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今天很高興能在此與各位分享修復受損大腦的可能性。這個領域令我十分振奮,因為身為神經學家,我相信這提供了最棒的治療方式之一,使我們能將希望帶給眾多病入膏肓且難以治癒的大腦疾病患者。
因此這是問題所在。你可以看見這是阿茲海默症患者的大腦圖,旁邊是健康的大腦。顯然在阿茲海默症患者的大腦,圈起的紅色區域明顯受損-萎縮和傷疤。我還可以展示其他同質疾病的圖片:多發性硬化症、運動神經元疾病、巴金森症,甚至亨丁頓舞蹈症,它們全部呈現類似情況。這些大腦疾病顯示當今公眾健康主要威脅之一,這些數字確實令人乍舌。如今有三千五百萬人罹患某種腦部疾病,全球每年治療花費高達七千億美元。我是指,思考一下,這大於全球GDP總額百分之一。情況還會更糟,因為這些數字持續攀升。因為大體上來說這些屬於老化疾病,而我們的壽命逐漸延長。因此我們真正要問自己的問題是:鑒於這些疾病對個人的毀滅性影響,更別提所造成的社會問題規模,為何沒有有效療法?
為了思考這個問題,首先我必須為你們上一堂關於大腦如何運作的速成課。換句話說,我必須告訴你們我在醫學院所學的一切。(笑聲)但相信我,不會花太久時間,可以嗎?(笑聲)因此大腦相當簡單:它由四種細胞組成,其中兩種如圖所示,這是神經細胞,這是髓鞘細胞或絕緣細胞,這稱為寡樹突細胞。當這四種細胞健康和諧地共同運作時,將產生一種特殊電流活動現象,正是這種電流活動賦予我們思考、表現情感、記憶、學習、行動、感受等能力。但同樣地,這四種細胞單獨或一起,都可能失常或死亡。當發生這種情況,你將受到損害。大腦線路受損,這種聯繫將受到干擾,如這裡所顯示的,傳輸減速。但最終,這種損害將以疾病形式呈現。如果開始邁向死亡的神經細胞是運動神經,你將罹患運動神經元疾病。
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I'm very pleased to be here today to talk to you all about how we might repair the damaged brain, and I'm particularly excited by this field, because as a neurologist myself, I believe that this offers one of the great ways that we might be able to offer hope for patients who today live with devastating and yet untreatable diseases of the brain.
So here's the problem. You can see here the picture of somebody's brain with Alzheimer's disease next to a healthy brain, and what's obvious is, in the Alzheimer's brain, ringed red, there's obvious damage -- atrophy, scarring. And I could show you equivalent pictures from other disease: multiple sclerosis, motor neuron disease, Parkinson's disease, even Huntington's disease, and they would all tell a similar story. And collectively these brain disorders represent one of the major public health threats of our time. And the numbers here are really rather staggering. At any one time, there are 35 million people today living with one of these brain diseases, and the annual cost globally is 700 billion dollars. I mean, just think about that. That's greater than one percent of the global GDP. And it gets worse, because all these numbers are rising because these are by and large age-related diseases, and we're living longer. So the question we really need to ask ourselves is, why, given the devastating impact of these diseases to the individual, never mind the scale of the societal problem, why are there no effective treatments?
Now in order to consider this, I first need to give you a crash course in how the brain works. So in other words, I need to tell you everything I learned at medical school. (Laughter) But believe me, this isn't going to take very long. Okay? (Laughter) So the brain is terribly simple: it's made up of four cells, and two of them are shown here. There's the nerve cell, and then there's the myelinating cell, or the insulating cell. It's called oligodendrocyte. And when these four cells work together in health and harmony, they create an extraordinary symphony of electrical activity, and it is this electrical activity that underpins our ability to think, to emote, to remember, to learn, move, feel and so on. But equally, each of these individual four cells alone or together, can go rogue or die, and when that happens, you get damage. You get damaged wiring. You get disrupted connections. And that's evident here with the slower conduction. But ultimately, this damage will manifest as disease, clearly. And if the starting dying nerve cell is a motor nerve, for example, you'll get motor neuron disease.
