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研究大脑不可见秘密的新方法

A new way to study the brain's invisible secrets | Ed Boyden

大家好
Hello, everybody.
今天我带来了婴儿纸尿布等一下
I brought with me today a baby diaper.
你们就知道为什么了
You’ll see why in a second.
婴儿纸尿布有些很有趣的特性
Baby diapers have interesting properties.
比如加水会膨胀
They can swell enormously when you add water to them,
每天有数百万的小孩在做这个实验
an experiment done by millions of kids every day.
(笑声)
(Laughter)
但尿布会膨胀的原因
But the reason why
是源于它们的巧妙设计
is that they’re designed in a very clever way.
它们是用可膨胀的材料制成
They’re made out of a thing called a swellable material.
如果把水加到这种特殊材料中
It’s a special kind of material that, when you add water,
它就会疯狂地膨胀
it will swell up enormously,
体积约胀到1000倍
maybe a thousand times in volume.
这是个非常有用的工业类聚合物
And this is a very useful, industrial kind of polymer.
我在麻省理工学院的研究团队
But what we’re trying to do in my group at MIT
想要尝试用类似的方法让大脑膨胀
is to figure out if we can do something similar to the brain.
试试我们能否把人脑胀大
Can we make it bigger,
大到可以让人窥视它的内部
big enough that you can peer inside
看里面的小组件和生物分子
and see all the tiny building blocks, the biomolecules,
看它们在三度空间的组合方式
how they’re organized in three dimensions,
看大脑的结构和里面的实况
the structure, the ground truth structure of the brain, if you will?
如果办得到
If we could get that,
也许我们能更理解人脑的组织
maybe we could have a better understanding of how the brain is organized
理解它如何产生思想和情感
to yield thoughts and emotions
行动和感觉
and actions and sensations.
或许我们可以知道究竟是什么产生了变化
Maybe we could try to pinpoint the exact changes in the brain
导致大脑发生病变
that result in diseases,
像是老年痴呆症、癫痫和帕金森氏症这些疾病
diseases like Alzheimer’s and epilepsy and Parkinson’s,
这些疾病只有少数相应疗法 极少人可以被治愈
for which there are few treatments, much less cures,
我们往往不知道这些疾病的原因或者起源
and for which, very often, we don’t know the cause or the origins
以及是什么引发了疾病
and what’s really causing them to occur.
我们在麻省理工学院的研究小组
Now, our group at MIT
正尝试采取不同的观点
is trying to take a different point of view
这些观点有别于过往百年研究神经科学的方法
from the way neuroscience has been done over the last hundred years.
我们既是设计师
We’re designers. We’re inventors.
又是发明家我们正在尝试怎样发明出新的科技
We’re trying to figure out how to build technologies
能让我们审视和修复大脑
that let us look at and repair the brain.
这么做的原因是
And the reason is,
大脑的复杂程度令人难以置信
the brain is incredibly, incredibly complicated.
回望脑神经科学研究的第一个百年
So what we’ve learned over the first century of neuroscience
我们得知了大脑是个很复杂的网络
is that the brain is a very complicated network,
由称做神经元的特殊细胞
made out of very specialized cells called neurons
以复杂的几何形状连结而成
with very complex geometries,
电流可以通过这些形状复杂的神经元此外
and electrical currents will flow through these complexly shaped neurons.
神经元被连接在网络中
Furthermore, neurons are connected in networks.
它们通过被称为突触的微小连接口来交换化学物质
They’re connected by little junctions called synapses that exchange chemicals
让神经元彼此间交流讯息
and allow the neurons to talk to each other.
大脑有着不可思议的高密度
The density of the brain is incredible.
在每一立方毫米的大脑中
In a cubic millimeter of your brain,
约有十万个神经元
there are about 100,000 of these neurons
可能有十亿个连接
and maybe a billion of those connections.
怎么可能进行研究
But it’s worse.
如果你能拉近神经元放大看当然
So, if you could zoom in to a neuron,
你们看到的这个只是我们的艺术家做的图像
and, of course, this is just our artist’s rendition of it.
你会看到成千上万种的生物分子
What you would see are thousands and thousands of kinds of biomolecules,
这些立体3D、纳米级的结构共同作用
little nanoscale machines organized in complex, 3D patterns,
产生电脉冲
and together they mediate those electrical pulses,
并交换化学物质 使神经元相互作用
those chemical exchanges that allow neurons to work together
以产生想法、
to generate things like thoughts and feelings and so forth.
