Neurodevelopmental disorders affect roughly 14% of children worldwide, and in Canada, just under one in every 10 children is estimated to be affected. This episode takes a deep dive into frontline research on childhood brain development to discover what neurodevelopmental disorders can teach us about the resilient yet vulnerable frontier that is a growing brain.
Neurodevelopmental disorders affect roughly 14% of children worldwide. In Canada, just under one in every 10 children is estimated to be affected. Disorders of the brain represent a huge spectrum of conditions: they can be genetic, or structural. They can arise following injuries or infections, or have no known cause. Some conditions are more common, and have treatment options available - like ADHD, or speech language disorders. Some are incredibly rare, and their uniqueness makes them difficult to study, understand and treat. This episode takes a deep dive into frontline research on childhood brain development to discover what neurodevelopmental disorders can teach us about the resilient yet vulnerable frontier that is a growing brain.
Featured guests:
Anthony Flamier, Assistant Professor in the Department of Neuroscience at l’Université de Montréal and Principal Investigator at CHU Sainte-Justine.
Benjamin De Leener, Associate Professor in the Department of Computer Engineering and Software Engineering at Polytechnique Montréal and Researcher at CHU Sainte-Justine.
Eric Samarut, Assistant Professor in the Department of Neuroscience at l’Université de Montréal and Principal Investigator at l’Université de Montréal Hospital Research Center.
This work is supported by the Azrieli Foundation.
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Dr. Éric Samarut 00:08
Having a clinical link to the fundamental research is, like, awesome to really have a concrete impact of what you’re doing and how it can impact people. You remain curious about the basic aspects of life and at the molecular level or whatever level. But when you just, like, lift your head, you realize that what you’re doing at the fundamental level can really have an impact. That’s a very good feeling.
Fiona 00:40
This is Bold Minds: Future Leaders in Canadian Brain Research. I’m your host Fiona Sanderson. I work at Brain Canada, where our mission is to bring together funders and researchers to enable health innovations for Canadians. The Future Leaders program is made possible thanks to an anchor gift from the Azrieli Foundation and matched by Brain Canada through the Canada Brain Research Fund. Come along with me as we journey into the bold minds and labs of researchers who are redefining our understanding of the brain. [music ends]
[rousing music] Neurodevelopmental disorders affect roughly 14% of children worldwide. And in Canada, just under one in every 10 children is estimated to be affected. Disorders of the brain represent a huge spectrum of conditions. They can be genetic or structural. They can arise following injuries or infections or have no known cause. Some conditions are more common and have treatment options available like ADHD or speech-language disorders. Some are incredibly rare and their uniqueness makes them difficult to study, understand and treat. This episode, we’re taking a deep dive into frontline research on childhood brain development and discovering what neurodevelopmental disorders can teach us about the resilient yet vulnerable frontier that is a growing brain. This is Bold Minds. [music ends]
Today, I’m joined by...
Dr. Anthony Flamier 02:16
Anthony Flamier, I’m an assistant professor at the University of Montréal in the Department of Neuroscience and principal investigator at CHU Sainte-Justine.
Fiona 02:26
Dr. Flamier and his team are investigating how the mutated gene MECP2 causes Rett syndrome, a severe neurological disorder that affects mainly girls in one out of 10,000 births. They hope to uncover how the MECP2 gene affects ability to communicate and other developmental challenges like difficulty with movement and repetitive behaviors.
[whooshing] I’m also joined by...
Dr. Benjamin De Leener 02:52
Benjamin De Leener, I’m an associate professor at Polytechnique Montréal and also a researcher at CHU Sainte-Justine.
Fiona 03:00
Dr. De Leener’s team uses neuroimaging and artificial intelligence to build brain growth curves for kids, much like the height and weight charts that we use to determine percentiles. Their goal is to provide reference standards of brain development, facilitate early detection of any issues, and potentially help guide policies aimed at preventing concussions among children.
[whooshing] And I’m also joined by...
