Neuroscience and Genetics: Dr. Geschwind on the Science of Autism

Dr. Daniel Geschwind is a distinguished professor of neurology, psychiatry, and human genetics at UCLA, and one of the world’s leading experts in autism science.  In this episode he explains what we can learn about autism and the brain through cutting-edge neuroscience and genetic research. 

Transcript

00:00:00 Johnandrew Slominski 

Hi everyone and welcome to a special episode of the Autism Annex podcast. I'm glad you're with us. 

00:00:09 Johnandrew Slominski 

There is a fundamental urge that I think most of us have to understand not just who we are, but why we are the way we are, and maybe even to understand others in a similar way. There's so much to learn through observation of things like speech and body language and behavior in general. And yet, there's an entire world invisible except for the most sophisticated research and technology that is being uncovered through neuroscience and genetics. Today, we're going to explore that world, guided by one of the field's leading experts. I'm your host, Johnandrew Slominski, and this is an episode unlike any other.  My guest is Dr.Daniel Geschwind at UCLA, which has long been an important center for autism study.  Dr. Geschwind conducts groundbreaking research in genetics, bioinformatics and neuroscience. It's hard to overstate the significance of his work, which over the last 30 years has transformed our understanding of autism, genetics and neurology, including identifying gene mutations xorrelated directly to autism. Dan Geschwind it's an honor, thank you for being here. 

00:01:33 Dr. Daniel Geschwind 

It's my pleasure to be here. You know, you do a lot of really interesting things and it's important to, you know, to be having these conversations and you know, making them available to people. So I'm really, really happy to be here. 

00:01:47 Johnandrew Slominski 

We're going to dive into some deep science in a moment, but for now, let's set the stage. We know intuitively, I think that there's something going on genetically or neurologically when it comes to autism. After all, we often use the terms neurotypical and neurodiverse. But deciphering the scientific literature to understand those connections might seem nearly impossible to non-scientists and non-experts in the field. What would you say to help us begin to understand some basic principles? 

00:02:24 Dr. Daniel Geschwind 

Sure, no, it's a really important point and there's a lot of sensitivity around it. My experience has been that once people understand it, it actually eases anxiety because the reality is before that kind of, let's call it the modern era of autism, the major causes were thought to be, you know, things like refrigerator mothers, right? And things that had to do with parenting styles or problems. And now, knowing that that’s actually not the case is really important, and so I want to frame it this way: that you, me none of us have any control over the genetics. And we have no control over what we pass on to our kids. And that's part of the wonder of life in some ways. And so all the things that make your child who they are: their individuality, their height, their weight, the way that they respond to their diet, blood, sugar, everything right is mediated and influenced by what you've passed on to them and that includes their behavior and cognition. And what we know is that autism has a huge genetic component. And in fact, in autism, it's one of these things where the heritability which is that which you inherit from parents, let's say or is passed on to children, is extremely high. So that's that's just just known and we can't do anything about that. But it's just like everything else that we pass on to our kids, right it, it's nobody's fault. We have no control over it. 

00:04:07 Johnandrew Slominski 

Right, right, and you've also set up a frame where the genetics of autism are not necessarily a risk in that they are also correlated with some enormous benefits. 

00:04:21 Dr. Daniel Geschwind 

Yes, and the other point is that you know we in the medical field, it's our nature to frame things as weaknesses because we're always trying to improve things and make things better and help people. But the reality is that same genetic risk that predisposes for autism also increases educational time, which is the number of years of school, increases IQ and is associated with the number of other very positive attributes, so utism is just one of the things. 

00:04:57 Johnandrew Slominski 

You mentioned that there is a genetic predisposition towards autism. Does this mean that there's also insight into the root causes? 

00:05:07 Dr. Daniel Geschwind 

Another piece that we've learned in the last 20 years is that up to about 1/5 of autism approximately is caused by large effect de Novo mutation, because all of that. 

It's stuff that's shared with other people. 

It's not unique to you, you know, so that common genetic variation that gets passed on has come through evolution, and so it must have adaptive functions to it as well. And so each little genetic variant; the common genetic variance can't cause autism. It's an accumulation of many of them that predisposes that increases the chance, the probability. So that's the one kind of risk, the common genetic variation. 

00:05:53 Johnandrew Slominski 

So an identified cause of autism, which I'm sure is going to interest people, is not a specific gene itself, but rather a type of genetic variation known as a de Novo mutation. 

