TED, Siddhartha Mukherjee: Soon we'll cure diseases with a cell, not a pil (1)

Siddhartha Mukherjee: Soon we'll cure diseases with a cell, not a pil (1)

0:11 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.

0:42 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

1:48 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, 0025 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.

3:35So 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.

4:31What'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.

5:33And 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.

6:22Or 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.

7:42Now, 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.

8:21Now, 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.

9:27(Laughter)

9:28And 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.

11:53 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.

12:16 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?

12:45 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

Siddhartha Mukherjee: Soon we'll cure diseases with a cell, not a pil (1) |Mukherjee||||||||||tabletka Siddhartha Muk||em breve||||||||| Siddhartha Mukherjee: Bald werden wir Krankheiten mit einer Zelle heilen, nicht mit einem Pil (1) Siddhartha Mukherjee: Pronto curaremos enfermedades con una célula, no con un pil (1) Siddhartha Mukherjee : Bientôt, nous soignerons les maladies à l'aide d'une cellule et non d'une pilule (1) シッダールタ・ムカルジーピルではなく細胞で病気を治す日も近い (1) Siddhartha Mukherjee: Em breve curaremos doenças com uma célula, não com uma pilha (1) Сиддхартха Мукерджи: Скоро мы будем лечить болезни клеткой, а не таблеткой (1) Siddhartha Mukherjee: Yakında hastalıkları bir pil ile değil, bir hücre ile tedavi edeceğiz (1) Сіддхартха Мукерджі: Незабаром ми будемо лікувати хвороби клітиною, а не пілюлею (1) 释迦牟尼：我们很快就能用细胞而不是皮尔来治疗疾病 (1) 悉達多·慕克吉：很快我們將用細胞而不是細胞來治癒疾病 (1)

0:11 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. Итак, на протяжении большей части недавней истории медицины мы думали о болезни и лечении с точки зрения очень простой модели. In fact, the model is so simple that you could summarize it in six words: have disease, take pill, kill something.

0:42 Now, the reason for the dominance of this model is of course the antibiotic revolution. |||||||||||||antibiotic| 0:42 Причина доминирования этой модели, конечно, в революции антибиотиков. 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. ||||||||||||||one hundredth||||||antibiotics|||| Muchos de ustedes pueden no saber esto, pero estamos celebrando el centésimo año de la introducción de antibióticos en los Estados Unidos. But what you do know is that that introduction was nothing short of transformative. |||||||||||||life-changing Pero lo que sí sabes es que esa introducción fue nada menos que transformadora. Но что вы знаете, так это то, что это знакомство было не чем иным, как трансформацией. 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. ||||||||||||produced artificially||||||||||||||||||||||||||||||||||||||remarkable|skillful precision|| |||||||||||||||||||||||||||||||||||||||||||||||||||z niezwykłą zręcznością|| Aquí tenía un producto químico, ya sea del mundo natural o sintetizado artificialmente en el laboratorio, y atravesaría su cuerpo, encontraría su objetivo, se fijaría en su objetivo, un microbio o alguna parte de un microbio, y luego Apague una cerradura y una llave con una habilidad exquisita, una especificidad exquisita. Ici, vous aviez un produit chimique, soit du monde naturel, soit synthétisé artificiellement en laboratoire, et il traverserait votre corps, il trouverait sa cible, se verrouillerait dans sa cible - un microbe ou une partie d'un microbe - et ensuite éteignez une serrure et une clé avec une adresse exquise, une spécificité exquise. Здесь у вас было химическое вещество либо из природного мира, либо искусственно синтезированное в лаборатории, и оно проходило через ваше тело, находило свою цель, замыкалось на своей цели — микробе или какой-то части микроба — и затем отпирать замок и ключ с изысканной ловкостью, изысканной конкретностью. And you would end up taking a previously fatal, lethal disease -- a pneumonia, syphilis, tuberculosis -- and transforming that into a curable, or treatable illness. |||||||||deadly||||syphilis disease|tuberculosis||changing||||treatable condition||manageable| Y terminaría tomando una enfermedad letal, previamente mortal, como neumonía, sífilis, tuberculosis, y transformándola en una enfermedad curable o tratable. И в конечном итоге вы берете ранее смертельную, смертельную болезнь — пневмонию, сифилис, туберкулез — и превращаете ее в излечимую или излечимую болезнь. You have a pneumonia, you take penicillin, you kill the microbe and you cure the disease ||||||antibiotic treatment|||||||||

