The following are important links Jeffrey talks about in the video above:
- Epigenome-wide association study (EWAS) for potential transgenerational disease epigenetic biomarkers in sperm following ancestral exposure to the pesticide methoxychlor
Transcription: Jeffrey’s Take: Rat research shows how exposure to Roundup (glyphosate) causes disease in their great grandchildren with Dr. Michael Skinner
This transcript has been edited slightly for clarity.
Jeffrey Smith (00:39):
I want to say that I’m with Dr. Michael Skinner, whom we’ve spent some time with in 2019 speaking about your amazing research on how exposure of rats to glyphosate caused damage in the great-grandchildren.
Dr. Michael Skinner:
Jeffrey Smith (1:10):
And you just published something new in the journal Epigenetics, where you discovered the mechanism, how exposure to the pregnant rat was passed down to the next generation, to the next generation and to the next generation. What it is, is not only a sobering demand on us living in an organic and glyphosate free lifestyle, but you actually have shed an understanding of a whole new way that disease is created–not from our genome, but from our epigenetics. We’re going to dive into the dangers of Roundup like we haven’t before, but also a new understanding of disease and how it relates to genes. (I’m going to see if I’m still breaking up like…there we come back.) First of all, let’s review what you did. You were at the University of Washington…
Dr. Michael Skinner (2:14):
Washington State University
Washington State University–sorry, wrong place. If you could tell us what you did at your lab to make the discovery, first about the intergenerational effects, and then we’ll get into the mechanisms and the nitty gritty.
Dr. Michael Skinner (02:30):
Sure. A few years ago we published this glyphosate paper and for about 20 years ago–let me step back–we’d identified the concept that there was this non-genetic form of inheritance. In other words, most inheritances were thought to only be genetics and code through your DNA sequence to your next generation, and this requires the sperm and the egg to come together that that DNA then sort of has certain mutations and things in it, and that causes this genetic sort of inheritance. About 20 years ago we identified the fact that using another environmental chemical called Chloselin, (which is the most commonly used fungicide in the world in agriculture), we exposed some outward rat models to these in Chloselin– we initially intentionally exposed to a gestating female, pregnant female, at a very specific time of sex determination for the fetus, whether they’re going to get ovaries or testes.
Dr. Michael Skinner (03:36):
And then basically found that the offspring had phenotypes, but then when he bred those out two more generations to the great-grand offspring, that essentially the disease that we saw in the first generation kept being passed generations, even though the only exposure was the F zero generation. So we termed that epigenetic transgenerational inheritance, and it wasn’t mediated through genetics. We knew it was actually epigenetics, because what the environmental chemical did, was it changed the epigenetic makeup of the sperm or the egg, and that actually makes that epigenetic change what was being inherited. It’s not a sequence thing. It’s more small molecules and factors around the DNA that regulate how it works, like chemical modifications and so forth. Those become permanently sort of put in place in the germline and it keeps going inherited for multiple generations. A plant species, for example, has been shown that that can be inherited a hundred generations–that there was a key to exposure, changing a flowering phenotype, and hydrogeneration is the same flowering phenotype and it was an epigenetic shift that was doing it. In Drosophila fruit flies it can go a thousand generations. It was a wing structure change, and it goes a thousand generations in this non-genetic inherited mechanism.
Jeffrey Smith (05:04):
Let me just jump in here and make it clear that the genome did not change–the sequence of the gene did not change. It was what was being expressed as a result of the molecules hanging around.
Dr. Michael Skinner (05:23):
Right. The chemical modifications of DNA, like DNA methylation…
Or chemicals, right.
Dr. Michael Skinner:
…Or the protein modifications, chemical modifications of the proteins the DNAs are wrapped around, called histones–those types of things, or the really small RNAs that hang around that actually help things work. These epigenetic components are what was changing, and it was becoming permanently programmed, and that’s what you were inheriting going forward. Now we realize that a significant, if not equally important form of inheritance of phenotypes and traits and so forth, comes from the epigenome and the environmental induced epigenome versus the genetic sequence that we inherit.
Jeffrey Smith (06:04):
Now from a practical standpoint, before we get into the glyphosate research, which by the way, from what I understand when they evaluated the social media coverage of your discovery from 2019, within a week it had 115 million mentions propelling it to one of the top five of all time of the scientific papers that in terms of social media devouring. So you were known. It was the shot heard around the world, and I’m sure Monsanto and in the other months, the glyphosate makers, were not happy about that. We’re coming back now to the concept that if something happens to your great-grandmother, they go through a trauma, or if they have a famine, or if they have something in their life, it may be affecting you. And you don’t have to believe in consciousness as a field–or even if you do, you don’t have to believe in some kind of energetic, psychic inheritance. It could be the way histones are wrapped around your DNA that happened because your grandmother was in a trauma. Am I getting this right?
