with an interest in cancer and in chemistry.

10年前我從芝加哥搬到波士頓，

You might know that chemistry is the science of making molecules

對癌症和化學滿懷興趣。

or, to my taste,

化學是一項製造分子的科學＝

new drugs for cancer.

或者對我而言，對抗癌症的新興藥劑。

And you might also know that, for science and medicine,

對於科學與醫藥行業而言，

Boston is a bit of a candy store.

波士頓好比是一個糖果店。

You can't roll a stop sign in Cambridge without hitting a graduate student.

在Cambridge你到處都能

The bar is called the Miracle of Science.

碰到研究所的學生。

The billboards say "Lab Space Available."

酒吧的名字叫做科學的奇蹟。

And it's fair to say that in these 10 years,

看板上寫著“實驗室開放”。

we've witnessed absolutely the start of a scientific revolution --

可以很肯定地說在這10年中

that of genome medicine.

我們已經目睹了

We know more about the patients that enter our clinic now

一場基因藥物革命的開始。

than ever before.

我們對現在來到診所的病患的瞭解

And we're able, finally, to answer the question

比從前任何時候都更多更詳細。

that's been so pressing for so many years:

我們終於可以回答

Why do I have cancer?

這個多年來的疑問：

This information is also pretty staggering.

為甚麼我會患癌症？

You might know that, so far, in just the dawn of this revolution,

這信息本身也是非常令人震驚。

we know that there are perhaps 40,000 unique mutations

你也許知道，

affecting more than 10,000 genes,

這場革命只是剛剛開始，

and that there are 500 of these genes that are bona-fide drivers,

我們瞭解到有大約4萬個獨特的異變

causes of cancer.

影響超過1萬個基因，

Yet comparatively,

其中有500個基因

we have about a dozen targeted medications.

是引發癌症的

And this inadequacy of cancer medicine

元兇和原因。

really hit home when my father was diagnosed with pancreatic cancer.

然而相比較下

We didn't fly him to Boston.

我們只有大約十來種標靶藥物。

We didn't sequence his genome.

癌症藥物稀缺的情況也出現在

It's been known for decades what causes this malignancy.

我的家庭，那時我的父親被

It's three proteins: ras, myc, p53.

診斷為胰腺癌。

This is old information we've known since about the 80s,

我們沒有帶他來到波士頓。

yet there's no medicine I can prescribe

也沒有為他進行基因組測序。

to a patient with this or any of the numerous solid tumors

導致這個惡性腫瘤的原因

caused by these three ...

數十年前就已明瞭。

Horsemen of the Apocalypse that is cancer.

就是這三個蛋白質

There's no ras, no myc, no p53 drug.

Ras, MIC和P53.

And you might fairly ask: Why is that?

這是自80年代起我們就知道的信息。

And the very unsatisfying yet scientific answer is:

即使是這樣我也不能

it's too hard.

為一位患上這種或者許多其他種

That for whatever reason,

由這三個癌症的誘因

these three proteins have entered a space, in the language of our field,

而發生的固態腫瘤的

that's called the undruggable genome --

病人開出藥方。

which is like calling a computer unsurfable

針對Ras, MIC, P53的藥並不存在。

or the Moon unwalkable.

你可能會質疑：為甚麼沒有呢？

It's a horrible term of trade.

儘管這樣的答案可能令人失望，但是卻是事實：

But what it means

太難了。

is that we've failed to identify a greasy pocket in these proteins,

由於某些原因，

into which we, like molecular locksmiths,

這些蛋白質，用行業術語來描述，

can fashion an active, small, organic molecule or drug substance.

就是無藥可醫的基因--

Now, as I was training in clinical medicine

就像一台電腦無法上網

and hematology and oncology and stem-cell transplantation,

或者不能登陸的月球。

what we had instead,

這是非常糟糕的贸易條件。

cascading through the regulatory network at the FDA,

我的意思是

were these substances:

在這些蛋白質中很難找到那個小孔，

arsenic,

好讓我們這些分子世界里的鎖匠

thalidomide,

能製作出一個小巧的有機分子

and this chemical derivative of nitrogen mustard gas.

或者是藥物。

And this is the 21st century.

