Avanish Srinivasan: Have you ever wondered how a three-pound organ containing billions of neurons manages to build itself? Why do some children develop neurological conditions like epilepsy or autism? Well, others don't. And what if the genetic mutations that influence brain disorders aren't always inherited, but can arise during brain development itself? For decades, scientists thought of our DNA as a fixed blueprint that remains largely unchanged throughout life. But what if every neuron in your brain carries its own unique genetic story? Today's research is revealing that brain development is far more dynamic than we once imagined. From the earliest stem cells in the embryo to the mature neurons that support thought, memory, and behavior, tiny genetic changes can shape how the brain develops and sometimes contribute to neurological disease. Hello, I'm Avnish, and this is the Early Perspective. A podcast where we explore how the brain works, how it changes, and what that means for how we learn, think, and live. Today we're going to be diving into one of the most fundamental questions in neuroscience. How does the human brain develop? We'll explore how genes guide the construction of the cerebral cortex, what happens when development goes off course, and how genetic mutations arising throughout life may influence conditions ranging from epilepsy and autism to Alzheimer's disease and dementia. To help break all of this down, I'm incredibly excited to welcome today's guest, Dr. Christopher Walsh. Dr. Walsh is the Chief of Genetics and Genomics at the Boston Children's Hospital, an investigator of the Howard Hughes Medical Institute, and a professor of pediatrics and neurology at Harvard Medical School. He earned both his MD and his PhD from the University of Chicago, completed his neurology residency, He earned both his MD and his PhD from the University of Chicago, completed his neurology residency at the Massachusetts General Hospital, and later trained in genetics at Harvard. His research uses genetics to understand how the human cerebral cortex develops and how disruptions in that process lead to neurological disorders. His lab has identified dozens of genes involved in brain development and linked them to conditions including epilepsy, intellectual disability, and autism spectrum disorders. More recently, his work has shown that mutations arising during development can contribute to disorders such as epilepsy, autism, and schizophrenia, and that individual neurons accumulate unique mutations throughout life, even after they stop dividing. These discoveries are helping reshape how scientists think about the brain and how it develops. Dr. Walsh has been elected to the National Academy of Medicine, the National Academy of Sciences. and the American Academy of Arts and Sciences. And he was also awarded the Gruber Neuroscience Prize in twenty twenty one and the Kavli Neuroscience Prize in twenty twenty two. Doctor Walsh, thank you so much for joining me today.
Chris Walsh: Thanks Avanish. I'm really glad to be here. It's always fun to talk
Avanish Srinivasan: Yeah.
Chris Walsh: about the brain.
Avanish Srinivasan: Of course. Okay, so to start off, I'd love to go back to the beginning. Could you tell us a little bit about your journey into neuroscience, medicine, and just brain development research in general?
Chris Walsh: Sure. I mean, I think in my case, my decision to go into neuroscience is really influenced by my teachers. I skipped my last year of high school and ended up in college just a month after I turned 17 with no idea what I was gonna do or what I was gonna study. And I I took two courses my first semester of freshman year, that really have defined my trajectory ever since. One was psychology. And one was organic chemistry. And ever since then I've been fascinated by this interaction between chemistry and the brain. and that got me on the road to neuroscience research that I, you know, continued to follow in college and then in graduate school. And so I'm really grateful to for those teachers that really inspired me, which is part of why I love to talk to people who are at a younger stage in their career than me.
Avanish Srinivasan: How was that process that transitioned from just skipping a year of high school to college straight?
Chris Walsh: Well, that happened 'cause I'm the I come from a big Irish Catholic family. I'm
Avanish Srinivasan: Mm-hmm.
Chris Walsh: the seventh of eight kids. And we, you know, we were comfortable but we didn't have a lot of money. So everybody had to save money on college somehow. And I was the only one who didn't go to Catholic school, so I was actually going to a private school. And so my parents left the choice up to me. They said you can skip a year of high school or you can skip a year of college like your older sister did. And I didn't particularly want to skip a year of either. but college seemed like it might be more fun than high school. And so that's how I ended up in college after three years of high
Avanish Srinivasan: Mm-hmm.
Chris Walsh: school. And like I said, I really wasn't thinking about doing that. So I, you know, compared to how much kids are prepared now for college and high school, I was like completely unprepared to
Avanish Srinivasan: Mm-hmm.
Chris Walsh: even have any idea. I'd I'd entered a with no major and no really idea what I was gonna do for a major, so If any
Avanish Srinivasan: Mm-hmm.
Chris Walsh: of your listeners feel like, you know, they don't are on aren't on enough of a path, I'm here to say you don't have to know what you're doing. You can figure it out as you go.
Avanish Srinivasan: Yeah, that's honestly wonderful advice. So what first drew you towards specifically the developing brain?
Chris Walsh: Well, that's a good question, and I'm not exactly sure why. I guess that was mostly in graduate school. When
Avanish Srinivasan: Mm-hmm.
Chris Walsh: I first went to graduate school, I wanted to work on schizophrenia because it illustrates this interaction of chemistry, namely dopamine and behavior. because we even way back then it was known that dopamine was important. But at my school there were a lot of great people doing great science, but nobody was doing great science in the area of schizophrenia. And so then I was in a little bit of a little bit of a crisis. I didn't know what I was gonna work on. And I just started again talking to a bunch of different professors, kind of trial and error, and I must have talked to fifteen different professors about their research. And so I met with Professor Ray Gillary, who was working on the development of the brain and in specifically genetic mutations that disrupt the development of the brain, and he just immediately inspired me. with the about the fact that you know the brain is like so specialized but it just starts out as a bunch of simple cells that look just like any other cells and then somehow this miracle happens that gives us this ability for you know consciousness and
Avanish Srinivasan: Mm-hmm.
Chris Walsh: free will and choice and intellect and creativity. and so I've always been fascinated by how that miracle comes about.
Avanish Srinivasan: Yeah, of course it's an incredibly fascinating topic to get into. So when you did start going into that topic, was there any particular discovery or experience that shaped your career and the future trajectory?
Chris Walsh: well, again, there are lots of things that have shaped my trajectory. I sometimes feel like I'm a blank slate and I just am imprinted by the people I encounter. You know, I had some really good research experiences in college that helped me along, but my you know, again it's been a series of things. I mean really my role model was Ray, my PhD
Avanish Srinivasan: Mm-hmm.
Chris Walsh: advisor. He showed me what it was like to do science, how it could be just a really fun thing, a little bit like art, except it's also, you know, a dispassionate search for truth. And so it's
Avanish Srinivasan: Right.
Chris Walsh: I just love the fact that you can be creative, but you're but you're bound by rules of trying to find something which is true and durable. and you know, just trying to, you know, help expand knowledge a little bit. And I had a very dramatic experience my first year of graduate school. because I I I mean, I discovered along the way the idea of doing a combined MD PhD degree.
Avanish Srinivasan: Mm-hmm.
Chris Walsh: and that was that was a moment for me. I I again I wasn't sure if I wanted to go to medical school or graduate school. I felt like I liked science more than I was enjoying my volunteering in hospitals because in the science lab anybody can do anything at any age. and so I was given a lot of responsibility, whereas in the hospital as an undergraduate, you just kind of follow other people around. And
Avanish Srinivasan: Right.
Chris Walsh: so I was wrestling a little bit with my decision between medicine and science. And one day I walked into my premed advisor's office and I saw this pile of pamphlets on the side and I still remember exactly where they were and where his bookcase was and I absentmindedly picked up one of these pamphlets and I'll never forget what it felt like. It's like this high quality sort of textured paper and
Avanish Srinivasan: Mm.
Chris Walsh: it has this burgundy color. And that was a p a pamphlet describing the combined MD PhD program at Cornell Rockefeller. And I must have read that pamphlet about a hundred times over and I and and that was a moment. that where a light bulb went off for me that this was
Avanish Srinivasan: Mm-hmm.
Chris Walsh: the way of doing this and they actually would pay you to do this, that it was free. And again, coming from a big family where we had to think about saving money, it was the it was a perfect thing from
Avanish Srinivasan: Mm-hmm.
Chris Walsh: my family perspective also. But this would and so, you know, that was really a moment that set me on the course to doing the combined degree programs.
Avanish Srinivasan: Right. So then once you did go to medical school and also graduate school combined, how'd you get to s choosing neurology as your specialty? What what guided your decisions in medicine?
Chris Walsh: Well, so I really enjoyed my PhD in n neuroscience. And so I decided I wanted to stick with neuroscience research. And you know, the first two years of medical school you're mostly in the classroom. And then I stepped away from medical school to do my PhD. and then I was thinking I would probably want to do neurology as a specialty, but wasn't certain. and from there You basically just try different specialties as rotations. You do a month of neurology, you do a month of or two months of internal medicine, and it's really very empirical. you know, I've talked to a lot of medical students about this choice because I was director of Harvard's MD PhD
Avanish Srinivasan: Mm-hmm.
Chris Walsh: program for a few years. And it's I think of it as like the wand chooses the wizard, because you walk into rotation. and there's some where you just feel comfortable. You just feel like you're at home. And there's others that you thought you might like, but they just don't feel right. And so it's it was
Avanish Srinivasan: They don't click, yeah.
Chris Walsh: yeah, and so it's really a g on the one hand it's a gut feeling. On the other hand, I've as a seventh of eight kids I've always looked to role models. And I told you that Ray, my PhD advisor, was a role model because you know, it looked like He just had a life that I could enjoy living. he worked in the lab, he chatted, he stopped for a cup of coffee, he'd go home, he'd have dinner with his family, and I knew that family was going to be important to me and that I'd want to have a family of my own, and then you know, he'd do reading and things like that in the evening. So he seemed like he had a life that be that was a good lifestyle, as well as a lot of fun. And so when I was doing those rotations, I looked around at the professors who were in the the medical specialties, the clinical specialties. And again I I could see myself identifying with the neurologists who again did a lot of research because we don't have cures for a lot of neurological diseases. So research is very important. and so that's valued by that specialty. But they also had a lifestyle that looked like it was gonna be, you know, one that I could that I could enjoy.
Avanish Srinivasan: And then has working with patients in general influenced the questions that you ask in your research?
