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

1. 0:00 – 2:08

   Dr. Oded Rechavi

   1. AHAndrew Huberman0:00

      (instrumental music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today my guest is Dr. Oded Rechavi. Dr. Oded Rechavi is a professor of neurobiology at Tel Aviv University in Israel. His laboratory studies genetic inheritance. Now, everybody is familiar with genetic inheritance as the idea that we inherit genes from our parents, and indeed that is true. Many people are also probably now aware of the so-called epigenome, that is ways in which our environment and experiences can change our genome and therefore the genes that we inherent or pass on to our children. What is less known, however, and what is discussed today, is the evidence that we can actually pass on traits that relate to our experiences. That's right. There is evidence in worms, in flies, in mice, and indeed in human beings that memories can indeed be passed from one generation to the next. And that turns out to be just the tip of the iceberg in terms of how our parents' experiences and our experiences can be passed on from one generation to the next, both in terms of modifying the biological circuits of the brain and body and the psychological consequences of those biological changes. During today's episode, Dr. Rechavi gives us a beautiful description of how genetics work. So even if you don't have a background in biology or science, by the end of today's episode, you will understand the core elements of genetics and the genetic passage of traits from one generation to the next. In addition, he makes it clear how certain experiences can indeed modify our genes such that they are passed from our parents to us and even trans-generationally across multi generations. That is, one generation could experience something and their grandchildren would still have genetic modifications that reflect those prior experiences of their grandparents. Dr. Rechavi takes us on an incredible journey explaining how our genes and different patterns of inheritance shape our experience of life and

2. 2:08 – 6:04

   Sponsors: ROKA, HVMN, Eight Sleep

   1. AHAndrew Huberman2:08

      who we are. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is ROKA. ROKA makes eyeglasses and sunglasses that are of the absolute highest quality. The company was founded by two all-American swimmers from Stanford, and everything about ROKA eyeglasses and sunglasses were designed with performance in mind. Now, I've spent a lifetime working on the biology of the visual system, and I can tell you that your visual system has to contend with an enormous number of challenges in order for you to be able to see clearly under any conditions. ROKA understands this and has designed their eyeglasses and sunglasses accordingly. Originally, ROKA eyeglasses and sunglasses were designed for sport, that is for things like running and cycling, and many of the features they have reflect that. So for instance, they are extremely lightweight, they won't slip off your face if you get sweaty, and they can indeed be worn for running and cycling and things of that sort. However, they also come in a number of different aesthetics and styles that make them perfectly suited not just for sport, but also for wearing to the office to work. If you'd like to try ROKA eyeglasses or sunglasses, go to ROKA, that's roka.com and enter the code Huberman to save 20% off your first order. Again, that's ROKA, roka.com, and enter the code Huberman at checkout. Today's episode is also brought to us by HVMN Ketone IQ. Ketone IQ is a ketone supplement that increases blood ketones. Now most everybody has heard of the so-called ketogenic diet. Most people, including myself, do not follow a ketogenic diet. That does not, however, mean that ketones cannot be valuable because ketones are one of the primary sources of brain fuel and body fuel that allows us to think clearly for long durations of time and to perform well physically. Which is all to say that even if you're somebody who's not on a ketogenic diet, such as myself, increasing your blood ketones can be immensely beneficial for cognitive and physical performance. Indeed, that's how I use Ketone IQ. I'll take one or two servings per day typically, sometimes before a workout, but most typically before doing a bout of cognitive work. So h- I'm going to sit down and prepare a podcast or focus on research for my lab or a writing project or anything that requires a high degree of concentration for a prolonged period of time. Ingesting Ketone IQ prior to that, I've noticed greatly increases my level of concentration and I can sustain that concentration for much longer periods of time than if I don't take Ketone IQ. If you'd like to try Ketone IQ, you can go to hvmn.com/huberman to save 20% off. Again, that's hvmn.com/huberman. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. As I've talked about many times before on the podcast, there's a critical relationship between sleep and temperature and indeed between waking up and temperature. That is, your body temperature needs to decrease by about one to three degrees in order for you to fall and stay deeply asleep at night. And when you wake up in the morning, in order to do that feeling refreshed, your body temperature actually needs to increase by about one to three degrees. So it's critical that you control the temperature of your sleeping environment and that that temperature be controlled very specifically across the night and into the morning. With Eight Sleep mattress covers, that's all extremely easy to do. You can program the temperature of your mattress in the beginning, middle, and throughout the night and when you wake up. I've been sleeping on an Eight Sleep mattress cover for over a year now and it has greatly improved the quality of my sleep, and indeed I know that because Eight Sleep also includes a terrific sleep tracker built directly into that mattress cover. If you'd like to try Eight Sleep, you can go to eightsleep.com/huberman to save $150 off their Pod 3 cover. Eight Sleep currently ships in the USA, Canada, UK, select countries in the EU, and Australia. Again, that's eightsleep.com/huberman. And now for my discussion with Dr. Oded Rechavi.

3. 6:04 – 14:36

   DNA, RNA, Protein; Somatic vs. Germ Cells

   1. AHAndrew Huberman6:04

      Oded, thank you so much for being here.

   2. OROded Rechavi6:06

      Totally my pleasure.

   3. AHAndrew Huberman6:07

      Yeah. This...... podcast has an, uh, somewhat unusual origin because I am familiar with your work, but we essentially met on Twitter, um, where you are known for many things, but, uh, lately, especially, um, (smacks lips) you have been focusing not just on the discoveries in your laboratory and other laboratories, but also, um, sort of meme-type humor-

   4. OROded Rechavi6:33

      (laughs)

   5. AHAndrew Huberman6:33

      ... that relates to the scientific process, and we'll return to this a little bit later. But, um, first of all, I think it's wonderful that you're so active on social media in this positive stance around science that also includes humor. But today, what I mainly want to talk about is the incredible questions that you probe in your lab, which are highly unusual, incredibly significant for each and all of our lives, and very controversial, and at times, even, um, a little bit dangerous or morbid.

   6. OROded Rechavi7:02

      (laughs)

   7. AHAndrew Huberman7:02

      Uh, so this is going to be a fun one for me and for the audience. Just to start off very basically, to get everyone up to speed, um, because people have different backgrounds, I think most people have a general understanding of what genes are, what RNA is, and so on, but maybe you could, um, 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 is a higher probability that they- their offspring will have blue eyes than brown eyes.

   8. OROded Rechavi7:32

      Mm-hmm.

   9. AHAndrew Huberman7:33

      Similarly, if two brown-eyed parents, higher probability that they will have brown eyes rather than blue eyes and so on, but that most people generally understand and accept that if they spend part of their life, um, let's say, studying architecture, that if they have children, that there's no real genetic reason, we assume, that their children would somehow be better at architecture because they contain the knowledge through the DNA of their parents. They might be exposed to it in the home, so-called nature-nurture-

   10. OROded Rechavi8:04

       Mm-hmm.

   11. AHAndrew Huberman8:04

       ... so nurture in that case, but that they wouldn't inherit knowledge or other traits. And 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 that opens up, including some evidence that, contrary to what we might think, uh, certain types of knowledge at the level of cells and systems can be inherited. So, that was a very long-winded opening, but to frame things up, what is DNA, what is RNA, and how does inheritance really work?

   12. OROded Rechavi8:38

       Okay. So DNA are the... is, is the material, the genetic instructions that is contained in every one of, of our cells. We have the set of genes containing, um, the entire set is called the genome, and this is present in every cell of our body, the same set of instructions. And genes are made of DNA, and they're al- they also contain, um, and chromosomes, th- they are contained in 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.

   13. AHAndrew Huberman9:11

       Sort of like s- um, thread on a, on a spool.

   14. OROded Rechavi9:14

       Right. Huge amounts that you have to condense. And we have the same genome, the same DNA in every cell in our body.

   15. AHAndrew Huberman9:21

       Can I just interrupt? And I'll do that periodically just to make sure that, um, uh, people are being carried along. I sometimes find that even remarkable, that a skin cell and a brain cell, a neuron, for instance, very different functions, but they all contain the full menu of genes and the same menu of genes.

