Now, I don't usually like cartoons,

平常我不怎麼喜歡連環漫畫

I don't think many of them are funny,

我覺得大部分的連環漫畫都很無趣

I find them weird. But I love this cartoon from the New Yorker.

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,

這個傢伙正告訴他的貓

don't you dare think outside the box.

別妄想跑到你的箱子外面

Well, I'm afraid I used to be the cat.

但是，恐怕我曾是那隻貓

I always wanted to be outside the box.

我總是喜歡待在箱子以外的地方

And it's partly because I came to this field

而這或許是因為，在我投身這個領域前

from a different background, chemist and a bacterial geneticist.

我是個化學家及細菌遺傳學家

So, what people were saying to me

因此，當人們跟我談論

about the cause of cancer, sources of cancer,

癌症的成因和種類

or, for that matter, why you are who you are,

或是我們為何長得這副模樣

didn't make sense.

對我來說並沒有意義

So, let me quickly try and tell you why I thought that

現在讓我來告訴各位，為什麼我會這麼想

and how I went about it.

以及我又是如何處理這些問題

So, to begin with, however,

無論如何，

I have to give you a very, very quick lesson

首先我必須給各位上一課

in developmental biology,

非常簡略的發展生物學

with apologies to those of you who know some biology.

並向那些學過生物的人說聲抱歉

So, when your mom and dad met,

當你爸媽遇到彼此時

there is a fertilized egg,

一個受精卵產生了

that round thing with that little blip.

那有個小亮點的圓形物體

It grows and then it grows,

它不斷的長呀長

and then it makes this handsome man.

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,

這名男子體內所有的細胞

all have the same genetic information.

全都擁有同樣的基因成分

So how did his nose become his nose, his elbow his elbow,

他的鼻子，手肘是如何長成的?

and why doesn't he get up one morning

或某天早上他起床時

and have his nose turn into his foot?

為何鼻子沒有忽然變成腳呢?

It could. It has the genetic information.

是有可能的，因為它含有足部細胞的成分

You all remember, dolly,

各位還記得桃莉羊

it came from a single mammary cell.

是由一個乳腺細胞發展而來的吧?

So, why doesn't it do it?

鼻子變成腳又怎麼不可能呢?

So, have a guess of how many cells he has in his body.

所以我們來猜猜他體內究竟有多少細胞吧

Somewhere between 10 trillion to 70 trillion cells in his body.

有界於十兆到七十兆之間個細胞

Trillion!

幾兆個細胞耶!

Now, how did these cells, all with the same genetic material,

這些擁有相同基因成分的細胞

make all those tissues?

是如何形成不同的組織呢?

And so, the question I raised before

所以，想到我們體內這些深澳的故事

becomes even more interesting if you thought about

我之前的問題會變得更加有趣

the enormity of this in every one of your bodies.

我之前的問題會變得更加有趣

Now, the dominant cancer theory would say

主流的癌症理論會這麼解釋

that there is a single oncogene

一個細胞內的一個致癌基因

in a single cancer cell, and it would make you

一個細胞內的一個致癌基因

a cancer victim.

會讓你罹患癌症

Well, this did not make sense to me.

在我看來這並沒有道理

Do you even know how a trillion looks?

你知道"一兆"是什麼樣子嗎?

Now, let's look at it.

我們就來看看吧

There it comes, these zeroes after zeroes after zeroes.

就像這樣，這些零一個接一個

Now, if .0001 of these cells got mutated,

那如果那萬分之一的細胞產生突變，

and .00001 got cancer, you will be a lump of cancer.

十萬分之一變成癌細胞，那你會變成一團癌細胞

You will have cancer all over you. And you're not.

全身上下無一處無癌症....但這種事並未發生

Why not?

為什麼呢?

So, I decided over the years,

這些年來我根據一系列的實驗

because of a series of experiments

下了一個結論

that this is because of context and architecture.

也就是生活環境與結構主控著一切

And let me quickly tell you

讓我很快的引用一些重要的實驗

some crucial experiment that was able to actually show this.

來向大家解釋

To begin with, I came to work with this virus

首先，我研究這種使雞隻長出

that causes that ugly tumor in the chicken.

醜陋腫瘤的病毒

Rous discovered this in 1911.

