5 challenges we could solve by designing new proteins | David Baker

譯者: Helen Chang 審譯者: Bruce Sung

I'm going to tell you about the most amazing machines in the world

我將講述世界上最神奇的機器

and what we can now do with them.

以及我們現在能用它來做什麼。

Proteins,

你在細胞中看到的一些蛋白質，

some of which you see inside a cell here,

carry out essentially all the important functions in our bodies.

基本上在我們體內 執行所有重要的功能。

Proteins digest your food,

蛋白質可消化食物、

contract your muscles,

收縮肌肉、

fire your neurons

激發神經元，

and power your immune system.

為免疫系統提供動力。

Everything that happens in biology --

生物學中發生的一切，

almost --

幾乎全都因蛋白質而發生。

happens because of proteins.

Proteins are linear chains of building blocks called amino acids.

蛋白質是由稱為「氨基酸」的 積木構成的線性鏈。

Nature uses an alphabet of 20 amino acids,

大自然用了 20 種氨基酸字母，

some of which have names you may have heard of.

你們可能聽過其中若干名稱。

In this picture, for scale, each bump is an atom.

這圖中比例相對的 每個凹凸都是個原子。

Chemical forces between the amino acids cause these long stringy molecules

氨基酸間的化學力 使這些長而細的分子

to fold up into unique, three-dimensional structures.

折疊成獨特的立體結構。

The folding process,

雖然折疊的過程看似隨機，

while it looks random,

is in fact very precise.

實際上非常的精確。

Each protein folds to its characteristic shape each time,

蛋白質總是折疊成其特徵的形狀，

and the folding process takes just a fraction of a second.

而折疊的過程只需幾分之一秒。

And it's the shapes of proteins

蛋白質的形狀

which enable them to carry out their remarkable biological functions.

使其能夠發揮卓越的生物功能。

For example,

例如，

hemoglobin has a shape in the lungs perfectly suited

肺裡的血紅蛋白

具有完全適合結合氧分子的形狀。

for binding a molecule of oxygen.

When hemoglobin moves to your muscle,

當血紅蛋白移到肌肉時，

the shape changes slightly

形狀會稍微改變，

and the oxygen comes out.

釋出氧氣。

The shapes of proteins,

蛋白質的形狀及其奇妙的功能

and hence their remarkable functions,

are completely specified by the sequence of amino acids in the protein chain.

完全由蛋白質鏈的氨基酸序列所定。

In this picture, each letter on top is an amino acid.

這張圖片頂部的每個字母都是氨基酸。

Where do these sequences come from?

這些序列來自哪裡？

The genes in your genome specify the amino acid sequences

基因組中的基因

訂定蛋白質的氨基酸序列。

of your proteins.

Each gene encodes the amino acid sequence of a single protein.

每個基因

為單個蛋白質的氨基酸序列編碼。

The translation between these amino acid sequences

這些氨基酸序列

與蛋白質的結構和功能之間的翻譯

and the structures and functions of proteins

is known as the protein folding problem.

被稱為蛋白質的折疊問題。

It's a very hard problem

這是個非常困難的問題，

because there's so many different shapes a protein can adopt.

因為蛋白質能有許多不同的形狀。

Because of this complexity,

由於它這麼複雜，

humans have only been able to harness the power of proteins

人類只能透由稍微更動

by making very small changes to the amino acid sequences

自然界蛋白質的氨基酸序列

of the proteins we've found in nature.

來利用蛋白質的能量。

This is similar to the process that our Stone Age ancestors used

這相當於石器時代祖先用來製作

to make tools and other implements from the sticks and stones

我們在周遭世界發現的

木棒、石製工具和其他工具的過程。

that we found in the world around us.

But humans did not learn to fly by modifying birds.

但是人類並非透由 修改鳥類來學習飛行。

(Laughter)

（笑聲）

Instead, scientists, inspired by birds, uncovered the principles of aerodynamics.

相反地，受鳥類啟發的科學家 發現氣體動力學的原理，

Engineers then used those principles to design custom flying machines.

接著工程師用這些原理 來設計和製作飛行機器。

In a similar way,

多年來，我們已經用類似的方式

we've been working for a number of years

to uncover the fundamental principles of protein folding

揭示蛋白質折疊的基本原理，

and encoding those principles in the computer program called Rosetta.

並用名為 Rosetta 的 電腦軟體將這些原理編碼。

We made a breakthrough in recent years.

我們近年來有了突破，

We can now design completely new proteins from scratch on the computer.

能夠在電腦上從頭開始 設計全新的蛋白質。

Once we've designed the new protein,

一旦設計出新的蛋白質，

we encode its amino acid sequence in a synthetic gene.

