Jay Bradner: Open-source cancer research

翻译人员: Ying Han 校对人员: Guo Tang

我在十年前从芝加哥搬到波士顿

I moved to Boston 10 years ago from Chicago,

with an interest in cancer and in chemistry.

有心研究癌症和化学

You might know that chemistry is the science of making molecules

你们可能知道化学是门研究分子形成的科学

or, to my taste,

但对我是门研究癌症药物的学问

new drugs for cancer.

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

你们也可能知道对科学和医药来说

Boston is a bit of a candy store.

波士顿有点像糖果店

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

在波士顿剑桥区的每一个十字路口

你都会碰到至少一名研究生

The bar is called the Miracle of Science.

在那里有叫科学奇迹的酒吧

The billboards say "Lab Space Available."

有叫“出租实验室”的广告牌

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

可以说这是近十年较常见的

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

其实这仅仅是我们所看到的

一个科学进化的结果，遗传基因科学的开始

that of genome medicine.

我们现在对来我们实验室的患者

We know more about the patients that enter our clinic now

要比以前知道得多

than ever before.

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

我们终于可以回答

这个困扰我们多年的问题

that's been so pressing for so many years:

Why do I have cancer?

那就是，我为什么得癌症？

This information is also pretty staggering.

这个问题的答案比较复杂

你们也许已经知道

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

至此在这科学革命之黎明

we know that there are perhaps 40,000 unique mutations

我们知道大约有四万种基因变异

影响大约一万个基因

affecting more than 10,000 genes,

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

这一万个基因中大约有五百个基因

是可恶变的

causes of cancer.

致癌的

相比之下

Yet comparatively,

we have about a dozen targeted medications.

我们只有大约十几个有针对性的治疗方法

And this inadequacy of cancer medicine

我对这种癌症治疗不足性的认识

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

深有体会是在我父亲被诊断为

胰腺癌

当时我们没有让他飞到波士顿

We didn't fly him to Boston.

We didn't sequence his genome.

我们没有测试他的基因顺序

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

因为多年来人类已知

基因变异原因

是三种蛋白质

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

Ras, MIC 和 P53

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

这是我们从八十年代就已经知道的老信息了，

yet there's no medicine I can prescribe

但至今我仍然没有药方

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

可以开给患者

不论是什么大肿瘤

caused by these three ...

由以上三种蛋白质引起的

Horsemen of the Apocalypse that is cancer.

癌症

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

没有针对Ras, MIC或P53的药物

And you might fairly ask: Why is that?

那么你可能要问：为什么会这样？

一个不令人满意的但科学的回答是

And the very unsatisfying yet scientific answer is:

它太难了

it's too hard.

That for whatever reason,

也就是说，不管什么原因

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

这三种蛋白质被这个领域称为

that's called the undruggable genome --

无药可治的基因－－

which is like calling a computer unsurfable

就像一台不能上网的电脑

或者是无法行走的月球

or the Moon unwalkable.

It's a horrible term of trade.

这是行业里很可怕的词汇

But what it means

但它意味着

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

我们是否无法辨别有害蛋白质

就像在锁定分子

into which we, like molecular locksmiths,

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

可以演变成小段活动有机分子一样

或者是药物替代品

现在我受训于临床医学，

Now, as I was training in clinical medicine

血液学，肿瘤学

and hematology and oncology and stem-cell transplantation,

及干细胞移植

what we had instead,

我们有的是

cascading through the regulatory network at the FDA,

从美国食品和药物管理局批下来的

这些药物，包括

were these substances:

arsenic,

砷， 莎利宝迈

thalidomide,

及化学引发物来自

and this chemical derivative of nitrogen mustard gas.

氮糜爛性的芥氣

And this is the 21st century.

我们已经是处在21世纪了

And so, I guess you'd say,

我想你们应该不满于

dissatisfied with the performance and quality of these medicines,

今天的医学表现和质量

I went back to school, in chemistry,

我因此回到了化学学院

想到

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

也许通过化学发现

and approaching it in the context of this brave new world

进入这个新的领域

of the open source,

以开发源码式，

群体合作式，

the crowd source,

the collaborative network that we have access to within academia,

通过一个学术研发合作网络

that we might more quickly bring powerful and targeted therapies

我们也许可以更快地

把有效的和有目标的治疗方法

带给我们的患者

to our patients.

