Paola Arlotta: Brain Development from Stem Cell to Organoid | Lex Fridman Podcast #32
the following is a conversation with Paulo Lara Lara she's a professor of stem cell and regenerative biology at Harvard University and is interested in understanding the molecular laws that govern the birth differentiation and assembly of the human brains cerebral cortex she explores the complexity of the brain by studying and engineering elements of how the brain develops this was a fascinating conversation to me it's part of the artificial intelligence podcast if you enjoy it subscribe on YouTube give it five stars and iTunes supported on patreon I simply connect with me on Twitter at Lex Friedman spelled Fri D ma a.m. and I'd like to give a special thank you to Amy Jeffress for support of the podcast on patreon she's an artist you should definitely check out her Instagram and love truth good three beautiful words your support means a lot and inspires me to keep the series going and now here's my conversation with Paola our Lada you studied the development of the human brain for many years so let me ask you and out-of-the-box question first how likely is it that there's intelligent life out there in the universe outside of Earth with something like the human brain so I could put it another way how unlikely is the human brain how difficult is it to build a thing through the evolutionary process well it has happened here I on this planet once yes once so that simply tells you that it could of course happen again other places is only a matter of probability what the probability that you would get a brain like the ones that we have like like the human brain so how difficult is it to make the human brain it's pretty difficult but most importantly I guess we know very little about how this process really happens and there is a reason for that actually multiple reasons for that most of what we know about how the mammalian brain so the brain of mammals developed comes from studying in labs other brains not our own brain the brain of mice for example but if I showed you a picture of a mouse brain and then you put it next to a picture of a human brain they don't look at all like each other so they're very different and and therefore there is a limit to what you can learn about how the human brain is made by studying the mouse brain the region there is a huge value and studying the mouse brain there are many things that we have learned but it's not the same thing so in having studied the human brain or through the mouse and through other methodologies that we'll talk about do you have a sense I mean you're one of the experts in the world how much do you feel you know about the brain and how much how often do you find yourself in awe of this mysterious thing yeah you pretty much find yourself you know all the time it's an amazing process it's a process which by means that we don't fully understand at the very beginning of embryogenesis the structure called the neural tube literally self-assembles and it happens in an embryo and it can happen also from stem cells in a dish okay and then from there these stem cells that are present within the neural tube give rise to all of the thousands and thousands of different cell types per present in the brain through time right with the interesting very intriguing interesting observation is that the time that it takes for the human brain to be made it's human time meaning that for me and you it took almost nine months of gestation to build the brain and then another twenty years of learning postnatally to get the brain we have today that allows us to this conversation a mouse takes twenty days or so too small for an embryo to be born and so and and so the brain is built in a much shorter period of time and the beauty of it is that if you take mouse stem cells and you put them in and culture - the brain the orbit the brain organoid that you get from a mouse is formed faster that if you took human stem cells and put them in the dish and let them make a human brain organoid so the very developmental process is controlled by the speed of the species which means it's by its own purpose it's not accidental or there is something in that temporal it's very exactly that is very important for us to get the brain we have and we can speculate for why that is you know it takes us a long time as as human beings after we're born to learn all the things that we have to learn to have the adult brain it's actually 20 years think about it from when a baby is born or - when a teenager goes through puberty to adults it's a long time do you think you can maybe talk through the first few months and then on to the first 20 years and then for the rest of their lives what is the development of the human brain look like what are the different stages at the beginning you have to build a brain right and the brain is made of cells what's the very beginning which beginning I were talking in the embryo as the embryo is developing in the womb in addition to making all of the other tissues of the embryo the muscle the heart the blood the embryo is also building the brain and it builds from a very simple structure called the neural tube which is basically nothing but a cube of cells that spans sort of the length of the embryo from the head all the way to the tail let's say of the embryo and then over in human means over many months of gestation from that neural tube which contains stem cell-like cells of the brain you will make many many other building blocks of the brain so all of the other cell types there are many many different types of cells in the brain that will form specific structures of the brain so you can think about embryonic development of the brain is just the time in which you are making the building blocks the cells at the stem cells relatively homogeneous like uniform or they all different ok good question