Datasets:

shubhamg2208
/

lexicap

	WEBVTT

	00:00.000 --> 00:03.360
	The following is a conversation with Paola Arlada.

	00:03.360 --> 00:06.400
	She is a professor of stem cell and regenerative biology

	00:06.400 --> 00:09.760
	at Harvard University and is interested in understanding

	00:09.760 --> 00:13.160
	the molecular laws that govern the birth, differentiation,

	00:13.160 --> 00:16.600
	and assembly of the human brain's cerebral cortex.

	00:16.600 --> 00:18.400
	She explores the complexity of the brain

	00:18.400 --> 00:21.000
	by studying and engineering elements

	00:21.000 --> 00:22.880
	of how the brain develops.

	00:22.880 --> 00:25.640
	This was a fascinating conversation to me.

	00:25.640 --> 00:28.560
	It's part of the Artificial Intelligence podcast.

	00:28.560 --> 00:30.600
	If you enjoy it, subscribe on YouTube,

	00:30.600 --> 00:32.360
	give it five stars on iTunes.

	00:32.360 --> 00:35.760
	Support on Patreon or simply connect with me on Twitter

	00:35.760 --> 00:39.960
	at Lex Freedman, spelled F R I D M A N.

	00:39.960 --> 00:43.120
	And I'd like to give a special thank you to Amy Jeffers

	00:43.120 --> 00:45.560
	for her support of the podcast on Patreon.

	00:45.560 --> 00:47.680
	She's an artist and you should definitely check out

	00:47.680 --> 00:52.680
	her Instagram at LoveTruthGood, three beautiful words.

	00:52.720 --> 00:55.640
	Your support means a lot and inspires me

	00:55.640 --> 00:57.720
	to keep the series going.

	00:57.720 --> 01:01.720
	And now here's my conversation with Paola Arlada.

	01:03.120 --> 01:05.320
	You studied the development of the human brain

	01:05.320 --> 01:06.680
	for many years.

	01:06.680 --> 01:10.520
	So let me ask you an out of the box question first.

	01:11.480 --> 01:14.600
	How likely is it that there's intelligent life out there

	01:14.600 --> 01:17.160
	in the universe outside of earth

	01:17.160 --> 01:19.320
	with something like the human brain?

	01:19.320 --> 01:20.760
	So I can put it another way.

	01:20.760 --> 01:24.320
	How unlikely is the human brain?

	01:24.320 --> 01:28.360
	How difficult is it to build a thing

	01:28.360 --> 01:30.400
	through the evolutionary process?

	01:30.400 --> 01:32.520
	Well, it has happened here, right?

	01:32.520 --> 01:33.360
	On this planet.

	01:33.360 --> 01:34.200
	Once, yes.

	01:34.200 --> 01:35.040
	Once.

	01:35.040 --> 01:39.960
	So that simply tells you that it could, of course,

	01:39.960 --> 01:44.120
	happen again, other places is only a matter of probability.

	01:44.120 --> 01:46.600
	What the probability that you would get a brain

	01:46.600 --> 01:51.200
	like the ones that we have, like the human brain.

	01:51.200 --> 01:54.000
	So how difficult is it to make the human brain?

	01:54.000 --> 01:55.400
	It's pretty difficult.

	01:56.480 --> 02:00.960
	But most importantly, I guess we know very little

	02:00.960 --> 02:04.440
	about how this process really happens.

	02:04.440 --> 02:06.320
	And there is a reason for that,

	02:06.320 --> 02:09.160
	actually multiple reasons for that.

	02:09.160 --> 02:13.400
	Most of what we know about how the mammalian brains

	02:13.400 --> 02:15.680
	or the brain of mammals develop,

	02:15.680 --> 02:18.960
	comes from studying in labs other brains,

	02:18.960 --> 02:22.560
	not our own brain, the brain of mice, for example.

	02:22.560 --> 02:25.400
	But if I showed you a picture of a mouse brain

	02:25.400 --> 02:28.400
	and then you put it next to a picture of a human brain,

	02:28.400 --> 02:31.160
	they don't look at all like each other.

	02:31.160 --> 02:33.040
	So they're very different.

	02:33.040 --> 02:36.240
	And therefore, there is a limit to what you can learn

	02:36.240 --> 02:40.560
	about how the human brain is made by studying the mouse brain.

	02:40.560 --> 02:43.320
	There is a huge value in studying the mouse brain.

	02:43.320 --> 02:45.080
	There are many things that we have learned,

	02:45.080 --> 02:46.600
	but it's not the same thing.

	02:46.600 --> 02:49.200
	So in having studied the human brain

	02:49.200 --> 02:51.440
	or through the mouse and through other methodologies

	02:51.440 --> 02:54.760
	that we'll talk about, do you have a sense?

	02:54.760 --> 02:57.560
	I mean, you're one of the experts in the world.

	02:57.560 --> 03:01.160
	How much do you feel you know about the brain?

	03:01.160 --> 03:05.920
	And how often do you find yourself in awe

	03:05.920 --> 03:07.840
	of this mysterious thing?

	03:07.840 --> 03:12.200
	Yeah, you pretty much find yourself in awe all the time.

	03:12.200 --> 03:15.360
	It's an amazing process.

	03:15.360 --> 03:17.960
	It's a process by which,

	03:17.960 --> 03:20.720
	by means that we don't fully understand

	03:20.720 --> 03:23.640
	at the very beginning of embryogenesis,

	03:23.640 --> 03:28.800
	the structure called the neural tube literally self assembles.

	03:28.800 --> 03:30.440
	And it happens in an embryo

	03:30.440 --> 03:33.720
	and it can happen also from stem cells in a dish.

	03:33.720 --> 03:34.960
	Okay.

	03:34.960 --> 03:38.720
	And then from there, these stem cells that are present

	03:38.720 --> 03:41.640
	within the neural tube give rise to all of the thousands

	03:41.640 --> 03:43.440
	and thousands of different cell types

	03:43.440 --> 03:46.560
	that are present in the brain through time, right?

	03:46.560 --> 03:51.760
	With the interesting, very intriguing, interesting observation

	03:51.760 --> 03:56.280
	is that the time that it takes for the human brain to be made,

	03:56.280 --> 04:01.480
	it's human time, meaning that for me and you,

	04:01.480 --> 04:04.560
	it took almost nine months of gestation to build the brain

	04:04.560 --> 04:08.080
	and then another 20 years of learning postnatally

	04:08.080 --> 04:09.360
	to get the brain that we have today

	04:09.360 --> 04:11.360
	that allows us to this conversation.

	04:11.360 --> 04:14.960
	A mouse takes 20 days or so

	04:14.960 --> 04:22.200
	for an embryo to be born and so the brain is built

	04:22.200 --> 04:24.840
	in a much shorter period of time and the beauty of it

	04:24.840 --> 04:27.160
	is that if you take mouse stem cells

	04:27.160 --> 04:29.880
	and you put them in a cultured dish,

	04:29.880 --> 04:34.840
	the brain organoid that you get from a mouse is formed faster

	04:34.840 --> 04:39.120
	that if you took human stem cells and put them in the dish

	04:39.120 --> 04:42.120
	and let them make a human brain organoid.

	04:42.120 --> 04:45.560
	So the very developmental process is...

	04:45.560 --> 04:49.000
	Controlled by the speed of the species.

	04:49.000 --> 04:54.080
	Which means it's by its own purpose, it's not accidental

	04:54.080 --> 04:59.800
	or there is something in that temporal dynamic to that development.

	04:59.800 --> 05:04.000
	Exactly, that is very important for us to get the brain we have

	05:04.000 --> 05:08.120
	and we can speculate for why that is.

	05:08.120 --> 05:13.000
	It takes us a long time as human beings after we're born

	05:13.000 --> 05:16.040
	to learn all the things that we have to learn

	05:16.040 --> 05:17.920
	to have the adult brain.

	05:17.920 --> 05:20.160
	It's actually 20 years, think about it.

	05:20.160 --> 05:23.440
	From when a baby is born to when a teenager

	05:23.440 --> 05:27.160
	goes through puberty to adults, it's a long time.

	05:27.160 --> 05:32.320
	Do you think you can maybe talk through the first few months

	05:32.320 --> 05:35.080
	and then on to the first 20 years

	05:35.080 --> 05:37.640
	and then for the rest of their lives?

	05:37.640 --> 05:41.080
	What does the development of the human brain look like?

	05:41.080 --> 05:43.360
	What are the different stages?

	05:43.360 --> 05:46.720
	At the beginning you have to build a brain, right?

	05:46.720 --> 05:48.840
	And the brain is made of cells.

	05:48.840 --> 05:51.960
	What's the very beginning? Which beginning are we talking about?

	05:51.960 --> 05:53.280
	In the embryo.

	05:53.280 --> 05:56.000
	As the embryo is developing in the womb,

	05:56.000 --> 05:59.680
	in addition to making all of the other tissues of the embryo,

	05:59.680 --> 06:02.040
	the muscle, the heart, the blood,

	06:02.040 --> 06:04.960
	the embryo is also building the brain.

	06:04.960 --> 06:08.480
	And it builds from a very simple structure

	06:08.480 --> 06:10.000
	called the neural tube,

	06:10.000 --> 06:13.160
	which is basically nothing but a tube of cells

	06:13.160 --> 06:15.800
	that spans sort of the length of the embryo

	06:15.800 --> 06:20.840
	from the head all the way to the tail, let's say, of the embryo.

	06:20.840 --> 06:23.360
	And then over in human beings,

	06:23.360 --> 06:25.520
	over many months of gestation,

	06:25.520 --> 06:28.240
	from that neural tube,

	06:28.240 --> 06:32.480
	which contains a stem cell like cells of the brain,

	06:32.480 --> 06:37.000
	you will make many, many other building blocks of the brain.

	06:37.000 --> 06:39.600
	So all of the other cell types,

	06:39.600 --> 06:43.080
	because there are many, many different types of cells in the brain,

	06:43.080 --> 06:46.640
	that will form specific structures of the brain.

	06:46.640 --> 06:49.800
	So you can think about embryonic development of the brain

	06:49.800 --> 06:54.440
	as just the time in which you are making the building blocks, the cells.

	06:54.440 --> 06:56.840
	Are the stem cells relatively homogeneous,

	06:56.840 --> 06:59.240
	like uniform, or are they all different types?

	06:59.240 --> 07:01.280
	It's a very good question. It's exactly how it works.

	07:01.280 --> 07:05.200
	You start with a more homogeneous,

	07:05.200 --> 07:09.120
	perhaps more multipotent type of stem cell.

