated, and then it went in. Well, when you differentiate, you’re programming, so that’s what’s going on. What we did is we brought the epigenome into the discussion of disease susceptibility, and it’s a major one.
Just like in your computer, I mean, when it goes down, it can go down because of hardware problems and/or software problems. It’s the same thing for us and our health. On the other way, it can be positive, too. If you optimize your computer and your programs, it’s going to run a heck of a lot better. It just works better. The analogy works incredibly well because we really are, the cells really are a programmable computer. Getting back, though, to how I got into it wasn’t from the Agouti mouse study. I mean, we got into this because of work we were doing at that time on the role of the IGF2 receptor in cancer formation, specifically liver cancer formation.
We identified it as being a tumor suppressor gene, first immuning us to chemically, which was in the early ’90s. Then, in 1995, genetically where we showed Knudson’s two hits, it knocked out both copies. Why is that important? In the early ’90s, the first genomically-imprinted gene was identified by an incredible scientist, who’s unfortunately now has died, but she changed literally my life because she discovered the IGF2 receptor was genomically imprinted and I had-
Dr. Kara Fitzgerald: Insulin-like growth factor, is it?
Dr. Randy Jirtle: Insulin-like growth factor 2, it’s also the mannose-6-phosphate receptor, so any protein that has M6P moieties will bind out to this receptor primarily for internalization on it if it’s on the outside and degradation of lysosomes, but it’s also involved in trafficking of lysosomes. It has a multitude of roles and it activates TGF-beta, so when you lose it, you lose the ability to activate a potent growth inhibitor, and at the same time, you lose an ability to degrade a very potent tumor stimulator, which is IGF2.
Dr. Kara Fitzgerald: Interesting.
Dr. Randy Jirtle: You lose two major things, the brakes, it’s like you cut your brakes and you step your accelerator to the floor when you lose the IGF2 receptor. It plays a role in basically every cancer there is.
Dr. Kara Fitzgerald: Wow. Okay, so what did this scientist like… Who was she and why-
Dr. Randy Jirtle: She discovered this gene to be imprinted, and the article was published in Nature, so it was the very first genomically-imprinted gene identified, and it was at-
Dr. Kara Fitzgerald: Define that, though. Define it because a lot of our listeners-
Dr. Randy Jirtle: I’ll define it. It was published in Nature and was the same thing. I said, “What the heck is this?” I mean, really, I was looking for everything in the literature for IGF2 receptor, but I wasn’t looking for everything for genomic imprinting or epigenetics because I really didn’t appreciate it at all at that time. So I read the paper and what it is is this. There’s a subset of genes in our genome and in all therian, which is what we show up, all therian mammals, which includes marsupials, and they also include us as eutherians, but it does not include monotremes, the platypus and the echidna and anything that’s more ancestral. It’s only present, these genes are only present in therian mammals which have placentation and live birth. Any animal that lays an egg doesn’t have imprinted genes
So what is it? Imprinted genes are genes that are expressed from only one copy. They’re autosomal genes, but even though you inherit one copy from mom and one copy from dad, only one of the copies works. The other one is silenced epigenetically, so that’s how I get into epigenetics. And it’s always from the same parent, so it’s parent of origin monoallelic expression of genes. One copy works, one copy doesn’t, and it’s always, depending on the gene, IGF2R, for example, in mice at least, is only expressed from the mother’s copy. The copy that’s in here always, whether you’re male or female, the copy the mouse gets from the mother works, the one from the father’s turned off.
IGF2 is expressed only from the father’s copy, that’s the growth factor. In general, imprinted genes, if you think about them from the role in cancer, which imprinted genes probably all of them play some role in some type of cancer because they’re growth regulatory, if it’s maternally expressed, they tend to be tumor suppressors like IGF2R. If they’re paternally expressed, they’re pro-growth and they’re called in the tumor world, oncogenic world, oncogenes.
Those are the yin and yang between breaks and gas, and that’s what they are. Then, you ask, “Well, why would something like,” because basically if you think about this, and this is what amazed me, I said, Why? Why evolutionarily would Mother Nature turn off a copy of a tumor suppressor gene? I mean it makes intellectually no sense. And you can’t understand it if you think about it from the standpoint of cancer. You can only understand it if you think about it from the standpoint of evolution, because evolution tries to get all species to the point where they reproduce, but in fact, really doesn’t care whether they get cancer after that. I’m not talking intellectually, but there’s no pressure on them to get rid of these genes afterwards because reproduction has occurred and your genes have been passed forward.
Dr. Kara Fitzgerald: Yeah.
Dr. Randy Jirtle: The rationale for why they evolved is this, and this is only a theory, but it’s probably… it’s a good one and it’s interesting. It suggests that they evolved because of a genetic battle between literally males and females to control the amount of nutrition that the offspring extracts from the mother, with the father trying to maximize the extraction to further his ability to get his genetic information forward at the expense of all other males, and the mother trying to dampen it down for one reason, actually, because it’s all-
Dr. Kara Fitzgerald: Survival.
Dr. Randy Jirtle: … remember in animals that have placentation and live birth, if the fetus grows too large, the mother will die in childbirth and there will be no species. I say that we found it evolved 150 million years ago, and I always make the comment that’s way before C-section.
Dr. Kara Fitzgerald: Yeah, right.
Dr. Randy Jirtle: They would all die, so it’s a balance between males and females to get the most out and to get it in a genetic growth advantage basically and that, it makes an important prediction that any animal that lays a hard-shelled egg will not have imprinted genes because there’s no way that a male can get any skin in that game because he cannot determine how much nutrition the mother puts in the yolk sac of that egg. Whereas, once placentation occurred, aah, now you can start manipulating physiology and extraction of nutrition through the placenta and the game began.
Dr. Kara Fitzgerald: Wow.
Dr. Randy Jirtle: I think it’s probably correct. We’re talking growth regulatory genes, so what does that mean? It means they’re involved in metabolism, they’re involved in apoptosis. They’re going to be involved basically in every cancer that we have. There’s no doubt about it, and frankly, they’re going to be involved in aging because of the apoptosis, that part of it. The whole thing is, then, what is our repertoire of imprinted genes? When this first started, everyone I think, including at least me because I was very naïve, and I told our lab, “We’re going to get our whole lab into this field because this is so amazingly important.” Mother Nature doesn’t do stupid things. It does things that are important.
Dr. Kara Fitzgerald: Yeah.
