Jay Bradner: Open-source cancer research

譯者: Boyang Zhu 審譯者: Ana Choi

10年前我從芝加哥搬到波士頓，

I moved to Boston 10 years ago from Chicago,

with an interest in cancer and in chemistry.

對癌症和化學滿懷興趣。

You might know that chemistry is the science of making molecules

化學是一項製造分子的科學＝

or, to my taste,

或者對我而言，對抗癌症的新興藥劑。

new drugs for cancer.

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

碰到研究所的學生。

The bar is called the Miracle of Science.

酒吧的名字叫做科學的奇蹟。

The billboards say "Lab Space Available."

看板上寫著“實驗室開放”。

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

可以很肯定地說在這10年中

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

我們已經目睹了

一場基因藥物革命的開始。

that of genome medicine.

我們對現在來到診所的病患的瞭解

We know more about the patients that enter our clinic now

比從前任何時候都更多更詳細。

than ever before.

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

我們終於可以回答

這個多年來的疑問：

that's been so pressing for so many years:

Why do I have cancer?

為甚麼我會患癌症？

This information is also pretty staggering.

這信息本身也是非常令人震驚。

你也許知道，

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

這場革命只是剛剛開始，

we know that there are perhaps 40,000 unique mutations

我們瞭解到有大約4萬個獨特的異變

影響超過1萬個基因，

affecting more than 10,000 genes,

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

其中有500個基因

是引發癌症的

causes of cancer.

元兇和原因。

然而相比較下

Yet comparatively,

we have about a dozen targeted medications.

我們只有大約十來種標靶藥物。

And this inadequacy of cancer medicine

癌症藥物稀缺的情況也出現在

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

我的家庭，那時我的父親被

診斷為胰腺癌。

我們沒有帶他來到波士頓。

We didn't fly him to Boston.

We didn't sequence his genome.

也沒有為他進行基因組測序。

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

導致這個惡性腫瘤的原因

數十年前就已明瞭。

就是這三個蛋白質

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

Ras, MIC和P53.

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

這是自80年代起我們就知道的信息。

yet there's no medicine I can prescribe

即使是這樣我也不能

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

為一位患上這種或者許多其他種

由這三個癌症的誘因

caused by these three ...

而發生的固態腫瘤的

Horsemen of the Apocalypse that is cancer.

病人開出藥方。

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

針對Ras, MIC, P53的藥並不存在。

And you might fairly ask: Why is that?

你可能會質疑：為甚麼沒有呢？

儘管這樣的答案可能令人失望，但是卻是事實：

And the very unsatisfying yet scientific answer is:

太難了。

it's too hard.

That for whatever reason,

由於某些原因，

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

這些蛋白質，用行業術語來描述，

that's called the undruggable genome --

就是無藥可醫的基因--

which is like calling a computer unsurfable

就像一台電腦無法上網

或者不能登陸的月球。

or the Moon unwalkable.

It's a horrible term of trade.

這是非常糟糕的贸易條件。

But what it means

我的意思是

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

在這些蛋白質中很難找到那個小孔，

好讓我們這些分子世界里的鎖匠

into which we, like molecular locksmiths,

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

能製作出一個小巧的有機分子

或者是藥物。

當我在接受臨床醫學，

Now, as I was training in clinical medicine

血液學，腫瘤學

and hematology and oncology and stem-cell transplantation,

和干細胞移植的培訓時,

what we had instead,

我們反而有的是，

cascading through the regulatory network at the FDA,

食品藥品管理局地管理網絡上充斥著的

是這些成份--

were these substances:

arsenic,

砷，鎮靜劑,

thalidomide,

還有氮介子氣

and this chemical derivative of nitrogen mustard gas.

的化學衍生物。

And this is the 21st century.

現在這是21世紀。

And so, I guess you'd say,

所以我想大家一定對這些

dissatisfied with the performance and quality of these medicines,

藥物的療效和質量並不滿意。

I went back to school, in chemistry,

我帶著這個想法

回到學校研究化學。

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

想著或許在這開源與

and approaching it in the context of this brave new world

外包的新世界中

of the open source,

做發現性的

化學研究。

the crowd source,

the collaborative network that we have access to within academia,

在學院所有的合作性網絡中，

that we might more quickly bring powerful and targeted therapies

我們或許可以

更快地把強力的標靶

療法帶給病患者。

to our patients.

And so, please consider this a work in progress,

這是一個還在進行中的作業，

我想向大家講述一個故事，

but I'd like to tell you today a story

是關於一種很稀有的癌症

about a very rare cancer called midline carcinoma,

稱為中線癌，

也是關於一個蛋白質目標，

about the undruggable protein target that causes this cancer,

導致癌症的無藥可醫的蛋白質目標，

稱為BRD4,

called BRD4,

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

還有一個分子

由我在Dana Farber癌症研究院的實驗室開發

called JQ1,

稱為JQ1,被我們親切地用Jun Qi的名字來命名，

which we affectionately named for Jun Qi,

他是製造出這個分子的化學家。

the chemist that made this molecule.