	07:09.120 --> 07:13.520
	That multipotent means that it has the potential

	07:13.520 --> 07:17.360
	to make many, many different types of other cells.

	07:17.360 --> 07:21.440
	And then with time, these progenitors become more heterogeneous,

	07:21.440 --> 07:22.840
	which means more diverse.

	07:22.840 --> 07:26.200
	There are going to be many different types of these stem cells.

	07:26.200 --> 07:28.760
	And also they will give rise to progeny,

	07:28.760 --> 07:31.760
	to other cells that are not stem cells,

	07:31.760 --> 07:33.320
	that are specific cells of the brain,

	07:33.320 --> 07:36.080
	that are very different from the mother stem cell.

	07:36.080 --> 07:40.360
	And now you think about this process of making cells from the stem cells

	07:40.360 --> 07:43.760
	over many, many months of development for humans.

	07:43.760 --> 07:48.200
	And what you're doing here, building the cells that physically make the brain,

	07:48.200 --> 07:52.400
	and then you arrange them in specific structures

	07:52.400 --> 07:55.440
	that are present in the final brain.

	07:55.440 --> 07:59.280
	So you can think about the embryonic development of the brain

	07:59.280 --> 08:02.120
	as the time where you're building the bricks.

	08:02.120 --> 08:05.520
	You're putting the bricks together to form buildings,

	08:05.520 --> 08:08.120
	structures, regions of the brain,

	08:08.120 --> 08:13.040
	and where you make the connections between these many different types of cells,

	08:13.040 --> 08:15.200
	especially nerve cells, neurons, right,

	08:15.200 --> 08:19.240
	that transmit action potentials and electricity.

	08:19.240 --> 08:22.280
	I've heard you also say somewhere, I think, correct me if I'm wrong,

	08:22.280 --> 08:25.080
	that the order of the way this builds matters.

	08:25.080 --> 08:26.040
	Oh, yes.

	08:26.040 --> 08:29.880
	If you are an engineer and you think about development,

	08:29.880 --> 08:34.960
	you can think of it as, well, I could also take all the cells

	08:34.960 --> 08:37.960
	and bring them all together into a brain in the end.

	08:37.960 --> 08:40.320
	But development is much more than that.

	08:40.320 --> 08:43.880
	So the cells are made in a very specific order

	08:43.880 --> 08:47.400
	that subserve the final product that you need to get.

	08:47.400 --> 08:52.200
	And so, for example, all of the nerve cells, the neurons, are made first.

	08:52.200 --> 08:56.760
	And all of the supportive cells of the neurons, like the glia, is made later.

	08:56.760 --> 09:02.080
	And there is a reason for that because they have to assemble together in specific ways.

	09:02.080 --> 09:05.720
	But you also may say, well, why don't we just put them all together in the end?

	09:05.720 --> 09:08.920
	It's because as they develop next to each other,

	09:08.920 --> 09:11.280
	they influence their own development.

	09:11.280 --> 09:15.400
	So it's a different thing for a glia to be made alone in a dish

	09:15.400 --> 09:19.360
	than a glia cell be made in a developing embryo

	09:19.360 --> 09:23.680
	with all these other cells around it that produce all these other signals.

	09:23.680 --> 09:27.840
	First of all, that's mind blowing, that this development process.

	09:27.840 --> 09:29.760
	From my perspective in artificial intelligence,

	09:29.760 --> 09:33.480
	you often think of how incredible the final product is,

	09:33.480 --> 09:35.200
	the final product, the brain.

	09:35.200 --> 09:40.400
	But you just, you're making me realize that the final product is just,

	09:40.400 --> 09:44.480
	is the beautiful thing is the actual development process.

	09:44.480 --> 09:51.640
	Do we know the code that drives that development?

	09:51.640 --> 09:53.640
	Do we have any sense?

	09:53.640 --> 09:59.320
	First of all, thank you for saying that it's really the formation of the brain.

	09:59.320 --> 10:05.120
	It's really its development, this incredibly choreographed dance

	10:05.120 --> 10:10.560
	that happens the same way every time each one of us builds the brain, right?

	10:10.560 --> 10:14.880
	And that builds an organ that allows us to do what we're doing today, right?

	10:14.880 --> 10:16.360
	That is mind blowing.

	10:16.360 --> 10:21.880
	And this is why developmental neurobiologists never get tired of studying that.

	10:21.880 --> 10:23.800
	Now, you're asking about the code.

	10:23.800 --> 10:26.520
	What drives this? How is this done?

	10:26.520 --> 10:29.720
	Well, it's millions of years of evolution

	10:29.720 --> 10:33.120
	of really fine tuning gene expression programs

	10:33.120 --> 10:37.480
	that allow certain cells to be made at a certain time

	10:37.480 --> 10:41.680
	and to become a certain cell type,

	10:41.680 --> 10:47.360
	but also mechanical forces of pressure bending.

	10:47.360 --> 10:50.280
	This embryo is not just, it will not stay a tube,

	10:50.280 --> 10:52.000
	this brain for very long.

	10:52.000 --> 10:55.720
	At some point, this tube in the front of the embryo will expand

	10:55.720 --> 10:58.160
	to make the primordium of the brain, right?

	10:58.160 --> 11:02.880
	Now, the forces that control the cells feel,

	11:02.880 --> 11:04.840
	and this is another beautiful thing,

	11:04.840 --> 11:09.240
	the very force that they feel, which is different from a week before,

	11:09.240 --> 11:11.080
	a week ago, will tell the cell,

	11:11.080 --> 11:13.640
	oh, you're being squished in a certain way,

	11:13.640 --> 11:16.560
	begin to produce these new genes,

	11:16.560 --> 11:18.400
	because now you are at the corner,

	11:18.400 --> 11:23.160
	or you are in a stretch of cells or whatever it is.

	11:23.160 --> 11:26.000
	And so that mechanical physical force

	11:26.000 --> 11:29.440
	shapes the fate of the cell as well.

	11:29.440 --> 11:31.880
	So it's not only chemical, it's also mechanical.

	11:31.880 --> 11:38.360
	So from my perspective, biology is this incredibly complex mess,

	11:38.360 --> 11:40.160
	gooey mess.

	11:40.160 --> 11:43.440
	So you're seeing mechanical forces.

	11:43.440 --> 11:50.000
	How different is a computer or any kind of mechanical machine

	11:50.000 --> 11:53.840
	that humans build and the biological systems?

	11:53.840 --> 11:57.000
	Have you been, because you've worked a lot with biological systems,

	11:57.000 --> 11:59.960
	are they as much of a mess as it seems

	11:59.960 --> 12:03.520
	from a perspective of an engineer, a mechanical engineer?

	12:03.520 --> 12:11.680
	Yeah, they are much more prone to taking alternative routes, right?

	12:11.680 --> 12:18.160
	So if you, we go back to printing a brain versus developing a brain,

	12:18.160 --> 12:20.440
	of course, if you print a brain,

	12:20.440 --> 12:23.960
	given that you start with the same building blocks, the same cells,

	12:23.960 --> 12:28.600
	you could potentially print it the same way every time.

	12:28.600 --> 12:32.520
	But that final brain may not work the same way

	12:32.520 --> 12:34.440
	as a brain built during development does,

	12:34.440 --> 12:38.680
	because the very same building blocks that you're using

	12:38.680 --> 12:41.440
	developed in a completely different environment, right?

	12:41.440 --> 12:43.000
	That was not the environment of the brain.

	12:43.000 --> 12:47.120
	Therefore, they're going to be different just by definition.

	12:47.120 --> 12:51.840
	So if you instead use development to build, let's say, a brain

	12:51.840 --> 12:55.840
	organoid, which maybe we will be talking about in a few minutes.

	12:55.840 --> 12:57.000
	Those things are fascinating.

	12:57.000 --> 13:01.960
	Yes, so if you use processes of development,

	13:01.960 --> 13:06.480
	then when you watch it, you can see that sometimes things can go wrong

	13:06.480 --> 13:07.520
	in some organoids.

	13:07.520 --> 13:10.880
	And by wrong, I mean different one organoid from the next.

	13:10.880 --> 13:14.840
	While if you think about that embryo, it always goes right.

	13:14.840 --> 13:18.960
	So it's this development, it's for as complex as it is.

	13:18.960 --> 13:23.680
	Every time a baby is born has, you know, with very few exceptions,

	13:23.680 --> 13:26.200
	the brain is like the next baby.

	13:26.200 --> 13:31.320
	But it's not the same if you develop it in a dish.

	13:31.320 --> 13:33.840
	And first of all, we don't even develop a brain.

	13:33.840 --> 13:36.080
	You develop something much simpler in the dish.

	13:36.080 --> 13:39.680
	But there are more options for building things differently,

	13:39.680 --> 13:46.080
	which really tells you that evolution has played a really

	13:46.080 --> 13:53.280
	tight game here for how in the end the brain is built in vivo.

	13:53.280 --> 13:55.360
	So just a quick maybe dumb question,

	13:55.360 --> 14:01.120
	but it seems like the building process is not a dictatorship.

	14:01.120 --> 14:06.680
	It seems like there's not a centralized high level mechanism

	14:06.680 --> 14:10.320
	that says, OK, this cell built itself the wrong way.

	14:10.320 --> 14:11.560
	I'm going to kill it.

	14:11.560 --> 14:15.480
	It seems like there's a really strong distributed mechanism.

	14:15.480 --> 14:18.440
	Is that in your sense for what you have?

	14:18.440 --> 14:20.920
	There are a lot of possibilities, right?

	14:20.920 --> 14:25.080
	And if you think about, for example, different species,

	14:25.080 --> 14:28.920
	building their brain, each brain is a little bit different.

	14:28.920 --> 14:31.360
	So the brain of a lizard is very different from that

	14:31.360 --> 14:36.560
	of a chicken, from that of one of us, and so on and so forth.

	14:36.560 --> 14:40.960
	And still is a brain, but it was built differently.

	14:40.960 --> 14:44.120
	Starting from stem cells, they pretty much

	14:44.120 --> 14:46.040
	had the same potential.

	14:46.040 --> 14:49.400
	But in the end, evolution builds different brains

	14:49.400 --> 14:51.520
	in different species, because that

	14:51.520 --> 14:54.040
	serves in a way the purpose of that species

	14:54.040 --> 14:56.680
	and the well being of that organism.

	14:56.680 --> 15:00.720
	And so there are many possibilities,

	15:00.720 --> 15:04.880
	but then there is a way, and you were talking about a code.

