- [Announcer] Welcome to
the Brain Coffee Podcast.
Where Doctors Eric
Leuthardt and Albert Kim
unlock life's little
mysteries about health,
wellness, entertainment, technology,
and how the brain makes sense of it all.
Sit back, relax, and open up your mind.
- It's a real pleasure
to have today with us
at our little coffee sessions
a real thought leader
in brain development.
Azad Bonni, Dr. Azad Bonni,
who is Chair of Neuroscience.
As an aside,
I also in some way am a sort
of developmental child of--
- Right, you've developed under him.
- Yeah, yeah, because I
was a post-doctoral fellow
in his lab maybe 10 years
ago or more ago now,
and that was a great time.
So it's great to have you.
Thank you for joining us.
- Thank you.
- Yeah, well, thanks for coming.
So maybe, really just to kinda frame it,
we should really talk, you know,
what is developmental neurobiology?
How does, you know, when
you hear those terms,
what does that mean to somebody
kind of at a coffee table?
- Well, I think that,
I think it's probably good
to start with the idea
that most people would agree,
that the brain is the most
complex organ in the body.
It's probably more
capable than any computer,
and there's great complexity in it
in terms of the types of cells and so on.
But it really all starts
from a few cells in the human embryo
and how you go from those few cells
to a very complex machine
is what brain development--
- It's really kinda staggering
when you think about it.
- [Azad] Absolutely.
- A few cells divide and then that becomes
this massively complex organ
that can do all the things that we do.
- Right, yeah.
So I think something
probably in terms of numbers
you could think about is, as you know,
the human brain contains
about 100 billion neurons
and trillions and trillions of connections
between these neurons,
and these are not random at all,
but actually quite specific.
So it is a huge problem in
terms of trying to understand
how this machine, how it's hardwired,
and that's really what
brain development is about
is to understand how
the brain is hardwired,
and of course, layered on top of that,
we wanna understand how it works and how--
- [Eric] And I guess how
it doesn't work, right?
- And how it doesn't work.
- Right.
- And we think,
from those of us who've
been really focused
on brain development think that
we can really bring a lot to the table
in terms of understanding
how the brain works,
how it functions,
as well as how it
doesn't work and diseases
by understanding how it's put together.
- [Albert] I see.
- What are some of the, I guess,
because I actually reference this
when we think about our kids and we just,
I've got a four-year-old
and a seven-year-old,
and you see kind of
their development, right?
- [Azad] Yes.
- You see how on a nearly weekly basis
how they start accumulating
new information, they start,
and again, it's a miracle to
behold in our everyday lives.
- Right.
- For sure.
- I guess what, from a
development standpoint,
what are some of the
fundamental things that I guess,
or principles of how some
of this hardwiring happens.
- Or maybe some steps,
like maybe the cells, the major cells.
- [Azad] Sure, yeah.
- Something like that.
That'd be great.
- So I think that it's
probably worthwhile to--
This happens in every part of the brain,
but we can start,
we can talk about the cerebral cortex,
which is this region that obviously
is the most evolved in the human brain.
So how do you get to that?
What are some of the key steps?
So a lot happens already in
the embryo and the fetus.
So first of all, you have
cells that are generated
in a particular region during development,
and from there, these
cells have to migrate,
have to move, actually,
to their proper places where
they're going to reside,
and there they mature,
and what that means is they
forms axons and dendrites.
These are the limbs of the neurons.
The axons allow the neurons to,
by and large to transmit information
from the center of the
neuron toward other neurons,
toward other nerve cells,
and then dendrites are the
receiving limbs of neurons.
I remember that phrase you
used in one of your reviews.
- I used to study dendrites, as well.
- I kinda think of it in simpler terms.
- And they receive information.
- It's like the pitcher and the catcher.
You know what I mean?
- No, that's a great way to put it.
- You know, like basically
you've got the neuron,
and then you've got, it's maybe the team,
and you've got the
pitcher, which is the axon,
and the catcher, which is
the dendrite, you know?
And the ball is the information.
- That's a really good
way of thinking about it.
So once, so those are formed,
and then, of course,
they have to make the
synaptic connections.
They have to actually make the connections
between neurons with each other,
and those are synapses.
But then a lot of other
things happen, too.
