- [Narrator] The human brain is one of the
most studied subjects in science,
but still much is a mystery,
including the interplay between the brain
and other organs, like the eye.
At the UC San Diego Stem Cell Program,
researchers are growing tiny brains from stem cells
in order to further their understanding,
and they're not the only ones using this approach.
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- In order to get the complete picture
of how the brain develops, we need to understand
what happens when the brain receives and processes
sensory information from other organs, such as the eye.
And that's where Karl Wahlin comes in.
- [Narrator] The connection between the eye and the brain
has fascinated scientists for hundreds of years.
It seems miraculous that rays of light
can be transformed into
a complex understanding of the world.
But sometimes, the system breaks down,
leaving people in the dark.
- [Karl] Photoreceptors, or ganglion cells, can die,
and once those cells are gone,
those cells are gone permanently.
And so we're looking at new ways
to restore function to the eye.
- [Narrator] Karl Wahlin is the director
of the Richard C. Atkinson Laboratory
for Regenerative Ophthalmology at UC San Diego.
His lab uses stem cells to create tiny human retinas
in order to study eye disease,
and hopefully one day cure blindness.
- One of the powerful things that we can do
with retinal organioids is to introduce
patient-specific mutations,
and this is something that's been made possible
over the past five years by new gene editing techniques.
- [Narrator] Wahlin's lab uses the CRISPR gene
editing technique to create retinas
with the exact mutations found in people with eye disease.
So he can study how they develop,
and what treatments might work on each mutation.
- [Karl] Previously, most of the studies that we would do
to study inherited retinal degenerations
would be done in animal models,
which take a long time to develop
and they're not very scalable.
The ability to make human organoids
with disease-relevant mutations
means that we can have many mutations,
we can have thousands of samples,
and we can test many of these with different drugs.
You just simply can't do this
with living animals in the same scale.
- [Narrator] He's teaming up with the Muotri Lab
which builds brain organoids to study how the brain and eye
influence each other during development.
- [Karl] But we knew from decades of research
in other species that sensory input is very important
for brain development, and vice versa.
The information that we can get from this kind of approach,
this cerebral organoid retina co-culture system
will allow us to understand how those connections are made.
There are diseases such as leber congenital amaurosis
in which photoreceptors die at a very early stage,
so this is childhood onset.
It's not clear what happens to the brain connections
once those photoreceptors are lost at a very early stage.
So if we're able to cure blindness,
this is gonna require knowledge of photoreceptor protection,
as well as to understand how those connections in the brain
could potentially be perturbed.
So over time as we've developed this
cerebral organoid retina co-culture system,
we recognized certain technical limitations,
and one of them is that the retinas, and the brains,
they tend to be absorbed by one another.
And so we need physical structures
in order to separate them.
Shaochen Chen's group has a lot of experience
developing biocompatible materials,
so they've been building three dimensional scaffold systems
for us to separate, physically separate,
the retinas and the brains,
and this is gonna be one of the critical components
that we use in order to build a better
integrated brain-retina circuit.
- [Narrator] At the same time, Wahlin's lab
is looking into a treatment for eye disease
straight out of the animal kingdom.
- There's a new area in retinal research
and it's a very fascinating area.
It's called endogenous regeneration.
And this is the process whereby specific support cells
in the eye can be reconverted into other retinal neurons
such as photoreceptors, or ganglion cells.
When you think about endogenous regeneration,
probably the most powerful example
is a lizard or an amphibian that has lost its tail.
A lizard that loses its tail can grow
a completely new tail in a relatively short period of time.
In the eye, there's a similar situation.
Some types of fish, such as zebra fish,
have been shown to regenerate
an entirely new eye once when lost.
In mammals we seem to have lost this capability,
at least naturally to do this.
There is recent literature that suggests that
this can actually happen if given the right instructions,
and so our lab is very interested in
taking knowledge from other species,
using this in our system in order to
endogenously regenerate retinal neurons.
In 10 years from now, what I really hope
we'll be able to accomplish with this system
that we're developing is a platform to test new therapies.
There are hundreds of mutations which need to be addressed,
and we can't do this on a case by case basis.
