Dr. Oded Rechavi: Genes & the Inheritance of Memories Across Generations
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Welcome to the huberman lab podcast, where we discuss science and science space tools for everyday life. I'm Andrew huberman and i'm a professor neurobiology and opposite logy at stanford school of medicine. Today my guest is doctor ordered rehab y dr od.

Rehab y is a professor neuber logy at televised versy 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 discuss 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, doctor or habbi gives us a beautiful description of how genetics work.

So even if you don't have a background in biology or science, by at 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 as they are past from our parents to us and even trans generation ally 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. Or harvey takes us on an incredible journey, explaining how our genes and different patterns of inherits shape our experience of life and who we are. Before we begin, i'd like to emphasize that this podcast is separate from my teaching and researchers at stanford is, however, part of my desired 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 element. Element is an electorate drink with everything you need and nothing you don't.

That means plenty of salt, magnesium in patasse, this so called electronic light, and no sugar. Now, salt, magnesium and potash are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electro lights need to be present in the proper ratios.

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Totally my pleasure.

Yeah this podcast has a somewhat unusual origin because I am familiar with your work but we essentially met on twitter where you are known for many things but lately especially um you have been focusing not just on the discoveries in your laboratories and other laboratories but also mean type humor that relates to the scientific process. And we will return to this little bit later.

But um first of all, I think it's wonderful that you are 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 regional of our lives and very controversial, and at times even a little bit dangerous or morbid. So this is going to be a fun one for me and for the audience.

Just to start off very basically, you get everyone up to speed because people have different backgrounds. I think most people have a general understanding what genes are, what R N A is and so on. But maybe you could explain to people in very basic terms, and i'll just prefer all this by saying that I think most people understand that if they have two blue eyed parents, that there's a higher probably that they their offspring will have blue eyes and Brown eyes similar leave to Brown parents hire, probably that they have Brown eyes rather than blues 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, the nurture in that case but that they went inherit knowledge or other trades and today i'm hoping you can explain us why eye color but not knowledge is thought to be inherited. And the huge landscape of interesting questions that this opens up, including some evidence that, contrary to what we might think, certain types of knowledge at the level of cells and systems can be inherited so that was a very long winded opening. But to frame things up, what is DNA, what is R N A and how does insurgents really work .

OK so DNA are the is is the material, the genetic instructions that is containing and everyone of ourselves we have the set of genes containing um the entire set is called the gene and this is present in every sale of our body. The same set of instructions and genes are made of DNA and they are they also contained um and chromosomes they are containing chromosomal zs is the DNA and the proteins that condense the D N A because we have a huge amount of D N A in every day if you .

need to conta thread.

huge amount that you have to conduct and we have the same gene on the same DNA and every sell in our body. Can I just interrupt .

t and i'll do that period ally, just to make sure that people are being Carried along? I sometimes find that even remarkable, that a skin cell in 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.

No, IT IT is a mait is main. It's good to have an analogy to to understand how which works. So this is I hope this is not the commercial, but this is like the E, K, A book that you have in every cell in your body instructions to make everything that you need in your house, the chairs, the the kitchen, the pictures, but in every in, but in every room you want something has.

So in the kitchen you want things that fit the kitchen, in in the toilet, you want things that is the toilet. So you only rea remove one particular page of instructions, which is the instructions of how to build the chair. And this you place in the key, in the, in the living room, okay, the toilet you put in the toilet.

So the DNA is the instruction to make the the genome 的 is the instructions to make everything。 This is the care book. And in every sale, we we take just the instructions for make one particular furniture.

And this is the irony. This is the irony. This is the set. And then the end, you you build the chair. The chair is the protein, so the the the r in our instructions to make one particular protein based on the entire sets of possibilities.

And and this is this is true for one particular attack of R N A, which won't be the style of of this conversation, which is a message and a this is the r nit contains information for making positive. In fact, this is just a small percent of our of the ra to cell. So we have a very big genome in less than two percent of which encode for this message. However, H A lot of the the the genomes transcribed to make our way that does other things. Some of these rines we understand and and many of them we don't is a beautiful .

description and I is not a sponsor of the podcast. So um this totally fair game to to use the idea catalogue as as the analogy for DNA, the specific instructions for specific pieces of furniture is the R N A and the furniture pieces being the proteins that are that are essentially made from ra using messenger or R N A. O K.

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 was, is IT fair to say that there was basically one very important exception, which is thematic cells versus germ cells. And would you mind sharing with us what .

that distinction is? So yes, every cell, every cell type is different because IT expresses IT, brings into action different genes from the entire collection and assumes the identity. And so we have, we have the cells in the legs.

We have cells in the brain we have in in the brain. We have cells to stop, cells to the certain and someone. And we can make a different separation, different distinctions.

But we can make one very important distinction between the Thomas tic cells and the germans. The germ says that was supposed to be the only sales that contribute to the next generation, that out of which the next generation will be made. So each of us is made just for a, uh, a combination of the experiment in eg.

These are two types of germ says, 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 summer, which, which are all the set, are not that the germs that should stay in the summer should not be able to contribute to the next year.

This is very important. And he thought to be whether the main billions for the inheritance of corrodes, the inheritance of memory and so on. For example, like the example that you gave in with learning architecture, if I learned about the architecture, the information is encoded in my brain, and since my brain cells can't to transfer information to the experimental egg because the information supposed to resides in cyn API connection between different oils in particular and circuits that h developed.

Ah so what what what happens to the brand shouldn't be able to transfer next generation. Even similar a similar example, you go to the gym and you build up muscles, you know that your kids will will have to work out on their own IT won't the this short that 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 selling the body has its own genome, and the next generation will only form from the combination of the genome in the sperm and diag. Even if you somehow acquire the mutation or change in D N A in one of particular, but says he wouldn't matter because this museum, there's no way to transfer IT to the D N A of the of the germs that that will contribute to the next ation.

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 want to put a big asterisk and underline in the 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 in the field of longevity, people sometimes will say anti aging. Some people say langevin, the anti aging folks held at longevity ity is more about longevity clinics. They don't like that the aging is related to some other kind of niche uh clinic.

Some M F D A proved 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 discuss?

Um there is this idea and i'll say IT so you don't have to that gates back to lemark and lemark evolution. Very controversial, right? And maybe not even controversial, I think it's very like offensive, even to certain people. This idea of the inherent ance of acquired traits, the idea that one could change themselves through some activity, use the example going to the gym.

We could also use example, somebody who becomes an durance runner then decide to have children with an another endurance runner, and has in mind the idea that because they did all this running, and not just because they were bias towards running in the first place, but because they of the distance they actually ran, that they are all spring, somehow would be fabulous runners. Okay, this lemkin concept is, we believe, wrong. So how do we talk about inheritance of acquired traits? What's the proper language, rust? To frame this discussion right.

we have to be very careful, let you said. And there are many complications of many ambiguities.

And maybe you could tell us wild a markey and evolution for those that don't know is so um so such a stained thing, right? So it's not polite helps.

Perhaps we will start with just to just say that we can talk about inheritances, acquired traits. The information of potentially poses inheritances of memory, all of these things. And we can also talk about epi genetics and and generation epigenetics and intergenerational pig ecs.

There are many terms that we need to to to make clear for for the audience the the reason that is so uh toxic or controversial, al is very complicated and goes a long time back, even way they sold in mark. So even that the greeks, they talked about the inherit tate la mark is associated with the term. But it's probably a mistake, although everyone talks about including people who studied.

So the mark worked. He published his book about a little more than two hundred years ago, and he 呃， he believed in the inherits, acquired traits, absolutely. But just like anyone else in his time, just everyone believed this is IT seemed obvious to them, they that IT was long before mandel and the holes of of genetic inheritance, and also when there was long before that, the understanding the DNA is the health of material.

So this happens a long time ago. Everyone believed that is, including Darwin. In Darwin was perhaps more land mark and the landmark. really? Yes.

absolutely right now. Now we're getting into the and .

this is in the in in the origin of the species. It's in all of his writing, la mark didn't even really make the distinction between the generations. He had many other reasons for being wronged, but he connected the terms, inherits for quite traits to evolution.

And this is some of the reason he, that he was very controversial. Even in this time. There were other reasons, for example, he dejected and day key mousy and thought that they can explain everything based on a italian fluid. Ds, earth, wind, fire and water.

there's still some people on the internet they think they can discard with chemistry. And in everything is.

And this wasn't only biology, was also the weather and everything is so. So that was proud of the reason. But lama, lama made many mistakes, but he did have a full deal of inheritances, which was a big step towards where we are today.

So he had important contributions. Nevertheless, though, he was a mistake about the mechanism, what he believed, like everyone else, and drives evolution, is the transmission of the traits that you acquire during your life hoder the things that you do, or don't you do. We talked about use and these use of of certain organs that shape the uh, uh, our organs, and eventually also the organs of the next innovation.

He sounds a little bit like the the first self help public figure, right? Well this idea you know this is heavily embedded into a lot of the health and fitness space on the twitter and increment on the internet, which is that and and it's the idea that we're sold um very early in life, at least here in the united it's 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 right .

and this is a very dangerous idea as a explain the second only LED to horrible things. This is part of the reason that this is such a tabo. It's not only cells help, you're helping all this, helping yourself. The problem is when you apply to others.

And this happened in a very, very a dramatic and horrible weight in in in recent in the recent past, as i'll tell in the second so the mark, this is what he believed and and he thought this was this is how evolution progressed, progressed and later Darwin and showed that this really natural selection, the selecting of the the people, that of of the organisms that are already um that already contain the the the particular qualities are selected based on the whether they survival or not in particular environments and therefore the um evolution progress, they become more common and take over. This is a very distance, two different explanations. The most common way this is contrast is the neck of the giraffe.

This is the classic example. According to to lemark, the giraffe had to stretch their next story of trees to eat when the treat, when the trees were high. And because of that, the they transmitted this straight, long next to the child also had long next, by the way, you only mention this example, you know, handful of time, just even really focus on that and a causing to that in just that the egalite will happen to be born with a long next survive because IT ates.

So it's genetic heritable materials know about genetics. But uh, uh, I take over and the rest of that you have to have different hair materials, just die. So this is natural election versus in her create. There are many reasons why a maksim and inhalants acquits became such a bad term. One of the biggest is what happened in the soviet union under stalling.

There was a uh uh scientist called since le who thought that mendelism Normal genetics is a modular science, shouldn't be done, and whether the Normal genetics was either killed or sent to the siberia and and he thought, it's 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, frozen field and raw potatoes there and so on. And this LED to massive travon of in agriculture, in, in, in, in, in the solitude, also go in sites for many, many years and put a very dark cloud on the entire field. And only probably in the eighties, or something like this, the field started to recover.

For that aside for that, which is a very tomato thing, there was also crazy stories around an attempt to to prove the inhalant great traits despite the realization of many scientists. This is something that is very rare, or that Normally doesn't happen. That is not a Normal way that in hance works. And I can tell you about to such thematic cases that will illustrate IT now.

please.

So so in the in the beginning of the twenty century viana, there was a researcher chair called pole camera, was a very famous and and also very colorful figure who did experiments on many different types of animals.

He did experiments on toes that I called the midwife told because the male and Carries the the eggs and um there's a beautiful book about IT from from castle telling the story of what happened up and he there there are a couple of types of of toys. Some of them live under water and some of them live on land. And these toys are different in the shape and in the behavior.

And so of course, the the capacity to live under water is one thing, but also the the moth logy and appearance changes. The toes that leave under water developed. These nuuk ital pets is black pets on their hands that allowed the males to grab onto the female without .

slippers for mating, for mating.

And the ones on then don't have them. He claimed that he can take the toes and train them to live under water, changing the temperature and all kinds of things is very difficult animals to work with. Eventually, according to camera, they will acquire the capacity to live under water, and also changed of biology and develop this no black, no IT kinds of their heads.

