Paola Arlotta: Brain Development from Stem Cell to Organoid
生物与进化音乐与艺术技术与编程心理与人性AI 与机器学习
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🔑 关键词
braincellsdevelopmentcellhumanstemorganoidbuildingneuronscortexdonembryomyelinmadetypesorganoidsstudygoingputhappens
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🎙️ 完整对话（1188 条）
Lex Fridman (00:00.000)
The following is a conversation with Paola Arlotta.
以下是与保拉·阿洛塔的对话。
Lex Fridman (00:03.360)
She's a professor of stem cell and regenerative biology
她是干细胞和再生生物学教授
Lex Fridman (00:06.380)
at Harvard University and is interested in understanding
在哈佛大学，有兴趣了解
Lex Fridman (00:09.760)
the molecular laws that govern the birth, differentiation,
控制出生、分化的分子法则，
Lex Fridman (00:13.160)
and assembly of the human brain's cerebral cortex.
以及人脑大脑皮层的组装。
Paola Arlotta (00:16.600)
She explores the complexity of the brain
她探索大脑的复杂性
Lex Fridman (00:18.400)
by studying and engineering elements
通过研究和工程元素
Paola Arlotta (00:21.000)
of how the brain develops.
大脑如何发育。
Lex Fridman (00:22.880)
This was a fascinating conversation to me.
这对我来说是一次有趣的谈话。
Paola Arlotta (00:25.640)
It's part of the Artificial Intelligence podcast.
这是人工智能播客的一部分。
Lex Fridman (00:28.560)
If you enjoy it, subscribe on YouTube,
如果您喜欢，请在 YouTube 上订阅，
Paola Arlotta (00:30.600)
give it five stars on iTunes, support it on Patreon,
在 iTunes 上给它五颗星，在 Patreon 上支持它，
Lex Fridman (00:33.800)
or simply connect with me on Twitter
或者直接在 Twitter 上与我联系
Paola Arlotta (00:35.800)
at Lex Friedman, spelled F R I D M A N.
在 Lex Friedman，拼写为 F R I D M A N。
Lex Fridman (00:39.960)
And I'd like to give a special thank you to Amy Jeffress
我要特别感谢艾米·杰弗里斯
Paola Arlotta (00:43.120)
for her support of the podcast on Patreon.
以表彰她对 Patreon 播客的支持。
Lex Fridman (00:45.560)
She's an artist and you should definitely check out
她是一位艺术家，你一定要看看
Paola Arlotta (00:47.660)
her Instagram at lovetruthgood, three beautiful words.
她的 Instagram 上的 lovetruthgood，三个美丽的词。
Lex Fridman (00:52.760)
Your support means a lot and inspires me
您的支持意义重大并激励着我
Paola Arlotta (00:55.640)
to keep the series going.
让这个系列继续下去。
Lex Fridman (00:57.720)
And now here's my conversation with Paola Arlotta.
Paola Arlotta (01:03.120)
You studied the development of the human brain
Lex Fridman (01:05.320)
for many years.
Lex Fridman (01:06.720)
So let me ask you an out of the box question first.
Lex Fridman (01:11.480)
How likely is it that there's intelligent life out there
Paola Arlotta (01:14.600)
in the universe outside of earth
Lex Fridman (01:17.160)
with something like the human brain?
Lex Fridman (01:19.320)
So I can put it another way.
Lex Fridman (01:20.760)
How unlikely is the human brain?
Lex Fridman (01:24.320)
How difficult is it to build a thing
Lex Fridman (01:28.320)
through the evolutionary process?
Lex Fridman (01:30.360)
Well, it has happened here, right?
Lex Fridman (01:32.480)
On this planet.
Paola Arlotta (01:33.320)
Once, yes.
Lex Fridman (01:34.160)
Once.
Lex Fridman (01:36.320)
So that simply tells you that it could, of course,
Lex Fridman (01:39.940)
happen again other places.
Paola Arlotta (01:42.120)
It's only a matter of probability.
Lex Fridman (01:44.080)
What the probability that you would get a brain
Paola Arlotta (01:46.560)
like the ones that we have, like the human brain.
Lex Fridman (01:51.200)
So how difficult is it to make the human brain?
Paola Arlotta (01:53.960)
It's pretty difficult, but most importantly,
Lex Fridman (01:59.040)
I guess we know very little
Paola Arlotta (02:00.920)
about how this process really happens.
Lex Fridman (02:04.400)
And there is a reason for that,
Paola Arlotta (02:06.280)
actually multiple reasons for that.
Lex Fridman (02:09.080)
Most of what we know about how the mammalian brain,
Lex Fridman (02:13.280)
so the brain of mammals develop comes from studying
Lex Fridman (02:17.000)
in labs other brains, not our own brain,
Paola Arlotta (02:20.440)
the brain of mice, for example.
Lex Fridman (02:22.520)
But if I showed you a picture of a mouse brain,
Lex Fridman (02:25.360)
and then you put it next to a picture of a human brain,
Lex Fridman (02:28.320)
they don't look at all like each other.
Lex Fridman (02:31.080)
So they're very different.
Lex Fridman (02:32.960)
And therefore there is a limit to what you can learn
Paola Arlotta (02:36.200)
about how the human brain is made
Lex Fridman (02:37.880)
by studying the mouse brain.
Paola Arlotta (02:41.000)
There is a huge value in studying the mouse brain.
Lex Fridman (02:43.240)
There are many things that we have learned,
Lex Fridman (02:45.000)
but it's not the same thing.
Lex Fridman (02:46.520)
So in having studied the human brain,
Paola Arlotta (02:49.120)
or through the mouse and through other methodologies
Lex Fridman (02:51.360)
that we'll talk about, do you have a sense?
Paola Arlotta (02:54.640)
I mean, you're one of the experts in the world.
Lex Fridman (02:57.440)
How much do you feel you know about the brain
Lex Fridman (03:01.040)
and how often do you find yourself
Lex Fridman (03:05.280)
in awe of this mysterious thing?
Paola Arlotta (03:07.720)
Yeah, you pretty much find yourself in awe all the time.
Lex Fridman (03:12.120)
It's an amazing process.
Paola Arlotta (03:15.240)
It's a process by which,
Lex Fridman (03:17.840)
by means that we don't fully understand,
Paola Arlotta (03:20.640)
at the very beginning of embryogenesis,
Lex Fridman (03:23.560)
the structure called the neural tube,
Paola Arlotta (03:26.240)
literally self assembles.
Lex Fridman (03:28.720)
And it happens in an embryo
Lex Fridman (03:30.360)
and it can happen also from stem cells in a dish.
Lex Fridman (03:33.680)
Okay.
Lex Fridman (03:34.840)
And then from there,
Lex Fridman (03:36.840)
these stem cells that are present within the neural tube
Paola Arlotta (03:39.800)
give rise to all of the thousands and thousands
Lex Fridman (03:42.200)
of different cell types that are present in the brain
Lex Fridman (03:45.040)
through time, right?
Lex Fridman (03:46.480)
With the interesting, very intriguing, interesting
Paola Arlotta (03:50.920)
observation is that the time that it takes
Lex Fridman (03:54.880)
for the human brain to be made, it's human time.
Paola Arlotta (03:58.760)
Meaning that for me and you,
Lex Fridman (04:02.120)
it took almost nine months of gestation to build the brain
Lex Fridman (04:05.240)
and then another 20 years of learning postnatally
Lex Fridman (04:08.680)
to get the brain that we have today
Paola Arlotta (04:09.960)
that allows us to this conversation.
Lex Fridman (04:12.080)
A mouse takes 20 days or so for an embryo to be born.
Lex Fridman (04:19.560)
And so the brain is built in a much shorter period of time.
Lex Fridman (04:23.760)
And the beauty of it is that if you take mouse stem cells
Lex Fridman (04:27.160)
and you put them in a culture dish,
Lex Fridman (04:29.840)
the brain organoid that you get from a mouse
Paola Arlotta (04:33.280)
is formed faster than if you took human stem cells
Lex Fridman (04:37.600)
and put them in the dish
Lex Fridman (04:39.080)
and let them make a human brain organoid.
Lex Fridman (04:41.960)
So the very developmental process is...
Paola Arlotta (04:45.520)
Controlled by the speed of the species.
Lex Fridman (04:49.040)
Which means it's on purpose, it's not accidental
Paola Arlotta (04:54.040)
or there is something in that temporal...
Lex Fridman (04:58.320)
It's very, exactly, that is very important
Paola Arlotta (05:01.440)
for us to get the brain we have.
Lex Fridman (05:04.000)
And we can speculate for why that is.
Paola Arlotta (05:08.080)
You know, it takes us a long time as human beings
Lex Fridman (05:11.560)
after we're born to learn all the things
Paola Arlotta (05:14.520)
that we have to learn to have the adult brain.
Lex Fridman (05:17.920)
It's actually 20 years, think about it.
Paola Arlotta (05:20.120)
From when a baby is born to when a teenager
Lex Fridman (05:23.400)
goes through puberty to adults, it's a long time.
Lex Fridman (05:27.160)
Do you think you can maybe talk through
Lex Fridman (05:30.240)
the first few months and then on to the first 20 years
Lex Fridman (05:35.040)
and then for the rest of their lives?
Lex Fridman (05:37.560)
What is the development of the human brain look like?
Lex Fridman (05:41.080)
What are the different stages?
Lex Fridman (05:42.480)
Yeah, at the beginning, you have to build a brain, right?
Lex Fridman (05:46.720)
And the brain is made of cells.
Lex Fridman (05:48.840)
What's the very beginning?
Lex Fridman (05:49.760)
Which beginning are we talking about?
Lex Fridman (05:52.000)
In the embryo, as the embryo is developing in the womb,
Paola Arlotta (05:56.000)
in addition to making all of the other tissues
Lex Fridman (05:58.520)
of the embryo, the muscle, the heart, the blood,
Paola Arlotta (06:02.040)
the embryo is also building the brain.
Lex Fridman (06:04.960)
And it builds from a very simple structure
Paola Arlotta (06:08.440)
called the neural tube, which is basically nothing
Lex Fridman (06:11.200)
but a tube of cells that spans sort of the length
Paola Arlotta (06:14.760)
of the embryo from the head all the way to the tail,
Lex Fridman (06:18.480)
let's say, of the embryo.