00:06:08 Dr. Daniel Geschwind 

Yes, yes, and exactly that is that. About 1/5 of autism is due to the types of mutations like Down syndrome where it's actually not an error from the parents, but it's yet it's still a genetic mutation that's causing autism, so that's about 1/5. You know 15 years ago, we basically didn't know any of these, or very few of them, and now the field has identified over 200, maybe even over 300, that are pretty high confidence, different genes. None of them are common. All of these rare mutations would at most currently add up to maybe 5 or 10%, but we can kind of predict that eventually they'll add up to about 1/5. 

00:06:50 Johnandrew Slominski 

Doctor Geschwind, your lab has been on the forefront of discoveries surrounding autism that until recently were essentially impossible. Could you point to some specific advances in science that have helped drive some of your work forward. 

00:07:08 Dr. Daniel Geschwind 

Yeah, it's a great question. A lot of things, but so one major thing that's happened are advances in technology that enable us to do very detailed molecular characterization of tissues and cells, both sequencing the DNA. Understanding what genes are turned on and turned off kind of at an exquisite resolution so we have all this biotechnology, let's call it. And on the other side, there's also a lot of change in computer power. Because if you're able to sequence a genome of 3 billion base pairs, you have to have a lot of computer power to analyze that, especially if you're looking at a lot of people. So the genetic technology has moved ahead the the ability to process the data has moved ahead and puts us in a really unique position today, so this this kind of genetic revolution has helped us understand causes of diseases from cancer to diabetes etc. So it's this kind of combination of the ability to discover causes. With regard to a particular disorder or condition, and then the ability to actually use that discovery to begin to understand disease mechanisms.  

And what I mean by that: if you take an analogy of the car not running. Right, the car may not run for a lot of reasons. It may be out of gas, you know, there may be some belts missing. You may not have tires you know, and so on. So when you bring it to a mechanic, they figure out the mechanism by which it's not working because they know what the mechanisms of function are, and they can kind of guess and they check and they fix it. 

Yeah, and it's not exactly the same, of course, but that analogy kind of stands. We're trying to understand, let's take the brain and the body and our whole, you know, as a set of kind of machines that are all interconnected that are doing things and so our brain is doing all this really complicated stuff related to our social part of our of our world and our functioning as well as our movement. 

And so a lot of technology that now allows us to look into the brain to manipulate brain cells, so there are all these revolutions that have occurred. 

We can genetically engineer animal models like mice and other mammals, to carry these mutations and then even though a mouse is not a small human, there are a lot of circuits that are preserved and a lot of the functions are very similar. So if we put that mutation in a mouse, we can check its behavior. We can then begin to explore at a microscopic and macroscopic level, what's causing that behavior? And it gives us clues as to the mechanisms that we might want to treat. 

00:09:58 Johnandrew Slominski 

You know, speaking of checking behavior, one of the advances in science and technology that has made big news in recent years as you know, is fMRI or functional MRI. I want to be sure to circle back to autism in a moment, but before we do, could you describe the big picture of how fMRI is helping identify behaviors within the brain? 

00:10:24 Dr. Daniel Geschwind 

Sure, well number one, I'll give a big caveat that I'm not an expert in functional MRI. In fact, one of the reasons why it's been so great to be at UCLA is because I have all these colleagues that I can collaborate with. We're all interested in studying autism and in helping families and children and adults with autism, but we come at it from different angles. Right, I come at it from genetic, molecular and you could say a biomedical perspective because I'm a neurologist, but there are people who are psychologists and people who are doing functional imaging. So with that caveat and I'll say that UCLA is a very unusual place for that, where we've really been able to do this to a a degree that you usually don't see in academia, where often in academia, people work in their own silos without collaborating. So you know the functional magnetic imaging allows you to look in a patient while they're sleeping, resting, or while they're doing something—doing something, usually thinking. This the functional is basically looking at brain activity as it relates to how do things hook up and how are those things that are unrelated to each other so-called networks. 

00:11:39 Dr. Daniel Geschwind 

In other words, regions of the brain, although they have specific functions, work together to produce cognition and behavior. And that working together is a network, so you know instead of looking at the brain as a black box, you can now look into it and see what it's doing. 

00:11:55 Johnandrew Slominski 

So let's talk for a minute about what used to be that black box and what fMRI can now tell us about how the networks of a neurodiverse brain might function. 

00:12:09 Dr. Daniel Geschwind 

So in autism, there's evidence that there's less connectivity of certain kind of resting state networks, especially related to social salience, and that there might even be hypersensitivity to sensory stimuli, for example. So we know that people with autism or autistic individuals,  the majority of them complain of some kind of sensory hypersensitivity, whether it be fluorescent lights or tags or you know, so touch or vision or even sound. And so you know, we can actually see those differences when we image the brain and see that there's maybe hyperconnectivity of some of those regions, or they're hyper-responsive where they don't tune down as well as people who don't have those problems. And so what's super interesting is somebody has sensory hypersensitivity and we can see that they're over activating sensory areas in a particular task is actually related to the their degree of social impairment. We can begin to make that you know that correlation and say wow, but it doesn't actually tell us, give us a clear causal arrow like we don't know which causes which we can, we've observed it. 

