Genes & the Inheritance of Memories Across Generations | Dr. Oded Rechavi

welcome to the huberman Lab podcast where we discuss science and science-based tools for everyday [Music] life I'm Andrew huberman and I'm a professor of neurobiology and Opthalmology at Stanford school of medicine today my guest is Dr ODed Ravi Dr ODed Ravi is a professor of neurobiology at Tel Aviv University in Israel his laboratory studies genetic inheritance now everybody is familiar with genetic inheritance as the idea that we inherit genes from our parents and indeed that is true many people are also probably now aware of the so-called epig genome that is ways in which our environment and experiences can change our genome and therefore the genes that we inherit or pass on to our children what is less known however and what is discussed today is the evidence that we can actually pass on traits that relate to our experiences that's right there is evidence in worms in flies in mice and indeed in human beings that memories can indeed be passed from one generation to the next and that turns out to be just the tip of the iceberg in terms of how our parents experiences and our experiences can be passed on from one generation to the next both in terms of modifying the biological circuits of the brain and body and the psychological consequences of those biological changes during today's episode Dr rahavi gives us a beautiful description of how genetics work so even if you don't have a background in biology or science by the end of today's episode you will understand the core elements of genetics and the genetic passage of traits from one generation to the next in addition he makes it clear how certain experiences can indeed modify our genes such that they are passed from our parents to us and even transgenerationally across multi-generations that is one generation could experience something and their grandchildren would still have genetic modifications that reflect those prior experiences of their grandparents Dr Ravi takes us on an incredible journey explaining how our genes and different patterns of inheritance shape our experience of life and who we are before we begin I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford it is however part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme I'd like to thank the sponsors of today's podcast our first sponsor is Roka Roa makes eyeglasses and sunglasses that are of the absolute highest quality the company was founded by two All-American swimmers from Stanford and everything about Roa eyeglasses and sunglasses were designed with performance in mind I've spent a lifetime working on the biology the visual system and I can tell you that your visual system has to contend with an enormous number of challenges in order for you to be able to see clearly under any conditions Roa understands this and has designed their eyeglasses and sunglasses 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in this positive stance around science that it also includes humor but today what I mainly want to talk about is the incredible questions that you probe in your lab which are highly unusual incredibly significant for each and all of our lives and very controversial and at times even um a little bit dangerous or morbid uh so this is going to be a fun one for me and for the audience just to start off very basically get everyone up to speed um because people have different backgrounds I think most people have a general understanding of what genes are what RNA is and so on but maybe you could um explain to people in very basic terms and I'll just preface all this by saying that I think most people understand that if they have two blue-eyed parents that there's a higher probability that they they their offspring will have blue eyes than brown eyes M similarly if to browneye parents higher probability that they will have brown eyes rather than blue eyes and so on but that most people generally understand and accept that if they spend part of their life um let's say studying architecture that if they have children that there's no real genetic reason we assume that their children would somehow be better at architecture because they contain the knowledge through the DNA of their parents they might be exposed to it in the home so-called nature nurture said nurture in that case but that they wouldn't inherit knowledge or other traits and today I'm hoping you can explain to us why eye color but not knowledge is thought to be inherited and the huge landscape of interesting questions that this opens up including some evidence that contrary to what we might think uh certain types of knowledge at the level of cells and systems can be inherited so that was a very long-winded opening but to frame things up what is DNA what is RNA and how does inheritance really work okay so DNA are the is is the material the genetic instructions that is containing every one of our cells we have the set of genes containing the entire set is called The genome and this is present in every cell of our body the same set of instructions and genes are made of DNA and and they all they also contain um and chromosomes they are containing chromosomes chromosomes is the DNA and the proteins that condense the DNA because we have a huge amount of DNA in every cell that you need to condense it to sort of like um thread on a on a spool right huge amount that you have to condense and we have the same genome the same DNA in every cell in our body can I just interrupt and I'll do that periodically just to make sure that um people are being carried along I sometimes find that even remarkable that a skin cell and a brain cell a neuron for instance very different functions but they all contain the full menu of jeans and the same menu of jeans no it is amazing it is amazing and perhaps it's good to have an analogy to to understand how it works so this is I hope this is not a commercial but this is like the Ika book that you have in every cell in your body the instructions to make everything that you need in your house the chairs the the the kitchen the the pictures but in every in but in every room you want something else so in the kitchen you want things that fit the kitchen and in the toilet you want things that fit the toilet so you only um remove one particular page of instructions which is the instruction of how to build a chair H and this you place in the in the in the living room okay and the toilet you put in the toilet so the DNA is the instruction to make the The genome the is the instruction to make everything this is the Ika book and in every sale we we take just the instructions for make one particular furniture and this is the RNA this is the RNA this is the set and then the end you you'll build a chair the chair is the protein so the DNA the RNA is are instructions to make one particular protein based on the entire set of possibilities and and this is uh this is true for one particular type of RNA which won't be the star of of this conversation which is messenger RNA this is the RNA that contains the information for making proteins and in fact this is just a small percent of our of the RNA in the cell so we have a very big genome and less than 2% of which encodes for this messenger RNA however a lot of the the the genome is transcribed to make RNA that does other things some of these rnas we understand and many of them we don't think it's a beautiful description and Ikea is not a sponsor of the podcast so um it's totally fair game to to use the Ikea catalog as as the analogy for DNA The Specific Instructions for specific pieces of furniture is the RNA and the furniture pieces being the proteins that are that are essentially made from RNA using messenger RNA right okay thank you for that so despite the fact that the same genes are contained in all the cells of the body there is a difference between certain cell types right I would is it fair to say that there is basically one very important exception which is somatic cells versus germ cells and would you mind sharing with us what that distinction is sure so so yes every cell every cell type is different because it expresses it brings into action different genes from the entire collection and assumes an identity and uh so we have uh we have cells in the legs we have cells in the brain we have in the in the brain we have cells that produce dopamine cells that produce serotonine and so one and we can make uh different separations different uh distinctions but we can make one very important distinction between the somatic cells and the germ cells The Germ cells are supposed to be the only cells that contribute to the Next Generation that out of which the next generation will be made so each of us is made just from a a combination of a sperm and and egg these are two types of germ cells and then they fuse and you make you you you get one fertilized egg and out of this one cell all the rest of the body will develop and what happens in the Soma which is which are all the cells that are not the The Germ cells should stay in the S should not be able to contribute to the Next Generation this is very important and it s to be one of the main barriers for the inheritance of acquired traits the inheritance of memory and so on because for example like the example that you gave in with learning architecture if I learn about architecture the information is encoded in my brain and since my brain cells can't transfer information to the sper and the Egg because the information is supposed to reside in synaptic connections between different neurons in particular circuits that developed H so what's what what happens the brain shouldn't be able to transfer to the Next Generation even simpler a simpler example if you go to the gym and you build up muscles you know that your kids will will will have to work out on their own it won't that this short out won't won't happen this is something that we know intuitively um even if we don't have any background in biology and this is connected to the fact that as we said at the beginning every cell in the body has its own genome and the next generation will only form from the combination of the genomes in the sperm and the Egg even if you somehow acquir the mutation or a change in your DNA in one of particular brain cell it wouldn't matter because this mutation there's no way to transfer it to the DNA of the of the germ cells that will contribute to the Next Generation so despite that there is as you will tell us some evidence for inheritance of experience let's call it or um and here we have to be careful with the language right I just want to put a big asteris and underline and a highlight that the language around what we're about to talk about is both confusing and and at the same time fairly simple and controversial right it's a little bit like in the um in the field of longevity people sometimes will say anti-aging some people say longevity the anti-aging folks feel that longevity is more about longevity clinics they don't like that anti-aging is related to some other kind of Niche uh clinics sometimes FDA approved or government approved sometimes not and so there's a lot of argument about the naming but it's all about living longer and living healthier in this field of acquiring traits or the passage of information to offspring what is the proper language to refer to what we're about to uh discuss um there is this idea and I'll say it so that you don't have to that dates back to Lamar and lamaran evolution very controversial right um and maybe not even controversial I think it's very like offensive even to certain people this idea of inheritance of acquired traits the idea that one could change themselves through some activity use the example of going to the gym we could also use the example of somebody who becomes an endurance Runner then decides to have children within another endurance Runner and has in mind the idea that because they did all this running and not just because they were biased towards running in the first place but because they of the distance they actually ran that their offspring somehow would be fabulous runners okay this lamaran uh concept is We Believe wrong so how do we talk about inheritance of acquired traits what's the proper language for us to frame this discussion right we have to be very careful as you said and there are many complications and many ambiguities and maybe you could tell us why lamaran Evolution for those that don't know is so um so such a stained thing is right so it's not polite right Perhaps Perhaps we'll start with just just say that we can talk about inheritance require traits transmission of Parental responses inheritance of memory all of these things and we can also talk about epigenetics and transgenerational epigenetics and intergenerational epigenetics there are many terms that we need to to to make clear for for the audience the the reason that is so uh toxic or controversial is very complicated and it goes a long time back even way before lar so even the the Greeks talked about inheritance trait Lamar is associated with the term but it's probably a mistake although everyone talks about including people who study it so Lamar worked he published his book about a little more than 200 years ago and he uh he believed in The Inheritance acquired traits absolutely but just like anyone else in his time just everyone believed in it this is it seemed obvious to them day that it was long before Mandel and the rules of of genetic inheritance and also Mandel was long before the the understanding that DNA is the heritable material this happens a long time ago everyone believed in it including darn darn was perhaps more lamaran than Lar really yes absolutely all right now we're now we're getting into the the me of it and and and this is in the in in the origin of the species it's in all of his writings Lamar didn't even really make the distinction between the generations he had many other reasons for being wrong but he connected the terms iner traits to Evolution and this is some of the reason that he was very controversial even in his time there were other reasons for example he rejected current day chemistry and thought that he can explain everything based on Aristotelian fluids Earth Wind Fire and Water there's still some people on the internet that think they can discard with chemistry and explain everything based on earth wind wi and and this wasn't only biology it was also the weather and everything so so that was part of the reason but um Lamar so so Lamar made many mistakes but he did have a a full theory of inheritance which was a big uh um step towards where we are today so he had important contributions nevertheless although he was mistake about the mechanism what he believed like everyone else drives evolution is the transmission of the traits that you acquire during your life or the the things that you do or don't you do we talked about use and disuse of of certain organs that shape the uh our organs and eventually also the organs of the Next Generation he sounds a little bit like the uh the first self-help public figure right well this idea you know this is heavily embedded into a lot of the um health and fitness space on the in Twitter and Instagram and on the internet which is that uh and it's the and it's the idea that we're sold um very early in life at least here in the United States and probably elsewhere which is that we can become anything that we want to become and that that will forever change The Offspring um either because of nature or nurture right and this is a very dangerous idea as I'll explain in a second and it led to horrible things this is part part of the reason that this is such a Taboo it's not only self-help that you're helping your or dis helping yourself the problem is when you apply to others and this happened in a very very dramatic and horrible way in in in recent in the recent past as I I'll tell in a second so Lamar this is what he believed and and he thought this what is this is how Evolution progress progress and later um Darin um showed that it's really natural selection the selecting of the the people that of of the organisms that are already um that already contain the the the particular qualities are selected based on the whether they survive or not in particular environments and therefore their um Evolution progresses they become more common and take over this is very different two different explanations the most common way this is contrasted is the neck of the giraffes this is the classic example according to to Lark the giraffes had to stretched their necks towards the trees to eat when the tree when the trees were high and because of that the they transmitted this Straits long necks to their children who also had long necks by the way he only mentioned this example you know a handful of times he didn't really focus on that and according to DAV just that the a girat that happened to be born with a long neck survived because it ate so it's genetic heritable materials you know about genetics but a takeover and the rest of the giraffes that have different heritable materials just die so this is natural selection versus inheritance for trats there are many reasons why lism and inheritance of white rates became such a bad term one of the biggest is what happened in the Soviet Union under Stalin there was a scientist called lenko who thought that mendelism normal genetics is a Bourgeois science shouldn't be