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优化遗传密码

The Genetic Code Sucks. Let’s Do Better

[music]
[音乐]
The genetic code is really neat with all the Cs As and Ts and stuff.
编写着核苷酸的基因序列看上去十分整洁
But under the hood, it’s actually extremely redundant.
实际上却相当冗余
And there are those who look at that redundancy
有些人仔细观察了这些“冗余”部分
and see a world of potential.
从中发现了相当大的潜力
Over the last few decades,
在过去几十年中
scientists have been experimenting with ways to take the familiar genetic code
科学家们对这些熟悉的基因序列做了各种实验
and use its redundancies to reprogram and expand it.
利用它们的冗余来重新编码或拓展
But what would you do with the rewritten genetic code?
但为什么要重新编写基因序列呢?
It works fine, right?
它本来也挺好的啊
Yes. But by rewriting it,
话是没错 但通过重写
scientiests are finding new ways
科学家们找到了
for life to build itself from the ground up.
生命从零开始自我发育的新方式
And that could help us do all kinds of things.
这给了我们很多启发
From understanding alien life,
像是去理解外星生命
to using cells as factories to build brand new molecules.
或是把细胞当工厂来制造新分子
So the start off,
那么开始之前
before we going to anything about redundancy or reprogramming,
在介绍那些冗余或重新编码之前
Let’s have a quick reminder of how
先来快速回顾一下
all of the stuff in your genome works.
你的基因组是怎么运作的
The basic idea is that your genome contains
基本的观点是你的基因组
information in the form of DNA.
以DNA的形式携带信息
This blueprint comes in the form of the nucleotides.
像这个图谱是由核苷酸构成的
The As, Gs, Ts and Cs,
有A G T C四种
as well as their precise order in which they are arranged.
它们会严格按固有的顺序排好
TTA or CCG, for example.
像TTA或CCG这样
When it comes time for your cells to make a new protein,
当细胞开始制造新的蛋白质时
your DNA unzips,
DNA就会展开
and the copy of the code made of molecule
并复制出一段分子代码
called the messenger RNA or mRNA is made.
称之为信使核糖核酸
It uses a molecule called uracil, U, instead of T.
它使用了特殊的尿嘧啶 而不是胸腺嘧啶
But it uses the same genetic code as DNA.
但其基因序列和DNA是一样的
This mRNA is then transported
然后信使核苷酸会来到
to a protein factory called ribosome.
被称为核糖体的蛋白质工厂
There, the ribosome reads the open phase of mRNA
核糖体会读取信使核苷酸上的信息
in three-letter chucks called codons.
分做三字一组称为密码子
Each of these codons corresponds to
每一组密码子又对应
one of the building blocks of proteins called amino acids.
一个构成蛋白质的基本单位 氨基酸
The ribosome reads the codons of a molecule called transfer RNA, or tRNA,
核糖体读取密码子后 一种被称为转运核苷酸的分子
brings in the magic amino acid.
就会接附相应的氨基酸
The ribosome brings everybody together
核糖体集合所有分子
and links the amino acids together in a chain
把氨基酸合成肽链
and in the same order as the codons in the mRNA.
按照信使核苷酸里的密码子顺序
This goes on until the ribosome hits a signal in the mRNA to stop,
直到核糖体读到信使核苷酸的停止信号
at which point, it releases the amino acid chain
这时 核糖体就会释放该肽链
which is now ready to become a finished protein.
同时该肽链也已成为了蛋白质
And in this way, our cells can turn just 20 amino acids
就这样 细胞仅仅用了20种氨基酸
into pretty much all of the stuff we are made of.
就几乎搭建了我们一整个的人
But here is what we talk about redundancy.
但接下来我们来谈谈其中的冗余
There are 20 amino acids
有20种氨基酸
that our body commonly uses as building blocks.
是构建我们身体的常用基本单位
Including the need for a stop signal,
再加一个表示停止信号的
there is really only 21 different signals you need for protein synthesize.
合成蛋白质就只需要21种信号
But there are 64 possible triplets. That’s just math.
但密码子却有64种可能性 只是从数学上来讲
4 options in the first space times 4 in the second
第一位4种可能 乘第二位4种
times 4 in the third equals 64.
