How early life experience is written into DNA | Moshe Szyf

翻译人员: Yan Gao 校对人员: Lipeng Chen

So it all came to life

这一切都是

in a dark bar in Madrid.

在马德里的一个黑暗的酒吧里发生的。

I encountered my colleague from McGill, Michael Meaney.

我遇到了麦吉尔大学的同事，迈克尔·梅尼。

And we were drinking a few beers,

我们喝着几杯啤酒，

and like scientists do,

像所有科学家一样，

he told me about his work.

他跟我聊他的工作。

And he told me that he is interested in how mother rats lick their pups

他告诉我，他感兴趣的是

小鼠出生后，母鼠如何舔它们的婴儿。

after they were born.

And I was sitting there and saying,

我呆住了，说：

"This is where my tax dollars are wasted --

“我交的税就浪费在这儿了啊，——

(Laughter)

（笑声）

就是这种软科学。”

on this kind of soft science."

And he started telling me

他开始给我讲，

that the rats, like humans,

老鼠和人类一样，

lick their pups in very different ways.

用不同的方式舔抚她们的孩子。

Some mothers do a lot of that,

一些母亲做的很多，

some mothers do very little,

一些母亲做的很少，

大多数介于两者之间。

and most are in between.

But what's interesting about it

但是有趣的是，

is when he follows these pups when they become adults --

当他跟踪这些小鼠直到成年——

like, years in human life, long after their mother died.

相当于人类的很多年后， 母亲去世后的很长时间。

They are completely different animals.

它们变成了完全不同的动物。

The animals that were licked and groomed heavily,

那些受到大量舔舐和梳毛的动物，

the high-licking and grooming,

即高舔舐和梳毛的动物，

are not stressed.

不会紧张不安。

They have different sexual behavior.

它们的性行为不同。

They have a different way of living

它们的生活方式

与没有被妈妈密切照顾的小鼠不同。

than those that were not treated as intensively by their mothers.

So then I was thinking to myself:

那么我问自己：

Is this magic?

这是魔法吗？

How does this work?

怎么会这样的？

As geneticists would like you to think,

遗传学家希望你这样想：

perhaps the mother had the "bad mother" gene

也许那些妈妈拥有“坏妈妈”基因，

导致她的婴儿紧张不安，

that caused her pups to be stressful,

and then it was passed from generation to generation;

然后这种基因代代相传；

it's all determined by genetics.

全部是遗传决定的。

Or is it possible that something else is going on here?

有没有别的可能？

In rats, we can ask this question and answer it.

在老鼠身上，我们可以 提出这个问题并解答它。

So what we did is a cross-fostering experiment.

所以我们做了交叉养育实验。

You essentially separate the litter, the babies of this rat, at birth,

基本上在一窝小鼠出生时 把它们分开，

to two kinds of fostering mothers --

分给两种不同类型的养母——

not the real mothers, but mothers that will take care of them:

不是生母，而是照顾小鼠的母鼠：

high-licking mothers and low-licking mothers.

高舔舐母鼠和低舔舐母鼠。

And you can do the opposite with the low-licking pups.

另外一边是低舔舐小鼠。

And the remarkable answer was,

令人惊奇的答案是，

it wasn't important what gene you got from your mother.

从母亲那里得到什么基因并不重要。

It was not the biological mother that defined this property of these rats.

定义这些老鼠的这种特征的不是生母，

It is the mother that took care of the pups.

而是照顾小鼠的母鼠。

So how can this work?

那么，这是怎么实现的？

I am an a epigeneticist.

我是一个表观遗传学家。

I am interested in how genes are marked

我的兴趣是在胚胎期间，

我们在母体子宫里时，

by a chemical mark

如何用化学记号标记基因，

during embryogenesis, during the time we're in the womb of our mothers,

and decide which gene will be expressed

并决定

哪个基因在哪个组织中表达。

in what tissue.

Different genes are expressed in the brain than in the liver and the eye.

大脑中表达的基因与肝脏和眼睛中的不同。

And we thought: Is it possible

我们怀疑：有没有可能

that the mother is somehow reprogramming the gene of her offspring

妈妈通过自己的行为

改写她后代的基因编码？

through her behavior?

And we spent 10 years,

我们花了10年，

and we found that there is a cascade of biochemical events

发现有一系列的生物化学事件，

by which the licking and grooming of the mother, the care of the mother,

母鼠的舔舐和梳毛，妈妈的照顾

被转化成生物化学信号，

is translated to biochemical signals

that go into the nucleus and into the DNA

这信号进入细胞核并进入DNA，

and program it differently.

