#3. The brain's immune cells | Makis Tzioras
Weekend at last! 💃🏿
How have you all been? I’m quite busy writing up my PhD an last month was a tough one on my end, not going to lie - but hey, my parents got vaccinated, so there’s that! And here is Episode #3!
This time, my guest is a fellow neuroscientist who studies the immune cells that live in the brain to work out what they’re up to when we’re healthy - and when we’re not. I cannot wait for y’all to meet Makis Tzioras. We also speak about ‘negative results’, staying sane in academia and Taylor Swift. Bonus: you will find out how to check if a mouse is dementing. The things you learn with this show…
Thank you everyone for your support, please keep spreading the word :)
Pablo
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Episode transcript
Your brain is not just full of neurons connected to each other, there are other cells living in it too. This includes immune cells which rush into the brain from the blood when you're just an embryo, and stay there ever since. In fact, about one in 10 cells inside your brain are immune cells, constantly scanning their surroundings to keep your brain in check.
They were first discovered by a Spanish scientist called Pío del Río Hortega. Hortega started off as a medic in a rural town but decided to move to Madrid to do research. He was shy and short and scrawny. He was also gay and very left wing. None of these things were helpful then and there - that was Spain 100 years ago. He used to work under Cajal. But their relationship wasn't always easy, either. Of Cajal, he said “he made me happy and bitter, stimulated and depressed.” Hortega got nominated for the Nobel Prize in Medicine twice, but unlike Cajal, he never won it. There was one thing, however, where he outperformed his mentor.
By tweaking the methods they used to stain brain samples, Hortega was capable of identifying cells that no one had quite spotted until then. These were full of branches like a tree and were very small. He called them microglia.
Others had seen and drawn these immune cells before, but no one before could see that they were different. Because their technique was not as good as Hortega’s, they could not tell them apart from the other cells. And no one before had given them a name. So in many ways, Hortega inaugurated what would become 100 years later, one of the most dynamic areas of neuroscience. We now know a lot more about how microglia are different from the other cells in your brain and about how they respond when the brain gets damaged. A lot of this work has been pioneered by people like Ben Barres, a transgender scientist from the US who this episode is dedicated to.
Hortega never lived to see this. When Franco's troops arrived in Madrid, during the Spanish Civil War, he fled to France and the UK and finally to Argentina where he died in exile with his partner Nicolás.
But we said microglia are immune cells that survey the brain and kill pathogens - fine. But do they talk to neurons as well?
We've seen microglia can help synapses form, and synapses are these points of connection between brain cells. So these neurons talk to each other, and microglia have been shown now to help form these connections. But also they help take away the connections that are not required.
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Welcome once again to How To Make A Scientist. My name is Pablo Izquierdo. I am a neuroscientist and science communicator and today I'm joined by a fellow queer immigrant researcher, Makis Tzioras. Makis looks at the immune cells in the brain and tries to figure out how they change if you get dementia or a psychiatric disorder so that we can learn how to use them to our advantage. Enjoy.
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Makis, you and I met at a conference in Portugal just a couple of years - actually that was 2019. Let's all just pretend it didn't happen. That was in Portugal, but you live in Edinburgh, Scotland. How long have you been living up there?
I've been there for seven and a half years now. I went in September of 2013 to start my undergrad there. And I've just stayed there since.
Okay, so does it feel home by now?
Absolutely. I love Edinburgh. I love the people there. I love living there. And it's such a great mix of - it's not a huge city so it's not chaotic, but there's so much to do as well. And you've got the sea close, the mountains close. And I love it. It definitely feels like home. I definitely feel like when I leave home, Greece home, I also feel like I'm still going home.
Yeah, no, it's a beautiful city. What do you like the most about not just the city, but like living there?
I think people there allow and embrace individuality and self expression a lot more. As a queer person in Greece, I don't always feel very comfortable being more campy or dressing more campy. Whereas in Edinburgh, I will easily put on some eyeliner or a nice eyeshadow, for example. And I wouldn’t think about it too much. Whereas here, I don't think I really could do that.
