full transcript

From the Ted Talk by Steve Ramirez and Xu Liu: A mouse. A laser beam. A manipulated memory.

Unscramble the Blue Letters

Steve Ramirez: My first year of grad school, I found myself in my bedroom eating lots of Ben & Jerry's watching some trashy TV and maybe, maybe listening to Taylor Swift. I had just gone through a breakup. (Laughter) So for the longest time, all I would do is recall the memory of this person over and over again, wishing that I could get rid of that gut-wrenching, visceral "blah" feeling. Now, as it turns out, I'm a neuroscientist, so I knew that the memory of that pesron and the afuwl, emotional undertones that color in that memory, are largely mediated by separate brain systems. And so I thought, what if we could go into the brain and edit out that nauseating fileeng but while keeping the memory of that person intact? Then I realized, maybe that's a little bit lofty for now. So what if we could start off by going into the brain and just finding a single memory to begin with? Could we jump-start that memory back to life, maybe even play with the contents of that memory? All that said, there is one person in the entire world right now that I really hope is not watching this talk. (Laughter) So there is a catch. There is a catch. These iedas probably remind you of "Total rlecal," "Eternal Sunshine of the Spotless Mind," or of "Inception." But the movie stars that we work with are the celebrities of the lab. Xu Liu: Test mice. (Laughter) As neuroscientists, we work in the lab with mice trying to understand how memory wkros. And today, we hope to convince you that now we are actually able to activate a memory in the brain at the speed of light. To do this, there's only two simple stpes to floolw. First, you find and lebal a memory in the brain, and then you activate it with a switch. As simple as that. (Laughter) SR: Are you convinced? So, tnrus out finding a memory in the brain isn't all that easy. XL: Indeed. This is way more dulfcifit than, let's say, finding a needle in a haystack, because at least, you know, the needle is still something you can physically put your fingers on. But memory is not. And also, there's way more cells in your brain than the nmuebr of straws in a typical hatycask. So yeah, this task does seem to be dnatnuig. But lickluy, we got help from the brain itself. It turned out that all we need to do is bialcslay to let the brain form a memory, and then the brain will tell us which cells are involved in that particular memory. SR: So what was going on in my brain while I was rialenclg the memory of an ex? If you were to just completely ignore human ethics for a second and slice up my biarn right now, you would see that there was an amazing number of brain roenigs that were active while recalling that memory. Now one brain region that would be robustly active in particular is called the hippocampus, which for dcaedes has been iltapcmied in processing the kinds of memories that we hold near and dear, which also makes it an ideal target to go into and to try and find and maybe reactivate a memory. XL: When you zoom in into the hippocampus, of course you will see lots of cells, but we are able to find which cells are involved in a particular memory, because whenever a cell is active, like when it's forming a memory, it will also leave a footprint that will later allow us to know these cells are recently active. SR: So the same way that building litghs at night let you know that somebody's probably working there at any given meonmt, in a very real sense, there are biological sensors within a cell that are turned on only when that cell was just working. They're sort of biological windows that light up to let us know that that cell was just avctie. XL: So we clipped part of this sensor, and attached that to a switch to control the cells, and we packed this switch into an engineered virus and injected that into the brain of the mice. So whenever a memory is being formed, any active cells for that memory will also have this switch installed. SR: So here is what the hippocampus looks like after forming a fear memory, for example. The sea of blue that you see here are densely packed brain cells, but the green brain cells, the green brain cells are the ones that are holding on to a specific fear memory. So you are looking at the crystallization of the flntieeg ftmroaoin of fear. You're actually looking at the cross-section of a memory right now. XL: Now, for the switch we have been tniaklg about, ideally, the switch has to act really fast. It shouldn't take minutes or hruos to work. It should act at the speed of the brain, in milliseconds. SR: So what do you think, Xu? Could we use, let's say, pharmacological drugs to activate or inactivate brain cells? XL: Nah. Drugs are prtety messy. They saerpd everywhere. And also it takes them forever to act on cells. So it will not allow us to control a memory in real time. So Steve, how about let's zap the brain with electricity? SR: So electricity is pretty fast, but we probably wouldn't be able to target it to just the specific cells that hold onto a mermoy, and we'd probably fry the brain. XL: Oh. That's true. So it looks like, hmm, indeed we need to find a better way to impact the brain at the speed of light. SR: So it just so happens that light taevlrs at the speed of light. So maybe we could activate or icintvae mrimoees by just using light — XL: That's pretty fast. SR: — and because normally brain cells don't respond to pulses of lhigt, so those that would respond to pseuls of light are those that contain a light-sensitive switch. Now to do that, first we need to trick brain clles to respond to laser bemas. XL: Yep. You heard it right. We are trying to shoot lasers into the brain. (Laughter) SR: And the tuchnieqe that lets us do that is optogenetics. Optogenetics gave us this light switch that we can use to turn brain cells on or off, and the name of that switch is channelrhodopsin, seen here as these geern dots attached to this brain cell. You can think of channelrhodopsin as a sort of light-sensitive switch that can be artificially ielsanltd in brain cells so that now we can use that switch to activate or inactivate the brain cell simlpy by clicking it, and in this case we click it on with pulses of light. XL: So we actath this light-sensitive switch