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Is the Secret to Treating Schizophrenia in... Engineering?
Is the Secret to Treating Schizophrenia in... Engineering?
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0:00
According to the World Health Organization,
0:01
more than 300 million people worldwide suffer from depression.
0:05
And an even larger number of people struggle with anxiety.
0:08
So it comes as no surprise that a lot of scientists
0:10
are trying to find treatments for mental disorders like these.
0:14
The most well-studied methods we have for treating them
0:16
involve tweaking the level of brain chemicals, like dopamine or serotonin.
0:20
We know that this strategy often works,
0:22
and that many patients do feel better when given these kinds of medications.
0:26
But, they don’t work for everyone,
0:27
and they can have some side effects that patients aren’t thrilled about.
0:31
Which is why one researcher is looking at the issue from a totally new perspective.
0:35
Instead of chemicals, Kafui Dzirasa is interested in the brain’s electrical activity.
0:40
Now, lots of neuroscientists have studied the brain’s electrical activity.
0:43
But up until now, there have been limited ways to do it.
0:46
One is to take an image of the whole brain at a particular moment in time,
0:49
like with an MRI brain scan.
0:51
Another is to measure electrical activity
0:53
over a longer time using a few electrodes poked into a tiny region of neurons.
0:58
But Dzirasa began his career as an engineer,
1:01
so he wants to know how the whole systems work, not just little pieces.
1:05
He studies the patterns of electrical signalling
1:07
across the entire brain over long stretches of time.
1:10
And the discoveries he and his team are making could totally rewire mental
1:15
illness treatment as we know it.
1:17
Which sounds like the kind of story that would be cool to tell in person.
1:20
That’s why we created SciShow Field Trips …
1:22
to see cutting edge research in action.
1:25
We sent our friend Madelyn Leembruggen to Dzirasa’s lab at Duke University
1:28
to learn how he is trying to engineer a better future for people with psychiatric disorders.
1:35
[INTRO music]
1:37
Kafui Dzirasa's title is almost as complex as the subject he studies.
1:41
My name is Kafui Dzirasa, and I am both an investigator
1:46
with the Howard Hughes Medical Institute and an endowed professor at Duke University.
1:51
But my favorite title is vision and value scientist.
1:54
I am also in the Department of Psychiatry and Behavioral Sciences.
1:58
I'm in the Department of Biomedical Engineering,
2:00
I'm in the Department of Neurobiology, and in the Department of Neurosurgery.
2:05
You sound like you get a lot of emails,
2:07
Yes, a lot of emails.
2:09
Just a little busy
2:10
But the story of how he got interested in the brain is a lot simpler.
2:13
It begins at the movies.
2:13
I grew up watching Star Wars, and there's this magical scene.
2:19
Luke Skywalker has gone off, and he's fighting this super villain, Darth Vader.
2:24
For those of you who haven't seen it, I want to give it away.
2:27
Turns out he's his dad, right?
2:29
Woah woah woah, spoiler alert!
2:31
Now, I’m sure that a lot of future scientists who watched the Star Wars movies
2:34
would have been inspired to try to invent a lightsaber.
2:37
But Dzirasa was more interested in something else.
2:40
And there's this scene where Luke Skywalker gets his arm cut off,
2:43
and at the end he's in this medical bay, and they've attached this robotic prosthetic arm,
2:50
and Luke Skywalker is doing this, and he's moving it again.
2:53
And I thought, wow, wouldn't it be so cool to take engineering and science
3:00
and figure out how to create body parts for people who are suffering
3:04
and then able to walk or unable to move.
3:07
Dzirasa studied chemical engineering in college,
3:09
and eventually got interested in biomedical engineering,
3:12
a field that combined healing and medicine with cutting-edge tech.
3:16
But for Dzirasa, becoming the best biomedical engineer he could,
3:19
meant understanding the body inside and out.
3:22
And that meant becoming a medical doctor, too.
3:24
He went into medical school with the dream of creating robotic arms,
3:27
but ended up focusing on a very different part of the body.
3:31
During one of Dzirasa’s first clinical rotations,
3:33
he was introduced to a patient in the psychiatric ward, a veteran with schizophrenia.
3:37
And I walked in, and I just asked him, you know, how you doing?
3:41
What brings you in, are you having difficulties?
3:44
And he starts telling me about how he's having this headache.
