#254 | Oded Rechavi; What can be inherited from our environment, epigenetics and memories

Guest [00:00:00] That people are

Vance Crowe [00:00:00] Irrational,

Guest [00:00:02] Okay? When it comes to their decisions. And when you say someone is

Vance Crowe [00:00:06] Irrational,

Guest [00:00:07] You, it, it sounds vague, but for economists, it's a very defined thing. It means that you don't maximize the value of your decisions, and you, you are not consistent. Hi, this is Jack Kleek baseball player and second grader from St. Louis, Missouri, and you are listening to the Vance Grow Podcast.

Vance Crowe [00:00:25] Welcome back to the podcast. I'm glad you're here today. We talked to ODed Avi, and this is another wild conversation we're having with a scientist that is way up on the edge of the wave, trying to figure out things that nobody's even thought to do before. In particular, today we start talking about epigenetics. The concept of the environment you're living in, the stresses that you're under. Do those get passed down to future generations in a mechanism that is different than DNA? Now, you might be thinking to yourself, I don't know very much about inheritance or DNA or, you know, genomes or epigenetics or any of this stuff, but ODed is one of the great explainers in the world. You will find that his examples are vibrant and exciting and really quite clear. I found this conversation to be enthralling. And then after we get done with his initial kind of core research, we start talking about his work on the Dead Sea Scrolls and the memories of worms and all kinds of fun and interesting things. So stay tuned for that. If you're the type of person that likes conversations like this and you enjoy listening to the podcast, maybe you're doing chores, maybe you're washing dishes, maybe it's just kind of on while you're driving your car, you should know that there is a community of people that after these podcasts air, they get together online and they talk about the episodes and they talk about things going on in the world. And it's a place where we are trying to have really interesting conversations. So unlike social media where you get points for instituting rage, you get more attention if you can drive up people's emotions.

Vance Crowe [00:02:03] This is a small private community that you can join and meet other people that are enjoying listening to these types of interviews. And you can do that by going to network dot Articulate Ventures and sign up. You can sign up for one month at a time, or put go for a whole year. You will be astounded by the interesting characters in there, by the conversations that are happening, and just a different way of looking at the world with a community of people that you'd love to meet if you had the chance. So without further ado, we're gonna get to the interview, but if you're interested in the network, go to Network dot Articulate Ventures. All right, without further ado, now on to this amazing interview, ODed. Ve welcome to the podcast.

Guest [00:02:49] Hi. Thanks for having me.

Vance Crowe [00:02:51] I was watching your Ted Talk the other day, and you have the most auspicious beginning to your career that I've ever heard where you described the Unabomber had a direct impact on how you got into the work you're doing right now. So if we were to start off from there, how did the Unabomber impact the work you're doing now?

Guest [00:03:08] Yeah, so in this talk, I, I described this the history of the field of memory inheritance. And in the seventies and eighties, there was a very controversial scientist, James McConnell, who studied these flatworms they're called planaria, which are animals that are very good at regeneration. If you cut them in half, they regenerate a new head, the new tail, within a few days. And, and this is not controversial, this is, I mean, this has been shown a million times, but what he said is that he can teach these planar, these worms certain things and then chop off the heads and they have a developed a relatively advanced brain with lobes and everything. And he said that the new brain that will regrow will contain the memories that the previous brain that was cut off learned, and later even did more controversial experiment, more crazy experiments where he taught certain paria, certain worms things and then fed them to other cannibalistic plantar and said that the memories transfer via feeding and, and these, these experiments that this was a big controversy in the 30 years ago. But in addition, his research ended because he got a letter from the buer and exploded. I don't think he died luckily, but I think he and perhaps his assistant were injured. And and I, I don't study this in exact thing, same thing, but I also study memory transfer between generations.

Guest [00:04:47] So there's some link between us across the years. And this is, it is a, it's a very good story for, for showing, for demonstrating just how controversial this idea is.

Vance Crowe [00:05:00] Yeah, it's funny when you, when you pose it like that, you can enter it from a controversial standpoint, but we, if we were just to bring it up, hey, I believe that memories can be transferred from a parent to a child. It doesn't seem controversial on its face, but what makes that something that's difficult for people to wrap their minds around?

Guest [00:05:18] Right. So you're right. It's about how you phrase it. And I also think, so if you tell me if, for example, now we are talking, we both, we might, if this will be a great talk, we might have a memory of it. I don't think that my future kids or your future kids would remember it. I don't think, I don't believe that at all. So I don't believe it's nothing, you know, mystic or it's not some telecommunication like that something crazy. It's not that, that is, that's something that obviously doesn't happen. On the other hand, it's pretty obvious that you and your kids share certain capabilities, which are related to the fact that, that you share with each kid. Half of your DNA and some of our even advanced complicated cognitive traits are encoded in the DNA. That's perfectly fine and not controversial at all. The question is, and this is the controversial part, and again, it's it's subtle, is whether your life experiences, what happens to you during your life somehow also affects the, your genetic material, your, or more, to put it more accurately, your heritable material. 'cause it doesn't have to be in the sheets, for example, if you train in the gym, would this make your kids stronger as a result? The answer to that is no. And we know that intuitively, you know that if you go to the gym and you are, you have very big muscles and your kids, you know, the it, it won't affect them at all. They will be born with the capacity to train. They won't be affected, but what you experience during your life.

Guest [00:06:52] So the question is, are there some experiences, some things that happen to your life that can affect your heritable material? And this is a controversial question, and I think that perhaps there are some things that could do it and some things that can do it. We studied in a very simple organism and other one, but the different ones than the one that McConnell studied, that allows us to, to study it very, with very high resolution and, and with excellent experimental controls because it's a warm, where you can really separate nature from nurture.

Vance Crowe [00:07:26] And so, I mean, this is a field kind of commonly known, I believe, is epigenetics, right? Where it's like, can you pass down genetic traits in, in that weren't necessarily there for your parents because of, of what happened to you? For me, when I approached the world of epigenetics from the ag background, they really were very, very dismissive of this concept. Very much like, it doesn't seem like it's something we can trace, or if it does have an impact, it's so small as to be not as worthwhile as doing something larger like genetic engineering where you're changing out entire genes. What do you think? Is it something that that's overlooked or is the impact of the epigenetics just really, really tiny?

