Mina Bissell: Experiments that point to a new understanding of cancer

103,102 views ・ 2012-07-16

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00:00
Translator: Morton Bast Reviewer: Thu-Huong Ha
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譯者: Vivian Mig 審譯者: Yuguo Zhang
00:15
Now, I don't usually like cartoons,
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平常我不怎麼喜歡連環漫畫
00:18
I don't think many of them are funny,
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我覺得大部分的連環漫畫都很無趣
00:20
I find them weird. But I love this cartoon from the New Yorker.
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我覺得它們頗怪的,但我很愛紐約人報紙上的漫畫
00:26
(Text: Never, ever think outside the box.) (Laughter)
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(內文:永遠不要往外想)
00:28
So, the guy is telling the cat,
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這個傢伙正告訴他的貓
00:31
don't you dare think outside the box.
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別妄想跑到你的箱子外面
00:36
Well, I'm afraid I used to be the cat.
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但是,恐怕我曾是那隻貓
00:39
I always wanted to be outside the box.
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我總是喜歡待在箱子以外的地方
00:42
And it's partly because I came to this field
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而這或許是因為,在我投身這個領域前
00:46
from a different background, chemist and a bacterial geneticist.
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我是個化學家及細菌遺傳學家
00:51
So, what people were saying to me
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因此,當人們跟我談論
00:54
about the cause of cancer, sources of cancer,
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癌症的成因和種類
00:57
or, for that matter, why you are who you are,
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或是我們為何長得這副模樣
01:00
didn't make sense.
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對我來說並沒有意義
01:02
So, let me quickly try and tell you why I thought that
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現在讓我來告訴各位,為什麼我會這麼想
01:05
and how I went about it.
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以及我又是如何處理這些問題
01:08
So, to begin with, however,
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無論如何,
01:10
I have to give you a very, very quick lesson
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首先我必須給各位上一課
01:14
in developmental biology,
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非常簡略的發展生物學
01:16
with apologies to those of you who know some biology.
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並向那些學過生物的人說聲抱歉
01:20
So, when your mom and dad met,
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當你爸媽遇到彼此時
01:23
there is a fertilized egg,
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一個受精卵產生了
01:26
that round thing with that little blip.
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那有個小亮點的圓形物體
01:28
It grows and then it grows,
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它不斷的長呀長
01:31
and then it makes this handsome man.
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最後變成了這位帥氣的男子
01:35
(Applause)
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(掌聲)
01:37
So, this guy, with all the cells in his body,
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這名男子體內所有的細胞
01:42
all have the same genetic information.
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全都擁有同樣的基因成分
01:47
So how did his nose become his nose, his elbow his elbow,
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他的鼻子,手肘是如何長成的?
01:51
and why doesn't he get up one morning
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或某天早上他起床時
01:53
and have his nose turn into his foot?
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為何鼻子沒有忽然變成腳呢?
01:56
It could. It has the genetic information.
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是有可能的,因為它含有足部細胞的成分
01:59
You all remember, dolly,
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各位還記得桃莉羊
02:00
it came from a single mammary cell.
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是由一個乳腺細胞發展而來的吧?
02:03
So, why doesn't it do it?
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鼻子變成腳又怎麼不可能呢?
02:05
So, have a guess of how many cells he has in his body.
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所以我們來猜猜他體內究竟有多少細胞吧
02:10
Somewhere between 10 trillion to 70 trillion cells in his body.
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有界於十兆到七十兆之間個細胞
02:18
Trillion!
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幾兆個細胞耶!
02:19
Now, how did these cells, all with the same genetic material,
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這些擁有相同基因成分的細胞
02:24
make all those tissues?
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是如何形成不同的組織呢?
02:26
And so, the question I raised before
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所以,想到我們體內這些深澳的故事
02:29
becomes even more interesting if you thought about
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我之前的問題會變得更加有趣
02:33
the enormity of this in every one of your bodies.
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我之前的問題會變得更加有趣
02:37
Now, the dominant cancer theory would say
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主流的癌症理論會這麼解釋
02:40
that there is a single oncogene
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一個細胞內的一個致癌基因
02:43
in a single cancer cell, and it would make you
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一個細胞內的一個致癌基因
02:46
a cancer victim.
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會讓你罹患癌症
02:49
Well, this did not make sense to me.