感觉等等我们不知道大脑中的神经元
Now, we don’t know how the neurons in the brain are organized
是如何形成网络系统的
to form networks,
我们也不知道生物分子
and we don’t know how the biomolecules are organized
是如何在神经元中
within neurons
形成这复杂有序的机制的
to form these complex, organized machines.
如果我们真想理解这些问题
If we really want to understand this,
就必须有新的技术
we’re going to need new technologies.
如果我们可以做出图像
But if we could get such maps,
让我们看得到分子和神经元的构造
if we could look at the organization of molecules and neurons
和神经元网络系统
and neurons and networks,
也许我们能真正了解大脑是如何传送
maybe we could really understand how the brain conducts information
来自感官区的信号
from sensory regions,
从而混合入情绪和情感
mixes it with emotion and feeling,
以产生决策和行动
and generates our decisions and actions.
也许我们可以确切查明
Maybe we could pinpoint the exact set of molecular changes that occur
病变大脑中产生变化的分子
in a brain disorder.
一旦我们弄清楚分子如何改变
And once we know how those molecules have changed,
不论是数目增加或是型态改变
whether they’ve increased in number or changed in pattern,
我们可以把这些分子用来开发新药
we could use those as targets for new drugs,
用来发明新的把能量传送到大脑的方式
for new ways of delivering energy into the brain
帮助受脑疾折磨的患者
in order to repair the brain computations that are afflicted
修复它们脑中受损的地方
in patients who suffer from brain disorders.
我们已经见证到 上个世纪有许多技术
We’ve all seen lots of different technologies over the last century
都尝试要解決这个问题
to try to confront this.
我们都见过核磁共振成像仪
I think we’ve all seen brain scans
被用来扫描脑部当然
taken using MRI machines.
这些仪器有不具侵入性
These, of course, have the great power that they are noninvasive,
所以可用于活体研究
they can be used on living human subjects.
但是它们的成像却很粗糙
But also, they’re spatially crude.
你可以看到的这些黄色块状物 或者立体像素
Each of these blobs that you see, or voxels, as they’re called,
可能包含有数以百万计的神经元
can contain millions and millions of neurons.
这样的分辨率
So it’s not at the level of resolution
仍不足以查明是哪些分子发生了变化
where it can pinpoint the molecular changes that occur
或哪些连接有了变化
or the changes in the wiring of these networks
正是这些使我们成为有意识的强大的生物
that contributes to our ability to be conscious and powerful beings.
另一个极端的仪器是显微镜
At the other extreme, you have microscopes.
显微镜利用光源来观察微小的东西
Microscopes, of course, will use light to look at little tiny things.
数百年来被用以观察像细菌这样的小东西
For centuries, they’ve been used to look at things like bacteria.
就神经科学来说
For neuroscience,
我们首次使用显微镜发现神经元
microscopes are actually how neurons were discovered in the first place,
大约是在130年前
about 130 years ago.
但”光”有极大的局限性
But light is fundamentally limited.
用普通的旧式光学显微镜人们无法看到单个分子
You can’t see individual molecules with a regular old microscope.
看不到这些微小的连接所以
You can’t look at these tiny connections.
如果我们要用更强而有力的方法
So if we want to make our ability to see the brain more powerful,
来观察大脑的结构
to get down to the ground truth structure,
我们需有更好的技术几年前
we’re going to need to have even better technologies.
我的研究小组开始思考
My group, a couple years ago, started thinking:
何不反向操作呢
Why don’t we do the opposite?
如果想试着拉近距离去观察大脑这么费劲
If it’s so darn complicated to zoom in to the brain,
我们为什么不把大脑变大呢
why can’t we make the brain bigger?
开始这个项目的是我组里的两个研究生Fei
It initially started
Chen和Paul Tillberg
with two grad students in my group, Fei Chen and Paul Tillberg.
现在有更多人加入进来帮着做
Now many others in my group are helping with this process.
我们决定要找出方法 尝试利用聚合物
We decided to try to figure out if we could take polymers,
就是婴儿纸尿裤中的那个材料
like the stuff in the baby diaper,
把它放在大脑中
and install it physically within the brain.
如果做得恰到好处
If we could do it just right, and you add water,
再加入水就可能把大脑放大到
you can potentially blow the brain up
足以把小分子个别地分辨出来的程度
to where you could distinguish those tiny biomolecules from each other.
这样你就可以看到脑中那些(神经元)连结的图像
You would see those connections and get maps of the brain.
