Paola Arlotta: Brain Development from Stem Cell to Organoid

00:00:00.000 | The following is a conversation with Paola Arlotta.

00:00:03.380 | She's a professor of stem cell and regenerative biology

00:00:06.400 | at Harvard University and is interested in understanding

00:00:09.780 | the molecular laws that govern the birth, differentiation,

00:00:13.180 | and assembly of the human brain's cerebral cortex.

00:00:16.620 | She explores the complexity of the brain

00:00:18.420 | by studying and engineering elements

00:00:21.020 | of how the brain develops.

00:00:22.900 | This was a fascinating conversation to me.

00:00:25.660 | It's part of the Artificial Intelligence Podcast.

00:00:28.580 | If you enjoy it, subscribe on YouTube,

00:00:30.620 | give it five stars on iTunes, support it on Patreon,

00:00:33.820 | or simply connect with me on Twitter

00:00:35.820 | at Lex Friedman, spelled F-R-I-D-M-A-N.

00:00:39.980 | And I'd like to give a special thank you to Amy Jeffress

00:00:43.140 | for her support of the podcast on Patreon.

00:00:45.580 | She's an artist, and you should definitely check out

00:00:47.660 | her Instagram at lovetruthgood, three beautiful words.

00:00:52.660 | Your support means a lot and inspires me

00:00:55.640 | to keep the series going.

00:00:57.740 | And now, here's my conversation with Paola Arlotta.

00:01:01.780 | You studied the development of the human brain

00:01:05.340 | for many years, so let me ask you

00:01:08.620 | an out-of-the-box question first.

00:01:10.540 | How likely is it that there's intelligent life out there

00:01:14.620 | in the universe, outside of Earth,

00:01:17.180 | with something like the human brain?

00:01:19.340 | So I could put it another way.

00:01:20.780 | How unlikely is the human brain?

00:01:24.340 | How difficult is it to build a thing

00:01:28.380 | through the evolutionary process?

00:01:30.420 | - Well, it has happened here, right, on this planet?

00:01:33.380 | - Once, yes. - Once.

00:01:34.660 | (Paola laughs)

00:01:36.340 | So that simply tells you that it could, of course,

00:01:39.980 | happen again other places.

00:01:42.140 | It's only a matter of probability,

00:01:44.140 | what the probability that you would get a brain

00:01:46.620 | like the ones that we have, like the human brain.

00:01:51.220 | So how difficult is it to make the human brain?

00:01:53.980 | It's pretty difficult, but most importantly,

00:01:57.900 | I guess we know very little

00:02:00.940 | about how this process really happens,

00:02:04.420 | and there is a reason for that,

00:02:06.300 | actually multiple reasons for that.

00:02:09.140 | Most of what we know about how the mammalian brains,

00:02:13.380 | or the brain of mammals, develop comes from studying,

00:02:17.060 | in labs, other brains, not our own brain,

00:02:20.460 | the brain of mice, for example.

00:02:22.580 | But if I showed you a picture of a mouse brain,

00:02:25.420 | and then you put it next to a picture of a human brain,

00:02:28.380 | they don't look at all like each other.

00:02:31.140 | So they're very different,

00:02:33.020 | and therefore there is a limit

00:02:35.300 | to what you can learn about how the human brain is made

00:02:37.940 | by studying the mouse brain.

00:02:39.780 | There is a huge value in studying the mouse brain.

00:02:43.300 | There are many things that we have learned,

00:02:45.060 | but it's not the same thing.

00:02:46.580 | - So in having studied the human brain,

00:02:49.220 | or through the mouse and through other methodologies

00:02:51.420 | that we'll talk about, do you have a sense,

00:02:54.700 | I mean, you're one of the experts in the world,

00:02:57.500 | how much do you feel you know about the brain?

00:03:01.100 | And how often do you find yourself

00:03:05.340 | in awe of this mysterious thing?

00:03:07.780 | - Yeah, you pretty much find yourself in awe all the time.

00:03:12.180 | It's an amazing process.

00:03:15.300 | It's a process by which,

00:03:17.940 | by means that we don't fully understand,

00:03:20.700 | at the very beginning of embryogenesis,

00:03:23.620 | the structure called the neural tube

00:03:26.260 | literally self-assembles.

00:03:28.780 | And it happens in an embryo,

00:03:30.420 | and it can happen also from stem cells in a dish.

00:03:33.740 | Okay.

00:03:34.900 | And then from there,

00:03:36.860 | these stem cells that are present within the neural tube

00:03:39.860 | give rise to all of the thousands and thousands

00:03:42.220 | of different cell types that are present in the brain

00:03:45.060 | through time, right?

00:03:47.540 | With the interesting, very intriguing,

00:03:49.980 | interesting observation is that the time that it takes

00:03:54.900 | for the human brain to be made, it's human time.

00:03:58.780 | Meaning that for me and you,

00:04:02.180 | it took almost nine months of gestation to build a brain,

00:04:05.300 | and then another 20 years of learning postnatally

00:04:08.700 | to get the brain that we have today

00:04:09.980 | that allows us to this conversation.

00:04:12.140 | A mouse takes 20 days or so to--

00:04:16.780 | - So it's mouse time. - For an embryo to be born.

00:04:19.220 | And so the brain is built in a much shorter period of time.

00:04:23.820 | And the beauty of it is that if you take mouse stem cells

00:04:27.220 | and you put them in a culture dish,

00:04:28.980 | the brain organoid that you get from a mouse

00:04:33.340 | is formed faster than if you took human stem cells

00:04:37.660 | and put them in the dish

00:04:39.140 | and let them make a human brain organoid.

00:04:42.020 | - So the very developmental process is--

00:04:45.580 | - Controlled by the speed of the species.

00:04:49.020 | - Which means it's on purpose, it's not accidental.

00:04:54.020 | Or there is something in that temporal--

00:04:58.380 | - It's very, exactly, that is very important

00:05:01.500 | for us to get the brain we have.

00:05:04.060 | And we can speculate for why that is.

00:05:07.340 | It takes us a long time as human beings after we're born

00:05:13.060 | to learn all the things that we have to learn

00:05:16.100 | to have the adult brain.

00:05:18.020 | It's actually 20 years, think about it.

00:05:20.220 | From when a baby is born to when a teenager

00:05:23.500 | goes through puberty to adults, it's a long time.

00:05:27.260 | - Do you think you can maybe talk through

00:05:30.340 | the first few months and then on through the first 20 years

00:05:35.140 | and then for the rest of their lives,

00:05:37.660 | what is the development of the human brain look like?

00:05:41.180 | What are the different stages?

00:05:42.620 | - Yeah, at the beginning you have to build a brain, right?

00:05:46.780 | And the brain is made of cells.

00:05:48.900 | - What's the very beginning,

00:05:49.780 | which beginning are we talking about?

00:05:52.020 | - In the embryo.

00:05:53.100 | - In the embryo.

00:05:53.940 | - As the embryo is developing in the womb,

00:05:56.060 | in addition to making all of the other tissues

00:05:58.580 | of the embryo, the muscle, the heart, the blood,

00:06:02.100 | the embryo is also building the brain.

00:06:05.020 | And it builds from a very simple structure

00:06:08.500 | called the neural tube, which is basically

00:06:10.860 | nothing but a tube of cells that spans

00:06:13.980 | sort of the length of the embryo from the head

00:06:16.980 | all the way to the tail, let's say, of the embryo.

00:06:19.940 | And then in human beings, over many months of gestation,

00:06:25.540 | from that neural tube, which contains stem cell-like cells

00:06:30.540 | of the brain, you will make many, many other

00:06:35.540 | building blocks of the brain.

00:06:37.020 | So all of the other cell types,

00:06:39.620 | 'cause there are many, many different types of cells

00:06:41.900 | in the brain, that will form specific structures

00:06:45.940 | of the brain.

00:06:46.780 | So you can think about embryonic development

00:06:49.260 | of the brain as just the time in which you are making

00:06:51.620 | the building blocks, the cells.

00:06:54.460 | - Are the stem cells relatively homogeneous,

00:06:56.860 | like uniform, or are they all different type?

00:06:59.300 | - That's a very good question.

00:07:00.180 | It's exactly how it works.

