Dr. Oded Rechavi: Genes & the Inheritance of Memories Across Generations | Huberman Lab Podcast

Andrew Huberman: [OPENING THEME MUSIC] Welcome to the Huberman Lab

podcast, where we discuss science and science-based tools for everyday life.

I'm Andrew Huberman, and I'm a Professor of Neurobiology and Ophthalmology

at Stanford School of Medicine.

Today, my guest is Dr.

Oded Rechavi.

Dr.

Oded Rechavi is a Professor of Neurobiology at Tel

Aviv University in Israel.

His laboratory studies genetic inheritance.

Now, everybody is familiar with genetic inheritance as the idea

that we inherit genes from our parents, and indeed, that is true.

Many people are also probably now aware of the so called epigenome,

that is, ways in which our environment and experiences can change our genome

and therefore the genes that we inherit or pass on to our children.

What is less known, however, and what is discussed today, is the evidence

that we can actually pass on traits that relate to our experiences.

That's right.

There is evidence in worms, in flies, in mice, and indeed in human beings,

that memories can indeed be passed from one generation to the next.

And that turns out to be just the tip of the iceberg in terms of how

our parents' experiences, and our experiences can be passed on from one

generation to the next, both in terms of modifying the biological circuits of

the brain and body and the psychological consequences of those biological changes.

During today's episode, Dr.

Rejave gives us a beautiful description of how genetics work.

So even if you don't have a background in biology or science, by the end of

today's episode, you will understand the core elements of genetics

and the genetic passage of traits from one generation to the next.

In addition, he makes it clear how certain experiences can indeed modify our genes

such that they are passed from our parents to us, and even transgenerationally

across multi generations.

That is, one generation could experience something, and their

grandchildren would still have genetic modifications that reflect those prior

experiences of their grandparents.

Dr.

Rechavi takes us on an incredible journey explaining how our genes and

different patterns of inheritance shape our experience of life and who we are.

Before we begin, I'd like to emphasize that this podcast is separate from my

teaching and research roles at Stanford.

It is, however, part of my desire and effort to bring zero cost to consumer

information about science and science related tools to the general public.

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And now for my discussion with Dr.

Oded Rechavi . Oded, thank you so much for being here.

Oded Rechavi: Totally my pleasure.

Andrew Huberman: 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, you have been focusing

not just on the discoveries in your laboratory and other laboratories,

but also sort of meme type humor that relates to the scientific process.

And we'll return to this a little bit later.

But first of all, I think it's wonderful that you're so active on social

media in this positive stance around science that also includes humor.

But today, what I mainly want to talk about is the incredible questions

that you probe in your lab, which are highly unusual, incredibly

significant for each and all of our lives, and very controversial, and

at times even 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 and get everyone up to speed, because people

have different backgrounds, I think most people have a general understanding of

what genes are, what RNA is, and so on.

But maybe you could explain to people in very basic terms, and I'll just preface

all this by saying that I think most people understand that if they have

two blue eyed parents, that there's a higher probability that their offspring

will have blue eyes than brown eyes.

Similarly, if two brown eyed parents, higher probability that they will have

brown eyes rather than blue eyes, and so on, but that most people generally

understand and accept that if they spend part of their life, let's say, studying

architecture, that if they have children, that there's no real genetic reason

we should assume that their children would somehow be better at architecture

because they contain the knowledge through the DNA of their parents.

They might be exposed to it in the home, so called nature nurture.

That's nurture in that case, but that they wouldn't inherit

knowledge or other traits.

And today I'm hoping you can explain to us why eye color, but not

knowledge is thought to be inherited.

And the huge landscape of interesting questions that 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 RNA, and how

does inheritance really work?

Oded Rechavi: Okay, so DNA is the material, the genetic instructions that

is contained in every one of our cells.

We have the set of genes containing the entire set, called the genome.

And this is present in every cell of our body.

The same set of instructions.

And genes are made of DNA, and they also contain chromosomes.

Chromosomes are the DNA and the proteins that condense the DNA, because we have

a huge amount of DNA in every cell that you need to condense it, too.

Andrew Huberman: Sort of like thread on a spool, right?

Oded Rechavi: Huge amount that you have to condense.

And we have the same genome, the same DNA in every cell in our body.

Andrew Huberman: Can I just interrupt?

And I'll do that periodically, just to make sure that people

are being carried along.

I sometimes find that even remarkable, that a skin cell and a brain

cell, a neuron, for instance, very different functions, but they all

contain the full menu of genes.

And the same menu of genes.

Oded Rechavi: No, it is amazing.

It is amazing.

And perhaps it's good to have an analogy to understand how it works.

So I hope this is not a commercial, but this is like the IKEA book that

you have in every cell in your body, the instructions to make everything

that you need in your house, the chairs, the kitchen, the pictures.

But in every room, you want something else.

So in the kitchen, you want things that fit the kitchen, and in the toilet,

you want things that fit the toilet.

So you only remove one particular page of instructions, which is the

instructions of how to build a chair.

And this you place in the living room.

And the toilet, you put in the toilet.

So the DNA is the instruction to make the genome, is the

instruction to make everything.

This is the IKEA book.

And in every cell, we take just the instructions to make one particular

furniture and this is the RNA.

This is the RNA.

This is a set.

And then in the end, you'll build a chair.

The chair is the protein.

So the RNA is our instructions to make one particular protein based

on the entire set of possibilities.

And this is true for one particular type of RNA, which won't be the star of this

conversation, which is messenger RNA.

This is the RNA that contains the information for making proteins.

In fact, this is just a small percent of the RNA in the cell.

So we have a very big genome, and less than 2% of it encodes

for this messenger RNA.

However, a lot of the genome is transcribed to make RNA

that does other things.

Some of these RNAs we understand, and many of them we don't.

Andrew Huberman: It's a beautiful description, and IKEA is not a

sponsor of the podcast, so it's totally fair game to use the IKEA

catalog as the analogy for DNA.

The specific instructions for specific pieces of furniture is the

RNA, and the furniture pieces being the proteins that are essentially

made from RNA using messenger RNA.

Oded Rechavi: Correct.

Andrew Huberman: Okay, thank you for that.

So, despite the fact that the same genes are contained in all the cells

of the body, there is a difference between certain cell types, right?

Is it fair to say that there was basically one very important exception, which

is somatic cells versus germ cells?

And would you mind sharing with us what that distinction is?

Oded Rechavi: Sure.

So, yes, every cell type is different because it brings into action

different genes from the entire collection and assumes an identity.

We have cells in the legs, we have cells in the brain.

We have in the brain.

We have cells that produce dopamine, cells that produce serotonin, and so on.

And we can make different separation, different distinctions, but we can make

one very important distinction between the somatic cells and the germ cells.

The germ cells are supposed to be the only cells that contribute to

the next generation, out of which the next generation will be made.

So each of us is made just from a combination of a sperm and an egg.

These are two types of germ cells, and then they fuse, and you get one

fertilized egg, and out of this one cell, all the rest of the body will develop.

And what happens in the soma, which are all the cells that are not the germ cells,

should stay in the soma, should not be able to contribute to the next generation.

This is very important and is thought to be one of the main barriers for

the inheritance of acquired traits, the inheritance of memory and so on.

Because, for example, like the example that you gave with learning architecture,

if I learn about architecture, the information is encoded in my brain.

And since my brain cells can't transfer information to the sperm and the egg,

because the information is supposed to reside in synaptic connections

between different neurons in a particular circuit that developed.

So, what happens is the brain shouldn't be able to transfer to the next generation.

Even simpler, a simpler example, if you go to the gym and you build

up muscles, you know that your kids will have to work out on their own.

This shortcut won't happen.

This is something that we know intuitively, even if we don't

have any background in biology.

And this is connected to the fact that, as we said at the beginning,

every cell in the body has its own genome and the next generation will

only form from the combination of the genomes in the sperm and the egg.

Even if you somehow acquire the mutation or a change in your DNA in one particular

brain cell, it wouldn't matter, because this mutation, there's no way to transfer

it to the DNA of the germ cells that will contribute to the next generation.

Andrew Huberman: So despite that, there is, as you will tell us, some evidence for

inheritance of experience, let's call it.

And here we have to be careful with the language.

I just want to put a big asterisk and underline and 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 field of longevity, people sometimes will say

anti-aging, some people say longevity.

The anti-aging folks feel that longevity is more about longevity clinics.

They don't like that anti-aging is related to some other kind of niche

clinics, sometimes FDA approved or government approved, sometimes not.

And so there's a lot of argument about the naming, but it's all about

living longer and living healthier.

In this field of acquiring traits or the passage of information to offspring,

what is the proper language to refer to what we're about to discuss?

There is this idea, and I'll say it so that you don't have to, that dates back

to Lamarck and Lamarckian evolution.

Very controversial, right?

And maybe not even controversial.

I think it's very offensive even to certain people.

This idea of inheritance of acquired traits, the idea that one could change

themselves through some activity, let's use the example of going to the gym.

We could also use the example of somebody who becomes an endurance runner, then

decides to have children within another endurance runner, and has in mind the

idea that because they did all this running and not just because they were

biased towards running in the first place, but because of the distance

they actually ran, that their offspring somehow would be fabulous runners.

Okay, this Lamarckian concept is, we believe, wrong.

So how do we talk about inheritance of acquired traits?

What's the proper language for us to frame this discussion?

Oded Rechavi: Right.

We have to be very careful, as you said, and there are many

complications and many ambiguities.

Andrew Huberman: And maybe you could tell us why Lamarckian evolution,

for those that don't know, is such a stained thing, r ight?

I t's not polite.

Oded Rechavi: Right.

Perhaps we'll start with, just say that we can talk about inheritance

of acquired traits, transmission of parental responses, inheritance

of memory, all of these things.

And we can also talk about epigenetics and transgenerational epigenetics

and intergenerational epigenetics.

There are many terms that we need to make clear for the audience.

The reason that is so toxic or controversial is very complicated,

and it goes a long time back, even way before Lamarck.

So even the Greeks talked about inheritance acquired.

Lamarck is associated with the term, but it's probably a mistake, although everyone

talks about including people who studied.

So Lamarck worked, he published his book a little more than 200 years ago.

And he believed in the inheritance of acquired traits.

Absolutely.

But just like anyone else in his time, just everyone believed in it.

It seemed obvious to them.

It was long before Mendel and the rules of genetic inheritance.

And also Mendel was long before the understanding that DNA

is the heritable material.

So this happened a long time ago.

Everyone believed in it, including Darwin.

Darwin was perhaps more Lamarckian than Lamarck.

Andrew Huberman: Really?

Oded Rechavi: Yes, absolutely.

Andrew Huberman: All right, now we're getting into the meat of it.

Oded Rechavi: And this is in The Origin of the Species . It's in all of his writings.

Lamarck didn't even really make the distinction between the generations.

He had many other reasons for being wrong, but he connected the terms inheritance

of acquired traits to evolution.

And this is some of the reasons that he was very controversial, even in his time.

There were other reasons.

For example, he rejected current day chemistry and thought that he could

explain everything based on Aristotelian fluids; earth, wind, fire and water.

Andrew Huberman: There's still some people on the Internet that think they can

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

Oded Rechavi: And this wasn't only biology, it was also

the weather and everything.

So that was part of the reason Lamarck made many mistakes, but he did have a

full tier of inheritance, which was a big step towards where we are today.

So he had important contributions nevertheless, although he was

mistaken about the mechanism.

What he believed, like everyone else, drives evolution, is the

transmission of the traits that you acquire during your life or

the things that you do or don't do.

We talked about use and disuse of certain organs that shape our

organs and eventually also the organs of the next generation.

Andrew Huberman: He sounds a little bit like the first

self-help public figure, right?

Well, this mean, this is heavily embedded into a lot of the health and

fitness space on Twitter and Instagram and on the Internet, which is that,

it's the idea that we're sold very early in life, at least here in the

United States and probably elsewhere, which is that we can become anything

that we want to become and that that will forever change the offspring,

either because of nature or nurture.

Oded Rechavi: Right.

And this is a very dangerous idea, as I'll explain in a second.

And it led to horrible things.

This is part of the reason that this is such a taboo.

It's not only self-help you're helping, or this helping yourself.

The problem is when you apply to others.

And this happened in a very, very dramatic and horrible way in the

recent past, as I'll tell in a second.

So Lamarck, this is what he believed and he thought this

is how evolution progressed.

And later Darwin showed that it's really natural selection.

The selecting of the organisms that already contain the particular qualities

are selected based on whether they survive or not in particular environments, and

therefore their evolution progresses, they are more common and take over.

This is very different.

Two different explanations.

The most common way this is contrasted is the neck of the giraffes.

This is a classic example.

According to Lamarck, the giraffes had to stretch their necks towards the

trees to eat when the trees were high.

And because of that, they transmitted these traits, long necks, to their

children, who also had long necks.

By the way, he only mentioned this example a handful of times,

he didn't really focus on that.

And according to Darwin, just a giraffe that happened to be born with

a long neck survived because it ate.

So its genetic, heritable materials didn't know about genetics, but take over.

And the rest of the giraffes that have different heritable materials just die.

So this is natural selection versus inheritance for acquired traits.

