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

0:00Welcome 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 ophthalmology at Stanford School of Medicine. And now for my discussion with Dr. Ode de Rahavi. Ode, 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 their offspring will have blue eyes than brown eyes. But most people generally understand and accept that if they spend part of their life, 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.

1:15They might be exposed to it in the home, so-called nature nurture, so a 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, certain types of knowledge at the level of cells and systems can be inherited. So DNA is the material, the genetic instructions that is containing everyone 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, 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. So like thread on a spoon. Right. Huge amounts that you have to condense. And we have the same genome, the same DNA in every cell in our body.

2:17It's good to have an analogy to understand how it works. This is like the IKEA book that you have in every cell in your body, the instructions to make everything that you need in your house, the chairs, the kitchen, the pictures, but in every room you want something else. So in the kitchen you want things that fit the kitchen in the toilet, you want things that fit the toilet. So you only remove one particular page of instructions, which is the instructions of how to build a chair. And this you place in the living room and the toilet you put in the toilet. So the genome is the instruction to make everything. This is the IKEA book. And in every cell we take just the instructions for make one particular furniture and this is the RNA. And then at 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. 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.

3:21Some of these RNAs we understand and many of them we don't. It's a beautiful description and IKEA is not a sponsor of the podcast. So it's a totally fair game to use the IKEA catalog 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 essentially made from RNA using messenger RNA. 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 somatic cells versus germ cells. And would you mind sharing with us what that distinction is? So yes, every cell type is different. We have cells in the legs, we have cells in the brain, we have cells that produce dopamine, cells that produce a rotten it 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 contributes to the next generation that out of which the next generation will be made. So each of us is made just from a combination of a sperm and an egg.

4:25These are two types of germ cells. And then they fuse and you make 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 summer, which is which are all the cells that are not the germ cells, should stay in the summer, should not be able to contribute to the next generation. This is very important. And we thought to be one of the main barriers for the inheritance of acquired traits, inheritance of memory and so on. Because for example, like the example that you gave her 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 connection between different neurons in particular circuits that developed. So what's what's what happens is that the brain shouldn't be able to transfer to the next generation. Even simpler, a simpler example should go to the gym and you build up muscles, you know that your kids will will have to work out on their own.

5:32It won't that this short out won't want to 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 in 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 acquire the mutation or change in your DNA in one of particular brain cells, it will matter because this mutation, there's no way to transfer it to the DNA of the germ cells that will contribute to the next generation. I'd like to take a quick break and acknowledge our sponsor, 8-Sleep. 8-Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. One of the best ways to ensure you get a great night's sleep is to make sure that the temperature of your sleeping environment is correct. And that's because in order to fall asleep and stay deeply asleep, your body temperature actually has to drop by about 1-3 degrees. And in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about 1-3 degrees.

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7:32And maybe not even controversial. I think it's very 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 going to the gym, we could also use the example 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 this running, and not just because they were biased towards running in the first place, but because of the distance they actually ran that they're offering somehow would be fabulous runners. And Lamarckian 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? Lamarck, this is what he believed, and he thought this is how evolution progressed, and later Darwin 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.

8:32And therefore, the evolution progresses, they become more common and take over. This is a very different two different explanations. The most common way this is contrasted is the neck of the giraffes. This is a classic example. According to Lamarck, the giraffes had to stretch their neck towards the trees to eat when the trees were high. And because of that, they transmitted these traits long next to the children who also had long neck. And then, we're causing to that with just that the giraffet will happen to be born with the long neck survived because it ate so it's genetic heritable materials in no 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 of acquired traits. And then we go back to these studies about inheritance for acquired traits. There were also theoretical problems 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.

9:33First barrier, we mentioned it. This is the separation of the soma from the germana. Right, the somatic cells, they can change in response to experience. The sperm and the egg, the so-called germ cells, cannot. Or they are isolated on what happens in the summer. Okay, the main who first thought about this barrier is called wise man, August wise man is what is in the 19th century. So it is called today the wise man barrier separation of the soma from the German only the germ line transmitting for metatoid 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 ripogaming, which is that we acquired our, this our cells, 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 sperm and the egg.

