Subtitle (366)
0:00Surgeons do surgery. Plumbers fix plumbing.
0:03Neuroscientists study neurons.
0:05No surprises, it's right there in the name.
0:07Except for that last one,
that's not always how it goes.
0:10In fact, this whole video is about a
neuroscientist who doesn't study neurons.
0:14She studies the other brain cells,
0:17the ones that generations of
neuroscientists completely ignored.
0:22And unlike neurons, nerve cells that
send chemical and electrical signals,
0:26glia are cells that scientists once thought of as
0:30little more than the glue that
held the neurons together.
0:33But Beth Stevens and her collaborators
are showing the world that these cells
0:38may be the key to understanding
Alzheimer's disease and Huntington's
0:42and schizophrenia and glaucoma and all
sorts of stuff that we want treatments for.
0:47That's exactly the kind of story
that inspired us to create this
0:50new series of videos called SciShow Field Trips,
0:53stories that call for a trip
outside of our comfy studio
0:57to see revolutionary science happening in the lab.
1:00So we sent our friend Jaida Elcock to
Boston to meet Stevens and learn why
1:04she had no intention of studying the thing
neuroscientists are supposed to study.
1:14Thanks, Hank. Today we're at
Boston Children's Hospital,
1:17which is just one of the many
places Beth Stevens does her work.
1:20She leads a giant team of
biochemists, computational biologists,
1:24psychologists, basically as
broad a group as she can find.
1:27Or maybe I should say as br-oh-d a group,
1:30since the lab is affiliated with the
Broad Institute of MIT and Harvard.
1:33The Stevens lab thrives thanks to this
diverse group of researchers bringing
1:36their perspectives together to answer
some huge questions about the brain.
1:39There are so many reasons
why having a group of people
1:42coming together that have
different backgrounds is really
1:45what makes science really
innovative and really exciting.
1:47I have immunologists in the lab,
I have geneticists in my lab,
1:50I have computational biologists in my lab.
1:52It really enables us to come up
with new ideas and to follow sort of
1:56new leads of science that I think are
taking us into some exciting directions.
2:00Obviously, there are billions of
neurons and trillions of synapses.
2:04It's very complex, right?
2:06But in the end of the day, if
you were to zoom in on any one of
2:08those circuits in the brain, you'd see all
these amazing connections and synapses,
2:12but underlying all those neurons, if you
could then label all the other cells,
2:17including the glia, you realize
that every one of those circuits
2:21contains all of those glia, right?
2:23And they're also intertwined
throughout the nervous system.
2:26Stevens and her team think glia might
explain why some of us stay mentally sharp
2:31into our 90s, and others face
severe cognitive decline,
2:34why some cells survive the
brain's spring cleaning process,
2:37and others are swept away, why everyone
wants to park the car in Harvard yard,
2:41even though you literally can't drive in there!
2:43Okay, that last one's a joke.
2:45What I'm trying to convey is Stevens is a badass,
2:47but all superstar scientists
had to start somewhere.
2:50And Stevens, like the cells she now
studies, was a little overlooked at first.
2:54I was just out of college.
2:55I had no idea what the NIH
really was all about back then,
2:58but I showed up and I put in my resume
3:01and then nothing because I
had no experience, really.
3:05And so I had to then figure out
how I was going to pay rent.
3:09So, I got a job as a waitress, and I
worked at Chili's, and I waited tables,
3:14and I carried fajitas over my head.
3:15And I kept putting my resume in
every single week until eventually
3:19I got a cold call from what then became,
3:22who then became my mentor, Doug
Fields, Doctor Doug Fields.
3:26He was looking for a technician and he
somehow, you know, found my application,
3:31and the rest was sort of history.
3:32I had an opportunity to
work in a neuroscience lab.
3:36And from there, I learned a
ton, and he gave me a chance.
3:40And it kind of took me on this path to
studying neuroscience and then glial cells.
3:44For more than a century after
their discovery in the 1850s,
3:48glia had a reputation as the
boring support crew for neurons.