	15:04.880 --> 15:07.560
	Nobody knows what the entire code of development is.

	15:07.560 --> 15:08.680
	Of course, we don't.

	15:08.680 --> 15:13.400
	We know bits and pieces of very specific aspects

	15:13.400 --> 15:15.680
	of development of the brain, what genes are involved

	15:15.680 --> 15:18.520
	to make a certain cell types, how those two cells interact

	15:18.520 --> 15:21.480
	to make the next level structure that we might know,

	15:21.480 --> 15:24.560
	but the entirety of it, how it's so well controlled.

	15:24.560 --> 15:26.160
	It's really mind blowing.

	15:26.160 --> 15:29.120
	So in the first two months in the embryo,

	15:29.120 --> 15:32.720
	or whatever, the first few weeks, few months.

	15:32.720 --> 15:37.120
	So yeah, the building blocks are constructed,

	15:37.120 --> 15:40.040
	the actual, the different regions of the brain,

	15:40.040 --> 15:42.760
	I guess, in the nervous system.

	15:42.760 --> 15:46.520
	Well, this continues way longer than just the first few months.

	15:46.520 --> 15:50.480
	So over the very first few months,

	15:50.480 --> 15:52.080
	you build a lot of these cells,

	15:52.080 --> 15:56.800
	but then there is continuous building of new cell types

	15:56.800 --> 15:58.480
	all the way through birth.

	15:58.480 --> 16:00.400
	And then even postnatally,

	16:01.520 --> 16:04.000
	I don't know if you've ever heard of myelin.

	16:04.000 --> 16:06.720
	Myelin is this sort of insulation

	16:06.720 --> 16:09.800
	that is built around the cables of the neurons

	16:09.800 --> 16:12.200
	so that the electricity can go really fast from.

	16:12.200 --> 16:13.520
	The axons, I guess they're called.

	16:13.520 --> 16:15.720
	The axons are called axons, exactly.

	16:15.720 --> 16:20.720
	And so as human beings, we myelinate ourselves

	16:22.920 --> 16:27.000
	postnatally, a kid, a six year old kid,

	16:27.000 --> 16:29.720
	as barely started the process of making

	16:29.720 --> 16:31.640
	the mature oligodendrocytes,

	16:31.640 --> 16:33.400
	which are the cells that then eventually

	16:33.400 --> 16:36.360
	will wrap the axons into myelin.

	16:36.360 --> 16:38.720
	And this will continue, believe it or not,

	16:38.720 --> 16:42.200
	until we are about 25, 30 years old.

	16:42.200 --> 16:45.080
	So there is a continuous process of maturation

	16:45.080 --> 16:46.600
	and tweaking and additions,

	16:46.600 --> 16:51.040
	and also in response to what we do.

	16:51.040 --> 16:53.960
	I remember taking api biology in high school,

	16:53.960 --> 16:57.040
	and in the textbook, it said that,

	16:57.040 --> 16:58.560
	I'm going by memory here,

	16:58.560 --> 17:02.000
	that scientists disagree on the purpose of myelin

	17:03.040 --> 17:04.720
	in the brain.

	17:04.720 --> 17:06.400
	Is that totally wrong?

	17:06.400 --> 17:10.000
	So like, I guess it speeds up the,

	17:12.000 --> 17:13.200
	okay, but I'd be wrong here,

	17:13.200 --> 17:15.280
	but I guess it speeds up the electricity traveling

	17:15.280 --> 17:17.680
	down the axon or something.

	17:17.680 --> 17:20.160
	So that's the most sort of canonical,

	17:20.160 --> 17:21.760
	and definitely that's the case.

	17:21.760 --> 17:24.880
	So you have to imagine an axon,

	17:24.880 --> 17:27.680
	and you can think about it as a cable or some type

	17:27.680 --> 17:29.520
	with electricity going through.

	17:29.520 --> 17:34.400
	And what myelin does by insulating the outside,

	17:34.400 --> 17:36.360
	I should say there are tracts of myelin

	17:36.360 --> 17:39.600
	and pieces of axons that are naked without myelin.

	17:39.600 --> 17:41.760
	And so by having the insulation,

	17:41.760 --> 17:44.040
	the electricity instead of going straight through the cable,

	17:44.040 --> 17:47.240
	it will jump over a piece of myelin, right?

	17:47.240 --> 17:49.960
	To the next naked little piece and jump again,

	17:49.960 --> 17:52.720
	and therefore, that's the idea that you go faster.

	17:53.920 --> 17:58.720
	And it was always thought that in order to build

	17:58.720 --> 18:01.840
	a big brain, a big nervous system,

	18:01.840 --> 18:04.160
	in order to have a nervous system

	18:04.160 --> 18:06.440
	that can do very complex type of things,

	18:06.440 --> 18:09.400
	then you need a lot of myelin because you wanna go fast

	18:09.400 --> 18:13.320
	with this information from point A to point B.

	18:13.320 --> 18:17.960
	Well, a few years ago, maybe five years ago or so,

	18:17.960 --> 18:20.680
	we discovered that some of the most evolved,

	18:20.680 --> 18:24.120
	which means the newest type of neurons that we have

	18:24.120 --> 18:26.520
	as non human primates, as as human beings,

	18:26.520 --> 18:29.120
	in the top of our cerebral cortex,

	18:29.120 --> 18:30.920
	which should be the neurons that do some

	18:30.920 --> 18:33.200
	of the most complex things that we do.

	18:33.200 --> 18:37.080
	Well, those have axons that have very little myelin.

	18:37.080 --> 18:42.080
	Wow. And they have very interesting ways

	18:42.080 --> 18:44.400
	in which they put this myelin on their axons,

	18:44.400 --> 18:46.400
	you know, a little piece here, then a long track

	18:46.400 --> 18:48.680
	with no myelin, another chunk there,

	18:48.680 --> 18:50.600
	and some don't have myelin at all.

	18:50.600 --> 18:53.120
	So now you have to explain

	18:54.760 --> 18:57.960
	where we're going with evolution.

	18:57.960 --> 19:01.360
	And if you think about it, perhaps as an electrical engineer,

	19:02.800 --> 19:06.000
	when I looked at it, I initially thought,

	19:06.000 --> 19:07.560
	I'm a developmental neurobiology,

	19:07.560 --> 19:10.880
	I thought maybe this is what we see now,

	19:10.880 --> 19:14.160
	but if we give evolution another few million years,

	19:14.160 --> 19:16.520
	we'll see a lot of myelin on these neurons too.

	19:16.520 --> 19:18.840
	But I actually think now that that's instead

	19:18.840 --> 19:22.000
	the future of the brain, less myelin,

	19:22.000 --> 19:24.720
	and my allow for more flexibility

	19:24.720 --> 19:26.720
	on what you do with your axons,

	19:26.720 --> 19:28.560
	and therefore more complicated

	19:28.560 --> 19:32.200
	and unpredictable type of functions,

	19:32.200 --> 19:34.320
	which is also a bit mind blowing.

	19:34.320 --> 19:38.480
	So it seems like it's controlling the timing of the signal.

	19:38.480 --> 19:40.160
	So they're in the timing,

	19:40.160 --> 19:43.320
	you can encode a lot of information.

	19:43.320 --> 19:44.680
	And so the brain...

	19:44.680 --> 19:48.600
	The timing, the chemistry of that little piece of axon,

	19:48.600 --> 19:52.160
	perhaps it's a dynamic process where the myelin can move.

	19:52.160 --> 19:57.160
	Now you see how many layers of variability you can add,

	19:57.520 --> 19:58.960
	and that's actually really good.

	19:58.960 --> 20:02.320
	If you're trying to come up with a new function

	20:02.320 --> 20:06.600
	or a new capability or something unpredictable in a way.

	20:06.600 --> 20:08.240
	So we're gonna jump right out a little bit,

	20:08.240 --> 20:12.880
	but the old question of how much is nature

	20:12.880 --> 20:14.560
	and how much is nurture,

	20:14.560 --> 20:17.360
	in terms of this incredible thing

	20:17.360 --> 20:18.920
	after the development is over,

	20:20.280 --> 20:25.160
	we seem to be kind of somewhat smart, intelligent,

	20:26.160 --> 20:27.600
	cognition, consciousness,

	20:27.600 --> 20:30.680
	all these things are just incredible ability of reason

	20:30.680 --> 20:32.080
	and so on emerge.

	20:32.080 --> 20:34.960
	In your sense, how much is in the hardware,

	20:34.960 --> 20:39.320
	in the nature and how much is in the nurtures

	20:39.320 --> 20:41.040
	learned through with our parents

	20:41.040 --> 20:42.480
	through interacting with the environment, so on.

	20:42.480 --> 20:43.800
	It's really both, right?

	20:43.800 --> 20:45.040
	If you think about it.

	20:45.040 --> 20:48.040
	So we are born with a brain as babies

	20:48.040 --> 20:53.040
	that has most of its cells and most of its structures

	20:53.640 --> 20:57.920
	and that will take a few years to grow,

	20:57.920 --> 21:00.640
	to add more, to be better.

	21:00.640 --> 21:04.160
	But really then we have this 20 years

	21:04.160 --> 21:07.080
	of interacting with the environment around us.

	21:07.080 --> 21:10.800
	And so what that brain that was so perfectly built

	21:10.800 --> 21:15.800
	or imperfectly built due to our genetic cues

	21:16.480 --> 21:20.200
	will then be used to incorporate the environment

	21:20.200 --> 21:22.760
	in its farther maturation and development.

	21:22.760 --> 21:27.000
	And so your experiences do shape your brain.

	21:27.000 --> 21:29.480
	I mean, we know that like if you and I

	21:29.480 --> 21:33.000
	may have had a different childhood or a different,

	21:33.000 --> 21:35.080
	we have been going to different schools,

	21:35.080 --> 21:36.480
	we have been learning different things

	21:36.480 --> 21:38.080
	and our brain is a little bit different

	21:38.080 --> 21:41.200
	because of that we behave differently because of that.

	21:41.200 --> 21:44.080
	And so especially postnatally,

	21:44.080 --> 21:46.040
	experience is extremely important.

	21:46.040 --> 21:48.800
	We are born with a plastic brain.

	21:48.800 --> 21:51.480
	What that means is a brain that is able to change

	21:51.480 --> 21:54.280
	in response to stimuli.

	21:54.280 --> 21:56.400
	They can be sensory.

