So I'm a neurosurgeon. And like most of my colleagues, I have to deal, every day, with human tragedies. I realize how your life can change from one second to the other after a major stroke or after a car accident. And what is very frustrating for us neurosurgeons is to realize that unlike other organs of the body, the brain has very little ability for self-repair. And after a major injury of your central nervous system, the patients often remain with a severe handicap. And that's probably the reason why I've chosen to be a functional neurosurgeon.
Son neurocirurxiá e coma moitos dos meus colegas teño que tratar a cotío con traxedias humanas. Doume conta de como a túa vida pode cambiar nun segundo tras unha embolia cerebral ou un accidente de coche. Faise moi frustrante para nós como neurocirurxiáns constatar que ao contrario que outros órganos do corpo, o cerebro ten moi pouca capacidade para autorrepararse. Despois dunha lesión grave do sistema nervioso central os pacientes polo xeral fican con secuelas graves. Esa é probablemente a razón pola que decidín ser neurociruxián funcional.
What is a functional neurosurgeon? It's a doctor who is trying to improve a neurological function through different surgical strategies. You've certainly heard of one of the famous ones called deep brain stimulation, where you implant an electrode in the depths of the brain in order to modulate a circuit of neurons to improve a neurological function. It's really an amazing technology in that it has improved the destiny of patients with Parkinson's disease, with severe tremor, with severe pain. However, neuromodulation does not mean neuro-repair. And the dream of functional neurosurgeons is to repair the brain. I think that we are approaching this dream.
Que é un neurocirurxián funcional? É un doutor que intenta mellorar unha función neurolóxica ao través de diferentes técnicas cirúrxicas. Seguramente escoitaron falar dunha moi coñecida chamada estimulación cerebral profunda, na cal implantamos un eléctrodo no interior do cerebro para modular un circuíto neuronal que mellore unha función neurolóxica. É unha tecnoloxía asombrosa que está a mellorar as probabilidades dos pacientes coa enfermidade de Párkinson, con fortes tremores, con moita dor. De calquera xeito, a neuromodulación non quere dicir neurorreparación. O soño dos neurocirurxiáns funcionais e reparar o cerebro. Penso que estamos achegándonos a este soño.
And I would like to show you that we are very close to this. And that with a little bit of help, the brain is able to help itself.
Gustaríame mostrarvos que estamos moi preto disto. Como cunha pequena axuda, o cerebro é quen de repararse a si mesmo.
So the story started 15 years ago. At that time, I was a chief resident working days and nights in the emergency room. I often had to take care of patients with head trauma. You have to imagine that when a patient comes in with a severe head trauma, his brain is swelling and he's increasing his intracranial pressure. And in order to save his life, you have to decrease this intracranial pressure. And to do that, you sometimes have to remove a piece of swollen brain. So instead of throwing away these pieces of swollen brain, we decided with Jean-François Brunet, who is a colleague of mine, a biologist, to study them.
Esta historia comezou hai 15 anos. Daquela, eu era xefa de residentes e pasaba días e días nas salas de urxencias A miúdo tiña que ocuparme de pacientes con traumas na cabeza Podedes imaxinar que cando un paciente vén cun trauma grave na cabeza, o seu cerebro inflámase e auméntalle a presión intracranial. Para salvar a súa vida, tes que diminuír esa presión intracranial, e para facer iso, ás veces tiñamos que extraer un anaco de cerebro inflamado No canto de tirar eses anacos decidimos, xunto con Jean-François Brunet, que é un colega meu, biólogo, estudalos.
What do I mean by that? We wanted to grow cells from these pieces of tissue. It's not an easy task. Growing cells from a piece of tissue is a bit the same as growing very small children out from their family. So you need to find the right nutrients, the warmth, the humidity and all the nice environments to make them thrive. So that's exactly what we had to do with these cells. And after many attempts, Jean-François did it. And that's what he saw under his microscope.