With this discovery, he travels the world, became very shameless. And this was in just the beginning of the previous century h, as the personal found the true for inheritances for corporates, despite the controversy and so on. And they are in the beginning of the realization of how IT actually works with DNA zone, not with DNA, but with a natural election.

And DNA came later, and the and people can believe in, he was actually under a lot of attacks. But IT seemed convincing at the end. What happens is that they found the tea injected ink to the toes to to make them become black to have this new pital pet.

So we fake the results. And um and he couldn't stand up with uh the the the accusations and and killed himself. Well in this book by castle suggest maybe IT was IT was the assistance to the.

Who killed them? No, no. I who we inject .

the to to sort of saving from because the the same as lost the coLoring or something. So IT might be.

who knows what? Well, in science, whenever there's a fraud accusation of controversy that is not uncommon to see a passing of responsibility, there are recent cases. There are ongoing cases now or it's a question of who did what is a actually I have two questions um um before the second story um i'm struck by the idea that he was traveling and talking.

I'm guessing this was before powerpoint in kino, but also before transparencies, which you're actually we're still in place when I was a graduate student. For those you don't know, transparency are basically transparent pieces of plastic paper that uh that you put on to a projector and then you can write on them and do uh demonstrations, but can show photographs and things like that. Um so how is he giving these talks? And would he .

traveled with the two? So he traveled with the simps. I see and I am basing this on this test lab, which she's only very control tion. More of a beautiful story than, you know, perhaps the truth, but and according to the story, that he had to stand one side of the lectures hall with his hands behind the back, while others would examine the temples and pass them around.

And so but he he did someone SHE.

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

interesting pp. This is just a point about replication. And actually another tragic example, not but a few years ago, saki, who was as far as we knew, was doing very accomplish work on the growth of retina, literally growing eyes in a dish.

I think everyone believes that result. But then there are some accusations about another result um that turned out to be fraudulent and sick. I killed himself. This was a recent, this was only but made five, ten years ago. Um so IT still happens.

Yeah that happens. I think it's rare, but he doesn't happen. It's in this hypothesis.

argue I love to know what your number is, but I would argue that ninety nine percent of scientists are seeking truth and are well meaning honest people.

I totally agree and I think that um even think when people are wrong, it's mostly not because they're evil and trying to active flag that maybe they really want to believe the results or there are all kinds of way to be wrong and and even to uh bend truth without you know just a blatant ant fraud. But but this is according to the story and an example of a very bad third, which is agree is rare because most scientists, as you said, this is also my opinion, address trying to to discover truth and do the best they can.

What what else would you go into IT? Because it's certainly not a profession to go into if you want to get right. How many I even profession to go into if you want to get famous, if you want to be famous, you go to hollywood or become a serial killer because they will make special but please don't, but please don't do either. No hollywood I suppose for some is fine, but in any case, um okay, a camera around one thousand nine, nine, seven, nine.

thousand six, this is slightly before the the controversial ke out after the first world war.

Okay, yeah great. So um cameras gone his toes with um either ink or whatever nuptial pads they have to go back to meeting on land. I'd like to take a quick break and acknowledge one of our sponsors, athletic Greens. Athletic Greens, now called ag one, is a vitamin, mineral, probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic Greens since two thousand and twelve, so i'm delighted that they are sponsoring the podcast.

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Yes, OK. So so this is forget about that. We also had the delco episodes, you know, that's A A very big thing.

And and then in the U. S. There was in the seventies and eighties, researchers name mcconnell who did very different experiments. And he was also a character he he worked on, so he was the joker type of thing can be published. Many of these results in the adora the tea published was called warms breeders because that and had many cartoons.

And so he started .

his own journal.

yes, publish.

But they also publish in in very expected to, as in pal, but he was even the psychology american psychologist, and he worked on a warm and which a flat warm, which is called this is very interesting. This is different than what will discuss today. The different type of warm and you know, warms are are very common.

So four out of five animals, and these planes, es, are warm, really? Yes, no. Mai, if just count individuals, so we are the exception.

And and h, so, but, but I talk about a very different warm later. This is a flat warm. This is called planet. And IT is remarkable in many ways, was also a model that many people worked on, including the the fathers of of genetics, of people who started genetics, like Morgan. They worked on the begin.

But it's very, very hard to study genetics in this warm, because unlike us, unlike what we explained before about how we all develop from experiment, and eg, these worms, most of the time they produce just by vision, they're r themselves apart. So they have the head and the tail, and the part of the head will just turn itself apart. Ts, on the tail grow, and you, the head will grow in new tail.

The tail will grow in your head. You can even cut them to two hundred pieces. Each piece will grow into a new one while. And, and they have centralized brains with lobes and everything and even this the generate eyes.

He said that his worms and he said that he can teach them certain things, associations by Carrying gold for I don't remember exactly what he did. I think IT was um either lights or electricity with shock them, with shock them with with other things that could train them to learn. And we remember party like that.

You might get shocked on one side of tank exact and then avoid that side of the tank. yes. And then I guess the question is whether or not there they are ripped apart cells and their subsequent generations will know to avoid that side tank without having ever been exposed to the shock.

right? So without ever been exposed to shock or the whether the the new generation, the new head, we will be able to remember to learn faster. That's another the study that you might help, okay? And and this what he said he had, he said he can teach them certain things, remove, cut off their heads.

And new heads with all the brain will will grow, and that will contain the memory. This was the start of the controversy, not the end of only the beginning. Then he said something even much wilder, which is he can train them to learn certain things, and then just stop them up, put them in a blender and feed them to other warms. Because they are konni ballistic, they eat each other, and that the memory will transfer through feeding.

This sounds such a dramatic field.

And by the way, this this opened the feet. So people did experiments that not only in the lenny a, but in golf, fish and certain rodents. And this is memory, brain transfer essays in planting brain. This is in the back when they they had the an idea that some memories could be molecular, could have a molecular phone, which is very appealing, is almost like some scientific tion. You can have a members in the two.

And like the way we think about memory Normally, which is something that is disabused in new hana circuits and encoded in the strength of particular sign, upset and so on, but but the idea that you can take a memory, reduce IT into a molecule and translate around this, very, very interesting. So this why it's attracted to so many people, this ended up in a catastrophe. So there was an n age investigation.

Couldn't no one can replicate anything. IT was a big mess. Although there were always the scientific who said, yes, we can replicate in this. They were in the back of mccoll. Staff was different.

Again, people thought that they couldn't, that their problems replicating, but IT wasn't necessarily, but some people replicated, but IT wasn't necessarily about replicating the whole thing. But the question was that the memory that transfer is specific oasis and overhaul sation that plants me. And so right.

like you could imagine that what gets transmitted as a hyper sensitivity to electricity as about the specific location that the electricity was introduced .

or or even more than that, even just, you know a hybrids of deep in in in gender more you're more vigilant and you will learn anything fast. That's also also but his problem wasn't accusation. He was much worse that he was targeted by the unable milk is still ways to send letters with bombs.

Too many scientists for fifty years. And and he is assistant against assistant, I think, exploded. And this is how his line of research ended.

Just recently, a few years go, a researcher from boston and mike living and the and his postdoc touch replicated some of mcconnel experiment with the cutting of the head. But in the very using very fancy equipment and automated tracking, they could say that they can replicate some of these. His um his his experience really yes.

And they don't open packages in that labor's they have .

they have interesting stories you should .

have mike over familiar with with a bit of his work. Now I didn't realize they done that.

So they published few years ago and this is very interesting. But of course, they they don't know how that happens. The mechanism is unclear.

Michael went a step further than this. And what fascinating. And is this, our experiments we're done in the seventies and eighties.

He said that he can not only transform memory is through chopped animals, but he can take there the animals that that learns and break you down into different fractions, just the D N A, just the R N A, just the facts, the the proteins, the sugars. And he said that the fraction that transmit the memory is the irony. And this is very, very interest because IT was a long time before everything that we know about our today.

As soon go into viruses, explain what what we do and then you'll see that you can actually feed warmth without an a and get and and have many things happen. This is everyone know this is uh, true. okay.

So this way was so appealing to to go back to and studied, by the way, at the time IT became popular knowledge, everyone knew this experiment. There's there was a start like episode about IT from eighty four. Those there are comics book about IT, books about IT.

So this was very, and people were eating our and a because they thought that was our ending memory. This was across complete nonsense. But but this was IT made a lot of noise in these years, which she's part of the reason IT was so toxic until recently.

You couldn't touch because it's it's just consider sea science likely sanci like time. So this was just something you you didn't want to touch IT all. And and then we go back to to to these studies about inherits of memory or inherits for quiet trades in other organisms, in, in members, in, in, in, in humans.

And aside from the dark clouds, the this and episodes left, there were also also theoretical problems. Why of why this can happen, barriers that have to be reached for this to happen. And you can, you can talk about many different types of barriers, and and, and you can also never IT down to two main barriers. First barrier, we mentioned that this is the separation ation of the sumer from the .

german right symmetry cells. They can change in response to experience the sperm and the egg. This so called germ cells cannot.

That's the idea. Or they are isolated. What happens in the same? The men who who would first thought about this failure is called wiseman, or whose wiseman was, is in the nineteen century.

So this is called today, the wise man, daily separation of the summer from the german, only the german line transmit information to the next generation. And this is also called the second love, biology. So this is very, very fundamental.

So natural selection is the first one. This is the same, because is so important to how we work, to how our bodies work. Wiseman, by, by the way, thought that if you will have direct influence of the environment on the germans, then perhaps this could transfer to the next generation.

So if he wasn't as strict as his barrier suggest, but, but this is not how most people remembered, okay, but he thought that this is unnecessary. It's possible that natural selection can explain everything. And he compared to to 呃， uh, a boat which is in the ocean, IT is sAiling and he has a sale open.

So you don't have to assume that he has an engine, the wind is blowing. You don't have to a sum pink. The natural selection might be enough.

So this barrier is still standing, but not entirely IT is breaching some organisms. We will go into that in the second. The other barrier is the if we now we have to to x to understand the other bear, we have to talk about epigenetics.

We have to define epigenetics and what IT is. And epigenetics is another term which people misuse horribly and sap out everything, that is epigenetics, even people from the field and the word itself that the term was defined in the forties by h wedding ton wedding tone. And he talked about the interaction between genes and that and and the products that that in in the end, bring about the phenotype of the consequences and how genes influences development.

Later, people discovered mechanisms that are that that change the action of genes, the different mechanisms, and started talking about these as epigenetics. For example, the DNA is built out of four basic elements, is out, the, the, the, the, A, T, G, N, C. And they can be most chemical 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 basis. The most common modification that has been started more than others is modification of the letter sea of sioco metivier addition of a metal group to the sea. And and, and this can be replicated. So after the the, the DNA, the cells divided and replicates the genetic material. In certain cases, also, these chemical modifications could be added on and the replicate and be preserved.

For those who aren't as familiar, we're thinking about genes and gene structure. And could we think of um these you mention for um the basis t gd um but could we imagine that through things like method tion IT sort like taking the primary colors and adding changing one of them a little bit, changing the hue just slightly, which then opens up an enormous number of new options of colored uh integration.

more combinations, 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, motivation is very common and modification. Saul ation, even scotland, the station of histones seaton's.

right?

This is a new paper from nature .

for a few years ago.

can change DNA. Not the DNA said, but the part that can.

Essentially, how, in the analogy I used before of of how the thread is wrapped around the school.

essentially and and this determines the the the degree of compensation of the DNA, whether the gene is now more or less accessible and therefore can perhaps be expressed more or less. This is, this is one way to affect the the gene expression and and bring about the the function of the gene, many additional ways, not the only one. So then when this was, when all of this was starting to be losted, people talked about epigenetics. I started talking about these modifications. Forget the original definition and when people said epigenetics, they talk about motivation and things like that.

