Welcome to Huberman Lab Essentials,
where we revisit past episodes for the
most potent and actionable science-based
tools for mental health, physical
health, and performance.
I'm Andrew Huberman, and I'm a professor
of neurobiology and opthalmology at
Stanford School of Medicine. And now for
my discussion with Dr. Oded Rakavi.
Oded, thank you so much for being here.
>> Totally my pleasure. Today, what I
mainly want to talk about is the
incredible questions that you probe in
your lab, which are incredibly
significant for each and all of our
lives. 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 they their offspring
will have blue eyes than brown eyesh.
Mhm.
>> But most people generally understand and
accept that if they spend part of their
life um let's say studying architecture
that if they have children that there's
no real genetic reason we assume that
their children would somehow be better
at architecture because they contain the
knowledge through the DNA of their
parents. They might be exposed to it in
the home so-called nature nurture
nurture in that case but that they
wouldn't inherit knowledge. 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 uh certain types of
knowledge at the level of cells and
systems can be inherited.
>> So DNA are the 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. Genes are made of DNA
and chromosomes that 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 um thread on a 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.
It's good to have an analogy to to
understand how it works. This is like
the IKA book that you have in every cell
in your body, the instructions to make
everything that you need in your house,
the chairs, the the kitchen, the
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 instruction of how to build a
chair. H and this you place in the
living room. Okay. And the toilet you
put in the toilet. So the genome the is
the instruction to make everything. This
is the care book. And in every cell we
we take just the instructions for make
one particular furniture. And this is
the RNA. And then the end you'll build a
chair. The chair is the protein. This is
true for one particular type of RNA
which is messenger RNA. And in fact this
is just a small percent of our of the
RNA in the cell. So we have a very big
genome and less than 2% of it 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 to use the IKEA catalog as as the
analogy for DNA. The specific
instructions for specific pieces of
furniture is the RNA and the furniture
pieces being the proteins that are that
are essentially made from RNA using
messenger RNA. Right.
>> Okay. Despite the fact that the same
genes are contained in all the cells of
the body, is it fair to say that there
is basically one very important
exception which is sematic cells versus
germ cells. And would you mind sharing
with us what that distinction is?
>> So yes, every cell every cell type is
different. We have cells in the legs. We
have cells in the brain. We have in the
in the brain we have cells that produce
dopamine, cells that produce serotonin
and so on. But we can make one very
important distinction between the
somatic cells and the germ cells. The
germ cells are supposed to be the only
cells that contribute
to the next generation that out of which
the next generation will be made. So
each of us is made just from a a
combination of a sperm and an egg. These
are two types of germ cells. And then
they fuse and you make you you you get
one fertilized egg and out of this one
cell all the rest of the body will
develop and what happens in the soma
which is which are all the cells that
are not the the germ cells should stay
in the soma should not be able to
contribute to the next generation. This
is very important and is sought to be
one of the main barriers for the
inheritance of acquired traits, the
inheritance of memory and so on because
for example like the example that you
gave in with learning architecture if I
learn about architecture the information
is encoded in my brain and since my
brain cells can't transfer information
to the sperm and the egg because the
information is supposed to reside in
synaptic connections between different
neurons. in particular circuits that
developed. H so what's what what happens
in the brain shouldn't be able to
transfer to the next generation. Even
simpler a simpler example if you go to
the gym and you build up muscles you
know that your kids will will will have
to work out on their own. It won't this
short out won't won't happen. This is
something that we know intuitively even
if we don't have any background in
biology. 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 h
acquire the mutation or a change in your
DNA in one of particular brain cells, it
wouldn't matter because this mutation,
there's no way to transfer it to the DNA
of the of the germ cells that will
contribute to the next generation. There
is this idea and I'll say it so that you
don't have to that dates back to Lamar
and Lamarian evolution very
controversial right um 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
running and not just because they were
biased towards running in the first
place but because they of the distance
they actually ran that their offspring
somehow would be fabulous runners. This
Lamarian 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? Lamak this is what he
believed and and he thought this what is
this is how evolution progress
progressed and and later
um Darvin showed that it's really
natural selection the selecting of the
organisms that already contain the
particular qualities are selected based
on the whether they survive or not in
particular environments and therefore
their um evolution progresses they
become more common and take over. This
is very different two different
explanations. Most common way this is
contrasted is the neck of the giraffes.