我們就會在合成基因中 將其氨基酸序列編碼。

We have to make a synthetic gene

我們必須合成基因

because since the protein is completely new,

是因為蛋白質是全新的，

there's no gene in any organism on earth which currently exists that encodes it.

目前地球上沒有任何生物體 有它的基因編碼。

Our advances in understanding protein folding

我們在理解蛋白質的折疊

和如何設計蛋白質方面取得的進展，

and how to design proteins,

coupled with the decreasing cost of gene synthesis

加上基因合成費用的降低，

and the Moore's law increase in computing power,

以及符合摩爾定律提高的運算能力，

now enable us to design tens of thousands of new proteins,

使我們現在能夠設計出成千上萬種

具有新形狀和新功能的新蛋白質，

with new shapes and new functions,

on the computer,

在電腦上設計，

and encode each one of those in a synthetic gene.

並編碼合成每個基因。

Once we have those synthetic genes,

一旦擁有這些合成的基因，

we put them into bacteria

我們將其置入細菌，

to program them to make these brand-new proteins.

讓它們製造這些全新的蛋白質。

We then extract the proteins

然後我們提取蛋白質，

and determine whether they function as we designed them to

看它們的功能是否符合我們的設計，

and whether they're safe.

以及它們是否安全。

It's exciting to be able to make new proteins,

能製造新的蛋白質令人振奮，

because despite the diversity in nature,

因為儘管自然界多姿多樣，

evolution has only sampled a tiny fraction of the total number of proteins possible.

卻只演化出

所有可能的蛋白質 總數中的一小部分。

I told you that nature uses an alphabet of 20 amino acids,

我說過大自然用了 20 個氨基酸字母，

and a typical protein is a chain of about 100 amino acids,

典型的蛋白質是 大約 100 個氨基酸的長鏈，

so the total number of possibilities is 20 times 20 times 20, 100 times,

所以可能性的總數

是 20 乘以 20 乘以 20，

乘 100 次，

which is a number on the order of 10 to the 130th power,

是 10 的 130 次方，

which is enormously more than the total number of proteins

遠遠超過自地球出現生命以來

which have existed since life on earth began.

曾經存在過的蛋白質總數。

And it's this unimaginably large space

而這正是我們現在能用運算能力 來設計和探索蛋白質的

we can now explore using computational protein design.

難以想像的廣大空間。

Now the proteins that exist on earth

現存地球的蛋白質以進化

evolved to solve the problems faced by natural evolution.

來解決自然演化所面臨的問題。

For example, replicating the genome.

例如，複製基因組。

But we face new challenges today.

但我們今天面臨新的挑戰。

We live longer, so new diseases are important.

我們活得更長， 因此新疾病極其重要。

We're heating up and polluting the planet,

我們正污染地球和令其升溫，

so we face a whole host of ecological challenges.

因此面臨著一系列的生態挑戰。

If we had a million years to wait,

如果我們能等百萬年，

new proteins might evolve to solve those challenges.

新的蛋白質演化 或許能解決這些挑戰。

But we don't have millions of years to wait.

但我們無法等上百萬年。

Instead, with computational protein design,

取而代之，透由運算來設計蛋白質，

we can design new proteins to address these challenges today.

我們能設計新的蛋白質 來對付當前的挑戰。

Our audacious idea is to bring biology out of the Stone Age

我們的大膽想法

是透由蛋白質設計的技術革命

through technological revolution in protein design.

帶生物學跳脫石器時代。

We've already shown that we can design new proteins

我們已經證明能夠設計出

具有新形狀、新功能的新蛋白質。

with new shapes and functions.

For example, vaccines work by stimulating your immune system

例如，疫苗透由刺激免疫系統

to make a strong response against a pathogen.

對病原體產生強烈的反應作用。

To make better vaccines,

為了製造更好的疫苗，

we've designed protein particles

我們設計蛋白質顆粒

to which we can fuse proteins from pathogens,

來融合病原體中的蛋白質——

like this blue protein here, from the respiratory virus RSV.

就像此處藍色的蛋白質，

取自呼吸道融合病毒 RSV。 （Respiratory Syncytial Virus）

To make vaccine candidates

為確認候選的疫苗 真的含有病毒蛋白，

that are literally bristling with the viral protein,

we find that such vaccine candidates

我們發現這候選疫苗 對病毒的免疫反應

produce a much stronger immune response to the virus

勝過先前已經測試過的任何疫苗。

than any previous vaccines that have been tested.

This is important because RSV is currently one of the leading causes

這很重要，因為 呼吸道融合病毒 RSV

目前是全球嬰兒夭折的主要原因之一。

of infant mortality worldwide.