it's exactly how it works you start with a more homogeneous perhaps more multipotent type of stem cell that most importantly means that it can it has the potential to make many many different types of other cells and then with time these progenitors become more heterogeneous which means more diverse there are going to be many different types of the stem cells and also they will give rise to progeny to other cells that are not themselves that are specific cells of the brain that are very different from the mothers themselves and now you think about this process of making cells from the stem cells over many many months of development for humans and and what you're doing you're building the cells they physically make the brain and then you arrange them in specific structures that are present in the final brain so you can think about the embryonic development of the brain as the time where you're building the bricks you're putting a bricks together to form buildings structures regions of the brain and where you make the connections between these many different type of cells especially nerve cells neurons right that transmit action potentials and electricity I've heard you also says somewhere I think correct me if I'm wrong that the order of the way this builds matters oh yes if you are an engineer and you think about development you can think of it as well I could also take all the cells and bring them all together into a brain in the end but development is much more than that so the cells are made in a very specific order that subserve the final product that you need to get and so for example all of the nerve cells the neurons are made first and all of the supportive cells of the neurons like the glia is made later and there is a reason for that because they have to assemble together in specific ways but you also may say well why don't we just put them all together in the end it's because as they develop next to each other they influence their own development so it's a different thing for a glia to be made alone in a dish then a glia be made in a glial cell be made in a developing embryo with all these other cells surrounded they produce all these other signals first of all that's mind-blowing that this development process from my perspective in artificial intelligence you often think of how incredible the final product is the final product the brain but you just you're making me realize that the final product is just is the the beautiful thing is the actual development and development process do we know the code that drives that development do we have any sense first of all thank you for saying that it's really the formation of the brain it's really its development this incredibly choreograph dance that happens the same way every time each one of us builds the brain right and that builds an organ that allows us to do what we're doing today right yeah that is mind blowing and this is why developmental neurobiologists never get tired in that now you're asking about the code what drives this how is this done well it's you know millions of years of evolution of really fine-tuning gene expression programs that allow certain cells to be made at a certain time and to be in to become a certain you know cell type but also mechanical forces of pressure bending this embryo is not just it will not stay a tube this this brain for very long at some point is tube in the front of the of the embryo will expand to make the primordium of the brain right now they the forces that control that these cells feel and this is another beautiful thing at the very force that they feel which is different from a week before a week ago will tell the cell oh you're being squished in a certain way begin to produce these new genes because now you are at the corner or you are you know in a stretch of cells or whatever it is and there so that mechanical physical force shapes the fate of the cell as well so nala chemical is also mechana mechanical so from my perspective biology is this incredibly complex mess gooey mess so you're seeing mechanical forces how different is a like a computer or any kind of mechanical machine that we humans build and the biological systems have you been because you've worked a lot with biological systems are they as much of a mess as it seems from a perspective of an engineer mechanical engineer yeah they are much more prone to taking alternative routes right so if you we go back to printing a brain versus developing a brain of course if you print a brain given that you start with the same building blocks the same cells you could potentially print it the same way every time but that final brain may not work the same way as a brain built during development does because the build very build very same building blocks that you're using developed in a completely different environment right there was not the environment of the brain therefore they're going to be different just by definition so if you instead use development to be able to say a brain organoid which maybe we'll be talking about in a future those things are fascinating yes so if you if you use processes of development then you when you watch it you can see that sometime things can go wrong in some organ weights and by wrong I mean different one organ way from the next well if you think about that embryo it always goes right so it's this development it's for as complexity as it is every time a baby is born has you know with very few exceptions so the brain is like the next baby but it's not the same if you develop it in a dish and first of all is we don't even develop a brain you develop something much simpler in the dish but there are more options for building things differently which really tells you the evolution as has played a really tight game here for how in the end the brain is built in vivo so just a quick may be dumb question but it seems