So, for example,
the axons have to become
insulated with myelin,
and that happens following
all of these steps,
generally speaking.
And then, interestingly, a lot of,
there are an excess of nerve cells.
I just said that there
are 100 billion neurons,
but probably twice that number
are generated during development.
- I think this is a
really interesting concept
that I think a lot of
people don't know about
is that people think that
more brain cells are better
and that more is always better,
but as it turns out that,
and I think you're getting at
this notion of pruning, right?
- Exactly.
- That basically you've
got all these neurons
and then you sculpt it down
to something that's highly functional.
So you've got this big messy blob
and then you kinda bring
it down to something--
- Absolutely.
And that's obviously, first of all,
you have excess number of neurons,
so those have to be eliminated,
the ones that are in excess,
but there are also excess
number of synapses, too,
and those have to be pruned,
and some of the pruning is of the axons,
and absolutely that's the case.
You need to sculpt it,
and more isn't necessarily better,
and I'll come back to that later,
in terms of diseases.
And so absolutely you need to sculpt
the number of neurons, the
axons, the synapses, and--
- Does that happen, do
the cells know to do that,
or is it, so is it
sorta programmed in them
to make this whole brain,
or is there any influence
of the outside coming in?
- Yeah, so we,
the truth is we still
don't really understand
why this happens and how,
what the basis is,
why do you need so many cells.
So some people think, well,
there's some sort of randomness to the,
can be some randomness to the connections,
to forming these connections,
and so what you need is a way to make sure
that only the correct connections stay.
And so you need to have
more cells, more synapses,
so that the ones that are accurate remain,
and the pruning is a way to--
- [Eric] It's kind of almost like this--
- But it's not really--
- It's almost like an evolution.
Like, you basically create
a messy, a big mess,
and then you let it,
your brain essentially auto-evolves
to something that works as best--
- The stuff that sticks
you wanna keep, right?
- So that's one thought.
But it's really not been,
we still don't really understand.
But maybe I'll tell you
in terms of the synapses.
Most people think, well, yeah,
the more synapses, the better,
because then maybe you have better memory
and things like that,
but that's not true.
In fact, we just had a study recently
where we found that if we take a gene
that's implicated in autism
and we take that out of the brain,
in this case, of a mouse brain,
we see that there are
actually more synapses,
and that is associated
with impaired memory.
And then what's really exciting is
we looked at a number of these genes
that are in a particular
class of genes, proteins.
We find the same thing.
So when we inhibit their function,
we see more synapses.
So that's a clear example
of having more synapses
is actually not good for you and for,
and we think this could be a
general mechanism in autism.
- Oh, so this is,
so these are a group of
genes involved in autism.
- [Azad] Yes.
- Okay, so this is a
super interesting topic.
What, just a step back.
Maybe not everybody knows.
I don't exactly know all
the details of autism.
But what, maybe we can define autism
or autism spectrum disorder.
- Sure.
So autism basically,
these kids were described some time ago,
several decades ago,
as having sort of
particular kind of problems,
and there are a few sort of
cardinal features to autism,
including difficulties
with social interaction.
So that's one major set of problems
that these kids may have.
Interactions with other kids,
with their parents, and so on.
Another problem that
they typically have is
in language development,
and they also have a motor component,
and that is repetitive behavior.
Now, there's a whole
range of kids with autism
that could be actually what's
called high-functioning
versus low-functioning,
and low-functioning meaning
that they often will have
intellectual disabilities
associated with autism.
- So it's not always overlapping.
It's some...
- That's right.
- ...have intellectual
disabilities, some do not.
- Right.
- Okay.
- I think often there is overlap
with intellectual disability,
but not always, absolutely.
- I see.
- And certainly people talk about people,
there's people who are
on autistic spectrum
who have elements that
are high-functioning.
- [Azad] Sure, sure.
- You know, kind of
mathematical proclivities.
- [Azad] Absolutely, yeah.
- Or computer programming skills.
- I mean, we all, we come across, I mean,
in our fields, even, when we say,
oh, this person or that
person is on the spectrum.
They could be brilliant,
but they may have a few social--
- Socially, perhaps.
Well, I was gonna say,
if the criterion for
poor social interaction
is a key element for autism,
neurosurgery may be well-represented,
you know what I mean?
