Insights Into the Brain of an Autistic Child

Stanford University good evening everyone I'm glad to see you all here this evening I wondered this morning when the storm was raging what did we do to our attendance tonight I would say from my point of view as a former northeastern ER there was only one thing wrong today with this storm and that is that it just produced rain I kept looking out waiting for the snow to fall and it just didn't happen but we're glad to see you all here tonight so we have in our continuing evolution of information I think a very very important topic this evening and this is going to be delivered by dr. Ricardo don't do much um he as I remember came from Columbia born in Columbia Mike got that right and spent his time also in the Northeast initially getting his education he went to Brown University and then came to Stanford to do his PhD in neuroscience and then flip back to Boston to Harvard to do a postdoc and we were fortunate enough to recruit him back here in 2003 and he has had really quite a remarkable career even at a relatively early stage of his own development with a large degree of awards and acknowledgments for research that is really cutting edge and one of the best exemplars of that is that he is one of 81 scientists in the United States to be the recipient of what's called an NIH Pioneer Award now just to give you a little context for this the NIH is the major source of funding for biomedical research in the United States and it's one of the reasons why the US has done so well in bio sciences over the decades but most of the research that the NIH funds just as is often the case is based upon if you will pre-existing data so you have to actually have done some of the work as you're applying for the grant to get the results and that can lead to a certain degree of constraint and cautiousness and thinking out of the box and so some years ago in fact five the NIH decided to do something really important and I must say quite different having been a scientist at the NIH for 23 years before I came here I know that institution quite well and this was I think a real step forward and it's a big award the NIH pioneer award is a two and a half million dollar over five years award and it's focused on individuals who they believe are really going to do cutting-edge research it is highly highly competitive and getting an NIH pioneer award is a badge of honor now I will brag a little bit and say that in addition to Ricardo Stanford is distinguished in having 15 of these 81 Awards so between the school of medicine and engineering primarily think about that for a moment there are 131 medical schools in the United States and each are competing for these and anyone would be privileged if there are only 81 to have won but here we have 15 and I think that speaks a lot to the environment that is I think yielding the faculty who are making great discoveries and who are speaking with you as part of this course now one of the things that we wanted to do as we began to drill down and over as you'll see for the winter and spring semester if you decide to re-enlist for continuing in that wonderful venue we're trying to focus on concepts that are also of real practical importance and the fact that Ricardo is decided to focus his presentation tonight on the brain on a specific problem that is particularly topical these days autism I think is a very important opportunity to learn not only about broad concepts but how they might be applied two individual problems so without further ado I'm very pleased to introduce Ricardo dolmage well thank you all for being here I was also a little bit worried that I was going to be talking to you know four people so it's uh it's it's nice to see that we have a good a good show okay so my goal in this lecture is to give you an overview of the nervous system and tell you a little bit about some of the organizing concepts that have helped us to understand how the brain works but I am NOT going to do this in a I guess I'm going to do this in a very practical way and in a way that as you'll see in a moment is personally very important for me and I'm going to do this through the lens of autism which is a as many of you probably know it's a devastating neurodevelopmental disorder that now affects somewhere between one in a hundred and fifty and one in a hundred children if any of you have children in the Palo Alto School District you will almost certainly know a few kids with autism so so let me just start by telling you a little bit about why I'm interested in autism as a sort of way of motivating the rest of the talk so okay so this is a picture of my two kids and from just looking at them you would never guess that I have the worst genes in the world but I do and I say that because real here is little but he has type 1 diabetes and Max has uh has a kind of high-functioning autism called Asperger's syndrome and today I'm going to focus a little bit on why I work on autism and how having max really changed the direction of my research and in doing that I hope to be able to tell you a little bit about how the brain works so let me just start sort of with the story of how it was that came to discover that Max had autism so you know Max was our first child who moved here from from Boston where I had been at Harvard and you know we had this this child that didn't sleep had to be you know rocked continuously to get him to take a nap we had to warm the bed and as he grew a little bit older he was not hugely interested in us he was very interested in spinning objects and now you see was her first kid and so we kind of assumed that this was the way kids were we wondered how people managed to have more than one kid you know and so and you know then after a little while and I should say it took us perhaps longer than we would have taken other people we started getting worried when he didn't start talking and now it took us a little bit longer than normal because you have to understand I'm a scientist I hang out with a lot of scientists and so being a little bit odd is sort of par for the course you know so so we started you know trying to we you know we took max to a bunch of places and ultimately he developed you know we we got a diagnosis initially you know when when he was very little it wasn't exactly clear what was wrong as he learned how to talk he was given the diagnosis of sort of high-functioning autism which means that he his IQ is is fine but as I'll tell you in a second he has some disabilities and and so I you know we spent the last few years trying to understand what we can do for him and also trying to to understand sort of the underlying biological basis of this disorder so let me before I go further let me tell you a little bit about about autism and really we owe the the definition or the name of autism to these two gentlemen Leo Kanner and Hans Asperger and in the 1940s there were two Austrian child psychiatrists I interestingly even though they were contemporaries they wrote on the same subject they never cited each other and they never talked to each other and so so Leo Kanner was a psychiatrist at Johns Hopkins and Hans's Rosen was in Vienna and in 1943 Cantor published a paper in a journal called nervous child now they don't name journals like this anymore this is this is you know being nervous is no longer seen as a problem and in this in this article he described his visit to describe actually five patients but one of them was a patient that he had seen in the house of a friend of his there was an engineer and this was a child called Donald and for Donald he described a set of symptoms that he came to call autism and so he wrote you know this Donald seemed self-satisfied and has no apparent affection when petted he seems to almost draw into a shell and live within himself and this defined one of the major areas of impairment in autistic children which is sort of social impairment a failure to interact properly with peers he also said words to him had a literal inflexible meaning he seemed unable to generalize and this is also relatively common sort of a difficulty with language often sort of a literal adherence to to language and now you might think that this is this is not a big deal but actually it's entirely disabling because it turns out that if you take language literally you misunderstand almost everything so so this was a second feature and then finally he said you know he he wandered around making stereotype movements with his fingers he spun with great pleasure anything he could seize upon to spin and so these sort of stereotyped and repetitive behaviors and interests are sort of the third defining feature of autism so autism like almost all psychiatric disease then it sort of defined by a set of behaviors and we've now come to understand that there you know at least three related but relatively independent syndromes one so autism sort of sits at the intersection of all three there's Asperger's syndrome which typically involve social impairment and restricted interests in compulsivity and there is something called pervasive developmental disorder not otherwise specified which is not hugely descriptive but it describes the overlap between restricted interest in compulsivity and communication impairment so so one of the things we've learned since the time of Asperger and caner is that autism is like in fact like most common diseases and certainly like most psychiatric diseases is not a single disease it's a spectrum of disorders which is why people talk about autism spectrum disorders and they they share these three common areas but very likely they are you know separate separate of disease entry entities and have separate different causations and I just thought I would just give you an example of sort of two extremes and I'm just going to show you a couple of videos the first one is a video of the man who is probably the most famous autistic individual in the United States he was the model for Rain Man and he's a man called Kim peek and hopefully you'll be able to hear this fran took dustin hoffman's advice to share him with the world the once introverted Kim has now appeared in front of more than 2 million P all eager to test his genius with obscure questions who was the game winning pitcher of Game three in the 1926 World Series the Cardinals wanted Grover Cleveland Alexander 714 four people on the George Washington cabbage Jefferson Knox Hamilton and Randolph go along with these displays of extraordinary ability the peaks preach a message about disability you don't have to be handicapped to be different everybody is different thank you Kim's gifts come at a price no we had to go here you know on this side Kimmy can we have as they're trying to keep you on the camera and you've got to be over here to be on camera it has to be on camera on either side right here okay you're calm yes I told you either side okay here they go like all savants Kim is an acutely different man sometimes understanding Kim can be a challenge I do I can't do it that's what I'm doing now you're starting now you know what friends patience is phenomenal now you get it well yeah okay so that's sort of one extreme and there are a very small number but there are some autistic savant and I think many high-functioning autistic individuals actually have unusual talents and you know it's it's I think one of the reasons why they are you know they're they're sort of at the at the border between being sort of functional and non-functional in some areas so they have often really great memories incredible powers of concentration but unfortunately these come at the price of not being able to communicate but it turns out that the vast majority of autistic children are not like that and this I think it's more representative and I will give you just another example just to show you the diversity and this is from a video from August you can't really take a day off of autism autism never took a day off on me she always had to have my attention and it's exhausting he doesn't speak much at all hey hey he has never spoken a single word everything about Daniel's