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

In this Huberman Lab Essentials episode, my guest is Dr. Oded Rechavi, a professor at Tel Aviv University who studies genetics, epigenetics and the inheritance of acquired traits. We discuss how DNA, RNA and epigenetic mechanisms determine what information can pass between generations, and why acquired traits are generally not thought to be inherited. We also explain research in C. elegans showing how small RNAs can transmit antiviral resistance and influence behavior across generations, what these findings might mean for mammals and humans, and potential future applications for reproductive health and diagnostics. Thank you to our sponsors AG1: https://drinkag1.com/huberman Eight Sleep: https://eightsleep.com/huberman LMNT: https://drinklmnt.com/huberman Timestamps (00:00:00) Oded Rechavi (00:00:24) DNA, Genome, RNA & Proteins (00:03:43) Somatic vs. Germ Cells; Inheritance (00:06:05) Sponsor: Eight Sleep (00:07:23) Lamarck vs. Darwin, Inheritance of Acquired Traits (00:09:45) Weismann Barrier, Epigenetic Reprogramming (00:13:05) RNA & Transgenerational Inheritance (00:13:54) Model Organisms, C. elegans (00:16:59) Inheritance of Acquired Traits in C. elegans (00:17:14) Sponsor: AG1 (00:18:40) RNA Interference, Small RNAs & Gene Silencing (00:22:46) Viral Resistance Across Generations (00:24:53) Small RNAs, Mammals & Inherited Effects (00:26:00) Brain Activity, Memory & Heritable Information (00:28:46) Neuronal Small RNAs & Behavior Across Generations (00:29:59) Germ Cells, Development & Heritable RNA (00:31:29) Sponsor: LMNT (00:33:11) Future Applications, Exercise, IVF & RNA Diagnostics (00:35:16) Acknowledgements Disclaimer & Disclosures Learn more about your ad choices. Visit megaphone.fm/adchoices

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Andrew D. Huberman?

  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 ophthalmology at Stanford School of Medicine. And now for my discussion with Dr. Oded Rechavi. Oded, thank you so much for being here.

• 0:22Speaker 01

  Totally, my pleasure.

• 0:23Andrew D. Huberman?

  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,

• 1:05Andrew D. Huberman?

  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, also 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.

• 1:39Speaker 01

  So DNA 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. It's 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. It's 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.

• 2:07Andrew D. Huberman?

  Sort of like thread on a spool.

• 2:09Speaker 01

  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 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. 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. And this you place in the living room. And in 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

• 2:53Speaker 01

  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 the RNA in the cells. 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.

• 3:24Andrew D. Huberman?

  I think it's a beautiful description. And IKEA is not a sponsor of the podcast, so it's 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.

• 3:42Speaker 01

  Right.

• 3:43Andrew D. Huberman?

  Okay. Despite the fact that the same genes are contained in all the cells of the body, is it fair to say that there's basically one very important exception, which is somatic cells versus germ cells? And would you mind sharing with us what that distinction is?

• 3:57Speaker 01

  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 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, 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. These are two types of germ cells. And then they fuse, and 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 are all the cells that are not the germ cells, should stay in the soma,

• 4:42Speaker 01

  should not be able to contribute to the next generation. This is very important, and it's thought 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 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. So what happens is the brain shouldn't be able to transfer to the next generation. Even simpler, a simpler example, if you go to the gym

• 5:25Speaker 01

  and you build up muscles, you know that your kids will have to work out on their own. It won't, this shortcut 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 acquire the mutation or 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 germ cells that will contribute to the next generation.

• 6:05Andrew D. Huberman?

  I'd like to take a quick break and acknowledge our sponsor, Eight Sleep. Eight 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 to 3 degrees. And in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about 1 to 3 degrees. Eight Sleep automatically regulates the temperature of your bed throughout the night according to your unique needs. I've been sleeping on an Eight Sleep mattress cover for nearly five years now, and it has completely transformed and improved the quality of my sleep. The latest Eight Sleep model is the Pod 5. This is what I'm now sleeping on, and I absolutely love it.

