Surgeons do surgery.

Plumbers fix plumbing. Neuroscientists study neurons.

No surprises, it's right there in the name. Except for that last one,  that's not always how it goes. In fact, this whole video is about a  neuroscientist who doesn't study neurons.

She studies the other brain cells, the ones that generations of  neuroscientists completely ignored. They're called glia. And unlike neurons, nerve cells that  send chemical and electrical signals, glia are cells that scientists once thought of as little more than the glue that  held the neurons together.

But Beth Stevens and her collaborators  are showing the world that these cells may be the key to understanding  Alzheimer's disease and Huntington's and schizophrenia and glaucoma and all  sorts of stuff that we want treatments for. That's exactly the kind of story  that inspired us to create this new series of videos called SciShow Field Trips, stories that call for a trip  outside of our comfy studio to see revolutionary science happening in the lab. So we sent our friend Jaida Elcock to  Boston to meet Stevens and learn why she had no intention of studying the thing  neuroscientists are supposed to study. [♪ INTRO] Thanks, Hank.

Today we're at  Boston Children's Hospital, which is just one of the many  places Beth Stevens does her work. She leads a giant team of  biochemists, computational biologists, psychologists, basically as  broad a group as she can find. Or maybe I should say as br-oh-d a group, since the lab is affiliated with the  Broad Institute of MIT and Harvard.

The Stevens lab thrives thanks to this  diverse group of researchers bringing their perspectives together to answer  some huge questions about the brain. There are so many reasons  why having a group of people coming together that have  different backgrounds is really what makes science really  innovative and really exciting. I have immunologists in the lab,  I have geneticists in my lab, I have computational biologists in my lab.

It really enables us to come up  with new ideas and to follow sort of new leads of science that I think are  taking us into some exciting directions. Obviously, there are billions of  neurons and trillions of synapses. It's very complex, right?

But in the end of the day, if  you were to zoom in on any one of those circuits in the brain, you'd see all  these amazing connections and synapses, but underlying all those neurons, if you  could then label all the other cells, including the glia, you realize  that every one of those circuits contains all of those glia, right? And they're also intertwined  throughout the nervous system. Stevens and her team think glia might  explain why some of us stay mentally sharp into our 90s, and others face  severe cognitive decline, why some cells survive the  brain's spring cleaning process, and others are swept away, why everyone  wants to park the car in Harvard yard, even though you literally can't drive in there!

Okay, that last one's a joke. What I'm trying to convey is Stevens is a badass, but all superstar scientists  had to start somewhere. And Stevens, like the cells she now  studies, was a little overlooked at first.

I was just out of college. I had no idea what the NIH  really was all about back then, but I showed up and I put in my resume and then nothing because I  had no experience, really. And so I had to then figure out  how I was going to pay rent.

So, I got a job as a waitress, and I  worked at Chili's, and I waited tables, and I carried fajitas over my head. And I kept putting my resume in  every single week until eventually I got a cold call from what then became, who then became my mentor, Doug  Fields, Doctor Doug Fields. He was looking for a technician and he  somehow, you know, found my application, and the rest was sort of history.

I had an opportunity to  work in a neuroscience lab. And from there, I learned a  ton, and he gave me a chance. And it kind of took me on this path to  studying neuroscience and then glial cells.

For more than a century after  their discovery in the 1850s, glia had a reputation as the  boring support crew for neurons. But Stevens and an early  collaborator, Douglas Fields, found some pretty convincing  reasons to care about them, like the fact that neurons depend on  glia to communicate with other neurons. You're able to think and move and  taste and do pretty much everything you do because one of your neurons  sends a signal to another neuron.

If you can tell that you're  looking at a screen right now, it's because the neurons that are sensitive  to light can detect what's in front of you and communicate that information to neurons deeper in the brain that  can make sense of the image. This communication from one neuron to  another can take the form of electricity flowing along the long arms of the first neuron, reaching out towards the second neuron. Those arms are called axons, and the  electrical message traveling down the axon is facilitated by a  layer of insulation called myelin.

But myelin doesn't just exist out of nowhere. You have to make it. And that's where glia come in.