And um again, to just frame the sub so we can imagine two identical twins so called money as I got twins um we could go I get further and say that their monochord they were in the same presentation. Sc, because twins can be raised in separate sax like the different early environments. But they say those two twins are raised separately. One experienced of certain things, the other other things. They eat different foods at a and there is the possibility through epigenetic mechanisms that through method tion, a simulation um saton in production eta that the expression of certain genes in one of the twins could be amplified relative to the other .

so yeah so we know that even I totally identical genetically they are identical. But they they look at different, and they are different. This we we experience, we all experiences.

And this is, this can happen because of these epigenetic changes, okay? Or we can happen because of other mechanisms, because genes response to the environment. Genes don't exist in a vacuum.

There are h genes are need to be activated by transcription factors, and there is a whole uh uh a lot of machinery that is responsible for making genes function. So we are a combination of our genetic material and the environment. So when people talk about epigenetics and talk that talk just about the modification, they're also not exactly right.

My definition of epigenetics is inheritance, which occurs either cause cell division. Oh, more interestingly also for this podcast, now access generations not because of changes to the D N A sequence by but through other mechanisms. I think this is the the, the, the most how best definition that that allows you to understand what you're talking about.

And then again and and then and then the question is, if this happens, then what are the molecules that actually transmit information questioners all day that these can become modifications to the DNA or to the proteins that condensate ing? Or are there other other agents that comes with the information? And which molecules can do IT? And I actually think that the most interesting players today are any molecules.

OK. Before I go into that, I just want to say that when we talk about the bills to epic genetic and herds, or the billions to inheritance of a quiet traits in addition to the separation of the summer from the german, that we discuss, the other main failure is called epigenetics program, which is that we acquired our different our sales. The the genetic material in in our sales acquires all kinds of changes.

These chemical changes, modifications with disgust. But these modifications are largely erased in the transition between generations. So in the china, in the, in the experiment, the egg, and also in the early employee e, most of them different modifications are removed.

So we can start the blank slate based on the genetic instructions. And this is costal. Otherwise, according to the theory, is not clear that actually true, because in some orgasms doesn't really happen.

We will just, we will not develop according to the species, typical genetic instructions. So to preserve this, we we raised to the the audience modification to start on you. And this is in in members and in humans. This is like to most of the magic ation on the in the spare any day and he moved about ninety percent of them, somebody name, which could be insisting.

So the idea to understand correctly is that there are some advantage uh to wiping the slate clean and returning to the original the a plan in in the context of the I chia furniture analogy.

The instruction book is the one that issue to everybody OK every cell, right? Only certain instructions are used for certain cells, say a skin cell, a neuron or a liver cellar um any other itself for that matter, through the course of the lifespan of the organism, those specific instructions are adjusted somewhat. Okay, so maybe like I K F insure sometimes you 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's so of changes the way that the thing works a little bit once that assuming furnace could reproduce. But here in the analogy of the furniture as as the cellar, where the organ in that makes with another organism that needs to be replicated. And so the ideas to take the instruction but go through in a race, all the pen and pencil Marks a race, all those additional little modifications that the the owner uh or introduced to IT and return to the original instruction, right?

Because if you want to bring back the instruction book you wanted to have all the potential to make all the renditch. You don't want you to be restricted to the ones that you made in the particular room.

So it's essentially the opposite of acquired traits. And character is based on your what we say in biogen geek speak lining age based experience, but what your parents experience, right? In some ways we want to eliminate all that and go back to just the genes they provided. Yes.

but it's more complicated. It's more complex that because we have some very striking examples, even in members, where were some of the of the Marks are maintained, for example, classic example is impacting is a very interesting phenomenon. The the way DNA works is that we you inhaled and a copy for every colum's m from your mother and your father, and then you have in every cell of your body, two copies, if you are a human of every content.

And then so, so every genes represented twice. These are called allies, the different versions of the genes. And the the thought is that once you at the the next generation, the two copies that you inherit out are equal IT doesn't matter IT whether you equal inquire, inquire them from your mother or from your father, right? There are some situations where he does matter.

There is there is a limited number of genes are called in linton genes. What IT does matter whether you inherited from your mother or your father. And and this is happening through epigenome. Tic enhaloed is not because of changes to the DNA sequence, but because of maintain maintenance of these and modifications across relations.

And as I recall from the beautiful work of Katherine, do lock at, however, that, especially in the brain, there is evidence that some cells contained the complete genome from mom, or the complete genome from dad.

and IT can also switch during your life. So for her work shows that early on in, in, in your life is different. What are you expressed that the martello copy then when you are more mature?

So parents and children take note, you know, for those who you there are saying, oh, you know, the child is more like you or more like me, that can change across the ice men. And if you're thinking about your parental linkage and wondering whether not you could and inherit some sort of trade from mother or from father IT can be, of course, both or 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 friends. But it's important to know that in this situation, they have environment played. No, all this was just whether IT passed to the mother or the father.

Is not that something that happened to the mother or the father affected? So this is slightly. The question is now, can the environment change the other mature? And so it's very important to understand that there is a difference between nature and nature.

And this is very confusing. People are, are, is, is a little sub. So for example, people tell me i'm growing horses for many years, and I just know that this horse has a particular a character very different from from the hse.

And so this is epigenetic inheritance. No, IT could be just genetically determined. Yes, this horse inherit a gift and set of genetic instructions. So IT is different, doesn't have to be about epigenetics, epigenetic inheritance, uh, h means that the environment of the parents somehow changed the the the children.

And there there are these two main barriers that are serious bad bottle next, that we have to think what type of molecule and how they can be bridged. So one possibility is that is really this limited number of chemical modifications that survive, and which is about ten percent. So that could be .

very interesting, not a small number.

not a small number. But perhaps, perhaps, okay, this is one one possibility. The other possibility that there are other mechanisms that the situation now in humans is that is just really unclear, what transmitted, if IT can transmit, in which molecule does IT.

We talk later about other organic worried IT is a lot more clear. But in humans and members in general, there are many examples for environments that change the children, whether they that you need to invoke an epigenetic mechanism to explain this phenomenon. This is unclear.

First of all, because this is how to separate a new nature of nature, and second, because the mechanism just not understood. So there are classic examples for in human, there were periods of famine, starvation in different places in the world, the netherlands, in china, in russia, where people need huge epitome ological study to study the next generations. And so that the children of women who are starved during, uh pregnant y are different, different in many ways. They have a different birthweight group sensitivity and also some biological a higher chances of getting some nooo gc diseases. And this has been shown in very large studies.

Is there ever an instance in which starvation or hardship of some kind, some chAllenge, a sensory chAllenge, uh, or, uh, survival base chAllenge, LED to adaptive traits?

Yes, they are in different organisms. IT could be as a result of a tradeoff. So that could be a downside as well.

As for examples are two examples are coming to my one of them is that if you stress male and my soul or or red, I don't remember this is work of isa belman soi in the T. H. And switzerland.

If you stress the males, you can do is in many different ways. And I don't remember exactly how they did. But you can do, you can separate them from their models.

You can do social defeat, all kinds of things. Then the next generations are less stress. He showed less anxiety .

to the threshold. Stresses is higher.

yes. However, I think they have memory deficits and an other .

make up the proof maybe an advantage for a dealing with stress could be, I don't have any direct evidence up there. There some simmering ideas that you know, our ability to anchor our thoughts in the past, present, our future seems very adaptive in certain context and other context that can keep us ruminating and not writing adaptively present to our .

current chAllenges. Example is that a new exposure? This is, I think the work of the Oliver handle h from U.

S. Is I am from from misty king. These are not my studies, but they improve the the tolerance to exposure to similar drugs in the next donation.

The interesting thing here that is a very nonspecific. So you you treat them with Nicole, but then in the nationality they are more talent and Nicole. But also to add, I think coco.

that's what what makes sense to me because um obviously nickey um activites the colony ic system, the dopa gic system ein F N and a um and you can imagine that there's cross over because other drugs like who can and feet in mainly target the catacomb min said the .

document in in this particular study, if I remember correctly, they show that this happens, this how little effect, even if you use an antigonus to block the neuter reset. So so so it's something more about clearance of example biotics and and heroic functions that is transmitted and is very nonspecific.

What I love about all the examples you give in today, and especially that one is, and I hope that people, if you you're just listening, i'm smiling because biology is so cyp tic sometimes, you know, the the obvious mechanism is rarely the the one that actually at play. And people always asked, what, why? Why is IT like this? And I would say, you know, the one thing I know for sure is that I wasn't consulted design phase. And if anyone claims they were, then you definitely want to back away very fast.

And there could be shot. So many trade of so many trade. So for for example, we started and also other many other people study effects, these are in in warms will go, will go deep into that in the second.

But uh, the show that when you started in the next generations live longer. And this I think would be a trade of other things like um like fertility. So the next generations are more sick and fair and less fair and perhaps because of this, they live long. So that could be it's not necessarily a good thing.

I don't, anna, draw you of course, because this is magnificent, what you're doing and and splaying out for us here. But to recall there was a few years ago, I actually ended very tragically, was an example. I think he was down in sand ago, county. There was A A cult of sorts that were interested in.

Um living forever and so they castrated the male self, castrated themselves in the idea that somehow um maintaining some pre per breast and state of reverting to a suda pre process ent state would somehow extend on getting the idea that a sexual behavior somehow limited lifespan. This has been an idea that's been thrown around in the kind of more wacky langevin communities um they also shaved their heads, they also wear the same sneakers but then they also all committed suicide right as the hill bot comment came through town. Um but that's just but one example of many cults aimed at sort of that obviously was not life extension that was like truncation but um aimed that kind of eternal life or some sort of uh to chloric restriction that's right.

This this called also is very into the whole idea that by through color restriction we can live much longer or which may actually turn out to be true. I think it's still debated um hence all the debate about internet and fasting is set a but also IT is known that you've over eat you short in life. This is this is clear.

It's known that big bodied members of a species live far shorter lives than the smaller members of a great game versus a choo offer since. So there is some like sort of shards of truths in all of these things. But IT seems to me that the real questions, like, what is the real mechanism and and why would something like this exist, right? And why questions are very dangerous, right?

right? But but very interesting also. And and so so when IT comes to metabolic changes and nutrition, there are numerous examples where you either overfeed or stars and gets effects in the next generations. Many of the sometimes the effects contrast depending on the the way you do this.

Uh, again, these are none of we don't do any of that in in members s but people show that you starving or overfeeding the mothers, all the fathers changes the body weight of the next generation and also the the locals tolerance and and other and also a productive, a success and and and so the fact that there's an effect that there is that something transmitted, this is clear. The question is how miracle lous is IT and whether you need new biology and epigenetics to explain. What do I mean by that? If you affect the next generation, IT doesn't necessarily has to go through the outside of spam and involves the epic ino.

You change the metabolic of the animal as IT develops and obviously will affected the when you, for example, a staff, we men that now pregnant as happened during the the the the same as elevation studies, the the babies already in you to exposed directly to the enviro. So it's not even the heritable effect. The baby is itself affected, they said, direct effect, very interesting, important and has many implications, and they will be separate from the genetics you have to take in into account to understand what's going on.

Doesn't requite necessarily new biology and new, new biology of inherits. Not only is the empire affected, the employee, while neutral already has, so it's also the next generation so is directly exposed. And you don't need any new biology necessarily to explain IT and IT doesn't have has to involve gene p. Genetics or f gently .

is clear to me that in the female feeds the total number of eggs that you will someday produced and a potentially have fertilized by sperm exist but in males with a sixty days sperm cycle, leave me the question. Do um fetal males um males as fetuses living as fuses in their moms already start producing sperm or it's the priority al cells that give .

rise to sperm? So i'm not to an so I don't wanna go into the details of exactly when in means. But but but T S exposure of the of the mother also affect the eventually the the the the transmission of the father of genetic information for the firms 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 f two generations, if you go two generations down the road, not to the kids, but to the grand kids, then IT is a really evidently a because uh because you you examine something that happens, although the the next was was never exposed to the original al chAllenge. So when we say about epigenetic inheritance in through the eternal linux, through the funders, we talk about, uh, two generations, and when you go through the mother is three generations to talk about to to when you need to uh, invoke some real epigenetic mechanism. And there the evidence becomes much more scarce, immense.