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在我看來這並沒有道理
02:53
Do you even know how a trillion looks?
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你知道"一兆"是什麼樣子嗎?
02:56
Now, let's look at it.
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我們就來看看吧
02:58
There it comes, these zeroes after zeroes after zeroes.
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就像這樣,這些零一個接一個
03:03
Now, if .0001 of these cells got mutated,
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那如果那萬分之一的細胞產生突變,
03:10
and .00001 got cancer, you will be a lump of cancer.
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十萬分之一變成癌細胞,那你會變成一團癌細胞
03:15
You will have cancer all over you. And you're not.
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全身上下無一處無癌症....但這種事並未發生
03:17
Why not?
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為什麼呢?
03:19
So, I decided over the years,
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這些年來我根據一系列的實驗
03:23
because of a series of experiments
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下了一個結論
03:25
that this is because of context and architecture.
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也就是生活環境與結構主控著一切
03:30
And let me quickly tell you
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讓我很快的引用一些重要的實驗
03:32
some crucial experiment that was able to actually show this.
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來向大家解釋
03:36
To begin with, I came to work with this virus
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首先,我研究這種使雞隻長出
03:40
that causes that ugly tumor in the chicken.
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醜陋腫瘤的病毒
03:43
Rous discovered this in 1911.
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勞氏於1911年發現這種病毒
03:47
It was the first cancer virus discovered,
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它是第一個被發現的癌症病毒
03:50
and when I call it "oncogene," meaning "cancer gene."
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我說的"致癌基因"指的是"使人罹癌的基因"
03:55
So, he made a filtrate, he took this filter
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勞斯將雞隻的腫瘤通過濾器
03:58
which was the liquid after he passed the tumor through a filter,
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製造出一種濾液
04:02
and he injected it to another chicken, and he got another tumor.
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並注入另外一隻雞體內,這隻雞同樣也長了腫瘤
04:06
So, scientists were very excited,
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科學家們因此感到非常興奮
04:09
and they said, a single oncogene can do it.
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他們認為只要一個致癌基因便能治癌
04:11
All you need is a single oncogene.
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單一一個致癌基因就夠了
04:14
So, they put the cells in cultures, chicken cells,
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他們將病毒放到雞的細胞上
04:16
dumped the virus on it,
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並開始培養
04:18
and it would pile up,
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接著這些細胞聚集成堆
04:20
and they would say, this is malignant and this is normal.
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然後他們就會評斷哪些是惡性的,哪些是正常的
04:23
And again this didn't make sense to me.
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這些對我來說也一樣沒有意義
04:25
So for various reasons, we took this oncogene,
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所以,基於各種原因
04:28
attached it to a blue marker,
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我們把這個致癌基因染成藍色
04:31
and we injected it into the embryos.
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並注入胚胎中
04:34
Now look at that. There is that beautiful feather in the embryo.
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看看這個,這是一個胚胎長出的羽毛
04:38
Every one of those blue cells are a cancer gene
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每個藍色的癌細胞裡都含有一個致癌基因
04:42
inside a cancer cell, and they're part of the feather.
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它們都是羽毛的一部份
04:46
So, when we dissociated the feather and put it in a dish,
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我們將羽毛取出並放進一個培養皿
04:51
we got a mass of blue cells.
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變成了大量的癌細胞
04:54
So, in the chicken you get a tumor,
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所以,在雞隻身上會長出腫瘤
04:55
in the embryo you don't,
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在胚胎中卻不會
04:57
you dissociate, you put it in a dish, you get another tumor.
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把羽毛分離放進培養皿,又變成一個腫瘤
05:01
What does that mean?
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這代表什麼呢?
05:02
That means that microenvironment
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這代表細胞生長的環境
05:05
and the context which surrounds those cells
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以及圍繞細胞的物質
05:09
actually are telling the cancer gene and the cancer cell what to do.
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在告訴致癌基因和癌細胞要做什麼
05:16
Now, let's take a normal example.
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舉個一般的例子
05:19
The normal example, let's take the human mammary gland.
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我們拿人類的乳腺細胞為例
05:23
I work on breast cancer.
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我研究乳癌
05:24
So, here is a lovely human breast.
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這是一個美麗的人類乳房
05:27
And many of you know how it looks,
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很多人都知道乳房是什麼樣子
05:29
except that inside that breast, there are all these
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但不知道內部那些延伸的美麗樹狀結構
05:32
pretty, developing, tree-like structures.
