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Welcome to Huberman Lab Essentials, where we review previous episodes to learn about the most powerful and practical science-based tools for mental health, physical health, and performance. I am Andrew Huberman and I am a professor of neurobiology and ophthalmology at Stanford School of Medicine. And now, my chat with Dr. Oded Rechavi. Oded, thank you so much for being here. It's a pleasure. Today, what I want to talk about primarily are the incredible questions you investigate in your laboratory, which are incredibly important to the life of each and every one of us. I think most people have a general understanding of what
genes, RNA, etc. are. But perhaps you could explain it to people in very basic terms. And I'll start by saying that I think most people understand that if they have two blue-eyed parents, there's a greater chance that their offspring will have blue eyes than brown eyes. But most people generally understand and accept that if they spend part of their lives, say, studying architecture, and if they have children, there is no real genetic reason, we assume, why their children would be better at architecture because they carry the knowledge through their parents' DNA. They might be exposed to it at home, which is known as innate or native, in that case, but they would not inherit the knowledge. Today I hope you can explain why eye color, but not
knowledge, is believed to be inherited, and the huge range of interesting questions this opens up, including some evidence that, contrary to what we might think, certain types of knowledge at the cellular and system level can be inherited. So, DNA is the material, the genetic instructions, that are contained in each of our cells. We have the set of genes it contains; the complete 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 contain chromosomes. Chromosomes are the DNA and the proteins that condense the DNA because we have a huge amount of DNA in each cell. If you need to condense it so that it's like a thread on a spool.
Correct. A huge amount that you have to condense. And we have the same genome, the same DNA in every cell of our body. It's helpful to have an analogy to understand how it works. This is like the IKEA book that you have in every cell of your body, the instructions for making everything you need in your house, the chairs, the kitchen, the paintings. But in each room you want something more. So, in the kitchen you want things that fit in the kitchen, and in the toilet you want things that fit in the toilet. So, you just remove one particular page of instructions, which is the instruction on how to make a chair. And you put this in the living room, okay? And you put it in the toilet. So, the genome is the instructions for doing everything. This is
the IKEA book. And in each cell, we take only the instructions to make a particular piece of furniture, and this is RNA. And in the end, you will build a chair. The chair is the protein. This is true for a particular type of RNA, which is messenger RNA. In fact, this is only a small percentage of the RNA in the cell. So, we have a very large genome and less than 2% of each one codes for this messenger RNA. However, much of the genome is transcribed to make RNA that does other things. We understand some of these RNAs, and many of them we do not.
I think it's a beautiful description, and IKEA isn't a sponsor of the podcast. So, it's totally fair to use the IKEA catalog as an analogy for DNA; the specific instructions for specific furniture are the RNA, and the furniture is the proteins that are essentially made of RNA using messenger RNA. Correct. OK. Even though the same genes are contained in all cells of the body, is it fair to say that there is basically one very important exception: somatic cells versus germ cells? Would you mind sharing with us what that distinction entails? Well yes. Every cell, every type of cell, is different. We have cells in our legs, cells in our brain. In the brain we have cells that produce dopamine, cells that produce serotonin, etc. But we can
make a very important distinction between somatic cells and germ cells. Germ cells are supposed to be the only cells that contribute to the next generation, the one from which the next generation will be formed. Thus, each one of us arises from the combination of a sperm and an egg. These are two types of germ cells. And then they fuse and a fertilized egg is obtained. And from this cell the rest of the body will develop. And what happens in the soma, which are all the cells that are not there, the germ cells, should remain in the soma. I shouldn't be able to contribute to the next generation. This is very important and is believed to be one of the main barriers to the inheritance of acquired traits, the inheritance
of memory, etc. Because, for example, like the example you gave here about learning architecture. If I learn about architecture, the information is encoded in my brain. And since my brain cells cannot transfer information to the sperm or the egg, because the information that is supposed to reside in the synaptic connections between different neurons, particularly the circuits that developed, then, what happens in the brain?, should not be able to be transferred to the next generation. An even simpler example: if you go to the gym and build muscle, you know your children will have to exercise on their own. Nothing will happen, nothing will happen. This is something we know intuitively, even if we have no knowledge of biology. This is
related to the fact that, as we said at the beginning, each cell in the body has its own genome and the next generation will only be formed from the combination of the sperm and egg genomes. Even if you were somehow to acquire the mutation or change in your DNA in one of your particular brain cells, it wouldn't matter because there's no way to transfer this mutation to the DNA of the germ cells that will contribute to the next generation. There is this idea, and I'll tell you so you do n't have to, that goes back to Lamarck and Lamarckian evolution, very controversial, right? And perhaps not even controversial. I think it's very offensive, even to some people. This idea of the inheritance of