There are examples, more of glaze convincing. The field is evolving and improving a lot. So for example, now to uh, many people use the cutting ages to use I V S in which of utilization or transact of employer s to make sure that you actually is the heat information, not the environment. Uh oh, and that IT goes through the germ line. So this is something that is being done out.

There are studies, three parent, I V F, where they take the DNA from mom, the sperm from dad, and they take the da from moment, put IT into a novel side of class or no.

not is all. Or just you just take the sperm and transfer IT and fertilized the, the.

the h an egg to a standard ibf. Yes.

standard I 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 inside and all the environment of the father, and to to control and separate nature from new .

to the environment.

becomes the culture dish. Yeah, so, so the family is is improving. People do experiment IT have a higher end, so more replicates and Better controlled.

And there are some examples for effects of transfer, and he depends who you ask, whether people believe IT or not. Many geneticists do not believe IT, and many people do believe, and IT depends on the community. There are strong resistance for many reasons.

Some of them are are justified, some less just. There are part of the scientific process of and how things work because it's it's it's a new it's chAllenging the document. So this is very interesting on its own. If you ask psychologists, many psychologists believe that was hurt about trauma and and things like population genetics less so.

So this really depends, and I think that h we are just a pointing time where we don't really know whether IT happens to what extent s and we need legal studies, even if you think about Normal, just genetic studies where people trying to understand the genetic and opinion of a complex straight, like any thing that involves the brain, pretty much we now know that you need to study many, many, many people. So now this big genomic de association studies, big genetic studies, involve hundreds of thousands of people. No one did the experiments like this for epigenetics, smarter, more complicated because you need to also take into account environment and to I don't i'm not even sure we know how to design such an experiment.

It's very, very chAllenging. So so the part of the resistance of resistance to the idea is based on toh geoeye grounds because of these barriers and because of the of the controversies. On the other hand, there's people really want to believe that people really want to believe IT, because IT sort of gives your life meaning if you can change you've biology through changing your of of your kids through changing your biological psychologically.

I can understand why many people want this to happen, even shading out the famous physicist. So he wrote a very important book in forty four. So this was before the the w hollies and um that it's called what is life.

This is actually a book that was drove many by physicists to establish molecule of biology. Very, very important. And he talked about the heritable material, also talks about evolution. And he said, unfortunately, the marches m or inherits of acquire is untainted.

IT doesn't happen and and IT, right? This is very, very sad, or unfortunately, because unlike Darwinism, natural selections, which is gloomy, doesn't matter what you do, the election and will be born based on the instruction in the experimental dozens met. You can influence IT, of course, you can give your kids money and education, but you can't biological influence.

You can also. So um one thing i'm fascinated for a number reasons is partner selection. I mean, in some ways we think so 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 the data, tell us with a David boss on the parts of how women, like men, that people are kind.

There's also a resource potential. There's also a beauty or a static, attractive. Most females, that male, male, female, male, as the case may be. But in terms of reproduction for egg, 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 in the idea that if we were to have offspring with somebody, that those trades would be selected for.

right? And we actually have have work on that, that I be happy to tell .

you about in the second after and .

where we understand the mechanism. And we go into that in the second but the or in a few minutes after, we we we dive into the warmth. But but yes, the original calculation of how population genetics work to simplify things and to do the math.

So we be that was renominate. Of course, he doesn't work like that. So it's complicated things because we know and there there was research about potential capacity to somehow sense immuno patients and things like this, which is, I don't know.

not an of course we're familiar with the other trades we look like for um like potential nurturing ability when then not someone is reliable, predicts something about their nurturing ability and offspring potential. You can draw lines between these things without any direct evidence, but but they seem so logical, right, that somebody kind, we'd also stick around or be honest, and these kinds of things that sense. But that one would be selecting for certain biological traits like immune function or some other form of robust that we're not aware of this I think a fascinating.

fascinating area of biology yeah so so this is where the the the the work in members stand. However, there's also one additional thing to to mention which is that on top of chemical modifications to the DNA and um and the porting set condenser DNA, which are called history, there are also other mechanisms that might transmit information, including transmission between generations of argent and there are different types of organic, not just the R N that we mentioned before, the message organic which in codes uh for h information for making quoting, but also other ironies that regulate the expression.

And this is, and I think that in recent tears, also in the malaria field, A R A as the molecule that has the potential to transmitting information between generation. Took center stage. So I think this is the cutting edge um a lot more to understand that no but irony has a lot of potential for doing that as we explain uh soon but we have to go to warmth first.

Thank you for that incredible overview of genetics and R N A and epi genetics and was essentially a survey of this very interesting and on the facebook of 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 there study on honey bees and caffeine and um flower preference at one point, but typically that's done in passing and we quickly rotate to humans.

I know that many, if not most of our listeners are focused on humans and human biology and health eta, but I cannot emphasize enough the importance of model organisms and the incredible degree to which we've informed us about human health, especially when IT comes to very basic functions in cells, right? I mean, one could argue, okay. And there's been some debate telemeter and mice to that really lead to the same sort of data.

And humans, okay, there are those cases, certainly, but most organisms are absolutely critical and have been and basically informed most of what we understand about human health. So before we start to go to the description about worm's persae, could you just explain to a general audience what a model organism is? right? They're not modeling, they're not posing for photos, 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 warm to study these fascinating topics that in there's a zero question also take place in in humans at sum level.

So it's it's a it's a real pleasure and an onno to represent the model logistic here. I am really happy just for that. This is IT was worthy uh because as you said, model of organisms are extremely important and we learned so much about about biology for them.

The the modern organisms mean that it's an it's an organism that many people work on. So there's a community of people that work on and people work, said IT, many type organizer, but not around every organized. There is A A A huge community of researchers that that combined sources to create all the the resources of the tools and understanding that accumulates.

There are just a hammer of model organisms in the in the short history of the field of biology. It's not so long. We learned about every hospital of biology through that, including many important diseases, uh, uh human diseases and these are uh equal bacterial page which is a virus of bacteria and flies warns that are called C A name though this is while we starting the lab fish which are called the ability it's a particular Daniel Daniel right and .

uh and of course there are also .

model organic other more enough and um and also plans important plans the most studies one is happy doxies and perhaps less so .

nowa ys but non human primates, macc monkeys, mama set square monkeys.

These I don't know exactly how to definitely, but emerging model organs are many of modern and communities from, including also around the planet a that we mentioned before. This flat, warm that regenerate is a great model for studying for generations. If we could develop new heads 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 share ed, we share a lot of our uh um our functions with them and O O O A lot of our genes c election. And they have the different model.

Organisms have different advantages that servus 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 elisia, where many of the discoveries were made. Because IT has big noise that you can easily study in an example.

And yes, snails learn.

Yes, they learn. Even see eleans. These methods that we study, learn, and they are not simply to the another important reason to sending them. Of course you can, you care, actually experiment on them. We can do this to humans, the things that we do to these animals, and and we can change our genes, do all kinds of things for them.

And in some, sorry, in true, but in some cases, think you're going to tell, for instance, and seal against in particular the the presence of particular south types is so stereotypes that you can look at several different worms and you can the community of people that study seal against is literally numbers and named each neuron so that two laboratories on opposite sides of the world can publish papers on the same neuron, knowing that it's the same neuron in the two different laboratories. Something that is extremely hard to do in any mamelon model, mouse or a, certainly in humans, and has posed huge chAllenges that give greater dangers to studies of things like aliens.

Yeah, so ceiling, and this is the star now of of what what and and this, what we study. These are nematodes small warmth round worms that are just one millimeter long, so you can see them with the naked, that you have to look under the scope.

Where do they live in the in the natural world?

So they, they, they used to call them, sold them, I thought. But this is not really true. They are, they are in many places, but they are most in in rotten fruits and leaves.

H and um you can find them in the ground as well, but you can also find them. And and there are free living, so there not pazz tes, but you can sometimes also find them in snails. Okay, but but the best way to isolate is from rotten fruits.

No, I like the idea that there are not parasites. I want these people to get you.

So they are not part. They are really fun to hand, because so small and easy, just them on with egg and equal like bacteria. This is what they eat in the lab.

You can just pick them with the um with the small pick uh wire pick and move them around and change the the genes and do many things for them. But they have many advantages for loyal science ends for studying inheritance. As you mentioned, they have always certain number of cells in the body so a sin against them are not always says nine hundred and fifty nine sets in. It's about that's .

IT OK not nine hundred and sixty.

not nine fifty eight, nine, fifty nine, okay? And out of which three hundred and two are noons always three hundred and two. There's a huge debate now over twitter on whether it's three hundred two or three hundred. I I mean, I don't want to get into trouble, okay, but people take this very, very hard. I think it's three hundred two, but less not to get into IT because I get into trap.

But we can equilibrate all things here. But you say three hundred and two, granted your far more informed in this mode, orgasm that I am, whatever will be, i'll say three hundred. And then we baLanced in terms of parties .

in politics, in the c elegant. So so and it's always the same. And each note on has a name like you said and we we not only does every noone has a named many of of them, we know what they do.

So there is a um a few sales that are sensory norms that the uh sense particular chemical in certain situations we know that and chemicals will be sense just by one oil on there are the moto oil and intel oil and not of that. We know how many doomy know once down. And so what do you know? And we know them all by their name.

Not only that, we know how they are connected to one another. We have a mac connect on since the eighties, like a subway map that tells us which knowing talks with which other knowing and IT is the same OK IT was used to think, people thought that he was exactly the same between genetically identical words. Now we know that slight difference, but by loud, IT is the same. And we have a map, old mapper.

we can use to study the so .

called connector. The connector, not only that, the worms are transparent, so we can actually see the noise on fire using particular tools, and we can activate genes and cillit genes using opto genetics. Like I was discussing the podcast, we can make the warmth go forward or backward, or lay a eg.

By shining different waves of light of of light on them uh and so we have uh very powerful, full of tools for manipulating the brain. On top of that we have great understanding of the genetics of the one of of the genome. This is silicon is the first animal to have its sequence, its genome sequence, before humans, for that, of course, bacteria that and and we know that.

And each warm produced, each mother produces about two hundred and fifty babies, which are almost genetically identical. So we can, and and we know what we, where we grow them, that the environment is very controlled over. We grow them in the plate with just bacteria, so we can easily separate between nature and nurture and and .

one thing that um I wonder about often is generation time, you know even though my are not humans myself certain branes because there are a million species, you can do all the bagnio ent things you can do and see elegans. And but one major issue with mice is that the generation time is somewhat long. You pair two mice, they made you get a mouse, a litter of mice twenty one days later might seem like, okay, that's only twenty one days or so. But if you are graduate to your post dog trying to do a project, I mean, that can extend the time to do experiments out three or four years. Come heard of what .

you could do in thea. You one of the major advantages, the generation time in the election is three days, three days. So you can do hundreds of warm generations in one P.

D. This is very important. Not only that, every warm will produce hundreds of progeny. Y, so you will have the augener tic identical, so you will have rates statistics for your experiment.

And the worms probably don't mind living on these agar plates lunching away um is the good you know it's a questionable whether not my or certainly a listen I I am a proponent of well controlled uh over and as long as this oversight um animal research is necessary for the development of treatments of diseases that that under humans.

But IT is always a little bit of of of a kind of a craning go kind of thing when you're dealing with with mamalis are living so far outside their natural environment. I be lying if I didn't say that he gets to you after while. And if IT doesn't get you, you can have wonder about your own psyche of that.

right? I also think that this is important, but for me, it's much easier to work on warmth. I don't have to. No, I feel bad about IT. Yeah.

they're happy.

They're happy. You also, I mean, if if a warm dies, it's less less painful to the human and if a uh and other more sensitive animals .

yeah I I would argue, yes, I agree.