改写了编码。

So now the animal can prepare itself for life:

所以现在这个动物能 为生活做更好的准备：

Is life going to be harsh?

生活会很艰难吗？

Is there going to be a lot of food?

会有很多食物吗？

Are there going to be a lot of cats and snakes around,

周围会有很多猫和蛇吗？

or will I live in an upper-class neighborhood

还是会住在上层社区，

where all I have to do is behave well and proper,

只要行为端正举止适当

就会赢得社会认可？

and that will gain me social acceptance?

And now one can think about how important that process can be

现在可以想想这个过程

对我们的生命有多重要了。

for our lives.

We inherit our DNA from our ancestors.

我们从祖先继承了DNA。

The DNA is old.

DNA历史悠久。

It evolved during evolution.

它在进化过程中演变。

But it doesn't tell us if you are going to be born in Stockholm,

但它并不告诉我们，

你会出生在夏季白天长、 冬季白天短的斯德哥尔摩，

where the days are long in the summer and short in the winter,

or in Ecuador,

还是出生在

where there's an equal number of hours for day and night all year round.

整年都白天黑夜一样长的厄瓜多尔。

And that has such an enormous [effect] on our physiology.

这对我们的生理有巨大的影响。

So what we suggest is, perhaps what happens early in life,

所以我们认为， 也许是在生命早期发生的事，

those signals that come through the mother,

通过母亲传递的那些信号，

tell the child what kind of social world you're going to be living in.

告诉子女将要在怎样的社会环境中生存。

It will be harsh, and you'd better be anxious and be stressful,

如果环境艰难，你最好焦虑紧张，

or it's going to be an easy world, and you have to be different.

或者如果环境轻松，你必定也不同。

Is it going to be a world with a lot of light or little light?

那世界会有很多光线还是很少光线？

Is it going to be a world with a lot of food or little food?

那世界会有很多食物还是很少食物？

If there's no food around,

如果周围没有食物，

you'd better develop your brain to binge whenever you see a meal,

你最好让大脑发育成 一旦看到食物马上大吃一顿，

or store every piece of food that you have as fat.

或者把拥有的每一块食物都 储存成脂肪。

So this is good.

所以，这很好。

Evolution has selected this

进化已经这样选择，

to allow our fixed, old DNA to function in a dynamic way

让我们固有的、陈旧的DNA

在新的环境中不断变化地发挥作用。

in new environments.

但有些事可能会出错：

But sometimes things can go wrong;

for example, if you're born to a poor family

例如，如果你出生在一个贫穷的家庭，

and the signals are, "You better binge,

信号是，“你最好快吃，

you better eat every piece of food you're going to encounter."

你最好把遇到的每一块食物都吃掉。”

But now we humans and our brain have evolved,

但是现在我们人类和人脑已经进化了，

have changed evolution even faster.

已经进化得更快。

现在你用一块钱就可以买麦当劳。

Now you can buy McDonald's for one dollar.

And therefore, the preparation that we had by our mothers

因此，母亲为我们所做的准备

is turning out to be maladaptive.

变得不适用了。

The same preparation that was supposed to protect us from hunger and famine

本应保护我们免受饥苦的 同样的准备工作

is going to cause obesity,

却会导致肥胖症、

cardiovascular problems and metabolic disease.

心血管问题和代谢疾病。

So this concept that genes could be marked by our experience,

所以，这个可以通过经历、 尤其是早期生活经历

and especially the early life experience,

来标记基因的概念

can provide us a unifying explanation

可以为我们提供

对健康和疾病的统一解释。

of both health and disease.

But is true only for rats?

但这只在老鼠身上才正确吗？

The problem is, we cannot test this in humans,

问题是，我们不能用人类做测试，

because ethically, we cannot administer child adversity in a random way.

因为从道德上，我们不能 随机地为儿童设置逆境。

So if a poor child develops a certain property,

所以，如果穷孩子养成某种特征，

we don't know whether this is caused by poverty

我们不知道它是由贫穷引起的

还是因为穷人有不良的基因。

or whether poor people have bad genes.

So geneticists will try to tell you that poor people are poor

所以，遗传学家试图告诉你

穷人之所以穷是因为基因让他们穷。

because their genes make them poor.