of channelrhodopsin to the sensor we've been talking about and inject this into the brain. So whenever a memory is being formed, any active cell for that particular memory will also have this light-sensitive stciwh installed in it so that we can cnorotl these cells by the flipping of a laser just like this one you see. SR: So let's put all of this to the test now. What we can do is we can take our mice and then we can put them in a box that looks exactly like this box here, and then we can give them a very mild foot shock so that they form a fear memory of this box. They learn that something bad happened here. Now with our sysetm, the cells that are active in the hicuampopps in the making of this memory, only those cells will now contain csalhnnhordpoein. XL: When you are as small as a mouse, it feles as if the whole world is trying to get you. So your best response of defense is trying to be undetected. Whenever a mouse is in fear, it will show this very typical behavior by staying at one corner of the box, trying to not move any part of its body, and this posture is called freezing. So if a mouse remembers that something bad happened in this box, and when we put them back into the same box, it will basically show freezing because it doesn't want to be detected by any potential threats in this box. SR: So you can think of freezing as, you're walking down the serett minding your own business, and then out of nowhere you almost run into an ex-girlfriend or ex-boyfriend, and now those terrifying two sencods where you start thinking, "What do I do? Do I say hi? Do I shake their hand? Do I turn around and run away? Do I sit here and pretend like I don't exist?" Those kinds of fleeting toughths that pcylsihlay incapacitate you, that temporarily give you that deer-in-headlights look. XL: However, if you put the mouse in a completely different new box, like the next one, it will not be afraid of this box because there's no reason that it will be afraid of this new environment. But what if we put the mouse in this new box but at the same time, we activate the fear memory using lrsaes just like we did before? Are we going to bring back the fear memory for the first box into this completely new enmnnrievot? SR: All right, and here's the million-dollar experiment. Now to bring back to life the memory of that day, I remember that the Red Sox had just won, it was a green spring day, perfect for going up and down the river and then maybe going to the North End to get some cannolis, #justsaying. Now Xu and I, on the other hand, were in a clelopmety wwsodniels black room not making any ocular movement that even remotely rbesemels an eye blink because our eyes were fixed onto a couptmer screen. We were looking at this mouse here trying to activate a memory for the first time using our technique. XL: And this is what we saw. When we first put the mouse into this box, it's exploring, sniffing around, walking around, minding its own business, because actually by nature, mice are pretty ciurous animals. They want to know, what's going on in this new box? It's interesting. But the moment we turned on the laser, like you see now, all of a sudden the mouse entered this freezing mode. It stayed here and tried not to move any part of its body. Clearly it's freezing. So indeed, it looks like we are able to bring back the fear memory for the first box in this completely new environment. While watching this, Steve and I are as shocked as the musoe itself. (Laughter) So after the experiment, the two of us just left the room without saying anything. After a kind of long, awkward period of time, svtee broke the silence. SR: "Did that just work?" XL: "Yes," I said. "Indeed it worked!" We're really excited about this. And then we published our findings in the journal Nature. Ever since the publication of our work, we've been receiving numerous cometmns from all over the Internet. Maybe we can take a look at some of those. ["OMGGGGG fnailly... so much more to come, virtual reality, neural manipulation, visual dream eloatimun... neural cdinog, 'writing and re-writing of memories', mtanel illnesses. Ahhh the ftuure is awesome"] SR: So the first thing that you'll notice is that people have really strong opinions about this kind of work. Now I hpaepn to completely agree with the optimism of this first quote, because on a scale of zero to Morgan Freeman's voice, it happens to be one of the most ecvvtoaie accolades that I've herad come our way. (luehgtar) But as you'll see, it's not the only opinion that's out there. ["This scares the hell out of me... What if they could do that easily in hunmas in a couple of years?! OH MY GOD WE'RE DOOMED"] XL: Indeed, if we take a look at the second one, I think we can all agree that it's, meh, probably not as positive. But this also reminds us that, although we are still working with mice, it's probably a good idea to start thinking and discussing about the possible ethical ramifications of memory control. SR: Now, in the spiirt of the third quote, we want to tell you about a recent percojt that we've been working on in lab that we've called Project Inception. ["They should make a miove about this. Where they plant ideas into peoples minds, so they can control them for their own personal gain. We'll call it: Inception."] So we reasoned that now that we can reactivate a memory, what if we do so but then begin to tinker with that memory? Could we possibly even turn it into a false memory? XL: So all memory is sophisticated and dynamic, but if just for simplicity, let's imagine memory as a movie clip. So far what we've told you is basically we can control this "play" button of the clip so that we can play this video clip any time, anywhere. But is there a plostiibsiy that we can actually get inside the brain and edit this movie clip so that we can make it different from the original? Yes we can. Turned out that all we need to do is basically reactivate a memory using lasers just like we did before, but at the same time, if we present new irfomaotnin and allow this new information to incorporate into this old memory, this will change the memory. It's sort of like mnkiag a remix tape. SR: So how do we do this? Rather than fnndiig a fear memory in the brain, we can strat by taking our animals, and let's say we put them in a blue box like this blue