You say here because you're in Athens now.
Yes, correct. I’m in Athens now, finishing the PhD thesis writing. So exciting times.
How do you feel about, now, coming back to Athens… just following up from what you said?
Well, the thing is, I'm actually not going outside at all because of the lockdown.
But I’ve really enjoyed being able to finish this last part of the writing at home in Athens with my family, because I was now just living on my own in Edinburgh, had just moved in on my own, which is great. And I loved living on my own. (But) I think it just got to a point where it was going on for too long. And you can see anyone, so being able to talk to humans, is just really nice.
Right! So you mentioned to research. I guess we're both neuroscientists although none of us actually look at neurons. Because, you know, there's all these other things in the brain, so neurons make up about half the cells in your brain, but there's also things called astrocytes and pericytes and microglia. And so you work on microglia. What are they, and what's most cool about them for you?
Right, so microglia are probably one of my favorite things in the world, I just love them so much. I love everything about them, I love studying them. And so the brain is very, very complex. And although we think of it as these nerve cells that choose made signals from one another, to make you talk and speak, and, and walk and everything, you need to have all these other cell types, to maintain those functions and help those functions to happen. And microglia are really important in doing that. So they are part of the immune system in a way of the brain. And they resemble these other cells that you find in the rest of the body called macrophages. But I think what it boils down to is that they are non neuronal cells in the brain, and they have so many functions in helping neurons do what they're supposed to do.
Specifically, one of the things that I'm interested in is that over the past few years, we've seen microglia can help synapses form. And synapses are these points of connections between brain cells, specifically the nerve cells, the neurons. So these neurons talk to each other, and microglia have been shown now to help form these connections, but also they help take away the connections that are not required.
So actually, your main interest is how these cells behave in the brain with with Alzheimer's, right?
Yes, so this process, which is called synaptic pruning, of removing the synapses that you don't need in the developing brain, has been recently shown to possibly be happening in a faster rate, in a more pathological context, in Alzheimer's disease. So Alzheimer's disease affects the elderly. And one of the main features of this disease is that there is very evident synapse loss, so a lot of the synapses are dying and degenerating. And microglia can go and eat away those synapses, so you can kind of think of them as the PacMan of the brain. Or if you want to think of synapses as cookies, they are the Cookie Monster, they just love them. So they will go and they will eat those synapses. Obviously, in the context of how the brain works, you have those connections between the neurons, and you pass on a signal from one cell to the other. And this is what makes you think, and remember and speak and all of that. But when those connections are going away, all of these functions are also going to start declining. So cognitive decline, and specifically memory loss is a key feature of Alzheimer's disease. This is why I'm interested in looking at how microglia are involved in this process.
Hang on, so if you if you take an Alzheimer's brain and a cognitively normal or a non-dementing brain, how are they different. Like, can you tell them apart?
Absolutely. First of all, from the size of the brain, you can see severe atrophy, it's shrunk a lot. And this atrophy is both because of neurone loss, losing those nerve cells, but also losing the synapses. So just looking at the brains, you can tell them apart.
But then at the microscope with more detail, you can definitely also see more of the synapse loss. And you can also see these pathological proteins that accumulate in the Alzheimer's brain.
And what these cells do in Alzheimer's, you said, is to eat those synapses up.
So this is one of the current theories that are being tested. There's some evidence know that from mainly mouse models of Alzheimer's disease. And my work is trying to translate that in humans. We have been very lucky to be able to work with human postmortem tissue that has been very generously donated. And we are trying to see in human brains, if this is relevant, and what we are seeing is that synapses in Alzheimer's brains are being eaten more by microglia.
Okay, what's the deal with human samples, though? Are there many donors around? Or is it very scarce resource to be able to use?
It's definitely not as common as maybe we would want it to be to be able to make more certain conclusions. You cannot pressure people to donate brains, you can only ask them to do so. And if someone chooses not to do it, is of course up to them. That is 100% their choice. It is however, really, really important to be able to look at human neurological diseases in human tissue.