3:51But Stevens and an early
collaborator, Douglas Fields,
3:54found some pretty convincing
reasons to care about them,
3:56like the fact that neurons depend on
glia to communicate with other neurons.
4:00You're able to think and move and
taste and do pretty much everything
4:04you do because one of your neurons
sends a signal to another neuron.
4:07If you can tell that you're
looking at a screen right now,
4:10it's because the neurons that are sensitive
to light can detect what's in front of you
4:13and communicate that information to neurons
4:15deeper in the brain that
can make sense of the image.
4:18This communication from one neuron to
another can take the form of electricity
4:22flowing along the long arms of the first neuron,
4:25reaching out towards the second neuron.
4:26Those arms are called axons, and the
electrical message traveling down
4:30the axon is facilitated by a
layer of insulation called myelin.
4:34But myelin doesn't just exist out of nowhere.
4:37And that's where glia come in.
4:39They add the myelin to axons
so that you can experience
4:42the world and function in it.
4:43But that also doesn't just happen.
4:45The complex dance of neurons needing
myelin, asking glia to help them out,
4:49and glia adding myelin to their axons requires
4:52a lot of communication between neurons and glia.
4:55And that's what Stevens put her
finger on in the Fields lab.
4:58We sort of early on realized that,
well, we shouldn't just study
5:01this from the neuron centric point of view.
5:04Like, what about, you know, how the
glia are regulating this process?
5:07And I think that is really where I came into this.
5:11But initially starting to study the
myelination process and how this is
5:15a really active communication
going on between the neurons
5:18and the glia that enables that wrapping process.
5:21But then later also at the synapse itself,
5:24all these non neuronal cells like
astrocytes and like microglia,
5:29they're also helping to build and also
refine these synaptic connections.
5:33And the big question we have been
asking is how what are the signals,
5:37what are the mechanisms and how does that work?
5:40Just like a wire is insulated, an axon,
5:43which can in some cases go the length of
a spinal cord all the way up to the brain.
5:48So to make that signal go all the way in
those long distances, it has insulation.
5:53And turns out the insulation is made by the glia.
5:56They wrap their long processes around axons.
6:00And that is enabling these sort of
electrical signals to move very efficiently.
6:05So those are myelinated axons,
right, to some extent red.
6:09So we talked, we started off
talking a lot about that insulation.
6:12There's the insulation in a mouse brain.
6:15I'm kind of thinking of it as like the neurons
and the glia are both sort of electricians.
6:20And the neurons are like, hey, we need
more electrical tape on this wire.
6:23And they're like, all right, I'm on
it. I'll go get the electrical tape.
6:27That is one definite way of describing,
and it makes a lot of sense.
6:30I think the other thing that we've
realized is that that insulation
6:33does more than just increase
the efficiency of a signal.
6:37Those glial cells release
a lot of important signals
6:39that keep neurons and axons healthy.
6:42And so when that doesn't happen
anymore, that can also lead to,
6:47you know, these, these, these kind
of neurodegenerative conditions
6:50that can lead to unhealthy
synapses in axons and neurons.
6:54Her discovery of glia in the myelination
process kickstarted her career.
6:58It turned Beth Stevens into Doctor Beth Stevens,
7:01but that was just the beginning of her
fascination with these overlooked cells.
7:05As she told colleagues about her research,
7:07the NIH director of the National Institute
of Neurological Diseases and Stroke
7:11personally encouraged her to
keep heading down that road.
7:14This led her to the lab of a trailblazer
in glial research, Ben Barres.
7:18When I was still at the NIH, I was studying
this process of myelination and realized,
7:23wow, it's not just sort of the support of glia.
7:26There's these dynamic interactions and
crosstalk going on along those long axons.
7:30At that time, the Barres lab was studying this
7:33dynamic crosstalk at those synaptic junctions.
7:36So that's where I'm like, wow,
I want to learn more about that.
7:39I want to learn more about
how synapses are forming,
7:41how they're developing, how
they're being remodeled.
7:44Ben Barres was the guy who discovered that glia
7:47are pretty badass in their own right.