box here and we find the brain cells that represent that blue box and we trick them to respond to pulses of light exactly like we had said before. Now the next day, we can take our animals and place them in a red box that they've never experienced before. We can shoot light into the brain to reactivate the memory of the blue box. So what would happen here if, while the animal is recalling the memory of the blue box, we gave it a couple of mild foot sochks? So here we're trying to afircialtily make an association between the memory of the blue box and the foot shocks themselves. We're just trying to connect the two. So to test if we had done so, we can take our animals once again and palce them back in the blue box. Again, we had just reactivated the memory of the blue box while the animal got a couple of mild foot shocks, and now the aimanl suddenly freezes. It's as though it's recalling being mildly shocked in this environment even though that never actually happened. So it formed a false memory, because it's falsely fearing an environment where, technically speaking, nothing bad actually happened to it. XL: So, so far we are only talking about this light-controlled "on" switch. In fact, we also have a light-controlled "off" switch, and it's very easy to imagine that by iasllitnng this light-controlled "off" switch, we can also turn off a memory, any time, anywhere. So everything we've been talking about today is based on this philosophically carhegd principle of neuroscience that the mind, with its seemingly moyriseuts pteorieprs, is actually made of physical stuff that we can tenkir with. SR: And for me personally, I see a wlrod where we can reactivate any kind of memory that we'd like. I also see a world where we can erase unwanted memories. Now, I even see a world where editing memories is something of a reality, because we're living in a time where it's possible to pluck qenstoius from the tree of science fiction and to ground them in experimental rlaetiy. XL: ndaoyaws, people in the lab and people in other gpruos all over the world are using similar methods to activate or edit memories, whether that's old or new, psovitie or negative, all srtos of memories so that we can understand how memory works. SR: For example, one gruop in our lab was able to find the brain cells that make up a fear memory and converted them into a pleasurable memory, just like that. That's exactly what I mean about editing these kdins of processes. Now one dude in lab was even able to reactivate memories of fmalee mice in male mice, which rumor has it is a pleasurable experience. XL: Indeed, we are living in a very exciting moment where science doesn't have any arbitrary speed limits but is only bound by our own imogaaiitnn. SR: And finally, what do we make of all this? How do we push this tohoglcney forward? These are the questions that should not remain just inside the lab, and so one goal of today's talk was to bring everybody up to speed with the kind of stuff that's possible in modern neuroscience, but now, just as importantly, to actively eggnae everybody in this conversation. So let's think together as a team about what this all maens and where we can and should go from here, because Xu and I think we all have some really big desoniics ahead of us. Thank you. XL: Thank you. (auaslppe)

Open Cloze

Steve Ramirez: My first year of grad school, I found myself in my bedroom eating lots of Ben & Jerry's watching some trashy TV and maybe, maybe listening to Taylor Swift. I had just gone through a breakup. (Laughter) So for the longest time, all I would do is recall the memory of this person over and over again, wishing that I could get rid of that gut-wrenching, visceral "blah" feeling. Now, as it turns out, I'm a neuroscientist, so I knew that the memory of that ______ and the _____, emotional undertones that color in that memory, are largely mediated by separate brain systems. And so I thought, what if we could go into the brain and edit out that nauseating _______ but while keeping the memory of that person intact? Then I realized, maybe that's a little bit lofty for now. So what if we could start off by going into the brain and just finding a single memory to begin with? Could we jump-start that memory back to life, maybe even play with the contents of that memory? All that said, there is one person in the entire world right now that I really hope is not watching this talk. (Laughter) So there is a catch. There is a catch. These _____ probably remind you of "Total ______," "Eternal Sunshine of the Spotless Mind," or of "Inception." But the movie stars that we work with are the celebrities of the lab. Xu Liu: Test mice. (Laughter) As neuroscientists, we work in the lab with mice trying to understand how memory _____. And today, we hope to convince you that now we are actually able to activate a memory in the brain at the speed of light. To do this, there's only two simple _____ to ______. First, you find and _____ a memory in the brain, and then you activate it with a switch. As simple as that. (Laughter) SR: Are you convinced? So, _____ out finding a memory in the brain isn't all that easy. XL: Indeed. This is way more _________ than, let's say, finding a needle in a haystack, because at least, you know, the needle is still something you can physically put your fingers on. But memory is not. And also, there's way more cells in your brain than the ______ of straws in a typical ________. So yeah, this task does seem to be ________. But _______, we got help from the brain itself. It turned out that all we need to do is _________ to let the brain form a memory, and then the brain will tell us which cells are involved in that particular memory. SR: So what was going on in my brain while I was _________ the memory of an ex? If you were to just completely ignore human ethics for a second and slice up my _____ right now, you would see that there was an amazing number of brain _______ that were active while recalling that memory. Now one brain region that would be robustly active in particular is called the hippocampus, which for _______ has been __________ in processing the kinds of memories that we hold near and dear, which also makes it an ideal target to go into and to try and find and maybe reactivate a memory. XL: When you zoom in into the hippocampus, of