How early life experience is written into DNA | Moshe Szyf

譯者: Regina Chu 審譯者: Marssi Draw

So it all came to life

這件事的起始發生在

in a dark bar in Madrid.

馬德里的一間昏暗酒吧裡。

I encountered my colleague from McGill, Michael Meaney.

我遇到麥吉爾大學的同事 邁克·梅尼。

And we were drinking a few beers,

幾杯啤酒下肚，

and like scientists do,

就像所有科學家一樣，

he told me about his work.

他跟我聊起了他的工作。

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

他告訴我他有興趣研究 老鼠媽媽怎麼舔

剛出生的小老鼠。

after they were born.

And I was sitting there and saying,

然後我吐槽說：

"This is where my tax dollars are wasted --

「我們納稅人的錢就這麼被你們浪費

(Laughter)

（笑聲）

on this kind of soft science."

在這種軟科學上。」

And he started telling me

然後他開始告訴我，

that the rats, like humans,

老鼠和人類一樣，

lick their pups in very different ways.

用各種不同的方法舔牠們的寶寶。

Some mothers do a lot of that,

有些媽媽很喜歡舔，

some mothers do very little,

有些媽媽就不怎麼舔，

and most are in between.

大多在中間值。

But what's interesting about it

有趣的是，

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

在這些小老鼠成年後繼續追蹤牠們，

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

就像人類成人以後一樣， 在媽媽死了很久以後，

They are completely different animals.

牠們變成完全不一樣的動物。

The animals that were licked and groomed heavily,

常常被媽媽又舔又理毛的，

the high-licking and grooming,

大量的舔和理毛，

are not stressed.

壓力會小些。

They have different sexual behavior.

牠們有不同的性行為，

They have a different way of living

牠們有不同的生活方式，

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

相較於沒有被母親密集舔過的。

So then I was thinking to myself:

所以我在想：

Is this magic?

有什麼魔力嗎？

How does this work?

為什麼這樣呢？

As geneticists would like you to think,

遺傳學家會讓你這樣想，

perhaps the mother had the "bad mother" gene

也許母親有「壞媽媽」的基因，

that caused her pups to be stressful,

使牠的小老鼠變得緊張，

and then it was passed from generation to generation;

然後一代又一代的傳承；

it's all determined by genetics.

這一切都是由遺傳學決定的。

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

或是還有別的東西在做怪？

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

我們可以在老鼠身上 問這個問題並得到答案。

So what we did is a cross-fostering experiment.

所以我們做了交叉寄養實驗。

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

基本上你把一窩剛出生的老鼠分開，

to two kinds of fostering mothers --

給兩種寄養母親代養──

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

不是真正的母親，但是會照顧牠們：

high-licking mothers and low-licking mothers.

密集舔的母親和不太舔的母親。

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

對不太被舔的小老鼠做相反的事情。

And the remarkable answer was,

值得注意的答案是，

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

你從母親得到什麼基因不重要。

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

造就成鼠這種特性的 不是親生母親，

It is the mother that took care of the pups.

而是寄養母親。

So how can this work?

為什麼這麼說呢？

I am an a epigeneticist.

我是表觀遺傳學家。

I am interested in how genes are marked

我對基因如何被標記非常感興趣，

by a chemical mark

這是一種化學標記，

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

在胚胎形成期間， 在母親的子宮內就有，

and decide which gene will be expressed

並決定哪種基因會在

in what tissue.

什麼組織中表現。

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

在大腦表現的基因， 跟在肝臟和眼睛的不一樣。

And we thought: Is it possible

我們猜想：是否有可能

that the mother is somehow reprogramming the gene of her offspring

母親通過她的行為

through her behavior?

改寫後代的基因？

And we spent 10 years,

我們花了 10 年時間，

and we found that there is a cascade of biochemical events

發現的確有一系列的生化反應，

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

會被母親的舔和梳理、 母親的照顧所引發，

is translated to biochemical signals

然後被翻譯成生化信號

that go into the nucleus and into the DNA

進入細胞核及 DNA，

and program it differently.

寫成不一樣的東西。

So now the animal can prepare itself for life:

所以現在動物可以為自己做好準備：

Is life going to be harsh?

生活會變得艱苦嗎？

Is there going to be a lot of food?

會有很多食物嗎？

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

會有很多貓和蛇在附近嗎？

or will I live in an upper-class neighborhood

或要是我住在上層階級社區裡，

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

我只要表現良好和適當，

and that will gain me social acceptance?

那我就會被社會接受？

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

我們可以想一下這個過程

for our lives.

對於生活的重要性。

We inherit our DNA from our ancestors.

我們從祖先繼承 DNA。

The DNA is old.

這些 DNA 很古老。

It evolved during evolution.