Chris Walsh: Absolutely. and that's that's you know one nice thing about doing medically related research is that I derive a lot of sense of purpose and meaning from doing research that that matters to people. you know, I mean I think it's a general question in our lives, how do we find purpose and meaning? And and for me, I like the idea of discovery. That I'm somehow advancing knowledge, but I also like the feeling that discoveries, those discoveries can help people. And so when I first started my lab, I would I thought I was going to do really basic stuff on like rats and mice. That's what I'd been doing for my postdoctoral fellowship. I was studying how the cerebral cortex develops from these undifferentiated cells, you know, marking stem cells and looking at the clones that they would form and how they would migrate to the cerebral cortex. But I kind of wanted to do something more related to patients because I was, after all, a neurologist at that time. And wasn't sure exactly how I was going to do that. And after I'd started my own lab, I went to a meeting to present my work. And one of my teachers from the University of Chicago, a pediatric neurologist by the name of Peter Huttenlocker, presented a family with an inherited malformation. of the cerebral cortex. And again, that was one of those aha moments for me when I realized that this is exactly what I want to do. This is a way of applying genetics to the study of the development of the brain. And a way of doing it in a way that's going to give us durable information, you know, that will always be true. Like if we find what that gene is that's abnormal in Peter's family, that's always
Avanish Srinivasan: Mm-hmm.
Chris Walsh: going to be true science. That's not going to be something which a new technology will come along and find was actually wrong. Because this is a problem in science that a lot of things
Avanish Srinivasan: Yeah.
Chris Walsh: we we discover, you know, one year turn out to not really be true or useful a couple of years later. And it's I find it important to try to do something that will be durable.
Avanish Srinivasan: So do you think that doctors and scientists think about problems differently? Or do they do you think they take the same approach and apply it in just different fields, I guess?
Chris Walsh: That's a great question. And doctors and scientists think about things very differently. There's a completely different theory of knowledge or epistemology between the medical side of taking care of patients and the research laboratory.
Avanish Srinivasan: Mm-hmm.
Chris Walsh: and that was and that's one of the challenges of the combined MD PhD program is because I came out of my PhD thinking I knew something. And I entered my final two years of clinical training thinking I knew something, and I knew nothing. about how to take care of patients or how the medical mind worked. And and so because a lot of it has to do with that interaction with patients and it's very empirical. and there's things that don't always necessarily make scientific sense that just work. Whereas in the lab, you know, you can reduce things down to a defined experiment and a hypothesis. On the other hand, physicians who do research They follow pretty much the same theory of knowledge and the same pattern of experimentation as, you know, PhDs who do research.
Avanish Srinivasan: Mm-hmm.
Chris Walsh: and you know that the and so you know, you really can't the at the highest quality of research you can't tell, you know, whether someone's coming from a medical background or a or a straight science background, if the if the work is good.
Avanish Srinivasan: Right. Yeah. So then you're saying of course there are a lot of differences, but ultimately could be similar. They might take a similar philosophy of approaching things, right? Mm-hmm.
Chris Walsh: Exactly. Right.
Avanish Srinivasan: And then just to pivot, since we're talking about your research, I just want to get into that specifically. For many people, it might seem that it's almost impossible that the brain is building itself. So starting from a fertilized egg, how does the cerebral cortex actually form?
Chris Walsh: Sure. Well, the early steps of forming the brain are, you know, generally similar to the formation of other organs like your heart or your gut. You know, you have to it has to be patterned and there's a whole science field about how, you know, the body knows that this is the head end and that's the tail end, and, you know, how the inside is formed versus the outside. So There's a lot of early patterning events that are kind of shared by the different organs. And then all of the different organs have stem cells, and they have to make you know, these are the grandmother cells that are undifferentiated that divide and produce more cells. and that's pretty similar in the different organs as well. and then you know, cells are sometimes formed i in places where the stem cells lived, and sometimes they have to move or migrate. To where they differentiate, and that happens a lot in the cerebral cortex. For some reason, the stem cells of the cerebral cortex are buried deep inside in the inner lining of the brain, and it forms the neurons which don't divide. And then after the neurons have withdrawn from the cell cycle, they migrate out to the outer surface of the cerebral cortex where they stop dividing and then they start forming connections. And so That's again somewhat similar to other organs, but then after that is where the brain gets really interesting. Because then what happens is the different brain cells, particularly the neurons, start talking to each other. And they regulate a lot of different things. The neurons that are formed start talking to the stem cells and start controlling how those stem cells proliferate. And then the neurons start forming connections with each other. And that in fact the neurons we've recently discovered. They undergo a Darwinian struggle for survival. They're formed in excess by about 30%, and
Avanish Srinivasan: Mm-hmm.
Chris Walsh: they compete to survive. And the ones that survive are the ones that successfully form connections called synapses with other neurons. And so it's this, like I say, it's this really competitive process right around the midpoint of fetal gestation in humans, where these neurons are competing like crazy. and so and then you know of course these connections continue to be elaborated throughout our whole life. That's what learning and memory is all about. But
Avanish Srinivasan: Right.
Chris Walsh: this aspect of the interactions between cells is under a less strict sort of genetic control. And so the early steps of the formation of the brain are under mostly genetic control, similar to the early development of the other organs. But then the brain has this extra level. of this interaction and this selection and this activity-based development that's fairly
Avanish Srinivasan: Right.
Chris Walsh: unique to the brain and that's where a lot of the magic is. And so although there are a lot of genetic disorders of the brain, we have a lot of the development of the brain is also non-genetic and is patterned by this sequential series of interactions.
Avanish Srinivasan: Right, so there is a sequential process of how it's developing, right? And then
Chris Walsh: Exactly, yeah.
Avanish Srinivasan: what's very interesting is I guess stem cells
Chris Walsh: Let's go!
Avanish Srinivasan: itself. These these cells are, I guess, undifferentiated and almost like a blueprint because they can become into other things. But how does that process work? Because these are the most versatile cells that we have, basically, right?
Chris Walsh: That's right, yeah. So again, like I said, the early steps are fairly strictly controlled by genes. And so for example, there are genetic disorders in humans where the stem cells just stop making neurons too soon. And so the brain ends up too small. So our brain might be reduced to the size of a chimpanzee's brain. so that's a gen that's a not an uncommon genetic disorder of kids. and or there are disorders where the neurons don't migrate properly. So they might migrate instead of all the way to the cortex, they migrate halfway and then for some reason stop in the middle of nowhere. So these early steps, like I say, are fairly strictly genetically regulated, and there's a host of hundreds or thousands of different rare genetic syndromes in humans, each one individually very rare, that disrupt it. But then, like I say, the neurons get to where they're going and they start making connections. Then there's a whole other series of conditions in humans that disrupt the way the connections are made and reinforced. And so in those connections, the brain might look pretty normal if you took an X-ray or an MRI scan, but it just doesn't work properly. And those kids will have some often have intellectual disabilities or autism spectrum disorders. Because even though they've got the right numbers of neurons and they're in the right places, they just don't connect properly.
Avanish Srinivasan: So first it's primarily just genes influencing and then it's another whole host of other factors which influence the development, right?
Chris Walsh: That's right, exactly. And these later steps are influenced progressively more and more heavily by what we experience.
Avanish Srinivasan: Right. And then another major part of your research has been cortical malformations and understanding what it is. So
Chris Walsh: Mm-hmm.
Avanish Srinivasan: of course that seems really complicated, but what exactly are cortical malformations?
Chris Walsh: Yeah. Well, so cortical malformation is is more or less the way it sounds. It's the it it's the the brain just doesn't get put together properly. and we diagnose them by putting a patient into an MRI scanner. And the MRI scanner can take a three-dimensional picture of your brain, you know, non-invasively. and so we can see it with tremendous detail now the inner structure of the human brain. And so we can characterize these ev sometimes even subtle disorders of the way the brain gets put together, you know, using the MRI scan. And then we can connect that to the genetics.
Avanish Srinivasan: And then how exactly do they arise and during development?
Chris Walsh: So the genetic mutations can be inherited or they can be spontaneous mutations. And so when it comes to things that affect the brain, they often are associated with social challenges or intellectual challenges. And so people that have disorders of the brain will often not have a family themselves. They might be might not you know be s smart enough to be able to manage it to get married and have kids. And so given that, the disorders that affect the brain that are inherited are often inherited in what we call a recessive fashion, where you have to have disruption of both copies of a gene. So just to back up for a minute, you know, most of our genes we have two copies of. We get a copy of every gene from our mom, we get a copy of every gene from our dad. Except for the X chromosome where females have two copies and then males have one X and one Y, of course. And so for most of the genes in our genome, one gene, one copy of the gene is all we need. And so we can actually have a disabled copy of one of the two copies of a gene and not know it. And it
Avanish Srinivasan: Right, yeah.
Chris Walsh: only is a problem if an unfortunate child. inherits a disabled copy of the same gene from both parents. And that's what a recessive disorder is about. And like I say, most of the disorders then of the brain that are inherited are inherited in this recessive fashion, where the parents didn't even know they were carriers, or these days sometimes people will get testing. And it's just bad luck that the disabled copy from both parents goes to the same child. But in fact a lot of the dis thing the genes that disrupt The development of this of the cerebral cortex or the function of the cerebral cortex are not inherited at all. They're spontaneous mutations that affect just a single sperm or less commonly a single egg of one of the two parents. And they affect a gene where you need both copies, because for some reason the brain needs both copies of the gene. we call those dosage sensitive. It's something where it that causes a condition, even if you're just missing one of the two copies. And these and so these are these are in theory would be inherited in dominant fashion. if, you know, for those of you read your listeners who've learned about dominant inheritance and recessive inheritance, but again, they're not usually inherited because of the fact that they're so disabling. and so we realize now that these mutations that loop that disrupt just one of the two copies of the genes are only appearing in our population because new mutations are constantly happening. And so it turns out that each of us has about 80 to 100 new mutations relative to our parents. fortunately, most of those aren't in the middle of a gene or disabling to the gene. Most of them are in the junk DNA that makes up, you know, 95 or more percent of our genome. but on in some unfortunate cases there can be a spontaneous mutation, just a bolt from the blue, nobody knew it was coming, that affects an essential gene. And that's a common cause of cortical malformations or autism and intellectual disabilities and epilepsies as well.