00:07:01.260 | You start with a more homogeneous,

00:07:04.220 | perhaps more multipotent type of stem cell.

00:07:09.140 | - What's multipotent?

00:07:09.980 | - Multipotent means that it has the potential

00:07:13.540 | to make many, many different types of other cells.

00:07:17.380 | And then with time, these progenitors

00:07:19.820 | become more heterogeneous, which means more diverse.

00:07:22.860 | There are gonna be many different types of the stem cells.

00:07:26.020 | And also, they will give rise to progeny,

00:07:28.780 | to other cells that are not stem cells,

00:07:31.780 | that are specific cells of the brain,

00:07:33.340 | that are very different from the mother stem cell.

00:07:36.100 | And now you think about this process of making cells

00:07:38.860 | from the stem cells over many, many months

00:07:41.580 | of development for humans.

00:07:43.860 | And what you're doing, you're building the cells

00:07:46.220 | that physically make the brain,

00:07:48.260 | and then you arrange them in specific structures

00:07:52.460 | that are present in the final brain.

00:07:55.460 | So you can think about the embryonic development

00:07:58.740 | of the brain as the time where you're building the bricks.

00:08:02.180 | You're putting the bricks together to form buildings,

00:08:05.580 | structures, regions of the brain,

00:08:08.180 | and where you make the connections

00:08:10.380 | between these many different type of cells,

00:08:13.100 | especially nerve cells, neurons, right,

00:08:15.300 | that transmit action potentials and electricity.

00:08:19.300 | - I've heard you also say somewhere, I think,

00:08:21.380 | correct me if I'm wrong,

00:08:22.300 | that the order of the way this builds matters.

00:08:25.180 | - Oh, yes.

00:08:26.100 | If you are an engineer and you think about development,

00:08:29.900 | you can think of it as, well, I could also take all the cells

00:08:34.900 | and bring them all together into a brain in the end.

00:08:38.020 | But development is much more than that.

00:08:40.380 | So the cells are made in a very specific order

00:08:43.900 | that subserve the final product that you need to get.

00:08:47.420 | And so, for example, all of the nerve cells,

00:08:49.940 | the neurons, are made first,

00:08:52.260 | and all of the supportive cells of the neurons,

00:08:54.420 | like the glia, is made later.

00:08:56.820 | And there is a reason for that,

00:08:58.420 | because they have to assemble together in specific ways.

00:09:02.140 | But you also may say, well,

00:09:03.380 | why don't we just put them all together in the end?

00:09:05.740 | It's because as they develop next to each other,

00:09:08.980 | they influence their own development.

00:09:11.300 | So it's a different thing for a glia

00:09:13.220 | to be made alone in a dish,

00:09:15.420 | than a glia cell be made in a developing embryo

00:09:19.380 | with all these other cells around it

00:09:21.340 | that produce all these other signals.

00:09:23.700 | - First of all, that's mind-blowing,

00:09:25.900 | this development process.

00:09:27.820 | From my perspective in artificial intelligence,

00:09:29.780 | you often think of how incredible the final product is,

00:09:33.500 | the final product, the brain.

00:09:35.220 | But you're making me realize that the final product

00:09:38.460 | is just, the beautiful thing

00:09:42.060 | is the actual development process.

00:09:44.460 | Do we know the code that drives that development?

00:09:49.460 | - Yeah.

00:09:51.980 | - Do we have any sense?

00:09:53.860 | - First of all, thank you for saying

00:09:55.820 | that it's really the formation of the brain.

00:09:59.300 | It's really its development,

00:10:00.700 | it's this incredibly choreographed dance

00:10:05.140 | that happens the same way every time

00:10:07.500 | each one of us builds the brain, right?

00:10:10.580 | And that builds an organ that allows us

00:10:12.660 | to do what we're doing today, right?

00:10:14.900 | That is mind-blowing,

00:10:16.380 | and this is why developmental neurobiologists

00:10:18.900 | never get tired of studying that.

00:10:21.900 | Now you're asking about the code.

00:10:23.820 | What drives this?

00:10:24.900 | How is this done?

00:10:26.500 | Well, it's millions of years of evolution,

00:10:29.740 | of really fine tuning gene expression programs

00:10:33.180 | that allow certain cells to be made at a certain time

00:10:37.460 | and to become a certain cell type,

00:10:41.700 | but also mechanical forces of pressure, bending.

00:10:46.700 | This embryo is not just, it will not stay a tube,

00:10:50.340 | this brain for very long.

00:10:52.020 | At some point, this tube in the front of the embryo

00:10:54.900 | will expand to make the primordium of the brain, right?

00:10:58.180 | Now the forces that control, that the cells feel,

00:11:02.860 | and this is another beautiful thing,

00:11:04.940 | the very force that they feel,

00:11:06.820 | which is different from a week before or a week ago,

00:11:10.260 | will tell the cell,

00:11:11.100 | "Oh, you're being squished in a certain way.

00:11:13.620 | "Begin to produce these new genes

00:11:16.540 | "because now you are at the corner,

00:11:18.380 | "or you are in a stretch of cells," or whatever it is.

00:11:23.180 | And so that mechanical physical force

00:11:26.020 | shapes the fate of the cell as well.

00:11:29.500 | So-

00:11:30.340 | It's not only chemical, it's also mechanical.

00:11:31.940 | - It's mechanical.

00:11:33.020 | So from my perspective,

00:11:34.520 | biology is this incredibly complex mess, gooey mess.

00:11:39.520 | So you're saying mechanical forces.

00:11:43.460 | - Yes.

00:11:44.300 | - How different is a computer

00:11:47.860 | or any kind of mechanical machine that we humans build

00:11:52.180 | and the biological systems?

00:11:53.900 | - Yeah.

00:11:54.740 | - 'Cause you've worked a lot with biological systems.

00:11:56.740 | - Yes.

00:11:57.580 | - Are they as much of a mess as it seems

00:12:00.740 | from a perspective of a mechanical engineer?

00:12:03.580 | - Yeah.

00:12:04.460 | They are much more prone

00:12:08.420 | to taking alternative routes, right?

00:12:11.740 | So if you,

00:12:13.080 | we go back to printing a brain versus developing a brain.

00:12:18.260 | Of course, if you print a brain,

00:12:20.500 | given that you start with the same building blocks,

00:12:23.100 | the same cells,

00:12:24.020 | you could potentially print it the same way every time.

00:12:28.660 | But that final brain may not work the same way

00:12:32.540 | as a brain built during development does

00:12:34.480 | because the very same building blocks that you're using

00:12:38.740 | developed in a completely different environment, right?

00:12:41.500 | It was not the environment of the brain.

00:12:43.060 | Therefore, they're gonna be different just by definition.

00:12:45.900 | So if you instead use development to build,

00:12:50.500 | let's say a brain organoid,

00:12:52.740 | which maybe we will be talking about in a few minutes.

00:12:54.860 | - For sure.

00:12:55.860 | Those things are fascinating.

00:12:57.020 | - Yes.

00:12:57.860 | So if you use processes of development,

00:13:02.020 | then when you watch it,

00:13:03.380 | you can see that sometimes things can go wrong

00:13:06.460 | in some organoids.

00:13:07.540 | And by wrong, I mean different one organoid from the next.

00:13:10.860 | While if you think about that embryo,

00:13:13.100 | it always goes right.

00:13:14.820 | So this development, for as complex as it is,

00:13:18.940 | every time a baby is born has,

00:13:21.420 | with very few exceptions,

00:13:23.700 | the brain is like the next baby.

00:13:26.180 | But it's not the same if you develop it in a dish.

00:13:31.180 | And first of all, we don't even develop a brain,

00:13:33.820 | you develop something much simpler in the dish.

00:13:36.100 | But there are more options for building things differently,

00:13:39.660 | which really tells you that evolution

00:13:42.940 | has played a really tight game here

00:13:47.940 | for how in the end the brain is built in vivo.

00:13:53.060 | - So just a quick, maybe dumb question,

00:13:55.380 | but it seems like this is not,

00:13:58.340 | the building process is not a dictatorship.

00:14:01.100 | It seems like there's not a centralized,

00:14:03.340 | like high level mechanism that says,

00:14:07.420 | okay, this cell built itself the wrong way,

00:14:10.300 | I'm gonna kill it.