course you will see lots of cells, but we are able to find which cells are involved in a particular memory, because whenever a cell is active, like when it's forming a memory, it will also leave a footprint that will later allow us to know these cells are recently active. SR: So the same way that building ______ at night let you know that somebody's probably working there at any given ______, in a very real sense, there are biological sensors within a cell that are turned on only when that cell was just working. They're sort of biological windows that light up to let us know that that cell was just ______. XL: So we clipped part of this sensor, and attached that to a switch to control the cells, and we packed this switch into an engineered virus and injected that into the brain of the mice. So whenever a memory is being formed, any active cells for that memory will also have this switch installed. SR: So here is what the hippocampus looks like after forming a fear memory, for example. The sea of blue that you see here are densely packed brain cells, but the green brain cells, the green brain cells are the ones that are holding on to a specific fear memory. So you are looking at the crystallization of the ________ _________ of fear. You're actually looking at the cross-section of a memory right now. XL: Now, for the switch we have been _______ about, ideally, the switch has to act really fast. It shouldn't take minutes or _____ to work. It should act at the speed of the brain, in milliseconds. SR: So what do you think, Xu? Could we use, let's say, pharmacological drugs to activate or inactivate brain cells? XL: Nah. Drugs are ______ messy. They ______ everywhere. And also it takes them forever to act on cells. So it will not allow us to control a memory in real time. So Steve, how about let's zap the brain with electricity? SR: So electricity is pretty fast, but we probably wouldn't be able to target it to just the specific cells that hold onto a ______, and we'd probably fry the brain. XL: Oh. That's true. So it looks like, hmm, indeed we need to find a better way to impact the brain at the speed of light. SR: So it just so happens that light _______ at the speed of light. So maybe we could activate or ________ ________ by just using light — XL: That's pretty fast. SR: — and because normally brain cells don't respond to pulses of _____, so those that would respond to ______ of light are those that contain a light-sensitive switch. Now to do that, first we need to trick brain _____ to respond to laser _____. XL: Yep. You heard it right. We are trying to shoot lasers into the brain. (Laughter) SR: And the _________ that lets us do that is optogenetics. Optogenetics gave us this light switch that we can use to turn brain cells on or off, and the name of that switch is channelrhodopsin, seen here as these _____ dots attached to this brain cell. You can think of channelrhodopsin as a sort of light-sensitive switch that can be artificially _________ in brain cells so that now we can use that switch to activate or inactivate the brain cell ______ by clicking it, and in this case we click it on with pulses of light. XL: So we ______ this light-sensitive switch of channelrhodopsin to the sensor we've been talking about and inject this into the brain. So whenever a memory is being formed, any active cell for that particular memory will also have this light-sensitive ______ installed in it so that we can _______ these cells by the flipping of a laser just like this one you see. SR: So let's put all of this to the test now. What we can do is we can take our mice and then we can put them in a box that looks exactly like this box here, and then we can give them a very mild foot shock so that they form a fear memory of this box. They learn that something bad happened here. Now with our ______, the cells that are active in the ___________ in the making of this memory, only those cells will now contain ________________. XL: When you are as small as a mouse, it _____ as if the whole world is trying to get you. So your best response of defense is trying to be undetected. Whenever a mouse is in fear, it will show this very typical behavior by staying at one corner of the box, trying to not move any part of its body, and this posture is called freezing. So if a mouse remembers that something bad happened in this box, and when we put them back into the same box, it will basically show freezing because it doesn't want to be detected by any potential threats in this box. SR: So you can think of freezing as, you're walking down the ______ minding your own business, and then out of nowhere you almost run into an ex-girlfriend or ex-boyfriend, and now those terrifying two _______ where you start thinking, "What do I do? Do I say hi? Do I shake their hand? Do I turn around and run away? Do I sit here and pretend like I don't exist?" Those kinds of fleeting ________ that __________ incapacitate you, that temporarily give you that deer-in-headlights look. XL: However, if you put the mouse in a completely different new box, like the next one, it will not be afraid of this box because there's no reason that it will be afraid of this new environment. But what if we put the mouse in this new box but at the same time, we activate the fear memory using ______ just like we did before? Are we going to bring back the fear memory for the first box into this completely new ___________? SR: All right, and here's the million-dollar experiment. Now to bring back to life the memory of that day, I remember that the Red Sox had just won, it was a green spring day, perfect for going up and down the river and then maybe going to the North End to get some cannolis, #justsaying. Now Xu and I, on the other hand, were in a __________ __________ black room not making any ocular movement that even remotely _________ an eye blink because our eyes were fixed onto a ________ screen. We were looking at this mouse here trying to activate a memory for the first time using our technique. XL: And this is what we saw. When we first put the mouse into this box, it's exploring, sniffing around, walking around, minding its own business, because actually by nature, mice are pretty _______ animals. They want to know, what's going on in this new box? It's interesting. But the moment we turned on the laser, like