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 Rehavi.

Dr. Oded Rehavi 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’s 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. Rehavi 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. Rehavi 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.

In keeping with that theme,

I’d like to thank the sponsors of today’s podcast.

Our first sponsor is Roka.

Roka makes eyeglasses and sunglasses

that are the absolute highest quality.

The company was founded by two all-American swimmers

from Stanford,

and everything about Roka eyeglasses and sunglasses

were designed with performance in mind.

I’ve spent a lifetime working on the biology

of the visual system,

and I can tell you that your visual system

has to contend with an enormous number of challenges

in order for you to be able to see clearly

under any conditions.

Roka understands this

and has designed their eyeglasses and sunglasses accordingly.

Originally, Roka eyeglasses and sunglasses

were designed for sport,

that is for things like running and cycling,

and many of the features they have reflect that.

So for instance, they are extremely lightweight,

they won’t slip off your face if you get sweaty,

and they can indeed be worn for running and cycling

and things of that sort.

However, they also come in a number

of different aesthetics and styles

that make them perfectly suited,

not just for sport,

but also for wearing to the office, to work.

If you’d like to try Roka eyeglasses or sunglasses,

go to Roka, that’s R-O-K-A.com,

and enter the code Huberman

to save 20% off your first order.

Again, that’s Roka, R-O-K-A.com,

enter the code Huberman at checkout.

Today’s episode is also brought to us by HVMN Ketone IQ.

Ketone IQ is a ketone supplement

that increases blood ketones.

Almost everybody has heard of the so-called ketogenic diet.

Most people, including myself,

do not follow a ketogenic diet.

That does not, however, mean

that ketones cannot be valuable

because ketones are one of the primary sources

of brain fuel and body fuel

that allows us to think clearly for long durations of time

and to perform well physically,

which is all to say that even if you’re somebody

who’s not on a ketogenic diet, such as myself,

increasing your blood ketones can be immensely beneficial

for cognitive and physical performance.

Indeed, that’s how I use ketone IQ.

I’ll take one or two servings per day typically,

sometimes before a workout,

but most typically before doing a bout of cognitive work.

So I’m going to sit down and prepare a podcast

or focus on research for my lab or a writing project

or anything that requires a high degree of concentration

for a prolonged period of time.

Ingesting ketone IQ prior to that,

I’ve noticed greatly increases my level of concentration

and I can sustain that concentration

for much longer periods of time

than if I don’t take ketone IQ.

If you’d like to try ketone IQ,

you can go to hvmn.com slash Huberman to save 20% off.

Again, that’s hvmn.com slash Huberman.

Today’s episode is also brought to us by Eight Sleep.

Eight Sleep makes smart mattress covers

with cooling, heating, and sleep tracking capacity.

So I’ve talked about many times before on the podcast,

there’s a critical relationship

between sleep and temperature

and indeed between waking up and temperature.

That is your body temperature needs to decrease

by about one to three degrees

in order for you to fall and stay deeply asleep at night.

And when you wake up in the morning,

in order to do that feeling refreshed,

your body temperature actually needs to increase

by about one to three degrees.

So it’s critical that you control the temperature

of your sleeping environment

and that that temperature be controlled very specifically

across the night and into the morning.

With Eight Sleep mattress covers,

that’s all extremely easy to do.

You can program the temperature of your mattress

in the beginning, middle, and throughout the night,

and when you wake up.

I’ve been sleeping on an Eight Sleep mattress cover

for over a year now,

and it has greatly improved the quality of my sleep.

And indeed, I know that because Eight Sleep

also includes a terrific sleep tracker

built directly into that mattress cover.

If you’d like to try Eight Sleep,

you can go to eightsleep.com slash Huberman

to save $150 off their pod three cover.

Eight Sleep currently ships in the USA, Canada, UK,

select countries in the EU and Australia.

Again, that’s eightsleep.com slash Huberman.

And now for my discussion with Dr. Oded Rahavi.

Oded, thank you so much for being here.

Totally my pleasure.

Yeah, this podcast has a somewhat unusual origin

because I am familiar with your work,

but we essentially met on Twitter,

where you are known for many things,

but lately, especially, 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,

you 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 assume,

that their children would somehow be better at architecture

because they contain the knowledge

through the DNA of their parents.

They might be exposed to it in the home,

so-called nature nurture, that’s a nurture in that case,

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?

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 is called the genome,

and this is present in every cell of our body,

the same set of instructions.

And genes are made of DNA,

and they also contain, and chromosomes,

they are containing chromosomes.

Chromosomes is the DNA and the proteins

that condense the DNA,

because we have a huge amount of DNA in every cell

that you need to condense it to.

Sort of like thread on a spool.

Right, huge amounts that you have to condense.

And we have the same genome,

the same DNA in every cell in our body.

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.

No, it is amazing.

It is amazing.

And perhaps it’s good to have an analogy

to understand how it works.

So this is, I hope this is not a commercial,

but this is like the Ikea book

that you have in every cell in your body,

the instructions to make everything

that you need in your house,

the chairs, the 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, okay.

And in the toilet, you put it 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

for make one particular furniture, and this is the RNA.

This is the RNA, this is the set.

And then the end, you’ll build a chair,

the chair is the protein.

So the DNA, the RNA are 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.

I think it’s a beautiful description,

and IKEA is not a sponsor of the podcast,

so it’s totally fair game to use the IKEA catalog

as the analogy for DNA, the specific instructions

for specific pieces of furniture is the RNA,

and the furniture pieces being the proteins

that are essentially made from RNA using messenger RNA.

Okay, thank you for that.

So despite the fact that the same genes

are contained in all the cells of the body,

there is a difference between certain cell types, right?

I would say, is it fair to say

that there’s basically one very important exception,

which is somatic cells versus germ cells?

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

Sure, so yes, every cell type is different

because it expresses, it brings into action

different genes from the entire collection,

and assumes an identity.