acquired traits. The idea that one could change oneself through some activity. Let's use the example of going to the gym. We could also use the example of someone who becomes an endurance runner, then decides to have children with another endurance runner and has in mind the idea that, because he ran so much, and not just because he had a predisposition to running in the first place, but because of the distance he actually ran, his offspring would somehow be fabulous runners. We believe this Lamarckian concept is wrong. So how do we talk about the inheritance of acquired traits? What is the appropriate language to
frame this discussion? Lamarck, this is what he believed, and he thought that this is how evolution progressed and progressed, and later Darwin showed that it is actually about natural selection: the selection of organisms that already contained the particular qualities is selected based on whether or not they survive in particular environments and, therefore, their evolution progresses; They become more common and take control. These are two very different explanations. The most common way to contrast this is with the neck of giraffes. This is the classic example. According to Lamarck, giraffes had to stretch their necks towards the trees to eat when they were high up. And that's why they passed on these traits,
long necks, to their children, who also had long necks. And according to Darwin, the giraffe that happened to be born with the longest neck survived simply because it managed to eat. So, hereditary genetic material is not about genetics, it takes over it. And the rest of the giraffes that have different genetic material simply die. Therefore, it is a matter of natural selection versus inheritance of acquired traits. And then we return to these studies on the inheritance of acquired traits. There were also theoretical problems about why this cannot happen. Barriers that must be overcome for this to happen. And it can be reduced to two main barriers. We mentioned the first barrier. This is the separation of the
soma from the germ line. Correct, somatic cells can change in response to experience. Sperm and egg, the so-called germ cells, cannot. That's the idea, isolated from what happens in the soma. Yes. Okay. The man who first thought of this barrier is named Weismann, August Weismann. This was in the 19th century. That is why it is called the Weismann barrier today. Separation of the soma from the germ line. Only the germline transmits information to the next generation. And this is also called the second law of biology. Therefore, it is very, very fundamental.
Natural selection is the first. This is the second one because it is very important for the functioning of our body. The other major barrier is called epigenetic reprogramming, which is that we acquire our cells, the genetic material of our cells acquires all kinds of chemical changes, but these modifications are largely erased in the transition between generations. Therefore, in the germline, in the sperm and egg, and also in the early embryo, most of those modifications are eliminated, so we can start from scratch based on the genetic instructions. And this is crucial. Otherwise, according to the
theory, it is not clear that it is actually true because in some organisms it does not actually occur; we simply do not develop according to the typical genetic instructions of the species. Mhm. So, to preserve this, we erased all these modifications and started over. And this is largely true in mammals and in humans. Most of the modifications in the sperm and egg are eliminated. Approximately 90% of them. So, the idea, if I understand correctly, is that there is some advantage to wiping the slate clean and going back to the original plan. In the context of the IKEA furniture analogy, the instruction manual Mhm. It's the one that's given to everyone, okay? Or to every cell, right?
Specific instructions are only used for specific cells, for example, a skin cell, a neuron, a liver cell, or any other cell. Throughout the life of the organism, those specific instructions are adjusted a little. Okay, maybe the idea is to take the instructions, but review them and erase all pencil and pen marks, erase all those little additional modifications that the owner used or introduced, and go back to the original instructions. Of course, because if you want to recover the instruction manual, you want it to have the full potential to make all the furniture. You don't want it to be limited to what you did in that particular room. Therefore, some of the resistance to the idea is based on theoretical grounds due to
these barriers and controversies. On the other hand, people really want to believe it because it somehow gives meaning to your life. If you can change your biology by changing your children's biology, then.Psychologically, I can understand why many people want this to happen. Even Schrödinger, the famous physicist, wrote a very important book in 1944. And he talks about hereditary material, he also talks about evolution and said "The inheritance of acquired traits is untenable, it does not occur." And he writes: "This is very, very sad or unfortunate because, unlike Darwinism or natural selection, which are pessimistic, no matter what you do, the next generation will be born based on the instructions of the sperm and
egg. It doesn't matter; you can't influence it. Of course, you can give your children money and an education, but you ca n't influence it biologically. However, there is one more thing to mention, which is that there are also other mechanisms that could transmit information, including the transmission of RNA between generations. And there are different kinds of RNA, not just messenger RNA that codes for the information to do important things, but also other RNAs that regulate gene expression. And I think in recent years, also in the field of mammals, RNA as a molecule that has the potential to transmit information between generations has become quite prominent. So I think this is the most advanced thing. There is much more to