Guest [00:08:09] Yeah, so first of all, when it comes to the definition of epigenetics, it's already con controversial and it has been abused. So now you can read headlines about epigenetics, you know, epigenetic face cream and what whatnot. You know, everything is epigenetic And, and it has a very complicated history. So the term was the first use or first popularized in the fifties of, of the previous century. And, and the way I see epigenetics is, is that it, these are changes that pass either after through cell division or across generations by and, and changes that are not encoded in the DNA sequence, okay? But via some other mechanism. Okay, this is the definition that I like. Other people, when you talk about epi epigenetics, they talk about chemical modifications to the, to the DNA or to the histone, the proteins that wrap DNA and condense it. But I think that the right definition is this changes that transmit across cell division or across generations that are not in the DNA sequence. And then the question is, is it there, is it not there? And it's, and and, and there we, we, I have to admit, we don't really know. So in the, there are very weak studies, many weak studies that show that everything transmits transgenerational epigenetic. And you can find, if you search it on Google, you'll find whatever you want. But the convincing stuff, it's much more rare. And we're getting there. I think that the field has advanced a lot. Part of the reason that it's so controversials in that many people didn't believe it.

Guest [00:09:43] And in the late eighties or or nineties or the early 2000, that the concept was pretty much dead. The, the reason was that first of all, there there was, there were these controversial studies that didn't hold on well, refuted okay? But moreover, in the, in the Soviet Union there, there's been an exploitation of the idea by Senco, who was someone working for Stalin was the in charge of over biology. In, in, in the Soviet Union who did horrible damage by promoting epigenetics, saying that genetics is a bourgeois science that can't be studied. And whoever studied it was, was sent to CB or killed and implemented it in agriculture, causing huge damage in the starvation of millions because this was just s science and a horrible period. And then it cast a very dark shadow on the entire field. Then with the rise of genetics and the success of genetics culminating in the, in the genome sequence, people thought that we got it figured out, and we don't need this iner science anymore. And plus there were theoretical barriers, reasons to believe that it can't happen. And one of the main ones is that many of the chemical changes that happen on the DNA and also on the proteins that condense the DNA are erased or deleted in something that's called epigenetic reprogramming.

Guest [00:11:16] When a new newborn generation is, is made in the germ cells, and then in the early embryo, most of these chemical marks are removed in two waves of reprogramming that starts the next generation as a sort of a blank slate.

Vance Crowe [00:11:31] Let me, lemme see if I understand that. When you're saying the germ cells, these are different than, say the skin cells or your muscle cells. These are the cells that are transferring. If you have sex with your wife or your husband, this is your contribution to the DNA mix up, right? That's the ger cells,

Guest [00:11:49] Right? The germ cells are the sperm and the egg and the, and these are the only two cells that actually contribute genetic information to the next generation. The next generation will be formed from the combination of the two. So what happens to the cells, the other cells of the body, the bodies of the cells of the brain or the liver or whatever, it doesn't matter. All that matters for genetics is the DNA in the sperm and in the egg that will be combined to create the next generation. And the next generation there will be a fertilized egg that will divide and all the rest of the cells will be created from it. And the DNA and also the proteins that condense it, the DNA is wrapped around these proteins that condense it. 'cause we have a lot of DNA in every cell. The chemical changes, the modifications of that some people refer to as epigenetic modifications are largely erased in the embryo and in the germ cells so that the next generation will start as a blank slate. So that all information will come from the DNA. However, what we now know is that there, there's additional real epigenetic information that survived this reprogramming and this epigenetic information resides in RNA molecules. And I will now explain about this. So RNA, now everyone knows about RNA since the vaccines. Okay? And, but what, and what we normally hear about is the messenger, RNA, the messenger, RNA used also for the, you know, BioNTech vaccine.

Guest [00:13:21] This is the, the link between DNA and protein. The RNA, you, you, it's good that I'm explaining this.

Vance Crowe [00:13:30] Yeah, yeah. This is actually really good. 'cause I was gonna give a ham fisted explanation, but if you, if you give just

Guest [00:13:34] A slow walk, no. So if you wanna do it or I can do it, no,

Vance Crowe [00:13:37] By all means I'll let the expert.

Guest [00:13:38] Okay, sure, sure. So, so the, the what actually does the stuff, the actions in the cell are the potents, potents are like machines that do everything that the cell needs, okay? In every cell we have the DNA, which are the instructions to make all the different potents that we need in the cell. This is of course a simplification, but by and large this is correct. And we have in every cell of the art body the same DNA instructions, the same genome. So you can think of it, I think this is convenient. You can think of it like in every cell of the body, you have the IKEA catalog, okay? With instruction to make everything that you need in your house in different cell, in different rooms in your house, you need different things. You need in the kitchen, you need things of the kitchen. And in the living room you need sofas and so on. But in the DNA in this catalog, you have the instructions to make everything right in every room or in every cell. You just take a few pages of instructions for the furniture that you need. So in the eyes, you need instruction to make pots that are required in the eyes that actually will build cells of the eyes, and then also a tissue. And in the liver you need potents of the liver. So you just copy a few pages from the insta, from the big instruction booked, which is the genome, the DNA genome that contains all the information for the potents that you need to make in this particular cell at that particular time. And these instructions are the RNA, the RNA is the what do you need to make?

Guest [00:15:09] Now, this is messenger, RNA, it conveys the message from the DNA to the protein. But in addition, there are also additional types of RNAs. In fact, only a very small part of the genome, small percentage of the DNA genome in codes for messenger, RNA less than 2%, but very, but many additional parts of the genome of the DNA in code for other types of RNA, many of them are still mysterious. One of these types of RNAs are small RNAs. They're called small RNAs because they're short, short stretches of RNA And these RNAs, what they do is they regulate the function of messenger RNAs. So they control which, which messenger, RNA will actually lead to the production of proteins and which won't. And what we found, and also others are studying it, and many people have contribution contributions in this field, is that in these simple nematodes that are called C elegance, I will elaborate on this in a second, small RNAs, some small RNAs can transmit between generations. And when they transmit between generations, they also transfer some of the parents' reactions to the environment across multiple generations and the fact the physiology and the life of the next generations. Okay, now this is the, the general background. Now some more details, first of all about these, these ones.

Vance Crowe [00:16:34] Can I, can I just clarify?

Guest [00:16:35] Yeah, sure, sure.