And so we have cells in the legs,

we have cells in the brain,

we have cells that produce dopamine,

cells that produce serotonin, and so on.

And we can make different separations,

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 it’s thought to be one of the main barriers

for the inheritance of acquired traits,

the inheritance of memory, and so on,

because for example, like the example that you gave

with learning architecture,

if I learn about architecture,

the information is encoded in my brain,

and since my brain cells can’t transfer information

to the sperm and the egg,

because the information’s supposed to reside

in synaptic connections between different neurons

in particular circuits 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,

it won’t, this short out 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 of particular brain cells,

it wouldn’t matter because this mutation,

there’s no way to transfer it to the DNA of the germ cells

that will contribute to the next generation.

So despite that, there is, as you will tell us,

some evidence for inheritance of experience, let’s call it.

Or, and here we have to be careful with the language,

right, 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 like offensive even to certain people,

this idea of inheritance of acquired traits.

The idea that one could change themselves

through some activity, use the example of going to the gym,

we could also use the example of somebody

who becomes an endurance runner,

then decides to have children

with 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?

We have to be very careful, as you said,

and there are many complications and many ambiguities.

And maybe you could tell us why Lamarckian evolution,

for those that don’t know, is such a stained thing.

It’s not polite.

Right, perhaps we’ll start with just to 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 goes a long time back,

even way before Lamarck.

So even the Greeks talked about inheritance of acquired traits.

Lamarck is associated with the term,

but it’s probably a mistake,

although everyone talks about it,

including people who studied.

So Lamarck worked, he published his book

about a little more than 200 years ago.

And he believed in inheritance of acquired traits,

absolutely, but just like anyone else in his time,

just everyone believed in it.

It seemed obvious to them that 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.

Really?

Yes, absolutely.

All right.

Now we’re getting into the meat of it.

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 can explain everything

based on Aristotelian fluids, earth, wind, fire, and water.

There’s still some people on the internet

that think they can discard with chemistry

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

And this wasn’t only biology.

It was also the weather and everything.

So that was part of the reason.

But Lamarck, so Lamarck made many mistakes,

but he did have a full theory 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 you do.

We talked about use and disuse of certain organs

that shape our organs

and eventually also the organs of the next generation.

He sounds a little bit like

the first self-help public figure, right?

Well, this idea, I 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, and 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 then that will forever change the offspring,

either because of nature or nurture.

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,

that you’re helping or dis-helping yourself.

The problem is when you apply it 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 progresses.

And later, Darwin showed that it’s really natural selection,

the selecting of the people, of the organisms

that already contain the particular qualities

are selected based on whether they survive

or not in particular environments.

And therefore, the evolution progresses.

They become more common and take over.

This is very different, two different explanations.

The most common way this is contrasted

is the neck of the giraffes.

This is the classic example.

According to Lamarck, the giraffes had to stretch

their necks towards the trees to eat

when the trees were high.

And because of that, they transmitted these traits,

long necks to their children who also had long necks.

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

because 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,

he 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 quiet traits.

There are many reasons why Lamarckism

and inheritance for quiet traits became such a bad term.

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

Under Stalin, there was a scientist called Lysenko

who thought that Mendelianism, 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 was also crazy stories around

and attempts to prove the inheritance of quiet traits.

Despite the realization of many scientists,

this is something that is very rare

or that normally doesn’t happen.

It is not a normal way that inheritance works.

And I can tell you about two such dramatic cases

that will illustrate it.

Yeah, please.

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 Kessler 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 the morphology and appearance changes.

The toads that live underwater

develop these nupital pads,

these black pads on their hands

that allow the males to grab onto the female

without slipping.

Formating.

Formating.

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 nupital pads on their heads.

With this discovery, he traveled the world,

became very famous.

And 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,

and 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 happened is that they found

that he injected ink to the toads

to make them become black, to have these nupital pads.

So he faked the results.

And he couldn’t stand up with the accusations

and killed himself.

Wow.

In this book by Kessler,

it’s just maybe it was the assistant who did it.

Who killed him?

No, no.

Who injected it to sort of save him

because the samples lost the coloring or something.

So it might be, who knows what happened.

Well, in science, whenever there’s a fraud accusation

or controversy, it’s not uncommon

to see a passing of responsibility.

Right.

There are recent cases, there are ongoing cases now

where it’s a question of who did what, et cetera.

Actually, I have two questions 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?

So he traveled with the samples.

I see.

And I’m basing this on this Kessler book,

which is on its own very controversial.

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

But according to the story there,

he had to stand in one side of the lecture hall

with his hands behind the back

while others would examine the samples

and pass them around and so on.

But he cheated.

Someone cheated.

He probably did it.

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.

Interesting.

This is just a point about replication.

And actually another tragic example,

not but a few years ago, Sakai,

who was, 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 Sakai killed himself.

This was only about five, 10 years ago.

So it still happens.

Yeah, it happens.

I think it’s rare, but it does happen,

especially in this very high profile situation.

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.

I totally agree.

And I think that even when people are wrong,

it’s mostly not because they’re evil

and trying to act,

like maybe they really want to believe the results,

or there are all kinds of ways to be wrong

and even to bend 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.

Well, why else would you go into it?

Because it’s certainly not a profession to go into

if you want to get rich.

It’s not the money.

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 it.

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?

This is slightly before,

the controversy broke out after the First World War.

Okay, great.

So Kammerer is gone, his toads with their either ink

or whatever, nupital pads,

they have to go back to mating on land.

Yeah, okay.

I’d like to take a quick break

and acknowledge one of our sponsors, Athletic Greens.

Athletic Greens now called AG1

is a vitamin mineral probiotic drink

that covers all of your foundational nutritional needs.

I’ve been taking Athletic Greens since 2012.

So I’m delighted that they’re sponsoring the podcast.

The reason I started taking Athletic Greens

and the reason I still take Athletic Greens

once or usually twice a day

is that it gets me the probiotics that I need for gut health,

our gut is very important.

