hannah_went (00:01.155)
In today’s episode, we talk with Dr. Randy Jirtle. Welcome to the Everything Epigenetics podcast, Dr. Jertle. I’m excited to have you today.
randy_jirtle (00:09.73)
Thank you for inviting me.
hannah_went (00:11.531)
Yeah, absolutely. So I’m not going to waste our listeners time. I’m really going to hop right into it. You are extremely famous and known for your 2003 Seminole Agouti mouse study. You know, it’s not only been talked about or described as one of the most cited papers in genetics, but in science. So I really want to focus on that for a large portion of our interview today. Can you just…
Tell us about this experiment, introduce the listeners, give us the idea of influence from the environment on phenotypic expression. Let’s really focus in on that study.
randy_jirtle (00:51.618)
Yeah, I mean, it’s interesting because if you do 2003 and 2023, this is a 20th anniversary.
hannah_went (00:58.8)
Yes, I didn’t even realize that. Well, no better way to celebrate. Yeah.
randy_jirtle (01:00.606)
Yeah, so you should have started that way. Yeah. I think I might actually write a paper on this because it is, it would be interesting, I think to people, not just your podcast will cover a lot of it, but when you sit and read it, it’s, it’s a little different. You can chew on it and things like that, which you can’t do as well when you’re talking.
And it doesn’t seem like it was that long ago. Obviously life doesn’t seem like that either, right? But it seems like it happened very, not very long ago at all, but yet it is 20 years ago that study was done. And just to put that in perspective, that study was done before the human genome was published. So there was no genomic information known either about humans or about mice. We were really in the dark when it came to genomic structure at that time.
And that makes a big difference on when you go back and listen to and read old papers because people now can’t understand how hard it was when you didn’t have that information readily available. Geneimprint.com, which is our website. And we started at, my son actually started that when he was like 10 or 12 years old in 1995. I mean, it’s a long time ago. And if you look at websites, you know, that was like when nothing was going on and you still had dial-up.
hannah_went (02:14.439)
I’m going to go to bed.
randy_jirtle (02:22.162)
And that was established originally to bring to scientists the let them know mutations that were occurring in the gene of the IGF-2 receptor. And that’s how I got into the whole field of epigenetics because there were no mutations, there were no SNP databases, none of that was available. It’s hard to believe that now, given all the information that’s available on the web.
hannah_went (02:48.813)
Yeah, it.
Right, you can download your raw genetic data into a plethora of platforms, right? I could think of at least 10 off the top of my head. So it’s really widely available now. So it’s crazy to think about all of the progress that we’ve made and how you’ve had such a profound impact on that.
randy_jirtle (03:09.654)
Yeah, and the impact of this paper wasn’t from the standpoint of information like we’re talking about data. It was a conceptual change. It totally changed the way people viewed disease susceptibility. We didn’t start this. Rob Waterlin was a postdoc in the lab and did these experiments in my laboratory. But there was a little history before that. I mean, originally we weren’t planning to use the Agouti mouse.
When he first came into, and you want to talk about this later on, when he first came into the laboratory, we were, and in fact, almost everybody that was working in the field of epigenetics at that time was working in the field of what’s still called genomic imprinting. And we’ll talk about that later on. But that’s how we got into it, because the IGF2 receptor was the very first gene to be identified as being genomic imprinted by Denise Barlow.
And right at that same time, we had the first evidence that gene was functioning as a tumor suppressor gene. And in 1995, we provided the first genetic information that indeed that was the case. And when that paper was published in Nature Genetics, Denise emailed me and she said she always thought that this gene might function as a tumor suppressor, but had no evidence that indeed was the case.
Unfortunately, Denise died. Otherwise, that would have been in 2017, that would have been someone else that you would have definitely wanted to interview because she was an amazing scientist and she totally changed my life because it’s the reason why we got into the field of epigenetics. And you say, well, how can these two things coming together get somebody? The other thing is that people don’t maybe know. I started my scientific career back in 1970.
hannah_went (04:29.453)
Mm-hmm.
randy_jirtle (04:59.39)
in the field even before that in nuclear engineering and radiation biology. So I have no formal training in epigenetics. I bungled into this field and I really have very little formal training, hardly any really, in the field of genetics. Most of my training was really in computer science and physics and math. So I come at it from a more quantitative aspect than I think many people.
hannah_went (05:03.78)
Mm-hmm.
hannah_went (05:09.636)
Yeah.
hannah_went (05:17.957)
Yeah.
randy_jirtle (05:27.474)
And I think that’s why the, we’ll get to this later, why the phenomena of the imprintome appeal to me so much because it’s an engineering computer-based approach to doing science. And I like where we are right now because we have a lot of data that we can analyze. And in the old days, that was not the case. So getting back to this here, we were just getting out and had just defined when the phenomena of genomic imprinting evolved.
hannah_went (05:45.531)
Mm-hmm.
randy_jirtle (05:56.682)
So here you have a radiation biologist, nuclear engineer, providing the very first evidence of when a phenomena of imprinting evolved, and we found that it evolved in mammals, in a common ancestor that gave rise to what’s called Thurian mammals, which are marsupials and the Eutherians, of which most mammals on Earth are a member of. And I’m just gonna decline this here, right.
hannah_went (05:59.399)
I’m going to go to bed.
hannah_went (06:22.68)
Oh, you’re okay.
randy_jirtle (06:25.463)
So we had just gotten out of this and that’s how we got into the field of epigenetics because if you think about it, when we found that this gene was…
hannah_went (06:39.235)
No worries, Dr. Dyrdahl.
randy_jirtle (06:40.471)
you
randy_jirtle (06:44.842)
I’m gonna turn my phone off.
hannah_went (06:46.959)
You’re okay, you’re a popular man. Ha ha ha.