   16. OROded Rechavi9:40

       No, it, it is amazing. It is amazing. And perhaps it's good to have an analogy to, to understand how it works. So this is... I hope this is not a commercial, but 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, the kitchen, the, the pictures. But in every s- in... 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 in the toilet. So you only re- um, remove one particular page of instructions, which is the instructions of how to build a chair, uh, and this you place in the ki- in the, in the living room, okay? And in- and the toilet, you put it in the toilet. So the DNA, uh, is the instruction to make the, the genome, the... is the instructions to make everything. This is the IKEA book. And in every cell, we, we take just the instructions for make one particular furniture, and this is the RNA. This is the RNA. This is the set. And then at the end, you'll, you'll build a chair. The chair is the protein. So the DNA... the RNAs, they're our instructions to make one particular protein based on the entire set of possibilities, and, and this is, uh, this is true for one particular type of RNA, which won't be the style of this conversation, which is messenger RNA. This is the RNA that contains the information for making proteins. 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 co- en- encodes for this messenger RNA. However, uh, a lot of the, the, the genome is transcribed to make RNA that does other things. Some of these RNAs we understand, and, and many of them we don't.

   17. AHAndrew Huberman11:23

       I think it's a beautiful description, and IKEA is not a sponsor of the podcast-

   18. OROded Rechavi11:27

       (laughs)

   19. AHAndrew Huberman11:27

       ... so, um, it's totally fair game to, to use the IKEA catalog as, as the analogy for DNA, the specific instructions for specific pieces of furniture is the RNA, and the furniture pieces being the proteins that are, that are essentially made from RNA using messenger RNA.

   20. OROded Rechavi11:43

       Correct.

   21. AHAndrew Huberman11:43

       Okay. Thank you for that. So despite the fact that the same genes are contained in all the cells of the body, there is a difference between certain cell types, right? I would s- 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?

   22. OROded Rechavi12:06

       Sure. So, so yes, every cell, every cell type is different because it expresses... it brings into action different genes from the entire collection and assumes an identity.... and, uh, so we have, uh- uh, we have the cells in the legs, we have cells in the brain. We have in the- in the brain, we have cells that produce dopamine, pr- cells that produce serotonin, and so on. And we can make, uh, different, uh, separations, different, uh, distinctions, but we can make one very important distinction between the somatic cells and the germ cells. The germ cells are supposed to be the only cells that contribute to the next generation, that- a- out of which the next generation will be made. So each of us is made just from a- a- a combination of a sperm and an egg, these are two types of germ cells, and then they fuse and you make- you- you- you get one fertilized egg, and out of this one cell, all the rest of the body will develop. And what happens in the soma, which is- which are all the cells that are not the- the germ cells, should stay in the soma, should not be able to contribute to the next generation. This is very important, and 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 in- with- t- 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, 'cause the information's supposed to reside in synaptic connections between different neurons, in particular, circuits that, uh, developed, uh, eh- s- so what's- what j- 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 and you build up muscles, you know that your kids will- will- will have to work out on their own. It won't, the- this shorthand won't- won't happen. This is something that we know intuitively and even if we don't have any background in biology, and 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, uh, acquire the mutation or a change in your DNA in one of particular brain cells, it wouldn't matter because this mutation, there's no way to transfer it to the DNA of the- of the germ cells that will contribute to the next generation.

4. 14:36 – 22:54

   Lamarckian Evolution, Inheritance of Acquired Traits

   1. OROded Rechavi14:36

   2. AHAndrew Huberman14:37

      So despite that, there is, as you will tell us, some evidence for inheritance of experience, let's call it, or, um, and here, we have to be careful with the language, right? I just wanna, uh, put a big asterisk and underline and a highlight that the language around what we're about to talk about is both confusing, and at the same time fairly simple and controversial, right? It's a little bit like in the, um, in the field of longevity. People sometimes will say anti-aging, some people will say longevity. The anti-aging folks feel that longevity is more about longevity clinics, they don't like that. Anti-aging is related to some other kind of niche, uh, clinics, sometimes FDA approved or government approved, sometimes not. And so there's a lot of argument about the naming, but it's all about living longer and living healthier. In this field of acquiring traits or the passage of information to offspring, what is the proper language to refer to what we're about to, um, discuss? Um, 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? Um, and maybe not even controversial, I think it- it's very like offensive even to certain people, this idea of inheritance of acquired traits, the idea that one could change themselves through some activity, use the example of going to the gym. We could also use the example of somebody who becomes an endurance runner then decides to have children within another endurance runner and has in mind the idea that because they did all this running-

   3. OROded Rechavi16:07

      Right.

   4. AHAndrew Huberman16:07

      ... and not just because they were biased towards running in the first place-

   5. OROded Rechavi16:10

      Right.

   6. AHAndrew Huberman16:10

      ... but because they, of the distance they actually ran that their offspring somehow would be fabulous runners. Okay, this Lamarckian, uh, 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?

   7. OROded Rechavi16:26

      Right, we have to be very careful, as you said, and there are many complications and many am- ambiguities.

   8. AHAndrew Huberman16:31

      And maybe you could tell us why Lamarckian evolution, for those that don't know, is so, um, so- such a stained thing.

   9. OROded Rechavi16:38

      Right. So-

   10. AHAndrew Huberman16:39

       It's not polite.

   11. OROded Rechavi16:41

       Right. Perhaps w- perhaps we'll start with just- just say that, uh, we can talk about inheritance of acquired traits, transmission of parental responses, inheritance of memory, all of these things, and we can also talk about epigenetics and transgenerational epigenetics and intergenerational epigenetics. There are many terms that we need to- to- to make clear for- for the audience. The- the reason it is so, uh, toxic or controversial is very complicated and it goes a long time back, even way before Lamarck. So even the- the Greeks d- talked about inheritance of acquired traits. Lamarck is associated with the term, but it's probably a mistake, although everyone talks about it, including people who study it. So Lamarck worked, uh, he published his book about, m- a little more than 200 years ago, and he, uh, he believed in inhe- inheritance of acquired traits, absolutely, but just like anyone else in his time. Just everyone believed in it. This is, it seemed obvious to them. They- it was long before Mendel and the rules of- of, um, genetic inheritance, and also Mendel was long before the- the understanding that DNA is the heritable material, so this happened a long time ago. Everyone believed in it, including Darwin. Darwin was perhaps more Lamarckian than Lamarck.

   12. AHAndrew Huberman17:59

       Really?

   13. OROded Rechavi17:59

       Yes, absolutely.

   14. AHAndrew Huberman18:00

       All right, now we're- now we're getting into the (laughs) -

   15. OROded Rechavi18:03

       Yeah, and, and, and-

   16. AHAndrew Huberman18:03

       ... into the meat of it.

   17. OROded Rechavi18:04

       ... and- and- and this is, uh, in the inher- in- in The Origin of the Species, it's in all of his writings. Lamarck didn't even really make the distinction between the generations. He had many other reasons for being wrong, but he connected the terms inheritance of acquired traits to evolution...... and this is some of the reasons he, that he was very controversial even in his time. There were other reasons. For example, he rejected current day chemistry and thought that he can explain everything based on, uh, on Aristotelian fluids, earth, wind, fire, and water.

   18. AHAndrew Huberman18:33

       Mm-hmm. There's still some people on the internet that think they can discard with chemistry and-

   19. OROded Rechavi18:37

       (laughs) Right, right.

   20. AHAndrew Huberman18:37

       ... explain everything based on earth, wind, fire, and water.

   21. OROded Rechavi18:39

       And this wasn't only biology, it was also the weather and everything. Uh, so, so that was part of the reason. But, um, LaMarck, so, so LaMarck made many mistakes, but he did have a, a, a full theory o- of inheritance, which was a, a big, uh, um, step towards where we are today. So, the... he had important contributions, nevertheless. Although he was mistake about the mechanism, what he believed, like everyone else, uh, uh, drives evolution is the transmission of the traits that you acquired during your life, or the, the, the things that you do or don't you do. We talked about use and disuse of, of certain organs that shape the, uh, uh, our organs and eventually also the organs of the next generation.