life that seems normal for a typical kid like going out to dinner or going to a park all that for us is work little bit more I'm almost done I still hope I won't be changing diapers when he's six and a half I didn't choose to do this I'm not the therapist I was drafted I have an autistic child everything I do is is about autism I have to stay home okay so you see then that you know there are you know is a huge diversity in behaviors and in fact it's a it's it's a series of diseases so I just kind of feel that I should tell you a little bit about the theories that people have had about autism before I actually get into sort of the underlying neurobiology and I am going to do this by just showing you what his has been in the news recently about the increased prevalence of autism so what you see here is the number of the number of children diagnosed with autism per 10,000 births and you know it was actually a very rare disease at the time of Asperger encounter and it was even quite rare until the 1980s but over the last couple of decades it has climbed dramatically in the most recent survey by the CDC suggested it's about one in a hundred children about 158 boys which is staggeringly high now the truth is we don't really know why and maybe at the end if any of you would like I can speculate as to you know some of the possibilities but you know there is as you probably know a lot of controversy as to whether this arises because there has been an increase in diagnosis or because there has been some sort of underlying biological change and I will give you my opinion later but I just simply wanted to tell you a little bit about sort of the theories for autism and you know so for a very long time you know really from the 40s all the way to the 70s you know the standard idea was that autism was actually caused by mothers if the the hypothesis was that they were refrigerator mothers they were cold and therefore the kids were weird and this how shall I put it it was not hugely successful in terms of treating anybody but it certainly made a lot of people feel bad and and so this this in fact was was was the view and until in 1976 what is what was really a pivotal paper was published in which a group of English investigators looked at the prevalence of autism in twins and what they what they found was that they so they looked at identical twins so called one is iconic twin so transit come from the same egg and then they looked at twins there were dizygotic so these were fraternal twins which are sort of like siblings right and what they found was that what they call the penetrance that is to say the concordance the chances that one twin will have autism if the other one has autism was somewhere between 60 and 90 percent if the twins were monozygotic but only about 6% of the twins for dizygotic that is to say if they came from separate eggs now the reason this was really interesting is because identical twins are identical they're not really identical but they're sort of identical and they're sort of identical because they share all of their genes right they came from the same egg and the same egg split and gave rise to two children right whereas of course died side with dizygotic twins shared the same mother they shared the same uterus they had the same maternal environment very likely they had the same household in the same rearing environment but they actually came from two eggs and so this difference are told us really two things the first is that it told us that in fact the whole hypothesis as this was due to cold mother's was not very plausible not that I think it was ever very plausible but and it told us that there was probably an important genetic component the other thing it told us is that it was likely not caused by just a single mutation in a single gene and let me tell you why so okay so when you have when you have monozygotic twins i say when two children share all the genes the concordance is between 60 and 90 percent so it's probably not a hundred percent because ah there well it's probably not percent simply because the diagnosis of autism like the diagnosis of most psychiatric diseases is a little bit fluffy and so you know there were probably some children there that were you know that had a different kind of autism but but the thing that's really interesting is not this number but this number which is 6% now of course you share we all share half of our genes with our siblings right so if it had been a single gene right then the prediction would have been that this would be 50% right and in fact it isn't it's more like 6 percent and so what that tells us then is that it's not a single gene it's probably a whole bunch of different genes and in this way it's similar to most common diseases that are caused not by single mutations but by the accumulation of mutations and so this then so once once it became clear that there was a genetic component to Otto's now let me just say that when I see a genetic component I mean exactly that I don't mean that necessarily a set of mutations cause the disease all I'm saying is that they predispose you to the disease and there may well also be an environmental component though I should say the environmental component is probably not huge given the concordance between identical twins right so if if the environmental component were very large then you would expect that siblings or dizygotic twins would have a very high current coordinates as well okay so so this gave rise then to a whole series of studies where people started trying to look for the genes that were important for that were important in conferring susceptibility to autism and the standard approach is sort of illustrated here this is a gene microarray you can have heard of this perhaps from one of the earlier lectures and what it is is a very large set of pieces of DNA that are complementary to pieces of DNA in your genome and this is one way that you can interrogate somebody's genome because it turns out that we all have even though all of our genomes are very similar that is to say we all share the same genetic material we also all a little bit different right and we're mostly different in really tiny ways and we're different mostly because we have little point mutations there are little bases that are a little bit different so we have the same genes but those point mutations seem to make a big difference and this is why you know I am different from somebody else okay so in order to interrogate this people started using these microarrays and in fact this technology was actually developed here at least largely developed here at Stanford by Pat Brown and by lewbert's dryer when he was at Affymetrix and this then led to the identification of not one but a large number of susceptibility regions so these are all of the chromosomes so there are as you know all 24 promo zones and they're all here and then what you see is a whole bunch of green or little red spots and all of these are areas that in which mutations are over-represented in families with autism okay and now ah-so so of course this tells us that it's highly heritable it also tells us that it's very likely that there are multiple multiple genes involved right but there was something actually very peculiar and I guess it's something that we should have expected and the thing that was very very strange is the fact that none of these mutations actually are segregates perfectly with the disease okay so what does that really mean well okay so if you look at a family right they may have a child with autism and in fact you may find that there is a particular mutation that only occurs in families with autism but it might be that in some of those families it's also found in some people that don't have autism so it means that those mutations are not penetrant that is to say that they're not enough to give you the disease right and so this has led to this this sort of model that I had over here and and actually before I continue I tell you about the model it just me let me just tell you about the kinds of changes that people have observed so there are basically three kinds of sort of differences that that essentially make us all individuals so the first kind of difference are these single point mutations told you about they're called snip single nucleotide polymorphisms right and they are single base pair changes in the genome that differentiate all of us there are now most of the snips that we look at are actually really common ones and the reason for that is that in fact when people were just sequencing the human genome and they were looking for regions that they were in which they could distinguish different individuals they looked for regions that were variable in in everybody and so in fact those variation at specific places in your genome is is actually in these specific snips is actually very common and actually even more interesting than that it turns out that almost all of these little that the variability and all these little genes is it's actually a very very ancient and so we share that with you know people in Africa and people in Norway and so these are sort of common common changes there are also some rare mutations and so these are ones that are where these are these are parts of the genome where really there isn't a lot of variability for most people but in a few people there there is some sort of a genetic change and then finally there is ah there are these deletions and duplications and they're called copy number variations and and let me just explain this to you for one second so what is a copy number variation well it turns out that our genomes are full of repeats we have all these genes right and you many of you may have heard that our genes have you know sort of coding regions that is to say the parts that ik that code for proteins but we also have large parts of our genome that don't seem to encode anything and it turns out that in many of those parts there are pieces that seem to have been duplicated and many of these probably came into our genome through through viruses and so we have all these duplications all over the genome and the interesting thing is that different people have different numbers of repeats so some people have hundreds of repeats and some people have you know just one or two and we didn't really know whether this was important or not but it's turned out that there are big differences in the copy number variants and some of these differences and copy numbers are actually associated with autism so this has led to the following model in which is sort of illustrated here and the idea then is that there's sort of a balance that determines whether you're going to develop normally or not there's you know you will probably have some genes that confer protection and then everybody has a large number of snips and this is what it's called the genetic background all the things that make you you that's your genetic background right and then superimposed on that are these copy number variants that probably arise ah a geneticist called this de novo so they arise again in an individual with autism or there are these rare mutations and so these are kind of tip a particular individual over the edge but by themselves may not be enough to give you autism so this is the current model for the current genetic model based on what we found from all these genome genome studies okay so so great so we we now think then that this is a genetic disease at least partly a genetic disease we have started to identify some of the genes that confer susceptibility and you know when they when people were pitching the sequencing of the human genome they often made the argument that well you know if we knew what mutations were associated with disease we would be able to develop treatments and that turned out to be true but only sort of half true and the reason it's only half true is because well you can know what's mutated in somebody's genome but unfortunately that doesn't tell you what is wrong because for the most part we don't know what many of these genes actually do and so the question then is how do you go from these