00:13:23 Johnandrew Slominski 

Well, now that's really exciting that the rMRI can observe a link in the brain to the lived experience of autistic people. So let's take the next step. How does that tie into genetics? 

00:13:40 Dr. Daniel Geschwind 

That's where the genetics really comes in. The genetics is a causal thing right? Having sensory hypersensitivity doesn't change your DNA, and so we can make a mutation. We can genetically engineer a mouse with the same mutations that might be seen in certain rare human conditions associated with autism. And we've done that. And we can show that those mice have abnormal social behavior. They have repetitive behaviors. And we can actually ameliorate some of the social dysfunctions, so now we can take the mouse and put it into a scanner, literally a small animal fMRI, and we can ask what happens. What does that mouse—what are their resting networks looking like? So it begins to allow us to connect that and we see a lot of things that are parallel to what is occurring in the published human studies. So that's pretty exciting, you know, but that's a functional thing. And we think that by certain kinds of therapy in certain patients, we're actually improving that so people are now using fMRI to study before and after treatments to see if we've actually changed the functional activation of brain in patients and children who have autism. We know which to me is a very exciting thing to do. If you can show that there's a change and you show improvement in behavior that is a causal experiment that you've done. You've shown, I target this behavior, I change it, the patient improves and that network that I was targeting is also looking more neurotypical. 

00:15:20 Johnandrew Slominski 

I mean what you're suggesting here has so many implications.  And just off the top of my head, stimming for instance, or repetitive behaviors as you mentioned, limited but really focused interests, social challenges. And that's just the tip of the iceberg of various behaviors that we maybe attribute to people with autism that we might have more now sensitivity for and understanding of. 

00:15:50 Johnandrew Slominski 

So I wonder if you could help me connect a few thoughts for a moment. So many of our listeners, and in fact, I think many educators are experts on behavior or on interventions such as ABA. Meanwhile, there's also this other almost parallel narrative that it sounds like neuroscience and genetics and imaging are writing about the autistic brain. Do you see a scenario where these two worlds of expertise could intersect, or maybe even shape one another? 

00:16:28 Dr. Daniel Geschwind 

I do, I do and let me make another couple of points about the autism treatment the most effective best treatments focus on not just symptoms, but actually getting to the core neural system. So I'm borrowing from my colleague Connie Kasari, who developed the notion of these core deficits, and saw that there was this thing called joint attention that was disrupted, and that's a clear antecedent to reciprocal social interactions and also probably very important for language development too. And so if you can intervene on that, that's a mechanistic kind of focused intervention with the right ingredients, I think the exciting stuff will be, you know you have to have an intervention of sort to kind of see causality, right? Like you do an experiment, you do something. And then you see you know, what does it change, right? And you know so. So in this case you have a young child who doesn't have good joint attention, is having some language difficulties. You intervene on that using state-of-the-art methods. You image them overtime and you identify the parts of the brain that are changing. 

00:17:48 Johnandrew Slominski 

In a perfect world, I love this idea of a system where science helps us to find root causes that can then inform interventions where we then study outcomes and the loop sort of continues. But let's be honest, this is complicated stuff, right? Even for the experts. And the reality is that kids spend most of their time with their parents and their teachers, who are experts but not necessarily in everything. 

00:18:17 Dr. Daniel Geschwind 

Yeah, exactly, you know exactly so, because here's the thing. It takes, to do some of these interventions, it takes a lot of lot of expertise and they need to get kind of, you know, individualized to the child, right, And so, how are we going to have an impact on society? You know, if we have to have, you know we don't enough psychologists to, you know, do that.  And kids spend as you said, most of their time with their parents and their teachers, so you know, because autism is not a rare condition. You know if it's present in one or 2% of the kids in the school system, that's a lot of kids in an area with eight or 10 million people, so I know that's a little digression, but I wanted to say that it's not, you know, the problem is that a child might be viewed as disruptive, or kind of it takes the teachers attention away from the other kids. You know, in all of that which is not the case. It should be looked at as an opportunity for everybody to learn. 