再乘第三位 等于64
64 is a lot more than 21.
64可比21多多了
The end result is that you have extra codons,
结果就是得到富余的密码子
extra combination of letters.
多余的字母组合
And rather than leave them blank,
但基因序列没有留白
the genetic code doubles up
而是反手一波超级加倍
and gives some amino acids double codons or more.
给了一些氨基酸两个或以上的密码子
For example, the amino acid, tyrosine,
比如酪氨酸
can be recruited by either the combination UAU,
既可以被表示为密码组合UAU
or the combination UAC.
也可以是UAC
It gets 2 different codons.
它就有了两个密码子
And the amino acids serine, leucine and arginine
还有像丝氨酸 亮氨酸 精氨酸
each gets 6 different combinations,
每个都有6种密码组合
which is what scientists mean when they say the genetic code is redundant.
这就是科学家们所谓的基因序列冗余了
Actually the technical term is degenerate.
专业术语叫作简并退化
And it’s this redundancy that scientists are looking to take advantage of.
这也是科学家们想要好好利用的地方
You might hear terms like redundant and, especially, degenerate and assume
当听到冗余 特别是退化 这样的术语时
that this is, you know, bad.
你会猜这是坏事
So why not reassign codons?
那为什么不重新分配密码子呢?
Plenty of room to work with, right?
有很大的操作空间啊 对吧?
But anyone who’s gotten a flat tire
但某个车爆了胎
and happen to have a spare hand may even tell you
刚好又有空的人 可能会告诉你
that there can be benifits to have some redundancy built in.
这些冗余和重复是有好处的
One of the major benifits to our redundant genetic code
基因序列冗余的主要好处之一是
may be protection against harmful point mutations.
可以避免有害的基因点突变
Those are changes to a single letter in the genetic code,
该突变可能会改变基因序列中的单个字母
such as swapping a T for an A.
比如说把T换成A
In a system with no room for error,
在没有容错率的系统中
this would translate into a different amino acid being added to the protein chain,
这会导致一个错误的氨基酸接附到肽链中
potentially running the protein
这可能会毁了那个蛋白质
or even making it dangerous to the cell.
甚至危及到细胞
By having a bit of redundancy built in,
但如果有一些冗余和重复的话
it means that sometimes those otherwise potentially harmful mutations fizzle out.
就可能让一些潜在的有害突变告吹
Go back to Tyrosine, for instance, a mutation that changes UAU to UAC.
还是用酪氨酸举例 UAU突变成了UAC
Well, that’s still a tyrosine.
结果还是酪氨酸
So, to the cell, everything is just the same.
那对细胞来说 一切照旧
On top of this, there may be more subtle benifits to this setup as well.
除此之外 这套系统还有些微妙的好处
It could also steer evolution towards chemically simpler amino acids.
它可以准确向化学上更简单的形态氨基酸进行转化
And scientists suggested that there may indeed be some differences between redundant codons.
科学家认为 冗余的序列之间的确存在着不同
Tweaking things like the speed of protein folding
比如调整蛋白质折叠的速度
or how strong a gene is expressed.
或者基因表达的强度
Nevertheless the genetic code being redundant
尽管如此 基因序列是有冗余的
does present scientists with an opportunity for tweaking
这就给了科学家一个调整
and filling in some brand new amino acids.
补充一些全新的氨基酸的机会
You see. Those 20 smino acids our DNA codes for
你看 我们DNA编码的20种氨基酸
have a special place in biology.
在生物学中都有不同的地位
Because they are enshrined in the genetic code.
因为它们被铭刻在基因序列中
They got a fancy name of the “canonical” amino acids,
科学家们给“传统的”氨基酸起了很花哨的名字
like molecular biology is a TV series or something.
就好像微生物学是一部电视剧什么的
But from a chemical point of view,
但从化学的角度看
those 20 aren’t especially special.
这20种氨基酸并不特殊
To a chemist calling something amino acid,
对化学家来说 氨基酸
just means it is a carbon-based compound with a chemical piece called amino group on one end,
不过是一种氨基在末尾 羧基在一边的