• 6:50Andrew D. Huberman?

  It has so many incredible features. For instance, the Pod 5 has a feature called Autopilot, which is an AI engine that learns your sleep patterns and then adjusts the temperature of your sleeping environment across different sleep stages. It'll even elevate your head if you're snoring, and it makes other shifts to optimize your sleep. If you'd like to try Eight Sleep, go to eightsleep.com/huberman to get up to $350 off the new Pod 5. Eight Sleep ships to many countries worldwide, including Mexico and the UAE. Again, that's eightsleep.com/huberman to save up to $350. There is this idea, and I'll say it so that you don't have to, that dates back to Lamarck and Lamarckian evolution, very controversial, right? And maybe not even controversial. I think it's very offensive even to certain people,

• 7:35Andrew D. Huberman?

  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 of the distance they actually ran, that their offspring somehow would be fabulous runners. This 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?

• 8:12Speaker 01

  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 whether they survive or not in particular environments. And therefore, their 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 giraffe. This is a classic example. According to Lamarck, the giraffes had to stretch their necks towards the trees to eat when the trees were high. And because of that, they transmitted these traits,

• 8:56Speaker 01

  long necks, to their children, who also had long necks. And according to Darwin, just a giraffe that happened to be born with a long neck survived because it ate. So its genetic, heritable materials, I don'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 of acquired traits. And then we go back to these studies about inheritance of 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. The first barrier, we mentioned it. This is the separation of the soma from the germline.

• 9:37Andrew D. Huberman?

  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.

• 9:45Speaker 01

  Or they are isolated from what happens in the soma. Okay? The man who first thought about this barrier is called Weisman, August Weisman, this was in the 19th century. So it's called today the Weisman Barrier. Separation of the soma from the germline. Only the germline transmitting information 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 cells, the genetic material in our cells acquires all kinds of chemical changes. But these modifications are largely erased

• 10:30Speaker 01

  in the transition between generations. So in the germline, in 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's actually true because in some organisms it doesn't really happen. We will not develop according to the species typical genetic instructions. So to preserve this, we erase all these modifications and start anew. And this is in mammals and in humans. This is largely true. Most of the modifications in the sperm and in the egg are removed, so about 90% of them.

• 11:15Andrew D. Huberman?

  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 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 cells, 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 owner used or introduced to it, and return to the original instruction.

• 11:59Speaker 01

  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 part of the resistance, the resistance to the idea, is based on theoretical grounds because of these barriers and because of the controversies. On the other hand, people really want to believe it because it sort of gives your life meaning. If you can change your biology through changing, of your kids, through changing your biology. Psychologically, I can understand why many people want this to happen. Even Schrödinger, the famous physicist, so he wrote a very important book in 44, and

• 12:43Speaker 01

  he talked about the heritable material, it also talks about evolution, and he said inheritance of acquired traits 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, it doesn't matter what you do, the next generation will be born based on the instruction in the sperm and the egg." 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 the information

• 13:27Speaker 01

  for making proteins, 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 generations took central stage. So I think this is the cutting edge, a lot more to understand than know, but RNA has a lot of potential for doing that, as we'll explain soon, but we have to go to worms first.

• 13:54Andrew D. Huberman?

  Many, if not most of our listeners are focused on humans and human biology and health, et cetera, 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 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 humans at some level?

• 14:33Speaker 01

  Model organisms mean that it's an organism. There's a huge community of researchers that combine sources to create all the resources and the tools and the understanding that accumulate. 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. 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 study them, of course, is 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.

• 15:17Andrew D. Huberman?

  The community of people that study C. elegans 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 mammalian model, a mouse or certainly in humans, and has posed huge challenges that give great advantages to studies of things like C. elegans.

• 15:42Speaker 01

  C. elegans, the model, always has 959 cells, out of which 302 are neurons. We have a map, a connectome, 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 silence genes using optogenetics. On top of that, we have great understanding of the genetics of the worm, of the genome. This is, C. elegans is the first animal to have its genome sequenced before humans.

