Siddhartha Mukherjee: Soon we'll cure diseases with a cell, not a pill Siddhartha Muk||||||||||| Siddhartha Mukherjee: Bald werden wir Krankheiten mit einer Zelle heilen, nicht mit einer Pille Siddhartha Mukherjee: Pronto curaremos enfermedades con una célula, no con una píldora Siddhartha Mukherjee : Bientôt, nous soignerons les maladies à l'aide d'une cellule et non d'une pilule シッダールタ・ムカルジー：薬ではなく細胞で病気を治す日も近い Siddhartha Mukherjee: Em breve curaremos doenças com uma célula, não com um comprimido Siddhartha Mukherjee: Yakında hastalıkları bir hapla değil, bir hücreyle tedavi edeceğiz 释迦牟尼：我们很快就能用细胞而不是药片治愈疾病

00:11I 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. En fait, le modèle est si simple qu'on pourrait le résumer en six mots : avoir une maladie, prendre une pilule, tuer quelque chose.

00:42Now, 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. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||precision Il s'agissait d'un produit chimique, issu du monde naturel ou synthétisé artificiellement en laboratoire, qui se répandait dans l'organisme, trouvait sa cible, s'y fixait - un microbe ou une partie d'un microbe - et en désactivait la serrure et la clé avec une habileté et une spécificité exquises. And you would end up taking a previously fatal, lethal disease -- a pneumonia, syphilis, tuberculosis -- and transforming that into a curable, or treatable illness. Il s'agirait de transformer une maladie auparavant mortelle - pneumonie, syphilis, tuberculose - en une maladie curable ou traitable. You have a pneumonia, you take penicillin, you kill the microbe and you cure the disease

01:48So 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. 01:48Cette idée était si séduisante, la métaphore de la serrure et de la clé et de la mise à mort si puissante, qu'elle s'est vraiment répandue dans la biologie. 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. Vous savez, si vous prenez l'univers entier de toutes les réactions chimiques dans le corps humain, toutes les réactions chimiques dont votre corps est capable, la plupart des gens pensent que ce nombre est de l'ordre d'un 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? |||||||||||||||||||pharmacopoeia|||| 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. |||||||||||||||||||||||||||||||||||||outer edge||||||||||||||||||||||||| Vous savez, si vous considérez la physiologie humaine comme un vaste réseau téléphonique mondial avec des nœuds et des éléments en interaction, toute notre chimie médicinale opère sur un petit coin au bord, au bord extérieur, de ce réseau. C'est comme si toute notre chimie pharmaceutique était un opérateur de poteau à Wichita, au Kansas, qui bricole environ 10 ou 15 lignes téléphoniques. 03:35So 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. |||||||in levels||||||||||||||semi-autonomous|||| En fait, le monde naturel est organisé de manière hiérarchique, non pas vers le bas, mais vers le haut, et nous commençons par une unité autorégulée 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. Ces unités autorégulées et semi-autonomes donnent naissance à des unités autorégulées et semi-autonomes appelées organes, et ces organes se regroupent pour former des êtres humains, et ces organismes vivent finalement dans des environnements qui sont en partie autorégulés et en partie semi-autonomes.