Now, BRD4 is an interesting protein.

BRD4是一個有趣的蛋白質。

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

你可能會好奇，癌症竭盡所能地殺死病患，

它自己怎麼記得自己是癌細胞？

how does it remember it's cancer?

當它收起自己的基因組

When it winds up its genome,

divides into two cells and unwinds again,

分裂成2個細胞再鬆開，

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

為甚麼它沒有變成一隻眼或者是一個肝臟，

儘管它所擁有的基因完全可以做到這些？

as it has all the genes necessary to do this?

It remembers that it's cancer.

它仍然記得自己是癌細胞。

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

其原因就是癌細胞就好像身體里的其他細胞

有一個小小的分子書簽，

places little molecular bookmarks,

一個小便條，

little Post-it notes,

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

提醒它自己「 我是癌細胞，我應該繼續生長。」

這些便條

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

包含它自己還有其他相同種類--

被稱為Bromodomains的蛋白質。

so-called bromodomains.

So we developed an idea, a rationale,

我們得出了一個想法，

that perhaps if we made a molecule

如果我們製造一個分子

that prevented the Post-it note from sticking

通過進入這個蛋白質底部

的小口袋中，來防止

by entering into the little pocket

at the base of this spinning protein,

這些便條黏在上面,

then maybe we could convince cancer cells,

這樣也許我們就可以告訴這些癌細胞

certainly those addicted to this BRD4 protein,

它們不是癌。特別是那些嗜BRD4

that they're not cancer.

蛋白質的細胞。

And so we started to work on this problem.

我們對這個問題展開工作，

We developed libraries of compounds

研製了各式各樣的成份

最終得到了這種物質

and eventually arrived at this and similar substances

叫做JQ1。

called JQ1.

Now, not being a drug company,

我們並不是一家醫藥公司，

we could do certain things, we had certain flexibilities,

所以有一些事情我們可以做，我們有這樣的自由度，

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

這是醫藥企業所沒有的。

We just started mailing it to our friends.

我們開始把樣本郵寄給朋友們。

我自己有一個小的實驗室。

I have a small lab.

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

我們想把這個樣本寄給別人來觀察這個分子表現如何。

我們寄了一份給英國牛津的

We sent it to Oxford, England,

一群才華橫溢的結晶學家提供了這幅圖片，

where a group of talented crystallographers provided this picture,

幫助我們瞭解了

which helped us understand exactly how this molecule is so potent

這個分子為何對這個蛋白質目標如此有效。

for this protein target.

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

我們稱之為完美的

形狀互補，非常緊密。

or hand in glove.

這是一種非常罕見的癌症。

Now, this is a very rare cancer,

這個嗜BRD4的癌症。

this BRD4-addicted cancer.

我們對從Brigham女性醫院

And so we worked with samples of material

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

年輕的病理學家採集的樣本展開研究。

當我們用這個分子來對付這些細胞

And as we treated these cells with this molecule,

we observed something really striking.

我們觀察到了一些非常驚人的現象。

這些癌細胞,

The cancer cells --

small, round and rapidly dividing,

這些小小的，圓形並快速的分裂著的癌細胞

grew these arms and extensions.

長出了「 手臂 」和其他延伸。

They were changing shape.

它們改變了形狀。

In effect,

實際上，這些癌細胞

the cancer cell was forgetting it was cancer

正忘記了自己是癌症,

並且變回了正常細胞。

and becoming a normal cell.

這令我們感到非常興奮。

This got us very excited.

下一步就是把這個分子應用在小白鼠身上。

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

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

問題是老鼠是沒有這種這種癌症的。

在我們進行此項研究的同時，

And so at the time we were doing this research,

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

我正在照看一個從康涅狄格州來的29歲的消防員,

他患了這種無藥可醫的癌症，

who was very much at the end of life

with this incurable cancer.

幾乎已處在在生命的終點。

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

這個BRD4成癮的癌症

在他左邊的肺部生長，

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

在他的胸腔處有一個導管抽取碎屑。

每一次護理換班,

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

這些物質都會被清理掉。

And so we approached this patient

因此我們接觸這位病患

and asked if he would collaborate with us.

詢問他是否願意與我們合作。

Could we take this precious and rare cancerous material

能不能從他胸口的導管中獲得這珍貴

from this chest tube

而稀有的癌症物質。

and drive it across town and put it into mice

然後運送到我們的實驗室植入小白鼠體內

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

使用一種試驗藥物

來做一個臨床試驗。

well, that would be, of course, impossible

因為在人身上這樣做的話這是非法的。

and, rightly, illegal to do in humans.