Dr. Randy Jirtle: It doesn’t use wimpy weapons to do genetic battle. These are incredibly important genes. They’re more equal than others. And now because they’re only expressed from one copy and one copy’s silenced epigenetically, you can now mess this system up by a single epigenetic change, which can cause either… It’s called loss of imprinting, either/or expression, which is bad, or under expression, which is bad. Usually, you’ll get divergent disease occurring at the same genetic location. It’s astonishing what this has done.
The other thing we learned as we got into it is every species has a different repertoire. Some are in common, but some are not. It looks like once the phenomena of imprinting evolved and the abilities to do so dramatically change the expression of these incredibly important genes, it was literally used then as a mechanism to speciate. This is why the repertoires are different. I make this point because the human imprintome will not be the same and is not the same as the mouse or the rat or the chimpanzee. If we want to know the role of imprinting in humans, we have got to know our imprintome.
Dr. Kara Fitzgerald: Right.
Dr. Randy Jirtle: Now, if you’re interested in the evolution and while how, in fact, possibly you even got here evolutionarily, that’s an important, interesting question, too, but now you start looking at imprinting in different animals. You see with Venn diagrams which are here, which aren’t, that kind of stuff you get a lot of information, I think, about how we literally got on Earth the way we are.
Dr. Kara Fitzgerald: Oh, that’s fascinating. That’s crazy. That’s really interesting.
Dr. Randy Jirtle: It’s involved in metabolism, so, I mean this is the type of stuff, type of work that, you know-
Dr. Kara Fitzgerald: Nutrition, metabolism-
Dr. Randy Jirtle: you are involved in-
Dr. Kara Fitzgerald: … yeah.
Dr. Randy Jirtle: So then I’m going to say one more thing, and then I’ll let you ask all the questions you want. We got to this point, we then defined and we got into the field of imprinting by defining when it evolved, but a thing that was always in the back of our mind was, can environmental exposures change these imprint regulatory elements? That was our original thought process. It’s not what we did ultimately, but that’s the way we got into the Agouti mouse study. We were interested in the regulation of the methylation groups and histone marks in these regions that control the silencing epigenetically of one of these imprinted alleles.
Dr. Kara Fitzgerald: Okay, so ’90s the study comes out. You’re interested in the insulin-like growth factor 2 receptor. You see that, you know, you learned that one of them is completely inhibited. I guess it’s maternally inhibited, right?
Dr. Randy Jirtle: Well it depends on the gene. IGF2 for example, the mother’s copy is inhibited and the father’s copy is expressed. It’s right around 50%. It’s not quite, I don’t remember which way it skewed, but it’s around 50-50, which is what you would expect if males and females are yin and yanging each other, they’re going to pick genes. If it’s pro-growth in the father, the mother’s going to find something to counter that-
Dr. Kara Fitzgerald: To ramp it down, right.
Dr. Randy Jirtle: … to ramp it down so that she can give birth.
Dr. Kara Fitzgerald: Yeah, that’s really extraordinarily interesting, and so you were wondering… you began to wonder whether or not these were environmentally –
Dr. Randy Jirtle: Labile.
Dr. Kara Fitzgerald: … but… yeah, were they labile? Yeah, so I mean, we know now that we can influence DNA methylation. I mean, that has in adults, that’s been and my focus of research. That question, you started to think about the environmental influence on the epigenome like way back, way back in the day. That’s so fascinating.
Dr. Randy Jirtle: No, no. Well, I think way before… People were thinking about environment, but it was almost like if you think about it and read the literature, it was like it was magic. You would say, “Well, 50% or 30% is genomic and the rest is environmental.” Then, what people that were working with the genetics would just blow off the environmental because we had no idea what the hell environmental meant. I mean, what’s environmental? At some point it has got to impinge upon the expression of a gene.
Dr. Kara Fitzgerald: Yes.
Dr. Randy Jirtle: Right? Or its mutation. I mean, those are the two things going on-
Dr. Kara Fitzgerald: Right, the expression or mutation
Dr. Randy Jirtle: But all the work was done with mutations to the genome. Nothing was being done, even thought about actually, about the role of epigenetics and programming-
Dr. Kara Fitzgerald: The software, the software.
Dr. Randy Jirtle: The software, right.
Dr. Kara Fitzgerald: The software was completely discarded. I mean, Moshe Szyf has been on my podcast and he’s just been an amazing mentor for me. He was in the world of epigenetics at the same time and, yeah, it was almost a bad word, like software was not cool.
Dr. Randy Jirtle: Well, he actually was even in it sooner than I was because he was in it through the… It started in the cancer field where people… It started actually with p16 in a way where p16 was shown to be epigenetically silenced by methylation in the promoter region. I won’t get… It’s an interesting story already, but he was in that field of cancer biology and he was actually told if he stayed in this field in cancer that he would have no future because everybody knows that cancer is a genetic disease. That was what he was told. That’s totally, totally wrong.
Dr. Kara Fitzgerald: Yeah. Well, thank God that you both persevered because obviously now he’s one of the highest regarded epigeneticists.
Dr. Randy Jirtle: But you wonder whether he’s still the high… whether we’re the highest regarded scientists. Have we made that transition yet?
Dr. Kara Fitzgerald: I mean, I would think so.
Dr. Randy Jirtle: At some point we are going to… It’s going to happen. It’s going to happen.
Dr. Kara Fitzgerald: We want to move over into thinking about environment like this black box. So it’s 2003, the human genome is getting mapped out. All eyes are on the Rosetta Stone that it’s going to be one mutation associated with one disease or… We really expected to have all the answers when the human genome was mapped. I think, I don’t know, you can speak to this better than I, but I project that it must have been disappointing to some of those scientists to realize, in fact, the answers weren’t there other than the most… There’s clearly obviously very genetically-driven conditions, but the chronic diseases that we’re grappling with that I treat in my clinic and that is pulling us down as a world, we couldn’t address those genetically.
Then, along come you and your postdoc Waterland looking at the Agouti mouse model where in pregnant dams you introduced a methylation cocktail of common nutrients, folate, B12, choline, and betaine, and you turned off a gene. I mean, that’s why I think time kind of stood still for anybody who was paying attention, but eventually time really stood still with that paper because you completely changed the phenotype of this mouse model. They’re blond and obese and you inhibited the gene with garden variety nutrients and completely changed phenotypic expression, what they looked like, and actually their health jouney-
Dr. Randy Jirtle: Exactly, because if they’re yellow, because of the way this system works, they will become obese, get diabetes, and ultimately because of that, they have an increased incidence of cancer formation. They’re absolutely one-to-one related.