3:46
and I'm filling out my form and finally
3:49
I asked him when the headache started,
3:50
and he tells me about how he was in Vietnam and how he was captured,
3:56
and how the people who captured him start drilling into his head.
4:00
And ultimately, the story ends with him telling
4:02
me the people who captured him implanted a chip in his head.
4:05
And my best guess at the time was that that is what we would call a delusion.
4:11
I actually got really curious about how his brain had generated
4:14
this experience that probably didn't match all of reality,
4:21
and how were the electrical signals in his head causing everything differently.
4:25
But while the other doctors knew which medicines tended to work for illnesses
4:29
like schizophrenia and bipolar disorder,
4:32
nobody had a solid answer for what exactly was going wrong in this patient’s brain,
4:36
nor the exact solution needed to fix it.
4:39
It was then that Dzirasa had a thought that would shape the rest of his career:
4:42
If we can engineer a robotic tool that restores function to someone’s arm,
4:48
why can’t we do the same with our brains?
4:50
I'm still an engineer.
4:51
It's still about the brain, it's still about electrical process,
4:53
and it's still about prosthetic devices.
4:55
It's just now, instead of thinking about the parts of the brain that create motor function,
4:59
you might be thinking about other parts of the brain,
5:01
things that you'd hear about,
5:02
like the amygdala or other parts of the brain that shape emotions
5:05
and creating prosthetic devices for that.
5:07
And because the animating force behind both robotics and the brain is electricity,
5:13
that’s where he decided to focus his efforts.
5:15
Dzirasa likes to compare the brain to a complex highway system,
5:18
with cars as the electrical signals driving on roads crisscrossing everywhere.
5:23
How does information travel in the brain?
5:26
Yeah, so for humans, for example, we have over 200 billion cells in the brain.
5:32
It's a ton, and half of those cells actually can create and move electricity.
5:39
When those cells create and move electricity,
5:41
can send those electricity down highways, right down highways and tunnels.
5:45
And in neuroscience, we tend to call those axons,
5:48
but they're basically highways and tunnels for electricity to move.
5:52
The cars are individual electrical signals,
5:54
and they move through our brains via neurons,
5:57
the cells in our brains that transmit information.
5:59
There are little gaps between each neuron called synapses,
6:02
and for the electrical signal to jump the gap,
6:05
it needs a chemical called a neurotransmitter to pass it along.
6:08
Those are the things like dopamine, serotonin, and noradrenaline.
6:11
For your brain to pass a message along,
6:13
the neuron releases a bunch of the neurotransmitter into the open space.
6:17
It binds to the next neuron, which triggers the electrical signal.
6:21
Then once the message gets sent,
6:23
those neurotransmitters unbind from the receptors,
6:26
get released back into the open space,
6:28
and then most are reabsorbed by the original neuron to be used again.
6:32
And while this is a nice, tidy system in lots of people,
6:35
people who struggle with mental illnesses
6:37
often don’t have the right amounts of the neurotransmitters they need
6:40
to keep the right parts of the brain actively signalling.
6:43
So what kind of treatments for psychiatric disorders currently exist,
6:47
and what are the benefits and downsides that you're trying to maintain or to solve for?
6:52
Brain cells release chemicals, which we call neurotransmitters,
6:56
and those neurotransmitters convey information to other cells.
7:00
So that is what people are typically targeting when they say, brain chemistry, right?
7:06
You're targeting either the synthesis or creation of these chemicals,
7:11
the release of these chemicals,
7:12
or the ability of these chemicals to connect with the other cells.
7:16
And many of our medications do that.
7:18
The greatest challenge with this, this class of chemistries,
7:23
is that the medication you take goes everywhere
7:27
And so it can have effects on cells that you don't want to be targeted
7:32
And so some of these same sort of connections or receptors,
7:36
things that connect to the chemistry, is in other parts of your body.
7:39
It's why you might take a medication for some form of psychiatric illness,
7:43
which may make you nauseous, right?
7:45
Because those same sort of connections,
7:47
those same sort of cells that produce electricity, are also in your gut.
7:50
Which is why Dzirasa thinks that looking at mental illness in a new way
7:54
could open up treatment opportunities for the people that can’t be helped
7:57
by what’s currently out there.
7:59
And it starts by considering the entire brain.
8:02
If you really want to understand the whole brain,
8:05
you have to look at what’s happening
8:06
with the flow of those electrical signals across regions,
8:10
and not just the chemicals in the synapses.
8:12
if you want to make sense of all of those cars and where they're going,
8:16
you ultimately need something like Google Maps or Waze, right?