randy_jirtle (06:48.799)
Yeah, yeah.
randy_jirtle (06:59.483)
Maybe I won’t turn this thing off.
randy_jirtle (07:09.322)
Anyway, when we first got, do you want to start this over again or is it okay to continue on with this at this point?
hannah_went (07:17.379)
No, just continue. Yeah, we’re good. I can always edit anything and everything out.
randy_jirtle (07:21.882)
Okay, because I’m sorry for that. I mean, it’s I don’t get that many phone calls, but this one rings on the computer. It comes through so you can hear it. But
hannah_went (07:27.01)
No worries.
randy_jirtle (07:34.294)
So we got into the field of epigenetics through this evolutionary biology approach to determining when the phenomena of imprinting evolved. And you’d say, well, why would you get into it through such a crazy angle? It’s because there were only two genes that were known to be imprinted, IGF2 at that point and the IGF2 receptor. And there were a number of really, really strong groups of people primarily in…
in England and in Europe working on those two genes from every angle that you could think of at that point. So getting into the field of epigenetics or even genomic imprinting when you had no background in it was not easy. So we chose this because we felt it was probably the least likely that anybody would really be interested in doing this type of work. So that’s how we
got into the field of epigenetics at that point through the evolutionary biology work. It’s interesting from my perspective too, because I did have to take a biology course when I was in high school. And biology at that point was primarily evolutionary biology. And I really did enjoy it at all, because all you were doing is memorizing things. And I said, I’m never gonna need to know this anyway. So I didn’t learn it very well.
hannah_went (08:40.859)
Ha ha.
hannah_went (08:52.007)
Hehehe Mm-hmm
randy_jirtle (08:54.378)
So I get to tell people that are listening to this that are young, you never know where science and life is going to take you. So here we are now in this field and we know about imprinting and we have a tumor suppressor in which one copy of that gene is turned off naturally by mother nature. And it’s the tumor suppressor and you ask, why would something like this crazy stuff, why would that have ever evolved? It makes no biological sense.
hannah_went (09:03.956)
Oh, yeah.
randy_jirtle (09:24.406)
to me anyway, it makes no logical sense. It probably makes a biological sense, otherwise it wouldn’t have evolved, but it makes no sense to me. And I said, this has got to be really important. And I decided then that we were gonna bring our whole field, our whole laboratory into the field of genomic imprinting and epigenetics. We got into it, as I said, through evolutionary biology. So the next question was, we knew already because of Denise Barlow’s work that there’s the imprint regulatory elements were what was controlling this.
hannah_went (09:24.507)
Mm-hmm.
randy_jirtle (09:54.606)
funny level of expression. So the question we had was, is it possible that an environmental, because I’ve always had sort of a toxicology sort of background and angle to my research, even in cancer biology, is it possible that exposures to toxicological agents like non-genotoxic agents could potentially alter the expression?
So now we’ve got a question, just a fundamental question, could alter it through altering the methylation of this imprint regulatory elements. And that’s when Rob Waterlin approached me to do a postdoctoral fellowship in the laboratory. And we were thinking about this originally to look at the role, he was a nutritionist, so that’s how nutrition got into this study. There’s not.
hannah_went (10:27.396)
Mm-hmm.
hannah_went (10:41.319)
I’m gonna go.
randy_jirtle (10:42.97)
not a lot of big logic on here. It’s just the way you came in from what angle you were coming in on this thing. And then the more we talked, the more we realized that even if we saw a 10 or 15% change in methylation levels at these imprint control regions, that the primarily geneticists would say, well, that’s not biologically relevant.
hannah_went (11:04.447)
Sure, yeah, absolutely. Yeah, there’s a, I remember discussing this and hearing your story a little bit when I first met you at PLMI at Dr. Jeffrey Blaine’s conference in Seattle last year. So it’s interesting to understand the background of everyone who is involved on this type of city. You all brought unique things to the table, right? Your specialties in each different area and you come up with this miraculous study, what I would call it, right? That
randy_jirtle (11:33.122)
It’s sort of just jammed together kind of. There were logical questions, but you’re right. I mean, what the angles we came at it from, we’re very different. So we, then both of us had read these papers about the agouti mouse and the beauty of the agouti mouse is that it would already been known that epigenetics was involved in controlling coat color. And as a consequence, also that was associated with
hannah_went (11:42.16)
Right.
randy_jirtle (11:59.894)
disease susceptibilities of obesity, and diabetes, and cancer.
hannah_went (12:03.76)
Gotcha. Is that why you chose that model, the Agouti mouse model? Perfect. Okay.
randy_jirtle (12:06.134)
That’s absolutely correct. Now I wanna make it clear that the Agouti mouse model is another class of epigenetically regulated genes that occurs very, very early in development. They’re not that those genes that are expressed that way are called metastable epi alleles. And that’s another set of what I call sort of epigenetic methylation dependent.
regulatory elements for genes. There’s two major classes, one’s the metastable epialyos and one other class is the genes that are genomically imprinted. And there’s a lot of other methylation that occur for differentiation and stuff like this, but the ones that are very, very early change that are involved in disease susceptibility are those two major classes. And Rob is now working on the metastable epialyos and he’s defined the metastable epialyos in humans.
That’s been done, and it was done before we were able to define the imprintome in humans for imprint gene regulation. But now both of these groups are defined.
hannah_went (13:12.251)
Right. So let’s.