00:14:11.540 | It seems like there's a really strong distributed mechanism.

00:14:15.460 | Is that in your sense?

00:14:17.500 | - There are a lot of possibilities, right?

00:14:20.940 | And if you think about, for example, different species,

00:14:25.100 | building their brain,

00:14:26.780 | each brain is a little bit different.

00:14:28.900 | So the brain of a lizard is very different

00:14:31.060 | from that of a chicken, from that of one of us,

00:14:35.540 | and so on and so forth, and still is a brain,

00:14:38.060 | but it was built differently,

00:14:40.980 | starting from stem cells

00:14:43.300 | that pretty much had the same potential.

00:14:46.020 | But in the end, evolution builds different brains

00:14:49.420 | in different species,

00:14:50.900 | because that serves in a way the purpose of that species

00:14:54.020 | and the wellbeing of that organism.

00:14:55.980 | - Right.

00:14:56.820 | - And so there are many possibilities,

00:15:00.740 | but then there is a way,

00:15:02.900 | and you were talking about a code.

00:15:04.860 | Nobody knows what the entire code of development is.

00:15:07.500 | Of course we don't.

00:15:08.660 | We know bits and pieces of very specific aspects

00:15:13.380 | of development of the brain,

00:15:14.500 | what genes are involved to make a certain cell types,

00:15:17.060 | how those two cells interact

00:15:18.540 | to make the next level structure.

00:15:20.380 | That we might know, but the entirety of it,

00:15:22.820 | how it's so well controlled, it's really mind blowing.

00:15:26.180 | - So in the first two months in the embryo,

00:15:29.140 | or whatever, the first few weeks, months, months.

00:15:32.740 | So yeah, the building blocks are constructed,

00:15:37.140 | the actual, the different regions of the brain, I guess,

00:15:40.420 | and the nervous system.

00:15:42.740 | - Well, this continues way longer

00:15:44.340 | than just the first few months.

00:15:46.500 | So over the very first few months,

00:15:50.460 | you build a lot of these cells,

00:15:52.060 | but then there is continuous building of new cell types

00:15:56.420 | all the way through birth.

00:15:58.420 | And then even postnatally,

00:16:00.420 | I don't know if you've ever heard of myelin.

00:16:03.980 | Myelin is this sort of insulation

00:16:06.660 | that is built around the cables of the neurons

00:16:09.780 | so that the electricity can go really fast from-

00:16:12.180 | - The axons, I guess they're called.

00:16:13.380 | - The axons, they're called axons, exactly.

00:16:15.980 | And so as human beings, we myelinate our cells

00:16:21.980 | postnatally.

00:16:24.300 | A kid, a six-year-old kid has barely started

00:16:28.700 | the process of making the mature oligodendrocytes,

00:16:31.860 | which are the cells that then eventually

00:16:33.620 | will wrap the axons into myelin.

00:16:36.580 | And this will continue, believe it or not,

00:16:38.940 | until we are about 25, 30 years old.

00:16:42.420 | So there is a continuous process of maturation

00:16:45.300 | and tweaking and additions,

00:16:46.580 | and also in response to what we do.

00:16:50.620 | - I remember taking AP Biology in high school,

00:16:53.940 | and in the textbook, it said that,

00:16:57.060 | I'm going by memory here,

00:16:58.580 | that scientists disagree on the purpose of myelin

00:17:01.980 | in the brain.

00:17:04.740 | Is that totally wrong?

00:17:06.340 | (both laughing)

00:17:07.300 | So I guess it speeds up the,

00:17:10.540 | okay, I might be wrong here,

00:17:13.220 | but I guess it speeds up the electricity

00:17:14.780 | traveling down the axon or something?

00:17:17.140 | - Yeah.

00:17:18.300 | That's the most sort of canonical,

00:17:20.140 | and definitely that's the case.

00:17:21.780 | So you have to imagine an axon,

00:17:24.860 | and you can think about it as a cable of some type

00:17:27.660 | with electricity going through.

00:17:29.380 | And what myelin does, by insulating the outside,

00:17:34.380 | I should say there are tracts of myelin

00:17:36.340 | and pieces of axons that are naked without myelin.

00:17:39.620 | And so by having the insulation,

00:17:41.740 | the electricity, instead of going straight through the cable,

00:17:43.980 | it will jump over a piece of myelin, right,

00:17:47.220 | to the next naked little piece and jump again.

00:17:49.940 | And therefore, that's the idea that you go faster.

00:17:52.700 | And it was always thought that in order to build

00:17:58.700 | a big brain, a big nervous system,

00:18:01.820 | in order to have a nervous system

00:18:04.140 | that can do very complex type of things,

00:18:06.420 | then you need a lot of myelin

00:18:07.820 | because you wanna go fast with this information

00:18:10.820 | from point A to point B.

00:18:13.180 | Well, a few years ago, maybe five years ago

00:18:17.100 | or so, we discovered that some of the most evolved,

00:18:20.660 | which means the newest type of neurons

00:18:23.140 | that we have as non-human primates, as human beings

00:18:26.500 | in the top of our cerebral cortex,

00:18:29.060 | which should be the neurons that do some

00:18:30.860 | of the most complex things that we do,

00:18:33.180 | well, those have axons that have very little myelin.

00:18:37.020 | - Wow.

00:18:38.460 | - And they have very interesting ways

00:18:42.020 | in which they put this myelin on their axons,

00:18:44.380 | you know, a little piece here,

00:18:45.500 | then a long track with no myelin, another chunk there,

00:18:48.580 | and some don't have myelin at all.

00:18:50.500 | So now you have to explain

00:18:53.020 | where we're going with evolution.

00:18:57.860 | And if you think about it,

00:18:59.380 | perhaps as an electrical engineer,

00:19:01.260 | when I looked at it, I initially thought,

00:19:05.900 | and I'm a developmental neurobiologist,

00:19:07.580 | I thought maybe this is what we see now,

00:19:10.780 | but if we give evolution another few million years,

00:19:14.140 | we'll see a lot of myelin on these neurons too.

00:19:16.500 | But I actually think now that that's instead

00:19:18.860 | the future of the brain. - Less myelin.

00:19:21.060 | - Less myelin might allow for more flexibility

00:19:24.700 | on what you do with your axons,

00:19:26.780 | and therefore more complicated

00:19:28.540 | and unpredictable type of functions,

00:19:32.180 | which is also a bit mind-blowing.

00:19:34.300 | - Well, so it seems like it's controlling

00:19:36.580 | the timing of the signal,

00:19:38.500 | so in the timing, you can encode a lot of information.

00:19:42.940 | - Yeah.

00:19:43.780 | - So the brain-

00:19:44.700 | - The timing, the chemistry of that little piece of axon,

00:19:48.620 | perhaps it's a dynamic process where the myelin can move.

00:19:52.180 | Now you see how many layers of variability you can add,

00:19:57.180 | and that's actually really good

00:19:58.980 | if you're trying to come up with a new function

00:20:02.340 | or a new capability or something unpredictable in a way.

00:20:06.620 | - So we're gonna jump around a little bit,

00:20:08.260 | but the old question of how much is nature

00:20:12.900 | and how much is nurture,

00:20:14.580 | in terms of this incredible thing

00:20:17.380 | after the development is over,

00:20:19.060 | we seem to be kind of somewhat smart, intelligent,

00:20:25.300 | cognition, consciousness, all of these things

00:20:28.340 | are just incredible ability to reason and so on, emerge.

00:20:32.100 | In your sense, how much is in the hardware, in the nature,

00:20:36.020 | and how much is in the nurture,

00:20:39.140 | is learned through with our parents,

00:20:41.100 | through interacting with the environment and so on?

00:20:42.540 | - It's really both, right?

00:20:43.820 | If you think about it,

00:20:45.060 | so we are born with a brain as babies

00:20:48.060 | that has most of his cells and most of his structures,

00:20:53.060 | and that will take a few years to grow,

00:20:57.940 | to add more, to be better,

00:21:00.660 | but really then we have this 20 years

00:21:04.140 | of interacting with the environment around us.

00:21:07.060 | And so what that brain that was so perfectly built

00:21:10.820 | or imperfectly built due to our genetic cues

00:21:15.820 | will then be used to incorporate the environment

00:21:20.180 | in its farther maturation and development.