you see now, all of a sudden the mouse entered this freezing mode. It stayed here and tried not to move any part of its body. Clearly it's freezing. So indeed, it looks like we are able to bring back the fear memory for the first box in this completely new environment. While watching this, Steve and I are as shocked as the _____ itself. (Laughter) So after the experiment, the two of us just left the room without saying anything. After a kind of long, awkward period of time, _____ broke the silence. SR: "Did that just work?" XL: "Yes," I said. "Indeed it worked!" We're really excited about this. And then we published our findings in the journal Nature. Ever since the publication of our work, we've been receiving numerous ________ from all over the Internet. Maybe we can take a look at some of those. ["OMGGGGG _______... so much more to come, virtual reality, neural manipulation, visual dream _________... neural ______, 'writing and re-writing of memories', ______ illnesses. Ahhh the ______ is awesome"] SR: So the first thing that you'll notice is that people have really strong opinions about this kind of work. Now I ______ to completely agree with the optimism of this first quote, because on a scale of zero to Morgan Freeman's voice, it happens to be one of the most _________ accolades that I've _____ come our way. (________) But as you'll see, it's not the only opinion that's out there. ["This scares the hell out of me... What if they could do that easily in ______ in a couple of years?! OH MY GOD WE'RE DOOMED"] XL: Indeed, if we take a look at the second one, I think we can all agree that it's, meh, probably not as positive. But this also reminds us that, although we are still working with mice, it's probably a good idea to start thinking and discussing about the possible ethical ramifications of memory control. SR: Now, in the ______ of the third quote, we want to tell you about a recent _______ that we've been working on in lab that we've called Project Inception. ["They should make a _____ about this. Where they plant ideas into peoples minds, so they can control them for their own personal gain. We'll call it: Inception."] So we reasoned that now that we can reactivate a memory, what if we do so but then begin to tinker with that memory? Could we possibly even turn it into a false memory? XL: So all memory is sophisticated and dynamic, but if just for simplicity, let's imagine memory as a movie clip. So far what we've told you is basically we can control this "play" button of the clip so that we can play this video clip any time, anywhere. But is there a ___________ that we can actually get inside the brain and edit this movie clip so that we can make it different from the original? Yes we can. Turned out that all we need to do is basically reactivate a memory using lasers just like we did before, but at the same time, if we present new ___________ and allow this new information to incorporate into this old memory, this will change the memory. It's sort of like ______ a remix tape. SR: So how do we do this? Rather than _______ a fear memory in the brain, we can _____ by taking our animals, and let's say we put them in a blue box like this blue box here and we find the brain cells that represent that blue box and we trick them to respond to pulses of light exactly like we had said before. Now the next day, we can take our animals and place them in a red box that they've never experienced before. We can shoot light into the brain to reactivate the memory of the blue box. So what would happen here if, while the animal is recalling the memory of the blue box, we gave it a couple of mild foot ______? So here we're trying to ____________ make an association between the memory of the blue box and the foot shocks themselves. We're just trying to connect the two. So to test if we had done so, we can take our animals once again and _____ them back in the blue box. Again, we had just reactivated the memory of the blue box while the animal got a couple of mild foot shocks, and now the ______ suddenly freezes. It's as though it's recalling being mildly shocked in this environment even though that never actually happened. So it formed a false memory, because it's falsely fearing an environment where, technically speaking, nothing bad actually happened to it. XL: So, so far we are only talking about this light-controlled "on" switch. In fact, we also have a light-controlled "off" switch, and it's very easy to imagine that by __________ this light-controlled "off" switch, we can also turn off a memory, any time, anywhere. So everything we've been talking about today is based on this philosophically _______ principle of neuroscience that the mind, with its seemingly __________ __________, is actually made of physical stuff that we can ______ with. SR: And for me personally, I see a _____ where we can reactivate any kind of memory that we'd like. I also see a world where we can erase unwanted memories. Now, I even see a world where editing memories is something of a reality, because we're living in a time where it's possible to pluck _________ from the tree of science fiction and to ground them in experimental _______. XL: ________, people in the lab and people in other ______ all over the world are using similar methods to activate or edit memories, whether that's old or new, ________ or negative, all _____ of memories so that we can understand how memory works. SR: For example, one _____ in our lab was able to find the brain cells that make up a fear memory and converted them into a pleasurable memory, just like that. That's exactly what I mean about editing these _____ of processes. Now one dude in lab was even able to reactivate memories of ______ mice in male mice, which rumor has it is a pleasurable experience. XL: Indeed, we are living in a very exciting moment where science doesn't have any arbitrary speed limits but is only bound by our own ___________. SR: And finally, what do we make of all this? How do we push this __________ forward? These are the questions that should not remain just inside the lab, and so one goal of today's talk was to bring everybody up to speed with the kind of stuff that's possible in modern neuroscience, but now, just as importantly, to actively ______ everybody in this conversation. So let's think together as a team about what this all _____ and where we can and should go from here, because Xu and I think we all have some really big _________ ahead of us. Thank you. XL: Thank you. (________)