Yeah, so can you define both of those groups? Just to make sure our listeners understand as you’re walking through this. And because you’ve mentioned, yeah.
randy_jirtle (13:21.886)
It’s hard to explain the epigenetics, the Goody mouse study without looking at these animals. So you’ve got coat color. Let’s just focus on coat color, but also disease susceptibility is dependent upon methylation of a transposable element that’s upstream of that gene. And this is a weird strain of animals. It’s not true in the normal mouse. This is a mutant basically, but a very, very…
hannah_went (13:28.699)
Mm-hmm.
randy_jirtle (13:47.366)
effective mutant and it provides a wonderful model system for addressing clearly as clearly as you can in biology what role for example in this situation nutrition and putting methyl groups in the diet which is like folic acid, betaine, I can’t remember there’s a number of couple of other gene groups of nutrients that are involved in providing methyl groups
all the methyl groups that are then put down on the DNA and the histones come in from our diet. So that’s why we thought if we loaded the hopper, in other words, fed the mother lots and lots of methyl groups, we might be able to shift the coat color to brown, which is the healthy animals and has lower disease susceptibility and et cetera, away from the yellow animals. And we could then demonstrate or test whether or not that was through
changes in the epigenome itself. And that’s what our study did for the very first time. And as a consequence, it really started the, what I call the field of environmental epigenomics. It started with the publication of that paper. There were a lot of people that were working on this, but they were primarily biochemists. So they were in the signal transduction pathways, but that wasn’t the memory system.
The memory system is putting the marks onto the DNA and histones and turning genes off and opening other genes up. And that’s how exposures early in development can cause or actually reduce the incidence of diseases in adulthood. So this then was and is the mechanism for the fetal origins of adult disease susceptibility. And that’s why this paper is so fundamentally important.
because it provided a mechanism for something that made no sense. And up until that paper was published, in reality, a lot of people just didn’t believe it, didn’t talk about it, and swept it under the rug. They don’t do that anymore. They might still be arguing about different aspects, but I think that point has now been made.
hannah_went (15:58.191)
Yeah.
hannah_went (16:03.531)
It’s something that can no longer be ignored. And I really want to point something out there when you talked about shifting methylation markers. I actually heard someone else say that, that I talked to. But that’s a great point because we want to shift methylation markers in our favor. A lot of healthcare providers that I even talk to now, when we talk about DNA methylation or epigenetics, they still think about the MTHFR gene and the CompT gene. They always think that this methylation is a bad thing.
But we’re trying to teach if you’re giving those methyl donors, you know, in the example with the Agouti mouse trial and you’re shifting that coke color to be favorable, you’re going to get that better outcome. So I love that study. I just think it’s groundbreaking. You know, it’s something that, yeah, you’re right, people can’t ignore now, right? They have to deal with it.
randy_jirtle (16:55.498)
You would hope so, but I mean, even still, I mean, you’ll, there, it takes a long time. I mean, 20 years is quite a long time, but I think it’s starting to become clear to a lot of people. And my analogy is, again, because of coming through computer science and engineering, I think of the DNA as being comparable to the hardware of your computer, and the epigenome is just simply the software that tells that computer when, where, and how to work.
hannah_went (16:56.935)
I’m sorry.
randy_jirtle (17:23.518)
And this is how you can get basically 260 or so different cell types in your body from a single cell that had the same, all cells have the same DNA. But every cell in our body, I mean, you look at us, we’re, everything is different. And the reason for this is because the programs running in those cells is different and they were established very, very early. That’s in during development. And that’s why that stage is so critical for
maintaining good health and also alternatively, messing up your health later on in adulthood.
hannah_went (17:58.639)
Yeah, and I actually used that example because I remember you said that at the conference and I loved it because I usually say, your eyes and your heart, they have the same genetic information, they have the same DNA, but what makes your eyes your eyes and your heart your heart? And it’s those epigenetic mechanisms, those on and off switches that are going through the central dogma or maybe not, and then resulting in a phenotypic outcome, or again, maybe not. So I really love the software and hardware example that you gave.
So rounding the end of the conversation about the Agouti trial and the mouse study, did you know you were gonna have such a profound impact on the scientific community? Or I know you talked about your background, but did you know you were ever gonna reach this level if you would call it success? I definitely would.
randy_jirtle (18:43.362)
Well, I told Rob, I said, if this experiment succeeds, and by that, I meant in this situation that it went according to our hypothesis. Now, I must say that many times in the field of epigenetics that what I hypothesize is not correct. There have been a many paper that I’ve already written in my head that ended up not being supported by the data once they’re out.
hannah_went (19:03.053)
Mm-hmm.
randy_jirtle (19:09.218)
But in this situation, it actually, it did end up the way we thought. But I told Rob, I said, either we’re gonna be going down in flames or we’re gonna probably be famous for this because of what it does fundamentally in providing a fundamental mechanism for the fetal origins of adult disease susceptibility. And what it also does is scientists don’t believe things very much. They like to be, you know, they’re the doubting Thomases of science, right?
hannah_went (19:18.168)
Yeah.
hannah_went (19:33.898)
Mm-mm.
randy_jirtle (19:37.666)
They want to be shown that this is correct. And that’s what our job is, is to be doubting on everything. And before there was a mechanism for this, the phenomena of the fetal origins of adult disease susceptibility, which was really mainly introduced by Barker, it was even called the Barker hypothesis back in the old days.