This is the classic example. According
to to Lamach, the giraffes had to
stretch their necks towards the trees to
eat when the tree when the trees were
high. And because of that the they
transmitted these traits long necks to
their children who also had long necks.
And according to Darin just that the a
gerat happened to be born with a long
neck survived because it ate. So it's
genetic heritable material. 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
acquired traits. And then we go back to
to to these uh studies about inheritance
of acquired traits. There were also
theoretical problems of why of why this
can't happen barriers that have to be
breached for this to happen. And you can
narrow it down to two main barriers. The
first barrier we mentioned it this is
the separation of the soma from the
germa
>> right the sematic 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
>> okay the man who 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 s from the germ line
only the germ line transmitting
information 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 our
bodies work. The other main barrier it's
called epigenetic reprogramming
which is that we acquired our diff our
cells the the genetic material in our
cells acquires all kinds of chemical
changes but these modifications are
largely erased in the transition between
generations. So in the germ line in the
in the the the sperm and the egg and
also in the early embryo most of 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 actually true because in some
organisms doesn't really happen.
We will just we will not develop
according to the
species typical genetic instructions.
Mhm. So to preserve this we erase all
these modifications that start a new and
this is in in mammals and in humans this
is largely true. Most of the
modifications on the in the sperm and in
the egg are removed. So about 90% of
them.
>> So the idea if I understand correctly is
that there's some advantage uh to wiping
the slate clean and returning to the
original uh plan in 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 cell,
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 the idea is to take the
instruction, but go through and erase
all the pen and pencil marks, erase all
those additional little modifications
that the the owner used or introduced to
it and return to the original
instruction,
>> right? Because if you want to bring back
the instruction book, you want it to
have all the potential to make all the
furniturees. You don't want it to be
restricted to the ones that you made in
the particular room. So, part of the
resistant resistant to the idea is based
on the theoretical grounds because of
these barriers.
And because of the of the controversies
on the other hand, people really want to
believe it because it sorts of gives
your life meaning if you can change your
biology
through changing of of your kids through
changing your biology. So
psychologically I can understand why
many people want this to happen. Even
shreddinger the famous physicist so he
wrote a very important book in 44 and he
talks about the heritable material. also
talks about evolution and he said
inheritance of a quiet trait is
untenable. doesn't happen and it and he
writes this is very very sad or
unfortunate because unlike Darvinism or
natural selection which is gloomy
doesn't matter what you do the next
generation will be born based on the
instruction in this the sperm and the
egg it doesn't m you can't influence it
of course you can give your kids money
and education but you can't biologically
influence it however there's one
additional thing to to mention which is
there are also other mechanisms that
might transmit information including
transmission between generations of RNA
and there are different types of RNA not
just messenger RNA which encodes for the
information for making protein but also
other RNAs that regulate gene expression
and I think that in recent years also in
the malian 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 a lot more to understand
and know but RNA has a lot of potential
for doing that as we'll explain uh soon
but we have to go to worms first. Many
if not most of our listeners are focused
on humans and human biology and health
etc. But I cannot emphasize enough the
importance of model organisms and the
incredible degree to which they've
informed us about human health
especially when it comes to very basic
functions in cells. Before we start to
go into the description about worms per
se, could you just explain to the a
general audience what a model organism
is 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
in humans at some level.
>> Model organisms mean that it's an it's a
an organism. there's a a huge community
of researchers that combine sources to
create all the the resources and the
tools and understanding that
accumulates. We learned about every
aspect of biology through them including
many important diseases. And the reason
that we can learn a lot also about
humans by studying these animals is that
we all evolve from the same ancestor. We
share a lot of our functions with them
and also a lot of our genes. They
sometimes have things that are much more
apparent in them that we can study.