1:48 So seductive was this idea, so potent the metaphor of lock and key and killing something, that it really swept through biology. ||||concept||||||||||||||||| |uwodzicielska|||||potężna||||||||||||||| 1:48 Tan seductora fue esta idea, tan potente la metáfora de la cerradura y la llave y matar algo, que realmente barrió la biología. 1:48 Настолько заманчивой была эта идея, настолько мощной была метафора замка и ключа и чего-то убивающего, что она буквально захлестнула всю биологию. It was a transformation like no other. Это была трансформация, как никакая другая. 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. |||||||||||||||||non-contagious||||||||high blood pressure||| 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. Вы знаете, если вы возьмете всю вселенную всех химических реакций в человеческом теле, каждую химическую реакцию, на которую способно ваше тело, большинство людей думают, что это число порядка миллиона. 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? |||||||||||||||||||collection of drugs|||| Y ahora hace la pregunta, ¿a qué número o fracción de reacciones puede dirigirse realmente la farmacopea completa, toda la química medicinal? That number is 250. The rest is chemical darkness. El resto es oscuridad química. In other words, 0025 percent of all chemical reactions in your body are actually targetable by this lock and key mechanism. En otras palabras, este mecanismo de cerradura y llave se puede dirigir 0025 por ciento de todas las reacciones químicas en su cuerpo. Другими словами, 0,025% всех химических реакций в вашем теле на самом деле являются целевыми для этого механизма замка и ключа. 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. Usted sabe, si piensa en la fisiología humana como una vasta red telefónica global con nodos interactivos y piezas interactivas, entonces toda nuestra química médica está operando en una pequeña esquina en el borde, el borde exterior, de esa red. Vous savez, si vous pensez à la physiologie humaine comme à un vaste réseau téléphonique mondial avec des nœuds et des éléments en interaction, alors toute notre chimie médicinale opère sur un petit coin au bord, le bord extérieur, de ce réseau. Вы знаете, если вы представляете человеческую физиологию как огромную глобальную телефонную сеть с взаимодействующими узлами и взаимодействующими частями, тогда вся наша медицинская химия работает в одном крошечном уголке на краю, на внешнем краю этой сети. 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. |||||pharmaceutical|||||pole operator||Wichita Kansas||||||||| ||||||||||||Wichita|Kansas|||majstruje||||| Es como que toda nuestra química farmacéutica es un operador de polos en Wichita, Kansas, que está jugando con unas 10 o 15 líneas telefónicas. Это похоже на то, что вся наша фармацевтическая химия — это оператор столба в Уичито, штат Канзас, который возится с 10 или 15 телефонными линиями.

3:35So what do we do about this idea? What if we reorganized this approach? |||restructured|| |||przeorganizowalibyśmy|| Et si nous réorganisions cette approche? 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. De hecho, resulta que el mundo natural nos da una idea de cómo uno podría pensar acerca de la enfermedad de una manera radicalmente diferente, en lugar de la enfermedad, la medicina, el objetivo. На самом деле оказывается, что мир природы дает нам представление о том, как можно радикально по-другому думать о болезни, а не о болезни, лекарстве, цели. 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. |||||||in levels||||||||||||||partially independent|||| De hecho, el mundo natural está organizado jerárquicamente hacia arriba, no hacia abajo, sino hacia arriba, y comenzamos con una unidad semiautónoma autorreguladora llamada célula. En fait, le monde naturel est organisé hiérarchiquement vers le haut, non pas vers le bas, mais vers le haut, et nous commençons par une unité auto-régulée et semi-autonome appelée cellule. 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. |||||||||||||||||||combine together||||||||||||||||||||| Estas unidades autorreguladoras, semiautónomas, dan lugar a unidades autorreguladoras, semiautónomas llamadas órganos, y estos órganos se unen para formar cosas llamadas humanos, y estos organismos finalmente viven en entornos, que son en parte autorregulados y en parte semi. -autónomo. Ces unités semi-autonomes autorégulatrices donnent lieu à des unités semi-autonomes autorégulatrices appelées organes, et ces organes fusionnent pour former des choses appelées humains, et ces organismes vivent finalement dans des environnements, qui sont en partie autorégulés et en partie semi-autonomes. -autonome. Эти саморегулирующиеся, полуавтономные единицы дают начало саморегулирующимся, полуавтономным единицам, называемым органами, и эти органы сливаются, образуя вещи, называемые людьми, и эти организмы в конечном итоге живут в средах, которые частично саморегулируются, а частично полуавтономны. -автономный.