Lex Fridman (06:20.800)
And then over in human beings, over many months of gestation
Lex Fridman (06:25.520)
from that neural tube, which contains stem cell
Paola Arlotta (06:30.280)
like cells of the brain, you will make many, many
Lex Fridman (06:35.120)
other building blocks of the brain.
Lex Fridman (06:36.960)
So all of the other cell types, because there are many,
Lex Fridman (06:40.160)
many different types of cells in the brain
Paola Arlotta (06:43.040)
that will form specific structures of the brain.
Lex Fridman (06:46.600)
So you can think about embryonic development of the brain
Paola Arlotta (06:49.760)
as just the time in which you are making
Lex Fridman (06:51.600)
the building blocks, the cells.
Paola Arlotta (06:54.400)
Are the stem cells relatively homogeneous, like uniform,
Lex Fridman (06:57.600)
or are they all different types?
Paola Arlotta (06:59.440)
It's a very good question.
Lex Fridman (07:00.280)
It's exactly how it works.
Paola Arlotta (07:01.240)
You start with a more homogeneous,
Lex Fridman (07:04.160)
perhaps more multipotent type of stem cell.
Paola Arlotta (07:09.160)
With multipotent.
Lex Fridman (07:10.000)
With multipotent it means that it has the potential
Paola Arlotta (07:13.520)
to make many, many different types of other cells.
Lex Fridman (07:17.200)
And then with time, these progenitors become
Paola Arlotta (07:20.200)
more heterogeneous, which means more diverse.
Lex Fridman (07:22.840)
There are gonna be many different types of the stem cells.
Lex Fridman (07:26.200)
And also they will give rise to progeny to other cells
Lex Fridman (07:30.080)
that are not stem cells, that are specific cells
Paola Arlotta (07:32.880)
of the brain that are very different
Lex Fridman (07:34.200)
from the mother stem cell.
Lex Fridman (07:35.880)
And now you think about this process of making cells
Lex Fridman (07:38.880)
from the stem cells over many, many months
Paola Arlotta (07:41.560)
of development for humans.
Lex Fridman (07:43.840)
And what you're doing, you're building the cells
Paola Arlotta (07:46.200)
that physically make the brain,
Lex Fridman (07:48.240)
and then you arrange them in specific structures
Paola Arlotta (07:52.440)
that are present in the final brain.
Lex Fridman (07:55.480)
So you can think about the embryonic development
Paola Arlotta (07:58.720)
of the brain as the time where you're building the bricks,
Lex Fridman (08:02.160)
you're putting the bricks together to form buildings,
Paola Arlotta (08:05.560)
structures, regions of the brain.
Lex Fridman (08:08.160)
And where you make the connections
Paola Arlotta (08:10.400)
between these many different type of cells,
Lex Fridman (08:13.080)
especially nerve cells, neurons, right?
Paola Arlotta (08:15.280)
That transmit action potentials and electricity.
Lex Fridman (08:19.280)
I've heard you also say somewhere, I think,
Paola Arlotta (08:21.360)
correct me if I'm wrong,
Lex Fridman (08:22.320)
that the order of the way this builds matters.
Paola Arlotta (08:25.160)
Oh yes.
Lex Fridman (08:26.080)
If you are an engineer and you think about development,
Paola Arlotta (08:29.920)
you can think of it as, well, I could also take all the cells
Lex Fridman (08:35.040)
and bring them all together into a brain in the end.
Lex Fridman (08:38.000)
But development is much more than that.
Lex Fridman (08:40.360)
So the cells are made in a very specific order
Paola Arlotta (08:43.920)
that subserve the final product that you need to get.
Lex Fridman (08:47.440)
And so, for example, all of the nerve cells,
Paola Arlotta (08:49.920)
the neurons are made first,
Lex Fridman (08:52.240)
and all of the supportive cells of the neurons,
Paola Arlotta (08:54.440)
like the glia, is made later.
Lex Fridman (08:56.840)
And there is a reason for that
Paola Arlotta (08:58.440)
because they have to assemble together in specific ways.
Lex Fridman (09:02.160)
But you also may say, well,
Lex Fridman (09:03.400)
why don't we just put them all together in the end?
Lex Fridman (09:05.800)
It's because as they develop next to each other,
Paola Arlotta (09:09.000)
they influence their own development.
Lex Fridman (09:11.360)
So it's a different thing for a glia
Paola Arlotta (09:13.280)
to be made alone in a dish,
Lex Fridman (09:15.480)
than a glia cell be made in a developing embryo
Paola Arlotta (09:19.440)
with all these other cells around it
Lex Fridman (09:21.400)
that produce all these other signals.
Paola Arlotta (09:23.760)
First of all, that's mind blowing,
Lex Fridman (09:25.960)
this development process.
Paola Arlotta (09:27.880)
From my perspective in artificial intelligence,
Lex Fridman (09:29.800)
you often think of how incredible the final product is,
Paola Arlotta (09:33.480)
the final product, the brain.
Lex Fridman (09:35.200)
But you're making me realize that the final product
Paola Arlotta (09:38.440)
is just, the beautiful thing
Lex Fridman (09:42.080)
is the actual development process.
Lex Fridman (09:44.480)
Do we know the code that drives that development?
Lex Fridman (09:51.160)
Yeah.
Lex Fridman (09:52.000)
Do we have any sense?
Lex Fridman (09:53.880)
First of all, thank you for saying
Paola Arlotta (09:55.800)
that it's really the formation of the brain.
Lex Fridman (09:59.320)
It's really its development.
Paola Arlotta (10:00.680)
It is this incredibly choreographed dance
Lex Fridman (10:05.120)
that happens the same way every time
Lex Fridman (10:07.480)
each one of us builds the brain, right?
Lex Fridman (10:10.560)
And that builds an organ that allows us
Lex Fridman (10:12.680)
to do what we're doing today, right?
Lex Fridman (10:14.920)
That is mind blowing.
Lex Fridman (10:16.360)
And this is why developmental neurobiologists
Lex Fridman (10:18.920)
never get tired of studying that.
Paola Arlotta (10:21.880)
Now you're asking about the code.
Lex Fridman (10:23.800)
What drives this?
Lex Fridman (10:24.880)
How is this done?
Lex Fridman (10:26.480)
Well, it's millions of years of evolution
Paola Arlotta (10:29.720)
of really fine tuning gene expression programs
Lex Fridman (10:33.160)
that allow certain cells to be made at a certain time
Lex Fridman (10:37.440)
and to become a certain cell type,
Lex Fridman (10:41.680)
but also mechanical forces of pressure bending.
Paola Arlotta (10:47.360)
This embryo is not just, it will not stay a tube,
Lex Fridman (10:50.320)
this brain for very long.
Paola Arlotta (10:52.000)
At some point, this tube in the front of the embryo
Lex Fridman (10:54.880)
will expand to make the primordium of the brain, right?
Paola Arlotta (10:58.160)
Now the forces that control that the cells feel,
Lex Fridman (11:02.840)
and this is another beautiful thing,
Paola Arlotta (11:04.960)
the very force that they feel,
Lex Fridman (11:06.840)
which is different from a week before, a week ago,
Paola Arlotta (11:10.240)
will tell the cell, oh, you're being squished
Lex Fridman (11:12.280)
in a certain way, begin to produce these new genes
Paola Arlotta (11:16.600)
because now you are at the corner
Lex Fridman (11:18.440)
or you are in a stretch of cells
Paola Arlotta (11:21.480)
or whatever it is, and that,
Lex Fridman (11:23.960)
so that mechanical physical force
Paola Arlotta (11:26.000)
shapes the fate of the cell as well.
Lex Fridman (11:29.480)
So it's not only chemical, it's also mechanical.
Lex Fridman (11:32.920)
So from my perspective,
Lex Fridman (11:34.440)
biology is this incredibly complex mess, gooey mess.
Lex Fridman (11:40.400)
So you're saying mechanical forces.
Lex Fridman (11:43.880)
How different is like a computer
Paola Arlotta (11:47.760)
or any kind of mechanical machine that we humans build
Lex Fridman (11:52.120)
and the biological systems?
Paola Arlotta (11:54.000)
Have you been,
Lex Fridman (11:54.840)
because you've worked a lot with biological systems.
Paola Arlotta (11:57.000)
Are they as much of a mess as it seems
Lex Fridman (12:00.680)
from a perspective of an engineer, a mechanical engineer?
Paola Arlotta (12:03.560)
Yeah, they are much more prone
Lex Fridman (12:08.400)
to taking alternative routes, right?
Lex Fridman (12:11.680)
So if you, we go back to printing a brain
Lex Fridman (12:16.040)
versus developing a brain,
Paola Arlotta (12:18.200)
of course, if you print a brain,
Lex Fridman (12:20.480)
given that you start with the same building blocks,
Paola Arlotta (12:23.040)
the same cells,
Lex Fridman (12:23.960)
you could potentially print it the same way every time,
Lex Fridman (12:28.640)
but that final brain may not work the same way
Lex Fridman (12:32.520)
as a brain built during development does
Paola Arlotta (12:34.440)
because the very same building blocks that you're using
Lex Fridman (12:38.720)
developed in a completely different environment, right?
Paola Arlotta (12:41.440)
It was not the environment of the brain.
Lex Fridman (12:43.040)
Therefore, they're gonna be different just by definition.
Lex Fridman (12:46.680)
So if you instead use development to build,
Lex Fridman (12:50.480)
let's say a brain organoid,
Paola Arlotta (12:52.720)
which maybe we will be talking about in a few minutes.
Lex Fridman (12:55.840)
Those things are fascinating.
Paola Arlotta (12:56.960)
Yes, so if you use processes of development,
Lex Fridman (13:01.960)
then when you watch it,
Paola Arlotta (13:03.360)
you can see that sometimes things can go wrong
Lex Fridman (13:06.440)
in some organoids and by wrong,
Paola Arlotta (13:08.120)
I mean different one organoid from the next.
Lex Fridman (13:10.840)
While if you think about that embryo, it always goes right.
Lex Fridman (13:14.800)
So this development, it's for as complex as it is.
Lex Fridman (13:18.920)
Every time a baby is born has, with very few exceptions,
Lex Fridman (13:23.600)
so the brain is like the next baby,
Lex Fridman (13:26.160)
but it's not the same if you develop it in a dish.
