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

Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health, and performance. I'm Andrew Huberman, and I'm a professor of neurobiology and opthalmology at Stanford School of Medicine. And now for my discussion with Dr. Oded Rakavi. Oded, thank you so much for being here. >> Totally my pleasure. Today, what I mainly want to talk about is the incredible questions that you probe in your lab, which are incredibly significant for each and all of our lives. I think most people have a general understanding of what genes are, what RNA is, and so on. But maybe you could 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 their offspring will have blue eyes than brown eyesh. Mhm. >> But 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 nurture in that case but that they wouldn't inherit knowledge. 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 DNA are the is the material the genetic instructions that is contained in 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. Genes are made of DNA and chromosomes that 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 amounts that you have to condense. And we have the same genome, the same DNA in every cell in our body. It's good to have an analogy to to understand how it works. 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 kitchen, the pictures, 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 remove one particular page of instructions, which is the instruction of how to build a chair. H and this you place in the living room. Okay. And the toilet you put in the toilet. So the genome the is the instruction to make everything. This is the care book. And in every cell we we take just the instructions for make one particular furniture. And this is the RNA. And then the end you'll build a chair. The chair is the protein. This is true for one particular type of RNA which is messenger RNA. 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 it encodes for this messenger RNA. However, a lot of the genome is transcribed to make RNA that does other things. Some of these RNAs we understand and many of them we don't. I think it's a beautiful description and IKEA is not a sponsor of the podcast. So 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. Despite the fact that the same genes are contained in all the cells of the body, is it fair to say that there is basically one very important exception which is sematic cells versus germ cells. And would you mind sharing with us what that distinction is? >> So yes, every cell every cell type is different. 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 serotonin and so on. 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 an 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 soma should not be able to contribute to the next generation. This is very important and is sought 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 sperm 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 in 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 this short out won't won't happen. This is something that we know intuitively even if we don't have any background in biology. 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 h acquire the mutation or a change in your DNA in one of particular brain cells, 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. There is this idea and I'll say it so that you don't have to that dates back to Lamar and Lamarian 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 with another endurance runner and has in mind the idea that because they did all 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. This Lamarian 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? Lamak this is what he believed and and he thought this what is this is how evolution progress progressed and and later um Darvin showed that it's really natural selection the selecting of the organisms that already contain 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. Most common way this is contrasted is the neck of the giraffes. This is the classic example. According to to Lamach, the giraffes had to stretch their necks towards the trees to eat when the tree when the trees were high. And because of that the they transmitted these traits long necks to their children who also had long necks. And according to Darin just that the a gerat happened to be born with a long neck survived because it ate. So it's genetic heritable material. didn't know about genetics but take over and the rest of the giraffes that have different heritable materials just die. So this is natural selection versus inheritance acquired traits. And then we go back to to to these uh studies about inheritance of acquired traits. There were also theoretical problems of why of why this can't happen barriers that have to be breached for this to happen. And you can narrow it down to two main barriers. The first barrier we mentioned it this is the separation of the soma from the germa >> right the sematic 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 from what happens in the soma >> okay the man who who first thought about this barrier is called wiseman August wiseman this was in the 19th century so it is called today the wiseman barrier separation of the s from the germ line only the germ line transmitting information from it 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 our bodies work. The other main barrier it's called epigenetic reprogramming which is that we acquired our diff our cells the the genetic material in our cells acquires all kinds of chemical changes but these modifications are largely erased in the transition between generations. So in the germ line in the in the the the sperm and the egg and also in the early embryo most of the modifications are removed. 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. Mhm. So to preserve this we erase all these modifications that start a new and this is in in mammals and in humans this is largely true. Most of the modifications on the in the sperm and in the egg are removed. So about 90% of them. >> 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. The instruction book >> is the one that's issued to everybody, okay? Or every cell, right? Only certain instructions are used for certain cell, say a skin cell or a neuron or a liver cell or any other cell for that matter through the course of the lifespan of the organism. Those specific instructions are adjusted somewhat. Okay. So, maybe 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, >> right? Because if you want to bring back the instruction book, you want it to have all the potential to make all the furniturees. You don't want it to be restricted to the ones that you made in the particular room. So, part of the resistant resistant to the idea is based on the theoretical grounds because of these