Dr. Kara Fitzgerald: Well, let me say this and then I want to hear about… I want you to bridge this to the imprintome. Other scientists picked your work up and showed… I know that you looked at the response to Generation Zero, so this methylation diet, Generation Zero, nothing outrageous, no drugs, these are nutrients you get in your food and it influenced gene expression for five generations. I mean, I think according to labs that picked up and followed it, five generations.
Dr. Randy Jirtle: Right. I don’t about… I don’t know if nutrition does it, but surely exposures to different environmental toxicants did that.
Dr. Kara Fitzgerald: Well, isn’t it true, though, that some people picked up your… used that betaine, choline, folate, B12 cocktail in Generation Zero and tracked changes to the Agouti gene for five generations out?
Dr. Randy Jirtle: I think they did, but I don’t keep up too much with that.
Dr. Kara Fitzgerald: Okay.
Dr. Randy Jirtle: It’s I’m lucky I can keep focused on one generation, but there’s little doubt now that, at least in my mind, that there is transgenerational inheritance of epigenetic marks and exactly what those marks are going to be and that type of thing where it’s going to be worked out in the future. This is no longer just a hypothesis. I think it’s definitely there. But I don’t do research in that area. It’s very difficult, as you can imagine, because you’re talking about keeping track of things for three and four and five generations. In humans that’s very, very hard because we don’t have really good model systems for that but it’s going to happen. It’s just going to take more time, and once the better idea of the mechanisms by which this happens, it will become more and more acceptable. The same thing really with the fetal origins of adult disease susceptibility. If you look at that historically, that was the Barker hypothesis and they were working-
Dr. Kara Fitzgerald: Yes, David Barker.
Dr. Randy Jirtle: … that’s what it was called. Frankly, I like the name better than DOHaD. I mean, I like human names attached to things because it gives you a better idea of who did the original work.
Anyway, looking at people that survived the Dutch Hunger at the end of World War II, and clearly showed epidemiologically that they had increased incidence, the offspring now that were exposed to greatly reduced food, the mother didn’t have any food, was starving probably during that first trimester, was very, very critical in sort of setting up the health trajectory of her offspring. And then, the next generation, they were born into sort of a land of plenty, so they could go back to eating normally, or even getting more food than they normally had because it was getting into better times. These people, then, ultimately became obese, got diabetes, doubling of the neurological disorder of schizophrenia. This was reproduced in China in the 1950s where they had huge problems in failures of crops during that period of time and a lot of hunger and starvation again. Same types of results occurred.
Yet, it didn’t get a lot of traction, Kara, and the reason for that is this, it’s really interesting, it’s very simple, there is no known mechanism by which this can occur. There’s one word in there that is very, very important. Known.
Dr. Kara Fitzgerald: Yeah.
Dr. Randy Jirtle: That doesn’t mean it doesn’t exist, it’s just not known at the time. And unless you have a mechanism that you can layer this thing onto, it just doesn’t get traction. It’s going to be the same thing for the transgenerational. Once it becomes clear what the mechanisms for this are with these epigenetic inheritance that we’re seeing epidemiologically and through lots of experiments, then it’ll all fall into place again, just like it did with our Agouti mouse model. I mean, it is epigenetic. If you look at the literature before 2003, there was not the use of epigenetics once in the literature of the fetal origins of adult disease susceptibility. It was never, ever, ever talked about. After 2003, I don’t think there’s a paper published that doesn’t say, “This is the mechanism for it.” It literally changed everything.
Dr. Kara Fitzgerald: Yeah.
Dr. Randy Jirtle: It’s incredible, actually, but there’s a mechanism now. You can see the mechanism is epigenetic, and I said, “We don’t know what the epigenetic changes are in that animal. We know we followed one, and there is going to be a whole bunch of-
Dr. Kara Fitzgerald: So, beyond the Agouti gene, beyond hypermethylating the Agouti gene, there’s all sorts of secondary influences. Yeah. Yeah, you would have to be.
Dr. Randy Jirtle: They have to be, and those are the ones that alter in humans, that vary in disease susceptibility. This is not the Agouti gene. The Agouti gene was just a model system for showing that DNA methylation was linked absolutely to a phenotypic change and change in disease susceptibility in the offspring in adulthood.
Dr. Kara Fitzgerald: It has to have incredibly broad influence… Well, obviously changing methylation pattern of the Agouti gene is influencing… Well, I mean, it’s influencing the imprintome because it’s influencing all the things that you’re attaching the imprintome to, like cardiovascular disease, obesity, metabolic fitness, all of that. I mean, is that true?
Dr. Randy Jirtle: Well, it does seem to be true, but we’ll be able to see it better now that we know the human imprintome. Here we were, so epidemiology in humans and animal models, you can control things. You can look at stuff a lot easier. In humans, it’s very difficult because you can’t… When we do a study and we’re interested, in fact, let’s say we’re interested in the role of epigenetics or imprinting in autism or Alzheimer’s disease, which is what we’re working on right now. We can’t go in and drill a hole in a person’s head and look for… get a brain sample and look at the DNA methylation. All epidemiologists have basically are buccal swabs and white blood cells really are the primary ones. I suppose they could get skin cells and things like this, but you can’t get often, samples from the organs that are giving you the problems disease-wise and look at the role of epigenetics directly in those. That’s always been a limitation of the epidemiology-type epigenetics research, but it’s not a limitation when you’re talking about genomic imprinting. That’s what’s so exciting about it.
Dr. Kara Fitzgerald: Talk about why, just to define.
Dr. Randy Jirtle: Because the imprints actually come in from the gametes differently marked. That’s why you get the parent of origin-dependent expression. They come in from the egg and the sperm. One copy is methylated, let’s say the mother’s copy is methylated. At the exact same genetic location, the mother’s copy is not methylated. If you look at and just grind up tissues and look at the methylation at that region, that imprint control region, it will look like it’s 50% methylated, which is oxymoronic because you can’t have half methylation. What it is is half the alleles are methylated. Let’s say in this case the ones that come in from the egg and the ones that came in from the sperm had no methylation at all. You put them together. I used to do this when I talk. I said, “Okay, if you add a hundred plus a zero and divide it by two, what do you get?” 50. Yeah?
Dr. Kara Fitzgerald: Yeah, yeah.
Dr. Randy Jirtle: That’s what you see, that everyone one of these imprint regulatory elements, you have 50% methylation, and since they’re inherited, you have 50% methylation in every tissue in the body.
Dr. Kara Fitzgerald: Right.