Lex Fridman (13:31.320)
And first of all, we don't even develop a brain,
Lex Fridman (13:33.800)
you develop something much simpler in the dish,
Lex Fridman (13:36.040)
but there are more options for building things differently,
Lex Fridman (13:39.640)
which really tells you that evolution
Paola Arlotta (13:42.920)
has played a really tight game here
Lex Fridman (13:48.000)
for how in the end the brain is built in vivo.
Lex Fridman (13:53.280)
So just a quick, maybe dumb question,
Lex Fridman (13:55.360)
but it seems like this is not,
Paola Arlotta (13:58.320)
the building process is not a dictatorship.
Lex Fridman (14:01.080)
It seems like there's not a centralized,
Paola Arlotta (14:04.760)
like high level mechanism that says,
Lex Fridman (14:07.400)
okay, this cell built itself the wrong way,
Paola Arlotta (14:10.240)
I'm gonna kill it.
Lex Fridman (14:11.480)
It seems like there's a really strong distributed mechanism.
Lex Fridman (14:15.440)
Is that in your sense for what you mean?
Lex Fridman (14:18.400)
There are a lot of possibilities, right?
Lex Fridman (14:20.880)
And if you think about, for example,
Lex Fridman (14:23.560)
different species building their brain,
Paola Arlotta (14:26.720)
each brain is a little bit different.
Lex Fridman (14:28.840)
So the brain of a lizard is very different
Paola Arlotta (14:31.000)
from that of a chicken, from that of one of us
Lex Fridman (14:35.480)
and so on and so forth and still is a brain,
Lex Fridman (14:38.000)
but it was built differently starting from stem cells
Lex Fridman (14:43.240)
that pretty much had the same potential,
Lex Fridman (14:45.960)
but in the end, evolution builds different brains
Lex Fridman (14:49.320)
in different species because that serves in a way
Paola Arlotta (14:52.480)
the purpose of that species
Lex Fridman (14:53.960)
and the wellbeing of that organism.
Lex Fridman (14:56.560)
And so there are many possibilities,
Lex Fridman (15:00.640)
but then there is a way and you were talking about a code.
Paola Arlotta (15:04.760)
Nobody knows what the entire code of development is.
Lex Fridman (15:07.440)
Of course we don't.
Paola Arlotta (15:08.600)
We know bits and pieces of very specific aspects
Lex Fridman (15:13.320)
of development of the brain,
Lex Fridman (15:14.440)
what genes are involved to make a certain cell types,
Lex Fridman (15:17.000)
how those two cells interact to make the next level structure
Paola Arlotta (15:20.320)
that we might know, but the entirety of it,
Lex Fridman (15:22.760)
how it's so well controlled, it's really mind blowing.
Lex Fridman (15:26.120)
So in the first two months in the embryo or whatever,
Lex Fridman (15:29.760)
the first few weeks, months,
Lex Fridman (15:32.680)
so yeah, the building blocks are constructed.
Lex Fridman (15:37.080)
The actual, the different regions of the brain,
Paola Arlotta (15:40.000)
I guess in the nervous system.
Lex Fridman (15:42.720)
Well, this continues way longer
Paola Arlotta (15:44.280)
than just the first few months.
Lex Fridman (15:46.440)
So over the very first few months,
Paola Arlotta (15:50.400)
you build a lot of the cells,
Lex Fridman (15:52.000)
but then there is continuous building of new cell types
Paola Arlotta (15:56.720)
all the way through birth.
Lex Fridman (15:58.360)
And then even postnatally,
Paola Arlotta (16:00.360)
I don't know if you've ever heard of myelin.
Lex Fridman (16:03.960)
Myelin is this sort of insulation
Paola Arlotta (16:06.680)
that is built around the cables of the neurons
Lex Fridman (16:09.800)
so that the electricity can go really fast from.
Paola Arlotta (16:12.160)
The axons, I guess they're called.
Lex Fridman (16:13.400)
The axons, they're called axons, exactly.
Lex Fridman (16:15.960)
And so as human beings,
Lex Fridman (16:19.680)
we myelinate our cells postnatally.
Paola Arlotta (16:24.320)
A kid, a six year old kid has barely started
Lex Fridman (16:28.720)
the process of making the mature oligodendrocytes,
Paola Arlotta (16:31.880)
which are the cells that then eventually
Lex Fridman (16:33.640)
will wrap the axons into myelin.
Lex Fridman (16:36.600)
And this will continue, believe it or not,
Lex Fridman (16:38.960)
until we are about 25, 30 years old.
Lex Fridman (16:42.440)
So there is a continuous process of maturation
Lex Fridman (16:45.320)
and tweaking and additions,
Lex Fridman (16:47.080)
and also in response to what we do.
Lex Fridman (16:51.040)
I remember taking AP Biology in high school,
Lex Fridman (16:53.960)
and in the textbook, it said that,
Lex Fridman (16:57.040)
I'm going by memory here,
Paola Arlotta (16:58.560)
that scientists disagree on the purpose
Lex Fridman (17:01.080)
of myelin in the brain.
Lex Fridman (17:04.720)
Is that totally wrong?
Lex Fridman (17:06.320)
So like, I guess it speeds up the,
Paola Arlotta (17:12.240)
okay, I might be wrong here,
Lex Fridman (17:13.200)
but I guess it speeds up the electricity
Paola Arlotta (17:14.760)
traveling down the axon or something.
Lex Fridman (17:17.160)
Yeah, so that's the most sort of canonical,
Lex Fridman (17:20.160)
and definitely that's the case.
Lex Fridman (17:21.720)
So you have to imagine an axon,
Lex Fridman (17:24.880)
and you can think about it as a cable of some type
Lex Fridman (17:27.680)
with electricity going through.
Lex Fridman (17:29.520)
And what myelin does, by insulating the outside,
Lex Fridman (17:34.400)
I should say there are tracts of myelin
Lex Fridman (17:36.360)
and pieces of axons that are naked without myelin.
Lex Fridman (17:39.640)
And so by having the insulation,
Paola Arlotta (17:41.760)
the electricity, instead of going straight
Lex Fridman (17:43.320)
through the cable, it will jump
Paola Arlotta (17:45.160)
over a piece of myelin, right,
Lex Fridman (17:47.240)
to the next naked little piece and jump again.
Lex Fridman (17:49.960)
And therefore, that's the idea that you go faster.
Lex Fridman (17:52.720)
And it was always thought that in order to build
Paola Arlotta (17:57.400)
a big brain, a big nervous system,
Lex Fridman (18:00.640)
in order to have a nervous system
Paola Arlotta (18:03.000)
that can do very complex type of things,
Lex Fridman (18:05.320)
then you need a lot of myelin
Paola Arlotta (18:06.640)
because you wanna go fast with this information
Lex Fridman (18:09.680)
from point A to point B.
Paola Arlotta (18:12.400)
Well, a few years ago, maybe five years ago or so,
Lex Fridman (18:16.840)
we discovered that some of the most evolved,
Paola Arlotta (18:19.520)
which means the newest type of neurons that we have
Lex Fridman (18:23.120)
as nonhuman primates, as human beings
Paola Arlotta (18:25.480)
in the top of our cerebral cortex,
Lex Fridman (18:28.040)
which should be the neurons that do some
Paola Arlotta (18:29.840)
of the most complex things that we do,
Lex Fridman (18:32.160)
well, those have axons that have very little myelin.
Paola Arlotta (18:36.120)
Wow.
Lex Fridman (18:36.960)
And they have very interesting ways
Paola Arlotta (18:41.000)
in which they put this myelin on their axons.
Lex Fridman (18:43.360)
You know, a little piece here,
Paola Arlotta (18:44.520)
then a long track with no myelin, another chunk there.
Lex Fridman (18:47.640)
And some don't have myelin at all.
Lex Fridman (18:49.840)
So now, you have to explain
Lex Fridman (18:52.400)
where we're going with evolution.
Lex Fridman (18:57.240)
And if you think about it,
Lex Fridman (18:58.760)
perhaps as an electrical engineer,
Paola Arlotta (19:01.880)
when I looked at it, I initially thought,
Lex Fridman (19:05.240)
and I'm a developmental neurobiologist,
Paola Arlotta (19:06.880)
I thought maybe this is what we see now,
Lex Fridman (19:10.160)
but if we give evolution another few million years,
Paola Arlotta (19:13.480)
we'll see a lot of myelin on these neurons too.
Lex Fridman (19:15.840)
But I actually think now that that's instead the future
Paola Arlotta (19:19.640)
of the brain.
Lex Fridman (19:20.480)
Less myelin.
Paola Arlotta (19:21.320)
Less myelin might allow for more flexibility
Lex Fridman (19:24.200)
on what you do with your axons,
Lex Fridman (19:26.200)
and therefore more complicated
Lex Fridman (19:28.000)
and unpredictable type of functions,
Paola Arlotta (19:31.640)
which is also a bit mind blowing.
Lex Fridman (19:33.800)
So it seems like it's controlling the timing of the signal.
Lex Fridman (19:37.960)
So they're in the timing, you can encode a lot of information.
Lex Fridman (19:42.800)
Yeah.
Lex Fridman (19:43.640)
And so the brain.
Lex Fridman (19:44.480)
The timing, the chemistry of that little piece of axon,
Paola Arlotta (19:48.520)
perhaps it's a dynamic process where the myelin can move.
Lex Fridman (19:52.080)
Now you see how many layers of variability you can add,
Lex Fridman (19:57.440)
and that's actually really good
Lex Fridman (19:58.880)
if you're trying to come up with a new function
Paola Arlotta (20:02.240)
or a new capability or something unpredictable in a way.
Lex Fridman (20:06.520)
So we're gonna jump around a little bit,
Lex Fridman (20:08.160)
but the old question of how much is nature
Lex Fridman (20:12.800)
and how much is nurture?
Paola Arlotta (20:14.480)
In terms of this incredible thing
Lex Fridman (20:17.240)
after the development is over,
Paola Arlotta (20:20.160)
we seem to be kind of somewhat smart, intelligent,
Lex Fridman (20:26.080)
cognition, consciousness,
Paola Arlotta (20:27.520)
all of these things are just incredible,
Lex Fridman (20:29.720)
ability to reason and so on emerge.
Paola Arlotta (20:31.960)
In your sense, how much is in the hardware,
Lex Fridman (20:34.880)
in the nature and how much is in the nurture
Paola Arlotta (20:39.000)
is learned through with our parents
Lex Fridman (20:40.960)
through interacting with the environment and so on.