done and whoever did normal genetics was either killed or sent to the Siberia and and he thought that just like you said we can not only we can become everything that we want but we can grow everything that we want in every field can take a frozen field and grow potatoes there and so on and this led to massive starvation ruin agriculture in in in in in the Soviet Union also ruined science for many many years and put a very dark cloud on the entire field and only probably in the 80s or something like this the field started to recuperate for that aside for that which is a very dramatic thing there was also crazy stories around and attempts to to prove the inheritance of acir traits despite the realization of many scientist this is something that is very rare or that normally doesn't happen that is not a normal way that inheritance works and I can tell you about two such dramatic cases that will Illustrated yeah please so so in the in the beginning of the 20th century in Vienna there was a researcher called Paul Cel was a very famous and and also very colorful figure who did experiments on many different types of animals he did experiments on toads that are called the Midwife toad because the male um carries the the eggs and um there's a beautiful book about it from from kastler telling the story of what happened there and he there are a couple of types of of toads some of them live under water and some of them live on land and these toads are different in their shape and in their behavior um so of course the the capacity to live underwater is one thing but also the their morphology and appearance changes the the Toads that live underwater develop these nupal pads these black pads on their hands that allow the males to grab onto the female without slipping for mating for mating and the ones on land don't have them he claimed that he can take the toads and train them to live underwater changing the temperature and all kinds of things it's a very difficult animal to work with eventually according to ca they will acquire the capacity to live underwater and also change their physiology and develop these black Nal PS on their heads with this disc he traveled the world became very famous and um this was um in just the beginning of the previous Century as the person who found the proof for inheritance of a traits despite the controversy and so on and the the beginning of the realization of how it actually works with DNA and so on not with DNA but with the um natural selection DNA came later and uh and people didn't believe him he was was actually under a lot of attacks but it seemed convincing at the end what happened is that they found that he injected ink to the Toads to to to make them become black to have this Nal so he faked the results and um and he couldn't stand the the accusations and killed himself wow in this book by Kesler suggested maybe it was it was the assistant who did it who killed him no no I who who injected it to to sort of save him from because the samples lost the coloring or something like that so it might be who knows what happened well in science whenever there's a a fraud accusation or controversy that it's not uncommon to see a passing of responsibility right there are recent cases there are ongoing cases now where it's a question of who did what Etc actually I have two questions um uh before the Second Story um I'm struck by the idea that he was traveling and talking I'm guessing this was before powerpointing keynote but also before transparencies uh which actually were still in place when I was uh a graduate student for those of you who don't know transparencies are basically um transparent uh pieces of plastic paper that uh that you put onto a projector and then you can write on them and do uh demonstrations but can show photographs and things like that um so how was he giving these talks and would he travel with the to so he traveled with a simpers I see and and I'm basing this on this Kesler book which is on its own very controversial it's more of a beautiful story then you know perhaps the truth but and and and according to the story there he had to stand in one side of the lecture hall with his hands behind the back While others would ex examine the samples and pass them around and so on but he cheated someone cheated he probably he probably did at least that that's the what most people think but this wasn't replicated I mean also I don't think anyone tried to replicate it interesting rep rep this is just a point about replication and actually another tragic example not but a few years ago um Sakai who was a as far as we knew was doing very accomplished work on um the growth of retinas literally growing eyes in a dish I think everyone believes that result but then there were some accusations about another result um that turned out to be fraudulent and Sakai killed himself this was a recent this was only about May five 10 years ago um so it still happens yeah it happen I think it's rare but it does happen especially in this high profile situ I would argue I'd love to know what your number is but I would argue that 99% of scientists are seeking truth and are well-meaning honest people I totally agree and I think that uh even when people are wrong it's mostly not because they're evil and trying to act ref like maybe they really want to believe the results or there are all kinds of way to be wrong and and even to bend truth without uh you know just blatant fraud but but this is according to the story an example of of very bad fraud which is I agree is rare because most scientists as you said this also my opinion just trying to to discover truth and do the best they can well why else would you go into it because it's certainly not a profession to go into if you want to get rich and it's um probably not even a profession to go into if you want to get famous if you want to be famous you should go to Hollywood or um become a serial killer because they'll make specials about please don't um but uh please don't do either no Hollywood I suppose for some is fine but in any case um okay so camer around 1907 1906 this is slightly before the the whole the the the controversy broke out after the first world war okay yeah great so um camera is gone his toads with their um either ink or whatever nupal pads they have to go back to mating on land yeah yeah okay I'd like to take a quick break and acknowledge one of our sponsors athletic greens athletic greens now called AG one is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs I've been taking athletic green since 2012 so I'm delighted that they're sponsoring the podcast the reason I started taking athletic greens and the reason I still take athletic greens once or usually twice a day is that it gets me the probiotics that I need for gut health our gut is very important it's populated by gut microbiota that communicate with the brain the immune system and basically all the biological systems of our body to strongly impact our immediate and long-term health and those probiotics and athletic greens are optimal and vital for microbiotic health in addition athletic greens contains a number of adaptogens vitamins and minerals that make sure that all of my foundational nutritional needs are met and it tastes great if you'd like to try athletic greens you can go to athletic greens.com huberman and they'll give you five free travel packs that make it really easy to mix up athletic greens while you're on the road in the car on the plane Etc and they'll give you a year supply of vitamin D3 K2 again that's athletic greens.com huberman to get the five free travel packs and the year supply of vitamin D3 K2 so so this is forget about that we um we also had the the lenko episode you know that's a very big thing and and then in the US there was in the 70s and 80s a researcher named McConnell who did very different experiments and he was also a character he wor he worked on he so he was a joker type of thing and he published many of his results in a journal that he published that was called worms breeders Gazette and had many cartoons and he started his own journal yes and it's one way to publish a lot yeah but he also published in in in very respected journals in parallel but he was it was a psychologist American psychologist and he worked on a worm which a flat worm which is called planaria this is very interesting this is a different than what we'll discuss today different type of warm um you know worms are are very common so four out of five animals on this planet is a worm really yeah numerically if you just count the individual so we are the exception and so but I'll talk about a very different worm later this is a flat worm this is called planaria and it is remarkable in many ways it was also a model that many people worked on including the the fathers of of genetics people who started genetics like Morgan they worked on it in the beginning but it's very very hard to study genetics in this worm because unlike us unlike what we explained before about how we all develop from sperm and an egg these worms most of the time reproduced just by fision they tears apart so they have a head and a tail and the part of the head would just tear itself apart from the tail grow a new the head will grow a new tail the tail will grow a new head you can even cut them to 200 pieces each piece will grow into a new warm wild and and they have centralized brains with loes and everything and even this degenerate eyes he studied these worms and he said that he can teach them certain things associations by pairing all for I don't remember exactly what he did I think it was U um either lights or electricity with shock them shock them with with other things and he could train them to learn and remember particular things like they might get shocked on one side of the tank exactly and then avoid that side of the tank yes and then I guess the question is whether or not they're all their ripped apart cells and their subsequent Generations will know to avoid that side of the tank without having ever been exposed to the shock right so without ever being exposed to the shock or they whether the the new generation the new head will be able to remember to learn faster that's another a subtlety that you know might happen okay and and this is what he said happens he said he can teach them certain things remove cut off their head heads and new heads with all the brain uh will will grow and that it will contain the memory this was the start of the controversy not the end of it only the beginning then he said something even much Wilder which is he can train them to learn certain things and then just chop them up put them in a blender and feed them to other worms because they are cannibalistic they eat each other and that the memo will transfer through feeding this sounds such a atic field yeah and by the way this this opened the field so people did experiments that not only in planaria but in gold fish and certain rodents and did these memory brain transfer essays implanting brain and this is in the back when they they had an idea that some memories could be moleculars could have a molecular form which is very appealing it's almost like science science fiction you can have a memory in a tube and like the way we think about memory normally which is something that is distributed in neuronal circuits and encoded in the strength of particular Sy upses and so on but but the idea that you can take a memory and reduce it into a molecule and transfer it around is very very you know interesting so this why it attracted so many people this ended up in a catastrophe so there was an N investigation couldn't no one can replicate anything it was a big mess although there were always scientists who said yes we can replicate this and this so they were in the background okay McConnell stuff was different again people thought that they couldn't that there are problems replicating but it wasn't necessarily but some people replicate but it wasn't necessarily about replicating the whole thing but the question was did the memory the transfer is specific or is it an overall sensitization that transmits and so on right like you could imagine that what gets transmitted is a hypers sensitivity to electricity as opposed to the specific location that the electricity was introduced oh or even more than that even just you know a hyper sensitiv in general more you're more Vigilant and you learn anything faster that's also a possibility but his problem wasn't the accusation it was much worse that he was targeted by the yab bomber this terrorist who sent letters with bombs to many scientist for 15 years and and his assistant again is the assistant I think exploded and this is how his line of research ended just recently a few years ago a researcher from Boston um Mike Levin and uh and his post tal shrat replicated some of McConnell's experiment with the cutting of the heads but in a very using very fancy equipment and automated tracking and they could say that they can replicate some of this his uh his um his experiments really yes and they don't open packages in that laboratory they have they have interesting stories you should have mic over yeah I'm familiar with his with a bit of his work not I didn't realize they had done that experiment so so they published it yet a few years ago and this is very interesting but of course they they don't know how it happens the mechanism is unclear McConnell went a step further than this and what's fascinating is that this these are experiments that were done in the 70s and 80s he said that he can not only transfer the memories through chopped animals but he can take the the animals that that learned and break it down into different fractions so just the DNA just the RNA just the the fats the the proteins the sugars and he said that the fraction that transmit the memory is the RNA and this is very very interesting because it was a long time before everything that we know about RNA today I'll soon go into my research explain what what we do and then you see that you can actually feed worms with RNA and get and and have many things happen and this is everyone knows this is true okay so this is why it was so appealing to to go back to that and and study it by the way at the time it became popular knowledge everyone knew this experiments there's a there's a Star Trek episode about it from 84 there there are Comics books about it books about it so this was very and people were eating RNA because they thought that there was RNA in memory this was of course complete nonsense but but this was it made a lot of noise in these years which is part of the reason it was so toxic until recently you couldn't touch it because it's it was considered pelo science like lenko like C and all of this so this was just something you you you didn't want to touch at all and and then we go back to to to these studies about inheritance of memory or inheritance of acquired traits in other organisms in in mammals in in in in humans and aside from the dark clouds that these um episodes left there were Al also theoretical problems why of why this can't happen barriers that have to be breached for this to happen and you can you can talk about many different types of barriers H and and and you can also narrow it down to two main barriers first barrier we mentioned it this is the separation of the Soma from The Germ line right the somatic cells they can change in response to experience the sperm and the Egg the so-called germ cells cannot that's the idea or they are isolated when what happens in the S okay the man who who first thought about this barrier is called wisman August wisman this was in the 19th century so it is called today the wisan barrier separation of the s from the German Only The Germ line transmit inform to the Next Generation and this is also called the second law of biology so this is very very fundamental so natural selection is the first one this is the second one because it's so important to how we work to how our bodies work wisan by by the way thought that if you will have direct influence of the environment on The Germ cells then perhaps this could transfer to the Next Generation so it he wasn't as strict as his barrier suggest but uh but this is not how most people remember it okay but he thought that this is unnecessary it's possible that natural selection can explain everything and compare it to to a boat which is in the ocean it is sailing and it has a sail open so you don't have to assume that it has an engine the wind is blowing you don't have to assume I do things the natural selection might be enough so this barrier is still standing but not entirely it is brid in some organisms we'll go into that in a second the other barrier is the now we have to to to understand the other barrier we have to talk about epigenetics we have to Define epigenetics and what it is and epigenetics is another term which people misuse horribly and say about everything that is epigenetics even people from the field okay the the the the the the word itself that the term was defined in the 40s by Weddington Conrad Weddington and he talked about the interactions between genes and that and and their products that that in in the end bring about the phenotype of the consequences and how genes influence development later people discovered mechanisms that are that that change the action of genes the different me mechanisms and started talking about these as