7:48He showed everyone that glia can
communicate using neurotransmitters
7:52and other molecules, so they were much more
7:54interesting than almost everyone thought.
7:56Neurons released signals to the glia that
say, okay, it's time to do something.
8:00And similarly, the glia released signals that
tell the neuron it's time to do something.
8:04Okay, so we should be thinking
about this as a two way
8:07dynamic conversation between the
non neuronal cells and the neurons.
8:11By the time Stevens joined the lab,
neuroscientists knew the basics of how
8:15the brain sets up neuron to neuron communications.
8:17A bunch of neurons make a bunch of axons.
8:20Some of them get myelinated by glia
and become stronger connections,
8:23while others are removed so you
don't waste your resources on them.
8:26This removal of excess inputs is called pruning,
8:29and it works just like pruning a tree.
8:31The idea is that, you know, you sort of
have sort of an excess of connections,
8:36and that's actually probably
good because you sort of
8:38have extra connections there ready to go.
8:40But then some of those connections
become meaningful, right?
8:43Where that's going to be
important for a particular action
8:47or particular kind of cognitive function.
8:50Some of those connections get strengthened.
8:51The ones that are meaningful and the
less relevant inputs get pruned away.
8:55So it's just sort of like, you
know, use it or lose that idea.
8:58At that point in time, neuroscientists
knew that you needed pruning,
9:02but they didn't fully understand how it worked.
9:04Stevens realized that there might
be a hint in the world of immunology
9:08where cells called macrophages act as
a kind of cleanup crew in the body.
9:12There's a lot known about how macrophages work.
9:14They help defend our body against
things like infections, right.
9:17They are really good at engulfing
or removing unwanted cells' debris,
9:24including bacteria, for example.
9:26So they do this by recognizing molecules
like they call "eat me" signals
9:31that essentially coat the surface of that
cell and through receptors on their surface
9:36that enables them both to
recognize and actually engulf.
9:39And almost every tissue in
your body has macrophages.
9:43Interestingly, some of those Eat
Me signals were showing up in
9:46the developing brain, but only on some neurons.
9:48The signals were complement proteins,
9:51which is a term borrowed from immunology.
9:53So it turns out that there were a lot of these
9:57complement molecules in the healthy brain.
9:59And it also made us realize, well, the
brain has a macrophage called microglia
10:05that had very similar receptors that
recognize these complement molecules.
10:10So that led us to wonder, instead of
removing a pathogen or unwanted debris
10:14in the body, could they be
playing a similar role in removing
10:18these extra synapses during development?
10:20And that's really what launched
a lot of the work I did
10:22as a postdoc in the Barres lab.
10:24And it really began the foundational
work that launched my lab here.
10:27This is an example of one microglia in green.
10:31And now you're looking at some synapses.
10:34So every one of these bumps are the
ending of an axon, a synaptic input.
10:38Some of them are touching.
10:40And we can also stain the brain
sections not only with synapses,
10:46but with these "eat me" signals like
complement, which is what's shown here.
10:50So in this case, it looks like the red
is a complement molecule called C3,
10:57and the green is a synaptic marker.
10:59And you can see if you were to
zoom in, you can see that there's
11:01almost like a tagging of
subsets of those synapses.
11:04The microglia are kind of our
gardeners of our neurological garden
11:09to make sure that we have everything
looking pretty and working properly.
11:13Exactly. What we're finding is that the
microglia help to do this sort of fine tuning
11:18and pruning and remodeling of connections.
11:21One of the ways that pruning happens is
through literally nibbling off and eating,
11:25which is what we've been studying with complement.
11:26So as it turns out, microglia play a really
11:29important role in pruning
during healthy development.
11:32But by the time you're an adult, that
process is supposed to shut down.
11:35When Stephens published some
of her findings in 2007,
11:38she hinted that pruning might
be a problem later in life.
11:41Could some of these same mechanisms
we've been studying in the healthy,
11:44developing brain become kind
of almost, like, reactivated?