- [Albert] Autobiographical, exactly.
- So it really is a
complex of disease, so--
- That's right.
But sort of in seriousness, though,
it's even these cardinal features
are really just features that
there's actually a lot more to it,
and if you talk to the child psychiatrists
and child neurologists who see a lot of...
I'm an adult neurologist.
Who see these kids with autism,
they often talk about
actually motor problems first.
- [Albert] Interesting.
- That they have a lot of motor problems.
Motor coordination.
So they might be walking on their toes.
They may be a bit clumsy.
And so that's actually,
it's quite interesting to me,
because I'm interested in a
number of regions of the brain,
but one of the regions that
I'm particularly interested
and have been for a while, as you know,
is this hindbrain structure
that's called the cerebellum,
which basically stands for little brain.
- Right, the back of our head, yeah.
- The back of the head.
So, but it's interesting.
We still don't really know where,
what part of the brain
really is involved in autism.
There are various ideas about that.
So it may be a number of
areas that are involved.
The cerebral cortex,
which is what we talked about earlier.
The cerebellum is thought
to be involved, as well,
and also some of the
other subcortical regions,
regions that are below
the cerebral cortex.
- And I think what you--
And I wanna return to the
point you said earlier,
which I think is a really
fascinating and fundamental thing,
is that in many ways in some of the things
you're seeing with the genetics is that
it's an overconnectivity problem.
- [Azad] Yes.
- That there's too many connections,
leading to, in some way, poor
informational processing,
or too much noise.
- Actually, I would probably,
I think that's a good
way to think about it.
I probably would define it
further as a disconnectivity.
There may be more connections
or there may be fewer connections.
It's just that the balance, there aren't,
the right number of
connections are not there
in the right numbers.
So it could be more connections,
but it could also be fewer connections.
We just found a particular
set of genes that are similar.
They all encode proteins
that are involved in what we study.
Albert has been studying this, too.
And protein turnover.
And those, it turns out
it's really interesting
when we incubate those.
It's quite early days.
But we see more synapses.
And so I think it could--
The real challenge with
autism research right now
is we don't really have sort
of a clear path right now
of what is actually happening.
So we're all trying to get at
this from different angles,
and so it's quite a challenge.
But the good news is
that in the last decade,
at the very least, the last decade,
we've learned a lot about
the genetics of autism.
So a lot of, you know,
in a proportion of autism cases,
there are mutations of genes
that have been implicated.
And so that's really advanced quite well,
but now the question
is what does this mean?
What does it, you know,
can we get a clear picture of what
the underlying pathogenic mechanisms are.
What goes wrong--
- They're not sculpting
appropriately, right?
- [Azad] Yes, yes.
- But we don't know what it is
that's sort of the causal
anatomic substrate, yeah.
- What is common?
Is there a common pathology in autism.
We don't really know that yet.
And so people are trying to get at that.
Now, one possibility might be
that it's really quite heterogeneous.
There are all sort of different autism.
- So autism is really
a common description.
- [Albert] It's like a
syndrome, I guess is what, yeah.
- But that there's a
number of different ways
you can get to that syndrome.
- And likely that's,
I think it's gonna be,
in my view right now,
what I think's gonna
happen is the following.
I think that it's definitely a case
there are multiple different diseases
that are all called right now autism,
but, or we could call them autisms.
But I think,
and they each will have a
different sort of process
that's taking place,
which means we have to
understand all of them.
But I think there are probably also
some common pathological mechanisms,
which is really important
to kinda keep in mind
because it's important to figure out
what those are, as well,
because those might allow us
then to develop therapeutics,
treatments that are gonna work
not just for one set of
disorders, but multiple.
- More generally.
- More generally.
- In some senses, this shares a lot,
just when I think about
descriptions and terms and causes,
it shares a lot with,
for instance, epilepsy.
- Absolutely, yes, yes.
- So for instance, you've got epilepsy,
which is having seizures
on a consistent basis,
but there's a lotta different causes
that lead into those symptoms,
and also potentially similar mechanisms
as the end pathology that
lead to those symptomatologies
that hopefully you can get at and treat.
- Yeah.
I think epilepsy is, could actually,
when you mentioned that,
could be a really great way
to start thinking about autism, as well,
because with epilepsy,
we don't have cures for some of them,
but, for many of them,
but there are ways to
treat it symptomatically.