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因此我讓各位觀看一個關於運動神經元疾病的實例。因此這是我的病人,名叫約翰。我上周才在診所見過約翰,我請約翰告訴我們當初他有什麼問題,導致初次被診斷為罹患運動神經元疾病。
約翰:我2011年10月接受診斷,主要是呼吸問題,呼吸困難。
Siddharthan Chandran:我不知道你們是否全聽得懂,約翰剛剛說的是呼吸困難,最終被診斷為運動神經元疾病。
因此目前約翰罹病已超過18個月。現在我請他告訴我們他目前的困境。
約翰:現在我呼吸更加困難,我的雙手、手臂及雙腿變得無力,因此基本上我大部分時間都坐在輪椅上。
SC:約翰剛剛告訴我們他大部分時間都坐在輪椅上。
因此這兩段影片不僅顯示這種疾病的嚴重後果,也告訴我們疾病惡化的驚人速度。因為僅過了18個月,一位健康的成年人就必須靠輪椅和呼吸器度日。讓我們正視這個事實:約翰可能是任何人的父親、兄弟或朋友。
因此這就是運動神經元死亡時的情形。但髓鞘細胞死亡時會如何?你會罹患多發性硬化症,因此左邊這張掃描圖是大腦影像及連接情形,重疊部份即受損區域,我們稱之為脫髓鞘病變。它們受到損傷,呈白色。
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So I'd like to give you a real-life illustration of what happens with motor neuron disease. So this is a patient of mine called John. John I saw just last week in the clinic. And I've asked John to tell us something about what were his problems that led to the initial diagnosis of motor neuron disease.
John: I was diagnosed in October in 2011, and the main problem was a breathing problem, difficulty breathing.
Siddharthan Chandran: I don't know if you caught all of that, but what John was telling us was that difficulty with breathing led eventually to the diagnosis of motor neuron disease.
So John's now 18 months further down in that journey, and I've now asked him to tell us something about his current predicament.
John: What I've got now is the breathing's gotten worse. I've got weakness in my hands, my arms and my legs. So basically I'm in a wheelchair most of the time.
SC: John's just told us he's in a wheelchair most of the time.
So what these two clips show is not just the devastating consequence of the disease, but they also tell us something about the shocking pace of the disease, because in just 18 months, a fit adult man has been rendered wheelchair- and respirator-dependent. And let's face it, John could be anybody's father, brother or friend.
So that's what happens when the motor nerve dies. But what happens when that myelin cell dies? You get multiple sclerosis. So the scan on your left is an illustration of the brain, and it's a map of the connections of the brain, and superimposed upon which are areas of damage. We call them lesions of demyelination. But they're damage, and they're white.
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我知道你們在想什麼。你們正想著:「天哪,這傢伙上台說他要談希望,卻盡說些悲慘且令人沮喪的事。」我說過這些疾病相當可怕、具毀滅性,罹病人數與日俱增,治療費用高昂,最糟的是我們無法治療。希望在哪裡?