04:31What'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. ||||||||||||||||||||||||||leukemia It's worked for some forms of breast cancer, but eventually you run to the ceiling of that approach. Cela a fonctionné pour certaines formes de cancer du sein, mais cette approche finit par plafonner. 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? |||||organism-level||||||||||||| In fact, it's led to the some of the most spectacular new medicines in cancer. 05:33And finally there's the level of the environment, isn't there? You know, we don't think of cancer as altering the environment. Vous savez, nous ne pensons pas que le cancer modifie l'environnement. But let me give you an example of a profoundly carcinogenic environment. ||||||||||cancer-causing| 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||||||||||||||||||||||||||||||||||||||||||||||| Vous prenez la solitude, la dépression, l'enfermement, et vous ajoutez à cela, enroulé dans une petite feuille de papier blanc, l'un des neurostimulants les plus puissants que nous connaissions, appelé nicotine, et vous ajoutez à cela l'une des substances addictives les plus puissantes que vous connaissiez, et vous obtenez un environnement pro-carcinogène. 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. 06:22Or 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. Nous savons maintenant que ce qu'il faut probablement faire, c'est changer la physiologie de l'organe, le cerveau, le recâbler, le remodeler, et cela, bien sûr, nous savons que des études successives ont montré que la thérapie par la parole fait exactement cela, et des études successives ont montré que la thérapie par la parole combinée à des médicaments, des pilules, est vraiment beaucoup plus efficace que l'une ou l'autre des deux combinaisons seules. Can we imagine a more immersive environment that will change depression? Can you lock out the signals that elicit depression? |||||||trigger| Pouvez-vous verrouiller les signaux qui provoquent la dépression? Again, moving upwards along this hierarchical chain of organization. |||||organizational structure||| 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. |||||||||||||||||joint disease|||||||||||||| Plutôt que de tuer quelque chose, dans le cas des grandes maladies dégénératives chroniques - insuffisance rénale, diabète, hypertension, arthrose - peut-être que nous devons vraiment changer la métaphore pour faire pousser quelque chose. And that's the key, perhaps, to reframing our thinking about medicine. 07:42Now, 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. 07:42Cette idée de changement, de création d'un changement de perception, pour ainsi dire, m'est revenue de manière très personnelle il y a une dizaine d'années Il y a une dizaine d'années - j'ai été coureur presque toute ma vie - je suis allé courir, un samedi matin, je suis revenu et je me suis réveillé et je ne pouvais pratiquement plus bouger. My right knee was swollen up, and you could hear that ominous crunch of bone against bone. Mon genou droit était enflé et on pouvait entendre le craquement sinistre des os l'un contre l'autre. And one of the perks of being a physician is that you get to order your own MRIs. Et l'un des avantages d'être médecin est que vous pouvez commander vos propres IRM. En een van de voordelen van een arts zijn, is dat u uw eigen MRI's kunt bestellen. 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 En fait, le ménisque, c'est-à-dire le cartilage qui se trouve entre les os, a été complètement déchiré et l'os lui-même a été brisé

08:21Now, 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. |||||||||||||||||||||||cartilage degeneration||| Si je faisais passer un IRM à chaque personne présente dans cette salle, 60 % d'entre vous présenteraient des signes de dégénérescence osseuse et cartilagineuse comme celui-ci. 85 percent of all women by the age of 70 would show moderate to severe cartilage degeneration. À l'âge de 70 ans, 85 % des femmes présentent une dégénérescence modérée à sévère du cartilage. 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. Nous avons essayé d'injecter des produits chimiques dans les genoux des animaux pour tenter d'inverser la dégénérescence du cartilage et, pour résumer un processus très long et douloureux, cela n'a rien donné. Nothing happened. And then about seven years ago, we had a research student from Australia. Puis, il y a environ sept ans, nous avons accueilli une étudiante australienne. The nice thing about Australians is that they're habitually used to looking at the world upside down Ce qu'il y a de bien avec les Australiens, c'est qu'ils ont l'habitude de voir le monde à l'envers 09:27(Laughter)

09:28And 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." C'est peut-être un problème de cellules souches. " 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. En d'autres termes, il avait deux hypothèses Numéro un, il existe une cellule souche squelettique - une cellule souche squelettique qui construit l'ensemble du squelette des vertébrés, les os, le cartilage et les éléments fibreux du squelette, tout comme il y a une cellule souche dans le sang, tout comme il y a une cellule souche dans le système nerveux. And two, that maybe that, the degeneration or dysfunction of this stem cell is what's causing osteochondral arthritis, a very common ailment. ||||||||||||||||bone and cartilage|joint inflammation|||| Deuxièmement, c'est peut-être la dégénérescence ou le dysfonctionnement de cette cellule souche qui est à l'origine de l'arthrite ostéochondrale, une affection très courante. So really the question was, were we looking for a pill when we should have really been looking for a cell. La question était donc de savoir si nous cherchions une pilule alors que nous aurions dû chercher une cellule. 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. La substance blanche est l'os, et les colonnes rouges que vous voyez ainsi que les cellules jaunes sont des cellules issues d'une seule cellule souche squelettique - des colonnes de cartilage, des colonnes d'os provenant d'une seule cellule. These cells are fascinating. They have four properties Number one is that they live where they're expected to live. Ils ont quatre propriétés La première est qu'ils vivent là où l'on attend d'eux qu'ils vivent. They live just underneath the surface of the bone, underneath cartilage. Ils vivent juste sous la surface de l'os, sous le 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? Vous pouvez les extraire du squelette des vertébrés, les cultiver dans des boîtes de Petri en laboratoire, et ils meurent pour former du cartilage.Vous vous souvenez que nous ne pouvions pas former de cartilage pour l'amour ou l'argent ? These cells are dying to form cartilage They form their own furls of cartilage around themselves. Ces cellules meurent pour former du cartilage. Elles forment leurs propres sillons de cartilage autour d'elles. Deze cellen sterven om kraakbeen te vormen. Ze vormen hun eigen kraakbeenhulzen om zich heen. 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. Il s'agit d'un petit os, un os de souris que nous avons fracturé et que nous avons laissé guérir tout seul. 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. ||||||||||||||||||||strange||||||||||||||||| À tel point que si vous les marquez avec un colorant fluorescent, vous pouvez les voir, comme une sorte de colle cellulaire particulière, arriver dans la zone d'une fracture, la fixer localement, puis arrêter leur travail. Now, the fourth one is the most ominous, and that is that their numbers decline precipitously, precipitously, tenfold, fiftyfold, as you age. La quatrième est la plus inquiétante : leur nombre diminue rapidement, rapidement, dix fois, cinquante fois, à mesure que l'on vieillit.