   22. AHAndrew Huberman19:24

       He sounds a little bit like the, uh, the first self-help public figure.

   23. OROded Rechavi19:28

       (laughs) .

   24. AHAndrew Huberman19:28

       Right? Well, this idea, you know, I mean, this is heavily embedded into a lot of the, um, health and fitness space on the, in Twitter and Instagram and on the internet, which is that, uh, and it's the, and it's the idea that we're sold, um, very early in life, at least here in the United States and probably elsewhere, which is that we can become anything that we want to become, and then that will forever change the offspring, um, either because of nature or nurture.

   25. OROded Rechavi19:53

       Right. And this is a very dangerous idea, as I'll explain in a second, and it led to horrible things. This is part of the reason that this is such a taboo. It's not only self-help, though you're helping your... or dis-helping yourself. The problem is wh- when you apply it to others, and this happened in a very, very dramatic and horrible way in, in, in recent, in the recent past, as I'll, I'll, I'll tell you in a second. So, Lamarck, this is what he believed, and, and, uh, he thought this what... is, uh, this is how evolution progress, progressed, and, and later, uh, um, Darwin, um, showed that it's really natural selection, the selecting of the, the people that... of, of, of the organisms that are already, um, that already contain the, the, the particular qualities are selected based on the, whether they survive or not in particular environments, and therefore, their, um, evolution progresses. They become more common and take over. This is very decent... two different explanations. The most common way this is, uh, contrasted with the neck of the giraffes. This is the classic example. According to, to LaMarck, the giraffes had to stretch their necks towards the trees to eat when the tree t- when the trees were high, and because of that, their, their, they transmitted these traits, long necks, to their children, who also had long necks. By the way, he only mentioned this example, you know, a handful of times. It's, he didn't really focus on that, and according to Darwin, just that, the, a giraffe that wa- happened to be born with a long neck survived because it ate, so its genetic heritable material, he didn't know about genetics, but, uh, uh, take over, and the rest of the giraffes that have different heritable materials just die. So this is natural selection versus inheritance for acquired traits. Th- there are many reasons why, uh, Lamarckism and inheritance of acquired traits became such a bad term. One of the biggest is what happened in the Soviet Union. Under Stalin, there was a, a, a scientist called Lysenko who thought that, uh, Mendelism, n- normal genetics is, uh, bourgeois science. It shouldn't be done. And whoever did normal genetics was either killed or sent to the Siberia. And, and he thought that, just like you said, we can... not only we can become everything that we want, but we can grow everything that we want in every field. We can take a frozen field and grow potatoes there and so on, and this led to massive starvation, ruined agriculture in, in, in, uh, in r- in the Soviet Union, also ruined science for many, many years, and put a very dark cloud on the entire field. And only probably in the '80s or something like this, the field started to recuperate for that. Aside for that, which is a very dramatic thing, there was also crazy stories, uh, around and attempts to, to prove the inheritance of acquired traits. Despite the realization of many scientists this is something that is very rare or that normally doesn't happen, is that it is not a normal way that inheritance works. And

5. 22:54 – 28:52

   Paul Kammerer & Toad Morphology

   1. OROded Rechavi22:54

      I can, uh, tell you about two such dramatic cases that will illustrate it.

   2. AHAndrew Huberman22:59

      Yeah, please.

   3. OROded Rechavi22:59

      So, so in the, in the beginning of the 20th century, in Vienna, there was a researcher called Paul Kammerer, was a very famous and, and also very colorful figure who did experiments on many different types of animals. He did experiments on toads that are called the midwife toad because the male, um, uh, carries the, the eggs. And, um, there's a beautiful book about it from, from, uh, Koestler telling the story of what happened there. And he... th- there are a couple of types of, of toads. Some of them live underwater and some of them live on land, and these toads are different in their shape and in their behavior. Um, so, of course, the cap- the capacity to live underwater is one thing, but also the, the morphology, uh, and appearance changes. The, the toads that live underwater develop these nuptial pads, these black pads on their hands that allow the males to grab onto the female without slipping.

   4. AHAndrew Huberman24:02

      For mating.

   5. OROded Rechavi24:03

      For mating. And the ones on land don't have them. He claimed that he can take the toads and train them to live underwater, changing the temperature and all kinds of things. It's a very difficult animal to work with. Eventually, according to Kammerer, they will...... acquire the capacity to live underwater and also changed their physiology and developed these n- black nupital pads on their heads. With this discovery, he traveled the world, became very famous, uh, eh, this was, um, uh, in just the beginning of the previous century, eh, as the person who found the proof for inheritance for acquired traits, despite the controversy and so on, and, and they are, and the beginning of the realization of how it actually works with DNA and so on. Not with DNA, but with, uh, um, natural selection. DNA came later. And, uh, and people didn't believe him. He was actually under a lot of attacks, but it seemed convincing. At the end, what happened is that they found that he injected ink to the toads to, to, to make them become black, to have these nupital pads. So, he faked the results and, um, and he couldn't stand up with, uh, the, the accusations and killed himself.

   6. AHAndrew Huberman25:21

      Wow.

   7. OROded Rechavi25:22

      In this book by Kessler, it suggests maybe it was, it was the assistant who did it, af-

   8. AHAndrew Huberman25:26

      Who killed him?

   9. OROded Rechavi25:27

      No, no.

   10. AHAndrew Huberman25:28

       Oh. (laughs)

   11. OROded Rechavi25:29

       Uh, who, who injected it to, to sort of save him from, because the, the samples lost the coloring or something like that. So, it might be. Who knows what happened?

   12. AHAndrew Huberman25:36

       Yeah. Well, in science, whenever there's a, a fraud accusation or controversy, the, it's not uncommon to see a passing of responsibility.

   13. OROded Rechavi25:43

       Right.

   14. AHAndrew Huberman25:44

       Uh, there are recent cases, there are ongoing cases now where it's a question of who did what, et cetera. Actually, I have two questions, um, uh, before the second story. Um, I'm struck by the idea that he was traveling and talking. I'm guessing this was before PowerPoint and Keynote, but also before transparencies, uh, which were actually were still in place when I was, uh, a graduate student. For those of you who don't know, transparencies are basically, um, transparent, uh, pieces of plastic paper that are, that, uh, that you put onto a projector and then you can write on them and do, uh, demonstrations, but you can show photographs and things like that.

   15. OROded Rechavi26:18

       Mm-hmm.

   16. AHAndrew Huberman26:18

       Um, so how was he giving these talks and would he travel with the toads?

   17. OROded Rechavi26:21

       So, he traveled with the samples.

   18. AHAndrew Huberman26:22

       I see.

   19. OROded Rechavi26:23

       And, and I'm basing this on this Kessler book, which is on its own, very controversial, and it's more of a beautiful story than, you know-

   20. AHAndrew Huberman26:30

       Mm-hmm.

   21. OROded Rechavi26:30

       ... perhaps, uh, the truth. But, and, and, and according to the story there, he had to stand one side of the lecture hall with his hands behind the back while others would ex- examine the samples and pass them around and so on.

   22. AHAndrew Huberman26:42

       But he cheated. Someone cheated.

   23. OROded Rechavi26:44

       He probably, he probably did it. Let, at least that's the, what most people think, but this wasn't replicated. I mean, also, I don't think anyone tried to replicate it.

   24. AHAndrew Huberman26:54

       Interesting, uh, rep- rep- this is just a point about replication, and actually another tragic example. Not but a few years ago, um, Sakai, who was a, as far as we knew, was doing very accomplished work on, um, the growth of retinas. Gra- literally growing eyes in a dish.

   25. OROded Rechavi27:10

       Mm-hmm.

   26. AHAndrew Huberman27:10

       I think everyone believes that result.

   27. OROded Rechavi27:12

       Mm.

   28. AHAndrew Huberman27:12

       But then there were some accusations about another result, um, that turned out to be fraudulent, and Sakai killed himself.

   29. OROded Rechavi27:19

       Right.

