The field of epigenetics has exploded in the last decade, thanks almost exclusively to the research of Randy Jirtle. His 2003 study on the effects of nutrition on epigenetic gene regulation is the most cited paper in the history of science, and his trailblazing discoveries have expanded our understanding of human health and the etiology of disease. In this week’s New Frontier’s podcast, Dr. Jirtle, who is a professor of epigenetics at North Carolina State University in Raleigh, NC, and a senior scientist at the McArdle Laboratory for Cancer Research at the University of Wisconsin in Madison, WI, talks to Dr. Fitzgerald about the details of his research, its implications for our understanding of disease development, and why its critical that more scientists undertake the study of epigenetics
In this podcast you’ll hear:
- Details about Jirtle’s seminal 2003 Agouti mouse study
- The foundational and indisputable science behind the statement “food is medicine”
- The science behind why more isn’t always better when it comes to supplementation with certain nutrients and antioxidants
- A discussion of antioxidant timing
- A definition of the human imprintome
- About the need for more researchers in the field of epigenetics
Professor Randy L. Jirtle headed the epigenetics and imprinting laboratory at Duke University until 2012. He is now a Professor of Epigenetics in the Department of Biological Sciences at North Carolina State University, Raleigh, NC, and a Senior Scientist in the McArdle Laboratory for Cancer Research at the University of Wisconsin, Madison, WI.
Jirtle’s research interests are in epigenetics, genomic imprinting, and the fetal origins of disease susceptibility. He has published over 200 peer-reviewed articles and was a featured scientist on theNOVA television program on epigenetics entitled Ghost in Your Genes.
He has delivered numerous endowed lectures and was invited to speak at the 2004 Nobel Symposia on Epigenetics.
He was honored in 2006 with the Distinguished Achievement Award from the College of Engineering at the University of Wisconsin-Madison. In 2007, Jirtle was nominated for Time Magazine’s “Person of the Year.”
He was the inaugural recipient of the Epigenetic Medicine Award in 2008, and received the STARS Lecture Award in Nutrition and Cancer from the National Cancer Institute in 2009. Jirtle was invited in 2010 to participate in the Aspen Ideas Festival in Colorado, and the Nestlé’s 7th International Nutrition Symposium in Switzerland. Jirtle organized the Keystone Environmental Epigenomics and Disease Susceptibility meeting, received the EHP Classic Paper of the Year Award, and was invited to speak again in the Nobel Forum at an epigenomics symposium sponsored by The Nobel Assembly at the Karolinska Institutet in Stockholm in 2011.
Dr. Jirtle was invited in 2012 to present the NIH Director’s WALS lecture. Jirtle participated in the World Science Festival in New York, gave the Killam Lecture at Dalhousie University, and published two books on Environmental Epigenomics in Health and Disease in 2013.
Dr. Jirtle received the Jean Andrews Centennial Faculty Fellowship in Human Nutrition from the University of Texas-Austin, delivered the Robert B. Church Lecture In Biotechnology at the University of Calgary, and received the Linus Pauling Award from the Institute of Functional Medicine in 2014.
In 2016, Jirtle delivered the commencement address in the Department of Biological Sciences at North Carolina State University. ShortCutsTV did an English documentary in 2017, Are You What Your Mother Ate? The Agouti Mouse Study, that is based upon Jirtle’s epigenetic research.
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Dr. Kara Fitzgerald: Hi everybody, welcome to New Frontiers in Functional Medicine. I am your host, Dr. Kara Fitzgerald. We are interviewing the best minds in functional medicine. Today is no exception. I am thrilled, thrilled, thrilled, thrilled to be with Dr. Randy Jirtle.
Randy Jirtle has put the field of Epigenetics on the map. If you’ve heard the term, likely it’s from his research. Just a little bit of his background, he headed the Epigenetics and Imprinting Laboratory at Duke University until 2012. He’s now a Professor of Epigenetics in the Department of Biological Sciences at North Carolina State University in Raleigh, North Carolina. He’s also a Senior Science in the McArdle Laboratory for Cancer Research at the University of Wisconsin – Madison.
Randy has over 200 peer-reviewed articles, and he’s got this amazing bio, which will actually pop up on the transcription notes if you want to read through it. In fact, you know Randy, your Wikipedia entry looks pretty good to me for people who want a nice background. Then you can link over to the University and read more about him.
He has been given really almost every award across the scientific platform, with the exception of the Nobel, but I’m sure you’ve got to be in the running for that at this point in the game with your work. You’ve been over at the Karolinksa Institute, so you’ve lectured globally on the field of Epigenetics. You’ve put the field of Environmental Epigenetics on the map, or just brought that into the scientific language.
I know Jeff Bland refers to what you’re doing as Nutritional Epigenetics. What else do I want to say? You’ve published not only in the peer-reviewed literature, but two books on Environmental Epigenetics. Recently you were on a English documentary in 2017 called Are You What Your Mother Ate? The Agouti Mouse Study, and I encourage folks to seek that out.
Oh, and incidentally, Dr. Jirtle was awarded the Linus Pauling Award from the Institute for Functional Medicine in 2014. I was at your lecture there, as were many of my friends and colleagues. Just again, we were wowed about what you have done. So welcome to New Frontiers, Dr. Jirtle.
Dr. Randy Jirtle: Thank you very much for inviting me to talk to you.
Dr. Kara Fitzgerald: You’ve developed this field of Environmental Epigenetics, and you’ve published a lot. You’ve used this Agouti Mouse model to really demonstrate this idea of the influence of environment on phenotypic expression. We’re going to talk about your background there, but I want to try to put into perspective beyond your bio, really what you’ve done. This is a quote I took from that 2017 documentary, Are You What Your Mother Ate? “They say the Agouti Mice study is the most widely cited study, not just in genetics, but in the history of science.” You were quoted in that documentary as saying when you embarked on that research, on the first agouti research study, which we will talk about, you said, “We’re either going to go down in flames, or this is gonna be huge.” Talk to me about epigenetics and give me the background on the Agouti Mice studies.
Dr. Randy Jirtle: I’ll try to make it short. I first want to say that I didn’t come out of a standard background for doing epigenetics research, at least the background that people now, that they really study in this area now and get degrees in epigenetics. My background initially as an undergraduate was nuclear engineering and computer science. I got into radiation biology because I had listened to a couple of lectures, which by someone, Kelly Clifton, who ended up being my major professor on the biological effects of ionizing radiation.
I was so amazed by the whole thing because DNA at that time, it’s hard to believe this, but this was back in around ’68, ’67. 1967, ’68. The structure of DNA had just been determined in what? 1959. Being a physicist mathematician, I didn’t know about DNA at that point. That was my first experience with that and as soon as I looked at it I said, “This is a computer.” It was amazing, and you can break that computer by exposing it to ionizing radiation. That’s how I got into the field of biology and then ultimately cancer biology.