genes which we know already give rise to proteins that are a little bit different and how do we go from this to a particular set of behaviors right and so this is where I start I'm going to start talking to you about neurobiology so far I've talked to you about psychiatry and genetics but now this is going to be neurobiology and the way this happens of course is that is that jeans gives rise to proteins and those proteins then change the structure and function of cells in the brain and and then those cells in turn change the function of specific circuits and it is those circuits that ultimately result in behavior now a lot of things are hidden in these arrows right so sometimes you don't really know exactly what the proteins do and how they would change the cells and I'm going to spend quite a lot a lot of time telling you about some of the approaches that we are taking as well as other people at Stanford to try and understand this question and then I'm going to tell you a little bit about how you actually go from cells to circuits and how you can try and use the anatomy of the brain to give you some clues about how that may change behavior but I would say that the biggest question mark actually sits here right so we at least conceptually can understand how it is that cells can give rise to a circuit but really trying to understand how it is that kind of squishy wet soft things like cells give rise to a sort of gauzy amorphous things like ideas and behaviors this is something that you know we're far away from from solving so okay so so what what are the cells of the nervous system okay so all of you may know that the nervous system has a very large number of cells and there are essentially three classes of cells and in fact we owe the idea that there are cells in the brain to the work of this man Santiago Ramon Eagle who was a Spanish aristocrat who decided that what he really wanted to do was to try and understand the underlying basis of the function of the brain now in Lamoni Kahala stay and this was sort of at the end of the 19th century the beginning of the 20th century the standard idea was that the brain actually didn't have cells it was just one huge continuous thing and so he set out to try and determine if this was really the and he he borrowed a technique from his competitor a man called Camillo Golgi who had developed an approach for staining just a small number of cells in the brain and so to really understand why that was important you have to understand that the brain is very very densely packed with cells and in a little while I'm going to show you a real human brain and I will pass it around and you will see that it is very densely packed with cells and so the problem is that because it is so densely packed with cells it's really difficult to figure out if in fact those cells are really separate cells or not so so what they needed that was some way of staining some cells and not saying the other ones and so this is what Ramon Iike had actually did so in fact they borrowed techniques from out the development of photography using sort of the reactivity of silver the precipitation of silver with light and they generated he generated a whole bunch of a slices of brains of a wide variety of species in which he could detect all these the lines and by very very carefully drawing them he discovered that in fact they were not connected to each other they came very close but they did not actually connect and so this helped them define some of the major classes of cells in the brain and so there are really three major while there are four major classes of brain of cells in the brain so one class of cells are the neurons right and this is a neuron and so neurons are in my opinion gorgeous cells they have you know sort of the cell body and they have this huge network of these sort of hairs which are called dendrites and they have an axon and I'll tell you all in a little while and tell you a little bit more about you know the various bits of a neuron because you're gonna have to understand this if I'm if I'm going to be for me to explain to you some of the hypotheses about the cellular basis of autism but but for now just just this is a prototypical neuron this is in fact a neuron from a mouse in my lab and and in fact you know there are many different classes of neurons this free examples of Purkinje cell and one of these is a is a spiny interneuron and these are found in different parts of the brain and they have some things in common they have this ability to carry electrical signals and they have this ability to communicate with each other but they're also as you can see quite different than they have sort of different shapes and I mean I would say we still don't really understand how it is that these shapes arise and we don't really understand why we need so many different kinds of neurons but we clearly have a large number of different kinds of neurons ok so what do neurons do they generate and they transmit electrical signals so they're in the business of carrying these electrical signals from one region of your brain to the other they are they process information so they're sort of the processing entity in your brain that is important for integrating things for for for storing information and for parsing out information in particular ways and then of course they activate the muscles and glands and all the other cells that kind of give your output ok so so they essentially carry the information but it turns out that they don't work by themselves oh I'm sorry this is just my little example of electrical activity neurosis is just a video from from our lab I just wanted to show you that neurons actually carry these electrical signals and this is a set of neurons that has been put on a glass coverslip and they've been loaded with a particular chemical that reacts every time that the cell has been activated electrically and so they turned from blue to green and in fact this is a one experiment that that I did this is you know when you when you start as an assistant professor you know you don't have you know anybody working for you so you actually do your own experiments and so I uh I know so I you know this is this is a you know one of my my better ones and so every time that the calcium goes up every time i stimulate you'll see that the cells turn green okay so so this is just to illustrate that these are cells that are electrically active okay so okay there's a second class of in the brain and these are called glial cells and there are really two kinds of glial cells there are astrocytes and this up here is an image from a very interesting genetically engineered mouse in which these glial cells are actually producing a protein from a jellyfish in fact they're producing different kinds different colors of proteins from a jellyfish and so these particular proteins are fluorescent proteins so if you illuminate them with the right frequency the right wavelength of light they emit light and so it turns out that in this particular Mouse and I will go into the details how I was made but sort of by accident they ended up staining these astrocytes in the brand you can see that astrocytes are quite different from neurons so these things up here at neurons but these things are astrocytes and they're kind of long and big and they essentially fill all the spaces and interestingly even though they're very abundant we don't really know what they do very well we have some sort of general ideas so we know for example that they're really important for modulating at the activity of neurons so they can for example maintain the amounts of ions and the brain so that your brain doesn't do bad things they're really important during strokes for example because they get activated and they prevent the brain from getting further damaged they also seem to play a really important role in maintaining and forming synapses and so for example been Barris was a faculty member here at Stanford has been actually one of the pioneers in trying to understand how it is that these astrocytes actually control the development of the brain and how they control the connections between neurons so that's the second class of brains and so this here okay is actually a V and in this in this movie it's not the neurons that are labeled it's actually the astrocytes and so one of the interesting discoveries of the last maybe decade or so is that it isn't only the neurons that are actually that are actually processing these electrical signals the astrocytes are also processing electrical signals but as you can see they look very different right you can see that they're kind of being activated in clumps it looks sort of like lightning and again I would say that we don't really understand what this means but it does suggest that there is you know sort of an extra element of processing in the brain that is somehow presumably important for brain function okay so I hope you can all see this kind of flashing that flashing is actually the change in this fluorescent dye every time one of these astrocytes becomes electrically active okay so the other kind of glial cell is a cell called an oligodendrocytes and all the good end recites are really important because they're actually the cells that provide the insulation in your brain and so the neurons right have have as I told you before these long processes and in particular they have these really long and I'll take you through this in one second but they have a long kind of output process called an axon and you know it turns out that some of these axons can be really long so you will have for example some neurons that are sitting at the very top of your brain and they're sending an axon that goes all the way down to the you know the bottom of your spinal cord it gives your motor neurons for example and and so because they are very long they have to actually transmit this electrical signal now I don't know if there are any electrical engineers here but you know when you try and transmit a signal through through a cable in fact that signal gets weaker and weaker and weaker over time and so neurons have developed this way of amplifying the signal as it goes along right and at the same time they've also prevented developed ways of preventing the sort of electrical signal from leaking out of the cell and so this is what the oligodendrocyte do they actually provide the insulation and so they have the wrapped themselves around the processes of the neurons to generate these things called myelin sheaths and in fact a number of diseases are caused by for example our immune attacks on the myelin sheath so for example multiple sclerosis is an attack on these mile of these myelinating cells that ultimately leads to the death of the neurons so it is very important that the cells actually be insulated now just parenthetically it turns out that that's not the only evolutionary solution right so you have two options if you want to transmit things fast and far you can either a have generate some sort of biological insulation or be you can make really big axons and it turns out that squid have done just that they have these giant axons now giant axons are kind of inconvenient because you know well you know you you don't want to have a gigantic brain we have a lot of neurons so you don't really want to have huge neurons but but if you're a squid that's just fine you know because you know you don't need that many neurons so okay so those are all the good end resides okay and then there's a third class of cells in the brain and these are microglia let me just go back one second here and hopefully we won't start playing oh I guess I'll start playing okay so so microglia are actually the immune cells of the brain and this is this is actually a movie from from from a relatively recent paper in which people for the first time we're actually looking at the activity of these microglia in the brain and so let's see if this happens start again okay so okay so at some point you'll see a flash hopefully here and at that point you'll see everything start to move so these things here are the microglia right there these