4:31What’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. |||||||hierarchical structure||||||||||||||||||||| 4: 31Lo bueno de este esquema, este esquema jerárquico que se construye hacia arriba y no hacia abajo, es que nos permite pensar en la enfermedad también de una manera algo diferente. 4:31 Что хорошо в этой схеме, в этой иерархической схеме, строящейся вверх, а не вниз, так это то, что она позволяет нам думать и о болезни несколько по-другому. Take a disease like cancer. Since the 1950s, we’ve tried rather desperately to apply this lock and key model to cancer. Desde la década de 1950, hemos intentado con bastante desesperación aplicar este modelo de candado y llave al cáncer. С 1950-х годов мы довольно отчаянно пытались применить эту модель замка и ключа к раку. 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. |||||||||cancer treatments|||||||||||||||||leukemia Hemos intentado matar las células utilizando una variedad de quimioterapias o terapias dirigidas, y como la mayoría de nosotros sabemos, funcionó para enfermedades como la leucemia. It’s worked for some forms of breast cancer, but eventually you run to the ceiling of that approach. Ha funcionado para algunas formas de cáncer de mama, pero eventualmente corres hacia el techo de ese enfoque. Это работало для некоторых форм рака молочной железы, но в конечном итоге вы упираетесь в потолок этого подхода. 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. Y solo en los últimos 10 años hemos empezado a pensar en usar el sistema inmunológico, recordando que, de hecho, la célula cancerosa no crece en el vacío. 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? |||||organism-level||||||||||||| Et pourriez-vous utiliser la capacité de l'organisme, le fait que les êtres humains ont un système immunitaire, pour attaquer le cancer? И могли бы вы использовать способность организма, тот факт, что у людей есть иммунная система, для борьбы с раком? In fact, it’s led to the some of the most spectacular new medicines in cancer. De hecho, ha llevado a algunos de los medicamentos nuevos más espectaculares en el cáncer. На самом деле, это привело к появлению одних из самых впечатляющих новых лекарств от рака.

