Now, I don't usually like cartoons, I don't think many of them are funny, I find them weird. But I love this cartoon from the New Yorker.
平常我不怎麼喜歡連環漫畫 我覺得大部分的連環漫畫都很無趣 我覺得它們頗怪的,但我很愛紐約人報紙上的漫畫
(Text: Never, ever think outside the box.) (Laughter)
(內文:永遠不要往外想)
So, the guy is telling the cat, don't you dare think outside the box. Well, I'm afraid I used to be the cat. I always wanted to be outside the box. And it's partly because I came to this field from a different background, chemist and a bacterial geneticist. So, what people were saying to me about the cause of cancer, sources of cancer, or, for that matter, why you are who you are, didn't make sense.
這個傢伙正告訴他的貓 別妄想跑到你的箱子外面 但是,恐怕我曾是那隻貓 我總是喜歡待在箱子以外的地方 而這或許是因為,在我投身這個領域前 我是個化學家及細菌遺傳學家 因此,當人們跟我談論 癌症的成因和種類 或是我們為何長得這副模樣 對我來說並沒有意義
So, let me quickly try and tell you why I thought that and how I went about it. So, to begin with, however, I have to give you a very, very quick lesson in developmental biology, with apologies to those of you who know some biology. So, when your mom and dad met, there is a fertilized egg, that round thing with that little blip. It grows and then it grows, and then it makes this handsome man.
現在讓我來告訴各位,為什麼我會這麼想 以及我又是如何處理這些問題 無論如何, 首先我必須給各位上一課 非常簡略的發展生物學 並向那些學過生物的人說聲抱歉 當你爸媽遇到彼此時 一個受精卵產生了 那有個小亮點的圓形物體 它不斷的長呀長 最後變成了這位帥氣的男子
(Applause)
(掌聲)
So, this guy, with all the cells in his body, all have the same genetic information. So how did his nose become his nose, his elbow his elbow, and why doesn't he get up one morning and have his nose turn into his foot? It could. It has the genetic information. You all remember, dolly, it came from a single mammary cell. So, why doesn't it do it? So, have a guess of how many cells he has in his body. Somewhere between 10 trillion to 70 trillion cells in his body. Trillion! Now, how did these cells, all with the same genetic material, make all those tissues? And so, the question I raised before becomes even more interesting if you thought about the enormity of this in every one of your bodies.
這名男子體內所有的細胞 全都擁有同樣的基因成分 他的鼻子,手肘是如何長成的? 或某天早上他起床時 為何鼻子沒有忽然變成腳呢? 是有可能的,因為它含有足部細胞的成分 各位還記得桃莉羊 是由一個乳腺細胞發展而來的吧? 鼻子變成腳又怎麼不可能呢? 所以我們來猜猜他體內究竟有多少細胞吧 有界於十兆到七十兆之間個細胞 幾兆個細胞耶! 這些擁有相同基因成分的細胞 是如何形成不同的組織呢? 所以,想到我們體內這些深澳的故事 我之前的問題會變得更加有趣 我之前的問題會變得更加有趣
Now, the dominant cancer theory would say that there is a single oncogene in a single cancer cell, and it would make you a cancer victim. Well, this did not make sense to me. Do you even know how a trillion looks? Now, let's look at it. There it comes, these zeroes after zeroes after zeroes. Now, if .0001 of these cells got mutated, and .00001 got cancer, you will be a lump of cancer. You will have cancer all over you. And you're not. Why not?
主流的癌症理論會這麼解釋 一個細胞內的一個致癌基因 一個細胞內的一個致癌基因 會讓你罹患癌症 在我看來這並沒有道理 你知道"一兆"是什麼樣子嗎? 我們就來看看吧 就像這樣,這些零一個接一個 那如果那萬分之一的細胞產生突變, 十萬分之一變成癌細胞,那你會變成一團癌細胞 全身上下無一處無癌症....但這種事並未發生 為什麼呢?
So, I decided over the years, because of a series of experiments that this is because of context and architecture.
這些年來我根據一系列的實驗 下了一個結論 也就是生活環境與結構主控著一切
And let me quickly tell you some crucial experiment that was able to actually show this. To begin with, I came to work with this virus that causes that ugly tumor in the chicken. Rous discovered this in 1911. It was the first cancer virus discovered, and when I call it "oncogene," meaning "cancer gene." So, he made a filtrate, he took this filter which was the liquid after he passed the tumor through a filter, and he injected it to another chicken, and he got another tumor.