Yes so yes. So there are many adventures for studying elegant. And in the one we now have very obvious and clear cut proof that there is inheritance of acquired traits. So much so that I don't think that anyone pretty much in the epigenetic field argues against this .

well and in large part thanks to you in the work you've done. So could you tell us what was the first experiment that you did on seal again that confirmed for you that there is inheritance of acquired traits because of course, the best experiments and experimenters always set out to disprove their hypothesis and when the hypothesis survives despite all the control experiments and poking and providing and um attempt to contradict oneself, then it's considered a Victory. But it's one that you have to be we all have to be very cautious about enjoying because of the tendency to want our our hypotheses to be true. So what was the first experiment where you were convinced that inheritance of acquired traits?

Israel, the first experiment I did was when I, in my post dog SHE, did with olive o hoppin. Universities, colombia. And we said to test whether warmth can produce tran generation for long, multiple generations of assistance to.

well, this is a very potent time.

which is a relevant thing, and and warms. These warmth don't have dedicated immune es like we do. They don't have tea cats or besets. They defend themselves from viruses very efficiently using irony. So in fact, when we started these experiments, there wasn't any natural BIOS that was known to infect the elegance, which is amazing, because viols are very good, as we all experience now in infecting. And the the worms are resistance to BIOS because of ani molecules showed any molecules that the sty voices, and these are called smaller ganes. Now we need to discuss them before I explain my experiment in um two thousand and six two researchers that were studying seal agence and do file and collect my look at the nobel tries for showing that there is a mechanism that regular jeans that happens for small organic, but they've shown is that if you inject the warms with I A molecules which are which are double stranded, they lead to the site to to they shut off the genes that corresponds that that match in sequence to this isa.

So it's sort of like taking the specific instructions for the coffee table from your kia and book and you sert a copy of that into the book. And in doing so you prevent the expression of, uh, some of a racist.

the original page, perfect exact. And for for they found that double stand and I needed to his two strength is what starts the response leading to the production of sml organic molecules, which are the ones that actually find the message of organic and leads to the destruction silent sets. So you don't get proto incipient for that.

They got the noble choice after people found that this is conserved in many organisms, including humans. And now they are now drugs. This was only in two thousand and six that the novel cries.

The paper was published ninety eight. There are now drugs that use this mechanism also in this. And I just introduction .

and say that not only a recent discovery in an incredibly important one, but andy fire and crag meller are also really nice people. Yeah, they just haven't very nice people. And craig mello and excEllent, I think, is a kite surfer.

When I the only time of medicine person was at a meeting and hand a black eye and I thought, okay well, I guess he's also dualist or something but turns out he had done that time surfing. So scientists actually do things other than um go to the laboratory nobel prize winning scientists that is okay. I'll let you continue. Thanks for along incredible .

scientists and there were also um uh h studies in many organisms on the mechanisms of how this happens. IT is called irna. Intel silence R N A interference in the expression of a gene. India, the functions of g and IT was also also called gene silencing, because this R N S enforce the silencing of genes instead of the changes being expressed, our silence IT.

And you don't many sister function k already in the the first paper that they published about this, where they've shown the Davis and aga is what leads to the silencing the control. They've shown two very important things. One of them is that if you inject the warmth with double cat and a, you don't only see the action in the cell that you injected or in the tissue that you injected, but you sit all over the worm's body.

Its friends IT wasn't exactly clear a wide spreads, but IT was clearly that he spreads. You see that silencing all over the body. This includes also the germans.

So if you injected up the stand just to pramathanath ys, even to the head, you will get also the effect in the jobs's end, in the next generation, kay, in the immediate pRogerin, the f one generation, the kids. So this was really clear proof that this is in hurt. However, this is just one generation OK.

There is occasion studies later that have shown something which will immediately remind what I taught you about with planning. A, that you can just take warms and feed them on bacteria that produce these organic, and that the distance and the silencing would move from the sight of injection from the gut, whether bacteria are eaten to the rest of the body and also to the next generation. So before we laugh, when I mentioned this Kenny ballistic experiments of my conal with the planet.

A and now you see that this can happen, and and this is not to ourselves. So this is being done routinely every day by any sea biologist in the world. But this is has been applications a million times now, tally, that you can also feed clannad, these other worms with organic. You can just put IT in shop liver and let them eat IT. And again, this will sign this throughout the body.

Child, okay.

And this is what we do thinly. We always, when we want, we use this technique to see what genes do. If you want to see whether particular genes important for a certain behavior of but a certain something, the way to studies is to neutralize the gene activity.

And we do IT by just introducing the warms with double stand gana that correspond in sequence, that matching sequence, this gene, this will lead to the silencing, this activate the genes activity. And then we, and if then the effect stops, we know these genes is involved in, and we never wanted just examine one warm. So we feed the mother with w stand, and then we examine all of its children, so we can have the statistics over hundreds of worms, or thousands of worms. So this is validator and not going to outside now. And totally, thing is IT fair .

to say that mconnais experiments of chop blending up these worms, graphic image blending up these worms and then feeding them to other worms plan area, that those experiments can yes be explained by um double stranded R N A, which enter R N A interposition .

ally hasn't been done yet. We are working on IT in in my left now with collabone without the left. But he wasn't publish.

But yes, this this could be the explanation. So I am. So five and mellow did this experiments. Some other people did this experiment. When I started my work, I wanted to see whether in addition to artificial w terray, some natural trades can can also plans me, cautioned because of organic.

because of small organize right because injecting R N A I um interpret shorter and fearing our is that is or you know putting worms into an environment with abundance of inhibitory R N A S as an experiment is very different. And worms experiencing something and then passing on that required trait to their offspring and it's a world apart in my opinion, because one is extreme manipulation that illustrates is an underlying principle. The other is something that in theory occurs in the passage of of generations, just naturally.

We're going from the less artificial to the more artificial h. The advantages, just like with modern logistic, that the more artificialities. The easy is to you know exactly what you did just now and reduce one fact, and you can follow the result. So this is always the trade.

What I did was in oliva's lab, is to see whether the magic, part of the magic for the worm's resistance to Violet is the capacity to transmit information in the form of alien molecules in hip italian named ord codes to the next generations. And IT has been shown before in silicas that the warmth resist BIOS be using this mechanism, the small organizes OK. In fact, this is probably the reason that these small organisms evolved in the first place to get rid of violence and other page etic genomic elements.

And this is a mechanism to fight them. And what I I did is a very simple experiment. I took warmth and I infected them with the virus.

When you do this, this also has been shown in the past. The warmth destroyed the virus. Okay, we demonstrate this very clearly using A A flow western vials.

So when if the, if the voice applications successfully, the warms us turns Green Green. And if the virus is destroyed, the warm stays black. This is very simple.

It's a clear cuttle. It's not this. You don't examine the warm and ask whether this feels good. You just see this Green .

light binary response. yes.

And so we we took warms. We infect them with the flow western balus David toys. This also has been done in the best.

But then work with you is we neutralized the machinery that makes more organize in the descendants of the warmth, so they cannot make smaller in is from the start on their own, because they just don't have the genes that you need to, to make this smaller, less. okay. And then we ask, when we, we, what will happen will will affect these worms with the voice.

Will they be Green or black? They can make their own smaller arnes so they can protect themselves on their own. The only way for them to stay black for have them not having the vial applicant is if inhered the smaller is on depends.

And this is exactly what happens, all the warmth progeny, although they don't have the gene that is needed for making the smaller ones. I have black, the signs of voice. And this also continues for additional .

generations OK. So the parent worms effectively. Put something into the genetic constructions of the offspring that would afford them. This, let's call IT an advantage in this case, but for them, an advantage if they were to be confronted with the same thing that the parents work right.

And we know exactly what these advantages the vantages are, small arms that match the viral genome and just chop up the virus in the next direction. And we can identify these small organize in the inhibit organize in the the sentence, although they don't have the machinery to make IT, just because he heard, we can identify them by sequencing, by are in a sequent, which is like the N A sequent. You actually get the extra sequence of the irony molecule. We can see that they call responder vows, and they have they inhaling smaller ganim only if the parents were infected with them.

So there's specificity there. There's a yeah it's not some just general a resilience passage. I have to be careful and drawing an acknowledge that isn't correct. And I want to acknowledge that what i'm about to say with certainty cannot be entirely correct.

But the the analogy that comes to mind in mamalis, this idea that if one generation is stressed, that their offspring may in some cases have a higher stress, real resilience to stress. I could imagine why that would be advantage, right? Your parents have a hard life.

They have offspring and they want their children to have a higher threshold distress, because stress can inhibit reproduction. And that so I say, you know, at at the end of the day and at the end of life, evolution is about the offspring, not about the parents. And every species pretty much seems to want to make more of itself and protective s Young one way or another, either nature or through nature.

This is a nature based protection of Young. Is IT fair to say that in the american experiment with a passengers stress resilience, that IT could be R N A based that that would be perhaps set some new threshold on luca cortical production here? I'm speculating, but I and I want to highlighting, i'm speculating. I'm speculating with a reason, which is, I think for people that are hearing about this in worms, you done a beautiful job of splaying out why on organisms are really important. But to think about how this may Operate in in our in the passage of human generations, I think is a reasonable .

thing to entertain, right? And and IT is true that also in members now, our nation and smaller is are a lending candidate for safety that could mediate the consumption of of stress protection or also harmful sector transact between generations, perhaps R N do IT. However, in warmth, the r nes have one more trick that we don't we don't know the equivalent in members yet.

This is something very crucial that we showed in that particular paper in the first paper, which is so they accept that I described the transmission of the assistance of violence through these are doesn't only affect the next generation IT also affect multiple additional generations. So IT gets past. IT gets past.

And you have to ask yourself, how doesn't IT get dialogue? why? Why isn't the diluted? right? Because I mean, everyone produces two hundred and fifty babies. So if they looked by two hand and fifty, and if something is, they looked for four generations ation.

So it's two hundred and fifty times to feature after four germination is the illusion of four billions completely on my patch would never work this just just nothing left. The secret of these worms is that they have a machinery for amplifying the smaller than in every generation. This is called ava dependent iran polyus.

It's uh um uh um complex, which uses the arana to find. And once IT finds the message organic, just create many, many, many, many small organize, so they don't get the looted and they passed on for additional generations. O and this is the the trick.

We later also identify genes that regulate for how long an effect would left otherwise. And if, if in beginning, we ask, why does how doesn't stop after one generation? Now we have to ask, why doesn't IT last forever? And IT doesn't? Typically, we see that the responses last not only with the value system, but also without rates. For a few generations, free to five generations, we found genes that function as a sort of a clock. The time is addition of the inherits.

what? What sorts of genes? others.

So we call these genes motel genes. mutteh. I don't know how is your hebrew, but motive IT means sweet heart in hebrew, but the aconite is modified.

Trans generation, elected genetic can help there. There are different, different types of genes like that. And for some of them, if you mute, if you disrupt their function now are now the effect which transmits stability for hundreds of generations.

That would never stop, because their role is to stop inheritance from going from, from just. You do not Carry over something forever. Otherwise, IT will no longer fit the environment of the parents, and you will be prepared for the wrong things.

So this is important. There are what type of genes are day one genes that we studied. It's called me too.

It's actually a gene that h functions in mutilation of the of the proteins that condensate DNA. So this is and there. But when the other genes that effect also pulled nature of smaller ones.

is there some mechanism that controls the duration of passage in a way that logically links up with the lifespan of the organism? So for instance, I knew my grandparents met them. I did not ever meet my great grandparents, and I certainly didn't me, my great, great grandparents.

I could imagine that my great, great grandparents or my great grandparents experiences certain things that were past into their children and perhaps into their children. But IT seems reasonable, given that humans live somewhere between zero and one hundred years. Typically, what now eighty years, is that the typical lifespan, more or less, okay, that the if I were going to design the system, and again, I was not consulted the design phase, I would want an adaptive, a trait to be passed for two generations.

