I want to talk to you about the future of medicine. But before I do that, I want to talk a little bit about the past. Now, throughout much of the recent history of medicine, we've thought about illness and treatment in terms of a profoundly simple model. In fact, the model is so simple that you could summarize it in six words: have disease, take pill, kill something.
我想跟各位聊聊未来的药物。 在聊未来之前, 我想稍稍回顾一下过去。 纵观医疗药物的历史, 我们对于疾病和药物治疗的观念 还停留在一个非常简单的模型上。 事实上这个模型简单到 可以用六个英语单词概括: 生病,吃药,杀死一些东西。
Now, the reason for the dominance of this model is of course the antibiotic revolution. Many of you might not know this, but we happen to be celebrating the hundredth year of the introduction of antibiotics into the United States. But what you do know is that that introduction was nothing short of transformative. Here you had a chemical, either from the natural world or artificially synthesized in the laboratory, and it would course through your body, it would find its target, lock into its target -- a microbe or some part of a microbe -- and then turn off a lock and a key with exquisite deftness, exquisite specificity. And you would end up taking a previously fatal, lethal disease -- a pneumonia, syphilis, tuberculosis -- and transforming that into a curable, or treatable illness. You have a pneumonia, you take penicillin, you kill the microbe and you cure the disease.
这个简单的模型占据主导地位 原因显然是由于抗生素革命带来的。 可能很少有人知道, 我们前不久 刚刚庆祝了抗生素 进入美国一百周年。 但你们一定知道, 抗生素的引入简直是个重大变革。 你拿到的化学制剂, 不管是从自然提取的 还是从实验室人工合成的, 服用之后它会遍布至你的全身 找到它的目标 然后锁定目标—— 一种微生物或者它的一部分—— 通过非常精巧和特别的手段 关闭目标的某一个功能。 结果就是当你感染了 过去的不治之症—— 例如肺炎,梅毒,肺结核—— 变成可以治愈的疾病。 如果你感染了肺炎, 你可以服用盘尼西林, 你杀死了微生物, 你治好了疾病。
So seductive was this idea, so potent the metaphor of lock and key and killing something, that it really swept through biology. It was a transformation like no other. And we've really spent the last 100 years trying to replicate that model over and over again in noninfectious diseases, in chronic diseases like diabetes and hypertension and heart disease. And it's worked, but it's only worked partly. Let me show you. You know, if you take the entire universe of all chemical reactions in the human body, every chemical reaction that your body is capable of, most people think that that number is on the order of a million. Let's call it a million. And now you ask the question, what number or fraction of reactions can actually be targeted by the entire pharmacopoeia, all of medicinal chemistry? That number is 250. The rest is chemical darkness. In other words, 0.025 percent of all chemical reactions in your body are actually targetable by this lock and key mechanism. You know, if you think about human physiology as a vast global telephone network with interacting nodes and interacting pieces, then all of our medicinal chemistry is operating on one tiny corner at the edge, the outer edge, of that network. It's like all of our pharmaceutical chemistry is a pole operator in Wichita, Kansas who is tinkering with about 10 or 15 telephone lines.
多么美妙的想法, 钥匙、锁的比喻多么贴切 还有杀死一些东西的归纳, 横扫了生物医学。 这种转变是史无前例的。 而过去100年间 我们一直不停的尝试复制这个模型 想要用到非感染导致的疾病上, 像是糖尿病、高血压、 心脏病之类的慢性病。 有些管用,有些不行。 让我来详细说明。 现在如果把你体内 所有可能的化学反应 都列举出来组成一个大集合 大部分人都会觉得至少得上百万种反应。 我们假设是100万种。 现在你会问, 在所有药物的医学化学反应中 有多少部分是真正能够有效锁定的? 答案是250个。 其他是未知的化学领域。 换句话说 你体内只有 0.025% 的化学反应 适用于现在的钥匙和锁的机制。 如果你将人体生理学 看成是一个巨大的全球的电话网络, 有着相互作用的节点和部分, 那么我们所有的化学药物加起来 也只是占据了 这个巨大网络的一个小小边角。 我们现有的药物加起来就像是 堪萨斯州州威奇托市的一个小小接线员 在笨拙地处理10条或15条电话线。
So what do we do about this idea? What if we reorganized this approach? In fact, it turns out that the natural world gives us a sense of how one might think about illness in a radically different way, rather than disease, medicine, target. In fact, the natural world is organized hierarchically upwards, not downwards, but upwards, and we begin with a self-regulating, semi-autonomous unit called a cell. These self-regulating, semi-autonomous units give rise to self-regulating, semi-autonomous units called organs, and these organs coalesce to form things called humans, and these organisms ultimately live in environments, which are partly self-regulating and partly semi-autonomous.