Que quero dicir? Quixemos cultivar células obtidas deses anacos de tecido. Non é unha tarefa sinxela. Cultivar células dun anaco de tecido é case coma criar meniños pequerrechos lonxe das súas familias. Así que necesitas atopar os nutrientes adecuados, a temperatura, a humidade e os ambientes adecuados para que saian adiante. Iso foi exactamente o que fixemos con esas células. Despois de moitos intentos, Jean-François conseguiuno. Isto foi o que vimos baixo o seu microscopio.
And that was, for us, a major surprise. Why? Because this looks exactly the same as a stem cell culture, with large green cells surrounding small, immature cells. And you may remember from biology class that stem cells are immature cells, able to turn into any type of cell of the body. The adult brain has stem cells, but they're very rare and they're located in deep and small niches in the depths of the brain. So it was surprising to get this kind of stem cell culture from the superficial part of swollen brain we had in the operating theater.
E foi, para nós, unha gran sorpresa. Por que? Porque parecía o mesmiño ca un cultivo de células nai, con células grandes e verdes, arredor das células pequenas e inmaturas. Lembraredes da clase de bioloxía que esas células nai son células inmaturas, capaces de transformarse en calquera célula do corpo. O cerebro adulto ten células nai, pero son moi escasas e atópanse en profundas e pequenas áreas do interior do cerebro. Foi sorprendente obter esta clase de cultivos de células nai provenientes de fragmentos de cerebro que conseguimos no quirófano.
And there was another intriguing observation: Regular stem cells are very active cells -- cells that divide, divide, divide very quickly. And they never die, they're immortal cells. But these cells behave differently. They divide slowly, and after a few weeks of culture, they even died. So we were in front of a strange new cell population that looked like stem cells but behaved differently.
Alí había outro achado intrigante: polo xeral as células nai son células moi activas-- células que se dividen, dividen e dividen moi rápido. Elas nunca morren, son células inmortais. Pero estas células eran diferentes Elas dividíanse de vagar, e despois dunhas semanas de cultivo, sempre morrían. Atopabámonos fronte a unha estraña nova poboación celular semellante ás células nai pero cun comportamento distinto.
And it took us a long time to understand where they came from. They come from these cells. These blue and red cells are called doublecortin-positive cells. All of you have them in your brain. They represent four percent of your cortical brain cells. They have a very important role during the development stage. When you were fetuses, they helped your brain to fold itself. But why do they stay in your head? This, we don't know. We think that they may participate in brain repair because we find them in higher concentration close to brain lesions. But it's not so sure. But there is one clear thing -- that from these cells, we got our stem cell culture. And we were in front of a potential new source of cells to repair the brain. And we had to prove this.
E levounos bastante tempo comprender de onde proviñan. Proveñen destas células. Esas células azuis e encarnadas son células positivas á doblecortina. Todos vós as tedes no voso cerebro. Representan o catro por cento das vosas células corticais cerebrais. Xogan un papel moi importante durante o estadio de desenvolvemento. Cando erades fetos, axudáronlle ao voso cerebro a formar as circunvolucións. Pero por que seguen na vosa cabeza? Iso non o sabemos. Cremos que poden intervir na reparación cerebral porque nós atopámolas en concentracións máis altas preto de lesións cerebrais. Pero non é seguro. Porén, unha cousa está clara... grazas a estas células, nós tivemos o noso cultivo de células nai. Estabamos fronte a unha posible fonte de células para reparar o cerebro. e tiñamos que demostralo.
So to prove it, we decided to design an experimental paradigm. The idea was to biopsy a piece of brain in a non-eloquent area of the brain, and then to culture the cells exactly the way Jean-François did it in his lab. And then label them, to put color in them in order to be able to track them in the brain. And the last step was to re-implant them in the same individual. We call these autologous grafts -- autografts.