5:33And finally there’s the level of the environment, isn’t there? You know, we don’t think of cancer as altering the environment. Sabes, no pensamos que el cáncer altere el medio ambiente. Знаете, мы не думаем о раке как об изменении окружающей среды. But let me give you an example of a profoundly carcinogenic environment. ||||||||||cancer-causing| Но позвольте мне привести вам пример глубоко канцерогенной среды. 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. ||||||||isolation||||||||||||||||||||neurostimulants|||||nicotine|||||||||||||||||||||| Tomas la soledad, tomas la depresión, te encierras y te sumas a eso, enrollado en una pequeña hoja de papel blanco, uno de los neuroestimulantes más potentes que conocemos, llamado nicotina, y le sumas uno de los más Potentes sustancias adictivas que usted conoce, y tiene un ambiente pro-carcinogénico. Vous prenez la solitude, vous prenez la dépression, vous prenez le confinement, et vous ajoutez à cela, enroulé dans une petite feuille de papier blanc, l'un des neurostimulants les plus puissants que l'on connaisse, appelé nicotine, et vous ajoutez à cela l'un des plus puissants. substances addictives puissantes que vous connaissez, et vous avez un environnement pro-cancérigène. Вы берете одиночество, берете депрессию, берете заключение и добавляете к этому, завернутый в маленький белый лист бумаги, один из самых мощных известных нам нейростимуляторов, называемый никотином, и вы добавляете к этому один из самых сильнодействующие вещества, вызывающие привыкание, которые вы знаете, и у вас есть проканцерогенная среда. But you can have anti-carcinogenic environments too There are attempts to create milieus, change the hormonal milieu for breast cancer, for instance. |||||||||||||environments|||hormone-related|||||| |||||||||||||środowiska||||||||| Pero también puede tener ambientes anticancerígenos. Hay intentos de crear ambientes, cambiar el medio hormonal para el cáncer de mama, por ejemplo. Mais vous pouvez aussi avoir des environnements anti-cancérigènes. Il y a des tentatives pour créer des milieux, changer le milieu hormonal pour le cancer du sein, par exemple. Но у вас может быть и антиканцерогенная среда. Есть попытки создать среду, изменить гормональную среду для рака молочной железы, например. We’re trying to change the metabolic milieu for other forms of cancer. ||||||środowisko metaboliczne||||| Estamos tratando de cambiar el medio metabólico para otras formas de cáncer. Мы пытаемся изменить метаболическую среду для других форм рака.

6:22Or take another disease, like depression. 6: 22 O toma otra enfermedad, como la depresión. 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. Nuevamente, trabajando hacia arriba, desde los años sesenta y setenta, intentamos, nuevamente, desactivar las moléculas que operan entre las células nerviosas (serotonina, dopamina) y tratar de curar la depresión de esa manera, y eso funcionó, pero luego alcanzado el limite Опять же, двигаясь вверх, начиная с 1960-х и 1970-х годов, мы снова отчаянно пытались выключить молекулы, которые действуют между нервными клетками — серотонин, дофамин — и пытались вылечить таким образом депрессию, и это сработало, но потом достиг предела. 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. ||||||||||||||||||||||||reshape|||||||||||||||||||||||||||||||medications||||||||| Y ahora sabemos que lo que realmente necesita hacer es cambiar la fisiología del órgano, el cerebro, volver a cablearlo, remodelarlo y, por supuesto, sabemos que el estudio en estudio ha demostrado que la terapia de conversación hace exactamente eso. y un estudio tras otro estudio ha demostrado que la terapia de conversación combinada con medicamentos, píldoras, en realidad es mucho más efectiva que cualquiera de las dos. И теперь мы знаем, что на самом деле вам, вероятно, нужно изменить физиологию органа, мозга, перестроить его, реконструировать, и что, конечно же, мы знаем, что исследование за исследованием показало, что разговорная терапия делает именно это, и исследование за исследованием показало, что разговорная терапия в сочетании с лекарствами, таблетками, действительно намного эффективнее, чем каждый из них по отдельности. Can we imagine a more immersive environment that will change depression? |||||engaging||||| |||||immersyjna||||| ¿Podemos imaginar un ambiente más envolvente que cambie la depresión? Kunnen we ons een meer meeslepende omgeving voorstellen die depressie zal veranderen? Можем ли мы представить более иммерсивную среду, которая изменит депрессию? Can you lock out the signals that elicit depression? ¿Se puede bloquear las señales que provocan la depresión? Pouvez-vous verrouiller les signaux qui provoquent la dépression? Можете ли вы заблокировать сигналы, вызывающие депрессию? Again, moving upwards along this hierarchical chain of organization. De nuevo, moviéndose hacia arriba a lo largo de esta cadena jerárquica de organización. What’s really at stake perhaps here is not the medicine itself but a metaphor. Lo que realmente está en juego quizás aquí no es la medicina en sí, sino una metáfora. Ce qui est vraiment en jeu ici n'est peut-être pas la médecine elle-même mais une métaphore. Возможно, здесь на карту поставлено не само лекарство, а метафора. 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. |||||||||||chronic progressive||kidney failure||||joint disease|||||||||||||| En lugar de matar algo, en el caso de las grandes enfermedades crónicas degenerativas (insuficiencia renal, diabetes, hipertensión, osteoartritis), tal vez lo que realmente necesitamos hacer es cambiar la metáfora para hacer crecer algo. Вместо того, чтобы что-то убивать, в случае серьезных хронических дегенеративных заболеваний — почечной недостаточности, диабета, гипертонии, остеоартрита — возможно, нам действительно нужно изменить метафору на выращивание чего-то. And that’s the key, perhaps, to reframing our thinking about medicine. ||||||reshaping|||| ||||||przekształceniu|||| Y esa es la clave, tal vez, para reformular nuestro pensamiento sobre la medicina. En dat is misschien de sleutel om ons denken over medicijnen te herzien. И это, возможно, ключ к переосмыслению нашего мышления о медицине.

