I moved to Boston 10 years ago from Chicago, with an interest in cancer and in chemistry. You might know that chemistry is the science of making molecules or, to my taste, new drugs for cancer. And you might also know that, for science and medicine, Boston is a bit of a candy store. You can't roll a stop sign in Cambridge without hitting a graduate student. The bar is called the Miracle of Science. The billboards say "Lab Space Available."
10年前我從芝加哥搬到波士頓, 對癌症和化學滿懷興趣。 化學是一項製造分子的科學= 或者對我而言,對抗癌症的新興藥劑。 對於科學與醫藥行業而言, 波士頓好比是一個糖果店。 在Cambridge你到處都能 碰到研究所的學生。 酒吧的名字叫做科學的奇蹟。 看板上寫著“實驗室開放”。
And it's fair to say that in these 10 years, we've witnessed absolutely the start of a scientific revolution -- that of genome medicine. We know more about the patients that enter our clinic now than ever before. And we're able, finally, to answer the question that's been so pressing for so many years: Why do I have cancer? This information is also pretty staggering. You might know that, so far, in just the dawn of this revolution, we know that there are perhaps 40,000 unique mutations affecting more than 10,000 genes, and that there are 500 of these genes that are bona-fide drivers, causes of cancer.
可以很肯定地說在這10年中 我們已經目睹了 一場基因藥物革命的開始。 我們對現在來到診所的病患的瞭解 比從前任何時候都更多更詳細。 我們終於可以回答 這個多年來的疑問: 為甚麼我會患癌症? 這信息本身也是非常令人震驚。 你也許知道, 這場革命只是剛剛開始, 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, 其中有500個基因 是引發癌症的 元兇和原因。
Yet comparatively, we have about a dozen targeted medications. And this inadequacy of cancer medicine really hit home when my father was diagnosed with pancreatic cancer. We didn't fly him to Boston. We didn't sequence his genome. It's been known for decades what causes this malignancy. It's three proteins: ras, myc, p53. This is old information we've known since about the 80s, yet there's no medicine I can prescribe to a patient with this or any of the numerous solid tumors caused by these three ... Horsemen of the Apocalypse that is cancer. There's no ras, no myc, no p53 drug.
然而相比較下 我們只有大約十來種標靶藥物。 癌症藥物稀缺的情況也出現在 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。 也沒有為他進行基因組測序。 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 Ras, MIC和P53. 這是自80年代起我們就知道的信息。 即使是這樣我也不能 為一位患上這種或者許多其他種 由這三個癌症的誘因 而發生的固態腫瘤的 病人開出藥方。 針對Ras, MIC, P53的藥並不存在。
And you might fairly ask: Why is that? And the very unsatisfying yet scientific answer is: it's too hard. That for whatever reason, these three proteins have entered a space, in the language of our field, that's called the undruggable genome -- which is like calling a computer unsurfable or the Moon unwalkable. It's a horrible term of trade. But what it means is that we've failed to identify a greasy pocket in these proteins, into which we, like molecular locksmiths, can fashion an active, small, organic molecule or drug substance.
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: 太難了。 由於某些原因, 這些蛋白質,用行業術語來描述, 就是無藥可醫的基因-- 就像一台電腦無法上網 或者不能登陸的月球。 這是非常糟糕的贸易條件。 我的意思是 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 能製作出一個小巧的有機分子 或者是藥物。
Now, as I was training in clinical medicine and hematology and oncology and stem-cell transplantation, what we had instead, cascading through the regulatory network at the FDA, were these substances: arsenic, thalidomide, and this chemical derivative of nitrogen mustard gas. And this is the 21st century. And so, I guess you'd say, dissatisfied with the performance and quality of these medicines, I went back to school, in chemistry, with the idea that perhaps by learning the trade of discovery chemistry and approaching it in the context of this brave new world of the open source, the crowd source, the collaborative network that we have access to within academia, that we might more quickly bring powerful and targeted therapies to our patients.
當我在接受臨床醫學, 血液學,腫瘤學 和干細胞移植的培訓時, 我們反而有的是, 食品藥品管理局地管理網絡上充斥著的 是這些成份-- 砷,鎮靜劑, 還有氮介子氣 的化學衍生物。 現在這是21世紀。 所以我想大家一定對這些 藥物的療效和質量並不滿意。 我帶著這個想法 回到學校研究化學。 想著或許在這開源與 外包的新世界中 做發現性的 化學研究。 在學院所有的合作性網絡中, 我們或許可以 更快地把強力的標靶 療法帶給病患者。
And so, please consider this a work in progress, but I'd like to tell you today a story about a very rare cancer called midline carcinoma, about the undruggable protein target that causes this cancer, called BRD4, and about a molecule developed at my lab at Dana-Farber Cancer Institute, called JQ1, which we affectionately named for Jun Qi, the chemist that made this molecule. Now, BRD4 is an interesting protein.