Dr. Éric Samarut 03:24
Éric Samarut, assistant professor at the University of Montréal, Department of Neuroscience, and principal investigator at the University of Montréal Hospital Research Centre.
Fiona 03:35
Dr. Samarut’s team identified variations in the gene THAP12 in individuals with Lennox-Gastaut syndrome, a rare and severe childhood epilepsy that is often resistant to current treatments. They are now working to understand the specific role of THAP12 in brain development in the hopes of identifying alternative therapeutic options for kids with LGS, and to potentially pave the way for new therapies for other neurodevelopmental disorders too. Ben, Anthony, Éric, welcome to Bold Minds.
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So, Ben, let’s start with you. You’re a biomedical engineer and your expertise is computational, having to do with AI, pattern analysis, machine intelligence, image processing. Tell us about your research and how it applies to neurodevelopment.
Dr. Benjamin De Leener 04:24
Yes, well, thank you for having me here. So, my background, as you said, is engineering. So, I’m a biomedical engineer at Polytechnique. I’m not a clinician. I don’t have a lot of expertise actually in the real medicine world, if I can say. But as an engineer, my research focuses on developing tools that are dedicated for other researchers mainly, so that they can discover things that they consider useful. So, my research lab, we’ve been focusing for the past few years on magnetic resonance imaging of the brain and the spinal cord, developing tools for other people to understand the mechanism of pathologies in the brain and the spinal cord. So, for example, we have projects in the developing brains looking at how the brain develops. So, MRI, we acquire the images of the brain of children, for example, at various ages, and we develop the tools so that you can interpret various things about it.
Fiona 05:18
So, your goal is to develop this atlas of a child’s developing brain. So, let’s say a child is brought into the doctor and they’re experiencing a neurological symptom. They’ve had a head injury. The doctor sends them for an MRI to get a picture of their brain, and then what happens? Does that picture get mapped onto this atlas as a snapshot in time, taking into account something like their age? Or is this maybe for a child that has a known or diagnosed issue and their brain scans over time are mapped onto this atlas to monitor development, like a child’s height and weight are graphed against a typical growth chart?
Dr. Benjamin De Leener 05:53
Usually when children, for example, with a concussion, they go into the hospital, they get a scan, and then it’s interpreted by the radiologist or the clinician and basically looking at the brain if there is any swelling or anything. So, for a mild concussion, usually we just look for bad things and then see how they’ve evolved. What we try to get into the clinic, since it’s a long, long project of developing this atlas, as you called it, is basically providing a way to quantify how the neurodevelopment works in terms of the structure. So, we look at the MRI, we look at the different regions, how they are supposed to develop. For example, if we look at the gray matter, we know that the gray matter develops through age. And we know also that the white matter, which connects all the regions of the gray matter, also develops, and we want to understand, okay, how they develop normally and how a child with a concussion, a mild concussion, for example, would differ from his expected trajectory. So, same example as the growth chart that we have for weight and height, so we expect a child to stay on his trajectory. For example, if a child is 50 percentile for weight, we expect him to stay that way. We don’t expect him to go down and up and down and up. So, we try to do the same with the brain.
Fiona 07:09
And how typical is the typical brain? So, I know that, you know, when you’re pregnant and you get a series of ultrasounds and they measure sort of the size, the length of the fetus, and they can tell you exactly your gestational age. Does that hold true once a baby is born and they’re developing over time?
Dr. Benjamin De Leener 07:26
I would actually say that that’s not all true, even for the ultrasound. It’s just statistics-- population statistics. And that’s the main issue that we have when we look at longitudinal changes of the brain or any structure. There is a lot of variability between people, but we still have to look into the statistics. And one thing that is very specific to the development, and neurodevelopment in particular in my case, is that we want to look into the changes of the brain of some structures and we want to see if there is a slight deviation of that development due to a pathology or due to a trauma concussion. But that change can be small compared to the growth of the brain. So, for example, if we have a child that we’re following from one-year-old to seven years old, well, his brain is growing. So, how do we measure that slight change-- that slight deviation from its expected trajectory compared to the variation that we see intra-individually, so the growth of the child, and inter-individually, which is basically the population, which is very variable?