7:42Now, 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. ||||||||||||||||||osiadła||||||||||||||||||||||||||||||||||||||| 7: 42 Ahora, esta idea de cambiar, de crear un cambio perceptivo, por así decirlo, llegó a mi casa para acomodarme de manera muy personal hace unos 10 años Hace unos 10 años, he sido un corredor la mayor parte de mi vida - Fui a correr, un sábado por la mañana, volví y me desperté y básicamente no podía moverme. 7: 42Maintenant, cette idée de changer, de créer un changement de perception, pour ainsi dire, m'est venue pour me percher d'une manière très personnelle il y a environ 10 ans il y a environ 10 ans - j'ai été un coureur presque toute ma vie - Je suis allé courir, courir samedi matin, je suis revenu et je me suis réveillé et je ne pouvais pratiquement pas bouger. 7:42 Так вот, эта идея измениться, создать сдвиг восприятия, так сказать, пришла ко мне очень лично, чтобы насестить около 10 лет назад. Около 10 лет назад — я был бегуном большую часть своей жизни. -- Я пошел на пробежку, субботнюю утреннюю пробежку, вернулся, проснулся и практически не мог двигаться. My right knee was swollen up, and you could hear that ominous crunch of bone against bone. |||||||||||złowieszczy||||| Mi rodilla derecha estaba hinchada, y se podía oír ese crujiente siniestro de hueso contra hueso. Мое правое колено распухло, и был слышен зловещий хруст кости о кость. And one of the perks of being a physician is that you get to order your own MRIs. |||||||||||||||||magnetic resonance imaging Y una de las ventajas de ser un médico es que puede ordenar sus propias resonancias magnéticas. Et l'un des avantages d'être médecin est que vous pouvez commander vos propres IRM. И одно из преимуществ профессии врача заключается в том, что вы сами можете заказать МРТ. And I had an MRI the next week, and it looked like that. Y tuve una resonancia magnética la próxima semana, y se veía así. Essentially, the meniscus of cartilage that is between bone had been completely torn and the bone itself had been shattered. ||cartilage structure||||||||||||||||| ||||chrząstki||||||||||||||| Esencialmente, el menisco del cartílago que se encuentra entre el hueso se había desgarrado completamente y el propio hueso se había roto. Essentiellement, le ménisque du cartilage qui se trouve entre les os avait été complètement déchiré et l'os lui-même avait été brisé. По сути, мениск хряща, который находится между костью, был полностью разорван, а сама кость разрушена.

