The World’s Rarest Diseases — And How They Impact Everyone | Anna Greka | TED

翻译人员: Sarah Liu 校对人员: Jacky He

I'd like to begin by telling you a story.

我想从一则故事开始。

It's a short story about a special family.

这是一则关于一个 特殊家庭的简短故事。

In 1960, a Utah man by the name of Roscoe Nelson,

1960 年，一位名叫 罗斯科·尼尔森的犹他州男子，

a father of six,

作为六个孩子的父亲，

died suddenly of unknown cause.

突然由未知原因去世。

He was 43 years old.

享年 43 岁。

As a surgeon himself,

作为一名外科医生，

Dr. Nelson knew that his progressive kidney failure

尼尔森博士知道， 他逐渐发展的肾功能衰竭

would ultimately take his life.

最终将夺去他的生命。

But he was in the dark as to the cause,

但他对病因一无所知，

and he had no access to treatment.

也无法接受治疗。

Within two decades,

接下来的二十年里，

tragedy struck again when four of Roscoe's six children

悲剧再次降临， 罗斯科的六个孩子中的四个

also developed kidney failure.

也患上了肾衰竭。

Looking back as far back as the 1800s,

回到 1800 年代，

every generation in this family has been struck down at a young age

这个家族的每一代人 都在年轻时受到过

by a mysterious and vicious disease.

这种神秘而严重的 疾病侵袭。

What could be the cause?

原因会是什么呢？

Fast forward to 2013.

快进到 2013 年，

A team of brilliant geneticists

一队杰出的遗传学家

identified the cause of Roscoe Nelson's deadly disease.

诊断出了罗斯科·尼尔森 致命疾病的本因。

It was a mutation,

这是一种突变，

a single extra letter in the DNA,

DNA 中额外的碱基，

hiding in a dark corner of a gene called MUC1.

位于名为 MUC1 的基因那里。

The mutation had been passed down from generation to generation,

这种突变代代相传，

leading to early deaths from kidney failure.

导致家族中的成员过早因 肾衰竭而去世。

The discovery of this mutation ended a decades-long diagnostic odyssey

对于这个家族以及 许多类似家庭而言，

for this family and many families like them.

这种突变的发现结束了 数十年的诊断过程。

Now, as a physician-scientist and cell biologist at Harvard,

现在，作为哈佛大学一位 医学科学家和细胞生物学家，

I have learned that studying this disease

我了解到研究这种疾病

and genetic diseases like it

以及类似的遗传疾病

is not only important to the families they so tragically affect.

不仅对那些受其影响 而遭遇悲剧的家庭挺重要，

This work is a critical scientific and research priority for all of us.

这项工作对我们大家均是 核心价值的科研任务。

Why?

为什么呢？

Because what my team and I uncovered by studying this seemingly obscure disease

因为通过研究这种 看似罕见的疾病，

is a series of portals into the inner workings of human cells,

我和我的团队发现了各种 人体细胞内部运作的细节，

gaining unexpected insights into fundamental biology.

给基础生物学 带来未曾预想的知识维度。

And best of all, we uncovered incredible opportunities

而且最重要的是， 我们发现了对于不止一种，

for the treatment of not one but many dozens of diseases.

而是数十种疾病的 新型治疗思路。

You see, the amazing thing about science,

你看，科学的奇妙之处在于，

the reason I love what I do

我热爱自己所做的事情

is that if you follow your curiosity,

是因为只要受好奇心的指引，

it can lead to untold scientific treasures.

它可能引领你 发掘未知的科学宝藏。

So in essence, my big idea for you today is ...

因此，我今天 给大家的中心概念是......

sleuthing.

细密侦察。

Not the kind that solves crimes,

不是解决犯罪的 那种侦探工作，

but the kind that solves scientific mysteries,

而是解决科学之谜的那种，

what I call molecular sleuthing

我称之为分子侦探学，

or what is otherwise known as hypothesis-driven science

也称为围绕假设的科学，

or curiosity-driven science.

或好奇心驱使的科学。

It is an idea as old as Aristotle,

这个想法可以追溯 到亚里士多德，

who was born more than 2,400 years ago,

他生于 2400 多年前，

not far actually from where I was born and raised,

而与我出生并 成长的地方相离不远，

in Thessaloniki, Greece.

我出生在希腊的塞萨洛尼基。

Aristotle taught that at the foundation of any scientific pursuit

亚里士多德教导我们， 任何科学探究的根本

is formulating a hypothesis,

是提出假设，

asking a question that can be tested experimentally.