So, it’s a huge challenge to understand how to calculate this deviation. Usually, the main critique is that there is nothing typical about the development. We expect something typical, and we have to navigate through that. So, that’s the main purpose of my research, basically. To provide tools so that we can navigate through the typical developments.
Fiona 08:52
That’s so interesting, and I can foresee so many uses for that in the future. So, Anthony, you also research neurodevelopment and neurodevelopmental disorders, in particular a disease called Rett syndrome. Can you tell us what exactly is Rett syndrome?
Dr. Anthony Flamier 09:08
Yeah, sure. Rett syndrome is a neurological or neurodevelopmental disease. It’s affecting about one birth into 10,000, and it’s affecting mostly girls. What’s happening in Rett syndrome is we are pretty sure that it’s neurodevelopmental. There is a delay in the neurodevelopment, but the symptoms appear quite later, so around six months of age to one-year-old. We kind of know the origin of the disease. It’s caused by these mutations in this gene, MECP2, but we don’t really know the mechanisms of the disease.
Fiona 09:47
So, you model Rett syndrome using cells in a dish, and in particular, a type of cell called a pluripotent stem cell. Can you explain to us what is a pluripotent stem cell? How do you and your team use it to model the disease?
Dr. Anthony Flamier 09:59
Yeah, sure. So, the pluripotent stem cells are basically corresponding to the very early cells of the embryo, as we call cells from the blastocysts. So, it’s the inner cell mass of the blastocysts. There are these transient cells that have the capacity to generate any cell type of the human body. So, that’s how the human body is formed. We can reproduce these kinds of cells directly from individuals, from patient cells. So, from patient blood samples, we can, what we call, reprogram them to have the same properties as these embryonic pluripotent stem cells. And again, we can form any tissue of the human body, and we use that to model the brain development, so we focus on the brain cells.
Fiona 10:53
Okay. So, you can use these cells to, you know, model how the brain develops in the dish in the lab. But Rett syndrome is actually quite behaviorally complex, like autism, so why is it important to understand what’s going on at a cellular level? What can the cells tell us?
Dr. Anthony Flamier 11:10
So, as you say, like, we have different models where we can introduce mutations or we start directly from the patient cells. A lot of the things that’s happening in the processes that are happening in the Rett syndrome is actually in the nucleus of the cells. So MECP2 binds the DNA and regulates many genes of our genome. That’s why we need to better understand what kind of gene is regulating at the molecular level in order to design new therapeutics that will target that.
Fiona 11:42
So, we really need to understand the fundamental nature of what’s going on within these cells to understand how it gives rise to the behavior and other aspects of this disease. Éric, your team also studies neurodevelopment and the effects of genetic mutations in neurodevelopmental disorders, but you use a less commonly known model to study this, the zebrafish. Can you explain to us what is a zebrafish? What does it look like? Why do we use it in research? Like what can a fish tell us about our brains?
Dr. Éric Samarut 12:13
So, zebrafish, they are vertebrates, and although they do not look like us, they-- we share about 75 to 80% of our genes with them. So, if you look at all the genes that are known to be associated with human disorders, about eight over 10 of these genes are found in zebrafish and they have the same function. So, these little guys are very nice biological models. You are in a real in vivo model. It means it’s a real animal. But they are tiny. They are easy to work with. Their development goes very fast and they are almost transparent. It means that we can really follow everything that happens in the fish larvae, especially at the brain level under your microscope. So, that’s a very, very convenient model.
And so, now we have a lot of tools to play with genetic engineering in those models. And so, what we are trying to achieve in my lab is to leverage those models to try to see if they could help us decipher if a specific genetic variant or a mutation could be associated with a particular disease. So, we are trying to model the same genetic background as found in patients and see, what is the phenotypes? What are the symptoms that we observe in those fish?