Dr. Randy Jirtle: Unless they’re goofed up early on, and that’s the only thing we’re looking at, early. How can that happen? Well, you think about it, when the two, the gametes come together. There’s a global demethylation that occurs.
Dr. Kara Fitzgerald: Right.
Dr. Randy Jirtle: The imprint regulatory elements have to be protected from that because if you knock the methylation marks off of there, you cannot get monoallelic expression in a parent-of-origin-dependent manner. So there are proteins that come in and protect it. If the protection doesn’t occur early, they’re messed up, so they’re no longer 50%, but they’re no longer 50% at the earliest stage of development. You’ll be able to see that problem in every cell in your body. That means if there’s deregulation of an imprinted gene, either up or down from the 50% level, that’s giving rise epidemiologically, let’s say, to schizophrenia or Alzheimer’s disease, you should be able to see that and have to be able to see that in every tissue in your body.
Dr. Kara Fitzgerald: Saliva would work, or a skin cell would work, or-
Dr. Randy Jirtle: Exactly, and particularly if you look at different germ layers, so buccal swabs and white cells, I believe, are on two different germ layers. If you see the same thing there in both germ layers, that’s important because these are surrogates basically for tissues from the very earliest stage of development. There’s only three germ layers, so if you had another sample that we have brain, liver, kidney, and that covers a lot. If you look at our imprintome paper, it’s really incredible. I mean, it’s absolutely, to me anyway because I’ve been thinking about this for 20-some years. We wanted to do this, but we couldn’t pull it off for various reasons that were dependent upon the timing.
One time we couldn’t do it because you couldn’t physically do it. The other time we didn’t have the money to do it and I thought, “That’s it. We’re not going to be able to do it.” Finally, we got it all together and we were able to finally get it done, but it’s absolutely beautiful, Kara. I mean, when you look down these imprint control regions, look down liver, kidney, brain, 50-50-50. Look at the sperm, zero. Look at the human oocyte, a hundred. The fingerprint of an imprint regulatory element, if that’s out of whack, you have trouble, and I mean major trouble. Mother Nature does not pick wimpy genes to do genetic battle like she’s done with these imprinted genes. These are incredibly important. They’re more equal than others.
Dr. Kara Fitzgerald: Well, let’s just for people listening, we’ll link to the paper and you can actually go through the genes and you’ll recognize some of them like the fox genes and… What else was I looking at? Well, the insulin-like growth factor and…
Dr. Randy Jirtle: What you can do, and it’s fun to do it actually, I recommend anybody that’s listening to this just for their own enjoyment. Whatever disease you’re interested in, you can get in through NCBI and through GeneCards, you can get a list of genes that are showing up over and over and over and over again, a link to let’s say, Alzheimer’s disease or schizophrenia or any… I mean, absolutely anything that we have, you can look at the potential role of imprinting in its development. That you can do now, and you can do it in silico. So you get all these genes and you’d see, now you cross and you do a Venn diagram with the known ICRs. Now, they’re not all going to be imprinted, but a good number of them are going to be imprinted. You’ll see already kind of a story of the imprinted genes that are potentially involved in whatever disease or disorder that you’re interested in. So the next thing is, how do you do this experimentally to confirm what you see in silico?
Dr. Kara Fitzgerald: Let me… well, and fold into that, so I think our audience, mostly functional medicine clinicians, are waiting to talk about how this is influenced, and probably a lot of them already have an idea. How is the disease process happening at this very early stage? I mean, we can look at your Agouti mouse study and see that you radically influenced gene expression. You radically influenced methylation patterns early on, so I’m assuming this is the rubber meets the road where environment is most influential.
Dr. Randy Jirtle: Right, and that’s why the early time points are so critical. It’s not that you can’t change them later in adulthood, too, but now you’ve got a lot of cells, so there could be enough cells that are still good that you won’t see a disease phenotype. If you alter something back at the early stages, you’re either going to get a yellow animal, which means that that change had to occur literally at probably the one- or two-cell stage. Otherwise, you don’t have a yellow animal. You’ll have some mottling occurring, which is what the primarily is, and that’s some are turned off, some are turned on.
Depending on how much of those things those cells are growing and involved in the different tissues, that can affect disease susceptibility. But if it’s very early in the embryonic stem cells, you’re going to be able to see those changes in every cell type in your body, particularly if it’s very early, and that’s what you’ll be looking for. You want to see genes that are altered in their methylation patterns, the ICRs that are altered in their methylation patterns significantly so that you can actually see it, irrespective, basically, of the tissue type that you’re looking at. Those are good candidate genes. Now, you’ve got candidate genes, but then you still have to do a lot of other biology around that, but at least you know where you’re looking finally.
Now, we don’t have any clue, and you can do this from blood samples, which means epidemiologists can now actually do experiments again that mean something. Otherwise, before, you’re just giving methylation levels and nobody knows what the heck they mean. It’s very difficult unless you’re looking at white fat or brown fat, or you’re in the cell type that would be involved in whatever you’re… or pancreatic cells for diabetes, let’s say. Most of the times, you can’t get those cell types, so this is the place to start. It’s not necessarily where you’ll end, but it’s where you’re going to start because people are not going to argue with you about the importance of these genes. Evolution has told me they’re important.
Dr. Kara Fitzgerald: Right.
Dr. Randy Jirtle: You’re not going to be able to argue about the fact that they’re going to have the variations between tissue types because these things are so early that there is no variation. You’re still in the embryonic stem cells and they’re being altered. There’s another way that this can, and I don’t want to get too much into it, but there’s not only an inherited, but some of these inherited marks actually set up secondary marks or somatic marks. If those are screwed up, now you’ll have imprinted gene regulations that are messed up again, but still very, very early in the embryonic stem cells. Anything that happens outside of that, we will not be able to look at that, and frankly, I personally don’t care because there’s enough information here to keep us going for a long time.
Dr. Kara Fitzgerald: Right, right, so looking at methylation patterns on different genes, the influence is less interesting than focusing specifically on the imprintome.
Dr. Randy Jirtle: To me, and I’m not saying they’re not important. Some of these are going to be incredibly important, but when you’re trying to start and show that there’s a correlation in humans, a strong correlation between alterations and imprint regulatory elements and disease type, you’ve got to be looking at something like this so that you can have samples that you can monitor easily and genes that you know are absolutely important in development and disease formation.