他答應了我們。

And he obliged us.

At the Lurie Family Center for Animal Imaging,

在Lurie家庭中心的動物照影部門，

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

我的同事Andrew Kung連培養皿都不需要使用就成功地在

小白鼠身上培育出了這種癌症。

without ever touching plastic.

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

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’)。

這癌症在小動物的

The cancer is growing

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

後肢這邊生長出紅色的一大塊。

在使用我們研製的成份處理過後，

And as we treat it with our compound,

這種對「 糖」的嗜好,

this addiction to sugar,

這種快速的生長，逐漸消失。

this rapid growth, faded.

And on the animal on the right,

而在右邊的小動物，

you see that the cancer was responding.

大家可以看到癌細胞對此產生反應。

We've completed, now, clinical trials

我們已經在四隻小白鼠

身上進行了這種疾病的臨床測試。

in four mouse models of this disease.

每次都得到相同的結果。

And every time, we see the same thing.

The mice with this cancer that get the drug live,

使用這種藥物的小白鼠存活了下來，

沒有使用此藥物的則很快就死亡了。

and the ones that don't rapidly perish.

我們就開始猜想，

So we started to wonder,

what would a drug company do at this point?

這種情況下如果是一家醫藥公司會怎麼做？

Well, they probably would keep this a secret

他們大概會將這個發現列為機密

until they turn the prototype drug

直到把這種試驗藥物做成

into an active pharmaceutical substance.

一種熱銷的藥品。

我們反其道而行，

So we did just the opposite.

發表了一篇論文。

We published a paper that described this finding

在最早的樣品階段

at the earliest prototype stage.

講述這個發現。

We gave the world the chemical identity of this molecule,

我們公佈了這個分子的化學名稱，

typically a secret in our discipline.

按規定通常這都應該屬於機密。

We told people exactly how to make it.

我們告訴人們怎麼製造它。

也附上了我們的電郵，

We gave them our email address,

suggesting that if they write us,

如果有人寫信給我們，

we'll send them a free molecule.

我們可以免費贈送一份分子的樣本。

(Laughter)

基本上我們是在為自己的實驗室

We basically tried to create the most competitive environment

嘗試創造一個競爭激烈的環境。

for our lab as possible.

不幸的是，我們成功地做到了。

And this was, unfortunately, successful.

（笑聲）

(Laughter)

Because now, we've shared this molecule,

自去年12月以來

just since December of last year,

我們與美國40所實驗室

with 40 laboratories in the United States

分享了這個分子。

還有歐洲的30家

and 30 more in Europe --

許多藥廠也參與進來

many of them pharmaceutical companies,

seeking now to enter this space,

研究這種

to target this rare cancer that, thankfully right now,

罕見的癌症。

令人欣慰的是這個課題

is quite desirable to study in that industry.

已經在行業裡變得熱門起來。

從收到我們發送的分子的其他實驗室

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

得來的反饋，

about the use of this molecule

給我們帶來了一些

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

我們原先並沒有的認知。

Leukemia cells treated with this compound

使用這種分子治理的血癌細胞

turn into normal white blood cells.

變回了普通的白細胞。

Mice with multiple myeloma,

有多重骨髓瘤的老鼠，

an incurable malignancy of the bone marrow,

一種生長在骨髓中無藥可醫的惡性腫瘤，

respond dramatically

對這種藥物的治療

to the treatment with this drug.

產生了極大的反應。

You might know that fat has memory.

你可能知道脂肪細胞也有記憶，

很高興可以親身為你們說明。

I'll nicely demonstrate that for you.

(Laughter)

In fact, this molecule

實際上這個分子

prevents this adipocyte, this fat stem cell,

能防止脂肪干細胞

from remembering how to make fat,

記住如何製造脂肪。

such that mice on a high-fat diet,

即使給予小白鼠高脂肪的飲食,

like the folks in my hometown of Chicago --

好像在芝加哥的人們那樣，

(Laughter)

它也沒有產生脂肪肝。

fail to develop fatty liver,

脂肪肝是一個重大的醫療課題。

which is a major medical problem.

這研究向我們展示的是--

What this research taught us --

not just my lab, but our institute,

不僅是我的實驗室，還有我們的研究所，

哈佛醫學院－

and Harvard Medical School more generally --

我們在學術界有獨特的

is that we have unique resources in academia

醫藥開發資源--

for drug discovery;

that our center, which has tested perhaps more cancer molecules

我們的實驗中心

或許已經科學地測試了比其他任何地方

in a scientific way

更多的抗癌分子，

than any other,

never made one of its own.

