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.
今天很高兴能在此 与你们探讨我们如何去修复 受损的大脑 研究这个领域使我倍感激动 因为我本身就是一名神经学家 我坚信这项研究足以带来最好的治疗 使我们可以将希望带给 众多病入膏肓且回天乏术 大脑疾病的患者
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?
那么请看我们面临的问题。 你们可以看到这是一张 老年痴呆患者的大脑图 旁边是健康的大脑图 明显可以看到 老年痴呆的患者的大脑 红色圈出来明显受损的区域——萎缩 有疤痕 我还可以向你们展示类似的 其他疾病的图片:多发性硬化 运动神经元疾病 帕金森症 甚至是亨廷顿氏舞蹈病 这些图片大同小异 这些大脑疾病共同显示了 当今威胁我们公众健康的主要疾病之一 现在患病人数令人乍舌 如今 共有三千五百万人 患有某种脑部疾病 并且全球每年用于治疗这些疾病的花费 均高达到七千亿美元 听听 仔细想想吧 这一数字比全球GDP总额的百分之一 还要多 情况正变得更糟 因为这一数字不断攀升 因为这类疾病总体上 与年龄相关 而我们的寿命在延长 所以我们真正要问自己的问题是 这类疾病会对个人的造成如此毁灭性的影响 这类疾病会对个人的造成如此毁灭性的影响 为什么我们还对此社会问题置若罔闻 为什么没有有效地治疗?
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.
为了思考这类问题 我现在必须上一堂让你们抓狂的课 关于大脑如何运作的 换而言之 我需要告诉你们 我在医学院学到的一切知识 (笑) 但是相信我 不会花很长时间的 行吗?(笑) 其实大脑很简单: 它由四种细胞组成 两个已经展示在这儿 了 这是神经细胞 而这是髓鞘细胞 或者是绝缘细胞 这个被称为少突细胞 当这四种细胞健康和谐地 共同工作时 会产生一种特殊的电流活动 而正是这种电流活动 加强了我们的能力去思考 去表现自己 去记忆 学习 行动 感受等等 但同样的 每一种细胞 单独或者一起 都有可能会失常或死亡 如果发生这种情况 大脑便受损 大脑的线路会损坏 大脑间的联系会被切断 这里的活动明显减速了 但最终 这种损害将恶化为疾病 但最终 这种损害将恶化为疾病 如果正走向于死亡的神经细胞 是元神经的话 你就会患神经元疾病
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.
我想给你们展示一个现实生活中的例子 如果患了神经元疾病会怎么样 这是我的一个病人叫做约翰 我上周才在诊所看到约翰 我让约翰告诉我们是什么样的问题 导致了他最初被诊断为 患有神经元疾病
John: I was diagnosed in October in 2011, and the main problem was a breathing problem, difficulty breathing.
约翰:我在2011年11月确诊 关键的问题出在呼吸上 呼吸很困难
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.
我不知道你们听懂了没 约翰刚说的是 他呼吸困难 最终确诊为 患有神经元疾病
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.
现在距离约翰患病过去了18个月 我让他告诉你们 他现在的困境
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.
约翰:我现在的呼吸更加了困难了 我的双手 胳膊和双脚没什么力气 所以现在基本上我都坐在轮椅上
SC: John's just told us he's in a wheelchair most of the time.
约翰刚刚告诉我他大部分时间 都坐在轮椅上
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.
所以这两个影音片段不仅证明了 疾病造成的后果是毁灭性的 并且疾病恶化的速度 也是十分惊人的 因为仅仅只过了18个月 一个健康的成年人就必须 依靠轮椅和呼吸器度日 让我们正视这个事实吧 约翰可能是一位父亲 一位兄长或是朋友
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.
所当神经元细胞死亡时就会出现这样的情况 那么如果是髓鳞脂细胞死亡 情况又是怎样的呢? 那就会得多发性硬化症 左边的这个扫描图 显示的是大脑内部 里面的各种连接 而这块叠加的地方 这是受损区域 我们称之为髓鞘脱失 细胞受损后呈现白色
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?
我知道你们在想什么 你们在想 “老天爷呀,这哥们儿跳出来 说是要谈谈希望 结果尽在这儿谈些惨淡压抑的事儿” 结果尽在这儿谈些惨淡压抑的事儿” 我确实说过这些疾病很可怕 又是毁灭性的 患病人数也在上升 花费惊人 最糟的是 我们没法儿治愈 希望在哪儿呢?
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.