   30. AHAndrew Huberman27:19

       This was a recent, this was only about maybe five, 10 years ago.
6. 28:52 – 30:06

   AG1 (Athletic Greens)

   1. AHAndrew Huberman28:52

      I'd like to take a quick break and acknowledge one of our sponsors, Athletic Greens. Athletic Greens, now called AG1, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking Athletic Greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking Athletic Greens and the reason I still take Athletic Greens once or usually twice a day, is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by, uh, gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long-term health. And those probiotics in Athletic Greens are optimal and vital for microbiotic health. In addition, Athletic Greens contains a number of adaptogens, vitamins and minerals that make sure that all of my foundational nutritional needs are met and it tastes great. If you'd like to try Athletic Greens, you can go to athleticgreens.com/huberman and they'll give you five free travel packs that make it really easy to mix up Athletic Greens while you're on the road, in the car, on the plane, et cetera, and they'll give you a year's supply of vitamin D3 K2. Again, that's athleticgreens.com/huberman to get the five free travel packs and the year's supply of vitamin D3 K2.

7. 30:06 – 37:31

   James McConnell & Memory Transfer

   1. AHAndrew Huberman30:06

   2. OROded Rechavi30:06

      So, so this is, forget about that, we, uh, we also had the Lysenko episode. You know, that's a, a very big thing. And, and then in the US, there was, in the '70s and '80s, a researcher named McConnell.... who did very different experiments, and he was also a character. He worked, he worked on, uh, he, so he was the joker type of thing, and he published many of his results in a, a journal that he published that was called Worm Breeder's Gazette, and had many cartoons and things like-

   3. AHAndrew Huberman30:34

      So he started his own journal?

   4. OROded Rechavi30:35

      Y- uh, yes, and, but-

   5. AHAndrew Huberman30:36

      That's one way to publish a book.

   6. OROded Rechavi30:37

      (laughs) Yeah, but he also published in, in, in very respected, uh, journals in parallel, but he was, he was a psychologist, American psychologist, and he worked on a worm, uh, which is a flatworm, which is called planaria, which is very interesting. Which is different than, than what we'll discuss today, different type of worm. Um, you know, worms are, uh, are very common. So four out of five animals on this planet is a worm.

   7. AHAndrew Huberman31:03

      Really?

   8. OROded Rechavi31:04

      Yes. Num- numerically, if you just count the individuals. So we are the exception. And, and, uh, so, uh, but, but I'll talk about a very different worm later. This is a flatworm. This is called planaria, and it is remarkable in many ways. It was also a model that many people worked on, including the, the fathers of, of genetics, uh, people who started genetics, like Morgan. They worked on it in the beginning, but it's very, very hard to study genetics in this worm because unlike us, unlike what we explained before about how we all developed from sperm and an egg, these worms, most of the time, they produce just by fission. They tear themselves apart. So they have a head and a tail, and the part of the head will just tear itself apart from the tail, grow a new... Uh, the, the head will grow a new tail. The tail will grow a new head. You can even cut them into 200 pieces. Each piece will grow into a new worm.

   9. AHAndrew Huberman31:55

      Wild.

   10. OROded Rechavi31:56

       And, and they have centralized brains with lobes and everything, and even de- degenerate eyes. He studied these worms, and he said that he can teach them certain things, associations, by pairing all, uh, for... I don't remember exactly what he did. I think it was, uh, um, either lights or electricity with-

   11. AHAndrew Huberman32:18

       Shock them, I think.

   12. OROded Rechavi32:19

       ... which will shock them and-

   13. AHAndrew Huberman32:20

       Yeah.

   14. OROded Rechavi32:20

       ... with, with other things, and he could train them to learn and remember particular things.

   15. AHAndrew Huberman32:24

       Like, that they might get shocked on one side of the tank-

   16. OROded Rechavi32:26

       Exactly.

   17. AHAndrew Huberman32:27

       ... and then avoid that side of the tank.

   18. OROded Rechavi32:29

       Yes.

   19. AHAndrew Huberman32:29

       And then I guess the question is whether or not their a- their ripped apart selves and their subsequent generations will know to avoid that side of the tank without having ever been exposed to the shock.

   20. OROded Rechavi32:40

       Right, so without ever being exposed to shock or they... whether the, the new generation, the new heads will be able to rememb- to learn faster. That's another... The subtlety that you know might happen. Okay? And, and this is what he said had- happened. He said he could teach them certain things, remove, cut off their heads, and new heads with all the brain, uh, will, will grow, and that it will contain the memory. This was the start of the controversy, not the end of it, only the beginning. Then he said something even much wilder, which is he can tr- train them to learn certain things, and then just chop them up, put them in a blender, and feed them to other worms, because they are cannibalistic, they eat each other, and that the memory will transfer through feeding. This sounds-

   21. AHAndrew Huberman33:27

       Such a dramatic field. (laughs)

   22. OROded Rechavi33:29

       Yeah. And by the way, this, this opened a field. So people did experiments then, not only in planaria, but in gold flea- fish and certain rodents-

   23. AHAndrew Huberman33:38

       Oh.

   24. OROded Rechavi33:38

       ... and did these memory brain transfer essays, implanting brain. And this is in the back when they, they had, uh, an idea that some memories could be moleculars, could have a molecular form, which is very appealing. It's almost like sci- science fiction. You can have memory in a tube, unlike the way we think about memory normally, which is something that is distributed in neuronal circuits and encoded in the strength of particular synapses and so on. But, but the idea that you can take a, a memory and reduce it into a molecule and transfer it around is very, very, you know-

   25. AHAndrew Huberman34:12

       Mm-hmm.

   26. OROded Rechavi34:13

       ... interesting. So this is why it attracted so many people. This ended up in a catastrophe. So there was an NIH investigation. Couldn't, no one could replicate anything. It was a big mess, although there were always scientists who said, "Yes, we can replicate this and this." So they were in the background. Okay? McConnell's stuff was different. Again, people thought that they couldn't, that, that, there, there are problems replicating, but it wasn't necessarily... But some people replicate, but it wasn't necessarily about replicating the whole thing, but the question was did the memory, the transfer is specific or is it an overall sensitization that transmits and so on?

   27. AHAndrew Huberman34:49

       Right, like you could imagine that what gets transmitted is a hypersensitivity to electricity as opposed to the specific location that the electricity was introduced.

   28. OROded Rechavi34:57

       Or, or even more than that, even just, you know, a hypersensitivity in, in, in general. More, you're more vigilant and you learn anything so faster.

   29. AHAndrew Huberman35:04

       Mm-hmm.

   30. OROded Rechavi35:04

       That's also possible. But his problem wasn't the accusation. It was much worse, that he was targeted by the UNABOMBER, this terrorist who sent letters with bombs to many scientists for 15 years, and h- and his assistant, again, it's the assistant, I think exploded, and this is how his line of research ended. Just recently, a few years ago, a researcher from Boston, um, Mike Levin, and, uh, and his postdoc, Tal Somrat, replicated some of McConnell's experiment with the cutting of the heads, but in a very, using very fancy equipment and automated tracking, and they could say that they can replicate some of this, his, uh, his, um, his experiments.
8. 37:31 – 45:13

   Weismann Barrier; Epigenetics

   1. OROded Rechavi37:31

      and then we go back to, to, to these, uh, studies about inheritance of memory or inheritance of acquired traits in other organisms, in, in mammals, in, in, in, in humans. And aside from the dark clouds that these, um, episodes left, there were als- also theoretical problems why... of, of why this can't happen, barriers that have to be breached for this to happen. And you can, you can talk about many different types of barriers, uh, and, and, and you can also narrow it down to two main barriers. First barrier, we mentioned it, this is the separation of the soma from the germline.

   2. AHAndrew Huberman38:11

      Right. The somatic cells, they can change in response to experience. The sperm and the egg, the so-called germ cells, cannot.

   3. OROded Rechavi38:19

      They are all-

   4. AHAndrew Huberman38:19

      That's the idea.

   5. OROded Rechavi38:20

      Or they are isolated from what happens in the soma.

   6. AHAndrew Huberman38:22

      Mm-hmm.