讓我很快的引用一些重要的實驗 來向大家解釋 首先,我研究這種使雞隻長出 醜陋腫瘤的病毒 勞氏於1911年發現這種病毒 它是第一個被發現的癌症病毒 我說的"致癌基因"指的是"使人罹癌的基因" 勞斯將雞隻的腫瘤通過濾器 製造出一種濾液 並注入另外一隻雞體內,這隻雞同樣也長了腫瘤
So, scientists were very excited, and they said, a single oncogene can do it. All you need is a single oncogene. So, they put the cells in cultures, chicken cells, dumped the virus on it, and it would pile up, and they would say, this is malignant and this is normal.
科學家們因此感到非常興奮 他們認為只要一個致癌基因便能治癌 單一一個致癌基因就夠了 他們將病毒放到雞的細胞上 並開始培養 接著這些細胞聚集成堆 然後他們就會評斷哪些是惡性的,哪些是正常的
And again this didn't make sense to me. So for various reasons, we took this oncogene, attached it to a blue marker, and we injected it into the embryos. Now look at that. There is that beautiful feather in the embryo. Every one of those blue cells are a cancer gene inside a cancer cell, and they're part of the feather. So, when we dissociated the feather and put it in a dish, we got a mass of blue cells. So, in the chicken you get a tumor, in the embryo you don't, you dissociate, you put it in a dish, you get another tumor. What does that mean? That means that microenvironment and the context which surrounds those cells actually are telling the cancer gene and the cancer cell what to do.
這些對我來說也一樣沒有意義 所以,基於各種原因 我們把這個致癌基因染成藍色 並注入胚胎中 看看這個,這是一個胚胎長出的羽毛 每個藍色的癌細胞裡都含有一個致癌基因 它們都是羽毛的一部份 我們將羽毛取出並放進一個培養皿 變成了大量的癌細胞 所以,在雞隻身上會長出腫瘤 在胚胎中卻不會 把羽毛分離放進培養皿,又變成一個腫瘤 這代表什麼呢? 這代表細胞生長的環境 以及圍繞細胞的物質 在告訴致癌基因和癌細胞要做什麼
Now, let's take a normal example. The normal example, let's take the human mammary gland. I work on breast cancer. So, here is a lovely human breast. And many of you know how it looks, except that inside that breast, there are all these pretty, developing, tree-like structures. So, we decided that what we like to do is take just a bit of that mammary gland, which is called an "acinus," where there are all these little things inside the breast where the milk goes, and the end of the nipple comes through that little tube when the baby sucks.
舉個一般的例子 我們拿人類的乳腺細胞為例 我研究乳癌 這是一個美麗的人類乳房 很多人都知道乳房是什麼樣子 但不知道內部那些延伸的美麗樹狀結構 但不知道內部那些延伸的美麗樹狀結構 我們決定取一點乳腺細胞 我們決定取一點乳腺細胞 也就是"腺胞" 裡面有這些乳房內的微小物質 乳汁流經其中,嬰兒吸吮母乳時 會從末端流出
And we said, wonderful! Look at this pretty structure. We want to make this a structure, and ask the question, how do the cells do that? So, we took the red cells -- you see the red cells are surrounded by blue, other cells that squeeze them, and behind it is material that people thought was mainly inert, and it was just having a structure to keep the shape, and so we first photographed it with the electron microscope years and years ago, and you see this cell is actually quite pretty. It has a bottom, it has a top, it is secreting gobs and gobs of milk, because it just came from an early pregnant mouse.
我們覺得太棒了! 瞧那美麗的結構 我們想以此做為架構,提出我們的問題 乳腺細胞究竟是如何辦到的呢? 所以我們取了紅色的細胞 他們被藍色細胞包圍著 其他細胞擠壓著他們, 更後面是一些無生命物質 它的結構是用來維持內部的形狀 多年前我們第一次用電子顯微鏡拍攝 多年前我們第一次用電子顯微鏡拍攝 你會發現這種細胞其實相當美麗 它有頂部和底部 不斷分泌大量的奶水 因為這是從一隻剛懷孕的老鼠身上取得的
You take these cells, you put them in a dish, and within three days, they look like that. They completely forget. So you take them out, you put them in a dish, they don't make milk. They completely forget. For example, here is a lovely yellow droplet of milk on the left, there is nothing on the right. Look at the nuclei. The nuclei in the cell on the left is in the animal, the one on the right is in a dish. They are completely different from each other.