10:36And also in the early embryo, most of them 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. So to preserve this, we erase all these modifications that start a new. And this is in in members and in humans. This is allowed to do most of the modifications on the in the sperm and in the egg are removed from about 90% of them. So the idea, if I understand correctly, is that there's some advantage to wiping the slate clean and returning to the original plan in in the context of the IKEA furniture analogy and the instruction book is the one that's issued to everybody, okay, or every cell, right? Only certain instructions are used for certain cells, say a skin cell or a neuron or a liver cell or any other cell for that matter.

11:42Through 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 owner use or introduce to it and return to the original instruction. And if you want to bring back the instruction book, you want it to have all the potential to make all the furniture, so you normally to be restricted to the ones that you made in the particular room. So part of the resistance resistance to the idea is based on to a little 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's sorts of gives your life, meaning. If you can change your biology through changing your of your kids through changing your biology sort of psychologically, I can understand why many people want this to happen, even shredding 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 right is untenable, it doesn't happen.

12:50And it writes this is very, very sad or unfortunate because unlike Darwinism or natural selection, which is gloomy. Doesn't matter what you do next generation will be born based on the instruction in the sperm and the egg doesn't met 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 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 mammalian 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 the know, but RNA has a lot of potential for doing that as we'll explain soon, but we have to go to worms first.

13:54Many, 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 and cells. Before we start to go into the description about worms per se, could you just explain to the 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 humans at some level. Model organisms mean that it's an organism. There's a huge community of researchers that combined sources to create all the resources, 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 evolved from the same ancestor.

14:58We 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 study them of course is you can actually experiment on them. We can't do these 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 sealigances 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 mammalian model, mouse or certainly in humans and as posed huge challenges that give great advantages to studies of things like sealigons. Sealigons nematode always says 959 says out of which 300 and two are neurons. We have a map a connect on since the 80s, like a subway map tells us which neuron talks with which other neurons and it is the same.

16:00That's the ones are transparent. So we can actually see the neurons fire using particular tools and we can activate genes and silage using optogenetics. On top of that we have great understanding of the genetics of the one of the genome. Sealigance is the first animal to have its genome sequenced before humans and we know that in each warm 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 sealigance is three days, three days. So you can do hundreds of warm generations in one PhD. This is very important. Not only that every warm will produce hundreds of progenies so you will have that are genetically identical so you will have great statistics for your experiment. In the warm we now have very obvious and clear cut 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.

17:13I'd like to take a quick break and acknowledge our sponsor AG1. AG1 just launched their newest formulation called AG1 Pro and right now you can get an extra 20% off your first subscription. AG1 takes the clinically backed AG1 formula which is a blend of vitamins minerals probiotics and adaptogens and adds three important new ingredients, creatine monohydrate, calcium HMB and zinc carnaxine. It has 5 grams of creatine monohydrate to support muscle strength and performance along with brain health calcium HMB to support muscle recovery and reduce muscle breakdown and zinc carnaxine to support and improve the lining of your gut. Some of these ingredients I personally was already taking separate from the AG1 formula so it's great to see all three of them now in the new AG1 Pro. As you may know I've been taking AG1 every single day for about 14 years now that means I discovered it and started taking it daily long before I even knew what a podcast was. I continued to take it and back it here on the podcast because it is an excellent formula and it's now even better with the AG1 Pro formula.

18:15For a limited time you can get an extra 20% off your first subscription to AG1 Pro by going to drink AG1.com slash Huberman and using the code back to routine. So that's what the numeral two back numeral two routine. Just go to drink AG1.com slash Huberman. What was the first experiment that you did on C elegans 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 smaller nays. 2006 two researchers that were studying C elegans and all fire and Craig Melog got the Nobel Prize for showing that there is a mechanism that regulate genes that happens for smaller nays.