While in cancer biology, we identified the IGF2 receptor, the insulin-like growth factor 2 receptor as being a tumor suppressor gene. Now why that’s so important from the standpoint of epigenetics, is that right at the same time, a scientist in Vienna, named Denise Barlow, who very unfortunately died last year in October, but she was an amazing scientist. She is really the single person that was responsible for me getting into the field of epigenetics because her paper that came out in the early 90s identified the very first gene that is called genomically imprinted.
What that means for your audience, is that even though you inherit a copy from your mother and father, these are on autosomes now, not on sex chromosomes, but they’re scattered all over the genome, basically. Most times when the gene is expressed, it’s expressed from both copies, but to genomically imprint the genes, one copy is functionally turned off and it’s always, depending on the gene, the one that’s inherited from the mother or from the father. The IGF2 receptor was shown by her to be only expressed from the maternal copy in mice.
We had just shown that that gene was a tumor suppressor. Now I was absolutely astounded, because if you think about it, the reason we have two copies is one’s a backup for the other in case something goes wrong. That’s like two engines on a plane, if one goes out you still got another one you can fly. Whereas, with imprinted genes, only one works, so if that one goes out you’re going down. It increases the susceptibility or the importance of these genes in tumor formation by over a million fold. It was astounding to me that on purpose, Mother Nature was turning off copies of genes that were involved in growth and were so important in cancer formation.
In effect, we identified the first imprinted tumor suppressor. I went back to my lab after I read Denise’s paper, I said, “We’re taking our whole lab into the field of epigenetics.” That’s how we got into epigenetics. Now a question that’s very, very important is, since these epigenetic marks were established very early, in this case, actually in the development of the gametes, or really right after fertilization, the question is then, can the environment, environment I mean like big things, nutrition, toxicants, anything that you would call environment. Even behavioral effects. Can that potentially alter these regulatory elements that are controlling the expression of genes epigenetically? And that’s how we got into the Agouti Mouse experiments.
Dr. Kara Fitzgerald: I just wanted to clarify for the listeners, just defining imprint, basically it’s epigenetically shut down, those marks.
Dr. Randy Jirtle: Correct.
Dr. Kara Fitzgerald: Yeah. And it’s consistent, and there’s no change in that. That mark is lasting through any cell division.
Dr. Randy Jirtle: There’s even, as you know, evidence that some of these marks actually might be altered such that they’re not even totally erased when they go through the germ line. I don’t know if that’s true with imprinted genes, but it’s surely true with other epigenetically regulated genes. So there’s potential for what’s called trans generational inheritance of epigenetic marks.
I don’t think we’ll be talking about that very much today because I don’t do work in this field, but it’s hugely important, because it’s a way in which things can be passed forward into future generations that are not mutations, but are actually problems in the software that continue to go forward.
That’s exactly right, these are epigenetically silenced copies. So with the IGF2R, the father’s copy is silenced epigenetically and only the mother’s copy works.
Dr. Kara Fitzgerald: Now give me a definition of epigenetics.
Dr. Randy Jirtle: Epigenetics simply just means above the genome. But I like to use the analogy, and I use it a lot because I think it’s really a good one, and it’s consistent with my background in computer science, I think of the DNA as being like the hardware of your computer. So then the epigenome is the software that tells the genes when, where, and how to work.
This is how you can have a single genome. If you were to look at DNA in every cell in your body, you could not determine what cell type you were looking at because the genomes are identical in every cell. But yet we have 260 different cell types. So you say, “Well how can that happen?” It’s because basically, the cell is a programmable computer and you have the same hardware. It’s like having 260 Mac, I’m a Mac user, 250 Mac computers lined up, right? Every computer is running a different software program, doing a different job but the hardware, i.e. the DNA, is the same in every situation. It’s all a portable Mac computer. That’s what we have in our body.
These programs are established not by somebody sitting at a desk and writing software, but they’re actually written into the genome, and on top of the genomes right on the DNA, and also on the histones that the DNA is wrapped around during early development. So you go from a clear portent stem cell, from a single cell basically, to all these differentiated cells. That all happens very, very early in development. By the end of the first trimester, basically all of the parts have been defined, now it’s just getting bigger and bigger and getting refined.
All those programs are established so the most vulnerable time for deregulating this programming that’s being done during development, is during the earliest stages of gestation. That’s why we ultimately used the Agouti Mouse model because we were looking at the offspring and what effect exposure to the mother, as far as nutrition was, how that ultimately altered the epigenome and the phenotypes of those offspring that were in utero.
Dr. Kara Fitzgerald: Talk about the seminal 2003 study, the one that’s been cited the most in all of Science, where you looked at early nutrition effects on epigenetic gene regulation. Give us the background of that Agouti Mouse study.
Dr. Randy Jirtle: Well the marks, particularly the ones that are on the DNA are methyl groups and they’re carbon with three hydrogens and they’re primarily bound on cytosine, which is one of the bases that pairs up with guanine when it’s adjacent to a guanine. I won’t go into why that’s important, but that’s usually cytosine guanine. Cytosine is five prime of guanine, it’s the cytosine that is five prime of guanine that will be methylated.
Usually, what happens is when it’s methylated it causes the DNA to compact. That means that transcription factors can’t get into the DNA and cause the gene to be turned on. So it’s this regulatory elements that are compacted down and in effect the gene is turned off. That’s usually what DNA methylation does.
There’s also marks, again, methyl groups, acetylations, et cetera on the histones in concert with the methylation of the DNA. Either causes the DNA to be compacted and non-functional or open and functional.
All those methyl groups that are used in the programming come from our diet. So what are they? Vitamin B12? Betaine? Cholin? And what is the other one?
Dr. Kara Fitzgerald: Folate?
Dr. Randy Jirtle: Folic Acid, right. Folic Acid. The big four.
So all these methyl groups … So our thought process, and this is what Rob Waterland, I’m not a nutritionist. I probably would have not done a nutrition study straight up like this because it’s not my background. I would have gone more toward what we did later on which are toxicants and things like this. But really, it was the best way to start because nutrition is where the marks are coming from. It’s coming in from our diet. It was a very simple question. If you load the hopper up with tons and tons of methyl groups in this model system, can you shift the phenotype of the offspring.
And interestingly, the phenotype that you’re looking at is really dramatic.
Dr. Kara Fitzgerald: Yes.
Dr. Randy Jirtle: Because there’s a, you wanted to know why did we put transposable element into the title. Well, one of the reasons is because there is a transposable element that is upstream of the Agouti gene in this one unique stream of mice.
It just sits there. It just jumped in. It’s a retrovirus and it went in there and now as a consequence it started up, potentially, an alternative start site for the regulation of the Agouti gene.