Dr. Kara Fitzgerald: Yes, so I guess… I mean, so the door is open, so now that you’ve identified the imprintome, and there’s almost 1500 genes that you’ve identified, then it seems to me like you want to begin to study different cohorts to see what it looks like. For instance, what’s the imprintome look like in really healthy centenarians? You know?
Dr. Randy Jirtle: Right.
Dr. Kara Fitzgerald: What is that? –
Dr. Randy Jirtle: I think it’s… In fact, I mean, we interact with TruDiagnostics and Ryan Smith because I was talking to Lucia Aronica about this one because I give a course in one of her courses. I said, “You know, my guess is that we will be able to do better at determining basically biological lifespan than is being done right now,” which is empirical if you think about it because you just sort of randomly, maybe not randomly, but you’re just taking CPG sites all over. And there’s surrogates for the CPG sites that might actually be causing the disease problem, which many of these are going to be imprinted.
If we use the imprintome ICRs to do this, my guess is that we’re going to be able to more accurately determine biological lifespan and maybe even be able to show if you do this, reversals of this. I don’t know that it’s possible, but you can look at it and even determine maybe which genes are giving rise more to aging than others. I don’t know if there’s such genes available at present, but my guess is they probably… there are going to be some imprinted genes that are heavily linked to aging. I don’t know what they are. It’s never been done.
Dr. Kara Fitzgerald: Well, I mean, certainly we know just because the tumor suppressor, I mean, if you look at the aging genome, aside from the epigenetic clocks, you see exactly what you’ve just described, the yin and the yang between men… the male and the female tumor suppressor. As we age, tumor suppressor genes are hypermethylated and inhibited. I mean, that’s just fundamental to the cancer pathogenic mechanism, I think across the board. Well, actually, let me say… actually, let me restate that. In the aging journey, tumor suppressor genes are inhibited. This is something that actually got me really interested in epigenetics in the first place. We turn off tumor suppressor genes, which increase our vulnerability to cancer. Then, the oncogenes are turned on, so it’s almost like the original imprintome that you described, that tension, that it sort of happens in this reverse, unfavorable way for us in the aging journey. Tumor suppressor genes are shut off, oncogenes are on. That’s what aging looks like at the epigenetic level, but also in cancer, but in cancer it’s-
Dr. Randy Jirtle: … but in cancer, there’s something even more fundamentally important. I just did… This is all in silico now, but it’s an interesting little study. I looked at breast, prostate, liver, glioblastoma, so brain cancer, and colon cancer. It’s epigenetically involved, it’s shown- So five different cancers. You can ask again. You go to NCBI and GeneCards and… and ask which genes are imprinted in those. Then, you overlap them. You do Venn diagrams on them. The important thing, Kara, is this, are there genes that are in common for all five cancers? And indeed there are. There are 28.
Dr. Kara Fitzgerald: Wow.
Dr. Randy Jirtle: 28, and they’re heavily involved in maintenance of cell life, apoptosis formation, which is exactly what you would expect. These are imprinted genes potentially that are involved in regulating apoptotic function. If a cell cannot die, it can now gain the additional oncogenic and loss of tumor suppressors that you’re talking about later in the development of the cancer and not croak, but the fundamental thing that has to happen is they have to have an ability to not die when that happens. Those fundamentally imprinted genes are involved to a great degree in apoptotic pathways.
I now know them. Now, are they correct? I don’t know, but now we can start screening and actually determine them experimentally. I’m telling you; it’s not going to take long before we start learning a lot about the earliest stages of cancer formation. We’re talking about, in effect, setting you up on a pathway to actually getting cancer.
Dr. Kara Fitzgerald: Yeah. Yeah, so who’s most vulnerable? And you would be able to identify this-
Dr. Randy Jirtle: To all kinds of cancer. Yeah.
Dr. Kara Fitzgerald: Well, not just cancer. I mean, like really any chronic disease or developmental disease. I think that’s what you’ve spoken about in your work, but we-
Dr. Randy Jirtle: This is cancer in general.
Dr. Kara Fitzgerald: Yeah, right.
Dr. Randy Jirtle: I don’t know, but when you start doing this, and we’re-
Dr. Kara Fitzgerald: I mean, could it just be disease in general, right? Could you back out and say, “Not just cancer in general,” but perhaps-
Dr. Randy Jirtle: Well, any disease. I published… I mean, I reported it, and I think some people are going to think it’s crazy, but it’s not. I said, “Now, we can actually now systematically determine the role of genomic imprinting in every human disease and disorder that we have, period. All of them.” We just have to have the appropriate samples.
Dr. Kara Fitzgerald: Do you think that they’ll be equal weight? Some will be-
Dr. Randy Jirtle: I don’t know.
Dr. Kara Fitzgerald: … yeah, okay.
Dr. Randy Jirtle: See, this is the interesting thing, so are there going to be genes that pop out over and over and over again? Or are they going to be… I don’t know, but I think within the next 10 years, and I might not be here in the next 10 years, but within the next 10 years we’re going to know a lot more about that question than we do right now because we know virtually nothing right now. But we’re on the first rung of the ladder because we just now have the human imprintome chip. Now, it’s version one and it covers, I think, about 1100 ICRs of the 1400. Whether we’re missing the most important, I don’t know, but we’ll keep working on that and we will keep working on determining if we can develop sequencing technologies to be able to assess all of those ICRs at one time.
The other thing that has to be done, and we’re also into doing that now, is sequence better the human oocyte methylome. Sperm was not a problem, as you could imagine. No problem. We got great data there, but human oocytes are really, really valuable. We now are in the process of doing that. Once that’s done, assuming we can pull that off, we will be able to determine which of these ICRs truly are a hundred percent and 0% at the gamete level. Now, we could only determine that for 300 of the genes with the weak data that we have right now on human oocyte methylome data. We hope to improve that, and that will enhance and increase the number of ICRs that have a very, very good probability to be involved as imprint regulatory elements.
Dr. Kara Fitzgerald: How, then… I guess I have two huge questions, then. I mean, if you’re looking at zero and 100, how can environment alter it so that you’re then susceptible to the disease? If it’s always zero and 100, where does… how does the disease phenomena root during this time?
Dr. Randy Jirtle: Well, it’s called loss of imprinting.
Dr. Kara Fitzgerald: So there is specific changes?
Dr. Randy Jirtle: Well, what you have is that you need… you need one copy and one copy only functional.
Dr. Kara Fitzgerald: Right.
Dr. Randy Jirtle: It’s a teeter-totter. You’re sitting like this balanced, I mean teetering. If you have no methylation, you lost and it goes this way and you get one set of diseases, literally. On the other side, remember now you have a hundred percent methylation, which will cause a diametrically opposed disease and disorders at the same location.
