Human Brain Development - Paola Arlotta, Professor, Harvard Stem Cell Institute

00:00:00.000 | (gentle music)

00:00:02.580 | - Do you think you can maybe talk through

00:00:10.920 | the first few months and then on through the first 20 years

00:00:15.720 | and then for the rest of their lives,

00:00:18.240 | what is the development of the human brain look like?

00:00:21.760 | What are the different stages?

00:00:23.200 | - Yeah, at the beginning you have to build a brain, right?

00:00:27.400 | And the brain is made of cells.

00:00:29.520 | - What's the very beginning?

00:00:30.440 | Which beginning are we talking about?

00:00:32.680 | - In the embryo.

00:00:34.000 | As the embryo is developing in the womb,

00:00:36.680 | in addition to making all of the other tissues

00:00:39.200 | of the embryo, the muscle, the heart, the blood,

00:00:42.740 | the embryo is also building the brain.

00:00:45.640 | And it builds from a very simple structure

00:00:49.160 | called the neural tube,

00:00:50.640 | which is basically nothing but a tube of cells

00:00:53.820 | that spans sort of the length of the embryo

00:00:56.440 | from the head all the way to the tail,

00:00:59.160 | let's say, of the embryo.

00:01:00.580 | And then in human beings, over many months of gestation,

00:01:06.200 | from that neural tube,

00:01:08.680 | which contains stem cell-like cells of the brain,

00:01:13.120 | you will make many, many other building blocks of the brain.

00:01:17.680 | So all of the other cell types,

00:01:20.280 | 'cause there are many, many different types of cells

00:01:22.560 | in the brain that will form specific structures

00:01:26.600 | of the brain.

00:01:27.440 | So you can think about embryonic development of the brain

00:01:30.440 | as just the time in which you are making

00:01:32.280 | the building blocks, the cells.

00:01:35.120 | - Are the stem cells relatively homogeneous, like uniform,

00:01:38.300 | or are they all different type?

00:01:40.000 | - It's a very good question.

00:01:40.840 | It's exactly how it works.

00:01:41.920 | You start with a more homogeneous,

00:01:44.840 | perhaps more multipotent type of stem cell.

00:01:49.800 | - What's multipotent?

00:01:50.640 | - Multipotent means that it has the potential

00:01:54.200 | to make many, many different types of other cells.

00:01:58.040 | And then with time,

00:01:59.480 | these progenitors become more heterogeneous,

00:02:02.080 | which means more diverse.

00:02:03.520 | There are gonna be many different types of the stem cells.

00:02:06.880 | And also, they will give rise to progeny,

00:02:09.440 | to other cells that are not stem cells,

00:02:12.400 | that are specific cells of the brain,

00:02:14.000 | that are very different from the mother stem cell.

00:02:16.760 | And now you think about this process of making cells

00:02:19.500 | from the stem cells over many, many months of development

00:02:22.980 | for humans.

00:02:24.480 | And what you're doing,

00:02:25.320 | you're building the cells that physically make the brain,

00:02:28.880 | and then you arrange them in specific structures

00:02:33.080 | that are present in the final brain.

00:02:36.100 | So you can think about the embryonic development

00:02:39.360 | of the brain as the time where you're building the bricks.

00:02:42.780 | You're putting the bricks together to form buildings,

00:02:46.200 | structures, regions of the brain,

00:02:48.800 | and where you make the connections

00:02:51.020 | between these many different type of cells,

00:02:53.700 | especially nerve cells, neurons, right?

00:02:55.900 | That transmit action potentials and electricity.

00:02:59.920 | - I've heard you also say somewhere,

00:03:01.540 | I think, correct me if I'm wrong,

00:03:02.940 | that the order of the way this builds matters.

00:03:05.800 | - Oh, yes.

00:03:06.720 | If you are an engineer and you think about development,

00:03:10.520 | you can think of it as,

00:03:11.840 | well, I could also take all the cells

00:03:15.640 | and bring them all together into a brain in the end.

00:03:18.620 | But development is much more than that.

00:03:20.980 | So the cells are made in a very specific order

00:03:24.520 | that subserve the final product that you need to get.

00:03:28.040 | And so, for example, all of the nerve cells,

00:03:30.540 | the neurons, are made first,

00:03:32.880 | and all of the supportive cells of the neurons,

00:03:35.040 | like the glia, is made later.

00:03:37.440 | And there is a reason for that,

00:03:39.040 | because they have to assemble together in specific ways.

00:03:42.760 | But you also may say,

00:03:43.600 | well, why don't we just put them all together in the end?