Vance Crowe [00:16:36] So the, the, the interesting thing here is that you could have the, the parent, the DNA, you think you understand everything about it. But when the child is born, some things are going to react differently because of the environment that the parent was in, but not necessarily changes to the DNA. So you could have two identical parents put into different environments and what they pass on to their children, if, if we were able to make them be exact copies based on the environment they were raised in, or the things that happened to them along the way is going to impact the offspring, but not at the DNA level. That is that

Guest [00:17:12] Right? And, and okay, that, that's accurate. And, and even within the same generation you do have these natural experiments which are called twins. Twins have the exact same, same DNA, although, but there are, you see that there are some that they are different. They have subtle different differences in their appearance and also of course in their character and many other things. And this is the result of the effect of the environment. 'cause their DNA identical twins share, they have the exact same DNA sequence. So yes, you're right, there are additional information that is not in the DNA. And we also know, so in the tooth when the genome was, was fully sequenced, people were kind of disappointed to see that we complicated humans. And these simple nematodes that are now, they will be the star of the, the rest of the, the podcast that are called sea elegance, which are, you know, millimeter long. You can't see them with a naked eye. They're very small and they only have 959 cells. So die tiny, we have billions of cells. Nevertheless, while we have 20,500 genes, they have 19,000 and, and 500 genes. So, you know, almost exactly like us. Okay? And corn, for example, has twice as many genes as we do. Okay? So it's not only in the number of genes, it's how you use them and, and how you use your genome. And, and part of it is also epigenetic information. So information that is inherited now in, in these, these nematodes, what the, the reason why we succeeded in showing that there's some epigenetic information transmitted between generations.

Guest [00:18:45] And like you said before that that was very, very controversial, is that these nematodes are very, very good for the sake of this type of research. And the reason that they're so good it that, that you have a new generation every three days. So it's very easy to study multiple generations. Not only that, each mother produces hundreds of progeny, which are of progeny. So kids which are genetically almost identical to one another, but they can be different depending on what the mother experienced. And so these are the big advantages for, and in addition, we can really control their environment. So when it comes to us, our environment is so in, you know, incredibly complex with the nematodes. We grow them in a, in a Petri dish, and we feed them with bacteria and we control the temperature and we control everything. So we know what is the result of the environment and what is the result of inheritance. And what we found in these worms is that in addition to DNA and cl elgan, these nematodes are excellent models for studying regular genetics. They are one of the major models for studying biology and molecular biology. So it's, it's a huge success. People just since the year 2000 people got six noble prizes for studying CL elegance. So it's not some, you know, weird hobby of mine. Thousands of people around the world are studying these worms. But in addition, what we found is that when you, when you, when these worms experience certain challenges, they transmit to the next generations in parallel to the DNA via, via different mechanism, also smaller molecules which regulate gene activity in the next generations.

Guest [00:20:25] And these RNAs are transmitting through a different mechanism. So the mechanism, the way DNA is inherited, we know this for a very long time, it was discovered a long time before even people knew about DNA or chromosomes. Already the monk Mandel in the 19th century found the laws of genetics, the, the laws of, of inheritance, how traits are transmitting before, before we knew about the actual molecular mechanism. But the RNA has a different rules of inheritance, and it is transmitted by a dedicated machinery, which is completely different from the machinery that transmits DNA between generations. And it allows different things. The DNA-based inheritance doesn't allow. One of the main thing is things is that DNA, as we explained, you have in every cell of your body, the same DNA, the same genome, the entire genome is in every cell, and DA doesn't transfer between cells. We stand by saying that what happened to you, the DNA of your hand doesn't matter to the next generation. It's only the sperm and the air. Okay? So even if you, let's say you worked in the gym and you change, you would've changed somehow the DNA of your muscle. Not that I'm saying that it happens, it doesn't happen, but let's say it did, even if it were to happen, the DNA from your, your muscles wouldn't transfer to the cell to the, to the egg or the sperm. So it doesn't matter. However, RNA molecules, at least in c elegance transmit systemically. They move between different cells. And this is something that we know for a very long time, since the discovery of the mechanism of how these small nase work, which awarded the researchers who found its fire and mellow in worms, in these c gas with the noble prize in 2006, already in the, in the first paper that led to the Noble prize, they showed that these RNA molecule molecules in worms moved between somatic cells, the regular cells, to the germline, to the sperm and the egg.

Guest [00:22:22] Okay? And this is something extremely robust and not controversial at all. So the way we can do it, we can just feed ones with RNA and the RNA moves from the side of ingestion, from the gut to the rest of the body, regulating the genes all over the body and also in the next generation. Okay? So this is the reason that these RNAs have the capacity to transmit our experiences or bodily reactions to the next generation, at least in wars.

Vance Crowe [00:22:51] I mean, I'm struck by lately, we've had a few people on the podcast, Michael Levin to Lee Cronin, many others that have started talking about really how memory or being passed for memory is essentially an intelligence, right? It, it allows you to be able to do things. I don't, I don't even really know how to phrase it other than it seems like the, the acceptance that RNA can pass information on in a different mechanism in this way that you're describing kind of changes the nature of how you see a human or, or what it is that they're passing on as you're discovering these things, what some of them have been around for a long time and what you're seeing now, how has this impacted how you view life or, or the generations? There's not really a clear question there, but do you see where I'm getting at?

Guest [00:23:46] Yeah, I, I I, I think so. I think so. So this is a, again, this has a long history. So, you know, first of all, I have to a disclaimer, I totally believe in, you know, natural sec selection being that the main mechanism of evolution. I think this is the definitely the case, okay? There are numerous explanations, e examples and proofs. This is not up for debate. However, the question is, are there additional mechanisms and can, can your life has a meaning for the next generation? Biologically speaking, obviously, you know, you transmit to your kids a lot more than, than just your biology. And this is something that was actually speculated on by Elvin Redinger, you know, the fathers of the father of quantum physics in the forties, he wrote this book, which is extremely influential, was extremely influential. It's called What Is Life? And this is probably the most important book in the history of molecular biology because it drove many people to, to actually establish the field of molecular biology, including Rick and Watson and these people that from the double lytics, but other people as well. And in this book it says, unfortunately, in inheritance of acquired trait doesn't happen. It's real shame that it doesn't happen. We, we, we, it failed. And he said that this is a shame because unlike Darwinian evolution, which is passive, and he calls it gloomy, I'm directly, it is a direct quote because it doesn't matter what what you do in your life, the next generation will start as a blank slate, biologically speaking.

