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

0:00Andrew 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. 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.

0:38Andrew Huberman: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. They might be exposed to it in the home, so-called nature nurture, that's a nurture in that case.

1:19Andrew Huberman: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 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.

2:00Chromosomes 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.

2:07Andrew Huberman:Sort of like thread 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 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.

2:42And this you place in the living room, okay? 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 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. 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.

3:20Some of these RNAs we understand and many of them we don't.

3:24Andrew 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. 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 somatic cells versus germ cells? And would you mind sharing with us what that distinction is? So yes, every cell type is different.

4:00We 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 speriment and 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.

4:36And what happens in the soma, which are all the cells that are not the germ cells, should stay in the soma. It 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.

5:18So 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 have to work out on their own. This shortout 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.

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7:13Andrew Huberman:8sleep ships to many countries worldwide, including Mexico and the UAE. Again, that's 8sleep.com slash 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. 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.

8:02Andrew Huberman: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? 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, the evolution progresses, they become more common and take over. This is very different, two different explanations. is the most common way this is contrasted is the neck of the giraffes.

8:43This is the 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, long necks to their children who also had long necks. And according to Darwin, just that a giraffe that happened to be born with a long neck survived because it ate. So it's genetic, heritable material. I 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 of acquired traits. And then we go back to these studies about inheritance of acquired traits.

9:22There 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. First barrier, we mentioned it. This is the separation of the soma from the germline.

9:37Andrew 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. Or they are isolated from what happens in the soma. The man who first thought about this barrier is called Weisman. August Weisman, this was in the 19th century. So it is called today the Weisman barrier. Separation of the soma from the germline, only the germline transmitting 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.

10:13The 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 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 it's actually true because in some organisms it doesn't really happen. We will not develop according to the species typical genetic instructions.

11:00So 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 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.

11:59Right. 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 a particular room. So part of the resistance to the ideal 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 of your kids through changing your biology. Psychologically, I can understand why many people want this to happen. Even Schrodinger, the famous physicist, so he wrote a very important book in 44th and he talked about the heritable material.

12:45It 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, doesn't matter what you do, the next generation will be born based on the instruction in the sperm endiac. 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.

13:20And there are different types of RNA, not just messenger RNA, which encodes the information 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 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 soon, but we have to go to worms first.

13:54Andrew Huberman: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 and 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? Model organisms mean that it's an organism.

14:36There's a a huge community of researchers that combined sources to create all 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 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.

15:10We 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.

15:16Andrew 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. C. elegans nematode always has 959 cells, out of which 302 are neurons. We have a connectome since the 80s, like a subway map that tells us which neuron talks with which other neurons, and it is the same.

15:59Not 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 the genome. This is, siligens is the first animal to have its genome sequenced before humans. And we know that in each worm produces, that 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.

16:41The generation time in C. elegans is three days. Three days. So you can do hundreds of warren generations in one PhD. This is very important. Not only that, every warren will produce hundreds of progenies that are genetically identical. because you will have great statistics for your experiments. 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.

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18:24Andrew Huberman:So that's with a numeral two, BACK, numeral two, ROUTINE. Just go to drinkag1.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 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 Feier and Craig Mello, got the Nobel Prize for showing that there is a mechanism that regulates genes that happens through small RNAs.

19:15What they've shown is that if you inject the worms with RNA molecules, which are double-stranded, they shut off the genes that match in sequence to this RNA.

19:28Andrew Huberman:So it's sort of like taking the specific instructions for the coffee table from your IKEA handbook and you insert a copy of that into the book. And in doing so, you prevent the expression of, you sort of erase the original page. 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.

20:08And now there are now drugs. This was only in 2006, 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. 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.

20:45It 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 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. elegans 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.

21:41Andrew Huberman:Right, because injecting RNAi, or short-end interfering 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. There are 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.

22:24Introduce one factor and you can follow the result. So this is always the trade. In fact, this is probably the reason that these small 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 cutoff. We took worms. We infect them with a fluorescent virus. They destroyed. it. This also has been done in the test.