So it all came to life in a dark bar in Madrid. I encountered my colleague from McGill, Michael Meaney. And we were drinking a few beers, and like scientists do, he told me about his work. And he told me that he is interested in how mother rats lick their pups after they were born. And I was sitting there and saying, "This is where my tax dollars are wasted --
這件事的起始發生在 馬德里的一間昏暗酒吧裡。 我遇到麥吉爾大學的同事 邁克·梅尼。 幾杯啤酒下肚, 就像所有科學家一樣, 他跟我聊起了他的工作。 他告訴我他有興趣研究 老鼠媽媽怎麼舔 剛出生的小老鼠。 然後我吐槽說: 「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 that the rats, like humans, lick their pups in very different ways. Some mothers do a lot of that, some mothers do very little, and most are in between. But what's interesting about it is when he follows these pups when they become adults -- like, years in human life, long after their mother died. They are completely different animals. The animals that were licked and groomed heavily, the high-licking and grooming, are not stressed. They have different sexual behavior. They have a different way of living than those that were not treated as intensively by their mothers.
然後他開始告訴我, 老鼠和人類一樣, 用各種不同的方法舔牠們的寶寶。 有些媽媽很喜歡舔, 有些媽媽就不怎麼舔, 大多在中間值。 有趣的是, 在這些小老鼠成年後繼續追蹤牠們, 就像人類成人以後一樣, 在媽媽死了很久以後, 牠們變成完全不一樣的動物。 常常被媽媽又舔又理毛的, 大量的舔和理毛, 壓力會小些。 牠們有不同的性行為, 牠們有不同的生活方式, 相較於沒有被母親密集舔過的。
So then I was thinking to myself: Is this magic? How does this work? As geneticists would like you to think, perhaps the mother had the "bad mother" gene that caused her pups to be stressful, and then it was passed from generation to generation; it's all determined by genetics. Or is it possible that something else is going on here?
所以我在想: 有什麼魔力嗎? 為什麼這樣呢? 遺傳學家會讓你這樣想, 也許母親有「壞媽媽」的基因, 使牠的小老鼠變得緊張, 然後一代又一代的傳承; 這一切都是由遺傳學決定的。 或是還有別的東西在做怪?
In rats, we can ask this question and answer it. So what we did is a cross-fostering experiment. You essentially separate the litter, the babies of this rat, at birth, to two kinds of fostering mothers -- not the real mothers, but mothers that will take care of them: high-licking mothers and low-licking mothers. And you can do the opposite with the low-licking pups. And the remarkable answer was, it wasn't important what gene you got from your mother. It was not the biological mother that defined this property of these rats. It is the mother that took care of the pups. So how can this work?
我們可以在老鼠身上 問這個問題並得到答案。 所以我們做了交叉寄養實驗。 基本上你把一窩剛出生的老鼠分開, 給兩種寄養母親代養── 不是真正的母親,但是會照顧牠們: 密集舔的母親和不太舔的母親。 對不太被舔的小老鼠做相反的事情。 值得注意的答案是, 你從母親得到什麼基因不重要。 造就成鼠這種特性的 不是親生母親, 而是寄養母親。 為什麼這麼說呢?
I am an a epigeneticist. I am interested in how genes are marked by a chemical mark during embryogenesis, during the time we're in the womb of our mothers, and decide which gene will be expressed in what tissue. Different genes are expressed in the brain than in the liver and the eye. And we thought: Is it possible that the mother is somehow reprogramming the gene of her offspring through her behavior? And we spent 10 years, and we found that there is a cascade of biochemical events by which the licking and grooming of the mother, the care of the mother, is translated to biochemical signals that go into the nucleus and into the DNA and program it differently. So now the animal can prepare itself for life: Is life going to be harsh? Is there going to be a lot of food? Are there going to be a lot of cats and snakes around, or will I live in an upper-class neighborhood where all I have to do is behave well and proper, and that will gain me social acceptance? And now one can think about how important that process can be for our lives.