Solution

  1. possibility
  2. shocks
  3. emulation
  4. means
  5. person
  6. recall
  7. project
  8. future
  9. finding
  10. hours
  11. nowadays
  12. decisions
  13. coding
  14. evocative
  15. groups
  16. feels
  17. engage
  18. thoughts
  19. technique
  20. installing
  21. animal
  22. artificially
  23. comments
  24. imagination
  25. light
  26. implicated
  27. kinds
  28. brain
  29. follow
  30. pulses
  31. physically
  32. sorts
  33. system
  34. positive
  35. label
  36. humans
  37. turns
  38. spread
  39. travels
  40. making
  41. steve
  42. movie
  43. works
  44. memory
  45. beams
  46. start
  47. mental
  48. seconds
  49. awful
  50. group
  51. control
  52. windowless
  53. female
  54. applause
  55. laughter
  56. decades
  57. finally
  58. hippocampus
  59. curious
  60. technology
  61. reality
  62. lights
  63. lasers
  64. cells
  65. environment
  66. mouse
  67. formation
  68. active
  69. daunting
  70. mysterious
  71. basically
  72. completely
  73. green
  74. channelrhodopsin
  75. properties
  76. simply
  77. installed
  78. number
  79. attach
  80. world
  81. tinker
  82. information
  83. talking
  84. computer
  85. resembles
  86. difficult
  87. moment
  88. regions
  89. place
  90. fleeting
  91. switch
  92. pretty
  93. spirit
  94. luckily
  95. happen
  96. steps
  97. feeling
  98. recalling
  99. inactive
  100. heard
  101. haystack
  102. questions
  103. charged
  104. street
  105. memories
  106. ideas

Original Text

Steve Ramirez: My first year of grad school, I found myself in my bedroom eating lots of Ben & Jerry's watching some trashy TV and maybe, maybe listening to Taylor Swift. I had just gone through a breakup. (Laughter) So for the longest time, all I would do is recall the memory of this person over and over again, wishing that I could get rid of that gut-wrenching, visceral "blah" feeling. Now, as it turns out, I'm a neuroscientist, so I knew that the memory of that person and the awful, emotional undertones that color in that memory, are largely mediated by separate brain systems. And so I thought, what if we could go into the brain and edit out that nauseating feeling but while keeping the memory of that person intact? Then I realized, maybe that's a little bit lofty for now. So what if we could start off by going into the brain and just finding a single memory to begin with? Could we jump-start that memory back to life, maybe even play with the contents of that memory? All that said, there is one person in the entire world right now that I really hope is not watching this talk. (Laughter) So there is a catch. There is a catch. These ideas probably remind you of "Total Recall," "Eternal Sunshine of the Spotless Mind," or of "Inception." But the movie stars that we work with are the celebrities of the lab. Xu Liu: Test mice. (Laughter) As neuroscientists, we work in the lab with mice trying to understand how memory works. And today, we hope to convince you that now we are actually able to activate a memory in the brain at the speed of light. To do this, there's only two simple steps to follow. First, you find and label a memory in the brain, and then you activate it with a switch. As simple as that. (Laughter) SR: Are you convinced? So, turns out finding a memory in the brain isn't all that easy. XL: Indeed. This is way more difficult than, let's say, finding a needle in a haystack, because at least, you know, the needle is still something you can physically put your fingers on. But memory is not. And also, there's way more cells in your brain than the number of straws in a typical haystack. So yeah, this task does seem to be daunting. But luckily, we got help from the brain itself. It turned out that all we need to do is basically to let the brain form a memory, and then the brain will tell us which cells are involved in that particular memory. SR: So what was going on in my brain while I was recalling the memory of an ex? If you were to just completely ignore human ethics for a second and slice up my brain right now, you would see that there was an amazing number of brain regions that were active while recalling that memory. Now one brain region that would be robustly active in particular is called the hippocampus, which for decades has been implicated in processing the kinds of memories that we hold near and dear, which also makes it an ideal target to go into and to try and find and maybe reactivate a memory. XL: When you zoom in into the hippocampus, of course you will see lots of cells, but we are able to find which cells are involved in a particular memory, because whenever a cell is active, like when it's forming a memory, it will also leave a footprint that will later allow us to know these cells are recently active. SR: So the same way that building lights at night let you know that somebody's probably working there at any given moment, in a very real sense, there are biological sensors within a cell that are turned on only when that cell was just working. They're sort of biological windows that light up to let us know that that cell was just active. XL: So we clipped part of this sensor, and attached that to a switch to control the cells, and we packed this switch into an engineered virus and injected that into the brain of the mice. So whenever a memory is being formed, any active cells for that memory will also have this switch installed. SR: So here is what the hippocampus looks like after forming a fear memory, for example. The sea of blue that you see here are densely packed brain cells, but the green brain cells, the green brain cells are the ones that are holding on to a specific fear memory. So you are looking at the crystallization of the fleeting formation of fear. You're actually looking at the cross-section of a memory right now. XL: Now, for the switch we have been talking about, ideally, the switch has to act really fast. It shouldn't take minutes or hours to work. It should act at the speed of the brain, in milliseconds. SR: So what do you think, Xu? Could we use, let's say, pharmacological drugs to activate or inactivate brain cells? XL: Nah. Drugs are pretty messy. They spread everywhere. And also it takes them forever to act on cells. So it will not allow us to control a memory in real time. So Steve, how about let's zap the brain with electricity? SR: So electricity is pretty fast, but we probably wouldn't be able to target it to just the specific cells that hold onto a memory, and we'd probably fry the brain. XL: Oh. That's true. So it looks like, hmm, indeed we need to find a better way to impact the brain at the speed of light. SR: So it just so happens that light travels at the speed of light. So maybe we could activate or inactive memories by just using light — XL: That's pretty fast. SR: — and because normally brain cells don't respond to pulses of light, so those that would respond to pulses of light are those that contain a light-sensitive switch. Now to do that, first we need to trick brain cells to respond to laser beams. XL: Yep. You heard it right. We are trying to shoot lasers into the brain. (Laughter) SR: And the technique that lets us do that is optogenetics. Optogenetics gave us this light switch that we can use to turn brain cells on or off, and the name of that switch is channelrhodopsin, seen here as these green dots attached to this brain cell. You can think of channelrhodopsin as a sort of light-sensitive switch that can be artificially installed in brain cells so that now we can use that switch to activate or inactivate the brain cell simply by clicking it, and in this case we click it on with pulses of light. XL: So we attach this light-sensitive switch of channelrhodopsin to the sensor we've been talking about and inject this into the brain. So whenever a memory is being formed, any active cell for that particular memory will also have this light-sensitive switch installed in it so that we can control these cells by the flipping of a laser just like this one you see. SR: So let's put all of this to the test now. What we can do is we can take our mice and then we can put them in a box that looks exactly like this box here, and then we can give them a very mild foot shock so that they form a fear memory of this box. They learn that something bad happened here. Now with our system, the cells that are active in the hippocampus in the making of this memory, only those cells will now contain channelrhodopsin. XL: When you are as small as a mouse, it feels as if the whole world is trying to get you. So your best response of defense is trying to be undetected. Whenever a mouse is in fear, it will show this very typical behavior by staying at one corner of the box, trying to not move any part of its body, and this posture is called freezing. So if a mouse remembers that something bad happened in this box, and when we put them back into the same box, it will basically show freezing because it doesn't want to be detected by any potential threats in this box. SR: So you can think of freezing as, you're walking down the street minding your own business, and then out of nowhere you almost run into an ex-girlfriend or ex-boyfriend, and now those terrifying two seconds where you start thinking, "What do I do? Do I say hi? Do I shake their hand? Do I turn around and run away? Do I sit here and pretend like I don't exist?" Those kinds of fleeting thoughts that physically incapacitate you, that temporarily give you that deer-in-headlights look. XL: However, if you put the mouse in a completely different new box, like the next one, it will not be afraid of this box because there's no reason that it will be afraid of this new environment. But what if we put the mouse in this new box but at the same time, we activate the fear memory using lasers just like we did before? Are we going to bring back the fear memory for the first box into this completely new environment? SR: All right, and here's the million-dollar experiment. Now to bring back to life the memory of that day, I remember that the Red Sox had just won, it was a green spring day, perfect for going up and down the river and then maybe going to the North End to get some cannolis, #justsaying. Now Xu and I, on the other hand, were in a completely windowless black room not making any ocular movement that even remotely resembles an eye blink because our eyes were fixed onto a computer screen. We were looking at this mouse here trying to activate a memory for the first time using our technique. XL: And this is what we saw. When we first put the mouse into this box, it's exploring, sniffing around, walking around, minding its own business, because actually by nature, mice are pretty curious animals. They want to know, what's going on in this new box? It's interesting. But the moment we turned on the laser, like you see now, all of a sudden the mouse entered this freezing mode. It stayed here and tried not to move any part of its body. Clearly it's freezing. So indeed, it looks like we are able to bring back the fear memory for the first box in this completely new environment. While watching this, Steve and I are as shocked as the mouse itself. (Laughter) So after the experiment, the two of us just left the room without saying anything. After a kind of long, awkward period of time, Steve broke the silence. SR: "Did that just work?" XL: "Yes," I said. "Indeed it worked!" We're really excited about this. And then we published our findings in the journal Nature. Ever since the publication of our work, we've been receiving numerous comments from all over the Internet. Maybe we can take a look at some of those. ["OMGGGGG FINALLY... so much more to come, virtual reality, neural manipulation, visual dream emulation... neural coding, 'writing and re-writing of memories', mental illnesses. Ahhh the future is awesome"] SR: So the first thing that you'll notice is that people have really strong opinions about this kind of work. Now I happen to completely agree with the optimism of this first quote, because on a scale of zero to Morgan Freeman's voice, it happens to be one of the most evocative accolades that I've heard come our way. (Laughter) But as you'll see, it's not the only opinion that's out there. ["This scares the hell out of me... What if they could do that easily in humans in a couple of years?! OH MY GOD WE'RE DOOMED"] XL: Indeed, if we take a look at the second one, I think we can all agree that it's, meh, probably not