like this is not the building process is not a dictatorship it seems like there's not a centralized like high-level mechanism that says ok this cell built itself the wrong way I'm going to kill it it seems like it's there's a really strong distributed mechanism is that is that in your sense for there are a lot of there are a lot of possibilities right and if you think about for example different species building their brain each brain is a little bit different so the brain of a lizard is very different from that of a chicken from that of a you know one of us and so on and so forth and still is a brain but it was built differently if starting from stem cells that pretty much had the same potential but in the end evolution builds different brains in different species because that serves in a way the purpose of the species and the well-being of that organism and so there are many possibilities but then there is a way and you were talking about a code nobody knows what the entire code of development is of course we don't we know bitten bits and pieces of very specific aspects of development of the brain what genes are involved to make a certain cell types out those two cells interact to make the next level structure that we might know but the entirety of it oh it's so well control it's really mind-blowing so in the first two months in the embryo or whatever the first few months so yeah the the building blocks are constructed the actual the different regions of the brain I guess in the nervous system well this continuous way longer than just the first few months so over the the very first in a few months you build a lot of the cells but then there is a continuous building of new cell types all the way through birth and then even post Natalie you know I don't know if you ever heard of myelin myelin is this shrub insulation that is build around a cable some of the neurons so that the electricity can go really fast the front axons I guess the axons are called axons exactly and and so as human beings we my alienate ourselves post Natalie a kid you know a six-year-old kid has barely started so making the mature oligodendrocytes which are the cells then eventually will wrap with the axons in to myelin and this will continue believe it or not until we are about you know 2530 years old so there is a continuous process of maturation and tweaking and additions and and also in response to what we do I remember taking ap biology in high school and in the textbook it said that I'm going by memory here that scientists disagree on the purpose of myelin in in the brain is that is that's totally wrong so like it I guess it speeds up the book okay might be wrong here but I guess it speeds up the electricity traveling down the axon or something that's the most sort of canonical and definitely that's the case so you have to imagine an axon and you can think about it as a cable or some type with electricity going through and what myelin does by insulating the outside I should say there are tracks of myelin and pieces of axons that are naked without my Elaine and so by having the insulation the electricity instead of going straight through the cable it would jump over a piece of myelin right to the next naked little piece and jump again and therefore you you know that's the idea that you go faster and it was always thought that in order to build a big brain a big nervous system in order to have a nervous system it can do very complex the type of things then you need a lot of myelin because you want to go fast with this information from point A to point B well a few years ago maybe five years ago or so we discovered that some of the most evolved which means the newest type of neurons that we have as non-human primates as as human beings in the top of our cerebral cortex which should be the neurons do some of the most complex things that we do well those F axons that have very little myelin and they have very interesting way in which they put the smiling on their axles you know a little piece here then a long track with no mining another chunk there and some don't have mining at all so now you have to explain where we're going with evolution and if you think about it perhaps as an electrical engineer when I looked at it I initially thought and I'm a developmental neurobiology I thought maybe this is what we see now but if we give evolution another few million years we see a lot of myelin on these neurons - but I actually think now that that's instead the future brain less myelin am i allow for more flexibility on what you do with your actions and therefore more complicated and unpredictable type of functions which is also a bit mind-blowing so it seems like it's controlling the timing of the signal so they're in the timing you can encode a lot of yes information yeah and so the brain I mean the chemistry of that little piece of axon perhaps is a dynamic process where the myelin can move now you see how many layers of variability you can add and that's actually really good if you're trying to to come up with a new function or a new capability or something unpredictable in a way so we're gonna jump around a little bit but the old question of how much is nature and how much is nurture in terms of this incredible thing after the development is over we seem to be kind of somewhat smart intelligent cognition consciousness all these things are just incredible ability reasons so on emerge in your sense how much is in the hardware in the nature and how much is in the nurture has learned through with our parents to interact in the environment so on it's really both right if you think about it so we are born with the brain as babies there has most of his South and most of structures and we'll take a few years to you know to grow to add more to be better but really then we have this 20 years of interacting with the environment around us and