这相当激励人心
This could potentially be quite dramatic.
我今天准备向各位演示一下
We brought a little demo here.
这有一些婴儿纸尿裤的原料
We got some purified baby diaper material.
在网上直接买这个
It’s much easier just to buy it off the Internet
比从纸尿布里提取少数原料要容易得多
than to extract the few grains that actually occur in these diapers.
我只放入一茶匙的
I’m going to put just one teaspoon here
精致聚合物
of this purified polymer.
然后加入一些水
And here we have some water.
接下来要做的
What we’re going to do
是看看这一茶匙的聚合物会不会
is see if this teaspoon of the baby diaper material
膨胀开来现在
can increase in size.
各位可以亲眼看到
You’re going to see it increase in volume by about a thousandfold
它大约会膨胀一千倍
before your very eyes.
我可以继续加水
I could pour much more of this in there,
但大家肯定已经知道会发生什么了
but I think you’ve got the idea
这是一种非常有意思的分子
that this is a very, very interesting molecule,
如果使用得当
and if can use it in the right way,
我们就可以观察到
we might be able to really zoom in on the brain
以前无法观察到的大脑细节好了
in a way that you can’t do with past technologies.
讲化学时间到
OK. So a little bit of chemistry now.
纸尿裤里的聚合物发生了什么呢
What’s going on in the baby diaper polymer?
如果你能拉近放大来看
If you could zoom in,
可能就像你现在在屏幕上看到的
it might look something like what you see on the screen.
这个聚合物正是由原子排成的众多细长的链条组成
Polymers are chains of atoms arranged in long, thin lines.
这些链条非常微小
The chains are very tiny,
大约是一个生物分子的宽度
about the width of a biomolecule,
而且这些聚合物非常密集
and these polymers are really dense.
它们之间的距离
They’re separated by distances
大约是一个生物分子的大小
that are around the size of a biomolecule.
这非常好
This is very good
因为我们就可能把大脑每一部分都分解开
because we could potentially move everything apart in the brain.
如果再加入水
If we add water, what will happen is,
这个会膨胀的物质会吸收水分
this swellable material is going to absorb the water,
聚合物链条彼此间的距离就会拉远
the polymer chains will move apart from each other,
整个体积就会变得更大
and the entire material is going to become bigger.
由于这些链条是如此的渺小
And because these chains are so tiny
而且原本的间距只有一个生物分子那么一丁点大
and spaced by biomolecular distances,
所以我们可能令让大脑膨胀
we could potentially blow up the brain
大到足以被观察
and make it big enough to see.
需要解决的一点是
Here’s the mystery, then:
我们要如何把聚合物链置入大脑中
How do we actually make these polymer chains inside the brain
让我们得以拉开生物分子的间距呢
so we can move all the biomolecules apart?
如果做得到
If we could do that,
或许我们就能得到大脑图的实况
maybe we could get ground truth maps of the brain.
观察到大脑的连接系统
We could look at the wiring.
及里面的分子状况
We can peer inside and see the molecules within.
我们准备了一个动画视频来解释这一点
To explain this, we made some animations
在这个艺术家的作品中 我们可以看到
where we actually look at, in these artist renderings,
生物分子的样貌和我们如何把它们分开的情况步骤一:
what biomolecules might look like and how we might separate them.
首先我们要做的是
Step one: what we’d have to do, first of all,
在每一个棕色的生物分子上
is attach every biomolecule, shown in brown here,
粘上一个小锚
to a little anchor, a little handle.
小把手想要把大脑中分子之间的距离拉远
We need to pull the molecules of the brain apart from each other,
我们需要利用这些小把手
and to do that, we need to have a little handle
让聚合物和分子连接起来
that allows those polymers to bind to them
因此让聚合物产生效应
and to exert their force.
如果只把尿布中的聚合物直接倒在大脑上很显然
Now, if you just take baby diaper polymer and dump it on the brain,
它们就只会堆在上面而已因此
obviously, it’s going to sit there on top.
我们需要找个方法让聚合物进到大脑里面去
So we need to find a way to make the polymers inside.
在研究过程中我们特别幸运
And this is where we’re really lucky.
发现我们可以利用一些建筑块
It turns out, you can get the building blocks,
一种被叫做”单体”的东西
monomers, as they’re called,
如果把它们放到大脑里面
and if you let them go into the brain
它们就会触发化学反应
and then trigger the chemical reactions,
然后在大脑组织里
you can get them to form those long chains,
形成细长的链条
right there inside the brain tissue.