它在進化過程中演變。

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

但是它不能告訴我們 你是在斯德哥爾摩出生，

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

那裡的白天在夏天很長，冬天很短；

or in Ecuador,

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

那裡一年四季晝夜相當。

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

而那對我們的生理學 有非常大的影響。

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

所以我們推斷，生命早期發生的事，

those signals that come through the mother,

即透過母親發出的那些信號，

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

會告訴孩子你將要生活 在什麼樣的社會。

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

是嚴苛的世界， 你可能會焦慮和壓力大，

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

或是安逸的世界，你最好與眾不同。

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

會是有很多陽光 還是很少陽光的世界？

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

會是有很多食物 還是很少食物的世界？

If there's no food around,

如果周圍沒有食物，

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

你最好訓練你的大腦 每次看到食物就大吃一頓，

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

或者把每一塊食物都轉成脂肪保存。

So this is good.

這很好。

Evolution has selected this

進化已經選擇了這一點，

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

讓我們不變、古老的 DNA

能在新的環境中隨機應變。

in new environments.

But sometimes things can go wrong;

但有時候事情可能會出錯；

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

例如，如果你出生在貧窮的家庭，

and the signals are, "You better binge,

信號是，「你最好大吃大喝，

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

你最好把每一塊 看得到的食物都吞下去。」

But now we humans and our brain have evolved,

但是現在我們人類和大腦都已演化，

have changed evolution even faster.

進化的速度更快了。

Now you can buy McDonald's for one dollar.

現在你可以花一美元買份麥當勞。

And therefore, the preparation that we had by our mothers

is turning out to be maladaptive.

變成不適當。

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

本來要保護我們 免於飢餓和飢荒的準備，

is going to cause obesity,

將導致肥胖、

cardiovascular problems and metabolic disease.

心血管問題和代謝疾病。

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

因此，基因可以透過我們的經驗，

and especially the early life experience,

特別是早期生活經驗來標記的概念，

can provide us a unifying explanation

可以為我們提供

對健康和疾病統一的解釋。

of both health and disease.

But is true only for rats?

但是只有老鼠才這樣嗎？

The problem is, we cannot test this in humans,

問題是，我們不能拿人類測這個，

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

因為在道德上，我們不能 隨機選孩子經歷逆境。

So if a poor child develops a certain property,

所以如果一個可憐的 小孩養成某種習慣，

we don't know whether this is caused by poverty

我們不知道這是由貧困造成的，

or whether poor people have bad genes.

還是窮人有壞的基因。

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

所以遺傳學家會試圖解釋 窮人之所以窮，

because their genes make them poor.

是因為他們的基因使他們貧窮。

Epigeneticists will tell you

poor people are in a bad environment or an impoverished environment

窮人處於惡劣或貧窮的環境中，

that creates that phenotype, that property.

創造出這種表現型，這種特性。

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

所以我們調查了我們的表親，猴子。

My colleague, Stephen Suomi, has been rearing monkeys

我的同事斯蒂芬·蘇米

以兩種不同的方式飼養猴子：

in two different ways:

randomly separated the monkey from the mother

隨機將被選取的猴子與母親分開，

and reared her with a nurse

找奶媽養育牠，

and surrogate motherhood conditions.

設下代理母親的條件。

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

所以這些猴子沒有媽媽； 牠們有奶媽。

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

而其他猴子則由生母養大。

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

當牠們老了， 牠們變成完全不同的動物。

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

由生母撫養的猴子不愛酒精，

they were not sexually aggressive.

牠們沒有性侵略性。

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

沒有母親的猴子 具侵略性、壓力很大，

and were alcoholics.

並且酗酒。

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

我們在牠們一出生 就檢查 DNA，想看：

Is it possible that the mother is marking?

媽媽有可能在標記嗎？

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

在後代的 DNA 中 有母親的「簽名」嗎？

These are Day-14 monkeys,

這些是 14 天大的猴子，

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

這裡你們看到的是我們 研究表觀遺傳學的現代方式。

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

我們可以定位這些化學標記， 我們稱做甲基化標記，

on DNA at a single nucleotide resolution.

解析度為在單核苷酸上 DNA 的情況。

We can map the entire genome.

我們可以定位整個基因組。

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

我們現在可以比較 有或沒有母親的猴子。

And here's a visual presentation of this.

這是視覺圖。

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

你可以看到 有更多甲基化的基因是紅的；

The genes that got less methylated are green.

少甲基化的是基因是綠色的。

You can see many genes are changing,

你們可以看到很多基因在改變，

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

因為沒有母親可不是小事一樁，

it affects the whole way;

這會影響整體；

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

它會送信號告訴我們

when you become an adult.

你長大後你的世界是什麼樣子。

And you can see the two groups of monkeys

你們可以看見兩組猴子

extremely well-separated from each other.

完全不一樣。

How early does this develop?