It’s populated by gut microbiota

that communicate with the brain, the immune system,

and basically all the biological systems of our body

to strongly impact our immediate and long-term health.

And those probiotics in Athletic Greens are optimal

and vital for microbiotic health.

In addition, Athletic Greens contains a number

of adaptogens, vitamins, and minerals that make sure

that all of my foundational nutritional needs are met.

And it tastes great.

If you’d like to try Athletic Greens,

you can go to athleticgreens.com slash Huberman,

and they’ll give you five free travel packs

that make it really easy to mix up Athletic Greens

while you’re on the road, in the car, on the plane, et cetera.

And they’ll give you a year’s supply of vitamin D3K2.

Again, that’s athleticgreens.com slash Huberman

to get the five free travel packs

and the year’s supply of vitamin D3K2.

So this is, forget about that,

we also had the Lysenko episode,

you know, that’s a very big thing.

And then in the U.S., there was, in the 70s and 80s,

a researcher named McConnell,

who did very different experiments,

and he was also a character.

He worked on, so he was a 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 and things like that.

So he started his own journal?

Yes.

That’s one way to publish a lot.

But they also published in very respected journals,

in parallel.

But he was a psychologist, American psychologist,

and he worked on a worm, a flatworm,

which is called planaria, which is very interesting.

This is different than what we’ll discuss today,

different type of worm.

You know, worms are very common.

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

Really?

Yes, numerically, it’s just count the individuals.

So we are the exception.

And so, 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,

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 an 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 would just tear itself apart

from the tail, grow a new, the head will grow a new tail,

the tail will grow a new head.

You can even cut them to 200 pieces,

each piece will grow into a new worm.

Wow.

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 all,

I don’t remember exactly what he did,

I think it was either lights or electricity with-

Shock them, I think.

Shock them with other things,

and he could train them to learn

and remember particular things.

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

Exactly.

And then avoid that side of the tank.

Yes.

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.

Right.

So without ever being exposed to shock,

or whether the new generation, the new heads,

will be able to learn faster.

That’s another, the subtlety that you might have, 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, 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.

This sounds-

It’s a dramatic field.

Yeah.

And by the way, this opened the field.

So people did experiments, then not only in planaria,

but in goldfish and certain rodents,

and did these memory brain transfer assays,

implanting brain, and this is in the,

back when they had an idea

that some memories could be moleculars,

could have a molecular form, which is very appealing.

It’s almost like science fiction.

You could 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 can replicate anything.

It was a big mess.

Although there were always scientists who said,

yes, we can replicate this and this.

So they were in the background, okay.

McConnell’s stuff was different.

Again, people thought that they couldn’t,

that there are problems replicating,

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

but it wasn’t necessarily about replicating the whole thing.

But the question was,

did the memory that transfer is specific,

or is it an overall sensitization that transmits, and so on.

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.

Or even more than that,

even just a hypersensitivity in general,

you’re more vigilant and you’ll learn anything so fast.

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, his 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, Tal Shomrat,

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.

Really? Yes.

And they don’t open packages in that laboratory.

They have interesting stories.

You should have Mike over.

Yeah, I’m familiar with a bit of his work.

I didn’t realize they had done that experiment.

They published it, yeah, 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 animal that learns

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 transmit 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.

No, this is true.

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 was a Star Trek episode about it from 84.

There are comics books about it, books about it.

So this was very, and people were eating RNA

because they thought that there was RNA in memory.

This was of course complete nonsense.

But this was, 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 the inheritance of memory

or inheritance of acquired traits in other organisms,

in mammals, in humans.

And aside from the dark clouds 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.

Right, the somatic cells,

they can change in response to experience,

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

That’s the idea.

Or they are isolated from what happens in the soma.

The man who first thought about this barrier

is called 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 transmitting from it

to the next generation.

And this is also called the second law of biology.

So this is very, very fundamental.

So natural selection is the first one,

this is the second one,

because it’s so important to how 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 barrier suggests,

but this is not how most people remember it.

Okay, but he thought that this is unnecessary.

It’s possible that natural selection can explain everything.

And he compared 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 rich in some organisms.

We’ll go into that in a second.

The other barrier is the,

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 field.

The word itself,

that the term was defined in the 40s

by Weddington, Conrad Weddington,

and he talked about the interaction between genes

and their products that in the end

bring about the phenotype, or 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, the DNA is built out of four basic elements.

These are the AT, G, and C, right?

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 this information

in the modification of the basis.

The most common modification

that has been studied more than others

is modification of the letter C of cytosine,

methylation, the addition of a methyl group to this C.

And this can be replicated,

so after the DNA, the cells divide

and replicate their genetic material.

In certain cases also, these chemical modifications

can be added on and replicate and be preserved.

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, D,

but could we imagine that through things like methylation,

it’s sort of like taking the primary colors

and adding, changing one of them a little bit,

changing the hue just slightly,

which then opens up an enormous number

of new options of colored integration?

Absolutely, 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.

Even serotonin, the serotonination of histones.

Serotonin.

Right, this is a new paper from Nature

from a few years ago.

Can change DNA.

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

Essentially how, in the analogy I used before,

of how the thread is wrapped around the spool, essentially.

Yes, and 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.

And again, to just frame this up so we can imagine

two identical twins, so-called monozygotic twins.

We can 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, et cetera.

And there is the possibility through epigenetic mechanisms

that through methylation, acetylation,

serotonin production, et cetera,

that the expression of certain genes in one of the twins

could be amplified relative to the other, correct?

So we know that even totally identical twins,

genetically they’re identical,

but they look different and they are different.

We experience, 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 whole, there’s a lot of machinery

that is responsible for making genes function.

So we are a combination of our genetic material

and the environment, okay?

So when people talk about epigenetics

and 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 again, 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 information

and which molecules can do it?

And I actually think that the most interesting players today

are RNA molecules, okay?

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.

So the idea, if I understand correctly,

is that there’s some advantage to wiping the slate clean

and returning to the original plant.