Lex Fridman (20:42.440)
It's really both, right?
Lex Fridman (20:43.760)
If you think about it.
Lex Fridman (20:45.000)
So we are born with a brain as babies
Lex Fridman (20:48.000)
that has most of its cells and most of its structures.
Lex Fridman (20:53.600)
And that will take a few years to grow,
Lex Fridman (20:57.880)
to add more, to be better.
Lex Fridman (21:00.600)
But really then we have this 20 years
Lex Fridman (21:04.120)
of interacting with the environment around us.
Lex Fridman (21:07.000)
And so what that brain that was so perfectly built
Lex Fridman (21:10.760)
or imperfectly built due to our genetic cues
Paola Arlotta (21:16.400)
will then be used to incorporate the environment
Lex Fridman (21:20.160)
in its further maturation and development.
Lex Fridman (21:22.720)
And so your experiences do shape your brain.
Lex Fridman (21:26.960)
I mean, we know that like if you and I
Paola Arlotta (21:29.440)
may have had a different childhood or a different,
Lex Fridman (21:32.960)
we have been going to different schools,
Paola Arlotta (21:35.040)
we have been learning different things
Lex Fridman (21:36.440)
and our brain is a little bit different because of that.
Paola Arlotta (21:38.760)
We behave differently because of that.
Lex Fridman (21:41.120)
And so especially postnatally
Paola Arlotta (21:44.000)
experience is extremely important.
Lex Fridman (21:46.000)
We are born with a plastic brain.
Lex Fridman (21:48.760)
What that means is a brain that is able to change
Lex Fridman (21:51.440)
in response to stimuli that can be sensory.
Lex Fridman (21:56.320)
So perhaps some of the most illuminating studies
Lex Fridman (22:01.000)
that were done were studies in which
Lex Fridman (22:03.400)
the sensory organs were not working, right?
Lex Fridman (22:06.720)
Like if you are born with eyes that don't work,
Paola Arlotta (22:09.520)
then your very brain, that piece of the brain
Lex Fridman (22:12.520)
that normally would process vision, the visual cortex,
Paola Arlotta (22:17.200)
develops postnatally differently
Lex Fridman (22:19.800)
and it might be used to do something different, right?
Lex Fridman (22:23.480)
So that's the most extreme.
Lex Fridman (22:25.600)
The plasticity of the brain, I guess,
Paola Arlotta (22:27.440)
is the magic hardware that it,
Lex Fridman (22:29.400)
and then it's flexibility in all forms
Paola Arlotta (22:32.920)
is what enables the learning postnatally.
Lex Fridman (22:36.280)
Can you talk about organoids?
Lex Fridman (22:39.200)
What are they?
Lex Fridman (22:40.840)
And how can you use them to help us understand the brain
Lex Fridman (22:44.320)
and the development of the brain?
Lex Fridman (22:45.680)
This is very, very important.
Lex Fridman (22:47.280)
So the first thing I'd like to say,
Lex Fridman (22:49.880)
please skip this in the video.
Paola Arlotta (22:52.680)
The first thing I'd like to say is that an organoid,
Lex Fridman (22:56.040)
a brain organoid is not the same as a brain.
Lex Fridman (23:00.680)
Okay?
Lex Fridman (23:01.600)
It's a fundamental distinction.
Paola Arlotta (23:03.600)
It's a system, a cellular system
Lex Fridman (23:08.520)
that one can develop in the culture dish,
Paola Arlotta (23:12.160)
starting from stem cells that will mimic some aspects
Lex Fridman (23:17.160)
of the development of the brain, but not all of it.
Paola Arlotta (23:21.360)
They are very small, maximum,
Lex Fridman (23:23.720)
they become about four to five millimeters in diameters.
Paola Arlotta (23:27.880)
They are much simpler than our brain, of course,
Lex Fridman (23:32.880)
but yet they are the only system
Paola Arlotta (23:35.960)
where we can literally watch a process
Lex Fridman (23:39.040)
of human brain development unfold.
Lex Fridman (23:42.040)
And by watch, I mean, study it.
Lex Fridman (23:44.600)
Remember when I told you that we can't understand
Paola Arlotta (23:47.520)
everything about development in our own brain
Lex Fridman (23:49.520)
by studying a mouse?
Paola Arlotta (23:51.000)
Well, we can't study the actual process
Lex Fridman (23:53.080)
of development of the human brain
Paola Arlotta (23:54.280)
because it all happens in utero.
Lex Fridman (23:55.760)
So we will never have access to that process ever.
Lex Fridman (23:58.800)
And therefore, this is our next best thing.
Lex Fridman (24:02.960)
Like a bunch of stem cells that can be coaxed
Paola Arlotta (24:06.960)
into starting a process of neural tube formation.
Lex Fridman (24:10.240)
Remember that tube that is made by the embryo early on.
Lex Fridman (24:13.200)
And from there, a lot of the cell types
Lex Fridman (24:15.640)
that are present within the brain,
Lex Fridman (24:19.200)
and you can simply watch it and study,
Lex Fridman (24:23.480)
but you can also think about diseases
Paola Arlotta (24:27.200)
where development of the brain
Lex Fridman (24:29.800)
does not proceed normally, right, properly.
Paola Arlotta (24:33.240)
Think about neurodevelopmental diseases.
Lex Fridman (24:34.880)
There are many, many different types.
Paola Arlotta (24:37.320)
Think about autism spectrum disorders.
Lex Fridman (24:39.160)
There are also many different types of autism.
Lex Fridman (24:41.680)
So there you could take a stem cell,
Lex Fridman (24:44.360)
which really means either a sample of blood
Paola Arlotta (24:46.600)
or a sample of skin from the patient,
Lex Fridman (24:50.080)
make a stem cell, and then with that stem cell,
Paola Arlotta (24:53.520)
watch a process of formation of a brain organ
Lex Fridman (24:56.200)
or a brain organoid of that person with that genetics,
Paola Arlotta (25:00.600)
with that genetic code in it.
Lex Fridman (25:02.200)
And you can ask, what is this genetic code doing
Lex Fridman (25:05.800)
to some aspects of development of the brain?
Lex Fridman (25:08.760)
And for the first time, you may come to solutions
Lex Fridman (25:12.000)
like what cells are involved in autism, right?
Lex Fridman (25:16.000)
So many questions around this.
Lex Fridman (25:17.360)
So if you take this human stem cell
Lex Fridman (25:20.520)
for that particular person with that genetic code,
Paola Arlotta (25:23.360)
how, and you try to build an organoid,
Lex Fridman (25:26.520)
how often will it look similar?
Paola Arlotta (25:28.840)
What's the, yeah, so.
Lex Fridman (25:31.800)
The reproducibility?
Lex Fridman (25:33.240)
Yes, or how much variability is the flip side of that?
Lex Fridman (25:36.600)
Yeah, so there is much more variability
Paola Arlotta (25:40.280)
in building organoids than there is in building brain.
Lex Fridman (25:44.520)
It's really true that the majority of us,
Paola Arlotta (25:47.280)
when we are born as babies,
Lex Fridman (25:49.560)
our brains look a lot like each other.
Paola Arlotta (25:52.440)
This is the magic that the embryo does,
Lex Fridman (25:54.880)
where it builds a brain in the context of a body
Lex Fridman (25:57.640)
and there is very little variability there.
Lex Fridman (26:01.240)
There is disease, of course,
Lex Fridman (26:02.280)
but in general, a little variability.
Lex Fridman (26:03.960)
When you build an organoid,
Paola Arlotta (26:07.000)
we don't have the full code for how this is done.
Lex Fridman (26:09.480)
And so in part, the organoid somewhat builds itself
Paola Arlotta (26:13.400)
because there are some structures of the brain
Lex Fridman (26:15.560)
that the cells know how to make.
Lex Fridman (26:18.120)
And another part comes from the investigator,
Lex Fridman (26:21.800)
the scientist adding to the media factors
Paola Arlotta (26:26.120)
that we know in the mouse, for example,
Lex Fridman (26:27.960)
would foster a certain step of development,
Lex Fridman (26:30.680)
but it's very limited.
Lex Fridman (26:33.160)
And so as a result,
Paola Arlotta (26:36.080)
the kind of product you get in the end
Lex Fridman (26:38.120)
is much more reductionist,
Paola Arlotta (26:39.640)
is much more simple than what you get in vivo.
Lex Fridman (26:42.600)
It mimics early events of development as of today,
Lex Fridman (26:46.120)
and it doesn't build very complex type of anatomy
Lex Fridman (26:49.040)
and structure does not as of today,
Paola Arlotta (26:52.480)
which happens instead in vivo.
Lex Fridman (26:54.840)
And also the variability that you see,
Paola Arlotta (26:59.040)
one organ to the next tends to be higher
Lex Fridman (27:02.720)
than when you compare an embryo to the next.
Paola Arlotta (27:05.480)
So, okay, then the next question is,
Lex Fridman (27:07.320)
how hard and maybe another flip side of that expensive
Lex Fridman (27:11.040)
is it to go from one stem cell to an organoid?
Lex Fridman (27:14.880)
How many can you build in like,
Paola Arlotta (27:16.680)
because it sounds very complicated.
Lex Fridman (27:18.400)
It's work definitely, and it's money definitely,
Lex Fridman (27:23.400)
but you can really grow a very high number
Lex Fridman (27:28.000)
of these organoids, can go perhaps,
Paola Arlotta (27:31.560)
I told you the maximum,
Lex Fridman (27:32.680)
they become about five millimeters in diameter.
Lex Fridman (27:35.320)
So this is about the size of a tiny, tiny raisin,
Lex Fridman (27:40.920)
or perhaps the seed of an apple.
Lex Fridman (27:43.120)
And so you can grow 50 to 100 of those
Lex Fridman (27:47.480)
inside one big bioreactors, which are these flasks
Paola Arlotta (27:51.240)
where the media provides nutrients for the organoids.
Lex Fridman (27:55.440)
So the problem is not to grow more or less of them.
Paola Arlotta (28:01.680)
It's really to figure out how to grow them in a way
Lex Fridman (28:06.440)
that they are more and more reproducible,
Paola Arlotta (28:08.360)
for example, organoid to organoid,
Lex Fridman (28:09.920)
so they can be used to study a biological process.