   7. OROded Rechavi38:23

      Okay? The man who, who, who first thought about this barrier is called Weismann, August Weismann. This was in the 19th century, so it is called today the Weismann barrier, separation of the soma from the germline. Only the germline transmit 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 we work, to how our bodies work. Weismann, by, by the way, thought that if you will have direct influence of the environment on the germ cells, then perhaps this could transfer to the next generation. So it... He wasn't as strict as his barrier suggests, but, uh, but this is not how most people remember it. Okay. But he thought that this is unnecessary. It, it's possible that natural selection can explain everything, and he compared to, to a s- uh, a boat, which is in the ocean. It is sailing, and it has a sail open, so you don't have to assume that it has an engine. The wind is blowing. You don't have to assume other things.

   8. AHAndrew Huberman39:25

      Mm-hmm.

   9. OROded Rechavi39:25

      The natural selection might be enough. So this barrier is still standing, but not entirely. It is breached in some organisms.

   10. AHAndrew Huberman39:35

       Hmm.

   11. OROded Rechavi39:35

       We'll go into that in a second. The other barrier is the, uh, it, it... Now, we have to, to ex- to understand the other barrier, we have to talk about epigenetics. We have to define epigenetics and what it is, okay? And epigenetics is another term which people misuse horribly and say about everything that it's epigenetics, even people from the field, okay? The, the, the, the, the, the word itself, that... The term was defined in the '40s by, uh, Waddington, Con- Conrad Waddington, and he talked about the interactions between genes and th- that... and, and their products that ac- that in, in the end bring about the phenotype or the consequences and how genes influence development. Later, people discovered mechanisms that are... that, that, uh, change the action of genes, uh, different mechanisms, and started talking about these as epigenetics. For example, the DNA is built out of four basic elements, is out-

   12. AHAndrew Huberman40:36

       Nucleotides.

   13. OROded Rechavi40:36

       ... the, the, uh, the A, T, G, and C, right?

   14. AHAndrew Huberman40:40

       Yeah. Yeah.

   15. OROded Rechavi40:40

       And they could be mod- chemically modified. So in addition to just the information that you have in the sequence of the DNA, you also have this, the information in the modification of the bases. The most common modification that has been studied more than others is modification of the letter C of cytosine, methylation, the addition of a methyl group to this, uh, C. And, and, and this can be, uh, replicated, so after the, the, the DNA... the cells divide and, and replicate their genetic material. In certain cases, also, th- these chemical modifications could be added on and replicate and be preserved.

   16. AHAndrew Huberman41:20

       For those who aren't, um, as familiar with thinking about genes, uh, and gene structure and epigenetics, could we think of, um, these... You mentioned the four, um, nucleotide bases, C, G, A, and T. Um, but could we imagine that, um, through things like methylation, it's sort of like taking the primary colors and adding a, a... changing one of them a little bit, changing the, the hue just slightly, which then opens up an enormous number of new options of color, uh, uh, integration?

   17. OROded Rechavi41:46

       Absolutely. Just more combinations-

   18. AHAndrew Huberman41:48

       Mm-hmm.

   19. OROded Rechavi41:48

       ... more ways, more information. There are the modifications of the DNA, and also there are the modifications of the proteins which condense the DNA that are called histones. So they are also modified by many different chemicals. Again, methylation is a very common, uh, modification, acetylation, even serotonin, the serotonination of, of histones.

   20. AHAndrew Huberman42:11

       Serotonin?

   21. OROded Rechavi42:12

       Right. This is a new paper from Nature from a few years ago.

   22. AHAndrew Huberman42:14

       Can change DNA?

   23. OROded Rechavi42:16

       The, the... Not the DNA itself, but the protein that condenses it.

   24. AHAndrew Huberman42:19

       Essentially, how, um... in the analogy I used before of, uh, of how the thread is wrapped around the spool, essentially.

   25. OROded Rechavi42:26

       Yes. And, and this determines w- the, the, the degree of condensation of the DNA, whether the gene is now more or less accessible and therefore can perhaps be expressed more or less.So this is, this is one way to affect the, the gene expression and, and bring about the f- the function of the gene. There are many additional ways. It's not the only one. So thence p- wh- when this was, when all of this was starting to be elucidated, people talked about epigenetics, they started talking about these modifications, forgot the original definition, and when people said, "Epigenetics," they talk about methylation and things like that.

   26. AHAndrew Huberman43:01

       And, um, again, to just frame this up so we could imagine two identical twins, so-called monozygotic twins. Um, we could go a step further and say that they're monochorionic as they were in the same placental sac-

   27. OROded Rechavi43:12

       Mm-hmm.

   28. AHAndrew Huberman43:12

       ... 'cause twins can be raised in separate sacs, slightly different early environments. Let's say those two twins are raised separately. One experiences certain things, um, the other, other things, they eat different foods, et cetera, and there is the possibility through epigenetic mechanisms that through methylation or acetylation, um, serotonin production, et cetera, that the expression of certain genes in one of the twins could be amplified relative to the other, correct?

   29. OROded Rechavi43:37

       Right. So yeah. So we know that, uh, even a totally identical twins, genetically, they're identical, but they, they look, uh, different and they are different. This w- we experience, we all experience it. And this is, this can happen because of these epigenetic changes, okay, or it can happen because of other mechanisms. Because genes respond to the environment. Genes don't exist in a vacuum. There are, uh, gene- genes are need to be activated by transcription factors, and there's a whole, uh, uh, there's, there's, there's a lot of machinery that is responsible for making genes function, so we are a combination of our genetic material and the environment, okay? So when people talk about epigenetics and talks that, talk just about the modification, they are also not exactly right. My definition of epigenetics is inheritance which occurs either across cell division or more interestingly also for this, uh, podcast now, across generations, not because of changes to the DNA sequence by but through other mechanisms. I think this is the, the, the most, uh, robust, uh, definition that, that allows you to understand what you're talking about. And then again, and, and then, uh, the, and then the question is if this happens, then what are the molecules that actually transmit information across generations? Are they the... these chemical modifications to the DNA or to the proteins that condense the DNA, or are there other modif- other agents that transmit the information and which molecules can do it? And I actually think that the most interesting players today are RNA molecules.

9. 45:13 – 50:43

   Epigenetic Reprogramming; Imprinted Genes

   1. OROded Rechavi45:13

      Okay? But before I'll go into that, I just wanna say that when we talk about the barriers to epigenetic inheritance or the barriers to inheritance of acquired traits in addition to the separation of the soma from the germ line that we discussed, the other main barrier, it's called epigenetic reprogramming, which is that we acquired our diff- our cells, the, the, the genetic material in, in our cells acquires all kinds of changes, these chemical changes, modifications we discussed. But these modifications are largely erased in the transition between generations. So in the germ line, in the, in the, the, the sperm and the egg and also in the early embryo, most of them d- 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, uh, um, species-typical genetic instructions.

   2. AHAndrew Huberman46:17

      Mm-hmm.

   3. OROded Rechavi46:18

      So to preserve this, we, we erase the mate- the, the, all these modifications and start anew. And this is in, in mammals and in humans, this is largely too, most of the modifications on the sp- in the sperm and in the egg are removed, so m- about 90% of them. Some remain, which could be interesting.

   4. AHAndrew Huberman46:36

      So the idea, if I understand correctly, is that there's some advantage, uh, to wiping the slate clean and returning to the original d- uh, plan. In, in the context of the IKEA furniture analogy, um, the instruction book-

   5. OROded Rechavi46:51

      Mm-hmm.

   6. AHAndrew Huberman46:52

      ... 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-

   7. OROded Rechavi47:00

      Mm-hmm.

   8. AHAndrew Huberman47:01

      ... or a, um, any other cell for that matter. Through the course of the lifespan of the organism, those specific instructions are adjusted somewhat. Okay, so maybe, uh, like IKEA furniture, uh, sometimes you, you c- they sent you seven, not eight, of particular screws or they sent you, um, the proper number but you put them in the wrong place and it sort of changes the way that the thing works a little bit-

   9. OROded Rechavi47:22

      Mm-hmm.

   10. AHAndrew Huberman47:24

       ... once that, assuming furniture could reproduce-

   11. OROded Rechavi47:26

       Uh-huh.