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但不知道內部那些延伸的美麗樹狀結構
05:35
So, we decided that what we like to do
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我們決定取一點乳腺細胞
05:38
is take just a bit of that mammary gland,
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我們決定取一點乳腺細胞
05:41
which is called an "acinus,"
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也就是"腺胞"
05:43
where there are all these little things inside the breast
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裡面有這些乳房內的微小物質
05:47
where the milk goes, and the end of the nipple
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乳汁流經其中,嬰兒吸吮母乳時
05:50
comes through that little tube when the baby sucks.
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會從末端流出
05:54
And we said, wonderful! Look at this pretty structure.
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我們覺得太棒了! 瞧那美麗的結構
05:57
We want to make this a structure, and ask the question,
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我們想以此做為架構,提出我們的問題
06:01
how do the cells do that?
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乳腺細胞究竟是如何辦到的呢?
06:03
So, we took the red cells --
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所以我們取了紅色的細胞
06:04
you see the red cells are surrounded by blue,
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他們被藍色細胞包圍著
06:08
other cells that squeeze them, and behind it
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其他細胞擠壓著他們,
06:11
is material that people thought was mainly inert,
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更後面是一些無生命物質
06:15
and it was just having a structure to keep the shape,
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它的結構是用來維持內部的形狀
06:18
and so we first photographed it
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多年前我們第一次用電子顯微鏡拍攝
06:21
with the electron microscope years and years ago,
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多年前我們第一次用電子顯微鏡拍攝
06:24
and you see this cell is actually quite pretty.
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你會發現這種細胞其實相當美麗
06:27
It has a bottom, it has a top,
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它有頂部和底部
06:30
it is secreting gobs and gobs of milk,
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不斷分泌大量的奶水
06:32
because it just came from an early pregnant mouse.
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因為這是從一隻剛懷孕的老鼠身上取得的
06:35
You take these cells, you put them in a dish,
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把這些細胞放入培養皿中
06:38
and within three days, they look like that.
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三天內他們便呈現這個樣貌
06:41
They completely forget.
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他們完全失去記憶
06:44
So you take them out, you put them in a dish,
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所以若將他們取出並放入培養皿
06:47
they don't make milk. They completely forget.
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產乳機制就停止了,他們完全忘了工作
06:50
For example, here is a lovely yellow droplet of milk
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舉個例子,左邊有一滴美麗的黃色乳汁
06:55
on the left, there is nothing on the right.
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右邊什麼都沒有
06:57
Look at the nuclei. The nuclei in the cell on the left
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看那細胞核,左邊細胞中的細胞核位於動物體內
07:01
is in the animal, the one on the right is in a dish.
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右邊的則在培養皿中
07:04
They are completely different from each other.
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兩者完全不一樣
07:07
So, what does this tell you?
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這告訴我們什麼呢?
07:09
This tells you that here also, context overrides.
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從這裡也可得知,周遭的環境主宰一切
07:14
In different contexts, cells do different things.
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細胞在不同的環境中會做不同的事
07:17
But how does context signal?
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但環境究竟給了細胞什麼指示呢?
07:20
So, Einstein said that
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愛因斯坦曾說過
07:23
"For an idea that does not first seem insane, there is no hope."
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"一個想法起初若不瘋狂,那之後就沒什麼希望了"
07:29
So, you can imagine the amount of skepticism
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現在你能想像我受到的質疑有多少了吧?
07:35
I received -- couldn't get money,
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我無法籌到經費
07:38
couldn't do a whole lot of other things,
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無法做許多事
07:39
but I'm so glad it all worked out.
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但我很高興一切都解決了
07:41
So, we made a section of the mammary gland of the mouse,
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我們製作了一個老鼠乳腺細胞的切片
07:45
and all those lovely acini are there,
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這些美麗的腺胞都在這兒
07:48
every one of those with the red around them are an acinus,
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每個被紅色物質包圍的都是一個腺胞
07:52
and we said okay, we are going to try and make this,
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很好,現在我們要來試著證明
07:56
and I said, maybe that red stuff
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我就想,也許那些圍繞腺胞的紅色物質藏著訊息
07:59
around the acinus that people think there's just a structural scaffold,
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只是人們認為那只是細胞的一部份結構
08:04
maybe it has information,
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只是人們認為那只是細胞的一部份結構
08:06
maybe it tells the cells what to do, maybe it tells the nucleus what to do.