and carboxyl group on the other,
侧链或者其它什么部分会脱离的
with a side chain or something else coming off.
碳基化合物而已
Because carbon-based compounds can take all kinds of forms,
因为碳基化合物可以成为任何一种形状
there are all kinds of things that can make of those side chains.
很多物质都可以成为侧链的组成部分
So technically, there’s a virtually indefinite number of amino acids,
所以 技术上 应该有无数多的氨基酸
all of which could be theoretically included during protein synthesize.
理论上 这些氨基酸应该都能够被用来合成蛋白质
These extra amino acids are called the “non-canonical” amino acids,
没有参与蛋白质合成的氨基酸就被称为“非传统”氨基酸
which, yes, does make the whole scenario seem a little like a millennial biology fan fiction.
没错 有点像千禧年的生物同人小说
I mean, some of these non-canonical amino acids
我是说 一些非传统氨基酸
could be really useful in a bunch of different ways.
真的有很多不同的用途
But before we get to that though, let’s talk about how.
但在这之前 让我们先看看怎么用
There are organisms that naturally use something different.
有些有机物 生来用途就不同
There’s a yeast that used CUG for serine instead of leucine, for example.
比如 有一种酵母用CUG来代替亮氨酸
Let’s start with a nice normal cell, and reprogram its entire genetic code
我们从一个正常的细胞讲起 重新编程它的基因序列
to include non-canonical amino acids,
好把非传统氨基酸加进去
ideally, somehow, without killing it.
最好是在它活着的基础上
For one thing, to even get this to work
首先 为了实现这一过程
you may have to change a bunch of cellular components.
你可能需要改变一些细胞成分
Remeber that both ribosomes and tRNAs are needed to assemble amino acids.
记住 核糖体和转运核苷酸都是合成氨基酸所必需的
Those may need to change, for example.
也可能需要一些改变
You may also need to go even deeper.
你可能需要更进一步
You might need to change not just tRNAs,
可能你要改变的不只是转运核苷酸
but the molecules that pair them with amino acids in the first place.
还有一开始与氨基酸配对的分子
And you need to get the organism to make your non-canonical amino acid,
你需要让有机体产生“非传统”氨基酸
or you have to keep providing it.
或者你要一直提供它们
But ok. Given that we can do all of that. Let’s get to the good stuff.
好吧 假设我们这些都可以做到 我们来看点有意思的
We’ve seen how the genome works
我们已经看到了基因组是如何工作的
with genes becoming blurprints, becoming proteins.
基因变成了模型 又变成蛋白质
We’ve talked about how there are some redundancies built in.
我们讨论过冗余是怎么产生的
Then we’ve talked about why changing stuff might be hard.
也说过为什么改变这些基因序列可能会有点难
Now, let’s talk about how we’ve done it.
现在 让我们谈谈怎么实现它吧
When we want to reprogram a code
我们想要重新组成一组基因序列时
is actually just to go ahead and add in more letters.
只需要直接多加几个碳基就行
For example, in 1992, researchers were able to tweak cytosine
比如 1992年 研究者通过调整胞嘧啶
to create what was essentially a 65th codon,
创造出来第65个密码子
which could then code for a non-canonical amino acid.
然后可以编码成为一种非传统氨基酸
More recently, we’ve also been able to make E. coli,
最近 我们已经能够制作大肠杆菌了
a common bacterium,
一种常见的细菌
with six base pairs
有六个碱基对
(the original A, C, T and G, as well as two dubbed X and Y).
原始的A C T和G 以及一对X和Y
And in 2019, scientists who felt like that wasn’t enough
2019年 科学家认为这还不够
created DNA with eight nucleotides.
制造了含有8个核苷酸的DNA
But there are other options, too, for reprogramming the genetic code,
但也有其它选择 比如重新编写基因序列
like, not just adding new codons,
不只是添加新的碱基
but repurposing the existing redundant ones.
而且还利用了现有的多余密码子
That is to say, not adding new bases,
也就是说 不是添加新碱基
but taking one of the existing 64 combos
而是从现有的64种组合中
and getting it to point toward something non-canonical.
让它们形成非传统氨基酸