If we can have a system where we can
study many different mutations,
in a system that's physiologically relevant
coupled to a brain, we would have a system
where we could test new therapies
like drug discovery, or gene therapies,
or in the best case scenario,
endogenous regeneration, and if it did work,
to cure hundreds of mutations,
this would be something that would be extremely powerful
and would transform the way medicine works.
(upbeat music)
- Karl's work show us the potential of stem cells
for not only restoring vision, but also for understanding
how our eyes and brain work together.
Next, we visit with a bioengineer
who is helping to advance this work.
- [Narrator] Measure twice, cut once the old adage goes.
An inch here or there can make a huge difference
in a construction project,
but when it comes to building a human body,
those measurements go from inches to microns.
One millionth of a meter.
Scientists at the UC San Diego Stem Cell Program
are working at a scale that small
to answer some of life's biggest questions.
- Our mission to understand brain development requires
we study the connection between the brain and the eye.
Bioengineer Shaochen Chen is helping us
thanks to his work connecting damaged spinal cords.
(soothing music)
- [Narrator] The human body is a massive network.
Signals traveling along neural pathways,
allowing us to see, smell, hear, and move.
But what happens when those connections are severed?
Can they be repaired, or are they lost forever?
- [Shaochen] For the case of spinal cord, imagine using
these kind of 3D printed live tissue
for that patient, and they can get recovered
within a couple months and walk again.
- [Narrator] Shaochen Chen is the founding director
of the Biomaterials and Tissue Engineering Center
at UC San Diego.
His lab creates functional
biological tissue using stem cells
and a complex 3D printing process.
- In bioprinting we print cells with gel,
and then we build a functional
biologically active materials.
So in the case of heart, when you print this tissue,
it can beat, it's not just a plastic model.
We have been working on this type
for the last almost 20 years.
We start from scratch, and we build
our own printing machines.
- [Narrator] Those machines shine light into a gel
full of stem cells using patterns derived from CT scans
to match liver, heart, and nerve tissue.
Any spot the light hits becomes solid.
- [Shaochen] These are from patients' own skin.
So you can take these cells and reprogram them
into functional cells like heart cells,
liver cell, nerve cells.
And then we can print these cells into the structure,
and in that case the piece is patient specific,
and you can put it back into the patient,
hopefully will help to grow the heart,
repair the livers, and also regrow the nerve tissue.
- [Narrator] Chen's lab has already found success
repairing severe spinal cord injuries in rats.
Now Chen's partnering with Alysson Muotri and Karl Wahlin
to help them understand how brain and eye development
influence each other.
He's devised a way to keep the tiny brains and retinas
they're studying separate,
just like they are in the womb.
- [Shaochen] It's a very exciting opportunity for us
to work together with Alysson's lab and Karl's lab,
all three of us are maximizing our strengths
to build this complex organoid system
that has the retina in one end,
and a brain on the other end.
Then there's a channel with the biomaterial
that we studied over the years
to bridge these two together in a very precise fashion.
- [Narrator] That channel allows the brain
and retinal organoids to form connections,
so researchers can see how those connections
influence brain development.
And the Muotri Lab is also hoping to use
Chen's bio-printing techniques
to create tiny blood vessels, allowing brain organoids
to become larger and more complex.
- [Shaochen] In our case we use a light,
and it can really focus the light into a tiny, tiny spot
or patterns, and then we can recreate
this very fine vasculation network.
- [Narrator] And bio-printing has
other revolutionary possibilities,
from speeding up drug testing.
- [Shaochen] It takes average 12 years
and two billion dollars for one drug.
Now we can print these human tissue.
They can directly test whether this drug
will be toxic, or whether this drug will be effective or not
in the situation of human tissue.
- [Narrator] To perhaps one day, patching the human heart.
- Imagine yourself in the future,
that we can create these functional human tissues
that can be used as a patch to put on the patient
and repair that heart damage.
And the heart will go back to normal,
and that's I think that's very exciting for me,
and I'm so excited to be involved
in this kind of research work.
- It is clear that bioengineering will be an important part
of any future use of stem cells
to fix damaged tissues and cure conditions.
Another method to discover cures
is to find the pathways within cells
that cause conditions to start, and find ways to stop them.
Brain organoids allow us to do that.
We'll be exploring this more on Building the Brain.
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