Think about your day for a second. You woke up, felt fresh air on your face as you walked out the door, encountered new colleagues and had great discussions and felt in awe when you found something new. But I bet there's something you didn't think about today, something so close to home, you probably don't think about it very often at all. And that's that all those sensations, feelings, decisions and actions are mediated by the computer in your head called your brain.
Pensen no seu día por un segundo. Espertaron, sentiron o aire fresco na cara ao saír pola porta, atoparon novos colegas e tiveron bos debates, e asombráronse ao atopar algo novo. Pero aposto a que hoxe non pensaron en algo tan próximo a nós que non atrae a nosa atención moi a miúdo. Que todas esas sensacións, sentimentos, decisións e accións son intermediadas por unha computadora na súa cabeza á que chamamos cerebro.
Now, the brain may not look like much from the outside -- a couple pounds of pinkish-gray flesh, amorphous. But the last 100 years of neuroscience have allowed us to zoom in on the brain and to see the intricacy of what lies within. And they've told us that this brain is an incredibly complicated circuit made out of hundreds of billions of cells called neurons. Now, unlike a human-designed computer, where there's a fairly small number of different parts, and we know how they work because we humans designed them, the brain is made out of thousands of different kinds of cells, maybe tens of thousands. They come in different shapes; they're made out of different molecules; they project and connect to different brain regions. They also change in different ways in different disease states.
E pode non parecer gran cousa dende fóra: un quilo de carne de cor gris rosácea, amorfa, pero os últimos cen anos de neurociencia permitíronnos entrar no cerebro e ve-la complexidade do seu interior. E dixéronnos que este cerebro é un circuíto incriblemente complicado composto de centos de miles de millóns de células chamadas neuronas. Agora ben, ao contrario dunha computadora deseñada por humanos con moitas menos pezas distintas --sabemos como funcionan, posto que as deseñamos nos-- o cerebro está composto de miles de tipos diferentes de células, quizais decenas de miles. De distintas formas, a partir de moléculas diversas, e que proxectan e conectan cara a distintas rexións do cerebro. E tamén cambian nos diferentes estadios da enfermidade.
Let's make it concrete. There's a class of cells, a fairly small cell, an inhibitory cell, that quiets its neighbors. It's one of the cells that seems to be atrophied in disorders like schizophrenia. It's called the basket cell. And this cell is one of the thousands of kinds of cell that we're learning about. New ones are being discovered every day. As just a second example: these pyramidal cells, large cells, can span a significant fraction of the brain. They're excitatory. And these are some of the cells that might be overactive in disorders such as epilepsy. Every one of these cells is an incredible electrical device. They receive inputs from thousands of upstream partners and compute their own electrical outputs, which then, if they pass a certain threshold, will go to thousands of downstream partners. And this process, which takes just a millisecond or so, happens thousands of times a minute in every one of your 100 billion cells, as long as you live and think and feel.
Sexamos máis concretos. Temos unha clase de células, unha célula moi pequena, inhibidora, que silencia as súas veciñas. É unha das células que se atrofiaría en trastornos como a esquizofrenia. É coñecida coma célula cesta; E é un dos miles de tipos de células acerca das cales estamos aprendendo. Descóbrense novos tipos tódolos días. Só un segundo exemplo: estas células piramidais, grandes células, que abarcan unha parte importante do cerebro. Son excitatorias. E estas son algunhas das células que poderían estar hiperactivas en trastornos como a epilepsia. Cada unha destas células é un dispositivo eléctrico incrible. Reciben sinais de miles de células da parte superior e calculan as súas propias respostas eléctricas que ao superar un determinado límite, pasarán a miles de células da parte inferior. E este proceso, que leva só un milisegundo máis ou menos, sucede miles de veces por minuto para cada unha das 100 mil millóns de células, mentres vostedes viven, e pensan e senten.
So how are we going to figure out what this circuit does? Ideally, we could go through this circuit and turn these different kinds of cell on and off and see whether we could figure out which ones contribute to certain functions and which ones go wrong in certain pathologies. If we could activate cells, we could see what powers they can unleash, what they can initiate and sustain. If we could turn them off, then we could try and figure out what they're necessary for. And that's the story I'm going to tell you about today. And honestly, where we've gone through over the last 11 years, through an attempt to find ways of turning circuits and cells and parts and pathways of the brain on and off, both to understand the science and also to confront some of the issues that face us all as humans.