These letters that have blueprints that don’t use just 20 amino acids, but 21,
这些字母的模型不止用20个而是21个氨基酸
or maybe even more, all within normal DNA.
或者还会更多 它们都存在于普通DNA里
One of the common targets of this kind of tweaking is stop codons.
这种调整的一种常见目标就是终止密码子
Those are the ones that don’t told the ribosome to add in any amino acids,
终止密码子是告诉核糖体不要再添加新的氨基酸
instead, they are the ones that tell them to stop and let go with the chain.
停下来 终止肽链延长的一种密码子
We have three of them. There is UAA, UAG and UGA.
有三种终止密码子 分别是UAA UAG和UGA
As for how this might work, the first step to using, say, UAG,
对于它们是怎么工作的 第一步是UAG
for a non-canonical amino acid
会告诉非传统氨基酸
would be freed up to their current job.
让它们停止现在的工作
We can use genetic engineering to change existing UAG sequences to something like UAA.
我们可以利用基因工程把UAG变成UAA
Now there will be way more UAA than normal,
所以UAA就会比平常多了
but the ribosome does not care about that– its’s still a stop codon.
但核糖体不在乎 它依然是一个终止密码子
Now this can be tricky because you have to make sure
比较麻烦的是 你必须要确保
that step happens everywhere in the genome.
这一步在每一个基因组都会发生
Otherwise, you might end up completely breaking some other,
否则 你可能会完全破坏其它一些
life-sustaining enzyme somewhere,
维持生命的酶
in which case you don’t end up with the cool new bacterium,
这样的话 你非但得不到新细菌
and you end up with a dead bacterium.
还会得到一个死细菌
But if things go right,
但如果一切顺利
this means that the cell now has no naturally occurring UAG sequences,
就意味着 现在的细胞已经没有自然产生的UAG序列了
but can still make all its necessary proteins.
但依然可以制造它所必需的蛋白质
You didn’t have to change anything fancy,
你并没改变任何花哨的东西
but you have freed up UAG for our own ends.
但你为了最终的目的释放了UAG
We could then say UAG is no longer a stop codon.
现在我们可以说UAG不再是终止密码子了
We’re gonna tweak the cell’s machinery
我们要调整一下细胞机制
to now think this is a new, strange amino acid instead.
现在把它当做一种新的 奇怪的氨基酸
Then a second round of genetic engineering
然后是第二轮基因工程
would introduce new DNA sequences that use our upgraded UAG.
将会引进新的DNA序列来升级UAG
This means that this new amino acid
这意味着新的氨基酸
could be inserted into existing protein blueprints
可以被插入到现有的蛋白质模型中
or even make entirely new ones.
甚至可以形成新的蛋白质模型
And this is not just theoretical.
这不只是理论
We have gotten this to work,
我们已经把它付诸实践了
and not just in bacteria, but in larger animals too,
不只是细菌 还有更大的动物
even up to live mice.
甚至是活老鼠
We’ve been able to do this to other codons as well.
我们也可以对其它密码子这样做
For example, a 2021 paper in Science
比如 2021年《科学》杂志上的一篇论文称
repurposed three codons-
改编了3个密码子
– one top codon and two serine codons.
即一个上密码子和两个丝氨酸密码子
They did this in the E. coli
他们在大肠杆菌成功改编了这三个密码子
and were able to use those three codons
并可以将它们用于
to insert three non-canonical amino acids into the genetic code.
将三种非传统氨基酸编入遗传密码中
Interestingly, doing this also made the cells resistant to viruses.
有趣的是 这样做可以使细菌产生抵抗病毒的能力
They test this at the point when they were essentially blank the codons,
他们是在将密码子基本清除后
but before they assign the new amino acids,
新氨基酸分配之前进行的测试
the viruses would send their genetic codes
病毒会把它们的遗传密码
to the cell’s ribosomes for reproduction,
发送到细胞核糖体进行繁殖
like, normal in the course of infection.
就像 感染过程一般会发生的一样
But the viral genomes had been tweaked like the E. coli had.
但病毒基因组已经像大肠杆菌一样被改编了
So when the bacteria’s ribosome
所以当细菌的核糖体
saw UCA codon and instead of adding a serine,
看到没有添加丝氨酸的UCA的密码子
it just couldn’t, and did not know what to do.