There were people that believed, but a lot more people that just didn’t believe it or just didn’t even think about it. You can’t do that anymore. I mean, I don’t think most people can realize that you can’t fix a computer unless you’re both looking at the software and the hardware, and it’s the same thing for disease susceptibility, period.
hannah_went (20:19.939)
Yeah, yeah, absolutely. And again, you’ve given us this great research now that we can build on top of. So, you know, to summarize there, your first experiment showed there’s this environmental and even nutritional exposures that can determine your phenotypes through epigenetic regulation and other mechanisms. This means our diet, our exercise, our lifestyle, all of these triggers are…
food, the exposome, the toxics that we’re exposed to, and even our mindset can actually impact our health outcomes. So yeah.
randy_jirtle (20:51.242)
And the other thing, excuse me, the other thing I was gonna say is that in an additional study later on with Dana Dolanoy, she demonstrated that the negative effects, for example, that we showed with bisphenol A, there we shifted the color towards yellow, could be completely negated by also supplementing the mother’s diet with methyl groups. So in effect, your diet was also, potentially can reverse or…
hannah_went (21:00.691)
Mm-hmm.
hannah_went (21:08.444)
Mm-hmm.
randy_jirtle (21:20.042)
reverse possibly or negate the negative effects of things that you’re being exposed to in the environment also. So it’s a yin and yang. It’s moving back and forth and it’s plastic.
hannah_went (21:31.535)
Yep, yeah, there’s this change occurring. So rounding all of that together, right? And this is why I wanted to have you on and how we’re working with you now, which we’ll get into. But that established the idea of the imprintome that you hinted at the beginning, right? So, yeah, I know. We’re just gonna have you explain what imprinting is, what’s the imprintome, give our listeners an insight and be as detailed and specific as possible because.
randy_jirtle (21:48.394)
Yeah, that’s keep going.
hannah_went (21:59.771)
this is still such a new idea, right? So feel free to go on a whim here.
randy_jirtle (22:07.618)
Well, I mean, I thought about this back when we were doing the original studies and the original evolutionary biology studies. In fact, I put a grant application in to determine the human imprintome back in around 2005 or so to the NIH, and it was obviously never was funded. And I want to make this point to students and stuff too. Everything that we are actually known for.
hannah_went (22:15.909)
Mm-hmm.
hannah_went (22:27.119)
Mm-hmm.
randy_jirtle (22:33.79)
was not originally actually supported by NIH. Ultimately, NIH supported things that came from this information, but not the original concepts. I mean, there’s no way I would support myself to do an evolutionary biology study, given my background, but yet we did it. And it’s the same thing with the Agouti mouse. I mean, it’s hard to believe.
hannah_went (22:42.311)
Mm-hmm.
hannah_went (22:47.939)
Hahaha
hannah_went (22:52.511)
Right, right. Yeah, it just seems.
randy_jirtle (22:58.614)
very many people would have supported it at all because a lot of people didn’t believe it. So it doesn’t, those kinds of changes then have to be supported by other kinds of money, more hardcore money, private money usually, and company money in some respects. And that brings up the agouti mao. So we had enough money set aside that we could do the experiments that we did.
hannah_went (23:18.008)
Yeah.
randy_jirtle (23:28.574)
So we didn’t need NIH to support that original study. The other ones were all supported by NIH. And there were great studies, too, and had great concepts, but the original ones.
And Rob Waterlin came in here and he was supported for two years as a postdoc by a grant from Dan and Yogurt. So I have a very, I have a soft spot in my heart for Dan and Yogurt. They helped me out when we needed it.
hannah_went (23:49.797)
I’m sorry.
hannah_went (23:54.88)
They helped you out.
randy_jirtle (23:58.574)
So we got that done. So even at that point, we were thinking about these imprint regulatory elements and the fact that we needed to know those. And it was from our evolutionary biology experiments and also other people’s experiments, it was becoming very clear that different animals had different repertoires of imprinted genes. So you can’t go to the mouse and say, well, I’m gonna do all these studies in the mouse and then I will know the repertoire and where all the imprint regulatory elements are for the human.
hannah_went (23:58.705)
Mm-hmm.
randy_jirtle (24:27.842)
It doesn’t work that way. We’re different. And in fact, it’s possible that one of the, once the phenomena of genomic imprinting evolved, that you theory, or theory in mammals basically evolved themselves on the backs of the development and formation of imprinted genes themselves. So they could potentially, and I do think this is correct, but I’m not sure how you would test it.
hannah_went (24:28.551)
Hahaha
hannah_went (24:48.472)
Mm-hmm.
randy_jirtle (24:54.07)
that was a driving force in mammals for evolution, rapid evolution, because you’re doing it on the back not only of mutational changes, but also now a phenomena that you can change the expression dramatically in time and space and sex. And if you think about that, that’s incredibly powerful. So we needed to know the imprint regulatory elements in humans.
And there was a lot of different diseases already at that point. Beckwith-Wiedemann syndrome, Prader-Willi syndrome, Angelman syndrome, on and on and on. There’s a number of syndromes that were known to be created in developmental disorders and cognitive disorders that were being affected by inappropriate expression of imprinted genes.
hannah_went (25:43.272)
Yeah, definitely. No, I love it. And we’re going to get into those disease states as well. For those listening, yeah, that’s where you were. And that’s what…
randy_jirtle (25:48.534)
So that’s where we were, Hannah. In around, that’s where we were at about 2007. I first defined then what the imprintome was in the first editorial for a journal called Epigenomics, which came out in 2007. What the imprintome was and why we needed to define it.
hannah_went (25:57.37)
Mm-hmm.
hannah_went (26:07.355)
Mm-hmm. Yep.
randy_jirtle (26:14.498)
But telling you why and doing it are two different things. Now I’m gonna let you ask another question and then we’ll get into what imprinting is and stuff. Is there anything you want?
hannah_went (26:19.265)
Definitely.
hannah_went (26:25.055)
Yes, well, I just wanted to add there, you know, my definition. I want to see if what I’m saying is correct. So for most genes, we have two working copies, right? One from mom, one from dad. But within printed genes, we only inherit one working copy. So depending on the actual gene itself, either the copy from the mom or the copy from the dad is epigenetically silenced, right? If something is methylated, it’s turned off. It’s not being expressed.