Fiona 13:26
So, that’s really cool. You can actually see through the fish, and you can see the brain developing through its body while it’s alive.
Dr. Éric Samarut 13:32
Exactly.
Fiona 13:33
That’s incredible. So, you have these fish that are swimming around in a tank and you can induce them to have specific genetic mutations, much like Anthony can do with cells in a dish, but in your case, you’re specifically looking at genetic mutations associated with a subset of epilepsy. So, what does that look like in a fish? Can you get the same sort of characteristic overabundance of brain electrical activity, characteristic of epileptic seizures in the zebrafish, or what else do you see?
Dr. Éric Samarut 14:00
Yeah, so the brain of a fish is much simpler than ours, for sure. But at the cellular level, a lot of things that happen in an epileptic brain in a human also happens in a brain in a zebrafish. So, basically, we are mainly working with zebrafish embryos or zebrafish larvae, so it takes, like, three to five days for them to develop as almost tiny little fishes. And when we induce a particular mutation in those fish, and if we are looking for an epileptic behavior, so basically, we have machines that can record live the swimming pattern of those little guys. And so, we know that if they are seizing, some seizures can trigger motor responses and so we know what to expect, some hyperactivity, for example, or some hypoactivity. But we can go much deeper than that, and so we can really look into the brain of those fish. You can go in the brain to really record the activity of these neurons. So, basically, having an EEG in a fish larvae.
But now we have more and more fancy tools that can really allow us to do kind of a live MRI in a zebrafish larvae, which is live under your microscope. So, we have some calcium sensors that become fluorescent when the neurons become active. And so, basically, you can just let your fish stay live under your microscope and record live the activity of all these neurons in a live fashion. So, that’s really cool. And you can trigger seizures, you can record spontaneous seizures, so that’s a very nice model for that.
Fiona 15:31
Wow! What a powerful model to be able to study that. So, brain development from the earliest stages, it’s so complex and yet so tightly controlled. So, I see it as, like, an orchestra playing a really complicated piece and every section has to get their part just right with the right timing, the right cadence, for everything to come together into, like, a beautiful song. And if, you know, one instrument plays something out of note, you can hear it.
So, similar to that, how do you go about teasing apart the contribution of a single genetic mutation or teaching a computer how to tell what a small alteration on a brain scan actually means?
Dr. Éric Samarut 16:05
I really like your metaphor of the orchestra because that’s exactly it. Everything is perfectly coordinated. What I’d like to add is just that we usually see problems when an instrument is not doing what it was asked to do, but sometimes it’s just giving a different song and it’s beautiful too. You know, this is why now we call them genetic variants more than mutations, because genetic variants is just what makes us different and so makes brain number one to act differently than brain number two. It becomes problematic when it brings, like, a deleterious competence, when it brings problems to the normal function of the brain. Just one little change in one little letter of our billions of DNA letters can just affect one gene, and this particular gene, if it’s not functioning properly, that can have, like, devastating consequences and cause, like, a lot of problems.
Those are so-called monogenic diseases, it means that one gene is involved, and they are “pretty easy”. And I put a lot of brackets for this word. They are pretty easy to study because it’s one gene, one genetic variation, one disease. But I think it’s much more complex than that. And so, when you start having multiple genes involved, sometimes it’s just different thresholds that play together and that together creates problems. Exactly, again, taking back your metaphor of the orchestra, you know, if just one instrument is doing something different, sometimes it’s just different and it’s interesting. But if you have two or three doing things that do not go along together, that creates a problem.