Because given the way that are, given how longer species lives, and certainly given the way the world looks now, is opposed to turn out the previous century, the turn the previous century, different different stressors, different adapt, you know, different life environments um and what I would want to pass on to my offspring, I can basically hedge pretty well. I can place a good bet on the next hundred years, maybe the next two hundred, but I don't have the fog as clue. What the world is going to look like in three hundred years is what i'm saying make any sense what?

So IT makes a lot of, and really we need to to talk about two pings in responsibly question, first of all. And yes, you can imagine that the reason that the ones in hurts, typically for three to five generations, is that this is elephant to something that happened in the violence, for example. And we also showed, when you stop the warmth, IT affects the next generations, again, for a few generations.

which itself is amazing. I just like want to highlight that that I mean, can imagine next generation, sort like a genetic version of be careful kids. But i'm going to give you this extra lunch pack in your genome that protects you against the possibility of starvation. But it's also saying and we're you to have kids, right?

They have IT also yeah so I have to but I I have to just make a this climb that we not done on that necessarily is adaptive, could also be damaged. As I said, when you stamp them, the next generations live longer. But this could be a trade of of a trade of for ferlie something.

So other labs is also have also shown following our work that if you stop the warms, the election additions are also more existence to how shall this sounds? This is not my our word, but this sounds adapter kay. But when whenever you're talking about the tension, you have to sit in the context of evolution.

There's also this famous thing, nothing in biology makes sense except in the lighter revolution. And so it's very hard to say without doing the lab revolution experiments, we actually see who wins, the ones that inherit or the ones who don't have who takes over. Otherwise, it's it's hard to talk about whether it's that people look.

But when IT comes to the decision of the response, yes, IT could be program to fit something. For example, if you are talking about the version warmed transition between periods of starvation and transparent s where they have a lot of foods. So lets say they find an apple for a few generations, they will consume the appel and then they will be started for a while.

Perhaps this is the number of generation that takes them to finish at IT. Or perhaps there are other responses also to hire the temperatures ah if you grow, warms and higher temperatures and offers are are different, they change how they made. So I looked at too before .

we're going to get back to this because IT related to call the exposure.

which many listeners are perhaps to this somehow coated with uh um the cycle of the year, kay, but to tell you the truth, I don't know. As I said, we we um we go from the more artificial to the less artificial. If double and organic is synthetic, organic is the most artificial. Starvation is more efficient and more natural. But it's not starvation in real the real context of the world in a real appeal.

It's a place weather without equal bacteria, but it's not an apple on the tree exposed to the elements with other worms, with bacteria, with all kinds of complications and IT could be that we will see different donations of herriton effects the more natural we go with, just much less controllable and hard to do. And again, when when we're talking about humans, part of the argument why people were the these believers, it's not about, say no, the critics say that this wouldn't happen in humans. They say, you know, the warm generation time is just three days.

The chances that the parents and will match the chiefs interment is very high because, uh, does not a lot of time to for for the environment to change IT glad they can go very far small. There are many examples of epigenetic inhalants in clause is a big field where the very established h proof for inheritances of acquired ate for for f genetic hit to be more careful if I in heart of which is more loaded them. But IT also happens. And then you also say these are style organisms. They can't run away, so the environment is more constant.

The ideas, maybe just a quick example that i've heard before, tell me if i'm wrong. I very well may be, for instance, a particular species of plant that grows a straight, maybe slightly bended, stock might be exposed to some environment where, in order to capture enough sunlight and other other countries might need to grow in a court screw form, the court screw form can be inherit several generations.

This is example that I don't know, but perhaps .

something like that. I someone will trust me the one thing we know about podcasting and youtube, but someone will tell us in the comments. So and please, do we invite that right?

But there's a long history of epigenetic inheritance studies in plants that excEllent studies welcome told, showing that IT happens also there. So this is very clear when IT comes to humans, you could say, maybe my kids will go off to live in a different continent, and they will be on the computer everyday. Everything will be different.

So IT makes less sense to prepare them for the same hardships of the experience. However, this, in my opinion, this is this argument comes a lot. It's not the best argument because IT depends on the scale, how you look at things we experience, we meet, for example, i'm not saying this is inherit, but in humans, but we experience the same patent and the same viruses, all the type of perhaps this is worth prepared for that. Again, i'm not saying that, that IT happens, but but IT depends on the on the on the scale. Well.

what you're describing makes perfect sense and I do want to acknowledge these critics ever they may be I do have the advantage that I work in this exact field and so I am happy to stand um to to to with those critics now and say that at least in terms of an inherited ance of reactions or adaptive or more adaptive traits to stress or to reward who you talk about nicki in before you know a passage of response to drugs of different kinds not being specific IT was also a more general um passage of of some sort of information related to uh reactions to chemicals present in sixteen but other other drugs.

I have long been irritated and a little bit tickled by the fact that people say, oh, you know we have this system for stress that was really designed to keep us safe from lions and sabor tigers, sure. But the hallmark of the stress system is that IT generalizes. I mean, if I get a troubling text message, or if I suddenly see a dark figure in in the hallway when I go to the bathroom at night, that I don't recognize, both of those have the sange and eric response, which is the deployment of a journal in both brain body, you know, changes in the optics of the eyes, quicking of the heart rate stress is, by design, generic.

And so one could imagine that a passage of some sort of stress resilience or a maladaptive passage distress would be also somewhat in eric. And that's actually advantages overall. Same thing with the reward system.

We have essentially have one or two chemical systems reward. I mean, there's the opposite system and there's a kit can abo ID system. But in large part, anticipation and reward is governed by the dopa mean circuits. And anticipation reward of an ice cream cone for a kid is the same neural circuitry that's going to be repurposed when they get to reproductive age. And they are anticipating creating children with their mate and assuming they want to do that, the government, eric stems going to engage.

So I am sex um you know stress to whether stress to famine, the the biology of of these more model systems, and especially in the nervous system, are again, I have to be with the words by design are certainly generic and so I don't see the need for for immense specificity. I mean, it's not like we're um coverage just happen. So could you imagine that there's the passage of a covey nineteen specific resilience? No, I think what would probably be pass along would be some sort of if IT does occur, would be some sort of resilience to viruses more generally. And that would be advantage.

right? So I I agree. And this this opens a question of what is the band wide of inheritance? How specifically that IT makes sense for you to be specific.

And in the case of c elegance, the response can be very specific fruin healths of armies, which are just sequence specific. They down regulate they, they control one particularity OK. In other cases, IT could be a very general response.

And it's very interesting to think about IT when we talk about in heats of memories, which is the most interesting thing we could have been in brain activity of some salt to me, at least in these words. I said, no, I I said, this is claim. And multiple times in in members, we don't know, times will tell.

In warm, we know a lot. So can warm stands to brain activity to to do they have the specificity to do OK. Before I said that, I just say that we, over the years learned a lot about the mechanisms that shuttle the alias between generations.

We know about the genes that are needed just for that. About worms will be perfectly okay, but just don't have the capacity to transfer agents to the next generations. We know about genes that will make the responses longer or shorter.

We know about genes that prevent the transfer of amErica between different issues, about genes that make certain smaller this. So we know a lot about that. And then the question arises, we can, we can finally ask, can memory answers betwen generation? I think that, first of all, we need to define memory for this.

And the bode's definition would be any changing your behavior because of what happened in the past, or in your response because what happened in the past of because of your history. The more interesting part, of course, to talk about memories that are encoded in the brain. And the reason is that the brain is capable of holding much more specific and elaborate memories.

Then I think that any tissues that transits transl to transmit on to the next generation and affect the next nation is interesting. The guards, muscles, everything but the brain can sympathize information about the environment and about internal state, and can also think ahead. And the most provocative thing you can say is that you could plan how, somehow, the fate of of national nation, using your blame, taking anything into out.

talking them without all right and instruction. So it's, again, we go back to this instruction manual. It's like writing something into the instruction manual based on .

your own experience, right? And and can IT happen. And and what is the band? What can we? and? And then I have to agree with you that I would imagine that what can transform, and I could be wrong, is a general something, sensitivity. So you can make the analogy to being inflamed or not with hyper sensitive to part genes, hyper vigil something. Okay, but you can also be something very specific.

We now we have to, we have to understand that the brain uses a different language, then the language of inheritance, the blame, the way we Normally think about the brain, is that IT keeps information in sign up, in the connections between different notes. When you learn something, you make, you make some connections stronger and some other connections weaker. And you why the nervous system in a different way, the information in the brain is synaptic IT is in the connections.

On the other hand, held able information of any thought has to go through a battle neck of one cell, the fertilized egg, because we all start from just one cell, so we cannot be in the connections, because this cell doesn't have any connection without the sell there alone. So we do. So hittable information has to be molecular, has to be inside this oneself. So the question is, can you or do you translate the information, this free structure information of signup says, and the connection between brains in the architecture of the brain? Can you somehow translate IT to help the people information to a molecular form?

It's an incredibly important and deep question IT brings to mind and something that was once told to me, which as soon as I heard IT, was obvious, but was very important in formulating my understanding of biology, which is that a map is just the transformation of one set of points into another set of points, right? So a map of of the world, essentially, is just you take what's been drawn out in terms of the architecture and the coastlines and sea and divisions between states, and you transfer that to an electronic map.

A piece of paper seems so obvious as sort of a duck. What are we talking about this? But just make sure that people understand what you're really talking about is, let's say, the memory and I have a very distinct memory for my childhood phone number.

Phone number doesn't exist anymore and I won't give IT out because then some other person might get you a with repeater calls. But in any case, I remember IT. It's totally a useless information.

But IT lives in my new cortex or my hip campus, or somewhere as a series of connections between irons at the locations, as you call synapses. Would my grandchildren know that phone number? There's no reason to them no right. Would my children know that unless there was some adaptive reason or some other reason for them to know in the in this passage of of acquired traits. Um and what you're saying is in order for that to happen, there has to be a transformation of the neural circuit, literally the wing of neuron A B C D that relates to encourage the information that number into the kind of nuclear tight sequences that are containing DNA or patterns of methylation or R N A more likely. So it's the transformation of one set of points in physical space to a translation of pots in genetic space.

right? And then we have many problems when IT. First, before we don't know a mechanism to translate between the two different languages, the language of the brain and the language of the, we are not familiar with the make.

Second, the next generation, if it's not a warm, if it's a memo, we will have a different brain. Even if IT, if, even if IT was genetically identical to the parent, the wiring of the brain and the particular and the other circles will be difference. This is true for twins.

IT will always be true because IT depends because it's partly random and IT depends on the environment, even if you have the same genetic sections. So let's say you somehow had the mechanism, medical mechanism, to take the freely information and translated to the magic to the language of you, would then the next generation have to translate IT again to the brain? Although IT is different, this sounds very unlikely. I I am playing a trick on you now, okay.

because you amazing the trick.

So but if this is how what happened, or if this was the wild IT, could never happen, in my opinion, which means, and I still think, that there are certain memories that cannot transfer from generation, these complex and things that you learn about the environment that i'll bitterly, if none of our listener's kids will remember this conversation. No way. This is impossible.

They are listening with. There are some families.

parents that cannot turn me because it's it's random and it's these are connection that are. So this seems to be a limitation. And what can transfer on the other hands? So so perhaps more general things, good path.

Some this type of things, I doubt IT. However, you can never the less imagine that some things that are very specific, some memories that are very, very specific, could never the less than me from the brain after learning to the next. And give you an example, you can teach warms, even if, although they have just three hundred two norms, you can teach some simple things about the world.

For example, you can take an, although that the worms, like the worms, have thousands of other, other settles, and they can recognize many, many, many molecules, they can smell them so they can find food to avoid enemy. You can take a food that the warmth, and although that the warmth like, and paid to something bad, like starvation and then the warms, we're learn to dislike this auto. We don't know that this learning involves necessarily changing in the strength of sign upset.