11:53And so what had happened, really, is that we found ourselves in a perceptual shift. 11:53Ce qui s'est passé, en fait, c'est que nous nous sommes retrouvés dans un changement de perception. We had gone hunting for pills but we ended up finding theories. Nous étions partis à la recherche de pilules, mais nous avons fini par trouver des théories. 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.

12:16And 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. Nous savons que l'exercice physique remodèle les os, mais aucun d'entre nous ne va faire de l'exercice. Weet je, we weten dat lichaamsbeweging botten remodelleert, maar kom op, niemand van ons gaat trainen. So could you imagine ways of passively loading and unloading bone so that you can recreate or regenerate degenerating cartilage?

12:45And 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. L'enjeu, comme je l'ai déjà dit, n'est pas de tuer quelque chose, mais de faire pousser quelque chose. 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? ||||||||harmful|||| Que ferions-nous pour arrêter la croissance maligne de ces cellules ? We heard about the problems of unleashing growth. Nous avons entendu parler des problèmes de libération de la croissance. 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? Pourriez-vous breveter un environnement ? 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. |||||||||||||||||||small scale 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. Dans le premier cas, il s'agit d'un changement d'échelle. The latter is a perceptual shift. |the second||||

14:37Now, 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. 14:37 Les antibiotiques ont entraîné un tel changement de perception dans notre façon de penser la médecine qu'ils ont vraiment coloré, déformé, avec beaucoup de succès, la façon dont nous avons pensé la médecine au cours des cent dernières années. That's what's at stake. C'est ce qui est en jeu. 14:58You 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. 14:58 Vous savez, il existe une idée reçue selon laquelle la raison pour laquelle nous n'avons pas eu d'impact transformateur sur le traitement des maladies est que nous n'avons pas de médicaments assez puissants, et c'est en partie vrai. But perhaps the real reason is that we don't have powerful-enough ways of thinking about medicines. Mais la vraie raison est peut-être que nous ne disposons pas de moyens suffisamment puissants pour penser les médicaments. 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. Mais peut-être que ce qui est réellement en jeu, ce sont trois M plus intangibles : mécanismes, modèles, métaphores. 15:34Thank you.

15:35(Applause)

15:44Chris Anderson: I really like this metaphor. How does it link in? There's a lot of talk in technology and 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? 16:06Siddhartha Mukherjee: It's a very interesting question. 16: 06Siddhartha Mukherjee: Het is een heel interessante vraag. We've thought about personalization of medicine very much in terms of genomics. We hebben sterk nagedacht over personalisatie van medicijnen in termen van genomica. 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. Je pense donc qu'à chaque étape, vous savez - il y a cette métaphore, il y a des tortues tout le long. Well, in this, there's personalization all the way. 16:54CA: So when you say medicine could be a cell and not a pill, you're talking about potentially your own cells. 17:01SM: Absolutely. CA: So converted to stem cells, perhaps tested against all kinds of drugs or something, and prepared. CA : Elles sont donc transformées en cellules souches, peut-être testées contre toutes sortes de médicaments ou autres, et préparées.

17:08SM: And there's no perhaps. ||||maybe 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. 17:25CA: Thank you so much.

17:27SM: Pleasure. Thanks.