Dr. Michael Skinner (07:27):
Correct. The environmental exposures–whether it be trauma, nutrition, environmental chemicals, and so forth–of an individual can change your physiology early in life so that it affects your disease later in life. But what it does do, is it changes your genetics of your sperm and egg, your germline, and that then becomes permanently programmed. It sets that when there’s a reproduction and you have a fertilization event, that epigenetics gets passed to the next generation. As that individual grows up and reproduces to the next generation, the same epigenetics gets passed. This keeps going and it’s called epigenetic inheritance. And you’re right–it has nothing to do with DNA sequence. It’s not mutations in the DNA or anything else. It basically is epigenetic inheritance. The unique thing about that scientifically is the environment can’t really change the DNA sequence. The vast majority of things are not mutagenic. They can’t change the sequence, but they have very significant impacts on the epigenomes. The way the organism responds to environmental stressors shifting the epigenome, is they will get phenotypic shifts that actually can cause diseases, or in some case allow an adaptation to allow them to survive better so that evolutionarily those are actually selected through natural selection, Darwinian evolution. Essentially this impacts all of biology, just not little things like our disease and so forth–it’s everything.
Jeffrey Smith (09:04):
I have to say that it’s one of the areas—it’s like I’ve often said that biology is not rocket science, it’s far more complicated. If you look at how they evaluate genetic engineering (which I’ve looked at for 25 years) it takes them 20 years to look at low dose endocrine disruptor effects after that’s been established, but they still avoid looking at these epigenetic effects. Finally, within the last few weeks, we discovered an article where epigenetic impacts from CRISPR cuts and additions were found 10 generations out. That means that if you genetically engineer something, you may make a change that no current research right now will be able to find, but it gets passed on generation after generation–which means it could theoretically take over the niche with an epigenetic change that can cause disease susceptibility to the plant or those who eat it, etc.
Correct. Now, to bring this back to your sort of focus here in glyphosate, for the field of toxicology, what toxicology is geared around, looks at, is what’s the effect of a compound or an exposure on the individual exposed? That’s called toxicology. Direct exposure toxicology is the only way we do toxicology today. Every single government agency only looks at direct exposure toxicology. What we found with glyphosate is if you do the direct exposure, we don’t really see significant effects in our models. It looks like glyphosate is exceedingly safe. This is the industry coming out and saying, This is a really safe compound–which it is for direct exposure.
Jeffrey Smith (10:58):
Well, you inject it into a pregnant rat and that particular rat didn’t have any untoward experiences.
Dr. Michael Skinner (11:06):
Correct. Or males being exposed their diet, or whatever. But if you take that individual and it gets bred to the next generation, or maybe another generation, essentially the disease rates go significantly higher so 90% of the animals are developing disease. We’re calling this generational toxicology. It’s not necessarily the direct exposure that’s a problem. It’s your effects on your great-grandchildren we need to worry about. So do we have a responsibility for our great-grandchildren’s health? I think most people would say, Yes. We need to actually expand our view of what toxicology is beyond the simple, direct exposure effects to a gen X [i.e. the Generation of people born between the early-to-mid 1960s and early 1980s. Ed.] in the next generation. Essentially the way this works is it’s through these epigenetic inheritance mechanisms. It’s not like Monsanto knew about this, because this is very new science; essentially this is new stuff. We should step back and try to reevaluate the way we do things and whether certain things…it turns out there’s a number of environmental chemicals that are agriculturally based, like atrazine does the same sort of thing, where there’s no effects in the first generation. It only appears in the second or third generation. And then the disease incidence is very high.
Jeffrey Smith (12:40):
I want to go into the specifics of what happens in the cells that allows this to occur. But first let’s catch everyone up. You mentioned 90% of the great-grandchildren of the rats that were injected, which was greater than the grandchildren, which was greater than the children. So there was a multiplication of the impact generation to generation. Can you just mention those diseases that you found in the great-grandchildren of the exposed rats?
Dr. Michael Skinner (13:11):
Sure. We see kidney disease in both males and females, prostate disease in the males, testes disease in the males. We see ovarian disease in the females. We also see oftentimes some behavioral effects. One of the bigger is, by the time the third generation comes around usually we see increases in obesity or susceptibility for obesity. Two animals that have this, basically one animal on the same diet, same exercise and so forth–this one will develop obesity and the other one doesn’t. So this one has a susceptibility–it’s not inducing the disease, it’s a susceptibility based on their environment. We see a number of different things. When I say 90% they’ll have one or more of these diseases in that third generation.
Jeffrey Smith (13:59):
All right. Now tell us the magic sauce. How did it go from grandmother, great-grandmother, to the great-grandchildren.
Dr. Michael Skinner (14:10):
The direct exposure, like the gestating female–essentially the female is directly exposed. That’s the F zero generation. All toxicology associated with that deals with direct exposure. Your organ systems are responding to whatever compound you’re looking at, so that’s causing them signal transduction things and things in the cell to actually alter. Then that potentially can promote a disease and a toxicology. That’s direct exposure toxicology. The fetus, the F1 generation, the only diseases you’re going to see in that when it’s born is direct exposure toxicology of the fetus. The offspring, the F1 generation, generally have much lower disease, because again, it’s a direct exposure to the fetus. There’s no germline media at the event. It’s the F1 generation that has this now programmed into the germline, the sperm or the egg, but then it’s the next generation, the grand offspring or the great-grand offspring where…now think about this, it’s a little complex.