And so, please consider this a work in progress,

请对这个正在运行的工作给予考虑

我今天给你们讲一个故事

but I'd like to tell you today a story

这是有关一种非常罕见的癌症

about a very rare cancer called midline carcinoma,

它叫中线癌

相关蛋白质目标，

about the undruggable protein target that causes this cancer,

是一种不可治愈的蛋白质目标引起这种癌症

它叫BRD4

called BRD4,

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

及相关分子

是由我在妲妠珐波尔癌症学院的实验室开放出来的

called JQ1,

叫JQ1，我们昵称它军齐(Jun Qi)，

which we affectionately named for Jun Qi,

与做出这个分子的化学家同名

the chemist that made this molecule.

Now, BRD4 is an interesting protein.

BRD4是一种有趣的蛋白质

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

你可能要问自己， 癌症在用各种方法试图杀害我们的患者，

它怎么会记得它是癌症呢？

how does it remember it's cancer?

当它把它的遗传物质卷起来，

When it winds up its genome,

divides into two cells and unwinds again,

分成两个细胞，再展开

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

为什么它不变成一只眼睛，一个肝脏

充分使用它所有的基因呢？

as it has all the genes necessary to do this?

It remembers that it's cancer.

它记得它是癌症

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

原因是它是癌症，就像人体内的每个细胞上

放有细小的分子标记，

places little molecular bookmarks,

就像便利贴

little Post-it notes,

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

提醒细胞“我是癌症，我应当不停的长大"

而那些便利贴

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

引进这个蛋白质和它同级的别种蛋白质

这些别种蛋白质叫做Bromodomains.

so-called bromodomains.

So we developed an idea, a rationale,

以此我们推理

that perhaps if we made a molecule

或许，如果我们造出一个分子

that prevented the Post-it note from sticking

避免让便利贴粘到它

让便利贴进入小口袋

by entering into the little pocket

at the base of this spinning protein,

口袋位置在这旋转的蛋白质基底上

then maybe we could convince cancer cells,

那么，也许我们能够让癌细胞相信

certainly those addicted to this BRD4 protein,

尽管染上BRD4蛋白质

that they're not cancer.

但它们不是癌细胞

And so we started to work on this problem.

于是我们开始着手解决这个问题

We developed libraries of compounds

我们开发了合成物储藏馆

我们逐渐得到今天的结果及类似的物质

and eventually arrived at this and similar substances

它叫JQ1.

called JQ1.

Now, not being a drug company,

因为我们不是制药公司，

we could do certain things, we had certain flexibilities,

我们能够做一些事情，有一些灵活度

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

这些是制药业所没有的

We just started mailing it to our friends.

我们刚刚开始把它寄给我们的朋友

我有个小实验室

I have a small lab.

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

我们想我们就把它寄给别人，看这分子如何表现

于是我们把它寄给了英国牛津

We sent it to Oxford, England,

那里的结晶师给了我们这个照片

where a group of talented crystallographers provided this picture,

它帮助我们了解到

which helped us understand exactly how this molecule is so potent

这个分子是如何对这种蛋白质目标准确地施力

for this protein target.

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

它就是我们所说的完美对象

拥有相配的外体，就像戴着手套的手

or hand in glove.

这是一种罕见的癌症

Now, this is a very rare cancer,

一种BRD4附体的癌症。

this BRD4-addicted cancer.

我们使用的样本材料

And so we worked with samples of material

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

来自布利格姆妇女医院的年轻病理学家

我们用我们的这种分子了治疗这些样本细胞

And as we treated these cells with this molecule,

we observed something really striking.

我们观察到非常惊人的结果

这些癌细胞

The cancer cells --

small, round and rapidly dividing,

又小又圆，快速分裂

grew these arms and extensions.

长出胳膊和延长部分

They were changing shape.

它们还变形

In effect,

实际上，癌细胞

the cancer cell was forgetting it was cancer

正在忘记它是癌细胞

而且在转变成正常细胞

and becoming a normal cell.

这个观察让我们很兴奋

This got us very excited.

下一步是把这分子注入的老鼠身上

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

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

我们唯一的问题是没有患有这种罕见癌症的老鼠

就在这个研究过程中

And so at the time we were doing this research,

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

我在康州治疗一位29岁的消防员

他已接近他的生命终点了

who was very much at the end of life

with this incurable cancer.

就是因为这种不可治愈的癌症

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

这种BRD4附体的癌症

正在他的左肺里扩散

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

他靠左胸上插的一细管来排除废物

每个护士轮班期间

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

都要把细管内废物清掉

And so we approached this patient

因此我们找到这位患者

and asked if he would collaborate with us.