Dr. Kara Fitzgerald: Yes, and then it’s gradation, so you’re identifying-
Dr. Randy Jirtle: Well, it won’t be gradation. It couldn’t be gradations if you’re talking about multiple cell proliferations before the decisions are made, but these are coming in like this. But it could be something like that, but more than likely you’re going to see ding ding-
Dr. Kara Fitzgerald: Too much on, too much off. Either balanced, or too much on, too much off. On or off, I guess, not too much, just on or off inappropriately.
Dr. Randy Jirtle: And if it grows for a while before it’s still in the embryonic stem cell stage, you will get skewing towards one side or skewing towards the other side. Some are fine and some aren’t. If enough of them are fine, then the person will be normal. If not, they have problems. It’ll be a mosaic. It’s kind of like females on the X chromosome. Females are mosaics. Sometimes you can see that, you know, the colors of their skin, the eye color, all that kind of shows up. Sometimes people have trouble, sometimes there’s not any problems.
Dr. Kara Fitzgerald: In the environmental influence during this time, what can play… what can skew it?
Dr. Randy Jirtle: Well, nutrition might be able to do it-
Dr. Kara Fitzgerald: For sure, right.
Dr. Randy Jirtle: … because otherwise we wouldn’t have these problems with… It’s severe. I mean, if you think about this, this is another thing that’s interesting. What do you get when you have a severe lack of food in the first trimester? If the mother is starving, what kind of neurological disorder do you get? Schizophrenia.
Dr. Kara Fitzgerald: Well, yes. Well, and cardiovascular disease and you get obesity-
Dr. Randy Jirtle: Yeah, but I’m talking neurological disorder, schizophrenia.
Dr. Kara Fitzgerald: Yeah.
Dr. Randy Jirtle: We don’t have starvation right now. We have an overabundance of calories, so what are was showing up right now? The diametrically opposed neurological disorder, which is autism.
Dr. Kara Fitzgerald: Oh, interesting. Wow.
Dr. Randy Jirtle: See, I think if you’re interested in this, there’s a book written by Christopher Badcock called The Imprinted Brain. Makes the case that when you have too much paternally expressed versus maternally expressed, you get… it gives rise to autism, and the other way around, if you have too much maternally-expressed genes relative to paternal, you get schizophrenia. In this theory, then, schizophrenia and autism are the antithesis of each other, and every other neurological disorder fits in between these two. It’s basically just like an Agouti mouse model and you skew things one way or another, literally by what type of nutrition level of nutrition the mother has when you’re in utero. You’re just jamming the distribution one direction versus another direction. I don’t know if it’s true, but it’s now testable potentially.
Dr. Kara Fitzgerald: Right. Well, and yeah, you could evolve the hypothesis. I mean, but we know though, that methylation patterns are inherited from dad. I mean, is it all about early nutrition in mom? Or that information is coming from dad-
Dr. Randy Jirtle: Oh no, I mean, either way. I just… It’s maternal/paternally imprinted genes, and they’re getting pushed one way or another. And that, then, gives rise to disease susceptibilities, and we’ll know about this once we start screening. We haven’t done anything yet.
Dr. Kara Fitzgerald: Yeah. Well, you have looked at Alzheimer’s. Can you talk about that? I know that’s in peer review now.
Dr. Randy Jirtle: Well, it is not published yet, so this is just the beginnings of it. This actually isn’t our real data, and we’re not using the imprintome chip, we’re sequencing it, so we determined the methylomes. This is work that Cathrine Hoyo has been doing in her lab and a graduate student that she’s working with Sebnem Cevik, I think is how you pronounce her name. Interestingly, the samples we use, Sebnem used the samples that we, meaning the scientific community, used to determine that APOE4 was the first genetic mutation to be shown to be involved in Alzheimer’s formation. Duke has a bank of Alzheimer’s brains, brains from Alzheimer’s patients and brains from controls.
We use the same tissue bank basically to look now at the roll of epigenetics in particularly imprinting in this phenomena, and found that… Cathrine looked at Blacks, African-American versus whites, European Americans, whatever you want to call the whites versus Blacks. Interestingly, we found imprinted genes that were involved, but the vast majority of the changes in imprint control regions were found in the Black population, three times more than in the white. Which suggests that even though… And blacks tend to get Alzheimer’s at a rate that’s about two to three times above what whites do, so where both groups are getting Alzheimer’s disease, it’s like you’re coming to Washington, D.C. One’s coming through one route and the other one’s coming through another route, and they both get to Washington D.C., which is Alzheimer’s, but they come through different routes. That’s interesting and important because if indeed that replicates, then to screen, to diagnose, even to treat is going to be potentially different for the two groups of people.
Dr. Kara Fitzgerald: Yeah. That’s right.
Dr. Randy Jirtle: Now, whether that’s true or not, I said, “It has to be replicated. This is the first shot over the bow,” but that’s what we found. Interestingly, on top of that, there was one gene that was common in both groups, and that was an inflammasome gene suggesting that it’s an inflammatory disorder. That’s basically our findings, and not… You say, “Well, that’s not,” it’s huge though if it’s correct.
Dr. Kara Fitzgerald: Yeah, it is. It will be… I mean, as this evolves, it will be game-changing. I mean, I think your position would be that we all need to know what our imprintome looks like and that we can make-
Dr. Randy Jirtle: Or maybe not, though, if you don’t want to know this, but if you’re… Until you can do something about it there… you maybe don’t want to know. I don’t know.
Dr. Kara Fitzgerald: Right, right, right. but yeah. Well, I mean, I guess we might be able to see what is possible to influence. We know that we can in real time as adults have a favorable influence on our health span and lifespan if we live in a certain way. Maybe we’ve got the imprintome bias, but we’re able to offset it in real time with a certain commitment.
Dr. Randy Jirtle: I was interviewed for in the journal Epigenomics, and I told… Storm Johnson was the Editor at that time that interviewed me, and I said, “I think of it, I think of epigenetics as a science of hope,” and it’s exactly what you’re talking about. It’s not absolutely a sentence of bad health. You potentially can do some things even to the genes that are being changed later on in life that might counteract some of these very early more deterministic changes in the epigenome, particularly in imprinted genes. Could be potentially overwhelmed to some degree, at least negated a certain ways that balances it out and doesn’t make it quite as bad as it would be if you had sort of did bad health type of things throughout your life.
Dr. Kara Fitzgerald: Yeah.