barriers. And because of the of the controversies on the other hand, people really want to believe it because it sorts 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 shreddinger the famous physicist so he wrote a very important book in 44 and he talks about the heritable material. also talks about evolution and he said inheritance of a quiet trait is untenable. doesn't happen and it and he writes this is very very sad or unfortunate because unlike Darvinism or natural selection which is gloomy doesn't matter what you do the next generation will be born based on the instruction in this the sperm and the egg 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 it however there's one additional thing to to mention which is there are also other mechanisms that might transmit information including transmission between generations of RNA and there are different types of RNA not just messenger RNA which encodes for the information for making protein but also other RNAs that regulate gene expression and I think that in recent years also in the malian 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 a lot more 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. 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. Before we start to go into the description about worms per se, could you just explain to the a general audience what a model organism is and why you've selected or elected to work on a particular type of worm to study these fascinating topics that there's zero question also take place in in humans at some level. >> Model organisms mean that it's an it's a an organism. there's a a huge community of researchers that combine sources to create all the the resources and the tools and understanding that accumulates. We learned about every aspect of biology through them including many important diseases. 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. We share a lot of our functions with them and also a lot of our genes. They sometimes have things that are much more apparent in them that we can study. 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 and we can change their genes do all kinds of things for them. The community of people that study segance has 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 mamalian model. mouse or certainly in humans and has posed huge challenges that u give great advantages to studies of things like sea elegance. >> Celigance neatode always has 959 cells out of which 302 are neurons. We have a me a conneto since the 80s like a subway map that tells us which neuron talks with which other neurons and it is the same. Not only that, the worms are transparent. So we can actually see the neurons fire using particular tools and we can activate genes and silage genes using optogenetics. On top of that we have great understanding of the genetics of the worm of of the genome. This is circans is the first animal to have its sequ it its genome sequenced before humans. And we know that and each worm produces each mother produces about 250 babies which are almost genetically identical. And we know 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. The generation time in silicance is 3 days. Three days. So you can do hundreds of worm generations in one PhD. This is very important. Not only that, every worm will produce hundreds of progeny. So you will have that are genetically identical. So you will have great statistics for your experiments. In the worm, we now have very obvious and clearcut proof that there is inheritance of acquired traits. So much so that I don't think that anyone pretty much in the epigenetic field argues against it. What was the first experiment that you did on Celeans that confirmed for you that inheritance of acquired traits is real? We said to test whether worms can produce transgenerational resistance to viruses. 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 using RNA that destroy viruses. And these are called small RNAs. 2006 two researchers that were studying segance Andrew Fire and Craig Melo got the Nobel Prize for showing that there is a mechanism that regulate genes that happens through small RNA. What they've shown is that if you inject the worms with RNA molecules which are which are double stranded, they shut off the genes that match in sequence to this RNA. So, it's sort of like taking the specific instructions for the coffee table from your IKEA uh handbook and you insert a copy of that into the book and in doing so you prevent the expression of uh you sort of erase the original page. >> Perfect explanation. 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 the paper was published in 98. There are now drugs that use this mechanism. It is called RNA interference. RNA interferes in the expression of a gene in the in the function of a gene. And it's al also called gene silencing because these RNAs enforce the silencing of genes instead of the genes being expressed. They are silenced and you don't manifest their function. They've shown two very important things. 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. This includes also the germ cells. So if you inject the double strand RNA just to summatic cells, even to the head, you will get also the effect in the germ cells and in the next generation. Later they've shown 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 injection from the gut where the bacteria are eaten to the rest of the body and also to the next generation and this is not controversial at all. This is being done routinely every day by any segance biologist in the world. This is has been replicated a million times. 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 smallerness, >> right? because um injecting RNAi or um in inter short 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 apart 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 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 tradeoff in fact this is probably the reason that these small evolved in the first place to get rid of viruses and other parasitic genomic elements and this is a mechanism to fight We demonstrated this very clearly using a fluorescent virus. If the virus replicates successfully, the worms just turns green. And if the virus is destroyed, the worm stays black. This is very simple. It's a clear cut off. We took worms, we infect them with a 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 RNAs 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 these small. And then we ask what will happen when we infect these worms with the vows? Will they be green or black? They can't make their own small RNAs. So they can't protect themselves on their own. The only way for them to stay black for them not having the virus replicate is if they inherit the small RNA from their pets. And this is exactly what happens. All the worms progeny although they don't have the gene