In the context of the IKEA furniture analogy,

the instruction book is the one that’s issued to everybody,

okay, or every cell, right?

Only certain instructions are used for certain cells,

say a skin cell or a neuron or a liver cell

or any other cell for that matter.

Through the course of the lifespan of the organism,

those specific instructions are adjusted somewhat.

Okay, so maybe 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 that mates with another organism,

that needs to be replicated,

and so the idea is to take the instruction book,

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 book.

Because if you want to bring back the instruction book,

you want it to have all the potential

to make all the furnitures.

You don’t want it to be restricted

to the ones that you made in the particular room.

So it’s essentially the opposite of acquired traits

and characteristics based on your,

what we say in biology, geek speak, lineage-based experience

but what your parents experienced, right?

In some ways, we want to eliminate all that

and go back to just the genes they provided.

Yes, but it’s more complicated than that.

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 phenomena.

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.

And then, so every gene is represented twice.

These are called alleles, the different versions

of the genes.

And the thought is that once you, 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, right?

There are some situations where it does matter.

There is a limited number of genes

that are called imprinting genes,

where it does matter whether you inherit it

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.

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.

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.

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, quote unquote,

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.

But it’s important to know that in this situation,

the environment played no role.

This was just whether it passed to 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.

People are, 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 horse.

And so this is epigenetic inheritance.

No, it could be just genetically determined.

Yes, this horse inherited a different set

of genetic instructions.

So it is different.

It doesn’t have to be about epigenetics.

Epigenetic inheritance means

that the environment of the parents

somehow changed the children.

And there are these two main barriers

that are serious bottlenecks

that we have to think 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.

Not a small number.

Not a small number, but perhaps, perhaps.

This is one possibility.

The other possibility 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 mammals in general,

there are many examples for 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 nurture from nurture.

And second, because the mechanism is just not understood.

So there are classic examples.

For in humans, there were periods of famine,

starvation in different places in the world.

In the Netherlands, in China, in Russia,

where people did huge epidemiological study

to study the next generation,

and saw that the children of women

who were starved during pregnancy are different.

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.

Is there ever an instance of which starvation

or hardship of some kind, some challenge,

sensory challenge, or survival-based challenge

led to adaptive traits?

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 work of Isabelle Mansui 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.

So the threshold for stress is higher.

Yes.

I think they have memory deficits

and other metabolic problems.

Which may be an advantage for dealing with stress.

Could be.

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.

Another example is that nicotine exposure.

This is, I think, the work of Oliver Handel

from UMass.

If I’m not mistaken, these are not my studies,

but they improved the tolerance to exposure

to similar drugs in the next generation.

The interesting thing here is that it’s very nonspecific.

So you treat them with nicotine,

but then in the next generation,

they are more tolerant to nicotine,

but also to other things, cocaine.

That sort of makes sense to me,

because obviously nicotine activates the cholinergic system,

the dopaminergic system, epinephrine, et cetera.

And you can imagine that there’s crossover,

because other drugs like cocaine and amphetamine

mainly target the catecholamines,

the dopamine and norepinephrine.

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.

Wow.

So it’s something more about clearance of xenobiotics

and hepatic functions that is transmitted

and is very nonspecific.

What I love about all the examples you’ve given today,

and 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?

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.

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 to show 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 there could be, it’s not necessarily a good thing.

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 they castrated,

the males self-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 wore the same sneakers,

but then they also all committed suicide

right as the Hale-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 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, et cetera.

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,

a Great Dane versus a Chihuahua, for instance.

So there is some like sort of shards of truths

in all of these things.

But it seems to me that the real question is like,

what is the real mechanism

and why would something like this exist?

Right.

And why questions are very dangerous in biology, right?

Right, but very interesting also.

And so 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.

Many of the, sometimes the effects contrast

depending on the way you do this.

And again, these are none of,

we don’t do any of that in mammals,

but people show that you’re 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 has to go

through the oocyte 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 this famous starvation studies,

that 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.

It doesn’t require necessarily new biology

and new biology of inheritance.

Not only is the embryo affected,

the embryo while in utero already has germ cells.

So it’s also the next generation, so it’s directly exposed.

And you don’t need any new biology necessarily

to explain it.

And it doesn’t have has to involve epigenetics

or epigenetics.

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 exists.

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?

So I’m not an expert, so I don’t wanna go into the details

of exactly when in mammals,

but yes, exposure of the mother also affect

eventually the transmission of the father,

of genetic information for the sperm’s father.

And there are also many examples

of just stressing the fathers,

affecting the sperm and affecting the next generation.

There, if you go to the F2 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

in 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 IVS, in vitro fertilization,

or transfer of embryos to make sure

that you actually, it’s the heritable information

and not the environment or that it goes through the germline.

So this is something that is being done now.

There are studies-

You’re talking about the three parent IVF

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

and they take the DNA from mom

and put it into a novel cytoplasm or-

No, not at all.

You just take the sperm and transfer it

and fertilize an egg.

So standard IVF.

Yes, 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 nature.

The environment becomes the culture dish.

Yes.

So the field is improving.

People do experiments that have a higher end,

so more replicates and better controlled.

And there are some examples for effects that transfer.

And it depends who you ask,

whether people believe it or not.

Many geneticists do not believe it.

And many people do believe it.

And it depends on the community.

There are strong resistance for many reasons.

Some of them are justified,

some less justified and are part of the scientific process

and how things work.

Because it’s a new, it’s challenging the dogma.

So this is very interesting on its own.

If you ask psychologists,

many psychologists believe that there’s heritable trauma

and things like that.

Population geneticists, less so.

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 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, 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.

So 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,

there’s people really want to believe it.

People really want to believe it

because it sort of gives your life meaning.

If you can change your biology through changing,

of 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 talked 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.

It doesn’t matter.

You can’t influence it.

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

but you can’t biologically influence it.

You can also, 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 the data tell us.

We had David Boss 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, et cetera.