Paola Arlotta (28:13.160)
Because if you have too much variability,
Lex Fridman (28:15.560)
then you never know if what you see
Paola Arlotta (28:17.080)
is just an exception or really the rule.
Lex Fridman (28:19.520)
So what does an organoid look like?
Lex Fridman (28:22.200)
Are there different neurons already emerging?
Lex Fridman (28:25.080)
Is there, well, first, can you tell me
Lex Fridman (28:28.520)
what kind of neurons are there?
Lex Fridman (28:29.920)
Yes.
Lex Fridman (28:30.880)
Are they sort of all the same?
Lex Fridman (28:35.560)
Are they not all the same?
Lex Fridman (28:38.200)
How much do we understand?
Lex Fridman (28:39.520)
And how much of that variance, if any,
Lex Fridman (28:43.440)
can exist in organoids?
Lex Fridman (28:45.800)
Yes.
Lex Fridman (28:47.000)
So you could grow,
Lex Fridman (28:49.400)
I told you that the brain has different parts.
Lex Fridman (28:52.440)
So the cerebral cortex is on the top part of the brain,
Lex Fridman (28:55.960)
but there is another region called the striatum
Paola Arlotta (28:57.960)
that is below the cortex and so on and so forth.
Lex Fridman (28:59.960)
All of these regions have different types of cells
Lex Fridman (29:03.760)
in the actual brain, okay?
Lex Fridman (29:05.640)
And so scientists have been able to grow organoids
Paola Arlotta (29:08.880)
that may mimic some aspects of development
Lex Fridman (29:11.440)
of these different regions of the brain.
Lex Fridman (29:13.960)
And so we are very interested in the cerebral cortex.
Lex Fridman (29:16.440)
That's the coolest part, right?
Paola Arlotta (29:17.760)
Very cool.
Lex Fridman (29:18.600)
I agree with you.
Paola Arlotta (29:20.880)
We wouldn't be here talking
Lex Fridman (29:22.040)
if we didn't have a cerebral cortex.
Paola Arlotta (29:23.880)
It's also, I like to think, the part of the brain
Lex Fridman (29:26.040)
that really truly makes us human,
Paola Arlotta (29:27.600)
the most evolved in recent evolution.
Lex Fridman (29:30.200)
And so in the attempt to make the cerebral cortex
Lex Fridman (29:33.600)
and by figuring out a way to have these organoids
Lex Fridman (29:37.200)
continue to grow and develop for extended periods of times,
Paola Arlotta (29:40.240)
much like it happens in the real embryo,
Lex Fridman (29:42.440)
months and months in culture,
Paola Arlotta (29:44.240)
then you can see that many different types of neurons
Lex Fridman (29:48.560)
of the cortex appear.
Lex Fridman (29:50.120)
And at some point, also the astrocytes,
Lex Fridman (29:52.120)
so the glia cells of the cerebral cortex also appear.
Lex Fridman (29:57.600)
What are these astrocytes?
Lex Fridman (30:00.320)
The astrocytes are not neurons, so they're not nerve cells,
Lex Fridman (30:03.360)
but they play very important roles.
Lex Fridman (30:06.120)
One important role is to support the neuron.
Lex Fridman (30:08.960)
But of course, they have much more active type of roles.
Lex Fridman (30:11.800)
They're very important, for example, to make the synapses,
Paola Arlotta (30:14.480)
which are the point of contact and communication
Lex Fridman (30:17.560)
between two neurons.
Lex Fridman (30:21.400)
So all that chemistry fun happens in the synapses,
Lex Fridman (30:25.600)
happens because of these cells?
Lex Fridman (30:28.120)
Are they the medium in which?
Lex Fridman (30:29.560)
It happens because of the interactions,
Paola Arlotta (30:31.960)
happens because you are making the cells
Lex Fridman (30:34.720)
and they have certain properties,
Paola Arlotta (30:36.280)
including the ability to make neurotransmitters,
Lex Fridman (30:40.320)
which are the chemicals that are secreted to the synapses,
Paola Arlotta (30:43.240)
including the ability of making these axons grow
Lex Fridman (30:46.440)
with their growth cones and so on and so forth.
Lex Fridman (30:49.120)
And then you have other cells around it
Lex Fridman (30:51.320)
that release chemicals or touch the neurons
Paola Arlotta (30:55.160)
or interact with them in different ways
Lex Fridman (30:57.120)
to really foster this perfect process,
Paola Arlotta (30:59.800)
in this case of synaptogenesis.
Lex Fridman (31:02.440)
And this does happen within organoids.
Lex Fridman (31:05.640)
So the mechanical and the chemical stuff happens.
Lex Fridman (31:09.720)
The connectivity between neurons,
Paola Arlotta (31:11.600)
this in a way is not surprising
Lex Fridman (31:13.320)
because scientists have been culturing neurons forever.
Lex Fridman (31:18.120)
And when you take a neuron, even a very young one,
Lex Fridman (31:20.760)
and you culture it, eventually finds another cell
Paola Arlotta (31:23.480)
or another neuron to talk to, it will form a synapse.
Lex Fridman (31:26.920)
Are we talking about mice neurons?
Lex Fridman (31:28.520)
Are we talking about human neurons?
Lex Fridman (31:29.640)
It doesn't matter, both.
Lex Fridman (31:30.600)
So you can culture a neuron, like a single neuron
Lex Fridman (31:33.240)
and give it a little friend and it starts interacting?
Paola Arlotta (31:37.920)
Yes, so neurons are able to, it sounds,
Lex Fridman (31:41.000)
it's more simple than what it may sound to you.
Paola Arlotta (31:44.600)
Neurons have molecular properties and structural properties
Lex Fridman (31:48.320)
that allow them to really communicate with other cells.
Lex Fridman (31:50.920)
And so if you put not one neuron,
Lex Fridman (31:53.200)
but if you put several neurons together,
Paola Arlotta (31:55.160)
chances are that they will form synapses with each other.
Lex Fridman (32:00.280)
Okay, great.
Lex Fridman (32:01.120)
So an organoid is not a brain.
Lex Fridman (32:03.360)
No.
Lex Fridman (32:04.200)
But there's some, it's able to,
Lex Fridman (32:09.240)
especially what you're talking about,
Paola Arlotta (32:10.440)
mimics some properties of the cerebral cortex, for example.
Lex Fridman (32:15.120)
So what can you understand about the brain
Lex Fridman (32:17.960)
by studying an organoid of a cerebral cortex?
Lex Fridman (32:21.080)
I can literally study all this incredible diversity
Paola Arlotta (32:25.800)
of cell type, all these many, many different classes
Lex Fridman (32:28.040)
of cells, how are they made?
Lex Fridman (32:30.760)
How do they look like?
Lex Fridman (32:32.520)
What do they need to be made properly?
Lex Fridman (32:34.960)
And what goes wrong if now the genetics of that stem cell
Lex Fridman (32:39.720)
that I used to make the organoid came from a patient
Lex Fridman (32:42.800)
with a neurodevelopmental disease?
Lex Fridman (32:44.320)
Can I actually watch for the very first time
Lex Fridman (32:47.640)
what may have gone wrong years before in this kid
Lex Fridman (32:51.400)
when its own brain was being made?
Paola Arlotta (32:53.520)
Think about that loop.
Lex Fridman (32:54.760)
In a way, it's a little tiny rudimentary window
Paola Arlotta (32:59.600)
into the past, into the time when that brain
Lex Fridman (33:04.280)
in a kid that had this neurodevelopmental disease
Paola Arlotta (33:07.680)
was being made.
Lex Fridman (33:10.120)
And I think that's unbelievably powerful
Paola Arlotta (33:12.880)
because today we have no idea of what cell types,
Lex Fridman (33:16.800)
we barely know what brain regions
Paola Arlotta (33:18.760)
are affected in these diseases.
Lex Fridman (33:20.880)
Now we have an experimental system
Paola Arlotta (33:23.720)
that we can study in the lab.
Lex Fridman (33:25.440)
And we can ask, what are the cells affected?
Lex Fridman (33:28.440)
When during development things went wrong?
Lex Fridman (33:31.840)
What are the molecules among the many, many
Lex Fridman (33:34.080)
different molecules that control brain development?
Lex Fridman (33:36.600)
Which ones are the ones that really messed up here
Lex Fridman (33:39.720)
and we want perhaps to fix?
Lex Fridman (33:42.160)
And what is really the final product?
Lex Fridman (33:44.520)
Is it a less strong kind of circuit and brain?
Lex Fridman (33:48.560)
Is it a brain that lacks a cell type?
Lex Fridman (33:51.000)
What is it?
Lex Fridman (33:52.040)
Because then we can think about treatment
Lex Fridman (33:54.920)
and care for these patients that is informed
Lex Fridman (33:59.360)
rather than just based on current diagnostics.
Lex Fridman (34:02.080)
So how hard is it to detect
Lex Fridman (34:04.560)
through the developmental process?
Paola Arlotta (34:06.360)
It's a super exciting tool
Lex Fridman (34:10.520)
to see how different conditions develop.
Lex Fridman (34:15.200)
How hard is it to detect that, wait a minute,
Lex Fridman (34:17.640)
this is abnormal development.
Paola Arlotta (34:20.800)
Yeah.
Lex Fridman (34:21.640)
How much signal is there?
Lex Fridman (34:24.760)
How much of it is it a mess?
Lex Fridman (34:26.480)
Because things can go wrong at multiple levels, right?
Paola Arlotta (34:29.440)
You could have a cell that is born and built
Lex Fridman (34:34.280)
but then doesn't work properly
Paola Arlotta (34:36.200)
or a cell that is not even born
Lex Fridman (34:38.280)
or a cell that doesn't interact with other cells differently
Lex Fridman (34:40.680)
and so on and so forth.
Lex Fridman (34:42.080)
So today we have technology
Paola Arlotta (34:44.360)
that we did not have even five years ago
Lex Fridman (34:47.720)
that allows us to look for example
Paola Arlotta (34:49.760)
at the molecular picture of a cell,
Lex Fridman (34:52.080)
of a single cell in a sea of cells with high precision.
Lex Fridman (34:56.560)
And so that molecular information
Lex Fridman (34:58.800)
where you compare many, many single cells
Paola Arlotta (35:01.720)
for the genes that they produce
Lex Fridman (35:03.600)
between a control individual
Lex Fridman (35:06.120)
and an individual with a neurodevelopmental disease,
Lex Fridman (35:10.080)
that may tell you what is different molecularly.