We've also designed new proteins to break down gluten in your stomach

我們還設計新的蛋白質 來分解胃中的麩質，

for celiac disease

對付腹腔疾病；

and other proteins to stimulate your immune system to fight cancer.

也設計其他的蛋白質 來刺激免疫系統對抗癌症。

These advances are the beginning of the protein design revolution.

這些進步是蛋白質設計革命的開始。

We've been inspired by a previous technological revolution:

我們受先前技術革命的啟發。

the digital revolution,

數位革命大大歸功於

which took place in large part due to advances in one place,

貝爾實驗室所取得的進步。

Bell Laboratories.

Bell Labs was a place with an open, collaborative environment,

貝爾實驗室是個開放、協作的環境，

and was able to attract top talent from around the world.

吸引世界各地的頂尖人才。

And this led to a remarkable string of innovations --

這引領一系列的創新：

the transistor, the laser, satellite communication

電晶體、雷射、衛星通信

and the foundations of the internet.

和網際網路的基礎。

Our goal is to build the Bell Laboratories of protein design.

我們的目標是建立 蛋白質設計的貝爾實驗室。

We are seeking to attract talented scientists from around the world

我們正尋求吸引 世界各地的優秀科學家

to accelerate the protein design revolution,

來一起加速蛋白質設計的革命，

and we'll be focusing on five grand challenges.

我們將專注於五大挑戰。

First, by taking proteins from flu strains from around the world

首先經由從世界各地的流感病毒株中

提取蛋白質，

and putting them on top of the designed protein particles

並將它們放在我之前展示的 蛋白質設計顆粒的頂部，

I showed you earlier,

we aim to make a universal flu vaccine,

我們著眼於製造 一種通用的流感疫苗，

one shot of which gives a lifetime of protection against the flu.

打一針就能保護終生免於流感。

The ability to design --

設計能力——

(Applause)

（掌聲）

The ability to design new vaccines on the computer

在電腦上設計新疫苗的能力

is important both to protect against natural flu epidemics

對於防止自然的流感疫情

and, in addition, intentional acts of bioterrorism.

和防範刻意的生物恐攻都很重要。

Second, we're going far beyond nature's limited alphabet

其次，我們用遠遠超出大自然

有限的 20 個氨基酸字母

of just 20 amino acids

to design new therapeutic candidates for conditions such as chronic pain,

來設計新的治療候選藥物，

來對付像是慢性疼痛，

using an alphabet of thousands of amino acids.

用的是數千種氨基酸字母。

Third, we're building advanced delivery vehicles

第三，我們正在建立先進的載運工具，

to target existing medications exactly where they need to go in the body.

以便將現有的藥物準確定位在 它們應該進入的體內位置。

For example, chemotherapy to a tumor

例如，腫瘤的化療，

or gene therapies to the tissue where gene repair needs to take place.

或修復組織的基因治療。

Fourth, we're designing smart therapeutics that can do calculations within the body

第四，我們正在設計 能在體內運算的智慧療法，

and go far beyond current medicines,

遠遠超出目前的藥物，

which are really blunt instruments.

那些是非常遲鈍的藥物。

For example, to target a small subset of immune cells

例如，目標對準

造成自身免疫疾病的 一小部分免疫細胞，

responsible for an autoimmune disorder,

and distinguish them from the vast majority of healthy immune cells.

將其與絕大多數 健康的免疫細胞區隔開來。

Finally, inspired by remarkable biological materials

最後，靈感來自

絲綢、鮑魚殼、牙齒等 非凡的生物材料，

such as silk, abalone shell, tooth and others,

以及其他材料，

we're designing new protein-based materials

我們正在設計新的蛋白質基底材料，

to address challenges in energy and ecological issues.

以對付能源和生態問題的挑戰。

To do all this, we're growing our institute.

為要做到這一切， 我們正在擴展我們機構。

We seek to attract energetic, talented and diverse scientists

我們尋求吸引世界各地

精力充沛、才華橫溢、 多元的科學家——

from around the world, at all career stages,

涵蓋所有的職涯階段——

to join us.

來加入我們。

You can also participate in the protein design revolution

你還可以透由我們線上的 折疊和設計遊戲「Foldit」

through our online folding and design game, "Foldit."

參與蛋白質設計革命。

And through our distributed computing project, Rosetta@home,

透由我們的分散式運算專案 Rosetta@home，

which you can join from your laptop or your Android smartphone.

可以在筆記型電腦 或安卓智慧手機上操作。

Making the world a better place through protein design is my life's work.

透由設計蛋白質使世界變得更好 是我的終生職志。

I'm so excited about what we can do together.

我們能一起做點什麼的想法 深深鼓舞著我。

I hope you'll join us,

希望你能加入我們。

and thank you.

謝謝。

(Applause and cheers)

（掌聲）