提出一个可以通过 实验验证的议题。

Sleuthing of this nature is central to the scientific method

这种性质的侦探工作 是科学方法的核心，

and has led humans to amazing discoveries.

它已经引导人类 获得超凡的发现。

So how did molecular sleuthing help us unlock the secrets

那么，分子侦探是 如何助力我们以解开

of the vicious mutation that killed Roscoe Nelson?

使罗斯科·尼尔森丧生 恶性突变的秘密呢？

Well, once the mutation was uncovered,

这样的突变既然被发现，

the next question was

接下来的问题便是，

how can a single extra letter in the DNA lead to so much trouble?

DNA 中的一块额外碱基 怎么会导致如此多的问题？

My team and I got to work,

我和我的团队开始着手研究，

using classical hypothesis-driven science,

利用经典的基于假设的科学方法，

but with a twist.

但稍加变化。

Our molecular detective work is now supercharged

我们的分子侦探工作

by our ability to use modern, scalable tools and technologies.

由我们前沿灵活的 技术工具所支持。

Let me explain.

请让我解释。

To understand how a single extra letter in the DNA can lead to disease,

为了理解 DNA 中额外的碱基 是如何导致疾病的，

I must first remind you of some basic biology.

我首先得给你重提 些基本的生物学知识。

In nearly every cell in our bodies,

在我们身体的几乎每个细胞中，

the three billion letters of genetic information, the DNA,

三十亿单位的 遗传信息，DNA，

is transcribed into RNA

被转录成 RNA，

and in turn, RNA churns out proteins,

而后 RNA 制出蛋白质，

which are the business end of what our cells use

这些蛋白质由我们细胞用来

to perform their basic functions.

执行基本功能。

The engine that turns DNA to RNA to proteins

将 DNA 转录为 RNA 再到 蛋白质的过程

works tirelessly in each of 37 trillion cells in our bodies.

在我们体内的 3700 亿细胞中 未曾停歇地运作。

So normally the MUC1 gene churns out a protein called mucin 1,

正常情况下 MUC1 基因会产生 一种名为粘附蛋白 (mucin 1) 的蛋白质，

which goes to the surface of cells

该蛋白质会处于细胞表面

and forms a protective blanket around them.

形成外围的保护层。

We hypothesized that the mutation in the MUC1 gene

我们假设 MUC1 基因中的突变

is generating a mucin 1 protein

产生了一种功能失常的

that is not doing what it is supposed to do.

粘附蛋白。

How could we test this hypothesis?

怎么验证这个假设呢？

A couple of decades ago, when I was a student,

几十年前，当我还是 一名学生的时候，

this type of work would have involved just a handful of petri dishes at a time.

这种工作可能只涉及 一小组培养皿。

This meant that in a day’s work,

这意味着在一天的工作中，

I could really only test five or six different experimental conditions

我只能测试五六种 不同的实验条件，

to see how the cells responded.

以观察细胞的反应。

And then I had to spend several long days at the microscope,

然后我不得不连续几天 待在显微镜前，

taking images one by one, analyzing them one by one,

逐个地拍照， 挨个地分析，

to finally make sense of the data.

最终才能得出数据的规律。

Instead, my students at Harvard and MIT

相比之下，我在哈佛大学 和麻省理工学院的学生，

have access to state-of-the-art computer-controlled

可以使用最先进的 计算机操作的

robotic systems and microscopes

机器人系统和显微镜，

and artificial intelligence-powered software, which enable them

以及由人工智能驱动的软件， 这使他们能够

to analyze thousands of images,

在一天的工作中

all in a day's work.

分析成千上万张图像。

As such, we can study cells grown in special dishes

因此，我们可以研究生长 在特殊培养皿中的细胞，

that allow us to test hundreds of experimental conditions at a time.

这些培养皿允许我们一次 测试数百种实验条件。

In fact, I estimate that our molecular sleuthing to date

实际上，我估计迄今为止 我们的分子侦探工作

has generated more than 50 million images

已经产生了 超过五千万张图像，

containing information derived from more than 100 billion cells.

包括来自超过 一千亿个细胞的信息。

That's as many cells as there are stars in the Milky Way.

这与银河系中的星星数量相当。

And in the end,

最终，

the vicious mutation that killed Roscoe Nelson

使罗斯科·尼尔森 丧命的恶性突变

revealed its secrets.