所以现在我们应该怎么办? 我们是否能够重新组织现有的方式? 事实上,我们发现自然界 为我们提供了一个完全不一样的视角 去看待疾病。 跟“疾病,药物,目标”模式不同。 自然界是自下向上的 一层一层发展起来的, 不是自上向下,而是自下而上。 我们首先有了一些能够自我控制、 半自主的单位,称为细胞。 这些基本的单元 结合在一起组成了器官, 这些器官有机地组合在一起,构成了人 这最终构造了这个丰富的生态系统。 这个系统也是能够自我约束, 是半自主的。
What's nice about this scheme, this hierarchical scheme building upwards rather than downwards, is that it allows us to think about illness as well in a somewhat different way. Take a disease like cancer. Since the 1950s, we've tried rather desperately to apply this lock and key model to cancer. We've tried to kill cells using a variety of chemotherapies or targeted therapies, and as most of us know, that's worked. It's worked for diseases like leukemia. It's worked for some forms of breast cancer, but eventually you run to the ceiling of that approach. And it's only in the last 10 years or so that we've begun to think about using the immune system, remembering that in fact the cancer cell doesn't grow in a vacuum. It actually grows in a human organism. And could you use the organismal capacity, the fact that human beings have an immune system, to attack cancer? In fact, it's led to the some of the most spectacular new medicines in cancer.
这种层次化的模式的好处在于, 相对于自上向下的模式而言, 它带给了我们一个完全不同的视角 去看待疾病。 拿癌症作为例子。 自从1950年代以来, 我们竭尽全力用锁和钥匙的模型去攻克癌症。 我们用了大量的靶向疗法 和放化疗手段去杀死细胞, 我们都知道这取得了一些效果。 对于白血病这样的疾病有效。 对于某些类型的乳腺癌有效, 但是最终你走到了这条路的尽头。 直到近10年前左右 我们开始考虑利用自身的免疫系统, 毕竟癌细胞并不是长在真空里的。 癌细胞确实是长在人体器官里的。 你可以用器官自身的机制来防御。 所以能够借用人类自身的 免疫系统去攻击癌细胞? 事实上这个思维转变诞生了 一些非常令人瞩目的新药物。
And finally there's the level of the environment, isn't there? You know, we don't think of cancer as altering the environment. But let me give you an example of a profoundly carcinogenic environment. It's called a prison. You take loneliness, you take depression, you take confinement, and you add to that, rolled up in a little white sheet of paper, one of the most potent neurostimulants that we know, called nicotine, and you add to that one of the most potent addictive substances that you know, and you have a pro-carcinogenic environment. But you can have anti-carcinogenic environments too. There are attempts to create milieus, change the hormonal milieu for breast cancer, for instance. We're trying to change the metabolic milieu for other forms of cancer.
最后还有环境级别的问题,不是么? 当我们改变环境的时候, 没想过癌症的问题 但是让我来给你展示一个 高度致癌物环境。 称之为「囚禁」。 你拿来孤独,你加上沮丧, 再加上约束, 都加上, 放在一张白纸上卷起来, 加上一种最为有效的 神经刺激物,尼古丁, 你把这种最容易成瘾的 致癌成分放进来, 你就有了一个容易 引发癌症的环境。 但是你也可以拥有抗癌症环境。 可以尝试自己创造一个小环境, 例如为了预防乳腺癌 而改变荷尔蒙环境。 我们正在尝试为其它癌症 而改变新陈代谢环境。
Or take another disease, like depression. Again, working upwards, since the 1960s and 1970s, we've tried, again, desperately to turn off molecules that operate between nerve cells -- serotonin, dopamine -- and tried to cure depression that way, and that's worked, but then that reached the limit. And we now know that what you really probably need to do is to change the physiology of the organ, the brain, rewire it, remodel it, and that, of course, we know study upon study has shown that talk therapy does exactly that, and study upon study has shown that talk therapy combined with medicines, pills, really is much more effective than either one alone. Can we imagine a more immersive environment that will change depression? Can you lock out the signals that elicit depression? Again, moving upwards along this hierarchical chain of organization. What's really at stake perhaps here is not the medicine itself but a metaphor. Rather than killing something, in the case of the great chronic degenerative diseases -- kidney failure, diabetes, hypertension, osteoarthritis -- maybe what we really need to do is change the metaphor to growing something. And that's the key, perhaps, to reframing our thinking about medicine.