cells they have all these little processes but they're not really neurons in fact they're they're the cleanup crew they're there to get rid of all the bad stuff and what the experimenter did in this particular experiment is he took a laser and he just and he and he made a hole in one of the blood vessels and when he did that all the blood started coming in this is what would happened to you for example if you if you had a if you know if you had a cerebral vascular accident or something if you you know and and so the microglia are there to essentially try and plug the hole as quickly as possible they move towards the vasculature so these are the other cells in your brain okay so let me tell it take you just through the function of a neuron very quickly and okay so first let me just tell you a little bit about the anatomy of of a neuron right so neurons have you know this thing here which is the cell body right and this has is similar to the cell body of many other kinds of cells so it has you know nucleus and it has DNA and has mitochondria and that's how it makes it makes energy ah then it has all these these hairs these are called dendrites right and then it has an axon and one of the interesting things of course is the dendrites and the axon are fundamentally different and so the dendrites are actually the input side of the of the neuron right and so neurons are actually getting getting information through connections to other cells and their dendrites and then at the cell body actually right after the cell body at a at a region called the axon hillock they are converting all the inputs that they're getting from all the other cells into a decision as to whether they should actually produce an output right and the output that they produce is an all-or-none response an all-or-none electrical response called an action potential okay now I have a feeling that I said that not very well and too quickly so if should I try it again no that's good okay good okay thank you okay let's try it again okay okay so neurons have two sides they have the input side the input side are these dendrites the dendrites make connections to other neurons and the input is and I'll tell you a little bit about the input in a second but for now you guys just got to trust me that the the way the input works is that the cell each one of these processes is actually kind of averaging all the inputs that it's getting from from its from its neighbors and the electrical signals that are generated by the input from the neighbors are actually going to travel down but they're traveling down in this kind of passive mode and they're being summed up over here in the cell body and actually they're really being summed up right after the cell body in a region at the very beginning of the axon called the axon hillock and at that specific point right if the total amount of input seeds a particular threshold then this neuron then fires an action potential and the action potential this is all or none regenerative electrical signal that goes all the way to the end and when it goes to the end it then will cause release of a neurotransmitter and I'll tell you about that in one second as well okay so that's how on your own works okay so let me just tell you about the action potential because it is really central to the brain yes in general there's only one axon printer on there are either many different kinds of neurons and there are some neurons actually that have an axon that can bifurcate at a particular point but typically there's only one one that leaves the cell body okay so okay so so what is this action potential thing well you know the brain is is in the business of neurons are in the business of carrying these electrical signals but if they because they are they're these sent these salt filled tubes if the electrical signal did not somehow get we regenerated every so often then the signal would die away and so Nature has developed what I guess evolution has evolved a mechanism for preventing these electrical signals from dying away and this mechanism is the action potential and really we owe most of what we know about the action potential to the work of these two guys Alan Hodgkin and Andrew Huxley and together they did a series of experiments on the squid giant axon and they chose the squid giant axon because while it is giant and they wanted to make electrical measurements and this was before there were any nano anything and so you have to actually put little cables inside cells and you can only do that if the cells really gigantic plus you know they were at Cambridge and be Englishmen they like going to Italy and this is where you got squid you know so they went to you know they went and they caught some squid did some experiments in the summer and then they spent the rest of the year thinking and lady and so what what they did is they they developed a model for how it is that this regenerative electrical signal gets propagated and this is a little illustration of exactly how this this works so first just focus on this I was going to play a little movie here of exactly what happens and so you don't constantly so so there's a kind of right so there's a signal right the travels all the way to the end and there it causes some release of some chemical entity that then allows the cell to activate the next cell so how exactly does this work well to really understand how an action potential works you have to know something about how it is that cells control the electricity across their membrane so every cell has on electrical potential and in fact at the beginning of the 19th century it was first discovered that if you applied an electrical signal to a two living to a living system in fact some of the the very first experiments of electricity we're done with sort of living organisms and it was discovered that they could generate these sort of electrical potentials and every cell has an electrical potential and what is an electrical potential well it's actually sort of a difference of charge between the outside and the inside of a cell and so cells as you probably know are surrounded by these lipid membranes so the lipid membranes here are not permeant to things that are charged and ions are charged okay so what does that really mean well it means that there are these these kind of salts out here and so typically the salt that's out here is sodium right and sodium when you put it into water salt when you put into water dissociates into sodium and chlorine and sodium is positively charged and it sensibly other side of this membrane right dismembering is a lipid membrane and at the other side you have not sodium but you have potassium and the reason that you have different concentrations of one ion in one side and another on the other side is that cells have these pumps that sit on the membrane and their job is to make sure that there is a difference in the number of ions at either side of the membrane so if you bear with me for one second I'll tell you why you should care okay okay so it turns out that this lipid membrane okay is not permeant to ions and it the only way that ions can get across is through these proteins right these are specialized proteins that sit at the membrane and they're called ion channels and they're called ion channels because scientists aren't all that creative and you know they are these channels that carry ions so okay so the ion channels are not open I are not all open at the same time in fact the ion channels have two really interesting properties the first is that the like specific kinds of ions more than others so their potassium channel and potassium channels like potassium they will carry potassium ions but they will not carry sodium ions and their calcium channels and they carry calcium but not other things and there are sodium channels and they carry sodium and not other things okay so at rest it turns out that the membrane is not very permanent to anything but if it's permanent to anything is permanent to potassium and because there's a pump here that has been using energy from sugar from lunch to generate this electrical potential the potassium tends to flow out and I won't go into the details of how this actually works but it turns out that because potassium is flowing out there is a net negative charge inside the cell there are more positive charges on the outside than on the inside and this is largely because there's more potassium on the inside than on the outside so potassium wants to move out right so things like going from places from high concentration to low concentrations right and sodium can't come in but because potassium is positively charged it actually leaves a net negative charge on the inside of a cell around 70 millivolts okay so this is how the resting membrane potential is established okay so when when a cell is about to fire an action potential the first thing that happens typically is that it somehow gets a signal from a neighboring cell and that signal from the neighboring cell causes some of these other ion channels to become open say for example a sodium channel right and so when that happens sodium which is now at much higher concentrations outside of the cell than inside right rushes into the cell now there are several different kinds of sodium channels some of them are activated by neighboring cells and some of them are activated by actually the change in the voltage the change in the charge across the membrane actually causes a change in the structure of this protein when that happens this designed channel gets activated so it rushes in and when it rushes in it changes the electrical potential it opens more sodium channels and then this leads to a change in the electrical potential inside of the cell and so why doesn't the cell just continue continue getting depolarize well it gets depolarize ah to a certain point but then it turns out that these sodium channels are very cleverly designed and they're designed so that they don't open all the time they open and they very rapidly close and this is called inactivation and really without inactivation we would not be able to transmit any electrical signals so these sodium channels open then they close so sodium rushes into the cell right it depolarizes the cell when the sodium channels closed the potassium channels again take over and as I told you before because potassium is higher on the inside than on the outside it tends to then push the electrical potential or the voltage down and so in this way you generate this spike okay and it turns out that these spikes are the currency of the brain this is this is how information is transferred every thought that you have every feeling every idea it's just a bunch of spikes a bunch of spikes in a really large number of cells now of course we don't know how those spikes actually you know give rise to the feelings and thoughts and ideas but really that's what it is okay so okay so what happens then once these action potential actually travels down the axon to the neighboring cell well when he gets the very end of that axon right so it travels as as electrical impulse and when it gets to the very end it gets to this this little structure called a terminal bouton that forms a connection with the neighbor and that connection is called the synapse and the synapse is possibly the most important part of the brain and the reason it's really important is because even though the neurons carry the information in fact a lot of how information is processed in the brain is determined not by the process of transporting the this electrical signal but by the by but by the strength of the connection between neurons and so that probably sounded a little bit like yours to you and so I let me just explain to you how that is the case okay so let's just think about the simplest possible circuit where you have just one neuron right that receives input from some something in the world say light okay and that neuron receives input from light and it has to make you do something like for example blink or it has to make your irises contract so that you know you don't let too much light into your