这些链条会缠绕住生物分子
They’re going to wind their way around biomolecules
也会占住生物分子间的空隙
and between biomolecules,
形成复杂的网络最终
forming those complex webs
这可以使
that will allow you, eventually, to pull apart the molecules
大脑中的分子被拉开
from each other.
在有小把手的地方
And every time one of those little handles is around,
聚合物就会粘住这些把手
the polymer will bind to the handle, and that’s exactly what we need
正好可以成为拉开分子的施力点好吧
in order to pull the molecules apart from each other.
讲到关键时刻
All right, the moment of truth.
我们得先用化学物质处理样本
We have to treat this specimen
让分子彼此分散开
with a chemical to kind of loosen up all the molecules from each other,
然后加水
and then, when we add water,
这个会膨胀的材料开始吸收水分
that swellable material is going to start absorbing the water,
聚合物链条会移动开来这一次
the polymer chains will move apart,
生物分子也会跟随着一起移动
but now, the biomolecules will come along for the ride.
就像一个被画了图画的气球
And much like drawing a picture on a balloon,
如果被吹大
and then you blow up the balloon,
气球上的画还是同一幅画
the image is the same,
但是上面的颜色分子间的距离被拉大了
but the ink particles have moved away from each other.
这正是我们所做的 不过是在三维空间里
And that’s what we’ve been able to do now, but in three dimensions.
还有最后一个点
There’s one last trick.
如你所见
As you can see here,
我们把所有的生物分子都标成棕色
we’ve color-coded all the biomolecules brown.
这是因为他们看起来都差不多是一样的
That’s because they all kind of look the same.
生物分子由相同的原子组成
Biomolecules are made out of the same atoms,
只是顺序有差异最后
but just in different orders.
我们还要做一件事
So we need one last thing
来把他们辨别出来
in order to make them visible.
我们需要利用发光的染料
We have to bring in little tags,
作为区分他们的标示
with glowing dyes that will distinguish them.
所以某一种生物分子可能会被标成蓝色
So one kind of biomolecule might get a blue color.
而另一种会被标成红色
Another kind of biomolecule might get a red color.
等等
And so forth.
这就是最后一步如此
And that’s the final step.
我们就可以观察到大脑
Now we can look at something like a brain
和一个个不同的分子
and look at the individual molecules,
因为我们已经把分子拉得足够开
because we’ve moved them far apart enough from each other
可以对它们进行分辨
that we can tell them apart.
我们愿望是把不可见的变成可见的
So the hope here is that we can make the invisible visible.
把小而模糊的东西放大
We can turn things that might seem small and obscure
并且不停地放大
and blow them up
直到它们看起来像是生命信息的星座图
until they’re like constellations of information about life.
这个视频正可以展现这个过程
Here’s an actual video of what it might look like.
碟里放着一個小小的脑
We have here a little brain in a dish —
实际上是一片脑标本的切片
a little piece of a brain, actually.
我们已在里面注入聚合物
We’ve infused the polymer in,
现在要加水
and now we’re adding water.
你们现在看到的
What you’ll see is that, right before your eyes —
是以加快了60倍速度放映的视频
this video is sped up about sixtyfold —
这小片脑组织将会胀大
this little piece of brain tissue is going to grow.
它的体积将会胀成百倍或更大
It can increase by a hundredfold or even more in volume.
最牛的是 因为聚合物是如此渺小
And the cool part is, because those polymers are so tiny,
我们能均匀地分开这些生物分子
we’re separating biomolecules evenly from each other.
这个过程会缓慢有序地进行
It’s a smooth expansion.
而且信息的型态不会失真
We’re not losing the configuration of the information.
我们只是把它变得更容易被观察
We’re just making it easier to see.
现在我们可以取一个真实的大脑神经组织
So now we can take actual brain circuitry —
例如这片与记忆有关的部分
here’s a piece of the brain involved with, for example, memory —
拉近放大后
and we can zoom in.
就可以看到实际的神经电路构造
We can start to actually look at how circuits are configured.
也许有一天我们能读出一段记忆
Maybe someday we could read out a memory.
也许我们能看到大脑在处理情绪的过程中
Maybe we could actually look at how circuits are configured
脑神经的回路状态
to process emotions,
以及脑内的神经是如何连结的
how the actual wiring of our brain is organized
正是这些决定了人与人思想之间的区别
in order to make us who we are.