8:19
Because there's constant movement
8:21
that you have to understand how all of those pieces are working together.
8:25
That's exactly why we ran into a problem.
8:27
Right?
8:27
As soon as you start thinking about how many cars are on the road,
8:31
you now need to make sense of the patterns.
8:34
What's changing from moment to moment and day to day?
8:37
So Dzirasa started studying the patterns of electrical activity that underlie emotions,
8:42
as well as what those patterns look like in people with psychiatric disorders,
8:46
or even people who are under a lot of stress.
8:48
We have this kind of electrical map for other body parts, by the way.
8:52
When a doctor wants to check how your heart is working,
8:54
they measure the electrical activity of your whole heart using something called an EKG.
8:59
Right, so I've had like, an EKG done before,
9:02
and that seems that, in itself, seems complicated,
9:05
but then you talk about the size of the brain.
9:07
So it's much, much harder to map something like the brain than it is the heart.
9:12
That's right, I came to appreciate this.
9:14
I'm also a physician, and so I also put those 12 leads of EKGs onto somebody's chest
9:21
to measure information, electrical information in the heart.
9:25
And from those, what we call 12 leads, or sort of 12, you know, stickers that you put on,
9:30
you can see 12 electrical waves.
9:32
So for each of those leads we put in the brain, we also get a wave.
9:38
But in this case, we're not getting 12 waves, we're getting 1000 waves.
9:43
And so you can see how quickly this becomes a challenge, right?
9:47
You're getting 1000 waves,
9:49
but then you're also getting another 2000, 3000 individual brain cells, in their activity,
9:56
and then you have to find patterns in all of that.
9:58
We want to find the patterns that show up over and over again
10:02
in this large electrical data set that includes brain waves like what you would get from EKG.
10:08
The data set, the scope of the brain, it's so much more complicated.
10:12
Electricity doesn't just flow in this direction.
10:14
It flows in every direction.
10:16
When Dzirasa was a postdoc researcher,
10:18
he decided he wanted to map how electrical activity in a mouse brain changes across time.
10:23
And he needed some very specific tech to be able to do it.
10:27
So, Dzirasa invented it himself.
10:29
It was the first example of Dzirasa using an engineering approach on a biological question.
10:34
We talked to lab manager Stephen Mague,
10:37
who walked us through some of the details.
10:39
So yeah. So this is how we build our electrodes in house,
10:42
based on an approach that Kaf developed when he was in grad school.
10:46
So we start off with a single wire.
10:48
As you can see,
10:49
I can barely see it!
10:50
That makes sense. It's only 50 microns in diameter.
10:54
And so this is tungsten wire that is insulated throughout so that only the exposed tip,
11:01
which will be implanted into the brain,
11:03
can record electricity and pass it along to the other end,
11:06
which will be attached to the other parts of the electrode.
11:10
And so we sort of gently put it into this grid,
11:14
and this allows us to tailor each electrode to the specifics or confirmation,
11:24
of the brain region that we want to target.
11:25
And so we can send those electrical pulses from one brain area down to the other.
11:31
If you look here on the screen, you can actually see those electrical pulses.
11:36
You can see them, and you can hear them,
11:38
and they sound like tiny crackles and pops in the background.
11:42
This is four different brain cells out of that 100 billion that can create electricity.
11:49
BRAIN AUDIO CRACKLE
11:54
That is the talking of brain cells sending that electrical information
11:58
down the highways and tunnels to other brain areas.
12:01
His ultimate goal is to create an electome,
12:04
which is like a genome, but for the human brain.
12:06
Can you tell me about the electome?
12:09
Yeah. So we came up with an idea.
12:12
It was, you know, 2015 or 2016
12:16
and the idea was having gone into the clinic and seeing what an EKG can do,
12:20
you could see the brain in action.
12:22
And from these patterns of these 12 leads,
12:25
you can determine what was going on with the heart.
12:27
We wondered if you could do the same type of thing with the brain.
12:31
So our idea was, well, maybe the brain generates emotions in the same way
12:36
by coordinating large parts of electrical activity together.
12:39
And could we find patterns,
12:41
which will say patterns of functional activity, or electrical activity,
12:46
and we ultimately call that the electome, electrical functional connectome.
12:51
And so you might have a pattern that shows up when you're happy,
12:54
or a pattern that shows up when you're sad,
12:57
or a pattern that shows up where you really want to hang out with your friends,
13:00
or a pattern that shows up when you might be a little bit anxious or scared.