00:21:22.740 | And so your experiences do shape your brain.

00:21:26.980 | I mean, we know that,

00:21:27.900 | like if you and I may have had a different childhood

00:21:31.940 | or a different, we have been going to different schools,

00:21:35.060 | we have been learning different things,

00:21:36.460 | and our brain is a little bit different because of that,

00:21:38.780 | we behave differently because of that.

00:21:41.140 | And so, especially postnatally,

00:21:44.020 | experience is extremely important.

00:21:46.020 | We are born with a plastic brain.

00:21:48.780 | What that means is a brain that is able to change

00:21:51.460 | in response to stimuli.

00:21:54.260 | They can be sensory.

00:21:56.340 | So perhaps some of the most illuminating studies

00:22:01.020 | that were done were studies

00:22:02.500 | in which the sensory organs were not working, right?

00:22:06.740 | Like if you are born with eyes that don't work,

00:22:09.540 | then your very brain, the piece of the brain

00:22:12.540 | that normally would process vision,

00:22:14.620 | the visual cortex, develops postnatally differently,

00:22:19.620 | and it might be used to do something different, right?

00:22:23.500 | So that's the most extreme.

00:22:25.580 | - The plasticity of the brain, I guess,

00:22:27.420 | is the magic hardware that it,

00:22:29.420 | and then its flexibility in all forms

00:22:32.900 | is what enables the learning postnatally.

00:22:36.260 | Can you talk about organoids?

00:22:39.220 | What are they? - Yes.

00:22:40.860 | - And how can you use them to help us understand the brain

00:22:44.300 | and the development of the brain?

00:22:45.700 | - This is very, very important.

00:22:47.300 | So the first thing I'd like to say,

00:22:49.860 | and please skip this in the video.

00:22:51.500 | (laughing)

00:22:52.660 | The first thing I'd like to say is that an organoid,

00:22:56.020 | a brain organoid, is not the same as a brain, okay?

00:23:00.020 | It's a fundamental distinction.

00:23:03.620 | It's a system, a cellular system,

00:23:08.540 | that one can develop in the culture dish,

00:23:12.140 | starting from stem cells,

00:23:14.100 | that will mimic some aspects

00:23:17.140 | of the development of the brain, but not all of it.

00:23:21.340 | They are very small.

00:23:23.100 | Maximum, they become about four to five millimeters

00:23:26.420 | in diameters.

00:23:27.860 | They are much simpler than our brain, of course,

00:23:33.380 | but yet they are the only system

00:23:36.460 | where we can literally watch a process

00:23:39.500 | of human brain development unfold.

00:23:42.380 | And by watch, I mean study it.

00:23:45.060 | Remember when I told you that we can't understand

00:23:47.980 | everything about development in our own brain

00:23:49.980 | by studying a mouse?

00:23:51.460 | Well, we can study the actual process of development

00:23:54.100 | of the human brain because it all happens in utero,

00:23:56.220 | so we will never have access to that process, ever.

00:24:00.300 | And therefore, this is our next best thing,

00:24:04.220 | like a bunch of stem cells that can be coaxed

00:24:08.300 | into starting a process of neural tube formation.

00:24:11.620 | Remember that tube that is made by the embryo, Leon?

00:24:14.580 | And from there, a lot of the cell types

00:24:17.060 | that are present within the brain,

00:24:20.620 | and you can simply watch it and study it,

00:24:24.900 | but you can also think about diseases

00:24:28.580 | where development of the brain

00:24:30.780 | does not proceed normally, right, properly.

00:24:34.100 | Think about neurodevelopmental diseases

00:24:35.820 | that are many, many different types.

00:24:38.220 | Think about autism spectrum disorders

00:24:40.100 | that are also many different types of autism.

00:24:42.540 | So there, you could take a stem cell,

00:24:45.220 | which really means either a sample of blood

00:24:47.460 | or a sample of skin from the patient,

00:24:50.860 | make a stem cell, and then with that stem cell,

00:24:54.300 | watch a process of formation of a brain organoid

00:24:57.380 | of that person, with that genetics,

00:25:00.540 | with that genetic code in it,

00:25:02.180 | and you can ask, what is this genetic code doing

00:25:05.780 | to some aspects of development of the brain?

00:25:08.740 | And for the first time, you may come to solutions

00:25:11.980 | like what cells are involved in autism, right?

00:25:15.980 | - So many questions around this.

00:25:17.300 | So if you take this human stem cell

00:25:20.460 | for that particular person with that genetic code,

00:25:23.020 | and you try to build an organoid,

00:25:26.500 | how often will it look similar?

00:25:28.820 | What's the-- - Yeah.

00:25:31.100 | - Yeah, so-- - Reproducibility.

00:25:33.260 | - Yes, or how much variability is the flip side of that.

00:25:36.620 | - Yeah, so there is much more variability

00:25:40.260 | in building organoids than there is in building brain.

00:25:44.500 | It's really true that the majority of us,

00:25:47.260 | when we are born as babies,

00:25:49.540 | our brains look a lot like each other.

00:25:52.420 | This is the magic that the embryo does,

00:25:54.860 | where it builds a brain in the context of a body,

00:25:57.620 | and there is very little variability there.

00:26:01.220 | There is disease, of course,

00:26:02.260 | but in general, a little variability.

00:26:03.940 | When you build an organoid,

00:26:05.540 | we don't have the full code for how this is done.

00:26:09.460 | And so in part, the organoid somewhat builds itself,

00:26:13.380 | because there are some structures of the brain

00:26:15.500 | that the cells know how to make.

00:26:17.180 | And another part comes from the investigator,

00:26:21.780 | the scientist, adding to the media factors

00:26:26.100 | that we know in the mouse, for example,

00:26:27.940 | would foster a certain step of development.

00:26:30.660 | But it's very limited.

00:26:33.140 | And so as a result,

00:26:36.060 | the kind of product you get in the end

00:26:38.100 | is much more reductionist,

00:26:39.620 | is much more simple than what you get in vivo.

00:26:42.580 | It mimics early events of development as of today,

00:26:46.100 | and it doesn't build very complex type of anatomy

00:26:49.020 | and structure, does not as of today.

00:26:51.700 | Which happens instead in vivo.

00:26:54.860 | And also the variability that you see

00:26:59.060 | one organoid to the next

00:27:01.380 | tends to be higher than when you compare

00:27:03.580 | an embryo to the next.

00:27:05.500 | - So, okay, then the next question is,

00:27:07.340 | how hard and maybe another flip side of that,

00:27:10.380 | expensive is it to go from one stem cell to an organoid?

00:27:14.900 | How many can you build in a life,

00:27:16.700 | 'cause it sounds very complicated.

00:27:18.420 | - It's work, definitely, and it's money, definitely.

00:27:23.420 | But you can really grow

00:27:26.740 | a very high number of these organoids.

00:27:29.820 | You know, can go, perhaps,

00:27:31.580 | I told you the maximum they become

00:27:33.100 | about five millimeters in diameter.

00:27:34.580 | - Yeah, which is how many cells, sorry to ask.

00:27:35.420 | - So this is about the size of a tiny, tiny, you know,

00:27:39.180 | raisin. - Yeah.

00:27:40.740 | - Or perhaps the seed of an apple.

00:27:43.180 | And so you can grow 50 to 100 of those

00:27:47.500 | inside one big bioreactors,

00:27:50.300 | which are these flasks where the media

00:27:52.260 | provides nutrients for the organoids.

00:27:55.500 | So the problem is not to grow more or less of them.

00:28:00.500 | It's really to figure out how to grow them in a way

00:28:06.500 | that they are more and more reproducible,

00:28:08.420 | for example, organoid to organoid,

00:28:09.980 | so they can be used to study a biological process.

00:28:13.220 | Because if you have too much variability,

00:28:15.620 | then you never know if what you see

00:28:17.140 | is just an exception or really the rule.

00:28:19.580 | - So what does an organoid look like?

00:28:22.060 | Are there different neurons already emerging?

00:28:25.140 | Is there, you know, well, first,

00:28:27.580 | can you tell me what kind of neurons are there?

00:28:29.980 | - Yes.

00:28:30.940 | - Are they sort of all the same?