so what that brain that was so you know perfectly built or imperfectly built due to our genetic cues will then be used to incorporate the environment in its further maturation and development and so your experiences do shape your your brain I mean we know that like if you know you and I may have had a different childhood or a different we have been going to different schools we have been learning different things and our brain is a little bit different because of that we behave differently because of that and and so especially postnatally experience is extremely important we are born with a plastic brain what that means it's a brain it is able to change in response to stimuli they can be sensory so perhaps some of the most illuminating studies that were done were studies in which the sensory organs were now working right if you are born with eyes that don't work then your very brain that no piece of the brain that normally would process vision the visual cortex develops postnatally differently and it might be used to do something different right so the most extreme the plasticity of the brain I guess is the magic hardware that it and then it's it's flexibility in all forms is what enables the learning yes Natalie can you talk about organoids what are they yes and how can you use them to help us understand the brain and the development of the brain this is very very important so the first thing I'd like to say please keep this in the video the first thing I'd like to say is that an organ or a brain organoid is not the same as a brain okay it's a fundamental distinction it's a system a cellular system that one can develop in the culture dish starting from stem cells that will mimic some aspects of the development of the of the brain but not all of it they are very small maximum they become about you know four to five millimeters in diameter they are much simpler than than our brain of course by yet they are the only system where we can literally watch a process of human brain development unfold and by watch I mean study it remember when I told you that we can't understand everything about development our own brain by studying a mouse well we can study the actual process of development of the human brain because it all happens in utero so we will never have access to that process ever and therefore this is our next best thing like a a bunch of stem cells that can be coaxed into starting a process of neural tube formation remember that cube that is made by the embryo early on and from there a lot of the cell types that are present within within the brain and you can simply watch it and study but you can also think about diseases where development of the brain does not proceed normally right properly think about neurodevelopmental diseases there are many many different types think about all these own spectrum disorders there are also many different types of autism so there you could take a stem cell which really means either a sample of blood or a sample of skin from the patient make a stem cell and then with that stem cell watch a process of formation of a brain organ with of their person the person with that genetics with that genetic code in it and you can ask what is this genetic code doing to some aspects of development of the brain for the first time you may come to solutions like what cells are involved in autism so right so many questions around this so if you take this human stem cell for that particular person with that genetic code how and you try to build an organized yeah how often will it look similar what's the produce ability yes or how much variability its website of that yeah so there is much more variability in building organoids than there than there is in building brain it's really true that the majority of us when we are born as babies our brains look a lot like each other this is the magic that the embryo does where it builds a brain in the context of a body and and there is very little variability there there is disease of course but in general little variability when you build an organizer you know we don't have the full code for how this is done and so in part the organoid somewhat built itself because there are some structures of the brain that the cells know how to make and another part comes from the investigator the scientist add in to the media factors that we know in the mouse for example would foster a certain step of development but it's very limited and so as a result the kind of product you get in the end is much more reduction is this much more simple than what you get in vivo it mimics early events of development as of today and it doesn't build very complex type of anatomy and structure does not as of today which happens is that in in vivo and also the variability that you see one organ or to the next tends to be higher than we'll compare an embryo to the next so okay then the next question is how hard and maybe another flip side of that expensive is it to go from one stem cell to an organized yeah how many can you build and like this sounds very complicated it's work definitely and it's money definitely but you can really grow a very high number of this organoids you know can go I told you the maximum they become about five millimeters in diameter so this is about the size of a of a tiny tiny you know raising or perhaps the seed of an apple and so you can grow 50 to 100 of those inside one big bioreactors which are these flasks where the media provides nutrients for the organoids so the problem is not to grow more or less of them it it's really to figure out how to grow them in a way that they are more and more reproducible for example orgonite organize so they can be used to study a biological process because if you have too much variability then you never know if what you see is just an exception or really the rule so what is an organize look like are there different