So, normally the Agouti gene is regulated developmentally. What that means is that in this animal what happens is that a black hair shaft is formed. Right at the end of the development of the hair shaft the Agouti gene is turned on developmentally and it puts a yellow band at the base of a black hair shaft. And you and I now see the animal not as black but as brown or Agouti. So it’s Agouti Mouse.
In this animal model that still happens but it only happens when that transposable element is totally methylated so it in effect blocks the alternative start site from working. So if that doesn’t happen, in other words, it’s unmethylated, the transposable element is unmethylated then the Agouti gene is driven inappropriately throughout the animal’s life and every tissue of the body. And that means that the hair shaft is now black or brown but actually is completely yellow.
So now you’ve got a phenotype or characteristic of a mouse that goes from brown to yellow with dependent upon totally the methylation level at this transposable element, which is epigenetics.
Dr. Kara Fitzgerald: That is so profound. So normally we’re looking at the promoter region like being the Agouti different than … we don’t think of transphosons as being necessarily promoter regions. Is that correct?
Dr. Randy Jirtle: That’s correct. What it did is once that bit of DNA, that transposable element jumped in there, it usurps normal developmental regulation of the gene. And the only way you will get normal developmental regulation in that gene back again, in other words you get a brown mouse and brown offspring, is if the transposable element is completely burned off through methylation.
Dr. Kara Fitzgerald: Yeah. That’s amazing. Can I just ask you? How you came upon using the Agouti model?
Dr. Randy Jirtle: We did not define the Agouti model. This was already known so my contribution to this was to use it and to ask the simple question: If you now, in effect, use nutritional supplements could you move the distribution of coat colors in the offspring through diet and if that did occur is it because of changes in the epigenal at the transposable element.
Dr. Kara Fitzgerald: Okay.
Dr. Randy Jirtle: That’s what we did. In other words we’ve linked nutrition, supplements, you know methyl donors, basically levels of methyl donors, to coat color but it’s even better than this because when the coat color is yellow the Agouti protein is expressed throughout the body including the satiation center of the brain and it binds to the myelin corton four receptor and as a consequence the Agouti mouse doesn’t realize that it’s full. And it literally eats itself into obesity, diabetes, and cancer.
Dr. Kara Fitzgerald: We’ll put a photo up on the show notes page so you can see this.
Dr. Randy Jirtle: [crosstalk 00:18:39]
Dr. Kara Fitzgerald: Yes, a normal, an Agouti mouse that’s normal size and brown and the Agouti mouse where the gene is not shut down.
Dr. Randy Jirtle: [crosstalk 00:18:49]
… Inappropriately expressed throughout the animal and the animal is just morbidly obese. So if the animal is yellow or has any kind of yellow there’s modeling because it depends on what stage of development the decision is made to methylate or not methylate this transposable element.
In between these two extremes of completely brown and completely yellow animals you have animals that look sort of like calico cats.
We’ve got a problem, can you hear that? Is that …
Dr. Kara Fitzgerald: No, I hear a little, no you’re fine.
Dr. Randy Jirtle: Anyway, the printer is going right now so there might be a little bit of a background.
Dr. Kara Fitzgerald: It’s fine.
Dr. Randy Jirtle: So anyway, that’s the distribution range that you’ve got going between those two extremes of brown and yellow. And if you have any yellow in the animal it’s absolutely the animal will be obese, get diabetes and cancer. It’s totally linked because it’s blocking the satiation center of the animal.
So that’s the system. So when we did this study, as I said we knew that there was a link between the – we thought we could shift these co-colors but we didn’t know whether we’d be able to demonstrate that it was due to methylation at the DNA level of the transposable element. Indeed, we were able to show this very clearly for the very first time.
Then, what this meant is that at least in animal models, sort of this fetal origins of adult disease susceptibility was for the first time demonstrated to be due to changes in the epigenome. So there is now a mechanism for something that in humans people really didn’t have any idea how this worked. It was a complete black box. And the problem with that is you would expect is that when people don’t understand a mechanism there’s not a mechanism for it to occur particularly like something that happened the first three to four weeks of life. In fact, effecting something out in time twenty and thirty years later in humans for example. What’s the link between this? A lot of people just thought it was BS.
That was basically the state of the art of this field of fetal origins of adult disease susceptibility up until our study in 2003. In fact this study ushered in the era of what we call environmental epigenomics. And the way we view diseases has been literally changed forever.
Dr. Kara Fitzgerald: Yeah. Profound.
Walk me through, ever so slightly, because I know we have a lot of other content to cover as far as your research goes. It must have been just incredible for you guys to publish this. Did you know that you were going to just rock the scientific world to the extent that you did?
Dr. Randy Jirtle: Yeah, that’s why I said either we were going to be famous or going down in flames. And he said why would you say that? Because we are not funded by government agencies for this research.
Now, Rob had a Dannon Yogurt post-doctoral fellowship so he had funding to do these kinds of studies. He really wanted to look at the effect of nutrition on the imprint regulatory elements. I said in fact that’s a great study. People now have done that and you can see it. But I said the problem is scientists are not, they’re not very accepting of things. Even if you saw five to ten percent change in methylation at an imprint regulatory element then you’ll spend the rest of your arguing why that is biologically significant.
We’ve got to get a model where it is much clearer. An absolute connection between methylation, exposure to methyl groups, DNA methylation, and a phenotype. And that’s why we use the Agouti mouse.
Dr. Kara Fitzgerald: Just so cool. And then your life is forever changed. Period. Both of you guys.
Dr. Randy Jirtle: Yeah, because, in a good way. We didn’t go down in flames. We did very well.
Because what happens now is you’re out giving a lot of talks. The ability to mind the shop goes down a little bit.
Dr. Kara Fitzgerald: You’re in high demand in the world.
Dr. Randy Jirtle: Yeah, and you’re not in the lab all the time. I like being in the lab and to me it’s my playpen. I love it. So, you are not there anymore because you’re out talking about what you did.
One of the reasons for this is because, for me anyways, you are trying to push forward constantly that epigenetics plays a huge role in deregulations of epigenetics and plays a huge role in disease formation. And up until that point, basically everybody thought, or a goodly number of people thought, the only way you can get cancer or any kind of disease is through mutations. And that’s not the case. It’s just like if your computer breaks it could be a problem with the hardware, the DNA, or like a mutation. It could be a chip is gone or something like that, that you have to replace in order to fix the chip. But, frankly most times the problem with the computer is not hardware, it’s software.
It’s the same thing in our cell. I think ultimately when all is said and done we’ll find out that really the tip of the iceberg is genetic mutations and the base of it is going to be programming problems.
Dr. Kara Fitzgerald: Yes. Right. That’s a really nice analogy. It appears that that is correct and ever since you guys published the field of epigenetics is exploding.