19:16But they've shown is that if you inject the worms with RNA molecules which are double-sturing that they shut off the genes that match in sequence to this RNA. So 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 sort of a race the original page. Perfect explanation. They found that double-strand RNA RNA that was 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 silences 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 now they are now drugs this was only 2006 that the Nobel Prize paper was published in 98. They are now drugs that use this mechanism it is called RNA interference RNA interferes in the expression of a gene in the and the function of a gene.

20:24And it's also 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 manage that 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 worms body it spreads this includes also the germ says. So if you inject the double-strand RNA just to thematic cells even to the head you will get also the effect in the germ cells and in the next generation later that you can just take worms and feed them on bacteria that produce this double-strand RNA and that the double-strand and the silencing would move from the site of ingestion 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 c elegance biologist in the world.

21:26This 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 also transmit across generations because of RNA because of small RNAs. Right because injecting RNAi or in the short and freeing RNAs that is or 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 generations just naturally. We're going from the less artificial to the more artificial the advantages just like with modern organisms that the more artificial it is the easier it is to know exactly what you did just now introduce one factor and you can follow the result.

22:26So this is always the trade in fact this is probably the reason that this smaller and is evolved in the first place to get rid of virus says and other parasitic genomic elements and this is a mechanism to fight them. We demonstrated this very clearly using a fluorescent virus if the virus replicate successfully the worms has turned green and if the virus is destroyed the worms stays black. This is very simple it's a clear cut off we took worms we infect them in the fluorescent virus they destroyed this also has been done in the past but then what we did is when you realize the machinery that makes smaller and is in the descendants of the worms so they cannot make smaller and is from the start on their own because they just don't have the genes that you need to make the smaller and then we ask what will happen will we affect these worms with the virus will they be green or black they can't make their own smaller and is so they can 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 the smallerness on the fence.

23:38And this is exactly what happens all the worms progeny although they don't have the gene that is needed for making the smaller and is are black they signs the valves and this also continues for additional generations. So the parent worms effectively put something into the genetic instructions of the offspring that would afford them this is let's call it an advantage in this case but for them an advantage if they were to be confronted with the same thing that the parents work. And we know exactly what is 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 smaller and is in the inhibitor RNAs in the descendants until they don't have the machinery to make it just because in her we can identify them by sequencing RNA sequencing which is like DNA sequencing you actually get the actual sequence of the RNA more or less. And we can see that they correspond to the virus and they have the inheritance smaller and is only the repair their parents were infected with them it is true that also in the members RNAs and smaller and is are a lending candidate for something that could mediate the transmission of stress protection or also harmful effects that are between generations perhaps RNA do it and it's very interesting to think about it when we talk about inheritance of memories can bring active.

25:04And then brain activity of some sort transmit at least in this world I said no I said this is claimed multiple times in in members we don't know times will tell in words we know a lot so can worms transmit brain activity to do they have the specific to do I think that any tissue that transmit transfer to transfer RNA to the next generation and affect the next generation is interesting regards. 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 of your nation using your brain. Without talking to them right without talking 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 synopsis in the connection between different neurons when you learn something you make you make some connection stronger and some other connections weaker and you wire nervous system in a different way.

26:16On 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 free this structure information of synopsis 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 they have just 300 to neurons you can teach them simple things about the world. For example, you can take an auto that their worms like the worms have thousands of auto contraceptals and they can recognize many many many molecules they can smell them so they can find food or avoid enemies you can take an auto that the worms like and pair it to something bad like starvation and then the worms will learn to dislike this auto. We don't know that this learning involves necessarily changing in the strengths of synopsis it's a possibility but it doesn't have to be the case it could be the just the receptor for this particular auto is being removed when they and this is how they now they won't have the receptor they won't smell they won't like the auto this is a possibility this type of thing you can perhaps not that anyone has showed it convincingly transmit to the next generation because only it would be the same.