00:28:35.620 | Are they not all the same?

00:28:37.500 | Is, how much do we understand?

00:28:39.580 | And how much of that variance, if any,

00:28:43.500 | can exist in organoids?

00:28:45.860 | - Yes.

00:28:47.020 | So you could grow,

00:28:49.420 | I told you that the brain has different parts.

00:28:52.500 | So the cerebral cortex is on top,

00:28:54.700 | the top part of the brain,

00:28:56.020 | but there is another region called the striatum

00:28:57.980 | that is below the cortex and so on and so forth.

00:28:59.980 | All of these regions have different types of cells

00:29:03.780 | in the actual brain, okay?

00:29:05.660 | And so scientists have been able to grow organoids

00:29:08.940 | that may mimic some aspects of development

00:29:11.460 | of these different regions of the brain.

00:29:13.940 | And so we are very interested in the cerebral cortex.

00:29:16.460 | - That's the coolest part, right?

00:29:17.780 | - Very cool.

00:29:18.620 | (laughing)

00:29:19.460 | I agree with you.

00:29:20.300 | (laughing)

00:29:21.140 | - Sorry.

00:29:21.980 | - We wouldn't be here talking

00:29:22.820 | if we didn't have a cerebral cortex.

00:29:23.940 | It's also, I like to think,

00:29:25.300 | the part of the brain that really truly makes us human,

00:29:27.700 | the most evolved in recent evolution.

00:29:30.300 | And so in the attempt to make the cerebral cortex,

00:29:33.700 | and by figuring out a way to have these organoids

00:29:37.300 | continue to grow and develop for extended periods of times,

00:29:40.340 | much like it happens in the real embryo,

00:29:42.500 | months and months in culture,

00:29:44.340 | then you can see that many different types

00:29:48.020 | of neurons of the cortex appear.

00:29:50.220 | And at some point, also the astrocytes,

00:29:52.220 | so the glia cells of the cerebral cortex also appear.

00:29:57.220 | - What are these?

00:29:59.020 | - Astrocytes.

00:29:59.860 | - Astrocytes.

00:30:00.700 | - The astrocytes are not neurons,

00:30:02.140 | so they're not nerve cells,

00:30:03.460 | but they play very important roles.

00:30:06.220 | One important role is to support the neuron,

00:30:09.060 | but of course they have much more active type of roles

00:30:11.900 | that are very important, for example,

00:30:13.340 | to make the synapses,

00:30:14.580 | which are the point of contact and communication

00:30:17.700 | between two neurons.

00:30:18.860 | - So all that chemistry fun happens in the synapses

00:30:25.740 | happens because of these cells?

00:30:28.220 | Are they the medium in which--

00:30:29.740 | - Happens because of the interactions.

00:30:32.100 | Happens because you are making the cells,

00:30:34.860 | and they have certain properties,

00:30:36.380 | including the ability to make neurotransmitters,

00:30:40.420 | which are the chemicals that are secreted to the synapses,

00:30:43.380 | including the ability of making these axons grow

00:30:46.540 | with their growth cones and so on and so forth.

00:30:49.260 | And then you have other cells around it

00:30:51.460 | that release chemicals or touch the neurons

00:30:55.260 | or interact with them in different ways

00:30:57.260 | to really foster this perfect process

00:30:59.940 | in this case of synaptogenesis.

00:31:02.540 | And this does happen within organoids.

00:31:05.700 | - Oh, with organoids.

00:31:06.540 | So the mechanical and the chemical stuff happens.

00:31:09.820 | - The connectivity between neurons.

00:31:11.660 | This, in a way, is not surprising

00:31:13.380 | because scientists have been culturing neurons forever.

00:31:18.220 | And when you take a neuron, even a very young one,

00:31:20.820 | and you culture it,

00:31:21.740 | eventually finds another cell or another neuron to talk to,

00:31:25.140 | it will form a synapse.

00:31:27.020 | - Are we talking about mice neurons?

00:31:28.580 | Are we talking about human neurons?

00:31:29.700 | - It doesn't matter, both.

00:31:30.660 | - So you can culture a neuron, like a single neuron,

00:31:33.300 | and give it a little friend, and it starts interacting?

00:31:37.980 | - Yes.

00:31:38.820 | So neurons are able to,

00:31:40.300 | it sounds, it's more simple than what it may sound to you.

00:31:43.580 | Neurons have molecular properties and structural properties

00:31:48.380 | that allow them to really communicate with other cells.

00:31:51.020 | And so if you put not one neuron,

00:31:53.260 | but if you put several neurons together,

00:31:55.220 | chances are that they will form synapses with each other.

00:31:59.460 | - Okay, great.

00:32:01.180 | So an organoid is not a brain.

00:32:03.460 | - No.

00:32:04.300 | (both laughing)

00:32:06.060 | - But there's some, it's able to,

00:32:09.260 | especially what you're talking about,

00:32:10.500 | mimic some properties of the cerebral cortex, for example.

00:32:15.140 | So what can you understand about the brain

00:32:18.020 | by studying an organoid of a cerebral cortex?

00:32:21.100 | - I can literally study

00:32:23.100 | how all this incredible diversity of cell type,

00:32:26.460 | all these many, many different classes of cells,

00:32:29.100 | how are they made?

00:32:30.820 | How do they look like?

00:32:32.540 | What do they need to be made properly?

00:32:34.940 | And what goes wrong if now the genetics of that stem cell

00:32:39.700 | that I used to make the organoid

00:32:41.140 | came from a patient with a neurodevelopmental disease?

00:32:44.300 | Can I actually watch for the very first time

00:32:47.580 | what may have gone wrong years before in this kid

00:32:51.380 | when its own brain was being made?

00:32:53.460 | Think about that loop.

00:32:54.700 | In a way, it's a little tiny rudimentary window

00:32:59.580 | into the past, into the time when that brain in a kid

00:33:05.060 | that had this neurodevelopmental disease was being made.

00:33:08.860 | And I think that's unbelievably powerful

00:33:12.820 | because today we have no idea of what cell types,

00:33:16.740 | we barely know what brain regions

00:33:18.700 | are affected in these diseases.

00:33:20.820 | Now we have an experimental system

00:33:23.660 | that we can study in the lab,

00:33:25.380 | and we can ask, what are the cells affected?

00:33:28.380 | When during development things went wrong?

00:33:31.780 | What are the molecules

00:33:33.100 | among the many, many different molecules

00:33:35.140 | that control brain development?

00:33:36.540 | Which ones are the ones that really messed up here

00:33:39.660 | and we want perhaps to fix?

00:33:42.100 | And what is really the final product?

00:33:44.460 | Is it a less strong kind of circuit and brain?

00:33:48.500 | Is it a brain that lacks a cell type?

00:33:50.460 | Is it a, what is it?

00:33:51.980 | Because then we can think about treatment

00:33:54.900 | and care for these patients that is informed

00:33:59.300 | rather than just based on current diagnostics.

00:34:02.020 | - So how hard is it to detect

00:34:04.580 | through the developmental process?

00:34:06.340 | It's a super exciting tool

00:34:09.420 | to see how different conditions develop.

00:34:14.020 | How hard is it to detect that, wait a minute,

00:34:17.660 | this is abnormal development?

00:34:20.820 | - Yeah.

00:34:21.660 | - How much signal is there?

00:34:24.860 | How much of it is it a mess?

00:34:26.580 | - 'Cause things can go wrong at multiple levels, right?

00:34:29.540 | You could have a cell that is born and built

00:34:34.380 | but then doesn't work properly

00:34:36.300 | or a cell that is not even born

00:34:38.380 | or a cell that doesn't interact

00:34:39.660 | with other cells differently and so on and so forth.

00:34:42.180 | So today we have technology

00:34:44.460 | that we did not have even five years ago

00:34:47.820 | that allows us to look, for example,

00:34:49.860 | at the molecular picture of a cell,

00:34:52.180 | of a single cell in a sea of cells with high precision.

00:34:56.700 | And so that molecular information

00:34:58.900 | where you compare many, many single cells

00:35:01.820 | for the genes that they produce

00:35:03.700 | between a control individual

00:35:06.220 | and an individual with a neurodevelopmental disease,

00:35:10.180 | that may tell you what is different molecularly.