13:04
And so that was the idea.
13:06
Could we discover these patterns in preclinical models,
13:10
and then see if these ultimately showed up in patients down the line as a diagnostic?
13:15
We as neuroscientists, have been pursuing this challenge for some time,
13:20
and we got really excited as a nation on this effort in around 2013.
13:27
There's a huge initiative launched called the BRAIN Initiative.
13:31
It's a great name for understanding the brain, right?
13:33
And the goal was to create a new class of technologies to make sense of the brain.
13:39
We realized at the time we were recording 20 or 30 brain cells at a time in preclinical models,
13:46
and we needed to get up into the 10s of 1000s or hundreds of 1000s.
13:50
Well, the brain is electricity, but it's also chemistry.
13:52
And so we also needed to create new sensors
13:56
for brain chemistry and brain electricity at the same time.
14:00
And then you needed machine learning or AI based tools to integrate all that information together,
14:05
and then that tells you sort of about physiology.
14:08
It's a massive undertaking,
14:10
but we're really optimistic about what this will tell us about the brain,
14:13
and ultimately, how changes in the brain produce illness
14:16
so that we can come up with treatments and cures.
14:18
Step one, build the map.
14:20
Step two, identify the road blocks.
14:23
Step three, figure out the detours!
14:26
It’s an exciting trajectory with a lot of potential,
14:29
even while we’re still at step one.
14:30
And one of their first big successes in building up these neurological highway maps
14:35
came when they identified the electrical signal network underlying stress resilience in mice.
14:40
Stress can work as a kind of switch that might turn
14:43
on any number of psychiatric disorders in certain people..
14:47
When I was training as a psychiatrist,
14:50
I would go in the hospital, and I would see different patients.
14:53
I kept seeing the same thing over and over,
14:55
and that was when they would end up in the inpatient psychiatric unit,
14:58
many of them had a major stressful event
15:02
a little bit before, right?
15:04
In some cases, somebody was having problems with a family member.
15:08
In some cases, the major stressor was just like a student going off
15:11
to college for the first time and missing home, the stress of exams.
15:15
So I what I ultimately came to realize was that if I understood
15:19
how stress triggered all of these things,
15:22
maybe I could come up with a brain pacemaker that helped with stress.
15:26
And if you do something like that,
15:27
maybe you can help everybody who might have problems down the line
15:31
before the problems start.
15:32
And they’re not just focused on the downers.
15:35
Long-term, they also want to understand other feelings or experiences
15:39
like love, pleasure, and even hunger.
15:42
He also wants to use those findings to correct the patterns
15:45
when they’re causing the symptoms of mental illnesses or neuropsychological disorders.
15:50
Dzirasa’s team is investigating a group of proteins called connexin proteins,
15:54
which sit on the ends of neurons.
15:56
Sticking with the whole roads analogy,
15:58
you could think of these proteins as two halves of a drawbridge.
16:02
The cars only get through when both halves are connected.
16:05
Not enough connections, and you get those neurological traffic jams,
16:09
or parts of the brain that should communicate, but don’t.
16:12
So if you need more cars to get through faster,
16:15
one way to do that might be building more bridges.
16:18
And in this case, they want to add more connexin proteins
16:21
to see if that makes signals travel better across neurons.
16:25
But not in humans, or even in mice.
16:28
This time, they wanted to look at worms.
16:31
I am Julia Derk, and I'm a senior scientist for Howard Hughes Medical Institute,
16:35
and I study Worms.
16:36
So why are C. elegans the right worm to use for this kind of study?
16:41
Yeah, so any invertebrate would be a clean system
16:44
because they express innexins,
16:46
not connexins.
16:47
So as opposed to …
16:49
We put the connexins into the mouse brain,
16:51
we have to worry about them potentially binding to something else in another connexin,
16:56
like their Connexin 36 is all over lots of neurons.
17:00
But the worms don't have that,
17:01
and so it's a really great way of understanding that the manipulation
17:05
is only really happening in that particular neuron subset and with those particular proteins.
17:11
So they’re basically adding in synthetic bridges
17:14
to see if the electrical signals would use them too.
17:17
It’s a specially engineered form of a connexin protein called LinCx.
17:21
LinCx stands for Long-term integration of circuits using connexin
17:25
Which is a mouthful.
17:26
So, LinCx for short.