Dr. Michael Skinner (15:16):
The sperm and the egg are coming together, and one of them or both of them have an altered epigenetics that sits over the top of the DNA to regulate what genes are on and off. When you have a fertilization event through the germline, the stem cells that are generated from that early embryo, developing what we call a stem cell, now has a different epigenetics and a different sort of gene expression profile. That stem cell generates every single cell type in your body–your brain, your heart, your lungs, your liver, all the different cell types are coming from that embryonic stem cell. Every single cell type in the body now has a shifted epigenetics and transcriptome. Some tissues, like the kidney, the prostate, the ovary, the testes, those are sensitive, fairly sensitive to those shifts and so we have a higher incidence of disease.
Dr. Michael Skinner (16:19):
Other tissues, like the heart or liver and so forth, those don’t really develop diseases that we’ve seen. So some tissues are resistant and some tissues are more sensitive. So essentially because of that germline transmission, all the cells in the body now have this shift and you have a higher incidence. When that individual reproduces to the next, the great-grand offspring, the same thing’s happening again and it keeps going, basically. A germline mediated event, a sperm or egg mediated event, has a very different mechanism to induce disease than the direct exposure F zero or F1 generation. That’s why glyphosate is very safe for direct exposure. It doesn’t really promote a lot of diseases in our animal models. There are some things that people have sort of identified in humans and other animal models that if it’s high enough, it actually can induce things.
Dr. Michael Skinner (17:13):
But for the most part, it’s one of the more safe compounds that we’ve actually generated. But it has a variability to change that epigenetics, that germline, so that the grand offspring, the great-grand offspring have higher disease rates. That’s a different mechanism. The thing is, it’s permanent, as we saw with the plants going out a hundred generations and the fruit flies for a thousand generations—it just keeps going. This is why we need to start thinking about this generational toxicology, because this is probably where the bigger impacts of these exposures really are, not so much on the people today. Back in the fifties when we used DDT, those had big effects, because they were used so much, and so we did have direct effects. The whole field of toxicology was developed in the sixties from those types of exposures, DDT and other things, and that’s why they only focused on direct exposure before. Now, with this new information, new science, we need to sort of start thinking about this generational sort of thing.
Jeffrey Smith (18:21):
In my area in collecting data and sharing it and interviewing scientists, I’ve come across different sets of data than you and your studies, in terms of the F zero for glyphosate. I could probably spend 15 minutes just recounting various F zero impacts, whether it’s damaging the actin in the cell causing collapse of the mitochondria, the gap junctions, the tight junctions, the genotoxicity, the antibiotic nature, the binding with minerals making them unavailable, etc. etc. Even though you could dismiss it as relatively little compared to some acutely toxic compounds, I would consider it to be significant. Yet where we can meet is, if you think that’s bad, you just wait, because then it’s going to change. I’ve found it fascinating, and you were very clear in the description how the embryonic stem cells become everything.
Jeffrey Smith (19:31):
If they’re messed up–the scientific word messed up–in a certain way, skewed in a certain way, they’ll pass that on. They’ll whisper that same mess-up to everything that they become, including the germline, which gets passed onto the next offspring, which gets passed onto the next offspring. When I ran the last interview with you, Doctor, I got a comment from a friend of mine, Dr. Michelle Perro, a pediatrician, and she said she really enjoyed the interview, but disagreed with you on one thing, so I’m just going to lay that out there. I said, I asked you the question, What can we do to reverse the trend of an epigenetic genetic issue that we’ve inherited? And you said, There’s nothing. But in her awareness, there are things that we can do, and that medicine is getting to a point where if we could see how the environment can cause a change in one direction, we can see how to create a new environment to undo that change. In that case, she was not taking it as a sentence for all future generations and that slum-smart fruit flies, if they just knew the right medicine, would have stopped at somewhere in the thousand generations.
Dr. Michael Skinner (20:56):
For example, I don’t disagree with her, but I think we’re 50 to a hundred years off from having the technology to make those decisions and this is why. She’s absolutely right–there are some therapeutics that can be used that right now are used in stage 3 cancer patients for a number of cancers. They take this therapeutic and they can extend their life for two or three months. It doesn’t make them survive, but it extends their life. Then they die after three months. You might ask why they die. It wasn’t because of the cancer or something. The therapeutic that they were using, the epigenetic changes that were so severe that were going on, eventually killed the patients. Yes, it extends it, but it has its costs. We today can’t target therapeutics at a specific site in the genome or a certain cell type and things like that.