Guest [00:25:19] And he said, if, if some of the information could transmit to the next generation would give us hope and meaning to life. And even the book is called What Is Life? Okay? So I, I see what you're getting there. I think this is something to think about. By the way, Davin believed in the inheritance for acquired traits, okay? So it's even in the, the origin of the species. He has a whole mechanism describing how traits can transmit twin generations, acquire traits, can transmit twin generations. He has a, because he didn't know genetics at all, he wrote his own theory of genetics that's called pathogenesis, which says that every cell in the body gets to vote on the constitution of the next generation by transmitting this some, you know, thing that he called gamers or these vesicles that transmit information to the German. So he totally believed it. Then the followers thought that this can't happen, but so that his legacy changed. But he was even more Lamar and the Lamar, Lamar was a, a person that had a theory of evolution before Darvin that is famous for thinking about inheritance of acquired traits and the world, Lamar is a dirty world in biology. If you say to biology, they completely flip, okay? Because it's supposed to be something that doesn't happen. But I think that these studies in in worms, they're not controversial anymore. So when I started working on this in my postdoc in 2010, this was controversial, but now I think pretty much everyone believes or agrees that in these simple nematodes are a transmit between generations and allows all kinds of non mendelian, non DNA based inheritance to happen.

Guest [00:26:58] For example, if you starve the worms, it affect next generations. If you put them in high temperatures, it affect next generations. If you transfect them with infect them with viruses, it leads to changes in the next generation. And, and we know a lot about the mechanism, we know about proteins that shuttle the RNA between cells. We know about proteins that replicate the RNA within every generations amplified. So it won't be diluted. We know a lot about the mechanism, we know about the mechanism about the timer that times the duration of the how many generations the effect would last. And this is all very replicable and has been done by many, many people, by many, many researchers. So it's not controversial anymore. The, the big question now, there are many big questions, but one of the big question is, is it also conserving other organisms? And here, unfortunately we don't have answers yet, time will tell. I I can of course elaborate on that. But we, I have to say very explicitly that we don't know. Well,

Vance Crowe [00:27:53] It's an interesting thing because if you start wrapping your mind around that, you pass on things more than your DNA and your just your culture, right? So you have a child and you raise that child typically. So I, I have a very kind of unique experience. It's not super unique, but my wife and I had our daughter via IVF, and this is, this puts you in a different plane of, of thinking about what it is to have a child because it's a moment in time, right? I was 30 something when you, when you make your contribution and then those, it's combined with the egg and now you have, you know, the, these like a fertilized egg ready to go and you start thinking about, well that kind of only makes you, for a while there I really thought about, well, when you're a parent, you really are only contributing your DNA and that wasn't really your DNA, somebody gave that to you. So it's almost like you're taking a bucket, you're passing it to the next generation and you didn't have anything to do with it. And your contribution is the cultural part of it, right? Like, I'm gonna raise my child in the right way when they eventually come. But to hear this now you start thinking, wait a second, you know, is how fit was i, is it, you know, how, how well did I deal with stress? How, how, you know, all of these other factors, are those things being transmuted? And if they are, you know, it makes you feel far more responsible for what you are passing on to future generations,

Guest [00:29:23] Right? So first of all, I think we, when it comes to humans, we can relax because we don't know yet. So, so, so that, you know, take some of the, of the guilt away. But, but, but, but you're right that in theory it could happen. I think that IVF is a very good way to show that something hap transmits biologically. So for example, if you do experiments in, in mice, that's a very important control to know that what transmits is actually because of the biology of the, of the heritable material and not because of the way that the parents raise the kid. So for, for example, you would have one mouse undergo something and then take the sperm and transmit it or, or, and, and transmit it to another mouse, a surrogate mouse, to show that the effect really happened because of the biology, the not because of the interaction of the mouse. Let's say the, the mouse was, I don't know, ran on a treadmill. So you don't want it to raise the child differently because of it. Okay? So it's a very good control and, and important, but, but even when you transmit it via IVF, the epigenetic changes should also be there. Okay? Not just it. So, so, so I don't know if there will be a difference between IVF and regular thing. There could be that the IVF procedure maybe does something, but, but by now we have millions of cases, you know, millions of people did it to know that this works out okay.

Vance Crowe [00:30:48] Yeah. I guess my, my perspective would be the children that we have now. So my wife is pregnant, she'll have a, we'll have a second daughter in July. Those will have been impacted by the epigenetics if this works in humans, right? Of whoever I was when I was, let's say 35 when that happened. But now, 35 to 40 that contribute, like those epigenetic things are not there now, there's not necessarily a point to, to hang on, right? Like the, those five year difference. It's just that, it's an interesting thing to contemplate that whatever the impact of the epigenetics for my future children all came from 30 5-year-old Vance as opposed to 40-year-old Vance.

Guest [00:31:34] That, that that is very true. That is true. And, and, and so changes that come with age, they are observed also when it comes to genetic inheritance. And there are all kinds of correlations between, for example, when, especially women when they are older, there's higher changes of problems with the DNA. But, but, and that could be also true for the epigenetic material, that it also changes with age. That won't surprise me. But in, in addition the, but the RNA or the, the epigenetic material should be more plastic and responsive to the environment. Again, if it exists in humans, then perhaps we will. So now for example, whenever many kid, many couples go to to have a baby, they do genetic testing, but at the moment, so in Israel it's pretty much everyone. But so, but in other countries it differs. But, and now you, you mostly look at the DNA, I mean you only look at the DNA, but what if you should also look at the RNA and this would reflect, you know, and then people will say, you know, the ideal point to have a baby is after, I don't know, you ate a tuna and I don't know, watch the Netflix photo. I dunno, Seinfeld, I don't know. I have no idea. But of course there will be, there could be perhaps if it happens in Newman again, all these disclaimers correlation with what you did. And this is very, that could be extremely important. I just wanna say that we, we don't know if it happens in humans because one, it's very difficult to study and it's only in the beginning, as I said, in wars, you can, you can examine many generations and many, you know, identical kids, very easily in humans though many problems to doing that.