Dr. Benjamin De Leener 17:36
I really love this conversation because it’s a perfect topic and a perfect analogy with what we do in research. I mean, I’m an engineer, again, I’m using MRI, but it’s a completely different level from what Anthony and Éric are doing. And so, when I look at the brain development, which is extremely complex, I’m looking at the macroscopic level. Not the microscopic level of the genes, I’m just looking at the brain as I can see it, and I can see the different regions, and I can see the white matter and the gray matter. And I don’t have a picture of what’s happening below in terms of level. I don’t see what’s directly happening. I don’t have a transparent brain. I would love to, but it would be weird with live children in the MRI. But that’s the reality of research. And that’s, I think, why you have to use different models and try to fit the pieces together to really understand what’s wrong when there is a pathology at the genetic level in the genome. But I’m just looking at the macroscopic, so I need to actually work with people that are understanding what’s working, how it’s working below.
Dr. Éric Samarut 18:43
So, you are doing mainly work in human-- having human brain images, but it’s very important to know that these reference images or these reference evolution of what’s supposed to happen, this is key to define a symptom or a phenotype. Because if you don’t know where it’s supposed to go, how do you know if what you’re observing is so-called normal, typical, non-typical, deleterious, pathogenic? So, having this description of what’s supposed to happen is, like, really crucial. Without that, you cannot do anything.
Dr. Anthony Flamier 19:13
And I would add, it’s very key, especially for the stem cell models that we are developing. Because it’s always based on what’s happening to the patient and to the normal course of neurodevelopment. And we use that because we are trying to mimic it in vitro. So, if we don’t have the reference, we cannot try to reproduce it in vitro.
And just also wanted to add on your analogy of the orchestra, you are thinking more of the genes and the different instruments. But I would tend to think also, like, the cell types of the brain could be the different instruments. And sometimes the gene would be expressed in a specific type of cells, like for-- in my case for MECP2, it’s mostly neurons, a little bit in the astrocytes, but the rest do not really express it. But the other cell types that do not express MECP2 still are deeply affected, and you have a big effect on the neurodevelopment. So, it’s because the neurons are affected that also affects all the cell types.
Fiona 20:14
And you all study neurodevelopment and the deviation from typical development that gives rise to a neurodevelopmental disorder, but you do it in such different ways. So, how did you get to where you are? Can you tell me a little bit about your journey? What drew you to the research that you’re doing now and how you’re doing it?
Dr. Anthony Flamier 20:32
So, the technology that I’m using, so the stem cell-based technology that is also called iPS, induced pluripotent stem cells, that was invented in 2006. And that’s where I started working on this technology and I pursued all my career working with these cells. So, it was natural for me to apply it to a different disease. And I started to study neurodevelopment, so that’s how I started to use this specific technology on neurodevelopment.
Dr. Benjamin De Leener 21:04
From my perspective, why I started working in-- a little bit of luck, actually. I just ended up working with MRI and looking at the spinal cord, which is something that was not studied a lot in terms of the brain. Everybody’s talking about the brain, but not a lot of people are looking at the spinal cord where a lot of things are happening and it’s important to. I’ve done my PhD on the spinal cord, again, MRI, developing tools, and I realized that once you develop the tools and they are efficient, then there is a lot of research that can go on because you provide tools. That I’m using AI, but not only just sometimes very simple things to make things work for the researchers to study the nervous system. And once I got at Sainte-Justine, I was saying, “Okay, I need to find something else,” and for me, children were the next challenge. Because, like, the spinal cord compared to the brain, children are not as studied as the adults. And so, for me, that’s why I started. And then again, building on my expertise, looking into MRI, developing tools. Not focusing only on one pathology or one syndrome or anything, just trying to provide new tools for other researchers and clinicians. So, mostly because people were not working a lot in this field, because it’s challenging. Getting a kid in an MRI, it’s really simple. [Fiona laughs] You just put them there and asking them to stay still. So, when they are neonates, it’s easy. You get them to sleep and then you scan. When they are three years old, it’s mostly a nightmare, but there are ways to do it. And so, we have a beautiful team at Sainte-Justine that has developed protocols to do so. It’s still a challenge, so there’s less data. So, when you do AI, it’s difficult. But we’re getting there and I think it’s a nice challenge to tackle and it’s important.