So that is exactly what we’re talking about. Silencing usually happens through the addition of those little tiny methyl groups during EGGER or sperm formulation. So these, you can call them epigenetic tags on imprinted genes usually stay put for the life of the organism. And that is really, really important, but they are…
randy_jirtle (27:13.17)
and they’re established extremely early in the gametes or right after fertilization.
hannah_went (27:19.035)
Exactly, and they are reset during the egg and sperm formation. So regardless of whether they came from mom or dad, certain genes are always silenced in the egg, and there’s always certain ones that are silenced in the sperm. So I believe I think this is correct. Humans have about 20,000 to 25,000 genes, and imprinting is unique to mammals. That’s where you started to do a lot of that work that you just mentioned in your biology classes.
randy_jirtle (27:45.474)
Let me add one other thing, Hannah. It’s not actually correct to say they’re unique to mammals. In animals, they’re unique to Thurian mammals, but there’s one other class of living things on earth that also has imprinted genes, and you know what it is. Exactly. But it evolved independently. So there’s two…
hannah_went (27:48.313)
Yeah.
hannah_went (27:58.299)
We’ll see you here.
hannah_went (28:05.319)
flowering plants. Is that correct? Good.
randy_jirtle (28:13.39)
classes basically of living things that have imprinted genes.
hannah_went (28:20.422)
Yep, and is it correct to say in mammals, only about 1% of those genes are actually imprinted, right? It’s a very, very small subset.
randy_jirtle (28:28.19)
It depends on what you say. Like some people say they’re 20,000 genes. Now I’ve read that, you know, if you look at splicing differences and all that kind of stuff and RNA and things are up to like 65,000 genes in the human. So it’s probably, somewhere’s about one to 5%, I would say. Somewhere’s in there, but it’s probably more dependent now about how many genes we have rather than the ICRs, because I think we pretty accurately define that number and that’s right around 1500.
hannah_went (28:34.681)
Mm-hmm.
hannah_went (28:43.705)
Okay.
hannah_went (28:49.851)
Hahaha
randy_jirtle (28:58.291)
Somewhere’s in that range.
hannah_went (29:00.647)
Correct, yeah, I was doing some research before I hopped on with you, and I know you just identified the entire list of those imprintome control regions. I have 1,488, so yes, 1,500 of them. So how did you identify those, those imprintome control regions? I know you just published that with NC State, and that’s how True Diagnostic, my company, and we’re working with you. How did you actually identify those and publish about that?
randy_jirtle (29:30.082)
Well, the first thing we had to do was get support to do it. And as I said, I failed when I tried in around 2005. I had another shot at it, even as, because all the work we were talking about before, I was on the faculty at Duke for 35 years. So the vast majority of work and research that I’ve done was done at Duke University. And before that, I was at the University of Wisconsin. So that’s how I got into radiation biology from nuclear engineering.
hannah_went (29:34.095)
Yep.
hannah_went (29:47.531)
Mm-hmm.
randy_jirtle (30:00.962)
But when I got to Duke, I was doing cancer research because that was sort of my background as a postdoc. And that’s how I said how we got into the phenomena of epigenetics. But when I retired, I thought I was retired. But after, in Pollo, and a number of my people moved over to North Carolina State University to set up an epigenetic and epidemiological group over there in humans.
hannah_went (30:07.597)
Mm-hmm.
hannah_went (30:16.111)
Hahaha
hannah_went (30:23.653)
Mm-hmm.
hannah_went (30:30.855)
Mm-hmm.
randy_jirtle (30:31.278)
And Catherine asked me if I’d be willing to help do that. So I am now an adjunct professor at NC State, which is a lot easier for me because I don’t have to take care of the day-to-day runnings of things and stuff like this, but I’m still involved in writing grants, reading papers, writing papers, all the things that not so much getting in the lab anymore and not even getting in the lab every day kind of safe, but now with Zoom, I can do that a little bit better because
hannah_went (30:38.779)
Mm-hmm.
hannah_went (30:58.375)
I’m gonna go.
randy_jirtle (30:59.702)
Durham where I live is about 30 miles from Raleigh. So I get over there, but not as much as I had to and did do and I loved to do when I was at Duke because I only lived three miles from my lab. So I kind of like lived in my laboratory except when I was home with the family. But that’s different now. So the whole thing then, the first thing is even though you have a great idea is getting support. And that was not easy.
hannah_went (31:15.641)
Yeah.
hannah_went (31:23.843)
Mm-hmm. Yeah.
randy_jirtle (31:27.106)
And that was really done by Katherine Hoyo. And she did that based upon the fact that we knew that imprinted genes were playing a big role in diseases and in the environmental responses in disease formation, because that’s the type of epidemiological research she was doing. And the support to do the human imprintome then came through NIH in this case, actually.
to do that. So about three, four years ago, we got the support to do it. So now the question that you had is, what do you do now that you’ve got money to do this? And when I first thought about doing this in 2005, we could have pulled this off, but the sequencing ability was so rudimentary compared to what it is now that it would probably have cost 10 to 100-fold more money and taken a lot longer to do than
hannah_went (32:06.671)
Mm-hmm. Ha ha ha.
hannah_went (32:19.416)
Mm-hmm.
randy_jirtle (32:25.526)
than we were able to ultimately do with the sequencing ability that we have now. A lot of science really does depend upon, it’s not just sequencing, as you know, because you’ve got all these little pieces and you’re looking for literally needles in the haystack is what you’re looking for now. So it’s the computer facilities. I could not have done this project at Duke. You say why? Because Duke does not have the computer.
hannah_went (32:28.389)
Wow
hannah_went (32:41.477)
Mm-hmm.
randy_jirtle (32:53.902)
capacity and the engineering bioinformatics capacity and the storage capacity that was needed to put all these little pieces together and to come out with the 1488 piece little regions which there are only hundreds of bases, some of them thousands, but tens of bases to hundreds of bases. They’re small little areas. Without that, without those facilities.