So this is natural selection versus inheritance for acquired traits.

There are many reasons why Lamarckism and inheritance for acquired

traits became such a bad term.

One of the biggest is what happened in the Soviet Union under Stalin.

There was a scientist named Lysenko, who thought that Mendelism, normal genetics,

is bourgeois science, shouldn't be done.

And whoever did normal genetics was either killed or sent to Siberia.

And he thought that, just like you said, not only we can become everything that

we want, but we can grow everything that we want in every field, can take a frozen

field and grow potatoes there and so on.

And this led to massive starvation, ruined agriculture in the Soviet Union, also

ruined science for many, many years, and put a very dark cloud on the entire field.

And only probably in the 80s or something like this, the

field started to recuperate.

For that aside, for that, which is a very dramatic thing, there were also

crazy stories around, and attempts to prove the inheritance of acquired traits.

Despite the realization of many scientists, this is something that

is very rare, or that normally doesn't happen, that is not a

normal way that inheritance works.

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

Andrew Huberman: Yeah, please.

Oded Rechavi: So, in the beginning of the 20th century, in Vienna, there

was a researcher called Paul Kammerer, who was a very famous and also very

colorful figure, who did experiments on many different types of animals.

He did experiments on toads that are called the midwife toad

because the male carries the eggs.

And there's a beautiful book about it from Koestler, telling

the story of what happened there.

And there are a couple of types of toads.

Some of them live underwater and some of them live on land.

And these toads are different in their shape and in their behavior.

So, of course, the capacity to live underwater is one thing, but also their

morphology and appearance changes.

The toads that live underwater develop these nuptial pads, these black pads

on their hands that allow the males to grab onto the female without slipping.

Andrew Huberman: For mating.

Oded Rechavi: For mating.

And the ones on land don't have them.

He claimed that he can take the toads and train them to live underwater, changing

the temperature and all kinds of things.

It's a very difficult animal to work with.

Eventually, according to Kammerer, they will acquire the capacity to

live underwater and also change their physiology and develop these

black nuptial pads on their hands.

With this discovery, he traveled the world, became very famous.

This was in just the beginning of the previous century, as the person who found

the proof for inheritance of acquired traits, despite the controversy and so on.

In the beginning of the realization of how it actually works with DNA and so on,

not with DNA, but with natural selection.

DNA came later and people didn't believe him.

He was actually under a lot of attacks, but it seemed convincing at the end.

What happens is that they found that he injected ink to the

toads to make them become black.

To have these nuptial pads.

So he faked the results, and he couldn't stand the accusations and killed himself.

Andrew Huberman: Wow.

Oded Rechavi: In this book by Koestler , it suggests maybe it

was the assistant who did it.

Andrew Huberman: Who killed?

Oded Rechavi: No, no.

Who injected it to sort of save him from failure.

Because the samples lost the coloring or something like that.

So it might be.

Who knows what happened?

Andrew Huberman: Well, in science, whenever there's a fraud accusation

or controversy, it's not uncommon to see a passing of responsibility.

Oded Rechavi: Right.

Andrew Huberman: There are recent cases, there are ongoing cases now where

it's a question of who did what, etc.

Actually, I have two questions.

Before the second story, I'm struck by the idea that he was traveling and talking.

I'm guessing this was before PowerPoint and Keynote, but also before

transparencies, which actually were still in place when I was a graduate student.

For those of you who don't know, transparencies are basically transparent

pieces of plastic paper that you put onto a projector, and then you can write

on them and do demonstrations, but can show photographs and things like that.

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

Oded Rechavi: So he traveled with the samples.

Andrew Huberman: I see.

Oded Rechavi: And I'm basing this on this Koestler book, which is,

on its own, very controversial.

It's more of a beautiful story than perhaps the truth.

And according to the story there, he had to stand on one side of the

lecture hall with his hands behind his back while others would examine the

samples and pass them around and so on.

Andrew Huberman: But he cheated.

Someone cheated.

Oded Rechavi: He probably did.

At least that's what most people think.

But this wasn't replicated.

I mean, also, I don't think anyone tried to replicate it.

Andrew Huberman: Interesting.

This is just a point about replication.

And actually, another tragic example, not but a few years ago, Sasai, who,

as far as we knew, was doing very accomplished work on the growth of

retinas, literally growing eyes in a dish.

I think everyone believes that result.

But then there were some accusations about another result that turned out to

be fraudulent, and Sasai killed himself.

This was only about maybe five, 10 years ago.

So it still happens.

Oded Rechavi: Yeah, it happens.

I think it's rare, but it does happen, especially in this

very high profile situation.

Andrew Huberman: I would argue.

I'd love to know what your number is, but I would argue that 99% of

scientists are seeking truth and are well meaning, honest people.

Oded Rechavi: I totally agree.

And I think that even when people are wrong, it's mostly not because they're

evil and trying to act inflated.

Maybe they don't really want to believe the results, or there are all kinds

of ways to be wrong and even to bend the truth without just blatant fraud.

But this is, according to the story, an example of very bad fraud,

which, I agree, is rare because most scientists, as you said, this is

also my opinion, are just trying to discover truth and do the best they can.

Andrew Huberman: Well, why else would you go into it?

Because it's certainly not a profession to go into if you want to get rich.

Oded Rechavi: Not for the money.

Andrew Huberman: And it's probably not even a profession to go

into if you want to get famous.

If you want to be famous, you should go to Hollywood or become

a serial killer because they'll make specials about please don't.

But please don't do either.

No, Hollywood, I suppose for some is fine, but in any case, okay,

so Kammerer, around 1907, 1906?

Oded Rechavi: This is slightly before the controversy broke

out after the First World War.

Andrew Huberman: Okay, yeah, great.

Kammerer is gone.

His toads with their either ink or whatever nuptial pads they

have to go back to mating on land.

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Oded Rechavi: Yeah, okay, forget about that.

We also had the Lysenko episode.

That's a very big thing.

And then in the US, there was the researcher named McConnell, who

did very different experiments.

And he was also a character.

So he was the joker type of thing.

And he published many of his results in a journal that he published

that was called Worms Breeders Gazette and had many cartoons.

Andrew Huberman: And so he started his own journal.

Yes, that's one way to publish a lot.

Oded Rechavi: But he also published in very respected journals in parallel.

He was a psychologist, an American psychologist, and he worked on

a worm, which is a flatworm, which is called Planaria.

This is very interesting.

This is different from what we'll discuss today, a different type of worm.

You know, worms are very common.

So four out of five animals on this planet is a worm.

Andrew Huberman: Really?

Oded Rechavi: Yes, numerically, if you just count the individuals.

So we are the exception.

But I'll talk about a very different worm later.

This is a flatworm.

This is called planaria, and it is remarkable in many ways.

It was also a model that many people worked on, including the

fathers of genetics, that people who started genetics, like Morgan,

they worked on it in the beginning.

But it's very, very hard to study genetics in this worm, because

unlike us, unlike what we explained before about how we all develop from

sperm and egg, these worms most of the time reproduce just by fission.

They tear themselves apart.

So they have a head and a tail.

And the part of the head will just tear itself apart from

the tail, grow a new one.

The head will grow a new tail, the tail will grow a new head.

You can even cut them into 200 pieces.

Each piece will grow into a new worm.

Andrew Huberman: Wow!

Oded Rechavi: And they have centralized brains with lobes and everything,

and even these degenerate eyes.

He studied these worms and he said that he can teach them certain things,

associations, by pairing them all, I don't remember exactly what he did.

I think it was either lights or electricity to shock them, which

shocked them with other things.

And he could train them to learn and remember particular things.

Andrew Huberman: Like they might get shocked on one side of the tank.

Oded Rechavi: Exactly.

Andrew Huberman: And then avoid that side of the tank.

Oded Rechavi: Yes.

Andrew Huberman: And then I guess the question is whether or not

their ripped apart selves and their subsequent generations will know to

avoid that side of the tank without having ever been exposed to the shock.

Oded Rechavi: Right.

So without ever being exposed to the shock or whether the new generation, the

new head will be able to learn faster.

That's another.

The subtlety that might happen.

Okay.

And this is what he said happened.

He said he can teach them certain things, remove, cut off their heads and

new heads with all the brain will grow and that it will contain the memory.

This was the start of the controversy.

Not the end of it, only the beginning.

Then he said something even much wilder, which is he can train them

to learn certain things and then just chop them up, put them in a

blender and feed them to other worms.

Because they are cannibalistic, they eat each other and that the memory

will transfer through feeding.

Andrew Huberman: This sounds like such a dramatic field.

Oded Rechavi: And by the way, this opened the field.

So people did experiments not only in planaria, but in goldfish and certain

rodents, and did these memory brain transfer assays, implanting brain.

And this is back when they had an idea that some memories could be

molecular, could have a molecular form, which is very appealing.

It's almost like science fiction.

You can have a memory in a tube, unlike the way we think about memory normally,

which is something that is distributed in neuronal circuits and encoded in the

strength of particular synapses and so on.

But the idea that you can take a memory and reduce it into a molecule and transfer

it around is very, very interesting.

So this is why it attracted so many people.

This ended up in a catastrophe.

So there was an NIH investigation.

No one could replicate anything.

It was a big mess, although there were always scientists who said,

yes, we can replicate this and this.

So they were in the background.

The McConnell stuff was different.

Again, people thought that there are problems replicating, but it

wasn't necessarily, but some people replicate, but it wasn't necessarily

about replicating the whole thing.

But the question was the memory, the transfer, specific, or is it an overall

sensitization that transmits and so on?

Andrew Huberman: Right.

Like you could imagine that what gets transmitted is a hypersensitivity

to electricity, as opposed to the specific location that the

electricity was introduced.

Oded Rechavi: Or even more than that, even just a hypersensitivity.

In general, you're more vigilant and you'll learn anything faster.

That's also a possibility.

But his problem wasn't the accusation.

It was much worse that he was targeted by the Unabomber, this

terrorist who sent letters with bombs to many scientists for 15 years.

And his assistant, again it is the assistant, I think, exploded.

And this is how his line of research ended just recently, a few years ago, a

researcher from Boston, Mike Levin, and his postdoc, [inaudible] , replicated

some of McConnell's experiment with the cutting of the head, but using very

fancy equipment and automated tracking.

And they could say that they can replicate some of his experiments.

Andrew Huberman: Really?

And they don't open packages in that laboratory.

Oded Rechavi: [LAUGHS] They have interesting stories.

You should have Mike over.

Andrew Huberman: Yeah, I'm familiar with a bit of his work.

I didn't realize they had done that experiment.

Oded Rechavi: They published it a few years ago.

And this is very interesting, but of course, they don't know how it happens.

The mechanism is unclear.

McConnell went a step further than this, and what's fascinating is

that these are experiments that were done in the 70s and 80s.

He said that he can not only transfer the memories through chopped animals, but

he can take the animals that learned and break it down into different fractions.

So just the DNA, just the RNA, just the fats, the proteins, the sugars.

And he said that the fraction that transmits the memory is the RNA.

And this is very, very interesting because it was a long time before

everything that we know about RNA today.

I'll soon go into my research, explain what we do, and then you'll see that

you can actually feed worms with RNA and have many things happen.

This is, everyone knows this is true.

Okay, so this is why it was so appealing to go back to that and study it.

By the way, at the time it became popular knowledge.

Everyone knew these experiments.

There's a Star Trek episode about it from '84.

There are comics, books about it, books about it.

And people were eating RNA because they thought that there was RNA in memory.

This was, of course, complete nonsense, but it made a lot of

noise in these years, which is part of the reason it was so toxic.

Until recently, you couldn't touch it because it was considered

pseudoscience, like Lysenko, like Kammerer, and all of this.

So this was just something you didn't want to touch at all.

And then we go back to these studies about inheritance of memory or

inheritance of acquired traits in other organisms, in mammals, in humans.

And aside from the dark cloud that these episodes left, there were also

theoretical problems of why this can't happen, barriers that have

to be breached for this to happen.

And you can talk about many different types of barriers, and you can also

narrow it down to two main barriers.

First barrier, we mentioned it.

This is the separation of the soma from the germline.

Andrew Huberman: Right.

The somatic cells, they can change in response to experience.

The sperm and the egg, the so-called germ cells cannot.

That's the idea.

Oded Rechavi: Or they are isolated from what happens in the soma.

Okay.

The man who first thought about this barrier is called Wiseman, August Wiseman.

This was in the 19th century, so it is called today the Wiseman Barrier,

separation of the soma from the germline.

Only the germline transmits information to the next generation.

And this is also called the second law of biology.

So this is very, very fundamental.

So natural selection is the first one, this is the second one,

because it's so important to how we work, to how our bodies work.

Wiseman, by the way, thought that if you will have direct influence

of the environment on the germ cells, then perhaps this could

transfer to the next generation.

So he wasn't as strict as his barriers suggest.

But this is not how most people remember it.

But he thought that this was unnecessary.

It's possible that natural selection can explain everything.

And he compared it to a boat, which is in the ocean, it is

sailing and it has a sail open.

So you don't have to assume that it has an engine.

The wind is blowing.

You don't have to assume other things.

The natural selection might be enough.

So this barrier is still standing, but not entirely.