epigenetics for example the DNA is built out of four basic elements is are the the the at G and C right and they can be mod chemically modified so in addition to just the information that you have in the sequence of the DNA you also have this the information in the modification of the bases the most common modification that has been studied more than others is modification of the letter c of cytosine mation addition of a meyl group to this C and and and this can be uh replicated so after the the the DNA the cells divide and replicate their genetic material in certain cases also these chemical modifications can be added on and replicate and be preserved for those who aren't um as familiar with thinking about genes uh and Gene structure and epigenetics could we think of these you mentioned the four um nucleotide bases CGA um but could we imagine that um through things like methylation it's sort of like taking the primary colors and adding a changing one of them a little bit changing the the Hue just slightly which then opens up an enormous number of new options of colored uh uh integration Abol it's just more combinations more ways more information there are the modifications of the DNA and also there are the modifications of the proteins which condense the DNA that are called histones so they are also Modified by many different chemicals again mation is a very common modification acation even serotonin there serotonin of of histon Serotonin right this is a new paper from nature from a few years ago can change DNA not the DNA itself but the protein that condenses it essentially how um in the analogy I used before of uh of how the thread is wrapped around the spool essentially yes and this determines the the the degree of condensation of the DNA whether the gene is now more or less accessible and therefore can perhaps be expressed more or less this is this is one way to affect the the gene expression and and bring about the the function of the gene there are many additional ways not the only one so then when this was when all of this was starting to be elucidated people talked about epigenetics they started talking about these modifications forgot the original definition and and when people said epigenetics they talk about metil and things like that and um again to just frame this up so we could imagine two identical twins so-call monozygotic twins um we could go a step further and say that they're monochorionic and they were in the same placental Sac because twins can be raised in separate sax slightly different early environments let's say those two twins are raised separately one experiences certain things um the other other things they eat different foods Etc and there is the possibility through epigenetic mechanisms that through methylation acation um serotonin production Etc that the expression of certain genes in one of the twins could be Amplified relative to the other correct so yeah so we know that even totally identical twins genetically they're identical but they they look different and they are different this we we experience we all experience it and this is this can happen because of these epigenetic changes okay or it can happen because of other mechanisms because genes respond to the environment genes don't exist in a vacuum are uh genes are need to be activated by transcription factors and there's a whole uh there there's a lot of Machinery that is responsible for making genes function so we are a combination of our genetic material and the environment okay so when people talk about epigenetics and talks talk just about the modification they're also not exactly right my definition of epigenetics is inheritance which occurs either across cell division or more interestingly also for this podcast now across Generations not because of changes to the DNA sequence by but through other mechanisms I think this is the the the most robust definition that that allows you to understand what you're talking about and then again and then H and then the question is if this happens then what are the molecules that actually transmit information action RA are they the these chemical modifications to the DNA or to the proteins that condense the DNA or are there other mod other agents that transmit information and which molecules can do it and I actually think that the most interesting players today are RNA molecules okay but before I go into that I just want to say that when we talk about the barriers to epigenetic inheritance or the barriers to inheritance of acquired traits in addition to the separation of the s from the ger that we discussed the other main barrier it's called epigenetic reprogramming which is that we acquired our different our cells the the the genetic material in our cells acquires all kinds of changes this chemical changes modification we discussed but these modifications are largely erased in the transition between Generations so in the germ line in the in the the sperm and the Egg and also in the early embryo most of the modifications are moved so we can start a blank slate based on the genetic instructions and this is crucial otherwise according to the theory it's not clear that actually true because in some organisms doesn't really happen we will just we will not develop according to the species typical genetic instructions so to preserve this we we erase the M the all these modifications that start a new and this is in in MERS and in humans this is larg to most of the modifications on the in the sperm and in the egg are removed so about 90% of them some remain which could be interesting so the idea if I understand correctly is that there's some Advantage uh to wiping the Slate clean and returning to the original uh plan in in the context of the IKEA furniture analogy um the instruction book is the one that's issued to everybody okay or every cell right only certain instru are used for certain cells say a skin cell or a neuron or a liver cell or um any other cell for that matter through the course of the lifespan of the organism those Specific Instructions are adjusted somewhat okay so maybe uh like Ikea furniture uh sometimes you you can't they sent you seven not eight of particular screws or they sent you um the proper number but you put them in the wrong place and it sort of changes the way that the thing works a little bit once that assuming Furniture could reproduce um but here in the analogy of the furniture as as the cell or or the organ in the mates with another organism that needs to be replicated and so the idea is to take the instruction but go through and erase all the pen and pencil marks erase all those additional little modifications that the the owner used or introduced to it and return to the original instruction B right because if you want to bring back the instruction book you want it to have all the potential to make all the Furnitures you don't want it to be restricted to the ones that you made in the particular room so it's essentially the opposite of acquired traits and characteristics based on your uh what we say in biology uh geek speak lineage based experience but what your parents experience right in some ways we want to eliminate all that and go back to just the genes they provided yes but it's more complicated than that it's more complicated than that because we have some very striking examples even in memo where some of the of the marks are maintained for example the classic example is imprint imprinting is a very interesting phenomena um the the way DNA works is that we you inherit um a copy for every chromosome from your mother and your father and then you have in every cell of your body two copies if you a human of every chromosome okay and then so so every Gene is represented twice these are called Al the different versions of the jeans and the the thought is that once you and the in the Next Generation the two copies that you inherited are are equal it doesn't matter whether you inquire acquire them from your mother or from your father right there are some situations where it does matter there's there is a limited number of genes that are imp called impr printes where it does matter whether you inherited from your mother or your father and and this is happening through epigenetic inheres not because of changes to the DNA sequence but because of maintain maintenance of this CH chemical modifications across generations and as I recall from the beautiful work of Katherine Dak uh at Harvard that especially in the brain there is evidence that some cells contain the complete genome from Mom or the complete genome from that and it can also switch during your life so her work showed that early on in in your life it's different whether you express the the maternal or paternal copy than when you're uh more mat true so parents and children take note you know for those of you that are saying oh you know uh the child is more like you or more like me that can change across the lifespan and if you're thinking about your parental lineage and wondering whether or not you quote unquote inherited some sort of trait um from mother or from father it can be of course both or it can be just one or just the other which I think most parents tend to see and describe in their children from time to time that's just like the father that's just like the mother for instance right right but it's important to know that in this situation the environment played no role this was just whether it passed to the mother or the father it's not that something that happened to the mother or the father affected this okay so this is slightly different the question is now can the environment change the heritable material okay so it's very important to understand that there is a difference between n and nature and this is is very confusing people are are it's it's a little subtle so for example people tell me I'm growing horses for many years and I just know that this horse has a particular uh character it's very different from from the other horse and so this is epigenetic inheritage no it could be just genetically determined yes this horse inherited a different set of genetic instructions so it is different doesn't have to be about epigenetics epigenetic inheritance uh mean that the environment of the parents somehow changed the the the children okay and there there are these two main barriers that are serious B battl necks that we have to think what type of molecule and how they can be bridged so one possibility is that it's really this limited number of chemical modifications that survive which is about 10% or so that could be very interesting not a small number not a small number but perhaps perhaps okay this is one one possibility the other possibility that there are other mechanisms the the situation now in humans is that is just really unclear what transmit if it can transmit and which molecule does it we'll talk later about other organisms where it is a lot more clear but in humans and in MERS in general there are many examples for a environments that change the children whether the you need to invoke an epigenetic mechanism to explain this phenomena this is unclear first of all because it's hard to separate nurture from nurture and second because the mechanism is just not understood so there are classic examples for in humans there were periods of famine starvation in different places in the world in the Netherlands in China Russia where people did huge epidemiological study to study the next Generations and saw that the children of women who were starved during uh pregnancy are different different in many ways they have um different birth weight uh glucose sensitivity and also some neurological higher chances of getting some neurological diseases and this has been shown uh in very large studies is there ever an instance in which starvation or hardship of some kind some challenge a sensory challenge uh or uh survival based challenge led to Adaptive traits yes there are in different organisms it could be as a result of a trade-off so there could be a downside as well but for example there are two examples that come to mind one of them is that if you stress male um um mice or or um or Reds I don't remember this is work of Isabel mansu in the eth in Switzerland if you stress the males you can do it in many different ways um I don't remember exactly how they did but you can you can do you can separate them from their mothers you can do social defeat all kinds of things then the next Generations are less stressed they show less anxiety so the threshold for stress is higher yes however I think they have memory deficits and and other metabolic which may be an advantage for dealing with stress could be it could I don't have any direct evidence of that but there's some there's some simmering ideas that you know our ability to Anchor our thoughts in the past present or future seems very adaptive in certain contexts in other contexts that can keep us ruminating and not right you know adaptively present to our current challenges another example is that um n nicotine exposure this is I think the work of Oliver Rando from ums is a if I'm not mistaken these are not my studies but they improve the the tolerance to exposure to similar drugs in the Next Generation the interesting thing here is that it's very non-specific so you you treat them with nicotine but then in the Next Generation they are more tolerant to nicotin but also to other I think COA cocaine or that sort of makes sense to me because U yeah obviously nicotine um activates the coleric system the dopaminergic system epinephrine and Etc um and you can imagine that there's crossover because other drugs like cocaine amphetamine mainly Target the cat colines the dopamine in or in in in in this particular study if I remember correctly they show that this happens this heritable effect even if you use an antagonist to block the nicotin receptor wow so so so it's something more about clearance of xenobiotics and and hepatic functions that is transmitted and is very nonspecific what I love about all the examples you given today and and especially that one is and I hope that people um if you're just listening I'm smiling because biology is so cryptic sometimes you know the the the obvious mechanism is rarely the the one that's actually at play and um people always ask well why why is it like this and I always say you know the one thing I know for sure is that I wasn't consulted in the design phase and if anyone claims they were then you definitely uh want to back away very fast and there could be show so many trade-offs so many tradeoffs so for for example we started and also other many many other people studied effects these are in in worms we'll go we'll go deep into that in a second but H that show that when you starve them the next Generations uh live longer and this I think could be a tradeoff with other things like um like fertility so the next Generations are more sick and F and less fertile and perhaps because of this they live longer so there could be it's not necessarily a good thing right I don't want to draw you off course uh because this is magnificent what you're doing and and and uh splaying out for us here but you recall there was a few years ago it actually ended very tragically it was an example I think it was down in San Diego County there was a a cult of sorts that were interested in um living forever uh and so they uh castrated the males self- castrated themselves in the idea that somehow um maintaining some pu prepubescent state or reverting to a pseudo prepubescent state would somehow extend longevity the idea that um sexual behavior somehow limited lifespan this has been an idea that's been thrown around in the kind of more wacky longevity communities um they also shaved their heads they also all wore the same Sneakers but then they also all committed suicide right as the hail Bop Comet came through town um but that's just but one example of many Cults aimed at sort of um that obviously was not life extension that was life truncation but um aimed at kind of eternal life or some sort of U through caloric restriction that's right this this cult also was very into the whole idea that by through caloric restriction we can live much longer which uh may actually turn out to be true I think it's still debated um hence all the debate about intermittent fasting Etc but also uh it is known that if you overeat you shorten life this is this is clear it's known that big bodied members of a species live far um shorter lives than the smaller members of a Great Dane versus a Chihuahua for instance so there is some like sort of shards of truths in all of these things but I I it seems to me that the real question is like what is the real mechanism and and why would something like this exist right and why questions are very dangerous in biology right right but but very interesting also and and so so when it comes to metabolic changes and nutrition there are numerous examples where you either overfeed or starve and get effects in the next Generations many of the sometimes the effects contrast depending on the way you do this H again these are none of we don't do any of that in in memers but people show that starving or overfeeding the mothers or the fs changes the body weight of the the Next Generation and also the the glucose tolerance and and other and and also reproductive uh success and um and and so the the fact that there's an effect that there's that something transmits this is