Paola Arlotta (35:13.760)
Or you could see that some cells are not even made,
Lex Fridman (35:18.520)
for example, or that the process of maturation
Paola Arlotta (35:20.720)
of the cells may be wrong.
Lex Fridman (35:22.560)
There are many different levels here
Lex Fridman (35:25.920)
and we can study the cells at the molecular level
Lex Fridman (35:29.520)
but also we can use the organoids to ask questions
Paola Arlotta (35:33.320)
about the properties of the neurons,
Lex Fridman (35:35.240)
the functional properties,
Lex Fridman (35:37.280)
how they communicate with each other,
Lex Fridman (35:38.880)
how they respond to a stimulus and so on and so forth.
Lex Fridman (35:41.320)
And we may get an abnormalities there, right?
Lex Fridman (35:46.320)
Detect those.
Lex Fridman (35:47.440)
So how early is this work in the,
Lex Fridman (35:51.760)
maybe in the history of science?
Paola Arlotta (35:54.240)
So, I mean like, so if you were to,
Lex Fridman (35:59.720)
if you and I time travel a thousand years into the future,
Paola Arlotta (36:05.160)
organoids seem to be, maybe I'm romanticizing the notion
Lex Fridman (36:09.880)
but you're building not a brain
Lex Fridman (36:12.720)
but something that has properties of a brain.
Lex Fridman (36:15.640)
So it feels like you might be getting close to,
Paola Arlotta (36:18.960)
in the building process, to build this to understand.
Lex Fridman (36:23.160)
So how far are we in this understanding
Lex Fridman (36:29.000)
process of development?
Lex Fridman (36:31.320)
A thousand years from now, it's a long time from now.
Lex Fridman (36:34.160)
So if this planet is still gonna be here
Lex Fridman (36:36.360)
a thousand years from now.
Paola Arlotta (36:38.160)
So, I mean, if, you know, like they write a book,
Lex Fridman (36:41.960)
obviously there'll be a chapter about you.
Paola Arlotta (36:43.960)
That's right, that science fiction book, today.
Lex Fridman (36:47.320)
Yeah, today, about, I mean, I guess where
Paola Arlotta (36:49.920)
we really understood very little about the brain
Lex Fridman (36:52.040)
a century ago, I was a big fan in high school
Paola Arlotta (36:55.880)
of reading Freud and so on, still am of psychiatry.
Lex Fridman (36:59.680)
I would say we still understand very little
Paola Arlotta (37:01.480)
about the functional aspect of just,
Lex Fridman (37:04.680)
but how in the history of understanding
Paola Arlotta (37:07.760)
the biology of the brain, the development,
Lex Fridman (37:09.640)
how far are we along?
Paola Arlotta (37:11.240)
It's a very good question.
Lex Fridman (37:12.960)
And so this is just, of course, my opinion.
Paola Arlotta (37:15.520)
I think that we did not have technology
Lex Fridman (37:19.720)
even 10 years ago or certainly not 20 years ago
Paola Arlotta (37:23.160)
to even think about experimentally investigating
Lex Fridman (37:27.760)
the development of the human brain.
Lex Fridman (37:30.160)
So we've done a lot of work in science
Lex Fridman (37:32.200)
to study the brain or many other organisms.
Paola Arlotta (37:35.480)
Now we have some technologies which I'll spell out
Lex Fridman (37:39.600)
that allow us to actually look at the real thing
Lex Fridman (37:43.120)
and look at the brain, at the human brain.
Lex Fridman (37:45.040)
So what are these technologies?
Paola Arlotta (37:46.840)
There has been huge progress in stem cell biology.
Lex Fridman (37:50.440)
The moment someone figured out how to turn a skin cell
Paola Arlotta (37:54.080)
into an embryonic stem cell, basically,
Lex Fridman (37:57.760)
and that how that embryonic stem cell
Paola Arlotta (38:00.160)
could begin a process of development again
Lex Fridman (38:02.480)
to, for example, make a brain,
Paola Arlotta (38:04.000)
there was a huge advance,
Lex Fridman (38:06.040)
and in fact, there was a Nobel Prize for that.
Paola Arlotta (38:08.160)
That started the field, really,
Lex Fridman (38:10.400)
of using stem cells to build organs.
Paola Arlotta (38:14.200)
Now we can build on all the knowledge of development
Lex Fridman (38:17.000)
that we build over the many, many, many years
Paola Arlotta (38:18.520)
to say, how do we make the stem cells
Lex Fridman (38:20.680)
now make more and more complex aspects
Lex Fridman (38:22.640)
of development of the human brain?
Lex Fridman (38:25.240)
So this field is young, the field of brain organoids,
Lex Fridman (38:28.440)
but it's moving faster.
Lex Fridman (38:30.080)
And it's moving fast in a very serious way
Paola Arlotta (38:32.520)
that is rooted in labs with the right ethical framework
Lex Fridman (38:35.920)
and really building on solid science
Paola Arlotta (38:40.680)
for what reality is and what is not.
Lex Fridman (38:44.680)
But it will go faster and it will be more and more powerful.
Paola Arlotta (38:49.080)
We also have technology that allows us
Lex Fridman (38:51.440)
to basically study the properties of single cells
Paola Arlotta (38:54.600)
across many, many millions of single cells,
Lex Fridman (38:59.200)
which we didn't have perhaps five years ago.
Lex Fridman (39:02.120)
So now with that, even an organoid
Lex Fridman (39:04.800)
that has millions of cells can be profiled in a way,
Paola Arlotta (39:08.440)
looked at with very, very high resolution,
Lex Fridman (39:11.280)
the single cell level to really understand
Lex Fridman (39:13.920)
what is going on.
Lex Fridman (39:14.880)
And you could do it in multiple stages of development
Lex Fridman (39:17.480)
and you can build your hypothesis and so on and so forth.
Lex Fridman (39:20.080)
So it's not gonna be a thousand years.
Paola Arlotta (39:22.560)
It's gonna be a shorter amount of time.
Lex Fridman (39:25.200)
And I see this as sort of an exponential growth
Paola Arlotta (39:29.440)
of this field enabled by these technologies
Lex Fridman (39:33.520)
that we didn't have before.
Lex Fridman (39:34.960)
And so we're gonna see something transformative
Lex Fridman (39:36.920)
that we didn't see at all in the prior thousand years.
Lex Fridman (39:41.840)
So I apologize for the crazy sci fi questions,
Lex Fridman (39:44.600)
but the developmental process is fascinating
Paola Arlotta (39:48.120)
to watch and study, but how far are we away from
Lex Fridman (39:53.320)
and maybe how difficult is it to build
Lex Fridman (39:57.240)
not just an organoid, but a human brain from a stem cell?
Lex Fridman (40:02.240)
Yeah, first of all, that's not the goal
Paola Arlotta (40:05.640)
for the majority of the serious scientists
Lex Fridman (40:07.680)
that work on this because you don't have to build
Paola Arlotta (40:12.640)
the whole human brain to make this model useful
Lex Fridman (40:16.040)
for understanding how the brain develops
Paola Arlotta (40:17.920)
or understanding disease.
Lex Fridman (40:20.400)
You don't have to build the whole thing.
Lex Fridman (40:22.400)
So let me just comment on this, fascinating.
Lex Fridman (40:25.160)
It shows to me the difference between you and I
Paola Arlotta (40:29.160)
as you're actually trying to understand
Lex Fridman (40:31.800)
the beauty of the human brain and to use it
Paola Arlotta (40:34.200)
to really help thousands or millions of people
Lex Fridman (40:36.880)
with disease and so on, right?
Paola Arlotta (40:38.800)
From an artificial intelligence perspective,
Lex Fridman (40:41.480)
we're trying to build systems that we can put in robots
Lex Fridman (40:45.600)
and try to create systems that have echoes
Lex Fridman (40:49.080)
of the intelligence about reasoning about the world,
Paola Arlotta (40:52.360)
navigating the world.
Lex Fridman (40:53.600)
It's different objectives, I think.
Paola Arlotta (40:56.000)
Yeah, that's very much science fiction.
Lex Fridman (40:57.560)
Science fiction, but we operate in science fiction a little bit.
Lex Fridman (41:00.480)
So on that point of building a brain,
Lex Fridman (41:03.400)
even though that is not the focus or interest, perhaps,
Lex Fridman (41:06.160)
of the community, how difficult is it?
Lex Fridman (41:08.480)
Is it truly science fiction at this point?
Paola Arlotta (41:11.160)
I think the field will progress, like I said,
Lex Fridman (41:13.920)
and that the system will be more and more complex
Lex Fridman (41:17.240)
in a way, right?
Lex Fridman (41:18.680)
But there are properties that emerge from the human brain
Paola Arlotta (41:23.840)
that have to do with the mind,
Lex Fridman (41:25.360)
that may have to do with consciousness,
Paola Arlotta (41:26.720)
that may have to do with intelligence or whatever
Lex Fridman (41:29.800)
that we really don't understand
Paola Arlotta (41:31.960)
even how they can emerge from an actual, real brain.
Lex Fridman (41:35.560)
And therefore, we can now measure or study in an organoid.
Lex Fridman (41:39.120)
So I think that this field, many, many years from now,
Lex Fridman (41:43.000)
may lead to the building of better neural circuits
Paola Arlotta (41:48.280)
that really are built out of understanding
Lex Fridman (41:50.320)
of how this process really works.
Lex Fridman (41:52.240)
And it's hard to predict how complex this really will be.
Lex Fridman (41:57.000)
I really don't think we're so far from,
Paola Arlotta (42:00.200)
it makes me laugh, really.
Lex Fridman (42:01.200)
It's really that far from building the human brain.
Lex Fridman (42:05.120)
But you're gonna be building something
Lex Fridman (42:07.800)
that is always a bad version of it,
Lex Fridman (42:11.600)
but that may have really powerful properties
Lex Fridman (42:14.840)
and might be able to respond to stimuli
Paola Arlotta (42:18.560)
or be used in certain context.
Lex Fridman (42:21.720)
And this is why I really think
Paola Arlotta (42:23.680)
that there is no other way to do this science,
Lex Fridman (42:25.800)
but within the right ethical framework,
Paola Arlotta (42:28.200)
because where you're going with this is also,
Lex Fridman (42:31.520)
we can talk about science fiction and write that book,
Lex Fridman (42:34.080)
and we could today,
Lex Fridman (42:36.600)
but this work happens in a specific ethical framework
Paola Arlotta (42:41.520)
that we don't decide just as scientists,
Lex Fridman (42:43.200)
but also as a society.