NC State is an engineering school. And they didn’t set up all these facilities to be nice to biologists. They primarily probably did this because of physics, because they generate a lot more data even than what we’re able to generate with sequencing. But because we’re at that facility now and at that university, we were able to use their incredible facilities and computers and storage and bioinformatics people to pull this off.
So what does pulling this off mean? You have to look at, you already said this, these imprint regulatory elements are, once they’re set, so one, at that imprint regulatory element, one copy of the genome will be unmethylated, it’ll be like this, and one will be methylated. So when you sequence that region,
hannah_went (33:56.088)
Hehehehe
hannah_went (34:18.095)
Mm-hmm.
randy_jirtle (34:21.822)
it’ll look like that little, little area is 50% methylated. Now that’s oxymoronic if you think about it, because there’s no such thing as 50% methylation, but what it means is one copy is shut off and the other one is functional.
hannah_went (34:26.833)
Mm-hmm.
hannah_went (34:37.863)
Mm-hmm. Yeah.
randy_jirtle (34:39.074)
that now gives you at that little area 50% methylation. So you’re looking through the whole three billion or there’s a three billion bases for areas where you have 50% methylation.
hannah_went (34:52.043)
really a needle in the haystack. You know, if I could.
randy_jirtle (34:55.974)
face that. But when you look at that website and look at those genes that damn near brings tears to your eyes, they are 50% methylated.
hannah_went (35:05.14)
Yeah, yeah, I know and your website is such a great resource for anyone listening. I’m definitely going to put it in the show notes. You know, if I could go back and redo schooling or recommend, you know, if I have children one day, I’m going to tell them, you know, I would, you know, hope or push them a little bit towards science first off, but put them toward the bioinformatics or, you know, the
computer programming and all the artificial intelligence models. We just can’t function without that. Like you said, NC State has such a great facility and without that we wouldn’t have even been able to identify these. I think that’s super important as well to know.
randy_jirtle (35:44.874)
Yeah, so the other thing that I knew and you knew too, is since these are established in the gametes or right after fertilization, that means in the embryonic stem cell stage of development, there are no differentiated cells at that point.
hannah_went (35:57.904)
Mm-hmm.
hannah_went (36:02.455)
Mm-hmm. Yeah, that was one of my questions too. If you kind of summed it up there, but if you want to explain the difference between the somatic and the germline and printome regions, right?
randy_jirtle (36:13.89)
Well, they’re the same regions, but they’re methylated differently. So if you look at somatic cells, because these marks were established either in the germ line, we’re one copy now in the germ line, if you look in mother or father, sperm and egg, in humans, now we have to be in humans, both.
hannah_went (36:18.705)
Mm-hmm.
randy_jirtle (36:32.406)
you will find that at these regions, one copy, either the sperm or the egg, will be 100% methylated in these regions, and the other one will be 0%, I mean, and you’ll be able to show this clearly. Now, when they come together in the formation of, after fertilization, one copy from mom and dad, in these areas, they show up as 50% methylated.
hannah_went (36:42.875)
Mm-hmm.
randy_jirtle (36:55.946)
So if you look down now where you have somatic cells, and that was the other thing we added because you had different cell types that we looked at rather than a single one. Why? Because it’s gotta be common and the same all over the body. If it’s not, it’s not an imprint regulatory element. It would be dependent upon differentiation, that kind of stuff. We don’t want those. It’s not that they’re not important, but they’re not imprint regulatory elements. So the whole trick was to find regions that were consistent.
across all cell types in the body, but were different. One methylated, un-methylated in the germ line. And when you see that, it darn near brings tears to your eyes because that is the imprintome. That is the imprint regulatory element. And you can see it as clear as day.
hannah_went (37:36.324)
Hehehe
hannah_went (37:44.343)
Right, right. I know it’s so groundbreaking. And again, something that I’m just really excited to work with you and NC State on and Dr. Hoyo, I definitely want her to have her on my podcast. I need to reach out to her. Right.
randy_jirtle (38:00.138)
Yeah, she’ll have a much more epidemiological spin to this whole thing. But I think, hopefully, she’ll explain that the importance of epidemiology and getting this funded. You’re right.
hannah_went (38:10.827)
Yeah, because I know that’s her background. I know that’s her specialty. So the entire reason, well, I would say one of the reasons we did this is to obviously make it, you know, for researchers to be able to study this and look into it a little bit more. So the imprintome control regions and just the imprintome itself, they’re critical spots for development and growth. They play a major role in developing diseases and disorders.
you know, obesity, Alzheimer’s, autism, bipolar disorder, I mean, we can name a lot, I’m sure. So, you know, schizophrenia even. So tell us how we can connect the imprintome to those different diseases. How are we starting to connect the dots here?
randy_jirtle (38:50.839)
Well…
randy_jirtle (38:54.19)
the theoretical reason why imprinting evolved. Because if you think about every one of these genes now are disease susceptibility to loci. The reason for it is because you only have a single functional copy. And they’re almost literally all growth regulatory. Either positive and in a tumor.
hannah_went (38:58.332)
Mm-hmm.
hannah_went (39:08.327)
Mm-hmm.
hannah_went (39:14.618)
Mm-hmm.
randy_jirtle (39:18.638)
In the cancer world, that would be called an oncogene, or their inhibitory, and in the cancer, that would be called a tumor suppressor gene. So my guess, and it’s just a guess, that there is no cancer, none, that doesn’t have dysregulated imprinting, potentially as some of the earliest changes in the development of the disorder. Why? Because these protect, when you dysregulate them, they protect the cell from dying.
they’re able to continue growing. So you inactivate a tumor suppressor gene. So now it continues to live. You inactivate the apoptosis signaling pathways. Many of these genes are involved in that phenomenon. And when that happens, the cell can continue to accumulate oncogenic events without dying and ultimately shows up as a lump in a bump that we call cancer. So that is, to me, is almost a given.