clear the question is how miraculous is it and whether you need new biology and epigenetics to explain it what do I mean by that if you affect the Next Generation it doesn't necessarily has to go through the allite or the sperm and involves the epigenome you change the metabolism of the animal as it develops and obviously it will affect it that when you for example starve women that are pregnant as happened during the the the this famous starvation studies the the the baby is already in uter exposed directly to the environment so it's not even a heritable effect the baby is itself affected they said direct effect very interesting important and has many implications and it will be separate from the genetics you'll have to take it into account to understand what's going on doesn't require necessarily new biology a new new biology of inheritance not only is the embryo affected the embryo while in uto already has gem cells so it's also the Next Generation so is directly exposed and you don't need any new biology necessarily to explain it and it doesn't have has to involve gene epigenetics or epigenetics it's clear to me that in the female fetus the total number of eggs that she will someday produce and potentially uh have fertilized by sperm exist but in males with a 60-day sperm cycle um leaves me to the question do um fetal males um males as fetuses living as fetuses in their moms already start producing sperm or it's the primordial cells that give rise to sperm so I'm I'm not exp so I don't want to go into the details of exactly when in me but but but yes exposure of the of the mother also affect the eventually the the the the transmission of the father of genetic information through the sperm's father and there are also many examples of just stressing the fathers affecting their sperm and affecting the Next Generation there if you go to the F2 Generation if you go two generations down the road not to the kids but to the grandkids then it is a real epigenetic effect because uh because you you examine something that happens although the next generation was was never exposed to the original challenge so when we say about epigenetic inheritance in through the paternal lineage through the fathers we talk about uh two generations and when you go through the mother it's three generations to talk about to to when you need to uh invoke some real epigenetic mechanism and there the evidence becomes much more in minutes there are examples more or less convincing the field is evolving and improving a lot so for example now to uh many people use The Cutting Edge is to use IVF in vitro fertilization or transfer of embryos to make sure that you actually it's the it's the heritable information and not the environment uh or and that it goes through the germ line so this is something that is being done now there are studies three parent IVF where they take the DNA from Mom the sperm from Dad and they take the DNA from Mom and put it into a novel cytoplasm or no not or or just you just take the sperm and transfer it and fertilize the the the an egg so standard IVF yeah standard IVF yeah you can do it in many different ways but this idea that you separate the the environmental the environment of the mother from The Inheritance or or the environment of the father and to to control and separate nature from nature environment becomes the culture dish yes yeah so so the field is is improving people do experiment that have a higher end so more replicates and better controlled and there are some examples for effects that transfer and it depends who you ask whether people believe it or not many geneticist do not believe it and many people do believe it and it depends on the community there are strong resistance for many reasons some of them are are Justified some less Justified and our part of the scientific process and how things work because it's it's it's a new it's challenging the Dogma so this is very interesting on its own if you ask psychologists many psychologists believe that there's heritable trauma and and things like that population geneticist less so okay so this really depends and I think that we are just at a point in time where we don't really know whether it happens and to what extent and we need bigger studies even if you think about normal just genetic studies where people trying to understand the genetic underpinning of complex traits like um any thing that involves the brain pretty much we now know that you need to study many many many people so now these big genome wide Association studies big genetic studies involve hundreds of thousands of people no one did an experiment like this for epigenetics it's much more complicated because you need to also take into account the environment and to it's I don't I'm not even sure we know how to design such an experiment it's very very challenging so so the part of the resistance resistance to the idea is based on theoretical grounds because of these barriers and because of of the controversies on the other hand there's people really want to believe it people really want to believe it because if sort of gives your life meaning if you can change your biology through changing of of your kids through changing your biology so psychologically I can understand why many people want this to happen even shreding the famous physicist so he wrote a very important book in 44 so this was before the the double helix and the um that it's called what is life this is actually a book that was drove many by physicists to establish molecular biology it's very very important and he talked about the heritable material it also talks about Evolution and he said unfortunately Laris or inheritance of acquired trait is untenable it doesn't happen and he writes this is very very sad or unfortunate because unlike Darwinism or natural selection which is gloomy doesn't matter what you do the next generation will be born based on the instruction in the the sperm and it doesn't M you can't influence it of course you can give your kids money and education but you can't biologically influence you can also SE um one thing I'm fascinated by for a number of reasons is partner selection I mean in some ways you know we think oh we we want to find someone who is you know kind that does seem to be by the way the primary feature at least in uh the data tell us we had David boss on the podcast of how women select men that people are kind there's also resource potential there's also beauty or um aesthetic attractiveness in males and females Etc um male male female female as the case may be but in terms of reproduction sperm egg uh male female obviously so we're selecting for a number of traits but presumably subconsciously we are also selecting for a number of traits related to Vigor and in the idea that if we were to have Offspring with somebody that those traits would be selected for right and we actually have a have work on that in nematodes that I'll be happy to tell you about in a second after we the dating and the dating the dating in worms and and and where we understand the mechanism and and we'll go into that in a second but uh or in a few minutes after we we we dive into the worms but uh but yes the the original um calculations of how population genetics work to simplify things and to do the math so it will be easy it was random mating of course it doesn't work like that so it complicates things to because we know and there there's research about potential capacity to somehow sense immune compatibility and things like this which is I don't know I'm not an expert on that but neither am I but my understanding is that of course we're familiar with the other traits we select for um like potential nurturing ability whether or not someone is reliable predicts something about their nurturing ability and for Offspring potentially I mean you can draw lines between these things without any um direct evidence but but they seem so logical right that somebody kind might also stick around or be honest and these kinds of things that that didn't make sense but that one would be selecting for certain biological traits like immune function or um some other form of robustness that we're not aware of is I think a fascinating fascinating area of biology yeah yeah yeah so so this is where the the the the work in MLS stand however there's also one additional thing to to mention which is that on top of um chemical modifications to the DNA and um and the proteins that condense the DNA which are called histon there are also other mechanisms that might transmit information including transmission between generations of RNA and there are different types of RNA not just the RNA that we mentioned before the messenger RNA which encodes for the information for making proteins but also other rnas that regulate gene expression and this is and I think that in recent Years also in the Maman field RNA as the molecule that has the potential to transmit information between generation took Center Stage so I think this is The Cutting Edge um a lot more to to understand and know but RNA has a lot of potential for doing that as we'll explain uh soon but we have to go to worms first I'd like to just take a brief moment and thank one of our podcast sponsors which is insid tracker inside tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals I've long been a believer in getting regular blood work done for the simple reason that blood work is the only way that you can monitor the markers such as hormone markers lipids metabolic factors Etc that impact your immediate and long-term Health one major challenge with blood work however is that most of the time it does not come back with any information about what to do in order to move the values for hormones metabolic factors lipids Etc into the ranges that you want with inside tracker changing those values becomes very straightforward because it has a personalized dashboard that you can use to address the nutrition-based behavior-based supplement based approaches that you can use in order to move those values into the ranges that are optimal for you Your vitality and your longevity inside tracker now includes a measurement of APO lipoprotein B so-called Apo in their ultimate plan apob is a key marker of cardiovascular health and therefore there's extreme value to knowing your apob levels if you'd like to try inside tracker you can go to insid tracker.com huberman to get 20% off any of insid tracker's plans again that's insid tracker.com huberman to get 20% off thank you for that incredible overview of genetics and RNA and uh epigenetics and was essentially a survey of this very interesting um and on the face of it of complex field but you've simplified it a great deal for us in our transition to talking about worms I would like to plant a flag in the uh in the huberman lab podcast and say that what we are about to discuss is the first time that anyone on this podcast has discussed so-called model organisms I may have mentioned a fly paper here or there or a study on honeybees and caffeine and um flower preference at one point but typically that's done in passing and we quickly rotate to humans I know that many if not most of our listeners are focused on humans and human biology and health Etc but I cannot emphasize enough the importance of model organisms and the incredible degree to which they've informed us about human health especially when it comes to very basic functions in cells right I mean one could argue okay there and there's been some debate tell and mice did that really lead to the same sort of data in humans okay there are these those cases certainly but model organisms are absolutely critical and have been and basically inform most of what we understand about human health so before we um start to go into the description about worms per se could you just explain to the a general audience what a model organism is right they're not modeling they're not posing for photographs obviously um what what that means and what some of the general model organisms are and why you you've selected or elected to work on a particular type of worm to study these fascinating topics that in there's zero question also take place in in humans at some level so it's it's a it's a real pleasure and an honor to represent the model organisms here I'm really happy just for that this is it was worth it h because as you said model organisms are extremely important and we learned so much about about bi through them the the model organisms mean that it's an it's an organism that many people work on so there's a community of people that work on people work study many types of organism but not around every organism there's a a a huge community of researchers that com that's combined forces to create all the the resources and the tools and understanding that accumulates there is just a handful of model organisms in the in the short history of the field of biology it's not so long we learned about every aspect of biology through them including many important diseases human diseases and these are eoli bacteria Fage which is a virus of bacteria um flies worms that are called sea elegant nemat this is what we study in the lab fish which are called zebra fish a par Dano Dano or something right yeah and and of course there are also model organis other and mou and um and also plants important plants the most studies one is arabidopsis yeah and perhaps less so nowadays but non-human primates maak monkeys maret squirrel monkeys mainly these I I don't know exactly how the definition is but emerging model organisms there are many model organisms that are emerging and there are communities that are formed including also around the planaria that we mentioned before this flat that regenerate this is a great model for studying regenerations if we could develop new heads it would be incredible and we can learn from these organisms and the reason that we can learn a lot also about humans by studying these animals is that we all evolve from the same ancestor so we shared we shared we share a lot of our uh um uh our functions with them and also a lot of our genes C elegant and and they have the different model organisms have different advantages that serve us they uh they sometimes have some things that are much more apparent in them that we can study for example learning and memory was largely studied in the beginning in a snail aesia where many of the discoveries were made because it has big neurons that you can easily study and and examine and yes snails learn yes they learn even see Elegance these nematodes that we study learn and they are much simpler than another important reason to sending them of course is you can you can actually experiment on them we can't do this to humans the things that we do to these animals um and we can change their genes do all kinds of things for them and in some sorry to interrupt but in some cases think you're going to tell us for instance in seans in particular the what the presence of particular cell types is so stereotyped that you can look at several different worms and you can the the community of people that study seans is literally numbered and named each neuron so that two laboratories on opposite sides of the world can publish papers on the same neuron knowing that it's the same neuron in the two different Laboratories something that is extremely hard to do in any Maman model a mouse or certainly in humans and um has posed huge challenges that uh give great advantages to studies of things like seans yes so seans this is the star now of of what what and and this is what what we study these are n small worms round worms that are just 1 mm long so you can't see them with a naked eye you have to look under the scope where do they live in the in the natural world so they they used to call them soil nemat but this is not really true they are they are in many places but they're mostly in rotten fruits and leaves and um you can find them in the ground as well but you can also find them and they're free living so they're not parasites but you can sometime also find them in snails okay but but but the best way to isolate them is from rotten fruits okay I like the idea that they're not parasites I'm one of these people that gets a little screamish about the notion of parasites yeah so so they're not parasites they're really fun to handle because they're so small and easy you just grow them on plates with eggar and eoli bacteria this is what they eat in the lab you can just pick them with the um with a small pick uh wire pick and move them around and change their their genes and do many things to them but they have many advantages for neuroscience and for studying inheritance as you mentioned they have always a certain number of cells in the body so San stod always has 959 cells in its body that's it okay not 960 not 958 959 okay and out of which 302 are neurons always 302 there's a huge debate now over Twitter on whether it's 302 or 300 I I mean I don't want to get into trouble okay but people take this very very U hard I think it's 302 but we let's not get into it because I'll get into trouble well we can equilibrate all things here by you say 302 granted you're far more informed in this model organism than I am or ever will be I'll say 300 and then we're balanced in terms of partisan politics in the seans community perfect so so so it's and it's always the same and each neuron has a name like you said and we we not only does every neuron has a