或者像是抑郁这样的疾病。 再次重申,自下向上地, 从1960和1970年代开始, 我们当时还是竭力地 尝试去关闭神经细胞 之间运行的分子 如血清素、多巴胺 尝试从这个角度治疗抑郁。 一开始有一些进展, 但是很快就走到了尽头。 现在我们知道,更好的方式 或许是改变组织的生理状况, 也就是大脑的结构 改变大脑的结构和连接, 而且,理所当然的,我们注意到 谈话疗法能够有效的做到这一点, 并且后续的研究也表明 谈话疗法和药物质量的结合 要比单独使用任何一种方法 都要更加有效。 我们能否构想出一种 能够改变抑郁的浸入式的环境? 你能够完全隔绝抑郁 发出的刺激信号吗? 再次重申,需要顺着组织构成的 层次自下向上地考虑。 在这里最重要的事情, 可能不是有药物本身, 而是比喻的说法 相比于现在的“杀死某些东西”, 对于大量的慢性退行性疾病—— 肾衰竭、糖尿病、高血压、关节炎 或许我们要做的反而 应该是“培养一些东西”。 而这之中的关键, 可能就是重塑我们的药物观。
Now, this idea of changing, of creating a perceptual shift, as it were, came home to me to roost in a very personal manner about 10 years ago. About 10 years ago -- I've been a runner most of my life -- I went for a run, a Saturday morning run, I came back and woke up and I basically couldn't move. My right knee was swollen up, and you could hear that ominous crunch of bone against bone. And one of the perks of being a physician is that you get to order your own MRIs. And I had an MRI the next week, and it looked like that. Essentially, the meniscus of cartilage that is between bone had been completely torn and the bone itself had been shattered.
这个想法, 即感知认识上的转变, 来自我10年前一次个人经历。 大概10年前——我常年跑步—— 我在周六早上照常跑了一会儿, 回来后从床上醒来时 发现腿动不了了。 我的右膝盖肿得厉害 而且能够听见骨头跟骨头摩擦的声音。 做医生有一样好处, 便是可以自己预约MRI扫描。 第二周我做了MRI扫描, 结果就像展示的那样 简单的说, 骨头之间的半月型软骨层 已经被彻底的磨掉了, 骨头也受损了。
Now, if you're looking at me and feeling sorry, let me tell you a few facts. If I was to take an MRI of every person in this audience, 60 percent of you would show signs of bone degeneration and cartilage degeneration like this. 85 percent of all women by the age of 70 would show moderate to severe cartilage degeneration. 50 to 60 percent of the men in this audience would also have such signs. So this is a very common disease. Well, the second perk of being a physician is that you can get to experiment on your own ailments. So about 10 years ago we began, we brought this process into the laboratory, and we began to do simple experiments, mechanically trying to fix this degeneration. We tried to inject chemicals into the knee spaces of animals to try to reverse cartilage degeneration, and to put a short summary on a very long and painful process, essentially it came to naught. Nothing happened. And then about seven years ago, we had a research student from Australia. The nice thing about Australians is that they're habitually used to looking at the world upside down.