问他是否愿意与我们合作

Could we take this precious and rare cancerous material

我们是否可以把他稀有的，拥有癌症的排泄物

from this chest tube

从细管里拿出来

and drive it across town and put it into mice

送到城的另一边，注入到老鼠身上

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

通过临床试验

做成药物初本？

well, that would be, of course, impossible

但是，这不可能，人体试验不道德，不合法

and, rightly, illegal to do in humans.

而且他已为我们尽了义务

And he obliged us.

At the Lurie Family Center for Animal Imaging,

在卢瑞家庭动物图像中心

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

我的同事安德鲁•康成功地把这癌症转到了老鼠身上

他在这过程中连塑料都没有碰

without ever touching plastic.

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

你可以看看这老鼠的PET扫描，我们叫它老鼠PET

这癌症在扩散

The cancer is growing

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

也就是这老鼠后肢上的大块红色组织

我们用我们的合成物对老鼠进行治疗

And as we treat it with our compound,

加上糖分

this addiction to sugar,

癌细胞不扩散了

this rapid growth, faded.

And on the animal on the right,

在这动物的右侧

you see that the cancer was responding.

你可以看到癌症在反应

We've completed, now, clinical trials

我们现在已完成动物实验

用了4个动物模本

in four mouse models of this disease.

每一次我们都看到同样的结果

And every time, we see the same thing.

The mice with this cancer that get the drug live,

患有癌症的老鼠用药后活了下来

而那些没有用药的就很快死掉了

and the ones that don't rapidly perish.

于是我们开始思考

So we started to wonder,

what would a drug company do at this point?

此时制药公司会做什么？

Well, they probably would keep this a secret

也许他们会把秘密保留下来

until they turn the prototype drug

直到他们把药物雏形

into an active pharmaceutical substance.

变成一种活跃的药物实体

而我们恰恰会做相反的事

So we did just the opposite.

我们发表了一篇文章

We published a paper that described this finding

描述了我们的发现

at the earliest prototype stage.

尽管是早期雏形

We gave the world the chemical identity of this molecule,

我们向世界提供了这种分子的化学身份

typically a secret in our discipline.

这是违反我们业内常规

We told people exactly how to make it.

我们准确告诉了所有人如何制作这种分子

我们提供了我们的电子信箱地址

We gave them our email address,

suggesting that if they write us,

向人们提议如果他们写信给我们

we'll send them a free molecule.

我们会为他们提供免费分子

(Laughter)

我们基本上是试图创造

We basically tried to create the most competitive environment

我们自己的实验室所能面对的最具竞争力的环境

for our lab as possible.

不幸的是， 很成功

And this was, unfortunately, successful.

（笑声）

(Laughter)

Because now, we've shared this molecule,

因为我们现在与众分享我们的分子

just since December of last year,

就从去年12月

with 40 laboratories in the United States

和美国的40家实验室，

欧洲30多家实验室，

and 30 more in Europe --

其中很多是来自制药公司

many of them pharmaceutical companies,

seeking now to enter this space,

开始进入这个领域

to target this rare cancer that, thankfully right now,

目标是这个罕见的癌症

有幸的是，现在这是

is quite desirable to study in that industry.

我们行业里比较合乎需求的

来自这些实验室的

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

对这分子的研究

about the use of this molecule

已经为我们提供

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

我们自己不可能得到的洞悉

Leukemia cells treated with this compound

用这种合成物治疗过的白血病细胞

turn into normal white blood cells.

会转变成正常白血球

Mice with multiple myeloma,

患有骨髓瘤的老鼠

an incurable malignancy of the bone marrow,

在骨髓里带有不可治愈的癌症，

respond dramatically

会明显的接受

to the treatment with this drug.

这种药物治疗

You might know that fat has memory.

你可能知道脂肪带有记忆

能够向你们演示这个真的很好

I'll nicely demonstrate that for you.

(Laughter)

In fact, this molecule

事实上，这种分子

prevents this adipocyte, this fat stem cell,

避免这种含脂肪细胞，这种肥胖干细胞

from remembering how to make fat,

记忆发胖

such that mice on a high-fat diet,

比如说高脂肪饮食的老鼠

like the folks in my hometown of Chicago --

就像我芝加哥故乡人

(Laughter)

不会得脂肪肝，

fail to develop fatty liver,

一个重大医学问题

which is a major medical problem.

这个研究教给我们 -

What this research taught us --

not just my lab, but our institute,

不止我的实验室，而且我们学院

及哈佛医学院，更广泛的讲 -

and Harvard Medical School more generally --

我们拥有学术界独有的资源

is that we have unique resources in academia

有助于药物发现 -

for drug discovery;

that our center, which has tested perhaps more cancer molecules

也就是说，我们中心

尽管我们以科学方式测试过很多癌症分子，

in a scientific way

远多于其他中心，

than any other,

never made one of its own.