8:21Now, if you’re looking at me and feeling sorry, let me tell you a few facts. 8: 21 Ahora, si me miras y sientes pena, déjame contarte algunos hechos. 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. |||||||||||||||||||||bone deterioration||||| Если бы я сделал МРТ каждого человека в этой аудитории, у 60 процентов из вас были бы признаки дегенерации костей и хрящей, подобные этим. 85 percent of all women by the age of 70 would show moderate to severe cartilage degeneration. У 85 процентов всех женщин к 70 годам наблюдается умеренная или тяжелая дегенерация хряща. 50 to 60 percent of the men in this audience would also have such signs. От 50 до 60 процентов мужчин в этой аудитории также имели бы такие признаки. 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. ||||||||||zaleta|||||||||||||||dolegliwości Entonces, esta es una enfermedad muy común. Bueno, la segunda ventaja de ser un médico es que puedes experimentar con tus propias dolencias. Итак, это очень распространенное заболевание. Что ж, второе преимущество профессии врача заключается в том, что вы можете экспериментировать со своими собственными недугами. 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. Así que hace unos 10 años que comenzamos, trajimos este proceso al laboratorio y comenzamos a hacer experimentos simples, tratando de reparar mecánicamente esta degeneración. 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. |||introduce|||||||||||||||||||||||||||||||nothing Tratamos de inyectar productos químicos en los espacios de las rodillas de los animales para tratar de revertir la degeneración del cartílago, y para poner un breve resumen de un proceso muy largo y doloroso, esencialmente no llegó a nada. Nous avons essayé d'injecter des produits chimiques dans les espaces des genoux des animaux pour essayer d'inverser la dégénérescence du cartilage, et de résumer brièvement un processus très long et douloureux, qui n'a essentiellement abouti à rien. Мы пытались вводить химикаты в коленные суставы животных, чтобы попытаться обратить вспять дегенерацию хрящей, и, если коротко, очень долгий и болезненный процесс, по сути, он ни к чему не привел. 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. ||||||||usually|||||||| ||||||||zwykle|||||||| Lo bueno de los australianos es que habitualmente están acostumbrados a mirar el mundo al revés. Что хорошо в австралийцах, так это то, что они привыкли смотреть на мир вверх ногами.

9:27(Laughter)