neurons already emerging is there you know well first can you tell me what kind of neurons are there yes are they sort of all the same are they not all the same as to how much do we understand and how much of that variance if any can exist in organoids yes so you could grow I told you that the brain has different parts so the cerebral cortex is on top at the top part of the brain but there is another region called the striatum that is below the cortex and so on and so forth all of these regions have different types of cells in the actual brain ok and so scientists have been able to grow organoids that may mimic some aspects of development of these different regions of the brain and so we are very interested in the cerebral cortex that's the coolest part you're talking if we didn't have a cerebral cortex it's also I like to think the part of the brain that really truly makes us human the most evolved in recent evolution and so in the attempt to make the cerebral cortex and by figuring out a way to have this organoids continue to grow and develop for extended periods of times much like it happens in the real embryo months and months in culture there you can see that there many different types of neurons of the cortex appear and at some point also the astrocytes to the glia cells of the cerebral cortex also appear what are these the astrocytes are not neuron so they're not nerve cells but they they play very important roles one important role is to support the neuron but of course they have much more active type of roles are very important for example to make the synapses which are the point of contacts and communication between two neurons they all that chemistry fun happens between the synapses happens because of these cells are they the medium in which it happens because of the interactions happens because you are making the cells and they have certain properties including the ability to make you know neurotransmitters which are the chemicals that are secreted to the synapses including the ability of making this axons grow with their growth cones and so on and so forth and then you have other cells around there that release chemicals or touch the neurons or interact with them in different ways to really foster this perfect process in this case of synaptogenesis and this does happen within within organized so the mechanical and the chemists and chemical stuff happens yes the connectivity between neurons this video why is not surprising because scientists have been culturing neurons forever and when you take a new don't even a very young one and you culture it eventually finds another cell or another neuron to talk to it will form a synapse are we talking about Meisner on my human neuron it doesn't matter both so you can culture and you out like a single neuron and give it a little friend and it starts interacting yes so neurons are able to it sounds it's more simple than what it may sound to you neurons have molecular properties and structural properties allow them to really communicate with other cells and so if you put not one neuron but if you put several neurons together chances are that they will form synapse is with each other okay great so an organized not a brain but but uh there's some it's able to especially what you're talking about mimic some properties of the cerebral cortex for example so what what can you understand about the brain by studying an organize of a cerebral cortex I can literally study how all this incredible diversity of cell type all these many many different classes of cells how are they made how do they look like what do they need to be made properly and what goes wrong if now the genetics of that stem cell that I used to make the organ we came from a patient with a neurodevelopmental disease can I actually watch for the very first time what may have gone wrong years before in this kid when its own brain was being made think about that loop in a way it's a little tiny rudimentary window into the past into the time when that brain in a kid they had this you know developmental disease was being made and I think that's unbelievably powerful because today we have no idea of what cell types we barely know what brain regions are affected in these diseases now we have an experimental system that we can study in the lab and we can ask what are the cells affected when during development things went wrong what are the molecules among the many many different molecules that that control brain development which ones are the ones they're really messed up here and we want perhaps to fix and what is really the final product is it a less strong kind of circuit and brain is it a brain that lacks a cell type is it what is it because then we can think about treatment and and care for these patients that is informed rather than just based on current diagnostics so how hard is it to detect through the development of process the super-exciting mech tool just to see how different conditions develop how hard is it to detect it wait a minute this is abnormal development yeah that's how hard is how much signal is there how much of it is is it a mess because things can go wrong multiple levels right you could have a cell that is born and built but then doesn't work properly or a self is not even born or a cell does interact with other cell differently and so on and so forth so today we have technology that we did not have even five years ago that allows us to look for example at the molecular picture of a cell of a single cell in a sea of cells with high precision and so that molecular information where you compare many many single cells for the genes they produce between a control individual and an individual with and your developmental disease that may tell you what is different molecular Li or you could see that some cells are not even made for example or that the process of maturation of the