27:36Because only it would take is an RNA that will control this particular receptor people have shown things like that not in c elegans but people have shown things like that in mammals. They said that you learn certain thing and then just in the next generation does a particular receptor would be ventilated 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 understand. 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 to separate 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 didn't see elegans is we showed that the brain can communicate with the next generations using smaller and this and the disk 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 warm and you change the production of smaller and is just in its brain in the next generations there 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 worms brain that are always made but you you change their.

29:03And 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. And this is the process of the production of the production of the small and is in the brain affects in the end the expression of a gene in the germ line one gene is called sage to we can do all kinds of controls where we manipulate activity of the gene in series also affects behavior. The gene works in the germ says the information needs to go from the brain to the jumps it doesn't need to go back from the jumps to the brain to affect behavior and this depends we know that this is a two epigenetic effect because it goes on for multiple generations and also because it requires the machinery. The transfers RNAs between generations if you don't have that port in the 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 the change.

30:03We sequence the actual RNAs the change in the next generation so it sounds weird that you change germ cells and it changes behavior spermanic but if you think about it the germ cells affect the summer including the brain in many ways by secreting certain chemicals and also because the other cells develop 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. The two cases that occur in the germ says and for example in members one of the explanations for how heritable information transmits is that it just affects something very own in development. I told you that the secrets to warms inheritance is that they have the capacity to amplify this smaller and as all the time this is what keeps it going and prevents the dilution in members we don't know of such an amplification mechanism so you ask how can a little bit of RNA or something without amplifying affect land lane.

31:03It could be that you just perturb something in the very beginning when you just have a few sets or even in the placenta that develops in pregnancy and this later throws everything off and because of that you have many problems in the carbonylism and so on and this is called the idea of the developed developmental origin of health and disease. So many of the things occur you're many of the functions occur early on in development. I'd like to take a quick break and acknowledge one of our sponsors element element is an electrolyte drink that has everything you need and nothing you don't that means the electrolytes sodium magnesium and potassium in the correct amounts but no sugar proper hydration is critical for optimal brain and body function. Even a slight degree of dehydration can diminish cognitive and physical performance. It's also important that you get adequate electrolytes the electrolytes sodium magnesium and potassium are vital for functioning of all the cells in your body especially your neurons or your nerve cells. Drinking element dissolved in water makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes to make sure that I'm getting proper amounts of hydration and electrolytes.

32:09I dissolve one packet of element in about 16 to 32 ounces of water when I first wake up in the morning and I drink that basically first thing in the morning. I'll also drink element dissolved in water during any kind of physical exercise that I'm doing especially on hot days when I'm sweating a lot and losing water and electrolytes. Element has a bunch of great tasting flavors. I love the raspberry I love the citrus flavor right now element has a limited edition lemonade flavor that is absolutely delicious. I hate to say that I love one more than all the others but this lemonade flavor is right up there with my favorite other one which is raspberry or watermelon again I can't pick just one flavor I love them all. If you'd like to try element you can go to drink element dot com slash uberman spelled drink lmnt dot com slash uberman to claim a free element sample pack with a purchase of any element drink mix again that's drink element dot com slash uberman to claim a free sample pack. In terms of the work in either c elegans or another model organism but in particular in c elegans 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 find I think there are many things you can do before you change it you could also change a barren inheritance by having the parent exercise for example.

33:29And some things like this have been done for example and their experiments in in rodents where they show that over feeding the the rodents creates problems for the next generations for the for the children however if you let the the rodent exercise then it corrects the parenting 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 I.V.S. if you do it with the realization 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 the agnostics 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 the DNA is not the same as the DNA.

34:39This unlike DNA it's plastic so we DNA this is your DNA perhaps we can choose another embryo but here you could say perhaps or again 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 know how it works in humans at all. Yes. Yes. But of course this is why why why so interesting today you taking 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. Thank you. It's been a real pleasure. Pleasure was all mine. Thanks a lot.