把這些細胞放入培養皿中 三天內他們便呈現這個樣貌 他們完全失去記憶 所以若將他們取出並放入培養皿 產乳機制就停止了,他們完全忘了工作 舉個例子,左邊有一滴美麗的黃色乳汁 右邊什麼都沒有 看那細胞核,左邊細胞中的細胞核位於動物體內 右邊的則在培養皿中 兩者完全不一樣
So, what does this tell you? This tells you that here also, context overrides. In different contexts, cells do different things. But how does context signal? So, Einstein said that "For an idea that does not first seem insane, there is no hope." So, you can imagine the amount of skepticism I received -- couldn't get money, couldn't do a whole lot of other things, but I'm so glad it all worked out.
這告訴我們什麼呢? 從這裡也可得知,周遭的環境主宰一切 細胞在不同的環境中會做不同的事 但環境究竟給了細胞什麼指示呢? 愛因斯坦曾說過 "一個想法起初若不瘋狂,那之後就沒什麼希望了" 現在你能想像我受到的質疑有多少了吧? 我無法籌到經費 無法做許多事 但我很高興一切都解決了
So, we made a section of the mammary gland of the mouse, and all those lovely acini are there, every one of those with the red around them are an acinus, and we said okay, we are going to try and make this, and I said, maybe that red stuff around the acinus that people think there's just a structural scaffold, maybe it has information, maybe it tells the cells what to do, maybe it tells the nucleus what to do. So I said, extracellular matrix, which is this stuff called ECM, signals and actually tells the cells what to do.
我們製作了一個老鼠乳腺細胞的切片 這些美麗的腺胞都在這兒 每個被紅色物質包圍的都是一個腺胞 很好,現在我們要來試著證明 我就想,也許那些圍繞腺胞的紅色物質藏著訊息 只是人們認為那只是細胞的一部份結構 只是人們認為那只是細胞的一部份結構 或許那些物質告訴細胞和細胞核該做什麼 這些細胞外間質,也就是ECM 指示並告訴細胞該做什麼
So, we decided to make things that would look like that. We found some gooey material that had the right extracellular matrix in it, we put the cells in it, and lo and behold, in about four days, they got reorganized and on the right, is what we can make in culture. On the left is what's inside the animal, we call it in vivo, and the one in culture was full of milk, the lovely red there is full of milk. So, we Got Milk, for the American audience. All right. And here is this beautiful human cell, and you can imagine that here also, context goes.
所以呢,我們決定像圖上這樣做 我們找了一些含有所需的胞外間質的黏稠物質 我們找了一些含有所需的胞外間質的黏稠物質 將細胞放入其中,觀察了四天左右 發現他們重新排列 右邊的圖是我們能在培養皿中製造的 左邊則是動物體內,也就是活的有機體內的情形 培養中所培養的細胞生產了許多奶水 紅色的部分充滿奶水 這裡的美國觀眾有奶喝了 很好,現在這是一個美麗的人類細胞 現在大家可以想像,細胞的周遭物質同樣主導一切
So, what do we do now? I made a radical hypothesis. I said, if it's true that architecture is dominant, architecture restored to a cancer cell should make the cancer cell think it's normal. Could this be done? So, we tried it. In order to do that, however, we needed to have a method of distinguishing normal from malignant, and on the left is the single normal cell, human breast, put in three-dimensional gooey gel that has extracellular matrix, it makes all these beautiful structures. On the right, you see it looks very ugly, the cells continue to grow, the normal ones stop. And you see here in higher magnification the normal acinus and the ugly tumor.