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 the idea

that if we were to have offspring with somebody,

that those traits would be selected for.

Right.

And we actually have work on that in nematodes

that I’ll be happy to tell you about in a second

after we-

The dating and the dating.

The dating in worms.

Fantastic.

And where we understand the mechanism

and we’ll go into that in a second,

but 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,

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, but-

Neither am I.

But 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 who might also stick around

or be honest in 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, fascinating area of biology.

Yeah.

Yeah, 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

for 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 generation

took center stage.

So I think this is the cutting edge,

and a lot more to understand than know,

but RNA has a lot of potential for doing that,

as we’ll explain soon, but we have to go to worms first.

I’d like to just take a brief moment

and thank one of our podcast sponsors,

which is InsideTracker.

InsideTracker is a personalized nutrition platform

that analyzes data from your blood and DNA

to help you better understand your body

and help you reach your health goals.

I’ve long been a believer in getting regular blood work done

for the simple reason that blood work

is the only way that you can monitor the markers,

such as hormone markers, lipids, metabolic factors,

et cetera, that impact your immediate and long-term health.

One major challenge with blood work, however,

is that most of the time it does not come back

with any information about what to do

in order to move the values for hormones, metabolic factors,

lipids, et cetera, into the ranges that you want.

With InsideTracker, changing those values

becomes very straightforward

because it has a personalized dashboard that you can use

to address the nutrition-based, behavior-based,

supplement-based approaches that you can use

in order to move those values into the ranges

that are optimal for you, your vitality,

and your longevity.

InsideTracker now includes a measurement

of apolipoprotein B, so-called ApoB,

in their ultimate plan.

ApoB is a key marker of cardiovascular health,

and therefore there’s extreme value

to knowing your ApoB levels.

If you’d like to try InsideTracker,

you can go to insidetracker.com slash Huberman

to get 20% off any of InsideTracker’s plans.

Again, that’s insidetracker.com slash Huberman

to get 20% off.

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 it, 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, et cetera,

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.

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.

The model organisms mean that it’s an organism

that many people work on.

So there’s a community of people that work on.

People 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

and 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 nematodes.

This is what we study in the lab.

Fish, which are called zebrafish.

It’s a particular-

Right.

And of course there are also model organisms and mouse.

And also plants, important plants.

The most studies, one is the Arabidopsis.

Yeah, and perhaps less so nowadays, but non-human primates,

macaque monkeys, marmoset, squirrel monkeys, mainly.

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

that have different advantages that serve us.

They sometimes have some things

that are much more apparent in them that we can study.

For example, learning and memory was largely studied

in the beginning in a snail, a plesia,

where many of the discoveries were made

because it has big neurons that you can easily study

and examine.

And yes, snails learn.

Yes, they learn.

Even C. elegans, these nematodes that we study learn,

and they are much simpler than most.

Another important reason to study them, of course,

is you can 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 for them.

And in some, 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 you can, 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.

Yes, so C. elegans, this is the star now of what,

and this is what we study.

These are nematodes, small worms, round worms,

that are just one millimeter long.

So you can’t see them with the naked eye.

You have to look under the scope.

Where do they live in the natural world?

So they used to call them soil nematodes,

but this is not really true.

They are in many places,

but they’re mostly in rotten fruits and leaves.

And you can find them in the ground as well,

but you can also find them,

and they’re 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.

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.

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 wire pick,

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 have always a certain number of cells in the body.

So a coelacanth nematode always has 959 cells in its body.

That’s it, okay?

960, not 958.

959, okay?

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 mean, I don’t want to get into trouble, okay?

But people take this very, very hard.

I think it’s 302, but let’s not get into it

because I’ll get into trouble.

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.

Perfect.

So, and it’s always the same.

And each neuron has a name, like you said.

And not only does every neuron has 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, okay?

It was used to think, people thought that it was

exactly the same between genetically identical neurons.

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.

The so-called connectome.

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 silent 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.

And 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.

This is, coelacanth is the first animal

to have its genome sequenced before humans.

Before that, of course, there were bacteria,

and we know that each worm produces,

each mother produces about 250 babies,

which are almost genetically identical.

So we can, 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.

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

You know, 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 in 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, I mean,

that can extend the time to do experiments

out three or four years

compared to what you could do in C. elegans.

You’re absolutely right.

This 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.

And the worms probably don’t mind

living on these agar plates,

you know, munching away on E. coli where-

It’s the good life.

You know, it’s questionable whether or not mice or,

certainly, listen, I’m a proponent of well-controlled over,

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.

You know, 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.

Right, I also think that this is important,

but for me, it’s much easier to work on worms.

I don’t have to, you know, feel bad about it.

Yeah, they’re happy.

They’re happy, and you also, I mean, if a worm dies,

it’s less painful to the human

than if other more sensitive animals.

Yeah, I would argue, yes, I agree, yeah.

So, yes, 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.

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 you have to be,

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?

The first experiment I did was when I, in my postdoc,

which I did with Oliver Hobart in University of Columbia.

We set to test whether worms can produce

transgenerational, multiple generation resistance to viruses.

Wow, this is a very pertinent topic.

Which is relevant.

And worms, 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 C. elegans, 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 regulate genes

that happens for small RNAs.

What they’ve shown is that if you inject the worms

with RNA molecules, which are double-stranded,

they lead to the site to, they shut off the genes

that correspond, that match in sequence to this RNA.

So it’s sort of like taking the specific instructions

for the coffee table from your Ikea handbook

and you insert a copy of that into the book.

And in doing so, you prevent the expression of,

you sort of erase the original page.

Perfect explanation, perfect explanation.

And they found that double-stranded RNA,

RNA that has two strands, is what starts the response,

leading to the production of small RNA molecules,

which are the ones that actually find the messenger RNA

and leads to its destruction.

Silence it so you don’t get proteins in the end.

For that, they got the Nobel Prize

after people found that this is conserved

in many organisms, including humans.

And now there are now drugs,

this was only in 2006, the Nobel Prize,

the paper was published in 98.