這是一個還在進行中的作業, 我想向大家講述一個故事, 是關於一種很稀有的癌症 稱為中線癌, 也是關於一個蛋白質目標, 導致癌症的無藥可醫的蛋白質目標, 稱為BRD4, 還有一個分子 由我在Dana Farber癌症研究院的實驗室開發 稱為JQ1,被我們親切地用Jun Qi的名字來命名, 他是製造出這個分子的化學家。 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, how does it remember it's cancer? When it winds up its genome, divides into two cells and unwinds again, why does it not turn into an eye, into a liver, as it has all the genes necessary to do this? It remembers that it's cancer. And the reason is that cancer, like every cell in the body, places little molecular bookmarks, little Post-it notes, that remind the cell, "I'm cancer; I should keep growing." And those Post-it notes involve this and other proteins of its class -- so-called bromodomains. So we developed an idea, a rationale, that perhaps if we made a molecule that prevented the Post-it note from sticking by entering into the little pocket at the base of this spinning protein, then maybe we could convince cancer cells, certainly those addicted to this BRD4 protein, that they're not cancer.
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? 當它收起自己的基因組 分裂成2個細胞再鬆開, 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? 它仍然記得自己是癌細胞。 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, 一個小便條, 提醒它自己「 我是癌細胞,我應該繼續生長。」 這些便條 包含它自己還有其他相同種類-- 被稱為Bromodomains的蛋白質。 我們得出了一個想法, 如果我們製造一個分子 通過進入這個蛋白質底部 的小口袋中,來防止 這些便條黏在上面, 這樣也許我們就可以告訴這些癌細胞 它們不是癌。特別是那些嗜BRD4 蛋白質的細胞。
And so we started to work on this problem. We developed libraries of compounds and eventually arrived at this and similar substances called JQ1. Now, not being a drug company, we could do certain things, we had certain flexibilities, that I respect that a pharmaceutical industry doesn't have. We just started mailing it to our friends. I have a small lab. We thought we'd just send it to people and see how the molecule behaves. We sent it to Oxford, England, where a group of talented crystallographers provided this picture, which helped us understand exactly how this molecule is so potent for this protein target. It's what we call a perfect fit of shape complementarity, or hand in glove.
我們對這個問題展開工作, 研製了各式各樣的成份 最終得到了這種物質 叫做JQ1。 我們並不是一家醫藥公司, 所以有一些事情我們可以做,我們有這樣的自由度, 這是醫藥企業所沒有的。 我們開始把樣本郵寄給朋友們。 我自己有一個小的實驗室。 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 一群才華橫溢的結晶學家提供了這幅圖片, 幫助我們瞭解了 這個分子為何對這個蛋白質目標如此有效。 我們稱之為完美的 形狀互補,非常緊密。
Now, this is a very rare cancer, this BRD4-addicted cancer. And so we worked with samples of material that were collected by young pathologists at Brigham and Women's Hospital. And as we treated these cells with this molecule, we observed something really striking. The cancer cells -- small, round and rapidly dividing, grew these arms and extensions. They were changing shape. In effect, the cancer cell was forgetting it was cancer and becoming a normal cell.
這是一種非常罕見的癌症。 這個嗜BRD4的癌症。 我們對從Brigham女性醫院 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 我們觀察到了一些非常驚人的現象。 這些癌細胞, 這些小小的,圓形並快速的分裂著的癌細胞 長出了「 手臂 」和其他延伸。 它們改變了形狀。 實際上,這些癌細胞 正忘記了自己是癌症, 並且變回了正常細胞。
This got us very excited. The next step would be to put this molecule into mice. The only problem was there's no mouse model of this rare cancer. And so at the time we were doing this research, I was caring for a 29-year-old firefighter from Connecticut who was very much at the end of life with this incurable cancer. This BRD4-addicted cancer was growing throughout his left lung. And he had a chest tube in that was draining little bits of debris. And every nursing shift, we would throw this material out. And so we approached this patient and asked if he would collaborate with us. Could we take this precious and rare cancerous material from this chest tube and drive it across town and put it into mice and try to do a clinical trial at a stage that with a prototype drug, well, that would be, of course, impossible and, rightly, illegal to do in humans. And he obliged us. At the Lurie Family Center for Animal Imaging, our colleague, Andrew Kung, grew this cancer successfully in mice without ever touching plastic.
