Approximately 30 years ago, when I was in oncology at the Children's Hospital in Philadelphia, a father and a son walked into my office and they both had their right eye missing, and as I took the history, it became apparent that the father and the son had a rare form of inherited eye tumor, retinoblastoma, and the father knew that he had passed that fate on to his son.
大約是在三十年前 當我還在費城一間兒童醫院的腫瘤科 工作的時候 一位爸爸帶著兒子走進我的辦公室 他們都失去了右眼 在我翻查病歷之中,明顯發現 父子倆都患有罕見形式的 遺傳性眼瘤,視網膜母細胞瘤, 爸爸知道是他將這個厄運 傳給他兒子的。
That moment changed my life. It propelled me to go on and to co-lead a team that discovered the first cancer susceptibility gene, and in the intervening decades since then, there has been literally a seismic shift in our understanding of what goes on, what genetic variations are sitting behind various diseases. In fact, for thousands of human traits, a molecular basis that's known for that, and for thousands of people, every day, there's information that they gain about the risk of going on to get this disease or that disease.
那一刻改變了我的人生。 它鼓勵我繼續工作 並且去領導一個首先發現 癌症易感基因的團隊。 從那時以來的幾十年之間, 簡直是發生了一場巨變, 對於我們所認知的一切, 以及各種疾病背後所隱藏的 遺傳變異。 事實上,數千個人類遺傳特徵 是已知的分子基礎。 而對於數千個人,每一天, 他們都會得到 關於患有此疾病或其他疾病 風險的訊息
At the same time, if you ask, "Has that impacted the efficiency, how we've been able to develop drugs?" the answer is not really. If you look at the cost of developing drugs, how that's done, it basically hasn't budged that. And so it's as if we have the power to diagnose yet not the power to fully treat. And there are two commonly given reasons for why that happens. One of them is it's early days. We're just learning the words, the fragments, the letters in the genetic code. We don't know how to read the sentences. We don't know how to follow the narrative. The other reason given is that most of those changes are a loss of function, and it's actually really hard to develop drugs that restore function.
同時,如果你問道: 「若它已經影響了功效, 我們要怎麼做才能開發出新藥?」 答案並不確定。 如果你去查看開發藥物的成本, 以及它是如何完成的, 基本上它並無太大改變。 所以這就像是我們有能力去診斷, 卻沒有能力去全力救治病人。 這裡有兩個常見的原因 說明為什麼會有這種狀況發生 : 其一是,還在初期階段, 我們才剛了解到遺傳密碼中的詞彙 片段還有字母。 我們並不知道如何讀出整段句子, 我們也不知道怎麼接續整個故事。 另一個原因是 大部分變化的發生是因為功能的喪失, 事實上,真的很難去開發 具有恢復功能的藥物。
But today, I want us to step back and ask a more fundamental question, and ask, "What happens if we're thinking about this maybe in the wrong context?" We do a lot of studying of those who are sick and building up long lists of altered components. But maybe, if what we're trying to do is to develop therapies for prevention, maybe what we should be doing is studying those who don't get sick. Maybe we should be studying those that are well. A vast majority of those people are not necessarily carrying a particular genetic load or risk factor. They're not going to help us. There are going to be those individuals who are carrying a potential future risk, they're going to go on to get some symptom. That's not what we're looking for. What we're asking and looking for is, are there a very few set of individuals who are actually walking around with the risk that normally would cause a disease, but something in them, something hidden in them is actually protective and keeping them from exhibiting those symptoms?
但今天,我要大家退一步, 問一個更基本的問題, 「如果我們假想 這是在個前後關係錯誤的情況又會怎麼樣?」 我們對於那些生病的人做了很多研究, 也建立了一長串 構成因素的列表。 但也許,若我們試著去做的 是開發一種預防疾病的療法; 也許我們應該做的 是去研究那些沒有生病的人; 也許我們真的該去研究那些 健康的人。 這些人絕大多數 未必攜帶著特定的 遺傳基因或危險因素。 這樣的人不會幫到我們什麼。 但他們未來將會是 潛在的高危險群 他們很有機會得到一些症狀, 但這也不是我們要找的。 我們正在尋找的是 有沒有少數的個體 在我們身邊活得好好的, 事實上卻處在隨時 會患上各種疾病的風險中, 但某個東西在他們身體裡,隱藏在深處 實際上是具保護性的, 並克制他們顯現出症狀?
If you're going to do a study like that, you can imagine you'd like to look at lots and lots of people. We'd have to go and have a pretty wide study, and we realized that actually one way to think of this is, let us look at adults who are over 40 years of age, and let's make sure that we look at those who were healthy as kids. They might have had individuals in their families who had had a childhood disease, but not necessarily. And let's go and then screen those to find those who are carrying genes for childhood diseases.
如果你打算進行此類研究,你可以想像 你會想要研究好多好多人。 我們必須去實施一個特別廣泛的研究, 並且我們發現事實上 有一種思考方式可以告訴我們這是什麼 讓我們先看看年過40的成人, 然後確保那些人 在孩提時代也是健康的。 在他們的家庭中也許有人 曾經在幼年發病 但卻不是十分嚴重。 讓我們去篩選那些 有攜帶兒童期疾病 基因的人。
Now, some of you, I can see you putting your hands up going, "Uh, a little odd. What's your evidence that this could be feasible?" I want to give you two examples.