當我在接受臨床醫學，

And so, I guess you'd say,

血液學，腫瘤學

dissatisfied with the performance and quality of these medicines,

和干細胞移植的培訓時,

I went back to school, in chemistry,

我們反而有的是，

with the idea that perhaps by learning the trade of discovery chemistry

食品藥品管理局地管理網絡上充斥著的

and approaching it in the context of this brave new world

是這些成份--

of the open source,

砷，鎮靜劑,

the crowd source,

還有氮介子氣

the collaborative network that we have access to within academia,

的化學衍生物。

that we might more quickly bring powerful and targeted therapies

現在這是21世紀。

to our patients.

所以我想大家一定對這些

And so, please consider this a work in progress,

藥物的療效和質量並不滿意。

but I'd like to tell you today a story

我帶著這個想法

about a very rare cancer called midline carcinoma,

回到學校研究化學。

about the undruggable protein target that causes this cancer,

想著或許在這開源與

called BRD4,

外包的新世界中

and about a molecule developed at my lab at Dana-Farber Cancer Institute,

做發現性的

called JQ1,

化學研究。

which we affectionately named for Jun Qi,

在學院所有的合作性網絡中，

the chemist that made this molecule.

我們或許可以

Now, BRD4 is an interesting protein.

更快地把強力的標靶

You might ask: with all the things cancer's trying to do to kill our patient,

療法帶給病患者。

how does it remember it's cancer?

這是一個還在進行中的作業，

When it winds up its genome,

我想向大家講述一個故事，

divides into two cells and unwinds again,

是關於一種很稀有的癌症

why does it not turn into an eye, into a liver,

稱為中線癌，

as it has all the genes necessary to do this?

也是關於一個蛋白質目標，

It remembers that it's cancer.

導致癌症的無藥可醫的蛋白質目標，

And the reason is that cancer, like every cell in the body,

稱為BRD4,

places little molecular bookmarks,

還有一個分子

little Post-it notes,

由我在Dana Farber癌症研究院的實驗室開發

that remind the cell, "I'm cancer; I should keep growing."

稱為JQ1,被我們親切地用Jun Qi的名字來命名，

And those Post-it notes involve this and other proteins of its class --

他是製造出這個分子的化學家。

so-called bromodomains.

BRD4是一個有趣的蛋白質。

So we developed an idea, a rationale,

你可能會好奇，癌症竭盡所能地殺死病患，

that perhaps if we made a molecule

它自己怎麼記得自己是癌細胞？

that prevented the Post-it note from sticking

當它收起自己的基因組

by entering into the little pocket

分裂成2個細胞再鬆開，

at the base of this spinning protein,

為甚麼它沒有變成一隻眼或者是一個肝臟，

then maybe we could convince cancer cells,

儘管它所擁有的基因完全可以做到這些？

certainly those addicted to this BRD4 protein,

它仍然記得自己是癌細胞。

that they're not cancer.

其原因就是癌細胞就好像身體里的其他細胞

And so we started to work on this problem.

有一個小小的分子書簽，

We developed libraries of compounds

一個小便條，

and eventually arrived at this and similar substances

提醒它自己「 我是癌細胞，我應該繼續生長。」

called JQ1.

這些便條

Now, not being a drug company,

包含它自己還有其他相同種類--

we could do certain things, we had certain flexibilities,

被稱為Bromodomains的蛋白質。

that I respect that a pharmaceutical industry doesn't have.

我們得出了一個想法，

We just started mailing it to our friends.

如果我們製造一個分子

I have a small lab.

通過進入這個蛋白質底部

We thought we'd just send it to people and see how the molecule behaves.

的小口袋中，來防止

We sent it to Oxford, England,

這些便條黏在上面,

where a group of talented crystallographers provided this picture,

這樣也許我們就可以告訴這些癌細胞

which helped us understand exactly how this molecule is so potent

它們不是癌。特別是那些嗜BRD4

for this protein target.

蛋白質的細胞。

It's what we call a perfect fit of shape complementarity,

我們對這個問題展開工作，

or hand in glove.

研製了各式各樣的成份

Now, this is a very rare cancer,

最終得到了這種物質

this BRD4-addicted cancer.

叫做JQ1。

And so we worked with samples of material

我們並不是一家醫藥公司，

that were collected by young pathologists at Brigham and Women's Hospital.

所以有一些事情我們可以做，我們有這樣的自由度，

And as we treated these cells with this molecule,

這是醫藥企業所沒有的。

we observed something really striking.