Another important reason to sending them
of course is you can 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. The
community of people that study segance
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 mamalian
model. mouse or certainly in humans and
has posed huge challenges that u give
great advantages to studies of things
like sea elegance.
>> Celigance neatode always has 959 cells
out of which 302 are neurons. We have a
me a conneto since the 80s
like a subway map that tells us which
neuron talks with which other neurons
and it is the same. Not only that, the
worms are transparent. So we can
actually see the neurons fire using
particular tools and we can activate
genes and silage genes using
optogenetics. On top of that we have
great understanding of the genetics of
the worm of of the genome. This is
circans is the first animal to have its
sequ it its genome sequenced before
humans. And we know that and each worm
produces each mother produces about 250
babies which are almost genetically
identical. And we know where we grow
them. The environment is very
controlled. So we grow them in the plate
with just bacteria. So we can easily
separate between nature and nurture. The
generation time in silicance is 3 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.
So you will have that are genetically
identical. So you will have great
statistics for your experiments. In the
worm, we now have very obvious and
clearcut 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.
What was the first experiment that you
did on Celeans that confirmed for you
that inheritance of acquired traits is
real? We said to test whether worms can
produce transgenerational resistance to
viruses. 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 using RNA
that destroy viruses. And these are
called small RNAs. 2006 two researchers
that were studying segance Andrew Fire
and Craig Melo got the Nobel Prize for
showing that there is a mechanism that
regulate genes
that happens through small RNA. What
they've shown is that if you inject the
worms with RNA molecules which are which
are double stranded, they shut off the
genes that match in sequence to this
RNA. So, it's sort of like taking the
specific instructions for the coffee
table from your IKEA uh handbook and you
insert a copy of that into the book and
in doing so you prevent the expression
of uh you sort of erase the original
page.
>> Perfect explanation. They found that
double strand RNA, RNA that has two
strands, is what starts the response
leading to the production of small RNA
molecules which are the ones that
actually find the messenger RNA and
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
there are now drugs this was only in
2006 that the Nobel Prize the paper was
published in 98. There are now drugs
that use this mechanism. It is called
RNA interference. RNA interferes in the
expression of a gene in the in the
function of a gene. And it's al also
called gene silencing because these RNAs
enforce the silencing of genes instead
of the genes being expressed. They are
silenced and you don't manifest their
function. They've shown two very
important things. 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. This includes also the germ
cells. So if you inject the double
strand RNA just to summatic cells, even
to the head, you will get also the
effect in the germ cells and in the next
generation. Later they've shown that you
can just take worms and feed them on
bacteria that produce this double strand
RNA and that the double and the
silencing would move from the site of
injection from the gut where the
bacteria are eaten to the rest of the
body and also to the next generation and
this is not controversial at all. This
is being done routinely every day by any
segance biologist in the world. This is
has been replicated a million times.
When I started my work, I wanted to see
whether in addition to artificial double
strand RNA, some natural traits can can
also transmit across generations because
of RNA because of smallerness,
>> right? because um injecting RNAi or um
in inter short shorter interfering RNAs
that is or um you know 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 and 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 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 easy 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
tradeoff in fact this is probably the
reason that these small evolved in the
first place to get rid of viruses and
other parasitic genomic elements and
this is a mechanism to fight
We demonstrated this very clearly
using a fluorescent virus. 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 cut off. We
took worms, we infect them with a
fluorescent virus, they destroy it. 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 to make these
small. And then we ask what will happen
when we infect these worms with the
vows? 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 RNA from their
pets. 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
science the virus and this also
continues for additional generations.
Okay. So the the parent worms
effectively
put something into the genetic
instructions of the offspring that would
afford them um this 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 the advantages are
small RNAs that match the viral genome
then just chop up the virus in the next
generation and we can identify these
small RNA
in the 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 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 have they inherit in
small RNAs only if their their parents
were infected with them. It is true that
also in mammals RNAs and small RNAs are
a linding candidate for something that
could mediate the transmission of of
stress protection or also of harmful
effects that transmit between
generations perhaps RNA do it and it's
very interesting to think about it when
we talk about inheritance of memories
can brain activity of some sort transmit
at least in these words I said no I I
said this disclaimer multiple times in
in members we don't Now times will tell
in worms we know a lot. H so can worms
transmit brain activity to to do they
have the specificity to do 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 states and can also think
ahead. And the most provocative thing
you can say is that you could plan how
somehow the fate of your of your nation
using your brain you know after taking
many things into the code. This is
>> without talking to them
>> right without talking.