	21:56.400 --> 22:01.040
	So perhaps some of the most illuminating studies

	22:01.040 --> 22:03.440
	that were done were studies in which

	22:03.440 --> 22:07.000
	the sensory organs were not working, right?

	22:07.000 --> 22:09.520
	If you are born with eyes that don't work,

	22:09.520 --> 22:12.520
	then your very brain, the piece of the brain

	22:12.520 --> 22:16.000
	that normally would process vision, the visual cortex

	22:17.240 --> 22:19.840
	develops postnatally differently

	22:19.840 --> 22:23.520
	and it might be used to do something different, right?

	22:23.520 --> 22:25.600
	So that's the most extreme.

	22:25.600 --> 22:27.480
	The plasticity of the brain, I guess,

	22:27.480 --> 22:29.480
	is the magic hardware that it,

	22:29.480 --> 22:32.960
	and then its flexibility in all forms

	22:32.960 --> 22:36.320
	is what enables the learning postnatally.

	22:36.320 --> 22:39.280
	Can you talk about organoids?

	22:39.280 --> 22:40.920
	What are they?

	22:40.920 --> 22:43.760
	And how can you use them to help us understand

	22:43.760 --> 22:45.760
	the brain and the development of the brain?

	22:45.760 --> 22:47.360
	This is very, very important.

	22:47.360 --> 22:49.920
	So the first thing I'd like to say,

	22:49.920 --> 22:51.440
	please keep this in the video.

	22:51.440 --> 22:56.040
	The first thing I'd like to say is that an organoid,

	22:56.040 --> 23:01.040
	a brain organoid, is not the same as a brain, okay?

	23:01.600 --> 23:03.640
	It's a fundamental distinction.

	23:03.640 --> 23:08.560
	It's a system, a cellular system,

	23:08.560 --> 23:12.200
	that one can develop in the culture dish

	23:12.200 --> 23:17.200
	starting from stem cells that will mimic some aspects

	23:17.200 --> 23:21.400
	of the development of the brain, but not all of it.

	23:21.400 --> 23:23.760
	They are very small, maximum,

	23:23.760 --> 23:27.920
	they become about four to five millimeters in diameters.

	23:27.920 --> 23:32.920
	They are much simpler than our brain, of course,

	23:33.400 --> 23:36.480
	but yet they are the only system

	23:36.480 --> 23:39.520
	where we can literally watch a process

	23:39.520 --> 23:42.560
	of human brain development unfold.

	23:42.560 --> 23:45.080
	And by watch, I mean study it.

	23:45.080 --> 23:48.000
	Remember when I told you that we can't understand

	23:48.000 --> 23:50.040
	everything about development in our own brain

	23:50.040 --> 23:51.560
	by studying a mouse?

	23:51.560 --> 23:53.600
	Well, we can't study the actual process

	23:53.600 --> 23:54.840
	of development of the human brain

	23:54.840 --> 23:56.320
	because it all happens in utero.

	23:56.320 --> 23:59.320
	So we will never have access to that process ever.

	24:00.400 --> 24:04.320
	And therefore, this is our next best thing,

	24:04.320 --> 24:08.400
	like a bunch of stem cells that can be coaxed

	24:08.400 --> 24:11.720
	into starting a process of neural tube formation.

	24:11.720 --> 24:14.680
	Remember that tube that is made by the embryo rion?

	24:14.680 --> 24:17.160
	And from there, a lot of the cell types

	24:17.160 --> 24:20.680
	that are present within the brain

	24:20.680 --> 24:24.960
	and you can simply watch it and study,

	24:24.960 --> 24:28.680
	but you can also think about diseases

	24:28.680 --> 24:30.880
	where development of the brain

	24:30.880 --> 24:34.200
	does not proceed normally, right, properly.

	24:34.200 --> 24:35.920
	Think about neurodevelopmental diseases

	24:35.920 --> 24:38.280
	that are many, many different types.

	24:38.280 --> 24:40.200
	Think about autism spectrum disorders,

	24:40.200 --> 24:42.640
	there are also many different types of autism.

	24:42.640 --> 24:45.320
	So there you could take a stem cell

	24:45.320 --> 24:47.520
	which really means either a sample of blood

	24:47.520 --> 24:50.960
	or a sample of skin from the patient,

	24:50.960 --> 24:54.360
	make a stem cell, and then with that stem cell,

	24:54.360 --> 24:57.480
	watch a process of formation of a brain organoid

	24:57.480 --> 25:00.640
	of that person, with that genetics,

	25:00.640 --> 25:02.240
	with that genetic code in it.

	25:02.240 --> 25:05.840
	And you can ask, what is this genetic code doing

	25:05.840 --> 25:08.800
	to some aspects of development of the brain?

	25:08.800 --> 25:12.040
	And for the first time, you may come to solutions

	25:12.040 --> 25:15.440
	like, what cells are involved in autism?

	25:15.440 --> 25:17.400
	So I have so many questions around this.

	25:17.400 --> 25:20.560
	So if you take this human stem cell

	25:20.560 --> 25:23.400
	for that particular person with that genetic code,

	25:23.400 --> 25:26.560
	how, and you try to build an organoid,

	25:26.560 --> 25:28.880
	how often will it look similar?

	25:28.880 --> 25:31.880
	What's the, yeah, so.

	25:31.880 --> 25:33.320
	Reproducibility.

	25:33.320 --> 25:37.360
	Yes, or how much variability is the flip side of that, yeah.

	25:37.360 --> 25:42.360
	So there is much more variability in building organoids

	25:42.360 --> 25:44.560
	than there is in building brain.

	25:44.560 --> 25:47.320
	It's really true that the majority of us,

	25:47.320 --> 25:49.600
	when we are born as babies,

	25:49.600 --> 25:52.480
	our brains look a lot like each other.

	25:52.480 --> 25:54.920
	This is the magic that the embryo does,

	25:54.920 --> 25:57.680
	where it builds a brain in the context of a body

	25:57.680 --> 26:01.280
	and there is very little variability there.

	26:01.280 --> 26:02.320
	There is disease, of course,

	26:02.320 --> 26:04.000
	but in general, little variability.

	26:04.000 --> 26:08.400
	When you build an organoid, we don't have the full code

	26:08.400 --> 26:09.520
	for how this is done.

	26:09.520 --> 26:13.440
	And so in part, the organoid somewhat builds itself

	26:13.440 --> 26:15.560
	because there are some structures of the brain

	26:15.560 --> 26:17.280
	that the cells know how to make.

	26:18.160 --> 26:21.840
	And another part comes from the investigator,

	26:21.840 --> 26:26.160
	the scientist, adding to the media factors

	26:26.160 --> 26:28.040
	that we know in the mouse, for example,

	26:28.040 --> 26:30.760
	would foster a certain step of development.

	26:30.760 --> 26:33.240
	But it's very limited.

	26:33.240 --> 26:36.160
	And so as a result,

	26:36.160 --> 26:38.200
	the kind of product you get in the end

	26:38.200 --> 26:39.720
	is much more reductionist.

	26:39.720 --> 26:42.680
	It's much more simple than what you get in vivo.

	26:42.680 --> 26:46.200
	It mimics early events of development as of today.

	26:46.200 --> 26:49.080
	And it doesn't build very complex type of anatomy

	26:49.080 --> 26:51.440
	and structure does not as of today,

	26:52.600 --> 26:54.920
	which happens instead in vivo.

	26:54.920 --> 26:59.120
	And also the variability that you see

	26:59.120 --> 27:02.800
	one organoid to the next tends to be higher

	27:02.800 --> 27:05.560
	than when you compare an embryo to the next.

	27:05.560 --> 27:08.960
	So, okay, then the next question is how hard

	27:08.960 --> 27:11.120
	and maybe another flip side of that expensive

	27:11.120 --> 27:14.960
	is it to go from one stem cell to an organoid?

	27:14.960 --> 27:16.760
	How many can you build in like,

	27:16.760 --> 27:18.480
	because it sounds very complicated.

	27:18.480 --> 27:23.480
	It's work, definitely, and it's money, definitely.

	27:23.480 --> 27:28.080
	But you can really grow a very high number

	27:28.080 --> 27:31.640
	of these organoids, you know, can go perhaps,

	27:31.640 --> 27:33.160
	I told you the maximum they become

	27:33.160 --> 27:34.800
	about five millimeters in diameter.

	27:34.800 --> 27:39.800
	So this is about the size of a tiny, tiny, you know, raising

	27:40.800 --> 27:43.160
	or perhaps the seed of an apple.

	27:43.160 --> 27:47.560
	And so you can grow 50 to 100 of those

	27:47.560 --> 27:51.360
	inside one big bioreactors, which are these flasks

	27:51.360 --> 27:55.520
	where the media provides nutrients for the organoids.

	27:55.520 --> 28:00.520
	So the problem is not to grow more or less of them.

	28:01.760 --> 28:06.480
	It's really to figure out how to grow them in a way

	28:06.480 --> 28:08.440
	that they are more and more reproducible.

	28:08.440 --> 28:10.000
	For example, organoid to organoid,

	28:10.000 --> 28:13.200
	so they can be used to study a biological process

	28:13.200 --> 28:15.640
	because if you have too much of variability,

	28:15.640 --> 28:17.160
	then you never know if what you see

	28:17.160 --> 28:19.560
	is just an exception or really the rule.

	28:19.560 --> 28:22.160
	So what does an organoid look like?

	28:22.160 --> 28:25.120
	Are there different neurons already emerging?

	28:25.120 --> 28:27.520
	Is there, you know, well, first,

	28:27.520 --> 28:29.920
	can you tell me what kind of neurons are there?

	28:29.920 --> 28:30.920
	Yes.

	28:30.920 --> 28:35.560
	Are they sort of all the same?

	28:35.560 --> 28:37.480
	Are they not all the same?

	28:37.480 --> 28:39.560
	Is how much do we understand

	28:39.560 --> 28:42.440
	and how much of that variance

	28:42.440 --> 28:45.800
	if any can exist in organoids?

	28:45.800 --> 28:49.360
	Yes, so you could grow,

	28:49.360 --> 28:52.440
	I told you that the brain has different parts.

	28:52.440 --> 28:56.000
	So the cerebral cortex is on the top part of the brain,

	28:56.000 --> 28:57.960
	but there is another region called the striatum

	28:57.960 --> 28:59.960
	that is below the cortex and so on and so forth.

	28:59.960 --> 29:03.760
	All of these regions have different types of cells

	29:03.760 --> 29:05.040
	in the actual brain.

	29:05.040 --> 29:05.880
	Okay.