But interestingly, because they evolved to control growth, because the reason why people think that they evolved in the first place was to control the amount of nutrition that the offspring extracts from the mother, with the father trying to maximize that extraction and the mother trying to tamp it down. And this is all basically, so it’s literally a battle between the sexes to propagate.
your genetic information forward. That’s the theory. Now, if indeed that’s the case, you can see why growth regulation is so very, very important because you’re really controlling the growth at the earliest stage to try to give your offspring the greatest opportunity and ability to grow and survive in the future. And then to propagate the genes forward into the next generation.
hannah_went (41:07.723)
Sure, yeah. And we also saw Dr. Michael Skinner from Washington speak about that, right? The translational or transgenerational epigenetics. And that’s a whole other world. I want him on my podcast too. So it’s all intertwined and worked together.
randy_jirtle (41:25.778)
Yeah, definitely. And some of the genes there that probably are being altered that are giving maybe rise even to transgenerational effects might be imprinted. I don’t know because that’s something that, but that’s something that can now be looked at. Because now you can screen. You don’t have to look at 3 billion bases. You’re down to 22,000 bases, 22,000 CPG sites is all you need to screen now.
hannah_went (41:36.591)
Mm-hmm.
Right. Yeah. Now because you’ve discovered it all.
randy_jirtle (41:55.45)
So it’s a much, much easier task. And as you know, in doing this, the first attempt to do this is to make a DNA methylation chip that’ll allow for relatively easy screening of these various ICRs in any kind of disease there is and determine whether or not imprinted genes are deregulated. And my guess is that…
hannah_went (41:55.718)
Yeah.
randy_jirtle (42:24.642)
there are going to be a lot of them.
hannah_went (42:26.567)
Right, yeah, and especially in those disease types that we just named. So, you know, again, wrapping this up, there’s about 1,500 Imprintome Control Regions and about 22,000 CPGs. So that’s really how Dr. Jertle and I started working together is because my company, True Diagnostic and NC State, we’re creating this, what we call, I’m pretty sure we’re calling it the Imprintome Array, where you can actually quantify the methylation at those positions. So now you’re able to measure this, and that just unlocks.
randy_jirtle (42:29.663)
Right.
hannah_went (42:56.567)
I mean, hundreds and hundreds, thousands, millions of doors into these different disease pathways. And the, you know, really the sky’s the limit now that we can measure these. So I’m super excited to see what people do with this and what comes of it.
randy_jirtle (43:12.642)
Well, it’s hard for people to put their heads around it. And when I wrote up, I don’t know where it was. Might have been in a review or another review that I had, I think one that was published. But it could be verbal too. But it’s not an overstatement. What you can do now once you have the imprintome is you can determine the role of genomic imprinting and its deregulation epigenetically.
hannah_went (43:29.191)
Mm-hmm.
randy_jirtle (43:42.778)
and really probably even ultimately even genetically, but for sure epigenetically for every, every disease and disorder that we have. Now that doesn’t mean that those genes are involved in all of those, but that can be done relatively easily and my guess is that many of the major and including behavioral disorders, you were talking about autism and schizophrenia.
hannah_went (43:54.148)
Yeah, no doubt.
hannah_went (43:58.259)
Mm-hmm.
hannah_went (44:11.859)
Mm-hmm.
randy_jirtle (44:12.394)
If people that are listening to this are interested in why those two diseases or disorders are so interesting, I would recommend you read, they read Christopher Bagcock’s book called The Imprinted Brain. It really outlines why that is probably, these two disorders are diametrically opposed and due to different imprinted genes being deregulated. In one case, in autism potentially, an over-expression of the
hannah_went (44:25.403)
Okay, gotcha.
randy_jirtle (44:41.846)
the paternally expressed genes in the brain in early development and then it continues on to give the phenomenon of autism and in the other case sort of an over expression of the inhibitory genes which tend to be more maternally controlled and that gives rise to potentially schizophrenia. That theory now with the imprintome being defined can actually be for the first time tested.
Now, whether someone is going to get the resources together to do this, and that doesn’t mean just monetary resources, it means getting the samples together to do this. I’m not sure, but I’m sure at some point this will be done.
hannah_went (45:14.348)
Hahaha
hannah_went (45:26.735)
Yeah, I don’t doubt it.
randy_jirtle (45:28.43)
Because again, Hannah, it’s of fundamental importance to know this.
hannah_went (45:33.623)
It is. Yeah, I couldn’t agree with you more on that. And that is something that we’ll just have to, again, hope and wait and see. I know there’s a lot of bio banks out there now with those disease samples in states. So hopefully those resources, after they have the monetary resource, they can move on and find a really great bank with some samples. So, Dr. Dirtel, one of my last questions for you, we’ll see where this takes us.
What are you excited about? You have all this work, you have this great background, you’re again, one of the most cited papers in history, in the scientific community. What are you looking forward to? What do you wanna understand and know?
randy_jirtle (46:14.622)
If I could live for a longer time, you’re asking me what would I address right now? What question?
hannah_went (46:17.581)
Yes.
hannah_went (46:24.317)
Yes, what excites you?
randy_jirtle (46:27.286)
I would work on the potential role of genomic imprinting in human evolution.
hannah_went (46:37.251)
and human evolution, okay? Okay, yeah, tying your past studies with what you know now and trying to dig a little bit deeper into that. Very interesting.
randy_jirtle (46:44.642)
Because what I feel is that we’re going to find that when we start looking at that, what you have to do is look at different imprintomes now in different species and start determining which imprinted genes, imprint regulatory elements. You keep focusing on the imprint regulatory elements because that’s the common thread through here. What genes these imprinted regulatory elements control, we don’t know. So in that list, in that paper, we’ve just put the gene that was.