retinas right well how does that actually work well the first time that happens that that neuron transfers the information to another neuron which is a motor neuron that then activates the muscle that then does whatever it is that you have to do okay okay so far so good now let's say for example that the strength of the light starts so let's say for example that you walk outside so you're in this room and the light seems bright to you right but in fact the light outside is about a hundred times brighter but you have to be able to see stuff outside right okay so the way that the nervous system deals with that is that it change the stretch it changes the strength with which the input cell actually communicates with the output cell so the the tweaking of those connections is really how how information is processed and it's how information is stored and that's why you're biologists are so excited about synapses right daily you know you go to any neurobiology department and three-quarters of the department works on synapses well they work on synapses because there's this idea that they are where stuff happens right okay so synapses live typically on dendrite and there are at least two classes of synapses there are excitatory synapses those are the synapses that cause cells to become more excited and there are inhibitory synapses and those are the cells that caught the synapses that cause cells to become less excited and the excitatory synapses live on these little spines here called synaptic spines and again neurobiologist really love studying these synaptic spines partly because we don't understand how they're made and how they're regulated but also because this is where all these synapses live and so one thing you should notice is that there are thousands and thousands of spines and that's because every neuron is getting you know ten or twenty thousand connections from its neighbors so we have the system that is it's very strongly connected okay so what does this actual synapse look like well there are a couple of parts to it there are they're two sides there's the presynaptic side that's the that's the part that is going to actually communicate with the receptive cell then there is the postsynaptic side and in the presynaptic side there are these little vesicles and the vesicles are full of chemicals and those chemicals are called neurotransmitters and the neurotransmitters are released every time an electrical signal travels all the way down to the bouton and they're released into this little space here called the synaptic cleft and when that happens they does this chemical then binds to another protein on the other side that for example could be a sodium channel and that will cause the postsynaptic cell to change its electrical potential and and then convey a signal and then this over here is actually an electron micrograph of a synapse and what you see here all these those things are these are the synaptic vesicles and this this dark stuff this is called the synaptic density and this is all the machinery that is required to make sure that when an electrical signal gets to the very end of the neuron it actually causes release of neurotransmitter okay so why do we care about neurotransmitters well we care about neurotransmitters because ah this is the way in which information is transferred from one cell to the other we also care about your transmitters because it turns out that they're very important targets for a whole bunch of neurological and psychiatric drugs and so I would say essentially all the drugs that affect the brain in some way change either the activity of a neurotransmitter or the response of the cell to the neurotransmitter right and so there are a whole bunch of different neurotransmitters so you may have heard of some of them like things like dopamine for example and acetylcholine in fact the most the most common the most prevalent or a transmitter in the brain is glutamate it's an excitatory neurotransmitter and it's the way in which cells communicate with other cells and excite the other cells okay so that's the synapse okay so so I I would be entirely remiss if I didn't spend at least one slide telling you about what least one of the things that I work on and so it turns out that that synapse you know so I told you about these ion channels right that are really important for generating the action potential and well there are many different kinds of ion channels but one kind of ion channel is an ion channel that carries calcium now you are all of course familiar with calcium you have drunk your milk and you know that calcium is really important for bones and for teeth and all that good stuff but of course calcium is really important for the signaling of essentially every cell in the nervous system and the reason it's really important is because calcium actually rushes into the cell and allows that synaptic vesicle release to occur right so okay just ignore that for a second okay so this is a synapse right this is the presynaptic side this is the postsynaptic side there are these calcium channels here and the calcium channels are gated by that change in potency can sense when the voltage across the membrane has changed and when that happens they let calcium into the cell and that calcium then causes these vesicles to fuse and allows transmission to occur across the synapse and that is the basis by which all transmission occurs in the brain I should just say just parenthetically that because of course nature is not minimalist in any way nature is extremely baroque it's all about making things incredibly complicated it's kind of the opposite of physics right you know so there are of course not just one kind of calcium channel there are many many different kinds of calcium channels and we're still trying to figure out why it is that the brain needs ten or twelve different kinds of calcium channels and we have all sorts of ideas but I won't get into them okay so okay now let's get back to autism okay so how do we figure out what a genetic mutation actually does to a cell so I told you a little bit about neurons I told you about all the different kinds of cells in the brain I told you about action potentials and ion channels and well you know the sort of thought is that there must be something about the there must be something about these mutations that is changing the way in which these cells either develop or it's changing the way in which the cells actually act so so how do we deal with it well there are two approaches one possibility is you can make a mouse okay so top biologists a neurobiologist in particular you know have a problem and the problem is that we study the brain and you know so you know if your is for example dermatologist you have plenty of access to the stuff that you study right you know you can take samples of people's skin that's okay but turns out you can't think samples of people's brain and you can't really do experiments on people's brain very easily and you know they don't so so so if you're molecular and cellular neurobiologist as I am you need some sort of a model system and so one approach that people have taken is to actually take these mutations that occur in humans that have been discovered in humans and try and introduce them into Mouse cells or in tor or genetically engineer a mouse and so we and other people have engineered mouse models of autism now because the autism mutations were only discovered relatively recently in fact there aren't that many models and in fact two of the models are actually I mean they're only three two of them were actually developed here at Stanford so I was going to tell you about one model so this is a mouse model of autism that we generated okay this and you'll see it in a second you'll see that this mouse is a very peculiar Mouse okay so normally mice are relatively calm but this guy is not calm this is this guy as you'll see in a second is is very hyperactive and it does one thing very well it does flips it's a kind of Cirque de Soleil Mouse and and so this is it turns out that this mouse actually has a point mutation in one of those calcium channels that is that is one of the very very rare mutations that is completely penetrant it's a mutation that if you have it it gives you autism now they're very very few of that and clearly that doesn't account for the vast majority of disease and I'll tell you in a second how we're trying to deal with that but you know in biology like in politics like in them almost anything else you know it's kind of the art of the possible and you know it's you know very difficult to study a mutation that doesn't actually give you give everybody the disease so we went for something that was really strong and it turns out that this calcium channel mutation is very strong okay so that's that's our mouse now the question is what is wrong with the mouse oh let's say described actually what the mutation is so this is kind of a what we call a topographic map of that calcium channel right and it crosses the membrane a million times right this is the membrane here each one of these is a piece of protein right and you can ignore most of it the only thing that's kind of interesting is that there's this mutation that occurs in these kids that have this disease called Timothy syndrome and all of them have autism okay and we know already that this does bad bad things to this calcium-channel so remember how I told you that ion channels when they open they closed they closed right away they have like this intrinsic timer so that's how the action potential is generated so it's limited how it limits itself it turns out that that's true for all iron channels so it's also true for calcium right so calcium channels have to open but they have to close right away and the way we know that is because we are very fortunate in actually being able to measure the current to those calcium channels so you see these little squib these little lines here okay so on this axis we have current and on this axis we have time and when and what we're doing here is we're actually stimulating the cell in such a way that we can actually see the activity of the channel and the only thing I want you to notice is that the channel initially opens this isn't responsive voltage and then it starts closing and this is in response to you know this is just the way the channel is designed it closes right and this mutation is preventing it from closing okay and that is we think it's a bad thing but we don't actually know why it's a bad thing we just know that it's different right okay so so so we we say is that it actually doesn't go into what we call the inactivated state okay so what does this actually do I'm not going to tell you about all the things we've done to the mouse I'm just going to give you one example because I think it's particularly cool it turns out that during development so when the brain so you know autism is a neurodevelopmental disease right and what this means is that there's some sort of a mutation that is altering the way that these cells are establishing connections with each other right and one of the things that happens as cells are establishing connections is that you know all those dendrites that you saw those beautiful dendrites that are forming connections to their neighbor well in fact they're not forming connections randomly they're forming connections to just some other neurons that they like and not nervous that they don't like now what do I mean by that well I don't really know they form they don't form connections randomly they form certain circuits most of which we don't really understand what we do know is that they explore the world a lot right so this is sort of a teenage neuron here okay it's not not frozen this is kind of pre-tenure right and it's exploring the world so you can see it's exploring the world right and just check out how those those dendrites are moving everywhere but they haven't formed any connections yet okay and in fact this is a very complicated process by which the dendrites extend and retract okay well it turns out that we can make those kinds of movies that