Dr. Michael Skinner (21:58):
I don’t disagree that eventually we will be able to potentially get there, but we’re quite a bit off of that. Now there’s another thing where there’s this compound called folate, which is a vitamin, basically. Folate is a methyl donor for the DNA methylation that we measure that’s changing. So you’d think that basically there’s too little folate, and you just gave enough folate that you might actually shift the epigenetics–which can occur–you guys can measure that. Unfortunately, you get too high in folate, guess what? It becomes toxic, causes the epigenetic changes to actually cause more disease than what you were trying to treat. Essentially if you take folate above maybe 200%, the daily dose recommended, it becomes toxic. We just don’t know enough science around these manipulations of the epigenome. We’re just in the early days for us to take any kind of measures like that. I think we will get there in 50 or a hundred years, but it’s down the line.
Jeffrey Smith (23:05):
It’s also possible that the ancient wisdom of health had an understanding of the impacts of food. They talk about food as intelligence or as knowledge, and that information gets transferred. I remember hearing about Ayurveda with this concept and then reading about the RNAs of food and herbs, and how that can modulate gene expression. It fit hand in glove with the description of the ancient understanding of food. What’s interesting here is we constantly upgrade—well, in this case with food, it’s not constant, it’s with these big leaps. It was vitamins, and vitamins and minerals, and then phytochemicals. Now we realize that the food that we eat has RNA, and the RNA may help reprogram or program gene expression. It might have other ways, as you mentioned, the methyl groups and also the histone, which was part of your research. It becomes much richer when you look at the quality of the food, as well as the quality of the toxins. It can cut both ways, that maybe there are qualities of the food in terms of its ability to inform our epigenetics, to chill and release the impact from the toxicity.
Dr. Michael Skinner (24:28):
It’s not necessarily…I mean, you’re absolutely right. Do you understand that RNAs, all those non-coding RNAs, those small RNAs–that’s an epigenetic component.
Dr. Michael Skinner (24:41):
One of the major components of epigenetics is those small non-coding RNAs, and that’s what you can actually ingest from food and have it maintained intact. It’s very stable and that’s what’s actually causing the effects. The big RNAs you think about from a protein or something–those get degraded very quickly. It’s the small RNAs are epigenetic and function. They have nothing to do with the DNA sequence and they basically regulate things completely independently, so that essentially it’s the epigenetics from the food. In addition, nowadays there actually is a resurgence in Chinese medicine and so forth, Asian sort of medicine–there’s a lot of these medical approaches taken out of Chinese medicine, classic sort of traditional Chinese medicine, which have the same type of thing you think about in terms of food. There are herbs and so forth in there actually, and they now realize that epigenetic sort of modifications and so forth, are part of those mechanisms that they’re looking at. I agree totally, in the future we probably need to be a little bit more open-minded to more classic and traditional approaches and bringing that into modern medicine sort of approaches, to have a better sort of eventual medical approach.
Jeffrey Smith (25:55):
Having talked about the epigenetic impact of small pieces of RNA you could probably understand why I’m a bit upset about the genetically engineered apple and potato, engineered with double-stranded RNA to silence the gene that produces browning. Because now you have an epigenetic stable molecule and the food that we eat that’s known to reprogram genetic expression and doesn’t necessarily limit itself to the apple or the potato, but we eat the apple or potato. Or the RNA interference sprays that have been approved to be pesticides, or you can spray it and imagine the poor person who gets sprayed because he’s the actual sprayer and he gets full of that spray, and it might have epigenetic effects on his own genome–but now what you’re saying is and his or her children and grandchildren, and great-grandchildren.
Dr. Michael Skinner (26:53):
You can genetically engineer an organism to make it different, like the CRISPR apple. The basic genome and the message RNA that’s actually generated if you eat that apple it’s degraded in your stomach and doesn’t go any farther. A normal sort of diet has lots of DNA. We ingest lots of RNA and lots of DNA, whether it’s from a cow, whether it’s from an apple, whatever it is, and we did digest it, so that should not be seen as a foreign, hazardous sort of thing. Now, if the genetic engineering generates a product that is toxic, then we potentially are ingesting that toxin. Now the CRISPR apple is much more of a genetically engineered plant where it’s in the basic DNA sequence, and there’s a different sort of RNA generated that actually is causing sort of the taste in whatever we’re getting out of it.
Jeffrey Smith (27:59):
That really doesn’t have the capacity to necessarily be harmful. It sounds very science fiction-like, but in terms of that, you have to understand that when we ingest things, we are going to digest classic DNA and classic RNA. Now, if they make a small non-coding RNA, most things are species specific in terms of their function, so just because it’s in an apple doesn’t mean it’s going to have a function in the human. It doesn’t mean that we shouldn’t test its toxicity, and that’s something that probably has not been done extensively. We need to test the toxicity of some of these things that are generated. If we actually test them and there are not major effects, then it’s probably not an issue.
Jeffrey Smith (28:45):
If we had more time to dive into this, I would point out some research that comes from a different angle. I did some research on RNA interference. I interviewed Jonathan Landsman, who used to work at the USDA, and who talks about how RNA from one species can impact another; and Dr. Jack Heineman from New Zealand, who points out that the regulatory agencies and the biotech industry claim that because RNA is broken down during digestion, we don’t have to worry about it. Yet they use it for regulating DNA expression in such a way that it has to survive to some degree in order for it to even do that. There was also some very specific research that shows that it is in fact stable, and some of the research that showed that it was stable was later attacked by Monsanto.