它不能也不知道该做什么
And I meant that the virus didn’t replicate.
我的意思是 病毒没有复制
Presumably, even if they test it later
很可能 即使科学家在重新分配密码子后
after they reassign the condons,
再进行测试
the virus will stilll be in trouble.
病毒还是会遇到大问题
Because instead of having the nice virus protein,
因为没有好的病毒蛋白质
it would be expecting that they’d be riddled with these random other amino acids.
它们估计会被其它随机的氨基酸所充满
So that’s cool. That’s what they are trying to do, but that’s cool.
所以这挺酷的 这是科学家正在尝试做的 但挺酷的
What were they trying to do?
但他们究竟在尝试做什么
What’s the point of any of this?
做这些有什么意义吗
Let’s go back to the thing we’ve talked about.
我们回到前面所谈论的话题
There are times when we want bateria to be safe from viral contamination.
有时候我们希望细菌不受病毒污染
There are real life biotech companies that
现实生活中有一些生物技术公司
use bacteria to create drugs and other compounds.
利用细菌制造药物和其它化合物
We could also use these reprogrammed organisms
我们也可以用这些重新编码的有机体
to make designer proteins,
制造设计蛋白质
which might include new medicines
有可能就包含了新型药物
or new ways to precisely deliver and control medicines.
或是精确输送和控制药物的新方法
Like, by adding in certain compounds,
比如说加入某些化合物
we could control protein function with light.
我们就可以用光控制蛋白质作用
So beyond that, experimenting with reprogramming genomes in non-canomical amino acids
除此之外 在非传统氨基酸进行的基因组重新编码的实验
could help us study things in new ways.
可以帮助我们用新的方式研究事物
We could attach amino acids with special tags that are easy to track,
我们可以在氨基酸上加上易于追踪的标记
helping us watch how cellular machinery actually works, for example.
来帮我们观察细胞机制是如何工作的
And also experimenting with different versions of lives fundamental blueprints
还有对不同生命体的基础生物模型进行的实验
might help us think about
都有可能帮助我们思考
the different forms life might take in the universe as well.
生命在宇宙中可能存在的不同形式
So the recap,
综上所述
scientists are able to tweak and reprogram the genetic code,
科学家能够对基因编码进行调整和重新编码
either by adding new letters
要么增加新碱基
or tweaking the redundancies inherent to our genomes.
要么调整我们基因组固有的冗余
And doing this allows us
这样做可以让我们
to add new amino acid building blocks to life’s arsenal.
在生命的武器库中添加氨基酸这样的新武器
And yes, for you and me and our dogs and most of life on earth,
是的 对于你 我 我们的狗还有地球上的其他生物
a littel redundancy sticking to biological cannon is not bad.
一点生物组上的冗余也不错
It can definitely be a good thing.
它肯定可以变成一件好事
But experimenting with these stuff
对这些事情做实验
may one day help us in all kinds of ways.
没准儿有朝一日会在某些地方帮到我们
Ways we are still discovering as the technology progresses.
研究方法仍然随着科学的进步在被发掘
Thanks for watching this episode of SciShow.
感谢您收看本期《科学秀》
It was a pretty deep dive.
本期对话题进行了非常深入的探讨
And I’m really happy with how this one turned out.
我也很期待本期的反响
So thanks everyone who is involved and making it .
感谢所有参与并制作本视频的各位
If you want to get involved,
如果你想加入的话
you can consider supporting us on patron.
你可以在“赞助者”这个网站支持我们
You’ll be able to join our community on discord.
你可以加入我们的社区
And you will help us make cool videos that anyone can enjoy for Free
还可以帮助我们制作很棒的视频 每个人都可以免费观看
To get started,Check out
如果想要加入我们 请登陆patriot dot com slash sideshow

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视频概述

科学家通过利用冗余遗传密码子优化我们的基因

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条条大鹿通罗馬

翻译译者

nano

审核员

审核员VS

视频来源

https://www.youtube.com/watch?v=9j7oEuFrGz4

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