So say, if I was interested in donating my brain or any other organ to science, how has that done? Like who do who do I speak to, I guess, or?
I believe there are certain forms you fill out. For example, in the UK, I know there are these NHS forms that you have to fill out. And I remember when I was registering for this, they said like, do you want to be an organ donor? And there's all these boxes that you check… I don't know if things have changed since then, maybe they have. But I think in terms of patients who donate their brains, it's also up to the families if they want to do that, because they have to consent to this as well.
And the way this helps science is that Alzheimer's disease is not modeled very well, in animal models. Mice are very commonly used in in research. None of the mouse models that we have can fully recapitulate all the different aspects of what happens in an Alzheimer's brain, you only model specific parts of it. So you're going to be missing a lot of information.
Because can a mouse naturally get dementia?
Mice don't. There are very few species that actually do get dementia. There is another rodent, which I don't remember its name right now. But interestingly, we are as a lab doing this collaboration with another group in Scotland, where they are seeing that dolphins and whales can also develop amyloid pathology in the brain. It's not known whether they develop dementia, but it's something that we've seen in some species.
But how can you figure out that mouse is dementing?
Sure. So there are cognitive tests are being done on mice to test different aspects of behavior, whether that is fear response or memory. So with Alzheimer's disease, you're most interested in memory because that's one of the first things to go. There are different mazes that you can use that are being set up to test memory in mice. There is the famous Morris water maze, developed by Richard Morris, who is in Edinburgh. And that's one of the most commonly used memory tests.
What’s that about?
So, the Morris water maze is basically a big tank of water, where you put a milky substance like milk powder, for example. So the water is not clear. And the stage has these smaller stages that are under the water so mice can see them because the water is milky. And the mice train in this maze. But then the mice that develop aspects of Alzheimer's disease, have memory impairments. So mice that are cognitively normal remember how to find one of these stages and go outside of the water. Because mice don’t like swimming, they don't like being wet. But then the mice that have the Alzheimer's tend to not be able to recall as well or as fast were that stage is to get out of the water - don't remember where the platform is. This is different to rats where I've never done a Morris water maze test, but I've been told rats like to swim. So you can’t do this with rats, because mice don't like to swim, and they want to find the platform, but rats will just swim around.
So you said microglia nibble on synapses as we grew up during development, and that's a good thing. But then that's not as good a thing when they do that in Alzheimer's. Do we know why they come back to do the same thing?
There are some theories about this there are being tested. And there's some papers that are coming out. This is a very new field. So what we know is that in development, the synapses that are a bit weaker, that are not needed, can be tagged with parts of the complement system. The complement system is part of the immune system, so immune cells can tag these pathogens, for example, in the body. “You need to be cleared away.” So they use the complement system to tag the synapses, so the microglia can recognize them and go on those synapses and nibble them away. In Alzheimer's disease, we are seeing that there is an increase, so patients with Alzheimer's disease have more of these complements in their brains. And specifically, from a study we did recently, we found that specifically in synapses of individuals with Alzheimer's disease, you get an upregulation of these complement proteins. So we're now testing this hypothesis that our microglia are recognizing its complement to come and take it away from the synapses basically, and in turn eat the synapses.
Okay, so it's like, there were loads of flags all over your brain saying “eat me” when in fact you shouldn't eat them.
Yes, that's pretty much what we think. And it's not exactly known why these tags are going up in the Alzheimer's brain. So that's definitely something that is being researched a lot right now. It is worth noting that although it's entirely possible that this is happening in a pathological way, this might also be happening in a beneficial way.
In the sense that if a synapse is degenerating, then it needs to be cleared away. And microglia liking to eat so much will go and need that synapse that is dying. That is actually pretty good. That's microglia doing what you're supposed to do the clear away debris in the brain.
Okay.
But if this happens non specifically, that's where it gets pathological. Because now you're starting to take away healthy synapses.
Okay, so microglia are not necessarily bad for the brain, are they?