They add the myelin to axons  so that you can experience the world and function in it. But that also doesn't just happen. The complex dance of neurons needing  myelin, asking glia to help them out, and glia adding myelin to their axons requires a lot of communication between neurons and glia.

And that's what Stevens put her  finger on in the Fields lab. We sort of early on realized that,  well, we shouldn't just study this from the neuron centric point of view. Like, what about, you know, how the  glia are regulating this process?

And I think that is really where I came into this. But initially starting to study the  myelination process and how this is a really active communication  going on between the neurons and the glia that enables that wrapping process. But then later also at the synapse itself, all these non neuronal cells like  astrocytes and like microglia, they're also helping to build and also  refine these synaptic connections.

And the big question we have been  asking is how what are the signals, what are the mechanisms and how does that work? Just like a wire is insulated, an axon, which can in some cases go the length of  a spinal cord all the way up to the brain. So, very long.

So to make that signal go all the way in  those long distances, it has insulation. And turns out the insulation is made by the glia. They wrap their long processes around axons.

And that is enabling these sort of  electrical signals to move very efficiently. So those are myelinated axons,  right, to some extent red. So we talked, we started off  talking a lot about that insulation.

There's the insulation in a mouse brain. I'm kind of thinking of it as like the neurons  and the glia are both sort of electricians. And the neurons are like, hey, we need  more electrical tape on this wire.

And they're like, all right, I'm on  it. I'll go get the electrical tape. That is one definite way of describing,  and it makes a lot of sense.

I think the other thing that we've  realized is that that insulation does more than just increase  the efficiency of a signal. Those glial cells release  a lot of important signals that keep neurons and axons healthy. And so when that doesn't happen  anymore, that can also lead to, you know, these, these, these kind  of neurodegenerative conditions that can lead to unhealthy  synapses in axons and neurons.

Her discovery of glia in the myelination  process kickstarted her career. It turned Beth Stevens into Doctor Beth Stevens, but that was just the beginning of her  fascination with these overlooked cells. As she told colleagues about her research, the NIH director of the National Institute  of Neurological Diseases and Stroke personally encouraged her to  keep heading down that road.

This led her to the lab of a trailblazer  in glial research, Ben Barres. When I was still at the NIH, I was studying  this process of myelination and realized, wow, it's not just sort of the support of glia. There's these dynamic interactions and  crosstalk going on along those long axons.

At that time, the Barres lab was studying this dynamic crosstalk at those synaptic junctions. So that's where I'm like, wow,  I want to learn more about that. I want to learn more about  how synapses are forming, how they're developing, how  they're being remodeled.

Ben Barres was the guy who discovered that glia are pretty badass in their own right. He showed everyone that glia can  communicate using neurotransmitters and other molecules, so they were much more interesting than almost everyone thought. Neurons released signals to the glia that  say, okay, it's time to do something.

And similarly, the glia released signals that  tell the neuron it's time to do something. Okay, so we should be thinking  about this as a two way dynamic conversation between the  non neuronal cells and the neurons. By the time Stevens joined the lab,  neuroscientists knew the basics of how the brain sets up neuron to neuron communications.

A bunch of neurons make a bunch of axons. Some of them get myelinated by glia  and become stronger connections, while others are removed so you  don't waste your resources on them. This removal of excess inputs is called pruning, and it works just like pruning a tree.

The idea is that, you know, you sort of  have sort of an excess of connections, and that's actually probably  good because you sort of have extra connections there ready to go. But then some of those connections  become meaningful, right? Where that's going to be  important for a particular action or particular kind of cognitive function.

Some of those connections get strengthened. The ones that are meaningful and the  less relevant inputs get pruned away. So it's just sort of like, you  know, use it or lose that idea.

At that point in time, neuroscientists  knew that you needed pruning, but they didn't fully understand how it worked. Stevens realized that there might  be a hint in the world of immunology where cells called macrophages act as  a kind of cleanup crew in the body. There's a lot known about how macrophages work.

They help defend our body against  things like infections, right. They are really good at engulfing  or removing unwanted cells' debris, including bacteria, for example. So they do this by recognizing molecules  like they call "eat me" signals that essentially coat the surface of that  cell and through receptors on their surface that enables them both to  recognize and actually engulf.