	29:05.880 --> 29:08.880
	And so scientists have been able to grow organoids

	29:08.880 --> 29:11.440
	that may mimic some aspects of development

	29:11.440 --> 29:13.920
	of these different regions of the brain.

	29:13.920 --> 29:16.480
	And so we are very interested in the cerebral cortex.

	29:16.480 --> 29:17.720
	That's the coolest part, right?

	29:17.720 --> 29:18.560
	Very cool.

	29:18.560 --> 29:20.880
	I agree with you.

	29:20.880 --> 29:23.880
	We wouldn't be here talking if we didn't have a cerebral cortex.

	29:23.880 --> 29:25.200
	It's also, I like to think,

	29:25.200 --> 29:27.600
	the part of the brain that really truly makes us human,

	29:27.600 --> 29:30.200
	the most evolved in recent evolution.

	29:30.200 --> 29:33.600
	And so in the attempt to make the cerebral cortex

	29:33.600 --> 29:37.200
	and by figuring out a way to have these organoids

	29:37.200 --> 29:40.240
	continue to grow and develop for extended periods of time,

	29:40.240 --> 29:42.400
	much like it happens in the real embryo,

	29:42.400 --> 29:44.240
	months and months in culture,

	29:44.240 --> 29:47.920
	then you can see that many different types

	29:47.920 --> 29:50.200
	of neurons of the cortex appear

	29:50.200 --> 29:52.200
	and at some point also the astrocytes,

	29:52.200 --> 29:57.200
	so the glia cells of the cerebral cortex also appear.

	29:57.640 --> 29:59.000
	What are these?

	29:59.000 --> 29:59.840
	Astrocytes.

	29:59.840 --> 30:00.680
	Astrocytes.

	30:00.680 --> 30:02.080
	The astrocytes are not neurons,

	30:02.080 --> 30:03.440
	so they're not nerve cells,

	30:03.440 --> 30:06.160
	but they play very important roles.

	30:06.160 --> 30:09.000
	One important role is to support the neuron,

	30:09.000 --> 30:11.880
	but of course they have much more active type of roles.

	30:11.880 --> 30:13.280
	They're very important, for example,

	30:13.280 --> 30:14.560
	to make the synapses,

	30:14.560 --> 30:17.640
	which are the point of contact and communication

	30:17.640 --> 30:21.480
	between two neurons, they...

	30:21.480 --> 30:25.680
	So all that chemistry fun happens in the synapses

	30:25.680 --> 30:28.160
	happens because of these cells?

	30:28.160 --> 30:29.680
	Are they the medium in which?

	30:29.680 --> 30:32.000
	Happens because of the interactions,

	30:32.000 --> 30:34.760
	happens because you are making the cells

	30:34.760 --> 30:36.320
	and they have certain properties,

	30:36.320 --> 30:40.360
	including the ability to make neurotransmitters,

	30:40.360 --> 30:43.320
	which are the chemicals that are secreted to the synapses,

	30:43.320 --> 30:46.480
	including the ability of making these axons grow

	30:46.480 --> 30:49.240
	with their growth cones and so on and so forth.

	30:49.240 --> 30:51.400
	And then you have other cells around there

	30:51.400 --> 30:55.200
	that release chemicals or touch the neurons

	30:55.200 --> 30:57.200
	or interact with them in different ways

	30:57.200 --> 30:59.880
	to really foster this perfect process,

	30:59.880 --> 31:02.480
	in this case of synaptogenesis.

	31:02.480 --> 31:05.680
	And this does happen within organoids.

	31:05.680 --> 31:06.520
	Or with organoids.

	31:06.520 --> 31:09.760
	So the mechanical and the chemical stuff happens.

	31:09.760 --> 31:11.640
	The connectivity between neurons.

	31:11.640 --> 31:13.320
	This, in a way, is not surprising

	31:13.320 --> 31:18.160
	because scientists have been culturing neurons forever.

	31:18.160 --> 31:20.760
	And when you take a neuron, even a very young one,

	31:20.760 --> 31:23.480
	and you culture it, eventually finds another cell

	31:23.480 --> 31:26.960
	or another neuron to talk to, it will form a synapse.

	31:26.960 --> 31:28.520
	Are we talking about mice neurons?

	31:28.520 --> 31:29.600
	Are we talking about human neurons?

	31:29.600 --> 31:30.600
	It doesn't matter, both.

	31:30.600 --> 31:33.280
	So you can culture a neuron like a single neuron

	31:33.280 --> 31:37.920
	and give it a little friend and it starts interacting?

	31:37.920 --> 31:40.240
	Yes. So neurons are able to...

	31:40.240 --> 31:44.560
	It sounds... It's more simple than what it may sound to you.

	31:44.560 --> 31:48.320
	Neurons have molecular properties and structural properties

	31:48.320 --> 31:51.120
	that allow them to really communicate with other cells.

	31:51.120 --> 31:53.160
	And so if you put not one neuron,

	31:53.160 --> 31:55.120
	but if you put several neurons together,

	31:55.120 --> 32:00.240
	chances are that they will form synapses with each other.

	32:00.240 --> 32:01.120
	Okay, great.

	32:01.120 --> 32:03.360
	So an organoid is not a brain.

	32:03.360 --> 32:03.880
	No.

	32:03.880 --> 32:07.600
	But there's some...

	32:07.600 --> 32:10.440
	It's able to, especially what you're talking about,

	32:10.440 --> 32:15.120
	mimic some properties of the cerebral cortex, for example.

	32:15.120 --> 32:17.960
	So what can you understand about the brain

	32:17.960 --> 32:21.040
	by studying an organoid of the cerebral cortex?

	32:21.040 --> 32:26.400
	I can literally study all this incredible diversity of cell type,

	32:26.400 --> 32:29.040
	all these many, many different classes of cells.

	32:29.040 --> 32:30.760
	How are they made?

	32:30.760 --> 32:32.520
	How do they look like?

	32:32.520 --> 32:34.920
	What do they need to be made properly?

	32:34.920 --> 32:36.280
	And what goes wrong?

	32:36.280 --> 32:39.680
	If now the genetics of that stem cell

	32:39.680 --> 32:42.800
	that I used to make the organoid came from a patient

	32:42.800 --> 32:44.320
	with a neurodevelopmental disease,

	32:44.320 --> 32:47.600
	can I actually watch for the very first time

	32:47.600 --> 32:51.400
	what may have gone wrong years before in this kid

	32:51.400 --> 32:53.480
	when its own brain was being made?

	32:53.480 --> 32:54.720
	Think about that loop.

	32:54.720 --> 32:59.600
	In a way, it's a little tiny rudimentary window

	32:59.600 --> 33:04.240
	into the past, into the time when that brain,

	33:04.240 --> 33:07.680
	in a kid that had this neurodevelopmental disease,

	33:07.680 --> 33:10.120
	was being made.

	33:10.120 --> 33:12.880
	And I think that's unbelievably powerful

	33:12.880 --> 33:16.800
	because today we have no idea of what cell types,

	33:16.800 --> 33:20.880
	we barely know what brain regions are affected in these diseases.

	33:20.880 --> 33:23.720
	Now we have an experimental system

	33:23.720 --> 33:25.440
	that we can study in the lab

	33:25.440 --> 33:28.440
	and we can ask what are the cells affected?

	33:28.440 --> 33:31.840
	When, during development, things went wrong.

	33:31.840 --> 33:35.200
	What are the molecules among the many, many different molecules

	33:35.200 --> 33:36.600
	that control brain development?

	33:36.600 --> 33:39.720
	Which ones are the ones that really messed up here

	33:39.720 --> 33:42.160
	and we want perhaps to fix?

	33:42.160 --> 33:44.520
	And what is really the final product?

	33:44.520 --> 33:48.560
	Is it a less strong kind of circuit and brain?

	33:48.560 --> 33:50.560
	Is it a brain that lacks a cell type?

	33:50.560 --> 33:52.040
	Is it a, what is it?

	33:52.040 --> 33:54.920
	Because then we can think about treatment

	33:54.920 --> 33:59.360
	and care for these patients that is informed

	33:59.360 --> 34:02.040
	rather than just based on current diagnostics.

	34:02.040 --> 34:06.240
	So how hard is it to detect through the developmental process?

	34:06.240 --> 34:09.920
	It's a super exciting tool

	34:09.920 --> 34:15.160
	to see how different conditions develop.

	34:15.160 --> 34:17.640
	How hard is it to detect that, wait a minute,

	34:17.640 --> 34:20.760
	this is abnormal development.

	34:20.760 --> 34:22.080
	Yeah.

	34:22.080 --> 34:24.840
	That's how hard it, how much signals there,

	34:24.840 --> 34:26.520
	how much of it is it a mess?

	34:26.520 --> 34:29.520
	Because things can go wrong at multiple levels, right?

	34:29.520 --> 34:34.360
	You could have a cell that is born and built

	34:34.360 --> 34:36.280
	but then doesn't work properly

	34:36.280 --> 34:38.360
	or a cell that is not even born

	34:38.360 --> 34:40.760
	or a cell that doesn't interact with other cells differently

	34:40.760 --> 34:42.160
	and so on and so forth.

	34:42.160 --> 34:44.440
	So today we have technology

	34:44.440 --> 34:47.800
	that we did not have even five years ago

	34:47.800 --> 34:49.800
	that allows us to look, for example,

	34:49.800 --> 34:52.160
	at the molecular picture of a cell,

	34:52.160 --> 34:56.840
	of a single cell in a sea of cells with high precision.

	34:56.840 --> 34:58.920
	And so that molecular information

	34:58.920 --> 35:01.840
	where you compare many, many single cells

	35:01.840 --> 35:03.720
	for the genes that they produce

	35:03.720 --> 35:06.240
	between a control individual

	35:06.240 --> 35:10.200
	and an individual with a neurodevelopmental disease,

	35:10.200 --> 35:13.880
	that may tell you what is different, molecularly.

	35:13.880 --> 35:18.640
	Or you could see that some cells are not even made,

	35:18.640 --> 35:20.840
	for example, or that the process of maturation

	35:20.840 --> 35:22.680
	of the cells may be wrong.

	35:22.680 --> 35:25.080
	There are many different levels here

	35:26.040 --> 35:29.640
	and we can study the cells at the molecular level

	35:29.640 --> 35:33.440
	but also we can use the organoids to ask questions

	35:33.440 --> 35:35.360
	about the properties of the neurons,

	35:35.360 --> 35:37.400
	the functional properties,

	35:37.400 --> 35:39.000
	how they communicate with each other,

	35:39.000 --> 35:41.440
	how they respond to a stimulus and so on and so forth

	35:41.440 --> 35:46.440
	and we may get abnormalities there, right?