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或許那些物質告訴細胞和細胞核該做什麼
08:11
So I said, extracellular matrix, which is this stuff
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這些細胞外間質,也就是ECM
08:15
called ECM, signals and actually tells the cells what to do.
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指示並告訴細胞該做什麼
08:20
So, we decided to make things that would look like that.
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所以呢,我們決定像圖上這樣做
08:23
We found some gooey material
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我們找了一些含有所需的胞外間質的黏稠物質
08:26
that had the right extracellular matrix in it,
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我們找了一些含有所需的胞外間質的黏稠物質
08:29
we put the cells in it, and lo and behold,
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將細胞放入其中,觀察了四天左右
08:32
in about four days, they got reorganized
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發現他們重新排列
08:35
and on the right, is what we can make in culture.
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右邊的圖是我們能在培養皿中製造的
08:38
On the left is what's inside the animal, we call it in vivo,
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左邊則是動物體內,也就是活的有機體內的情形
08:42
and the one in culture was full of milk,
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培養中所培養的細胞生產了許多奶水
08:45
the lovely red there is full of milk.
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紅色的部分充滿奶水
08:48
So, we Got Milk, for the American audience.
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這裡的美國觀眾有奶喝了
08:51
All right. And here is this beautiful human cell,
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很好,現在這是一個美麗的人類細胞
08:57
and you can imagine that here also, context goes.
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現在大家可以想像,細胞的周遭物質同樣主導一切
09:02
So, what do we do now?
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接著我們要做什麼呢?
09:04
I made a radical hypothesis.
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我做了一個極端的假設
09:06
I said, if it's true that architecture is dominant,
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如下: 若細胞周圍的物質主宰著細胞的工作
09:13
architecture restored to a cancer cell
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修復癌細胞的胞外物質
09:18
should make the cancer cell think it's normal.
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會讓癌細胞誤以為正常的繼續運作
09:21
Could this be done?
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這有可能發生嗎?
09:22
So, we tried it.
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為此我們做了實驗
09:25
In order to do that, however,
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為了達成我們的目的
09:27
we needed to have a method of distinguishing normal from malignant,
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我們需要有個區別好壞細胞的方法
09:32
and on the left is the single normal cell,
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左邊是一個正常的細胞
09:36
human breast, put in three-dimensional gooey gel
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一個放在含有3D黏稠膠質中的人乳細胞
09:40
that has extracellular matrix, it makes all these beautiful structures.
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黏液中含有胞外間質,這些美麗的結構都是來自於此
09:43
On the right, you see it looks very ugly,
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右邊的卻非常醜陋
09:46
the cells continue to grow,
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這些細胞不斷增長
09:48
the normal ones stop.
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正常的那邊卻停止了
09:49
And you see here in higher magnification
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把圖放的更大來看
09:52
the normal acinus and the ugly tumor.
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兩邊分別是正常的腺胞和醜陋的腫瘤
09:57
So we said, what is on the surface of these ugly tumors?
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我們很好奇腫瘤的表面究竟有什麼?
10:01
Could we calm them down --
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有辦法使這些細胞平靜下來嗎?
10:03
they were signaling like crazy and they have pathways all messed up --
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他們之間的訊號非常雜亂,訊息傳遞的路徑一蹋糊塗
10:08
and make them to the level of the normal?
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如何使他們回歸正軌呢?
10:11
Well, it was wonderful. Boggles my mind.
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這實在太棒了,我感到驚訝不已
10:16
This is what we got.
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這是之後我們所得到的
10:18
We can revert the malignant phenotype.
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我們成功的改正了細胞的惡性顯型
10:22
(Applause)
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(掌聲)
10:24
And in order to show you that the malignant phenotype
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為了讓各位看到細胞的惡性顯型
10:27
I didn't just choose one,
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我準備了另外的東西
10:29
here are little movies, sort of fuzzy,
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這些小型影片,有點模糊
10:32
but you see that on the left are the malignant cells,
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但我們能看到左邊那些是不正常的細胞
10:35
all of them are malignant,
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全部都是惡性的
10:37
we add one single inhibitor in the beginning,
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我們在一開始加入了一個抗化劑
10:42
and look what happens, they all look like that.