好,知道嗎?我認為希望確實存在。希望存在於多發性硬化症患者腦部另一個區域,因為它顯示了大腦驚人的自我修復能力,只是還不夠好。因此我想再讓各位看兩張圖,首先是多發性硬化症患者的受損部位。同樣地,另一張是白色物質分佈圖,但重點是,紅色圈出的區域顯現淺藍色區域,但這片淺藍區域曾經是白色的,因此它曾經受損,現在修復了。先說明一下:這並非醫生的功勞,與醫生無關,不是因為醫生,這是自發性修復,十分神奇,但確實發生了。因為大腦中也有幹細胞,能產生新的髓鞘質、新的絕緣細胞,覆蓋在受損神經上。這項發現十分重要,有兩個原因。首先是它挑戰了我們在醫學院所受的正統教育,或至少我上世紀所接受的教育,即大腦無法自我修復,不像骨頭或肝臟。但它確實可以,只是不夠完善。第二點是,它為我們提供了新療法明確的方向-我是指,你不需要是頂尖科學家也知道該怎麼做,你只需找到促進這種內生性自發修復過程的方法。
因此問題是,為何-如果我們已知道這件事一段時間,確實如此-為何尚未出現治療方法?這部分反映了藥物研發的複雜性。好,你或許認為藥物研發是相當昂貴、但風險極大的豪賭,這場賭注的賠率大概是這樣:一萬比一,因為你需要篩選約一萬種化合物才有機會找到可能的勝利者。然後你需要花15年時間、超過十億美元,即使如此,也可能徒勞無功。
因此我們面臨的問題是,你是否能改變遊戲規則或降低賠率?為了達成這個目標,你必須思考藥物研發的瓶頸為何?瓶頸之一在於藥物發展初期,所有篩選均以動物模型為基礎,但我們知道,適用於研究人類的對象就是人-借用Alexander Pope(英國詩人)的話-因此問題是,我們能使用人體組織研究這些疾病嗎?當然,絕對可以,我們可使用幹細胞。具體來說,我們可使用人類幹細胞。人類幹細胞是與眾不同、但十分簡單的細胞,能進行兩件事:它們能自行更新或自行增生,但它們也能進行特化,成為骨骼、肝臟細胞,或最重要的-神經細胞,也許甚至是運動神經元細胞或髓鞘質細胞。長期以來所面臨的挑戰是,我們是否能駕馭這種力量,幹細胞毋庸置疑的力量,藉此瞭解它們對於再生神經學的潛能?
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So I know what you're thinking here. You're thinking, "My God, this bloke came up and said he's going to talk about hope, and all he's done is give a really rather bleak and depressing tale." I've told you these diseases are terrible. They're devastating, numbers are rising, the costs are ridiculous, and worst of all, we have no treatment. Where's the hope?
Well, you know what? I think there is hope. And there's hope in this next section, of this brain section of somebody else with M.S., because what it illustrates is, amazingly, the brain can repair itself. It just doesn't do it well enough. And so again, there are two things I want to show you. First of all is the damage of this patient with M.S. And again, it's another one of these white masses. But crucially, the area that's ringed red highlights an area that is pale blue. But that area that is pale blue was once white. So it was damaged. It's now repaired. Just to be clear: It's not because of doctors. It's in spite of doctors, not because of doctors. This is spontaneous repair. It's amazing and it's occurred because there are stem cells in the brain, even, which can enable new myelin, new insulation, to be laid down over the damaged nerves. And this observation is important for two reasons. The first is it challenges one of the orthodoxies that we learnt at medical school, or at least I did, admittedly last century, which is that the brain doesn't repair itself, unlike, say, the bone or the liver. But actually it does, but it just doesn't do it well enough. And the second thing it does, and it gives us a very clear direction of travel for new therapies -- I mean, you don't need to be a rocket scientist to know what to do here. You simply need to find ways of promoting the endogenous, spontaneous repair that occurs anyway.
So the question is, why, if we've known that for some time, as we have, why do we not have those treatments? And that in part reflects the complexity of drug development. Now, drug development you might think of as a rather expensive but risky bet, and the odds of this bet are roughly this: they're 10,000 to one against, because you need to screen about 10,000 compounds to find that one potential winner. And then you need to spend 15 years and spend over a billion dollars, and even then, you may not have a winner.
So the question for us is, can you change the rules of the game and can you shorten the odds? And in order to do that, you have to think, where is the bottleneck in this drug discovery? And one of the bottlenecks is early in drug discovery. All that screening occurs in animal models. But we know that the proper study of mankind is man, to borrow from Alexander Pope. So the question is, can we study these diseases using human material? And of course, absolutely we can. We can use stem cells, and specifically we can use human stem cells. And human stem cells are these extraordinary but simple cells that can do two things: they can self-renew or make more of themselves, but they can also become specialized to make bone, liver or, crucially, nerve cells, maybe even the motor nerve cell or the myelin cell. And the challenge has long been, can we harness the power, the undoubted power of these stem cells in order to realize their promise for regenerative neurology?