Avanish Srinivasan: Right. So you're saying that the genetic component could be something inherited from parents who are carriers and they have both the they have a recessive copy of the gene and they don't even know it. And then that unfortunately the two recessive copies
Chris Walsh: Right.
Avanish Srinivasan: leads to the disorder. But then it could also be mutations itself arising randomly and that could ultimately lead to a dominant kind of fashion of it showing up, right?
Chris Walsh: Exactly. And once the dominant mutation occurs, in theory, it could be inherited if the affected child grows up and has kids, they would then transmit
Avanish Srinivasan: Mm-hmm.
Chris Walsh: it because they have that mutation in their, you
Avanish Srinivasan: Right.
Chris Walsh: know, the in their sperm or in their eggs. but again, those kids are often unable to have a family themselves, and so therefore the mutation is not transmitted. and so it it often it really only appears in children because of this. constant creation of new mutations in our in our sperm and egg cells.
Avanish Srinivasan: And how do these seemingly small scale mutations lead to large scale developmental disorders like epilepsy, autism, or schizophrenia?
Chris Walsh: Well, that's a complicated question. I'll try to give a few examples to try to make it simpler. One way is in the case of epilepsy. So epilepsy is uncontrolled electrical activity of the brain. you know, it can cause epileptic seizures that are, you know, repetitive movements usually associated with loss of consciousness and control. and so that those epilepsy mutations are frequently mutations in the ion channels that regulate the excitability of neurons. And so it disrupts the pattern of electrical activity of the neurons and every and periodically that can become unleashed to drive a seizure. In the case of intellectual disabilities or autism spectrum disorders, again they are the genes are often the genes of the synapse that are actually required for neurons to connect to one another. And they're the genes that are active when we're when we're undergoing when we're trying to learn something. those genes are upregulated or altered in their pattern of expression. and again, missing then one of the two copies of that gene can disrupt that whole process of learning, which is what w what it results in intellectual disabilities.
Avanish Srinivasan: I see. So then these mutations are affecting larger scale processes which end up causing these disorders in a way, right?
Chris Walsh: That's exactly right. Yeah.
Avanish Srinivasan: Okay. And then of course your lab has identified dozens of genes that are involved in human brain development. So how do researchers go from studying families with neurological disorders to discover discovering entirely new genes?
Chris Walsh: Well, you know, that's been a that that approach has evolved dramatically over the time that I've been doing science. you know, we've now had we just celebrated the twenty-fifth anniversary of the sequencing of the human genome, and that was a revolution in terms of the our ability to find new genes and assign a function and a disease to those genes. And so You know, you could see how like we are discovering genes at this slow rate, and then all of a sudden it just like accelerated exponentially after the sequencing of the genome. Now it's sort of leveling off. Because with the sequencing of the whole genome, now the way we discover new genes is we see a kid in the clinic and it's become a routine clinical test when it's indicated to sequence the genome of the child, and we always have to compare that genome to the genome of the parents. and we usually will find a gene that's previously characterized as causing that child's condition, but sometimes we'll find you know, a a a mutation in a gene that hasn't previously been described to cause intellectual disability or epilepsy or autism. And then we call up colleagues who are doing the same thing. And you know, they may I've also seen another family in another part of the world that also had an unexplained mutation. in that same gene and then we know that it's a new gene for a new disease.
Avanish Srinivasan: Yeah, that's that's a very interesting approach to it. But then you said that it's drastically evolved since I guess just a couple of decades ago. So
Chris Walsh: Yeah.
Avanish Srinivasan: how's this process like when you first started?
Chris Walsh: Well when we you know at when I first started, we didn't really have a map of the genome. we didn't know where any of the genes were. You know, we knew that how many chromosomes there were and stuff like that, but we didn't really have the beginnings of a sequence. And so when we cloned our first couple of genes, we actually had to identify you know, we narrowed down the gene. To a certain portion of the genome, and we knew it was maybe, you know, five or ten million letter. You know, you know, the genome, of course, is just four letters, A, T, C, and G. And we narrowed it down to about a segment of maybe 10 million letters long, which probably had like a couple of dozen or maybe a hundred genes in it, but we didn't know what those hundred genes were. and so we had to just start like sequencing that place. And try to figure out what are the genes in there. And so, you know, the first gene that we ended up identifying is called double corten, because it disrupts the migration of the neurons. And so some of the neurons migrate halfway to the cortex. And so instead of having one cortex, you have two cortexes, an outer one and an inner one. And when we discovered that gene, it was not known to be a gene. It was just like a random piece of DNA that hadn't really been put together. And so that's what it was like when we first started back in the 1990s. and like I say, then around 2000, the genome was sequenced. And then a couple of years later, there were ways of basically just sequencing at least the coding parts of the genome in every patient. So we didn't have to map the gene anymore. We just would go right to sequencing every gene in the person's every, you know, all 20,000 genes in the genome in that person. And so that's how we do it now. You just basically you don't have to do any mapping, no cloning. you just go right to sequencing every single gene in the genome. and we know so much now about the patterns of variation of the genome in normal people that it's very easy to recognize a variant which doesn't obey the you know, which is not which is out of the bounds of the normal variation.
Avanish Srinivasan: Right, so technology has revolutionized the process, made it much more efficient and I guess given a lot more knowledge and ability to physicians and scientists alike, right?
Chris Walsh: That's right. And now it's like I say, now it's not really a job for research labs anymore. It's now a clinical test. and it's the clinical labs
Avanish Srinivasan: Yeah.
Chris Walsh: that are, you know, continuing to discover new genes, which is great because now this is a service we can offer our patients.
Avanish Srinivasan: Mm-hmm. Yeah. And then of course you've studied a lot of these disorders and conditions, but what have what has that taught you about normal brain development in general?
Chris Walsh: Well, I think it's taught me a bit of what I was describing about the this sequence of events that regulates how the brain develops. this fact that the early steps are governed more strictly by genes and the later steps are more governed by interactions. That was something that I have a much greater appreciation for now than when I first started. it's taught me just some amazing things about just how variable the development of the human brain can be and then somebody can still be basically normal. and so s the first gene we started studying, a subset of the neurons never migrate at all and they form these blobs of cell of neurons way deep in the brain, nowhere close to where the cerebral cortex is supposed to be. And we identify those patients Because most of those patients will have epilepsy, although sometimes the epilepsy is pretty mild. But some of those patients are really smart. They're like totally normal. They can be medical students, they can be CEO. I've seen people that are CEOs of companies, computer programmers, you know, like way smarter than I am. And like they have all
Avanish Srinivasan: Yeah.
Chris Walsh: these neurons in the middle of nowhere. And it's kind of a mystery to me whether those neurons that are all out of place, do they actually wire up to the rest of the brain? Like are are people thinking? With those neurons that are in these irregular blobs, because you know, the people like me who's who are obsessed with the brain, we're obsessed with the beauty of the organization of the neurons in the cerebral cortex. They form these six layers like a like a layer cake, and they have this beautiful shape and morphology and these beautiful long connections.
Avanish Srinivasan: Mm-hmm.
Chris Walsh: And we think, and it's natural to assume that this beautiful Organization is essential for its normal function. And yet I see patients who've got cells all over the place. And they seem to be some of them are doing just fine. Not all of them. They have a higher rate at which they might have you know, cognitive challenges, but some of them are amazing. So I'm really impressed with just how diverse a normal human brain can be.
Avanish Srinivasan: You buy it.
Chris Walsh: and that there's no like one path. you know, that the brain has to follow in order to develop, and that, you know, genetics is important, but it's by no means the whole deal.
Avanish Srinivasan: Right. Yeah, and then since we're talking about how I guess diverse a normal brain could actually look like, what exactly does determine whether a mutation or a malformation is clinically significant? Because of course a lot of it could be ex there, but that might not even show up, right?
Chris Walsh: Right. Well, you know, I think the I think there are a lot of things that regulate that. And we don't understand most of them. this is a phenomenon in genetics that's referred to as variable penetrance. and this is true of all genetic disorders, that they show variable penetrance. And in fact, the more we sequence the genome of people, of normal people, the more we find that some of them like have mutations where they oughta have a disease, but don't. and or they have some very mild form of a disease. For example, cystic fibrosis is a very severe disease of kids where they can't breathe properly, they get pneumonia, they typically die be f by the age of twenty or so. they have a lot of trouble absorbing food, so they're malnourished. and so when I was a medical student, this was a uniformly fatal diagnosis, or so we thought. now with genome sequencing we find that certainly some kids with cystic fibrosis have that severe course, although now we have drugs that can treat that thanks to harnessing the genetics of cystic fibrosis. However, we also discover that some people have like those exact same mutations and they don't have any of the lung problems or any of the gut problems. And that's a mystery, exactly how that happens. And that's very true in the brain, where particularly girls are protected from mutations that affect the brain. And we see this most drastically in autism spectrum disorders, where autism is four or five times more common in boys than girls. and that's been a bit of a mystery, but it's something we've been studying a lot lately. And we think we have some thoughts about what might be regulating that. but it is but it's it's very poorly understood, this phenomenon of variable penetrance. it might have to do with the genetic background. It's in part determined by the other genes that people have, because genes kind of interact in complex networks.
Avanish Srinivasan: Mm-hmm.
Chris Walsh: it's probably also regulated in part by random mutations that we all develop as our bodies develop. since we all have patches of cells that are abnormal and that's a kind of a r a somewhat random process. and then it may and it's probably governed by other things that we don't we don't understand yet.
Avanish Srinivasan: Yeah, that's incredibly interesting because I never realized that gender could really influence, I guess, the number of people who had a disease like four or five times is a huge difference. So how much do we understand? Do is it just mostly an understanding of the factors, but have we pinned down any real conclusion from that?