揭示了它的秘密。

Remember, we hypothesized that the mutation in the MUC-1 gene

请记住，我们假设 MUC-1 基因中的突变

is generating a mucin 1 protein

产生了一种功能异常的

that is not doing what it is supposed to do.

粘附蛋白 1 蛋白质。

Normally mucin 1 goes to the surface of cells.

正常情况下，粘附蛋白 1 会到达细胞表面。

However, we found that the mutation in the MUC-1 gene

然而，我们发现 MUC-1 的基因突变

is generating a mangled, misshapen mutant protein

产生了一种奇怪、 扭曲的突变蛋白质，

that does not go to the surface of cells,

不会前往细胞表面，

but instead accumulates inside.

而是在细胞内积聚。

This led to a new hypothesis.

这引出了一个新的假设。

Is the mutant protein getting trapped inside cells,

这种突变蛋白质 是否会被困在细胞内，

and how does this happen?

这是什么原因？

After some more molecular sleuthing,

经过更多的分子侦探后，

we learned that the misshapen protein accumulates inside cells

我们了解到这种畸形蛋白质 会积聚在细胞内，

because of another molecule,

是由于另一种分子，

a so-called cargo receptor.

一个所谓的载体受体。

Thinking they're being helpful,

为起到辅助作用，

these cargo receptors grab the mangled proteins

这些载体受体会依附 畸形蛋白质，

and throw them on board

积攒它们，

like cargo trucks carrying a growing heap of nasty trash

像承载越来越多无用垃圾

with nowhere to go.

却无处可去的货车。

Unable to get rid of this toxic waste,

无法清除这种有毒废物，

cells begin to die,

细胞便开始凋亡，

leading to the progressive kidney failure that killed Roscoe Nelson.

这导致了罗斯科·尼尔森的 渐行性肾功能性衰竭，直到死亡。

Well, now that we had insight into the root cause of the problem,

现在我们已经理解了 问题的根本因素，

we could also look for a way to fix it.

我们也可以寻找解决办法。

We went to work, testing thousands of chemical compounds

我们在工作中，测试了 成千上万种化合物，

across millions of cell images.

覆盖了数百万个细胞图像。

And in the end,

最终，

we identified one compound that could specifically remove the mutant protein.

我们找到了一种特定的化合物， 其能有效清除这种突变蛋白质。

After some more molecular detective work,

在进行更多的 分子侦探工作后，

we learned that this drug-like compound

我们了解到， 这种类似药物的化合物

can clear heaps of mangled proteins

通过引导这些

by steering the cargo trucks,

装满恶心垃圾的货车，

the ones full of nasty trash,

进入溶酶体，

into the lysosome,

细胞的垃圾处理与回收设施，

the cell's trash disposal and recycling facility,

在那里将畸形蛋白质

where proteins get shredded into tiny pieces.

彻底分解。

The results were amazing.

结果令人惊奇。

After giving the drug to mice with kidney disease for one week,

在将这种药物施给 患肾疾病的小鼠一周后，

the mutant protein had all but disappeared from these kidneys.

这些肾脏中的 突变蛋白质完全消失。

And yet our greatest insight was not our success

然而，我们主要的发现并不是

in removing the mutant protein from these kidney cells.

将这种突变蛋白质 从肾脏细胞中清除，

We realized that our curiosity-driven work

我们意识到， 这项好奇心驱使的工作

had solved a bigger and much more important puzzle.

解决了一个更大、 更关键的难题。

This mysterious kidney disease

这类神秘的肾脏疾病

was not so strange or mysterious after all.

也许并不是那么怪诞神秘。

In fact, we learned that it belongs to a group of disorders

事实上，我们了解到，它属于

collectively known as toxic proteinopathies.

“有毒蛋白质病”的疾病类型。

You may have heard of some of them,

你也许听闻过 其中一些疾病，

all terrible, incurable diseases

均是严重、无法治愈的疾病，

like ALS and Alzheimer's disease.

如 ALS 和阿尔茨海默病。

OK. Now you can probably guess what happened next.

那么，你可能预料到 接下来发生的事情。

The incredibly talented scientists on my team --

我团队里才华横溢的科学家们——

Here they are.

是这边几位。

They asked --

他们提出了——

(Applause)

（掌声）

Thank you. They deserve it. Thank you.

谢谢。他们值得表扬。

They asked the next logical question.