- That's right.
- And so with autism,
we don't even really have that,
so it'd be nice if we could come up with,
you know, with epilepsy,
we know that the nerve cells
are firing excessively, abnormally.
We don't have a sense of
something like that for autism
that we could even for, in
terms of symptomatic treatment.
But my view,
so I started out in neurology,
and the reason, and then,
this was a long time ago.
Maybe I don't care to tell
you how long ago was this.
I was doing neurology.
But at the time,
I realized that really
we don't have a lot of,
we don't have really good treatments,
we don't have treatments,
good treatments for many of them,
and for actually many
others, we had nothing.
We have nothing, right?
So I thought it was really
important to understand
how the brain is put together
to try to get at that,
and I'm really,
it's really gratifying to
see in the field as a whole
and the discipline of,
in the neurosciences.
I feel that brain development
is actually touching
all of these diseases,
and there's a way to think about
how these different
neurological diseases come about
from a developmental perspective.
- I think it's really
interesting, and I think--
- Including epilepsy,
including autism, including--
- Or brain tumors.
- Brain tumors, for sure.
- Including brain tumors, yeah.
- One thing, you know,
there's both treatment and
there's prevention, right?
And so how can you intervene early.
Now, one thing I probably, you should ask,
and we should bring up,
'cause I think it's controversial,
is that people worry about what could
quote-unquote "cause" autism.
And, you know, again,
the elephant in the room is
people talk about immunizations.
So maybe just to put it on the table,
'cause I have my personal opinions.
- Yeah, and it can be super brief.
We don't have to get into the literature.
- Exactly.
What is your general thought on--
- I really sort of,
I completely agree with you,
and I think this sort of definitely
gets into the popular culture.
And it's a real concern,
because as you know,
there have been celebrities who have been
promoting the idea that there's a link
between vaccination and autism,
but to the best of my knowledge
of what I'm aware of in
terms of the literature,
there's no link.
- [Albert] And you know
as much as anyone ever.
- As one of the world
leaders in this field.
- There is no link.
There is no link between that.
And I'm really concerned about,
of course we know that vaccines are,
have done wonders for, in terms of--
- Saving lives.
- Saving lives.
And so I'm really worried
that children are not,
if they're not vaccinated
because of this concern,
that we're gonna have--
- That is unfounded.
- That is unfounded, absolutely.
And so I would say there's
no link between the two.
- Right, that's good to think about, yeah.
- Just to get that out there,
because I was gonna reduce this
to somewhat more of an
erudite kinda conclusion
that it's complete b*******.
But I will defer to you.
- No, but that's important.
But how about, stepping
back just for a second,
how much of it's genetic?
How much of it's not thought
to be genetic, you know?
- Yeah, it's a very good question.
I think that there is definitely,
it's a fraction that's genetic.
I can't give you a specific number
because we're discovering,
of course there are
some that are inherited.
- Right, right.
- [Azad] That's a really small proportion.
- I see.
- Very, very small proportion.
But we're discovering,
the genetic studies,
we're discovering that there
are de novo, new mutations,
and those are still considered genetic.
So beyond that,
there could well be also polygenic causes.
- That'll be harder to
figure out, for sure.
- That's harder to figure out.
So I think it's a substantial fraction,
but it's still a fraction.
- I see.
- Now, and not just genetics, though,
but also I guess theoretically,
and it's probably worth introducing
the concept of epigenetics.
- That's right.
- That it's not just your gene,
whether you have a gene or not a gene,
but whether a gene is modified...
- [Azad] How the gene's regulated, right.
- ...or activated or inhibited.
- Right, right.
So of course the genes are, you know,
if you take a DNA,
look at DNA like a strand,
these are, the genes are parts of the DNA,
but the DNA and the proteins that are,
that basically occupy
these regions are modified.
They're changed.
And those changes are
epigenetic, called epigenetic.
And the reason they're epigenetic,
because they can actually
also be transmitted
from the mother to the fetus.
And so those are epigenetic changes.
And so yes, the people are
interested, for example.
This is not about vaccination,
but they are interested in terms of
the maternal/fetal interactions.