Guest [00:33:18] And in addition, there is some to theoretical reason to believe that this mechanism would be more prominent or more important in worms than it would be in humans. But this is only theoretically doesn't have to be the case. What am I talking about? So the likelihood that the environment of the parents would resemble the environments of the progeny in nematodes, it's much higher than in humans because the generation time until you have the next generation is just three days. So the chances and they don't go very far. So the chances is that the environment would, would be the same is high. So it is worth it to prepare your kids for the same environment that you experienced with my kids. I dunno, perhaps they will live in a completely different country in a totally different world 20 years from now. So perhaps it is less, it makes less sense to prepare them for my environment

Vance Crowe [00:34:14] And that they might not have been selected for having RNA, you know, being changing the epigenetics. You know, it struck, I'm struck by one time I was out in California visiting a test plot for jalapeno peppers. And what they were showing with jalapenos is when they first started putting pivot irrigation in there, it was really easy to irrigate your jalapenos. All of a sudden, nationwide, the, the temperature, the spiciness of those jalapenos started going down really rapidly and they figured out, oh, it's because the capsaicin, the oil that makes jalapenos spicy actually goes up when the plant is stressed. So then they were going out there and like ripping and tearing the, the, the jalapenos. And it turns out that several generations later would be impacted by increased levels of capsaicin. If you were stressing this, the, the, you know, the original plants, is this kind of like what you're talking about?

Guest [00:35:14] It, it's, it's, it's still di difficult to disentangle the genetics from the epigenetics. 'cause there could have been selection at the DNA level for the more or less spicy papers, but there could also be epigenetic effects there in when in plants we know of epigenetic effects that are very robust. So that that's something that happens there. But we don't know about the, the situation in humans, and this will be something to, to study in. But, but in, in, in, in plants there are certainly epigenetic effects that are very, very strong, that have been known for years changes that transmit because of epigenetic information, not information in the DNA. However, it's less clear in, in plants with how the environment affected. That is something that we know much more in warmth than in plants. In plants it's still controversial. But for, but for example, in Malaysia there are these big, big forests where they plant palm oils. Okay? And these palm oils, it's, and growing palm oils is a big part of, of the, of the economy in Malaysia. And you, so you plant this, these trees and only few years later, I think it's something like seven years, you have the actual tree and you can make pine pine oil. However, only after seven years later, after you planted it, you discover whether the tree is good or not. And there's a gene that affected, it's called bed karma.

Guest [00:36:47] Okay? But what they found is that, and it is a nature paper from I think 2016, so one of the best Jons what they found that this is the work of Rob Malsin from Cold Spring Harbor is that the, the, the information of whether the the tree would be good or not. It's not in the DNA, it's epigenetically transmitted across generations. There are RNAs involved and also DNA methylation transmitted. But the, the cause if I remember correctly, is actually a small RNA that starts it on. And then only later on, seven years later, you find out whether you have to burn the entire forest at huge, huge losses and also damage to the environment or not. And now they can actually look at the epigenetic information and say in advance whether they should plant this seed or not. So that's a very striking, a striking example.

Vance Crowe [00:37:38] So let's imagine, you know, hit the fast forward button. What are the advances or what are the, the tests that you would run to be able to discover whether this, this thing that you're seeing in worms and in palm oil can be converted into mammals and then, you know, presumably humans as well.

Guest [00:37:56] So the, the, the thing is that it's very, very difficult. It's very difficult. Difficult because, so people are doing the experiments and there are some experiments that look more and more convincing. For example, now people use IVF to control for the environmental effects or, or the, the, the cultural transmission. But, but it's not, if it's not very easy because even when it comes to genetics and complex traits, we now know that the, the individual contribution of each gene to complex trait is very small. There are some traits that are, you know, encoded by, that are governed by, that are Mendelian traits where, you know, a single gene controls the entire effect of the, of the, the entire, the, the entire effect. But when it comes to complicated traits, like let's say your height, this is affected by thousands of genes. And to uncover these genes and to, to, to get good results, statistically significant results, you have to look, and I'm talking about regular genetics now, DNA at many thousands of individuals. It only works these big genome-wide association studies. When you look at many thousands of people, no one did such an experiment when it comes to epigenetics. And I'm not even sure we know how to design the experiment because they will also have to control for their environment. It's not enough just to con collect, you know, the, the, the, the sperm or something you need to, to, to do the right comparisons. So it's really difficult and we can't have people undergo sentence stresses in a very confined way, co controlled way and look at the, the fact.

Guest [00:39:32] So we need to start with the molecular biology to see whether the mechanisms actually exist at the cellular level. And then to, to go from there to to, to extrapolate on the changes that this would happen, actually happened at the organismal level in worms. We can do these experiments in mice. No one did large studies, you know, about thousands of mice with the right statistics and you know, people don't do this. It's extremely difficult and expensive. And so, so I, I think we'll get there, but it's difficult. I'm happy studying worms now because we are getting at the mechanisms. And I, I have to say also another something at the to, to, to say, to explain how great warms are. And this is actually also collected to collected, connected to agriculture. It is important to remember, so when people say you study warms how relevant it is to the world, it's important to remember that four out of five animals on this planet is a worm. Okay? So we are the exception, okay? And worms are so abundant that if we took out worms that just the entire warm world would just crumble and fall apart. 'cause they are everywhere and they affect every process just in the soil. They affect the, the, the composition of the soil, the microorganisms that they eat, the, the, the, the fertility of the soil exchanges of gases with the atmosphere, everything. And there are many, many also types of worms. And I think that that the chances that, that we found just in this one particular worm that is one of the five, you know, maybe five model organisms of biology, that it happens just in this seal.

Guest [00:41:10] I think it's, it's relatively rare, probably it exists in other organisms just by chance. I mean the chance is that we land on it just in this organisms is small. So I think that the relevance to understanding the world is high anyway. Of course, I'm hoping that it will be conserved in other organisms. I would also say that this is, you know, pure speculation that I think it's too good of a trick to give up on. So I, I imagine that you perhaps not the exact same mechanism, but some other mechanisms might exist because it just makes sense. People thought that it's impossible because it doesn't fit the regular mechanisms of genetics the way DNA NA is inherited across generation. It doesn't fit DNA based inheritance. So people thought it's too completely impossible. But I think that when you consider other mechanisms, they are there and maybe they can allow it to happen also in other,

Vance Crowe [00:42:02] You know, if you think about some people are motivated just to answer a question, right? I, i just wanna know. But then there's some, something about like, once you know that once you know the answer to whatever that question was, there's kind of a, so then what, how would you describe your motivation here? Do you have a, so then what if, if you answer these questions?