Just a couple of years ago I did a PubMed search on the term epigenetics and this was couple of years ago and I got 84,000 hits.
Dr. Randy Jirtle: Wow.
Dr. Kara Fitzgerald: Yeah.
Dr. Randy Jirtle: And if you had done it year by year, remember we were doing these studies, initially when I started this was the ’90s, the early ’90s. Everybody that was working in the field of epigenetics at that time was primary people in cancer research and very, very few and in the field of genomic imprinting. They could literally fit in a room that held a hundred to hundred fifty people all over the world.
Now, it’s incredible, the number of people.
Dr. Kara Fitzgerald: Yes.
Dr. Randy Jirtle: In 2005, we had the first, because we coined the term environmental epigenetics, we had the first meeting in 2005 here in Durham. We took over the big hotel here in Durham. We had, I think 450 people.
When our paper came out in 2003, “The Agouti Mouse”, and then we filled the Washington Duke Inn, completely. And had 450 people in attendance three years later.
Dr. Kara Fitzgerald: Yeah, just an incredible jump. Well, I have to say, I love your papers and would like you to have stayed sequestered in the lab. But I appreciate, so many of us appreciate, clinicians, those of us in functional medicine, around the world. We appreciate the fact that you have really kind of lit the way. You’ve validated what we’ve been doing in functional medicine. You’ve really opened the door for the recognition in nutrition as profoundly fundamental.
Dr. Randy Jirtle: Nutrition is medicine.
Dr. Kara Fitzgerald: Yes.
Dr. Randy Jirtle: We have showed that very clearly with our Bisphenol A study. So, we went from nutrition. Now we know that this is the mechanism, at least it is in mice. Now, I think in another week or so paper’s coming out in Science Report looking at the Dutch Famine people. Now, it’s very clear that people that were exposed to famine early in development have, they are the ones that have increased obesity and stuff is due to changes in the epigenome.
Dr. Kara Fitzgerald: Yes.
Dr. Randy Jirtle: That has now been demonstrated and it’s an exciting paper. Not our paper, someone else has done it. But it should be coming out next week I think.
Dr. Kara Fitzgerald: Okay. I’ll look for that folks and I’ll make sure we get that in the show notes. And I just want to say it’s the “Dutch Hunger Winter” if you just put that in your Google search you’ll be able to pull up information on that. Yeah, that moved epigenetics from an animal model really firmly into human …
Dr. Randy Jirtle: 2013 to 20 … it took 13 years and now we know that what we see in mice also happens in humans. It’s very, very satisfying.
Dr. Kara Fitzgerald: Give me the background on the Dutch Hunger Winter and what they’re about to publish if you can and then I want to jump back to …
Dr. Randy Jirtle: I probably shouldn’t say too much more but I can tell you that the Dutch, what we know right now, is that the Dutch Famine, there was an embargo placed on the Dutch placed people in the Western part of the country in 1944 – 45 in the winter just before the Nazi redeem fell. That winter was particularly severe and literally no food got into that part of Holland. People were relegated to eating something like 800 calories a day, which is really a starvation diet. I think 20 or so thousand people died. Well some people were pregnant during that period of time. They found the offspring when born later, after liberation, were smaller than normal. Then they followed this offspring into adulthood and found, this was Barker was the epidemiologist that followed first this done this and it’s often called the “Barker Hypothesis”. Where he found that these offspring that were in utero particularly in the first trimester had increased instances of cardiovascular disease, obesity, diabetes, and around a doubling of the incidents of schizophrenia. This was a number of people that had done these studies.
This was also replicated in China, unfortunately because they had another huge famine in the 1950s and ’60s. And in fact, the same type of phenomena were occurring. But again, the problem is how can something that is happening so early in development be effecting people 30 years later? What’s the memory system, the gravity?
We showed with the Agouti mouse system that that memory system, at least at that time in mice, was epigenetic modifications. That’s the mechanism.
Dr. Kara Fitzgerald: Yes. And it’s heritable. I mean, that’s what the Dutch Hunger Winter is showing.
Dr. Randy Jirtle: Yes, because sometimes these marks are not erased completely when they go through the gametes.
So there were three papers that came out 2003. Which was our paper, that ushers in the environmental epigenetics era. 2005 motion shifted to Michael Meaney published that epigenetic modifications can also occur after birth and then environmental effect was not necessarily what we were looking nutrition. It can be behavioral, maternal behavior. I mean it was astounding. Completely changed though they might not know it yet, the field of psychology and sociology completely.
Dr. Kara Fitzgerald: Right.
Dr. Randy Jirtle: And then the next 2005 Michael Skinner showed that there was potential for transgenerational inheritance of epigenetic marks. Those three papers – bang, bang, bang – defined the whole outside of the jigsaw puzzle for environmental epigenomics.
Dr. Kara Fitzgerald: It’s extraordinary.
Dr. Randy Jirtle: We’re filling in the blanks. Now there’s a lot of blanks and a lot of pieces missing still. So, people out there that are thinking about getting into this exciting field there is a lot of work to do yet.
Dr. Kara Fitzgerald: Listen … yeah, no doubt. It’s terribly exciting. We’ve gotta back up and color in the SEF paper, the 2005 paper showing the grooming habits and outcome. Can you talk about what he looked at and demonstrated there?
Dr. Randy Jirtle: Well, this is not my research but it’s basically maternal licking and grooming, they called it. The offspring were born, I hope I can get this right. Lickers and groomers, they were looking at only the females now. The females became lickers and groomers whereas the ones that were hands off did not lick and groom very much, the daughters of mothers like that also didn’t groom their offspring very much. So it almost looks like a genetic inheritance, it’s just inherited.
Then they did a mix and match experiment. When the offspring were born they took the offspring from the lickers and groomers and put them with the non-lickers and they put non-lickers with the lickers and groomers. They found out that it was totally dependent on what the mother did. They were also nervous, so the mothers that didn’t lick and groom were very hyper whereas the other ones were very laid back and nice, having a good life.
Dr. Kara Fitzgerald: Right. That’s right. It dictated the resilience of the stress response. It impacted stress response big time as well as the behavior.
Dr. Randy Jirtle: Then what they did, they looked at the hippocampus because they were looking more at stress and they know that’s due in part to the glucocorticoid receptor and they found lo and behold, the licking and grooming. The mothers licking and grooming of their offspring caused release of DNA methylations in the promoter regions of the glucocorticoid receptor and turned it on. And they were happy. The other ones that stayed methylated were hyper. It was totally dependent upon epigenetic marks. But the behavior was a different environmental factor that could do this and it was done after birth. Whereas all of it occurred primarily, though not totally, in the first trimester of defertilization.
And as I said, then Michael Skinner just took it and advanced it out into time.
Dr. Kara Fitzgerald: Right, that’s right.
Dr. Randy Jirtle: It’s astounding.