>> All right. Again we go back to this
instruction manual. It's like writing
something into the instruction manual
based on your own experience.
>> Right? We have to understand that the
brain
uses a different language than the
language of inheritance. It keeps
information in synapses in the
connections between different neurons.
When you learn something, you make you
make some connections stronger and some
con other connections weaker and you
wire the nervous system in a different
way. 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 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? You can
teach worms even though although 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
odor ant receptors and they can
recognize many many many molecules. They
can smell them so they can find food or
avoid enemies. You can take an order
that the worms like and pair it to
something bad like starvation and then
the worms will learn to dislike this
order.
We don't know that this learning
involves necessarily changing in the
strength of sinapses. It's a possibility
but it doesn't have to be the case. It
could be that just the receptor for this
particular Odo
is being removed when they and this is
how they live. Now they won't have the
receptor. They won't smell. They won't
like the order. 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.
People have shown things like that not
in segance but people have shown things
like this in mammals.
They said that you learn certain thing
and then
just in the next generation thus a
particular receptor would be metated 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 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 elegance is we showed
that the brain can communicate with the
next generations using small RNAs and
that this can change behavior and it
doesn't require any translating between
any language. It is very simple. What
we've shown is that if you take a worm
and you change the production of small
RNA just in its brain
in the next generations their behavior
will be different even though you don't
mess with their brains. This is a paper
that we published in 2019 in cell. We
show that you just manipulate the
production of endogenous natural RNAs in
the worm's brain that are always made,
but you you change their amount and this
changes the capacity of the worms in the
next generation to find food 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
germ line. One gene is called sage 2. We
can do all kinds of controls where we
manipulate activity of the gene and see
that this also affects behavior. And
this gene works in the germ cells. The
information needs to go from the brain
to the germs. 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 RNA between generations.
If you don't have the protein that
physically carries the RNA between
generation, doesn't happen.
>> So it has to be RNA.
>> It has to be RNA. We can also find the
RNAs in the next generation that change.
We sequence the actual RNAs that change
in the next generation. So it sounds
weird that you change germ cells and it
changes behavior sperm and egg. But if
you think about it, the germ cells
affect the soma including the brain in
many ways by secretreting certain
chemicals and also because the other
cells develop from the from the germ
cells. So some information could be
transmitted over development or the
course of development could be altered
because of changes that occur in the
germ cells. For example, in mammals, one
of the explanations for how heritable
information transmits is that it just
affects something very own in
development. I I 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
if in the placenta that develops in
pregnancy and this later throws
everything off and because of that you
have many problems metabolisms and so
on. And this is called the idea of the
develop developmental origin of health
and disease that many of the things
occur dur many of the of the functions
occur early on in development
>> in terms of the work in either segans or
in other model organisms but in
particular in segans where do you see
this going next?
>> So assuming that we will discover
similar things in in humans which we
don't know that this is the case but
let's say we we find it. I think there
are many things you can do before you
change it. You could also change a
parent inheritance by having the the
parent exercise. For example, and some
things like this have been done. For
example, there are experiments in in
rodents where they show that overfeeding
the u the rodent creates problems for
the next generations for the for the
children. However, if you let the the
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 if you do IVF if you
vital fertilization you could perhaps
change the composition of the RNAs in
the 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 for most couples. You can look at
the DNA and look for genetic disease.
But no one look 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. 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 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
>> yet. Yes. But of course this is why why
why it's so interesting
>> today. You've taken us on an amazing
journey through the genome RNA in
particular the work in your laboratory
which is just incredible and also this
introduction of model organisms. So
thank you so much.
>> Thank you.
>> It's been a real pleasure.
>> Pleasure was all mine. Thanks a lot.