that's a movie of a neuron by the way developing on the stage of a microscope for a few days and and we can make movies of neurons in either wild-type animals or in animals that have this mutation of these two autism and surprisingly the mutation that leads to autism you know the neurons don't explore the world quite as well and in fact they end up with these kind of puny pathetic and dreaded Garber's and in fact we explore this further and it turns out that they do extend but they're just not as good at making connections with their neighbors and so they actually then retract and so what that means is that a neuron in the cortex and the outside of the brain of one of these mice is making connections to its neighbors but it's not making connections to as many neighbors in fact it's making more connections but it's making more local connections and so we have the hypothesis that that might help to explain why it is that many autistic kids are really good at certain things but they're not very good at integrating multiple modalities so you know for example my son is fantastic at certain kinds of math okay incredible I mean as a little boy used to remember all the license plates in a car and cars in the parking lot which was a wonderful party trick but odd and but but he has huge problems for example doing like for example word problems or things that require integration across multiple modalities now we don't really know where that is but one hypothesis is that in fact they have sort of over over integration of local information and a failure to extend these long connections and that would be approximately consistent with the defect that we see in the cells now the other interesting thing is that once we see a defect in the cell we can then try and see if we can do something to reverse it and I won't tell you will show you this but we have you know now then gone to see whether we can actually find some drugs that will reverse this defect okay now there's there's another very interesting mouse model of autism at Stanford this was developed by Tom suit off who's a faculty member here and he's actually been one of the pioneers in figuring out all this information about how how it is that the synapses work and so he actually has cloned a lot of the and identified a lot of the proteins that are presynaptic that are important for this vesicle release process but kind of as a sideline he also started working working on these molecules that are really important for the formation and function of these synapses and he worked on two particular ones one is called no axon and the elements called neuro ligand and it turns out that sort of when he was doing this one of these large expensive genetic studies identified a mutation in neuro ligand and so that is associated with autism and he made some mice that have this mutation and what he found is that it actually alters the function not of every synapse it alters a function of just a small set of a specific class of synapses the inhibitory synapses the synapses that turn cells off okay so so that's that's one approach okay so okay so so this is great right but I told you that you know there are like you know 15 Timothy patients in the world I mean it's not quite but not many and you know it's a great way of getting insight and we hope that it'll tell us a lot about autism but it's not exactly what we want and one problem of course is that there are many genes that that lead to autism and it's really really difficult to to replicate all those mutations in a mouse it's for one thing it's very expensive so you know every time you make a mouse it's like $100,000 if you have to make you know 20 mutations forget it I mean there's no pioneer word that would pay for that right so so we need to have some other approach now the other problem of course is that and this is subtle but it turns out that that that mice are not human and now you laugh but you know in fact it turns out that we've been really great at curing diseases in mice so for example if you've got multiple sclerosis the thing to do is to be a mouse because we've heard multiple sources in my a bunch of times you know but we're not so good at treating people and it turns out that I mean part of the problem is that in fact we diverged from from rodents a long long time ago so you know you know we have there's at least 60 million years between you know your standard you know Mickey Mouse and you know Ricardo dolmage right and so so that that means that there are lots of differences and there are these two classes of differences I mean one class of difference is simply that of course our brain is way larger and in fact it takes much much longer to generate all those neurons in the human brain and and that the other problem is that the neurons themselves are different so for example here this is a particular class of neuron from from a rat and you know you see that it fires in particular ways but you know neuron from a monkey is really different okay so we really need to study human neurons um but you know I told you you can't just go up to you know your average kid and ask for a brain biopsy so what to do well you know we were stymied for a long time but then we were sort of saved by what has really been a remarkable a remarkable discovery that only happened over the last couple of years and and this is this idea that you can in fact generate stem cells from adults from from children but also from adults and you can generate stem cells from the skin of an adult now you know if you told me this a few years ago I said science fiction in fact when I saw the paper polish I said science fiction you know because I like no scientist I'm skeptical and I you know fundamentally believe that my fellow scientists are doing it wrong right and so and but it turned out that this Japanese group led by Shinya Yamanaka and a group in in Michigan led by Jamie Thompson actually had developed this method of reprogramming skin cells to generate stem cells now a stem cell by definition is a cell to make any other cell in your body right including a neuron okay now what I told you before is that we think that there's this genetic predisposition in kids with autism and now the genes in your skin are the same as the genes in your brain right so the idea then is to take these skin cells reprogram them and then make neurons and then see if we can figure out what's wrong with the neurons okay and I should tell you this is this is something that really has never been tried in psychiatry if psychiatry has been all about just testing stuff but not really knowing what it was hitting right and so so this is sort of what we have been doing so we harvest skin cells from patients we reprogram them into pluripotent stem cells we're going to convert them into neurons we're going to phenotype in neurons and I'm going to go through this quickly because I'm running out of time here but we're you know we have these these patients in fact we have a very healthy collaboration with the Autism Center and with a genetics clinic at Stanford and so we are always recruiting new classes of patients so for example we have patients that have deletions in 22 q13 these about half these kids develop schizophrenia half the time we don't know why you know we have you know kids with Timothy syndrome we have kids with Williams syndrome Williams syndrome is a fascinating disorder the kids are exactly the opposite of autistic they're hyper friendly and and they're you know they're sweet wonderful kids they're but they're not really good at spatial tasks they are often a little bit mentally and we don't know why okay so we would like to know what's wrong with their neurons and which neurons are affected okay so then we can be programmed with skin cells until a pluripotent stem cells and I'll go through this very quickly because this is well I mean it's still amazing that this works because you know there's just some magic here but you can put these viruses that contain these these like proteins and you can take these things that are fibroblasts and convert them into stuff that looks like this and this is not a fibroblast any longer this is a pluripotent stem cell and we know it's a pluripotent stem cell because if you do it from a mouse you can actually make a new Mouse it can make a new Mouse from the skin cell of an old Mouse this is incredible right and and so we you know you know we're not going to make people but we do want to make sells from people so so that's that's how we're doing it so okay so then you have to make these things into neurons and it turns out that nobody had done that either so it's been you know a bit of a hard slog but we can do that now and so you can make for example these cells that and I just ignore most of these things but these things here are actually neurons generated from a patient that has you know what schizophrenia for example you know and and we generate not just one class of neuron we actually generate what is actually kind of a mini brain a whole variety of neurons and glial cells and oligodendrocytes and again i think it'll give us this ability to finally study a human neuron okay the final thing is you know how do you figure out what's wrong and you know there are lots of ways of trying to figure this out you know you can for example look for changes in gene expression and things like that but I want to focus actually on a specific class of assays so you know I told you that you can actually measure the electrical activity of the cell by looking at the calcium so we can for example measure calcium signals in these neurons and in some of these patients we have hypotheses as to what might be wrong so we're trying to address those hypotheses we can also measure the electrical activity of these cells and you can see that these are now human neurons and so we have multiple classes of neurons and we can figure out if there are problems in the currents and if there are problems in the synapses and we can also do things like look at the spine so you can see the spines here and we can count them and we can measure them and we can figure out how it is that they're forming so then this gives us then this way of actually looking for cellular phenotypes okay how much time do I have I have about okay okay so okay so so I told you then how we're going then from the genes and the proteins for the cells now the question then is how are we going to go from the cells to the behavior and I have to say that you know the future I hope is bright but you know we're still a ways of from from actually being able to do it in a very efficient way you know we have to somehow figure out how it is that these cells give rise to circuits and try and understand these circuits so in sort of the circuit part of my talk I will try and make it relevant to autism but I should point out that we don't really know what the circuits are most of all we know about the circuits of the brain are really derived from well I really based on the anatomy of the brain ok so ok so how do we go from defects themselves to defects and behavior well you know you have circuits and you know the human brain has about 100 billion neurons and about 100 trillion synapses which is about 80 times the US budget deficit you know so it's a lot but you know the budget deficit is catching up and okay so so so how do you what do we know about the circuits so let me just tell you a little bit about the anatomy of the brain I think it'll be helpful and for this I'm going to both show you and I actually brought a brain on a spinal cord with me that I'm going to show you and you can welcome to come up and touch it later if you like it's a little freaky but you know okay so I'm going to do both one second here while I get some gloves so you don't want to you know touch the brains with your hands because they have lots of formaldehyde and well it's not very good for your skin doesn't leave your hands silky soft okay so this is here okay this is a human brain take it out here so so this was this was an adult I don't know exactly how old they come from the from the sort of tissue donation