Dr. Kara Fitzgerald: It is.
Dr. Randy Jirtle: [crosstalk 00:34:26] As I said, I never liked doing jigsaw puzzles. When I did it I would always do the ones on the edge because I wanted to see how big the puzzle was. And that’s what I did also in my research. We now know how big the puzzle is. It’s huge.
Dr. Kara Fitzgerald: Yes.
Dr. Randy Jirtle: We don’t know what’s inside.
Dr. Kara Fitzgerald: Just extraordinary. Extraordinary. Extraordinary. Extraordinary. And terribly exciting.
Let’s go back to your work. I want to first talk about Genistein, and what you looked at in regard to methylation with Genistein, the soy isoflavone. Talk about that.
Dr. Randy Jirtle: Well we did that study, the first nutritional study we did we were looking at compounds we knew could donate methyl groups. So Genistein is a weak phytoestrogenic compound that’s present in soya products. Soya is eaten by Asians to a great degree and there’s environmental effects. In other words, from cancer formation if you have somebody in Asia and they move over here and they start eating a Western diet they start gaining an incidence of cancer that’s more like with the West than what they had back in Asia. It’s possible, we thought, that there could be something in the soya itself that’s involved in protecting these people from cancer. So that was the general hypothesis.
Dr. Kara Fitzgerald: That’s how you picked Genistein?
Dr. Randy Jirtle: Genistein, because it’s an active compound that people were looking at from the role of equating cancer formation.
Dr. Kara Fitzgerald: Wow.
Dr. Randy Jirtle: We added, this is work now done by Dana Dolinoy who is now at the University of Michigan. We did the same kind of study, and lo and behold, we found that at the level in the blood of the offspring that is comparable to what Asians have in their blood. We found, again, there was a positive response. In other words, there was many more brown animals and it was due to hypermethylation and the turning off of this transposal element.
The interesting thing about this study is that Genistein can’t donate a methyl group.
Dr. Kara Fitzgerald: Boom. Yeah. So what the heck?
Dr. Randy Jirtle: The first thing is how to [crosstalk 00:36:47].
Dr. Kara Fitzgerald: Right. This is not a methyl donor. You didn’t give them methyl donor rich diet. You just used Genistein.
Dr. Randy Jirtle: Just Genistein.
Dr. Kara Fitzgerald: Alright.
Dr. Randy Jirtle: I’m going to tell you a story because it’s very interesting and it’s inappropriately asked over and over. People will say what’s the mechanism by which that happens, Dr. Jirtle? I know the mechanism. The mechanism of this is that the transposable element in the promoter region upstream of the Agouti gene has been through a greater degree, or higher probability, is methylated so that region is turned off and the animals are brown. That is the absolute mechanism by which this happen.
So what you’re asking is a very different question, but still important, but you didn’t ask it correctly. What you’re asking is how can Genistein be perceived by the cell to produce the machinery that’s giving rise to these methylations that’s causing the inactivation, this transposable element. So there’s a signal transduction pathway in here that’s being activated or pathways. Right now we don’t know what it is but from the radiation studies we did later on, I think it somehow has to do with the generation with of free radicals in the redox state of the cell. That is the perception system within all of ourselves. Different compounds, whether they’re Genestein, maybe even something is not subtle, something even like methyl donors might be doing things like this. That are switching this redox state back and forth and that’s connected to the methylation machinery and is either causing increased probability of causing methylations or decreasing the probability of having that happening and that’s probably going to be dose responsive.
Dr. Kara Fitzgerald: Okay, are you talking about the hormesis type of reaction?
Dr. Randy Jirtle: I think many of these chemical or radiation, this is just a guess. You can test this but we have not done it. I think hormesis in the fetal origin of adult disease susceptibility are the same phenomena with different names.
Dr. Kara Fitzgerald: Okay. And so, a smidge of oxidated stress induced by the Genistein actually suppressed the Agouti gene.
Dr. Randy Jirtle: It ended up we had a positive adaptor response. In this system, at this dose, it is a good effect, if brown animals are good. In other words they don’t become obese, don’t get diabetes. That’s good. We didn’t do this, if you up the levels of Genistein, we didn’t do this, we always did single doses at that time. You would get to a level of Genistein it no longer was positive adapted and actually changed to be negative.
So the curve would always “U” or “J” shaped depending on how you graph them. It gets down even to the fact of folic acid. Not this bad but my guess is that too much is also bad.
You can also hit a sweet spot. Now where that sweet spot is I don’t know but these are the kinds of things that a nutritionist should be done now.
Dr. Kara Fitzgerald: Yes, absolutely.
Dr. Randy Jirtle: Here’s what you’re thinking about doing but doing them in a more of a dose response manner because I think you’re going to see “U” shaped curves.
Dr. Kara Fitzgerald: There is some suggestion now that we’ve got mandatory folate fortification. We have seen some kind of a “J” curve or “U” shaped curve with folates. It appears to have the potential to promote cancer.
It seems like when cancer is present it might have, the ability to promote. Whereas if you’re deficient in folate your risk for cancer goes up as well.
Dr. Randy Jirtle: Because it’s too low.
Dr. Kara Fitzgerald: Exactly, yeah. That’s right. We’re seeing that. That’s why I’m doing my study, I don’t want to go off on that tangent but a lot of us in my world, the nutrition/functional medicine world, have leaned on methyl donors heavily.
This was the original question that I developed in being a clinician in practice and paying attention to the science as much as I could. We started seeing this quote-unquote aberrant methylation pattern of DNA being associated with cancer. Hypermethylation of promoter patterns. Hypomethylation of other regions of oncogenes. So, there’s this pattern of sometimes methylation is too intense and it’s shutting down a tumor suppressor gene and that’s promoting cancer.
And then likewise, if there’s insufficient methylation of the DNA. That’s associated with problems. So there’s just this imbalanced methylation activity associated …
Dr. Randy Jirtle: And this is the problem you run into with one suit fits all. In other words, one dose fits all. You lace your flower with folic acid so that you have it high, you might not have a problem except for maybe people that have a problem metabolizing folic acid or maybe even as you get older your ability to metabolize it goes down. So now the level of folic acid …
Dr. Kara Fitzgerald: … Gets very high …
Dr. Randy Jirtle: … is much higher and could potentially cause hypermethylation of promoter regions of suppressors and could enhance the formation of cancer.
Dr. Kara Fitzgerald: That’s exactly right.
Dr. Randy Jirtle: Yeah, and one suit doesn’t fit all.