name many of of them we know what they do so there's a a few cells that are sensory neurons that sense particular chemicals in certain situations we know that a a chemical will be sens just by one neuron there are other motor neurons and Inter neurons and all of that we know how many dopamine neurons there are and serotonin neurons and we know them all by their name not only that we know how they are connected to one another we have a me a conom since the 80s like a Subway map that tells us which neuron talks with which other neurons and it is the same okay it was used to think to people thought that it was exactly the same between genetically agentic and morms now we know that there are slight differences but by and large it is the same and we have a map a road map that we can use to study the so-called connecto the connecto not only that the worms are transparent so we can actually see the neurons fire using particular tools and we can activate genes and Sil genes using optogenetics like was discussing on the podcast we can make the worms go forward or backward or lay an egg by shining different waves of L of of light on them H and so we have very powerful full tools for manipulating the brain on top of that we have great understanding of the genetics of the worm of of the genome this is silans is the first animal to have its SE its gen genome sequenced before humans before that of course they were bacteria but and um and we know that in each worm produces each mother produces about 250 babies which are almost genetically identical so we can and and we know what we where we grow them the environment is very controlled so we grow them in the plate with just bacteria so we can easily separate between nature and nurture and and one thing that uh I want wonder about often is Generation time you know even um though mice are not humans mice have certain advantages because they're Mamon species you can't do all the Magnificent things you can do in seans and mice but uh one major issue with mice is that the generation time is somewhat long you pair two mice they mate you get a mouse or litter of mice 21 days later it might seem like okay uh that's only 21 days or so but if you are a graduate student or postdoc trying to do a project I mean that can extend the time to do experiments out three or four years compared to what you could do in seans you're absolutely right this is one of the major advantages the generation time in Seance is three days three days so you can do hundreds of warm Generations in one PhD this is very important not only that every worm will produce hundreds of progen so you will have that are genetically identical so you will have great statistics for your experiments and the worms probably don't mind living on these AAR plates you know munching away on eoli where um good you know it's question whether or not mice or certainly listen I I I'm a proponent of well-controlled uh over and as long as there's oversight um animal research it's necessary for the development of treatments of diseases that that um hinder humans but it is always a little bit of of a of a kind of a a cringe and go kind of thing when you're dealing with with mammals that are living so far outside their natural environment you know I'd be lying if I didn't say that it gets to you after a while and if it doesn't get to you you kind of have to wonder about your own psyche a bit right I also think that this is important but for me it's much easier to work on worms I don't have to uh you know um feel bad about it yeah they're happy they're happy and you also I mean if if if a worm dies it's l less painful to the human than if and other more sensitive animals yeah I I would argue yes I agree yeah so yes there so there are many advantages for studying sea elegance and in the warm we now have very obvious and clearcut proof that there is inheritance of aquir traits so much so that I don't think that anyone pretty much in the epigenetic field argues against it well and in large part thanks to you and the work you've done so could you tell us what was the first experiment that you did on seans that confirmed for you that there is inheritance of acquired traits because of course the best experiments and experimenters um always set out to disprove their hypothesis and when the hypothesis survives despite all the control experiments and poking and prodding and um attempts to contradict oneself then it's considered a victory but it's one that you have to we all have to be very cautious about enjoying because uh of the tendency to want our our hypothesis to be true so what was the first experiment where you were convinced that inheritance of acquired traits is real the first experiment I did was when I in my postdoc which I did with Oliver hbert in University of colia um we set to test whether worms can produce trans generational for long multiple generation resistance to viruses oh wow this is a very pertinent topic which is relevant and and worms these worms don't have dedicated immune cells like we do they don't have T cells or B cells they defend themselves from viruses very efficiently using RNA so in fact when we started these experiments there wasn't any natural virus that was known to infect C Elegance which is amazing because viruses are very good as we all experience now in infecting and the worms are resistant to viruses because of RNA molecules short RNA molecules that destroy viruses and these are called small rnas now we we need to discuss them before I explain my experiment in um 2006 two researchers that were studying sea Elegance Andrew fire and Craig Melo got the Nobel Prize for showing that there is a mechanism that regulate genes that happens through small rnas what they've shown is that if you inject the worms with RNA molecules with are which are double stred they lead to the S to to they shut off the genes that correspond that that match in sequence to this RNA so it's sort of like taking the specific instructions for the coffee table from your Ikea handbook and you insert a copy of that into the book and in doing so you prevent the expression of uh you you sort of erase the original page perfect explanation perfect explanation and for for they found that double strand RNA RNA that has two strands is what starts the response leading to the production of small RNA molecules which are the ones that actually find the messenger RNA and leads to its destruction silence it so you don't get proteins in the end for that they got the Nobel Prize after people found that this is conserved in many organisms including humans and there are now drugs this was only in 2006 that the Nobel Prize paper was published in 98 there are now drugs that use this mechanis ISM also in in in humans and I'll just interject and say that not only is it a recent discovery and an incredibly important one but Andy fire and Craig melow are also really nice people yeah they just happen to be very nice people and Craig melow is an excellent um I think he's a kite Surfer when I the only time I met him in person was at a meeting and he had a black eye and I thought okay wow I guess he's also a pugilist or something but turns out he had done that kite surfing um so scientists actually do things other than um uh go to the laboratory Nobel prize winning scientist that is okay I'll let you continue thanks for allowing that incredible scientist and there were also um studies in many organisms on the mechanisms of how this happens it is called RNA interference RNA interferes in the expression of a gene in the end in the function of a gene and it's also called gene silencing because these rnas enforce the silencing of genes instead of the genes being expressed they are silenced you don't manifest their function okay already in this first paper that they published about this where they've shown the double strand RNA is what leads to the silencing or the control they've shown two very important things one of them is that if you inject the worms with double sand RNA you don't only see the action in the cell that you injected or in the tissue that you injected but you see it all over the worm's body it spreads it wasn't exactly clear what spreads but it was clear that it spreads you see the silencing all over the body this includes also The Germ cells so if you inject the double strand RNA just to somatic cells even to the head you will get also the effect in The Germ cells and in the Next Generation okay in the immediate pren the F1 generation the kids so this was really clear proof that this is inherited however this is just one generation okay in this original studies later they've shown something which will immediately remind you what I told you about with planaria that you can just take worms and feed them on bacteria that produce this double strand RNA and that the double and the silencing would move from the site of inje from the gut where the bacteria are eaten to the rest of the body and also to the Next Generation okay so before we left when I mentioned this cannibalistic experiments of mcon with the planaria and now you see that it can happen and and this is not controversial at all this is being done routinely every day by any Seance biologist in the world this is has been replicated a million times not only that you can also feed planaria these other worms with RNA you can just put it in chopped liver and let them eat it and again this will sign Ines throughout the body okay wild okay and this is what we do routinely we always when we want we use this technique to see what genes do if we want to see whether particular Gene is important for a certain Behavior a certain something the way to study this is to neutralize the gene activity and we do it by just introducing the worms with double strand RNA that correspond in sequence that match in sequence this Gene this will lead to the silencing this activate the gen activity and then we and if then the the effect stops we know this Gene is is involved in the in the function and we never want to just examine one worm so we feed the mother with double strand RNA and then we examine all of its children so we can have the statistics over hundreds of worms or thousands of worms so this is validated and not controversial and all and totally routine is it fair to say that McConnell's experiments of um chop blending up these worms a graphic image blending up these worms and then uh feeding them to other worms uh plan area that those experiments can yes be explained by um double stranded RNA which and through RNA interference potentially it hasn't been done yet we are working on it in in my lab now in collaboration with other labs Fant but it wasn't published but yes this this could be the explanation okay so um so fire and Mello did these experiments some other people did these experiments when I started my work I wanted to see whether in addition to artificial double strand RNA some natural traits can can also transmit across Generations because of RNA because of small RNA right because um injecting RNA or um in inter shorter interfering rnas that is or um you know putting worms into an environment with an abundance of inhibitory rnas as an experiment is very different than worms experiencing something and then passing on that acquired trait to their offspring and it's a world aart in my opinion because one is an extreme manipulation that illustrates an underlying principle the other is something that in theory occurs in the passage of of generations just naturally we're going from the less artificial to the more artificial and the advantages just like with model organisms that the more artificial it is the easy it is to you know exactly what you did just now introduce one factor and you can follow the result so this is always the trade what I did was in Oliver's lab is to see whether the magic part of the magic for the worms resistance to viruses is their capacity to transmit information in the form of RNA molecules inhibitory RNA molecules to the next Generations and it has been shown before in cgans that the worms resist viruses using this mechanism this small Ras okay in fact this is probably the reason that these small Ras evolved in the first place to get rid of viruses and other um parasitic genomic elements and this is a mechanism to fight them and what I I did is a very simple experiment I took worms and I infected them with the virus when you do this this also has been shown in the past the worms destroy the virus okay we demonstrated this very clearly using a flues virus so when if the if the virus replicates successfully the worm just turns green and if the virus is destroyed the worm stays black this is very simple it's a clear cut off it's not this you don't examine the worm and ask whether it feels good you just see this green light binary response yes yeah and so we we took worms we infect them with the fluorescent virus they destroy it this also has been done in the past but then what we did is we neutralized the Machinery that makes small Ras in the descendants of the worms so they cannot make small rnas from the start on their own because they just don't have the genes that you need to to make this more okay and then we ask when we will what will happen will we affect these worms with the vowes will they be green or black they can't make their own small arise so they can't protect themselves on their own the only way for them to stay black for have them not having the virus replicate is if they inherit a small from their pth and this is exactly what happens all the worms progeny although they don't have the gene that is needed for making the small Ras are black they sign the virus and this also continues for additional Generations okay so the the parent worms effectively put something into the genetic instructions of The Offspring that would afford them um this let's call it an advantage in this case but afford them an advantage if they were to be confronted with the same thing that the parents were right and we know exactly what this Advantage is that the advantage is are small rnas that match the viral genome and just chop up the virus in the Next Generation and we can identify the small rnas in the the inhibitory rnas in the Des sentence although they don't have the Machinery to make it just because they inherit it we can identify them by sequencing by RNA sequencing which is like DNA sequencing you actually get the actual sequence of the RNA molecules and we can see that they correspond to the virus and they have they inherited small only if their their parents were infected with them so there's specificity there there's specificity yeah it's not some just general resilience passage right I have to be careful in drawing an analogy that isn't correct and I want to acknowledge that what I'm about to say with certainty cannot be entirely correct but the the analogy that comes to mind in mammals is this idea that if one generation is stressed that their offspring May in some cases have a higher stress threshold or resilience to stress I could imagine why that would be advantageous right your parents have a hard life they have Offspring and they want their children to have a higher threshold to stress because stress can inhibit reproduction Etc and as I always say you know at the at the end of the day and at the end of life um evolution is about The Offspring not about the parents and every species pretty much seems to want to make more of itself and protect young one way or another either through nature or through nurture this is a nature-based protection of young is it fair to say that in the Maman experiment with a passage of stress resilience that it could be RNA based that that would be perhaps uh set some new threshold on glucocorticoid production here I'm speculating but I and I want to highlight that I'm speculating I'm speculating with a reason which is I think for people that are hearing about this in worms you've done a beautiful um job of explay out why model organisms are really important but to think about how this may operate in in our in the passage of human Generations I think is a reasonable thing to entertain right and and it it is true that also in mamals now rnas and small rnas are a lending candidate for something that could mediate the transmission of of stress protection or also of harmful effects that transmit between Generations perhaps RNA do it however in worms the RNA is have one more trick that we don't we don't know the equivalent in memal yet and this is something very crucial that we showed in that particular paper in the first paper which is so the effect that I described this transmission of resistance to viruses through this RNA doesn't only affect the Next Generation it also affect multiple additional Generations so it gets passed it get passed and you have to ask yourself how doesn't it get dilute why why isn't it diluted right because I mean everyone produces 250 babies so you dilute by 250 and if something is diluted for four generations so it's 250 * 250 after four generations it's a dilution of four billions completely homeopathic would never work okay just there's nothing left the secret of these worms is that they have a machinery for amplifying the small Ras in every generation okay this is called RNA dependent RNA polymerus it's a a a complex which uses the RNA to find and once it finds the messenger RNA just create many many many many small R so they don't get diluted and they pass