00:19:18 Johnandrew Slominski 

You know, I find it so interesting that as someone who's been responsible for so many breakthroughs in autism, neurology and genetics, you're framing things through a very human lens. And in that vein, I have a sort of impossible question, but I'm going to try to ask it anyway. Dan, you have this formidable body of work and 50 or a hundred years from now, what do you envision as the impact or legacy that you'd hope to have had in the field and in the lives of people on the spectrum? 

00:19:57 Dr. Daniel Geschwind 

Oh boy, that's a great question. Well, I'm going to answer that in a few ways because I do think about that and in fact, after college I did not go into medical school directly. I went to work in management consulting which I really enjoyed and was very challenging. At that time, at least in my life, I was trying to think about having an impact and kind of having what one of my parents friends called a significant life, right? How do you, how do you do that? And you know, of course, there's no question that the most significant aspects of life are around friends and family. But in the time when you're not doing that, how do you try to have an impact and for everybody that's going to be a very different answer. I think that I was fortunate enough that I kind of figured out something that I was good at, or something that I could do. And that really motivated me and gave me great joy and satisfaction, which was going into medicine and doing biomedical research and working on the brain. And so you know from that perspective, when I started as a PhD student and MD PhD student, let's say in 1984, which is when I started, it was impossible to really predict some of the technologies that we have now, and where we'd be. And at that point, I could say my dream would be to do something that impacted patients that improved the lives of patients and their families, whatever that was. And at that point it wasn't autism. I didn't, I didn't really know, you know, it was a it was, I was beginning the journey. When I started to work in autism, the thought was well if we can identify some of the genes like people have done in cancer, that will give us a toehold to begin to develop therapeutics because it gives us a starting point and you know 35 years ago that essentially wasn't done. And so that's a kind of example to me, and so because there's an aspect of autism around 1/5. That's a collection of these rare disorders, some of which may have shared mechanisms. If we can understand those mechanisms, we can treat them so at the time when I was starting the dream was to find some genes and maybe that would lead to some mechanistic understanding that would lead to the kind of therapies that we've alluded to as we've been talking, and I think more and more research accelerated to the point where we now have in the field have identified hundreds of genes. Yeah, so from my perspective I I really do feel blessed that I I I do feel like that what we've done as a field and it's it's obviously not just me, but there are a whole slew of us who have came into autism research in the last 30 years. And even those before us you know, really, that whole trajectory is really made, you know, making a difference, and it is. It is significant because we know so much more about autism than we did, let's say 40 or 50 years ago. But we still have a long, long way to go. The more we learn, the more we, the more we learn how hard it is. 

00:23:25 Johnandrew Slominski 

It's so interesting to hear that your route towards science and medicine was not linear and that you were motivated really to find a path toward—what was the term you used just a minute ago?  A meaningful life, was that it? 

00:23:42 Dr. Daniel Geschwind 

Yeah, a significant life. Yeah, yeah, I mean meaningful is a nice, meaningful life is part of it. I guess meaningful is a little different in that, uyou know, I like to tell people in my lab. Again, you don't want to be doing what everybody else is doing. You know this is going to sound really morbid, but it's just one of my little ways, you know. Like, imagine you know, I imagine sometimes you know I die in a car accident next week, so of course my family and everybody's gonna miss me. So that's meaningful, right? That's meaningful, but the significant part of it is, is what I'm doing significant enough that there'll be kind of a hole left? In other words, we're often competing to publish papers and stuff, and my view of that is if I'm competing with somebody else, what am I doing that's really significant, if there are two or three other labs doing it at the same time now? I say that somewhat tongue in cheek, and that it's not entirely true, and that sometimes that race is very, very meaningful. But I do, I do think it's worth stepping back for a second and thinking about how can you put your own personal significance and your own touch on the world and research. And you know, do the thing that's the most you and so that's that's really what I I try to tell people. 

00:24:59 Johnandrew Slominski 

You've been listening to my conversation with Dr.Dan Geschwind, one of the world's leading authorities on the intersections of autism, genetics and neuroscience.  This has been a tremendous honor. Thank you for being here. 

00:25:14 Dr. Daniel Geschwind 

Now it's, your questions have been great. It's been a delight talking with you. Thanks for all that you do with this podcast and thanks for having me on. 

00:25:26 Johnandrew Slominski 

Listeners, if you're like me, this conversation may have just opened up entirely new possibilities for understanding autism, and it's just scratching the surface of the Dr. Geschwind's work. 

00:25:39 Johnandrew Slominski 

Thanks very much for joining us for the episode. And if you like what you've heard, please subscribe and leave us a review. It helps other people to find us too. The Autism Annex podcast was developed by Star Autism support until next time, I'm Johnandrew Slominski.  Take good care of yourself and one another.