Dr. Kara Fitzgerald: Yes, that’s exactly right. And that’s what started us on our journey to research it. We’re not using any methyl donor supplements in our study at all. We’re using diet and some other things to fine tune it. Actually, we can circle back to that at the end but I wanted to just say with regard to your paper on Genistein you’re talking about oxidative stress. But, in your paper you actually, if I’m recalling correctly, in your discussion posited the idea of a change in the histone …
Dr. Randy Jirtle: Only one other time, Dana did this also, that we looked at histone levels and they’re altered in such a way that they would go in concert with hypermethylation or hypomethylation at the DNA level. They tend to work in concert. We didn’t know the radiation effects at the time we wrote the Genistein paper, either.
I’m looking at the last study we did, actually, was the radiation study.
Dr. Kara Fitzgerald: Before we go to the radiation study, and we’ll get there. Maybe I’m being too anal here …
Dr. Randy Jirtle: No, I want to go to the Bisphenol A study.
Dr. Kara Fitzgerald: Yes, let’s talk about the Bisphenol A study.
Dr. Randy Jirtle: So the next thing we wanted to ask, the question. I’m not a toxicologist but I’ve always had a fascination with toxicology. I’m a member of the Society of Toxicology and stuff like this.
There’s a whole class of compounds that are called nongenotoxic agents. In other words, they cause cancer in animals but they don’t mutate. Then you can say if they don’t mutate, if you think that’s the only thing that’s important then you can make the assumption that if they don’t mutate then they’re not a problem. Right?
That’s what people can do but that’s not probably appropriate. Because if they’re not mutating it’s potentially possible that they’re altering the epigenome. But if you’ve never looked at the epigenome and thought of that as being potentially important in the etiology of cancer coordinator or any kind of disease formations. You’ve never ever looked at it before.
This is the very first study that looked at the nongenotoxic compound that is an estrogenic compound and it causes cancer in animal models. There is a simple study by Dana Dolinoy was whether or not it altered the epigenome. Doing the same class of study we did with nutritional supplements and with Genistein, lo and behold that exposure of the mother gave comparable levels to what – we’re all exposed to Bisphenol A because it’s all over. It’s in plastics, particularly in the older days it was in baby bottles, water bottles. Coatings of your teeth, every time you picked up a receipts there’s Bisphenol A on the paper. We’re going to have a lot of exposure to Bisphenol A in the environment.
So we did this study and we found that Bisphenol A was negative. It caused a shift toward yellow animals. Which is what we expected it to do. It fit more with its role that it potentially was involved with cancer formation.
That was interesting but what was the most important part of this study – Then what Dana did was add to the mother’s diet Genistein or methyl donors. And in both of those situations we were able to negate the negative effect of Bisphenol A on the epigenome and on the phenotype of the offspring.
It clearly shows that indeed when you’re talking about epigenetically regulated situations that are giving rise to chronic disease problems, food is medicine.
Dr. Kara Fitzgerald: Yes.
Dr. Randy Jirtle: It’s incredible.
Dr. Kara Fitzgerald: Yes. Elegant, just beautiful, simple.
Dr. Randy Jirtle: Simple. I mean an idiot can understand this. It’s that clear.
Dr. Kara Fitzgerald: Right.
Dr. Randy Jirtle: The problem is that we don’t know what the targets are, what the dose response levels are. I don’t know if it’s even that important but it’s going to be dependent on people like yourself doing studies on humans and looking at it from these perspectives i.e. not knowing what the target genes that are important but also the dose response manner.
We need to know this information otherwise we’re not really going to understand. You’re going to get one person saying, “well, it causes an increase in problems,”. Another one actually might say, “no, it’s advantageous,”. Well it’s probably because it’s a dose response problem.
Dr. Kara Fitzgerald: Yes, that’s right. I get it.
But, by in large your Agouti studies are, what you’ve said, epigenetics the science of hope. These are just very elegant examples of why it is. So here is BPA, it’s ubiquitous, it’s an endocrine disruptor, and you inhibited toxicity by using methyl donors and by using Genistein and again …
Dr. Randy Jirtle: A methyl donor and a non-methyl donor yet we can still shift that curve back.
Dr. Kara Fitzgerald: Yes. That’s, it’s just lovely.
Dr. Randy Jirtle: When we get back, what’s the sensing system in the cell? How is it connected to a machinery that is in fact setting up our epigenome. Those are the fundamentally important biochemistry problems. We’re going to have to get chemists and biochemists that are interested in that type of biology. To come in and start helping us sort out those pathways.
Dr. Kara Fitzgerald: You and I were talking about funding at the beginning of the study and I’m grateful that the company Metagenics is funding my research. You talked about Dannon funded your original Agouti study. This is nutritional science and I don’t know that it is very robustly funded but that’s where we need to be answering these questions and looking at the dose response. Hopefully, the money stream will step up and allow us to really get in there and answer the questions.
Dr. Randy Jirtle: Yeah, I hope so but as I said from my experience everything we are really known for it’s not only the Agouti mouse but also the imprinting, most people don’t even know what it is. A study that I’m particularly excited about is we discovered the evolution of the phenomena of genomic imprinting, when it happened. If you think about it, what we showed clearly is the phenomena of genomic imprinting is only present in theory in mammals. Those are animals that give rise to live births. Marsupials eutherians have imprinted genes but monotremes, which are mammal like the platypus and echidna but lay eggs. Birds, lizards, et cetera all the way down do not have imprinted genes and that’s what we showed.
So we were the ones that demonstrated that the phenomena of genomic imprinting, the machinery that is required of the mother and father to selectively inactivate one copy of different genes arose about 150 to 200 million years ago and we still have them.
Dr. Kara Fitzgerald: Alright.
Dr. Randy Jirtle: This is phenomenal.
Dr. Kara Fitzgerald: Can you tell me about that study? Now that you’ve thrown that teaser out.
Dr. Randy Jirtle: That is the study.
Dr. Kara Fitzgerald: How did you do it?
Dr. Randy Jirtle: What we did was we got tissues from all these different mammalian, non-mammalian species and this is before any genetic information was even known. There was no genal information available on the web and I’m telling you it was not easy to do this. This is work done by Killian when he was in my laboratory.
We had a frozen zoo and we just went phylogenetically down all the way from humans to monkeys, lemurs, because we have a lemur colony at Duke. And down to the near primates and down to mouse and all the way down to birds and lizards. We found that the only animals that have imprinted genes are marsupials and eutherian mammals. Marsupials being like kangaroos and opossums, that kind of thing. They have live birth. They’re very immature but they’re live.
Eutherians, like us, have live births too but monotremes lay eggs and they hatch them like chickens. And they do not have imprinted genes.
So imprinting arose with the advent of live birth.
Dr. Kara Fitzgerald: Isn’t that fascinating? I mean the implications …
Dr. Randy Jirtle: That occurred about 150 to 200 million years ago.
Dr. Kara Fitzgerald: God, that’s fascinating. And again just to remind you folks so the imprinting is actually epigenetic marks that inhibit completely through the …
Dr. Randy Jirtle: Either the mother or father’s copy depending on the being.