on for additional Generations okay and this is the the trick we later also identify genes that regulate for how long an effect would last otherwise I if if in beginning we ask why does how doesn't it stop after one generation now we have to ask why doesn't it last forever and it doesn't typically we see that the responses last not only with the Val but also with other traits for a few Generations three to five generations we found genes that function as a sort of a a clock that times the duration of The Inheritance what sorts of genes are those so we call these genes moic genes MK I don't know how is your Hebrew but M it means sweetheart in Hebrew but the acronym is modified transgenerational epigenetic in kinetics there are different types of gen like that and for some of them if you mutate if you disrupt their function now now the effect would transmit stably for hundreds of generations it would never stop because their role is to stop the inheritance from going from from just you don't want to carry over something forever otherwise you it will no longer fit the environment of the parents and you'll be prepared for the wrong things so this is important there are what type of genes are they one gene that we studied it's called metu it's actually a gene that functions in metil of the of the proteins that condense the DNA so this is uh and there but then there are other genes that affect also production of smaller is there some mechanism that controls the duration of passage in a way that logically links up with the lifespan of the organism so for instance uh I knew my grandparents met them uh I did not ever meet my great-grandparents and I certainly didn't meet my great great-grandparents I could imagine that my great great grandparents or my great-grandparents experienced certain things that were passed into their children and uh perhaps into their children but it seems reasonable given that humans live somewhere between zero and uh 100 years typically what now 80 years is that the typical lifespan more or less okay that the if I were going to design the system and again I was not consulted the design phase I would want an Adaptive uh trait to be passed for two generations because given the way that our given how long our species lives and certainly given the way the world looks now as opposed to the turn of the the previous Century or the turn of the previous Century different stressors different adapt you know different life environments um and what I would want to pass on to my Offspring I can basically Hedge pretty well I can place a good bet on the next 100 years maybe the next 200 but I don't have the foggiest clue what the world is going to look like in 300 years is what I'm saying make any sense whatsoever it makes a lot of sense and really it we need to to talk about two things in response to this question first of all um yes you can imagine that the reason that the worms inherit typically for three to five generations is that this is relevant to something that happened in their environments for example uh we also show that when you star the WMS it affects the next Generations again for a few Generations which itself is amazing right I just like want to highlight that that I mean you can imagine Next Generation sort of like a genetic version of be careful kids but I'm going to give you this extra lunch pack in your genome that protects you against the possibility of starvation but it's also saying and were you to have kids they have it also yeah so I have to but just I have to just make a disclaimer that we not don't know that necessarily it's adaptive could also be damaged and as I said when you starve them the next Generations live longer but this could be a trade-off of a trade-off for fertility or something so other labs also have also shown following our work that if you starve the worms the next Generations are also more resistant to harsher starvation this sounds this is not my artwor but this sounds adaptive okay but when whenever you're talking about adaptation you have to see it in the context of evolution there's also this famous saying nothing in biology makes sense except in the light of evolution and so it's very hard to say without doing the lab Evolution experiments we actually see who wins the ones that in hurt or the ones that don't H who takes over otherwise it's it's hard to talk about whether it's adaptive or not but when it comes to the duration of the response yes it could be programmed to fit something for example if you're talking about starvation worms transition between periods of starvation and trans periods where they have a lot of food so let's say they find an Apple for a few Generations they will consume the apple and then they will be stared for a while perhaps per this is the number of generations that takes them to finish an app or perhaps there are other responses also to higher temperatures H if you grow worms in higher temperatures the offerings are are different they change how they mate so what I'm i l the two before we're going to get back to this because it relates to cold exposure which many listeners are interest and perhaps it is somehow correlated with uh um um the cycle of the Year okay but to tell you the truth I don't know as I said we we um we go from the more artificial to the less artificial if double strand RNA just synthetic RNA is the most artificial starvation is more artificial more natural but it's not starvation in real the real context of the world in a real Apple it's a plate with or without eoli bacteria but it's not an apple on a tree exposed to the elements with other worms with bacteria with all kinds of complications and it could be that we will see different do ation of heritable effects the more natural we go it's just much less controllable and hard to do and again when we're talking about humans part of the argument why people were the disbelievers it's not about faith but you know the critics say that this wouldn't happen in humans is they say you know the worm's generation time is just three days the chances that the parents environment would match the children's environment is very high because there's not a lot of time to for for the environment to change and plus they can go very far small there are many examples of epigenetic inheritance in Plants this is a big field where there are very established uh proof for inheritance of acquired trait for for epigenetic inheritance be more careful epigenetic inheritance is more loaded 10 but in Plants it also happens and there you also say these are cile organisms they can't run away so the environment is more constant well ideas maybe just a quick example that I've heard before tell me if I'm wrong I very well may be uh for instance a particular species of plant that grows a a straight maybe slightly bended stock might be exposed to some environment where in order to capture enough um sunlight and other other nutrients might need to grow in a cork screw form the cork screw form can be inherited several Generations this is an example that I don't know but perhaps it something like that I seem to someone will tell trust me the one thing we know about podcasting and YouTube is someone will tell us in the comments so uh please do we invite that right but there's a long history of epigenetic inheritance studies in plants with excellent studies well controlled showing that it happens also there so this is very clear when it comes to humans you could say maybe my kids will go off to live in a different continent and they will be on the computer every day and everything will be different so it makes less sense to prepare them for the same hardships that I experience however this in my opinion this is this argument comes a lot it's not the best argument because it depends on the scale of of how you look at things we experience we meet for example I'm not saying that this is inherited but in humans but we experience the same pathogens and the same viruses all the time so perhaps it is worth preparing for that again I'm not saying that that it happens but but it depends on the on the on the scale well what you're describing makes perfect sense and I do want to acknowledge these critics whoever they may be I do have the advantage that I don't work in this exact field and so I'm I'm happy to stand um on toe-to-toe with those critics now and say that at least in terms of an inheritance of reactions or adaptive or maladaptive traits to stress or to reward you talked about nicotine before you know passage of response to drugs of different kinds not being specific to nicotine it was sort of a more General um passage of of some sort of information related to uh reactions to chemicals present in nicotine but other other drugs I have long been irritated um and a little bit tickled by the fact that people say oh you know we have this system for stress that was really designed to keep us you know um safe from lions and saber-tooth tigers sure but the Hallmark of the stress system is that it generalizes I mean if I get a troubling text message or if I suddenly see a dark figure in the in the hallway when I go to the bathroom at night that I don't recognize both of those have the same generic response which is the deployment of adrenaline uh in both brain and body you know changes in the Optics of the eyes quickening of the heart rate stress is by Design generic and so one could imagine that a passage of of some sort of stress resilience um or a maladaptive passage to stress would be also somewhat generic and that's actually advantageous overall same thing with the reward system you know we have essentially have one or two chemical systems of reward I mean there's the opioid system and there's the canono system but in large part anticipation and reward is governed by the dopamine circuits and anticipation reward of an ice cream cone for a kid is the same neural circuitry that's going to be repurposed when they get to reproductive age and they are anticipating creating children with their mate and assuming they want to do that the dopam energic system is going to be engaged so ice cream sex um you know uh stress to weather stress to famine the the biology of of these more modal systems in especially in the nervous system are again I have to be careful with the words by Design are certainly generic and so I don't see the need for so for immense specificity I mean it's not like we're um well covid just happened so could you imagine that there's the passage of a a covid-19 specific resilience no I think what would probably be um pass along would be some sort of if it does occur would be some sort of resilience to viruses more generally and that would be advantageous right so I I agree and this this opens the question of what is the bandwidth of inheritance how spefic specific can it be does it make sense for it to be specific and in the case of C Elegance the response can be very specific through this inheritance of rnas which are just sequence specific they done regulate they they control one particular Gene okay in other cases it could be a very general response and and and and it's very interesting to think about it when we talk about inheritance of memories which is the most interesting thing we could imagine can brain activity of some sort transmit at least in these worms I said you know I I said this disclaimer multiple times in in memers we don't know times will tell in worms we know a lot H so can worms transmit brain activity to to do they have the specificity to do it okay before I'll say that I just say that we over the years learned a lot about the mechanisms that shuttle the rnas between Generations we know about genes that are needed just for that about worms be perfectly okay but just don't have the capacity to transfer the rnas to the next Generations we know about genes that will make the responses longer or shorter we know about genes that prevent the transfer of RNA between different tissues about genes that make certain small rnes so we know a lot about that and then the question arises we can we can finally ask can memory transfer between generation I think that first of all we need to Define memory for this and the broadest definition would be any uh change in your behavior because of what happened in the past or in your response because what happened in the past or because of your history the more interesting part of course is to talk about memories that are encoded in the brain and the reason is that the brain is capable of holding much more specific and elaborate memories then I think that any tissues that transmit transfer to transmit RNA to the Next Generation and affect the next generation is interesting the guts muscles everything but the brain can synthesize information about the environment and about internal State and can also think ahead and the most provocative thing you can say is that you could plan how somehow the fate of your n of your n generation using your brain but you know after taking many things into the code this is without talking to them right without talking right and instruction so it's again we go back to this instruction manual it's like writing something into the instruction manual based on your own experience right and and can it happen okay and what is the Ben but can we transfer specific things and and then I have to agree with you that I would imagine that what can transfer and I could be wrong is a a general something sensitivity okay you can make the analogy to a being inflamed or not hyper sensitive to pathogens hyper Vigilant something like this okay but it can also be something very specific now we have to we have to understand that the brain uses a different language than the language of inheritance the brain the way we normally think about the brain is that it keeps information in Sy upses in the connections between different neurons when you learn something you make you make some connections stronger and some con other connections weaker and you wire the nervous system in a different way the information in the brain is synaptic and it is in the connections on the other hand heritable information of any sort has to go through a bottleneck of one cell the fertilized egg because we all start from just one cell so it cannot be in the connections because this cell doesn't have any connections with other cell it's there alone so it so heritable information has to be molecular it has to be inside this one cell so the question is can you or do you translate the information this fre structure information of Sy upses and the connection between in the architecture of the brain can you somehow translate it to heritable information to a molecular form it's an incredibly important and deep question H it brings to mind something that was once told to me which as soon as I heard it was obvious but was very important in formulating my uh understanding of biology which is that uh a map is just the transformation of one set of points into another set of points right so a map of of the world essentially is just you take the what's been drawn out in terms of the architecture and the the coastlines Etc and divisions between states and you transfer that to an electronic map or a piece of paper seems so obvious it's sort of a duh why are we talking about this but just to make sure that people understand what you're really talking about is let's say the memory and I have a very distinct memory for um my childhood phone number phone number doesn't exist anymore and I won't give it out because then some other person might get IR with repeated calls but in any case I remember it it's totally useless information but it lives in my neocortex or my hippocampus or somewhere as a series of connections between neurons at the locations as you call synapses would my grandchildren know that phone number there's no reason abely no right would my children know that unless there was some adaptive reason or some other reason for them to know and the and this passage of of acquired traits um and what you're saying is in order for that to happen there has to be a transformation of the neural circuit literally the wiring of Neuron a b c d that relates to and carries the information of that number into the kind of nucleotide sequences that are contained in DNA or patterns of methylation or RNA more likely so it's the transformation of one set of points in physical space to a translation of points in genetic space right right and then we have many problems when it first of all we don't know of a mechanism to translate between the two different languages the language of the brain and the language of inheritance we are not familiar with a mechanism like that second the Next Generation if it's not a worm if it's a mamal would have a different brain even if it's if even if it was genetically identical to the parent the the wiring of the brain and the particular neuronal circuits will be different this is true for twins it will always be true because it depends because it's partly random and it depends on the environment even if you have the same genetic instructions so let's say you somehow had a mechanism Miracle mechanism to take the 3D information and translate it to the magic to the language of inheritance you would then in the Next Generation have to translate it again to the brain although it is different this sounds very unlikely I I'm playing a trick on you now okay because I believe it I'm eing the trick so that's but