现在,如果你为我感到难过, 那么让我来告诉你一些信息。 如果给在做的所有人都做一次MRI, 在座各位中60%以上的人 会看到跟我一样的 骨头和软骨退化的迹象。 70岁以上女性中有85%的人 会出现中度或重度的软骨退化。 在座的男性中有50%到60% 已经出现了这种症状。 所以这是非常常见的疾病。 作为医生的第二个好处 是你可以自己给自己治病。 所以大约10年前,我们开始着手, 把这些方法带到实验室。 并且开始做一些简单的实验, 呆板地想解决退化的问题。 我们尝试了将一些化学成分 注入动物的关节囊 尝试反转退化现象, 经过了痛苦而漫长的尝试, 结果简单概括就是, 基本上没有任何效果。 一点用都没有,什么都没发生。 直到大概7年前, 我们来了个澳大利亚研究生。 澳洲人的优点 就是他们习惯把世界倒转来看。
(Laughter)
(笑声)
And so Dan suggested to me, "You know, maybe it isn't a mechanical problem. Maybe it isn't a chemical problem. Maybe it's a stem cell problem." In other words, he had two hypotheses. Number one, there is such a thing as a skeletal stem cell -- a skeletal stem cell that builds up the entire vertebrate skeleton, bone, cartilage and the fibrous elements of skeleton, just like there's a stem cell in blood, just like there's a stem cell in the nervous system. And two, that maybe that, the degeneration or dysfunction of this stem cell is what's causing osteochondral arthritis, a very common ailment. So really the question was, were we looking for a pill when we should have really been looking for a cell. So we switched our models, and now we began to look for skeletal stem cells. And to cut again a long story short, about five years ago, we found these cells. They live inside the skeleton. Here's a schematic and then a real photograph of one of them. The white stuff is bone, and these red columns that you see and the yellow cells are cells that have arisen from one single skeletal stem cell -- columns of cartilage, columns of bone coming out of a single cell. These cells are fascinating. They have four properties. Number one is that they live where they're expected to live. They live just underneath the surface of the bone, underneath cartilage. You know, in biology, it's location, location, location. And they move into the appropriate areas and form bone and cartilage. That's one. Here's an interesting property. You can take them out of the vertebrate skeleton, you can culture them in petri dishes in the laboratory, and they are dying to form cartilage. Remember how we couldn't form cartilage for love or money? These cells are dying to form cartilage. They form their own furls of cartilage around themselves. They're also, number three, the most efficient repairers of fractures that we've ever encountered. This is a little bone, a mouse bone that we fractured and then let it heal by itself. These stem cells have come in and repaired, in yellow, the bone, in white, the cartilage, almost completely. So much so that if you label them with a fluorescent dye you can see them like some kind of peculiar cellular glue coming into the area of a fracture, fixing it locally and then stopping their work. Now, the fourth one is the most ominous, and that is that their numbers decline precipitously, precipitously, tenfold, fiftyfold, as you age.
这个名叫丹的学生跟我说, “或许这不是机能问题,” “或许也不是化学问题, 或许是干细胞问题。” 换句话说,他有两个假想: 第一,假設真有这样的骨干细胞-- 构造了整个脊椎骨架, 骨头、软骨组织、 以及骨架周边的支持物, 就像是血液中的造血干细胞, 就像是神进系统中的神经干细胞。 假设二,可能是因为 骨干细胞的退化或失能, 导致了关节炎这种常见的疾病。 所以问题根源可能在于 我们一直在找治疗药物 但是实际上我们应该寻找的是这种细胞。 于是我们换用了新模型, 开始寻找这种骨干细胞。 长话短说, 大概五年前我们终于找到了。 它们存在于骨架内部。 图上是原理图和真实的骨头 白色的是骨头, 你看到的红色管狀的,黄色的细胞 都是由一个单独的 干细胞生长而来的—— 软骨、骨组织都来自同一个干细胞, 这些细胞太神奇了, 它们有四个特点。 第一,它们就存在于 我们预期的位置。 它们就存在于骨头表面之下, 存在于软骨组织下面。 你或许知道在生物学上, 位置是很重要的, 所以这些干细胞移动到了 合适的位置方便生成骨和软骨。 这是第一个特点。 还有一个有意思的特点。 你可以将这些细胞从 脊椎动物骨架中分离出来 放在实验室的培养皿中, 它们会拼命的构造软骨组织。 要知道我们无论用多少钱和 爱都没办法生成软骨。 它们会拼命的构造软骨组织。 它们通过构造软骨组织把自己卷起来。 第三点, 它们是我们见过的最神速的修补匠。 这是一个老鼠的骨头 被我们掰断了 然后任由其自然恢复。 骨干细胞出现 修复了骨头(黄色部分) 修复了软骨(白色部分) 基本上完好如初。 所以基本上 如果你给这些细胞染上颜色 你就能够看到 它们就像是某种细胞胶水 填充到骨折的地方, 修复好,然后收工。 现在,第四点也是最不好的, 这些细胞的数量 下降地出乎意料的快, 随着你的年龄 十倍或者十五倍的减少。
And so what had happened, really, is that we found ourselves in a perceptual shift. We had gone hunting for pills but we ended up finding theories. And in some ways we had hooked ourselves back onto this idea: cells, organisms, environments, because we were now thinking about bone stem cells, we were thinking about arthritis in terms of a cellular disease.