Así que para demostralo, decidimos deseñar un paradigma experimental. A idea foi biopsiar un anaco de cerebro nunha parte non esencial do cerebro, e despois cultivar as células do mesmo xeito que Jean-François fixera no seu laboratorio. E despois etiquetalas, colorealas de xeito que fósemos capaces de rastrexalas no cerebro. O derradeiro paso sería reimplantalas no mesmo individuo. Nós chamámoslle a isto enxertos autólogos -- autoenxertos.
So the first question we had, "What will happen if we re-implant these cells in a normal brain, and what will happen if we re-implant the same cells in a lesioned brain?" Thanks to the help of professor Eric Rouiller, we worked with monkeys.
A primeira pregunta que nos fixemos foi: "Que ocorrería se reimplantásemos esas células nun cerebro normal, e que ocorrería se as reimplantásemos nun cerebro lesionado?" Grazas a axuda do profesor Eric Rouiller, traballamos con monos.
So in the first-case scenario, we re-implanted the cells in the normal brain and what we saw is that they completely disappeared after a few weeks, as if they were taken from the brain, they go back home, the space is already busy, they are not needed there, so they disappear.
No primeiro suposto, reimplantamos as células nun cerebro san e o que vimos foi que desapareceran por completo ás poucas semanas coma se fosen sacadas do cerebro, volveron á casa, o lugar xa estaba ocupado, alí non eran necesarias, así que desapareceron.
In the second-case scenario, we performed the lesion, we re-implanted exactly the same cells, and in this case, the cells remained -- and they became mature neurons. And that's the image of what we could observe under the microscope. Those are the cells that were re-implanted. And the proof they carry, these little spots, those are the cells that we've labeled in vitro, when they were in culture.
No segundo suposto, nós recreamos a lesión, reimplantamos exactamente as mesmas células, e neste caso, as células permaneceron... e convertéronse en neuronas maduras. Esta foi a imaxe que nós puidemos observar baixo o microscopio Estas son as células que reimplantáramos. A proba que portan, estas pequenas manchas, esas son as células que nos etiquetamos in vitro, cando elas estaban no cultivo.
But we could not stop here, of course. Do these cells also help a monkey to recover after a lesion? So for that, we trained monkeys to perform a manual dexterity task. They had to retrieve food pellets from a tray. They were very good at it. And when they had reached a plateau of performance, we did a lesion in the motor cortex corresponding to the hand motion. So the monkeys were plegic, they could not move their hand anymore. And exactly the same as humans would do, they spontaneously recovered to a certain extent, exactly the same as after a stroke. Patients are completely plegic, and then they try to recover due to a brain plasticity mechanism, they recover to a certain extent, exactly the same for the monkey.
Non nos detivemos aí, por suposto. Poderían esas células tamén axudarlle a un mono a recuperarse tras unha lesión? Para isto, adestramos os monos para dominar unha tarefa manual. Tiñan que tirar boliñas de comida dunha bandexa. Facíano moi ben. Cando alcanzaron unha certa habilidade, causámoslles unha lesión no córtex motor correspondente ao control da man. De xeito que os monos quedaron eivados, xa non eran quen de mover a man. Igual que ocorrería nos seres humanos, recuperáronse espontaneamente ata certo nivel, igualiño ca despois dunha embolia cerebral. Pacientes totalmente eivados, que intentan recuperarse grazas ao mecanismo de plasticidade cerebral, facéndoo ata un certo nivel, exactamente o mesmo para os monos.
So when we were sure that the monkey had reached his plateau of spontaneous recovery, we implanted his own cells. So on the left side, you see the monkey that has spontaneously recovered. He's at about 40 to 50 percent of his previous performance before the lesion. He's not so accurate, not so quick. And look now when we re-implant the cells: Two months after re-implantation, the same individual.
Entón, cando nos aseguramos que os monos alcanzaran o seu límite de recuperación espontánea, reimplantámoslles as súas propias células, No lado esquerdo, vese o mono que se recuperou espontaneamente. Isto é arredor do 40 ao 50 por cento da súa destreza previa á lesión. Non é moi preciso, nin moi rápido. Mirade agora, ao reimplantar as células, dous meses despois da reimplantación, o mesmo individuo.