我是表觀遺傳學家。 我對基因如何被標記非常感興趣, 這是一種化學標記, 在胚胎形成期間, 在母親的子宮內就有, 並決定哪種基因會在 什麼組織中表現。 在大腦表現的基因, 跟在肝臟和眼睛的不一樣。 我們猜想:是否有可能 母親通過她的行為 改寫後代的基因? 我們花了 10 年時間, 發現的確有一系列的生化反應, 會被母親的舔和梳理、 母親的照顧所引發, 然後被翻譯成生化信號 進入細胞核及 DNA, 寫成不一樣的東西。 所以現在動物可以為自己做好準備: 生活會變得艱苦嗎? 會有很多食物嗎? 會有很多貓和蛇在附近嗎? 或要是我住在上層階級社區裡, 我只要表現良好和適當, 那我就會被社會接受? 我們可以想一下這個過程 對於生活的重要性。
We inherit our DNA from our ancestors. The DNA is old. It evolved during evolution. But it doesn't tell us if you are going to be born in Stockholm, where the days are long in the summer and short in the winter, or in Ecuador, where there's an equal number of hours for day and night all year round. And that has such an enormous [effect] on our physiology. So what we suggest is, perhaps what happens early in life, those signals that come through the mother, tell the child what kind of social world you're going to be living in. It will be harsh, and you'd better be anxious and be stressful, or it's going to be an easy world, and you have to be different. Is it going to be a world with a lot of light or little light? Is it going to be a world with a lot of food or little food? If there's no food around, you'd better develop your brain to binge whenever you see a meal, or store every piece of food that you have as fat.
我們從祖先繼承 DNA。 這些 DNA 很古老。 它在進化過程中演變。 但是它不能告訴我們 你是在斯德哥爾摩出生, 那裡的白天在夏天很長,冬天很短; 或厄瓜多爾, 那裡一年四季晝夜相當。 而那對我們的生理學 有非常大的影響。 所以我們推斷,生命早期發生的事, 即透過母親發出的那些信號, 會告訴孩子你將要生活 在什麼樣的社會。 是嚴苛的世界, 你可能會焦慮和壓力大, 或是安逸的世界,你最好與眾不同。 會是有很多陽光 還是很少陽光的世界? 會是有很多食物 還是很少食物的世界? 如果周圍沒有食物, 你最好訓練你的大腦 每次看到食物就大吃一頓, 或者把每一塊食物都轉成脂肪保存。
So this is good. Evolution has selected this to allow our fixed, old DNA to function in a dynamic way in new environments. But sometimes things can go wrong; for example, if you're born to a poor family and the signals are, "You better binge, you better eat every piece of food you're going to encounter." But now we humans and our brain have evolved, have changed evolution even faster. Now you can buy McDonald's for one dollar. And therefore, the preparation that we had by our mothers is turning out to be maladaptive. The same preparation that was supposed to protect us from hunger and famine is going to cause obesity, cardiovascular problems and metabolic disease. So this concept that genes could be marked by our experience, and especially the early life experience, can provide us a unifying explanation of both health and disease.
這很好。 進化已經選擇了這一點, 讓我們不變、古老的 DNA 能在新的環境中隨機應變。 但有時候事情可能會出錯; 例如,如果你出生在貧窮的家庭, 信號是,「你最好大吃大喝, 你最好把每一塊 看得到的食物都吞下去。」 但是現在我們人類和大腦都已演化, 進化的速度更快了。 現在你可以花一美元買份麥當勞。 因此,我們母親所做的準備 變成不適當。 本來要保護我們 免於飢餓和飢荒的準備, 將導致肥胖、 心血管問題和代謝疾病。 因此,基因可以透過我們的經驗, 特別是早期生活經驗來標記的概念, 可以為我們提供 對健康和疾病統一的解釋。
But is true only for rats? The problem is, we cannot test this in humans, because ethically, we cannot administer child adversity in a random way. So if a poor child develops a certain property, we don't know whether this is caused by poverty or whether poor people have bad genes. So geneticists will try to tell you that poor people are poor because their genes make them poor. Epigeneticists will tell you poor people are in a bad environment or an impoverished environment that creates that phenotype, that property.