It is breached in some organisms.

We'll go into that in a second.

The other barrier is now we have to understand the other barrier.

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 say

about everything that is epigenetics.

Even people from the fields.

The word itself, that the term was defined in the 40s by

Weddington, Conrad Weddington.

And he talked about the interactions between genes and their products

that, in the end, bring about the phenotype of the consequences and

how genes influence development.

Later, people discovered mechanisms that change the action of genes.

There are different mechanisms and started talking about these as epigenetics.

For example, DNA is built out of four basic elements.

These are the A,T, G, and C, and they can be chemically modified.

So in addition to just the information that you have in the sequence of the

DNA, you also have the information in the modification of the bases.

The most common modification that has been studied more than others is

modification of the letter C of cytosine methylation, the addition of a metal group

to this C, and this can be replicated.

So after the cells divide and replicate their genetic material, in certain cases

also, these chemical modifications can be added on and replicate and be preserved.

Andrew Huberman: For those who aren't as familiar with thinking

about genes and gene structure and epigenetics, could we think of these?

You mentioned the four nucleotide bases, C, G, A, T, but could we imagine that

through things like methylation, it's sort of like taking the primary colors

and changing one of them a little bit, changing the hue just slightly,

which then opens up an enormous number of new options of color integration.

Oded Rechavi: It's just 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, methylation is a very common modification.

Acetylation, even serotonin, serotoninlation of histones.

Andrew Huberman: Serotonin, right.

Oded Rechavi: This is a new paper from nature.

Andrew Huberman: From a few years ago, can change.

Oded Rechavi: DNA, not the DNA itself, but the protein that

condenses it, essentially.

Andrew Huberman: How, in the analogy I used before, of how the thread is

wrapped around the spool, essentially?

Oded Rechavi: Yes, a nd this determines the degree of condensation of the

DNA, whether the gene is now more or less accessible, and therefore can

perhaps be expressed more or less.

This is one way to affect the gene expression and bring

about the function of the gene.

There are many additional ways, not the only one.

So then, when all of this was starting to be elucidated, people talked

about epigenetics, they started talking about these modifications,

forgot the original definition.

And when people said epigenetics, they talk about methylation

and things like that.

Andrew Huberman: And again, to just frame this up so we could imagine two

identical twins, so called monozygotic twins, we could go a step further and

say that they're monochorionic and they were in the same placental sac, because

twins can be raised in separate Sacs, slightly different early environments.

Let's say those two twins are raised separately.

One experiences certain things, the other things, they eat different foods, etc.

And there is the possibility, through epigenetic mechanisms, that through

methylation, acetylation, serotonin production, etc., that the expression of

certain genes in one of the twins could be amplified relative to the other, correct?

Oded Rechavi: Yeah.

So we know that even totally identical twins, genetically,

they're identical, but they look different, and they are different.

We all experience it.

And this can happen because of these epigenetic changes, or it can happen

because of other mechanisms, because genes respond to the environment.

Genes don't exist in a vacuum.

Genes need to be activated by transcription factors, and there's a

lot of machinery that is responsible for making genes function.

So we are a combination of our genetic material and the environment.

So when people talk about epigenetics and talk just about the modification,

they're also not exactly right.

My definition of epigenetics is inheritance, which occurs either across

cell division or more interestingly, also for this podcast, now across generations,

not because of changes to the DNA sequence, but through other mechanisms.

I think this is the most robust definition that allows you to

understand what you're talking about.

And then the question is, if this happens, then what are the molecules that actually

transmit information across generations?

Are they these chemical modifications to the DNA or to the

proteins that condense the DNA?

Or are there other agents that transmit the information and

which molecules can do it?

And I actually think that the most interesting players

today are RNA molecules.

But before I go into that, I just want to say that when we talk about the

barriers to epigenetic inheritance or the barriers to inheritance of acquired

traits, in addition to the separation of the soma from the germline that

we discussed, the other main barrier, it's called epigenetic reprogramming,

which is that we acquired our cells.

The genetic material in our cells acquires all kinds of changes, these chemical

changes, modifications we discussed.

But these modifications are largely erased in the transition between generations.

So, in the germline, in the sperm and the egg, and also in the early embryo,

most of the modifications are removed.

So we can start a blank slate based on the genetic instructions.

And this is crucial.

Otherwise, according to the theory, it's not clear that's actually true, because in

some organisms it doesn't really happen.

We will not develop according to the species typical genetic instructions.

So to preserve this, we erase all these modifications and start anew.

And this is in mammals and in humans, this is largely true.

Most of the modifications in the sperm and in the egg are removed.

So about 90% of them, some remain, which could be interesting.

Andrew Huberman: So the idea, if I understand correctly, is that there's

some advantage to wiping the slate clean and returning to the original plan.

In the context of the IKEA furniture analogy, the instruction

book is the one that's issued to everybody or every cell, right?

Only certain instructions are used for certain cells, say a skin cell or a neuron

or a liver cell or any other cell for that matter, through the course of the

lifespan of the organism, those specific instructions are adjusted somewhat.

Okay, so maybe like IKEA furniture, sometimes they sent you seven, not eight,

of particular screws, or they sent you the proper number, but you put them in

the wrong place and it sort of changes the way that the thing works a little bit once

that, assuming furniture could reproduce.

But here in the analogy of the furniture as the cell or the organ

in it mates with another organism that needs to be replicated.

And so the idea is to take the instruction, but go through and erase

all the pen and pencil marks, erase all those additional little modifications that

the owner used or introduced to it, and return to the original instruction, right?

Oded Rechavi: Because if you want to bring back the instruction

book, you want it to have all the potential to make all the furniture.

You don't want it to be restricted to the ones that you made in a particular room.

Andrew Huberman: So it's essentially the opposite of acquired traits

and characteristics, based on what we say in biology, geek

speak, lineage 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.

Oded Rechavi: Yes, but it's more complicated.

It's more complicated than that because we have some very striking

examples, even in mammals, where some of the marks are maintained.

For example, the classic example is imprinting.

Imprinting is a very interesting phenomenon.

The way DNA works is that you inherit a copy for every chromosome from your

mother and your father, and then you have in every cell of your body, two copies,

if you're a human, of every chromosome.

So every gene is represented twice.

These are called alleles, the different versions of the genes.

And the thought is that, in the next generation, the two copies

that you inherited are equal.

It doesn't matter whether you acquire them from your mother or from your father.

There are some situations where it does matter.

There is a limited number of genes that are called imprinted genes, where

it does matter whether you inherited from your mother or your father.

And this is happening through epigenetic inheritance, not because of changes

to the DNA sequence, but because of maintenance of these chemical

modifications across generations.

Andrew Huberman: And as I recall from the beautiful work of Catherine Dulac

at Harvard, that, especially in the brain, there is evidence that some

cells contain the complete genome from mom or the complete genome from dad.

Oded Rechavi: And it can also switch during your life.

So her work showed that early on in your life, it's different whether

you express the maternal or paternal copy than when you're more mature.

Andrew Huberman: So parents and children take note.

For those of you that are saying, oh, the child is more like you or more like

me, that can change across the lifespan.

And if you're thinking about your parental lineage and wondering

whether or not you "inherited" some sort of trait from mother or from

father, it can be, of course, both.

Or it can be just one or just the other, which I think most

parents tend to see and describe in their children from time to time.

That's just like the father, or that's just like the mother, for instance.

Oded Rechavi: Right.

But it's important to know that in this situation, the environment played no role.

This was just whether it passed to the mother or the father.

It's not that something that happened to the mother or the father affected this.

So this is slightly different.

The question is now, can the environment change the heritable material?

So it's very important to understand that there is a difference

between nurture and nature.

And this is very confusing, and people are confused.

It's a little subtle.

So, for example, people tell me, I'm growing horses for many

years, and I just know that this horse has a particular character.

It's very different from the other horsess.

And so this is epigenetic inheritance?

No, it could be just genetically determined.

Yes.

This horse inherited a different set of genetic instructions.

So it is different.

Doesn't have to be about epigenetics.

Epigenetic inheritance means that the environment of the parents

somehow change the children.

And there are these two main barriers that are serious bottlenecks that

we have to think about what type of molecule and how they can be breached.

So one possibility is that it's really this limited number of

chemical modifications that survive, which is about 10% or so.

That could be very interesting.

Andrew Huberman: Not a small number?

Oded Rechavi: Not a small number.

But perhaps.

Perhaps.

Okay, this is one possibility.

The other possibility is that there are other mechanisms.

The situation now in humans is that it's just really unclear what transmits, if it

can transmit, and which molecule does it.

We'll talk later about other organisms where it is a lot more clear.

But in humans and in mammals in general, there are many examples of

environments that change the children.

Whether you need to invoke an epigenetic mechanism to explain

this phenomena, this is unclear.

First of all, because it's hard to separate nature from

nurture, and second, because the mechanism is just not understood.

So there are classic examples for humans, there were periods of famine, starvation

in different places in the world.

In the Netherlands, in China, in Russia, where people did huge

epidemiological study to study the next generations and saw that the children

of women who were starved during pregnancy are different in many ways.

They have different birth weight, glucose sensitivity, and also some

neurological, higher chances of getting some neurological diseases.

And this has been shown in very large studies.

Andrew Huberman: Is there ever an instance in which starvation or

hardship of some kind, some challenge, sensory challenge or survival based

challenge led to adaptive traits?

Oded Rechavi: Yes, there are.

In different organisms, it could be as a result of a trade off.

So there could be a downside as well.

But, for example, there are two examples that come into mind.

One of them is that if you stress male mice or rats, I don't remember.

This is the work of Isabel Mansuy in the ETH in Switzerland.

If you stress the males, you can do it in many different ways.

I don't remember exactly how they did, but you can separate them

from their mothers, you can do social defeat, all kinds of things.

Then the next generations are less stressed, they show less anxiety.

Andrew Huberman: So the threshold for stress is higher?

Oded Rechavi: Yes.

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

Andrew Huberman: Which may be a n advantage for dealing with stress.

Oded Rechavi: Could be.

Andrew Huberman: I don't have any direct evidence of that.

But there's some simmering ideas that our ability to anchor our thoughts

in the past, present or future seems very adaptive in certain contexts.

In other contexts, it can keep us ruminating and not adaptively

present to our current challenges.

Oded Rechavi: Another example is that of nicotine exposure.

This is, I think, the work of Oliver Rando from UMass, if I'm not mistaken.

These are not my studies, but they improve the tolerance to exposure to

similar drugs in the next generation.

The interesting thing here is that it's very non-specific.

So you treat them with nicotine, but then in the next generation they

are more tolerant to nicotine, but also to others, I think cocaine.

Andrew Huberman: That sort of makes sense to me, because obviously nicotine

activates the cholinergic system, the dopaminergic system, epinephrine, etc.

And you can imagine that there's crossover because other drugs

like cocaine, amphetamine, mainly target the catecholamines, the

dopamine and norepinephrine.

Oded Rechavi: In this particular study, if I remember correctly, they

show that this happens, this heritable effect, even if you use an antagonist

to block the nicotine receptor.

Andrew Huberman: Wow.

Oded Rechavi: So it's something more about clearance of xenobiotics

and hepatic functions that is transmitted and is very nonspecific.

Andrew Huberman: What I love about all the examples you've given today,

especially that one, is, and I hope that people, if you're just listening, I'm

smiling, because biology is so cryptic sometimes the obvious mechanism is

rarely the one that's actually at play.

And people always ask, well, why is it like this?

And I always say, the one thing I know for sure is that I wasn't

consulted at the design phase.

And if anyone claims they were, then you definitely want to back away very fast.

Oded Rechavi: And there could be so many trade offs.

So many trade offs.

So, for example, we studied, and also many other people studied effects.

These are in worms.

We'll go deep into that in a second.

But that shows that when you starve them, the next generations live longer.

And this, I think, could be a trade off with other things like fertility.

So the next generations are more sick and less fertile.

And perhaps because of that they live longer.

So it's not necessarily a good thing.

Andrew Huberman: I don't want to draw you off course, because this

is magnificent, what you're doing and splaying out for us here.

But do you recall there was a few years ago, it actually ended very tragically.

It was an example, I think it was, down in San Diego county,

there was a cult of sorts that were interested in living forever.

And so the males castrated themselves in the idea that somehow maintaining

some pre-pubescent state or reverting to a pseudo pre-pubescent state

would somehow extend longevity.

The idea that sexual behavior somehow limited lifespan.

This has been an idea that's been thrown around in the kind of

more wacky longevity communities.

They also shaved their heads.

They also all wore the same sneakers.

But then they also all committed suicide, right, as the Halle-Bopp

comet came through town.

But that's just, but one example of many cults aimed at sort of that

obviously was not life extension, that was life truncation, but aimed

at a kind of eternal life or some sort of through caloric restriction.

That's right, this cult also was very into the whole idea that through caloric

restriction, we can live much longer, which may actually turn out to be true.

I think it's still debated, hence all the debate about intermittent fasting, etc.

But also it is known that if you overeat, you shorten life.

This is clear.

It's known that big bodied members of a species live far shorter lives

than the smaller members of a great Dane versus a Chihuahua, for instance.