Absolutely not. They are really, really good for the brain. In fact, there was a case study where there was a baby born without microglia, because of some genetic mutations. And that turned out to be a lethal. The brain was malformed, there were parts of the brain that never formed at all, and parts of the brain that grew in ways that they shouldn't. So this is suggesting that microglia are really helping sculpt neural networks in the brain. So they're absolutely necessary and beneficial. And like most things, they can have a bit of a dark side.
And is that sort of nibbling on neuronal connections, something that happens in in other diseases as well? Or is this specific to Alzheimer's?
So first of all, we are seeing that this happens in the aging brain. So in the absence of disease, synaptic pruning still is happening. But in other diseases, we've seen that this is happening as well. So for example, in multiple sclerosis, there's been a few papers to suggest synapse elimination by microglia.
Right. So it's a sort of mechanism that happens in different disorders. You've also just published some research looking at microglia in people with schizophrenia. What did you find in them?
So yes, that's true. So what we found was that when you look at postmortem brains of individuals who have have schizophrenia versus individuals who have been neurologically intact, you do not see a difference in microglia ingesting those synapses. The reason why we did this is because there has been some recent evidence to show that microglia might be involved in excessive synaptic pruning, in the schizophrenia brain, like for example in Alzheimer's disease.
But in a larger cohort, while it would be better to do is studying the age of onset, in the sense that if microglia are responsible for eating synapses in the schizophrenia brain, it is very possible that they do this close to the age of onset, whereas we get tissue that may have been donated many years after the onset. So if microglia have been involved in nibbling more synapses in a schizophrenia brain, we would no longer be able to capture that, because we're looking at the end stage of a disease. So although human tissue is super important, it has this really big limitation, that you cannot really track things.
Right. But as far as you know, as far as we know, there's just as many synapses within microglia.
Yes. So that's what we found, we found very comparable levels between the two.
Okay, would you call that a negative result?
I think so, I think this is in science, while we could determine a negative result, because you don't find a significant change between two things. I don't like the term negative result, because inherently, it has something negative or bad about it, which is not true. The fact that we did not see a difference between two groups, does not mean that this is not a cool finding, or an exciting finding.
Right. But yet, you know, a lot of times we’re told that we need to throw results in a drawer just because they didn't fit in with the hypothesis or didn't come out the sort of way we expected. So yeah, like you said, it's pretty cool that we can actually publish them and get them out there. Just to let people know that, hey, we've asked this question, and we've got this answer. Whether it's a yes or no, here's the answer, and the community can can see it and judge it, right?
Absolutely. I think one of my favorite things about this paper was the fact that the journal and specifically the editor was very happy with publishing negative results. And this was a small study. It wasn't, you know, years and years and years of work. It was just a finding that we thought was interesting. And they were happy to publish it. You know, I think that is sometimes just as important as those massive papers because you have quick progression of science, rather than having a paper being worked on for six years, sometimes more to go into a massive journal.
What do you think is more important as you walk into academia, your specific research question or your institution, your lab environment, your supervisor perhaps?
That's a great question. I think it's a great question because it really involves so many factors. And it can really make a difference in your experience. So I can safely say, having a good supervisor is make or break. And actually, you know, every PhD is difficult. There's no easy PhD, it's inherently a difficult process. But a good supervisor can make it worth the ride and they can support you whether or not you decide to stay in academia. A good supervisor is going to make sure that you don't suffer while you're doing what you're doing.
No, absolutely. Who's your supervisor? Let's give credit where it's due.
So my main supervisor is Tara Spires-Jones, who is an incredible, incredible human being. She is - I don't know, sometimes I try to think of the words, I was just writing my acknowledgments for my thesis. And I was trying to put into words just how much she's meant to me. And I struggle, because she has this magical ability to do great science. She has such great insight. She has so much knowledge. She's so well connected, but also, she has time for the people in her lab. She'll give you feedback, and I really do feel like she is a friend to me because she cares about you. She cares about how you're feeling, she cares about your success and your progression. And she's just really cool. Like, we went to Pride together. And she's just great.