但是只有老鼠才這樣嗎? 問題是,我們不能拿人類測這個, 因為在道德上,我們不能 隨機選孩子經歷逆境。 所以如果一個可憐的 小孩養成某種習慣, 我們不知道這是由貧困造成的, 還是窮人有壞的基因。 所以遺傳學家會試圖解釋 窮人之所以窮, 是因為他們的基因使他們貧窮。 表觀遺傳學家會告訴你, 窮人處於惡劣或貧窮的環境中, 創造出這種表現型,這種特性。
So we moved to look into our cousins, the monkeys. My colleague, Stephen Suomi, has been rearing monkeys in two different ways: randomly separated the monkey from the mother and reared her with a nurse and surrogate motherhood conditions. So these monkeys didn't have a mother; they had a nurse. And other monkeys were reared with their normal, natural mothers. And when they were old, they were completely different animals. The monkeys that had a mother did not care about alcohol, they were not sexually aggressive. The monkeys that didn't have a mother were aggressive, were stressed and were alcoholics. So we looked at their DNA early after birth, to see: Is it possible that the mother is marking? Is there a signature of the mother in the DNA of the offspring?
所以我們調查了我們的表親,猴子。 我的同事斯蒂芬·蘇米 以兩種不同的方式飼養猴子: 隨機將被選取的猴子與母親分開, 找奶媽養育牠, 設下代理母親的條件。 所以這些猴子沒有媽媽; 牠們有奶媽。 而其他猴子則由生母養大。 當牠們老了, 牠們變成完全不同的動物。 由生母撫養的猴子不愛酒精, 牠們沒有性侵略性。 沒有母親的猴子 具侵略性、壓力很大, 並且酗酒。 我們在牠們一出生 就檢查 DNA,想看: 媽媽有可能在標記嗎? 在後代的 DNA 中 有母親的「簽名」嗎?
These are Day-14 monkeys, and what you see here is the modern way by which we study epigenetics. We can now map those chemical marks, which we call methylation marks, on DNA at a single nucleotide resolution. We can map the entire genome. We can now compare the monkey that had a mother or not. And here's a visual presentation of this. What you see is the genes that got more methylated are red. The genes that got less methylated are green. You can see many genes are changing, because not having a mother is not just one thing -- it affects the whole way; it sends signals about the whole way your world is going to look when you become an adult. And you can see the two groups of monkeys extremely well-separated from each other. How early does this develop? These monkeys already didn't see their mothers, so they had a social experience. Do we sense our social status, even at the moment of birth?
這些是 14 天大的猴子, 這裡你們看到的是我們 研究表觀遺傳學的現代方式。 我們可以定位這些化學標記, 我們稱做甲基化標記, 解析度為在單核苷酸上 DNA 的情況。 我們可以定位整個基因組。 我們現在可以比較 有或沒有母親的猴子。 這是視覺圖。 你可以看到 有更多甲基化的基因是紅的; 少甲基化的是基因是綠色的。 你們可以看到很多基因在改變, 因為沒有母親可不是小事一樁, 這會影響整體; 它會送信號告訴我們 你長大後你的世界是什麼樣子。 你們可以看見兩組猴子 完全不一樣。 這是在多早期就發展出來? 這些猴子早就看不到自己的母親, 所以牠們有了某種社會經驗。 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 that had different social status. What's interesting about social rank is that across all living beings, they will structure themselves by hierarchy. Monkey number one is the boss; monkey number four is the peon. You put four monkeys in a cage, there will always be a boss and always be a peon. And what's interesting is that the monkey number one is much healthier than monkey number four. And if you put them in a cage, monkey number one will not eat as much. Monkey number four will eat [a lot]. And what you see here in this methylation mapping, a dramatic separation at birth of the animals that had a high social status versus the animals that did not have a high status.
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。 社會階級有趣的地方 就是所有的生物, 都會把自己分成幾個等級。 猴子一號是老大; 猴子四號是小兵。 你把四隻猴子關在一個籠子裡, 一定會產生一隻老大和一隻小兵。 有趣的是猴子一號 一定比猴子四號更健康。 如果你把牠們關在一個籠子裡, 猴子一號不會吃太多。 猴子四號會吃很多。 你們在這裡看到的是甲基化定位, 把出生時被迫分離 但社會地位高的動物, 與社會地位沒那麼高的動物相比。
So we are born already knowing the social information, and that social information is not bad or good, it just prepares us for life, because we have to program our biology differently if we are in the high or the low social status.
所以我們出生時 已經對社會訊息略有所知, 這種社會訊息沒有什麼好壞, 只是幫助我們預備好過人生, 因為我們必須針對高或低的社會地位 編寫不同的生物學程式。
But how can you study this in humans? We can't do experiments, we can't administer adversity to humans. But God does experiments with humans, and it's called natural disasters.