这里最重要的, 是我们发现自己的观念转变了。 我们一开始是为了寻找药物而努力 最后却发现了新的理论。 从某个角度看, 我们回到了一开始的想法上: 细胞,组织,环境, 现在我们从骨干细胞的角度出发 我们开始将关节炎 当作是细胞疾病来看待。
And then the next question was, are there organs? Can you build this as an organ outside the body? Can you implant cartilage into areas of trauma? And perhaps most interestingly, can you ascend right up and create environments? You know, we know that exercise remodels bone, but come on, none of us is going to exercise. So could you imagine ways of passively loading and unloading bone so that you can recreate or regenerate degenerating cartilage?
接下来的问题就是 那么器官级别的呢? 我们能在体外培育这样的器官么? 我们能够在磨损的位置直接植入软骨么? 还有更加有趣的, 我们能否继续向上 创造出适宜的环境? 当然,我们都知道运动可以重塑骨骼, 但是得了吧,没人愿意运动。 所以你想过有一天 你能把骨头拆下来再装回去 这样你就可以重塑 已经退化的软骨组织了?
And perhaps more interesting, and more importantly, the question is, can you apply this model more globally outside medicine? What's at stake, as I said before, is not killing something, but growing something. And it raises a series of, I think, some of the most interesting questions about how we think about medicine in the future. Could your medicine be a cell and not a pill? How would we grow these cells? What we would we do to stop the malignant growth of these cells? We heard about the problems of unleashing growth. Could we implant suicide genes into these cells to stop them from growing? Could your medicine be an organ that's created outside the body and then implanted into the body? Could that stop some of the degeneration? What if the organ needed to have memory? In cases of diseases of the nervous system some of those organs had memory. How could we implant those memories back in? Could we store these organs? Would each organ have to be developed for an individual human being and put back? And perhaps most puzzlingly, could your medicine be an environment? Could you patent an environment? You know, in every culture, shamans have been using environments as medicines. Could we imagine that for our future? I've talked a lot about models. I began this talk with models. So let me end with some thoughts about model building. That's what we do as scientists. You know, when an architect builds a model, he or she is trying to show you a world in miniature. But when a scientist is building a model, he or she is trying to show you the world in metaphor. He or she is trying to create a new way of seeing. The former is a scale shift. The latter is a perceptual shift.
最有意思、也是最重要的, 这个模型能否 更加广泛的在医疗界推广? 重要的是,如我之前所言, 不是杀死什么 而是培育什么 这进一步的引发了 一系列有趣的问题, 影响到我们未来对于药物观念。 (未来)你的药物有没有可能 不是药片而是细胞? 我们如何培育这些细胞? 我们如何阻止这些细胞的恶性增殖? 我们已经听说了不受控的细胞增殖。 我们能否在细胞中植入一些自杀基因 来阻止它们的增长? 未来你的药物有没有可能 就是一个身体器官 在体外培育然后植入体内? 这样能否阻止器官的老化? 如果这些器官需要记忆呢? 例如神经系统中的一些器官保存了记忆。 我们怎么把这些记忆移植回来? 我们能保存这些器官么? 这些器官能否根据 患者的不同而分别培育 然后再移植回去? 最后可能是最令人困惑的, 你的药物可以是环境么? 治疗的环境能否 (像药物一样)申请专利? 每个人类文化里 都有巫师这样的角色, 将环境视为治疗的药物。 你能想象我们未来是那样的么? 我们聊了很多模型, 也是从模型开始说起的。 让我在结束的时候 再聊一聊如何构造模型。 我们科学家就是做这个的。 你知道,当建筑师建造一个模型, 他(她)会尝试用微型图 向你展示想象的世界 但是当一个科学家构造模型的时候, 他(她)给你展示的是世界的隐喻。 他(她)尝试从新的角度看这个世界。 前者是比例的变化, 后者是观念的变化。
Now, antibiotics created such a perceptual shift in our way of thinking about medicine that it really colored, distorted, very successfully, the way we've thought about medicine for the last hundred years. But we need new models to think about medicine in the future. That's what's at stake.