• 16:23Speaker 01

  And we know that 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 C. elegans is three 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 progenies that are genetically identical, so you will have great statistics for your experiment. In the worm, we now have very obvious and clear-cut proof that there is inheritance

• 17:05Speaker 01

  of acquired traits, so much so that I don't think that anyone pretty much in the epigenetic field argues against it.

• 17:13Andrew D. Huberman?

  I'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 carnecine. It has five 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 carnecine 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.

• 17:58Andrew D. Huberman?

  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 continue 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. For a limited time, you can get an extra 20% off your first subscription to AG1 Pro by going to drinkag1.com/huberman and using the code BACKTORROUTINE. So that's with a numeral two, back numeral two, routine. Just go to drinkag1.com/huberman. What was the first experiment that you did on C. elegans that confirmed for you that inheritance of acquired traits is real?

• 18:40Speaker 01

  We set 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 C. elegans, Andrew Fire and Craig Mello, got the Nobel Prize for showing that there is a mechanism that regulates genes that happens through small RNAs. What they've shown is that if you inject the worms with RNA molecules which are double-stranded,

• 19:25Speaker 01

  they shut off the genes that match in sequence to this RNA.

• 19:29Andrew D. Huberman?

  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 erase the original page?

• 19:45Speaker 01

  Perfect explanation. They found that double-stranded 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 function of a gene. And it's also called gene silencing because these RNAs enforce the silencing of genes.

• 20:29Speaker 01

  Instead of the genes being expressed, they are silenced and you don't manifest the 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-stranded RNA just to somatic 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-stranded RNA, and that the silencing would move from the site of ingestion, from

• 21:14Speaker 01

  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. elegans biologist in the world. This has been replicated a million times. When I started my work, I wanted to see whether in addition to artificial double-stranded RNA, some natural traits can also transmit across generations because of RNA, because of small RNAs.

• 21:41Andrew D. Huberman?

  Right, because injecting RNAi, or shorter interfering RNAs, that is, or, you know, putting... Worms into an environment with an abundance of inhibitory RNAs. As an experiment, it's very different than worms experiencing something and then passing on that acquired trait to their offspring. It's a world apart, in my opinion, because one is extreme manipulation that illustrates an underlying principle. The other is something that, in theory, occurs in the passage of generations just naturally.

• 22:13Speaker 01

  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 easier 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 trait. In fact, this is probably the reason that these smaller RNAs evolved in the first place, to get rid of viruses 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 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.

• 22:56Speaker 01

  We took worms, we infect them with a fluorescent virus, they destroyed. This also has been done in the past. But then what we did is, we neutralized the machinery that makes smaller RNAs in the descendants of the worms. So they cannot make smaller RNAs from the start on their own, because they just don't have the genes that you need to make these smaller RNAs. And then we asked, what will happen when we infect these worms with a virus? Will they be green or black? They can't make their own smaller 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 smaller RNAs from their parents. And this is exactly what happens.

• 23:41Speaker 01

  All the worms progeny, although they don't have the gene that is needed for making the smaller RNAs, are black. They sense the virus. And this also continues for additional generations.

• 23:50Andrew D. Huberman?

  So the parent worms effectively put something into the genetic instructions of the offspring that would afford them, 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.

• 24:07Speaker 01

  Right. And we know exactly what this advantage is. The advantages are small RNAs that match the viral genome and just chop up the virus in the next generation. And we can identify these smaller RNAs in 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 inherited smaller RNAs only if their parents were infected with them. It is true that also in mammals, RNAs and smaller RNAs are a leading candidate for something

• 24:50Speaker 01

  that could mediate the transmission 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 worms? I said, Noah, I said this disclaimer multiple times, in mammals, we don't know, times will tell. In worms, we know a lot. So can worms transmit brain activity to, do they have the specificity to do it? I think that any tissues that transmit RNA to the next generation and affect the next generation is interesting. The gut, muscles, everything.