program typically they are you know in their you know 60s 70s 80s something like that this is not a child okay so okay that's that's one I'll I'll go through it in one second I just simply have a couple of other things here okay now for brain so you know a few years actually when I was a grad student here I uh I was the I was a TA for the neuroanatomy course and I it was my job to go and get the brains before the class started which meant that I didn't have a car so I had to go and get it on my bike which was just you know very suboptimal and you know I was I was terrified because I would go around on my bike which had this this thing on the back of these these buckets and you know well I mean I'm Colombian and I was just you know scared that the police was going to stop me and because how do you explain that you know okay so okay here we go okay and hopefully we have yeah we have some meninges here and the spinal cord we have a spinal oh no we don't have okay here we go spinal cord spinal cord oh well we have a piece of spinal cord that got partially partially cut okay so okay so uh this is the meninges so let me just start from the very beginning here okay so so the brain right so the brain is covered by a series of membranes okay and this is one of them and this is a really really tough membrane actually and there are three of them they're called the meninges and maybe I should stand over here so you guys can hear me okay and the meninges have this important role of protecting the brain from well actually what they do is that they hold the fluid that your brain floats in and this is really important because it turns out that your brain and neurons in general are very are very fragile and so you know if you run and you hit your head if your brain was in direct contact with your skull that would be the end of you know a large number of memories not to mention you know your capacity to do a lot of things so the solution has been to suspend the brain in what is called cerebrospinal fluid which is this liquid that surrounds the brain and that's held together by this stuff which is the meninges okay so there are three of them and the outer one is called the dura the middle one is called the arachnoid and the internal one is called the Pia and you have probably all heard of meningitis and meningitis is an infection is a swelling of the meninges and it's potentially you know life-threatening okay so now I'm going to just take you through first the bits of the brain and uh-oh bad for my pointer okay well try not to do this I will just kind of show you okay so okay so let's start from the very beginning here okay so this thing this thing here right so this is the cerebrum right the brain has two hemispheres right there's a left one or the right one and you see this little thing back here right that's called the cerebellum okay and it's and it means literally mini brain okay and if you look at the brain from the top you can see that there is something called the central fissure right that divides the two hemispheres and if you are and now we tend to subdivide the brain into things we call lobes and the reason we do that and I should say that there are a very very large number of names for everything in the brain which is one reason why medical students don't always like neuroanatomy though though it's getting better and so there are we divide the brain in two lobes and so this thing here is the frontal lobe this is the front of the brain so this would sit like this right okay so this this would sit this is the frontal lobe okay this here right behind sort of it right behind the frontal lobe here okay is the parietal lobe right this is the parietal lobe back here is what is called the occipital lobe back there okay and then it's hard to see here but this thing here okay this is called the temporal lobe okay so who cares right well it turns out that in fact one of the sort of guiding principles those guiding organizational principles of the brain is that different parts of the brain do different things so start from the back okay so the occipital lobe here is actually important in vision so if you hit yourself ah in the back of your head you could well become blind even though your eyes are perfectly normal and that's because information is going from your retina to the inside of your brain and I'll tell you about that in one second something called the thalamus but then it's going from the thalamus to the back an area back here called area v1 which is the main visual cortex okay okay the the the parietal lobe the lobe right here right is actually a sensory lobe so this is the part of your brain where all the information about stuff that you touch and you know the position of your limbs and in fact there is something called the homunculus and a monk ulis is a latin term for a little man what that really means is that all the parts of your body are actually represented in this part of your brain and if you were to for example go in there with an electrode and and stimulate it would feel to you as if you were touching something with say your your toe or your or your thumb or your lips and the interesting thing about that representation is that as you would expect the parts of your body that are the most sensitive are over-represented so for example your lips occur occupy a huge amount of real estate but your you know your back doesn't right you don't you don't really need to discriminate two points in your back unless you know you have some strange fetishes right but uh but you need you need to figure out what you're eating you need to figure out what it is that you're touching right so so there's this proportional representation and right in front of it right there is ah there is the part of your brain that controls movement and if you stick an electrode and you stimulate there it will cause some one of your one of your arms or legs whoops legs to move right and so that's this is sort of motor cortex okay now the very front okay is the frontal lobe and it turns out that we don't really know what the frontal lobe does but this is what we know we know that it's really important for social interactions we know it's really important for personality and a large part of what we know about the frontal lobe actually comes from people who have had either accidents or have had strokes that have altered their frontal lobe and the most famous patient you may have read about him at least some of you will have it was a man called Phineas Gage who worked in the railroad tracks in the 19th century he was using a tamping rod to just put some dynamite into a hole he was a model worker he was the head of his work crew the thing exploded it shot the metal pole out it went through his eye and at the top of his head people thought that he was going to be dead and to everybody's surprise he just sat up and sort of said what happened and but he you know it had essentially eliminated his frontal and at first people thought he was he was fine right and then gradually it became clear that he was not fine at all I mean he he could function he could walk but he could no longer keep a job he got into fights he drank a lot so kind of his moral character was somehow altered you know it's a you know it's kind of a a problem with report no say anything I just - okay no no not not fair but it's a good one uh okay so what one one more thing here okay I I don't know if you've you noticed but the brain is full of all these little squiggles right and the squiggles so there are there are all these all these bits of stuff here now there are two interesting things about that okay the first is that there are all these these sort of convolutions and those convolutions are there because it turns out that we humans and primates in general have large amounts of the very outer part of the brain which is called the cortex which is this very outer part here okay and it's easier to see for example in this section here okay I hope you can see this okay but it's easier to see here okay so this very outer part you hopefully whoops hopefully you can see that there is kind of a white sort of lighter area in the middle right and then there is darker stuff at the edges that darker stuff is the cortex and that's where most of the cell bodies are and then the lighter stuff there aren't very many cell bodies there that's the axons that are going to you know other parts of the brain that are sort of connecting different parts of the brain well it turns out that the cortex is this gigantic sheet but we have to fit it into you know a head that is small enough to go through the birth canal and so how to do that and one approach is just to fold it a lot so our brain has all these folds because we're trying to compress this flat sheet into a small space and now that's one thing now the second thing is that these things actually have names so in general the mountains are called gyri and the little valleys the whole the the kind of these these these things they're called sulci okay and there are a couple of important ones there is something called the central sulcus which is here and it's in the very center of the brain and it divides the motor area from the sensory area which is back here this is motor area this is the sensory area right okay okay so so now let me just tell you let me just see how much time I have okay so um let me just okay let's see how this goes okay there we go control fissure okay okay you've gone through this okay so with regards to ACTU to other interesting parts of the brain so there's another interesting feature of our brain which is that it is actually lateralized now it turns out that the brain of almost every the brain of all mammals is lateralized our brain is lateralized as well this is why we are either left-handed or right-handed it also means that different functions are in different sides of your brain so now this as I told you before this thing here right is the temporal lobe and the temporal lobe sort of at the very edge of the temporal lobe is a region which is very important it's called Broca's area and it's very important because it is the region that is important for language and we know this because when people strokes that damage this area they can no longer talk and depending on exactly which part of the area is damaged you get a different kind of speech disorder something called an aphasia so for example if you lose all of Broca's area and I should say it's only on your left side right for most right-handed people for left-handed people half of you will have it on the right side and the rest will have some language on either side which actually is a bit of an advantage because if you happen to have a hopefully you won't but if you happen to have a stroke on one side you will have some language left um okay well it turns out that uh there this Broca's area which is oh I hate doing this okay got brain juice on my pointer okay so uh okay so this is this is this is Broca's area right there right and this here is uh this this over here is Verna Keyes area so Verna keys area is kind of important for meaning so people who've got damage here actually have no problem producing sound speech but it doesn't mean anything and in fact you can get interesting kinds of smaller strokes by what we're by for example you will suddenly acquire a Norwegian accent you think I'm doing it but it's true it's not exactly Norwegian but it sounds kind of Norwegian ah and you know and then you can get damaged if you have damaged sort of in between then you'll have a sort of communication kind of aphasia whereby you will be able to produce language but you'll have trouble sort of understanding oh you'll have trouble with grammar okay so it's actually kind of remarkable that we can localize something as complicated as speech to a specific part of the brain right of course we can localize it but we actually don't know exactly how it is that that part of the brain does it right okay so let me just talk about a few things using this this brain here okay so okay so now I just want to go back up one last time to autism and okay so we have here a