這令我們感到非常興奮。 下一步就是把這個分子應用在小白鼠身上。 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, 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, 幾乎已處在在生命的終點。 這個BRD4成癮的癌症 在他左邊的肺部生長, 在他的胸腔處有一個導管抽取碎屑。 每一次護理換班, 這些物質都會被清理掉。 因此我們接觸這位病患 詢問他是否願意與我們合作。 能不能從他胸口的導管中獲得這珍貴 而稀有的癌症物質。 然後運送到我們的實驗室植入小白鼠體內 使用一種試驗藥物 來做一個臨床試驗。 因為在人身上這樣做的話這是非法的。 他答應了我們。 在Lurie家庭中心的動物照影部門, 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。
And you can see this PET scan of a mouse -- what we call a pet PET. The cancer is growing as this red, huge mass in the hind limb of this animal. And as we treat it with our compound, this addiction to sugar, this rapid growth, faded. And on the animal on the right, you see that the cancer was responding. We've completed, now, clinical trials in four mouse models of this disease. And every time, we see the same thing. The mice with this cancer that get the drug live, and the ones that don't rapidly perish.
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 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, 這種對「 糖」的嗜好, 這種快速的生長,逐漸消失。 而在右邊的小動物, 大家可以看到癌細胞對此產生反應。 我們已經在四隻小白鼠 身上進行了這種疾病的臨床測試。 每次都得到相同的結果。 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。
So we started to wonder, what would a drug company do at this point? Well, they probably would keep this a secret until they turn the prototype drug into an active pharmaceutical substance. So we did just the opposite. We published a paper that described this finding at the earliest prototype stage. We gave the world the chemical identity of this molecule, typically a secret in our discipline. We told people exactly how to make it. We gave them our email address, suggesting that if they write us, we'll send them a free molecule.
我們就開始猜想, 這種情況下如果是一家醫藥公司會怎麼做? 他們大概會將這個發現列為機密 直到把這種試驗藥物做成 一種熱銷的藥品。 我們反其道而行, 發表了一篇論文。 在最早的樣品階段 講述這個發現。 我們公佈了這個分子的化學名稱, 按規定通常這都應該屬於機密。 我們告訴人們怎麼製造它。 也附上了我們的電郵, 如果有人寫信給我們, 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 for our lab as possible. And this was, unfortunately, successful.
嘗試創造一個競爭激烈的環境。 不幸的是,我們成功地做到了。 (笑聲)
(Laughter)
自去年12月以來
Because now, we've shared this molecule, just since December of last year, with 40 laboratories in the United States and 30 more in Europe -- many of them pharmaceutical companies, seeking now to enter this space, to target this rare cancer that, thankfully right now, is quite desirable to study in that industry. But the science that's coming back from all of these laboratories about the use of this molecule has provided us insights we might not have had on our own. Leukemia cells treated with this compound turn into normal white blood cells. Mice with multiple myeloma, an incurable malignancy of the bone marrow, respond dramatically to the treatment with this drug. You might know that fat has memory. I'll nicely demonstrate that for you.
我們與美國40所實驗室 分享了這個分子。 還有歐洲的30家 許多藥廠也參與進來 研究這種 罕見的癌症。 令人欣慰的是這個課題 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 得來的反饋, 給我們帶來了一些 我們原先並沒有的認知。 使用這種分子治理的血癌細胞 變回了普通的白細胞。 有多重骨髓瘤的老鼠, 一種生長在骨髓中無藥可醫的惡性腫瘤, 對這種藥物的治療 產生了極大的反應。 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。
(Laughter)
實際上這個分子
In fact, this molecule prevents this adipocyte, this fat stem cell, from remembering how to make fat, such that mice on a high-fat diet, like the folks in my hometown of Chicago --
能防止脂肪干細胞 記住如何製造脂肪。 即使給予小白鼠高脂肪的飲食, 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, which is a major medical problem.
脂肪肝是一個重大的醫療課題。
What this research taught us -- not just my lab, but our institute, and Harvard Medical School more generally -- is that we have unique resources in academia for drug discovery; that our center, which has tested perhaps more cancer molecules in a scientific way than any other, never made one of its own. For all the reasons you see listed here, we think there's a great opportunity for academic centers to participate in this earliest, conceptually tricky and creative discipline of prototype drug discovery.