And so there is interest
in the field in terms of
changes that may take place in the mother
and how they may be
transmitted to the fetus
that could lead to autism.
- I think this is a really,
I think that epigenetics is really,
so it's how environment and how...
- [Azad] Absolutely.
- ...your physiology
can affect your genome
and kinda what genes you turn on and off,
and that kind of affects
transmission of information.
- Yeah, no, that's right.
- So it's kind of different
from Darwinian genetics, right?
- [Azad] Yeah, you could say that.
- And just to drive it home,
just to make it a little clearer,
I mean, we're talking,
epigenetics is a really huge phenomenon.
I mean, we're talking about
every cell in our body
has the same DNA,
and yet we have skin cells, brain cells,
different types of brain cells.
So that's encapsulated in epigenetics.
So it's a huge phenomenon, for sure.
But now we're drilling down on the ability
of things like experience
or maybe the mom's
contribution to affect the kid
having autism or not, maybe, that's--
- Right, and it's relevant
also even beyond that.
In the kid, the kinds of
experiences they may have,
the kind of environment is absolutely,
it's not all about Darwin, right?
In terms of what the environment,
it plays an important role in
the development of the child.
And one thing that we,
coming back to the development,
a long time ago,
people were thinking that,
okay, the kid is born.
Development is largely done.
Maybe the first year,
they're getting myelination,
and that's why they're
becoming coordinated.
At first a baby's not very
coordinated, as you know.
But after a year, they're walking,
and that is, probably that's
the end of development.
But it turns out now that actually
development continues in the brain.
There's a lot that goes on.
- Into your mid-20s, isn't that right?
- [Azad] Even beyond that.
- Oh, that's interesting.
- Up to around age 40.
So maybe you guys are still
there, but I'm beyond that.
- I think we've just
emerged out the other side.
- I've now developed.
Yeah, exactly, right.
- We've come through the other side now.
- So actually what happens
in terms of epigenetics,
the experiences that children have
could potentially have an
impact on their adulthood, even.
So I think it's really
important to consider that
and that you do need to
provide the right environment
as a society, that we--
- [Eric] This is really profound.
- [Azad] So that's how I think about it.
- No, so is there any,
okay, short of not locking
a kid in a attic forever,
are there things--
- [Eric] And giving 'em cigarettes.
- Yeah.
Are there positive things
that one could intuit from--
I know this is super controversial.
There's some people say that there's no
sorta reproducible parenting mechanism
that leads to a predictable outcome.
I get that.
But are there some principles to consider
given what we know about development and--
- Or let's blow it down
to something personal,
like given everything you know,
what have, kind of how has
that influenced your parenting,
or what things you emphasize.
- Well, I wanted to be a
little more nuanced about it,
but yeah, okay.
- So basically, I think of
it in the following ways.
I think that the brain is quite resilient,
of a normal child, it's quite resilient.
But at the same time,
I think environment is really critical.
And, I don't know, I think,
one particular example might be
if a kid learns two
languages, for example.
- [Albert] Okay, this is good, yeah.
- The likelihood is that it will be easier
for them to learn a third language.
I think that there's something about,
from an epigenetic standpoint, I feel.
I mean, I have no evidence for this,
but I feel that the epigenetics
probably works there
so that it keeps some of those
genes open to more signals
to activate that otherwise
may not be still active.
- It keeps the tools available.
- It keeps the tools available sort of,
and rather than closing
them down and saying,
"Okay, you don't need these genes."
- [Eric] We're done.
- And we're done, you're
done, that basically,
and this comes to the idea of
that we don't really use most,
a lot of our brain is probably not used.
There's lots of potential.
And so I think that it would be nice
if this could continue,
and I have an experiment that
I'm actually doing right now.
I don't know if I'll be able to do it.
- Is that right?
- [Azad] But on myself, but--
- I see, I see.
But you mean about critical periods.
- Yes, yes, because--
- So the idea of critical periods being
it's only during a certain time
you can learn a certain task, right?
- [Eric] Well, there's a--
- Because I think it might even impact
neurodegeneration later, as well.
- Because you could basically
bring the tools back.
- I wanna keep the tools open, right,
in my brain so that there's,
at least from an experiential,
from an experimental,
experiential point of view,
in terms of the environment,
that I minimized basically the odds
of having brain degeneration.