All right, well, neuroscience folks, go and apply for her lab! Let's get back to Athens for a moment, what was school like for you?
So high school was not something I loved, I have to say. I think if you have any sort of difference in school, it just gets magnified. And you're kind of tagged and labeled with them. So for example, me being gay, and also being overweight, those are things that just get stuck in you that like, these are the things that you are. But I had a big change in mentality in high school where I thought “wait, do these things really define who I am?” And when I realized that, “no, they're not”... That's when I started having a better time in high school.
And that's when I also felt like, “Okay, I know what I'm good at”. And what I felt I was good at was science. And I felt like, okay, I can do this, I can make it. And it's not that the people who say, you know, it's really tough, they have negative feeling towards you. But it's just so much better to surround yourself with people who say, go for it. Take that leap of faith, you know, trust yourself, you're good at what you do, you can make it.
No, absolutely. You touched on the struggles of doing a PhD. What's kept you sane throughout it?
Am I sane? (laughs) No, I think in terms of the supervision, there were times where I meant it and also times were didn't mean it, where I said," “I'm quitting”. Having someone pull you back from that and say that, “listen, if you really want to do it, and you're suffering, you should, but you have potential, you shouldn't drop out just because things sometimes get a bit tough.” And that's a life lesson. That's not a PhD thing.
For me, other things have kept me sane have been really good friends, that will understand you and really just hear you out. There's this thing that people say, which is that communication is key. And communication is key. Because if you're able to communicate your feelings, you're more likely to have people around you that can support you, when those things get really, really tough in the PhD. That's what keeps you sane.
And before all of that, you need to do the really difficult self work of remembering why you're doing why you're doing and say, “am I doing a PhD for me, or for someone else? Am I doing it to get other people's satisfaction and make them feel good? Or am I doing this for me? Because if I'm doing this for me, I will endure.” Not always. There are points where I think it is perfectly justifiable to walk away from a PhD that doesn't do you any good.
Yeah, no, that's, can we just frame those words? Like, that's so important, I think it is, I think we all, possibly yourself, have felt at points that “I just want to quit this. Why am I doing this?”
Oh, yeah.
Right. It's just it happens so much. What you really need to do, it's so tough but it's so worth it. Not just for a PhD but as a life lesson. We get so accustomed to the fact that we're surrounded by people with PhDs and people who are doing PhDs that you forget… That's the thing, like remember how special you are and make the people around you feel special as well.
Yeah, no, that's really important. And like you'd said, it's about you know, reflecting yourself and knowing what you're doing it but also having that sort of net of support, right?
This is coming to an end. But do you have a favorite band or singer?
Well, how did you know? (laughs) At the moment, I really, really, really loving Taylor Swift. I've been into Taylor Swift's music from Love story, from her second album, and I've always liked her. And through the years that love has just been growing and growing. Coming up to now, where I feel like a little part of my personality has been shaped by Taylor Swift. You know, some of her recent albums especially they can take you to the PhD process. Listen to albums like Evermore. This is a PhD in a nutshell, go back to the previous album with Folklore. Listen to This is me trying. Tell me if there's been a PhD student who hasn't wanted to go up to a mountain and just yell “This is me trying. I am doing my best” Taylor Swift has been pretty iconic in my life.
Well, if people want to have their mind shaped by Taylor Swift, they can go listen to Folklore. I can't actually play it because copyright. Makis Tzioras, thank you so much.
Thank you. I could just keep talking more and more about all of this especially, you know, we can talk about Taylor Swift on a whole new podcast. If you want my thoughts on why I think Taylor Swift is America's greatest poet of the 21st century.
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Thank you for listening. I hope you enjoyed this conversation. If you did, please remember to like, follow, share with your friends… you know the drill. You can get on the newsletter at howtosci.substack.com or follow on Twitter at @HowToSci. The music for this episode was by Scott Buckley and Vasily Novikov. I’m Pablo Izquierdo. And this is How To Make A Scientist.