cells may be wrong there are many different levels here and and we can study these cells at the molecular level but also we can use the organ is to ask questions about the properties of the neurons the functional properties how they communicate with each other out they respond to a stimulus and so on and so forth and we may get at abnormalities their detectors so how early is this work in a maybe in the history of science so I mean like so if you were to if you and I time travel a thousand years into the future organize seem to be maybe I'm romanticizing the notion but you're building not a brain but something that has properties of a brain so you it feels like you might be getting close to in the building process thought to build us to understand so how how far are we in this understanding process of development thousand years from now it's a long time from now so if this planet is still gonna be here and a thousand years from now you know like they write a book obviously you there'll be a chapter about you that science fiction book today today but I mean I guess where we really understood very little about the brain a century ago was big fan in high school reading Freud and so on and still AM of Psychiatry I would say we still understand very little about the functional aspect of just yeah but how in the history of understanding the biology of the brain the development how far are we alone it's a very good question and so this is just of course my opinion I think that we did not have technology even ten years ago or 20 certainly not 20 years ago to even think about experimentally investigating the development of the human brain so we've done a lot of work in science to study the brain or many other organisms now we have some technologies which I'll spell out that allow us to actually look at the real thing and look at the brain at the human brain so what are these technologies there is been huge progress in stem cell biology the moment someone figured out how to turn a skin cell into an embryonic stem cell basically and that out that embryonic stem cell could begin a process of development again to correct for example make a brain there was a huge and you know advance and in fact there was a Nobel Prize for that that started the field really of using stem cells to build organs now we can build on all the knowledge of development that we build over the many many many years to say how do we make the stem cells now make more and more complex aspects of development of the human brain so this field is younger the field of brain organics but is moving faster and it's moving fast in a very serious way that is rooted in labs with the right ethical framework and and really building on you know solid science for reality is and what is not and but it will go faster and it will be more and more powerful we also have technology that allows us to basically study the properties of single cells across many many millions of single cells which we didn't have perhaps five years ago so now with that even an organ or that has millions of cells can be profiled in a way looked at very very high resolution the single cell level to really understand what is going on and you could do it in multiple stages of development and you can build your hypothesis and so on and so forth so it's not going to be a thousand years it's gonna be a shorter amount of time and I see this as sort of a an exponential growth of this field enabled by these technologies that we didn't have before and so we're gonna see something transformative that we didn't see at all in the prior thousand years so I apologize for the crazy sci-fi questions but the developmental process is fascinating to watch and study but how far are we away from and maybe how difficult is it to build not just an organ or but a human brain okay from us themself yeah first of all that's not the goal for the majority of the serious scientists that work on this because you don't have to build the whole human brain to make this model useful for understanding of the brain develops or understanding disease you don't have to build the whole thing so let me is let me just comment on that it's fascinating it shows to me the difference between you and I is you're actually trying to understand the beauty of the human brain and to use it to really help thousands or millions of people disease and so on right from an artificial intelligence but we're trying to build systems that we can put in robots and try to create systems that have echoes of the intelligence about reasoning about the world navigating the world its its different objectives I think we operate in size fix a little bit but so so on that point of building a brain even though that is not the focus or interest perhaps of the community how difficult is it is it truly science fiction at this point I think the field will progress like I said and that the system will be more and more complex in a way right but there are properties that emerge from the human brain they have to do with the mind they may have to do with conscious name I have to do with intelligence or whatever that we don't really don't don't understand even now they can emerge from an actual real brain and therefore we cannot measure or study in an organized so so I think that this field many many years from now may lead to the building of better neural circuits of you know that really are built out of understanding about this process really works and it's hard to predict how complex this really will be I really don't think we're so far from it makes me laugh really it's really that far from building the human the human brain but you're gonna be building something that is you know always a bad version of it but that may have really powerful properties and might be able to you know respond to stimuli or or be used in in certain context and this is why I really think that