There are now drugs that use this mechanism,

also in humans.

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 me to interject.

Yeah, incredible scientists.

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 the function.

Already in the first paper that they published about this,

where they’ve shown the double-stranded RNAs

which leads to the silencing or the control,

they’ve shown two very important things.

One of them is that if you inject the worms

with double-stranded 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-stranded RNA

just to somatic cells, even to the head,

you will get also the effect in the germ cells

and in the next generation,

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-stranded RNA.

And that 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 this 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.

Okay, so 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 sign in just throughout the body.

Wild.

Okay, and this is what we do routinely.

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 is to neutralize the gene activity.

And we do it by just introducing the worms

with double-stranded RNA that correspond in sequence,

that match in sequence this gene.

This will lead to the silencing,

this activate the genes 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-stranded 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.

Is it fair to say that McConnell’s experiments

of chop blending up these worms,

the 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?

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 Fio and Melo did these experiments.

Some other people did these experiments.

When I started my work,

I wanted to see whether in addition

to artificial double-stranded RNA,

some natural traits can also transmit across generations

because of RNA, because of small RNAs.

Right, because injecting RNAi

or shorter-interfering RNAs, that is,

or putting worms into an environment

with an abundance of inhibitory RNAs

as an experiment is very different

than worms experiencing something

and then passing on that acquired trait

to their offspring.

It’s a world apart, in my opinion,

because one is an extreme manipulation

that illustrates an underlying principle.

The other is something that, in theory,

occurs in the passage of generations just naturally.

We’re going from the less artificial

to the more artificial.

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 trait.

What I did was, in Oliver’s lab,

is to see whether the magic,

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, okay?

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 worms just turns green.

And if the virus is destroyed, the worm stays black.

This is very simple.

It’s a clear cutoff.

It’s not this, you don’t examine the worm

and ask whether it feels good.

You just see this green light.

Binary response.

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

when we infect 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, 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.

Right.

And we know exactly what this advantage is.

The advantages are small RNAs that match the viral genome

and just chop up the 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 inherit it.

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 inherit these small RNAs

only if their parents were infected with them.

So there’s specificity there.

There’s specificity.

Yeah, it’s not some just general resilience passage.

Right.

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, resilience to stress.

I could imagine why that would be advantageous, right?

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, et cetera.

And I always say, you know, 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 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.

Right, and it is true that also in mammals,

now RNAs and small RNAs are a lending candidate

for something that could mediate

the transmission of stress protection

or also harmful effects that transmit between generations.

Perhaps RNA do it.

However, in worms, the RNAs have one more trick

that we don’t know the equivalent in mammals yet.

This is something very crucial

that we showed in that particular paper

Which is?

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.

So it gets passed.

It gets passed, and you have to ask yourself,

how doesn’t it get diluted?

Why isn’t it diluted, right?

Because, I mean, 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, okay?

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, okay?

This is called RNA-dependent RNA polymerase.

It’s a complex which uses the RNA to find,

and once it finds the messenger RNA,

it just creates many, many, many, many smaller RNAs.

So they don’t get diluted,

and they pass on for additional generations, okay?

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.

What sorts of genes are those?

So we call these genes MOTEC genes.

MOTEC, I don’t know how is your Hebrew,

but MOTEC, it means sweetheart in Hebrew.

But the acronym is Modified Transgenerational

Epigenetic Kinetics.

There are different types of genes like that.

And 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

from just, you don’t wanna 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.

There are, what type of genes are they?

One gene that we studied, it’s called MET2.

It’s actually a gene that functions in methylation

of the proteins that condense the DNA.

So this is, but then there are other genes

that affect also production of smaller RNAs.

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.

I 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 the 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 turn of the previous century

or the turn of the previous century,

different stressors, 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?

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.

Which itself is amazing.

I just want to highlight that.

I mean, you can imagine next generation

is 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.

Yeah, so I have to just make a disclaim

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 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 harsher starvation.

This sounds, 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 that don’t inherit, 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 offsprings are different.

They change how they mate.

It’s what I alluded to before.

We’re gonna get back to this

because it relates to cold exposure,

which many listeners are interested in.

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-stranded 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.

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 why people,

why the disbelievers, it’s not about faith.

The critics say that this wouldn’t happen in humans

is 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 it,

plus they can go very far, they’re small.

There are many examples of epigenetic inheritance in plants.

This is a big field where there are very established proof

for inheritance of acquired traits,

for epigenetic inheritance.

Be more careful, epigenetic inheritance

requires more loaded time.

But in plants, it also happens.

And then you also say these are sessile organisms,

they can’t run away, so the environment is more constant.

Well, ideas, maybe just a quick example

that I’ve heard before, tell me if I’m wrong.

I very well may be.

For instance, a particular species of plant

that grows a straight, maybe slightly bended 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 several generations.

This is an example that I don’t know,

but perhaps it-

Something like that.

I seem to, someone will tell, 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.

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 off 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 experienced.

However, this, in my opinion, this argument comes 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 them.

Again, I’m not saying that it happens,

but it depends on the scale.

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 on toe-to-toe

with those critics now and say that,

at least in terms of an inheritance of reactions

or adaptive or maladaptive traits to stress or to reward.

You talked about nicotine before,

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, you know, 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 the 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 where 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.

Right, so I agree.

And this opens the question

of what is the bandwidth of inheritance?

How specific can it be

that it makes 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, okay?

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, Noah, I said this disclaimer multiple times,

in mammals, we don’t know, times will tell.

In worms, we know a lot.

So can worms transmit brain activity to,

do they have the specificity to do it, okay?

Before I say that, I 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, it 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 generation?

I think that, first of all,

we need to define memory for this.

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.

Then 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 how, somehow,

the fate of your next generation using your brain,

after taking many things into the code.

This is the most-

Without talking to them.

Right, without talking to them.

And instruction, so it’s, again,

we go back to this instruction manual.