Chris Walsh: well, so you know, there are certain diseases that are more common in girls and boys, and then there are other conditions that are more common, sorry, there are certain conditions more common in girls and boys. There are other conditions more common in you know boys than girls. It's more frequent that things affect males more than females. things that affect females are more commonly diseases of adulthood and things that affect the immune system. Things like Lupus, systemic lupus erythematosis, multiple sclerosis, a lot of autoimmune diseases tend to be more common in females than males. And it's not not totally clear why. But then a lot of it's often the developmental conditions that affect boys more commonly than girls. And it's not just developmental conditions related to the brain, but it's very prominently developmental conditions related to the brain. That includes not just autism spectrum disorders, but attention deficit, hyperactivity disorder, schizophrenia, but then also developmental disorders of other tissues. So also developmental conditions that affect our gut and our heart. Congenital heart disease for some reason is one is a one and a half to two times more common in boys than in girls. And so this probably relates to something about how the sex chromosomes interact with the rest of the genome. so again, girls have two copies of the X chromosome. Boys have an X and a Y. The Y is the small, is a very tiny chromosome that has very few active genes on it. And so girls actually have, you know, two copies of a lot of genes. So they have potent the potential for higher expression of some of those genes. And it may be that the our going theory is that there's something about those two X chromosomes that tends to protect females from a lot of childhood diseases.
Avanish Srinivasan: Right. So the interaction of the sex chromosomes as allowing potentially for this kind of protection, right?
Chris Walsh: Right. There for example, there are genes on the X chromosome that encode regulators of other genes. there are genes that encode proteins called transcription factors, which
Avanish Srinivasan: Yeah.
Chris Walsh: regulate how a gene somewhere else in the genome is turned on or turned off. And so they may particularly for these diseases where you need both copies of the gene to work, they seem to maybe boost the expression of that gene elsewhere in the genome and boosting the expression of a little bit might protect someone from losing one of the two copies.
Avanish Srinivasan: Right, I see. And then since we're on the topic of disorders, have we seen their pathways overlap? Because I know we previously discussed that a lot of it is caused by mutations of a specific system and that's like kind of causing a chain reaction, but then are there overlaps in that system or pathway?
Chris Walsh: Yeah, well there's a lot of overlap in terms of the genes associated with autism spectrum disorders. they highlight aga it it's a mysterious condition because it also can be caused by hundreds of different genes. Can cause a condition which when you see the child in the clinic is indistinguishable. These a hundred different kids can look the same, but they can have different genetic mutations. and that's
Avanish Srinivasan: Mm-hmm. It's all causing the same thing, yeah.
Chris Walsh: Yeah, and that's different than the way genetics usually works. You know, most of the time there's a there might only be one or two or maybe a dozen different genes that cause a particular condition. It's rare to have this level of diverse different genes that can cause a seemingly indistinguishable condition. That seems to reflect the fact though that a lot of these genes function at these connection points between one neuron and another called synapses. And those synapses are just really complicated structures. And they have about a thousand more different proteins in them. and all of those proteins look like they're really important. And so it looks like you knock out any one of them, and the there's something not quite right about the synapse. And if the synapses aren't quite right, then you have difficulty learning things, and you have difficulty learning social interactions, which is some of the most challenging things actually that humans have to learn. You know, one of the hardest things to learn is how to interact with other people. we learn that long after we learn to walk. We learn that after we learn to talk. You know, it's only like in kindergarten that we really start learning how to interact with people and how to how to detect social cues. And because that's a really hard thing for the brain to do.
Avanish Srinivasan: Right, I see. And I also wanted to pivot into one final topic before we close for today. So I know your research also suggests that mutations accumulate faster in neurodegenerative diseases. So how
Chris Walsh: Yeah.
Avanish Srinivasan: might that connect to conditions like Alzheimer's disease or dementia?
Chris Walsh: Right. Well, so we're very interested in how that connects. and so yeah, we this has been some findings that have really kind of been mind blowing to me, because you know I was I've been in neuroscience like for a long time. I'm an old person. And all that time I just thought that, you know, neurons are not dividing cells, and nature made them to be non dividing so that Their genome would be protected and it would stay the same their whole life. Unlike other cells, like skin cells and you know, blood cells that are dividing all the time, and we know that they can sometimes form cancers. But neurons in the brain, since they don't divide, they never form cancers. And so, yeah, we thought their genomes were very stable. And so we started sequencing the genome of a single neuron. by amplifying it, you know, taking one neuron and putting it into a well and isolating its genome and then sequencing it. And to our wonderment we found that the genome in every neuron is different from the genome in the neuron next to it, and that it's a dynamically changing thing. That each one of our neurons accumulates about twenty mutations every year, like a clock. It these mutations measure our age with incredible precision. And if we live to be a hundred, we accumulate 20 mutations the first year of life in each one of our neurons, and 20 years of our 100th year of life in those neurons if we don't have any disease. And then we find that if if you have a degenerative disease like Alzheimer's disease or ALS, Luke Eric's disease, all of these conditions that we've studied so far, the neurons develop extra mutations. And it looks like those extra mutations are caused by the disease because the pattern in which the mutations occur, the particular number letter sub substitutions are different. The ones that accumulate with age are generally changing a C to a T or changing a T to a C. but in in Alzheimer's disease, we most commonly see that it now we're changing a C to an A, and that's a change which almost never happens in a normal neuron. And that's something which is probably caused by the disease and it's probably caused be by the fact that the brain is inflamed, that the immune cells of the brain called microglia are a little out of control, and they're secreting things that are probably damaging to the neurons.
Avanish Srinivasan: So then these mutations could potentially contribute to direct neuronal damage, he said.
Chris Walsh: We think that they do. We think that the age the ones that occur in normal aging, even though it's twenty per year and even though it's, you know, thousands by the time you're my age, that they don't seem to be necessarily terribly damaging to the way the neurons work. But anything that increases that more than a little bit, can be very damaging. So in fact, some of the patterns of damage we see in Alzheimer's disease, a neuron Would have an excess of mutations equivalent to more than a hundred years of normal aging. And so that's probably very damaging to the function of the neurons.
Avanish Srinivasan: And then has this entire narrative been complicated a little bit by the discovery of neurogenesis or like I guess the proliferation of neurons throughout life?
Chris Walsh: So yeah, the the proliferation of neurons throughout life is a fascinating topic. and that it does not happen so much in the cerebral corte in the neocortex of the cerebral cortex. So the vast part, the biggest part of our s of our cerebral cortex is a part that's called the neocortex or new cortex that appeared relatively recently in evolution. There's another part of the cerebral cortex called the hippocampus. Which is a s an essential center for memory. And that is much more highly conserved over evolution. And so we see it in a lot of animals that we diverge from a much longer time ago. So it's called the archicortex or the old cortex. So that ongoing formation of neurons looks like it happens in that hippocampus, in that old cortex. and That's a fascinating process, both in terms of how it might regulate normal learning and memory and aging, but also we're finding some connections to age-related diseases that might relate to that process as well.
Avanish Srinivasan: Mm-hmm. Yeah, I see. Okay, so before we wrap up for today, I just wanted to do a quick rapid fire round of of questions. I just want
Chris Walsh: Okay.
Avanish Srinivasan: you to give me your honest, quick answer to each of these questions. Okay.
Chris Walsh: Okay, great.
Avanish Srinivasan: So what do you think are the biggest unanswered questions in brain development research today?
Chris Walsh: Well, I think the b biggest one is like what is memory? like how do we remember things? We we know that it has to do with changes in these connections called synapses. But exactly how that happens, still a huge mystery.
Avanish Srinivasan: Still unknown, yeah.
Chris Walsh: Yeah. There's a lot, you know, we we still don't know a lot about this disorder, schizophrenia, that I went into neuroscience wanting to study. Many, many decades later, we still don't understand a lot about. Exactly how that how can it be that people start hearing voices? so those are
Avanish Srinivasan: Right.
Chris Walsh: just a couple of big questions. There's lots I could talk about them all day.
Avanish Srinivasan: And then what do you think is something that researchers are getting close to understanding that once seemed impossible to understand?
Chris Walsh: well I think one thing we're getting close to understanding is the genetic basis particularly of pediatric disease. the genetic basis of a lot of diseases we understand pretty well. you know, we there's it it I mean you can say we're close to understanding it or you can say we're far from understanding it. For most conditions If we have a kid that comes into clinic and we think, he's probably got a genetic condition or she's got a genetic condition and we sequence their genome, you know, we have about a one out of three chance of finding the genetic basis of that. So compared to when I started, that's really, really good. Compared to where we'd like to be, that's still really bad. What's that other two thirds? and
Avanish Srinivasan: Mm-hmm.
Chris Walsh: so you know, that's both something that we understand well and something we understand poorly at the same time. So we we you know, we we really have a a lot we are We are, as I say, we're starting to level off in our discovery of new disease genes. And so we're starting to saturate that. And so we're starting to have a really a pretty good sense of the annotation of our genome. But there's still lots of families out there that still need our help to understand what's what's the matter with their child.
Avanish Srinivasan: And then for students who are listening and they want to go into neuroscience, medicine, genetics, or just developmental biology, what advice would you give to them?
Chris Walsh: Well, you know, I think the best advice is to try to see if you can find a way to give it a shot working in a laboratory. If you're near a big city or if you're near a university, the chances are pretty good that if you reach out to some of the laboratories there and ask there's a good chance you might be able to, you know, volunteer over a summer or something like that. And I think it's important to try that because, like I say, for me, I didn't know what I wanted to do, and I only learned what I wanted to do by trying stuff. because we don't really know ourselves that well and we don't know really what we're gonna like and what we're not gonna like and the only way of finding if you're gonna like something is to just kinda like walk in and give it a shot. But also I think it's important to try to see if you can find a connection to a lab because y you know, people think of scientists as cloistered in these white coats and being, you know, really formal and structured and and science is exactly the opposite. You know, it's something where everybody's like wearing t shirts to work and they come and go as they please, and they're trying to really be creative. and so it's really different than the way scientists are portrayed.
Avanish Srinivasan: Mm-hmm, of course. And then since you're talking about how there is a misconception about science, what do you think is a misconception about being a physician?
Chris Walsh: well, I think I'd also some one thing that people don't realize about physicians is that it's there are tremendous range of career choices for a physician, other than just being a physician. Being a physician is tough these days, with the insurance companies and things like that. A lot of burnout among physicians, but there's all sorts of career trip paths you can take after medical training. and so it's very empowering. and the other thing about, you know, medicine is just that it's just an incredible privilege to be a physician and to have the opportunity to talk to people at their time of greatest need and to feel like you might be able to, you know, play some small part in helping out.