Así pois, como imos descifrar qué fai este circuíto? O ideal sería ir a través del e acender e apaga-los distintos tipos de células e ver se podemos esclarecer cales contribúen a determinadas funcións e cales funcionan mal en certas patoloxías. Se puideramos activalas poderíamos ver qué potencial liberan, e qué poden iniciar e manter. Se puideramos apagalas, entón poderíamos tentar ver para que son precisas. E esa é unha historia que lles vou contar hoxe. E, honestamente, por onde pasamos nos últimos 11 anos na busca de maneiras de acender e apagar circuítos e células e rutas do cerebro, tanto para entende-la ciencia, como para facerlles fronte a algúns dos problemas cos que todos batemos como humanos.
Now, before I tell you about the technology, the bad news is that a significant fraction of us in this room, if we live long enough, will encounter, perhaps, a brain disorder. Already, a billion people have had some kind of brain disorder that incapacitates them. The numbers don't do it justice, though. These disorders -- schizophrenia, Alzheimer's, depression, addiction -- they not only steal away our time to live, they change who we are. They take our identity and change our emotions and change who we are as people.
Pero antes de falarlles da tecnoloxía, a mala nova é que unha parte significativa de nós nesta sala, se vivímo-lo suficiente, probablemente suframos un trastorno cerebral. Xa mil millóns de persoas tiveron algún tipo de trastorno cerebral que as incapacita, e, porén, as cifras non lle fan xustiza. Estes trastornos --a esquizofrenia, o alzheimer, a depresión, a adicción-- non só nos rouban tempo de vida, cambian o noso ser. Quítannos a nosa identidade e cambian as nosas emocións e cambian o que somos como persoas.
Now, in the 20th century, there was some hope that was generated through the development of pharmaceuticals for treating brain disorders. And while many drugs have been developed that can alleviate symptoms of brain disorders, practically none of them can be considered to be cured. In part, that's because, if you think about it, we're bathing the brain in a chemical -- this elaborate circuit, made of thousands of different kinds of cell -- is being bathed in a substance. That's also why most of the drugs, not all, on the market can present some kind of serious side effect too.
Agora ben, no século XX xerouse algo de esperanza grazas ao desenvolvemento de fármacos para trastornos cerebrais. E aínda que se desenvolveron moitas medicinas que poden alivia-los síntomas deses trastornos, na práctica ningún deles pode considerarse curable. En parte porque estamos inundando o cerebro con química. Este elaborado circuíto composto de miles de tipos de células diferentes está sendo bañado nunha substancia. Por iso, a maior parte das medicinas pode presentar algún tipo de efecto secundario importante.
Now some people have gotten some solace from electrical stimulators that are implanted in the brain, for Parkinson's disease or cochlear implants. These have indeed been able to bring some kind of remedy to people with certain kinds of disorders. But electricity also will go in all directions -- the path of least resistance -- which is where that phrase, in part, comes from, and will also affect normal circuits, as well as the abnormal ones you want to fix. So again, we're sent back to the idea of ultraprecise control: Could we dial in information precisely where we want it to go?
Agora, algunhas persoas recibiron algún consolo de estimuladores eléctricos que se implantan no cerebro. E para o párkinson, os implantes cocleares, foron capaces de fornecer algún alivio a persoas con certos tipos de trastornos. Pero a electricidade tamén irá cara a todas partes pola ruta de menor resistencia, e de aí, en parte, vén esta expresión. E isto afectará aos circuítos normais pero tamén aos que queremos corrixir. Así que de novo, volvemos á idea do control ultrapreciso. Podemos dirixi-la información exactamente cara a onde queremos?
So, when I started in neuroscience 11 years ago -- I had trained as an electrical engineer and a physicist -- the first thing I thought about was, if these neurons are electrical devices, all we need to do is to find some way of driving those electrical changes at a distance. If we could turn on the electricity in one cell but not its neighbors, that'd give us the tool to activate and shut down these different cells to figure out what they do and how they contribute to the networks in which they're embedded. It would also allow us to have the ultraprecise control we need to fix the circuit computations that have gone awry.
Cando comecei na neurociencia hai 11 anos formárame como enxeñeiro eléctrico e como físico, e o primeiro que pensei foi: se as neuronas son dispositivos eléctricos todo o que fai falla é atopa-lo modo de manexar a distancia eses cambios eléctricos. Se puideramos acende-la electricidade nunha célula, pero non nas veciñas, iso daríanos o que necesitamos para activar e apaga-las células, para descubrir que fan e como contribúen ás redes nas que están inseridas. E tamén nos permitiría o control ultrapreciso necesario para corrixi-los cálculos do circuíto que estiveran mal.