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看看會發生什麼事,他們看起來就像這樣
10:45
We inject them into the mouse, the ones on the right,
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我們將之注射到老鼠體內,如同右邊影片顯示
10:48
and none of them would make tumors.
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沒有半個細胞會變成腫瘤
10:51
We inject the other ones in the mouse, 100 percent tumors.
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我們將另一邊注入老鼠體內,腫瘤發生率卻變成100%
10:54
So, it's a new way of thinking about cancer,
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這是對於癌症的一個新觀點
10:57
it's a hopeful way of thinking about cancer.
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也是一個具有希望的新看法
10:59
We should be able to be dealing with these things at this level,
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我們有能力以這樣的水準來處理問題
11:03
and these conclusions say that growth and malignant behavior
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從這些結論得知,細胞的成長與惡性演變
11:09
is regulated at the level of tissue organization
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發生於組織層面
11:13
and that the tissue organization is dependent
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而組織則受到細胞外間質
11:17
on the extracellular matrix and the microenvironment.
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和微小環境的影響
11:21
All right, thus form and function interact dynamically and reciprocally.
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因此,細胞的形態與功能活力的進行互動
11:28
And here is another five seconds of repose,
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現在這五秒鐘是一段沉澱時間
11:33
is my mantra. Form and function.
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我用來沉澱心情的禱文: 形態與功能
11:37
And of course, we now ask, where do we go now?
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現在各位當然很好奇,接下來我們該如何發展呢?
11:41
We'd like to take this kind of thinking into the clinic.
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我們想把這個想法放進臨床治療中
11:44
But before we do that, I'd like you to think
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在那之前,請各位想想
11:48
that at any given time when you're sitting there,
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任何一個時刻,當你坐在那邊時
11:51
in your 70 trillion cells,
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你體內的七十兆個細胞
11:54
the extracellular matrix signaling to your nucleus,
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胞外間質傳遞訊息給細胞核
11:58
the nucleus is signaling to your extracellular matrix
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細胞核也傳遞訊息給胞外間質
12:01
and this is how your balance is kept and restored.
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因此你體內維持著這樣的平衡
12:07
We have made a lot of discoveries,
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我們發現許多東西
12:09
we have shown that extracellular matrix talks to chromatin.
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我們呈現了細胞外的母體與染色質的對話
12:12
We have shown that there's little pieces of DNA
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我們展示了乳腺細胞特定的某個基因中,有一小部份的
12:15
on the specific genes of the mammary gland
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DNA會對細胞外間質產生回應
12:19
that actually respond to extracellular matrix.
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DNA會對細胞外間質產生回應
12:22
It has taken many years, but it has been very rewarding.
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研究雖然花了許多年的時間,但卻收穫滿滿
12:26
And before I get to the next slide, I have to tell you
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在跳到下張投影片之前,我必須告訴各位
12:30
that there are so many additional discoveries to be made.
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還有許多未知的探索等待進行
12:35
There is so much mystery we don't know.
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仍有太多秘密是我們尚未了解的
12:38
And I always say to the students and post-docs I lecture to,
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我常告訴我的學生和博士後研究員
12:42
don't be arrogant, because arrogance kills curiosity.
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千萬別傲慢,因為傲慢會扼殺對探索的好奇心
12:48
Curiosity and passion.
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以及熱情
12:50
You need to always think, what else needs to be discovered?
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時時刻刻,你都必須想著還有什麼事情等待發掘?
12:54
And maybe my discovery needs to be added to
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或許我的發現需要更多補充
12:57
or maybe it needs to be changed.
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或是經過修改
12:59
So, we have now made an amazing discovery,
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現在我們有了這項驚人的發現
13:02
a post-doc in the lab who is a physicist asked me,
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實驗室裡的一個博士後研究員兼物理學家,問我
13:05
what do the cells do when you put them in?
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當你把細胞放入時他們發生了什麼事?
13:07
What do they do in the beginning when they do?
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一開始他們產生什麼變化?
13:11
I said, I don't know, we couldn't look at them.
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我說我不曉得,我們無從觀察
13:12
We didn't have high images in the old days.
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早期我們還沒有高品質影像
13:15
So she, being an imager and a physicist,
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這名學生呢,既是一個夢想家和物理學家
13:18
did this incredible thing.