Lex Fridman (42:44.880)
So the ethical framework here is a fascinating one,
Lex Fridman (42:48.560)
is a complicated one.
Paola Arlotta (42:49.720)
Yes.
Lex Fridman (42:51.120)
Do you have a sense, a grasp
Paola Arlotta (42:53.320)
of how we think about ethically of building organoids
Lex Fridman (43:00.040)
from human stem cells to understand the brain?
Paola Arlotta (43:04.160)
It seems like a tool
Lex Fridman (43:06.280)
for helping potentially millions of people cure diseases
Paola Arlotta (43:11.080)
or at least start the cure by understanding it.
Lex Fridman (43:14.960)
But is there more, is there gray areas
Lex Fridman (43:17.840)
that we have to think about ethically?
Lex Fridman (43:22.400)
Absolutely.
Paola Arlotta (43:23.240)
We must think about that.
Lex Fridman (43:25.600)
Every discussion about the ethics of this
Paola Arlotta (43:29.640)
needs to be based on actual data
Lex Fridman (43:32.720)
from the models that we have today
Lex Fridman (43:34.520)
and from the ones that we will have tomorrow.
Lex Fridman (43:36.360)
So it's a continuous conversation.
Paola Arlotta (43:37.880)
It's not something that you decide now.
Lex Fridman (43:39.880)
Today, there is no issue really.
Paola Arlotta (43:42.080)
Very simple models that clearly can help you in many ways
Lex Fridman (43:47.320)
without much think about,
Lex Fridman (43:49.920)
but tomorrow we need to have another conversation
Lex Fridman (43:52.240)
and so on and so forth.
Lex Fridman (43:53.080)
And so the way we do this
Lex Fridman (43:54.680)
is to actually really bring together constantly
Paola Arlotta (43:57.920)
a group of people that are not only scientists,
Lex Fridman (44:00.440)
but also bioethicists, the lawyers, philosophers,
Paola Arlotta (44:03.400)
psychiatrists and so on,
Lex Fridman (44:04.880)
psychologists and so on and so forth
Paola Arlotta (44:06.720)
to decide as a society really what we should
Lex Fridman (44:13.040)
and what we should not do.
Lex Fridman (44:15.320)
So that's the way to think about the ethics.
Lex Fridman (44:17.600)
Now, I also think though, that as a scientist,
Paola Arlotta (44:21.240)
I have a moral responsibility.
Lex Fridman (44:23.720)
So if you think about how transformative it could be
Paola Arlotta (44:29.480)
for understanding and curing a neuropsychiatric disease,
Lex Fridman (44:34.120)
to be able to actually watch and study
Lex Fridman (44:37.320)
and treat with drugs the very brain
Lex Fridman (44:40.640)
of the patient that you are trying to study.
Lex Fridman (44:43.240)
How transformative at this moment in time this could be.
Lex Fridman (44:47.200)
We couldn't do it five years ago,
Lex Fridman (44:48.760)
we could do it now, right?
Lex Fridman (44:50.720)
If we didn't do it.
Paola Arlotta (44:51.560)
Taking a stem cell of a particular patient.
Lex Fridman (44:52.960)
Patient and make an organoid for a simple
Lex Fridman (44:56.120)
and different from the human brain,
Lex Fridman (44:58.880)
it still is his process of brain development
Paola Arlotta (45:02.160)
with his or her genetics.
Lex Fridman (45:04.720)
And we could understand perhaps what is going wrong.
Paola Arlotta (45:08.320)
Perhaps we could use as a platform,
Lex Fridman (45:09.960)
as a cellular platform to screen for drugs,
Lex Fridman (45:12.160)
to fix a process and so on and so forth, right?
Lex Fridman (45:15.280)
So we could do it now, we couldn't do it five years ago.
Lex Fridman (45:18.840)
Should we not do it?
Lex Fridman (45:20.480)
What is the downside of doing it?
Paola Arlotta (45:24.760)
I don't see a downside at this very moment.
Lex Fridman (45:27.320)
If we invited a lot of people,
Paola Arlotta (45:30.040)
I'm sure there would be somebody who would argue against it.
Lex Fridman (45:33.440)
What would be the devil's advocate argument?
Paola Arlotta (45:37.920)
Yeah, yeah.
Lex Fridman (45:39.680)
So it's exactly perhaps what you alluded at
Paola Arlotta (45:42.960)
with your question,
Lex Fridman (45:44.280)
that you are enabling some process of formation of the brain
Paola Arlotta (45:51.640)
that could be misused at some point,
Lex Fridman (45:54.400)
or that could be showing properties
Paola Arlotta (45:59.040)
that ethically we don't wanna see in a tissue.
Lex Fridman (46:03.960)
So today, I repeat, today, this is not an issue.
Lex Fridman (46:07.720)
And so you just gain dramatically from the science without,
Lex Fridman (46:11.680)
because the system is so simple and so different
Paola Arlotta (46:15.240)
in a way from the actual brain.
Lex Fridman (46:17.800)
But because it is the brain,
Lex Fridman (46:19.960)
we have an obligation to really consider all of this, right?
Lex Fridman (46:23.920)
And again, it's a balanced conversation
Paola Arlotta (46:27.160)
where we should put disease and betterment of humanity
Lex Fridman (46:30.320)
also on that plate.
Lex Fridman (46:32.400)
What do you think, at least historically,
Lex Fridman (46:35.400)
there was some politicization,
Paola Arlotta (46:37.240)
politicization of embryonic stem cells,
Lex Fridman (46:44.280)
a stem cell research.
Lex Fridman (46:46.480)
Do you still see that out there?
Lex Fridman (46:49.440)
Is that still a force that we have to think about,
Paola Arlotta (46:53.520)
especially in this larger discourse
Lex Fridman (46:55.520)
that we're having about the role of science
Lex Fridman (46:57.520)
in at least American society?
Lex Fridman (47:00.560)
Yeah, this is a very good question.
Paola Arlotta (47:03.440)
It's very, very important.
Lex Fridman (47:04.960)
I see a very central role for scientists
Paola Arlotta (47:08.440)
to inform decisions about what we should
Lex Fridman (47:12.000)
or should not do in society.
Lex Fridman (47:14.400)
And this is because the scientists
Lex Fridman (47:16.360)
have the firsthand look and understanding
Paola Arlotta (47:20.400)
of really the work that they are doing.
Lex Fridman (47:23.480)
And again, this varies depending on
Lex Fridman (47:26.040)
what we're talking about here.
Lex Fridman (47:27.440)
So now we're talking about brain organoids.
Paola Arlotta (47:31.080)
I think that the scientists need to be part
Lex Fridman (47:33.760)
of that conversation about what is,
Paola Arlotta (47:36.480)
will be allowed in the future
Lex Fridman (47:37.960)
or not allowed in the future to do with the system.
Lex Fridman (47:40.760)
And I think that is very, very important
Lex Fridman (47:43.320)
because they bring the reality of data to the conversation.
Lex Fridman (47:48.840)
And so they should have a voice.
Lex Fridman (47:51.640)
So data should have a voice.
Paola Arlotta (47:53.320)
Data needs to have a voice.
Lex Fridman (47:55.160)
Because in not only data,
Paola Arlotta (47:57.280)
we should also be good at communicating
Lex Fridman (48:01.120)
with non scientists, the data.
Lex Fridman (48:04.200)
So there has been often time,
Lex Fridman (48:06.800)
there is a lot of discussion and, you know,
Paola Arlotta (48:11.000)
excitement and fights about certain topics
Lex Fridman (48:16.280)
just because of the way they are described.
Paola Arlotta (48:19.280)
I'll give you an example.
Lex Fridman (48:20.960)
If I called the same cellular system
Paola Arlotta (48:23.360)
we just talked about a brain organoid,
Lex Fridman (48:27.040)
or if I called it a human mini brain,
Paola Arlotta (48:30.280)
your reaction is gonna be very different to this.
Lex Fridman (48:34.560)
And so the way the systems are described,
Paola Arlotta (48:37.720)
I mean, we and journalists alike need to be a bit careful
Lex Fridman (48:42.480)
that this debate is a real debate and informed by real data.
Paola Arlotta (48:46.040)
That's all I'm asking.
Lex Fridman (48:47.920)
And yeah, the language matters here.
Lex Fridman (48:49.560)
So I work on autonomous vehicles
Lex Fridman (48:51.280)
and there the use of language
Paola Arlotta (48:53.000)
could drastically change the interpretation
Lex Fridman (48:56.440)
and the way people feel about
Lex Fridman (48:58.480)
what is the right way to proceed forward.
Lex Fridman (49:01.480)
You are, as I've seen from a presentation, you're a parent.
Paola Arlotta (49:06.200)
I saw you show a couple of pictures of your son.
Lex Fridman (49:09.800)
Is it just the one?
Paola Arlotta (49:11.400)
Two.
Lex Fridman (49:12.240)
Two.
Paola Arlotta (49:13.080)
Son and a daughter.
Lex Fridman (49:13.920)
Son and a daughter.
Lex Fridman (49:14.760)
So what have you learned from the human brain
Lex Fridman (49:17.320)
by raising two of them?
Paola Arlotta (49:20.040)
More than I could ever learn in the lab.
Lex Fridman (49:24.480)
What have I learned?
Paola Arlotta (49:25.560)
I've learned that children really have
Lex Fridman (49:27.480)
these amazing plastic minds, right?
Paola Arlotta (49:30.480)
That we have a responsibility to, you know,
Lex Fridman (49:34.800)
foster their growth in good, healthy ways.
Paola Arlotta (49:38.360)
That keep them curious, that keeps them adventurous,
Lex Fridman (49:41.360)
that doesn't raise them in fear of things.
Lex Fridman (49:45.800)
But also respecting who they are,
Lex Fridman (49:47.920)
which is in part, you know,
Paola Arlotta (49:49.040)
coming from the genetics we talked about.
Lex Fridman (49:51.360)
My children are very different from each other
Paola Arlotta (49:53.560)
despite the fact that they're the product of
Lex Fridman (49:55.560)
the same two parents.
Paola Arlotta (49:58.440)
I also learned that what you do for them comes back to you.