這是在多早期就發展出來？

These monkeys already didn't see their mothers,

這些猴子早就看不到自己的母親，

so they had a social experience.

所以牠們有了某種社會經驗。

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

我們在出生時就會感受到 自己的社會地位嗎？

So in this experiment, we took placentas of monkeys

所以在這項實驗中，

我們從不同社會地位的 猴子身上取出胎盤。

that had different social status.

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

社會階級有趣的地方 就是所有的生物，

they will structure themselves by hierarchy.

都會把自己分成幾個等級。

Monkey number one is the boss;

猴子一號是老大；

monkey number four is the peon.

猴子四號是小兵。

You put four monkeys in a cage,

你把四隻猴子關在一個籠子裡，

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

一定會產生一隻老大和一隻小兵。

And what's interesting is that the monkey number one

有趣的是猴子一號

is much healthier than monkey number four.

一定比猴子四號更健康。

And if you put them in a cage,

如果你把牠們關在一個籠子裡，

monkey number one will not eat as much.

猴子一號不會吃太多。

Monkey number four will eat [a lot].

猴子四號會吃很多。

And what you see here in this methylation mapping,

你們在這裡看到的是甲基化定位，

a dramatic separation at birth

把出生時被迫分離

of the animals that had a high social status

但社會地位高的動物，

versus the animals that did not have a high status.

與社會地位沒那麼高的動物相比。

So we are born already knowing the social information,

所以我們出生時 已經對社會訊息略有所知，

and that social information is not bad or good,

這種社會訊息沒有什麼好壞，

it just prepares us for life,

只是幫助我們預備好過人生，

because we have to program our biology differently

因為我們必須針對高或低的社會地位

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

編寫不同的生物學程式。

But how can you study this in humans?

但是你要怎麼在人體做這種研究？

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

我們不能做實驗， 不能施加厄運給人類。

But God does experiments with humans,

但是神的確在人身上做了實驗，

and it's called natural disasters.

那就是天災。

One of the hardest natural disasters in Canadian history

加拿大史上有一場嚴重天災，

happened in my province of Quebec.

就發生在我的省分魁北克，

It's the ice storm of 1998.

即 1998 年的冰暴。

We lost our entire electrical grid because of an ice storm

我們因這場冰暴 而失去整個輸電網路，

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

當時的溫度，在魁北克的隆冬，

minus 20 to minus 30.

是零下 20、30 度。

And there were pregnant mothers during that time.

當時有些懷孕的母親。

And my colleague Suzanne King followed the children of these mothers

我的同事金蘇珊持續追蹤

這些母親生下的孩子 15 年。

for 15 years.

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

她發現到，隨著壓力愈來愈高，

and here we had objective measures of stress:

我們有客觀的方法測量壓力：

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

你有多久無電可用？你在哪裡避難？

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

是在婆家的公寓，還是鄉村別墅？

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

把這些加起來得到社會壓力強度，

and you can ask the question:

然後你問：

How did the children look?

孩子狀況如何？

And it appears that as stress increases,

顯然隨著壓力增加，

the children develop more autism,

孩子得到自閉症的情況也增加，

they develop more metabolic diseases

他們更容易得到代謝疾病，

and they develop more autoimmune diseases.

也更容易發展出自體免疫疾病。

We would map the methylation state,

我們會定位甲基化程度，

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

跟之前一樣，綠色的基因 會隨著壓力增加而轉紅，

the red genes becoming green as stress increases,

紅色的基因會因壓力增加而變綠，

an entire rearrangement of the genome in response to stress.

基因組會因應壓力而重新排列組合。

So if we can program genes,

所以如果我們可以編寫基因，

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

如果我們不受限於基因的來源，

that they could be programmed, can we deprogram them?

而是能編寫，我們可以抹去 壓力造成的影響嗎？

Because epigenetic causes can cause diseases like cancer,

因為表觀遺傳會造成疾病，如癌症、

metabolic disease

新陳代謝疾病、

and mental health diseases.

及精神疾病。

Let's talk about cocaine addiction.

來看一下古柯鹼上癮。

Cocaine addiction is a terrible situation

古柯鹼上癮是一種很糟的情況，

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

會導致死亡，失去生命。

We asked the question:

我們問這個問題：

Can we reprogram the addicted brain

我們能不能重新改寫上癮的腦部，

to make that animal not addicted anymore?

讓成癮的動物完全戒掉？

We used a cocaine addiction model

我們使用一種古柯鹼成癮模式，

that recapitulates what happens in humans.

概述一下人類的狀況。

In humans, you're in high school,

在人類是這樣的，你在高中時

some friends suggest you use some cocaine,

一些朋友要你試試古柯鹼，

you take cocaine, nothing happens.

你吸了一點，沒事。

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

幾個月後，某個契機 讓你回想起第一次的狀況，

a pusher pushes cocaine,

毒販又給了你一點古柯鹼，

and you become addicted and your life has changed.