00:35:13.820 | Or you could see that some cells are not even made,

00:35:18.620 | for example, or that the process of maturation

00:35:20.820 | of the cells may be wrong.

00:35:22.660 | There are many different levels here

00:35:26.660 | and we can study the cells at the molecular level,

00:35:29.620 | but also we can use the organoids to ask questions

00:35:33.420 | about the properties of the neurons,

00:35:35.380 | the functional properties,

00:35:37.420 | how they communicate with each other,

00:35:38.980 | how they respond to a stimulus and so on and so forth.

00:35:41.420 | And we may get at abnormalities there, right?

00:35:46.420 | - Detect those.

00:35:47.540 | So how early is this work in a,

00:35:50.660 | maybe in the history of science?

00:35:54.340 | (laughing)

00:35:55.180 | - That's an easy question.

00:35:57.180 | - I mean, like, so if you were to,

00:35:59.820 | if you and I time travel a thousand years into the future,

00:36:04.820 | organoids seem to be,

00:36:06.980 | maybe I'm romanticizing the notion,

00:36:09.980 | but you're building not a brain,

00:36:12.820 | but something that has properties of a brain.

00:36:15.740 | So it feels like you might be getting close to,

00:36:19.060 | in the building process, to build this, to understand.

00:36:23.300 | So how far are we in this understanding

00:36:28.300 | process of development?

00:36:30.300 | - A thousand years from now, it's a long time from now.

00:36:34.300 | So if this planet is still gonna be here

00:36:36.500 | a thousand years from now.

00:36:38.220 | - So I mean, if, you know, like they write a book,

00:36:42.060 | obviously there'll be a chapter about you.

00:36:44.020 | - Let's write the science fiction book today.

00:36:47.340 | - Yeah, today.

00:36:48.180 | I mean, I guess where we really understood

00:36:50.820 | very little about the brain a century ago.

00:36:53.100 | I was a big fan in high school of reading Freud and so on.

00:36:57.260 | Still am of psychiatry.

00:36:58.740 | I would say we still understand very little

00:37:01.460 | about the functional aspect of just,

00:37:03.700 | but how in the history of understanding

00:37:07.780 | the biology of the brain, the development,

00:37:09.660 | how far are we along?

00:37:11.260 | - It's a very good question.

00:37:12.980 | And so this is just, of course, my opinion.

00:37:15.540 | I think that we did not have technology,

00:37:19.740 | even 10 years ago or 20, certainly not 20 years ago,

00:37:23.180 | to even think about experimentally investigating

00:37:27.780 | the development of the human brain.

00:37:30.180 | So we've done a lot of work in science

00:37:32.220 | to study the brain or many other organisms.

00:37:35.500 | Now we have some technologies which I'll spell out

00:37:39.620 | that allow us to actually look at the real thing

00:37:43.140 | and look at the brain, at the human brain.

00:37:45.060 | So what are these technologies?

00:37:46.900 | There has been huge progress in stem cell biology.

00:37:50.500 | The moment someone figured out how to turn a skin cell

00:37:54.140 | into an embryonic stem cell, basically,

00:37:57.820 | and that how that embryonic stem cell

00:38:00.220 | could begin a process of development again

00:38:02.540 | to, for example, make a brain,

00:38:04.060 | there was a huge advance.

00:38:06.100 | And in fact, there was a Nobel Prize for that.

00:38:08.220 | That started the field really of using stem cells

00:38:12.380 | to build organs.

00:38:14.260 | Now we can build on all the knowledge of development

00:38:17.060 | that we build over the many, many, many years

00:38:18.580 | to say, how do we make the stem cells

00:38:20.740 | now make more and more complex aspects of development

00:38:23.340 | of the human brain?

00:38:24.420 | So this field is young, the field of brain organoids,

00:38:28.500 | but it's moving faster.

00:38:30.140 | And it's moving fast in a very serious way

00:38:32.580 | that is rooted in labs with the right ethical framework

00:38:35.980 | and really building on solid science

00:38:40.740 | for what reality is and what is not.

00:38:43.540 | And, but it will go faster

00:38:46.100 | and it will be more and more powerful.

00:38:49.100 | We also have technology that allows us

00:38:51.460 | to basically study the properties of single cells

00:38:54.620 | across many, many millions of single cells,

00:38:59.180 | which we didn't have perhaps five years ago.

00:39:02.140 | So now with that, even an organoid

00:39:04.780 | that has millions of cells can be profiled in a way,

00:39:08.420 | looked at with very, very high resolution,

00:39:11.260 | the single cell level to really understand what is going on.

00:39:14.900 | And you could do it in multiple stages of development

00:39:17.460 | and you can build your hypothesis and so on and so forth.

00:39:20.060 | So it's not gonna be a thousand years.

00:39:22.540 | It's gonna be a shorter amount of time.

00:39:25.180 | And I see these as sort of an exponential growth

00:39:29.420 | of this field enabled by these technologies

00:39:33.500 | that we didn't have before.

00:39:34.980 | And so we're gonna see something transformative

00:39:36.940 | that we didn't see at all in the prior thousand years.

00:39:41.860 | - So I apologize for the crazy sci-fi questions,

00:39:44.620 | but the developmental process

00:39:47.420 | is fascinating to watch and study,

00:39:50.180 | but how far are we away from

00:39:53.340 | and maybe how difficult is it to build,

00:39:57.220 | not just an organoid, but a human brain?

00:39:59.660 | - Okay. - From a stem cell.

00:40:02.260 | - Yeah.

00:40:03.100 | First of all, that's not the goal

00:40:05.620 | for the majority of the serious scientists

00:40:07.660 | that work on this,

00:40:09.380 | because you don't have to build the whole human brain

00:40:14.140 | to make this model useful

00:40:16.060 | for understanding how the brain develops

00:40:17.980 | or understanding disease.

00:40:20.420 | You don't have to build the whole thing.

00:40:22.380 | - So let me just comment on that.

00:40:24.140 | It's fascinating.

00:40:25.140 | It shows to me the difference between you and I

00:40:29.140 | is you're actually trying to understand

00:40:31.780 | the beauty of the human brain

00:40:33.380 | and to use it to really help

00:40:35.500 | thousands or millions of people with disease and so on.

00:40:37.820 | Right.

00:40:38.820 | From an artificial intelligence perspective,

00:40:41.460 | we're trying to build systems that we can put in robots

00:40:45.580 | and try to create systems that have echoes

00:40:49.100 | of the intelligence about reasoning about the world,

00:40:52.380 | navigating the world.

00:40:53.580 | It's different objectives, I think.

00:40:55.980 | - Yeah, that's very much science fiction.

00:40:57.540 | - Science fiction.

00:40:58.700 | But we operate in science fiction a little bit.

00:41:00.500 | So on that point of building a brain,

00:41:03.460 | even though that is not the focus or interest

00:41:05.820 | perhaps of the community, how difficult is it?

00:41:08.540 | Is it truly science fiction at this point?

00:41:11.220 | - I think the field will progress, like I said,

00:41:13.980 | and that the system will be more and more complex in a way.

00:41:18.740 | But there are properties that emerge from the human brain

00:41:23.740 | that have to do with the mind,

00:41:25.420 | that may have to do with consciousness,

00:41:26.820 | may have to do with intelligence or whatever,

00:41:29.860 | that we really don't understand

00:41:31.980 | even how they can emerge from an actual real brain.

00:41:35.580 | And therefore we can now measure or study in an organoid.

00:41:39.140 | So I think that this field, many, many years from now,

00:41:43.020 | may lead to the building of better neural circuits

00:41:47.020 | that really are built out of understanding

00:41:50.300 | of how this process really works.

00:41:52.260 | And it's hard to predict how complex this really will be.

00:41:57.020 | I really don't think we're so far from,

00:42:00.220 | it makes me laugh really, it's really that far

00:42:02.620 | from building the human brain,

00:42:05.180 | but you're gonna be building something

00:42:07.820 | that is always a bad version of it,

00:42:11.660 | but that may have really powerful properties

00:42:14.860 | and might be able to respond to stimuli

00:42:18.580 | or be used in certain context.