but but but if if this is how it happened or if this was required it could never happen in my opinion which means and I still think that certain memories that cannot transfer transgeneration these is complex and things that you learn about the environment that are arbitrary if none of our listeners kids will remember this conversation no way this is impossible unless unless they're listening there are some families or parents that tell me they listen but but but it cannot transmit because it's it's random and it's these are connections that are arbitrary so this seems to be a limitation on what can transfer on the the other hand so so perhaps more General things could pass some the these type of things I doubt they can however you can never the less imagine that something that are very specific some memories that are very very specific could nevertheless transmit from the brain after learning to the Next Generation I'll give you an example you can teach worms even though they have just 32 neurons you can teach some simple things about the world for example you can take an Odo that the worms like the worms have thousands of odorant receptors and they can recognize many many many molecules they can smell them so they can find food or avoid enemies you can take a food that the worms like an order that the worms like and pair it to something bad like starvation and then the worms will learn to dislike this uto we don't know that this learning involves necessarily changing in the strength of copses it's a possibility but it doesn't have to be the case it could be that just the receptor for this particular order is being removed when they and this is how they live now they won't have the receptor they won't smell they won't like the othero this is a possibility this type of thing you can perhaps not that anyone has showed it convincingly transmit to the Next Generation because all it would take is an RNA that would will control this particular receptor okay so this is a possible people have shown things like that not in Sea Elegance but people have shown things like this in mammals they said that you learn certain thing and then just in the next Generation does a particular receptor would be meated or would change and this would transmit the response and on the one hand it could be true on the other hand you need to understand they need to prove and this wasn't done convincingly enough yet how exactly does the information transfer from the brain to The Germ cells and then in the Next Generation from The Germ cells back to the brain to where the receptor need receptor need to operate and this is a challenge this is the current state of of the field that this is something that needs to be proven what we did in C Elegance is we showed that certain that the brain can communicate with the next Generations using smaller M and that this can change behavior and it doesn't require any translating between any language it is very simple what we've shown is that if you take a worm and you change the production of small Ras just in its brain in the next Generations their behavior will be different even though you don't mess with their brains this is a paper that we published in 201 19 in sale we show that you just manipulate the production of endogenous natural rnas in the worm's brain that are always made but you you change their amount and this changes the capacity of the worms in the Next Generation to find food to find not only in one generation but three generations down the road and the way that it works is that perturbing the production of these small Ras in the brain affects in the end the expression of a gene in The Germ line one gene is called sage two don't know how it works but we can do all kinds of controls where we manipulate the activity of the Gene and see that is also affects behavior and this Gene works in the jum set the information needs to go from the brain to The Germ cells it doesn't need to go back from The Germ cells to the brain to affect behavior and this depends we know that this is a to epigenetic effect because it goes on for multiple generations and also because it requires the Machinery the transfers RNA between Generations if you don't have the protein that physically carries the RNA between generation doesn't happen so it it has to be RNA it has to be RNA and and we can actually we can also find the rnas in the Next Generation that change we sequence the actual rnas the change in the Next Generation you mentioned that you don't know what Sage this Gene Sage does but is it reasonable to assume that it does something in the context of the nervous system or that's unclear as well it is possible it is possible but we have reasons to believe or experiments to to show although there could be alternative explanations that it functions through the germ line now you may ask how can you affect Behavior just by changing the germ cells right well it would have to change the germ cells in very specific ways because as uh people probably recall the germ line germ cells are where the inheritable information is contained but you could imagine it for instance um adjusting the gain or sensitivity rather on um some sort of uh sensory foraging system right right and and the the the interesting thing is it again can be quite unspecific so it sounds weird that you change cells and it changes Behavior sperm and egg but if you think about it is triv if you castrate a dog it behaves differently right sadly yeah I did that to my dog and I ended up putting him on testosterone therapy later and it brought him back yeah just as a as a as an aside yes this is because the germ cells affect the Soma including the brain in many ways by secreting certain chemicals and also because the other cells devel develop from the from the germ cells so some information could be transmitted over development or the course of development could be altered because of changes that occur in the germ cells and for example in MLS one of the explanations for how heritable information transmits is that it just affects something very own in development I I I told you that the secrets to worms inheritance is that they have the capacity to amplify the smaller all the time this is what keeps it going and prevents the dilution in mammals we don't know of such an amplification me so you ask how can a little bit of RNA or something without amplifying affect the entire organism and it could be that you just perturb something in the very beginning when you just have a few cells or even if the in the placenta that develops in pregnancy and this later throws everything off and because of that you you have many problems in metabolisms and so on and this is called the the it's an idea of the develop developmental origin of health and disease many of the of the functions occur early on in development so you raised a number of incredibly fascinating aspects of this I I do have a question about one particular aspect and feel free to pass on this for a future episode if it's going to take us too far off track but something you said it really captured my attention um although I was listening to all of it which is that the germ cells so in the case of males it's going to be sperm and in the case of females is can be eggs something perhaps not coincidental about those cells in the environment that they live in is that yes they contain the genetic information a past to offspring right of course you explain how that works but also it's a those cells live in a region that is Rich with hormones that can be secreted and in fact are secreted and through so-called endocrine signaling communicate with other cells not just at the level of receptors on their surface but also can enter the genomes of those cells and modify those cells in other words it seems to me that the micro environment of the germ cells the testes and the ovaries are rich with information not just for the passage to next Generations but also for all the as you said all the sematic cells of the body they're telling the sematic cells of the body what to do and what to become and the best example I can think about this would be puberty right I mean I would argue that the that one of the greatest um rates of aging and and transitions we go through in life is from puberty I mean a child becomes a very different person after puberty they look at the world differently they think about it differently the growth of it's not just about the growth of the hair and the jaw and the atoms apple and breasts and so on it's a transformation of the somatic cells from the same micro environment that the DNA containing uh cells reside right so once you think about it like this it becomes obvious that just by affecting the germ cells you can affect the rest of the body and in cgans there are experiment that show it very clearly so for example if you take just take worms and prevent sperm production it changes their capacity to smell these are experiments done by others which is obviously a brain function and in a castrated dog you're not just eliminating the the possibility of transfer of DNA information to subsequent uh Generations you're also limiting communication of the yeah oh without question my Bulldog costell changed after castration and it was a wonderful dog but at some point developed some health issues the introduction of a small amount of testosterone every other day changed him fundamentally mentally in that case for the better um back to a version of himself that I had only observed earlier but also a different version of the same dog and know he wasn't humping everything maybe the occasional me um particular bble who whose names I won't mention but it was absolutely clear that the hormone was not just taking a system and amplifying it it was actually modifying the system so anyway I just wanted to um highlight that and then now um thank you for indulging me uh let's um if you will let's continue down this path of uh that we were going on because I want to make sure that we absolutely get to this issue of transmission of information about sex choice of Offspring so the worms are herodes which means that they make both sperm and an egg but there are also males which are much more rare and they can choose to mate with males or not and when they mate with a male it's a huge decision because it's very costly energetically and they also risk predation and all kinds of troubles the males hurt them and reduce their lifespan when they met with them people are going to draw all sorts of analogies here but it's inevitable but hey here we go yes and and most importantly for evolution when you mate with another animal you dilute your genome in half because the worms can just self fertilize and transmit the exact same genome to the Next Generation but when they make they dilute it in half so this is a big price to pay on the other hand when you mate you diversify your genome so so maybe some combination of Gene will be good and we know that in humans I mean you know it's kind of interesting that the brain circuits that are associated um with a with a verion and with approach are um fairly hardwired for a number of things like puddle of vomit almost everybody kind of cringes plate of cookies if you like cookies you move towards it but there's one particular word in uh the English and particular the Israeli language that that ought to evoke disgust and that's incest because incest is actually not just disgusting as a practice but it's Danger ous genetically right because of the in breeding creates aerious mutation right so there are studies on how people in Israel kibuts for example where they all grow together the children live together it used to be like that don't date each other but this is their classic thing I talked to someone from the told me that's not true but but yes there are studies like this that say but it makes sense and in some countries Scandinavian countri or in Lapland and Iceland where populations are small they keep Exquisite records of lineage in order to avoid inbreeding right yeah right so you're absolutely right but the worms it's the safe choice for them is to self mate and and if they mate with a male they take a risk but they diversify okay what what we found is that if you take the hermaphrodites the the we can call it the the female for just one second and you stress it with high temperatures then the next Generations of worms for three generations mate much more with males and they do it because the female starts secreting a pheromone that attracts the males ah it's very cryptic uh mechanism it's not that she somehow changes and then goes seeking males it's that it draws males in it draws M we know how it works we think we know how it works what happens is that the stress the high temperatures compromise the production of sperm in the hermaphrodites so the hermaphodite don't they make sperm enough to to make next Generations but the sperm because of defective small RNA inheritance because the RNA are not inherited okay the sperm is not made optimally so they make less sperm and when they don't make a lot of sperm they feel that they don't sell fertilize correctly so they call the males by secreting the feromon so that it would provide its own sperm and they can continue to make babies okay and we know this also from experiment you just take herodes and you kill it sperm start secting the pheromone and the males come it's a need based system exactly exactly incredible and I I hope people can appreciate as they're hearing this that none of this we assume I don't know how to speak worm none of this we assume is a conscious decision in these animals they much like human mating behavior which to us always seems so conscious but is being governed by both conscious and subconscious decisionmaking none of this is an active decision to secrete the hormone to draw in more males it's simply a biasing of probabilities right the hormone is now secreted in in Greater quantities or more greater frequency the Nails therefore approach more so it's just increasing probability of interactions is that right right what happens naturally normally if you don't stress the the ancestors is that the worms start secreting the Fone only when they are old this also no people will when they're run when they're running out of of their own fertility ex exactly because they only make the sperm at a particular time and then they run out of Steal sperm they can sell fertiliz so they have to call the males if they want to continue to M well this is sort of the uh plastic surgery approach okay I'll take the heat for that one but you know but it's true I think as as certain people age to a certain point and they feel that their fertility is waning if they want Offspring they need to take any number of different approaches they could get a here we're talking about a female but we could also do the reverse right we um a sperm donor right or but if they want to attract a lifelong ma or co-parent with somebody often times they will um do things to adjust their uh attractiveness in any number of different ways psychological attractiveness or physical attractiveness I'm not afraid to bring this up because I think that the parallels are very important because I do think that every species and individuals within a species of course decides whether or not they want to reproduce or not but has an inherent understanding conscious or subconscious about where they reside in the Arc of their lifespan I do believe that not just based on experience um some people are very attuned to the the uh passage of time being very fast others very slow I think that knowing how long your parents and their parents lived makes a big difference I have friends whose um fathers in particular died fairly young and all these guys basically got married and had kids really young right so here the luckily for me I don't have to get into psychology of the worms the explanation is just like an instinct when they run out of sperm they start secting the fermon and attract the males there are studies also in humans about older fathers that children of older fathers have more has a higher chance of have of becoming autistic there are studies 40 and up basically however in this case it's not clear that this is not that this is something epigenetic could be just because of DNA damage you know because it accumulates and actually nowadays there uh we have an episode on fertility coming up both male and female fertility and there's um uh there're actually DNA fragmentation kits for uh at home DNA fragmentation kits or sperm analysis you send the sperm back in you don't do the DNA people pipeing on um Sean at home would be an odd picture let's not go there but the um but there are clinics that do this for a for a nominal charge but the um but it's I did want to ask about autism and human disease in particular um another thing that you hear sometimes and here I want to acknowledge autism is on a spectrum some people get upset if you call it a disorder there are some adaptive autistic traits and Etc but one thing that um often comes up is this idea that two people who are more of the kind of engineering um hard science if you will of phenotype mate and have children higher probability of The Offspring being on the Spectrum um some people would argue op but that's already selecting for people that might have already been partially on the Spectrum so maybe it's a gene copy issue I'm not asking you to comment on autism