Jeffrey Smith (29:45):
When I interviewed the woman she was outraged, because it was clear that what Monsanto was doing with double stranded RNA was dangerous, based on her research. They were trying to discredit her research because it showed that they were playing with regulatory fire. In addition, like when honey bees were fed double stranded RNA for a meal, they had over 1400 genes that became dysregulated over a few weeks, but it came from a jellyfish and it was cross species. Anyway, as I say, I know enough…I have steep walls where at a certain point I’m like, Oh, I can’t talk to you about histone–histone differentiation and all that, because that’s not where I have the background. I’ll just say that my concern is that what we learned here in talking to you about the multi-generational effects, about the epigenetic effects–the small pieces of RNA, etc. We compare that to the regulatory reviews, whether it’s toxicology and the F zero, or GMOs, which has even less than a standard toxicological review–it shows that we’re playing with fire here.
Dr. Michael Skinner (31:02):
I would say that you’re absolutely right. There’s not a lot of science done in these toxicology analyses, and it’s not in depth enough to actually make some of the conclusions that it’s not present or something, and it needs to be investigated. But there are lots of normal examples of non-coding RNAs or just RNA in general, which is not sort of the toxicity that you’re suggesting. So you need to be cautious of not overreacting with these types of things. For example engineered…you have to understand that when we engineer plants, we’ve been doing that for thousands of years. When they actually look out over a corn field and they have one plant that actually is a little higher, bigger, and has higher production, and you go out and pull that out of the ground and you propagate that in the next farm, that’s a form of genetic engineering. We didn’t go in and actually do something experimentally, but we’ve selected those types of things for literally a thousand years. So to a degree some of these are some natural products that are just shifted, therefore you get the creature that’s an ingrained form.
Jeffrey Smith (32:17):
I have no problem with natural selection and wide cross breeding. I have no problem with that. I am aware that the process of genetic engineering done in laboratories introduces specific risks that are different from those that are injectables.
Dr. Michael Skinner (32:31):
I wouldn’t disagree, and they need to be tested. It doesn’t mean we terminate them. They need to be tested if there are heath effects down the line.
Jeffrey Smith (32:40):
We’ve stepped out of the box. I’ve been doing the evaluations of these things for 25 years and traveling 45 countries and interviewing some of the regulators and the scientists and whatnot, and compiling them in books. I love talking about this stuff, but I actually would prefer in terms of talking with you, learning from you in areas that I don’t know, and this is an area where you are one of the world’s experts. I would like to just share before we finish, I would like for those of us who are really into the science, if you could explain very specifically how the epigenetics works in the sperm cells that you tested–the histone and the methyl groups–and then finally how we need to rethink in terms of genes as expressions of diseases. We had a little bit of that, but let’s just burn that myth completely and introduce a new understanding. But let’s start with the simple mechanics that most people never get to.
Dr. Michael Skinner (33:53):
Okay, sure. Epigenetics is defined as molecular factors and processes that are around the DNA sequence that can regulate what genes are on and off, genome activity, completely independent of the DNA sequence. The sequence has no impact on epigenetic regulation, it doesn’t care. If there was DNA sequence dependent, the process would be genetics, so by having it completely independent, then essentially it has nothing to do with genetics. The main types of epigenetics are: there’s a chemical modification of DNA in it, a methyl group, a small carbon group with a couple of hydrogens gets attached to the DNA. That attachment can actually change the structure of the DNA slightly, but it can also interfere with proteins and things binding to the DNA, so it completely changes things.
Dr. Michael Skinner (34:57):
The DNA methylation is what we study extensively, so that was the first epigenetic component identified. The second one was called histones. There’s a core of eight histones that get together and actually form this spherical structure and the DNA gets wrapped around it, just like a string wrapped around a bead. It takes a couple of hundred nucleotides to get it wrapped around it. Essentially DNA is not like this naked strand of DNA; its DNA is wrapped around these histones. So you get this bead, and then this bead, and this bead, and so it’s beads on a string. And then those get twisted and the whole thing comes together and it forms this double helix. Basically everything comes together with these histones supporting this DNA structure. It turns out that the proteins make up these histones.
Dr. Michael Skinner (35:55):
If you chemically modify these histones, guess what? You can actually turn genes on and off based on the histone modification. It doesn’t care what the sequence is, so that’s epigenetics. The first one is DNA methylation, the second was histone modifications. The third one identified was the chromatin structure. Let’s say the DNA is going along and all of a sudden you have a loop that goes around…this thing on this piece of DNA can interact with this DNA. It turns out if there’s a gene sitting there it can turn the gene on or off. If you break down that loop, you can actually have an effect as well. So the structure of the DNA we call chromatin structure has a significant impact on genes going on and off. That’s the third sort of epigenetic component identified. The fourth one that we identified was theses non-coding RNAs, not the message RNAs that are making proteins.