And almost every tissue in  your body has macrophages. Interestingly, some of those Eat  Me signals were showing up in the developing brain, but only on some neurons. The signals were complement proteins, which is a term borrowed from immunology.

So it turns out that there were a lot of these complement molecules in the healthy brain. And it also made us realize, well, the  brain has a macrophage called microglia that had very similar receptors that  recognize these complement molecules. So that led us to wonder, instead of  removing a pathogen or unwanted debris in the body, could they be  playing a similar role in removing these extra synapses during development?

And that's really what launched  a lot of the work I did as a postdoc in the Barres lab. And it really began the foundational  work that launched my lab here. This is an example of one microglia in green.

And now you're looking at some synapses. So every one of these bumps are the  ending of an axon, a synaptic input. Some of them are touching.

And we can also stain the brain  sections not only with synapses, but with these "eat me" signals like  complement, which is what's shown here. So in this case, it looks like the red  is a complement molecule called C3, and the green is a synaptic marker. And you can see if you were to  zoom in, you can see that there's almost like a tagging of  subsets of those synapses.

The microglia are kind of our  gardeners of our neurological garden to make sure that we have everything  looking pretty and working properly. Exactly. What we're finding is that the  microglia help to do this sort of fine tuning and pruning and remodeling of connections.

One of the ways that pruning happens is  through literally nibbling off and eating, which is what we've been studying with complement. So as it turns out, microglia play a really important role in pruning  during healthy development. But by the time you're an adult, that  process is supposed to shut down.

When Stephens published some  of her findings in 2007, she hinted that pruning might  be a problem later in life. Could some of these same mechanisms  we've been studying in the healthy, developing brain become kind  of almost, like, reactivated? If you look at a couple of  animal models of Alzheimer's, do we see complement tagging  those vulnerable synapses?

And indeed very early on using  multiple different models, we saw some evidence of these  sort of "eat me" signals. And those microglia that have all  these other roles beyond pruning, also started looking a little different. And they had evidence that they might  also be kind of engulfing these synapses.

So we said if we block the "eat me"  signals or the receptors on microglia that recognize and enables them to engulf  and nibble off these synapses, right. Is that a good thing? Can we protect synapses?

And if so, does that at least  for a mouse, does that help them, you know, to do better cognitively? And the answer, at least in  these animal models, was yes. Suddenly glia were at the  center of the pruning story and connected to one of the most challenging  diseases of the brain to study.

So how did other neuroscientists kind  of respond to these findings about glia? Were there a lot of people talking  about these at neuroscience conferences? Back when I started out?

No. Well, I would say if I think about  a typical neuroscience conference, there were very few talks or  posters that kind of focused on, you know, neuro immunology back then. So when we started initially, sort  of publishing our work there were definitely questions and almost some  skepticism that this was going on.

So if you're a neuroscientist  with an underappreciated appreciation for glia, where do you go? You give a speech at an immunology seminar. I can remember being invited,  as a new faculty member in the neuroscience department  here at Children's Hospital to give a talk in the big  immunology lecture series.

I think I'd only been in the lab about a year. I was petrified, really petrified. Because I had never really  formally studied immunology.

Of course, I read a lot, and I learned  a lot about complement, for example. But the idea of getting up in front of  this group of experienced immunologists and then presenting this work, was  very, sort of unnerving, if you will. But I decided to do it anyway.

And it was probably one of the most  important lectures of my career, not because of the talk itself,  but because I communicated the same story I'd been giving to neuroscientists. But the questions I got and the ideas that stemmed from those questions were really  unique to the immunology community. They were seeing connections that  I could not possibly have seen based on their own experience and  their own expertise in immunology.

And that sparked lots of new projects  in the lab, lots of new questions, new collaborations that  continue to drive our research. That talk essentially launched the Stevens Lab, which started with two main projects  that she wanted to investigate. One was to continue basic  research into how microglia and those complement proteins  operate in the brain.

The other was a project applying all of  these new findings to Alzheimer's disease. So, as Beth mentioned, we're very interested in what we call the borders of the brain. And the particular border  that we're studying here is the outermost layer of the  meninges or the dura mater.