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我認為我們現在能做到這一點,原因在於過去一、二十年有幾項重大發現,其中之一發生在愛丁堡。牠肯定是唯一一隻出名的綿羊-桃麗。因此桃麗製造於愛丁堡。桃麗是第一個由成年細胞複製出的哺乳動物,但我認為以我們今天討論的主題來說,更意義深遠的一項突破來自一位名叫山中伸彌的日本科學家2006年所做的研究。山中伸彌所做的是,以某種神奇的科學融合法,他證明以四種成分,僅僅四種,就能有效地將任何細胞,成年細胞,轉變成幹細胞。這項發現的意義難以言喻,因為這意味著這房間裡的任何人,尤其是病人,可產生量身訂做、個人化的組織修復工具。取一個皮膚細胞,使它成為多功能細胞,你可藉此製造與疾病有關的細胞,也可進行研究及作為潛在療法。好,醫學院的觀點-這是反覆出現的主題,對嗎?我和醫學院-曾經認為這荒謬至極,但如今卻是不容置疑的事實,我將它視為再生、修復與希望的基石。
既然談到關於希望的主題,那些在學校表現不佳的人,這也是你們的希望,因為這是John Gerdon的學習評語:(我相信他有成為科學家的想法,以他目前表現來說根本不可能。)因此他們當時並不看好他。但你或許不知道,他獲得諾貝爾醫學獎,就在三個月前。
因此回到最初的問題:這些幹細胞,或這種顛覆性技術有多少修復受損大腦的可能性,即我們所謂的再生神經學?我認為我們可由兩方面思考這一點:它可成為21世紀極佳的藥物研發工具或治療方法。因此接下來幾分鐘我想稍微說明一下這兩點。
人們通常說這是在培養皿中進行藥物研發,十分簡單:以一位罹病患者做測試,假設是運動神經元疾病,你取一些皮膚樣本,進行多功能重組,如我之前所說的,產生活的運動神經元細胞,簡單明瞭,因為這就是多功能細胞的作用。但關鍵是,你可將它們與同種健康細胞進行比較,最好取樣自健康的親屬,你可藉此比對遺傳變異。
這正是我們所做的研究。這是全體同事的合作成果:倫敦的Chris Shaw、美國的Steve Finkbeiner和Tom Maniatis。你所看到的相當驚人。這些活生生、正在生長的運動神經元細胞來自一位運動神經元疾病患者,正如同遺傳形式。我是指,思考一下,10年前根本無法想像這種情形。因此除了觀察細胞生長及消失過程,我們還能使它們發出螢光,但關鍵在於我們能追蹤個別細胞的健康情況,將受損的運動神經元細胞與健康細胞進行比較。當你進行這一切並彙整結果,將發現受損細胞-以紅線表示-死亡率為健康細胞的2.5倍,其中關鍵在於你因此擁有研發藥物的極佳測試法,因為你對藥物的要求-可藉由高通量自動化篩選系統達成-你要求藥物達成某種標準:找出一種使紅線盡可能接近藍線的藥物,因為這種藥物將是高潛力候選者,或許能直接用於人體試驗,幾乎可繞過我所提過的藥物研發過程中關於動物模型的瓶頸。如果可行,這將十分了不起。
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And I think we can now, and the reason we can is because there have been several major discoveries in the last 10, 20 years. One of them was here in Edinburgh, and it must be the only celebrity sheep, Dolly. So Dolly was made in Edinburgh, and Dolly was an example of the first cloning of a mammal from an adult cell. But I think the even more significant breakthrough for the purposes of our discussion today was made in 2006 by a Japanese scientist called Yamanaka. And what Yamaka did, in a fantastic form of scientific cookery, was he showed that four ingredients, just four ingredients, could effectively convert any cell, adult cell, into a master stem cell. And the significance of this is difficult to exaggerate, because what it means that from anybody in this room, but particularly patients, you could now generate a bespoke, personalized tissue repair kit. Take a skin cell, make it a master pluripotent cell, so you could then make those cells that are relevant to their disease, both to study but potentially to treat. Now, the idea of that at medical school -- this is a recurring theme, isn't it, me and medical school? — would have been ridiculous, but it's an absolute reality today. And I see this as the cornerstone of regeneration, repair and hope.