勞氏於1911年發現這種病毒

It was the first cancer virus discovered,

它是第一個被發現的癌症病毒

and when I call it "oncogene," meaning "cancer gene."

我說的"致癌基因"指的是"使人罹癌的基因"

So, he made a filtrate, he took this filter

勞斯將雞隻的腫瘤通過濾器

which was the liquid after he passed the tumor through a filter,

製造出一種濾液

and he injected it to another chicken, and he got another tumor.

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,

科學家們因此感到非常興奮

and they said, a single oncogene can do it.

他們認為只要一個致癌基因便能治癌

All you need is a single oncogene.

單一一個致癌基因就夠了

So, they put the cells in cultures, chicken cells,

他們將病毒放到雞的細胞上

dumped the virus on it,

並開始培養

and it would pile up,

接著這些細胞聚集成堆

and they would say, this is malignant and this is normal.

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.

這些對我來說也一樣沒有意義

So for various reasons, we took this oncogene,

所以，基於各種原因

attached it to a blue marker,

我們把這個致癌基因染成藍色

and we injected it into the embryos.

並注入胚胎中

Now look at that. There is that beautiful feather in the embryo.

看看這個，這是一個胚胎長出的羽毛

Every one of those blue cells are a cancer gene

每個藍色的癌細胞裡都含有一個致癌基因

inside a cancer cell, and they're part of the feather.

它們都是羽毛的一部份

So, when we dissociated the feather and put it in a dish,

我們將羽毛取出並放進一個培養皿

we got a mass of blue cells.

變成了大量的癌細胞

So, in the chicken you get a tumor,

所以，在雞隻身上會長出腫瘤

in the embryo you don't,

在胚胎中卻不會

you dissociate, you put it in a dish, you get another tumor.

把羽毛分離放進培養皿，又變成一個腫瘤

What does that mean?

這代表什麼呢?

That means that microenvironment

這代表細胞生長的環境

and the context which surrounds those cells

以及圍繞細胞的物質

actually are telling the cancer gene and the cancer cell what to do.

在告訴致癌基因和癌細胞要做什麼

Now, let's take a normal example.

舉個一般的例子

The normal example, let's take the human mammary gland.

我們拿人類的乳腺細胞為例

I work on breast cancer.

我研究乳癌

So, here is a lovely human breast.

這是一個美麗的人類乳房

And many of you know how it looks,

很多人都知道乳房是什麼樣子

except that inside that breast, there are all these

但不知道內部那些延伸的美麗樹狀結構

pretty, developing, tree-like structures.

但不知道內部那些延伸的美麗樹狀結構

So, we decided that what we like to do

我們決定取一點乳腺細胞

is take just a bit of that mammary gland,

我們決定取一點乳腺細胞

which is called an "acinus,"

也就是"腺胞"

where there are all these little things inside the breast

裡面有這些乳房內的微小物質

where the milk goes, and the end of the nipple

乳汁流經其中，嬰兒吸吮母乳時

comes through that little tube when the baby sucks.

會從末端流出

And we said, wonderful! Look at this pretty structure.

我們覺得太棒了! 瞧那美麗的結構

We want to make this a structure, and ask the question,

我們想以此做為架構，提出我們的問題

how do the cells do that?

乳腺細胞究竟是如何辦到的呢?

So, we took the red cells --

所以我們取了紅色的細胞

you see the red cells are surrounded by blue,

他們被藍色細胞包圍著

other cells that squeeze them, and behind it

其他細胞擠壓著他們，

is material that people thought was mainly inert,

更後面是一些無生命物質

and it was just having a structure to keep the shape,

它的結構是用來維持內部的形狀

and so we first photographed it

多年前我們第一次用電子顯微鏡拍攝

with the electron microscope years and years ago,

多年前我們第一次用電子顯微鏡拍攝

and you see this cell is actually quite pretty.

你會發現這種細胞其實相當美麗

It has a bottom, it has a top,

它有頂部和底部

it is secreting gobs and gobs of milk,

不斷分泌大量的奶水

because it just came from an early pregnant mouse.

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,

把這些細胞放入培養皿中

and within three days, they look like that.

三天內他們便呈現這個樣貌

They completely forget.