00:03:46.360 | It's because as they develop next to each other,

00:03:49.600 | they influence their own development.

00:03:51.920 | So it's a different thing for a glia

00:03:53.860 | to be made alone in a dish

00:03:56.060 | than a glia cell be made in a developing embryo

00:04:00.020 | with all these other cells around it

00:04:01.980 | that produce all these other signals.

00:04:04.340 | - First of all, that's mind-blowing,

00:04:06.540 | this development process.

00:04:08.460 | From my perspective in artificial intelligence,

00:04:10.380 | you often think of how incredible the final product is,

00:04:14.100 | the final product, the brain.

00:04:15.840 | But you're making me realize that the final product

00:04:19.060 | is just, the beautiful thing

00:04:22.680 | is the actual development process.

00:04:25.100 | Do we know the code that drives that development?

00:04:30.100 | - Yeah.

00:04:32.620 | - Do we have any sense?

00:04:34.500 | - First of all, thank you for saying

00:04:36.420 | that it's really the formation of the brain.

00:04:39.940 | It's really its development,

00:04:41.300 | it's this incredibly choreographed dance

00:04:45.740 | that happens the same way every time

00:04:48.100 | each one of us builds the brain, right?

00:04:51.200 | And that builds an organ that allows us

00:04:53.300 | to do what we're doing today, right?

00:04:55.540 | That is mind-blowing,

00:04:56.980 | and this is why developmental neurobiologists

00:04:59.540 | never get tired of studying that.

00:05:02.500 | Now you're asking about the code.

00:05:04.420 | What drives this?

00:05:05.500 | How is this done?

00:05:07.140 | Well, it's millions of years of evolution,

00:05:10.380 | of really fine-tuning gene expression programs

00:05:13.820 | that allow certain cells to be made at a certain time

00:05:18.100 | and to become a certain cell type,

00:05:22.340 | but also mechanical forces of pressure, bending.

00:05:27.340 | This embryo is not just, it will not stay a tube,

00:05:30.980 | this brain, for very long.

00:05:32.660 | At some point, this tube in the front of the embryo

00:05:35.500 | will expand to make the primordium of the brain, right?

00:05:38.820 | Now the forces that control, that the cells feel,

00:05:43.500 | and this is another beautiful thing,

00:05:45.580 | the very force that they feel,

00:05:47.460 | which is different from a week before or a week ago,

00:05:50.900 | will tell the cell,

00:05:51.740 | "Oh, you're being squished in a certain way.

00:05:54.260 | "Begin to produce these new genes

00:05:57.180 | "because now you are at the corner,

00:05:59.020 | "or you are in a stretch of cells," or whatever it is.

00:06:04.020 | So that mechanical, physical force

00:06:06.660 | shapes the fate of the cell as well.

00:06:10.140 | So it's not only chemical, it's also mechanical.

00:06:12.580 | - Mechanical.

00:06:13.620 | So from my perspective,

00:06:15.140 | biology is this incredibly complex mess, gooey mess.

00:06:20.140 | So you're saying mechanical forces.

00:06:24.100 | - Yes.

00:06:24.940 | - How different is a computer

00:06:28.460 | or any kind of mechanical machine that we humans build

00:06:32.820 | and the biological systems?

00:06:34.500 | - Yeah.

00:06:35.340 | - 'Cause you've worked a lot with biological systems.

00:06:37.340 | - Yes.

00:06:38.180 | - Are they as much of a mess as it seems

00:06:41.380 | from a perspective of a mechanical engineer?

00:06:44.220 | - Yeah.

00:06:45.100 | They are much more prone

00:06:49.060 | to taking alternative routes, right?

00:06:52.340 | So if you,

00:06:53.700 | we go back to printing a brain versus developing a brain.

00:06:58.860 | Of course, if you print a brain,

00:07:01.140 | given that you start with the same building blocks,

00:07:03.700 | the same cells,

00:07:04.620 | you could potentially print it the same way every time.

00:07:09.300 | But that final brain may not work the same way

00:07:13.180 | as a brain built during development does

00:07:15.100 | because the very same building blocks that you're using

00:07:19.380 | developed in a completely different environment, right?

00:07:22.100 | It was not the environment of the brain.

00:07:23.700 | Therefore, they're gonna be different just by definition.

00:07:26.540 | So if you instead use development to build,

00:07:31.140 | let's say a brain organoid,

00:07:33.380 | which maybe we will be talking about in a few minutes.

00:07:35.500 | - For sure.

00:07:36.500 | Those things are fascinating.

00:07:37.620 | - Yes.