So there is some sort of, shard of truths in all of these things.

But it seems to me that the real question is, what is the real mechanism and

why would something like this exist?

Oded Rechavi: Right.

Andrew Huberman: And why?

Questions are very dangerous in biology.

Oded Rechavi: Right, right.

But very interesting also, when it comes to metabolic changes and nutrition,

there are numerous examples where you either overfeed or starve and

get effects in the next generations.

Sometimes the effects contrast depending on the way you do this.

Again, we don't do any of that in mammals, but people show that starving

or overfeeding the mothers or the fathers changes the body weight of the

next generation and also the glucose tolerance and also reproductive success.

And so the fact that there's an effect that something transmits, this is clear.

The question is, how miraculous is it?

And whether you need new biology and epigenetics to explain it.

What do I mean by that?

If you affect the next generation, it doesn't necessarily have to go

through the oöcyte or the sperm, and involves the epigenome, you change the

metabolism of the animal as it develops, and obviously it will affect it.

When you, for example, starve women that are pregnant, as happened during

the famous starvation studies, the baby is already in utero, exposed

directly to the environment.

So it's not even a heritable effect.

The baby is itself affected.

It's a direct effect, very interesting, important, and has many implications.

And it will be separate from the genetics.

You'll have to take it into account to understand what's going on.

Doesn't require, necessarily, a new biology, a new biology of inheritance.

Not only is the embryo affected, the embryo, while in utero, already has

germ cells, so it's also the next generation, so is directly exposed.

And you don't need any new biology necessarily, to explain it.

And it doesn't have to involve genetic epigenetics or epigenetic gender.

Andrew Huberman: It's clear to me that in the female fetus, the

total number of eggs that she will someday produce and potentially

have fertilized by sperm exist.

But in males with a 60 day sperm cycle leads me to the question, do fetal

males, males as fetuses, living as fetuses in their moms, already start

producing sperm, or it's the primordial cells that give rise to sperm.

Oded Rechavi: So I'm not an expert, so I don't want to go into the details

of exactly when in mammals but yes, exposure of the mother also has an affect,

eventually the transmission of genetic information through the sperm's father.

And there are also many examples of just stressing the fathers, affecting their

sperm and affecting the next generation.

There.

If you go to the F2 generation, if you go two generations down the road, not

to the kids, but to the grandkids, then it is a real epigenetic effect, because

you examine something that happens, although the next generation was never

exposed to the original challenge.

So when we say about epigenetic inheritance through the paternal

lineage, through the fathers, we talk about two generations.

And when you go through the mother, it's three generations to talk

about when you need to invoke some real epigenetic mechanism.

And there the evidence becomes much more scarce in mammals.

There are examples, more or less convincing.

The field is evolving and improving a lot.

So, for example, now many people use, the cutting edge is to use IVF, in-vitro

fertilization, or transfer of embryos, to make sure that actually it's the heritable

information and not the environment, and that it goes through the germline.

So this is something that is being done now.

There are studies.

Andrew Huberman: You're talking about the three parent IVF, where they

take the DNA from mom, the sperm from dad, and they take the DNA from mom

and put it into a novel cytoplasm?

Oded Rechavi: No, not at all.

You just take the sperm and transfer it and fertilize an egg.

Andrew Huberman: So standard IVF?

Oded Rechavi: Yeah, standard IVF.

You can do it in many different ways.

But this idea that you separate the environment of the mother from

the inheritance or the environment of the father, and to control

and separate nature from nurture.

Andrew Huberman: The environment becomes the culture dish.

Oded Rechavi: Yes, so the field is improving.

People do experiments that have a higher end, so more replicate

and are better controlled.

And there are some examples for effects that transfer.

And it depends who you ask whether people believe it or not.

Many geneticists do not believe in it, and many people do believe it,

and it depends on the community.

There is strong resistance for many reasons.

Some of them are justified, some are less justified and are part of the

scientific process and how things work, because it's challenging the dogma.

So this is very interesting on its own.

If you ask psychologists, many psychologists believe that there's

heritable trauma and things like that, population geneticists less.

So this really depends, and I think that we are just at a point

in time where we don't really know whether it happens and to what

extent, and we need bigger studies.

Even if you think about normal, just genetic studies, where people

a trying to understand the genetic underpinning of complex traits, like

anything that involves the brain, pretty much, we now know that you

need to study many, many people.

So now these big genome wide association studies, big genetic studies, involve

hundreds of thousands of people.

No one did an experiment like this for epigenetics.

It's much more complicated because you need to also take

into account the environment.

I'm not even sure we know how to design such an experiment.

It's very, very challenging.

Part of the resistance to the idea is based on theoretical grounds

because of these barriers and because of the controversies.

On the other hand, people really want to believe it.

People really want to believe it because it sort of gives your life meaning if you

can change your biology through changing your kids, through changing your biology.

So psychologically, I can understand why many people want this to happen.

Even Schrodinger, the famous physicist, so he wrote a very important book in

'44, so this was before the double helix, and it's called What is Life ? This

is actually a book that drove many physicists to establish molecular biology.

It's very, very important and he talks about the heritable material.

It also talks about evolution.

And he said, unfortunately, Lamarckism or inheritance of acquired traits

is untenable, it doesn't happen.

And he writes, this is very, very sad or unfortunate because unlike

Darwinism or natural selection, which is gloomy, it doesn't matter what you

do, the next generation will be born based on the instruction in the sperm

and the egg, you can't influence it.

Of course, you can give your kids money and education, but you

can't biologically influence it.

Andrew Huberman: One thing I'm fascinated by for a number of

reasons, is partner selection.

I mean, in some ways we think, oh, we want to find someone who is kind.

That does seem to be, by the way, the primary feature, at

least in what the data tell us.

We had David Buss on the podcast of how women select men, that people are kind.

There's also resource potential.

There's also beauty or aesthetic attractiveness in males and females, etc.

Male, male, female, female, as the case may be.

But in terms of reproduction, sperm, 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 and in the idea that if

we were to have offspring with somebody, that those traits would be selected for.

Oded Rechavi: Right.

And we actually have work on that in nematodes that I'll be happy to

tell you about in a second after we--

Andrew Huberman: --The dating in worms--

-- Oded Rechavi: The dating in worms , where we understand the mechanism, and we'll

go into that in a second or in a few minutes after we dive into the worms.

But yes, the original calculations of how population genetics work to

simplify things and to do the math, so it will be easy, it was random mating.

Of course, it doesn't work like that.

So it complicates things because we know, and there's research

about potential capacity to somehow sense immune compatibility

and things like this, which is.

I don't know, I'm not an expert on that.

Andrew Huberman: Neither am I, b ut my understanding is that, of course, we're

familiar with the other traits we select for, like potential nurturing ability.

Whether or not someone is reliable predicts something

about their nurturing ability.

And for offspring, potentially.

I mean, you can draw lines between these things without any direct evidence,

but they seem so logical, right?

That somebody kind might also stick around or be honest and these kinds

of things, that it makes sense.

But that one would be selecting for certain biological traits like

immune function or some other form of robustness that we're not aware of is,

I think, a fascinating area of biology.

Oded Rechavi: So this is where the work in mammals stands.

However, there's also one additional thing to mention, which is that on

top of chemical modifications to the DNA and the proteins that condense

the DNA, which are called histones, there are also other mechanisms that

might transmit information, including transmission between generations of RNA.

And there are different types of RNA, not just the RNA that we mentioned before,

the messenger RNA, which encodes the information for making proteins, but also

other RNAs that regulate gene expression.

And this is, and I think that in recent years, also in the mammalian

field, RNA as the molecule that has the potential to transmit information

between generations, took center stage.

So I think this is the cutting edge, a lot more to understand and know.

But RNA has a lot of potential for doing that, as we'll explain soon.

But we have to go to worms first.

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Thank you for that incredible overview of genetics and RNA and epigenetics,

and it was essentially a survey of this very interesting and on the

face of a 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 Huberman Lab podcast and say that what

we are about to discuss is the first time that anyone on this podcast has

discussed so called model organisms.

I may have mentioned a fly paper here or there, or a study on honeybees and

caffeine and 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, etc., but I cannot emphasize enough the importance

of model organisms and the incredible degree to which they've informed us

about human health, especially when it comes to very basic functions in cells.

I mean, one could argue, okay, and there's been some debate, telomeres

in mice, did that really lead to the same sort of data in humans?

Okay, there are those cases, certainly, but model organisms are

absolutely critical and have been and basically inform most of what

we understand about human health.

So before we start to go into the description about worms per se,

could you just explain to a general audience what a model organism is?

Right.

They're not modeling.

They're not posing for photographs, obviously, what that means and what

some of the general model organisms are and why you've selected or elected

to work on a particular type of worm to study these fascinating topics

that there's zero question also take place in humans at some level.

Oded Rechavi: So it's a real pleasure and an honor to represent

the model organisms here.

I'm really happy just for that.

It was worth it, because, as you said, model organisms are

extremely important, and we learn so much about biology through them.

Model organisms mean that it's an organism that many people work on.

So there's a community of people that work on them.

People work, study many types of organisms, but not around every organism.

There's a huge community of researchers that combine sources to create all

the resources, the tools and the understanding that accumulates.

There are just a handful of model organisms in the short history of the

field of biology, it's not so long.

We learned about every aspect of biology through them, including many

important diseases, human diseases.

And these are E.

coli bacteria, phage - which is a virus of bacteria, flies, worms that are called C.

elegans, and nematodes.

This is what we studied in the lab.

Fish which are called zebrafish.

Andrew Huberman: Danio rerio, or something, right?

Oded Rechavi: Yeah, and of course, there are also model organisms, and mouse,

and also plants, important plants.

The most studied one is arabidopsis.

Andrew Huberman: And perhaps less so nowadays, but non-human

primates, macaque monkeys, marmosets, squirrel monkeys, mainly.

Oded Rechavi: These, I don't know exactly how the definition is,

but emerging model organisms.

There are many model organisms that are emerging, and there are communities that

are formed, including also around the planaria that we mentioned before, this

flatworm that regenerates, this is a great model for studying regenerations.

If we could develop new heads, it would be incredible.

And we can learn from these organisms.

And the reason that we can learn a lot also about humans by studying

these animals is that we all evolved from the same ancestor.

So we share a lot of our functions with them and also a lot of our genes.

C.

elegans, and they have, the different model organisms have

different advantages that serve us.

They sometimes have things that are much more apparent in them that we can study.

For example, learning and memory was largely studied in the beginning

in a snail, aplysia, where many of the discoveries were made,

because it has big neurons that you can easily study and examine.

Andrew Huberman: And yes, snails learn.

Oded Rechavi: Yes, they learn, even C.

elegans, these nematodes that we study, learn, and they are much

simpler than another important reason to study them, of course, is can

you actually experiment on them?

We can't do this to humans, the things that we do to these animals.

And we can change their genes, do all kinds of things to them.

Andrew Huberman: And sorry to interrupt, but in some cases, I think you're

going to tell us, for instance, in C.

elegans in particular, the presence of particular cell types is so

stereotyped that you can look at several different worms and the

community of people that study C.

elegans has literally numbered and named each neuron so that two laboratories on

opposite sides of the world can publish papers on the same neuron, knowing that

it's the same neuron in the two different laboratories, something that is extremely

hard to do in any mammalian model, a mouse, or certainly in humans, and has

posed huge challenges that give great advantages to studies of things like C.

elegans.

Oded Rechavi: Yes.

So, C.

elegans, this is the star now, and this is what we study.

These are nematodes, small worms, roundworms that are just 1 mm long, so

you can't see them with the naked eye.

You have to look under the scope.

Andrew Huberman: Where do they live in the natural world?

Oded Rechavi: So they used to call them soil nematodes,

but this is not really true.

They are in many places, but they are mostly in rotten fruits and leaves.

And you can find them in the ground as well.

But you can also find them, and they are free living, so they're not

parasites, but you can sometimes also find them in snails, but the best way

to isolate them is from rotten fruits.

Andrew Huberman: Okay, I Like the idea that they're not parasites.

I'm one of these people that gets a little squeamish about the notion of parasites.

Oded Rechavi: Yeah, so they're not parasites.

They're really fun to handle because they're so small and easy.

You just grow them on plates with agar and E.

Coli bacteria, this is what they eat in the lab.

You can just pick them with a small pick, wire pick, and move them around and change

their genes and do many things to them.

But they have many advantages for neuroscience and for studying inheritance.

As you mentioned, they always have a certain number of cells in the body.

So a silicon nematode always has 959 cells in its body, that's it.

Andrew Huberman: Not 960.

Not 958.

Oded Rechavi: 959, and out of which 302 are neurons, always 302.

There's a huge debate now over Twitter on whether it's 302 or 300.

I don't want to get into trouble, okay?

But people take this very hard.

I think it's 302, but let's not get into it because I'll get into trouble.

Andrew Huberman: Well, we can equilibrate all things here by, you, say, 302.

Granted, you're far more informed in this model organism than I am or ever will be.

I'll say 300, and then we're balanced in terms of partisan politics in the C.

elegans community.

Oded Rechavi: Perfect.

And it's always the same.

And each neuron has a name, like you said.

And not only does every neuron have a name, many of them, we know what they do.