Dr. Michael Skinner (36:55):
It’s these really small…the smallest ones are let’s say 15 to 20 base pairs. They’re really short. Bigger ones are maybe a hundred, and a long arm non- coding RNA a few hundred. These small ones, they again don’t really make proteins, but they bind to proteins or they bind to DNA, or they have structures associated with them that facilitate protein interactions–lots of things going on. They can actually go in and directly turn genes on and off independent of sequence because they’re interacting with proteins and things in the DNA. That was the fourth one identified, and those are probably just a tip of an iceberg. I think we’re going to see lots of new epigenetic components that we don’t even know about today because the field’s that young that I think we’re going to see a whole plethora of new epigenetic components.
Dr. Michael Skinner (37:46):
These different epigenetic components get together, they interact with each other, actually then turn genes on and off, completely independent of DNA sequence. You have to have a gene there, you’re going to have to have a promoter there, and basically the epigenetics is what basically turns them off. In your neuron you can have this set of genes turned on, and in your liver cell you’d have this set of genes turned on. The reason they’re turned on in this cell and this cell is because the epigenetics in those two cell types is different, and so they regulate different genes. You have 200 cell types in your body. Every single cell type in your body has completely the same DNA sequence, so why is it you have 200 cell types in your body, if the sequence is exactly the same? I’m sorry, the genetic sequence can’t drive 200 different cell types. It just doesn’t do that.
Dr. Michael Skinner (38:42):
But the epigenetics in every single cell type is completely different and unique to that cell type to give it that cell specificity. What generates the genome–the expression pattern in the neuron versus the liver–is not the DNA sequence as much as it is the epigenetics in those two cell types. The way to think about is it…I’m not going to say one’s more important than the other, but basically the DNA sequence is just as important as the epigenetics in terms of regulating biology. We just never paid attention to the epigenetics before. For the past 120 years all we’ve thought about is genetics and the DNA sequence. Most of our science gears towards looking at genetic mutations. There’s nothing wrong with that, but it’s like you get this small piece of a really big story here, and you’re not paying attention to the rest of it. We have a paradigm shift in science occurring right now, and it’s been occurring for the past 20 years and it will probably take another 20 years to get a complete shift in the paradigm. But where we’re going is having equal contributions of every genetics and genetics in terms of our thinking about evolutionary biology or disease etiology, or just basically how things work. So that’s basically sort of a quick discussion of the field of epigenetics.
Jeffrey Smith (40:10):
We have the genome and we have the epigenomes. I know that when a gene creates a protein it creates first the RNA, and then the RNA can get alternatively spliced and form different sequences, which can then produce different proteins. What in the cell determines that alternate splicing? Is that also the epigenetics or is that a third field?
Dr. Michael Skinner (40:42):
It’s basically epigenetics that’s determining whether the splicing occurs at this point or this point, so therefore…epigenetics and genetics are completely integrated. You can’t really separate the two. The way the genetics works is by having epigenetics, how many of these functions turning things on and off and so forth. Without the DNA sequence, the epigenetics is somewhat pointless. And so they really are sort of these integrated things. It’s not like one’s more important than the other; they’re a unit and you really can’t separate them. Now we need to start thinking about these epigenetic things that we haven’t really thought about before, like epigenetic inheritance we talked about. That’s a completely new concept. When we first identified the phenomena, for 10 years I fought this because this is heresy. This is genetic illiteracy, to say that there’s a form of inheritance, not genetics?
Dr. Michael Skinner (41:34):
It took about 10 years, and finally other people started doing the experiments and realizing, Oh, this looks like it’s actually working. Now hundreds in the of labs and probably almost a hundred different species have done the same thing and basically identified epigenetic inheritance as a real thing, but it took that long. There’s a fellow, Kuhn, and in the 1970s he came up with the theory that a paradigm shift in science takes at least a generation of scientists because the current scientists are so ingrained in that dogma, they’re not going to change. The new scientists coming up, they realize, Oh, this is a better way to think about it. They have no restrictions. They have no invested interest, and so they’ll step in and they create the new science of moving forward. It’s the same thing with epigenetics. We just started in the nineties when it was really pushed forward; in 2000 we got a little bit farther. We need another 20 years and we’ll probably be there where it needs to be sort of looked at.
Jeffrey Smith (42:39):
One thing that you found in your study that was just published in the journal, Epigenetics, was that when you looked at the rats where the great-grandchildren of the injected female rats, what was passed down were certain histones or methyl groups on particular genes associated with the particular diseases suffered by the rat in the prostate. You had mentioned obesity, you had mentioned the ovaries and the testes, and kidneys, I believe. This shows you can look at and evaluate…‘cause right now it says, Okay, I have 23 and me, and I’ve done the medical thing, I have ancestry.com and I’ve done the medical thing, so now I know what I am susceptible to. But there may be, according to your research, a future at looking at our epigenome to see where these methyl groups are and if they’re sitting on top of specific genes that are related to certain diseases. Is that right?