但我们从来没有制作过任何癌症分子

For all the reasons you see listed here,

从那些你们能够看到的理由

we think there's a great opportunity for academic centers

我们认为学术研究中心有很好的机会

to participate in this earliest, conceptually tricky

参与早期，概念化，

和有创意的领域

and creative discipline

of prototype drug discovery.

去发现药物雏形

那么，下一步是什么？

So what next?

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

我们有了这个分子，但它还不是药片

它还不可口服。

It's not orally bioavailable.

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

我们需要改变它，以便可以送给我们的患者。

And everyone in the lab,

每一位在实验室工作的人，

especially following the interaction with these patients,

特别是那些与患者直接打交道的人，

深刻体会

feels quite compelled to deliver a drug substance

把这分子变成药物的紧迫性。

based on this molecule.

It's here where I'd say

我在这里要说的是

that we could use your help and your insights,

我们可以使用你们的帮助，你们的洞悉，

your collaborative participation.

你们的合作参与。

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

不像制药公司，

我们不需要有储放这些分子的管道。

that we can deposit these molecules into.

我们不一定要有一批销售人员和市场开发人员，

We don't have a team of salespeople and marketeers

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

不需要有这些人告诉我们如何给这药定位。

What we do have is the flexibility of an academic center

我们拥有的是学术中心的灵活度

以便集中合作与有能力，有动力，

to work with competent, motivated,

enthusiastic, hopefully well-funded people

有激情，又最好有资助的人

to carry these molecules forward into the clinic

来把这些分子推入临床

while preserving our ability to share the prototype drug worldwide.

同时保留我们有

与世界分享药物雏形的能力。

This molecule will soon leave our benches

这种分子将很快离开我们

走向一家小的创业公司

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

它叫Tensha Therapeutics。

And, really, this is the fourth of these molecules

这真的是第四种分子

to kind of "graduate" from our little pipeline

从我们小小的药物发现管道里毕业

of drug discovery,

其它两种 - 一种是常用药

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

用于治疗皮肤癌，

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

另一种是治疗几种骨髓癌的口服药 -

will actually come to the bedside for the first clinical trial

将很快来到床边

今年7月进入初期临床试验。

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

对我们来说，这是一个重大及令人兴奋的里程碑

I want to leave you with just two ideas.

我想要给你们留下两个主意。

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

第一个是

如果我们这个研究有什么特别的话，

it's less the science than the strategy.

那是较少的科学更多的战略

This, for us, was a social experiment --

给了我们一个社会试验

它向我们显示了什么是可能发生的，

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

如果我们开放和诚实

at the earliest phase of discovery chemistry research

在发现化学研究最早期

as we could be?"

尽我们所及之力。

This string of letters and numbers

这一串字母和数字

and symbols and parentheses

标码和括弧

that can be texted, I suppose,

我想是可以通过短信发出

or Twittered worldwide,

或者是微博到全世界

是我们这个合成物的化学身份。

is the chemical identity of our pro compound.

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

我们最需要的信息

来自制药公司，

the information on how these early prototype drugs might work.

这信息

是有关早期药物雏形如何工作。

Yet this information is largely a secret.

至今，这样的信息大多数是行业秘密。

And so we seek, really, to download

所以我们正在寻求的

是下载惊人的成功，

from the amazing successes of the computer-science industry,

两个原则，来自计算机学行业：

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

那就是开放源码和群体源码

尽快地，负责地，

to quickly, responsibly accelerate the delivery of targeted therapeutics

把目标治疗法送给

to patients with cancer.

癌症患者

Now, the business model involves all of you.

这个商业模式需要我们都参与

This research is funded by the public.

这个研究借助于公共资源

It's funded by foundations.

它是由基金会资助的

And one thing I've learned in Boston

另外，我在波士顿学到一样东西

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

那就是，你们所有人将都会为癌症治疗做事 - 我很喜欢。

有人骑单车跨州，有人走路过河

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

（笑声）

(Laughter)

我在哪里都没有见过

I've never seen, really, anywhere,

如此独特地

this unique support for cancer research.

支持癌症研究。

And so I want to thank you

我还要感谢你们

for your participation, your collaboration

感谢你们的参与，你们的合作

and most of all,

更多的是你们对我们的信心。

for your confidence in our ideas.

（鼓掌）

(Applause)