understand and know, but RNA has a lot of potential to do so, as we will soon explain. But we have to go to the worms first. Many, if not most, of our Listeners tend to focus on humans, human biology, and health, etc. But I ca n't stress enough the importance of model organisms and the incredible degree to which they have informed us about human health, especially regarding the most basic functions of cells. Before we begin with the description of the worms themselves, could you explain to the general public what a model organism is and why you have selected or chosen to work with a particular type of worm to study
these fascinating topics that undoubtedly also occur in humans at some level? Model organisms are organisms that have a large community of researchers who have combined resources to create all the resources, tools, and understanding that they have accumulated. We have learned about all aspects of biology through them, including many important diseases. And the reason we can also learn so much about humans by studying these animals is that we all evolved from the same ancestor. We share many of our functions with them and also many of our genes. Sometimes they have things that are much more evident in them that we can study. Another important reason to study them, of course,
is that you can Experimenting with them. We ca n't do this with humans. The things we do with these animals-we can change their genes, do all sorts of things with them. The community of people studying C. elegans has literally numbered and named every single neuron so that two labs on opposite sides of the world can publish papers about the same neuron, knowing it's the same neuron in both different labs. Something that is extremely difficult to do in any mammalian model, a mouse, or certainly in humans, and it has posed enormous challenges that provide huge advantages to the study of things like C. elegans A C. elegans nematode always has 959 cells, of which 302 are neurons. We have a map, a connectome, from the 1980s, like a
subway map, that tells us which neuron is talking to which other neurons. And it's the same. Not only that, the worms are transparent. So, we can see how the neurons are fired using specific tools. And we can activate genes and silent genes using optogenetics. In addition, we have a great deal of knowledge about genetics. of the worm and the genome. This is C. elegans, the first animal to have its genome sequenced before humans. And we know that each worm produces around 250 offspring that are almost genetically identical. And we know that where we culture them, the environment is very controlled. So we culture them in a dish with only bacteria. So we can easily separate between nature and nurture.
The generation time in C. elegans is 3 days. So you can make hundreds of generations of worms in a PhD. This is very important. Not only that, each worm will produce hundreds of offspring. So you will have that are genetically identical. So you will have excellent statistics for your experiment. In the worm, we now have very obvious and clear evidence that there is inheritance of acquired traits. So much so that I don't think virtually anyone in the field of epigenetics would dispute this What was the first experiment you did with C. elegans that confirmed for you that the inheritance of acquired traits is real?
We set out to test whether the worms can produce resistance. transgenerational to viruses. These worms don't have specific immune cells like we do. They don't have T cells or B cells. They defend themselves against viruses using RNA that destroys them. And these are called small RNAs. In 2006, two researchers studying C. elegans, Andrew Fire and Craig Mello, won the Nobel Prize for demonstrating that there is a gene-regulating mechanism that occurs with small RNAs. What they showed is that if double-stranded RNA molecules are injected into the worms, they deactivate the genes that match the sequence of this RNA. It's like taking the specific instructions for the coffee table from the IKEA manual and inserting a copy into
the book, and in doing so, preventing the expression of the gene or erasing the original page. Perfect explanation. They discovered that double- stranded RNA is what initiates the response that leads to the production of small RNA molecules, which are the ones that actually find the messenger RNA and lead to its destruction. They silence it so that ultimately no proteins are produced. That's why they won the Nobel Prize after People discovered that this is conserved in many organisms, including humans, and now it's being used in medicine. This was only in 2006, when the article about the 1998 Nobel Prize was published. Now there are medicines that use this mechanism. It's called
RNA interference. RNA interferes with the expression of a gene and ultimately with the function of a gene. And it's also called gene silencing because these RNAs reinforce the silencing of genes; instead of the genes being expressed, they are silenced and don't perform a function. They've demonstrated two very important things. You don't just see the effect in the cell you injected or the tissue you injected, but you see it throughout the entire body of the worm. It spreads. This also includes germ cells. So, if you inject the double-stranded RNA only into somatic cells, even into the head, you'll also get the effect in the germ cells and in the next generation. Later, they showed that you can take worms
and feed them bacteria that produce this double-stranded RNA. And that the double-stranding and the silencing would then spread. By injection, from the intestine, where the bacteria are consumed, to the rest of the body and also to the next generation. And this is not at all controversial. This is done routinely every day by any C. elegans biologist in the world. Okay, this has been replicated a million times. When I started my work, I wanted to see if, in addition to artificial double-stranded RNA, some natural traits could also be passed on from generation to generation thanks to RNA, to small RNAs. Of course, because injecting RNAi or introducing short interfering RNAs, that is, putting worms in an environment with an abundance of inhibitory RNAs as an