Guest [00:42:26] Yeah, totally. So it, it, it's, it's a, it's a midlife crisis for me. You know, you're right. It was something that shouldn't have happened and now it happens in a, a major way in some organisms at least. So it's not impossible. And then the question is what, what are what next? What are the big questions yet? So for example, one of the big questions for me is can epigenetic information affect the process of evolution? Evolution is normally thought of as something that happens over a long period of time. A very slow process that takes many, many, many generations. And most of the epigenetic information that transmits a code generation is transient. It goes away after a fluid generation. So can it nevertheless affect the process of evolution? And this is one of the big questions that we're studying. And I think it can, I think there are ways by that it can, and also I'm thinking about what are, what can happen and what can happen? What type of characters can you influence with epigenetics and what can't be influenced, what type of information can transmit it one, what can't, for example, is it enough for the worms to just think about something without the environment changing for this to affect the next generation? I mean, at the end, when you think about something, it also affects your physiology, it affects your stress levels. So, so thoughts have a con have biological consequences. And it's nothing mystical. It is just the fact that that, you know, our bodies are connected to our, to our, to our brains and, and, and many bodily reactions are controlled by our bi, you know, cognitive processes.

Guest [00:44:04] So we are now trying to just manipulate the thought process of the worms to see whether this would have an impact. But in worms we can do it in a very precise and powerful way. 'cause the worm just has 302 neurons, that's it. And we know each neuro by its name and we know with which other neurons it is connected. And we can activate the warms neurons using light, and we can, we can using light, make the warm move like a, you know, a remote control car, you shine, one light goes forward, you, you shine another light, another wavelength that goes backward, you can shine a light and it'll lay an egg. So we can, you know, activate its brain with this is called optogenetics and see whether this leads to effect in the next generations. By the way, the warm is transparent, so you can actually see the warm, the neurons fire, you can see them in action. So it's a, it's a, it's a very, very powerful model organism also for studying neuroscience.

Vance Crowe [00:45:05] So you've won some awards for your work, you're relatively new, you know, you just said it was about 10 years ago that you did your postdoc. What is it that you are getting awards for? Why is it that people are recognizing what you're doing?

Guest [00:45:19] So I think that what we're saying is new, that's one thing. And, and, and it changes the way we think about certain things. It's not more of the same. So this is something that I get recognition for. And in addition, in my lab, we do many other things. We, we study a very wide range of topics. So people who appreciate interdisciplinary science, they also sometimes like that. So we studied the genetics of the Deady scores. We studied brain parasites, we studied the economic decision making, rational decision making, all kinds of things that are very different. The core is still epigenetic inheritance, but we also are interested in many additional things in the lab.

Vance Crowe [00:46:08] Let's hear about these dead sea scrolls.

Guest [00:46:11] Sure. So this is probably the weirdest study that I did, but perhaps also the most fun. And it, it starts with a, with an interesting, so you, you might ask yourself, how did I end up studying the dead scores? I will tell about the, I will explain about the dead scores in a second. But what happened was that when I just joined the university as a new faculty, that was in 2012, there was a retreat for new faculty. And in my university, I'm in Tel Aviv University there researchers a study every field. And there was a retreat for everyone that's new. And on the bus, on the way to dinner, I sat for, it was a 20 minutes drive, not long. I sat next to a, a person, his name is no Rhi, who was then a, a new researcher studying the debt school. He's a biblical scholar really far from what I specialize in.

Vance Crowe [00:47:04] And what are the Dead Sea Scrolls? I mean, I have a vague recollection from seventh grade sociology.

Guest [00:47:09] Sure, sure. So the Dead Sea scrolls are probably the most important histo archeological finding found in Israel. And in Israel we have many historical findings and one of the most important historical findings of the 20th century. They were found in the forties and fifties, these parchments that contain, that were written about 2000 years old, 2000 years ago. So 150 years before and after, within this range of the year zero. And they are the oldest, they contain the oldest Bible. The next one is 800 years older. And they also contain the, the, the writings of people who lived in this area at that time, which was a crucial time for Christianity. Jesus was there. And also for, for, for the, for for Judaism. Okay. So it's a very, very important time at Western history. And these squads were found in the desert in caves by a shepherd that lost one of these, of his animals, his cows or his goats or ships. And one of them got into this cave, so he had to, to, he wanted to call it back. So he flew stones into the cave and he heard vessels breaking. He got into the, the cave and found these, these vessels filled with, with scrolls. And, and then people over the years, over 70, for, for the last 70 or 80 years, they looked at this skull, many of them are degraded, but they found more than 25,000 pieces of skull that they tried to assemble to assemble the text and learn about the history of the period.

Guest [00:48:59] And Noam, who was sitting next to me on this bus, is an expert, expert on the, on the dead skull from the biblical side and pa the pornography though. So understanding the, the text and, and we started talking between us. And this sounds like a very, very difficult different topic of what Einstein, but he explained about the dead skull. I didn't know much about it as well. And I told him about worms and he told me, you know, there are some holes also of worms in the parchments. And actually people in the past tried to look at the patterns of the holes of the worms and see, no, maybe if a worm called here and exited there, maybe this mean that these two parchments pieces fit together because, you know, they share the wo so, so, so, so, so we said, you know, perhaps there are additional biological information that can help us piece together pieces of skull. And of course the obvious thing is DNA and these parchments are written, are made out of a skin of animals, goats and ships and cows and other animals. Okay? So we thought perhaps we can use this information to piece together different pieces. As I told you, there are 25,000 fragments and, but, and people assembled most of them one by one by, you know, putting them on big tables and trying to connect the pieces. But there are many cases where the interpretations are still debated and it's not clear, perhaps this fragment should go with this piece or that piece.

Guest [00:50:31] So what we did to, to answer this is we extracted engine DNA from these 2000 year old fragments, and we sequenced the DNA from each piece, and then we said, this piece should go with that piece and not with that piece because they come from the same particular ship. No, and this piece come from a different ship. Okay. So it's just like what the, you know, CSI do, you know, in the, in the crime scene, right? And so we pieced together and pieced apart different fragments of skull. And this told us new things about the history of particular writings and also about the history of the collection as a whole. And it was a very, very big challenge because first of all, when you look at the pictures of the people assembling the skull, you see in the fifties that they didn't wear gloves. Sometimes they were, you know, smoking while they were pissing them. And, and so, so when you sequence the DNA, you found find a lot of human DNA and other contaminations. So you have to get rid of that. So all the sequencing and all the extractions of the DNA NA is done in clean rooms, in astronaut suits and everything. But in addition, so, and there are many, the DNA itself is very fragmented in many cases, and some pieces are lost also. And plus the materials are precious. We can't just take a piece and grind it. This is all kept in a museum, you know, and each piece cost a million dollars or something. People actually buy them, you know, whoever can get his hand on something that's not in a museum.