Dr. Michael Skinner (43:43):
Absolutely. So what we’ve been talking about, put in simple terms, is: What your great-grandmother got exposed to, or grandfather, is going to cause a disease in you. And you may never see that exposure, that environmental sort of factor, but you still get a disease and then you’re going to pass it onto your grandkids. So I’m sorry, this is pretty doom and gloom.
[Laughs] Thank you!
Dr. Michael Skinner (44:14):
In other words, you can’t control anything your grandparents did and it’s difficult to actually control what your grandkids are going to do, so essentially this is pretty doom and gloom. I’ve been thinking about this for decades, and so I say, OK, how do we go to the next step? How do we take this basic information and take it to the next step? Now, the initial steps were we’ve looked at the effects of 16 or so different environmental toxicants and that we’ve promoted models with all of them. They all promote transgenerational inheritance. But the epigenetic changes for each exposure turn out to be unique to that exposure.
Dr. Michael Skinner (44:55):
In other words, there is hardly any overlap. That gave us the idea that, Oh, you got kidney disease coming up with all of them. Why is it coming up? We’re starting to get a better understanding of basically how disease develops. But what we started doing is getting biomarkers for exposure. The next thing we ended up doing is sort of starting getting biomarkers for the given diseases. The recent study is we used a glyphosate model that we generated in 1990 and 2019. We actually take those animals out, we analyze all the diseases they have, and then we actually isolate all of the animals with kidney disease, nothing else, just kidney disease. We take those as firm analysis from the father that’s causing the kidney disease, and we basically get a biomarker for just kidney disease, epigenetic changes that are just kidney disease in the sperm.
Dr. Michael Skinner (45:53):
We do the same thing for ovarian disease and test these and so forth. So we have these disease specific biomarkers, and we did this with I think six or eight different environmental exposures to actually show that indeed we have these epigenetic disease biomarkers. Now these overlap a little bit more than the exposures did, so now we’re using that. With glyphosate we have epigenetic biomarkers for each of the diseases that the glyphosate was inducing transgenerationally three generations later. Now, think about this: If you could actually use a biomarker, epigenetic biomarker, and determine what your great-grandparents were exposed to, and by knowing that exists, what diseases you potentially are going to pass to your grandkids, we can actually use that biomarker to say, Okay, early in life for your grandchild or your child, you basically say, if you do the epigenetic tests, here’s the biomarker that’s present.
Dr. Michael Skinner (46:58):
We know you have a such and such percentage chance of developing breast cancer, or basically kidney disease, or whatever. And so because of that, now you can step in before the disease develops in the individual and actually come up with some treatment–either a lifestyle change, dietary or whatever, or a therapeutic to actually treat the individual before they have the disease, to delay or prevent the onset of that disease later in life. Now, we weren’t the first one to show the feasibility of this. The first observations were done in the cancer field for breast cancer. Breast cancer has had a number of chemotherapies developed to actually treat breast cancer after it develops. One of the treatments that came about was called Tamoxifen. Tamoxifen’s a chemotherapy. It doesn’t really work well to treat breast cancer after it develops.
Dr. Michael Skinner (47:55):
But what they found was if you actually were in your thirties (most breast cancer occurs they say between 50 and 60, maybe up to 70 years) and so if you went into your thirties and you took Tamoxifen for two or three years as sort of a preventative therapeutic, it would delay the onset of the breast cancer by 10 or 20 years and sometimes inhibit it from happening in the first place. That’s called a preventative therapeutic. The reason we don’t have more therapeutics like that is we do not have any way to test whether you’re susceptible to get the disease later in life. Epigenetic diagnostics will give us that capacity. This is what this particular study did–it said that with the glyphosate induction of this transgenerational, we have these biomarker specific diseases to show the proof of principle we could have those
Dr. Michael Skinner (48:51):
and then basically now in the future it won’t be that useful in a rat model, but in an era, in the human model we could actually develop those types of things like the Tamoxifen treatment for breast cancer. What epigenetics is going to do…and genetics actually thought that it would in 2000, when they sequenced the genome they thought that they would get these sorts of things from the genetic mutations, but it wasn’t realized because the mutations turned out to be extremely low frequency events. Epigenetics is a very high frequency sort of issue and so it doesn’t have that problem. And our models are telling us that we can actually use those diagnostics to treat them. So we may not be able to fix the problems that glyphosate has induced, but we may be able to treat them in our subsequent generations as a preventative treatment, to actually treat the diseases.
Dr. Michael Skinner (49:43):
We won’t be able to get rid of it, but we can treat the diseases to improve our health accordingly. So now it’s not quite as doom and gloom–in other words, because of the technology, we might be able to do something about it in the future, basically ushering in this preventative medicine approach and preventative therapeutics that we really couldn’t do efficiently until now. I think that the current glyphosate paper is really giving that first sort of proof of principle that indeed those types of epigenetic sort of diagnostics exist. Going to the human now, we’ve recently published this last week that we could do this in autism in humans. We could take a father’s sperm basically, and actually assess their epigenetics and potentially tell whether they have a susceptibility to have an autistic child. The nice thing about that is if you can catch autism early in life before the age of one and two and do some treatments, then you could actually decrease the severity of the autism dramatically.