接著我們要做什麼呢? 我做了一個極端的假設 如下: 若細胞周圍的物質主宰著細胞的工作 修復癌細胞的胞外物質 會讓癌細胞誤以為正常的繼續運作 這有可能發生嗎? 為此我們做了實驗 為了達成我們的目的 我們需要有個區別好壞細胞的方法 左邊是一個正常的細胞 一個放在含有3D黏稠膠質中的人乳細胞 黏液中含有胞外間質,這些美麗的結構都是來自於此 右邊的卻非常醜陋 這些細胞不斷增長 正常的那邊卻停止了 把圖放的更大來看 兩邊分別是正常的腺胞和醜陋的腫瘤
So we said, what is on the surface of these ugly tumors? Could we calm them down -- they were signaling like crazy and they have pathways all messed up -- and make them to the level of the normal? Well, it was wonderful. Boggles my mind. This is what we got. We can revert the malignant phenotype.
我們很好奇腫瘤的表面究竟有什麼? 有辦法使這些細胞平靜下來嗎? 他們之間的訊號非常雜亂,訊息傳遞的路徑一蹋糊塗 如何使他們回歸正軌呢? 這實在太棒了,我感到驚訝不已 這是之後我們所得到的 我們成功的改正了細胞的惡性顯型
(Applause)
(掌聲)
And in order to show you that the malignant phenotype I didn't just choose one, here are little movies, sort of fuzzy, but you see that on the left are the malignant cells, all of them are malignant, we add one single inhibitor in the beginning, and look what happens, they all look like that. We inject them into the mouse, the ones on the right, and none of them would make tumors. We inject the other ones in the mouse, 100 percent tumors.
為了讓各位看到細胞的惡性顯型 我準備了另外的東西 這些小型影片,有點模糊 但我們能看到左邊那些是不正常的細胞 全部都是惡性的 我們在一開始加入了一個抗化劑 看看會發生什麼事,他們看起來就像這樣 我們將之注射到老鼠體內,如同右邊影片顯示 沒有半個細胞會變成腫瘤 我們將另一邊注入老鼠體內,腫瘤發生率卻變成100%
So, it's a new way of thinking about cancer, it's a hopeful way of thinking about cancer. We should be able to be dealing with these things at this level, and these conclusions say that growth and malignant behavior is regulated at the level of tissue organization and that the tissue organization is dependent on the extracellular matrix and the microenvironment. All right, thus form and function interact dynamically and reciprocally. And here is another five seconds of repose, is my mantra. Form and function.
這是對於癌症的一個新觀點 也是一個具有希望的新看法 我們有能力以這樣的水準來處理問題 從這些結論得知,細胞的成長與惡性演變 發生於組織層面 而組織則受到細胞外間質 和微小環境的影響 因此,細胞的形態與功能活力的進行互動 現在這五秒鐘是一段沉澱時間 我用來沉澱心情的禱文: 形態與功能
And of course, we now ask, where do we go now? We'd like to take this kind of thinking into the clinic. But before we do that, I'd like you to think that at any given time when you're sitting there, in your 70 trillion cells, the extracellular matrix signaling to your nucleus, the nucleus is signaling to your extracellular matrix and this is how your balance is kept and restored.
現在各位當然很好奇,接下來我們該如何發展呢? 我們想把這個想法放進臨床治療中 在那之前,請各位想想 任何一個時刻,當你坐在那邊時 你體內的七十兆個細胞 胞外間質傳遞訊息給細胞核 細胞核也傳遞訊息給胞外間質 因此你體內維持著這樣的平衡
We have made a lot of discoveries, we have shown that extracellular matrix talks to chromatin. We have shown that there's little pieces of DNA on the specific genes of the mammary gland that actually respond to extracellular matrix. It has taken many years, but it has been very rewarding.
我們發現許多東西 我們呈現了細胞外的母體與染色質的對話 我們展示了乳腺細胞特定的某個基因中,有一小部份的 DNA會對細胞外間質產生回應 DNA會對細胞外間質產生回應 研究雖然花了許多年的時間,但卻收穫滿滿
And before I get to the next slide, I have to tell you that there are so many additional discoveries to be made. There is so much mystery we don't know. And I always say to the students and post-docs I lecture to, don't be arrogant, because arrogance kills curiosity. Curiosity and passion. You need to always think, what else needs to be discovered? And maybe my discovery needs to be added to or maybe it needs to be changed.