Now, how are we going to do that? Well, there are many molecules that exist in nature which are able to convert light into electricity. You can think of them as little proteins that are like solar cells. If we install these molecules in neurons somehow, then these neurons would become electrically drivable with light, and their neighbors, which don't have this molecule, would not. There's one other magic trick you need to make this happen: the ability to get light into the brain. The brain doesn't feel pain. Taking advantage of all the effort that's gone into the internet, telecommunications, etc., you can put optical fibers connected to lasers to activate -- in animal models, for example, in preclinical studies -- these neurons and see what they do.
Agora, como imos facer iso? Ben, na natureza haiche moitas moléculas capaces de converte-la luz en electricidade. Imaxínenas como pequenas proteínas que son como celas fotovoltaicas. Se, dalgún xeito, podemos instalar estas moléculas nas neuronas entón estas neuronas poderían manipularse electricamente coa luz. E as súas veciñas, que non teñen a molécula, non. Cómprenos outro truco de maxia para que isto suceda: a capacidade de meter luz no cerebro. E para logralo --o cerebro non sente dor-- pódese poñer --aproveitando o esforzo investido en Internet, comunicacións, etc-- fibra óptica conectada a láseres que pode usarse para activar, por exemplo en modelos animais, en estudios preclínicos, estas neuronas e ver qué fan.
So how do we do this? Around 2004, in collaboration with Georg Nagel and Karl Deisseroth, this vision came to fruition. There's a certain alga that swims in the wild, and it needs to navigate towards light in order to photosynthesize optimally. And it senses light with a little eyespot, which works not unlike how our eye works. In its membrane, or its boundary, it contains little proteins that indeed can convert light into electricity. These molecules are called channelrhodopsins. And each of these proteins acts just like that solar cell that I told you about. When blue light hits it, it opens a little hole and allows charged particles to enter the eyespot; that allows this eyespot to have an electrical signal, just like a solar cell charging a battery.
Entón, como o facemos? Arredor de 2004, en colaboración con Gerhard Nagel e Karl Deisseroth esta visión fíxose realidade. Hai unha alga que nada no mundo silvestre e que ten que navegar cara á luz para face-la fotosíntese de forma óptima. E detecta a luz cun pequeno ocelo que funciona non moi distinto ca os nosos ollos. Na súa membrana, ou no seu bordo, contén pequenas proteínas que, de feito, poden converte-la luz en electricidade. Estas moléculas denomínanse canalrodopsinas. E cada unha actúa como esa cela fotovoltaica da que falei. Ante a presenza de luz azul, abre un pequeno orificio que deixa pasar partículas cargadas ao ocelo. o que lle permite ter un sinal eléctrico como unha cela fotovoltaica que carga unha batería.
So what we need to do is take these molecules and somehow install them in neurons. And because it's a protein, it's encoded for in the DNA of this organism. So all we've got to do is take that DNA, put it into a gene therapy vector, like a virus, and put it into neurons. And this was a very productive time in gene therapy, and lots of viruses were coming along, so this turned out to be fairly simple. Early in the morning one day in the summer of 2004, we gave it a try, and it worked on the first try. You take this DNA and put it into the neuron. The neuron uses its natural protein-making machinery to fabricate these little light-sensitive proteins and install them all over the cell, like putting solar panels on a roof. And the next thing you know, you have a neuron which can be activated with light. So this is very powerful.
Daquela,temos que toma-las moléculas e poñelas dalgún xeito nas neuronas. E dado que é unha proteína, está codificada no ADN deste organismo. Así que o que temos que facer é toma-lo ADN, colocalo nun vector de terapia xénica, coma un virus, E poñelo nas neuronas. Resultou ser un momento moi produtivo en terapia xénica, e empezaron a aparecer moitos virus. Así que resultou moi simple de facer. E unha mañanciña do verán de 2004 tentámolo e funcionou á primeira. Tómase este ADN e colócase nunha neurona. A neurona usa o seu mecanismo natural de elaboración de proteínas para facer pequenas proteínas fotosensibles e colocalas por toda a célula, como paneis solares nun tellado, e o seguinte que sabemos é que temos unha neurona activable por luz. E isto é moi valioso.