there is no other way to do this science but within the right ethical framework because where you're going with this is also you know we can talk about science fiction and write that book and we could today but this work happens in a specific ethical framework that we don't decide just a scientist but also as a society so the ethical framework here is a fascinating one is the complicated one do you have a sense a grasp of how we think about ethically of building organoids from human stem cells to understand the brain it seems like a tool for helping potentially millions of people cure diseases are at least start the cure by understanding it but is there more is there gray areas that are at the that we have to think about ethically absolutely we must think about that every discussion about the ethics of this needs to be based on actual data from the models that we have today and from the ones that we will have tomorrow so it's a continuous conversation it's not something that you decide now today there is no issue really very simple models they that clearly can help you in many ways without much much think about but tomorrow we need to have another conversation and so on and so forth and so the way we do this is to actually really bring together constantly a group of people that are not only scientists but also bioethicists the lawyers philosophers psychiatrist and so on as a psychologist and so on and so forth to decide as a society really what we should and what we should not do so that's the way to think about the ethics now I also think though that as a scientist I have a moral responsibility so if you if you think about how transformative it could be for understanding and curing a neuropsychiatrist to be able to actually watch and study and treat with drugs the very brain of the patient that you are trying to study how transformative at this moment in time this could be we couldn't do it five years ago we could do it now right if taking of a particular patient patient and make an organ or for a simple and you know different from the from the human brain he still is his process of brain development with his with his or her genetics and we could understand perhaps what is going wrong perhaps we could use as a platform as a cellular platform to screen for drugs to fix a process and so on and so forth right so we could do it now we couldn't do it five years ago should we not do it what is the downside of doing it I don't see a downside if you would but if we invited a lot of people yes if I'm sure there would be somebody who would would argue against it what would be the devil's advocate argument yeah so it's exactly perhaps what you eluded it with your question that you are making as enabling you know some some process of formation of the brain that could be misused at some point or there could be showing properties that ethically we don't want to see in a tissue so today today this is not an issue and so you you just gain dramatically from the science without because the system is so simple and and so different in a way from from the actual brain but but because it is the brain we have an obligation to really consider all of this right and again it's it's a balanced conversation where we should put disease and betterment of humanity also on that plate what do you think at least historically there were some politicization of embryonic stem cells a stem cell research do you still see that out there is there is that still a force that we have to think about especially in this larger discourse that we're having about the role of science in at least American society yeah this is a very good question it's very very important I see a very central role for scientist to inform decisions about what we should or should not do in society and this is because the scientists have the first-hand look and understanding of really the work that they are doing and again this varies depending on what we're talking about here so now we're talking about Brian organoids I think the scientists need to be part of that conversation about what is will be allowed in the future or not allowed in the future to do with the system and I think it's that is very very important because they bring reality of data to the conversation and and and so they should have a voice so data should have a voice it needs to have a voice because a not only data we should also be good at communicating with non scientists the data so there has been often time there is a lot of discussion and you know excitement and fights about certain topics just because of the way they are described I'll give you an example if I call that the same cellular system we just talked about a brain organoid or if i called it a human mini brain your reaction is going to be very different yes to this and so the way the systems are described I mean we and journalists alike need to be a bit careful that this debate is a real debate and inform burial data that's all I'm asking and yeah the language matters here so I work on autonomous vehicles and their the use of language could it could it could drastically change the interpretation and the way people feel about what is the right way to proceed forward you are as I've seen from a presentation you're a parent as I show a couple pictures of your son is it just the one to sign a daughter so what have you learned from the human bracing two of them what have I learned I've learned that children really have this amazing plastic minds right that we have a responsibility to you know foster their growth in good healthy ways that keep them curious that keeps adventures that doesn't raise them in fear of things but also respecting who they are which is in part you know coming from their genetics we talked about my children are very different from each other despite the fact that they're the product of the same two parents I also learned