從來沒有自己製造藥物。

For all the reasons you see listed here,

因為所有這些提到的理由，

we think there's a great opportunity for academic centers

我們覺得這對學術中心來講是一個非常好的機會

to participate in this earliest, conceptually tricky

來參與到這最早期的

充滿挑戰與創造性的

and creative discipline

of prototype drug discovery.

樣品藥物開發階段。

然後呢？

So what next?

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

我們有了這個分子，但它還不是一片藥丸。

不能口服。

It's not orally bioavailable.

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

我們需要解決這點，以便向病患提供。

And everyone in the lab,

實驗室裡的所有人，

especially following the interaction with these patients,

特別是在與病患者們有過交流後，

都覺得自己有義務

feels quite compelled to deliver a drug substance

來提供一種以這個分子為主要成份的藥品。

based on this molecule.

It's here where I'd say

在這裡我不得不說

that we could use your help and your insights,

我們有需要獲得你們的幫助與意見，

your collaborative participation.

以及合作性的參與。

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

與藥品公司不同的是,

我們沒有一個生產流水線。

that we can deposit these molecules into.

我們沒有一只銷售軍團來告訴我們

We don't have a team of salespeople and marketeers

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

如何針對其他產品來定位這藥物。

What we do have is the flexibility of an academic center

我們所有的是學術界的自由度

與能幹，積極，熱情,

to work with competent, motivated,

enthusiastic, hopefully well-funded people

最好也能得到投資的人

to carry these molecules forward into the clinic

來一起努力將這些分子推向診所。

while preserving our ability to share the prototype drug worldwide.

同時保留我們

與全世界分享樣品的能力。

This molecule will soon leave our benches

很快這個分子將離開我們

進入到一個小的新創辦的公司

and go into a small start-up company called Tensha Therapeutics.

叫做 Tensha Therapeutics。

And, really, this is the fourth of these molecules

這是從我們這藥物開發

to kind of "graduate" from our little pipeline

過程中得到的第四個分子。

of drug discovery,

一種治療皮膚上的

two of which -- a topical drug for lymphoma of the skin

淋巴瘤的局部用藥。

and an oral substance for the treatment of multiple myeloma --

還有一種是口服治療多重骨髓瘤

will actually come to the bedside for the first clinical trial

會在今年7月送達病床邊

進行第一次臨床試驗。

in July of this year -- for us, a major and exciting milestone.

對我們來說是一個重大的令人激動的里程碑。

I want to leave you with just two ideas.

我想為大家留下兩個構想。

The first is: if anything is unique about this research,

第一個是

這個研究特別之處在於，

it's less the science than the strategy.

與科技相比其中的策略更重要--

This, for us, was a social experiment --

對我們來說這是一個社會試驗，

這個試驗可以進行，如果

an experiment in "What would happen if we were as open and honest

我們在化學研究發現

at the earliest phase of discovery chemistry research

的最初階段保持

as we could be?"

開放和誠信，

This string of letters and numbers

我們的這成分的化學名稱

and symbols and parentheses

一系列的字母和數字

that can be texted, I suppose,

符號和括孤號

or Twittered worldwide,

都可以用簡訊發送,

或者在全世界範圍發佈微網誌，

is the chemical identity of our pro compound.

It's the information that we most need from pharmaceutical companies,

這些是我們最需要從

醫藥公司得到的，

the information on how these early prototype drugs might work.

是些關於

這些早期試驗藥物是如何生效的信息。

Yet this information is largely a secret.

然而它們在很大程度上仍然被列為機密。

And so we seek, really, to download

我們努力嘗試應用

兩個非常成功的

from the amazing successes of the computer-science industry,

計算機科學行業的原則,

two principles -- that of open source and that of crowdsourcing --

就是開放原始代碼和群眾外包

來快速，負責地

to quickly, responsibly accelerate the delivery of targeted therapeutics

加快向癌症病人提供

to patients with cancer.

標靶療法的速度。

Now, the business model involves all of you.

這個商業模式需要所有人的參與。

This research is funded by the public.

這項研究是由

It's funded by foundations.

公眾和基金會集資。

And one thing I've learned in Boston

我在波士頓所學到的一件事是

is that you people will do anything for cancer, and I love that.

人們願意為戰勝癌做出任何努力，我很欣賞這熱情。

騎單車跨越全州，在河流中穿行。

You bike across the state, you walk up and down the river.

（笑聲）

(Laughter)

我從來沒有在任何地方

I've never seen, really, anywhere,

看見對癌症研究

this unique support for cancer research.

這樣特別的支援。

And so I want to thank you

所以我想感謝大家

for your participation, your collaboration

的參與和合作

and most of all,

以及對我們的理念所持有的信心。

for your confidence in our ideas.

（掌聲）

(Applause)