Guest [00:52:03] So, so, so, so we can't just grind them. So what we, we can't touch them. So what we do is, first of all, we had to prove the people in the research and ticket the authorities that we can do this. So we, when, when in the fifties, when they found two pieces that they look like they should be joined together, this is something, it wasn't, they shouldn't have done it, but this is what they did. They glued them together with that. Anyway, they also did worse things. So they also glued them to with with hot glue, to purse to no to, and then it's dead. And then it's dead. But when they them with the, with duct tape, they glue them with duct tape. And then for the last 20 years or so, they have been removing the duct tape one by one, you know, and when they remove the duct tape, they keep it next to, they know which duct tape was removed from which piece. So as a pilot, we first sequence from the duct tape, and then we need, need did another pilot to show that what we sequenced from the pilot, from the, from the, from the duct tape actually matches the DNA of the piece from which it was removed, from where it was removed. And then after approving all of that, we moved to real samples. And we, and we, and when it comes to the real samples, we didn't take samples and, you know, grind them. We can't do this. The people that work in the museum and the research antiquity, they just scrape off a little bit of skull dust from the un inscribed side of each piece. And this is what we secret No, so it is, is tiny amounts. So we had to really improve the mat, the, the methods, and we worked on it for close to seven, seven or eight years of this project.

Guest [00:53:40] So also a big collaboration with many people. And then, but in the end we, we were able to do it and we were able to, to join some pieces and also to show that some pieces that were thought to go together shouldn't go together. Yeah.

Vance Crowe [00:53:54] So that must have been a somewhat surreal experience to be able to take something that is, you know, as important or as, as deep to people's culture as the Dead Sea Scrolls and say, ah, we think they're put together differently. How, what was the experience of doing this day in and day out like?

Guest [00:54:14] You are, you're right. It was surreal, surreal. It was really fun because the people that you interact with are not a normal scientist that I'm used to interact with. For example, Noam Noam Ishi, my partner of, in this collaboration, his scholarship is just amazing. You know, this is something that we biologists relatively, you know, simple. He knows, you know, 12 languages and, and just every piece, you know exactly what is written in every version. So I would never, you know, dare to question an interpretation of the text without his guidance. So we do the biology, but the interpretations we leave to the experts and, and we learn so much. And we were open to a completely new world also of a way of thinking, this is really, really impressive. The thing that they know. And it's fun to interact with them.

Vance Crowe [00:55:03] So, you know, you think about the imagination that you'd had to have, had to have come up with things like, let's take the tape and, and scrape that, and we'll use that as proof. Where do your ideas come from to be able to, to think of like, I mean, part of it's contextual, you know, the tape's there, but a whole nother part of it is even thinking to do that.

Guest [00:55:25] I think that the, you, you don't know where information inspiration come from. There's a, you know, a famous Leonard quote, coin quote that says, if I knew where inspiration come from, I would go there more often. So you don't know. But, but I think many times it's from interactions with very different people. If you meet the same, you know, specialist over and over, then you are caught in the loop. But it's, it's meeting with other people that have different way of looking at things. So Norm is the perfect example. Another example, we had a, a, a project on economic nationality that started for studying economic decision making in nematode in war. That sounds real. I can tell you about if you want.

Vance Crowe [00:56:07] Yeah,

Guest [00:56:08] Go on. Yeah,

Vance Crowe [00:56:08] Of course.

Guest [00:56:09] This is, and this again, started with a collab with, with just by a nice conversation with an economist, another economist. So I'll tell you about this. So people got a Nobel Prize. Again, these, these are Israelis that is kaki for showing something that now is kind of obvious that people are irrational, okay? When it comes to their decisions. And when you say someone is irrational, you, it, it sounds vague, but for economists it's a very defined thing. It means that you don't maximize the value of your decisions and you're, you are not consistent. One example, for example, is that if I tell you, you have, you have, what do you prefer? This orange. Orange or a pale, you say, I like oranges better. Okay? And then I say, okay, but there's also a third option, an apple. You say, huh? Now I actually prefer the p over the orange. Why would you, I mean, if you prefer orange over apples, why? Why does it matter if there's an apple or not? But these things have been shown in humans and in bees and in birds and in many other organizations is one type of irrationality, economic irrationality.

Vance Crowe [00:57:23] Yeah. My favorite one is the, is the, if you invite somebody over to move your furniture, right? And like, are you, you wanna like move outta your house and people come over, you say, oh, I'll buy you beer and, and pizza and we'll do this together. And they're all happy with that. But then you get all the way done moving and you're like, you know what guys? I didn't have enough time to buy beer and pizza. So here's the $7 that I was gonna spend on each of you that collectively would've equaled this thing. People would be outraged, right? You would just, you would lose your mind to be like, what? Because you've now put a time cost on their time as opposed to the, the familial relationship that you would've had the these kinds of ideas. Right?

Guest [00:58:02] Right. This, this is one example, for example also of, of cognitive dissonance where, I mean, in hindsight, these people will have to extend themselves, why did I move the couch? Did I move it for $7 or to or for the fun of it and the experience? And so, so yeah, but there are many, many example. It's very, very interesting. But, and this is used practically, for example, the example that I gave in, in menus of restaurants where they put something very expensive, you know, to throw you off. However, when it comes to the explanation to understanding why is this happening, how is this happening in the brain? Then it be becomes vague. And, and the, the explanations come from the realm of psychology. Maybe it's cognitive load, maybe it's regret. But what are these words as biologists, we want to understand how it actually, you know, happens in the neurons. So this is why we did it in worms because as I told you, these nematodes have a very, very simple nervous system. We have billions of neurons we know, and the connectivity is changing all the time and we don't, we can't trace it. These worms connectivity is fixed, hard wired. And we know each neuron with which other neurons it top with. And there are only 302 neurons. So we did this exact same test like with the orange and apple and worms choose between two different ants od that they like worms smell, they're very good at smelling things. That's the most important thing for them. They have to find food. So we let the worms choose between order A and other B.

