(gentle music)
- [Narrator] All animals need to know
and communicate with their own.
So evolution has developed, in every brain,
the ways we all recognize and socialize with each other.
But while other brains are social,
no other brain is as social
or can do what the human brain can.
And it also seems that no other brain
can experience conditions like autism.
Are these two fates somehow intertwined?
Alysson Muotris' lab at the Sanford Consortium
for Regenerative Medicine
is using brain organoids to unravel this mystery.
And with the help of an understanding
of our evolutionary cousins, new insights are emerging.
(upbeat rock music)
- A focus of our lab is autism,
conditions which make it difficult or impossible
for individuals to communicate
and make emotional connections.
There are many complex aspects
to these different conditions,
but they all share one thing in common.
Their roots are in the cerebral cortex,
this thin outer layer of neurons
that fire trillions of times per second in our brains
to understand and respond to the world around us.
With all this complexity, where do we start looking
for abnormalities that cause these conditions?
Katerina Semendeferi's work in comparative neuroanatomy
helps to guide us.
She share what she has discovered
about what makes brains social
and how that could be a source of conditions like autism.
- Humans have a brain that's about three times larger
than that of the great apes, our closest relatives.
And that's a huge difference.
So, in terms of absolute volume
and absolute numbers of neurons,
the brain is much much larger.
So the question is, are these larger brains that humans have
just larger versions of a smaller primate brain?
And we now know that that is not the case.
So, humans are three times larger
than the brains of the apes,
but at the same time, they have also been reorganized.
So, it's not like you're taking a brain
of a chimpanzee and you zoom it out to three times,
and you get the human brain.
That's not what's going on.
The challenge is to see what is exactly is it
in that larger human brain that has changed,
either differentially enlarged as a whole
or differently enlarged in terms of specific parameters.
For example, it can be the size of the neurons
or numbers of the neurons,
or the way the cortex and the gray matter's organized.
We have known for a long time now
that the larger the brain gets,
of course the more neurons it has,
but the density of the neurons go down.
And what does that mean?
Well, when the brain gets bigger,
connectivity gets even bigger.
So larger brains have more neurons,
but they have even more connections.
And that special connectivity between specific structures,
is it what allows for social behavior,
for example, to take place?
So, often, we view the brain
from the perspective of the cortex.
We're very cortical-centric in a way.
In reality, the cortex is selectively interconnected
with other structures, and one very important one
for the social brain is the amygdala.
And it sits in the very frontal part of the temporal lobe.
Amygdala is known now to modulate and categorize stimuli
and then also allow the individual to process
that information, and then be in a position
to transfer emotional stimuli.
It has a lot to do also with fear or lack of fear,
our ability or inability to process the intentions
of people who surround us,
and it's a critical of the social brain.
In the amygdala of humans, when compared to great apes,
there are a lot of things that have changed,
specifically with the lateral nucleus of the amygdala.
The lateral nucleus is the gateway
to the amygdala from the cortex.
And it connects to the prefrontal cortex.
We know that the frontal cortex
is actually of critical importance
when it comes to complex social behaviors in humans
to social behaviors,
and to pretty much everything that we define
as characteristic of our own species.
And it just so happens that, at that area,
seems to also be a hotspot when it comes
to neurodevelopmental disorders like autism
and Williams syndrome, because it is heavily affected.
So, in the case of autism, one of the things
that we have observed is that the neurons,
the numbers and the density in the frontal cortex,
goes way up.
The dendritic trees are collapsed.
The neurons are closer to each other.
And the connectivity is affected, specifically in areas
that have to do with social interactions.
In the case of autism, we have an avoidance
of social interaction and avoidance of eye gazing.
In Williams syndrome, we have the opposite.
We have areas in the orbitofrontal cortex that seem to have
lower density of neurons, fewer neurons.
The way that the neurons are organized
allows for more connectivity in those areas
that are involved in social cognition.
So, we have more branching.
We have larger neurons.
We have more opportunities for receiving stimuli,
in specific, those areas in the brain
that do social brain kinds of things.
Williams syndrome individuals are eager to come close,
are eager to get to know strangers,
have no fear of approaching people.
Their language is extremely expressive
and full of emotions.
In addition to the frontal cortex, the amygdala.
In amygdala, we have this very interesting phenomenon
where the lateral nucleus in Williams is bigger,
and in autism, it's smaller.
Two very different aspects of behavior,
and interestingly enough, we have the same areas
in the brain affected in the two syndromes
in different directions, in opposite directions.
In Williams, we have the deletion of genes
in chromosome seven.
That makes it an ideal opportunity for scientists to look
and try to find associations
between the deletion of these genes
and compromises or changes in the brain structure,
because it's a very specific, small set of genes.
In the case of autism, in many cases,
what we have is duplication of genes.
And it is clear that we have two different mechanisms,
deletion on one hand, duplication on the other,
that may be leading to alterations in the neural systems
that end up either compromising or overextending
the social capabilities of humans.
Some of those same genes may also be involved
in how the human brain got so much bigger
in human evolution, and that's made our brain
much more susceptible, probably, to disorders
like autism or Williams syndrome.
What this line of work with the human tissue can give us
is a full description of how a typical brain,
or an atypical human brain, looks like.
It is very important to be able to compare
the kinds of information we get directly.
How is it that this cortical layers look like?
What kinds of neurons do we have in one layer
as opposed to another?
How many, and what is the density of the neurons
in the frontal cortex?
The power of what the cortical organoid can do for science
is to modify the parameters,
to create different kinds of pathways,
using different genetic mechanisms,
by altering the typical cell migration,
the typical duplication, by really controlling parameters
to see which way we get into typically-looking brain
as opposed to an atypical one.
And what kind of an atypical one?
How is it that we got from point A to point B?
So, putting the two lines of work together
is very powerful, I think.
It is certainly our hope that the discoveries
that will come from techniques like the stem cells
and these cortical organoids will lead to early preventions
to help our fellow humans who have these disorders.
- Brain organoids like these are a unique
and powerful tool to understand autism.
In Katerina's work, comparing the organization
and the structure of the brain
has helped us focus on where to look for abnormalities.
But we also wanna know where the genetics
of our highly social brain originated,
and if those genetics carry the vulnerability for autism.
This will tell us more about the causes of autism.
To do that, we are taking a page from Katerina's book
and making a comparison of brain anatomy,
by comparing our brain with that of our closest
evolutionary relative, the Neanderthals.
And only brain organoids can help us do that.
We'll explore these another time
on "Building the Brain".
(upbeat rock music)