Basically it comes to the idea
of use it or lose it, right?
- Right, right.
- Right.
- So the more that you use
your brain, the better it is.
And this we know.
For people who are,
later in life, the one,
if you're not really active,
actually, even physically,
but also mentally, if you're not active,
you're more likely to succumb
to the problems of dementia
and age-associated brain degeneration.
- [Albert] Yeah, for sure, yeah.
- So I think that,
and fortunately for us,
'cause we still don't really understand
how these critical periods work.
That's why, for example,
a kid who's learning,
who learns languages before puberty
typically will learn them
well without even an accent,
but later if you learn new
things, it's really hard.
But, I mean, it becomes
really hard to learn, anyway,
a new language, but--
- Now, have you ever heard
of the valproate experience
and perfect pitch?
- [Albert] It's Takao Hensch's work.
- Oh, okay, yes, yes, I know of his work.
- So basically, so again,
apparently there's a developmental period
where you can learn perfect pitch,
and once you get past that period,
people can't learn perfect pitch.
So what they did is they gave just,
they did an experiment with random adults.
- Young adults.
- Young.
- Young adults, yeah.
- But, like, 20s.
- [Albert] Yeah, young adults, right?
- And they gave them valproate,
and those people were able
to learn perfect pitch in two weeks, and--
- Or at least more than
would've otherwise.
- Well, no, they can't, you know?
Like, people otherwise can't.
And so that was one--
- No, you're right, you're
right, you're right.
- That was one drug.
And what I think is interesting
and how this plays to kinda
connectivity and plasticity and--
valproate is an epilepsy drug.
- Right.
- And--
- But it has effects on epigenetics.
- That's exactly right.
- It's a histone deacetylase inhibitor.
So basically it leads to
modifications of the epigenome
that allow for the genes
to become more active.
- [Eric] That's right, that's right.
- So that's conceivable.
I mean, it's hard to imagine
that that particular drug
in itself would be able to do that,
but I guess it needs to be--
- Further validated.
- Further validated.
- No, it's certainly intriguing,
'cause, I mean, perfect
pitch is supposed to stop
age five, seven, something like that.
And so it is certainly
intriguing to think about and--
- You know, I do think that the brain
is more plastic than
we give it credit for,
and that there's ways
to trick it into being,
again, with our experience
with brain-computer interfaces,
people said you couldn't
recover function in stroke
six months after the stroke,
and we have patients several years out
using a brain-computer interface
that then allows them to
recover their hand function.
And so you can do tricks, I think,
to essentially allow returning--
- I think another way,
in terms of, you were
talking about parenting,
and one of the, I don't know where your,
I know you have 11-year-old, so--
- [Albert] I know you better.
- Yeah.
I met her in the lab.
So basically, but as your
kids come to teen years,
from personal experience,
what I can say is that actually,
there's a lot that's going
on in a teenage brain,
and you just have to
be, as a parent, I feel,
you have to be patient,
because there's a period
of turbulence, basically,
and it's really,
it's not just because
there's a lot going on
in their environment
because they're coming across
meeting other young adults
and teenagers and--
But they might, you know,
there are actually changes
that are taking place
in the teenage brain.
- That's really fascinating.
- And so, and it's,
of course there are also
the effects of hormones,
which have definitely major
effects on brain development.
So what you have to remember as a parent
is that you have to
continue to be consistent,
which is hard to do, I can assure you.
But you have to be consistent
in providing a positive environment,
and then hope,
and I think likely what happens is
as they reach their early 20s,
they really change,
and so it's really a positive thing,
and you just hope that you
come out the other end.
- In some sense, you
know, it makes me think--
- [Azad] So that's important to remember.
- That's a really good point,
because I think there is
an emerging neuroscience
of the teenage brain,
and it makes me think
of actually going back,
even with early development,
I feel like they're developing this chaos
of behavioral and cognitive state,
and then they have to
resculpt to the person
that they're gonna be
for their adult years.
And that requires a lot of exploration,
going in different directions, opposition,
and if you can provide
the right framework,
then eventually they sculpt
to the right direction.
- Right, right.
No, I think that's good.
I'm gonna remember this next time I
maybe get a little mad at my kid.
That'll help me.
(laid-back music)