Avanish Srinivasan: And then the last question I want to ask you today is if some listeners could only remember one thing from this entire episode, what would you want that to be?
Chris Walsh: Gosh. Well I think it would be something like, you know, just science is fun, you know. Science is like really different and people think of it. It's and it's a really creative thing. and and it's it's and like I say, it's a it's a fun life. So I I highly recommend
Avanish Srinivasan: Mm-hmm.
Chris Walsh: it.
Avanish Srinivasan: Okay, great. Dr. Walsh, thank you so much for joining me today and for helping us better understand one of the most remarkable processes in biology.
Chris Walsh: Well, thanks very much, Avanese. It's been a real pleasure.
Avanish Srinivasan: Yep, of course. The human brain doesn't simply appear, but it is built cell by cell and through an intricate developmental process shaped by genetics, experience, and just time. And by studying how that process unfolds, scientists are able to discover new insights into disorders ranging from epilepsy and autism to Alzheimer's disease and dementia. For listeners, if this episode gave you a new perspective on how the brain develops, be sure to share it with somebody who you think would enjoy the conversation. I'm Ovnish, this is the Early Perspective, and I'll see you in the next episode.
Chris Walsh: Thanks Avanish. I'm really glad to be here. It's always fun to talk
Avanish Srinivasan: Yeah.
Chris Walsh: about the brain.
Avanish Srinivasan: Of course. Okay, so to start off, I'd love to go back to the beginning. Could you tell us a little bit about your journey into neuroscience, medicine, and just brain development research in general?
Chris Walsh: Sure. I mean, I think in my case, my decision to go into neuroscience is really influenced by my teachers. I skipped my last year of high school and ended up in college just a month after I turned 17 with no idea what I was gonna do or what I was gonna study. And I I took two courses my first semester of freshman year, that really have defined my trajectory ever since. One was psychology. And one was organic chemistry. And ever since then I've been fascinated by this interaction between chemistry and the brain. and that got me on the road to neuroscience research that I, you know, continued to follow in college and then in graduate school. And so I'm really grateful to for those teachers that really inspired me, which is part of why I love to talk to people who are at a younger stage in their career than me.
Avanish Srinivasan: How was that process that transitioned from just skipping a year of high school to college straight?
Chris Walsh: Well, that happened 'cause I'm the I come from a big Irish Catholic family. I'm
Avanish Srinivasan: Mm-hmm.
Chris Walsh: the seventh of eight kids. And we, you know, we were comfortable but we didn't have a lot of money. So everybody had to save money on college somehow. And I was the only one who didn't go to Catholic school, so I was actually going to a private school. And so my parents left the choice up to me. They said you can skip a year of high school or you can skip a year of college like your older sister did. And I didn't particularly want to skip a year of either. but college seemed like it might be more fun than high school. And so that's how I ended up in college after three years of high
Avanish Srinivasan: Mm-hmm.
Chris Walsh: school. And like I said, I really wasn't thinking about doing that. So I, you know, compared to how much kids are prepared now for college and high school, I was like completely unprepared to
Avanish Srinivasan: Mm-hmm.
Chris Walsh: even have any idea. I'd I'd entered a with no major and no really idea what I was gonna do for a major, so If any
Avanish Srinivasan: Mm-hmm.
Chris Walsh: of your listeners feel like, you know, they don't are on aren't on enough of a path, I'm here to say you don't have to know what you're doing. You can figure it out as you go.
Avanish Srinivasan: Yeah, that's honestly wonderful advice. So what first drew you towards specifically the developing brain?
Chris Walsh: Well, that's a good question, and I'm not exactly sure why. I guess that was mostly in graduate school. When
Avanish Srinivasan: Mm-hmm.
Chris Walsh: I first went to graduate school, I wanted to work on schizophrenia because it illustrates this interaction of chemistry, namely dopamine and behavior. because we even way back then it was known that dopamine was important. But at my school there were a lot of great people doing great science, but nobody was doing great science in the area of schizophrenia. And so then I was in a little bit of a little bit of a crisis. I didn't know what I was gonna work on. And I just started again talking to a bunch of different professors, kind of trial and error, and I must have talked to fifteen different professors about their research. And so I met with Professor Ray Gillary, who was working on the development of the brain and in specifically genetic mutations that disrupt the development of the brain, and he just immediately inspired me. with the about the fact that you know the brain is like so specialized but it just starts out as a bunch of simple cells that look just like any other cells and then somehow this miracle happens that gives us this ability for you know consciousness and
Avanish Srinivasan: Mm-hmm.
Chris Walsh: free will and choice and intellect and creativity. and so I've always been fascinated by how that miracle comes about.
Avanish Srinivasan: Yeah, of course it's an incredibly fascinating topic to get into. So when you did start going into that topic, was there any particular discovery or experience that shaped your career and the future trajectory?
Chris Walsh: well, again, there are lots of things that have shaped my trajectory. I sometimes feel like I'm a blank slate and I just am imprinted by the people I encounter. You know, I had some really good research experiences in college that helped me along, but my you know, again it's been a series of things. I mean really my role model was Ray, my PhD
Avanish Srinivasan: Mm-hmm.
Chris Walsh: advisor. He showed me what it was like to do science, how it could be just a really fun thing, a little bit like art, except it's also, you know, a dispassionate search for truth. And so it's
Avanish Srinivasan: Right.
Chris Walsh: I just love the fact that you can be creative, but you're but you're bound by rules of trying to find something which is true and durable. and you know, just trying to, you know, help expand knowledge a little bit. And I had a very dramatic experience my first year of graduate school. because I I I mean, I discovered along the way the idea of doing a combined MD PhD degree.
Avanish Srinivasan: Mm-hmm.
Chris Walsh: and that was that was a moment for me. I I again I wasn't sure if I wanted to go to medical school or graduate school. I felt like I liked science more than I was enjoying my volunteering in hospitals because in the science lab anybody can do anything at any age. and so I was given a lot of responsibility, whereas in the hospital as an undergraduate, you just kind of follow other people around. And
Avanish Srinivasan: Right.
Chris Walsh: so I was wrestling a little bit with my decision between medicine and science. And one day I walked into my premed advisor's office and I saw this pile of pamphlets on the side and I still remember exactly where they were and where his bookcase was and I absentmindedly picked up one of these pamphlets and I'll never forget what it felt like. It's like this high quality sort of textured paper and
Avanish Srinivasan: Mm.
Chris Walsh: it has this burgundy color. And that was a p a pamphlet describing the combined MD PhD program at Cornell Rockefeller. And I must have read that pamphlet about a hundred times over and I and and that was a moment. that where a light bulb went off for me that this was
Avanish Srinivasan: Mm-hmm.
Chris Walsh: the way of doing this and they actually would pay you to do this, that it was free. And again, coming from a big family where we had to think about saving money, it was the it was a perfect thing from
Avanish Srinivasan: Mm-hmm.
Chris Walsh: my family perspective also. But this would and so, you know, that was really a moment that set me on the course to doing the combined degree programs.
Avanish Srinivasan: Right. So then once you did go to medical school and also graduate school combined, how'd you get to s choosing neurology as your specialty? What what guided your decisions in medicine?
Chris Walsh: Well, so I really enjoyed my PhD in n neuroscience. And so I decided I wanted to stick with neuroscience research. And you know, the first two years of medical school you're mostly in the classroom. And then I stepped away from medical school to do my PhD. and then I was thinking I would probably want to do neurology as a specialty, but wasn't certain. and from there You basically just try different specialties as rotations. You do a month of neurology, you do a month of or two months of internal medicine, and it's really very empirical. you know, I've talked to a lot of medical students about this choice because I was director of Harvard's MD PhD
Avanish Srinivasan: Mm-hmm.
Chris Walsh: program for a few years. And it's I think of it as like the wand chooses the wizard, because you walk into rotation. and there's some where you just feel comfortable. You just feel like you're at home. And there's others that you thought you might like, but they just don't feel right. And so it's it was
Avanish Srinivasan: They don't click, yeah.
Chris Walsh: yeah, and so it's really a g on the one hand it's a gut feeling. On the other hand, I've as a seventh of eight kids I've always looked to role models. And I told you that Ray, my PhD advisor, was a role model because you know, it looked like He just had a life that I could enjoy living. he worked in the lab, he chatted, he stopped for a cup of coffee, he'd go home, he'd have dinner with his family, and I knew that family was going to be important to me and that I'd want to have a family of my own, and then you know, he'd do reading and things like that in the evening. So he seemed like he had a life that be that was a good lifestyle, as well as a lot of fun. And so when I was doing those rotations, I looked around at the professors who were in the the medical specialties, the clinical specialties. And again I I could see myself identifying with the neurologists who again did a lot of research because we don't have cures for a lot of neurological diseases. So research is very important. and so that's valued by that specialty. But they also had a lifestyle that looked like it was gonna be, you know, one that I could that I could enjoy.
Avanish Srinivasan: And then has working with patients in general influenced the questions that you ask in your research?
Chris Walsh: Absolutely. and that's that's you know one nice thing about doing medically related research is that I derive a lot of sense of purpose and meaning from doing research that that matters to people. you know, I mean I think it's a general question in our lives, how do we find purpose and meaning? And and for me, I like the idea of discovery. That I'm somehow advancing knowledge, but I also like the feeling that discoveries, those discoveries can help people. And so when I first started my lab, I would I thought I was going to do really basic stuff on like rats and mice. That's what I'd been doing for my postdoctoral fellowship. I was studying how the cerebral cortex develops from these undifferentiated cells, you know, marking stem cells and looking at the clones that they would form and how they would migrate to the cerebral cortex. But I kind of wanted to do something more related to patients because I was, after all, a neurologist at that time. And wasn't sure exactly how I was going to do that. And after I'd started my own lab, I went to a meeting to present my work. And one of my teachers from the University of Chicago, a pediatric neurologist by the name of Peter Huttenlocker, presented a family with an inherited malformation. of the cerebral cortex. And again, that was one of those aha moments for me when I realized that this is exactly what I want to do. This is a way of applying genetics to the study of the development of the brain. And a way of doing it in a way that's going to give us durable information, you know, that will always be true. Like if we find what that gene is that's abnormal in Peter's family, that's always
Avanish Srinivasan: Mm-hmm.