So there's a few cells that are sensory neurons that sense particular chemicals.

In certain situations, we'll know that a chemical will be

sensed just by one neuron.

There are other motor neurons and interneurons and all of that.

We know how many dopamine neurons there are, and serotonin neurons,

and we know them all by their name.

Not only that, we know how they are connected to one another.

We have a map, a connectome since the 80s, like a subway map that tells

us which neuron talks with which other neurons, and it is the same.

People thought that it was exactly the same between genetically identical warms.

Now we know that there are slight differences, but by

and large, it is the same.

And we have a map, a roadmap that we can use to study.

Andrew Huberman: The so-called connectome.

Oded Rechavi: The connectome.

Not only that, the worms are transparent, so we can actually see

the neurons fire using particular tools, and we can activate genes and

silage genes using optogenetics, like was discussed here on the podcast.

We can make the worms go forward or backward or lay an egg by shining

different waves of light on them.

So we have very powerful tools for manipulating the brain.

On top of that, we have great understanding of the genetics

of the worm, of the genome.

The C.

elegans is the first animal to have its genome sequenced before humans.

Before that, of course, there were bacteria, and we know that.

And each worm produces, each mother produces about 250 babies, which

are almost genetically identical.

And we know where we grow them.

The environment is very controlled, so we grow them in the plate with

just bacteria, so we can easily separate between nature and nurture.

Andrew Huberman: And one thing that I wonder about often is generation time.

Even though mice are not humans, mice have certain advantages

because they're mammalian species.

You can't do all the magnificent things that you can do in C.

elegans and mice.

But one major issue with mice is that the generation time is somewhat long.

You pair two mice, they mate.

You get a mouse or litter of mice.

21 days later.

It might seem like, okay, that's only 21 days or so.

But if you are a graduate student or postdoc, trying to do a project

that can extend the time to do experiments out three or four years

compared to what you could do in C.

elegans.

Oded Rechavi: You're absolutely right, t his is one of the major advantages.

The generation time in C.

elegans is three days.

Three days.

So you can do hundreds of worm generations in one PhD.

This is very important.

Not only that, every worm will produce hundreds of progeny that are genetically

identical, so you will have great statistics for your experiments.

Andrew Huberman: And the worms probably don't mind living on these

agar plates munching away on E.

coli, where it's the good life.

It's questionable whether or not mice, or certainly, listen, I'm a proponent

of well-controlled and as long as there's oversight, animal research.

It's necessary for the development of treatments of diseases that hinder humans.

But it is always a little bit of a kind of a cringe and go kind of thing when you're

dealing with mammals that are living so far outside their natural environment.

I'd be lying if I didn't say that it gets to you after a while, and if it

doesn't get to you, you kind of have to wonder about your own psyche a bit.

Oded Rechavi: Right.

I also think that this is important, but for me, it's much easier to work on worms.

I don't have to feel bad about it.

Andrew Huberman: Yeah, they're happy.

Oded Rechavi: They're happy.

If a worm dies, it's less painful to the human than if other,

more sensitive animals do.

Andrew Huberman: Yes, I agree.

Oded Rechavi: So there are many advantages for studying C.

elegans.

And in the worm, we now have very obvious and clear cut proof that there

is inheritance of acquired traits.

So much so that I don't think that anyone pretty much in the

epigenetic field argues against it.

Andrew Huberman: Well, and in large part thanks to you and the work you've done.

So, could you tell us, what was the first experiment that you did on C.

elegans 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 prodding and attempts to contradict oneself, then it's considered a victory.

But it's one that we all have to be very cautious about enjoying

because of the tendency to want our hypotheses to be true.

So what was the first experiment where you were convinced that

inheritance of acquired traits is real?

Oded Rechavi: The first experiment I did was in my postdoc, which I did with

Oliver Hubbard in University of Columbia.

We set out to test whether worms can produce transgenerational, prolonged

multi-generational resistance to viruses.

Andrew Huberman: Wow.

This is a very pertinent topic, which is relevant.

Oded Rechavi: These worms don't have dedicated immune cells like we do.

They don't have T cells or B cells.

They defend themselves from viruses very efficiently using RNA.

So, in fact, when we started these experiments, there wasn't any

natural virus that was known to infect clients, which is amazing

because viruses are very good, as we all experience now, in infecting.

And the worms are resistant to viruses because of RNA molecules, short

RNA molecules that destroy viruses.

And these are called small RNAs.

Now, we need to discuss them before I explain my experiment.

In 2006, two researchers that were studying C.

elegans, Andrew Fire and Craig Mello, got the Nobel Prize for showing that

there is a mechanism that regulates genes that happens through small RNAs.

What they've shown is that if you inject the worms with RNA molecules,

which are double-stranded, they shut off the genes that correspond

that match in sequence to this RNA.

Andrew Huberman: So it's sort of like taking the specific instructions

for the coffee table from your IKEA handbook, and you insert a copy of

that into the book, and in doing so, you prevent the expression of.

You sort of erase the original page.

Oded Rechavi: Perfect explanation.

Perfect explanation.

And they found that double-strand RNA, RNA that has two strands is what starts

the response leading to the production of small RNA molecules, which are the

ones that actually find the messenger RNA and lead to its destruction, silence it.

So you don't get proteins in the end for that.

They got the Nobel Prize after people found that this is conserved

in many organisms, including humans, and there are now drugs.

This was only in 2006 that the Nobel Prize, the paper was published in 98.

There are now drugs that use this mechanism also in humans.

Andrew Huberman: And I'll just interject and say that not only is it

a recent discovery and an incredibly important one, but Andy Fire and Craig

Mello are also really nice people.

Yeah, they just happen to be very nice people.

And Craig Mello is an excellent, I think he's a kite surfer.

The only time I met him in person was at a meeting, and he had a black eye,

and I thought, okay, wow, I guess he's also a pugilist or something, but turns

out he had done that kite surfing.

So scientists actually do things other than go to the laboratory.

Nobel Prize winning scientists, that is.

Okay, I'll let you continue.

Thanks for allowing that.

Oded Rechavi: Incredible scientist.

And there were also studies in many organisms on the

mechanisms of how this happens.

It is called RNA interference.

RNA interferes in the expression of a gene, in the function of a gene, and it's

also called gene silencing, because these RNAs enforce the silencing of genes.

Instead of the genes being expressed, they are silenced, and

you don't manifest their function.

Already in the first paper that they published about this, where they've

shown that double-strand RNA is what leads to the silencing of the control.

They've shown two very important things.

One of them is that if you inject the worms with double-strand RNA,

you don't only see the action in the cell that you injected or in

the tissue that you injected, but you see it all over the worm's body.

It spreads.

It wasn't exactly clear what spreads, but it was clear that it spreads.

You see the silencing all over the body.

This includes also the germ cells.

So, if you inject the double-strand RNA just to somatic cells, even

to the head, you will also get the effect in the germ cells and in the

next generation, in the immediate progeny, the F1 generation, the kids.

So this was really clear proof that this is inherited.

However, this is just one generation in these original studies.

Later they've shown something which will immediately remind you what I

told you about with planaria, that you can just take worms and feed them on

bacteria that produce this double-strand RNA, and that the double-strand and

the silencing would move from the site of ingestion, from the gut where the

bacteria are eaten, to the rest of the body and also to the next generation.

So before we left, when I mentioned these cannibalistic experiments of

McConnell with the planaria, and now you see that it can happen, and

this is not controversial at all.

This is being done routinely every day by any C.

elegans biologist in the world.

This has been replicated a million times.

Not only that, you can also feed planaria, these other worms with RNA.

You can just put it in chopped liver and let them eat it.

And again, this will spread throughout the body.

Andrew Huberman: Wild.

Oded Rechavi: And this is what we do routinely.

We always, when we want, we use this technique to see what genes do.

If we want to see whether a particular gene is important for a certain behavior

or a certain something, the way to study it is to neutralize the gene activity.

And we do it by just introducing the worms with double-strand RNA that correspond

in sequence, that match in sequence this gene, this will lead to the silencing,

this activates the gene's activity.

And if then the effect stops, we know this gene is involved in the function.

And we never want to just examine one worm, so we feed the mother

with double-strand RNA 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 validated and not controversial at all and totally routine.

Andrew Huberman: Is it fair to say that McConnell's experiments of chop-blending

up these worms - [LAUGHS] very graphic image - blending up these worms and

then feeding them to other worms, planaria, that those experiments can,

yes, be explained by double-stranded RNA and through RNA interference?

Oded Rechavi: Potentially.

It hasn't been done yet.

We are working on it in my lab now in collaboration with other

labs, but it wasn't published.

But yes, this could be the explanation.

So Fire and Mello did these experiments, some other people did these experiments.

When I started my work, I wanted to see whether, in addition to

artificial double-strand RNA, some natural traits can also transmit

across generations because of RNA.

Because of small RNAs, right?

Andrew Huberman: Because injecting siRNA, or short interfering RNAs, that is, or

putting worms into an environment with an abundance of inhibitory RNAs as an

experiment, is very different from worms experiencing something and then passing

on that acquired trait to their offspring.

It's a world apart, in my opinion, because one is an extreme manipulation

that illustrates an underlying principle, the other is something

that, in theory, occurs in the passage of generations, Just naturally

. Oded Rechavi: We're going from the less artificial to the more artificial,

the advantages, just like with model organisms, that the more artificial

it is, the easier it is to, you know exactly what you did just now.

Introduce one factor and you can follow the result.

So this is always the trade.

What I did was, in Oliver's lab, was to see whether part of the magic for the

worms' resistance to viruses is their capacity to transmit information in

the form of RNA molecules, inhibitory RNA molecules, to the next generations.

And it has been shown before in C.

elegans that the worms resist viruses using this mechanism, these small RNAs.

In fact, this is probably the reason that these small RNAs evolved in the

first place, to get rid of viruses and other parasitic genomic elements,

and this is a mechanism to fight them.

And what I did is a very simple experiment.

I took worms and I infected them with a virus.

When you do this, this also has been shown in the past.

The worms destroy the virus.

Okay.

We demonstrated this very clearly using a fluorescent virus.

So if the virus replicates successfully, the worm just turns green.

And if the virus is destroyed, the worm stays black.

This is very simple.

It's a clear cut off.

You don't examine the worm and ask whether it feels good, you just see.

Andrew Huberman: This green light binary response.

Oded Rechavi: Yes.

And so we took worms, we infected them with the fluorescent virus they destroyed.

This also has been done in the past.

But then what we did is we neutralized the machinery that makes small RNAs

in the descendants of the worms, so they cannot make small RNAs from

the start on their own, because they just don't have the genes that

you need to make these small RNAs.

Okay?

And then we ask, what will happen?

Will we affect these worms with the virus?

Will they be green or black?

They can't make their own small RNAs, so they can't protect

themselves on their own.

The only way for them to stay black for them, not having the virus

replicate is if they inherit the small RNAs from their parents.

And this is exactly what happens.

All the worms' progeny, although they don't have the gene that is needed

for making the small RNAs, are black.

They silence the virus.

And this also continues for additional generations.

Andrew Huberman: Okay, so the parent worms effectively put something

into the genetic instructions of the offspring that would afford them.

Let's call it an advantage in this case, but afford them an advantage

if they were to be confronted with the same thing that the parents were.

Oded Rechavi: Right.

And we know exactly what this advantage is.

The advantages are small RNAs that match the viral genome and just chop

up that virus in the next generation.

And we can identify these small RNAs in the inhibitory RNAs in the descendants,

although they don't have the machinery to make it, just because they inherited.

We can identify them by sequencing, by RNA sequencing, which is like DNA sequencing.

You actually get the actual sequence of the RNA molecules, and we can see

that they correspond to the virus.

And they inherited small RNAs only if their parents were infected with them.

Andrew Huberman: So there's specificity there.

Oded Rechavi: There's specificity.

Andrew Huberman: Yeah, it's not just some general resilience passage.

Oded Rechavi: Right.

Andrew Huberman: I have to be careful in drawing an analogy that isn't

correct, and I want to acknowledge that what I'm about to say with

certainty cannot be entirely correct.

But the analogy that comes to mind in mammals is this idea that

if one generation is stressed, that their offspring may, in

some cases, have a higher stress threshold, a resilience to stress.

I could imagine why that would be advantageous.

Your parents have a hard life.

They have offspring, and they want their children to have a higher threshold

to stress because stress can inhibit reproduction, etc., and as I always

say, 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 protect

its young one way or another, either through nature or through nurture.

This is a nature-based protection of its young.

Is it fair to say that in the mammalian experiment with a passage of stress

resilience, that it could be RNA-based, that that would perhaps set some new

threshold on glucocorticoid production?

Here I'm speculating, and I want to highlight that I'm speculating, but

I'm speculating with a reason, which is, I think for people that are hearing

about this in worms, you've done a beautiful job of splaying out why model

organisms are really important, but to think about how this may operate in the

passage of human generations, I think is a reasonable thing to entertain.

Oded Rechavi: Right, and it is true that also in mammals now, RNAs and small RNAs

are a leading candidate for something that could mediate the transmission of

stress protection or also of harmful effects that transmit between generations.

Perhaps RNA does it.