in particular but when you hear things like that that uh the children of older fathers um born from older fathers tend the higher probability of of autism what is that at the level of intuition does that strike you as an epigenetic phenomenon as a nature nurture um mishmash or the possibility that it's RNA passage um or anything does anything sort of um trigger the whiskers uh your your your your spidey sense so in that case I would go with the most parsimonious explanation which is it just less Fidelity of of DNA less DNA maintenance and some damage that passes on it doesn't have to be an epigenetic thing but the sperm are generated at once every 60 days so the damage must be at the level of The Germ cells not having the proper Machinery mitochondria or something like that or or the DNA repair Machinery the DNA repair Machinery could be defective or or could work less well in older people leading to the constant production of germ cells with more mutation this is a possibility do we know exactly what the DNA repair Machinery is yes there are many types of DNA repair there's one that use uh other copies of the DNA to to uh uh to correct there there are ones that just recognize all kind of lesions on the DNA and and remove it that it it's a very elaborate and complicated system and is it a system that is now tractable that can be uh modified through pharmacology or through anything like that so I don't know about drugs that correct that improve it maybe they exist and I'm not aware but it's very well understood and uh many people are studying these Direction yeah one thing that um came across in the uh exploration of the fertility work is that what I'm about to describe is not legal in the US it is illegal but is legal in the UK and in other countries is this notion of three parent um IVF where it does seem that some of the eggs that persist in older females um don't uh even if fertilized don't produce healthy embryos they have chromosomal abnormalities replications and and um deletions that are problematic for the development of the embryo such as tric 21 AKA Down syndrome in part or in large part because of deficits in the mitochondrial genome so what they now do is they take the um because the mitochondrial genome resides mainly in the cytoplasm they'll take the uh an egg from the the mother the sperm from the father but they'll take the nucleus from the mother and put that into a cytoplasm of a younger woman whose mitochondrial DNA is healthy then use the sperm to fertilize that egg and a and that's why it's called three parent IVF then implant that into the mother and this has been done several times for in cases of mitochondrial damage or or um mutation in the in the mother it works the question is whether or not those Offspring will grow up to be healthy so this of course is not just a pure Divergence it raises a bigger question that I have for you which is in terms of the work in either cagans or in other model organisms but in particular in cigan where do you see this going next and if you would indulge us I would love you to tell us a little bit about the admittedly unpublished work that you're doing on temperature uh exposure and environments I mean how Mal is this system because to me it just seems incredibly malleable um and yet a lot of is still cloaked off to us there's still a ton to learn so assuming that we will discover similar things in in humans which we don't know that this is the case but let's say we we find it I think there are many things you can do before you change it for example you could you could also change it change a barent inheritance by having the the parent exercise for example and some things like this have been done for example there are experiments in in rodents where they show that overfeeding the U the the radent creates problems for the next Generations for the for the children however if you let the the the rodent exercise then it corrects The barent Inheritance so this is one possibility and you can also manipulate it at the at the source you can change if it's rnas let's say you could in the future perhaps if we we understand how it works actually change the composition of the heritable rnas by eating rnas just like the worms RNA sandwich no so the RNA sandwich will be difficult because it's not I don't know but but you could if you do IVF if you do VTO fertilization you can perhaps change the composition of the rnas in the the stuff that you introduce but way before that what you could do perhaps even in the not so far future is use this for Diagnostics DNA based diagnostics for every couple that wants to have a kid uh you can in Israel this is done for for most couples you can look at the DNA and look for genetic disease but no one look is looking at the RNA at the moment if we understand how it works better we'll have another level A Whole New World to look at and perhaps there will be some rnas that correlate with disease that that will say okay you know the beauty is that this Unlike DNA it's plastic so with DNA this is your DNA perhaps we can choose embryo but here you could say perhaps again in the future this is science fiction doesn't happen now but if we understand this and it's true we can say maybe you should run on the tread mid a little bit this will change the profile of your rnas and then we will use it for IVF this seems more because just it correlates with healthy profiles of rnas this is a level that no one looks at now and holds great potential again with a disclaimer that we don't know how it works in humans at all yes yes but of course this is why why why so interesting yeah it's super interesting um incredibly promising so along the lines of things that one can do in the short term and your experiments on celegans I'd love for you to share with us what you're observing about cold exposure and how that impacts subsequent generations of celegans and uh and if you would indulge us with the story of this discovery um like some of the earlier stories you told us it is a a surprise in and fascinating one I'll gladly tell you about this is not a story about transgenerational inheritance it's a story about memory within one generation ah excuse me within one generation okay and and as you said the story of how it happens is it's it's it's totally by accent it's a funny story and I'm I'm bringing this up because I know Dana L is a huge fan of your post will really you know be happy that this her work this is her work and this is unpublished work it's it's even we didn't even finish it so we're working in okay well when published we will feature the paper because I love this story great so so what happened is that when you we talked about transgenerational memories and I said that in worms there are very long transgenerational memories if if a generation time for Sagan just 3 days some memories last for many generations so Way Beyond the the lifespan of the of the worm the lifespan of the worm is three weeks okay gener you have a new generation every three days but every worm lives for three weeks but there's a lot of research that shows that unlike heritable memory which can be very long the memories that the worms acquire during their lifetime is very shortlived so if you teach it something after two hours it forgets okay so for example you can teach the worm you can take an order that it likes and pair it with starvation and then it would dislike the order and then there's a simple test you just put it in a plate you put the the order in one side and the control order in the other side and you whether it prefers this order or not and it stops preferring it okay there is 30 years or more of research 40 Years of research on on this showing that the worms forget after two hours the reason I went to study C Elegance is that I wanted to understand memory because such a simple nervous system you say maybe I have the potential to actually understand how it works but this is slightly disappointing because they forget after two hours so what is it exactly okay my idea was and I tried to convince students to do it for 10 years is to take the worms teach them this Association to dislike the oo that they innately like and then just put the worms in minus 80 and freeze them freeze them completely th them and see whether they still remember after they are thought the Han Solo experiment and and I didn't want to do it because of cryo preservation or something like this I wanted to do it because as you know better than me many theories about memory say that you need electrical activity to maintain the memory you need to rate it in the brain during dreams or replay of the thing or whatever and if the memories will nevertheless be kept even though the worms were frozen in minus 80 it would mean that it was kept in the absence of of electricity because there's no electricity in minus 80 degrees this was the idea I asked many students no one wanted to do it because of it's it's not so easy and also a little crazy well and when the pi the principle investigator lab has a pet experiment no one wants to do that experiment that is University tool so and then Dan I agreed to do it Dan L shift I was very happy only later to find out that she ignored me completely and did a different experiment the experiment that dat did in in instead is to just take the worms teach them the association and place them on Ice she wanted to see how the kinetics of memory and forgetting change in low temperature because maybe whatever memory is the breakdown of the memory is affect by the temperature a very simple idea we know different experiment a different experiment but a cool experiment very cool and what she found is that when you place the worms on ice after you teach them they just don't forget if even 10 times longer than control worms at that point after 24 hours if normal worms forget after two hours after 24 hours the worms will become sick so normally we do shorter experiments okay but for 2 hours the worms don't forget this is cool but it was only the beginning because the boing explanation is just what I just said that everything slows down in low temperatures so the breakdown of memory again we don't know what it is but whatever it is happens slower in low temperatures but this is not the case it's not merely the physical it's the response it's the changing of the internal state of the worms which affects the memory kinetics how do we know this there's a beautiful work over the last one years on cold tolerance in Seance nematodes if you take the one and you place them on ice like she did but longer for 48 hours they all die however if you take the worms acclimate them to lower temperatures for a few hours five hours it's a minimum and then place them on Ice they all survive they become cold tolerant and people who study this show that this involves changes in lipid metabolism and many things so Dana took the worms acclimated them to slightly lower temperatures made them cold resistant and then taught them the association and placed them on ice and now they forgot immediately which means that when they change their internal state to become cold tolerant they no longer extend memories on night which means it's not only the temperature because the temperature is anyway low now they don't remember we took this as a starting point to understand what which genes change when the worms are becoming cold tolerant on and off ice and we found genes that when you mutate them the worms just remember longer always even when they're off ice because these are the genes that normally change when they are surprised on the ice and these genes are expressed just in one pair of neurons just two out of the 302 notice he said 302 not 300 and we can manipulates the activities of these genes in these neurons to extend memory and then the punch line of everything that happen is that we found out that this this neuron where this genes function this one pair of neuron is the only neuron in silance which is sensitive to lithium and lithium is a drug that is being given to bipolar disorder patients for decades although it's not entirely clear how it works it's very very interesting is also interesting there's an episode of course in your podcast about this you know more about this than me a lot but it's also interesting because it's just an atom created in the big bank yet it works on our brains in such a fundamental way and we wanted to see whether it works on also on the worms because this neuron was tied to this memory extension phenotype that we found so Dan grew the worms on lithium remov them from lithium taught them the association and found out that they learn a lot long they they remember a lot longer than control worms not only that if you first make the worms called tolerant and then lithium doesn't work on them so lithium switches this forgetfulness mechanism on and off amazing and it it all and it all connected to C tolerance amazing and amazing for a number of reasons and so at risk of being long-winded in my response I just wanted to highlight something um that I think will be of relevance to most people which is when uh at some point we did a few episodes on memory um and I highlighted a review that was written by the great James mcau one of the great malean memory researchers who's worked a lot on humans and mice and I was um shocked pun in ended and uh amused to learn that in medieval times if people wanted children to remember lessons they could be religious lessons or School Doctrine or whatever it was mathematics what they would take children teach them and then throw them into cold water to introduce a a memory instilling event and we now know that the memory instilling event is the release of adrenaline in the body which makes perfect sense if you think about traumatic events but it also this whole General mechanism also applies to the learning of other types of information and so if I understand correctly about the role of lithium and the role of cold in the experiments that you just described there's some General State switch some internal State switch that says what happened in the uh minutes or hours preceding this was important it acts as sort of like a highlighter pen in in the book of experiences exactly um and I'm absolutely curious to know whether or not this is an RNA dependent mechanism in some way so is this literally like the highlighter in the Ikea instruction book this we don't know this we don't know and as I said this is not even a finished work it's not peer-reviewed it's just the state that I told you about but um but it's it's very exciting for for me to to go into this new field and you know once it's out I'd be happy to to talk more about it uh and think about the implications and the connection to other things and more about the mechanisms yeah well thank you for uh sharing it with us despite the fact that it's not finished we um people now know that it's also not finished and I love a good Cliffhanger so we we await the full the full conclusion and interpretation of these results today you've taken us on an amazing journey through the genome RNA uh short interfering rnas um a ton of history of Prior experiments some of which ended tragically many of which unfortunately did not they were true triumphs and um in particular the work in your laboratory which is just incredible and also this introduction of model organisms so and I mentioned a short handful of the things that uh you've taught us about today so first I want to extend thanks for the incredible teaching I also want to say thank you for um something equally important which is uh that absolutely came through but is what initially um brought me to explore you and your work more although I had certainly heard of you which is that your spirit and kind of approach to biology um is an is an extremely unique and intoxicating one it's even I venture to call it seductive it's you know there's a I I do believe that whether or not it's music or poetry or science or uh mathematics that um the spirit behind something dictates the amount of intelligence and and precision with which that thing is is carried out and um it absolutely comes through so if I'm making you feel on the spot about this I've succeeded thank you thank you very much but I I know that the listeners can can feel it it's it's a felt thing so thank you there there are um many scientists out there a fewer with this phenotype and even fewer that um you know I think that can communicate with such uh articulate Precision so thank you so much thank you it's been a real pleasure pleasure was all mine thanks a lot great well we'll do it again and we'll learn about all the incredible things you're doing trying to transform science as it were at the level of publishing at the level of social media because there's a whole other discussion there meanwhile we will of course Point people in the direction of you and um to learn more about your work and um I look forward to hearing the conclusion of Dana's studies thanks a lot it's been a real pleasure thank you for joining me today for my discussion with Dr ODed Ravi about genetics inheritance The epig genome and transgenerational passage of traits if you're learning from and or enjoying the podcast please subscribe to our YouTube channel that's a terrific zeroc cost way to support us in addition please subscribe to the podcast on Spotify and apple and on both Spotify and apple you can leave us 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