然後你就上癮，生命因此改變。

In rats, we do the same thing.

我們也在老鼠身上做同樣的事。

My colleague, Gal Yadid,

我的同事亞迪德

he trains the animals to get used to cocaine,

他訓練動物習慣古柯鹼，

then for one month, no cocaine.

然後一個月不給古柯鹼。

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

然後他讓牠們想起第一次古柯鹼趴，

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

就是把牠們關在一樣顏色的籠子裡。

And they go crazy.

然後牠們就瘋了。

They will press the lever to get cocaine

牠們會不斷地壓控制桿要古柯鹼，

until they die.

直到死亡為止。

We first determined that the difference between these animals

我們首先確定了這兩者的差別，

is that during that time when nothing happens,

是在什麼都沒發生的那段期間，

there's no cocaine around,

沒有古柯鹼，

their epigenome is rearranged.

牠們的表觀基因組已經重新排列。

Their genes are re-marked in a different way,

牠們的基因以不同的方式重新標記，

and when the cue comes, their genome is ready

所以當暗示來時， 牠們的基因組已經準備好

to develop this addictive phenotype.

要發展成這種上癮表型。

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

所以我們以藥物治療這些動物， 要不就是增加 DNA 甲基化，

which was the epigenetic marker to look at,

這是表觀基因標記要看的，

or decrease epigenetic markings.

或是減少表觀基因標記。

And we found that if we increased methylation,

我們發現如果我們增加甲基化，

these animals go even crazier.

這些動物會更瘋。

They become more craving for cocaine.

牠們會更渴望想要古柯鹼。

But if we reduce the DNA methylation,

但是如果我們減低 DNA 甲基化，

the animals are not addicted anymore.

這些動物就不再成癮。

We have reprogrammed them.

我們重新編碼了。

And a fundamental difference between an epigenetic drug

表觀遺傳用藥跟其他藥物

and any other drug

根本上的不同，

is that with epigenetic drugs,

在於用表觀遺傳藥物，

we essentially remove the signs of experience,

我們基本上抹去了經驗的足跡，

and once they're gone,

一旦足跡消失了，

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

它們就不會回頭找你， 直到你再碰到相同的經驗為止。

The animal now is reprogrammed.

這些動物現在被重新編碼了。

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

所以我們在 30 天、60 天後 再去看這些動物，

which is in human terms many years of life,

相對於人類就是好幾年後，

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

牠們仍然沒有上癮── 只要一次表觀遺傳治療就夠了！

So what did we learn about DNA?

所以關於 DNA，我們學到什麼？

DNA is not just a sequence of letters;

DNA 不僅是一串字母序列；

it's not just a script.

也不只是指令碼。

DNA is a dynamic movie.

DNA 是動態電影。

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

我們的經驗被寫進 這場互動式的電影裡。

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

你就像跟 DNA 一起 看人生走馬燈，

with your remote control.

還有遙控器。

You can remove an actor and add an actor.

你可以隨時增減角色。

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

所以就算你有命中注定的遺傳碼，

you have control of the way your genes look,

你還是能控制基因的表現，

and this has a tremendous optimistic message

而這帶出非常樂觀的訊息，

for the ability to now encounter some of the deadly diseases

就是你現在面對致命的疾病，

like cancer, mental health,

像癌症、精神健康，

with a new approach,

都可以用新的方法治療，

looking at them as maladaptation.

把它們看成適應不良即可。

And if we can epigenetically intervene,

如果我們可以用 表觀遺傳學的方法干預，

[we can] reverse the movie by removing an actor

就可以把某個角色撤掉，

and setting up a new narrative.

換一個新的故事來改寫電影。

So what I told you today is,

所以我今天要說的是，

our DNA is really combined of two components,

我們的 DNA 的確有兩個組成部分，

two layers of information.

兩層訊息。

One layer of information is old,

一層是古老的，

evolved from millions of years of evolution.

由數百億年的進化而來。

It is fixed and very hard to change.

這一層是固定的，而且很難改變。

The other layer of information is the epigenetic layer,

另一層則是表觀遺傳層，

which is open and dynamic

開放並充滿動態，

and sets up a narrative that is interactive,

以互動法編寫故事，

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

以相當大的程度 讓我們能控制自己的命運，

to help the destiny of our children

改變孩子的命運，

and to hopefully conquer disease

而且很有希望能戰勝疾病，

and serious health challenges

及嚴重的健康挑戰，

that have plagued humankind for a long time.

讓人類擺脫長久以來的困擾。

So even though we are determined

所以即使我們的確

by our genes,

受基因操控著命運，

we have a degree of freedom

我們還是有一定程度的自由

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

能建立自己的人生，為人生負責。

Thank you.

謝謝！

(Applause)

（掌聲）