However, in worms, the RNAs have one more trick that we don't know

the equivalent of in mammals yet.

This is something very crucial that we showed in that particular

paper, in the first paper.

Andrew Huberman: Which is?

Oded Rechavi: So the effect that I described, this transmission of resistance

to viruses through these RNAs, doesn't only affect the next generation, it also

affects multiple additional generations.

Andrew Huberman: So it gets passed?

Oded Rechavi: It gets passed.

And you have to ask yourself, how doesn't it get diluted?

Why isn't it diluted?

Because everyone produces 250 babies, so you dilute by 250, and if something

is diluted for four generations, so it's 250 times 250 after four generations,

it's a dilution of four billions.

Completely homeopathic, would never work.

It's just there's nothing left.

The secret of these worms is that they have a machinery for amplifying

the small RNAs in every generation.

This is called RNA-dependent RNA polymerase.

It's a complex which uses the RNA to find, and once it finds the

messenger RNA, just create many, many small RNAs so they don't get diluted

and they pass on for additional generations, and this is the trick.

We later also identify genes that regulate for how long an effect would last.

Otherwise, if in the beginning we ask how doesn't it 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 viral

resistance, but also with other traits.

For a few generations, three to five generations, we found genes that

function as a sort of a clock that times the duration of the inheritance.

Andrew Huberman: What sorts of genes are those?

Oded Rechavi: So we call these genes MoTeC genes.

MoTeC.

I don't know how is your Hebrew...

Andrew Huberman: Not great.

Oded Rechavi: ...but MoTeC means sweetheart in Hebrew,

but the acronym is Modified Transgenerational Epigenetic kinetics.

There are different types of genes like that, and for some of them,

if you mutate, if you disrupt their function, now the effect would transmit

stably for hundreds of generations.

It would never stop because their role is to stop the inheritance.

You don't want to carry over something forever, otherwise it will no longer

fit the environment of the parents and you'll be prepared for the wrong things.

So this is important.

What type of genes are they?

One gene that we studied, it's called Met-2, it's actually a gene

that functions in methylation of the proteins that condense the DNA.

But then there are other genes that also affect production of small RNAs.

Andrew Huberman: 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

meet my great great grandparents.

I could imagine that my great great grandparents or my great grandparents

experienced certain things that were passed into their children

and perhaps into their children.

But it seems reasonable given that humans live somewhere between zero and

100 years, typically what now, 80 years?

Is that the typical lifespan?

More or less, okay?

That if I were going to design the system, and again, I was not consulted at design

phase, I would want an adaptive trait to be passed for two generations, because

given how long our species lives, and certainly given the way the world looks

now, as opposed to the previous century or the turn of the previous century,

different stressors, different adaptation, different life environments, 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 100 years, maybe the next 200, but I don't

have the foggiest clue what the world is going to look like in 300 years.

Does what I'm saying make any sense whatsoever?

Oded Rechavi: It makes a lot of sense.

And really we need to talk about two things in response to this question.

First of all, yes, you can imagine that the reason that the worms inherit,

typically for three to five generations, is that this is relevant to something

that happened in their environment.

For example, we also show that when you starve the worms, it affects the next

generations again for a few generations.

Andrew Huberman: Which in itself is amazing.

I just want to highlight that you can imagine the next generation, it's

sort of 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, were you to have kids, they have it also."

Oded Rechavi: Yeah.

So I have to just make a disclaimer that we don't know

that necessarily, it's adaptive.

It could also be damaged.

As I said, when you starve them, the next generations live longer.

But this could be a trade off of a trade off for fertility or something.

So other labs have also shown, following our work, that if you starve the

worms, the next generations are also more resistant to harsh starvation.

This is not our work, but this sounds adaptive.

Okay, but whenever you're talking about adaptation, you have to see

it in the context of evolution.

There's also this famous saying, "nothing in biology makes sense

except in the light of evolution."

And so it's very hard to say without doing the lab evolution experiments, we actually

see who wins, the ones that inherit or the ones who don't hit, who takes over.

Otherwise, it's hard to talk about whether it's adaptive or not.

But when it comes to the duration of the response, yes, it could

be programmed to fit something.

For example, if you're talking about starvation, worms transition between

periods of starvation and periods where they have a lot of food.

So let's say they find an apple for a few generations, they will consume the apple,

and then they will be starved for a while.

Perhaps this is the number of generations that takes them to finish an apple.

Or perhaps there are other responses also to higher temperatures.

If you grow worms in higher temperatures, the options are different.

They change how they mate.

What I alluded to before.

Andrew Huberman: We're going t o get back to this because it

relates to cold exposure, which many listeners are interested in.

Oded Rechavi: And perhaps it is somehow correlated with the cycle of the year.

But to tell you the truth, I don't know.

As I said, we go from the more artificial to the less artificial.

If double-strand RNA, just synthetic RNA, is the most artificial,

starvation is more natural.

But it's not starvation in the real context of the world.

In a real apple, it's a plate with or without E.

Coli bacteria.

But it's not an apple on a tree exposed to the elements, with other worms, with

bacteria, with all kinds of complications.

And it could be that we will see different durations of heritable

effects the more natural we go.

It's just much less controllable and hard to do.

And again, when we're talking about humans, part of the argument is, why

people, why the disbelievers, it's not about fate, but the critics say

that this wouldn't happen in humans.

If they say the worms' generation time is just three days, the chances

that the parents' environment will match the children's environment is

very high because there's not a lot of time for the environment to change.

Plus they can't go very far, they're small.

There are many examples of epigenetic inheritance in plants.

This is a big field where there is very established proof for

inheritance of acquired traits.

For epigenetic inheritance, be more careful.

Epigenetic inheritance of acquired traits is a more loaded term,

but in plants it also happens.

And there you also say these are sessile organisms.

They can't run away.

So the environment is more constant.

Andrew Huberman: 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 bent stalk might be exposed to some environment where in order to capture

enough sunlight and other nutrients might need to grow in a corkscrew form.

The corkscrew form can be inherited for several generations.

Oded Rechavi: This is an example that I don't know, but perhaps it--

-- Andrew Huberman: something like that.

Trust me, the one thing we know about podcasting and YouTube is

someone will tell us in the comments, and please do, we invite that.

Oded Rechavi: Right, but there's a long history of epigenetic

inheritance studies in plants, with excellent studies, well controlled,

showing that it happens also there.

So this is very clear when it comes to humans, you could say, maybe my kids

will go to live in a different continent, and they will be on the computer every

day and everything will be different, so it makes less sense to prepare them for

the same hardships that I experience.

However, in my opinion, this argument comes up a lot.

It's not the best argument, because it depends on the scale of how

you look at things we experience.

We meet, for example, I'm not saying that this is inherited, but in humans,

but we experience the same pathogens and the same viruses all the time.

So perhaps it is worth preparing for that.

Andrew Huberman: Right.

Oded Rechavi: Again, I'm not saying that it happens, but it depends on the scale.

Andrew Huberman: Well, what you're describing makes perfect sense.

And I do want to acknowledge these critics, whoever they may be.

I do have the advantage that I don't work in this exact field.

And so I'm happy to stand toe to toe with those critics now and say that,

at least in terms of inheritance of reactions or adaptive or maladaptive

traits, to stress or to reward.

You talked about nicotine before, a passage of response

to drugs of different kinds.

Not being specific to nicotine.

It was sort of a more general passage of some sort of information

related to reactions to chemicals present in nicotine, but other drugs.

I have long been irritated and a little bit tickled by the fact that people

say, oh, we have this system for stress.

That was really designed to keep us safe from lions and saber-toothed 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 the

hallway when I go to the bathroom at night that I don't recognize, both of those

have the same generic response, which is the deployment of adrenaline in both

brain and body, changes in the optics of the eyes, quickening 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 to stress would be also somewhat generic, and

that's actually advantageous overall.

Same thing with the reward system.

We essentially have one or two chemical systems of reward.

I mean, there's the opioid system and there's a cannabinoid system, but in

large part, anticipation and reward is governed by the dopamine circuits.

And anticipation and 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 dopaminergic

system is going to be engaged.

So ice cream, sex, stress to weather, stress to famine.

The biology of these more modal systems, especially in the nervous

system, are, again, I have to be careful with the words, by design,

are certainly generic, and so I don't see the need for immense specificity.

I mean, it's not like we're, well, COVID just happened.

So could you imagine that there's the passage of a COVID-19 specific resilience?

No, I think what would probably be passed along would be some sort of, if

it does occur, would be some sort of resilience to viruses more generally,

and that would be advantageous.

Oded Rechavi: Right.

So I agree.

And this opens a question of what is the bandwidth of inheritance?

How specific can it be?

Does it make sense for it to be specific?

And in the case of C.

elegans, the response can be very specific through this inheritance

of RNAs, which are just sequence specific, they downregulate,

they control one particular gene.

In other cases, it could be a very general response.

And it's very interesting to think about it when we talk about inheritance

of memories, which is the most interesting thing we could imagine,

can brain activity of some sort transmit, at least in these worms?

I said no.

I said this disclaimer multiple times in memories, we don't know.

Time will tell in worms.

We know a lot.

So, can worms transmit brain activity?

Do they have the specificity to do it?

Okay, before I'll say that, I'll just say that we, over the years, learned

a lot about the mechanisms that shuttle the RNAs between generations.

We know about genes that are needed just for that, about worms, that

would be perfectly okay, but just don't have the capacity to transfer

the RNAs 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 RNA between different tissues,

about genes that make certain small RNAs.

So we know a lot about that.

And then the question arises, we can finally ask, can memory

transfer between generations?

I think that, first of all, we need to define memory for that.

And the broadest definition would be any change in your behavior because of

what happened in the past or in your response because of what happened in

the past or because of your history.

The more interesting part, of course, is 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.

I think that any tissues that transmit, transfer to transmit RNA

to the next generation and affect the next generation is interesting.

The gut, muscles, everything.

But the brain can synthesize 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 somehow the fate

of your nerve generation using your brain after taking many things into the code.

Andrew Huberman: This is without talking to them.

Oded Rechavi: Right.

Without talking.

Andrew Huberman: Right.

So again, we go back to this instruction manual.

It's like writing something into the instruction manual

based on your own experience.

Oded Rechavi: Right, and can it happen and what is the bandwidth?

Can we transfer specific things?

And then I have to agree with you that I would imagine that what can

transfer, and I could be wrong, is a general something, sensitivity.

You can make the analogy to being inflamed or not, hypersensitive to pathogens,

hyper vigilant, something like this.

But it can also be something very specific.

Now, we have to understand that the brain uses a different language

than the language of inheritance.

The brain, the way we normally think about the brain is that it keeps

information in synapses, in the connections between different neurons.

When you learn something, you make some connections stronger and another

connection weaker, and you wire the nervous system in a different way.

The information in the brain is synaptic, and it is in the connection.

On the other hand, heritable information of any sort has to go

through a bottleneck of one cell.

The fertilized egg, because we all start from just one cell, so it cannot be in

the connections, because this cell doesn't have any connections with other cells.

It's there alone.

So heritable information has to be molecular.

It has to be inside this one cell.

So the question is, can you or do you translate the information, this

3D structure information of synapses and the connection between brains in

the architecture of the brain, can you somehow translate it to heritable

information to a molecular form?

Andrew Huberman: It's an incredibly important and deep question.

It brings to mind 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 the world, essentially, is just, you take what's been drawn out

in terms of the architecture and the coastlines, etc., and divisions between

states, and you transfer that to an electronic map or a piece of paper.

It seems so obvious.

It's sort of a duh, why are we talking about this?

But just to 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 repeated calls.

But in any case, I remember it.

It's totally useless information, but it lives in my neocortex or my

hippocampus or somewhere as a series of connections between neurons at

the locations as you call synapses.

Would my grandchildren know that phone number?

There's no reason.

Oded Rechavi: Absolutely no.

Andrew Huberman: Right.

Would my children know that unless there was some adaptive reason or

some other reason for them to know, and this passage of acquired traits?

And what you're saying is, in order for that to happen, there has to

be a transformation of the neural circuit, literally the wiring of

neuron ABCD, that relates and carries the information of that number into

the kind of nucleotide sequences that are contained in DNA or patterns

of methylation or RNA, more likely.

So it's a transformation of one set of points in physical space to a

translation of points in genetic space.

Does that make sense?

Oded Rechavi: Right.

And then we have many problems.

First of all, we don't know of a mechanism to translate between the two

different languages, the language of the brain and the language of inheritance.

We are not familiar with a mechanism like that.

Second, the next generation, if it's not a worm, if it's a mammal would

have a different brain even if it was genetically identical to the parent.

The wiring of the brain and the particular neuronal circuits will be different.

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 infections.

So let's say you somehow had a mechanism, a miracle mechanism, to take the 3D

Information and translate it to the magic, to the language of inheritance.

You would then in the next generation have to translate it again to the

brain, although it is different.

This sounds very unlikely.

I'm playing a trick on you now.

Andrew Huberman: Okay, I'm easy to trick.

[LAUGHS]

Oded Rechavi: But if this is how it happened or if this was required, it

could never happen, in my opinion, which means, and I still think that

there are certain memories that cannot transfer transgeneration and these

complex and things that you learn about the environment that are arbitrary.