One of the tricks you have to do is figure out how to deliver these genes to the cells you want and not all the other neighbors. And you can do that; you can tweak the viruses so they hit some cells and not others. And there's other genetic tricks you can play in order to get light-activated cells. This field has now come to be known as "optogenetics." And just as one example of the kind of thing you can do, you can take a complex network, use one of these viruses to deliver the gene just to one kind of cell in this dense network. And then when you shine light on the entire network, just that cell type will be activated.
Un dos trucos que tes que facer é atopar como leva-los xenes ás células que queres E non a tódalas súas veciñas. E pode facerse; pódese axusta-lo virus para que acade unhas células e non outras. E hai outros trucos xenéticos aos que recorrer co fin de obter células fotoactivadas. Este campo coñécese como optoxenética. E, como exemplo de cousas que se poden facer, podes tomar unha rede complexa, usar un destes virus para entrega-lo xene a un só tipo de célula nesta densa rede. E despois cando a luz ilumina toda a rede só se activará ese tipo de célula.
For example, let's consider that basket cell I told you about earlier, the one that's atrophied in schizophrenia and the one that is inhibitory. If we can deliver that gene to these cells -- they won't be altered by the expression of the gene, of course -- then flash blue light over the entire brain network, just these cells are going to be driven. And when the light turns off, these cells go back to normal; there don't seem to be adverse events. Not only can you study what these cells do, what their power is in computing in the brain, you can also use this to try to figure out if we could jazz up the activity of these cells if indeed, they're atrophied.
Por exemplo, pensemos nesa célula cesta que lles mencionei antes, a que se atrofia na esquizofrenia e que é inhibitoria. Se podemos levar ese xene a esas células e que non se vexan alteradas pola expresión dese xene, por suposto, e despois iluminamos de azul toda a rede cerebral só se verán afectadas esas células. E cando apagamos a luz as células volven á normalidade, así que iso non parece afectalas . Non só se usa para estuda-lo funcionamento celular, o seu poder de cómputo no cerebro, senón tamén para tratar de descubrir se poderiamos animar a actividade desas células se realmente están atrofiadas.
I want to tell you some short stories about how we're using this both at the scientific clinical and preclinical levels. One of the questions that we've confronted is: What signals in the brain mediate the sensation of reward? Because if you could find those, those would be some of the signals that could drive learning; the brain will do more of what got that reward. These are also signals that go awry in disorders such as addiction. So if we could figure out what cells they are, we could maybe find new targets for which drugs can be designed or screened against or maybe places where electrodes could be put in for people who have severe disability. To do that, we came up with a very simple paradigm in collaboration with the Fiorillo group, where, if the animal goes to one side of this little box, it gets a pulse of light. And we'll make different cells in the brain sensitive to light. If these cells can mediate reward, the animal should go there more and more. And that's what happens.
Agora quero contarlles un par de historias breves acerca do uso que facemos disto, a nivel científico, clínico e preclínico. Unha das preguntas a que nos enfrontamos é cales son os sinais cerebrais implicados na sensación de recompensa? Porque se puideramos atopalos serían os sinais que poderían guia-la aprendizaxe. O cerebro repetirá o que o gratifica. E ademais, estes sinais funcionan mal nos trastornos adictivos. Así, se descubrísemos esas células quizais poderiamos atopar novas dianas para as que deseñar ou probar medicamentos, ou quizais lugares nos que colocar eléctrodos para persoas con discapacidades moi graves. Para isto, ocorréusenos un paradigma moi simple en colaboración co grupo Fiorella, nun lado desta pequena caixa, se o animal vai alí, recibe un pulso de luz que fará fotosensibles varias células cerebrais. Así, se estas células participan na recompensa, o animal debería ir alí cada vez máis. Iso é o que sucede.
The animal goes to the right-hand side and pokes his nose there and gets a flash of blue light every time he does it. He'll do that hundreds of times. These are the dopamine neurons, in some of the pleasure centers in the brain. We've shown that a brief activation of these is enough to drive learning. Now we can generalize the idea. Instead of one point in the brain, we can devise devices that span the brain, that can deliver light into three-dimensional patterns -- arrays of optical fibers, each coupled to its own independent miniature light source. Then we can try to do things in vivo that have only been done to date in a dish, like high-throughput screening throughout the entire brain for the signals that can cause certain things to happen or that could be good clinical targets for treating brain disorders.