我們開始把樣本郵寄給朋友們。

The cancer cells --

我自己有一個小的實驗室。

small, round and rapidly dividing,

我們想把這個樣本寄給別人來觀察這個分子表現如何。

grew these arms and extensions.

我們寄了一份給英國牛津的

They were changing shape.

一群才華橫溢的結晶學家提供了這幅圖片，

In effect,

幫助我們瞭解了

the cancer cell was forgetting it was cancer

這個分子為何對這個蛋白質目標如此有效。

and becoming a normal cell.

我們稱之為完美的

This got us very excited.

形狀互補，非常緊密。

The next step would be to put this molecule into mice.

這是一種非常罕見的癌症。

The only problem was there's no mouse model of this rare cancer.

這個嗜BRD4的癌症。

And so at the time we were doing this research,

我們對從Brigham女性醫院

I was caring for a 29-year-old firefighter from Connecticut

年輕的病理學家採集的樣本展開研究。

who was very much at the end of life

當我們用這個分子來對付這些細胞

with this incurable cancer.

我們觀察到了一些非常驚人的現象。

This BRD4-addicted cancer was growing throughout his left lung.

這些癌細胞,

And he had a chest tube in that was draining little bits of debris.

這些小小的，圓形並快速的分裂著的癌細胞

And every nursing shift, we would throw this material out.

長出了「 手臂 」和其他延伸。

And so we approached this patient

它們改變了形狀。

and asked if he would collaborate with us.

實際上，這些癌細胞

Could we take this precious and rare cancerous material

正忘記了自己是癌症,

from this chest tube

並且變回了正常細胞。

and drive it across town and put it into mice

這令我們感到非常興奮。

and try to do a clinical trial at a stage that with a prototype drug,

下一步就是把這個分子應用在小白鼠身上。

well, that would be, of course, impossible

問題是老鼠是沒有這種這種癌症的。

and, rightly, illegal to do in humans.

在我們進行此項研究的同時，

And he obliged us.

我正在照看一個從康涅狄格州來的29歲的消防員,

At the Lurie Family Center for Animal Imaging,

他患了這種無藥可醫的癌症，

our colleague, Andrew Kung, grew this cancer successfully in mice

幾乎已處在在生命的終點。

without ever touching plastic.

這個BRD4成癮的癌症

And you can see this PET scan of a mouse -- what we call a pet PET.

在他左邊的肺部生長，

The cancer is growing

在他的胸腔處有一個導管抽取碎屑。

as this red, huge mass in the hind limb of this animal.

每一次護理換班,

And as we treat it with our compound,

這些物質都會被清理掉。

this addiction to sugar,

因此我們接觸這位病患

this rapid growth, faded.

詢問他是否願意與我們合作。

And on the animal on the right,

能不能從他胸口的導管中獲得這珍貴

you see that the cancer was responding.

而稀有的癌症物質。

We've completed, now, clinical trials

然後運送到我們的實驗室植入小白鼠體內

in four mouse models of this disease.

使用一種試驗藥物

And every time, we see the same thing.

來做一個臨床試驗。

The mice with this cancer that get the drug live,

因為在人身上這樣做的話這是非法的。

and the ones that don't rapidly perish.

他答應了我們。

So we started to wonder,

在Lurie家庭中心的動物照影部門，

what would a drug company do at this point?

我的同事Andrew Kung連培養皿都不需要使用就成功地在

Well, they probably would keep this a secret

小白鼠身上培育出了這種癌症。

until they turn the prototype drug

這邊有一幅對小白鼠做的陽電子掃描，我們稱為pet PET(pet意為‘寵物’)。

into an active pharmaceutical substance.

這癌症在小動物的

So we did just the opposite.

後肢這邊生長出紅色的一大塊。

We published a paper that described this finding

在使用我們研製的成份處理過後，

at the earliest prototype stage.

這種對「 糖」的嗜好,

We gave the world the chemical identity of this molecule,

這種快速的生長，逐漸消失。

typically a secret in our discipline.

而在右邊的小動物，

We told people exactly how to make it.

大家可以看到癌細胞對此產生反應。

We gave them our email address,

我們已經在四隻小白鼠

suggesting that if they write us,

身上進行了這種疾病的臨床測試。

we'll send them a free molecule.