And the really important thing  about the dura mater is that it's a key immune hub for  the central nervous system. So if we take a look at the screen,  we have a skull cap from a mouse. Our goal here is to actually  extract this meninges in one piece so that we can better study the  types of immune cells that are there.

And I'm just going to start by kind  of grabbing onto the skull cap here and starting to cut around using  this small pair of scissors to just trim the skull down to kind  of a consistent size like this. So now that I've cut the skull, I want to go back and carefully start  to peel the meninges out of the skull. But we can start by kind of grabbing the meninges at the edge of the skull and  starting to peel it away.

Here again, being very careful  not to scrape the bone too much. And so, you know, once we are  able to extract the meninges, we study it in many different ways. We do a lot of imaging on the meninges.

So we actually can take this whole piece out, stain it again with different  antibodies, and learn more about where these different types of immune cells  are and with whom they may interact. Stevens also makes sure that the people  working on the two big projects in her lab are talking to each other regularly, because she has seen how much of a  difference that can make for breakthroughs. The work I talked about on  complement was one example where I clearly could benefit from  an immunologist to kind of help us think more about how to study  these immune molecules more deeply, but also provide new perspectives and  new ideas, new techniques and approaches that immunologists use that, you know,  neuroscientists might not think to use.

By learning about glia and  Alzheimer's in tandem with each other, the Stevens lab is making huge discoveries today. There are already some good  biomarkers in Alzheimer's disease. A lot of focus has been on this amyloid,  this toxic protein in the brain.

And tau, another misfolded protein that can be very harmful to neurons and synapses. But what it doesn't capture is what's happening to the immune cells and the microglia. Could they also be combined  with those other markers to try to then bring the  microglia into the picture?

To be able to both stratify  patients, try to understand where they are and disease progression. And many of these patients have  multiple different pathologies. There's not, at this time, a way  to be able to disentangle that.

So a lot of the work going on in  the lab, but also in the field, is to try to then try to translate some  of the findings that we're uncovering here into new biomarkers that one can  read out in a non-invasive way to see how these microglia are  changing across disease in humans. But the reason glia research  is so groundbreaking right now isn't just for their involvement in Alzheimer's. They're such fundamental cells in your brain that understanding them better has huge  potential to explain all sorts of diseases.

So it's not just Alzheimer's disease. There's now evidence to suggest  that some of these immune and glial related mechanisms could be relevant across many other brain disorders as well, ranging from ALS to Huntington's  disease, Parkinson's and others. So there's a lot of people in  the field becoming increasingly interested in the immune  system and in glial cells, in this case, because the genetics  are really pointing right to them.

And more and more, we're finding that  there is a desire and an excitement to start working together, because  what one person found in one, you know, experiment in their lab may very much  relate to what we're interested in, but they don't know what we're  talking about or working on. How would they ever connect the dots? Exactly.

So we're really starting  to realize if we're going to tackle really hard problems like understanding  neurodegenerative disease or, you know, brain development, we  need to team up and work with folks, you know, in many different contexts. And I think that's going to change not  only how rapidly we make discoveries, but also much more fun to work with people that are sharing their insights and data. Yeah, absolutely.

So are the tides changing a little bit? Are neuroscientists you know,  becoming more interested in glia? Oh yes.

I think that that is just so much more. If you walk into, let's say, one of the biggest neuroscience conferences in  our field is international. It's called the Society for Neuroscience meeting, and it used to be when I was starting out, you could search for glia and you would  see a few talks, a few rows of posters.

Fast forward now, 20 years later, you search glia. It's in every row, every talk, one way or another. Even if it's not the main title, it's coming up.

Right? Because, you know, glia are  part of the brain, not surprisingly. And, neuroscientists and glial  biologists are no longer separate fields.

I think that is more and more  evident now than ever before. And I'm so happy that's the case. There's just no end to where to take this, because there's so many unanswered  questions a lot of them really took away.

Thanks to Stevens and other  like-minded researchers, the cells nobody cared about  are now widely recognized as the key to understanding some of  the brain's biggest mysteries. SciShow Field Trips are made with our  friends at HHMI Tangled Bank Studios. We've come together to bring you  face to face with researchers at the cutting edge of scientific discovery.

You can watch more of Tangled Bank's  science content at tangledbankstudios.org. [♪ OUTRO]