17:27
But what's really wild is that we've now,
17:30
through mutagenesis of changing one amino acid at a time,
17:34
changed these Connexin proteins that are usually found in a white perch fish,
17:38
and so they should only bind to each other.
17:41
And that's really a huge component of what makes LinCx special
17:45
is that it's not any of the connexins that were found out in the wild.
17:49
It's slightly modified Connexin proteins that should only specifically dock to
17:55
and work with and bind to each other.
17:57
But then, they tried the DIY connexin proteins on mice,
18:00
which was trickier because they’re mammals, and mammals do have their own connexin proteins.
18:05
That means there’s the potential for the proteins to link up with ones that are already there,
18:10
and totally mess up the signalling.
18:12
One errant protein might result in your fancy bridge getting built to nowhere.
18:16
To overcome that problem, more engineering!
18:19
So we use viruses that target specific brain regions and or different cell types.
18:26
And so, for instance, a virus essentially is just a replication machine,
18:32
but we can sort of remove the parts of a virus that we don't,
18:36
you know, don't want, and don't want replicated,
18:38
but use the inherent machinery that basically replicates its own, own genome,
18:44
and then we can put in, put a splice in the parts that we want to have,
18:48
sort of made for us.
18:50
So you kind of scoop out the virus, stuff inside the virus,
18:54
and use it as a little delivery vehicle?
18:56
Exactly.
18:56
So what part of the brain are we looking at right now,
18:59
and what is it responsible for?
19:01
This part of the brain is called the striatum, or nucleus accumbens,
19:06
and it plays a really big role in how the brain experiences reward.
19:10
So in the case of illness like depression,
19:12
the activity in this part of the brain might be altered or changed or decreased.
19:17
So is the red that's showing up there, the Connexin protein.
19:21
That's exactly right.
19:22
What we're trying to do is see how well the Connexin proteins are expressing in these brains.
19:28
The idea is, in the future,
19:29
we will use this Connexin proteins as a potential treatment.
19:32
So we want to make sure that we can get them in the brain
19:36
and that they change the way the brain is functioning.
19:38
So the goal with all this is to find treatments for mental health disorders
19:42
that work for the people that can’t take traditional medications,
19:46
and to have another tool in the tool belt
19:48
when it comes to treatment-resistant disorders.
19:50
What would a treatment based on Connexin protein look like in a human eventually? Maybe?
19:56
If you want to get certain proteins in the body, it's pretty easy, right?
19:59
You can either ingest it, or if you go to the doctor and you have a syringe,
20:03
you can get an injection
20:04
Now, getting into the brain is a little more complicated,
20:06
because your brain has a lining that prevents things from getting in.
20:10
And as part of the BRAIN initiative,
20:13
they were creating tools to overcome that challenge of getting things in the brain.
20:18
One used this type of technology where they created nanoparticles,
20:23
these really small particles in which you can put things inside.
20:26
And you could use a device
20:28
to open up this barrier just slightly so the nanoparticles could go through.
20:32
This device uses sound energy, and so you basically put sound waves in the brain.
20:38
They gently shake the blood brain barrier,
20:39
it opens up and the nanoparticles go through.
20:41
It's called focused ultrasound.
20:43
If we get our connexin proteins inside these nanoparticles,
20:47
we could open up the blood brain barrier and it'll carry them into the brain.
20:50
The second type of tool that the field was creating was called adeno associated viruses,
20:56
or AAV viruses.
20:58
So the virus is sort of the delivery mechanism.
21:01
So down the line, that's sort of the treatment
21:05
that we could anticipate someone would go into the doctor's office, and in the doctor's office,
21:10
they might, one time in life, open up the blood brain barrier
21:13
or give them this essentially vaccine,
21:16
which carries the connection proteins to the right location in the brain,
21:19
forms these connections and then makes individuals more resilient to the impacts of stress.
21:26
Dzirasa’s work is pushing the boundaries of how we think about mental illness and psychiatric care.
21:31
These innovations could be the start of some truly phenomenal breakthroughs,
21:35
and help a lot of people who need it.
21:37
The road may be long, but at least we have people like Dzirasa building bridges.
21:43
SciShow Field Trips
21:44
are made with our friends at HHMI Tangled Bank Studios.
21:47
We’ve come together to bring you face to face
21:49
with researchers at the cutting edge of scientific discovery.
21:52
You can watch more of Tangled Bank’s science content
21:54
at tangledbankstudios.org.
21:57
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