Dr. Randy Jirtle: That’s my guess. You can monitor it.
Dr. Kara Fitzgerald: Well, in the book that I wrote, I just sort of waxed philosophically about my own family coming from Poland. We migrated to the U.S. like many of us did, probably because there was some sort of a food scarcity. There was a hardship reason that brought us to Cleveland, Ohio. And then my grandparents opened delis and there was a lot of food and all sorts of abundance. Everyone in my family, if we’re not really very intentionally doing interventions to control blood sugar or in cardiovascular disease, that is our trajectory. I wonder if there wasn’t an influence in that in our time, in whatever struggles we were experiencing in our home country.
Dr. Randy Jirtle: Yeah. Well, I mean, it is possible. You’re talking about some transgenerational things coming through.
Dr. Kara Fitzgerald: Or the Overkalix work, yeah, were the… but is that the imprintome? Or is the imprintome exclusively what’s happening with the immediate parents?
Dr. Randy Jirtle: Just remember, the imprintome was only one part of it.
Dr. Kara Fitzgerald: Yeah.
Dr. Randy Jirtle: I don’t want to get people to think that this is the only thing. It’s right now it’s very important and it happens early and you can study it as cleanly as we can study epigenetic changes in humans, but it’s only one portion of the epigenetic changes. I’m not saying that’s the only thing there, but it’s the easiest thing for us to look at right now that are the most important genes. That’s where you always start. I mean, why did we pick the Agouti mouse? You could see the changes. In fact, Rob was talking about, and we were recently talking about looking at changes in methylation of the IGF2 ICR. I remember we were discussing it and said, “Well, if we did this, though, the problem is that the genomics people primarily are going to say, ‘Even if you found a 10 or 15% difference between disease, let’s say, versus controls at the ICR level of methylation,’ they’re going to say, ‘Well, that’s not biologically relevant.'”
Dr. Kara Fitzgerald: Right.
Dr. Randy Jirtle: I said “We’ll be spending the rest of our life trying to explain why a 10 or 15% change in an ICR is biologically relevant.” I said, “That’s not where we want to start. We want to start with something where you can link methylation all the way to a disease susceptibility and show that you can manipulate this back and forth and not only change coat color and disease susceptibility, but also have it linked directly to the methylation changes.” Thus-
Dr. Kara Fitzgerald: The Agouti.
Dr. Randy Jirtle: … the Agouti mouse. What was it? EO Wilson said that for every science question, there is a biological model system that’s best for studying it. For looking at the fetal origins of adult disease susceptibility, which is what we were doing at that time, actually, the best model was the Agouti mouse. For looking at the role of epigenetics in human disease, the best model is looking at the Imprintome of imprinted genes.
Dr. Kara Fitzgerald: Well, I’ve got a ton more questions on this, but we’re just… we’re at time. I’m incredibly excited to see where this goes, and we’re working with Ryan over at TruDiagnostic as well, and so he kind of keeps us posted of what’s going on in the world of the imprintome, but I would imagine pretty soon we’re going to all be able to measure our imprintomes. Maybe not immediately. I know you can’t get it on the Illumina. The Illumina misses most of it, I think, but-
Dr. Randy Jirtle: Quite a bit of it, but even as I said, we got version one, hopefully version two will have more ICRs on it. As I said, as we get the better idea of the methylome and human oocytes, it will define of those 1400 or 1500 ICRs better which ones are truly juicy, juicy good ones, and which ones maybe not so good, so that’ll happen.
Dr. Kara Fitzgerald: You think it’s happening really pretty quickly that we’ll be able to start to get this information real time and maybe make some lifestyle choices around perhaps our, the biases.
Dr. Randy Jirtle: Yeah, and then you can monitor. For example, with the imprintome, you could, and I mean, I don’t know if it’s possible, you put people on different diets or whatever, different things that you do, you can start asking then, Does that change? We know what it was here, what was it when we do this for half a year or a year or a week or whatever?” Does it alter it? I don’t know.
Dr. Kara Fitzgerald: Well, I mean, you said at the beginning that it’s very reliably reproducible, but because it happened in the gamete, those changes were wrought in the gamete stage, that it’s reproducible through every cell. I mean, one would think that we really put a lot of effort into continuing to maintain it. We’re not going to be necessarily changing the imprintome, but if the imprintome itself is regulatory for secondary gene expression, then we might be changing those associated genes, right?
Dr. Randy Jirtle: … that’ll be a little harder to tease out, but it could be that that’s the case. In other words, the ones that are primary, which I think the imprinted genes, they’re going to be primary. You could possibly get other changes in other more secondary things that are involved in metabolism and stuff that can modify the negative effects, let’s say, of the ones that- Not everything is going to be negative. Sometimes people are going to luck out. It’ll be positive, right?
Dr. Kara Fitzgerald: Well, that’s why it would be kind of cool to study like centenarians’ imprintome, right? As an example of-
Dr. Randy Jirtle: The aging, if they’re lucky.
Dr. Kara Fitzgerald: Yeah. Right. What does it look like?
Dr. Randy Jirtle: But luck is based on something. I mean, it’s not just luck-
Dr. Kara Fitzgerald: Yeah.
Dr. Randy Jirtle: … I don’t think.
Dr. Kara Fitzgerald: Right. Well, I mean, yeah. It looks like they have certain lifestyle habits and genetics and maybe epigenetics play a bigger role. Maybe the imprintome plays a bigger role in these centenarians than genetics.
Dr. Randy Jirtle: And that can be looked at now, can’t it?
Dr. Kara Fitzgerald: It’s very, very, very interesting.
Dr. Randy Jirtle: Wouldn’t that be an interesting experiment?
Dr. Kara Fitzgerald: Yeah, totally.
Dr. Randy Jirtle: I mean, to me, that would be more interesting to look at right now, to some degree, than its role in different diseases in some cases.
Dr. Kara Fitzgerald: Yeah, right.
Dr. Randy Jirtle: It’s very fundamental in why some people seem to be really healthy all the time, and some people really aren’t.
Dr. Kara Fitzgerald: Yeah. It would be nice for us to train our lens on what wellness maps out to versus disease. We’re really obsessed with sort of the disease process, but let’s look at what wellness maps out to and have a route for us to take.
Dr. Randy Jirtle: I think scientists always tend to think more on the negative side because we’re so disease-oriented, but on the other side, nutritionists primarily, I think, look more at it the other way around, health-wise stuff.