that is needed for making the small RNAs are black. They science 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 the the advantages are small RNAs that match the viral genome then just chop up the virus in the next generation and we can identify these small RNA in the the inhibitory RNAs in the descendants although they don't have the machinery to make it just because they inherit it we can identify them by sequencing 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 inherit in small RNAs only if their their parents were infected with them. It is true that also in mammals RNAs and small RNAs are a linding 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 and it's very interesting to think about it when we talk about inheritance of memories can brain activity of some sort transmit at least in these words I said no I I said this disclaimer multiple times in in members we don't Now 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 I think that any tissues that transmit transfer to transmit RNA to the next generation and affect the next generation is interesting. The gut muscles everything but the brain can synthesize information about the environment and about internal states and can also think ahead. And the most provocative thing you can say is that you could plan how somehow the fate of your of your nation using your brain you know after taking many things into the code. This is >> without talking to them >> right without talking. >> All right. Again we go back to this instruction manual. It's like writing something into the instruction manual based on your own experience. >> Right? We have to understand that the brain uses a different language than the language of inheritance. It keeps information in synapses 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. 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 the question is can you or do you translate the information this 3D structure information of synapses and the connection between brains in the architecture of the brain. Can you somehow translate it to heritable information to a molecular form? You can teach worms even though although they have just 302 neurons you can teach them simple things about the world. For example you can take an odor that the worms like. The worms have thousands of odor ant receptors and they can recognize many many many molecules. They can smell them so they can find food or avoid enemies. You can take an order that the worms like and pair it to something bad like starvation and then the worms will learn to dislike this order. We don't know that this learning involves necessarily changing in the strength of sinapses. It's a possibility but it doesn't have to be the case. It could be that just the receptor for this particular Odo 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 order. 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 will control this particular receptor. Okay. People have shown things like that not in segance but people have shown things like this in mammals. They said that you learn certain thing and then just in the next generation thus a particular receptor would be metated 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'll 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 the field that this is something that needs to be proven. What we did in C elegance is we showed that the brain can communicate with the next generations using small RNAs 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 RNA 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 2019 in cell. 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 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 RNAs in the brain affects in the end the expression of a gene in the germ line. One gene is called sage 2. We can do all kinds of controls where we manipulate activity of the gene and see that this also affects behavior. And this gene works in the germ cells. The information needs to go from the brain to the germs. 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 true epigenetic effect because it goes on for multiple generations. And also because it requires the machinery that transfers RNA between generations. If you don't have the protein that physically carries the RNA between generation, doesn't happen. >> So it has to be RNA. >> It has to be RNA. We can also find the RNAs in the next generation that change. We sequence the actual RNAs that change in the next generation. So it sounds weird that you change germ cells and it changes behavior sperm and egg. But if you think about it, the germ cells affect the soma including the brain in many ways by secretreting certain chemicals and also because the other cells 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. For example, in mammals, 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 secret to worms inheritance is that they have the capacity to amplify these small RNAs all the time. This is what keeps it going and prevents the dilution. In mammals, we don't know of such an amplification mechanism. 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 in the placenta that develops in pregnancy and this later throws everything off and because of that you have many problems metabolisms and so on. And this is called the idea of the develop developmental origin of health and disease that many of the things occur dur many of the of the functions occur early on in development >> in terms of the work in either segans or in other model organisms but in particular in segans where do you see this going next? >> 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. You could also change a parent 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 rodent creates problems for the next generations for the for the children. However, if you let the the the rodent exercise, then it corrects the parent inheritance. So this is one possibility and you can also manipulate it at the source you can change if it's RNAs let's say you could in the future perhaps if we understand how it works actually change the composition of the heritable RNAs if you do IVF if you vital fertilization you could 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 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. The beauty is that this unlike DNA, it's plastic. So with DNA, this is your DNA. Perhaps we can choose another embryo. But here you could say perhaps or 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 treadmill 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 >> yet. Yes. But of course this is why why why it's so interesting >> today. You've taken us on an amazing journey through the genome RNA in particular the work in your laboratory which is just incredible and also this introduction of model organisms. So thank you so much. >> Thank you. >> It's been a real pleasure. >> Pleasure was all mine. Thanks a lot.