9:28And 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." Tal vez sea un problema de células madre ". Может быть, это проблема со стволовыми клетками». 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. ||||||||||||||||related to skeleton||||||||||||||||||connective tissue||||||||||||||||||||| ||||||||||||||||||||||||||||kręgowca||||||||||||||||||||||||||| En otras palabras, tenía dos hipótesis, número uno: existe una célula madre esquelética: una célula madre esquelética que forma el esqueleto de los vertebrados, el hueso, el cartílago y los elementos fibrosos del esqueleto, como si fuera un vástago. Célula en la sangre, al igual que hay una célula madre en el sistema nervioso. Другими словами, у него было две гипотезы. Во-первых, существует такая вещь, как скелетная стволовая клетка — скелетная стволовая клетка, которая строит весь скелет позвоночного, кость, хрящ и волокнистые элементы скелета, точно так же, как есть ствол. клетка в крови, точно так же, как есть стволовая клетка в нервной системе. And two, that maybe that, the degeneration or dysfunction of this stem cell is what’s causing osteochondral arthritis, a very common ailment. ||||||||malfunction||||||||joint cartilage|joint inflammation||||condition ||||||||||||||||osteochondralna||||| Y dos, que tal vez eso, la degeneración o disfunción de esta célula madre es lo que está causando la artritis osteocondral, una enfermedad muy común. Во-вторых, возможно, дегенерация или дисфункция этой стволовой клетки вызывает остеохондральный артрит, очень распространенное заболевание. So really the question was, were we looking for a pill when we should have really been looking for a cell. Entonces, realmente la pregunta era si estábamos buscando una píldora cuando deberíamos haber estado buscando una célula. So we switched our models, and now we began to look for skeletal stem cells. |we (first person plural)||||||||||||| Así que cambiamos nuestros modelos, y ahora empezamos a buscar células madre esqueléticas. Так что мы поменяли наши модели, и теперь мы начали искать скелетные стволовые клетки. And to cut again a long story short, about five years ago, we found these cells. Y para recortar una larga historia corta, hace unos cinco años, encontramos estas células. They live inside the skeleton. Here’s a schematic and then a real photograph of one of them. ||diagram|||||||one of|| Aquí hay un esquema y luego una fotografía real de uno de ellos. 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. El material blanco es hueso, y estas columnas rojas que ves y las células amarillas son células que surgieron de una sola célula madre esquelética: columnas de cartílago, columnas de hueso que salen de una sola célula. Белое вещество — это кость, а эти красные столбики, которые вы видите, и желтые клетки — это клетки, возникшие из одной-единственной скелетной стволовой клетки — столбики хрящей, столбики кости, выходящие из одной клетки. These cells are fascinating. Эти клетки очаровательны. They have four properties Number one is that they live where they’re expected to live. Tienen cuatro propiedades El número uno es que viven donde se espera que vivan. They live just underneath the surface of the bone, underneath cartilage. Viven justo debajo de la superficie del hueso, debajo del cartílago. Они живут прямо под поверхностью кости, под хрящом. You know, in biology, it’s location, location, location. And they move into the appropriate areas and form bone and cartilage. И они перемещаются в соответствующие области и формируют кости и хрящи. 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? Puedes sacarlos del esqueleto de vertebrados, puedes cultivarlos en placas de petri en el laboratorio y se están muriendo por formar cartílago. ¿Recuerdas cómo no pudimos formar cartílago por amor o por dinero? Vous pouvez les sortir du squelette des vertébrés, vous pouvez les cultiver dans des boîtes de Pétri en laboratoire, et ils meurent d'envie de former du cartilage. Вы можете извлечь их из скелета позвоночного, вы можете культивировать их в чашках Петри в лаборатории, и они умирают, чтобы сформировать хрящ. Помните, как мы не могли формировать хрящи ради любви или денег? These cells are dying to form cartilage.They form their own furls of cartilage around themselves. |||||||||||layers|||| |||||||||||fałdy|||| Estas células se están muriendo para formar cartílago. Forman sus propios enrollamientos de cartílago a su alrededor. Ces cellules meurent d'envie de former du cartilage, elles forment autour d'elles leurs propres enroulements de cartilage. Эти клетки умирают, чтобы сформировать хрящ. Они формируют вокруг себя собственные хрящевые завитки. 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. |||||||healers||bone breaks|||||||||||||||||||||| También son, número tres, los reparadores más eficientes de las fracturas que hemos encontrado. Este es un pequeño hueso, un hueso de ratón que fracturamos y luego dejamos que se cure por sí solo. Они также, номер три, самые эффективные восстанавливающие переломы, с которыми мы когда-либо сталкивались. Это маленькая кость, мышиная кость, которую мы сломали, а затем позволили ей срастись самой. These stem cells have come in and repaired, in yellow, the bone, in white, the cartilage, almost completely. Estas células madre han entrado y reparado, en amarillo, el hueso, en blanco, el cartílago, casi por completo. Эти стволовые клетки пришли и восстановили, желтые, кость, белые, хрящи, почти полностью. 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. |||||||||||fluorescent marker||||||||||||||||||break or injury|||in that area||||| Tanto es así que si los etiqueta con un tinte fluorescente puede verlos como una especie de pegamento celular peculiar que entra en el área de una fractura, la fija localmente y luego detiene su trabajo. Настолько, что если пометить их флуоресцентным красителем, то можно увидеть, как какой-то своеобразный клеточный клей попадает в область перелома, фиксирует его локально, а затем останавливает свою работу. Now, the fourth one is the most ominous, and that is that their numbers decline precipitously, precipitously, tenfold, fiftyfold, as you age. |||||||||||||||sharply||by ten times|fifty times||| |||||||||||||||drastycznie|||pięćdziesięciokrotnie||| Ahora, el cuarto es el más siniestro, y es que sus números disminuyen precipitadamente, precipitadamente, diez veces, cincuenta veces, a medida que envejece. Maintenant, le quatrième est le plus inquiétant, et c'est que leur nombre diminue précipitamment, précipitamment, décuplé, cinquante, avec l'âge. Итак, четвертый — самый зловещий, и он состоит в том, что их количество резко, стремительно, в десять, пятьдесят раз уменьшается с возрастом.