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她做了這件驚人的設計
13:19
This is a single human breast cell in three dimensions.
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這是一個以3D影像顯示的人乳細胞
13:24
Look at it. It's constantly doing this.
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你看,它不斷的重複這個循環
13:26
Has a coherent movement.
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有一個一致的動作
13:28
You put the cancer cells there, and they do go all over,
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若換成癌細胞,它們就全亂掉了
13:33
they do this. They don't do this.
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而不是規律的運作
13:35
And when we revert the cancer cell, it again does this.
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當我們把癌細胞修復後,它又重回正軌
13:39
Absolutely boggles my mind.
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完全令我驚訝不已
13:41
So the cell acts like an embryo. What an exciting thing.
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所以細胞的活動就像胚胎,這是多麼令人興奮的事啊
13:46
So I'd like to finish with a poem.
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我想以一首詩來做結
13:49
Well I used to love English literature,
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我以前很熱愛英國文學
13:52
and I debated in college, which one should I do?
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大學時我猶豫主修該選什麼?
13:55
And unfortunately or fortunately, chemistry won.
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不幸的或是幸運的,化學獲得了勝利
13:59
But here is a poem from Yeats. I'll just read you the last two lines.
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但這邊有首葉慈的詩,我想為各位朗誦最後兩行
14:05
It's called "Among the School Children."
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詩名是"兒戲"
14:08
"O body swayed to music / O brightening glance /
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"噢 身體隨著音樂起舞/噢 閃爍生輝的一瞥"
14:12
How [can we know] the dancer from the dance?"
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我們如何在舞蹈中找到舞者呢?
14:15
And here is Merce Cunningham,
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這位是摩斯康寧漢
14:17
I was fortunate to dance with him when I was younger,
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我年輕時有幸和他一起跳舞
14:20
and here he is a dancer,
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這裡的他是一名舞者
14:22
and while he is dancing, he is both the dancer and the dance.
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當他在跳舞的時候,他既是舞者也是舞蹈本身
14:26
The minute he stops, we have neither.
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在他停止的那刻,我們兩者都沒有了
14:29
So it's like form and function.
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這就像形態與功能
14:33
Now, I'd like to show you a current picture of my group.
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現在我想給各位看看我的研究團隊
14:39
I have been fortunate to have had these magnificant
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我很榮幸有這些了不起的學生
14:42
students and post-docs who have taught me so much,
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和博士後研究員,從他們身上我學到很多
14:45
and I have had many of these groups come and go.
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我帶過許多團隊,他們來了又去
14:49
They are the future and I try to make them not be afraid
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他們就是未來的希望,而我也試著叫他們別擔心
14:53
of being the cat and being told,
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不要怕當漫畫中的那隻貓
14:57
don't think outside the box.
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不敢異想天開
14:59
And I'd like to leave you with this thought.
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我想留給各位這個問題
15:01
On the left is water coming through the shore,
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左邊是海流流入海岸的情景
15:06
taken from a NASA satellite.
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由太空總署的衛星所拍攝
15:08
On the right, there is a coral.
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右邊則是一座珊瑚
15:11
Now if you take the mammary gland and spread it
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若你把乳腺取走並展開
15:15
and take the fat away, on a dish it looks like that.
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把脂肪移除,在培養皿中看起來就像這樣
15:18
Do they look the same? Do they have the same patterns?
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看起來和之前的一樣嗎?兩者的圖案相同嗎?
15:21
Why is it that nature keeps doing that over and over again?
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為什麼大自然會一再重複這些循環呢?
15:25
And I'd like to submit to you
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我想向各位報告
15:28
that we have sequenced the human genome,
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我們列出了人類的基因組
15:30
we know everything about the sequence of the gene,
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我們知道所有跟基因組有關的事
15:33
the language of the gene, the alphabet of the gene,
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基因的語言,字母....
15:35
But we know nothing, but nothing,
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但我們對形態的語言以及字母
15:39
about the language and alphabet of form.
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卻是一無所知
15:43
So, it's a wonderful new horizon,
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這一切都是條美好的地平線
15:46
it's a wonderful thing to discover for the young
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探索對於年輕人來說是件美好的事
15:50
and the passionate old, and that's me.
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對熱情的老年人也是如此,而那就是我
15:52
So go to it!
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去吧!
15:55
(Applause)
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(掌聲)
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