現在,我可以看到你們有些人 手想要舉起來說:「蛤?這有點怪。 你有什麼證據 可以證明這是可行的?」 我想給你們舉兩個例子。
The first comes from San Francisco. It comes from the 1980s and the 1990s, and you may know the story where there were individuals who had very high levels of the virus HIV. They went on to get AIDS. But there was a very small set of individuals who also had very high levels of HIV. They didn't get AIDS. And astute clinicians tracked that down, and what they found was they were carrying mutations. Notice, they were carrying mutations from birth that were protective, that were protecting them from going on to get AIDS. You may also know that actually a line of therapy has been coming along based on that fact. Second example, more recent, is elegant work done by Helen Hobbs, who said, "I'm going to look at individuals who have very high lipid levels, and I'm going to try to find those people with high lipid levels who don't go on to get heart disease." And again, what she found was some of those individuals had mutations that were protective from birth that kept them, even though they had high lipid levels, and you can see this is an interesting way of thinking about how you could develop preventive therapies.
第一個是發生在舊金山, 1980 到 1990 年代這個時期, 你也許知道這個情況: 曾經有些人被高水平的 人類免疫缺陷病毒(HIV)所感染, 他們接著患上了愛滋病。 但有少部分人 同樣也有高水平的 HIV 病毒, 他們卻沒有得愛滋病。 機敏的臨床醫生追蹤下來, 發現他們身上帶有基因變異。 注意!他們是自從出生就有此 保護作用的變異, 讓他們不至於得到愛滋。 你也許知道事實上有一連串治療 是根據這事實而研發出來的。 第二個較近來的例子,是個漂亮的工作 由海倫·霍布斯完成。 她說 : 「我要去研究那些 高脂肪水平的人。 然後再從這些 高血脂水平的人裡面 找出沒有得到心臟疾病的人。」 再一次,她也發現 在這之中的一些人也有變異, 也是從他們出生時就開始保護著他們, 儘管他們的脂肪水平很高。 各位可以看到這是個有趣的方式 去思考我們該如何發展出 預防疾病的療法。
The project that we're working on is called "The Resilience Project: A Search for Unexpected Heroes," because what we are interested in doing is saying, can we find those rare individuals who might have these hidden protective factors? And in some ways, think of it as a decoder ring, a sort of resilience decoder ring that we're going to try to build. We've realized that we should do this in a systematic way, so we've said, let's take every single childhood inherited disease. Let's take them all, and let's pull them back a little bit by those that are known to have severe symptoms, where the parents, the child, those around them would know that they'd gotten sick, and let's go ahead and then frame them again by those parts of the genes where we know that there is a particular alteration that is known to be highly penetrant to cause that disease.
而現在我們正在做的計畫 叫做「恢復力計畫: 搜索潛藏的基因英雄。」 因為我們感興趣的就是 我們是否能夠找到那些 可能擁有保護作用遺傳基因的少數人? 在某些方面,想像它是個解碼環, 一種我們正試著建立的 一個恢復力的解碼環。 我們已了解到必須有條理的方式去建立, 所以就之前提過的,我們先來看每一個 兒童期發病的遺傳性疾病。 我們先全部研究一遍, 退後一步, 透過那些嚴重症狀病患 身邊知道他們曾生病過的 父母、子女和其他人, 接著我們透過已知的 某些特定的世道交替原則, 而得出有些變異位於 有著很高遺傳機率的基因上 再去發展並表達出這些基因片段。
Where are we going to look? Well, we could look locally. That makes sense. But we began to think, maybe we should look all over the world. Maybe we should look not just here but in remote places where their might be a distinct genetic context, there might be environmental factors that protect people. And let's look at a million individuals.
我們會關注哪些地方? 我們可以從當地開始,這合乎情理。 但我們又想,也許我們應該關注 這整個世界。 我們該關注的不只是在一個地方, 還有偏遠地區, 那裡可能會有與其他不同的遺傳基因背景, 更有可能會有某些 保護人們的環境因素。 讓我們來檢視一百萬個人。
Now the reason why we think it's a good time to do that now is, in the last couple of years, there's been a remarkable plummeting in the cost to do this type of analysis, this type of data generation, to where it actually costs less to do the data generation and analysis than it does to do the sample processing and the collection. The other reason is that in the last five years, there have been awesome tools, things about network biology, systems biology, that have come up that allow us to think that maybe we could decipher those positive outliers.