Lex Fridman (50:03.440)
Like, you know, if you're a good parent,
Paola Arlotta (50:05.000)
you're gonna, most of the time,
Lex Fridman (50:08.000)
have, you know, perhaps a decent kids at the end.
Lex Fridman (50:11.240)
So what do you think, just a quick comment,
Lex Fridman (50:12.960)
what do you think is the source of that difference?
Paola Arlotta (50:16.920)
That's often the surprising thing for parents.
Lex Fridman (50:20.400)
Is that they can't believe that our kids,
Paola Arlotta (50:23.880)
oh, they're so different,
Lex Fridman (50:26.360)
yet they came from the same parents.
Paola Arlotta (50:28.000)
Well, they are genetically different.
Lex Fridman (50:29.560)
Even they came from the same two parents
Paola Arlotta (50:31.880)
because the mixing of gametes,
Lex Fridman (50:33.600)
you know, we know this genetics,
Paola Arlotta (50:35.640)
creates every time a genetically different individual,
Lex Fridman (50:39.760)
which will have a specific mix of genes
Paola Arlotta (50:43.680)
that is a different mix every time from the two parents.
Lex Fridman (50:46.480)
And so they're not twins.
Paola Arlotta (50:50.280)
They are genetically different.
Lex Fridman (50:52.800)
Even just that little bit of variation,
Paola Arlotta (50:55.320)
because you said really from a biological perspective,
Lex Fridman (50:58.320)
the brains look pretty similar.
Paola Arlotta (51:00.600)
Well, so let me clarify that.
Lex Fridman (51:02.400)
So the genetics you have, the genes that you have,
Paola Arlotta (51:05.440)
that play that beautiful orchestrated symphony
Lex Fridman (51:08.680)
of development, different genes
Paola Arlotta (51:12.040)
will play it slightly differently.
Lex Fridman (51:13.920)
It's like playing the same piece of music,
Lex Fridman (51:16.120)
but with a different orchestra and a different director.
Lex Fridman (51:20.000)
The music will not come out.
Paola Arlotta (51:21.480)
It will be still a piece by the same author,
Lex Fridman (51:25.440)
but it will come out differently
Paola Arlotta (51:27.080)
if it's played by the high school orchestra
Lex Fridman (51:28.960)
instead of the Scala in Milan.
Lex Fridman (51:34.680)
And so you are born superficially with the same brain.
Lex Fridman (51:39.360)
It has the same cell types,
Paola Arlotta (51:41.240)
similar patterns of connectivity,
Lex Fridman (51:43.440)
but the properties of the cells
Lex Fridman (51:45.240)
and how the cells will then react to the environment
Lex Fridman (51:47.600)
as you experience your world will be also shaped
Paola Arlotta (51:51.320)
by who genetically you are.
Lex Fridman (51:53.680)
Speaking just as a parent,
Paola Arlotta (51:55.120)
this is not something that comes from my work.
Lex Fridman (51:56.880)
I think you can tell at birth that these kids are different,
Lex Fridman (52:01.080)
that they have a different personality in a way, right?
Lex Fridman (52:05.560)
So both is needed, the genetics,
Paola Arlotta (52:08.720)
as well as the nurturing afterwards.
Lex Fridman (52:11.600)
So you are one human with a brain,
Paola Arlotta (52:15.480)
sort of living through the whole mess of it,
Lex Fridman (52:17.680)
the human condition, full of love, maybe fear,
Paola Arlotta (52:21.520)
ultimately mortal.
Lex Fridman (52:24.480)
How has studying the brain changed the way you see yourself?
Paola Arlotta (52:27.680)
When you look in the mirror, when you think about your life,
Lex Fridman (52:30.480)
the fears, the love, when you see your own life,
Paola Arlotta (52:33.440)
your own mortality.
Lex Fridman (52:34.640)
Yeah, that's a very good question.
Paola Arlotta (52:38.520)
It's almost impossible to dissociate some time for me.
Lex Fridman (52:43.520)
Some of the things we do or some of the things
Paola Arlotta (52:46.200)
that other people do from,
Lex Fridman (52:48.520)
oh, that's because that part of the brain
Paola Arlotta (52:52.320)
is working in a certain way.
Lex Fridman (52:54.400)
Or thinking about a teenager,
Paola Arlotta (52:59.560)
going through teenage years and being at time funny
Lex Fridman (53:02.160)
in the way they think.
Lex Fridman (53:03.840)
And impossible for me not to think it's because
Lex Fridman (53:07.480)
they're going through this period of time
Paola Arlotta (53:09.680)
called critical periods of plasticity
Lex Fridman (53:13.040)
where their synapses are being eliminated here and there,
Lex Fridman (53:16.200)
and they're just confused.
Lex Fridman (53:17.560)
And so from that comes perhaps a different take
Paola Arlotta (53:22.080)
on that behavior, or maybe I can justify it scientifically
Lex Fridman (53:27.880)
in some sort of way.
Paola Arlotta (53:29.880)
I also look at humanity in general,
Lex Fridman (53:32.080)
and I am amazed by what we can do
Lex Fridman (53:36.840)
and the kind of ideas that we can come up with.
Lex Fridman (53:39.760)
And I cannot stop thinking about how the brain
Paola Arlotta (53:43.480)
is continuing to evolve.
Lex Fridman (53:46.200)
I don't know if you do this,
Lex Fridman (53:47.120)
but I think about the next brain sometimes.
Lex Fridman (53:49.480)
Where are we going with this?
Paola Arlotta (53:50.880)
Like, what are the features of this brain
Lex Fridman (53:53.680)
that evolution is really playing with
Lex Fridman (53:57.680)
to get us in the future, the new brain?
Lex Fridman (54:02.320)
It's not over, right?
Paola Arlotta (54:04.040)
It's a work in progress.
Lex Fridman (54:06.960)
So let me just a quick comment on that.
Lex Fridman (54:09.040)
Do you think there's a lot of fascination
Lex Fridman (54:14.240)
and hope for artificial intelligence
Lex Fridman (54:15.960)
of creating artificial brains?
Lex Fridman (54:17.720)
You said the next brain.
Paola Arlotta (54:20.080)
When you imagine over a period of a thousand years,
Lex Fridman (54:23.360)
the evolution of the human brain,
Lex Fridman (54:25.480)
do you sometimes envisioning that future
Lex Fridman (54:28.680)
see an artificial one, artificial intelligence,
Paola Arlotta (54:32.400)
as it is hoped by many, not hoped,
Lex Fridman (54:34.920)
thought by many people would be actually
Lex Fridman (54:37.440)
the next evolutionary step in the development of humans?
Lex Fridman (54:40.440)
Yeah, I think in a way that will happen, right?
Paola Arlotta (54:45.240)
It's almost like a part of the way we evolve.
Lex Fridman (54:48.520)
We evolve in the world that we created,
Paola Arlotta (54:51.160)
that we interact with, that shape us as we grow up
Lex Fridman (54:55.280)
and so on and so forth.
Paola Arlotta (54:58.200)
Sometime I think about something that may sound silly,
Lex Fridman (55:00.880)
but think about the use of cell phones.
Paola Arlotta (55:04.480)
Part of me thinks that somehow in their brain,
Lex Fridman (55:07.000)
there will be a region of the cortex
Paola Arlotta (55:09.000)
that is attuned to that tool.
Lex Fridman (55:13.560)
And this comes from a lot of studies
Paola Arlotta (55:16.440)
in modern organisms where really the cortex,
Lex Fridman (55:20.840)
especially adapts to the kind of things you have to do.
Lex Fridman (55:24.080)
So if we need to move our fingers in a very specific way,
Lex Fridman (55:28.440)
we have a part of our cortex that allows us
Paola Arlotta (55:30.600)
to do this kind of very precise movement.
Lex Fridman (55:34.200)
An owl that has to see very, very far away
Paola Arlotta (55:36.800)
with big eyes, the visual cortex, very big.
Lex Fridman (55:39.800)
The brain attunes to your environment.
Lex Fridman (55:43.120)
So the brain will attune to the technologies
Lex Fridman (55:47.440)
that we will have and will be shaped by it.
Lex Fridman (55:51.040)
So the cortex very well may be.
Lex Fridman (55:52.800)
Will be shaped by it.
Paola Arlotta (55:54.480)
In artificial intelligence, it may merge with it,
Lex Fridman (55:57.200)
it may get, envelop it and adjust.
Paola Arlotta (56:01.120)
Even if it's not a merge of the kind of,
Lex Fridman (56:04.040)
oh, let's have a synthetic element together
Paola Arlotta (56:06.800)
with a biological one.
Lex Fridman (56:08.640)
The very space around us, the fact, for example,
Paola Arlotta (56:11.680)
think about we put on some goggles of virtual reality
Lex Fridman (56:15.120)
and we physically are surfing the ocean, right?
Paola Arlotta (56:18.680)
Like I've done it.
Lex Fridman (56:19.960)
And you have all these emotions that come to you.
Paola Arlotta (56:22.600)
Your brain placed you in that reality.
Lex Fridman (56:27.000)
And it was able to do it like that
Paola Arlotta (56:29.520)
just by putting the goggles on.
Lex Fridman (56:31.000)
It didn't take thousands of years of adapting to this.
Paola Arlotta (56:35.840)
The brain is plastic.
Lex Fridman (56:37.320)
So adapts to new technology.
Lex Fridman (56:39.160)
So you could do it from the outside
Lex Fridman (56:41.600)
by simply hijacking some sensory capacities that we have.
Lex Fridman (56:47.480)
So clearly over recent evolution,
Lex Fridman (56:51.440)
the cerebral cortex has been a part of the brain
Paola Arlotta (56:53.800)
that has known the most evolution.
Lex Fridman (56:55.840)
So we have put a lot of chips
Paola Arlotta (56:58.240)
on evolving this specific part of the brain.
Lex Fridman (57:02.440)
And the evolution of cortex is plasticity.
Paola Arlotta (57:05.800)
It's this ability to change in response to things.
Lex Fridman (57:10.120)
So yes, they will integrate.
Paola Arlotta (57:12.240)
That we want it or not.
Lex Fridman (57:14.800)
Well, there's no better way to end it, Paola.
Paola Arlotta (57:18.000)
Thank you so much for talking today.
Lex Fridman (57:19.320)
You're very welcome.
Paola Arlotta (57:20.160)
This is very exciting.
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