他們完全失去記憶

So you take them out, you put them in a dish,

所以若將他們取出並放入培養皿

they don't make milk. They completely forget.

產乳機制就停止了，他們完全忘了工作

For example, here is a lovely yellow droplet of milk

舉個例子，左邊有一滴美麗的黃色乳汁

on the left, there is nothing on the right.

右邊什麼都沒有

Look at the nuclei. The nuclei in the cell on the left

看那細胞核，左邊細胞中的細胞核位於動物體內

is in the animal, the one on the right is in a dish.

右邊的則在培養皿中

They are completely different from each other.

兩者完全不一樣

So, what does this tell you?

這告訴我們什麼呢?

This tells you that here also, context overrides.

從這裡也可得知，周遭的環境主宰一切

In different contexts, cells do different things.

細胞在不同的環境中會做不同的事

But how does context signal?

但環境究竟給了細胞什麼指示呢?

So, Einstein said that

愛因斯坦曾說過

"For an idea that does not first seem insane, there is no hope."

"一個想法起初若不瘋狂，那之後就沒什麼希望了"

So, you can imagine the amount of skepticism

現在你能想像我受到的質疑有多少了吧?

I received -- couldn't get money,

我無法籌到經費

couldn't do a whole lot of other things,

無法做許多事

but I'm so glad it all worked out.

但我很高興一切都解決了

So, we made a section of the mammary gland of the mouse,

我們製作了一個老鼠乳腺細胞的切片

and all those lovely acini are there,

這些美麗的腺胞都在這兒

every one of those with the red around them are an acinus,

每個被紅色物質包圍的都是一個腺胞

and we said okay, we are going to try and make this,

很好，現在我們要來試著證明

and I said, maybe that red stuff

我就想，也許那些圍繞腺胞的紅色物質藏著訊息

around the acinus that people think there's just a structural scaffold,

只是人們認為那只是細胞的一部份結構

maybe it has information,

只是人們認為那只是細胞的一部份結構

maybe it tells the cells what to do, maybe it tells the nucleus what to do.

或許那些物質告訴細胞和細胞核該做什麼

So I said, extracellular matrix, which is this stuff

這些細胞外間質，也就是ECM

called ECM, signals and actually tells the cells what to do.

指示並告訴細胞該做什麼

So, we decided to make things that would look like that.

所以呢，我們決定像圖上這樣做

We found some gooey material

我們找了一些含有所需的胞外間質的黏稠物質

that had the right extracellular matrix in it,

我們找了一些含有所需的胞外間質的黏稠物質

we put the cells in it, and lo and behold,

將細胞放入其中，觀察了四天左右

in about four days, they got reorganized

發現他們重新排列

and on the right, is what we can make in culture.

右邊的圖是我們能在培養皿中製造的

On the left is what's inside the animal, we call it in vivo,

左邊則是動物體內，也就是活的有機體內的情形

and the one in culture was full of milk,

培養中所培養的細胞生產了許多奶水

the lovely red there is full of milk.

紅色的部分充滿奶水

So, we Got Milk, for the American audience.

這裡的美國觀眾有奶喝了

All right. And here is this beautiful human cell,

很好，現在這是一個美麗的人類細胞

and you can imagine that here also, context goes.

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?

接著我們要做什麼呢?

I made a radical hypothesis.

我做了一個極端的假設

I said, if it's true that architecture is dominant,

如下: 若細胞周圍的物質主宰著細胞的工作

architecture restored to a cancer cell

修復癌細胞的胞外物質

should make the cancer cell think it's normal.

會讓癌細胞誤以為正常的繼續運作

Could this be done?

這有可能發生嗎?

So, we tried it.

為此我們做了實驗

In order to do that, however,

為了達成我們的目的

we needed to have a method of distinguishing normal from malignant,

我們需要有個區別好壞細胞的方法

and on the left is the single normal cell,

左邊是一個正常的細胞

human breast, put in three-dimensional gooey gel

一個放在含有3D黏稠膠質中的人乳細胞

that has extracellular matrix, it makes all these beautiful structures.

黏液中含有胞外間質，這些美麗的結構都是來自於此

On the right, you see it looks very ugly,

右邊的卻非常醜陋

the cells continue to grow,

這些細胞不斷增長

the normal ones stop.

