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2017诺贝尔化学奖:冷冻电子显微镜

The 2017 Nobel Prize in Chemistry: Cryo-electron microscopy explained

雅克·杜波什 约阿基姆·弗兰克 理查德·亨德森
Jacques Dubochet, Joachim Frank, and Richard Henderson
共同获得了今年的诺贝尔化学奖
have claimed this year’s Nobel Prize in Chemistry,
将生物化学 或许还有医学 带入了一个新时代
taking biochemistry–and perhaps medicine–into a new era,
根据诺贝尔委员会的说法
according to the Nobel committee.
这三位科学家因在冷冻电子显微镜技术方面的研究获得了诺贝尔奖
The trio earned the prize for their work on cryo-electron microscopy,
这是一种成像技术 可以让研究人员看到蛋白质
which is an imaging technique that lets researchers see proteins
和其他具有原子精度的大型生物分子
and other large biomolecules with atomic precision.
知道分子中所有口袋和裂隙所在的位置
Knowing where all the pockets and crevices are in a molecule
能帮助化学家设计出适合它们的药物
helps chemists design drugs that fit into them,
这使得成像技术
which makes imaging techniques vital
对于理解和治疗疾病和紊乱至关重要
to understanding and treating diseases and disorders.
研究人员暂时已经有很强大的工具来实现生物分子成像
Researchers have had really powerful tools for imaging biomolecules for a while,
特别是X射线晶体学和核磁共振光谱
particularly X-ray crystallography and nuclear magnetic resonance spectroscopy.
事实上 许多诺贝尔奖已经颁给了那些
In fact, lots of Nobel Prizes have already gone to researchers
对使生命成为可能的分子进行成像的研究人员
who have imaged the molecules that make life possible.
那为什么又颁发了一个?
So why another one?
好吧 即使是装饰最华丽的方法也有缺点
Well, even the most-decorated methods have shortcomings.
例如 核磁共振光谱法最适合小生物分子
NMR spectroscopy works best for smallish biomolecules,
如果你想知道病毒的样子 这是一个累赘
which is a drag if you want to know what a virus looks like, for example.
如果你想用X射线晶体学
And if you want to use x-ray crystallography,
你感兴趣的生物分子必须结晶
the biomolecule you’re interested in has to crystallize,
不是所有的生物分子都能做到
which not all biomolecules do.
冷冻电镜能在不牺牲分辨率的情况下绕过这些问题
Cryo-EM gets around these problems without sacrificing resolution.
一般来说 电子显微镜使用的是电子束而不是光
Generally speaking, electron microscopy uses an electron beam, rather than light,
将样品放大到原子分辨率
to magnify samples to atomic resolution.
但是普通的老式电子显微镜并没有对生物和其分子进行优化
But plain old electron microscopy isn’t optimized for living things and their molecules.
用电子束撞击生物分子会损伤或破坏它们
Hitting biomolecules with an electron beam can damage or destroy them.
电子显微镜在真空中工作 也会损伤或破坏生物分子
And electron microscopes work in vacuums–which can also damage or destroy biomolecules.
不过 我们今天看到的病毒 蛋白质
Still, today we’re seeing viruses, proteins,
和其他亚细胞结构前所未有 这多亏了冷冻电镜技术
and other subcellular structures like never before, thanks to cryo-EM.
了解这是如何成为可能的 也揭示了
Understanding how this is possible also sheds some light on
这三位获奖者被选中的原因
why these three laureates were selected.
在1960年代末
In the late 1960s,
理查德·亨德森使用X射线晶体学成像蛋白 获得了博士学位
Richard Henderson earned his Ph.D. imaging proteins using x-ray crystallography,
所以他通晓这项技术的局限性
so he was well-versed in the limitations of the technique.
他决定利用电子显微镜来研究细菌调理素
He decided to give electron microscopy a go to study bacteriorhodopsin,
一种蛋白质 古生菌用它来泵送质子通过细胞膜
a protein that Archaea use to pump protons across cell membranes.
亨德森把这些蛋白紧贴在细胞膜上
Henderson kept the proteins snug in their membranes,
然后用葡萄糖溶液覆盖样品
then coated the samples with a glucose solution
使其免受显微镜真空的破坏
to protect them from the microscope’s vacuum.
他还使用了低强度电子束
He also used a low-intensity electron beam,
这通常会导致图像质量差
which would normally result in poor image quality.
但是由于蛋白质在膜内固定的方式
But because of how the protein secures itself inside the membrane,
亨德森和他的同事能够从仪器中得到足够的信号
Henderson and his colleague were able to get enough signal out of the instrument
在1975年发表了噬菌调理素的一种粗粒化模型
to publish a rough model of bacteriorhodopsin in 1975.
在接下来的15年里 研究人员改进了这项技术
Over the next 15 years, researchers improved the technique and
并开始用液氮冷却样品
started cooling samples with liquid nitrogen.
这样就能更好地保护它们免受电子显微镜的危害
This better protected them from the hazards of electron microscopy
增强了冷冻电子显微镜的冷冻部分
hence the cryo part of cryo-EM.
1990年 亨德森公布了噬菌调理素的一种新的原子冷冻电镜结构
In 1990, Henderson unveiled an atomic cryo-EM structure of bacteriorhodopsin