但是你要怎麼在人體做這種研究? 我們不能做實驗, 不能施加厄運給人類。 但是神的確在人身上做了實驗, 那就是天災。
One of the hardest natural disasters in Canadian history happened in my province of Quebec. It's the ice storm of 1998. We lost our entire electrical grid because of an ice storm when the temperatures were, in the dead of winter in Quebec, minus 20 to minus 30. And there were pregnant mothers during that time. And my colleague Suzanne King followed the children of these mothers for 15 years.
加拿大史上有一場嚴重天災, 就發生在我的省分魁北克, 即 1998 年的冰暴。 我們因這場冰暴 而失去整個輸電網路, 當時的溫度,在魁北克的隆冬, 是零下 20、30 度。 當時有些懷孕的母親。 我的同事金蘇珊持續追蹤 這些母親生下的孩子 15 年。
And what happened was, that as the stress increased -- and here we had objective measures of stress: How long were you without power? Where did you spend your time? Was it in your mother-in-law's apartment or in some posh country home? So all of these added up to a social stress scale, and you can ask the question: How did the children look? And it appears that as stress increases, the children develop more autism, they develop more metabolic diseases and they develop more autoimmune diseases. We would map the methylation state, and again, you see the green genes becoming red as stress increases, the red genes becoming green as stress increases, an entire rearrangement of the genome in response to stress.
她發現到,隨著壓力愈來愈高, 我們有客觀的方法測量壓力: 你有多久無電可用?你在哪裡避難? 是在婆家的公寓,還是鄉村別墅? 把這些加起來得到社會壓力強度, 然後你問: 孩子狀況如何? 顯然隨著壓力增加, 孩子得到自閉症的情況也增加, 他們更容易得到代謝疾病, 也更容易發展出自體免疫疾病。 我們會定位甲基化程度, 跟之前一樣,綠色的基因 會隨著壓力增加而轉紅, 紅色的基因會因壓力增加而變綠, 基因組會因應壓力而重新排列組合。
So if we can program genes, if we are not just the slaves of the history of our genes, that they could be programmed, can we deprogram them? Because epigenetic causes can cause diseases like cancer, metabolic disease and mental health diseases.
所以如果我們可以編寫基因, 如果我們不受限於基因的來源, 而是能編寫,我們可以抹去 壓力造成的影響嗎? 因為表觀遺傳會造成疾病,如癌症、 新陳代謝疾病、 及精神疾病。
Let's talk about cocaine addiction. Cocaine addiction is a terrible situation that can lead to death and to loss of human life. We asked the question: Can we reprogram the addicted brain to make that animal not addicted anymore? We used a cocaine addiction model that recapitulates what happens in humans. In humans, you're in high school, some friends suggest you use some cocaine, you take cocaine, nothing happens. Months pass by, something reminds you of what happened the first time, a pusher pushes cocaine, and you become addicted and your life has changed.
來看一下古柯鹼上癮。 古柯鹼上癮是一種很糟的情況, 會導致死亡,失去生命。 我們問這個問題: 我們能不能重新改寫上癮的腦部, 讓成癮的動物完全戒掉? 我們使用一種古柯鹼成癮模式, 概述一下人類的狀況。 在人類是這樣的,你在高中時 一些朋友要你試試古柯鹼, 你吸了一點,沒事。 幾個月後,某個契機 讓你回想起第一次的狀況, 毒販又給了你一點古柯鹼, 然後你就上癮,生命因此改變。
In rats, we do the same thing. My colleague, Gal Yadid, he trains the animals to get used to cocaine, then for one month, no cocaine. Then he reminds them of the party when they saw the cocaine the first time by cue, the colors of the cage when they saw cocaine. And they go crazy. They will press the lever to get cocaine until they die. We first determined that the difference between these animals is that during that time when nothing happens, there's no cocaine around, their epigenome is rearranged. Their genes are re-marked in a different way, and when the cue comes, their genome is ready to develop this addictive phenotype.