Epigeneticists will tell you

表观遗传学家会告诉你

poor people are in a bad environment or an impoverished environment

穷人所在的不良环境或贫穷环境

that creates that phenotype, that property.

环境创造了那些表型，那种贫穷。

So we moved to look into our cousins, the monkeys.

所以我们转而观察我们的表亲：猴子。

My colleague, Stephen Suomi, has been rearing monkeys

我的同事斯蒂芬·苏米

以两种不同的方式饲养猴子：

in two different ways:

randomly separated the monkey from the mother

随机地将猴子与母亲分离，

and reared her with a nurse

通过护理员和代养条件

and surrogate motherhood conditions.

来培养她。

So these monkeys didn't have a mother; they had a nurse.

所以这些猴子没有妈妈， 只有护理员。

And other monkeys were reared with their normal, natural mothers.

而其他猴子是正常的亲生妈妈养育的。

And when they were old, they were completely different animals.

当他们年老时，他们变成了完全不同的动物。

The monkeys that had a mother did not care about alcohol,

有妈妈的猴子不嗜酒，

they were not sexually aggressive.

他们没有性暴力倾向。

The monkeys that didn't have a mother were aggressive, were stressed

没有妈妈的猴子有攻击性，紧张，

还是酒鬼。

and were alcoholics.

So we looked at their DNA early after birth, to see:

我们在出生后的早期观察他们的DNA：

Is it possible that the mother is marking?

看看有没有可能是妈妈在标记？

Is there a signature of the mother in the DNA of the offspring?

后代的DNA里有没有妈妈的签名？

These are Day-14 monkeys,

这些是14天的猴子，

and what you see here is the modern way by which we study epigenetics.

这里看到的是我们研究 表观遗传学的现代方式。

We can now map those chemical marks, which we call methylation marks,

我们能把这些化学标记—— 称为甲基化标记，

以单核苷酸分辨率绘制到DNA上。

on DNA at a single nucleotide resolution.

We can map the entire genome.

我们能够绘制整个基因组。

We can now compare the monkey that had a mother or not.

现在我们可以比较 有妈妈或没有妈妈的猴子了。

And here's a visual presentation of this.

这里是直观展示。

What you see is the genes that got more methylated are red.

你看到的是 较多甲基化的基因呈现红色。

较少甲基化的基因呈现绿色。

The genes that got less methylated are green.

You can see many genes are changing,

你能看到很多基因在改变，

because not having a mother is not just one thing --

因为没有妈妈不只是简单一件事——

it affects the whole way;

它影响所有的一切；

it sends signals about the whole way your world is going to look

它传递着关于你

成年后的世界 是什么样子的全部信号。

when you become an adult.

And you can see the two groups of monkeys

你可以看到两组猴子

extremely well-separated from each other.

它们极其明显的大不相同。

这种发育从多早开始？

How early does this develop?

These monkeys already didn't see their mothers,

这些猴子已经没见过妈妈，

so they had a social experience.

所以它们有社交经历。

Do we sense our social status, even at the moment of birth?

我们在出生的时刻也能 感受自己的社会地位吗？

So in this experiment, we took placentas of monkeys

所以在这个实验中，

我们采用具有不同 社会地位的猴子的胎盘。

that had different social status.

What's interesting about social rank is that across all living beings,

关于社会秩序，有趣的是 在所有的生物中，

they will structure themselves by hierarchy.

他们都用等级制度构建社会。

Monkey number one is the boss;

一号猴子是老板；

monkey number four is the peon.

四号猴子是苦力。

You put four monkeys in a cage,

在一个笼子里放四只猴子，

there will always be a boss and always be a peon.

总是有一个老板，一个苦力。

And what's interesting is that the monkey number one

并且，有趣的是，一号猴子

比四号猴子健康得多。

is much healthier than monkey number four.

And if you put them in a cage,

如果把它们放在一个笼子里，

monkey number one will not eat as much.

一号猴子吃得不多。

Monkey number four will eat [a lot].

四号猴子能吃（很多）。

And what you see here in this methylation mapping,

在这个甲基绘制图中可以看到，

a dramatic separation at birth

社会地位高的动物与社会地位低的动物

of the animals that had a high social status

在刚出生时的明显不同

versus the animals that did not have a high status.

的对比图。

So we are born already knowing the social information,

所以我们出生时已经知道社会信息，

and that social information is not bad or good,

该社会信息并无好坏之分，

它只是帮我们为生活做准备，

it just prepares us for life,

because we have to program our biology differently

因为我们要根据所处的 高社会地位或低社会地位，

if we are in the high or the low social status.