他们提出了下一个 逻辑性的问题：

What if these cargo receptors,

假设这些载体受体

what if they grab and accumulate misshapen proteins

抓住畸形蛋白，使其在身体的

in different cells and organs in the body?

其他细胞与器官中积聚会怎样？

What about the eye, for example?

例如眼睛？

Their curiosity paid off

他们的好奇心得到了回报，

because we are now learning that this newly uncovered biology

因为我们现在了解到 这个生物学议题

is operative in a form of blindness called retinitis pigmentosa,

显现为一种名为 视网膜色素变性的失明症状，

which is caused by a different misshapen protein

这是眼睛中细胞积聚的

accumulating in cells in the eye.

另一种畸形蛋白质引起的。

In preliminary studies shown here at TED for the first time,

这些前期研究在 TED 这边首次展示；

here is a mouse I cleared of mutant protein.

我给这只小鼠清除了突变蛋白质。

(Applause)

（掌声）

And in ongoing studies, we are finding that the same may be true

在目前的研究中， 我们发现

for different misshapen proteins accumulating in cells in the brain,

大脑细胞中积聚的变异蛋白质也是类似的，

causing some forms of Alzheimer's disease.

其会导致几种阿尔茨海默病。

In all, we estimate that more than 50 disorders

总而言之，我们估计 多达 50 种疾病

could be amenable to this approach.

可以采用这种方法治疗。

So understanding one disorder has unlocked a nodal biological mechanism

因此，探究一种疾病揭露了 一个重要的生物学机制，

and insights for the treatment of many more diseases

和治疗其他影响身体各个部位，

affecting surprisingly distant parts of the body,

像大脑和肾脏的

like the brain and the kidney.

疾病之妙方。

And so in our quest to save kidneys,

因此，在拯救肾脏的过程中，

we are now poised to save eyes, livers, brains and more.

我们也将能够修复、 肝脏、大脑等器官。

And in our efforts to save a handful of families,

我们尝试挽救数个家庭，

we can now save thousands more.

现在却能拯救上千个家庭。

Just think of the possibilities.

看看这些可能性。

If our work could unlock treatments for thousands,

如果我们的工作可以为 上千人开发治疗途径，

imagine what solving the next medical mystery can do.

解决下一个 医学谜团会带来什么。

And the next one and the one after that.

之后一个接一个， 源源不断。

And remember,

请记住，

rare genetic diseases are collectively common.

罕见的遗传疾病 总体上是常见的。

They affect 10 percent of all people in North America.

它们影响了北美 所有人口的 10％，

That's hundreds of millions of people all around the globe

这意味着全球 数亿人受到影响，

or 120 of you right here in this room.

也等于这个房间里 影响到 120 人。

And yet, out of 8,000 genes known to cause genetic diseases,

不过尽管已知 8000 片 导致遗传疾病的基因，

we have only developed a treatment for, at best, 500 of them.

我们最多只能为其中大约 500 种 开发出治疗方案。

And this is not taking into account disorders

而且这还没有考虑到 许多基因

in which many genes conspire to cause trouble,

合作造成问题，

like schizophrenia or cancer or heart disease.

如精神分裂症、 癌症或心脏疾病。

We have a lot of sleuthing to do,

我们有大量待办的侦探任务，

and yet this is the perfect moment

而现在正是利用

to harness recently developed scalable tools and technologies

最近出现的 灵活工具和技术

and take this challenge head on.

对付这个挑战的绝佳时机。

And mind you, patients and their families are up for the challenge, too.

更何况，患者及其家庭 也愿意贡献力量。

They're using social media to organize and raise awareness,

他们利用社交媒体 传播讯息、增强意识，

and they are becoming our true partners on scientific journeys into the unknown.

成为我们在未知 科学道路上真正的伙伴。

This is definitely true of the Nelsons.

这对于尼尔森家族而言是如此。

They have been our partners for many years now.

多年来，他们一直是 我们的合作伙伴。

Here's the next generation of Nelsons.

如今是尼尔森家族的后一代。

Our work has given them hope

我们的工作给予他们希望，

that their children and their children's children

使他们的子孙

can live longer, fuller, and healthier lives.

能够过上更长寿、 更充实、更健康的生活。

And they are proud to have ignited a sleuthing revolution.

他们为引发这些 革新性研究感到自豪。

From a few to more and more

从个例转向更多的人，

until we have precision cures for all.

直到掌握适用所有人的精准疗法。

Thank you.

谢谢大家。

(Applause)

(掌声)