但是你们知道吗?我认为希望就在这儿 在某个多发性硬化症患者脑部的 另一个区域出现了希望 因为它展示了 大脑的惊人自愈能力 只是这种能力不是特别强而已 所以 我想再一次的向你展示两幅图 首先是多发性硬化症的图 另外一张是有白色物质的图 但重要的是 用红色圈出的区域 有浅蓝色的物质 但是这片蓝色曾经也是白色的 它之前受损 但现在它自己修复了 要明白的是:这不是医生的功劳 这与医生无关 并不是因为他们 这是一种自发的修复 令人称奇但确实发生了 因为大脑中的干细胞 能够创造新的髓磷脂 新的绝缘细胞 覆盖在受损的神经上 这一观察十分重要,有两个原因 一是它挑战了医学院所教授的 正统权威 至少是我上世纪念医学院的时候所接受的教育 医学院的权威认为大脑不能自我修复 不像是骨头或者是肝脏 但大脑确实有这能力只是不够强大而已 二是我们知道大脑有这样的再生机制 这为我们提供了新式治疗的明确方向—— 我是说 即使不是造火箭的专家 也知道该怎么做 你只需找到方法来推动 这一自发性治愈的进程
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.
问题是 假使我们知道这一事实 我们现在就知道了 为什么我们还没有治疗方案呢? 这至少从局部反映出 药品研发的复杂性 你们可能认为制药虽然昂贵 却值得一试 这一尝试的概率大概是这样的: 万分之一的机会 因为我们需要从一万种化合物中 找到可能有效的某一种 这可能需要花上15年时间 以及10亿不止 即使如此 也可能徒劳无功
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?
所以现在的问题是 我们能否改变游戏规则 或者我们能否加大胜算? 为了达到这一目标 就必须思考 药品研发的瓶颈在哪儿? 瓶颈之一就是在制药发现的早期阶段 所有的筛选都以动物为研究对象 但是我们知道研究人类才是合适的 这句话出自亚历山大蒲伯之口 问题是 我们能用人类的材料 来研究这些疾病吗? 当然 我们绝对可以 我们可以利用干细胞 具体就是说我们可以利用人类干细胞 人类干细胞是十分特别 但也很简单的细胞 能做两件事情: 干细胞能自我更新或者自我利用 但是他们能变得更细化 分裂出骨骼细胞 肝脏细胞 最重要的是神经细胞 甚至是神经元细胞 或者是髓磷脂细胞 长期以来的挑战都是 我们能否驾驭这种力量 驾驭干细胞毋庸置疑的力量 去开发细胞的潜能 发展再生长神经学?
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.
我认为我现在有能力了 原因就在于 在过去的10年20年中有了 些许重大的发现 其中一个便是在这儿 爱丁堡出现的 这肯定是唯一的一只出名的绵羊了 多莉 多莉就是爱丁堡制造 它是第一个克隆的哺乳动物 它是第一个克隆的哺乳动物 来自于一个小小的成年细胞 但是我认为更加重要的一项突破 同时也是今天我们讨论的基础 是2006年一位日本科学家 名为山中 他用了一种 令人称奇的科学方式将 四种成分如烹调般混在一起 仅仅四种 就能有效地转换任何一个细胞 任何成年细胞 使之变成干细胞 这项研究意义之重大难以言喻 因为这就意味着在这间会议室的任何一个人 尤其是病人 可以生长出 一套私人定制 个性化的成套修复工具 取一个皮肤细胞 将其培育成多功能细胞, 这样便能生长出许多 与疾病相关的细胞 可以用于研究也能用于未来的治疗 现在 医学院对此的看法 是觉得很荒谬 这是一个无限循环的主题 不是吗:我 医学院 但今时今日这是绝对的现实 我认为这是一个 再生长 修复以及希望的转折点
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.
既然说到了希望的主题 那些在学校表现欠佳的人 你们也应心存希望 因为这是一篇约翰戈登的学校报告 “我相信他有科学家的想法;但他呈现的东西很荒谬” 所以他们当时不是很看好他 但是你可能不知道的是他获得了诺贝尔医学奖 就在三个月前
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.
再回来说说最先前的问题 这些干细胞 或者是分裂技术能提出怎样的机遇 帮助修复受损大脑 发展再生长神经学? 我们可以从两个方面来看再生神经学: 它可以成为本世纪一个极佳的药品研发工具 以及/或者作为治疗的手段 我想再花一点时间说说 这两方面
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.