Guest [00:59:35] Okay? And we first established that od A is preferable over order B. So this is just the orange and the pill. And then we say, what happens when we add the third option C? Does it change the preference of A over B? Okay. And what we found is that most of the time it doesn't change, but we find also situations where it does change. And this is where we are going to really high resolution to understand how it happens. So what we can do, and this is impossible in humans, is that we know that other A is sensed by one neuron that has a name, it's called A WC on other B is sensed by another order that called a WC off and other C we can play with it, we can decide. So for, and what we found it is, is that if auto C is sensed by the two sensor anos that sense auto A and other B at the same level, then other C doesn't confuse the one, it would still prefer A over B. But if OC is sensed more by the no that senses auto, auto A, it take more resources from the sensation of auto A, then there are relatively more resources now available to sensing order B. And then it becomes preferable o over auto A. So it's like a short circuit. It's very, very simple. It can be explained by a limited bandwidth of computational in the brain and the power of c elegance. And again, this is something that's extremely difficult or impossible to do in other organisms that we can then genetically change the worm to give more, to allocate more resources to auto A and it's, this fixes the rationality, they become rational again.

Guest [01:01:18] They don't get confused and we can give less resources and then they become more irrational. Okay? So we can really understand how rationality or rationality, how it happens in the brain, and then we can also model it and see whether it fits. Well we know about certain decisions in, in, in humans. And what we found that is that the same mathematical model for how neuro ones work, that explains why we see some visual illusions in humans explain why we make bad decisions. So this is like decision, decision making illusions, you know, but it's the same computational limitation. And the, the reason that the worms behave irrationally is not because of, you know, regret or emotions. It is because there are limits for how it's no's fire. Whether it's the same case in humans, we don't know. But I think it is.

Vance Crowe [01:02:10] I think it's, I I mean I, I've been biting my tongue this whole time. So my wife and I, we have a daughter that is absolutely a wonderful eater. She'll eat fish, she'll eat vegetables, she'll eat anything. But my wife, when she's feeding her gets excited and says, oh, look how good she's eating. And she adds, we usually have two options for her. She'll add a third one in and you watch my baby just explode. Like now all of a sudden, like this pattern of eating well just completely breaks down. And no matter how many times I've told my wife like, Hey, really just keep her down to two options, she'll do a lot better. Because I've seen this happen so many times that it became intuitive. I, I don't know that I could have articulated in the way you're saying, but it is that there's some mechanism going on in Violet's brain about what she wants that gets distorted when she has more options.

Guest [01:02:59] Yeah. So I I I think that no, you have to, you go, you have to go to the simplest thing to understand it, you know? And this, it's weird that people don't understand it when it comes to biology because it's obvious. For example, when it come to physics, if you wanna understand, you know, how atoms work, you study hydrogen, not some much more complicated atom, right? So I think it, it's the same also with, with animals. You have to start with the simplest to understand the more complicated ones.

Vance Crowe [01:03:30] So on this podcast, I often ask people, it's kind of a difficult question, so I don't ask everybody, but I ask one of my favorite questions, which is, I call it the Peter Teal paradox, which is, what is one thing that you believe is true that almost no one agrees with you on?

Guest [01:03:49] So I have an an funny answer. Funny answer. So I think that it's funny, I don't even wanna say it, but, but I think that Gaelic is not healthy.

Vance Crowe [01:04:02] Okay?

Guest [01:04:03] That's my thing.

Vance Crowe [01:04:03] You just, by the way, you have offended all of the Midwest of the United States

Guest [01:04:07] 'cause

Vance Crowe [01:04:07] This is primary ingredient. Yeah.

Guest [01:04:10] So I apologize. I think it could be ta it's tasty, but I, I, but, you know, but it's, it's, it's based on nothing. I said it half as a joke, I just said it, worms feel it and they escape it.

Vance Crowe [01:04:22] Oh, that's super

Guest [01:04:23] Interesting. Yeah. So, so maybe it would be, it's, it's good when you are, when you are, you know, you, you're living in a contaminated environment if you want to keep your food, that, that's different thing. But I think in, when, when the food is clean, then I think it's very, very reactive, but it's nonsense. Okay. So please take it like that. It just,

Vance Crowe [01:04:42] Well, I mean, you could, you could add logic to it. So I run a book club and we read Dracula and I, I don't, I don't know if you've read that, but I have read

Guest [01:04:49] It. I that a long time ago. Yeah.

Vance Crowe [01:04:51] And I did not realize like it's, it's got some sexual innuendo in there that you don't really understand. And the garlic, you can, you could throw in as the function of like really breaking down romance and passion because the, you know, Dracula doesn't wanna be sucking the blood of a woman with garlic all around her neck. So there's gotta be some parallel there. And then finally, I guess the, the, the last question I would have for you,

Guest [01:05:15] It's a joke. I don't wanna offend any

Vance Crowe [01:05:17] Anyone's

Guest [01:05:18] Growing garlic.

Vance Crowe [01:05:19] That's all right. Let the audience be offended by this. They, they

Guest [01:05:21] Can

Vance Crowe [01:05:22] Handle it. So one of my favorite questions to ask people that are doing really innovative science is what science fiction were you reading as a kid?

Guest [01:05:31] Yeah, so I have to say, I didn't read much science fiction. I read a lot. I read a lot. But science fiction is not my preferred genre. But I did read some things that did influence me. One book that I really like is City. Yeah, it, I don't know if you know this book, it's a book from the fifties. It's an basic book. What is the name of the author? Clifford Sac. It's a, it's a science and, and it's, it's a book where there's fast evolution and hence eventually take over the world. But it's all, it sounds weird when I explain it like, but it's a classic of science fiction. It's, it's, it is described from the perspective of dogs in the future where after humans gone extinct, there are these talking dogs that tell the stories of whether there were once humans on the planet. It's an amazing book, highly recommended, beautifully written. So I really like this one, this particular one.

Vance Crowe [01:06:33] Well, I will, I'll throw that in the show notes. I,

Guest [01:06:35] We found some, yeah.

Vance Crowe [01:06:36] We've found some fantastic books this way, man. I, I did, I had no idea how this conversation would go. I was very interested in your writing, but I can say you are now a friend of the podcast and I would love to have you back on. Thank you so much for coming, man.

Guest [01:06:51] Thank you. Totally. My pleasure. I really enjoyed the conversation. Thank you very much.