用不同方式给自己进行生物编码。

但如何在人类中研究这种现象？

But how can you study this in humans?

We can't do experiments, we can't administer adversity to humans.

我们不能做实验， 不能给人类制造逆境。

但上帝在用人类做实验，

But God does experiments with humans,

and it's called natural disasters.

它叫做自然灾害。

One of the hardest natural disasters in Canadian history

加拿大历史上最严重的自然灾害之一

happened in my province of Quebec.

发生在我来自的魁北克省。

It's the ice storm of 1998.

是1998年的冰暴。

We lost our entire electrical grid because of an ice storm

因为冰暴，我们整个电网坏掉，

when the temperatures were, in the dead of winter in Quebec,

当时是魁北克最冷的冬天，

minus 20 to minus 30.

温度在零下20至零下30。

And there were pregnant mothers during that time.

在那段时间有怀孕的妈妈们。

And my colleague Suzanne King followed the children of these mothers

我同事苏珊娜·金对这些妈妈们的孩子

for 15 years.

跟踪调查了15年。

And what happened was, that as the stress increased --

事实是，随着压力增大——

and here we had objective measures of stress:

我们这里有对压力的客观度量：

How long were you without power? Where did you spend your time?

你停电多长时间？在哪里度日？

Was it in your mother-in-law's apartment or in some posh country home?

在婆婆的小公寓还是 奢侈的乡间别墅？

So all of these added up to a social stress scale,

所有这些加起来得出社会压力评级，

and you can ask the question:

你可以问的是：

How did the children look?

孩子们看上去如何？

And it appears that as stress increases,

显然，随着压力增大，

the children develop more autism,

孩子们的自闭症更多，

they develop more metabolic diseases

他们的代谢疾病更多，

and they develop more autoimmune diseases.

自身免疫性疾病也更多。

We would map the methylation state,

我们绘制甲基化状态，

再一次看到，随着压力增大 绿色基因变成红色，

and again, you see the green genes becoming red as stress increases,

the red genes becoming green as stress increases,

随着压力增大，红色基因变成绿色，

an entire rearrangement of the genome in response to stress.

基因组响应于压力进行完全重排。

So if we can program genes,

所以，如果我们能编写基因，

if we are not just the slaves of the history of our genes,

如果我们不仅仅做我们基因历史的奴隶，

that they could be programmed, can we deprogram them?

如果基因可以编写， 那我们能抹掉对基因的编写吗？

Because epigenetic causes can cause diseases like cancer,

因为表观遗传因素会导致癌症、

代谢疾病

metabolic disease

and mental health diseases.

和精神健康疾病等。

Let's talk about cocaine addiction.

我们来谈谈可卡因成瘾。

Cocaine addiction is a terrible situation

可卡因成瘾是一种可怕的状态

that can lead to death and to loss of human life.

会导致死亡和丧命。

我们问了一个问题：

We asked the question:

Can we reprogram the addicted brain

我们可以重新编写上瘾的大脑，

to make that animal not addicted anymore?

让上瘾的动物不再有瘾吗？

We used a cocaine addiction model

我们使用可卡因成瘾模型，

that recapitulates what happens in humans.

该模型概括了人类成瘾的情况。

In humans, you're in high school,

对于人类，你上高中时，

some friends suggest you use some cocaine,

某些朋友建议你用点可卡因，

you take cocaine, nothing happens.

你用了可卡因，没发生什么事。

Months pass by, something reminds you of what happened the first time,

几个月后，突然想起第一次的事，

a pusher pushes cocaine,

毒贩子在卖可卡因，

and you become addicted and your life has changed.

然后你上瘾了，然后生活彻底改变。

In rats, we do the same thing.

我们用老鼠做同样的事。

My colleague, Gal Yadid,

我同事加尔·雅迪

he trains the animals to get used to cocaine,

他训练这些动物习惯可卡因，

then for one month, no cocaine.

然后一个月没有可卡因。

Then he reminds them of the party when they saw the cocaine the first time

然后他提醒动物们 第一次看到可卡因的场景，

by cue, the colors of the cage when they saw cocaine.

提示方法是 看到可卡因时笼子的颜色。

And they go crazy.

动物们疯了。

They will press the lever to get cocaine

它们一直按动会提供可卡因的杠杆，

until they die.