It’s like writing something into the instruction manual

based on your own experience.

Right, and can it happen?

Okay, 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,

hypervigilant, something like this, okay?

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 connection between different neurons.

When you learn something,

you make some connections stronger

and other connections weaker,

and you wire the nervous system in a different way.

The information in the brain is synaptic,

and it is in the connections.

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, they’re 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?

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, et cetera,

and divisions between states,

and you transfer that to an electronic map

or a piece of paper.

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 irritated

with 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 for them-

Absolutely no.

No, 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 A, B, C, D

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 the transformation of one set of points

in physical space to a translation of points

in genetic space.

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 partially random

and it depends on the environment,

even if you have the same genetic instructions.

So let’s say you somehow had a mechanism,

a miracle mechanism to take the 3D information

and translate it 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, okay?

Because-

I believe it.

I’m easy to trick, so that’s good.

But if this is how it happens, 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 is complex.

And things that you learn about the environment

that are arbitrary.

If I, none of our listeners’ kids

will remember this conversation.

No way.

This is impossible.

Unless they’re listening with them.

There are some families or parents

that tell me they listen.

Right, right, but it cannot transmit

because it’s random and it’s,

these are connections that are arbitrary.

So this seems to be a limitation of what can transfer.

On the other hand, so perhaps more general things

could pass, some, these type 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, many molecules.

They can smell them so they can find food

or avoid enemies.

You can take a food that the worms,

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 in 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

when they, and this is how they learn.

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 showed it convincingly,

transmit to the next generation because

all it would take is an RNA that will

control this particular receptor, okay?

So this is a possibility.

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,

that’s 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 need 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 certain, 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 showed 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 is called SAGE2.

Don’t know how it works,

but we can do all kinds of controls

where we manipulate the 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.

So it has to be RNA.

It has to be RNA.

We can also find the RNAs in the next generation

that change.

We sequence the actual RNAs that change

in the next generation.

You mentioned that you don’t know what 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?

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?

Well, it would have to change the germ cells

in very specific ways, because as people probably recall,

the germline, the 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, right?

Right, and 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?

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.

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.

And for example, in mammals, one of the explanations

for how heritable information transmits

is that it just affects something very early 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.

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

to pass to offspring, right?

Of course, you explained 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.

The growth of, it’s not just about the growth

of the hair and the jaw and the atoms,

apple and breasts and so on.

It’s a transformation of the somatic cells

from the same microenvironment

that the DNA-containing cells reside.

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.

And in a castrated dog, you’re not just eliminating

the possibility of transfer of DNA information

to subsequent generations.

You’re also limiting communication of, yeah.

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.

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.

Let’s, 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.

So the worms are hermaphrodites,

which means that they make both sperm and eggs.

But there are also males, which are much more rare,

and they can choose to mate with the males or not.

And 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.

People are going to draw all sorts of analogies here,

but it’s inevitable, but hey, here we go.

Yes, 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 gene will be good.

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 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 particularly the 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 the inbreeding creates a deleterious mutation.

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, because this is the classic thing.

I talked to some of them, they told me that’s not true,

but yes, there are studies like this that say,

but it makes sense.

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.

Right, right.

So you’re absolutely right.

But the worms, it’s 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.

Ah, that’s a very cryptic mechanism.

It’s not that she somehow changes and then goes seeking

males, it’s that it draws males.

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 hermaphrodite don’t, they make sperm enough

to make next generations, but the sperm,

because of defective small RNA inheritance,

because 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 experiments.

You just take hermaphrodites and you kill its sperm,

starts secreting a pheromone, and the males come.

It’s a need-based system.

Exactly.

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, right?

The hormone is now secreted in greater quantities

or greater frequency.

The males therefore approach more.

So it’s just increasing probability of interactions.

Is that right?

Right.

What happens naturally, normally,

if you don’t stress the ancestors,

is that the worm starts secreting the pheromone

only when they are old.

This is also, you know, people will…

When they’re running out of their own fertility.

Exactly, because they only make the sperm

at a particular time.

And then they run out of stealth sperm.

They can’t self-fertilize,

so they have to call the males.

They want to continue to make.

Well, this is sort of the plastic surgery approach.

Okay, I’ll take the heat for that one.

But, you know, 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.

They could get a…

Here we’re talking about a female,

but we could also do the reverse, right?

If we get a sperm donor, right?

Or, 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.

Right, so here, luckily for me,

I don’t have to get into psychology of the worms.

The explanation is just like an instinct.

When they run out of sperm,

they start secreting the pheromones and attract the males.

There are studies also in humans about older fathers,

that children of older fathers

have a higher chance of becoming autistic.

There are studies-

40 and up, basically.

However, in this case, it’s not clear

that this is something epigenetics could be

just because of DNA damage,

because it accumulates.

Yeah, and actually nowadays,

we have an episode on fertility coming up,

both male and female fertility,

and there are actually DNA fragmentation kits,

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.

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 and et cetera.

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, ah,

but that’s already selecting for people

that might’ve 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,

higher probability of autism,

what does that, at the level of intuition,

does that strike you as an epigenetic phenomenon,

as a nature nurture mishmash,

or the possibility that it’s RNA passage or anything?

Does anything sort of trigger the whiskers,

your spidey sense?

So in that case,

I would go with the most parsimonious explanation,

which is just less fidelity of DNA,

less DNA maintenance and some damage that passes on.

It doesn’t have to be an epigenetic thing.

But the sperm are generated at once every 60 days.

So the damage must be at the level of the germ cells,

not having the proper machinery.

Right.

Mitochondria or something like that?

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.

Do we know exactly what the DNA repair machinery is?

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.

And is it a system that is now tractable,

that can be modified through pharmacology

or through anything like that?

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 these directions.

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,

don’t, even if fertilized, don’t produce healthy embryos.

They have chromosomal abnormalities or 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

for 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.

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.

And 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 generation,

for the children.

However, if you let the rodent exercise,

then it corrects the parent 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.