that what you do for them comes back to you like you know if you're a good parent you're gonna most of the time have you know perhaps a decent kids at the end what do you think just a quick comment what what do you think is the source of that difference it's often the surprising thing for parents is it can't believe that our kids oh they're so different yet they came from the same parents well they are genetically different even they came from the same two parents because the mixing of gametes I mean you know we know these genetics creates every time a genetically different individual which will have a specific mix of genes that is a different mix every time from the two parents and so so they're not twins so they are genetically different is that a little bit of variation as you said really from a biological perspective the brains look pretty similar well so let me clarify that so the genetics you have the genes that you have at that play that beautiful orchestrated symphony of development different genes will play it slightly differently it's like playing the same piece of music but with the different orchestra and a different director right the music will not come out it will be still a piece by the same you know author but it will come out differently if it's played by the high school orchestra instead of and so you are born superficially with the same brain it has the same cell types similar patterns of connectivity but the properties of the cells and how the cells we then react to the environment as you experience your word will be also shaped by pujan ethically you are speaking just as a parent this is not something that comes from my work I think you can tell a birth differently that they have a different personality in a in a way right so both is needed the genetics as well as the nurturing afterwards so you are one human with a brain instead of living through the whole mess of it the human condition full of love maybe fear ultimately mortal how has studying the brain changed the way you see yourself and you look in the mirror when you think about your life the fear is the love when you see your own life your own mortality yeah that's a very good question it's almost impossible to dissociate sometime for me some of the things we do or some of the things that other people do from oh that's because that part of the brain is working in a certain way or thinking about a teenager you know going through teenage years and being at I'm funny in the way they think and impossible for me not to think it's because they're going through this period of time called critical periods of plasticity where their synapses are being eliminated here and there and they're just confused and so from that comes perhaps a different take on the behavior or maybe I can justify scientifically in some sort of way I also look at humanity in general and I am amazed by what we can do and the kind of ideas that we can come up where then I cannot stop thinking about how the brain is continuing to evolve I don't know if you do this but I think about the next brain sometimes what are we going with it's like what are the features of this brain that you know evolution is really plain wait to get us you know in the future the new brain it's not over right it's it's a work in progress so let me just a quick comment on do you see do you think there's a there's a lot of fascination and hope for artificial intelligence of creating artificial brains you said the next brain when you imagine over a period of a thousand years the evolution of the human brain do you sometimes envisioning that future see an artificial one artificial intelligence as it is hoped by many not hoped thought by many people would be actually the next evolutionary step in the development yeah yeah I think in a way that will happen right it's almost like a part of the way we evolved we evolved in the world that we created that we interact with the shape has as we grow up and so on and so forth sometimes I think about something that may sound silly but think about the use of of cell phones part of me thinks that somehow in their brain there will be a region of the cortex that is this much attuned to that tool and and this comes from a lot of studies in in in model organisms where really the cortex especially adapts to the kind of things you have to do so if we need to move our fingers in a very specific way we have a part of our cortex that allows us to do this kind of very precise movement in an owl that has to see very very far away with big eyes the visual cortex very big it's the brain attuned to your environment so the brain will attune to the to the technologies that we will have and will be shaped by it so the cortex very well maybe we shaped by it in the artificial intelligence it may merge with it they may get a envelop it and adjust if it's not you know emerge of the kind of oh let's have a synthetic element together with a biological one the very space around us the fact for example think about we put on some goggles of virtual reality and we physically are surfing the ocean right like I've done it and you have all these emotions that come to you you brain placed you in that reality and it was able to do it like that just by putting the goggles on it didn't take thousands of years of adapting to this the brain is plastic so adapts to new technology so you could do it from the outside by simply hijacking some sensory capacities that we have so clearly over you know recent evolution the cerebral cortex has been a part of the brain that has known the most evolution so we have put a lot of chips on evolving this specific part of the brain and the evolution of cortex is plasticity it's this ability to change in response to things so yes they will integrate that we want it or not well there is no better way to end it Paula thank you so much for talking about you