00:07:38.460 | So if you use processes of development,

00:07:42.620 | then when you watch it,

00:07:44.020 | you can see that sometimes things can go wrong

00:07:47.100 | in some organoids.

00:07:48.140 | And by wrong, I mean different one organoid from the next.

00:07:51.500 | While if you think about that embryo,

00:07:53.740 | it always goes right.

00:07:55.420 | So this development, for as complex as it is,

00:07:59.580 | every time a baby is born has,

00:08:02.020 | with very few exceptions,

00:08:04.300 | the brain is like the next baby.

00:08:06.820 | But it's not the same if you develop it in a dish.

00:08:11.820 | And first of all, we don't even develop a brain,

00:08:14.460 | you develop something much simpler in the dish.

00:08:16.700 | But there are more options for building things differently,

00:08:20.300 | which really tells you that evolution

00:08:23.580 | has played a really tight game here

00:08:28.580 | for how in the end the brain is built in vivo.

00:08:33.660 | - So just a quick, maybe dumb question,

00:08:35.980 | but it seems like this is not,

00:08:38.940 | the building process is not a dictatorship.

00:08:41.700 | It seems like there's not a centralized,

00:08:43.940 | like high level mechanism that says,

00:08:48.020 | okay, this cell built itself the wrong way,

00:08:50.900 | I'm gonna kill it.

00:08:52.140 | It seems like there's a really strong distributed mechanism.

00:08:56.060 | Is that in your sense?

00:08:58.100 | - There are a lot of possibilities, right?

00:09:01.540 | And if you think about, for example, different species,

00:09:05.700 | building their brain,

00:09:07.380 | each brain is a little bit different.

00:09:09.500 | So the brain of a lizard is very different

00:09:11.660 | from that of a chicken, from that of one of us,

00:09:16.140 | and so on and so forth, and still is a brain,

00:09:18.700 | but it was built differently,

00:09:21.580 | starting from stem cells

00:09:23.940 | that pretty much had the same potential.

00:09:26.660 | But in the end, evolution builds different brains

00:09:30.020 | in different species, because that serves in a way

00:09:33.180 | the purpose of that species

00:09:34.660 | and the wellbeing of that organism.

00:09:36.580 | So there are many possibilities,

00:09:41.340 | but then there is a way,

00:09:43.500 | and you were talking about a code.

00:09:45.460 | Nobody knows what the entire code of development is.

00:09:48.140 | Of course we don't.

00:09:49.260 | We know bits and pieces of very specific aspects

00:09:54.020 | of development of the brain,

00:09:55.140 | what genes are involved to make a certain cell type,

00:09:57.620 | how those two cells interact

00:09:59.180 | to make the next level structure.

00:10:01.020 | That we might know, but the entirety of it,

00:10:03.420 | how it's so well controlled, it's really mind-blowing.

00:10:06.780 | - So in the first two months in the embryo,

00:10:09.740 | or whatever, the first few weeks, months, months.

00:10:13.340 | So yeah, the building blocks are constructed,

00:10:17.740 | the actual, the different regions of the brain,

00:10:20.660 | I guess, and the nervous system.

00:10:23.380 | - Well, this continues way longer

00:10:24.940 | than just the first few months.

00:10:27.100 | So over the very first few months,

00:10:31.060 | you build a lot of these cells,

00:10:32.660 | but then there is continuous building of new cell types

00:10:37.060 | all the way through birth.

00:10:39.060 | And then even postnatally,

00:10:41.060 | I don't know if you've ever heard of myelin.

00:10:44.580 | Myelin is this sort of insulation

00:10:47.300 | that is built around the cables of the neurons

00:10:50.420 | so that the electricity can go really fast from--

00:10:52.820 | - The axons, I guess they're called.

00:10:53.980 | - The axons, they're called axons, exactly.

00:10:56.580 | And so as human beings, we myelinate our cells

00:11:02.580 | postnatally.

00:11:04.900 | A kid, a six-year-old kid has barely started

00:11:09.300 | the process of making the mature oligodendrocytes,

00:11:12.460 | which are the cells that then eventually

00:11:14.220 | will wrap the axons into myelin.

00:11:17.180 | And this will continue, believe it or not,

00:11:19.540 | until we are about 25, 30 years old.

00:11:23.020 | So there is a continuous process of maturation

00:11:25.900 | and tweaking and additions,

00:11:27.220 | and also in response to what we do.

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00:11:48.340 | Thanks for watching.

Human Brain Development - Paola Arlotta, Professor, Harvard Stem Cell Institute | AI Podcast Clips

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