	35:46.440 --> 35:51.440
	And detect those, so how early is this work in the,

	35:51.920 --> 35:54.400
	maybe in the history of science?

	35:54.400 --> 35:59.400
	So, so, I mean, like, so if you were to,

	35:59.840 --> 36:04.840
	if you and I time travel a thousand years into the future,

	36:05.280 --> 36:10.040
	organoids seem to be, maybe I'm romanticizing the notion

	36:10.040 --> 36:12.880
	but you're building not a brain

	36:12.880 --> 36:15.800
	but something that has properties of a brain.

	36:15.800 --> 36:19.120
	So it feels like you might be getting close to,

	36:19.120 --> 36:23.320
	in the building process, to build us to understand.

	36:23.320 --> 36:28.320
	So how far are we in this understanding

	36:29.160 --> 36:30.360
	process of development?

	36:31.520 --> 36:34.320
	A thousand years from now, it's a long time from now.

	36:34.320 --> 36:36.560
	So if this planet is still gonna be here,

	36:36.560 --> 36:38.280
	a thousand years from now.

	36:38.280 --> 36:42.080
	So I mean, if, you know, like they write a book,

	36:42.080 --> 36:44.120
	obviously there'll be a chapter about you.

	36:44.120 --> 36:47.320
	That's probably the science fiction book today.

	36:47.320 --> 36:48.160
	Yeah, today.

	36:48.160 --> 36:50.840
	But I mean, I guess where we really understood

	36:50.840 --> 36:53.400
	very little about the brain a century ago,

	36:53.400 --> 36:55.920
	where I was a big fan in high school,

	36:55.920 --> 36:58.760
	reading Freud and so on, still am of psychiatry.

	36:59.680 --> 37:01.480
	I would say we still understand very little

	37:01.480 --> 37:04.720
	about the functional aspect of just,

	37:04.720 --> 37:07.760
	but how in the history of understanding

	37:07.760 --> 37:09.640
	the biology of the brain, the development,

	37:09.640 --> 37:11.240
	how far are we along?

	37:11.240 --> 37:12.960
	It's a very good question.

	37:12.960 --> 37:15.520
	And so this is just, of course, my opinion.

	37:15.520 --> 37:19.720
	I think that we did not have technology,

	37:19.720 --> 37:23.160
	even 10 years ago or certainly not 20 years ago,

	37:23.160 --> 37:27.760
	to even think about experimentally investigating

	37:27.760 --> 37:30.160
	the development of the human brain.

	37:30.160 --> 37:32.200
	So we've done a lot of work in science

	37:32.200 --> 37:35.480
	to study the brain on many other organisms.

	37:35.480 --> 37:39.600
	Now we have some technologies which I'll spell out

	37:39.600 --> 37:43.120
	that allow us to actually look at the real thing

	37:43.120 --> 37:45.040
	and look at the brain, at the human brain.

	37:45.040 --> 37:46.840
	So what are these technologies?

	37:46.840 --> 37:50.440
	There has been huge progress in stem cell biology.

	37:50.440 --> 37:54.080
	The moment someone figured out how to turn a skin cell

	37:54.080 --> 37:57.760
	into an embryonic stem cell, basically,

	37:57.760 --> 38:00.160
	and that how that embryonic stem cell

	38:00.160 --> 38:02.480
	could begin a process of development again

	38:02.480 --> 38:04.000
	to, for example, make a brain,

	38:04.000 --> 38:06.040
	there was a huge, you know, advance.

	38:06.040 --> 38:08.200
	And in fact, there was a Nobel Prize for that.

	38:08.200 --> 38:10.440
	That started the field, really,

	38:10.440 --> 38:14.240
	of using stem cells to build organs.

	38:14.240 --> 38:17.080
	Now we can build on all the knowledge of development

	38:17.080 --> 38:18.560
	that we build over the many, many, many years

	38:18.560 --> 38:20.720
	to say, how do we make these stem cells?

	38:20.720 --> 38:22.680
	Now make more and more complex aspects

	38:22.680 --> 38:25.280
	of development of the human brain.

	38:25.280 --> 38:28.480
	So this field is young, the field of brain organoids,

	38:28.480 --> 38:30.120
	but it's moving fast.

	38:30.120 --> 38:32.560
	And it's moving fast in a very serious way

	38:32.560 --> 38:35.960
	that is rooted in labs with the right ethical framework

	38:35.960 --> 38:39.720
	and really building on, you know,

	38:39.720 --> 38:43.520
	solid science for what reality is and what is not.

	38:43.520 --> 38:46.120
	And, but it will go fast

	38:46.120 --> 38:49.120
	and it will be more and more powerful.

	38:49.120 --> 38:52.480
	We also have technology that allows us to basically study

	38:52.480 --> 38:54.640
	the properties of single cells

	38:54.640 --> 38:59.240
	across many, many millions of single cells,

	38:59.240 --> 39:02.160
	which we didn't have perhaps five years ago.

	39:02.160 --> 39:04.840
	So now with that, even an organoid

	39:04.840 --> 39:08.480
	that has millions of cells can be profiled in a way,

	39:08.480 --> 39:11.320
	looked at with very, very high resolution,

	39:11.320 --> 39:14.960
	the single cell level to really understand what is going on.

	39:14.960 --> 39:17.520
	And you could do it in multiple stages of development

	39:17.520 --> 39:20.120
	and you can build your hypothesis and so on and so forth.

	39:20.120 --> 39:22.600
	So it's not gonna be a thousand years.

	39:22.600 --> 39:25.240
	It's gonna be a shorter amount of time.

	39:25.240 --> 39:29.480
	And I see this as sort of an exponential growth

	39:29.480 --> 39:33.560
	of this field enabled by these technologies

	39:33.560 --> 39:35.000
	that we didn't have before.

	39:35.000 --> 39:36.960
	And so we're gonna see something transformative

	39:36.960 --> 39:41.880
	that we didn't see at all in the prior thousand years.

	39:41.880 --> 39:44.640
	So I apologize for the crazy sci fi questions,

	39:44.640 --> 39:48.840
	but the developmental process is fascinating to watch

	39:48.840 --> 39:53.360
	and study, but how far are we away from

	39:53.360 --> 39:57.280
	and maybe how difficult is it to build

	39:57.280 --> 40:02.280
	not just an organoid, but a human brain from a stem cell?

	40:02.280 --> 40:05.640
	Yeah, first of all, that's not the goal

	40:05.640 --> 40:09.400
	for the majority of the serial scientists that work on this

	40:09.400 --> 40:14.160
	because you don't have to build the whole human brain

	40:14.160 --> 40:17.000
	to make this model useful for understanding

	40:17.000 --> 40:20.440
	how the brain develops or understanding disease.

	40:20.440 --> 40:22.440
	You don't have to build the whole thing.

	40:22.440 --> 40:25.200
	So let me just comment on that, it's fascinating.

	40:25.200 --> 40:29.200
	It shows to me the difference between you and I

	40:29.200 --> 40:32.240
	is you're actually trying to understand the beauty

	40:32.240 --> 40:35.520
	of the human brain and to use it to really help

	40:35.520 --> 40:38.800
	thousands or millions of people with disease and so on, right?

	40:38.800 --> 40:41.480
	From an artificial intelligence perspective,

	40:41.480 --> 40:45.600
	we're trying to build systems that we can put in robots

	40:45.600 --> 40:49.080
	and try to create systems that have echoes

	40:49.080 --> 40:52.360
	of the intelligence about reasoning about the world,

	40:52.360 --> 40:53.600
	navigating the world.

	40:53.600 --> 40:56.040
	It's different objectives, I think.

	40:56.040 --> 40:57.520
	Yeah, that's very much science fiction.

	40:57.520 --> 41:00.280
	Science fiction, but we operate in science fiction a little bit.

	41:00.280 --> 41:03.440
	But so on that point of building a brain,

	41:03.440 --> 41:05.800
	even though that is not the focus or interest,

	41:05.800 --> 41:08.520
	perhaps, of the community, how difficult is it?

	41:08.520 --> 41:11.200
	Is it truly science fiction at this point?

	41:11.200 --> 41:13.960
	I think the field will progress, like I said,

	41:13.960 --> 41:17.960
	and that the system will be more and more complex in a way,

	41:17.960 --> 41:18.720
	right?

	41:18.720 --> 41:23.880
	But there are properties that emerge from the human brain

	41:23.880 --> 41:26.640
	that have to do with the mind, that may have to do with consciousness,

	41:26.640 --> 41:29.840
	that may have to do with intelligence or whatever.

	41:29.840 --> 41:33.720
	We really don't understand even how they can emerge

	41:33.720 --> 41:36.880
	from an actual real brain, and therefore, we cannot measure

	41:36.880 --> 41:40.160
	or study in an organoid.

	41:40.160 --> 41:43.040
	So I think that this field, many, many years from now,

	41:43.040 --> 41:48.240
	may lead to the building of better neural circuits

	41:48.240 --> 41:50.640
	that really are built out of understanding of how

	41:50.640 --> 41:52.400
	this process really works.

	41:52.400 --> 41:57.000
	And it's hard to predict how complex this really will be.

	41:57.000 --> 42:01.200
	I really don't think we're so far from, it makes me laugh, really.

	42:01.200 --> 42:05.120
	It's really that far from building the human brain.

	42:05.120 --> 42:10.040
	But you're going to be building something that is always

	42:10.040 --> 42:14.800
	a bad version of it, but that may have really powerful properties

	42:14.800 --> 42:18.560
	and might be able to respond to stimuli

	42:18.560 --> 42:21.880
	or be used in certain contexts.

	42:21.880 --> 42:24.800
	And this is why I really think that there is no other way

	42:24.800 --> 42:28.200
	to do this science, but within the right ethical framework.

	42:28.200 --> 42:31.440
	Because where you're going with this is also,

	42:31.440 --> 42:34.160
	we can talk about science fiction and write that book,

	42:34.160 --> 42:36.600
	and we could today.

	42:36.600 --> 42:41.520
	But this work happens in a specific ethical framework

	42:41.520 --> 42:44.880
	that we don't decide just as scientists, but also as a society.

	42:44.880 --> 42:48.560
	So the ethical framework here is a fascinating one,

	42:48.560 --> 42:51.120
	is a complicated one.

	42:51.120 --> 42:55.680
	Do you have a sense, a grasp of how we think about ethically,

	42:55.680 --> 43:04.160
	of building organoids from human stem cells to understand the brain?