制药发现就是人们常常 讨论的话题 很简单:有一个身患疾病的病人 比如说患了神经元疾病 我们取一点他皮肤样本 然后进行多功能重组 就像我先前说的那样 生长出新的神经元细胞 直观明了 因为这就是 多功能细胞的强大之处 但重要的是 我们能将病人的行为 与健康的人 最好是他们健康的亲人进行比较 这样 他们能为基因变体做配对
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.
这就是我们的研究 这是全体同事的共同努力: 伦敦的肖克里斯 美国的芬克贝勒斯蒂夫和马力特斯汤姆 你所看到的 是很了不起的 这些鲜活的 正在生长的运动神经元细胞 是来自于一名身患运动神经元疾病的病人 细胞处在遗传阶段的状态 仔细想想吧 这在10年之前是想都没法儿想的 除了能够观察细胞的生长以及干预过程外 我们还能设计细胞使其发出荧光 但是重要的是 我们能追踪单个细胞的健康情况 并将患病的神经元细胞与健康细胞进行比较 并将患病的神经元细胞与健康细胞进行比较 当我们将这些细胞放在一起时 我们发现患病细胞 就是由红色线代表的 相较健康细胞而言死亡的几率 高达2.5倍 重要的一点是接下来我们 能用神奇的试验来发现制药 因为我们对药物的要求 只需要通过高流通量 自动化的筛选系统完成 我们将要求制药者一件事 发明一种药能把这条红线更加 靠近这条蓝线 因为这样的药物是一种高价值的备份 能直接用于人类实验 并且能绕过在制药发现中 以动物为模型的 瓶颈问题 如果可行 这将妙不可言
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.
但是我想再回头说说 我们如何能直接利用干细胞 来修复大脑损伤 同样要通过两方面来思考 这两方面可以相通 第一 我觉得长远来说 能为我们带来巨大回报的 让我们以不同视角去看待问题的 是这些干细胞已经 存在于我们大脑中的事实 我已经说过了 我们的大脑中都有干细胞 即使受损大脑中也有 当然明智的方法是 想办法去促进并且激活 这些已经存在于大脑中的干细胞 使之正确应对大脑损伤 将其修复 这是未来的远景 未来会有具有这样疗效的药物
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.
另外一种办法是有效地 移植这些细胞 让其代替死亡或消逝的细胞 我想跟你们说说一项实验 这是我们做的一项临床试验 刚结束不久 是和在伦敦大学学院的同事一起做的 尤其是米勒大卫 这项研究其实很简单 我们选出患有多发性硬化症的患者 问自己一个简单的问题: 来自于骨髓的干细胞 能保护他们的神经么? 所以我们选取了这一骨髓细胞 在实验室培植出干细胞 再将其注射进血管里 我尽量将这一过程简化描述 这花了我们整整五年时间 我头发都白了 期间尽是这样那样的问题 但这一概念本质上还是很简单的 于是我们把干细胞注射进了血管 为了测量我们成功与否 我们测量了视觉神经 作为我们成果的测量 这在多发性硬化症中很有效 因为多发性硬化症的患者很不幸的 会出现视力问题—— 失明 视线模糊 所以我们测量了视觉神经 通过对米勒大卫进行扫描 总共三次——12个月前一次 6个月前一次 以及注射前一次—— 你们可以看到红线有轻微的下降 这就是说视觉神经正在减少 确实说得通 因为这一神经细胞正在死亡 然后我们注射了干细胞 并且连续测量了两次—— 三个月一次及六个月一次—— 令我们吃惊的是 这条线上升了 这意味着这一干预 奏效了 我个人认为 这些干细胞并没有生长出新的髓磷脂 或者新的神经 我认为是促进了 内生的干细胞或者是前体细胞 唤醒了他们使之能覆盖新的髓磷脂 研究证明了这一点 我对此十分激动
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.
最后结束时我想再提先前的主题 即再生长以及希望 我又问了约翰 他未来的希望是什么
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.
约翰:我希望 未来的某一天 通过你们的研究 我们的疾病得以治愈 像我这样的病人就能过正常的生活了
SC: I mean, that speaks volumes.
这已经说的很明白了
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. (Applause)
在结束这次演讲时 我首先想先感谢约翰 使我能够与你们分享他的 见解以及这些片段 我想对约翰及其他人补充的是 我个人的想法是 我对未来充满希望 我相信这样的极具颠覆性的技术 例如我前面解释的干细胞一样 确实给了我们希望 我坚信我们能够 修复受损大脑的那一天 一定会提早到来 谢谢 (掌声)