   12. AHAndrew Huberman47:27

       ... uh, but here in the analogy of the furniture as, as the cell or, uh, or the organ in the... mates with another organism, th- that needs to be replicated, and so the idea is to take the instruction but go through and erase all the pen and pencil marks, erase all those additional little modifications that the, the owner used, uh, or introduced to it and return to the original instruction book.

   13. OROded Rechavi47:48

       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 a particular, uh, room, yeah.

   14. AHAndrew Huberman47:57

       So it's essentially the opposite of acquired traits and characteristics based on your, uh, what we say in biology, uh, geek speak, lineage-based experience but what your parents experienced, right? In some ways, we want to eliminate all that and go back to just the genes they provided.

   15. OROded Rechavi48:11

       Yes, but it's more complicated than that. It's more complicated than that because we have some very striking examples even i- in mammals where some of the, of the marks are maintained, for example, the classic example is imprinting. Imprinting is a very interesting phenomena. Um, the, the way DNA works is that we... you, you inherit, um, a copy for every chromosome from your mother and your father-... and then you have, in every cell of your body, two copies, if you are a human, uh, of every chromosome, okay? And then, eh, so, so, every gene is represented twice. These are called alleles, the different versions of the genes. And the, the thought is that once you... and that in the next generation, the two copies that you inherited are, are equal. It doesn't matter whether you eco- inquire, acquire them from your mother or from your father, right? There are some situations where it does matter. There is, there is a limited number of genes that are impre- are called imprinted genes, where it does matter whether you inherit it from your mother or your father, and, and this is happening through epigenetic inheritance, um, not because of changes to the DNA sequence, but because of maintain- maintenance of these, uh, chemo- chemical modifications across generations.

   16. AHAndrew Huberman49:29

       And as I recall from the beautiful work of Catherine Dulac, uh, at Harvard that, especially in the brain, there is evidence that some cells contain the complete genome from mom, or the complete genome from dad. Um...

   17. OROded Rechavi49:44

       And it can also switch during your life. So for her work showed that, eh, early on in, in, in your life, it's different, whether you express the, the maternal or paternal copy than when you are, uh, more, eh, mature.

   18. AHAndrew Huberman49:57

       So parents and children take note, you know. For those of you that are saying, "Oh, you know, uh, the child is more like you or more like me," that can change across the lifespan-

   19. OROded Rechavi50:05

       Uh-huh.

   20. AHAndrew Huberman50:05

       ... and if you're thinking about your parental lineage and wondering whether or not you, quote-unquote, "inherited" some sort of trait, um, from mother or from father, it can be, of course, both, or it can be just one or just the other, which I think most parents tend to see and describe in their children from time to time. "That's just like the father." Or, "That's just like the mother."

   21. OROded Rechavi50:28

       Right.

   22. AHAndrew Huberman50:28

       For instance.

   23. OROded Rechavi50:28

       Right, right. But it's important to know that in this situation, day of environment played no role. This was just whether it passed through the mother or the father. It's not that, uh, something had happened to the mother or the father-

   24. AHAndrew Huberman50:41

       Mm-hmm.

   25. OROded Rechavi50:41

       ... affected this, okay?

10. 50:43 – 59:06

    Nature vs. Nurture; Epigenetics & Offspring

    1. OROded Rechavi50:43

       So this is slightly different. The question is now, can the environment change the heritable material? Okay? So it's very important to understand that there is a difference between nurture and nature, uh, and this is very confusing. People are, are, eh, it's, it's a little subtle, so for example, people tell me, "I'm growing horses for many years, and I just know that this horse has a particular, uh, character. He's very different from, from the other horse, and so this is epigenetic inheritance." No. It could be just genetically determined. Yes, this horse inherited a different set of genetic instructions, so it is different. Doesn't have to be ab- about epigenetics. Epigenetic inheritance, uh, uh, means that the environment of the parents somehow changed the, the, the children, okay? And there, eh, there are these two main barriers that are serious bad bottlenecks that we have to think what type of molecule and how they can be bridged, right? So one possibility is that there's really this limited number of chemical modifications that survive, which is about 10% or so. That could be very interesting.

    2. AHAndrew Huberman51:51

       Not a small number.

    3. OROded Rechavi51:52

       Not a small number, per- perhaps.

    4. AHAndrew Huberman51:53

       Mm-hmm.

    5. OROded Rechavi51:54

       Perhaps, okay? This is one, one possibility. The other possibility, that there are other mechanisms. The, the situation now in humans is that it's just really unclear what transmits, if it can transmit, and which molecule does it. We'll talk later about other organisms where it, it is a lot more clear. But in humans and mammals in general, there are many examples for, eh, environments that change the children. Whether they, the, you need to invoke an epigenetic mechanism to explain this phenomena, it is unclear. First of all because it's hard to separate na- nurture from nurture, and second because, uh, um, the mechanism is just not understood. So, there are classic examples, for in humans there were periods of famine, starvation in different places in the world.

    6. AHAndrew Huberman52:49

       Okay.

    7. OROded Rechavi52:50

       In the Netherlands, in China, in Russia, where people did huge epidemiological study to study the next generations and saw that the children of women who were starved during, uh, pregnancy, are different. They're different in many ways. They have, uh, um, eh, eh, different, uh, birth weight, uh, glucose sensitivity, and also some neurological, uh, ch- uh, higher chances of getting some neurological diseases-

    8. AHAndrew Huberman53:19

       Okay.

    9. OROded Rechavi53:19

       ... and this has been, uh, shown, uh, uh, in very large studies.

    10. AHAndrew Huberman53:24

        Is there ever an instance in which starvation or hardship of some kind, some challenge, uh, sensory challenge, uh, or, uh, survival-based challenge, led to adaptive traits?

    11. OROded Rechavi53:36

        Yes. There are in different organisms. It could be as a result of a trade-off, so there could be a downside as well, but for example, there are two examples that come into mind. One of them is that if you stress male, um, um, mice or, or, um, or rats, I don't remember, this is work of Isabelle Mansuy in the ETH in Switzerland. If you stress the males, you can do it in many different ways, um, I don't remember exactly how they did, but you can, you can do m- you can separate them from their mothers, you can do social defeat, all kinds of things, then the next generations are less stressed. They show less anxiety.

    12. AHAndrew Huberman54:15

        So their threshold for stress is higher.

    13. OROded Rechavi54:18

        Yes. However, I think they have memory deficits and, and other metabolic problems.

    14. AHAndrew Huberman54:22

        Which may be, which may be an advantage for dealing with stress.

    15. OROded Rechavi54:24

        Could be. It could-

    16. AHAndrew Huberman54:25

        Yeah. I don't have any direct evidence for that, but there's some, there's some simmering ideas that, you know, our ability to anchor our thoughts in the past, present, or future seems very adaptive-

    17. OROded Rechavi54:34

        Mm-hmm.

    18. AHAndrew Huberman54:34

        ... in certain contexts. In other contexts it can keep us ruminating and not-

    19. OROded Rechavi54:38

        Right.

    20. AHAndrew Huberman54:39

        ... you know-

    21. OROded Rechavi54:39

        Right.

    22. AHAndrew Huberman54:39

        ... adaptively present to our current challenges.

    23. OROded Rechavi54:41

        Another example is that, uh, um, ni- nicotine exposure, this is, uh, I think the work of Oliver Hando from UMass, is, uh, eh, if I'm not mistaken, these are not my studies, but they improved the, the tolerance to exposure to similar drugs in the next generation.... the interesting thing here is that it's very non-specific, so you, you treat them with nicotine, but then, in the next generation, they are more tolerant to nicotine, but also to other, uh, I think cocai- cocaine or...

    24. AHAndrew Huberman55:11

        That sort of makes sense to me because, um, yeah, obviously nicotine, um, activates the cholinergic system, the dopaminergic system, epinephrine, and et cetera. Um, and you can imagine that there's crossover, because other drugs like cocaine, amphetamine mainly target the catecholamines, uh, the dopamine and norepinephrine.

    25. OROded Rechavi55:28

        But in, in the, in, in this particular study, if I remember correctly, they show that this happens, this heritable effect, even if you use an antagonist to block the nicotine receptor.