正常的那邊卻停止了

And you see here in higher magnification

把圖放的更大來看

the normal acinus and the ugly tumor.

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?

我們很好奇腫瘤的表面究竟有什麼?

Could we calm them down --

有辦法使這些細胞平靜下來嗎?

they were signaling like crazy and they have pathways all messed up --

他們之間的訊號非常雜亂，訊息傳遞的路徑一蹋糊塗

and make them to the level of the normal?

如何使他們回歸正軌呢?

Well, it was wonderful. Boggles my mind.

這實在太棒了，我感到驚訝不已

This is what we got.

這是之後我們所得到的

We can revert the malignant phenotype.

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

為了讓各位看到細胞的惡性顯型

I didn't just choose one,

我準備了另外的東西

here are little movies, sort of fuzzy,

這些小型影片，有點模糊

but you see that on the left are the malignant cells,

但我們能看到左邊那些是不正常的細胞

all of them are malignant,

全部都是惡性的

we add one single inhibitor in the beginning,

我們在一開始加入了一個抗化劑

and look what happens, they all look like that.

看看會發生什麼事，他們看起來就像這樣

We inject them into the mouse, the ones on the right,

我們將之注射到老鼠體內，如同右邊影片顯示

and none of them would make tumors.

沒有半個細胞會變成腫瘤

We inject the other ones in the mouse, 100 percent tumors.

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,

這是對於癌症的一個新觀點

it's a hopeful way of thinking about cancer.

也是一個具有希望的新看法

We should be able to be dealing with these things at this level,

我們有能力以這樣的水準來處理問題

and these conclusions say that growth and malignant behavior

從這些結論得知，細胞的成長與惡性演變

is regulated at the level of tissue organization

發生於組織層面

and that the tissue organization is dependent

而組織則受到細胞外間質

on the extracellular matrix and the microenvironment.

和微小環境的影響

All right, thus form and function interact dynamically and reciprocally.

因此，細胞的形態與功能活力的進行互動

And here is another five seconds of repose,

現在這五秒鐘是一段沉澱時間

is my mantra. Form and function.

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?

現在各位當然很好奇，接下來我們該如何發展呢?

We'd like to take this kind of thinking into the clinic.

我們想把這個想法放進臨床治療中

But before we do that, I'd like you to think

在那之前，請各位想想

that at any given time when you're sitting there,

任何一個時刻，當你坐在那邊時

in your 70 trillion cells,

你體內的七十兆個細胞

the extracellular matrix signaling to your nucleus,

胞外間質傳遞訊息給細胞核

the nucleus is signaling to your extracellular matrix

細胞核也傳遞訊息給胞外間質

and this is how your balance is kept and restored.

因此你體內維持著這樣的平衡

We have made a lot of discoveries,

我們發現許多東西

we have shown that extracellular matrix talks to chromatin.

我們呈現了細胞外的母體與染色質的對話

We have shown that there's little pieces of DNA

我們展示了乳腺細胞特定的某個基因中，有一小部份的

on the specific genes of the mammary gland

DNA會對細胞外間質產生回應

that actually respond to extracellular matrix.

DNA會對細胞外間質產生回應

It has taken many years, but it has been very rewarding.

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

在跳到下張投影片之前，我必須告訴各位

that there are so many additional discoveries to be made.

還有許多未知的探索等待進行

There is so much mystery we don't know.

仍有太多秘密是我們尚未了解的

And I always say to the students and post-docs I lecture to,

我常告訴我的學生和博士後研究員

don't be arrogant, because arrogance kills curiosity.

千萬別傲慢，因為傲慢會扼殺對探索的好奇心

Curiosity and passion.

以及熱情

You need to always think, what else needs to be discovered?

時時刻刻，你都必須想著還有什麼事情等待發掘?

And maybe my discovery needs to be added to

或許我的發現需要更多補充

or maybe it needs to be changed.

或是經過修改

So, we have now made an amazing discovery,

現在我們有了這項驚人的發現

a post-doc in the lab who is a physicist asked me,

實驗室裡的一個博士後研究員兼物理學家，問我

what do the cells do when you put them in?