Fiona 22:54
I can’t even get mine to sit still for dinner, so. [chuckles]
Dr. Benjamin De Leener 22:57
[laughs]
Dr. Éric Samarut 22:59
Well, on my side, I mean, I’ve always loved fish. And actually, the first time I touched a zebrafish, it was because I was looking for a summer job. And so, there was a lab doing fish and I was cleaning the aquarium, and then I was just looking at what they were doing and got interested into this. And then the first time I watched, like, a zebrafish embryo develop under the microscope, I was like, “Wow! I have to do something with that.” During my PhD, I was really using zebrafish to study the evolution of signaling pathways. So, really away from translational research. And then when I moved in Montréal for postdoc, I thought I would like to apply that and have a more translational vision for my research. And so, this is how I got interested into trying to model some human diseases in zebrafish. And I’m definitely not the only one to do that, so it was then being part of this big community doing this. And something I’d like to emphasize is, I mean, I love this model, but I know it has a lot of limitations. And so, what I like to do now is, really, to work with my colleagues. And Anthony is one good example because his models are so complementary to ours that it would be stupid just to reinvent the wheels in every lab. You know, let’s work together and let’s just put different pieces together to make a much nicer puzzle.
Fiona 24:16
So, you know, just as you said, sort of this idea of collaboration and research, more and more we understand that research is really key to solving problems and answering questions. So, you all have sort of interdisciplinary aspects within your own work, but has working with researchers from other disciplines influenced your thinking at all or prompted new ideas?
Dr. Benjamin De Leener 24:36
For me, it’s really important to understand how to work with people that know more than me about how it works and how it develops. I’m working with neonatologists, I’m working with other types of clinicians that are working directly with children. It’s really important for me to be close to the clinics because I want the tools that I’m developing to be useful for the actual clinical practice. I’m not a fundamentalist. I’m an engineer, I really want to be practical. But it’s also really important to build tools that are built upon something that is fundamental. So, I’m also working with, I would say, fundamentalists to understand that what I’m building just makes sense and it’s not just a funny tool to use in the context of research. So, research is important, but I really like to collaborate with other people in that it all comes into a really big piece. That every single one of us, we don’t fully understand the big picture, but together it works.
Dr. Anthony Flamier 25:31
My background is more initially in molecular biology and now I’ve moved towards neuroscience. So, it’s really key for me to interact with other people, like other professors in the neuroscience field, because I feel like I still have a lot to learn. And also in the exchanging models, as Éric said, I like to complement the different models that we’re using. It’s really key to collaborate for that.
Dr. Éric Samarut 25:57
Yeah. I think it’s so exciting to talk to people where you don’t understand anything. This is one of the best moments that I have when I’m just, like, sitting with some colleagues at a conference and you have, I don’t know, a bioengineer, you have a chemist and you have a structural biologist. And it’s like four nerds at the same table, and at the end, you need to trust their expertise. And together, you just, like, create this flow of analogies between what you’re doing, and this is beautiful when that happens, to be honest. I really love it; to work with people where I don’t understand a word of what they’re saying. That’s fascinating.
Fiona 26:35
Wow! That’s really amazing. Thank you, Ben, Anthony and Éric for chatting with me today, and to all of our listeners, thank you all for joining us on Bold Minds.
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Dr. Benjamin De Leener 26:44
Thank you.
Dr. Anthony Flamier 26:45
Thank you.
Dr. Éric Samarut 26:45
Thank you.
Fiona 26:47
Bold Minds is a Brain Canada production with support from the Azrieli Foundation. Our executive producers are Jillian Donnelly and Kate Shingler. Our lead producer is Jess Schmidt, with editing by Morgane Chambrin. Thanks for listening.
If you enjoyed this episode, we’d appreciate it if you could send it to a friend. If you want to learn more about Brain Canada and our Future Leaders program, please visit our website at braincanada.ca. [music ends]