None of our listeners' kids will remember this conversation.

No way.

This is impossible.

Andrew Huberman: Unless they're listening with them [LAUGHS] . There

are some families or parents that tell me they listen with their kids.

Oded Rechavi: But it cannot transmit because it's random and these are

connections that are arbitrary.

So this seems to be a limitation on what can transfer.

On the other hand, perhaps more general things could pass, these types of things.

I doubt they could pass.

However, you can nevertheless imagine that some things that are very specific,

some memories that are very, very specific could nevertheless transmit from the brain

after learning to the next generation.

I'll give you an example.

You can teach worms, even though they have just 302 neurons, you can teach

them simple things about the world.

For example, you can take an odor that the worms like.

The worms have thousands of odorant receptors and they can

recognize many, many molecules.

They can smell them so they can find food or avoid enemies.

You can take an odor that the worms like and pair it to

something bad, like starvation.

And then the worms will learn to dislike this odor.

We don't know that this learning involves necessarily changing

the strength of synapses.

It's a possibility, but it doesn't have to be the case.

It could be that just the receptor for this particular odor is being

removed and this is how they live now.

They won't have the receptor.

They won't smell.

They won't like the odor.

This is a possibility.

This type of thing, you can perhaps, not that anyone has shown it convincingly,

transmit to the next generation because all it would take is an RNA that will

control this particular receptor.

So this is possible.

People have shown things like that not in C.

elegans, but people have shown things like this in mammals.

They said that you learn a certain thing, and then just in the next

generation, thus a particular receptor would be methylated or would change,

and this would transmit the response.

And on the one hand, it could be true.

On the other hand, you need to understand, they'll need to prove, and

this wasn't done convincingly enough yet, how exactly does the information

transfer from the brain to the germ cells, and then in the next generation,

from the germ cells back to the brain to where the receptor needs to operate?

And this is a challenge.

This is the current state of the field, that this is something

that needs to be proven.

What we did in C.

elegans is we showed that the brain can communicate with the

next generations using small RNAs, and that this can change behavior.

And it doesn't require any translating between any language.

It is very simple.

What we've shown is that if you take a worm and you change the production

of small RNAs just in its brain, in the next generations, their behavior

will be different, even though you don't mess with their brains.

This is a paper that we published in 2019 in Cell.

We show that you just manipulate the production of endogenous natural RNAs

in the worm's brain that are always made, but you change their amount, and

this changes the capacity of the worms in the next generation to find food,

to find not only in one generation, but three generations down the road.

And the way that it works is that perturbing the production of these small

RNAs in the brain affects, in the end, the expression of a gene in the germline.

One gene, it is called SAGE-2, we don't know how it works, but we can

do all kinds of controls where we manipulate activity of the gene and

see that this also affects behavior.

And this gene works in the germ cells.

The information needs to go from the brain to the germ cells.

It doesn't need to go back from the germ cells to the brain to affect behavior.

And this depends, we know that this is a true epigenetic effect because it

goes on for multiple generations, and also because it requires the machinery

that transfers RNAs between generations.

If you don't have the protein that physically carries the RNA between

generations it doesn't happen.

Andrew Huberman: So it has to be RNA.

Oded Rechavi: It has to be RNA.

We can also find the RNAs in the next generation that change.

We sequence the actual RNAs that change in the next generation.

Andrew Huberman: You mentioned that you don't know what SAGE, this gene SAGE

does, but is it reasonable to assume that it does something in the context of the

nervous system or, that's unclear as well?

Oded Rechavi: It is possible.

It is possible, but we have reasons to believe or experiments to show, although

there could be alternative explanations, that it functions through the germline.

Now, you may ask, how can you affect behavior just by changing the germ cells?

Right?

Andrew Huberman: Well, it would have to change the germ cells in very specific

ways, because, as people probably recall, the germline, germ cells are where the

inheritable information is contained.

But you can imagine it, for instance, adjusting the gain or sensitivity, rather,

on some sort of sensory foraging system.

Oded Rechavi: Right.

The interesting thing is it, again, can be quite unspecific.

So it sounds weird that you change germ cells and it changes

behavior, sperm and egg, but if you think about it, it's trivial.

If you castrate a dog, it behaves differently, right?

Andrew Huberman: Sadly, yeah, I did that to my dog and I ended up

putting him on testosterone therapy later and it brought him back.

Just as an aside.

Oded Rechavi: Yes.

This is because the germ cells affect the soma, including the brain,

in many ways by secreting certain chemicals, and also because the other

cells develop from the germ cells.

So some information could be transmitted over development, or the course of

development could be altered because of changes that occur in the germ cells.

For example, in mammals, one of the explanations for how heritable information

transmits is that it just affects something very early on in development.

I told you that the secret to worms' inheritance is that they have the capacity

to amplify these small RNAs all the time.

This is what keeps it going and prevents the dilution.

In mammals, we don't know of such an amplification mechanism.

So you ask, how can a little bit of RNA or something without amplifying

affect the entire organism?

And it could be that you just perturb something in the very beginning when

you just have a few cells or even in the placenta that develops in pregnancy,

and this later throws everything off.

And because of that, you have many problems in metabolism and so on.

And this is called, it's an idea of the developmental

origin of health and disease.

Many of the functions occur early on in development.

Andrew Huberman: So you've raised 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 going to take us too far off track.

But something you said, it really captured my attention, although I was

listening to all of it, which is that the germ cells so in the case of males,

it's going to be sperm, and in the case of females, it's going to be eggs.

Something perhaps not coincidental about those cells and the environment that they

live in is that, yes, they contain the genetic information of past offspring.

Of course, you explain how that works.

But also those cells live in a region that is rich with hormones that can be

secreted and in fact, are secreted, and through so called endocrine 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 microenvironment of the germ

cells, the testes and the ovaries are rich with information, not just

for the passage to next generations, but also for all the, as you said,

all the somatic cells of the body.

They're telling the somatic cells of the body what to do and what to become.

And the best example I can think about this would be puberty, right?

I mean, I would argue that one of the greatest rates of aging and transitions

we go through in life is from puberty.

I mean, a child becomes a very different person after puberty.

They look at the world differently, they think about it differently.

It's not just about the growth of the hair and the jaw and the

Adam's apple and breasts and so on.

It's a transformation of the somatic cells from the same microenvironment

that the DNA containing cells reside.

Oded Rechavi: Right.

So once you think about it like this, it becomes obvious that just

by affecting the germ cells, you can affect the rest of the body.

And in C.

elegans, there are experiments that show it very clearly.

So, for example, if you just take worms and prevent sperm production,

it changes their capacity to smell.

These are experiments done by others, which is obviously a brain function.

Andrew Huberman: And in a castrated dog, you're not just eliminating the

possibility of transfer of DNA information to subsequent generations, you're also--

Oded Rechavi: --Limiting their personality.

Andrew Huberman: Without question, my bulldog Costello changed 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, back to a version of himself

that I had only observed earlier, but also a different version of the same dog.

And no, he wasn't humping everything, maybe the occasional knee?

[LAUGHS] Particular people, whose names I won't mention.

But it 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, if you will, let's continue down this path 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.

Oded Rechavi: So the worms are hermaphrodites, which means that they make

both sperm and an egg, but they are also males, which are much more rare, and they

can choose to mate with the males or not.

When they mate with a male, it's a huge decision because it's very costly

energetically, and they also risk predation and all kinds of troubles.

The males hurt them and reduce their lifespan when they mate with them.

Andrew Huberman: People are going to draw all sorts of analogies

here, but it's inevitable.

But, hey, here we go.

Oded Rechavi: And most importantly for evolution, when you mate with

another animal, you dilute your genome in half, because the worms can just

self fertilize and transmit the exact same genome to the next generation.

But when they mate, they dilute it in half.

So this is a big price to pay.

On the other hand, when you mate, you diversify your genome.

So maybe some combination of genes will be good.

Andrew Huberman: And we know that in humans.

I mean, it's kind of interesting that the brain circuits that are associated

with aversion and with approach are fairly hardwired for a number

of things, like a puddle of vomit, almost everybody kind of cringes.

Plate of cookies.

If you like cookies, you move towards it.

But there's one particular word in the English and presumably Israeli language

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 of inbreeding, it creates a deleterious mutation.

Oded Rechavi: Right, so there are studies on how people in Israeli

kibbutz, for example, where they all grow together, the children live together.

It used to be like that, don't date each other.

This is the classic thing.

I talked to some of whom the kibbuti told me that's not true,

but yes, there are studies like this that say, but it makes sense.

Andrew Huberman: And in some countries, Scandinavian countries, or in Lapland

and Iceland, where populations are small, they keep exquisite records of

lineage in order to avoid inbreeding.

Oded Rechavi: Right?

So you're absolutely right.

But the worms, the safe choice for them is to self mate.

And if they mate with a male, they take a risk, but they diversify.

Okay, what we found is that if you take the hermaphrodites, we can call it

the female for just one second and you stress it with high temperatures, then

the next generations of worms, for three generations, mate much more with males.

And they do it because the female starts secreting a pheromone

that attracts the males.

Andrew Huberman: It's a very cryptic mechanism.

It's not that she somehow changes and then goes seeking males.

It draws males.

Oded Rechavi: It draws males.

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 sperm in the hermaphrodites.

So the hermaphrodites don't, they make sperm enough to make next

generations, but the sperm, because of defective small RNA, inherited.

Because the RNAs are not inherited, okay?

The sperm is not made optimally, so they make less sperm.

And when they don't make a lot of sperm, they feel that they

don't self-fertilize correctly.

So they call the males by secreting the pheromones so that it would

provide its own sperm and they can continue to make babies.

And we know this also from experiment.

You just take hermaphrodites and you kill its sperm, it starts secreting

pheromone and the males come.

Andrew Huberman: It's a need-based system.

Oded Rechavi: Exactly.

Andrew Huberman: Incredible.

And I hope people can appreciate as they're 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, much like

human mating behavior, which to us always seems so conscious, but is

being governed by both conscious and subconscious decision making.

None of this is an active decision to secrete the hormone to draw in more males.

It's simply a biasing of probabilities.

The hormone is now secreted in greater quantities or greater frequency.

The males therefore approach more.

So it's just increasing the probability of interactions.

Is that right?

Oded Rechavi: Right.

What happens naturally, normally, if you don't stress the ancestors, is

that the worms start secreting the pheromone only when they are old.

This is also people will--

Andrew Huberman: --When they're running out of their own fertility.

Oded Rechavi: Exactly.

Because they only make the sperm at a particular time and then

they run out of self sperm.

They can't self-fertilize.

So they have to call the males if they want to continue to mate.

Andrew Huberman: Well, this is sort of the plastic surgery approach.

Okay, I'll take the heat for that one.

But it's true, I think as certain people age to a certain point and they

feel that their fertility is waning.

If they want offspring, they need to take any number of different approaches.

Here we're talking about a female, but we could also do the reverse.

Right.

Sperm donor.

Oded Rechavi: Right.

Andrew Huberman: But if they want to attract a lifelong mate or co-parent

with somebody, oftentimes they will do things to adjust their attractiveness

in any number of different ways.

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 or not they want to reproduce or not,

but has an inherent understanding, conscious or subconscious, about where

they reside in the arc of their lifespan.

I do believe that not just based on experience.

Some people are very attuned to 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 in particular died fairly young.

And all these guys basically got married and had kids really young.

Oded Rechavi: Right.

So here, luckily for me, I don't have to get into the psychology of the worms.

The explanation is just like an instinct.

When they run out of sperm, they start secreting the

pheromone and attract the males.

There are studies also in Newman's about older fathers, that children

of older fathers have a higher chance of becoming autistic.

There are studies--

Andrew Huberman: --40 and up, basically.

Oded Rechavi: However, in this case, it's not clear that this is something

in epigenetics, could be just because of DNA damage, because it accumulates.

Andrew Huberman: And actually nowadays, we have an episode on fertility

coming up, both male and female fertility, and there are actually

DNA fragmentation kits for at home.

DNA fragmentation kits or sperm analysis.

You send the sperm back in, you don't do the DNA.

People pipetting semen at home would be an odd picture, let's not go there.

But there are clinics that do this for a nominal charge.

But I did want to ask about autism and human disease in particular.

Another thing that you hear sometimes, and here I want to

acknowledge, autism is on a spectrum.

Some people get upset if you call it a disorder.

There are some adaptive autistic traits, etc.

But one thing that often comes up is this idea that two people who are more of the

kind of engineering hard science, if you will, of phenotype mate and have children.

Higher probability of the offspring being on the spectrum, some people

would argue, but that's already selecting for people that might have

already been partially on the 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 born from older fathers tend

to have a higher probability of autism.

At the level of intuition, does that strike you as an epigenetic phenomenon,

as a nurture mishmash or the possibility that it's RNA passage or anything?

Does anything sort of trigger the whiskers, your spidey sense?

Oded Rechavi: So in that case, I would go with the most parsimonious

explanation, which is it's just less fidelity, less DNA maintenance

and some damage that passes on.

It doesn't have to be an epigenetic thing.