O animal vai ir mete-lo nariz ao lado dereito e cada vez que o fai recibe un flash azul. E farao centos e centos de veces. Son as neuronas dopamina, que como saberán, participan dos centros cerebrais do pracer. Demostramos que activalas brevemente é suficiente para guia-la aprendizaxe. Podemos xeneraliza-la idea. En lugar de un só punto no cerebro podemos idear dispositivos para todo o cerebro, que leven a luz en patróns tridimensionais --matrices de fibra óptica, cunha minifonte luminosa independente. E podemos tratar de facer en vivo o que, ata o momento, se fixo só nunha placa, como a visualización completa do cerebro para sinais que fan que sucedan certas cousas. Ou poderían ser bos obxectivos clínicos para o tratamento de trastornos cerebrais.
One story I want to tell you about is: How can we find targets for treating post-traumatic stress disorder, a form of uncontrolled anxiety and fear? One of the things that we did was to adopt a very classical model of fear. This goes back to the Pavlovian days. It's called Pavlovian fear conditioning, where a tone ends with a brief shock. The shock isn't painful, but it's a little annoying. And over time -- in this case, a mouse, which is a good animal model, commonly used in such experiments -- the animal learns to fear the tone. It will react by freezing, sort of like a deer in the headlights. Now the question is: What targets in the brain can we find that allow us to overcome this fear? So we play that tone again, after it's been associated with fear. But we activate different targets in the brain, using that optical fiber array I showed on the previous slide, in order to try and figure out which targets can cause the brain to overcome that memory of fear.
E outra historia que quero contarlles é como atopamos dianas para trata-lo estrés postraumático, unha forma de ansiedade e medo descontrolados. E unha das cousas que fixemos foi adopta-lo modelo máis clásico do medo. Remóntase aos días de Pavlov. Denomínase medo condicionado pavloviano, e nel un ton remata cunha breve descarga. A descarga non doe, pero molesta un pouco. E co tempo --un rato, un bo modelo animal, usado a miúdo en experimentos, aprende a temerlle ao ton. O animal reaccionará paralizándose, coma un cervo diante dos faros. Agora, a pregunta é, que dianas podemos atopar no cerebro que nos permitan superar ese temor? Para iso reproducimos o ton novamente despois de que se asocie co medo. Pero activamos novas dianas no cerebro, usando esa matriz de fibra óptica que lles mostrei antes para tratar de desvelar qué dianas poden facer que o cerebro supere esa memoria do medo.
This brief video shows you one of these targets that we're working on now. This is an area in the prefrontal cortex, a region where we can use cognition to try to overcome aversive emotional states. The animal hears a tone. A flash of light occurs. There's no audio, but you see that the animal freezes -- the tone used to mean bad news. There's a little clock in the lower left-hand corner. You can see the animal is about two minutes into this. This next clip is just eight minutes later. And the same tone is going to play, and the light is going to flash again. OK, there it goes. Right ... now. And now you can see, just 10 minutes into the experiment, that we've equipped the brain, by photoactivating this area, to overcome the expression of this fear memory.
Este breve vídeo mostra unha das dianas con que traballamos. Unha área do córtex prefrontal, unha rexión na que pode usarse a cognición para superar estados aversivos. Cando o animal oe un ton, aparece un flash. Non o oen, pero ven que o rato se paraliza. O ton adoitaba representar malas noticias. Hai un reloxo na esquina inferior esquerda para que poidan ver que o animal queda así uns 2 minutos. E agora, o seguinte vídeo, de só 8 minutos despois. Vaise reproduci-lo ton, e a luz dispárase outra vez. Ben, aí vai. Xusto agora. E agora poden ver, en só 10 minutos de experimento, que preparamos o cerebro, fotoactivando esta zona, para supera-la expresión desta memoria do medo.
Over the last couple years, we've gone back to the tree of life, because we wanted to find ways to turn circuits in the brain off. If we could do that, this could be extremely powerful. If you can delete cells for a few milliseconds or seconds, you can figure out what role they play in the circuits in which they're embedded. We surveyed organisms from all over the tree of life -- every kingdom of life but animals; we see slightly differently. We found molecules called halorhodopsins or archaerhodopsins, that respond to green and yellow light. And they do the opposite of the molecule I told you about before, with the blue light activator, channelrhodopsin.