与X射线晶体学有关
with resolution on par with x-ray crystallography.
但是记住 这是一种蛋白质
But remember, this was one protein.
为了使电子显微镜有更广泛的应用价值
In order for electron microscopy to be widely useful,
需要做更多的工作 而不仅是噬菌调理素
it needed to work for more than bacteriorhodopsin,
这意味着
which meant, for one,
研究人员需要更好的方法来制备任意样本
researchers needed better ways to prepare arbitrary samples.
尽管冷冻样本在电子显微镜下保护它们
Although freezing samples protected them inside an electron microscope,
但冰晶实际上干扰了成像
ice crystals actually interfered with imaging.
走进雅克·杜波切特和他的团队
Enter Jacques Dubochet and his team.
1982年 他们发现可以将水玻璃化
In 1982, they found they could vitrify water
通过加入液氮冷却的乙烷
by adding ethane that had been chilled by liquid nitrogen.
玻璃化的水是玻璃状的 是随机排列的
Vitrified water is glass-like and randomly ordered
而不是晶体状且有序排列的
rather than crystal-like and ordered
所以它不会干扰成像
so it wouldn’t interfere with the imaging.
冷冻电镜的另一个早期障碍是图像处理能力
Another early obstacle for cryo-EM was image processing power.
在雅克·杜波什突破前不久
Shortly before Jacques Dubochet’s breakthrough,
约阿希姆·弗兰克发明了一种算法
Joachim Frank had developed an algorithm that
可以让计算机查看一堆模糊的电子显微图
enabled computers to look at a bunch of fuzzy electron micrographs
并将它们平均地变成一个清晰的图像
and average them into one sharp image.
然后他在这个软件上建立了高分辨率的三维微图
He then built on this software to create high-resolution 3-D micrographs
它是由显微镜生成的二维图像计算得到的
from the 2-D images generated by microscopes.
它将我们带到80年代中期
That takes us to the mid-80s,
但几十年前 冷冻电镜已经为它的黄金时间做好了准备
but it’d be decades before cryo-EM was ready for prime time.
在这之后的几年里 电脑变得越来越好
In the intervening years, computers got way better and,
当然 研究人员越来越擅长使用这种技术
of course, researchers got better at using the technique.
但在过去的5年里 电子探测器技术也取得了巨大进步
But there have also been big advances in the past five years to electron detector technology,
这导致了高分辨率冷冻电镜结构的技术革命
which led to an avalanche of high-resolution cryo-EM structures.
冷冻电镜技术处理了各种复杂的蛋白质 核孔复合物
Cryo-EM’s tackled all sorts of complex proteins, the nuclear pore complex,
甚至是最近爆发的塞卡病毒
even the Zika virus during the recent outbreak
都是原子分辨率级别
all with atomic resolution.
我们谈论了生物学 医学 甚至还有一点物理
We’ve talked about biology, medicine and even a little bit of physics,
但是请记住这是一个化学奖
but remember this was a chemistry prize.
美国化学学会主席艾莉森·坎贝尔解释了原因
Here’s the president of the American Chemical Society, Allison Campbell, explaining why.
对我来说 这就是化学
Campbell: To me, this is all about chemistry
因为它能使我们作为科学家 研究分子
because this enables us as scientists to look at molecules.
分子中原子的排列及形成的结构
and the arrangement of atoms in molecules and the resulting structure.
这都是关于化学的
And that’s all about chemistry.
它是一个生物分子 并不重要
It doesn’t really matter that it’s a biomolecule.
重要的是分子如何与它周围的环境
It’s how that molecule is interacting with its environment,
或其它分子相互作用
or other molecules which is important.
对我来说 这都是关于化学
To me, this is all about chemistry.
你可以看一个生物样本
You can look at a biological sample,
你可以看看人类的生物样本
you can look at a human biological sample,
你可以看看微生物系统
you can look at a microbial system,
你甚至可以看到用于工业应用的聚合物样品
you might even be able to look at polymer samples or enzymatic materials
或酶材料
that are used for industrial applications.
所以对我而言这都是关于化学的
So it’s all about chemistry to me.
同时 不要低估这项工作对化学 医学或其他任何事情的重要性
Also, not to downplay the importance of this work to chemistry or medicine or anything,
但冷冻电镜技术制作了一些非常非常棒的图像
but cryo-EM has produced some really, really amazing images.
我们在描述中引入了一些链接是通过冷冻电镜得到的一些非常棒的结构
We’ve got a collection of links in the description with some awesome structures revealed by cryo-EM.
请在评论中告诉我们你最喜欢的
Let us know your favorites in the comments.

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视频概述

今年的诺贝尔化学奖为何会颁发给冷冻电镜技术?是不是离化学有点远?它使科学家能够以接近原子分辨率水平来确定溶液里的分子结构,实至名归。

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翻译译者

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审核员

审核团HY

视频来源

https://www.youtube.com/watch?v=026rzTXb1zw

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