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It was also very exciting results for us, I tell you. Since that time, we've understood much more about these cells. We know that we can cryopreserve them, we can use them later on. We know that we can apply them in other neuropathological models, like Parkinson's disease, for example. But our dream is still to implant them in humans. And I really hope that I'll be able to show you soon that the human brain is giving us the tools to repair itself.
Foron uns resultados moi emocionantes para nós, en serio. Dende ese intre, nós comprendemos moito mellor estas células. Sabemos que podemos criopreservalas, para empregalas máis adiante. Sabemos que podemos empregalas noutros modelos neuropatolóxicos, coma a enfermidade de Párkinson. Pero o noso soño é aínda implantalas nos humanos. Eu teño a esperanza de sermos quen de mostrarvos axiña que o cerebro humano estanos a dar as ferramentas para autorrepararse.
Thank you.
Grazas.
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Bruno Giussani: Jocelyne, this is amazing, and I'm sure that right now, there are several dozen people in the audience, possibly even a majority, who are thinking, "I know somebody who can use this." I do, in any case. And of course the question is, what are the biggest obstacles before you can go into human clinical trials?
Bruno Giussani: Jocelyne, isto é asombroso. Estou seguro de que agora mesmo, hai ducias de persoas no público posiblemente a maioría, que están a pensar,"Eu sei de alguén que pode usar isto." Eu estou, desde logo. E por suposto a pregunta é: cales son os maiores obstáculos antes de que poidas facer ensaios clínicos en humanos?
Jocelyne Bloch: The biggest obstacles are regulations. (Laughs) So, from these exciting results, you need to fill out about two kilograms of papers and forms to be able to go through these kind of trials.
Jocelyne Bloch: Os meirandes obstáculos son as regulacións. (Risos) Así que, a partir destes bos resultados, necesitas obter arredor de dous kg de papeis e formularios para ser quen de desenvolver este tipo de ensaios.
BG: Which is understandable, the brain is delicate, etc.
BG: O cal é comprensible, o cerebro é delicado, etc.
JB: Yes, it is, but it takes a long time and a lot of patience and almost a professional team to do it, you know?
JB: Si, así é, pero cómpre moito tempo e moita paciencia e case un equipo profesional para facelo, sabes.
BG: If you project yourself -- having done the research and having tried to get permission to start the trials, if you project yourself out in time, how many years before somebody gets into a hospital and this therapy is available?
BG: Se te imaxinas a ti mesma... despois da investigación, intentando obter os permisos para comezar os ensaios, se te proxectas a ti mesma no tempo, cantos anos pasarán antes de que alguén chegue a un hospital e dispoña desta terapia?
JB: So, it's very difficult to say. It depends, first, on the approval of the trial. Will the regulation allow us to do it soon? And then, you have to perform this kind of study in a small group of patients. So it takes, already, a long time to select the patients, do the treatment and evaluate if it's useful to do this kind of treatment. And then you have to deploy this to a multicentric trial. You have to really prove first that it's useful before offering this treatment up for everybody.
JB: Isto é moi difícil de dicir. Depende, primeio, da aprobación do ensaio. Permitiránolo a regulación de aquí a pouco? Despois, tes que preparar este tipo de estudo nun pequeno grupo de pacientes. Vai levar, seguro, moito tempo seleccionar os pacientes, facer o tratamento e avaliar se é axeitado empregar esta clase de tratamento. E despois haberá que desenvolver isto nun ensaio multicéntrico. Primeiro haberá que demostrar realmente que é útil antes de ofrecerlle este tratamento para todo o mundo
BG: And safe, of course. JB: Of course.
BG: E seguro, por suposto. JB: Por suposto.
BG: Jocelyne, thank you for coming to TED and sharing this. BG: Thank you.
BG: Jocelyne, grazas por vir a TED e contarnos isto. JB: Grazas.
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