Durante os últimos dous anos, volvemos atrás na árbore da vida porque queriamos atopar modos de apaga-los circuítos cerebrais. Se puideramos facelo sería algo moi poderoso. Se podes suprimir células durante uns milisegundos ou segundos, podes darte de conta da súa relevancia nos circuítos en que están inseridas. E estudamos toda a árbore da vida, seres de tódolos reinos salvo o animal, que é levemente distinto. E atopamos moléculas chamadas halorrodopsinas ou arqueorrodopsinas, que responden á luz verde e amarela. E que fan o oposto da molécula anterior, a do activador de luz azul, a canalrodopsina.
Let's give an example of where we think this is going to go. Consider, for example, a condition like epilepsy, where the brain is overactive. Now, if drugs fail in epileptic treatment, one of the strategies is to remove part of the brain, but that's irreversible, and there could be side effects. What if we could just turn off that brain for the brief amount of time until the seizure dies away, and cause the brain to be restored to its initial state, like a dynamical system that's being coaxed down into a stable state? This animation tries to explain this concept where we made these cells sensitive to being turned off with light, and we beam light in, and just for the time it takes to shut down a seizure, we're hoping to be able to turn it off. We don't have data to show you on this front, but we're very excited about this.
Vexamos un exemplo de cara a onde pensamos que vai isto. Consideren, por exemplo, unha doenza como a epilepsia, na que o cerebro é hiperactivo. Se falla a medicación no tratamento da epilepsia, pode eliminarse parte do cerebro. Pero isto é irreversible e ten efectos secundarios. Que pasaría se puideramos apaga-lo cerebro por un breve instante ata que o ataque esvaecera e facer que o cerebro volvera ao seu estado inicial? Algo así coma un sistema dinámico dirixido cara a un estado estable. Esta animación tenta explicar este concepto onde creamos células sensibles a desactivarse coa luz, e enfocámo-la luz sobre elas, e só durante o tempo que dura a convulsión esperamos ser capaces de apagalas. Non temos datos para amosar neste campo, pero estamos moi ilusionados.
I want to close on one story, which we think is another possibility, which is that maybe these molecules, if you can do ultraprecise control, can be used in the brain itself to make a new kind of prosthetic, an optical prosthetic. I already told you that electrical stimulators are not uncommon. Seventy-five thousand people have Parkinson's deep-brain stimulators implanted, maybe 100,000 people have cochlear implants, which allow them to hear. Another thing -- you've got to get these genes into cells. A new hope in gene therapy has been developed, because viruses like the adeno-associated virus -- which probably most of us around this room have; it doesn't have any symptoms -- have been used in hundreds of patients to deliver genes into the brain or the body. And so far, there have not been serious adverse events associated with the virus.
Agora quero rematar cunha historia, que nos parece outra posibilidade e que, se acadamos un control ultrapreciso, talvez permita usar estas moléculas no propio cerebro para facer un novo tipo de prótese óptica. Xa dixen que os estimuladores eléctricos son comúns hoxe. 75 mil persoas teñen estimuladores cerebrais para o párkinson. Talvez 100 mil teñan implantes cocleares, que lles permiten oír. Outra cosa é que temos que meter eses xenes nas células. E xurdiu unha nova esperanza en terapia xénica grazas a virus como o virus adenoasociado, que probablemente a maioría de vostedes terá sen presentar síntomas, e que se empregou en centos de pacientes para repartir xenes no cerebro e no corpo. E, ata o de agora, non houbo efectos adversos graves asociados co virus.
There's one last elephant in the room: the proteins themselves, which come from algae, bacteria and funguses and all over the tree of life. Most of us don't have funguses or algae in our brains, so what will our brain do if we put that in? Will the cells tolerate it? Will the immune system react? It's early -- these haven't been done in humans yet -- but we're working on a variety of studies to examine this. So far, we haven't seen overt reactions of any severity to these molecules or to the illumination of the brain with light. So it's early days, to be upfront, but we're excited about it.
Tamén adoitamos ignorar outro gran problema: as propias proteínas, procedentes de algas, bacterias e fungos, e toda a árbore da vida. A maioría non temos fungos nin algas no cerebro, así que, que fará o cerebro se llas inserimos? Tolerarano as células? E o sistema inmunolóxico? Estamos comezando, non se probou en humanos pero estamos a traballar en varios estudos tratando de examinalo, e, ata o de agora, non atopamos reaccións graves cara a estas moléculas ou cara á iluminación do cerebro con luz. Sinceramente, estamos comezando pero estamos entusiasmados.