experiment, is very different from the worms experiencing something and then passing that acquired trait on to their offspring. 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 naturally over generations. We go from the least artificial to the most artificial. And the advantage, as with model organisms, is that the more artificial it is, the easier it is to know exactly what you've done. You simply introduce a factor and you can follow the result. So This is always the job. In fact, this is probably the reason these small RNAs evolved in the first place: to get rid of
viruses and other parasitic genomic elements. This is a mechanism for fighting them. We demonstrated this very clearly using a fluorescent virus. If the virus replicates successfully, the worms turn green. And if the virus is destroyed, the worm remains black. It's very simple. It's straightforward. We take worms, infect them with a fluorescent virus, and they destroy it. This has been done in the past. But then what we did was neutralize the machinery that produces small RNAs in the worms' offspring. That's why they can't produce small RNAs on their own from the start. Because they simply don't have the genes needed to produce small RNAs. And then we ask ourselves, what will happen when we infect these worms with a virus
? Will they be green or black? They can't produce their own small RNAs. Therefore, they can't protect themselves. The only way for them to remain black, for the virus not to replicate, is. If they inherit the small RNAs from their parents. And this is exactly what happens. All the worms' offspring, even though they don't have the gene needed to produce the small RNAs, are black and silence the virus. And this continues for additional generations, okay? So the parent worms put something in the offspring's genetic instructions that would give them, let's call it, an advantage in this case. But it would give them an advantage if they were faced with the same thing as the parents.
Right. And we know exactly what this advantage is. The advantage is that they are small RNAs that match the viral genome. Then, they simply cut off the virus in the next generation. And we can identify the small RNAs in the inhibitory RNAs in the offspring, even though they don't have the machinery to produce them. Simply because they inherited them, we can identify them by sequencing. RNA sequencing, which is like DNA sequencing, actually gets the actual sequence of the RNA molecules. And we can see that they match the viruses and that they inherited small RNAs only if their parents were infected with They do. It's true that in
mammals, RNA and small RNAs are a prime candidate for something that could mediate the transmission of protection against stress or also of harmful effects passed down between generations. Perhaps RNA does. And it 's very interesting to think about this when we talk about the inheritance of memories. Can brain activity of some kind be transmitted, at least in these worms? I said no, I've stated this disclaimer several times: in mammals, we don't know. Time will tell. In worms, we know a lot. So, can worms transmit brain activity? Do they have the necessary specificity? I think any tissue that transmits RNA to the next generation and affects the next generation is interesting. Guts, muscles, everything. But the brain
can synthesize information about the environment and about the internal state, and it can also think about the future. And the most provocative thing you can say is that you could somehow plan the fate of a nation using the brain. After taking many things into account, this is without talking to them. Right, without Let's talk. Right. Again, we're back to this instruction manual. It's like writing something in the instruction manual based on your own experience. Right. We have to understand that the brain uses a different language than the language of heredity. It stores information in the synapses, in the connections between different neurons. When you learn something, you make some connections stronger and some
weaker, and you wire the nervous system differently. On the other hand, hereditary information of any kind has to go through a bottleneck of a single cell, the fertilized egg, because we all start from a single cell. So, the question is, can you translate this information-this information about the three-dimensional structure of the synapses and the connections between neurons in the brain's architecture- can you somehow translate it into hereditary information in a molecular form? You can teach worms, even though they only have 302 neurons; you can teach them simple things about the world. For example, you can take a smell that worms like. Worms have thousands of olfactory receptors. And they can recognize a great many molecules.
They can smell them to find food or avoid enemies. You can take a smell that worms like and associate it with something bad like hunger. And then the worms will learn to dislike that smell. We don't know if this learning necessarily involves a change in the strength of the synapses. It's a possibility, but it doesn't have to be that way. It could be that only the receptor for this particular smell is being eliminated. When they. And that's how they learn. Now they won't have the receptor, they won't smell, they won't like the smell. This is one possibility. This kind of thing you could perhaps, although no one has convincingly demonstrated it, pass on to the next generation because all it would take is an RNA that
controls this particular receptor. Okay? This has been shown not to happen in C. elegans, but it has been shown to happen in a similar way in mammals. They said that you learn a certain thing and then, in the next generation, that particular receptor would get methylated or changed, and this would pass on the response. And on one hand, it could to be true. On the other hand, you need to understand that they will have to prove-and this hasn't yet been done convincingly enough- exactly how information is transferred from the brain to the germ cells and then, in the next generation, from the germ cells back to the brain, where the receptor needs to operate. And this is a challenge.