It's a possibility, but he doesn't have to be the case. IT could be the just the accept for this particular, although is being removed when they and this is how they are now, they won't have the access or they won't smell, they won't like the, although this is a possibility, this type of thing you can perhaps not that anyone has showed that convincingly turns me to the next generation, because all IT would take is an irony that we will, this particular, accept OK. So this is a possible, people have shown things like that, not in the elegance, but people have shown things like this in memory.

They said that you learn certain thing, and then just in next generation, that a particular sector would be matilde or or would change, and this would transmitted the response. And on the one hand, IT could be true. On the other hand, you need to understand, they'll need to prove.

And this wasn't done convincingly enough yet. How exactly does the information transfer from the brain to the germ cells? And then in the next generation, from the germ is back to the brain, to where the access, accept or need to Operate.

And this is a chAllenge. This is the current state of of the field, that this is something that needs to be proven. What we didn't see elegance is we showed that certain that the brain can communicate with the next generations using smaller ones, and that this can change, behave and IT doesn't require any translating between any language. IT is very simple. Why we've shown is that if you take a warm and you change the production of smaller anise, Justin, its brain in the next generations, their behavior, and we would be different if though you don't mess with their brain.

This is a paper that we published in two thousand and uh h in nineteen in in self we showed you just manipulate the production of original natural alias in the worms brain that are always made, but you you change your amount and these changes the capacity of the worms in the next generation to find food, to find not only in one generation but three generations down the vote and the way and IT works is that pertab ing, the production of the smaller ganis in the brain affects the end. The expression of a gene in the germany, one gene is called stage to don't know how IT works, but we can do all kinds of controls where we many pull at activity of the gene city. That is also effective behavior.

And these gene, watching the jumps, the information needs to go funder brain to the jumps. IT doesn't need to go back from the juices to the brain to affect behavior. And this depends, we know that this is a two other genetic effect because he goes on for multiple generations, and also because IT requires the machinery that transfers organised between generations. If you don't have the porting that physically Carries the garage, betwen generation doesn't happen.

So IT has to be our .

IT has to be irony and and not we can actually, we can also find out, and in the next election to change, we sequence the actual organic, the change in the next generation.

You mentioned that you don't know what sage the scene does, but is IT reasonable to assume that IT does something in the context of the nervous system, or that's unclear as well?

IT is possible. IT is possible. But we have reasons to believe, or experiments to to show, although there could be alternative explanations that its functions for the german. Now you may ask, how can you affect behavior just by changing the germans?

right? Well, I would have to change the germ cells in very specific ways because people probably recall the germ line. The germ cells are where the inheritable information is contained. But you can imagine that, for instance, um adJusting the gain or sensitivity rather on some sort of sensory fogging system right right and and the the .

the interesting thing is that again can be quite unspecific. So IT sounds weird that you change germ cells and its changes behave permanent. But if you think about this is trivial if you cast late a dog, if behaves differently, right sadly. Yeah.

I did that to my dog, and I ended up putting him on his stock. Strong therapy later. And I brought back yet, just as a, as a side.

as an a side. Yes, this is because the germ is affect the somma, including the blame in many ways, bicc creating certain chemicals, and also because the other cells the developed from the, from the germ cells. So some information could be transmitted over the development, oh, the course of development could be altered because of changes that OK in the germans, and for example, in members.

One of the explanations and for how habitable information transmit is that IT just affects something very own in development. I, I, I told you that the secret to warms inheritance is that they have the capacity to amplify. The smaller is all the time. This is what keeps you going and prevents the dilution in members.

We don't know of such an appliance ation that can show you ask, how can a little bit of aga or something without amplifying affect and lentile organic and IT could be that you just perturb something in the very beginning in when you just have a few sales or even if in the class, santa that develops important cy and these letters grows everything off. And because of the U. S, you have many problems in the paris and so on. And this is called the the. It's an idea of the develop developmental origin of health and disease, many of the of the functions of care early on in development.

So you raise a number of incredibly fascinating aspects to this. I do have a question about one particular aspect and feel free to pass on this for a future episode if it's gna take us too far off track but something you said I really captured my attention um although I was listening to all of IT which is that the germ cells so in the case of males, it's gonna sperm in the case of females can be eggs, something perhaps not coincidental about those cells in the environment that they live in is that, yes, they contain the genetic information to pass the offspring right? Of course, you explain how that works, but also it's a IT.

Those cells live in a region that is rich with hormones that can be secreted and in fact, are secreted, and through so called indre signaling, communicate with other cells not just at the level of receptors on their surface, but also can enter the genomes of those cells and modify those cells. In other words, IT seems to me that the micro environment of the germ cells, the testis and the covers, are rich with information, not just for the passage, the next generations, but also for all the, as you said, all the symmetry cells of the body. They're telling the symmetry cells of the body what to do and what to become.

In the best example I can think about this would be puberty, right? I mean, I would argue that the that one of the greatest rates of aging and and transitions we go through in life is from puberty. And a child becomes a very different person after puberty.

They look at the world differently. They think about IT differently. The growth of it's not just about the growth of the hair and in the jail, the adam is apple and breast and on it's a transformation of the symmetry cells from the same microenvironment that the DNA containing uh cells reside, right? So once you .

think about IT like this, IT becomes obvious that just by affecting the germ sales, you can affect the rest of the body. And in seal against, there are experiment to show is very clearly. So for example, if we just take warmth and prevent firm production, IT changes the capacity to smell. These are experiments done by others, which is obviously a drain function and an .

a castrated dog. You're not just eliminating the possibility of transferred of DNA information to subsequent generations are also limited communication of A H without question my bad dog cost to change after castration and IT was a wonderful dog but at some point developed some health issues the introduction of a small amount of testosterone every other day changed him fundamentally in that case for the Better um back to a version of himself that I only observed earlier, but also a different version of the same dog.

I know he wasn't humping everything, maybe the occasion, particularly people who I was, the names I want to mention. But I was absolutely clear that the hormone was not just taking a system and amplifying IT IT was actually modifying the system. So anyway, I just wanted to highlight that. And then now thank you for indulging me. Let's um if you will, let's continue down this path of that we were going on because I want to make sure that we absolutely get to this issue of transmission of information about sex choice of offspring.

So the worms are here much, which means that they make both sperm and enemies, but they are also made, which are much more rare, and they can choose to mate with the males or not. And when they made with the male is a huge decision, because it's very costly, energetically. And they also risk predation in all kinds of troubles. The males hurt them and .

reduce their life's men when they met with people raw of vital.

So most importantly for evolution, when you made with another animal, you dilute your genome half, because the ones can just sell, fertilize and permits the exact same genes to the next ation. But when they make they, they looted in half. So this is a big Price to pay on the other hand, and you mate you diversity biogenic. So maybe some combination of gene would be good.

And we know that in humans. I mean, you know it's kind of interesting that the brain circuits are associated with a with a version and with approach are um fairly hard wired for a number of things like pottle of vomit. Almost everybody kind of changes played of cookies.

If you like cookies, you move towards IT. But there's one particular word in a the english from the israeli language that. That ought to evoke disgust, and that's incest, because incest is actually not just disgusting as a practice, but it's dangerous genetically, right? Because the inbreeding creates a diller's ous mutation.

So there are studies of how people in israeli key boots, for example, where they all grow together, the children live together. They used to be like that, don't h date each other. But this is the classic thing. I talk to some the body me that's not true. But but yes, study like say that makes sense .

and in some counties can in in a lapland and ice where populations or small, they keep exquisite records of lineage in order to avoid in breeding.

right? So you are absolutely but the worms, it's the safe choice for them is to self mate and and if they made with a male, they take a risk, but they diversified. Okay, what what we found is that if you take the hair method, we can call IT the the female for just one second, and you stress IT with high temperatures, then the next generations of warmth for free generations made much more with males. And they do IT because the female starts secreting a film on that attracts the males.

It's very cryptic mechanism. It's not that he somehow changes and then go seeking males that IT drama. And we know how IT works.

We think we know how IT works. What happens is that the stress the high temperatures compromise the production of spare in the hermetic dites. So the her method that don't they make Better enough to to make make generations.

But the um because of effective smaller name here is because I are not inherit, okay the spam is not made optimal so they make less spare. And when they don't make a lot of spare, they feel that they gone sell fatalities ed correctly. So they called the maize by secreting the seven months so that IT would provide its own sperm and they can continue to make babies. And we know this also form service. You just take a method that and you kill IT sperm started to a fell .

on in the male is a need base system.

exactly.

incredible. And I hope people can appreciate us are hearing this, that none of this we assume, I don't know how to speak, worm. None of this we assume, is a conscious decision in these animals that, much like human mating behavior, which to us always seem so conscious, but is being governed by both conscious and subconscious decision making.

None of this is an active decision to secret the hormone to draw more males is simply a biasing of probabilities, right? The hormones is now secreted in greater quantities or more greater frequency. The males there for approach more. So it's just an increasing probability of interactions.

Is that right? What happens naturally, Normally, if you don't the the ancestors, is that the warm starts secreting the film on only when they are old is also know people will when .

they're when they're running out of of their .

own for you exactly because they only make the spare at a particular time and then they ran out of sells term. They can sell satellites, so they have to call the main if they .

want to continue to meet a plastic surgery approach. Okay, i'll take the heat for that one. But you know but it's true.

I think as a certain people age to a certain point and they feel that their flight lite is waiting. If they want off spring, they need to take any number of different approaches. They could get a here, we tell him out of female.

But we could also do the reverse, right? We a sperm donor, right? Or but if they want to attract a fellow matter compared with somebody, often times they will um do things to adjust their a attractiveness in any number differently psychological attractiveness or physical attractiveness.

I'm not afraid to bring this up because I think that the parallels are very important because I do think that every species and individuals within a species, of course, decides whether not they want to reproduce or not, but has an inherent understanding, conscious or so conscious about where they resided in the art of their lifespan. I do believe that not just based on experience, some people are very attuned to the the passage of time being very fast. Others very slow. I think that knowing how long your parents and their parents lived makes a big difference. I have friends whose fathers and particular died fairly Young, and all these guys based got married, had kids really Young.

right? So here, the luckily for me, I don't have to get into psychology of the warmth. The explanation is just like an instinct.

When they ran out of spare, they start getting the phenomenon in, attract the may. There are studies also in newness about older fathers. The children of older fathers have more, has a higher chance of of becoming autistic. There are study forty and up.

But however.

in this case is not clear that this is not that this is something epigenetic could be just because of D N. A damage. No, because IT accumulates.

Yes, and actually nobody is there. We have an episode fertility coming up with male and female ratio ity. And there's h they're actually DNA fragmentation kits for uh, at home D N.

A fragmentation kits for sperm else. If you send the sperm back and you don't do the DNA people by petting, seeing at home when be in an odd picture, let's not go there. But the um but there are a clinics that do this for for a nominal charge.

But the um but it's I didn't want to ask about autism and human disease in particular. Another thing that you hear sometimes here, I want to acknowledge autism is on a spectrum. Some people get upset if you call IT a disorder. There are some adapt of autistic traits and inside. But one thing that um often comes up is this idea that two people who are more of the kind of engineering um hard science, if you will, monotype mate and have children higher probability of the offspring being on the spectrum some people would argue up, but that's already selecting for people that might have already been partially on this spectrum. So maybe it's a gene copy issue.

I'm not asking you to comment on autism in particular but when you hear things like that that the children of older fathers um born from older fathers, ten higher probability of autism, what is that at the level of intuition? Does that strike you as an epigenetic phenomenon, as a nature nurture michmash or the possibility that R N A passage um or anything does anything sort of um trigger the whiskers? Uh your spy decent.

So in that case I would go with the most polite manual explanation, which is is just less fidelity of, less deny maintenance and some damage that passes on IT doesn't have to be an epigenetic thing.

but the sperm generated at once every sixty days. So the damage must be at the level of the germ cells, not having the proper machinery, right?

My country or something, the DNA, the the dinner pam machinery could be effective or or could work less well in older people, leading to the constant production of jm says with more mutation, this is a .

possibility. Do we know exactly what the .