    26. AHAndrew Huberman55:38

        Wow.

    27. OROded Rechavi55:39

        So, so, so it's-

    28. AHAndrew Huberman55:39

        Okay.

    29. OROded Rechavi55:39

        ... something more about clearance of xenobiotics and, and hepatic functions that is transmitted and is very non-specific.

    30. AHAndrew Huberman55:48

        What I love about all the examples you've given today, and, and especially that one, is... And I hope that people, um, if you're just listening, I'm smiling because biology is so cryptic sometimes, you know? The, the, the obvious mechanism is rarely the, the one that's actually at play.
11. 59:06 – 1:09:03

    Generational Epigenetic Inheritance

    1. OROded Rechavi59:06

       and, and so the, the fact that there's an effect, that there's s- that something transmits this is clear. The question is, how miraculous is it and whether you need new biology and epigenetics to explain it.

    2. AHAndrew Huberman59:17

       Mm-hmm.

    3. OROded Rechavi59:17

       What do I mean by that? If you affect the next generation, it doesn't necessarily has to go through the oocyte or the sperm and involve the epigenome. You change the metabolism of the animal as it develops, and obviously it will effect it, right? The... When you, for example, uh, uh, starve women that are pregnant, as happened during the, the, the, this, uh, famous, uh, starvation studies, the, the, the baby's already, in utero, exposed directly to the environment. So it's not even a heritable effect. The baby is itself di- affected. It's a direct effect. Very interesting, important, and has many implications, and it will be separate from the div- the genetics. You have to take it into account to understand what's going on.

    4. AHAndrew Huberman1:00:04

       Mm-hmm.

    5. OROded Rechavi1:00:05

       Uh, doesn't require necessarily new biology, a new, new biology of inheritance. Not only is the embryo affected, the embryo while in utero already has germ cells. So it's also the next generation, so it's directly exposed. And you don't need any new biology necessarily to explain it, and it doesn't have, has to involve genet- epigenetics or epigenetics in general.

    6. AHAndrew Huberman1:00:29

       It's clear to me, uh, that in the female fetus, the total number of eggs that she will someday produce and, uh, potentially f- uh, have fertilized by sperm exists. But in males with a 60-day sperm cycle, um, leads me to the question, do, um, fetal males, um, males as fetuses, living as fetuses in their moms already start producing sperm? Or it's the primordial cells that give rise to sperm.

    7. OROded Rechavi1:00:54

       Uh, uh, uh, so I'm, I'm not a- an expert, so I don't want to, uh, go into the details of exactly when in mammals.

    8. AHAndrew Huberman1:01:00

       Sure, that's okay. Yeah.

    9. OROded Rechavi1:01:01

       But, but, but yes, exposure of the, of the mother also affect the, uh, eventually the, the, the, the transmission of the father... Of, of genetic information for the sperm's father. And there are also many examples of just stressing the fathers...... affecting the sperm and affecting the next generation. There, if you go to the F2 generati- so if you go two generations down the road, not to the kids, but to the grandkids, then it, it is a real epigenetic effect because, uh, because, uh, you, you examine something that happens, although the, the next generation was, was never exposed to the original challenge. Okay? So when we say about epigenetic inheritance in, through the paternal lineage, through the fathers, we talk about, uh, two generations, and when you go through the mother, it's three generations. To talk about s- to, to, when you need to, uh, invoke some real epigenetic mechanism. And there, the evidence becomes much more scarce in mammals. There are examples, more or less convincing. The field is e- evolving and improving a lot. So for example now, to, uh, m- many people use, uh, the cutting edge is to use IVS, in vitro fertilization, or transfer of embryos to make sure that you actually, it's the, it's the heritable information and not the environment, uh, or, uh, and that it goes through the germ line.

    10. AHAndrew Huberman1:02:22

        Mm-hmm.

    11. OROded Rechavi1:02:23

        So this is something that is being done now. There are studies-

    12. AHAndrew Huberman1:02:25

        You're talking about the three parent IVF where they take the DNA from mom, the sperm from dad, and they take the DNA from mom and put it into a novel cytoplasm? Or ...

    13. OROded Rechavi1:02:33

        No, not nec- or you, or just, you just take the sperm and transfer it and fertilize the, the, the, uh, an egg-

    14. AHAndrew Huberman1:02:41

        So standard IVF?

    15. OROded Rechavi1:02:42

        Yes. Standard IVF.

    16. AHAndrew Huberman1:02:43

        Yeah. Yeah.

    17. OROded Rechavi1:02:43

        Yeah. You can do it in many different ways, but this idea that you separate the, the, the environmental, the environment of the mother from the inheritance or, or the environment of the father, and, uh, to, to control and separate nature from nurture.

    18. AHAndrew Huberman1:02:55

        The, the environment becomes the culture dish.

    19. OROded Rechavi1:02:57

        Yes.

    20. AHAndrew Huberman1:02:57

        Yeah.

    21. OROded Rechavi1:02:59

        So, so the field is, is improving. Uh, p- people do experiment at, have a higher end, so more replicates and better controlled, and there are some examples for effects that transfer, and it depends who you ask whether people believe it or not. Many geneticists do not believe it, and many people do believe it, and it depends on the community. There are strong resistance for many reasons. Some of them are, are justified, some less justified in our, uh, part of the scientific process of and how things work, because it's, it's, it's a new, it's challenging the dogma. So this is very interesting on its own. If you ask psychologists, many psychologists believe that there's heritable trauma and, and things like this.

    22. AHAndrew Huberman1:03:41

        Mm-hmm.

    23. OROded Rechavi1:03:42

        Population geneticists, less so. Okay? So this really depends, and I think that, uh, uh, we are just at a point in time where we don't really know whether it happens and to what extent, and we need bigger studies. Even if you think about normal just genetic studies, where people trying to understand the genetic underpinning of, uh, complex traits, like, um, anything that involves the brain pretty much, we now know that you need to study many, many, many people. So now these big genome-wide association studies, big genetic, uh, studies involve hundreds of thousands of people. No one did an experiment like this for epigenetics. It's much more complicated because you need to also take into account the environment and to, it's, I don't, I'm not even sure we know how to d- d- design such an experiment. It's very, very challenging. Okay? So, so the part of the resistance, resistance to the idea, is based on tolo- uh, theoretical grounds because of these barriers and because of the, of the controversies. On the other hand, there's, people really want to believe it. People really want to believe it because it sort of gives your life meaning. If you can change your b- biology through changing y- uh, of, of your kids through changing your biology. So, so psychologically, I can understand why many people want this to happen. Even Schrodinger, the famous physicist, so he wrote a, a very important book in '44, so this was before the, the double helix and um, um, h- that, it's called What Is Life? This is actually a book that was, drove many bi- physicists to establish molecular biology. It's very, very important. And he talks about the heritable material, it also talks about evolution and he said, "Unfortunately, Lamarckism or inheritance of acquired trait is untenable. It doesn't happen." And he, and he, 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 s- the sperm and the egg. It doesn't mat- you can't influence it. Of course you can give your kids money and education, but you can't biologically influence it.

    24. AHAndrew Huberman1:05:56

        You can also s- so, um, uh, one thing I'm fascinated by for a number of reasons is partner selection. I mean, in some ways, you know, we think, oh, we, we want to find someone who is, you know, kind, that does seem to be, by the way, the primary feature, at least in, uh-

    25. OROded Rechavi1:06:10

        Mm-hmm.

    26. AHAndrew Huberman1:06:10

        ... the data tell us. We had David Buss on the podcast of how women select men, that people who are kind. There's also resource potential, there's also beauty or um-

    27. OROded Rechavi1:06:18

        Right.

    28. AHAndrew Huberman1:06:18

        ... uh, aesthetic attractiveness in males and females, et cetera. Um, male/male, female/female, as the case may be. But in terms of reproduction, sperm/egg, uh, male/female obviously. So we're selecting for a number of traits, but presumably subconsciously, we are also selecting for a number of traits related to vigor and in, th- the idea that if we were to have offspring with somebody, that those traits would be selected for.