Dr. Michael Skinner (50:46):
So the clinical management of the disease might be a preventative sort of approach to the end of this from the epigenetic analysis of the father’s sperm. I think in the human we now have some indications too, that this is going to work, or at least the proof of principle. Now we need to do larger clinical trials and so forth and sort of move forward. That’s why we’re spending a lot of time now, because now that we’ve identified the phenomena, the next step was, Well, what can we do about these phenomena, because it’s basically now ingrained in our population and the increase in disease we’ve seen over the past few decades is because of all these environmental factors. Sure, we should try to clean it up. Sure, we should try not to use them and so forth. But what do we do about the people that were exposed and so this sort of starts to address that.
Jeffrey Smith (51:34):
I think we talked last time about we’re a generation whose parents or grandparents were exposed to DDT, and that might explain obesity or something like that coming out now because of the epigenetic markers. Even though I’m going to be even more optimistic than you and say that we’re going to be able to do a kind of treatment that may not even be pharmaceutical, but more holistic, where we can use the intelligence of the body to restructure the environment around and intertwined in the DNA so we could shed this stuff. I also find it fascinating that like I now that people will say, Well, I’ve got the particular genome or the gene for breast cancer. I’ve got the gene for Alzheimer’s. Pretty soon they’re going to say, Yeah, but do you have the epigenome sitting on top of that? So is it actually that you look at the particular location of the gene and you look at the vicinity around the gene to see if the methyl group and the histone and the chromatin and all that right there at the place of the suspect gene–and that’s where you do your looking?
Dr. Michael Skinner (52:50):
When we do an epigenome map, first of all we do genome-wide analysis. I think in the glyphosate diseases there were 300 or 400 epigenetic sort of sites that we identified. My opinion is it’ll never be one site. It’ll never be even a few sites. It’s all 200 or 300 or a thousand sites. We have to stop thinking about the fact that one thing could do something. That’s called a reductionist view, in science. A reductionist view is not getting us anywhere. We really need to step back and look at this as a system and so when we do an epigenome map we do the whole genome. And the way you’re going to think about this is, here’s the diagnostic and if you’re going to do some sort of therapeutic treatment, it has to affect the entire epigenome so it fixes it. With genetics it was very difficult to do large numbers, and you have to understand if they get a genetic mutation for Alzheimer’s or whatever, and a hundred people have the disease, it’s in one individual. It’s that low–it’s usually less than 1% of any kind of disease biomarker like that, or mutation that’s within the population.
Dr. Michael Skinner (54:03):
It’s a very low frequency event. Yet in the case we just did, we took 15 individuals that had autistic children, and we identified 800 of them that were present in every single individual. So it’s a much higher frequency event. We have to start doing more global genome-wide stuff, and stop doing this reductionist approach and we’ll actually get someplace, I think. I’m not sure if that answers your question, but….
Jeffrey Smith (54:34):
Oh no, it’s even better. I’ve been railing against reductionist thinking for a long time. In fact, I’m excited. Some day I’d like to visit you when the pandemic is over, or at least get on another Zoom call, and based on your understanding of the shortcomings of F zero toxicology and the potential impacts of manipulating DNA–which could change RNA and can change regulatory impacts of RNA on the same and few other species–what I’d love to do with you is to map out what a more ideal assessment for GMOs would be. So that unless it gets this, this and this, you’re putting future generations at risk. You’re ignoring…they don’t even do genomic, they don’t do any “omics” right now. They don’t look at anything when they create a GMO for food. They just say, Well, it seems to be creating the pesticide or resisting the herbicide,
Jeffrey Smith (55:35):
so we won’t even sequence the protein that we expected to be created…and then they found out later it wasn’t at all what they wanted. Anyway, I’m not going to rail against that. That’s just my area. Thanks, Doctor. I said when we started I said the last time we talked for 47 minutes–I don’t think it’s going to be that long. I just love talking to you. First of all, as a scientist you’re not only on the cutting edge of what you do, but you’re also brilliant at explaining it so everyone can understand. I feel that people like you, and you in particular can speed up the way that the generation takes before the paradigm shifts, because it’s not obscure. It’s not held off on the far reaches of geekdom, tied down by jargon. You’re explaining it in such a way that feels right, and you’re also creating, most importantly, practical steps which can save lives, which always speeds up implementation.
Dr. Michael Skinner (56:39):
That’s one of the problems with being a professor. You sort of basically have it because you’re communicating it to people that have to start it from scratch. That’s part of the professional hazard of being a professor, basically. But I appreciate the comment.
Jeffrey Smith (56:58):
Okay. Thank you so much. Anything else you want to add?
Dr. Michael Skinner (57:01):
No, I think that that covered it and I appreciate the interest in the study.
Jeffrey Smith (57:06):
All right. Thank you so much.