I wanted to close with one story, which we think could potentially be a clinical application. Now, there are many forms of blindness where the photoreceptors -- light sensors in the back of our eye -- are gone. And the retina is a complex structure. Let's zoom in on it so we can see it in more detail. The photoreceptor cells are shown here at the top. The signals that are detected by the photoreceptors are transformed via various computations until finally, the layer of cells at the bottom, the ganglion cells, relay the information to the brain, where we see that as perception. In many forms of blindness, like retinitis pigmentosa or macular degeneration, the photoreceptor cells have atrophied or been destroyed. Now, how could you repair this? It's not even clear that a drug could cause this to be restored, since there's nothing for the drug to bind to. On the other hand, light can still get into the eye. The eye is still transparent and you can get light in. So what if we could take these channelrhodopsins and other molecules and install them on some of these other spared cells and convert them into little cameras? And because there are so many of these cells in the eye, potentially, they could be very high-resolution cameras.
Quero rematar cunha historia, que, cremos, podería ser unha aplicación clínica. Hoxe en día hai moitas formas de cegueira nas que os fotorreceptores, os sensores de luz que están no fondo do ollo, non funcionan. E a retina é unha estrutura complexa. Agora ampliémolo, para velo mellor. As células fotorreceptoras amósanse aquí arriba e os sinais detectados por elas son transformados por varios cálculos ata que, ao final, a capa de células ganglionares de abaixo transmite a información ao cerebro, onde vemos iso como percepción. En moitas formas de cegueira, como a retinite pigmentosa, ou a dexeneración macular, as células fotorreceptoras atrofiáronse ou destruíronse. Como arranxar isto? Nin sequera está claro que un fármaco poida facelo porque non ten nada ao que ligarse. Por outra banda, a luz aínda pode entrar no ollo. O ollo aínda é transparente e permite o paso da luz. Así que, e se collemos as canalrodopsinas e outras moléculas e as poñemos nalgunha destoutras células libres e as convertemos en pequenas cámaras? E, xa que hai moitas destas células no ollo, potencialmente, poderían ser cámaras de moi alta definición.
This is some work that we're doing, led by one of our collaborators, Alan Horsager at USC, and being sought to be commercialized by a start-up company, Eos Neuroscience, which is funded by the NIH. What you see here is a mouse trying to solve a six-arm maze. There's a bit of water to motivate the mouse to move or he'll just sit there. The goal of this maze is to get out of the water and go to a little platform that's under the lit top port. Mice are smart, so this one solves the maze eventually, but he does a brute-force search. He's swimming down every avenue until he finally gets to the platform. He's not using vision to do it. These different mice are different mutations that recapitulate different kinds of blindness that affect humans. So we're being careful in trying to look at these different models so we come up with a generalized approach.
Velaquí o noso traballo en curso. Está dirixido por un dos nosos colaboradores, Alan Horsager na USC, e procuramos que sexa comercializado por unha empresa nova, Eos Neuroscience, financiada polo NIH. Aquí vemos un rato tentando saír dun labirinto. É un labirinto de 6 brazos con auga para que o rato se mova e non quede sentado. O obxectivo deste labirinto, por suposto, é saír da auga e subir a unha plataforma baixo a comporta superior iluminada. Hoxe os ratos son listos, así que este sae do labirinto, pero busca por forza bruta. Nada por tódalas vías ata que, finalmente, chega á plataforma. E non está usando a visión para logralo. Estes ratos son mutacións distintas que sintetizan distintos tipos de cegueira que afectan aos humanos. Por iso pomos moito coidado cando observamos aos nosos modelos de xeito que chegamos a un enfoque xeneralizado.
So how can we solve this? We'll do exactly what we outlined in the previous slide. We'll take these blue light photo sensors and install them onto a layer of cells in the middle of the retina in the back of the eye and convert them into a camera -- just like installing solar cells all over those neurons to make them light-sensitive. Light is converted to electricity on them. So this mouse was blind a couple weeks before this experiment and received one dose of this photosensitive molecule on a virus. And now you can see, the animal can indeed avoid walls and go to this little platform and make cognitive use of its eyes again. And to point out the power of this: these animals can get to that platform just as fast as animals that have seen their entire lives. So this preclinical study, I think, bodes hope for the kinds of things we're hoping to do in the future.