brain that has been section sort of down the middle on the central sulcus right and I'm just going to point out a few a few critical areas actually well put this down here I'll do it with my pointer now that it's been permanently sullied it probably doesn't matter okay so there we go okay so okay so this thing here right I told you about this this this here thing here is the cerebellum right and the cerebellum is is a very mysterious part of the brain so it's most famous for its ability to control movement and it turns out to be really important for your capacity to plan a specific actions and in fact there's a faculty member at Stanford who's one of the world experts on this Jennifer Raymond and she actually has tried to understand how it is that the neurons and the cerebellum are a plan for example of reaching behavior okay so that's that's the cerebellum here and and I'll tell you I'll tell you why it's important in one second now in addition to this there's this thing here okay and this thing here is called the corpus callosum and the corpus callosum is really important because it is this set of fibers that communicate one side of your brain to the other side so it communicates one ah one one of the hemispheres to the other hemisphere and it turns out that there are in fact two sets of these there's this corpus callosum and then there are a couple of other pathways called the kama sure's there's something called the anterior commissure that also is one of the ways in which neurons from one side of the brain communicate for the other side of the brain okay so remember this thing here now I should just point this out so this down here because it's you know very important especially if you're for example say a neurosurgeon okay this down here is the something called the medulla oblongata and this thing here is called the pons and it turns out that this part of the brain is really important for awaking for sort of the autonomic functions of your of your nervous system so your brain also controls so you don't know anything about so it controls for example your digestion and it controls your heartbeat and it controls your breathing and because this thing here is at the bottom of your brain and the spinal cord would go down here well if you have some sort of an accident and your brain starts swelling this thing starts getting pushed out the sort of bottom of your skull something called the foramen magnum and so what whoops is it what happened oh well that's bad I I thought I had to connect it ok well it's ok we will we will we will continue ok and huh well we I have a plug but it stopped being plugged ok well it's ok we will we will just be able just continue so ok is it okay so it's gonna be a little harder to do this way but will will continue okay we'll just go play here and if it suddenly runs out of juice try and remember carefully I know I'm running okay you're going to just test your capacity to remember stuff no hmm okay well I let's see how good you are dealing with distractions ah okay so oh great thank you wonderful okay good okay excellent okay so so I'm almost done okay so so this thing here right is the corpus callosum and there's another thing called the anterior commissure and then if you have an accident this thing might actually get herniated which is to say it come kind of starts being pressed against the side of your skull and because it controls your breathing and it also controls your sleeping and waking in your consciousness ah you will die and so this is one of the reasons why if you have an accident the neurosurgeons do everything they can to reduce the swelling of your brain okay now I just want to finish here by just telling you by just finishing by bringing all this back to autism and what you see here is actually an MRI of Kim peeks brains you remember Kim peek right I showed you the video at the very beginning of my lecture and there are a couple of things that are very interesting about Kim peek spring so one of them is that he has no purpose callosum in fact not only does he have no corpus callosum he actually has no anterior commissure either and he can do a remarkable trick he can read a book and he can read the two sides two pages at the same time with either eye and actually you know understand which in itself is amazing you know so so you know the recently those this report that you know people can't really multitask but you know we may have a solution for this you know so so he has no purpose callosum there's some other interesting thing heeey this is a cerebellum here this is a normal a normal person and you can see that the cerebellum is really tiny and it's really shrunk and in fact he has huge coordination problems and his father has to comb his hair and stuff because the cerebellum is really tiny um there's another really interesting thing so over here and I didn't really tell you this but but talked right there in the brain is a part of your brain called your hippocampus and it's really small but it's received a huge amount of attention because it turns out to be this really important center for learning and memory now it's not that that's where the information is stored it's simply that somehow it's important for making this those associations that are required for you to remember stuff now check out his is hippocampus ok so ok not there ok check out his hippocampus ok so here's this gigantic hippocampus right and and you know way bigger than the hippocampus there you can see that it's kind of eluted and there's almost nothing there so so clearly you know he is very good at making associations and you know at remembering stuff this part over here on the other hand this is this frontal lobe this is this part that controls you know social interactions and all the stuff you can see that something bad has happened right so you see we can actually get some some insight into you know behavior by looking at the anatomy now it's not always as clean and as beautiful as it is with compete in fact and for most autistic kids the brains look more or less normal except that they're maybe a little bit bigger so but you know but in this case it's kind of you know I think it shows you the power of well of trying to understand the anatomy of the brain and of course this is what I tell the medical students because none of them want to learn Anatomy right so you know I kind of thought well you know if you know the anatomy you might be able to you know read somebody's mind it could be useful so ok so let me just finish here and just just just bring you back to a couple of things so first of all I always finished my lectures by just thanking my lab because I showed you a whole bunch of work that we have actually done and this is a lab and so in fact you know most of the time when I say a we I actually mean them so so you know without these guys I wouldn't do anything and then this is this is this is Max and I should say just parenthetically that you know one great thing has happened you know you should always end on a hopeful note and which is that you know it turns out that you know of course genetics is important but it turns out that the environment is really important too and so you know we know in a sort of by you know taking him to a whole bunch of really intensive behavioral classes you know max has gone from being you know 3d autistic to just being just a little bit weird I mean in fact he fit right in many like faculty meetings I mean you know he's so you know I mean III think that you know there is hope we know we this plasticity of the brain you know you know gives us a little bit of hope for some of these diseases so anyway thank you very much I think your reaction spoke what I was feeling this was truly a phenomenal presentation and I think it covered such a broad depth of information it's going to take you a while to I'm sure assimilate this but you've been treated to a real tour de force so Ricardo really thank you again and I think we're just about at the wishing hour but if you're willing to take a couple of questions we can do that yeah but right here yeah so yes so is there is there any connection between immunizations and autism at MIT and I would say that the so this has been addressed extensively in general the answer is no um let me just that's let me just give you I guess what people have actually looked at and what so that you know it's sort of a satisfying answer so you know the initial idea was that perhaps part of the reason for the increase in the prevalence of autism had to do with thimerosal which is a mercury containing compound that is added to vaccines and it's used as a preservative and we've known for a very long time that mercury is really bad for you and in fact this led to the phasing out of thimerosal in vaccines and thimerosal has not been in childhood vaccines for quite a while now um but uh in fact this has made no difference in the increase in the rate of autism so that's one reason why people don't think it's important the second thing is that the epidemiology of autism actually doesn't really go with that explanation so when we and other people have looked at who gets autism and where it turns out that in fact the increase is not uniform there are certain areas that have much higher rates of autism than others but more or less everybody gets vaccinated okay so for example around here their rate of increase has been much higher than in other places in some areas in you know in Southern California in San Diego and in Pasadena there are the sort of nuclei of increased autism prevalence and but you know most people get the same vaccines and actually one of the things that tells us that it's very unlikely to be something that everybody uses like plastic or something like that the other thing that it's kind of interesting is that the autism is a lot more common among among people of a sort of higher socio-economic group and so it is in that way it's actually unlike other diseases for example cancer and asthma and things like that that are sort of environment at least partly environmental diseases you get them if you live next to the factory you know so I would say that you know in generally the evidence suggests that no vaccines don't onto it and rheumatoid arthritis um well I don't know how relevant it is uh yeah I don't you know I actually yeah I don't think I have much to say about my boyfriend why are you so it's a very different process and it really is a disorder of joints primarily and it's inflammatory but not related about the central nervous system functions okay so the two different categories of things we thought one was you sure that Kim's explained the brain itself has been loved in a way just horribly way otherwise you sure to some cells function where McCallum floor quotation closer so how are these different things that's an excellent question that's one of the things we'd like to know right I mean how is it so so I'm sorry so the question was I talked about two things I talked about defects in cells and I also talked about these neuroanatomical defects and the question is how is it that a defect in a cell can lead to a neuro anatomical defect and I think the answer is that these processes that can affect that well that are affected by some of the mutations alter the development of the brain and so when the brain develops it the the precursor cells the cells that are going to become the neurons divide and they migrate and if that is altered in any way that really changes the way the brain is organized and so in a few cases we can actually see it by using imaging so I know that there are many more questions and I wish we had time to do it but it is a school night so thank you all for being here and next week we're on to genomics for more please visit us at stanford.edu

Channel: Stanford

Views: 73,556

Keywords: Science, medicine, biology, genetics, nervous system, brain, Asperger's syndrome, IQ, Leo Kanner, Hans Asperger, language, Rain Man, disability, savant, child care, genetic mutations, genome, SNP, point mutation

Id: MM-x25z-i7w

Length: 108min 37sec (6517 seconds)

Published: Thu Feb 04 2010