    29. OROded Rechavi1:06:42

        Right. And we actually have a, a, a, have work on that in nematodes that I'll be happy to tell you about in a second after we-

    30. AHAndrew Huberman1:06:47

        The dating-
12. 1:09:03 – 1:10:20

    Sponsor: InsideTracker

    1. OROded Rechavi1:09:03

    2. AHAndrew Huberman1:09:03

       I'd like to just take a brief moment and thank one of our podcast sponsors, which is InsideTracker. InsideTracker is a personalized nutrition platform. They analyze data from your blood and DNA to help you better understand your body and help you reach your health goals. I've long been a believer in getting regular blood work done for the simple reason that blood work is the only way that you can monitor the markers such as hormone markers, lipids, metabolic factors, et cetera, that impact your immediate and long-term health. One major challenge with blood work, however, is that most of the time, it does not come back with any information about what to do in order to move the values for hormones, metabolic factors, lipids, et cetera, into the ranges that you want. With InsideTracker, changing those values becomes very straightforward because it has a personalized dashboard that you can use to address the nutrition-based, behavior-based, supplement-based approaches that you can use in order to move those values into the ranges that are optimal for you, your vitality, and your longevity. InsideTracker now includes a measurement of apolipoprotein B, so-called apo b, in their Ultimate Plan. Apo b is a key marker of cardiovascular health, and therefore there's extreme value to knowing your apo b levels. If you'd like to try InsideTracker, you can go to insidetracker.com/huberman to get 20% off any of InsideTracker's plans. Again, that's insidetracker.com/huberman to get 20%

13. 1:10:20 – 1:21:50

    Model Organisms, C. elegans

    1. AHAndrew Huberman1:10:20

       off. Thank you for that incredible overview of genetics and RNA and, uh, epigenetics, and was essentially a survey of this very interesting, um, and on the face of it, complex field, but you've simplified it a great deal for us. In our transition to talking about worms, I would like to plant a flag in the, uh, in the Huberman Lab Podcast and say that what we are about to discuss is the first time that anyone on this podcast has discussed so-called model organisms. I may have mentioned a fly paper here or there, or a study on honeybees and caffeine and, um, flower preference at one point, but typically that's done in passing and we quickly, uh, rotate to humans. I know that 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 ho- the incredible degree to which they've informed us about human health, especially when it comes to very basic functions in cells, right? I mean, one could argue, okay, there, and there's been some debate, telomeres in mice, did that really lead to the same sort of data in humans? Okay, there are these, those cases certainly, but model organisms are absolutely critical and have been, and basically inform most of what we understand about human health. So before we, um, start to go into the description about worms per se, could you just explain to a general audience what a model organism is, right? They're not modeling, they're not posing for photographs obviously. Um, what, what that means and what some of the general model organisms are and why you've selected or elected to work on a particular type of worm to study these fascinating topics that in- in there's zero question also take place in, in humans at some level.

    2. OROded Rechavi1:12:10

       So it's, it's a, it's a real pleasure and an honor to represent the model organisms here. I'm really happy just for that, this is, it was worth it, uh, because as you said, model organisms are extremely important and we learn so much about, about biology through them. The, the model organisms mean that it's an, it's a, um, an organism that many people work on, so there's a community of people that work on. People work study many types of organisms, but not around every organism there's a gr- a huge community of researchers that com- that sh- uh, combine sources to create all the, the resources and the tools and understanding that accumulate. There's just a handful of model organisms in the his- in the short history of the field of biology. It's not so long. We learned about every aspect of biology through them, including many important diseases, uh, uh, human diseases, and these are, uh, E. coli bacteria, phage, which is a, a virus of bacteria, and flies...... worms that are called C. elegans nematodes. This is what we study in the lab. Fish, which are called zebra fish, so particularly-

    3. AHAndrew Huberman1:13:23

       Danio danio or something?

    4. OROded Rechavi1:13:25

       Right. (laughs)

    5. AHAndrew Huberman1:13:25

       Yeah?

    6. OROded Rechavi1:13:26

       And, uh, and of course they are also model organisms, other... And mouse.

    7. AHAndrew Huberman1:13:30

       Mm-hmm.

    8. OROded Rechavi1:13:31

       And, um, and also, uh, plants, important plants, the most studied one is Arabidopsis.

    9. AHAndrew Huberman1:13:37

       Yeah. And perhaps less so nowadays, but non-human primates, macaque monkeys, marmosets, squirrel monkeys mainly.

    10. OROded Rechavi1:13:43

        Primates. These, I, I don't know exactly how the definition is, but emerging model organisms. There are many model organisms that are emerging and there are communities that are formed, including also around the planaria that we mentioned before. This flatworm that regenerates, it is a great model for studying regenerations. If we could develop new heads, it would be incredible. And we can learn from these organisms 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. So we shared, we shared, we share a lot of our, uh, um, uh, our functions with them and also a lot of our genes. C. elegans, and, and they have the different model organisms, have different advantages that serve us. They, uh, they sometimes have some things that are much more apparent in them that we can study. For example, learning and memory was largely studied in the beginning in a snail, Aplysia, when many of the discoveries were made because it has big new ones that you can easily study and, uh, uh, examine.

    11. AHAndrew Huberman1:14:46

        And yes, snails learn.

    12. OROded Rechavi1:14:48

        Yes, they learn.

    13. AHAndrew Huberman1:14:48

        Yeah. Yeah.

    14. OROded Rechavi1:14:48

        Even C. elegans, th- these nematodes that we study learn, and they are much simpler, uh, than worms. Another important reason to study them, of course, is you can look at, actually experiment on them. We can't do this to humans, the things that we do to these animals. And, uh, and we can change their genes, do all kinds of things to them.

    15. AHAndrew Huberman1:15:08

        And in some, uh... Sorry to interrupt, but in some cases, think you're going to tell us, for instance, in C. elegans in particular, the wha- the presence of particular cell types is so stereotyped that you can look at several different worms and you can... THE, 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-

    16. OROded Rechavi1:15:33

        Absolutely.

    17. AHAndrew Huberman1:15:33

        ... in the two different laboratories, something that is extremely hard to do in any mammalian model-

    18. OROded Rechavi1:15:39

        Right.

    19. AHAndrew Huberman1:15:39

        ... a mouse or certainly in humans, and, um, has posed huge challenges that, uh, give great advantages to studies of things like C. elegans.

    20. OROded Rechavi1:15:48

        Yes. So C. elegans, this is the star now of, of what, what... And, and this is what, what we study. These are nematodes, small worms, round worms that are just one millimeter long. So you can't see them with the naked eye. You have to look under the scope.

    21. AHAndrew Huberman1:16:03

        Where do they live in the, in the natural world?

    22. OROded Rechavi1:16:05

        So they, they used to call them soil nematodes, but this is not really true. They are, they are in many places, but they're mostly in, in rotten fruits and leaves. Uh, and, um, you can find them in the ground as well, but you can also find them... And, and they're free living, so they're not parasites, but you can sometimes also find them in snails, okay? But, but the best way to isolate them is from rotten fruits.

    23. AHAndrew Huberman1:16:28

        Okay.

    24. OROded Rechavi1:16:28

        Yeah.

    25. AHAndrew Huberman1:16:28

        I like the idea that they're not parasites. I'm one of these people that gets a little squeamish about the notion of parasites.

    26. OROded Rechavi1:16:33

        Yeah. Yeah, so, so they're not parasites. They're really fun to handle because they're so small and easy. You just grow them on plates with agar and E. coli bacteria. This is what they eat in the lab. You can just pick them with a, um, with a small, uh, pick, uh, wire pick, and move them around and change their, their, uh, genes and do many things to them. But, but they have many advantages for neuroscience and for studying inheritance. As you mentioned, they have always a certain number of cells in the body. So a C. elegans nematode always has 959 cells in its body. That's it, okay?

    27. AHAndrew Huberman1:17:08

        Not 960.

    28. OROded Rechavi1:17:09

        No.

    29. AHAndrew Huberman1:17:09

        Not 958.

    30. OROded Rechavi1:17:10

        959, okay?

Episode duration: 2:32:00