This is the current state of the field, and it's something that still needs to be demonstrated. What we did in C. elegans: we showed that the brain can communicate with subsequent generations using smaller RNAs and that this can change behavior. And it doesn't require any translation between languages. It's very simple. What we've shown is that if you take a worm and change the production of smaller RNAs only in its brain in subsequent generations, their behavior will be different even if you don't alter their brains. This is a paper we published in 2019 in Cell. We showed that you simply manipulate the production of naturally occurring endogenous RNAs in the worm's brain, which are always being
produced, but you change their quantity, and this changes the ability of the next generation of worms to find food. Not just in one generation, but in three generations. later. And the way it works is that disrupting the production of these small RNAs in the brain ultimately affects the expression of a gene in the germline. For a gene called Sage2, we can do all sorts of tests where we manipulate the gene's activity and see that it also affects behavior. And this gene operates in the germ cells. The information has 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 this is a true epigenetic effect because it continues for several generations,
and also because it requires the machinery that transfers RNA between generations. If you don't have that protein that physically transports the RNA between generations, it doesn't happen. So, it has to be RNA. It has to be RNA. We can also find the RNAs in the next generation that change. We sequence the actual RNAs that change in the next generation. So, it sounds strange that you change the germ and it changes behavior-the sperm and the egg. But if you think about it, germ cells affect the soma, including the brain, in many ways by secreting certain chemicals. And also because the other cells develop from germ cells. So, some of the information could be passed on
during development, or the course of development could be altered due to changes that occur in the germ cells. And if, for example, in mammals, one of the explanations for how hereditary information is passed on is that it affects something very early in development. I already told you that the secret of worm inheritance is that they have the ability to amplify these little RNAs all the time. This is what keeps it active and prevents dilution. In mammals, we don't know of an amplification mechanism of this kind. So you ask yourself, how can a little bit of RNA, or something unamplified, affect the whole organism? And it could be that you simply disrupt something at the beginning, when you only have a
few cells, or even if they are in the placenta that develops during pregnancy, and this then throws everything off. And because of that, you have many problems with metabolism, and so on. And this is called the idea of the developmental origin of health and disease. Many things happen, many functions occur. Early development. In terms of the work in C. elegans or other model organisms, but particularly in C. elegans, where do you think this will go now? So, assuming we discover similar things in humans-we don't know they're like this, but let's say we find them-I think there are many things you can do before changing it.
You could also change the inheritance from the parents by having the parents exercise, for example. And things like this have been done, for example, and there are experiments in rodents where it's shown that overfeeding rodents creates problems for the next generation, for the offspring. However, if you let the rodents exercise, then it corrects the inheritance from the parents. So, this is one possibility. And you can also manipulate it at the source. You can change it if it's RNA. Let's say in the future, if we understand how it works, you could actually change the composition of hereditary RNAs. If you do IVF, if you do in vitro fertilization, maybe you can change the composition of the RNAs in the things that You introduce. But long before that
, what you could do, even in the not-too-distant future, is use this for diagnostics. DNA-based diagnostics for every couple who wants to have a child. In Israel, this is already being done. For most couples. You can look at DNA and search for genetic diseases. But nobody is looking at RNA right now. If we better understand how it works, we will have another level, a whole new world to observe. And perhaps there are some RNAs that correlate with the disease. The good thing is that, unlike DNA, it's plastic. So, with the DNA, this is your DNA, maybe we can choose another embryo. But here you could say, maybe 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 that maybe you should run a little on the treadmill. This will change your RNA profile and then we will use it for IVF. This seems more likely because it simply correlates with healthy RNA profiles. This is a level that nobody is looking at now and it has great potential. Again, with a caveat that we don't know how it works in humans at all. Yes. But of course, that's why it's so interesting. Today you have taken us on an incredible journey through the genome, RNA, in particular the work in your lab, which is simply amazing, and also this introduction of model organisms. So, thank you very much. Thank you. It has been a real pleasure. The
pleasure has been all mine. Thank you so much.