	43:04.160 --> 43:09.720
	It seems like a tool for helping potentially millions of people

	43:09.720 --> 43:14.960
	cure diseases, or at least start to cure by understanding it.

	43:14.960 --> 43:20.560
	But is there more, is there gray areas that are ethical,

	43:20.560 --> 43:22.320
	that we have to think about ethically?

	43:22.320 --> 43:23.160
	Absolutely.

	43:23.160 --> 43:25.520
	We must think about that.

	43:25.520 --> 43:29.560
	Every discussion about the ethics of this

	43:29.560 --> 43:34.480
	needs to be based on actual data from the models that we have today

	43:34.480 --> 43:36.280
	and from the ones that we will have tomorrow.

	43:36.280 --> 43:37.800
	So it's a continuous conversation.

	43:37.800 --> 43:39.840
	It's not something that you decide now.

	43:39.840 --> 43:42.000
	Today, there is no issue, really.

	43:42.000 --> 43:47.240
	Very simple models that clearly can help you in many ways

	43:47.240 --> 43:49.880
	without much to think about.

	43:49.880 --> 43:52.200
	But tomorrow, we need to have another conversation,

	43:52.200 --> 43:53.160
	and so on and so forth.

	43:53.160 --> 43:57.120
	And so the way we do this is to actually really bring together

	43:57.120 --> 44:00.440
	constantly a group of people that are not only scientists,

	44:00.440 --> 44:04.160
	but also bioethicists, lawyers, philosophers, psychiatrists,

	44:04.160 --> 44:06.680
	and psychologists, and so on and so forth,

	44:06.680 --> 44:13.040
	to decide as a society, really, what we should

	44:13.040 --> 44:15.320
	and what we should not do.

	44:15.320 --> 44:17.600
	So that's the way to think about the ethics.

	44:17.600 --> 44:21.440
	Now, I also think, though, that as a scientist,

	44:21.440 --> 44:23.840
	I have a moral responsibility.

	44:23.840 --> 44:28.360
	So if you think about how transformative

	44:28.360 --> 44:32.640
	it could be for understanding and curing a neuropsychiatric

	44:32.640 --> 44:37.320
	disease, to be able to actually watch and study

	44:37.320 --> 44:41.480
	and treat with drugs the very brain of the patient

	44:41.480 --> 44:44.720
	that you are trying to study, how transformative

	44:44.720 --> 44:47.200
	at this moment in time this could be.

	44:47.200 --> 44:47.960
	We couldn't do it.

	44:47.960 --> 44:50.800
	Five years ago, we could do it now.

	44:50.800 --> 44:53.440
	Taking a stem cell of a particular patient

	44:53.440 --> 44:57.480
	and make an organoid for a simple and different

	44:57.480 --> 45:01.160
	from the human brain, it still is his process

	45:01.160 --> 45:04.720
	of brain development with his or her genetics.

	45:04.720 --> 45:08.280
	And we could understand perhaps what is going wrong.

	45:08.280 --> 45:10.960
	Perhaps we could use as a platform, as a cellular platform,

	45:10.960 --> 45:13.720
	to screen for drugs, to fix a process,

	45:13.720 --> 45:15.280
	and so on and so forth.

	45:15.280 --> 45:18.840
	So we could do it now, we couldn't do it five years ago.

	45:18.840 --> 45:20.480
	Should we not do it?

	45:20.480 --> 45:24.760
	What is the downside of doing it?

	45:24.760 --> 45:27.320
	I don't see a downside at this very moment.

	45:27.320 --> 45:30.880
	If we invited a lot of people, I'm sure there would be

	45:30.880 --> 45:33.440
	somebody who would argue against it,

	45:33.440 --> 45:37.680
	what would be the devil's advocate argument?

	45:39.680 --> 45:42.960
	So it's exactly perhaps what you alluded at

	45:42.960 --> 45:47.120
	with your question, that you are making a,

	45:47.120 --> 45:51.680
	enabling some process of formation of the brain

	45:51.680 --> 45:54.440
	that could be misused at some point,

	45:54.440 --> 45:59.080
	or that could be showing properties

	45:59.080 --> 46:03.960
	that ethically we don't wanna see in a tissue.

	46:03.960 --> 46:07.760
	So today, I repeat, today this is not an issue.

	46:07.760 --> 46:11.280
	And so you just gain dramatically from the science

	46:11.280 --> 46:13.720
	without, because the system is so simple

	46:13.720 --> 46:17.840
	and so different in a way from the actual brain.

	46:17.840 --> 46:20.000
	But because it is the brain,

	46:20.000 --> 46:23.960
	we have an obligation to really consider all of this, right?

	46:23.960 --> 46:27.160
	And again, it's a balanced conversation

	46:27.160 --> 46:30.360
	where we should put disease and betterment of humanity

	46:30.360 --> 46:32.440
	also on that plate.

	46:32.440 --> 46:35.440
	What do you think, at least historically,

	46:35.440 --> 46:37.280
	there was some politicization,

	46:37.280 --> 46:42.280
	politicization of embryonic stem cells,

	46:44.360 --> 46:45.960
	a stem cell research.

	46:47.160 --> 46:49.160
	Do you still see that out there?

	46:49.160 --> 46:53.600
	Is that still a force that we have to think about,

	46:53.600 --> 46:55.600
	especially in this larger discourse

	46:55.600 --> 46:57.600
	that we're having about the role of science

	46:57.600 --> 47:00.640
	in at least American society?

	47:00.640 --> 47:03.520
	Yeah, this is a very good question.

	47:03.520 --> 47:05.040
	It's very, very important.

	47:05.040 --> 47:08.480
	I see a very central role for scientists

	47:08.480 --> 47:12.040
	to inform decisions about what we should

	47:12.040 --> 47:14.440
	or should not do in society.

	47:14.440 --> 47:16.400
	And this is because the scientists

	47:16.400 --> 47:20.440
	have the firsthand look and understanding

	47:20.440 --> 47:23.520
	of really the work that they are doing.

	47:23.520 --> 47:26.080
	And again, this varies depending on

	47:26.080 --> 47:27.480
	what we're talking about here.

	47:27.480 --> 47:30.800
	So now we're talking about brain organoids.

	47:30.800 --> 47:33.800
	I think that the scientists need to be part

	47:33.800 --> 47:36.520
	of that conversation about what is,

	47:36.520 --> 47:38.040
	will be allowed in the future

	47:38.040 --> 47:40.840
	or not allowed in the future to do with the system.

	47:40.840 --> 47:43.400
	And I think that is very, very important

	47:43.400 --> 47:47.880
	because they bring reality of data to the conversation.

	47:48.880 --> 47:51.720
	And so they should have a voice.

	47:51.720 --> 47:53.400
	So data should have a voice.

	47:53.400 --> 47:55.200
	Data needs to have a voice.

	47:55.200 --> 47:59.360
	Because in not only data, we should also be good

	47:59.360 --> 48:04.240
	at communicating with non scientists the data.

	48:04.240 --> 48:06.840
	So there has been, often time,

	48:06.840 --> 48:11.840
	there is a lot of discussion and excitement

	48:12.280 --> 48:16.320
	and fights about certain topics

	48:16.320 --> 48:19.320
	just because of the way they are described.

	48:19.320 --> 48:21.000
	I'll give you an example.

	48:21.000 --> 48:23.400
	If I called the same cellular system,

	48:23.400 --> 48:27.080
	we just talked about a brain organoid.

	48:27.080 --> 48:30.320
	Or if I called it a human mini brain,

	48:30.320 --> 48:34.600
	your reaction is gonna be very different to this.

	48:34.600 --> 48:37.760
	And so the way the systems are described,

	48:37.760 --> 48:40.720
	I mean, we and journalists alike

	48:40.720 --> 48:43.720
	need to be a bit careful that this debate

	48:43.720 --> 48:46.080
	is a real debate and informed by real data.

	48:46.080 --> 48:47.960
	That's all I'm asking.

	48:47.960 --> 48:49.600
	And yeah, the language matters here.

	48:49.600 --> 48:51.280
	So I work on autonomous vehicles

	48:51.280 --> 48:54.960
	and there the use of language could drastically

	48:54.960 --> 48:57.480
	change the interpretation and the way people feel

	48:57.480 --> 49:01.520
	about what is the right way to proceed forward.

	49:01.520 --> 49:04.720
	You are, as I've seen from a presentation,

	49:04.720 --> 49:06.240
	you're a parent.

	49:06.240 --> 49:09.840
	I saw you show a couple of pictures of your son.

	49:09.840 --> 49:11.440
	Is it just the one?

	49:11.440 --> 49:12.280
	Two.

	49:12.280 --> 49:13.120
	Two.

	49:13.120 --> 49:13.960
	Son and a daughter.

	49:13.960 --> 49:14.800
	Son and a daughter.

	49:14.800 --> 49:17.360
	So what have you learned from the human brain

	49:17.360 --> 49:20.120
	by raising two of them?

	49:20.120 --> 49:22.800
	More than I could ever learn in a lab.

	49:22.800 --> 49:25.600
	What have I learned?

	49:26.840 --> 49:28.640
	I've learned that children really have

	49:28.640 --> 49:31.520
	these amazing plastic minds, right?

	49:31.520 --> 49:35.880
	That we have a responsibility to, you know,

	49:35.880 --> 49:38.440
	foster their growth in good, healthy ways

	49:39.360 --> 49:42.320
	that keep them curious, that keep some adventures,

	49:42.320 --> 49:45.920
	that doesn't raise them in fear of things.

	49:46.840 --> 49:48.920
	But also respecting who they are,

	49:48.920 --> 49:51.320
	which is in part, you know, coming from the genetics

	49:51.320 --> 49:53.840
	we talked about, my children are very different

	49:53.840 --> 49:55.240
	from each other despite the fact

	49:55.240 --> 49:57.840
	that they're the product of the same two parents.

	49:59.320 --> 50:03.080
	I also learned that what you do for them

	50:03.080 --> 50:04.280
	comes back to you.

	50:04.280 --> 50:05.840
	Like, you know, if you're a good parent,

	50:05.840 --> 50:09.800
	you're gonna, most of the time have, you know,

	50:09.800 --> 50:12.200
	perhaps decent kids at the end.

	50:12.200 --> 50:13.760
	So what do you think, just a quick comment,

	50:13.760 --> 50:17.760
	what do you think is the source of that difference?

	50:17.760 --> 50:20.960
	It's often the surprising thing for parents.