现在,抗生素创造了观念的变化 非常成功地改变了过去 百年来我们对药物的看法 以前的看法是过度夸张和歪曲事实。 但是未来我们需要新的模型。 这是最重要的。
You know, there's a popular trope out there that the reason we haven't had the transformative impact on the treatment of illness is because we don't have powerful-enough drugs, and that's partly true. But perhaps the real reason is that we don't have powerful-enough ways of thinking about medicines. It's certainly true that it would be lovely to have new medicines. But perhaps what's really at stake are three more intangible M's: mechanisms, models, metaphors.
你知道的,现在有种论调很流行 说我们之所以在疾病的治疗上 没有改革性的影响 是因为我们还没有找到足够强大的药物, 这倒说对了一半。 但是可能真正的原因是 我们对药物没有足够强大的思维模式。 有一点是肯定的 有新的药物自然是令人喜悦的。 但是可能当前最紧要的 还是这三个难以理解的" M " 机制、模型、隐喻。
Thank you.
感谢大家。
(Applause)
(掌声)
Chris Anderson: I really like this metaphor. How does it link in? There's a lot of talk in technologyland about the personalization of medicine, that we have all this data and that medical treatments of the future will be for you specifically, your genome, your current context. Does that apply to this model you've got here?
Chris Anderson:我真的喜欢这种隐喻方法。 它们怎么联系起来的? 科技领域有很多的讨论 都提到了个体化医疗, 说我们汇集所有的数据,然后 未来的药物会基于你的基因组 和所处环境量身定做 这种说法跟你提到的模型是契合的吗?
Siddhartha Mukherjee: It's a very interesting question. We've thought about personalization of medicine very much in terms of genomics. That's because the gene is such a dominant metaphor, again, to use that same word, in medicine today, that we think the genome will drive the personalization of medicine. But of course the genome is just the bottom of a long chain of being, as it were. That chain of being, really the first organized unit of that, is the cell. So, if we are really going to deliver in medicine in this way, we have to think of personalizing cellular therapies, and then personalizing organ or organismal therapies, and ultimately personalizing immersion therapies for the environment. So I think at every stage, you know -- there's that metaphor, there's turtles all the way. Well, in this, there's personalization all the way.
SM:这个问题很有意思。 我们已经从基因角度考虑个体化医疗 有一段时间了。 那是因为基因本身就是主流的隐喻, 同样也是这个词,在今天的医疗界 我们认为基因组会主导 个体化医疗的进展。 但是显然的,基因组这个概念 只是这个链条最基础的部分。 这个链条最开始真正有 组织的单元是“细胞”。 所以如果我们真的要开始个体化医疗了, 我们需要考虑的是个性化的" 细胞疗法 ", 然后是个性化的组织和器官疗法, 最后的最后是个性化的 浸入式的环境疗法。 我觉得現在每个阶段...你知道 用一个比喻可以形容 -“龟速”。 也因如此,才可以做到醫療个性化。
CA: So when you say medicine could be a cell and not a pill, you're talking about potentially your own cells.
CA:所以当你说未来的药物是细胞 而不是药物的时候 你说的是有可能是自己的细胞?
SM: Absolutely. CA: So converted to stem cells, perhaps tested against all kinds of drugs or something, and prepared.
SM:绝对地。 CA:转换成干细胞, 可能还会跟各种药物或者 别的东西做测试,然后准备好。
SM: And there's no perhaps. This is what we're doing. This is what's happening, and in fact, we're slowly moving, not away from genomics, but incorporating genomics into what we call multi-order, semi-autonomous, self-regulating systems, like cells, like organs, like environments.
SM:这不是可能。我们现在就在做。 这是正在发生的事情, 实际上,我们正在慢慢取得进展。 并没有脱离基因组, 而是跟基因组结合 我们称之为多层级、半自动、自制系统, 像是细胞、器官、环境。
CA: Thank you so much.
CA:非常感谢。
SM: Pleasure. Thanks.
SM:很荣幸。谢谢。