Chris Walsh: going to be true science. That's not going to be something which a new technology will come along and find was actually wrong. Because this is a problem in science that a lot of things
Avanish Srinivasan: Yeah.
Chris Walsh: we we discover, you know, one year turn out to not really be true or useful a couple of years later. And it's I find it important to try to do something that will be durable.
Avanish Srinivasan: So do you think that doctors and scientists think about problems differently? Or do they do you think they take the same approach and apply it in just different fields, I guess?
Chris Walsh: That's a great question. And doctors and scientists think about things very differently. There's a completely different theory of knowledge or epistemology between the medical side of taking care of patients and the research laboratory.
Avanish Srinivasan: Mm-hmm.
Chris Walsh: and that was and that's one of the challenges of the combined MD PhD program is because I came out of my PhD thinking I knew something. And I entered my final two years of clinical training thinking I knew something, and I knew nothing. about how to take care of patients or how the medical mind worked. And and so because a lot of it has to do with that interaction with patients and it's very empirical. and there's things that don't always necessarily make scientific sense that just work. Whereas in the lab, you know, you can reduce things down to a defined experiment and a hypothesis. On the other hand, physicians who do research They follow pretty much the same theory of knowledge and the same pattern of experimentation as, you know, PhDs who do research.
Avanish Srinivasan: Mm-hmm.
Chris Walsh: and you know that the and so you know, you really can't the at the highest quality of research you can't tell, you know, whether someone's coming from a medical background or a or a straight science background, if the if the work is good.
Avanish Srinivasan: Right. Yeah. So then you're saying of course there are a lot of differences, but ultimately could be similar. They might take a similar philosophy of approaching things, right? Mm-hmm.
Chris Walsh: Exactly. Right.
Avanish Srinivasan: And then just to pivot, since we're talking about your research, I just want to get into that specifically. For many people, it might seem that it's almost impossible that the brain is building itself. So starting from a fertilized egg, how does the cerebral cortex actually form?
Chris Walsh: Sure. Well, the early steps of forming the brain are, you know, generally similar to the formation of other organs like your heart or your gut. You know, you have to it has to be patterned and there's a whole science field about how, you know, the body knows that this is the head end and that's the tail end, and, you know, how the inside is formed versus the outside. So There's a lot of early patterning events that are kind of shared by the different organs. And then all of the different organs have stem cells, and they have to make you know, these are the grandmother cells that are undifferentiated that divide and produce more cells. and that's pretty similar in the different organs as well. and then you know, cells are sometimes formed i in places where the stem cells lived, and sometimes they have to move or migrate. To where they differentiate, and that happens a lot in the cerebral cortex. For some reason, the stem cells of the cerebral cortex are buried deep inside in the inner lining of the brain, and it forms the neurons which don't divide. And then after the neurons have withdrawn from the cell cycle, they migrate out to the outer surface of the cerebral cortex where they stop dividing and then they start forming connections. And so That's again somewhat similar to other organs, but then after that is where the brain gets really interesting. Because then what happens is the different brain cells, particularly the neurons, start talking to each other. And they regulate a lot of different things. The neurons that are formed start talking to the stem cells and start controlling how those stem cells proliferate. And then the neurons start forming connections with each other. And that in fact the neurons we've recently discovered. They undergo a Darwinian struggle for survival. They're formed in excess by about 30%, and
Avanish Srinivasan: Mm-hmm.
Chris Walsh: they compete to survive. And the ones that survive are the ones that successfully form connections called synapses with other neurons. And so it's this, like I say, it's this really competitive process right around the midpoint of fetal gestation in humans, where these neurons are competing like crazy. and so and then you know of course these connections continue to be elaborated throughout our whole life. That's what learning and memory is all about. But
Avanish Srinivasan: Right.
Chris Walsh: this aspect of the interactions between cells is under a less strict sort of genetic control. And so the early steps of the formation of the brain are under mostly genetic control, similar to the early development of the other organs. But then the brain has this extra level. of this interaction and this selection and this activity-based development that's fairly
Avanish Srinivasan: Right.
Chris Walsh: unique to the brain and that's where a lot of the magic is. And so although there are a lot of genetic disorders of the brain, we have a lot of the development of the brain is also non-genetic and is patterned by this sequential series of interactions.
Avanish Srinivasan: Right, so there is a sequential process of how it's developing, right? And then
Chris Walsh: Exactly, yeah.
Avanish Srinivasan: what's very interesting is I guess stem cells
Chris Walsh: Let's go!
Avanish Srinivasan: itself. These these cells are, I guess, undifferentiated and almost like a blueprint because they can become into other things. But how does that process work? Because these are the most versatile cells that we have, basically, right?
Chris Walsh: That's right, yeah. So again, like I said, the early steps are fairly strictly controlled by genes. And so for example, there are genetic disorders in humans where the stem cells just stop making neurons too soon. And so the brain ends up too small. So our brain might be reduced to the size of a chimpanzee's brain. so that's a gen that's a not an uncommon genetic disorder of kids. and or there are disorders where the neurons don't migrate properly. So they might migrate instead of all the way to the cortex, they migrate halfway and then for some reason stop in the middle of nowhere. So these early steps, like I say, are fairly strictly genetically regulated, and there's a host of hundreds or thousands of different rare genetic syndromes in humans, each one individually very rare, that disrupt it. But then, like I say, the neurons get to where they're going and they start making connections. Then there's a whole other series of conditions in humans that disrupt the way the connections are made and reinforced. And so in those connections, the brain might look pretty normal if you took an X-ray or an MRI scan, but it just doesn't work properly. And those kids will have some often have intellectual disabilities or autism spectrum disorders. Because even though they've got the right numbers of neurons and they're in the right places, they just don't connect properly.
Avanish Srinivasan: So first it's primarily just genes influencing and then it's another whole host of other factors which influence the development, right?
Chris Walsh: That's right, exactly. And these later steps are influenced progressively more and more heavily by what we experience.
Avanish Srinivasan: Right. And then another major part of your research has been cortical malformations and understanding what it is. So
Chris Walsh: Mm-hmm.
Avanish Srinivasan: of course that seems really complicated, but what exactly are cortical malformations?
Chris Walsh: Yeah. Well, so cortical malformation is is more or less the way it sounds. It's the it it's the the brain just doesn't get put together properly. and we diagnose them by putting a patient into an MRI scanner. And the MRI scanner can take a three-dimensional picture of your brain, you know, non-invasively. and so we can see it with tremendous detail now the inner structure of the human brain. And so we can characterize these ev sometimes even subtle disorders of the way the brain gets put together, you know, using the MRI scan. And then we can connect that to the genetics.
Avanish Srinivasan: And then how exactly do they arise and during development?
Chris Walsh: So the genetic mutations can be inherited or they can be spontaneous mutations. And so when it comes to things that affect the brain, they often are associated with social challenges or intellectual challenges. And so people that have disorders of the brain will often not have a family themselves. They might be might not you know be s smart enough to be able to manage it to get married and have kids. And so given that, the disorders that affect the brain that are inherited are often inherited in what we call a recessive fashion, where you have to have disruption of both copies of a gene. So just to back up for a minute, you know, most of our genes we have two copies of. We get a copy of every gene from our mom, we get a copy of every gene from our dad. Except for the X chromosome where females have two copies and then males have one X and one Y, of course. And so for most of the genes in our genome, one gene, one copy of the gene is all we need. And so we can actually have a disabled copy of one of the two copies of a gene and not know it. And it
Avanish Srinivasan: Right, yeah.
Chris Walsh: only is a problem if an unfortunate child. inherits a disabled copy of the same gene from both parents. And that's what a recessive disorder is about. And like I say, most of the disorders then of the brain that are inherited are inherited in this recessive fashion, where the parents didn't even know they were carriers, or these days sometimes people will get testing. And it's just bad luck that the disabled copy from both parents goes to the same child. But in fact a lot of the dis thing the genes that disrupt The development of this of the cerebral cortex or the function of the cerebral cortex are not inherited at all. They're spontaneous mutations that affect just a single sperm or less commonly a single egg of one of the two parents. And they affect a gene where you need both copies, because for some reason the brain needs both copies of the gene. we call those dosage sensitive. It's something where it that causes a condition, even if you're just missing one of the two copies. And these and so these are these are in theory would be inherited in dominant fashion. if, you know, for those of you read your listeners who've learned about dominant inheritance and recessive inheritance, but again, they're not usually inherited because of the fact that they're so disabling. and so we realize now that these mutations that loop that disrupt just one of the two copies of the genes are only appearing in our population because new mutations are constantly happening. And so it turns out that each of us has about 80 to 100 new mutations relative to our parents. fortunately, most of those aren't in the middle of a gene or disabling to the gene. Most of them are in the junk DNA that makes up, you know, 95 or more percent of our genome. but on in some unfortunate cases there can be a spontaneous mutation, just a bolt from the blue, nobody knew it was coming, that affects an essential gene. And that's a common cause of cortical malformations or autism and intellectual disabilities and epilepsies as well.
Avanish Srinivasan: Right. So you're saying that the genetic component could be something inherited from parents who are carriers and they have both the they have a recessive copy of the gene and they don't even know it. And then that unfortunately the two recessive copies
Chris Walsh: Right.
Avanish Srinivasan: leads to the disorder. But then it could also be mutations itself arising randomly and that could ultimately lead to a dominant kind of fashion of it showing up, right?
Chris Walsh: Exactly. And once the dominant mutation occurs, in theory, it could be inherited if the affected child grows up and has kids, they would then transmit
Avanish Srinivasan: Mm-hmm.
Chris Walsh: it because they have that mutation in their, you
Avanish Srinivasan: Right.
Chris Walsh: know, the in their sperm or in their eggs. but again, those kids are often unable to have a family themselves, and so therefore the mutation is not transmitted. and so it it often it really only appears in children because of this. constant creation of new mutations in our in our sperm and egg cells.
Avanish Srinivasan: And how do these seemingly small scale mutations lead to large scale developmental disorders like epilepsy, autism, or schizophrenia?