現在,我們覺得這時候 是這麼做的好時機, 因為在過去的幾年, 從事此類型分析的花費、 這數據生成類型的費用 明顯地暴跌。 事實上數據生成以及分析 比樣本處理及收集 花的錢還要少。 另一個原因是在最近五年裡 有很不錯的工具以及 有關網路生物學、系統生物學的東西, 被發明出現來讓我們思考 我們能夠解碼 這絕對異常值的可能性。
And as we went around talking to researchers and institutions and telling them about our story, something happened. They started saying, "This is interesting. I would be glad to join your effort. I would be willing to participate." And they didn't say, "Where's the MTA?" They didn't say, "Where is my authorship?" They didn't say, "Is this data going to be mine? Am I going to own it?" They basically said, "Let's work on this in an open, crowd-sourced, team way to do this decoding."
就當我們到處和研究人員 及機構談話, 告訴他們我們的故事, 有件事發生了。 他們進而開始說:「這真是有趣。 我願意加入幫忙, 我很樂意參與。」 他們並沒有問:「有醫療技術助理嗎? 」 他們也沒有問:「我有沒有著作權? 」 他們更沒有問:「這資料會不會是我的?我能夠擁有它嗎? 他們基本上只說了:「我們就一起 用開放的、大眾資源、團隊的方式 來解碼吧!」
Six months ago, we locked down the screening key for this decoder. My co-lead, a brilliant scientist, Eric Schadt at the Icahn Mount Sinai School of Medicine in New York, and his team, locked in that decoder key ring, and we began looking for samples, because what we realized is, maybe we could just go and look at some existing samples to get some sense of feasibility. Maybe we could take two, three percent of the project on, and see if it was there. And so we started asking people such as Hakon at the Children's Hospital in Philadelphia. We asked Leif up in Finland. We talked to Anne Wojcicki at 23andMe, and Wang Jun at BGI, and again, something remarkable happened. They said, "Huh, not only do we have samples, but often we've analyzed them, and we would be glad to go into our anonymized samples and see if we could find those that you're looking for." And instead of being 20,000 or 30,000, last month we passed one half million samples that we've already analyzed.
六個月前,我們鎖定了 這解碼環的篩選鍵。 我的共同領導,艾里克沙特,一個出色的科學家, 在紐約的伊坎西奈山醫學院, 以及他的團隊, 鎖定了一個解碼環的鑰匙圈, 所以我們開始尋找樣本, 因為我們了解到的是 也許我們可以直接去看 那些存在的樣本,去發現一些可行性。 也許這個計畫我們可以先做個兩三成 然後再看看可不可行。 所以我們就開始詢問人們 比如在費城兒童醫院的哈康主任、 在芬蘭的雷夫、 基因技術公司 23andMe 的創辦人安妮.沃西基、 華大基因的王俊。 又一次,一些顯著的事情發生了。 他們說:「哈, 我們不只有樣本, 我們還要去分析他們, 我們很樂意去檢視 匿名的樣本, 去看看我們能不能找到 你們正在找的東西。」 我們分析的樣本不只是兩、三萬而已, 上個月我們已分析超過 50 萬。 所以你一定會說
So you must be going, "Huh, did you find any unexpected heroes?" And the answer is, we didn't find one or two. We found dozens of these strong candidate unexpected heroes.
「嘿!你找到潛藏的基因英雄了嗎?」 答案是,我們不只找到一、兩個。 我們找到了許多個強大的 基因英雄候選人。 所以我們認為現在是時候
So we think that the time is now to launch the beta phase of this project and actually start getting prospective individuals. Basically all we need is information. We need a swab of DNA and a willingness to say, "What's inside me? I'm willing to be re-contacted."
展開這個計劃的測試階段, 實際上也開始有了預期中的對象。 基本上我們所需要的是資訊。 我們需要棉棒來取樣基因, 以及自願說出「我身體裡面有什麼?」 我願意再次得到聯繫。」 當涉及到健康與疾病,
Most of us spend our lives, when it comes to health and disease, acting as if we're voyeurs. We delegate the responsibility for the understanding of our disease, for the treatment of our disease, to anointed experts. In order for us to get this project to work, we need individuals to step up in a different role and to be engaged, to realize this dream, this open crowd-sourced project, to find those unexpected heroes, to evolve from the current concepts of resources and constraints, to design those preventive therapies, and to extend it beyond childhood diseases, to go all the way up to ways that we could look at Alzheimer's or Parkinson's, we're going to need us to be looking inside ourselves and asking, "What are our roles? What are our genes?" and looking within ourselves for information we used to say we should go to the outside, to experts, and to be willing to share that with others.
我們大部分都為此傾注了心血 表現地就像是偷窺狂一樣。 我們將責任委託給 能了解疾病、 能治療疾病的 權威專家們。 為了幫助我們讓計畫有所成效, 我們需要有人站出來 以一個不同的角色來參與, 去實現這個夢想, 也需要這對外開放的大眾資源計畫 來找到那些潛藏的英雄們, 從目前我們對資源與限制的概念 逐漸發展到 發明出預防疾病的治療、 擴展範圍到兒童期疾病之外, 在整個過程中,我們可以發展到 研究阿茲海默症及帕金森氏症, 我們需要 捫心自問: 「我們的角色是什麼? 我們的基因是什麼?」 看看我們自己,想想以前 我們常說應該到走到外面 去找專家們, 然後樂意與人分享。 非常感謝各位。
Thank you very much.
(掌聲)
(Applause)