By eating RNAs just like the worms?

RNA sandwich?

No, so the RNA sandwich will be difficult

because it’s not, I don’t know.

But if you do IVF, if you do vitro fertilization,

you could 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, or again,

in the future, this is science fiction,

it doesn’t happen now, but if we understand this

and it’s true, we can say,

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 just 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.

Yeah.

Yes.

But of course, this is why it’s so interesting.

Yeah, it’s super interesting.

Incredibly promising.

So along the lines of things that one can do

in the short term and your experiments on C. 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.

I’ll gladly tell you about it.

This is not a story about transgenerational inheritance.

It’s a story about memory within one generation.

Ah, excuse me, okay.

Within one generation, okay?

And as you said, the story of how it happens,

it’s totally by accident.

It’s a funny story.

And I’m bringing this up because I know Dana Landshaft

who’s a huge fan of your postdocs

will really, you know, be happy that I mentioned.

This is her work.

And this is unpublished work.

We didn’t even finish it.

So we’re working on it.

Okay, well, when it’s published,

we will feature the paper because I love this story.

So great.

So what happened is that when you,

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, okay?

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 memories that the worms acquired

during their lifetime is very short lived.

So if you teach something, after two hours, it forgets.

So for example, you can teach the worm

that 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 the control odor on 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,

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 such a simple nervous system,

you say, maybe I have the potential

to actually understand how it works.

But this is slightly disappointing

because they forget after two hours.

So what is it exactly, okay?

My idea was, and I tried to convince students

to do it for 10 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 minus 80

and freeze them, freeze them completely,

thaw them and see whether they still remember

after they are thawed.

The Han Solo experiment.

And I didn’t want 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.

Need to reverberate it in the brain.

During dreams or replay of the thing or whatever.

And if the memories will nevertheless be kept,

even though the worms were frozen in minus 80,

it would mean that it was kept in the absence of electricity

because there’s no electricity in minus 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.

Well, and when the PI, the principal investigator

or lab has a pet experiment,

no one wants to do that experiment.

That is true.

That is the university too.

So, and then I agreed to do it, done a land shift.

I was very happy, only later to find out

that she ignored me completely

and did a different experiment.

The experiment that I 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 that-

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 10 times longer than control worms.

At that point, after 24 hours,

if no one wants to forget after two hours,

after 24 hours, the worms will become sick.

So normally we do shorter experiments, okay?

But for two 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 a beautiful work over the last 20 years

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,

five hours is the 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 at any way low,

now they don’t remember.

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.

Notice he said 302, not 300.

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 is being given

to bipolar disorder patients for decades,

although it’s not entirely clear how it works,

it’s very, very interesting.

It’s 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.

So lithium switches this forgetfulness mechanism on and off.

Amazing.

And it’s all connected to cold tolerance.

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 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?

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’d be happy to talk more about it

and think about the implications

and the connections to other things

and more about the mechanism.

Yeah, well, thank you for sharing 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.

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,

and 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.

It’s even, I venture to call it seductive.

You know, there’s a,

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.

Thank you, thank you very much.

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, you know,

I think that can communicate with such articulate precision.

So thank you so much.

Thank you.

It’s been a real pleasure.

Pleasure was all mine.

Thanks a lot.

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.

Thanks a lot.

It’s been a real pleasure.

Thank you for joining me today

for my discussion with Dr. Oded Rakhavi

about genetics, inheritance, the epigenome,

and transgenerational passage of traits.

If you’re learning from and are enjoying the podcast,

please subscribe to our YouTube channel.

That’s a terrific zero-cost way to support us.

In addition, please subscribe to the podcast

on Spotify and Apple.

And on both Spotify and Apple,

you can leave us up to a five-star review.

If you have questions for us, or comments,

or suggestions about topics you’d like us to cover,

or guests you’d like me to include

on the Huberman Lab podcast,

please put those in the comments section on YouTube.

I do read all the comments.

In addition, please check out the sponsors

mentioned at the beginning and throughout today’s episode.

That’s the best way to support this podcast.

Not so much on today’s episode,

but on many previous episodes of the Huberman Lab podcast,

we discuss supplements.

While supplements aren’t necessary for everybody,

many people derive tremendous benefit from them

for things like improving sleep,

improving focus, and for hormone support.

The Huberman Lab podcast is proud to partner

with Momentus Supplements.

We’ve done that for several reasons.

First of all, Momentus Supplements

are the very highest quality.

Also, they tend to focus on single-ingredient formulations,

which makes it very straightforward

to build the most cost-effective

and biologically effective supplement regimen for you.

We’ve also partnered with Momentus

because we realized that many listeners of this podcast

reside outside of the United States,

and fortunately, Momentus ships internationally.

If you’d like to learn more about the supplements

discussed on the Huberman Lab podcast,

you can go to LiveMomentus, spelled O-U-S,

so that’s livemomentus.com slash Huberman.

If you’re not already following us on social media,

please feel free to do so.

We are Huberman Lab on Instagram, Twitter,

Facebook, and LinkedIn.

And at all those places, I cover information,

some of which overlaps with the content

of the Huberman Lab podcast,

but much of which is distinct from content

on the Huberman Lab podcast.

So again, it’s Huberman Lab on all social media channels.

The Huberman Lab podcast

also has a so-called neural network newsletter.

This is a zero-cost monthly newsletter

that consists of podcast summaries and so-called toolkits,

and those toolkits range from things like a toolkit

for sleep, for focus, for controlling dopamine,

deliberate cold exposure,

for increasing focus, and much, much more.

If you want to sign up for that newsletter,

you can go to HubermanLab.com,

go to the menu, scroll down to newsletter.

You simply provide your email,

and I assure you, we do not share your email with anybody.

And again, it’s a completely zero-cost newsletter.

Find it at HubermanLab.com.

Thank you once again for joining me for today’s discussion

with Dr. Oded Rehavi.

And last, but certainly not least,

thank you for your interest in science.

♪♪