Chris Walsh: Well, that's a complicated question. I'll try to give a few examples to try to make it simpler. One way is in the case of epilepsy. So epilepsy is uncontrolled electrical activity of the brain. you know, it can cause epileptic seizures that are, you know, repetitive movements usually associated with loss of consciousness and control. and so that those epilepsy mutations are frequently mutations in the ion channels that regulate the excitability of neurons. And so it disrupts the pattern of electrical activity of the neurons and every and periodically that can become unleashed to drive a seizure. In the case of intellectual disabilities or autism spectrum disorders, again they are the genes are often the genes of the synapse that are actually required for neurons to connect to one another. And they're the genes that are active when we're when we're undergoing when we're trying to learn something. those genes are upregulated or altered in their pattern of expression. and again, missing then one of the two copies of that gene can disrupt that whole process of learning, which is what w what it results in intellectual disabilities.
Avanish Srinivasan: I see. So then these mutations are affecting larger scale processes which end up causing these disorders in a way, right?
Chris Walsh: That's exactly right. Yeah.
Avanish Srinivasan: Okay. And then of course your lab has identified dozens of genes that are involved in human brain development. So how do researchers go from studying families with neurological disorders to discover discovering entirely new genes?
Chris Walsh: Well, you know, that's been a that that approach has evolved dramatically over the time that I've been doing science. you know, we've now had we just celebrated the twenty-fifth anniversary of the sequencing of the human genome, and that was a revolution in terms of the our ability to find new genes and assign a function and a disease to those genes. And so You know, you could see how like we are discovering genes at this slow rate, and then all of a sudden it just like accelerated exponentially after the sequencing of the genome. Now it's sort of leveling off. Because with the sequencing of the whole genome, now the way we discover new genes is we see a kid in the clinic and it's become a routine clinical test when it's indicated to sequence the genome of the child, and we always have to compare that genome to the genome of the parents. and we usually will find a gene that's previously characterized as causing that child's condition, but sometimes we'll find you know, a a a mutation in a gene that hasn't previously been described to cause intellectual disability or epilepsy or autism. And then we call up colleagues who are doing the same thing. And you know, they may I've also seen another family in another part of the world that also had an unexplained mutation. in that same gene and then we know that it's a new gene for a new disease.
Avanish Srinivasan: Yeah, that's that's a very interesting approach to it. But then you said that it's drastically evolved since I guess just a couple of decades ago. So
Chris Walsh: Yeah.
Avanish Srinivasan: how's this process like when you first started?
Chris Walsh: Well when we you know at when I first started, we didn't really have a map of the genome. we didn't know where any of the genes were. You know, we knew that how many chromosomes there were and stuff like that, but we didn't really have the beginnings of a sequence. And so when we cloned our first couple of genes, we actually had to identify you know, we narrowed down the gene. To a certain portion of the genome, and we knew it was maybe, you know, five or ten million letter. You know, you know, the genome, of course, is just four letters, A, T, C, and G. And we narrowed it down to about a segment of maybe 10 million letters long, which probably had like a couple of dozen or maybe a hundred genes in it, but we didn't know what those hundred genes were. and so we had to just start like sequencing that place. And try to figure out what are the genes in there. And so, you know, the first gene that we ended up identifying is called double corten, because it disrupts the migration of the neurons. And so some of the neurons migrate halfway to the cortex. And so instead of having one cortex, you have two cortexes, an outer one and an inner one. And when we discovered that gene, it was not known to be a gene. It was just like a random piece of DNA that hadn't really been put together. And so that's what it was like when we first started back in the 1990s. and like I say, then around 2000, the genome was sequenced. And then a couple of years later, there were ways of basically just sequencing at least the coding parts of the genome in every patient. So we didn't have to map the gene anymore. We just would go right to sequencing every gene in the person's every, you know, all 20,000 genes in the genome in that person. And so that's how we do it now. You just basically you don't have to do any mapping, no cloning. you just go right to sequencing every single gene in the genome. and we know so much now about the patterns of variation of the genome in normal people that it's very easy to recognize a variant which doesn't obey the you know, which is not which is out of the bounds of the normal variation.
Avanish Srinivasan: Right, so technology has revolutionized the process, made it much more efficient and I guess given a lot more knowledge and ability to physicians and scientists alike, right?
Chris Walsh: That's right. And now it's like I say, now it's not really a job for research labs anymore. It's now a clinical test. and it's the clinical labs
Avanish Srinivasan: Yeah.
Chris Walsh: that are, you know, continuing to discover new genes, which is great because now this is a service we can offer our patients.
Avanish Srinivasan: Mm-hmm. Yeah. And then of course you've studied a lot of these disorders and conditions, but what have what has that taught you about normal brain development in general?
Chris Walsh: Well, I think it's taught me a bit of what I was describing about the this sequence of events that regulates how the brain develops. this fact that the early steps are governed more strictly by genes and the later steps are more governed by interactions. That was something that I have a much greater appreciation for now than when I first started. it's taught me just some amazing things about just how variable the development of the human brain can be and then somebody can still be basically normal. and so s the first gene we started studying, a subset of the neurons never migrate at all and they form these blobs of cell of neurons way deep in the brain, nowhere close to where the cerebral cortex is supposed to be. And we identify those patients Because most of those patients will have epilepsy, although sometimes the epilepsy is pretty mild. But some of those patients are really smart. They're like totally normal. They can be medical students, they can be CEO. I've seen people that are CEOs of companies, computer programmers, you know, like way smarter than I am. And like they have all
Avanish Srinivasan: Yeah.
Chris Walsh: these neurons in the middle of nowhere. And it's kind of a mystery to me whether those neurons that are all out of place, do they actually wire up to the rest of the brain? Like are are people thinking? With those neurons that are in these irregular blobs, because you know, the people like me who's who are obsessed with the brain, we're obsessed with the beauty of the organization of the neurons in the cerebral cortex. They form these six layers like a like a layer cake, and they have this beautiful shape and morphology and these beautiful long connections.
Avanish Srinivasan: Mm-hmm.
Chris Walsh: And we think, and it's natural to assume that this beautiful Organization is essential for its normal function. And yet I see patients who've got cells all over the place. And they seem to be some of them are doing just fine. Not all of them. They have a higher rate at which they might have you know, cognitive challenges, but some of them are amazing. So I'm really impressed with just how diverse a normal human brain can be.
Avanish Srinivasan: You buy it.
Chris Walsh: and that there's no like one path. you know, that the brain has to follow in order to develop, and that, you know, genetics is important, but it's by no means the whole deal.
Avanish Srinivasan: Right. Yeah, and then since we're talking about how I guess diverse a normal brain could actually look like, what exactly does determine whether a mutation or a malformation is clinically significant? Because of course a lot of it could be ex there, but that might not even show up, right?
Chris Walsh: Right. Well, you know, I think the I think there are a lot of things that regulate that. And we don't understand most of them. this is a phenomenon in genetics that's referred to as variable penetrance. and this is true of all genetic disorders, that they show variable penetrance. And in fact, the more we sequence the genome of people, of normal people, the more we find that some of them like have mutations where they oughta have a disease, but don't. and or they have some very mild form of a disease. For example, cystic fibrosis is a very severe disease of kids where they can't breathe properly, they get pneumonia, they typically die be f by the age of twenty or so. they have a lot of trouble absorbing food, so they're malnourished. and so when I was a medical student, this was a uniformly fatal diagnosis, or so we thought. now with genome sequencing we find that certainly some kids with cystic fibrosis have that severe course, although now we have drugs that can treat that thanks to harnessing the genetics of cystic fibrosis. However, we also discover that some people have like those exact same mutations and they don't have any of the lung problems or any of the gut problems. And that's a mystery, exactly how that happens. And that's very true in the brain, where particularly girls are protected from mutations that affect the brain. And we see this most drastically in autism spectrum disorders, where autism is four or five times more common in boys than girls. and that's been a bit of a mystery, but it's something we've been studying a lot lately. And we think we have some thoughts about what might be regulating that. but it is but it's it's very poorly understood, this phenomenon of variable penetrance. it might have to do with the genetic background. It's in part determined by the other genes that people have, because genes kind of interact in complex networks.
Avanish Srinivasan: Mm-hmm.
Chris Walsh: it's probably also regulated in part by random mutations that we all develop as our bodies develop. since we all have patches of cells that are abnormal and that's a kind of a r a somewhat random process. and then it may and it's probably governed by other things that we don't we don't understand yet.
Avanish Srinivasan: Yeah, that's incredibly interesting because I never realized that gender could really influence, I guess, the number of people who had a disease like four or five times is a huge difference. So how much do we understand? Do is it just mostly an understanding of the factors, but have we pinned down any real conclusion from that?
Chris Walsh: well, so you know, there are certain diseases that are more common in girls and boys, and then there are other conditions that are more common, sorry, there are certain conditions more common in girls and boys. There are other conditions more common in you know boys than girls. It's more frequent that things affect males more than females. things that affect females are more commonly diseases of adulthood and things that affect the immune system. Things like Lupus, systemic lupus erythematosis, multiple sclerosis, a lot of autoimmune diseases tend to be more common in females than males. And it's not not totally clear why. But then a lot of it's often the developmental conditions that affect boys more commonly than girls. And it's not just developmental conditions related to the brain, but it's very prominently developmental conditions related to the brain. That includes not just autism spectrum disorders, but attention deficit, hyperactivity disorder, schizophrenia, but then also developmental disorders of other tissues. So also developmental conditions that affect our gut and our heart. Congenital heart disease for some reason is one is a one and a half to two times more common in boys than in girls. And so this probably relates to something about how the sex chromosomes interact with the rest of the genome. so again, girls have two copies of the X chromosome. Boys have an X and a Y. The Y is the small, is a very tiny chromosome that has very few active genes on it. And so girls actually have, you know, two copies of a lot of genes. So they have potent the potential for higher expression of some of those genes. And it may be that the our going theory is that there's something about those two X chromosomes that tends to protect females from a lot of childhood diseases.
Avanish Srinivasan: Right. So the interaction of the sex chromosomes as allowing potentially for this kind of protection, right?
Chris Walsh: Right. There for example, there are genes on the X chromosome that encode regulators of other genes. there are genes that encode proteins called transcription factors, which
Avanish Srinivasan: Yeah.