Andrew Huberman: But the sperm are generated once every 60 days, so the

damage must be at the level of the germ cells not having the proper machinery.

Oded Rechavi: Right.

Andrew Huberman: Mitochondria or something like that.

Oded Rechavi: Or the DNA repair machinery.

The DNA repair machinery could be defective or could work less well in older

people, leading to the constant production of germ cells with more mutation.

This is a possibility.

Andrew Huberman: Do we know exactly what the DNA repair machinery is?

Oded Rechavi: Yes, there are many types of DNA repair.

There's one that use other copies of the DNA to correct.

There are ones that just recognize all kinds of lesions on the DNA and remove it.

It's a very elaborate and complicated system.

Andrew Huberman: And is it a system that is now tractable, that can

be modified through pharmacology or through anything like that?

Oded Rechavi: So I don't know about drugs that correct that, improve it.

Maybe they exist and I'm not aware, but it's very well understood and many

people are studying this direction.

Andrew Huberman: Yeah.

One thing that came across in the exploration of the fertility work is

that what I'm about to describe is not legal in the US, it is illegal, but is

legal in the UK and in other countries, is this notion of three parent IVF,

where it does seem that some of the eggs that persist in older females, even if

fertilized, don't produce healthy embryos.

They have chromosomal abnormalities, replications, and deletions that are

problematic for the development of the embryo, such as trisomy 21 aka down

syndrome, in part or in large part because of deficits in the mitochondrial genome.

So what they now do is they take the, because the mitochondrial genome resides

mainly in the cytoplasm, they'll take an egg from the mother, the sperm

from the father, but they'll take the nucleus from the mother and put that

into a cytoplasm of a younger woman whose mitochondrial DNA is healthy, then

use the sperm to fertilize that egg.

And that's why it's called three parent IVF, then implant that into the mother.

And this has been done several times in cases of mitochondrial damage or

mutations in the mother, it works.

The question is whether or not those offspring will grow up to be healthy.

So this, of course, is not just a pure divergence.

It raises a bigger question that I have for you, which is in

terms of the work in either C.

elegans or in other model organisms, but in particular in C.

elegans.

Where do you see this going next?

And if you would indulge us, I would love for you to tell us a

little bit about the admittedly unpublished work that you're doing on

temperature exposure and environments.

I mean, how malleable is this system?

Because to me, it just seems incredibly malleable.

And yet a lot of it's still cloaked off to us.

There's still a ton to learn.

Oded Rechavi: So, assuming that we will discover similar things in

humans, which we don't know that this is the case, but let's say we find

it, I think there are many things you can do before you change it.

For example, you could also change a parent inheritance by having

the parent exercise, for example.

Some things like this have been done.

For example, there are experiments in rodents where they show that overfeeding

the rodents creates problems for the next generations, for the children.

However, if you let the rodent exercise, then it corrects the aberrant inheritance.

So this is one possibility.

And you can also manipulate it at the source.

You can change, if it's RNAs, let's say you could, in the future, perhaps, if we

understand how it works, actually change the composition of the heritable RNAs.

Andrew Huberman: By eating RNAs, just like the worms RNA sandwich.

Oded Rechavi: No.

So the RNA sandwich will be difficult because it's not.

I don't know.

But if you do IVF, if you do any vitro fertilization, you can perhaps

change the composition of the RNAs in the stuff that you introduce.

But way before that, what you could do, perhaps even in the not so far

future, is use this for diagnostics, DNA based diagnostics for every

couple that wants to have a kid.

In Israel, this is done for most couples.

You can look at the DNA and look for genetic disease, but no one is

looking at the RNA at the moment.

If we understand how it works better, we'll have another level,

a whole new world to look at.

And perhaps there will be some RNAs that correlate with disease that

will say, okay, the beauty is that this, unlike DNA, it's plastic.

So with DNA, this is your DNA, perhaps we can choose another embryo.

But here you could say, perhaps again in the future.

This is science fiction, it doesn't happen now, but if we understand this

and it's true, we can say, maybe you should run on the treadmill a little bit.

This will change the profile of your RNAs, and then we will use it for IVF.

This seems more, because it correlates with healthy profiles of RNAs.

This is a level that no one looks at now and holds great potential.

Again, with a disclaimer that we don't know how it works in humans at all yet.

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

Andrew Huberman: 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.

elegans, I'd love for you to share with us what you're observing

about cold exposure and how that impacts subsequent generations of C.

elegans.

And if you would indulge us with the story of this discovery, like some of

the earlier stories you told us, it is a surprising and fascinating one.

Oded Rechavi: I'll gladly tell you about it.

This is not a story about transgenerational inheritance.

It's a story about memory within one generation.

Andrew Huberman: Excuse me.

Oded Rechavi: Within one generation.

Okay, and as you said, the story of how it happens is it's totally by accident.

It's a funny story.

And I'm bringing this up because I know Dana Lanchev, who's a huge fan of your

podcast, will really be happy, that this is her work and this is unpublished work.

We didn't even finish it, so we're working on it.

Andrew Huberman: Okay, well, when it's published, we will feature the

paper, Because I love this story.

Oded Rechavi: Great.

What happened is that we talked about transgenerational memories, and I

said that in worms, there are very long transgenerational memories.

If a generation time for C.

elegans is three days, some memories last for many generations.

So way beyond the lifespan of the worm.

The lifespan of the worm is three weeks.

You have a new generation every three days, but every

worm lives for three weeks.

But there's a lot of research that shows that unlike heritable memory,

which can be very long, the memory that the worms acquired during

their lifetime Is very short lived.

So if you teach something after 2 hours, it forgets.

So, for example, you can teach the worm, you can take an odor that it

likes and pair it with starvation, and then it would dislike the odor.

And then there's a simple test.

You just put it in a plate.

You put the odor in one side and a control order in the other side, and

you see whether it prefers this odor or not, and it stops preferring it.

Okay.

There is 30 years or more of research or 40 years of research on this showing

that the worms forget after two hours.

The reason I went to study C.

elegans is that I wanted to understand memory because of

such a simple nervous system.

Maybe I have the potential to actually understand how it works,

but this is slightly disappointing because they forget after 2 hours.

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 worms, teach them this assocIation to dislike the odor that

they innately like, and then just put the worms in -80 and freeze them, freeze them

completely, thaw them and see whether they still remember after they are thawed.

Andrew Huberman: The Han Solo experiment.

Oded Rechavi: And I didn't w ant to do it because of cryopreservation

or something like this.

I wanted to do it because as you know better than me, many theories about

memory say that you need electrical activity to maintain the memory.

You need to reverberate it in the brain.

Andrew Huberman: During dreams or replay of the thing or whatever.

Oded Rechavi: And if the memories will nevertheless be kept even

though the worms were frozen in -80 it would mean that it was kept in

the absence of electricity because there's no electricity in -80 degrees.

This was the idea.

I asked many students, no one wanted to do it because it's not

so easy and also a little crazy.

Andrew Huberman: Well, and when the PI, the principal investigator

or lab has a pet experiment, no one wants to do that experiment.

[LAUGHS]

Oded Rechavi: That is universally true.

And then Dana agreed to do it.

Dana Lanchev I was very happy only later to find out that she ignored me

completely and did a different experiment.

The experiment that Dana did instead is to just take the worms, teach them

the association and place them on ice.

She wanted to see how the kinetics of memory and forgetting

change in low temperature.

Because maybe whatever memory is, the breakdown of the memory

is affected by the temperature.

A very simple idea, we know, different experiment.

A different experiment, but a cool experiment, very cool.

And what she found is that when you place the worms on ice after you teach

them, they just don't forget even ten times longer than control worms at

that point, after 24 hours, if normal worms forget after 2 hours, after 24

hours, the worms will become sick.

So normally we do shorter experiments, but for 2 hours, the worms don't forget.

This is cool, but it was only the beginning because the boring explanation

is just what I just said, that everything slows down in low temperatures.

So the breakdown 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 the response.

It's the changing of the internal state of the worms which

affects the memory kinetics.

How do we know this?

There's been beautiful work over the last year on cold tolerance in C.

elegans nematodes.

If you take the worms and you place them on ice like she did, but

longer, for 48 hours, they all die.

However, if you take the worms, acclimate them to lower temperatures for a few

hours, 5 hours is a minimum, and then place them on ice, they all survive.

They become cold tolerant.

And people who study this show that this involves changes in

lipid metabolism and many things.

So Dana took the worms, acclimated them to slightly lower temperatures, made

them cold resistant, and then taught them the association and placed them on ice.

And now they forgot immediately, which means that when they change their internal

state to become cold tolerant, they no longer extend memories on ice, which means

it's not only the temperature, because the temperature was in any way low.

Now they know the memory.

We took this as a starting point to understand which genes change

when the worms are becoming cold tolerant on and off ice.

And we found genes that when you mutate them, the worms just remember longer,

always, even when they're off ice, because these are the genes that normally change

when they are surprised on the ice.

And these genes are expressed just in one pair of neurons, just two out of the 302.

Andrew Huberman: Notice he said 302, not 300.

Oded Rechavi: And we can manipulate the activities of these genes in

these neurons to extend memory.

And then the punchline of everything that happened is that we found

out that this neuron, where these genes function, this one pair of

neurons, is the only neuron in C.

elegans which is sensitive to lithium.

And lithium is a drug that has being given to bipolar disorder patients for decades.

Although it's not entirely clear how it works, it's very, very interesting.

It is also interesting, there's an episode, of course,

in your podcast about this.

You know more about this than me, a lot.

But it's also interesting because it's just an atom created in the

Big Bang, yet it works on our brains in such a fundamental way.

And we wanted to see whether it works also on the worms, because

this neuron was tied to this memory extension phenotype that we found.

So Dana grew the worms on lithium, removed them from lithium, taught them

the association, and found out that they remember a lot longer than control worms.

Not only that, if you first make the worms cold tolerant and then lithium

doesn't work on them, lithium switches this forgetfulness mechanism on and off.

Andrew Huberman: Amazing.

Oded Rechavi: And it's all connected to cold tolerance.

Andrew Huberman: Amazing and amazing for a number of reasons.

And so, at risk of being long winded in my response, I just wanted to

highlight something that I think will be of relevance to most people,

which is when, at some point, we did a few episodes on memory.

And I highlighted a review that was written by the great James McGaugh, one

of the great mammalian memory researchers who's worked a lot on humans and mice.

And I was shocked, pun intended, and amused to learn that in medieval

times, if people wanted children to remember lessons, they could be

religious lessons or school doctrine or whatever it was, mathematics, they

would take children, teach them, and then throw them into cold water to

introduce a memory instilling event.

And we now know that the memory instilling event is the release of adrenaline in

the body, which makes perfect sense if you think about traumatic events.

But 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 in the experiments that you just described, there's some general state

switch, some internal state switch that says, what happened in the minutes or

hours preceding this was important.

It acts as sort of like a highlighter pen in the Book of Experiences.

And I'm absolutely curious to know whether or not this is an RNA

dependent mechanism in some way.

So, is this literally like the highlighter in the IKEA instruction book?

Oded Rechavi: This we don't know.

This we don't know, and as I said, this is not even a finished work.

It's not peer reviewed.

It's just the state that I told you about.

But it's very exciting for me to go into this new field, and once it's

out, I'll be happy to talk more about it and think about the implications

and the connection to other things and more about the mechanisms.

Yeah.

Andrew Huberman: Well, thank you for sharing it with us.

Despite the fact that it's not finished, people now know

that it's also not finished.

And I love a good cliffhanger.

So we await the full conclusion and interpretation of these results.

Today, you've taken us on an amazing journey through the genome.

RNA, short interfering RNAs, a ton of history of prior experiments,

some of which ended tragically, many of which, unfortunately, did not.

They were true triumphs, and in particular, the work in your

laboratory, which is just incredible.

And also this introduction of model organisms.

And I only mentioned a short handful of the things that

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 something equally important, which is

that absolutely came through, but is what initially brought me to explore you and

your work more, although I had certainly heard of you, which is that your spirit

and kind of approach to biology is an extremely unique and intoxicating one.

Oded Rechavi: Thank you.

Andrew Huberman: Even I venture to call it seductive.

I do believe that whether or not it's music or poetry or science or mathematics,

that the spirit behind something dictates the amount of intelligence and precision

with which that thing is carried out.

And it absolutely comes through.

So if I'm making you feel on the spot about this, I've succeeded.

Oded Rechavi: Thank you.

Thank you very much.

Andrew Huberman: But I know that the listeners can feel it.

It's a felt thing.

So thank you.

There are many scientists out there, fewer with this phenotype and even

fewer that I think that can communicate with such articulate precision.

So thank you so much.

Oded Rechavi: Thank you.

Andrew Huberman: It's been a real pleasure.

Oded Rechavi: Pleasure was all mine.

Thanks a lot.

Andrew Huberman: Great.

Well, we'll do it again, and we'll 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, of course, point people in the direction of you

and to learn more about your work.

And I look forward to hearing the conclusion of Dana's studies.

Oded Rechavi: Thanks a lot.

It's been a real pleasure.

Andrew Huberman: Thank you for joining me today for my discussion with Dr.

Oded Rechavi about genetics, inheritance, the epigenome and

transgenerational passage of traits.

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