And whilst we're on the theme of hope, for those of you who might have failed at school, there's hope for you as well, because this is the school report of John Gerdon. ["I believe he has ideas about becoming a scientist; on his present showing this is quite ridiculous."] So they didn't think much of him then. But what you may not know is that he got the Nobel Prize for medicine just three months ago.
So to return to the original problem, what is the opportunity of these stem cells, or this disruptive technology, for repairing the damaged brain, which we call regenerative neurology? I think there are two ways you can think about this: as a fantastic 21st-century drug discovery tool, and/or as a form of therapy. So I want to tell you a little bit about both of those in the next few moments.
Drug discovery in a dish is how people often talk about this. It's very simple: You take a patient with a disease, let's say motor neuron disease, you take a skin sample, you do the pluripotent reprogramming, as I've already told you, and you generate live motor nerve cells. That's straightforward, because that's what pluripotent cells can do. But crucially, you can then compare their behavior to their equivalent but healthy counterparts, ideally from an unaffected relative. That way, you're matching for genetic variation.
And that's exactly what we did here. This was a collaboration with colleagues: in London, Chris Shaw; in the U.S., Steve Finkbeiner and Tom Maniatis. And what you're looking at, and this is amazing, these are living, growing, motor nerve cells from a patient with motor neuron disease. It happens to be an inherited form. I mean, just imagine that. This would have been unimaginable 10 years ago. So apart from seeing them grow and put out processes, we can also engineer them so that they fluoresce, but crucially, we can then track their individual health and compare the diseased motor nerve cells to the healthy ones. And when you do all that and put it together, you realize that the diseased ones, which is represented in the red line, are two and a half times more likely to die than the healthy counterpart. And the crucial point about this is that you then have a fantastic assay to discover drugs, because what would you ask of the drugs, and you could do this through a high-throughput automated screening system, you'd ask the drugs, give me one thing: find me a drug that will bring the red line closer to the blue line, because that drug will be a high-value candidate that you could probably take direct to human trial and almost bypass that bottleneck that I've told you about in drug discovery with the animal models, if that makes sense. It's fantastic.
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但我想回到如何直接利用幹細胞修復大腦損傷的話題。同樣有兩種思考方式,兩者息息相關。首先,我認為長遠來看,這將使我們受益無窮。但我們不曾以這種角度思考,那就是,思考這些已存在於我們大腦中的幹細胞。如我說過的,所有人大腦中都有幹細胞,即使受損的大腦。當然,明智的方法是,找出能促進與激發已存在於大腦中之幹細胞的方法,適當地因應大腦損傷,進行修復。這是未來的願景,將出現能達成這個目標的藥物。
但另一種方法是有效地導入細胞、植入細胞,代替死亡或凋零的細胞,甚至在大腦中。我想分享一項實驗,我們所做的臨床試驗,剛完成不久,這是與倫敦大學學院同事David Miller共同合作。因此這項研究十分簡單。我們選擇多發性硬化症患者,提出一個簡單問題:來自骨髓的幹細胞是否能保護他們的神經?因此我們所做的是取出骨髓,在實驗室培養幹細胞,然後將它注入血管。這是輕描淡寫的說法,這花了我們五年時間和許多人力,瞭解嗎?讓我多了不少白髮,發生過各式各樣的問題,但其中概念相當簡單。因此我們將它注入血管,對嗎?因此為了測試成功與否,我們測量視覺神經作為成果指標。這對多發性硬化症患者來說是很好的指標,因為多發性硬化症患者不幸地會出現視力問題-失明、視線模糊,因此我們藉由David Miller的掃描測量視覺神經大小,總共三次-12個月前、6個月前及注射前-你可以看見緩緩下降的紅線,這表示視覺神經逐漸萎縮。這是合理的,因為神經逐漸死亡。然後我們注入幹細胞,重複進行兩次測量-三個月及六個月-出乎我們意料地,這條線逐漸上升,意味著這項干預具有保護作用。我個人認為這並非因為幹細胞製造新髓鞘質或新神經,我認為它們所做的是激發內生性幹細胞或前驅細胞,喚醒它們、使其運作、形成新髓鞘質。因此這是這項概念的證明,令我振奮不已。
因此我打算以開場主題做結束,即再生和希望。因此我詢問約翰,他未來的希望是什麼?