直到死亡。

We first determined that the difference between these animals

我们首先确定的是， 这些动物之间的区别

is that during that time when nothing happens,

是在什么都没发生的那段时间里

周围没有可卡因时，

there's no cocaine around,

their epigenome is rearranged.

它们的表观基因组重新排列。

Their genes are re-marked in a different way,

它们的基因以不同的方式重新标记，

and when the cue comes, their genome is ready

当提示出现时，

它们的基因组已经准备好 发展出成瘾表型。

to develop this addictive phenotype.

So we treated these animals with drugs that either increase DNA methylation,

然后我们用药治疗这些动物，

药物要么增加DNA甲基化—— 对象是表观基因标记物，

which was the epigenetic marker to look at,

or decrease epigenetic markings.

要么减少表观基因标记。

And we found that if we increased methylation,

我们发现，如果增加甲基化，

these animals go even crazier.

这些动物会更疯狂。

They become more craving for cocaine.

它们对可卡因更渴望。

But if we reduce the DNA methylation,

但如果减少DNA甲基化，

the animals are not addicted anymore.

动物不再有瘾。

We have reprogrammed them.

我们把这些动物重新编码了。

And a fundamental difference between an epigenetic drug

表观基因药物与其他药物

and any other drug

的基本区别是，

is that with epigenetic drugs,

通过表观基因药物，

we essentially remove the signs of experience,

我们在根本上去除了经历的印记，

and once they're gone,

一旦去除印记，

它不会回来，除非再经历一遍。

they will not come back unless you have the same experience.

现在动物被重新编码。

The animal now is reprogrammed.

So when we visited the animals 30 days, 60 days later,

所以在30天、60天后—— 等于人类的很多年，

which is in human terms many years of life,

再造访这些动物时，

they were still not addicted -- by a single epigenetic treatment.

它们仍然没有瘾—— 只通过单一的表观基因治疗。

So what did we learn about DNA?

那么关于DNA，我们学到了什么？

DNA is not just a sequence of letters;

DNA不仅仅是一系列的字母;

it's not just a script.

它不只是一个脚本。

DNA is a dynamic movie.

DNA是一部动态电影。

Our experiences are being written into this movie, which is interactive.

我们的经历正在写入这部电影中， 它是互动的。

You're, like, watching a movie of your life, with the DNA,

就像用遥控器看电影一样，

with your remote control.

你在用DNA来观看你的人生。

You can remove an actor and add an actor.

你可以去掉一个演员、增加一个演员。

And so you have, in spite of the deterministic nature of genetics,

因此，尽管遗传学具有确定性，

你仍可以控制基因的表达方式，

you have control of the way your genes look,

and this has a tremendous optimistic message

这为我们面对某些致命疾病的能力

for the ability to now encounter some of the deadly diseases

例如癌症、心理疾病等

like cancer, mental health,

提供了非常乐观的信息，

with a new approach,

提供了新的方法，

可以把这些疾病看作适应不良。

looking at them as maladaptation.

And if we can epigenetically intervene,

如果我们能进行表观基因干预，

[we can] reverse the movie by removing an actor

我们就可以去掉一个演员，让电影倒退

and setting up a new narrative.

并设置新的故事线。

So what I told you today is,

所以我今天告诉你的是，

our DNA is really combined of two components,

我们的DNA实际由两个部分组成，

two layers of information.

两层信息。

One layer of information is old,

一层信息是古老的，

evolved from millions of years of evolution.

从数百万年的进化演变而来。

It is fixed and very hard to change.

它是固定的，很难改变。

The other layer of information is the epigenetic layer,

另一层信息是表观遗传层，

which is open and dynamic

它是开放和动态的，

并设置了一个可以互动的故事线，

and sets up a narrative that is interactive,

that allows us to control, to a large extent, our destiny,

让我们能够在很大程度上 控制自己的命运，

to help the destiny of our children

帮助改变我们下一代的命运，

and to hopefully conquer disease

并且有希望征服那些

and serious health challenges

长期困扰人类的

疾病和严峻的健康挑战。

that have plagued humankind for a long time.

So even though we are determined

所以即使我们

已经被我们的基因决定，

by our genes,

we have a degree of freedom

我们还是有一定程度的自由，

that can set up our life to a life of responsibility.

能够把自己的生命设置成 有责任担当的生命。

Thank you.

谢谢。

(Applause)

（掌声）