00:42:21.740 | And this is why I really think

00:42:23.740 | that there is no other way to do this science,

00:42:25.820 | but within the right ethical framework,

00:42:28.260 | because where you're going with this is also,

00:42:30.660 | we can talk about science fiction and write that book

00:42:34.100 | and we could today,

00:42:36.620 | but this work happens in a specific ethical framework

00:42:41.580 | that we don't decide just as scientists,

00:42:43.220 | but also as a society.

00:42:44.940 | - So the ethical framework here is a fascinating one,

00:42:48.580 | is a complicated one.

00:42:49.780 | - Yes.

00:42:51.180 | - Do you have a sense, a grasp

00:42:53.340 | of how we think about ethically of building organoids

00:42:58.340 | from human stem cells to understand the brain?

00:43:04.180 | It seems like a tool for helping

00:43:07.540 | potentially millions of people cure diseases

00:43:11.100 | or at least start the cure by understanding it,

00:43:14.980 | but is there more, is there gray areas

00:43:17.860 | that we have to think about ethically?

00:43:22.420 | - Absolutely, we must think about that.

00:43:25.620 | Every discussion about the ethics of this

00:43:29.620 | needs to be based on actual data

00:43:32.700 | from the models that we have today

00:43:34.500 | and from the ones that we will have tomorrow.

00:43:36.340 | So it's a continuous conversation,

00:43:37.860 | it's not something that you decide now.

00:43:39.900 | Today, there is no issue really,

00:43:42.060 | very simple models that clearly can help you in many ways

00:43:47.060 | without much think about,

00:43:49.940 | but tomorrow we need to have another conversation

00:43:52.220 | and so on and so forth.

00:43:53.060 | And so the way we do this is to actually

00:43:55.980 | really bring together constantly a group of people

00:43:58.940 | that are not only scientists, but also bioethicists,

00:44:01.860 | the lawyers, philosophers, psychologists,

00:44:04.140 | and so on and so forth,

00:44:06.700 | to decide as a society really,

00:44:10.780 | what we should and what we should not do.

00:44:15.260 | So that's the way to think about the ethics.

00:44:17.580 | Now, I also think though, that as a scientist,

00:44:21.220 | I have a moral responsibility.

00:44:23.740 | So if you think about how transformative it could be

00:44:28.740 | for understanding and curing a neuropsychiatric disease,

00:44:34.100 | to be able to actually watch and study

00:44:37.300 | and treat with drugs the very brain

00:44:40.620 | of the patient that you are trying to study.

00:44:43.220 | How transformative at this moment in time, this could be.

00:44:47.220 | We couldn't do it five years ago, we could do it now.

00:44:49.980 | Right?

00:44:50.820 | - Taking a stem cell of a particular patient.

00:44:52.940 | - Patient and make an organoid for a simple

00:44:56.100 | and different from the human brain,

00:44:58.860 | it still is his process of brain development

00:45:02.140 | with his or her genetics.

00:45:04.700 | And we could understand perhaps what is going wrong.

00:45:08.260 | Perhaps we could use as a platform, as a cellular platform

00:45:10.980 | to screen for drugs, to fix a process

00:45:13.580 | and so on and so forth, right?

00:45:15.220 | So we could do it now, we couldn't do it five years ago.

00:45:18.780 | Should we not do it?

00:45:20.460 | - What is the downside of doing it?

00:45:24.740 | - I don't see a downside at this very moment.

00:45:27.300 | - If we invited a lot of people,

00:45:30.020 | I'm sure there would be somebody who would argue against it.

00:45:33.420 | What would be the devil's advocate argument?

00:45:37.580 | - So it's exactly perhaps what you alluded at

00:45:42.980 | with your question, that you are making it,

00:45:47.140 | enabling some process of formation of the brain

00:45:51.660 | that could be misused at some point,

00:45:54.420 | or that could be showing properties

00:45:59.060 | that ethically we don't wanna see in a tissue.

00:46:03.980 | So today, I repeat, today, this is not an issue.

00:46:07.740 | And so you just gain dramatically from the science

00:46:11.260 | without because the system is so simple

00:46:14.340 | and so different in a way from the actual brain.

00:46:17.820 | But because it is the brain,

00:46:19.980 | we have an obligation to really consider all of this, right?

00:46:23.980 | And again, it's a balanced conversation

00:46:27.180 | where we should put disease and betterment of humanity

00:46:30.380 | also on that plate.

00:46:32.460 | - What do you think, at least historically,

00:46:35.420 | there was some politicization of embryonic stem cells

00:46:40.420 | or stem cell research.

00:46:45.420 | Do you still see that out there?

00:46:49.140 | Is that still a force that we have to think about,

00:46:53.540 | especially in this larger discourse

00:46:55.580 | that we're having about the role of science

00:46:57.540 | in at least American society?

00:47:00.580 | - Yeah, this is a very good question.

00:47:03.460 | It's very, very important.

00:47:04.980 | I see a very central role for scientists

00:47:08.460 | to inform decisions about what we should

00:47:12.020 | or should not do in society.

00:47:14.420 | And this is because the scientists

00:47:16.380 | have the firsthand look and understanding

00:47:20.420 | of really the work that they are doing.

00:47:23.500 | And again, this varies

00:47:25.220 | depending on what we're talking about here.

00:47:27.460 | So now we're talking about brain organoids.

00:47:30.780 | I think that the scientists need to be part

00:47:33.780 | of that conversation about what is,

00:47:36.500 | will be allowed in the future

00:47:37.980 | or not allowed in the future to do with the system.

00:47:40.780 | And I think that is very, very important

00:47:43.340 | because they bring reality of data to the conversation.

00:47:47.840 | And so they should have a voice.

00:47:51.660 | - So data should have a voice.

00:47:53.340 | - Data needs to have a voice because not only data,

00:47:57.300 | we should also be good at communicating

00:48:01.140 | with non-scientists the data.

00:48:04.220 | So there has been often time,

00:48:06.780 | there is a lot of discussion and excitement

00:48:11.780 | and fights about certain topics

00:48:16.280 | just because of the way they are described.

00:48:19.260 | I'll give you an example.

00:48:20.980 | If I called the same cellular system

00:48:23.340 | we just talked about a brain organoid,

00:48:27.060 | or if I called it a human mini brain,

00:48:30.300 | your reaction is gonna be very different to this.

00:48:34.580 | And so the way the systems are described,

00:48:37.740 | I mean, we and journalists alike need to be a bit careful

00:48:42.500 | that this debate is a real debate and informed by real data.

00:48:46.020 | That's all I'm asking.

00:48:47.940 | - And yeah, the language matters here.

00:48:49.580 | So I work on autonomous vehicles

00:48:51.260 | and there the use of language

00:48:53.020 | could drastically change the interpretation

00:48:56.420 | and the way people feel about

00:48:58.460 | what is the right way to proceed forward.

00:49:01.480 | You are, as I've seen from a presentation, you're a parent.

00:49:06.220 | I saw you show a couple of pictures of your son.

00:49:09.820 | Is it just the one?

00:49:11.380 | - Two.

00:49:12.220 | - Two. - Son and a daughter.

00:49:13.260 | - Son and a daughter.

00:49:14.140 | So what have you learned from the human brain

00:49:17.300 | by raising two of them?

00:49:20.060 | - More than I could ever learn in a lab.

00:49:22.660 | (laughs)

00:49:24.460 | What have I learned?

00:49:26.820 | I've learned that children really have

00:49:28.620 | these amazing plastic minds, right?

00:49:31.540 | That we have a responsibility to foster their growth

00:49:36.540 | in good, healthy ways that keep them curious,

00:49:40.780 | that keep some adventures,

00:49:42.380 | that doesn't raise them in fear of things.

00:49:45.760 | But also respecting who they are,

00:49:48.940 | which is in part coming from the genetics we talked about.

00:49:52.340 | My children are very different from each other

00:49:54.500 | despite the fact that they're the product

00:49:56.020 | of the same two parents.

00:49:57.800 | I also learned that what you do for them comes back to you.

00:50:04.300 | If you're a good parent, you're gonna,

00:50:07.620 | most of the time, have perhaps a decent kids at the end.

00:50:12.180 | - So what do you think, just a quick comment,

00:50:13.740 | what do you think is the source of that difference?

00:50:17.760 | That's often the surprising thing for parents.