Chris Walsh: regulate how a gene somewhere else in the genome is turned on or turned off. And so they may particularly for these diseases where you need both copies of the gene to work, they seem to maybe boost the expression of that gene elsewhere in the genome and boosting the expression of a little bit might protect someone from losing one of the two copies.
Avanish Srinivasan: Right, I see. And then since we're on the topic of disorders, have we seen their pathways overlap? Because I know we previously discussed that a lot of it is caused by mutations of a specific system and that's like kind of causing a chain reaction, but then are there overlaps in that system or pathway?
Chris Walsh: Yeah, well there's a lot of overlap in terms of the genes associated with autism spectrum disorders. they highlight aga it it's a mysterious condition because it also can be caused by hundreds of different genes. Can cause a condition which when you see the child in the clinic is indistinguishable. These a hundred different kids can look the same, but they can have different genetic mutations. and that's
Avanish Srinivasan: Mm-hmm. It's all causing the same thing, yeah.
Chris Walsh: Yeah, and that's different than the way genetics usually works. You know, most of the time there's a there might only be one or two or maybe a dozen different genes that cause a particular condition. It's rare to have this level of diverse different genes that can cause a seemingly indistinguishable condition. That seems to reflect the fact though that a lot of these genes function at these connection points between one neuron and another called synapses. And those synapses are just really complicated structures. And they have about a thousand more different proteins in them. and all of those proteins look like they're really important. And so it looks like you knock out any one of them, and the there's something not quite right about the synapse. And if the synapses aren't quite right, then you have difficulty learning things, and you have difficulty learning social interactions, which is some of the most challenging things actually that humans have to learn. You know, one of the hardest things to learn is how to interact with other people. we learn that long after we learn to walk. We learn that after we learn to talk. You know, it's only like in kindergarten that we really start learning how to interact with people and how to how to detect social cues. And because that's a really hard thing for the brain to do.
Avanish Srinivasan: Right, I see. And I also wanted to pivot into one final topic before we close for today. So I know your research also suggests that mutations accumulate faster in neurodegenerative diseases. So how
Chris Walsh: Yeah.
Avanish Srinivasan: might that connect to conditions like Alzheimer's disease or dementia?
Chris Walsh: Right. Well, so we're very interested in how that connects. and so yeah, we this has been some findings that have really kind of been mind blowing to me, because you know I was I've been in neuroscience like for a long time. I'm an old person. And all that time I just thought that, you know, neurons are not dividing cells, and nature made them to be non dividing so that Their genome would be protected and it would stay the same their whole life. Unlike other cells, like skin cells and you know, blood cells that are dividing all the time, and we know that they can sometimes form cancers. But neurons in the brain, since they don't divide, they never form cancers. And so, yeah, we thought their genomes were very stable. And so we started sequencing the genome of a single neuron. by amplifying it, you know, taking one neuron and putting it into a well and isolating its genome and then sequencing it. And to our wonderment we found that the genome in every neuron is different from the genome in the neuron next to it, and that it's a dynamically changing thing. That each one of our neurons accumulates about twenty mutations every year, like a clock. It these mutations measure our age with incredible precision. And if we live to be a hundred, we accumulate 20 mutations the first year of life in each one of our neurons, and 20 years of our 100th year of life in those neurons if we don't have any disease. And then we find that if if you have a degenerative disease like Alzheimer's disease or ALS, Luke Eric's disease, all of these conditions that we've studied so far, the neurons develop extra mutations. And it looks like those extra mutations are caused by the disease because the pattern in which the mutations occur, the particular number letter sub substitutions are different. The ones that accumulate with age are generally changing a C to a T or changing a T to a C. but in in Alzheimer's disease, we most commonly see that it now we're changing a C to an A, and that's a change which almost never happens in a normal neuron. And that's something which is probably caused by the disease and it's probably caused be by the fact that the brain is inflamed, that the immune cells of the brain called microglia are a little out of control, and they're secreting things that are probably damaging to the neurons.
Avanish Srinivasan: So then these mutations could potentially contribute to direct neuronal damage, he said.
Chris Walsh: We think that they do. We think that the age the ones that occur in normal aging, even though it's twenty per year and even though it's, you know, thousands by the time you're my age, that they don't seem to be necessarily terribly damaging to the way the neurons work. But anything that increases that more than a little bit, can be very damaging. So in fact, some of the patterns of damage we see in Alzheimer's disease, a neuron Would have an excess of mutations equivalent to more than a hundred years of normal aging. And so that's probably very damaging to the function of the neurons.
Avanish Srinivasan: And then has this entire narrative been complicated a little bit by the discovery of neurogenesis or like I guess the proliferation of neurons throughout life?
Chris Walsh: So yeah, the the proliferation of neurons throughout life is a fascinating topic. and that it does not happen so much in the cerebral corte in the neocortex of the cerebral cortex. So the vast part, the biggest part of our s of our cerebral cortex is a part that's called the neocortex or new cortex that appeared relatively recently in evolution. There's another part of the cerebral cortex called the hippocampus. Which is a s an essential center for memory. And that is much more highly conserved over evolution. And so we see it in a lot of animals that we diverge from a much longer time ago. So it's called the archicortex or the old cortex. So that ongoing formation of neurons looks like it happens in that hippocampus, in that old cortex. and That's a fascinating process, both in terms of how it might regulate normal learning and memory and aging, but also we're finding some connections to age-related diseases that might relate to that process as well.
Avanish Srinivasan: Mm-hmm. Yeah, I see. Okay, so before we wrap up for today, I just wanted to do a quick rapid fire round of of questions. I just want
Chris Walsh: Okay.
Avanish Srinivasan: you to give me your honest, quick answer to each of these questions. Okay.
Chris Walsh: Okay, great.
Avanish Srinivasan: So what do you think are the biggest unanswered questions in brain development research today?
Chris Walsh: Well, I think the b biggest one is like what is memory? like how do we remember things? We we know that it has to do with changes in these connections called synapses. But exactly how that happens, still a huge mystery.
Avanish Srinivasan: Still unknown, yeah.
Chris Walsh: Yeah. There's a lot, you know, we we still don't know a lot about this disorder, schizophrenia, that I went into neuroscience wanting to study. Many, many decades later, we still don't understand a lot about. Exactly how that how can it be that people start hearing voices? so those are
Avanish Srinivasan: Right.
Chris Walsh: just a couple of big questions. There's lots I could talk about them all day.
Avanish Srinivasan: And then what do you think is something that researchers are getting close to understanding that once seemed impossible to understand?
Chris Walsh: well I think one thing we're getting close to understanding is the genetic basis particularly of pediatric disease. the genetic basis of a lot of diseases we understand pretty well. you know, we there's it it I mean you can say we're close to understanding it or you can say we're far from understanding it. For most conditions If we have a kid that comes into clinic and we think, he's probably got a genetic condition or she's got a genetic condition and we sequence their genome, you know, we have about a one out of three chance of finding the genetic basis of that. So compared to when I started, that's really, really good. Compared to where we'd like to be, that's still really bad. What's that other two thirds? and
Avanish Srinivasan: Mm-hmm.
Chris Walsh: so you know, that's both something that we understand well and something we understand poorly at the same time. So we we you know, we we really have a a lot we are We are, as I say, we're starting to level off in our discovery of new disease genes. And so we're starting to saturate that. And so we're starting to have a really a pretty good sense of the annotation of our genome. But there's still lots of families out there that still need our help to understand what's what's the matter with their child.
Avanish Srinivasan: And then for students who are listening and they want to go into neuroscience, medicine, genetics, or just developmental biology, what advice would you give to them?
Chris Walsh: Well, you know, I think the best advice is to try to see if you can find a way to give it a shot working in a laboratory. If you're near a big city or if you're near a university, the chances are pretty good that if you reach out to some of the laboratories there and ask there's a good chance you might be able to, you know, volunteer over a summer or something like that. And I think it's important to try that because, like I say, for me, I didn't know what I wanted to do, and I only learned what I wanted to do by trying stuff. because we don't really know ourselves that well and we don't know really what we're gonna like and what we're not gonna like and the only way of finding if you're gonna like something is to just kinda like walk in and give it a shot. But also I think it's important to try to see if you can find a connection to a lab because y you know, people think of scientists as cloistered in these white coats and being, you know, really formal and structured and and science is exactly the opposite. You know, it's something where everybody's like wearing t shirts to work and they come and go as they please, and they're trying to really be creative. and so it's really different than the way scientists are portrayed.
Avanish Srinivasan: Mm-hmm, of course. And then since you're talking about how there is a misconception about science, what do you think is a misconception about being a physician?
Chris Walsh: well, I think I'd also some one thing that people don't realize about physicians is that it's there are tremendous range of career choices for a physician, other than just being a physician. Being a physician is tough these days, with the insurance companies and things like that. A lot of burnout among physicians, but there's all sorts of career trip paths you can take after medical training. and so it's very empowering. and the other thing about, you know, medicine is just that it's just an incredible privilege to be a physician and to have the opportunity to talk to people at their time of greatest need and to feel like you might be able to, you know, play some small part in helping out.
Avanish Srinivasan: And then the last question I want to ask you today is if some listeners could only remember one thing from this entire episode, what would you want that to be?
Chris Walsh: Gosh. Well I think it would be something like, you know, just science is fun, you know. Science is like really different and people think of it. It's and it's a really creative thing. and and it's it's and like I say, it's a it's a fun life. So I I highly recommend
Avanish Srinivasan: Mm-hmm.
Chris Walsh: it.
Avanish Srinivasan: Okay, great. Dr. Walsh, thank you so much for joining me today and for helping us better understand one of the most remarkable processes in biology.
Chris Walsh: Well, thanks very much, Avanese. It's been a real pleasure.
Avanish Srinivasan: Yep, of course. The human brain doesn't simply appear, but it is built cell by cell and through an intricate developmental process shaped by genetics, experience, and just time. And by studying how that process unfolds, scientists are able to discover new insights into disorders ranging from epilepsy and autism to Alzheimer's disease and dementia. For listeners, if this episode gave you a new perspective on how the brain develops, be sure to share it with somebody who you think would enjoy the conversation. I'm Ovnish, this is the Early Perspective, and I'll see you in the next episode.