Así que, como imos resolver isto? Faremos o que esbozamos na outra diapositiva. Imos coller estes fotosensores de luz azul e ímolos instalar nunha capa de células no medio da retina na parte posterior do ollo para convertela nunha cámara como se instalásemos celas fotovoltaicas nas neuronas para facelas sensibles á luz. Nelas a luz convértese en electricidade. Así que este rato era cego un par de semanas antes do experimento e recibiu unha dose desta molécula fotosensible nun virus. E agora poden velo, o animal evita paredes e vai a esa pequena plataforma e fai novamente un uso cognitivo dos seus ollos. E para destaca-lo poder que ten isto: os animais poden chegar á plataforma tan rápido coma os que viron toda a vida. Por iso penso que este estudo preclínico é un bo presaxio para o tipo de cousas que esperamos facer no futuro.
We're also exploring new business models for this new field of neurotechnology. We're developing tools and sharing them freely with hundreds of groups all over the world for them to study and try to treat different disorders. Our hope is that by figuring out brain circuits at a level of abstraction that lets us repair them and engineer them, we can take some of these intractable disorders I mentioned earlier, practically none of which are cured, and in the 21st century, make them history.
Para acabar, quero sinalar que tamén estamos a explorar novos negocios neste campo da neurotecnoloxía. Desenvolvemos estas ferramentas, pero compartímolas con grupos de todo o mundo de xeito que se estudan e tratan moitos trastornos. E esperamos que, ao entender os circuítos cerebrais a un nivel de abstracción que nos permita reparalos e deseñalos, poidamos tomar algún dos trastornos incurables dos que lles falei, practicamente ningún deles ten cura, e facer que no século XXI sexan historia.
Thank you.
Grazas.
(Applause)
(Aplausos)
Juan Enriquez: So some of this stuff is a little dense.
Juan Enriquez: Algunhas das cousas son un pouco densas.
(Laughter)
(Risas)
But the implications of being able to control seizures or epilepsy with light instead of drugs and being able to target those specifically is a first step. The second thing that I think I heard you say is you can now control the brain in two colors, like an on-off switch.
Pero as consecuencias de poder controla-las convulsións ou a epilepsia con luz en vez de medicamentos, e poder identificalos especificamente é un primeiro paso. Outra cosa que creo que dixeches é que agora ti podes controla-lo cerebro con dúas cores, como un interruptor de acender/apagar.
Ed Boyden: That's right.
Ed Boyden: Correcto.
JE: Which makes every impulse going through the brain a binary code.
JE: O que transforma cada impulso cerebral nun código binario.
EB: Right. With blue light, we can drive information, and it's in the form of a one. And by turning things off, it's more or less a zero. Our hope is to eventually build brain coprocessors that work with the brain so we can augment functions in people with disabilities.
EB: Correcto, si. Coa luz azul, podemos conduci-la información en forma de un. E apagándoa sería, máis ou menos, un cero. Así esperamos, ao final, construír procesadores cerebrais que funcionen co cerebro para poder aumenta-las función das persoas con discapacidade.
JE: And in theory, that means that, as a mouse feels, smells, hears, touches, you can model it out as a string of ones and zeros.
JE: E en teoría, iso significa que, o xeito en que un rato sente, ole, oe, toca, ti podes modelalo como unha cadea de uns e ceros.
EB: Yeah. We're hoping to use this as a way of testing what neural codes can drive certain behaviors and certain thoughts and certain feelings and use that to understand more about the brain.
EB: Sí, claro. Esperamos usalo para comprobar qué códigos neurais guían certos comportamentos, e certos pensamentos e sentimentos, e para entender máis sobre o cerebro.
JE: Does that mean that someday you could download memories and maybe upload them?
JE: Significa iso que algún día poderanse descargar recordos e quizais actualizalos?
EB: That's something we're starting to work on very hard. We're now working on trying to tile the brain with recording elements, too, so we can record information and then drive information back in -- sort of computing what the brain needs in order to augment its information processing.
EB: Ben, estamos empezando a traballar a fondo niso. Agora estamos traballando en revesti-lo cerebro con elementos de gravación. Así, poderemos gravar información e despois recuperala como calculando o que necesita o cerebro para aumenta-lo seu procesamento de información.
JE: Well, that might change a couple things. Thank you.
JE: Ben, iso podería cambiar algunhas cousas. Grazas.
EB: Thank you.
EB: Grazas.
(Applause)
(Aplausos)