Dr. Kara Fitzgerald: Yeah. Well, and there’s a dearth of information here. Because we always focus on disease. Science focuses on disease, and so, yeah, we need to be looking at what wellness, what resilience looks like epigenetically. I mean, I’m very interested in that.
Dr. Randy Jirtle: And then can be modified.
Dr. Kara Fitzgerald: Yeah. Can you take the person who doesn’t have that and influence it favorably? Yeah, for sure. When we look at offspring of Holocaust survivors, I mean, we know that there were patterns of resilience, but I don’t think that … we don’t know epigenetically necessarily, I think, what that looks like. People survive with varying degrees or people have inherited varying degrees of imbalances from that original Holocaust cohort. There’s resilience and then there’s vulnerability to some of the downstream trauma. Does that make sense?
Dr. Randy Jirtle: Mm-hmm.
Dr. Kara Fitzgerald: All right. Well, it was great to talk to you. Let me just ask you one more question. You were pretty strong in saying that the imprintome is stably reproducible, or just stable over in all of our cells, and maybe I misunderstood you. You do think there may be interventions and even lifestyle interventions that could in adulthood shift the imprintome?
Dr. Randy Jirtle: Possibly. I think it’s not going to be easy, but I’m going to say it this way. Many things that I’ve hypothesized in the area of epigenetics and have already written the paper in my brain were absolutely incorrect.
Dr. Kara Fitzgerald: You’ve had some key rights, though. You’ve been right in some-
Dr. Randy Jirtle: Yeah, but I what I’m saying is it’s hard to predict, because we know so little about this whole game in a way, how this is regulated in the effect of an environment. There’s stuff on this that it’s sometimes hard to really predict. You really have to go measure it. Even as I said, with the work that we have with Alzheimer’s disease, it needs to be replicated, and we have to… We and other people need to look at it ultimately. My guess is that some of these genes will fall out and some of them will stay, and the ones that stay are going to be probably involved in the formation of Alzheimer’s disease. Now, whether or not Blacks still have a greater degree of epigenetic changes in imprint control regions than whites, I don’t know, but that’s the way it’ll evolve out. This is just the beginnings of the whole voyage.
Dr. Kara Fitzgerald: Yeah.
Dr. Randy Jirtle: We started it 20 years ago by showing with the Agouti mouse that the fetal origins of adult disease susceptibility was due to epigenetics. Now, we’re trying to dissect it a little bit more in that we know it’s epigenetic, but what are potentially the genes that are altered and are most labile and important in the different disease and health projection… What do you call it? Projections, I guess, journeys in our life?
Dr. Kara Fitzgerald: How we can shift them. Can we shift them in real time? Yeah, so lots of questions, but-
Dr. Randy Jirtle: Because you can measure now, potentially. We couldn’t do that before.
Dr. Kara Fitzgerald: So very exciting. I’m just thrilled that you’re doing this work and that I got to catch up with you on it. I’ll just… We’ll be paying attention here, just excited for you-
Dr. Randy Jirtle: Yeah, it’ll be people like yourself that’ll be doing these types of studies and making, hopefully, some sense out of it. It won’t be easy, but I can guarantee you one thing. It’s going to be unbelievably exciting.
Dr. Kara Fitzgerald: Yeah, it already is.
Dr. Randy Jirtle: I mean, it’s astonishing, actually.
Dr. Kara Fitzgerald: Yeah. Well, Dr. Jirtle, thank you so much for your brilliance and your commitment to this work and being so gracious with your time, making time for me and my audience today. I just really appreciate it. Really appreciate-
Dr. Randy Jirtle: It’s my honor and pleasure. Thank you.
Dr. Kara Fitzgerald: Thank you. As always, thank you for listening to New Frontiers in Functional Medicine, where our sponsors help bring the very best minds in functional medicine, and today is no exception. Not everyone can be a sponsor on my platform, and I so appreciate the good work, relentless research, and generous support from my friends at Rupa Health, Biotics and Integrative Therapeutics. These are brands I know and trust in my own clinic and can confidently recommend to you. Visit them at RupaHealth.com, BioticsResearch.com and IntregrativePro.com, and please, tell them you learned about them on New Frontiers.
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Professor Randy Jirtle was at Duke University from 1977 to 2012. He is now a Professor of Epigenetics at North Carolina State University. Jirtle’s research interests are in epigenetics, genomic imprinting, and the fetal origins of disease susceptibility. He is known for his groundbreaking studies linking environmental exposures early in life to the development of adult diseases through changes in the epigenome, and for determining the evolutionary origin of genomic imprinting in mammals and the human imprintome. He has published over 200 peer-reviewed articles and has edited three books. He has received numerous awards including being nominated for Time Magazine’s Person of the Year in 2007, the Linus Pauling Award in 2014, and the Alexander Hollaender Award in 2019. ShortCutsTV also produced an English documentary, Are You What Your Mother Ate? The Agouti Mouse Study, based upon his pioneering epigenetic research.
Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003 Aug;23(15):5293-300. doi: 10.1128/MCB.23.15.5293-5300.2003. PMID: 12861015; PMCID: PMC165709.
Dereje D. Jima, David A. Skaar, et al. (2022) Genomic map of candidate human imprint control regions: the imprintome, Epigenetics, 17:13, 1920-1943, DOI: 10.1080/15592294.2022.2091815
Human ICR.org – A resource for integrated genetical genomic analysis of the human Imprint Control Regions (ICRs)
Draft paper on some of the racial impacts of the imprintome: Association of DNA Methylation of Imprint Control Regions with Alzheimer’s Disease in Non-Hispanic Blacks and Non-Hispanic Whites
Skaar DA, Li Y, Bernal AJ, Hoyo C, Murphy SK, Jirtle RL. The human imprintome: regulatory mechanisms, methods of ascertainment, and roles in disease susceptibility. ILAR J. 2012;53(3-4):341-58. doi: 10.1093/ilar.53.3-4.341. PMID: 23744971; PMCID: PMC3683658.
Jima DD, Skaar DA, Planchart A, Motsinger-Reif A, et al. Genomic map of candidate human imprint control regions: the imprintome. Epigenetics. 2022 Dec;17(13):1920-1943. doi: 10.1080/15592294.2022.2091815. Epub 2022 Jul 4. PMID: 35786392; PMCID: PMC9665137.
Imprinted and More Equal Why silence perfectly good copies of important genes? The answer may lie in a battle between mother and father staged in the genome of their offspring. by Randy Jirtle, Jennifer Weidman. American Scientist. March-April 2007.
TruDiagnostic Epigenetic laboratory testing