11:53 And so what had happened, really, is that we found ourselves in a perceptual shift. 11:53 Entonces, lo que realmente sucedió, es que nos encontramos en un cambio de percepción. 11:53 Итак, на самом деле произошло то, что мы оказались в сдвиге восприятия. We had gone hunting for pills but we ended up finding theories. Habíamos ido a buscar pastillas, pero terminamos encontrando teorías. 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. ||||||przyczepiliśmy się|||||||||||||||||||||||||||| И в некотором смысле мы снова зацепились за эту идею: клетки, организмы, окружающая среда, потому что теперь мы думали о костных стволовых клетках, мы думали об артрите с точки зрения клеточного заболевания.

12:16 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? |||||||injury or damage Можно ли имплантировать хрящ в области травмы? And perhaps most interestingly, can you ascend right up and create environments? ||||||rise up||||| ||||||wznosić się||||| Y quizás lo más interesante, ¿puedes ascender y crear entornos? И, пожалуй, самое интересное, можете ли вы подняться прямо вверх и создать окружение? You know, we know that exercise remodels bone, but come on, none of us is going to exercise. ||||||reshapes||||||||||| ||||||przekształca||||||||||| Sabes, sabemos que el ejercicio remodela los huesos, pero vamos, ninguno de nosotros va a hacer ejercicio. So could you imagine ways of passively loading and unloading bone so that you can recreate or regenerate degenerating cartilage? |||||||||removing|||||||||deteriorating| ||||||biernie||||||||||||| Entonces, ¿podría imaginar formas de cargar y descargar pasivamente el hueso para poder recrear o regenerar cartílago degenerativo? Итак, можете ли вы представить себе способы пассивной загрузки и разгрузки кости, чтобы вы могли воссоздать или регенерировать дегенерирующий хрящ?

12:45 And perhaps more interesting, and more importantly, the question is, can you apply this model more globally outside medicine? 12:45 И, возможно, более интересный и важный вопрос: можно ли применить эту модель более глобально за пределами медицины? What’s at stake, as I said before, is not killing something, but growing something. Lo que está en juego, como dije antes, no es matar algo, sino hacer crecer algo. L'enjeu, comme je l'ai déjà dit, n'est pas de tuer quelque chose, mais de faire pousser quelque chose. На кону, как я уже сказал, не что-то убить, а что-то вырастить. 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? Y plantea una serie de, creo, algunas de las preguntas más interesantes sobre cómo pensamos sobre la medicina en el futuro ¿Podría su medicina ser una célula y no una píldora? How would we grow these cells? What we would we do to stop the malignant growth of these cells? ||||||||harmful|||| Que ferions-nous pour arrêter la croissance maligne de ces cellules? Что бы мы сделали, чтобы остановить злокачественный рост этих клеток? We heard about the problems of unleashing growth. ||||||uwolnienia| Escuchamos sobre los problemas de desencadenar el crecimiento. Мы слышали о проблемах развязывания роста. 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? ¿Podría su medicamento ser un órgano que se crea fuera del cuerpo y luego se implanta en el cuerpo? Может ли ваше лекарство быть органом, созданным вне тела, а затем имплантированным в него? 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? ¿Podríamos almacenar estos órganos? Would each organ have to be developed for an individual human being and put back? ¿Tendría que desarrollarse cada órgano para un ser humano individual y devolverlo? And perhaps most puzzlingly, could your medicine be an environment? |||most perplexing|||||| |||najbardziej zagadkowo|||||| И, пожалуй, самое загадочное, может ли ваше лекарство быть окружающей средой? Could you patent an environment? ||obtain a patent|| ¿Podrías patentar un ambiente? Могли бы вы запатентовать окружающую среду? You know, in every culture, shamans have been using environments as medicines.Could we imagine that for our future? |||||healers||||||||||||| Usted sabe, en todas las culturas, los chamanes han estado utilizando los entornos como medicamentos. ¿Podríamos imaginar eso para nuestro futuro? I’ve talked a lot about models. He hablado mucho sobre modelos. 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. Sabes, cuando un arquitecto construye un modelo, él o ella está tratando de mostrarte un mundo en miniatura. But when a scientist is building a model, he or she is trying to show you the world in metaphor. Но когда ученый строит модель, он или она пытается показать вам мир в метафоре. He or she is trying to create a new way of seeing