這研究向我們展示的是-- 不僅是我的實驗室,還有我們的研究所, 哈佛醫學院- 我們在學術界有獨特的 醫藥開發資源-- 我們的實驗中心 或許已經科學地測試了比其他任何地方 更多的抗癌分子, 從來沒有自己製造藥物。 因為所有這些提到的理由, 我們覺得這對學術中心來講是一個非常好的機會 來參與到這最早期的 充滿挑戰與創造性的 樣品藥物開發階段。
So what next? We have this molecule, but it's not a pill yet. It's not orally bioavailable. We need to fix it so we can deliver it to our patients. And everyone in the lab, especially following the interaction with these patients, feels quite compelled to deliver a drug substance based on this molecule. It's here where I'd say that we could use your help and your insights, your collaborative participation. Unlike a drug company, we don't have a pipeline that we can deposit these molecules into. We don't have a team of salespeople and marketeers to tell us how to position this drug against the other. What we do have is the flexibility of an academic center to work with competent, motivated, enthusiastic, hopefully well-funded people to carry these molecules forward into the clinic while preserving our ability to share the prototype drug worldwide.
然後呢? 我們有了這個分子,但它還不是一片藥丸。 不能口服。 我們需要解決這點,以便向病患提供。 實驗室裡的所有人, 特別是在與病患者們有過交流後, 都覺得自己有義務 來提供一種以這個分子為主要成份的藥品。 在這裡我不得不說 我們有需要獲得你們的幫助與意見, 以及合作性的參與。 與藥品公司不同的是, 我們沒有一個生產流水線。 我們沒有一只銷售軍團來告訴我們 如何針對其他產品來定位這藥物。 我們所有的是學術界的自由度 與能幹,積極,熱情, 最好也能得到投資的人 來一起努力將這些分子推向診所。 同時保留我們 與全世界分享樣品的能力。
This molecule will soon leave our benches and go into a small start-up company called Tensha Therapeutics. And, really, this is the fourth of these molecules to kind of "graduate" from our little pipeline of drug discovery, two of which -- a topical drug for lymphoma of the skin and an oral substance for the treatment of multiple myeloma -- will actually come to the bedside for the first clinical trial in July of this year -- for us, a major and exciting milestone. I want to leave you with just two ideas. The first is: if anything is unique about this research, it's less the science than the strategy. This, for us, was a social experiment -- an experiment in "What would happen if we were as open and honest at the earliest phase of discovery chemistry research as we could be?"
很快這個分子將離開我們 進入到一個小的新創辦的公司 叫做 Tensha Therapeutics。 這是從我們這藥物開發 過程中得到的第四個分子。 一種治療皮膚上的 淋巴瘤的局部用藥。 還有一種是口服治療多重骨髓瘤 會在今年7月送達病床邊 進行第一次臨床試驗。 對我們來說是一個重大的令人激動的里程碑。 我想為大家留下兩個構想。 第一個是 這個研究特別之處在於, 與科技相比其中的策略更重要-- 對我們來說這是一個社會試驗, 這個試驗可以進行,如果 我們在化學研究發現 的最初階段保持 開放和誠信,
This string of letters and numbers and symbols and parentheses that can be texted, I suppose, or Twittered worldwide, is the chemical identity of our pro compound. It's the information that we most need from pharmaceutical companies, the information on how these early prototype drugs might work. Yet this information is largely a secret. And so we seek, really, to download from the amazing successes of the computer-science industry, two principles -- that of open source and that of crowdsourcing -- to quickly, responsibly accelerate the delivery of targeted therapeutics to patients with cancer.
我們的這成分的化學名稱 一系列的字母和數字 符號和括孤號 都可以用簡訊發送, 或者在全世界範圍發佈微網誌, 這些是我們最需要從 醫藥公司得到的, 是些關於 這些早期試驗藥物是如何生效的信息。 然而它們在很大程度上仍然被列為機密。 我們努力嘗試應用 兩個非常成功的 計算機科學行業的原則, 就是開放原始代碼和群眾外包 來快速,負責地 加快向癌症病人提供 標靶療法的速度。
Now, the business model involves all of you. This research is funded by the public. It's funded by foundations. And one thing I've learned in Boston is that you people will do anything for cancer, and I love that. You bike across the state, you walk up and down the river.
這個商業模式需要所有人的參與。 這項研究是由 公眾和基金會集資。 我在波士頓所學到的一件事是 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。
(Laughter)
(笑聲)
I've never seen, really, anywhere, this unique support for cancer research. And so I want to thank you for your participation, your collaboration and most of all, for your confidence in our ideas.
我從來沒有在任何地方 看見對癌症研究 這樣特別的支援。 所以我想感謝大家 的參與和合作 以及對我們的理念所持有的信心。 (掌聲)
(Applause)