Dr. Kara Fitzgerald: Right, so that particular copy is shut down.
Alright, so let’s talk about, we’re getting toward the end of our time together, sadly.
I want to talk about the low dose ionizing radiation study and your findings there. That’s very interesting, again.
Dr. Randy Jirtle: Yeah, this is work done by Autumn Bernal, she was my last graduate student at Duke. As I said, I got my background in Engineering and got into biology through radiation biology. We’ve done now nutrition, methyl group donors, nutritional supplemental compound that doesn’t donate donors, and we got into this Bisphenol A which is a nongenotoxic agent, endocrine disrupting agent. And then so the finish off, and almost to come full circle, I wanted to know whether a physical agent could potentially also alter epigenome early in development.
Something like ionizing radiation in particular very low doses. The kinds of doses that you would get, for example, if you had a chest x-ray or CT scan. That’s the levels we’re talking about, very low, not the high ones that most everybody works with. High doses we know are not good. Low doses you don’t know because there’s a lot of evidence, the phenomena is called hormesis and I’ve known about this since I was in graduate school. It was the same thing. Low doses of a toxic agent were showing up as being positively adaptive. In other words, individuals that were being exposed to low doses of radiation in this one rad or one centigrade level of radiation, which is about what you would get for the CT scan.
We’re showing up with reduced incidences of cancer. Not increases, but reduced. Not even neutral but reduced incidences of cancer.
Dr. Kara Fitzgerald: That’s fascinating. In humans?
Dr. Randy Jirtle: In animal models.
Dr. Kara Fitzgerald: In animal models. Okay.
Dr. Randy Jirtle: Most people in it, the data, if anybody is interested, the person that has done the most as far as accumulating this kind of information, his name is Edward Calabrese from the University of Massachusetts-Amherst. Just look up his name and you’ll see, he documented, there’s a lot of evidence that this is correct.
The problem again is this is the same thing you have with the fetal origins of adult disease susceptibility. When you only think about genomes being the problem that causes anything like cancer for example, it is impossible for something like this to occur. There’s no mechanism. There’s no known mechanism but there’s a difference between no known mechanism and no mechanism. The word known…
Dr. Kara Fitzgerald: Right.
Dr. Randy Jirtle: What we’ve shown with low doses of radiation is that those low doses of one to three centigrade actually cause a positive adaptive response. I’ll tell you what happened, it’s a great story. Autumn came in, she’s the one doing these studies, they’re difficult studies because they have to time pregnancies and all that. We hit the developing fetus right at the time of implantation. So the embryonic cells were hit when they were embryonic stem cells. Very, very early in development. And then the dose is gone. I mean that’s it. It’s not like chemicals where we didn’t know because we gave them two weeks before and up to the time basically the animals were weaned.
This is not the case, one microsecond and the dose was delivered and we knew exactly when it was. I said, “How’s the experiment going?”. And this is a her direct quote. She said, “It’s freaky!”. And I’m thinking, this is like someone coming into my office and saying, “Can I talk to you,”. Not a good thing.
I said, “What’s freaky?”. She said, “There are no yellow animals. The offspring are all either heavily modeled or brown. All of them.”
Dr. Kara Fitzgerald: In other words, healthy.
Dr. Randy Jirtle: Healthy. In this system, healthy.
Dr. Kara Fitzgerald: Isn’t that incredible?
Dr. Randy Jirtle: Now, I said a little more flavorful way of saying it, in which I won’t repeat. But I said, “Oh no”.
We’re in the middle of hormesis.
Dr. Kara Fitzgerald: Wow.
Dr. Randy Jirtle: And we are going to have to do a dose response curve, and when we did that we found the “J” shaped type dose response. The optimal for positive dose response was somewhere between one and three centigrade. When you get higher you start losing that and it looks like it crosses the abscissa and we were not able to go up that high because the direct effects of radiation, which is direct damage to DNA resulted in a reduction in the number of offspring or percentage of animals or mothers that became pregnant. So, you’re seeing direct damage from radiation.
Radiation causes damage both through an indirect phenomena and a direct. One is it directly breaks DNA backbone and stuff like it causes DNA to knockout electrons and causes damage. At 80 percent of the damage is through the generation free radicals. By interacting with water those free radicals can be sucked up by antioxidants.
So 80 percent of the damage we know in any radiated biological material is because of the generation free radicals. So once we found this positive adaptive effect, it was clear that if because of the way radiation works, that if indeed this was real and wasn’t just an artifact you’ll then see if we put antioxidants, fed the mother antioxidants at this optimal dose of radiation for inducing positive adaptive responses we should be able to eliminate it. And indeed that’s what we did and showed that clearly.
In this study, everything is turned on its head. Low doses of radiation are advantageous. And antioxidants are not advantageous.
Dr. Kara Fitzgerald: Right. You know where we see that in humans, there’s limited, limited research. There was older study that really got me excited was looking at exercise. Exercise is oxidative.
Dr. Randy Jirtle: Oxidative damage.
Dr. Kara Fitzgerald: Yes, so that it turns on this beautiful robust, endogenous response.
Dr. Randy Jirtle: [crosstalk 00:59:46] in generation of reactive oxygen species.
Dr. Kara Fitzgerald: Exactly, yes. It’ll turn on glutathione synthesis also. We have this really nice, robust response system as well that our body can dictate and control. This oxidative process, turning on this hormedic reaction is healthy.
Dr. Randy Jirtle: And then we bulk up and that’s why you have to exercise, you lift weights and then you wait a day or so. And then you lift them again.
Dr. Kara Fitzgerald: What you guys showed is a smidge of ionizing radiation induced beneficial outcome. It actually supported the appropriate methylation of the Agouti gene.
Dr. Randy Jirtle: It was dependent upon the generation of reactive oxygen species because when we eliminated that through the use of antioxidants the effect was that it was totally eliminated.
Dr. Kara Fitzgerald: And one of the things we’ve been thinking about in my world is that for all of, we all need to be exercising, and most of us are taking antioxidants of one form or another. Certainly in our diets, what we’re consuming and some of us are doing it supplementally. We can measure oxidative damage, you can do that with eight hydroxy, two deoxy, guanosine or F2 isoprostane. We can measure that in the urine or in the blood of people. So some people need extra antioxidants and so on and so forth.
But one of the things we’ve been thinking about is if somebody exercises, you don’t want to take your antioxidants right after exercise. Not just a dose response but also a timing.
Dr. Randy Jirtle: Kara, these are the kind of studies that need to be teased out. Because everybody says oxy – this is terrible. Well that’s not necessarily true. In new responses we have this too and it kills things and sometimes it’s in things that are not good for us. So it gets rid of bad things. You wouldn’t want to knock down this response necessarily but if you over stimulate. You get too much, now you’re in the toxic range.