hannah_went (46:53.98)
Mm-hmm.
randy_jirtle (47:12.682)
Like it was right, the imprint regulatory element was right in the middle of the gene or it was very close to it. But it could be that gene and it could be other genes that it controls or even some of them they’re not actually true imprint regulatory elements but a goodly number are going to be. But if you focus on the ICR as imprint control regions, then you can compare one species to the other species to the other species and you can start getting an idea what, how.
hannah_went (47:18.983)
Gotcha.
randy_jirtle (47:41.302)
those regions changed as animals evolved from basically, we don’t have a precursor to marsupials and eutherians, but you can get down into that region by going to the marsupials, and you could even use platypus as your out group. They don’t have imprinted genes or the echidna, or chickens, which is what we use in our out group. And follow that. Again, you need great bioinformatics.
hannah_went (47:59.364)
Hehehe
Yeah.
randy_jirtle (48:11.034)
and great ability to store and manipulate tons and tons of data. So it appealed to me a lot from my engineering background.
hannah_went (48:16.027)
sure. Yeah, making out this. Yeah, it’s almost like a map you would be creating, right, between all of the different species and figuring out where are the connections, how are these intertwined. So I think that’s, yeah, that’s just.
randy_jirtle (48:23.283)
Exactly.
randy_jirtle (48:30.126)
You can never prove anything, Hannah, like this, but you can start seeing trends. And this becomes ultimately the weight of the evidence suggests that this is something that was really critical, let’s say, the addition of imprinted gene or how it was regulated is not in the chimpanzee or is there, and it’s, you know what I’m saying? And you can go back and forth and you can start. So you say, well, what is this gene? What is it doing? So you’re starting to get a better feel for an effect.
hannah_went (48:51.525)
Yeah.
hannah_went (48:57.061)
Yeah.
randy_jirtle (48:59.742)
made us uniquely human at the genetic and epigenetic level in our evolution.
hannah_went (49:07.835)
Yeah, yeah, understanding patterns, connections. I think there’s, yeah, that, you know, someone out there listening needs to study that. And it’s all about, you know, I could ask you hundreds of more questions. It’s all about asking the right questions. And, you know, I mean, as you…
randy_jirtle (49:22.53)
But the pragmatic ones are the ones we’re working with true diagnostics and other people are gonna be the multitude of behavioral diseases and disorders and my guess is ultimately cancers too. I mean, I really do believe that it is an important thing that individuals are very, very interested in. And it’s gonna be an important thing to dig out the role that imprinting plays because
hannah_went (49:28.101)
Yeah.
hannah_went (49:35.172)
Right.
randy_jirtle (49:48.914)
it potentially provides an epigenetic mechanism by which you can treat. And an epigenetic mechanism by which you can diagnose.
hannah_went (49:53.72)
Of course. Yeah, and it’s like, you know what?
Exactly, exactly, and identify early and again stop that disease from maybe even happening.
randy_jirtle (50:00.754)
Right. And maybe even these markers are in the blood. I mean, I don’t know, but I mean, that’s where that those are more what I would say immediate pragmatic things that are important to people who are here. But you asked me a different question. What would I do if I had unlimited money and unlimited time? I would work on the role that imprinting played in the evolution of mammals. That’s what I would like to do.
hannah_went (50:16.313)
Yes.
hannah_went (50:25.475)
Yeah, still important, but understand the pragmatic answer as well. So it’s like you have the answer to one question and then that opens or that causes you to have a ton of other questions. So it’s like we keep learning and evolving ourselves. So I think it’s super exciting. Well, Dr. Jertle, I appreciate your time today. This is my final question to you. I think you will find it especially interesting. If you could be any animal in the world, what would you be and why?
randy_jirtle (50:38.796)
Right.
hannah_went (50:54.595)
And I know you have your stuffed animals there behind you as well. So this, this I’m excited to hear your answer.
randy_jirtle (51:03.502)
That’s a weird question. That’s giving me time to think about a weird answer. I don’t know, I mean, you know, it sounds not very exciting, but I like what I am. Yeah, because other animals can’t do what I’m able to do and what I’m able to study and find with the technology and techniques that we have right now.
hannah_went (51:05.583)
Ha ha ha!
Yeah
hannah_went (51:15.263)
Really? Okay.
hannah_went (51:31.127)
Very valid answer. No, your answer is valid.
randy_jirtle (51:32.854)
I mean, it’s extremely, I’m not kidding, it’s extremely exciting. I’ve never been in my research career at such an exciting time as right now. And yeah, the only thing I would like is make sure that I’m around long enough to do it.
hannah_went (51:39.783)
Thank you.
hannah_went (51:51.955)
There you go. Well, that just proves, you know, how devoted you are to your work and uncovering more and just, you know, making new findings and discoveries. So, no, Dr. Dirtle, I really appreciate your time. Where people can find you is your website, geneimprint.com, is that correct?
randy_jirtle (52:12.11)
That’s our website, yes.
hannah_went (52:14.9)
Okay, your website and I’ll put that like I mentioned before in the show notes for everyone. So thank you for joining the Everything Epigenetics podcast and remember you have control over your epigenetics so tune in next time to learn more. Thanks so much Dr. Dirtle.
randy_jirtle (52:28.03)
And that’s the, but I said, I want to be still. I’d want to be a human.
hannah_went (52:32.74)
No, answer is definitive and I don’t, that’s very unique. I don’t think we’ll ever have anyone else say that same answer. So I’ll have to keep a tally and come back to you. All right, thanks Dr. Turtle.
randy_jirtle (52:35.47)
Thanks for watching!
randy_jirtle (52:40.514)
Yep. OK.
Bye.
hannah_went (52:50.061)
All right.