	50:20.960 --> 50:24.000
	I can't believe that our kids,

	50:25.640 --> 50:28.080
	they're so different, yet they came from the same parents.

	50:28.080 --> 50:29.640
	Well, they are genetically different.

	50:29.640 --> 50:31.920
	Even they came from the same two parents

	50:31.920 --> 50:33.640
	because the mixing of gametes,

	50:33.640 --> 50:35.720
	so when we know these genetics,

	50:35.720 --> 50:39.800
	creates every time a genetically different individual

	50:39.800 --> 50:43.760
	which will have a specific mix of genes

	50:43.760 --> 50:46.560
	that is a different mix every time from the two parents.

	50:46.560 --> 50:50.320
	And so they're not twins.

	50:50.320 --> 50:52.960
	They're genetically different.

	50:52.960 --> 50:55.320
	Just that little bit of variation.

	50:55.320 --> 50:58.320
	As you said, really from a biological perspective,

	50:58.320 --> 51:00.600
	the brains look pretty similar.

	51:00.600 --> 51:02.400
	Well, so let me clarify that.

	51:02.400 --> 51:05.400
	So the genetics you have, the genes that you have,

	51:05.400 --> 51:08.680
	that play that beautiful orchestrated symphony

	51:08.680 --> 51:12.040
	of development, different genes

	51:12.040 --> 51:13.920
	will play it slightly differently.

	51:13.920 --> 51:16.120
	It's like playing the same piece of music

	51:16.120 --> 51:17.960
	but with the different orchestra

	51:17.960 --> 51:20.000
	and a different director, right?

	51:20.000 --> 51:21.440
	The music will not come out.

	51:21.440 --> 51:25.400
	It will be still a piece by the same author

	51:25.400 --> 51:27.040
	but it will come out differently

	51:27.040 --> 51:28.920
	if it's played by the high school orchestra

	51:28.920 --> 51:33.440
	instead of the, instead of the Scala in Milan.

	51:34.680 --> 51:39.160
	And so you are born superficially with the same brain.

	51:39.160 --> 51:43.440
	It has the same cell types, similar patterns of connectivity

	51:43.440 --> 51:45.200
	but the properties of the cells

	51:45.200 --> 51:47.600
	and how the cells will then react to the environment

	51:47.600 --> 51:51.320
	as you experience your world will be also shaped

	51:51.320 --> 51:53.680
	by who genetically you are.

	51:53.680 --> 51:55.120
	Speaking just as a parent,

	51:55.120 --> 51:56.880
	this is not something that comes from my work.

	51:56.880 --> 51:58.840
	I think you can tell at birth

	51:58.840 --> 52:01.120
	that these kids are different

	52:01.120 --> 52:04.560
	and that they have a different personality in a way, right?

	52:05.560 --> 52:07.600
	So both is needed.

	52:07.600 --> 52:10.800
	The genetics as well as the nurturing afterwards.

	52:11.760 --> 52:14.600
	So you are one human with a brain

	52:14.600 --> 52:17.200
	sort of living through the whole mess of it.

	52:17.200 --> 52:21.000
	The human condition, full of love, maybe fear,

	52:21.000 --> 52:22.880
	ultimately mortal.

	52:23.880 --> 52:27.080
	How has studying the brain changed the way you see yourself?

	52:27.080 --> 52:29.880
	When you look in the mirror, when you think about your life,

	52:29.880 --> 52:31.880
	the fears, the love.

	52:31.880 --> 52:34.040
	When you see your own life, your own mortality.

	52:34.040 --> 52:36.840
	Yeah, that's a very good question.

	52:37.960 --> 52:43.160
	It's almost impossible to dissociate some time for me.

	52:43.160 --> 52:45.880
	Some of the things we do or some of the things

	52:45.880 --> 52:48.200
	that other people do from,

	52:48.200 --> 52:51.080
	oh, that's because that part of the brain

	52:51.960 --> 52:54.080
	is working in a certain way.

	52:54.080 --> 52:57.840
	Or thinking about a teenager,

	52:59.080 --> 53:01.800
	going through teenage years and being a time funny

	53:01.800 --> 53:03.560
	in the way they think.

	53:03.560 --> 53:07.200
	And impossible for me not to think it's because

	53:07.200 --> 53:10.480
	they're going through this period of time called

	53:10.480 --> 53:12.640
	critical periods of plasticity.

	53:12.640 --> 53:13.480
	Yeah.

	53:13.480 --> 53:16.400
	Where their synapses are being eliminated here and there

	53:16.400 --> 53:17.760
	and they're just confused.

	53:17.760 --> 53:22.280
	And so from that comes perhaps a different take

	53:22.280 --> 53:27.280
	on that behavior or maybe I can justify scientifically

	53:28.080 --> 53:30.120
	in some sort of way.

	53:30.120 --> 53:32.280
	I also look at humanity in general

	53:32.280 --> 53:37.040
	and I am amazed by what we can do

	53:37.040 --> 53:39.960
	and the kind of ideas that we can come up with.

	53:39.960 --> 53:42.840
	And I cannot stop thinking about

	53:42.840 --> 53:46.440
	how the brain is continuing to evolve.

	53:46.440 --> 53:47.360
	I don't know if you do this,

	53:47.360 --> 53:49.720
	but I think about the next brain sometimes.

	53:49.720 --> 53:51.080
	Where are we going with this?

	53:51.080 --> 53:53.920
	Like what are the features of this brain

	53:53.920 --> 53:57.920
	that evolution is really playing with

	53:57.920 --> 54:02.920
	to get us in the future, the new brain?

	54:03.080 --> 54:04.280
	It's not over, right?

	54:04.280 --> 54:07.200
	It's a work in progress.

	54:07.200 --> 54:09.280
	So let me just a quick comment on that.

	54:09.280 --> 54:14.280
	Do you see, do you think there's a lot of fascination

	54:14.520 --> 54:16.240
	and hope for artificial intelligence

	54:16.240 --> 54:17.960
	of creating artificial brains?

	54:17.960 --> 54:20.320
	You said the next brain.

	54:20.320 --> 54:23.600
	When you imagine over a period of a thousand years

	54:23.600 --> 54:25.760
	the evolution of the human brain,

	54:25.760 --> 54:28.920
	do you sometimes envisioning that future

	54:28.920 --> 54:31.440
	see an artificial one?

	54:31.440 --> 54:34.280
	Artificial intelligence as it is hoped by many,

	54:34.280 --> 54:36.840
	not hoped, thought by many people

	54:36.840 --> 54:39.120
	would be actually the next evolutionary step

	54:39.120 --> 54:40.680
	in the development of humans.

	54:40.680 --> 54:45.480
	Yeah, I think in a way that will happen, right?

	54:45.480 --> 54:48.760
	It's almost like a part of the way we evolve.

	54:48.760 --> 54:51.400
	We evolve in the world that we created,

	54:51.400 --> 54:55.520
	that we interact with, that shape us as we grow up

	54:55.520 --> 54:56.840
	and so on and so forth.

	54:58.440 --> 55:01.120
	Sometime I think about something that may sound silly,

	55:01.120 --> 55:04.720
	but think about the use of cell phones.

	55:04.720 --> 55:07.240
	Part of me thinks that somehow in their brain

	55:07.240 --> 55:09.160
	there will be a region of the cortex

	55:09.160 --> 55:13.720
	that is attuned to that tool.

	55:13.720 --> 55:16.600
	And this comes from a lot of studies

	55:16.600 --> 55:21.000
	in model organisms where really the cortex

	55:21.000 --> 55:24.280
	especially adapts to the kind of things you have to do.

	55:24.280 --> 55:28.640
	So if we need to move our fingers in a very specific way,

	55:28.640 --> 55:31.040
	we have a part of our cortex that allows us to do

	55:31.040 --> 55:33.080
	this kind of very precise movement.

	55:34.440 --> 55:37.000
	An owl that has to see very, very far away

	55:37.000 --> 55:39.440
	with big eyes, the visual cortex, very big.

	55:39.440 --> 55:43.280
	It's the brain attunes to your environment.

	55:43.280 --> 55:47.600
	So the brain will attune to the technologies

	55:47.600 --> 55:51.200
	that we will have and will be shaped by it.

	55:51.200 --> 55:53.000
	So the cortex very well may be.

	55:53.000 --> 55:54.640
	Will be shaped by it.

	55:54.640 --> 55:57.360
	In artificial intelligence, it may merge with it,

	55:57.360 --> 56:01.240
	it may get enveloped and adjusted.

	56:01.240 --> 56:04.200
	Even if it's not a merge of the kind of,

	56:04.200 --> 56:07.000
	oh, let's have a synthetic element together

	56:07.000 --> 56:08.800
	with a biological one.

	56:08.800 --> 56:11.840
	The very space around us, the fact, for example,

	56:11.840 --> 56:15.280
	think about we put on some goggles of virtual reality

	56:15.280 --> 56:18.840
	and we physically are surfing the ocean, right?

	56:18.840 --> 56:21.800
	Like I've done it and you have all these emotions

	56:21.800 --> 56:26.800
	that come to you, your brain placed you in that reality.

	56:27.200 --> 56:29.720
	And it was able to do it like that

	56:29.720 --> 56:31.160
	just by putting the goggles on.

	56:31.160 --> 56:36.040
	I didn't take thousands of years of adapting to this.

	56:36.040 --> 56:39.360
	The brain is plastic, so adapts to new technology.

	56:39.360 --> 56:41.840
	So you could do it from the outside

	56:41.840 --> 56:46.840
	by simply hijacking some sensory capacities that we have.

	56:47.680 --> 56:51.640
	So clearly over recent evolution,

	56:51.640 --> 56:54.040
	the cerebral cortex has been a part of the brain

	56:54.040 --> 56:56.040
	that has known the most evolution.

	56:56.040 --> 57:00.840
	So we have put a lot of chips on evolving

	57:00.840 --> 57:02.640
	this specific part of the brain

	57:02.640 --> 57:06.000
	and the evolution of cortex is plasticity.

	57:06.000 --> 57:10.320
	It's this ability to change in response to things.

	57:10.320 --> 57:13.840
	So yes, they will integrate that we want it or not.

	57:15.000 --> 57:18.200
	Well, there's no better way to end it, Paola.

	57:18.200 --> 57:19.520
	Thank you so much for talking to me.

	57:19.520 --> 57:20.360
	You're very welcome.

	57:20.360 --> 57:21.200
	That's great.

	57:21.200 --> 57:31.200
	Thank you.