我們也在老鼠身上做同樣的事。 我的同事亞迪德 他訓練動物習慣古柯鹼, 然後一個月不給古柯鹼。 然後他讓牠們想起第一次古柯鹼趴, 就是把牠們關在一樣顏色的籠子裡。 然後牠們就瘋了。 牠們會不斷地壓控制桿要古柯鹼, 直到死亡為止。 我們首先確定了這兩者的差別, 是在什麼都沒發生的那段期間, 沒有古柯鹼, 牠們的表觀基因組已經重新排列。 牠們的基因以不同的方式重新標記, 所以當暗示來時, 牠們的基因組已經準備好 要發展成這種上癮表型。
So we treated these animals with drugs that either increase DNA methylation, which was the epigenetic marker to look at, or decrease epigenetic markings. And we found that if we increased methylation, these animals go even crazier. They become more craving for cocaine. But if we reduce the DNA methylation, the animals are not addicted anymore. We have reprogrammed them. And a fundamental difference between an epigenetic drug and any other drug is that with epigenetic drugs, we essentially remove the signs of experience, and once they're gone, they will not come back unless you have the same experience. The animal now is reprogrammed. So when we visited the animals 30 days, 60 days later, which is in human terms many years of life, they were still not addicted -- by a single epigenetic treatment.
所以我們以藥物治療這些動物, 要不就是增加 DNA 甲基化, 這是表觀基因標記要看的, 或是減少表觀基因標記。 我們發現如果我們增加甲基化, 這些動物會更瘋。 牠們會更渴望想要古柯鹼。 但是如果我們減低 DNA 甲基化, 這些動物就不再成癮。 我們重新編碼了。 表觀遺傳用藥跟其他藥物 根本上的不同, 在於用表觀遺傳藥物, 我們基本上抹去了經驗的足跡, 一旦足跡消失了, 它們就不會回頭找你, 直到你再碰到相同的經驗為止。 這些動物現在被重新編碼了。 所以我們在 30 天、60 天後 再去看這些動物, 相對於人類就是好幾年後, 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? DNA is not just a sequence of letters; it's not just a script. DNA is a dynamic movie. Our experiences are being written into this movie, which is interactive. You're, like, watching a movie of your life, with the DNA, with your remote control. You can remove an actor and add an actor. And so you have, in spite of the deterministic nature of genetics, you have control of the way your genes look, and this has a tremendous optimistic message for the ability to now encounter some of the deadly diseases like cancer, mental health, with a new approach, looking at them as maladaptation. And if we can epigenetically intervene, [we can] reverse the movie by removing an actor and setting up a new narrative.
所以關於 DNA,我們學到什麼? DNA 不僅是一串字母序列; 也不只是指令碼。 DNA 是動態電影。 我們的經驗被寫進 這場互動式的電影裡。 你就像跟 DNA 一起 看人生走馬燈, 還有遙控器。 你可以隨時增減角色。 所以就算你有命中注定的遺傳碼, 你還是能控制基因的表現, 而這帶出非常樂觀的訊息, 就是你現在面對致命的疾病, 像癌症、精神健康, 都可以用新的方法治療, 把它們看成適應不良即可。 如果我們可以用 表觀遺傳學的方法干預, 就可以把某個角色撤掉, 換一個新的故事來改寫電影。
So what I told you today is, our DNA is really combined of two components, two layers of information. One layer of information is old, evolved from millions of years of evolution. It is fixed and very hard to change. The other layer of information is the epigenetic layer, which is open and dynamic and sets up a narrative that is interactive, that allows us to control, to a large extent, our destiny, to help the destiny of our children and to hopefully conquer disease and serious health challenges that have plagued humankind for a long time.
所以我今天要說的是, 我們的 DNA 的確有兩個組成部分, 兩層訊息。 一層是古老的, 由數百億年的進化而來。 這一層是固定的,而且很難改變。 另一層則是表觀遺傳層, 開放並充滿動態, 以互動法編寫故事, 以相當大的程度 讓我們能控制自己的命運, 改變孩子的命運, 而且很有希望能戰勝疾病, 及嚴重的健康挑戰, 讓人類擺脫長久以來的困擾。
So even though we are determined by our genes, we have a degree of freedom that can set up our life to a life of responsibility.
所以即使我們的確 受基因操控著命運, 我們還是有一定程度的自由 能建立自己的人生,為人生負責。
Thank you.
謝謝!
(Applause)
(掌聲)