約翰:我希望未來某天,藉由你們的研究,我們能找到治療方法,使像我這樣的病人能過正常生活。
SC:他說出了大家的心聲。
但演講結束前,我想先感謝約翰,感謝約翰同意讓我分享他的看法及這些影片。但我還想對約翰和其他人補充一點。我個人的觀點是,我對未來充滿希望,我確實相信這些顛覆性技術,如我之前向各位解釋的,幹細胞確實提供相當光明的希望。我確實相信能修復受損大腦的那天將比我們想像中來的快。謝謝。(掌聲)
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But I want to come back to how you might use stem cells directly to repair damage. And again there are two ways to think about this, and they're not mutually exclusive. The first, and I think in the long run the one that will give us the biggest dividend, but it's not thought of that way just yet, is to think about those stem cells that are already in your brain, and I've told you that. All of us have stem cells in the brain, even the diseased brain, and surely the smart way forward is to find ways that you can promote and activate those stem cells in your brain already to react and respond appropriately to damage to repair it. That will be the future. There will be drugs that will do that.
But the other way is to effectively parachute in cells, transplant them in, to replace dying or lost cells, even in the brain. And I want to tell you now an experiment, it's a clinical trial that we did, which recently completed, which is with colleagues in UCL, David Miller in particular. So this study was very simple. We took patients with multiple sclerosis and asked a simple question: Would stem cells from the bone marrow be protective of their nerves? So what we did was we took this bone marrow, grew up the stem cells in the lab, and then injected them back into the vein. I'm making this sound really simple. It took five years off a lot of people, okay? And it put gray hair on me and caused all kinds of issues. But conceptually, it's essentially simple. So we've given them into the vein, right? So in order to measure whether this was successful or not, we measured the optic nerve as our outcome measure. And that's a good thing to measure in M.S., because patients with M.S. sadly suffer with problems with vision -- loss of vision, unclear vision. And so we measured the size of the optic nerve using the scans with David Miller three times -- 12 months, six months, and before the infusion -- and you can see the gently declining red line. And that's telling you that the optic nerve is shrinking, which makes sense, because their nerves are dying. We then gave the stem cell infusion and repeated the measurement twice -- three months and six months -- and to our surprise, almost, the line's gone up. That suggests that the intervention has been protective. I don't think myself that what's happened is that those stem cells have made new myelin or new nerves. What I think they've done is they've promoted the endogenous stem cells, or precursor cells, to do their job, wake up, lay down new myelin. So this is a proof of concept. I'm very excited about that.
So I just want to end with the theme I began on, which was regeneration and hope. So here I've asked John what his hopes are for the future.
John: I would hope that sometime in the future through the research that you people are doing, we can come up with a cure so that people like me can lead a normal life.
SC: I mean, that speaks volumes.
But I'd like to close by first of all thanking John -- thanking John for allowing me to share his insights and these clips with you all. But I'd also like to add to John and to others that my own view is, I'm hopeful for the future. I do believe that the disruptive technologies like stem cells that I've tried to explain to you do offer very real hope. And I do think that the day that we might be able to repair the damaged brain is sooner than we think. Thank you.