The question that is really interesting, we never addressed, what happens if we went up a little bit higher in the radiation. Where we still didn’t have direct damage and we’re getting closer to crossing that abscissa. We weren’t seeing any positive adaptive response. If we use antioxidants there, would we now drop down into the part of the curve where we had a beneficial effect. That would then demonstrate that antioxidants are good and radiation is bad.
Dr. Kara Fitzgerald: Yes, at a particular dose.
Dr. Randy Jirtle: Too much damage.
I was very aware of this when our original study we talked about with the Agouti mouse, I said we have to be careful that people did not go out and by a tub-load of folic acid. People think a little is good, a lot must be really good. I always used the analogy, there’s good evidence that maybe a little bit of wine a day is good for your cardiovascular system but I can guarantee a gallon a day is not.
You’ve got to be careful about dose. And as you said, timing.
Dr. Kara Fitzgerald: Right, it’s just so fascinating. There was a study, I think it was Cochran, that looked at food folate and negative outcome. There is no negative association with food based folates. That’s actually one of the reasons why in our study we’re using a methyl donor rich diet, we’re not actually supplying supplemental methyl donors.
Dr. Randy Jirtle: Part of this is maybe you couldn’t eat enough folate in food. You know what I mean?
Dr. Kara Fitzgerald: Yes.
Dr. Randy Jirtle: To get it up to a toxic level, whereas, when you’re taking supplements. I mean it’s just a bottle of it.
Dr. Kara Fitzgerald: Yes, that’s right. I do think that clearly with the field of epigenomics, which you’ve put on the map, my massive take home is that we need to be paying attention. More is not better. We have to look at what we’re doing and take responsibility.
Dr. Randy Jirtle: I was saying we have to now look at it, we have to be aware that the problem of dose is important. As I said things that may be good may be good when levels are high and not when they’re in the optimal range. All this kind of stuff needs to be sorted out.
Animal models are great. With our animal models, people would say – I think this can be extrapolated to humans. I said if you think about it this is a model system. In reality another mouse brain would not even react in the same way this mouse brain does because they don’t have the transposable development upstream of the Agouti gene.
The concept that epigenetic phenomena is responsible, basically, for the fetal origins of adult disease susceptibility. In other words, deregulation or reprogramming is the mechanism for this I think extractable to all mammalian species. And as I have said it has now been shown absolutely to be the case also in humans. It’s nice to demonstrate that.
What are the target genes in the mouse versus what’s in the human? I don’t have any idea. It couldn’t be the Agouti gene in most mice because it doesn’t have this transposable element. The concept that it is epigenetic can be extrapolated.
Now you’re working out, as I said, we defined the border, now we have to fill in the pieces. It has to be filled in to a great degree in humans and maybe come back out when you have your associations to see if you can demonstrate these kinds of effects also in animal models. You’re going to be going back and forth between humans and animals. Continuously or using human systems like these organoid cultures that are coming out now that are really powerful. Where we don’t have to extrapolate as much as going into another animal because you’re using human cells.
Dr. Kara Fitzgerald: I think this study that we’re doing is pretty pricey. I mean, not perhaps from the Big Pharma vantage but from our world it’s going to be pushing $200,000. One thing that needs to come from the field of epigenetics is clinical access to testing the epigenome. And I know that we need to identify those regions that are worth looking at but right now it’s completely limited to research.
If we had some ability to measure the epigenome directly, in our world that would be really exciting. To begin to see what actually impacts it, that we’re doing. I know that we’re impacting it all the time. We know lifestyle habits, diet, the supplements that we’re using, medication, et cetera, the toxins we’re exposed to are influencing it. I hope that one of the things that is available to us at some point is clinical access to epigenetic measurements.
Dr. Randy Jirtle: One of the last questions, what are you doing now? And then we can probably …
Dr. Kara Fitzgerald: Yeah, we do, we need to wrap up here.
Dr. Randy Jirtle: What we want to know is what epigenetic labile targets or regions in the genome are most susceptible to environmental changes and give rise to some of the most significant, severe problems that we have: development disorders, schizophrenia, autism, cancer, those big things; maybe diabetes and obesity even. The role that genomic imprinting plays in all of these is quite clear. We don’t know the repertoire of imprinted genes even in a mouse, let alone in human.
Even more important we don’t know the regulatory elements that are epigenetic regulatory elements that are controlling this monoallelic expression and origin dependent manner. So all of those regulatory elements within our genome, which probably I am guessing are in the thousands, because the imprinted genes that they control are probably more in the hundreds.
We need to define that. Collectively we call those regulatory elements the human imprintome. Not the genes, the genes are not the imprintome. It’s the regulatory elements that control the monoallelic expression that we need to define. That’s what we’re doing right now at NC State.
If we can pull this off and get a good handle on the human imprintome what does this mean? It means now that you for example can literally screen a thousand sites. Not necessarily will you find changes with nutrition later on but you might find things that are incredibly important in maternal nutrition during embryogenesis. They ultimately might give rise to bad problems if they weren’t appropriately methylated or unmethylated depending on what way you want to look at it.
Dr. Kara Fitzgerald: Then we’ll obviously need to define the set of clinical tools that best augment the imprintome.
Dr. Randy Jirtle: It keeps those things from getting screwed up. But you can’t do that unless you know the targets.
Dr. Kara Fitzgerald: Yeah, that’s right.
Dr. Randy Jirtle: And that’s where we are.
Dr. Kara Fitzgerald: That’s quite exciting. It’s just really exciting. I’ll certainly be paying attention to your journey.
Dr. Randy Jirtle: Somebody might say why can’t you do this in mice, it would be a lot easier. The reason is because the repertoire of imprinted genes in a mouse is different than in humans. It looks like once this phenomena arose that the phenomena of imprinted genes literally was used to drive evolution speciation.
You have different repertoires, it gives me goosebumps thinking about it, different repertoires or different genes depending on the species you’re looking at.
If we can pull this off in humans we can then look at the same phenomena in chimps and go on down the line and potentially find those genes in those regions that might have been involved in the speciation itself.
Dr. Kara Fitzgerald: Extraordinary.
Dr. Randy Jirtle: I don’t know if we’ll be able to pull that off ourselves, I see that this is where this field has got and will go. It’s so damn exciting and important.
Dr. Kara Fitzgerald: It’s extraordinary.
Listen, Dr. Jirtle, I just want to thank you so much for spending your Wednesday afternoon with me.
Dr. Randy Jirtle: It was a real pleasure and hopefully someday I’ll get to meet you.
Dr. Kara Fitzgerald: Yes, absolutely. Indeed. Our paths will cross. I’ll keep you posted on our study and once we have those data I’ll ping you with them. If you want to take a look at them, that would be wonderful.
Dr. Randy Jirtle: Okay, thank you very much.
Dr. Kara Fitzgerald: Absolutely.