在跳到下張投影片之前,我必須告訴各位 還有許多未知的探索等待進行 仍有太多秘密是我們尚未了解的 我常告訴我的學生和博士後研究員 千萬別傲慢,因為傲慢會扼殺對探索的好奇心 以及熱情 時時刻刻,你都必須想著還有什麼事情等待發掘? 或許我的發現需要更多補充 或是經過修改
So, we have now made an amazing discovery, a post-doc in the lab who is a physicist asked me, what do the cells do when you put them in? What do they do in the beginning when they do? I said, I don't know, we couldn't look at them. We didn't have high images in the old days. So she, being an imager and a physicist, did this incredible thing. This is a single human breast cell in three dimensions. Look at it. It's constantly doing this. Has a coherent movement. You put the cancer cells there, and they do go all over, they do this. They don't do this. And when we revert the cancer cell, it again does this. Absolutely boggles my mind. So the cell acts like an embryo. What an exciting thing.
現在我們有了這項驚人的發現 實驗室裡的一個博士後研究員兼物理學家,問我 當你把細胞放入時他們發生了什麼事? 一開始他們產生什麼變化? 我說我不曉得,我們無從觀察 早期我們還沒有高品質影像 這名學生呢,既是一個夢想家和物理學家 她做了這件驚人的設計 這是一個以3D影像顯示的人乳細胞 你看,它不斷的重複這個循環 有一個一致的動作 若換成癌細胞,它們就全亂掉了 而不是規律的運作 當我們把癌細胞修復後,它又重回正軌 完全令我驚訝不已 所以細胞的活動就像胚胎,這是多麼令人興奮的事啊
So I'd like to finish with a poem. Well I used to love English literature, and I debated in college, which one should I do? And unfortunately or fortunately, chemistry won. But here is a poem from Yeats. I'll just read you the last two lines. It's called "Among the School Children." "O body swayed to music / O brightening glance / How [can we know] the dancer from the dance?" And here is Merce Cunningham, I was fortunate to dance with him when I was younger, and here he is a dancer, and while he is dancing, he is both the dancer and the dance. The minute he stops, we have neither. So it's like form and function.
我想以一首詩來做結 我以前很熱愛英國文學 大學時我猶豫主修該選什麼? 不幸的或是幸運的,化學獲得了勝利 但這邊有首葉慈的詩,我想為各位朗誦最後兩行 詩名是"兒戲" "噢 身體隨著音樂起舞/噢 閃爍生輝的一瞥" 我們如何在舞蹈中找到舞者呢? 這位是摩斯康寧漢 我年輕時有幸和他一起跳舞 這裡的他是一名舞者 當他在跳舞的時候,他既是舞者也是舞蹈本身 在他停止的那刻,我們兩者都沒有了 這就像形態與功能
Now, I'd like to show you a current picture of my group. I have been fortunate to have had these magnificant students and post-docs who have taught me so much, and I have had many of these groups come and go. They are the future and I try to make them not be afraid of being the cat and being told, don't think outside the box.
現在我想給各位看看我的研究團隊 我很榮幸有這些了不起的學生 和博士後研究員,從他們身上我學到很多 我帶過許多團隊,他們來了又去 他們就是未來的希望,而我也試著叫他們別擔心 不要怕當漫畫中的那隻貓 不敢異想天開
And I'd like to leave you with this thought. On the left is water coming through the shore, taken from a NASA satellite. On the right, there is a coral. Now if you take the mammary gland and spread it and take the fat away, on a dish it looks like that. Do they look the same? Do they have the same patterns? Why is it that nature keeps doing that over and over again?
我想留給各位這個問題 左邊是海流流入海岸的情景 由太空總署的衛星所拍攝 右邊則是一座珊瑚 若你把乳腺取走並展開 把脂肪移除,在培養皿中看起來就像這樣 看起來和之前的一樣嗎?兩者的圖案相同嗎? 為什麼大自然會一再重複這些循環呢?
And I'd like to submit to you that we have sequenced the human genome, we know everything about the sequence of the gene, the language of the gene, the alphabet of the gene, But we know nothing, but nothing, about the language and alphabet of form. So, it's a wonderful new horizon, it's a wonderful thing to discover for the young and the passionate old, and that's me.
我想向各位報告 我們列出了人類的基因組 我們知道所有跟基因組有關的事 基因的語言,字母.... 但我們對形態的語言以及字母 卻是一無所知 這一切都是條美好的地平線 探索對於年輕人來說是件美好的事 對熱情的老年人也是如此,而那就是我
So go to it!
去吧!
(Applause)
(掌聲)