00:50:20.460 | - Yeah.

00:50:21.300 | - Is that they can't believe that our kids,

00:50:25.580 | they're so different, yet they came from the same parents.

00:50:28.020 | - Well, they are genetically different.

00:50:29.620 | Even they came from the same two parents

00:50:31.900 | because the mixing of gametes,

00:50:33.660 | and we know this genetics,

00:50:35.700 | creates every time a genetically different individual

00:50:39.780 | which will have a specific mix of genes

00:50:43.740 | that is a different mix every time from the two parents.

00:50:46.540 | And so they're not twins, they are genetically different.

00:50:51.540 | - Even just that little bit of variation.

00:50:55.340 | 'Cause you said really from a biological perspective,

00:50:58.340 | the brains look pretty similar.

00:51:00.580 | - Well, so let me clarify that.

00:51:02.420 | So the genetics you have, the genes that you have

00:51:05.420 | that play that beautiful orchestrated symphony

00:51:08.700 | of development, different genes

00:51:12.040 | will play it slightly differently.

00:51:13.900 | It's like playing the same piece of music,

00:51:16.100 | but with a different orchestra

00:51:17.980 | and a different director, right?

00:51:19.980 | The music will not come out,

00:51:21.460 | it will be still a piece by the same author,

00:51:25.420 | but it will come out differently

00:51:27.060 | if it's played by the high school orchestra

00:51:28.940 | instead of the-

00:51:29.780 | (laughing)

00:51:31.860 | Instead of La Scala in Milan.

00:51:33.480 | And so you are born superficially with the same brain.

00:51:39.220 | It has the same cell types,

00:51:41.220 | similar patterns of connectivity,

00:51:43.460 | but the properties of the cells

00:51:45.220 | and how the cells will then react to the environment

00:51:47.620 | as you experience your world

00:51:49.580 | will be also shaped by who genetically you are.

00:51:53.740 | Speaking just as a parent,

00:51:55.160 | this is not something that comes from my work.

00:51:56.940 | I think you can tell at birth

00:51:58.860 | that these kids are different,

00:52:01.180 | that they have a different personality in a way, right?

00:52:04.600 | So both is needed, the genetics

00:52:08.780 | as well as the nurturing afterwards.

00:52:10.700 | - So you are one human with a brain,

00:52:15.500 | sort of living through the whole mess of it,

00:52:17.700 | the human condition full of love,

00:52:19.900 | maybe fear, ultimately mortal.

00:52:23.420 | How has studying the brain changed the way you see yourself

00:52:27.700 | when you look in the mirror,

00:52:28.620 | when you think about your life,

00:52:30.500 | the fears, the love,

00:52:32.420 | when you see your own life, your own mortality?

00:52:34.660 | - Yeah, that's a very good question.

00:52:37.380 | It's almost impossible to dissociate sometime for me.

00:52:43.540 | Some of the things we do

00:52:45.340 | or some of the things that other people do from,

00:52:48.780 | oh, that's because that part of the brain

00:52:51.660 | is working in a certain way.

00:52:54.660 | Or thinking about a teenager,

00:52:58.380 | going through teenage years

00:53:01.140 | and being at times funny in the way they think.

00:53:04.060 | And impossible for me not to think

00:53:06.340 | it's because they're going through this period of time

00:53:09.920 | called critical period of plasticity

00:53:13.300 | where their synapses are being eliminated here and there

00:53:16.420 | and they're just confused.

00:53:17.780 | And so from that comes perhaps a different take

00:53:22.300 | on that behavior or maybe I can justify it scientifically

00:53:27.300 | in some sort of way.

00:53:30.100 | I also look at humanity in general

00:53:32.260 | and I am amazed by what we can do

00:53:37.060 | and the kind of ideas that we can come up with.

00:53:39.940 | And I cannot stop thinking about

00:53:42.820 | how the brain is continuing to evolve.

00:53:46.420 | I don't know if you do this,

00:53:47.320 | but I think about the next brain sometimes.

00:53:49.680 | Where are we going with this?

00:53:51.060 | Like what are the features of this brain

00:53:53.860 | that evolution is really playing with

00:53:57.860 | to get us in the future the new brain?

00:54:02.500 | It's not over, right?

00:54:04.220 | It's a work in progress.

00:54:07.140 | - So let me just a quick comment on that.

00:54:09.220 | Do you think there's a lot of fascination

00:54:14.220 | and hope for artificial intelligence

00:54:16.220 | of creating artificial brains?

00:54:17.940 | You said the next brain.

00:54:20.300 | When you imagine over a period of a thousand years,

00:54:23.560 | the evolution of the human brain,

00:54:25.700 | do you sometimes envisioning that future

00:54:28.900 | see an artificial one?

00:54:31.420 | Artificial intelligence as it is hoped by many,

00:54:34.260 | not hoped, thought by many people

00:54:36.780 | would be actually the next evolutionary step

00:54:39.080 | in the development of humans.

00:54:40.620 | - Yeah, I think in a way that will happen, right?

00:54:45.420 | It's almost like a part of the way we evolve.

00:54:48.700 | We evolve in the world that we created,

00:54:51.340 | that we interact with,

00:54:53.220 | that shape us as we grow up and so on and so forth.

00:54:56.660 | Sometime I think about something that may sound silly,

00:55:01.080 | but think about the use of cell phones.

00:55:04.660 | Part of me thinks that somehow in their brain

00:55:07.220 | there will be a region of the cortex

00:55:09.140 | that is attuned to that tool.

00:55:13.720 | And this comes from a lot of studies in modern organisms

00:55:18.720 | where really the cortex especially adapts

00:55:22.800 | to the kind of things you have to do.

00:55:24.260 | So if we need to move our fingers in a very specific way,

00:55:28.620 | we have a part of our cortex that allows us

00:55:30.760 | to do this kind of very precise movement.

00:55:33.060 | An owl that has to see very, very far away

00:55:37.000 | with big eyes, the visual cortex, very big.

00:55:39.960 | The brain attunes to your environment.

00:55:43.280 | So the brain will attune to the technologies

00:55:47.600 | that we will have and will be shaped by it.

00:55:51.200 | - So the cortex very well may be-

00:55:52.920 | - Will be shaped by it.

00:55:54.640 | - In artificial intelligence, it may merge with it,

00:55:57.360 | it may get an envelope it and adjust to it.

00:56:01.240 | - Even if it's not a merge of the kind of,

00:56:04.200 | oh, let's have a synthetic element together

00:56:06.960 | with a biological one.

00:56:08.780 | The very space around us, the fact, for example,

00:56:11.820 | think about we put on some goggles of virtual reality

00:56:15.240 | and we physically are surfing the ocean, right?

00:56:18.820 | Like I've done it and you have all these emotions

00:56:21.760 | that come to you.

00:56:22.760 | Your brain placed you in that reality

00:56:27.160 | and it was able to do it like that

00:56:29.680 | just by putting the goggles on.

00:56:31.160 | It didn't take thousands of years of adapting to this.

00:56:36.040 | The brain is plastic, so adapts to new technology.

00:56:39.320 | So you could do it from the outside

00:56:41.800 | by simply hijacking some sensory capacities that we have.

00:56:46.800 | So clearly over recent evolution,

00:56:51.600 | the cerebral cortex has been a part of the brain

00:56:54.000 | that has known the most evolution.

00:56:56.000 | So we have put a lot of chips on evolving this specific brain

00:57:01.000 | and the evolution of cortex is plasticity.

00:57:06.000 | It's this ability to change in response to things.

00:57:10.320 | So yes, they will integrate, that we want it or not.

00:57:13.820 | - Wow, there's no better way to end it.

00:57:17.840 | Paola, thank you so much for talking to me.

00:57:19.520 | - You're very welcome.

00:57:20.360 | - That was great. - This is very exciting.

00:57:22.400 | (upbeat music)

00:57:24.980 | (upbeat music)

00:57:27.560 | (upbeat music)

00:57:30.140 | (upbeat music)

00:57:32.720 | (upbeat music)

00:57:35.300 | (upbeat music)

00:57:37.880 | [BLANK_AUDIO]

Paola Arlotta: Brain Development from Stem Cell to Organoid | Lex Fridman Podcast #32

Chapters