每次都得到相同的結果。

(Laughter)

使用這種藥物的小白鼠存活了下來，

We basically tried to create the most competitive environment

沒有使用此藥物的則很快就死亡了。

for our lab as possible.

我們就開始猜想，

And this was, unfortunately, successful.

這種情況下如果是一家醫藥公司會怎麼做？

(Laughter)

他們大概會將這個發現列為機密

Because now, we've shared this molecule,

直到把這種試驗藥物做成

just since December of last year,

一種熱銷的藥品。

with 40 laboratories in the United States

我們反其道而行，

and 30 more in Europe --

發表了一篇論文。

many of them pharmaceutical companies,

在最早的樣品階段

seeking now to enter this space,

講述這個發現。

to target this rare cancer that, thankfully right now,

我們公佈了這個分子的化學名稱，

is quite desirable to study in that industry.

按規定通常這都應該屬於機密。

But the science that's coming back from all of these laboratories

我們告訴人們怎麼製造它。

about the use of this molecule

也附上了我們的電郵，

has provided us insights we might not have had on our own.

如果有人寫信給我們，

Leukemia cells treated with this compound

我們可以免費贈送一份分子的樣本。

turn into normal white blood cells.

基本上我們是在為自己的實驗室

Mice with multiple myeloma,

嘗試創造一個競爭激烈的環境。

an incurable malignancy of the bone marrow,

不幸的是，我們成功地做到了。

respond dramatically

（笑聲）

to the treatment with this drug.

自去年12月以來

You might know that fat has memory.

我們與美國40所實驗室

I'll nicely demonstrate that for you.

分享了這個分子。

(Laughter)

還有歐洲的30家

In fact, this molecule

許多藥廠也參與進來

prevents this adipocyte, this fat stem cell,

研究這種

from remembering how to make fat,

罕見的癌症。

such that mice on a high-fat diet,

令人欣慰的是這個課題

like the folks in my hometown of Chicago --

已經在行業裡變得熱門起來。

(Laughter)

從收到我們發送的分子的其他實驗室

fail to develop fatty liver,

得來的反饋，

which is a major medical problem.

給我們帶來了一些

What this research taught us --

我們原先並沒有的認知。

not just my lab, but our institute,

使用這種分子治理的血癌細胞

and Harvard Medical School more generally --

變回了普通的白細胞。

is that we have unique resources in academia

有多重骨髓瘤的老鼠，

for drug discovery;

一種生長在骨髓中無藥可醫的惡性腫瘤，

that our center, which has tested perhaps more cancer molecules

對這種藥物的治療

in a scientific way

產生了極大的反應。

than any other,

你可能知道脂肪細胞也有記憶，

never made one of its own.

很高興可以親身為你們說明。

For all the reasons you see listed here,

實際上這個分子

we think there's a great opportunity for academic centers

能防止脂肪干細胞

to participate in this earliest, conceptually tricky

記住如何製造脂肪。

and creative discipline

即使給予小白鼠高脂肪的飲食,

of prototype drug discovery.

好像在芝加哥的人們那樣，

So what next?

它也沒有產生脂肪肝。

We have this molecule, but it's not a pill yet.

脂肪肝是一個重大的醫療課題。

It's not orally bioavailable.

這研究向我們展示的是--

We need to fix it so we can deliver it to our patients.

不僅是我的實驗室，還有我們的研究所，

And everyone in the lab,

哈佛醫學院－

especially following the interaction with these patients,

我們在學術界有獨特的

feels quite compelled to deliver a drug substance

醫藥開發資源--

based on this molecule.

我們的實驗中心

It's here where I'd say

或許已經科學地測試了比其他任何地方

that we could use your help and your insights,

更多的抗癌分子，

your collaborative participation.

從來沒有自己製造藥物。

Unlike a drug company, we don't have a pipeline

因為所有這些提到的理由，

that we can deposit these molecules into.

我們覺得這對學術中心來講是一個非常好的機會

We don't have a team of salespeople and marketeers

來參與到這最早期的

to tell us how to position this drug against the other.

充滿挑戰與創造性的

What we do have is the flexibility of an academic center

樣品藥物開發階段。

to work with competent, motivated,

然後呢？

enthusiastic, hopefully well-funded people

我們有了這個分子，但它還不是一片藥丸。

to carry these molecules forward into the clinic

不能口服。

while preserving our ability to share the prototype drug worldwide.