• 25:29Speaker 01

  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 next generation using your brain, you know, after taking many things into the code.

• 25:48Andrew D. Huberman?

  Without talking to them.

• 25:49Speaker 01

  Right, without talking.

• 25:50Andrew D. Huberman?

  Again, we go back to this instruction manual. It's like writing something into the instruction manual based on your own experience.

• 25:56Speaker 01

  Right. We have to understand that the brain uses a different language than the language of inheritance. It keeps information in synapses, in the connection between different neurons. When you learn something, you make some connections stronger and some 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?

• 26:41Speaker 01

  You can teach worms, even though 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 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 an odor that the worms like and pair it to something bad like starvation. And then the worms will learn to dislike this odor. We don't know that this learning involves necessarily changing in the strength of synapses. It's a possibility, but it doesn't have to be the case. It could be that just the receptor for this particular odor is being removed. And this is how they learn.

• 27:25Speaker 01

  Now they won't have the receptor, they won't smell, they won't like the odor. 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. People have shown things like that, not in C. elegans, 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 methylated 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

• 28:07Speaker 01

  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 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 elegance is we showed that the brain can communicate with the next generations using smaller 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 smaller RNAs just in its brain, in the next generations, their behavior will be different, even though you don't mess with their brains.

• 28:51Speaker 01

  This is a paper that we published in 2019 in Cell. We showed that you just manipulate the production of endogenous natural RNAs in the worm's brain that are always made, but 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 smaller RNAs in the brain affects, in the end, the expression of a gene in the germline. One gene, it's called SAGE2, we can do all kinds of controls where we manipulate the activity of the gene and see that it also affects behavior. And this gene works in the germ cells.

• 29:35Speaker 01

  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 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 that protein that physically carries the RNA between generations, it doesn't happen.

• 29:57Andrew D. Huberman?

  So it has to be RNA?

• 29:59Speaker 01

  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 secreting certain chemicals. And also because the other cells develop 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 mammals, one of the explanations for how heritable information transmits is that it just affects something very own in development.

• 30:44Speaker 01

  I told you that the secret to worms' inheritance is that they have the capacity to amplify these smaller 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 then 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 in the placenta that develops in pregnancy. And this later throws everything off. And because of that, you have many problems, metabolism and so on. And this is called the idea of the developmental origin of health and disease. Many of the things occur, many of the functions occur early on in development.

• 31:29Andrew D. Huberman?

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• 32:14Andrew D. Huberman?

  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 drinklmnt.com/huberman, spelled drink L-M-N-T dot com slash huberman, to claim a free Element sample pack with a purchase of any Element drink mix.

• 32:56Andrew D. Huberman?

  Again, that's drinklmnt.com/huberman to claim a free sample pack. In terms of the work in either C. elegans or in other model organisms, but in particular in C. elegans, where do you see this going next?

• 33:11Speaker 01

  Assuming that we will discover similar things in humans, which we don't know that this is the case, but let's say we find it. I think there are many things you can do before you change it. You could also change aberrant inheritance by having the parent exercise, for example. Some things like this have been done. For example, there are experiments in rodents where they show that overfeeding the rodents creates problems for the next generation, for the children. However, if you let the rodent exercise, then it corrects the aberrant inheritance. So this is one possibility. And you can also manipulate it at the source.

• 33:52Speaker 01

  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 do vital fertilization, you can perhaps change the composition of the RNAs in 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 most couples. You can look at the DNA and look for genetic disease. But no one 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.

• 34:35Speaker 01

  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, it 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 no know how it works in humans at all.

• 35:12Andrew D. Huberman?

  Yet.

• 35:12Speaker 01

  Yes, but of course, this is why it's so interesting.

• 35:16Andrew D. Huberman?

  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.

• 35:29Speaker 01

  Thank you.

• 35:29Andrew D. Huberman?

  It's been a real pleasure.

• 35:31Speaker 01

  Pleasure was all mine. Thanks a lot.