11:48If you look at a couple of
animal models of Alzheimer's,
11:51do we see complement tagging
those vulnerable synapses?
11:55And indeed very early on using
multiple different models,
11:58we saw some evidence of these
sort of "eat me" signals.
12:01And those microglia that have all
these other roles beyond pruning,
12:06also started looking a little different.
12:07And they had evidence that they might
also be kind of engulfing these synapses.
12:12So we said if we block the "eat me"
signals or the receptors on microglia
12:16that recognize and enables them to engulf
and nibble off these synapses, right.
12:20Is that a good thing?
12:21Can we protect synapses?
12:22And if so, does that at least
for a mouse, does that help them,
12:25you know, to do better cognitively?
12:28And the answer, at least in
these animal models, was yes.
12:31Suddenly glia were at the
center of the pruning story and
12:33connected to one of the most challenging
diseases of the brain to study.
12:37So how did other neuroscientists kind
of respond to these findings about glia?
12:41Were there a lot of people talking
about these at neuroscience conferences?
12:44Back when I started out?
12:45No. Well, I would say if I think about
a typical neuroscience conference,
12:51there were very few talks or
posters that kind of focused on,
12:55you know, neuro immunology back then.
12:57So when we started initially, sort
of publishing our work there were
13:01definitely questions and almost some
skepticism that this was going on.
13:05So if you're a neuroscientist
with an underappreciated
13:09appreciation for glia, where do you go?
13:11You give a speech at an immunology seminar.
13:13I can remember being invited,
as a new faculty member in the
13:18neuroscience department
here at Children's Hospital
13:21to give a talk in the big
immunology lecture series.
13:24I think I'd only been in the lab about a year.
13:26I was petrified, really petrified.
13:29Because I had never really
formally studied immunology.
13:32Of course, I read a lot, and I learned
a lot about complement, for example.
13:37But the idea of getting up in front of
this group of experienced immunologists
13:42and then presenting this work, was
very, sort of unnerving, if you will.
13:48But I decided to do it anyway.
13:50And it was probably one of the most
important lectures of my career,
13:54not because of the talk itself,
but because I communicated
13:59the same story I'd been giving to neuroscientists.
14:01But the questions I got and the ideas that stemmed
14:05from those questions were really
unique to the immunology community.
14:09They were seeing connections that
I could not possibly have seen
14:12based on their own experience and
their own expertise in immunology.
14:16And that sparked lots of new projects
in the lab, lots of new questions,
14:20new collaborations that
continue to drive our research.
14:23That talk essentially launched the Stevens Lab,
14:26which started with two main projects
that she wanted to investigate.
14:29One was to continue basic
research into how microglia
14:32and those complement proteins
operate in the brain.
14:35The other was a project applying all of
these new findings to Alzheimer's disease.
14:39So, as Beth mentioned, we're very interested
14:42in what we call the borders of the brain.
14:44And the particular border
that we're studying here is
14:47the outermost layer of the
meninges or the dura mater.
14:51And the really important thing
about the dura mater is that
14:53it's a key immune hub for
the central nervous system.
14:58So if we take a look at the screen,
we have a skull cap from a mouse.
15:03Our goal here is to actually
extract this meninges in one piece
15:08so that we can better study the
types of immune cells that are there.
15:11And I'm just going to start by kind
of grabbing onto the skull cap here
15:15and starting to cut around using
this small pair of scissors
15:18to just trim the skull down to kind
of a consistent size like this.
15:23So now that I've cut the skull,
15:26I want to go back and carefully start
to peel the meninges out of the skull.
15:30But we can start by kind of grabbing the meninges
15:32at the edge of the skull and
starting to peel it away.
15:35Here again, being very careful
not to scrape the bone too much.
15:40And so, you know, once we are
able to extract the meninges,
15:43we study it in many different ways.
15:45We do a lot of imaging on the meninges.
15:48So we actually can take this whole piece out,
15:51stain it again with different
antibodies, and learn more about where
15:54these different types of immune cells
are and with whom they may interact.