DNA repair machinery is? Yes, are many types of DNA pay. Uh the those one that use uh other copies of the D N A to to uh uh to correct there are ones just recognized kind of religions on the DNA and and remove IT it's a very elaborate and complicated system and is IT a system that .

is now tractable that can be a modified through pharmacology through anything like that.

So I don't know about drugs that correct that improve IT. Maybe the exist and i'm not a uh well but it's very well understood and uh many people are study history。

Yeah one thing that um came across in the uh exploration of the fertility work is that what am about to describe is not legal in the U. S. A, is illegal but is legal in the U. K. And in other countries as this notion of three parent f where IT does seem that some of the eggs that persist in older females don't, even if fertilized, don't produce healthy embryos, they have promise all abNormalities, replications and and delicious, that are problematic to the development of the embro, such as tries to me twenty one A K down in syndrome, in part or in large, far because of deficits in the medical real genome.

So what they now do is they take the, because the microbial gene resides mainly in the cytoplasm m, they'll take the h an egg from the, the mother, the sperm from the father, but they'll the nucleus from the mother, and put that into a cytoplasm m of a Younger woman whose ma control DNA is healthy, then use the sperm to fertilize that egg. And and that's why it's called three parent ivf, then in plant that into the mother. And this has been done several times for in cases of mica contro the image or or or mutations in in the mother IT works.

The question is whether or not those osprey will grow up to be healthy. So this, of course, is IT not just appear divergence IT raises a bigger question that I have for you, which is in terms of the work in either sel gans or in other model organisms, in particular in seal. Again, where do you see this going next? And if you would indulge us, I would love you to tell us a little bit about the admittedly unpublish worth that you're doing on temperature, uh, exposure and environment.

I mean, how malleable is the system because to me, IT just seems incredibly valuable. And yet a lot of us still closed off to us. They're still a turn to learn.

So assuming that we will discover similar things in in humans, which we don't know that this is the case, but let's say we we find I think there are many things you can do before you change IT.

For example, um um you you could also change IT, change a apparent in head and by having the the parent exercise for example and some things like this have been done, for example the experiments in in holdouts where they showed that the over feeding the um the the road and creates problems for the next innovation for the f for the children. However, if you let the the road and exercise and IT correct, they are Better. So this is one possibility. And you can also manipulated at at the source. You can change if it's R N A that say you could in the future, perhaps if we understand how IT works, actually changed the composition of the .

help of A G by eating R N, just like the worms R N A.

So the R N age would be difficult because it's not, I don't know, but you could, if you do I V S, if you in view of utilization, you can perhaps change the composition of the organs in the the staff that you introduce. But away before that, what you could do, perhaps even in the not so far future, is use this for diagnostics. DNA based the diagnostics for every couple that wants to have a kid.

Uh, you can in israel, this is done for for most couples. You can look at the DNA, look forward genetic disease. But no one look is looking at the R A.

At the moment, if we understand how IT works Better, we'll have another level, a whole new world to look at. And perhaps there will be some oranges that coal ate with disease that that will say, okay, you know, the beauty is that this, unlike DNA, is plastic. So with DNA, this is your DNA.

Perhaps we can choose another embry. But here you could say perhaps, or again in the future, this is science fiction doesn't happen now. But if we will understand this, and it's sure we can say, maybe you should run on the thread me a little bit, this will change the profile of your gaze, and then we will use IT.

For this seems more because just IT create with healthy profiles of violence. This is a level that no one looks at now and holds great potential. Again, with a disclaimer that we now know how IT works in humans at all. Yeah but of course, this is why why so interesting?

Yeah, it's super interesting, incredibly promising. So along the lines of things that one can do in the short term and your experiments on c elegance, i'd love for you to share with us that what you're observing about cold exposure and how that impact subsequent generations of c elegance and and if you would indulge us with the story of this discovery um like some of the earlier stories you told us, IT is a surprising and fascinating one and lady tell .

you about IT this is not that a story about time and something and it's a story about memory within one generation excuse me, within one generational O K and and as you said, the story how what happens is it's it's it's totally by accident and is a funny story. And i'm bringing this up because I know dana lunch with a huge fan of your posters. We really, you know be happy.

This is her work. This is her work and this is unpublished work if we didn't even finish IT. So we're working in okay.

when it's publish, we will feature the paper because I love this story so great.

So so what happened is that when you, we talked about times and actions, memories, and I said that in warmth, there are a very long time, generation and memories. If if a generation time for silents for three days, some memory is less for many generations. So weigh beyond the the lifespan of the of the warm.

The lifespan of the warm is three weeks. You have a new generation that every three days, but every warm leaves for three. But there is a lot of research that show that, unlike hilliard able memory, which can be very long, the memo is that the warmth acquired during the lifetime is very short lived.

So if you teach something after two hours, IT forgets. So for example, you can teach the warm. You can take an order that he likes and pill IT with starvation and then IT with dislike the order.

And then there's a simple test, just put IT in a plate. You put the the order in one side and the control order and the other side, and you see whether he is preferred this order order or not. And IT stops preferring IT.

Okay, there is thirty years or more of research, forty years of research on on this, showing that the warmth forget after two hours. The reason I went to study, see elegance is that I wanted to understand memory because such a simple nerve system. You say, maybe I have the contention to action and send IT works. But this is slightly to disappointing, because they forget off to out.

So what is IT exactly? okay. My idea was, and I tried to convince students to do IT for ten years, is to take the arms, teach them this association, to dislike the, although they take a native like, and then just put the worms in minus eighty and freeze them, freeze them completely, throw them and see what that they still remember after they have thought.

The home solo experts and .

and I didn't want to do IT because of cloud novation or something like this. I wanted to do IT because, as you know Better than me, many T O is about memory. Say that you need the electrical activity to maintain the memory.

need to have IT during dreams or replay of the thing or whatever.

And if the memories will never the less be kept, even though the worms were closing in minus eighty IT would mean that IT was kept in the absence of electricity because there there was no electricity. Minor safety quds, this was the idea I asked many students, no one wanted to do IT because of this is not so easy and .

also such a little crazy. Well, and when the P. I, the principal in the lab has a pet experiment.

no one wants to. So, uh and then then agreed to do a than a launched. I was very happy only later to find out that he ignored me completely and did the different experiment, the experiment the data did in instead is to just take the warms, teach them the association and place them nice SHE wanted to see how the kenneticook of memorials forgetting change in low temperature, because maybe whatever memory is, the breakdown of the memory is affected by the temperature. A very simple idea with different experiment.

a different experiment by a good experiment, very good.

And what you found is that when you place the worms or nice a solo teaching, they just don't forget then even ten times longer than controller. Ms, at that point, after twenty four hours, if no one warns, forget after two hours. After twenty four hours, the warns will become six.

So Normally we do shorter experiment, but for two hours they want to forget this is cool. But he was only the beginning, because the boeing explanation is just what I just said, that everything slows down in low temperatures. So they are back down of memory.

again. We don't know what IT is, but whatever IT is happens slower in low temperatures. But this is not the case.

It's not merely the physical. It's delhi sponsors the changing of the internal state of the ones which affects the memory genetics. How do we notice there's a beautiful work over the last one years on called tolerance in silo against imitations?

If you take the warmth and you place them on ice, like SHE did, but longer, for forty eight hours, they all died. However, if you take the warms, actually mate into local temperatures for a few hours, five hours in the minimum, and then place them on ice, they also vive. They become cold tolerance.

And and people who study show that this involve changes in lipid, metabolic and manifest. So danna took the warms, activate them to slightly lower temperatures, made them cold resistance, and then told them their association and place them on ise. And now they forgot immediately, which means that when they change in tender state to become cold tolerant, they no longer extend memory is on, which means it's not only the temperature, because the temperature is anyway low.

Now they know we took this as a starting point to understand what which genes change when the worms are becoming cold tolerant of ice. And we found genes that when you mute ate them, the warms. Just remember, the longer always, even when they are off ice, because there was a genes that Normally change when their surprise on the ice. And these genes are expressed just in one pair of royales, just two out of the three hundred two notes.

he said, three hundred and .

two and three hundred. And we can manipulate the activities of these genes in these no ones to extend memory. And then the punch line of everything that, uh uh happened is that we found out this this no one where this genes function.

This one pair of no one is the only known in silicon, which is sensitive to lithium. And lithium is a drug that is being given to bipolar, uh, these other patients for decades, although it's not entirely clear how this works, is really very interesting. This is also interesting as an episode, of course, in your coat cast about if you know more about this in mealor.

But he is also interesting because it's just an atomic ated, the big bank. Yet IT works on our blades in such a fundamental way. And we wanted to see whether IT works on all, also on the world, because this noyon m was tied to this memory extension final, we found.

So then I go, the worms, only you remove them from with you got them, the association, and found out that they learn a lot long, they remember a lot longer than control ones. Not only that, if you first make their warms called tolerances, and then lizio doesn't work on them. So let you switch. Is this forgetfulness mechanism and enough and IT, IT and IT is all connected to call tolerances .

amazing and amazing for a number of reasons. And so at risk of being long winded in my response, I just wanted to highlights something um that I think we will be of relevance most people which is when at some point we did a few episodes on memory and highlighted a review that was writing by the great James mega, one of great mammalian memory researchers who is work a lot on humans and mice and I was shocked upon intended and amused to learn the in medieval times, if people wanted children to remember lessons, they could be religious lessons, or school doctor, or whatever IT was mathematics, they would take children, teach them and then throw them into cold water to introduce A A memory in stealing event.

And we now know that the memory in still ling event is the release of a gentle in the body, which makes perfect sense if you think about traumatic events. But IT also, this whole general mechanism also applies to the learning of other types of information. And so if I understand correctly about the role of lithium and the role of cold and the experiments that you just described, there are some general state switch, some internal state switch that says what happened in the minutes or hours proceeding.

This was important that actually work like a highlighter pen in in the book of experiences. And i'm absolutely curious ous to know whether or not this is an R N A dependent mechanism in some way. This literally like the highlighter in the key instruction book.

This we don't know. This we don't know. And as I said, this is not even a finished work. It's not be reviewed, the just the state that I told you about. But um but it's it's very exciting for for me to to go into this new feeling and once each other be happy to to talk more about IT and and think about the implications of the connection. So out of things .

are more about the mechanisms. Yeah well, thank you for a sharing with us despite the fact that it's not finished. Um people now know that is also not finishing. I love a good Cliff hanger, so we await. The the full conclusion and interpretation of these results today, you taken us on an amazing journey through the genome.

R N A uh short interfering iron is um a ton of history of prior experiments, some of which ended tragically, many of which unfortunately did not and they were true triumph in particularly the work in your laboratory, which is just incredible, and also this introduction of model organism. So and I only mentioned a short handful of the things that uh, you've taught us about today. So first I want to extend thanks for the incredible teaching.

I also want to say thank you for um something equally important which is that absolutely came through but is what initially brought me to explore you in your work more although I had certainly heard of you which is that your spirit and kind of approach to biology is is an extremely unique and intoxicating one even I venture to call a seductive know there I do believe that whether not it's music or poetry or science or mathematics that um the spirit behind something dictate tes the amount of intelligence and and precision with which that thing is is Carried out and IT absolutely comes through so if i'm making you feel on the spot about this, i've succeeded. Thank you very much. But I I know that the listeners feel IT it's it's a felt thing.

So thank you. There are many scientists out there, a fewer with this finn type and even fewer that um you know I think that can communicate with such a articular precision. So thank you so much. It's been a real pleasure.

Pleasure was all mine. Thanks a lot. Well.

we'll do IT again and we learn about all the incredible things you're doing trying to transform science as IT were at the level of publishing, at the level of social media because there's a whole other discussion there. Meanwhile, we will course point people in the direction of you, and i'm to learn more about your work, and I look forward to hearing the conclusion of data studies.

Thanks a lot. Been a real pleasure.

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