当然我们也更希望
And of course, we can pinpoint, hopefully,
能在脑分子层面上分析出脑部病变的原因试想
the actual problems in the brain at a molecular level.
假如我们真的深入到大脑细胞里
What if we could actually look into cells in the brain
发现原来大脑组织中的有17个分子发生了病变
and figure out, wow, here are the 17 molecules that have altered
所以病人患了癫痫
in this brain tissue that has been undergoing epilepsy
或者帕金森氏综合症
or changing in Parkinson’s disease
以及其它疾病
or otherwise being altered?
那就太好了如果我们能有系统地把这些变异列表
If we get that systematic list of things that are going wrong,
这就会变成我们治疗的目标
those become our therapeutic targets.
我们可以针对那些目标来制药
We can build drugs that bind those.
或许我们能集中精力研究不同的大脑部位
We can maybe aim energy at different parts of the brain
以帮助世界各地
in order to help people with Parkinson’s or epilepsy
患有帕金森症、
or other conditions that affect over a billion people
癫痫病或其他病症的
around the world.
十亿人口 有一种有意思的现象正在发生原来
Now, something interesting has been happening.
这个方法对整个生物医药界的研究
It turns out that throughout biomedicine,
也许都能帮得上忙
there are other problems that expansion might help with.
这是来自一个乳腺癌患者的活体标本实际上
This is an actual biopsy from a human breast cancer patient.
癌症
It turns out that if you look at cancers,
免疫系统老化
if you look at the immune system,
生长
if you look at aging, if you look at development —
所有这些过程都与大规模的生物系统有关当然
all these processes are involving large-scale biological systems.
问题是从纳米级的分子开始的
But of course, the problems begin with those little nanoscale molecules,
这些分子正是引发细胞和器官活动的机器
the machines that make the cells and the organs in our body tick.
我们目前正在试着理清
So what we’re trying to do now is to figure out
是否真的能用这个技术描绘出 各式各样疾病
if we can actually use this technology to map the building blocks of life
中基础生命结构组成的脉络
in a wide variety of diseases.
我们能否精确地看到肿瘤的分子变化
Can we actually pinpoint the molecular changes in a tumor
从而更有效地应对
so that we can actually go after it in a smart way
并将药物直接传送到我们想要的位置内呢要知道
and deliver drugs that might wipe out exactly the cells that we want to?
很多药物的风险非常高
You know, a lot of medicine is very high risk.
有的药物并未被确定真正有效
Sometimes, it’s even guesswork.
我希望我们不只以高风险的登月思维做事
My hope is we can actually turn what might be a high-risk moon shot
而是发现更可靠的方式
into something that’s more reliable.
如果仔细想想我们的登月计划
If you think about the original moon shot,
宇航员登陆月球的壮举
where they actually landed on the moon,
是基于扎实的科学研究的
it was based on solid science.
我们通晓重力
We understood gravity;
通晓空气动力学
we understood aerodynamics.
知道如何建造火箭
We knew how to build rockets.
科学的风险在我们的掌控之中至今
The science risk was under control.
登月仍是个伟大的工程壮举
It was still a great, great feat of engineering.
但在医学上 我们未必有定律可循
But in medicine, we don’t necessarily have all the laws.
我们未必能研究出类似重力
Do we have all the laws that are analogous to gravity,
和类似空气动力学的所有定律我认为
that are analogous to aerodynamics?
以我今天所谈论的技术
I would argue that with technologies
也许某天我们真的能够
like the kinds I’m talking about today,
导出那些定律来
maybe we can actually derive those.
我们能描绘和测绘生命系统的模型
We can map the patterns that occur in living systems,
找出方法来克服困扰我们的疾病
and figure out how to overcome the diseases that plague us.
我妻子和我有两个年幼的孩子
You know, my wife and I have two young kids,
身为一个生物工程学家 我有个心愿是
and one of my hopes as a bioengineer is to make life better for them
希望孩子们未来的生活能比目前我们的更美好
than it currently is for us.
我希望我们能把生物学和医学的研究
And my hope is, if we can turn biology and medicine
从偶然和运气支配又高风险的努力
from these high-risk endeavors that are governed by chance and luck,
转向以技艺和勤奋支配却真正有效的工作
and make them things that we win by skill and hard work,
那么这将是一个巨大的进步
then that would be a great advance.
非常感谢
Thank you very much.
(掌声)
(Applause)

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https://www.youtube.com/watch?v=CDdpQSLr7YE

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