15:59Stevens also makes sure that the people
working on the two big projects in her lab
16:04are talking to each other regularly,
16:06because she has seen how much of a
difference that can make for breakthroughs.
16:09The work I talked about on
complement was one example
16:11where I clearly could benefit from
an immunologist to kind of help us
16:16think more about how to study
these immune molecules more deeply,
16:20but also provide new perspectives and
new ideas, new techniques and approaches
16:24that immunologists use that, you know,
neuroscientists might not think to use.
16:28By learning about glia and
Alzheimer's in tandem with each other,
16:31the Stevens lab is making huge discoveries today.
16:34There are already some good
biomarkers in Alzheimer's disease.
16:37A lot of focus has been on this amyloid,
this toxic protein in the brain.
16:40And tau, another misfolded protein that can be
16:43very harmful to neurons and synapses.
16:45But what it doesn't capture is what's happening
16:48to the immune cells and the microglia.
16:51Could they also be combined
with those other markers
16:54to try to then bring the
microglia into the picture?
16:57To be able to both stratify
patients, try to understand
16:59where they are and disease progression.
17:01And many of these patients have
multiple different pathologies.
17:04There's not, at this time, a way
to be able to disentangle that.
17:07So a lot of the work going on in
the lab, but also in the field,
17:10is to try to then try to translate some
of the findings that we're uncovering here
17:15into new biomarkers that one can
read out in a non-invasive way
17:19to see how these microglia are
changing across disease in humans.
17:23But the reason glia research
is so groundbreaking right now
17:26isn't just for their involvement in Alzheimer's.
17:29They're such fundamental cells in your brain that
17:31understanding them better has huge
potential to explain all sorts of diseases.
17:35So it's not just Alzheimer's disease.
17:38There's now evidence to suggest
that some of these immune
17:40and glial related mechanisms could be relevant
17:42across many other brain disorders as well,
17:45ranging from ALS to Huntington's
disease, Parkinson's and others.
17:48So there's a lot of people in
the field becoming increasingly
17:51interested in the immune
system and in glial cells,
17:55in this case, because the genetics
are really pointing right to them.
17:58And more and more, we're finding that
there is a desire and an excitement
18:03to start working together, because
what one person found in one, you know,
18:07experiment in their lab may very much
relate to what we're interested in,
18:10but they don't know what we're
talking about or working on.
18:12How would they ever connect the dots?
18:13Exactly. So we're really starting
to realize if we're going to tackle
18:16really hard problems like understanding
neurodegenerative disease or,
18:20you know, brain development, we
need to team up and work with folks,
18:24you know, in many different contexts.
18:25And I think that's going to change not
only how rapidly we make discoveries,
18:29but also much more fun to work with people
18:31that are sharing their insights and data.
18:34So are the tides changing a little bit?
18:37Are neuroscientists you know,
becoming more interested in glia?
18:41Oh yes. I think that that is just so much more.
18:46If you walk into, let's say, one of the biggest
18:48neuroscience conferences in
our field is international.
18:52It's called the Society for Neuroscience meeting,
18:53and it used to be when I was starting out,
18:56you could search for glia and you would
see a few talks, a few rows of posters.
19:02Fast forward now, 20 years later, you search glia.
19:06It's in every row, every talk, one way or another.
19:09Even if it's not the main title, it's coming up.
19:12Right? Because, you know, glia are
part of the brain, not surprisingly.
19:16And, neuroscientists and glial
biologists are no longer separate fields.
19:20I think that is more and more
evident now than ever before.
19:22And I'm so happy that's the case.
19:23There's just no end to where to take this,
19:26because there's so many unanswered
questions a lot of them really took away.
19:29Thanks to Stevens and other
like-minded researchers,
19:32the cells nobody cared about
are now widely recognized as
19:36the key to understanding some of
the brain's biggest mysteries.
19:41SciShow Field Trips are made with our
friends at HHMI Tangled Bank Studios.
19:45We've come together to bring you
face to face with researchers
19:48at the cutting edge of scientific discovery.
19:50You can watch more of Tangled Bank's
science content at tangledbankstudios.org.