as positive. But this also reminds us that, although we are still working with mice, it's probably a good idea to start thinking and discussing about the possible ethical ramifications of memory control. SR: Now, in the spirit of the third quote, we want to tell you about a recent project that we've been working on in lab that we've called Project Inception. ["They should make a movie about this. Where they plant ideas into peoples minds, so they can control them for their own personal gain. We'll call it: Inception."] So we reasoned that now that we can reactivate a memory, what if we do so but then begin to tinker with that memory? Could we possibly even turn it into a false memory? XL: So all memory is sophisticated and dynamic, but if just for simplicity, let's imagine memory as a movie clip. So far what we've told you is basically we can control this "play" button of the clip so that we can play this video clip any time, anywhere. But is there a possibility that we can actually get inside the brain and edit this movie clip so that we can make it different from the original? Yes we can. Turned out that all we need to do is basically reactivate a memory using lasers just like we did before, but at the same time, if we present new information and allow this new information to incorporate into this old memory, this will change the memory. It's sort of like making a remix tape. SR: So how do we do this? Rather than finding a fear memory in the brain, we can start by taking our animals, and let's say we put them in a blue box like this blue box here and we find the brain cells that represent that blue box and we trick them to respond to pulses of light exactly like we had said before. Now the next day, we can take our animals and place them in a red box that they've never experienced before. We can shoot light into the brain to reactivate the memory of the blue box. So what would happen here if, while the animal is recalling the memory of the blue box, we gave it a couple of mild foot shocks? So here we're trying to artificially make an association between the memory of the blue box and the foot shocks themselves. We're just trying to connect the two. So to test if we had done so, we can take our animals once again and place them back in the blue box. Again, we had just reactivated the memory of the blue box while the animal got a couple of mild foot shocks, and now the animal suddenly freezes. It's as though it's recalling being mildly shocked in this environment even though that never actually happened. So it formed a false memory, because it's falsely fearing an environment where, technically speaking, nothing bad actually happened to it. XL: So, so far we are only talking about this light-controlled "on" switch. In fact, we also have a light-controlled "off" switch, and it's very easy to imagine that by installing this light-controlled "off" switch, we can also turn off a memory, any time, anywhere. So everything we've been talking about today is based on this philosophically charged principle of neuroscience that the mind, with its seemingly mysterious properties, is actually made of physical stuff that we can tinker with. SR: And for me personally, I see a world where we can reactivate any kind of memory that we'd like. I also see a world where we can erase unwanted memories. Now, I even see a world where editing memories is something of a reality, because we're living in a time where it's possible to pluck questions from the tree of science fiction and to ground them in experimental reality. XL: Nowadays, people in the lab and people in other groups all over the world are using similar methods to activate or edit memories, whether that's old or new, positive or negative, all sorts of memories so that we can understand how memory works. SR: For example, one group in our lab was able to find the brain cells that make up a fear memory and converted them into a pleasurable memory, just like that. That's exactly what I mean about editing these kinds of processes. Now one dude in lab was even able to reactivate memories of female mice in male mice, which rumor has it is a pleasurable experience. XL: Indeed, we are living in a very exciting moment where science doesn't have any arbitrary speed limits but is only bound by our own imagination. SR: And finally, what do we make of all this? How do we push this technology forward? These are the questions that should not remain just inside the lab, and so one goal of today's talk was to bring everybody up to speed with the kind of stuff that's possible in modern neuroscience, but now, just as importantly, to actively engage everybody in this conversation. So let's think together as a team about what this all means and where we can and should go from here, because Xu and I think we all have some really big decisions ahead of us. Thank you. XL: Thank you. (Applause)

Frequently Occurring Word Combinations

ngrams of length 2

collocation frequency
brain cells 7
fear memory 7
blue box 7
mild foot 3
memory works 2
switch installed 2
green brain 2
brain cell 2
bad happened 2
movie clip 2

Important Words

  1. accolades
  2. act
  3. activate
  4. active
  5. actively
  6. afraid
  7. agree
  8. ahhh
  9. amazing
  10. animal
  11. animals
  12. applause
  13. arbitrary
  14. artificially
  15. association
  16. attach
  17. attached
  18. awful
  19. awkward
  20. bad
  21. based
  22. basically
  23. beams
  24. bedroom
  25. behavior
  26. ben
  27. big
  28. biological
  29. bit
  30. black
  31. blink
  32. blue
  33. body
  34. bound
  35. box
  36. brain
  37. breakup
  38. bring
  39. broke
  40. building
  41. business
  42. button
  43. call
  44. called
  45. cannolis
  46. case
  47. catch
  48. celebrities
  49. cell
  50. cells
  51. change
  52. channelrhodopsin
  53. charged
  54. click
  55. clicking
  56. clip
  57. clipped
  58. coding
  59. color
  60. comments
  61. completely
  62. computer
  63. connect
  64. contents
  65. control
  66. conversation
  67. converted
  68. convince
  69. convinced
  70. corner
  71. couple
  72. crystallization
  73. curious
  74. daunting
  75. day
  76. dear
  77. decades
  78. decisions
  79. defense
  80. densely
  81. detected
  82. difficult
  83. discussing
  84. dots
  85. dream
  86. drugs
  87. dude
  88. dynamic
  89. easily
  90. easy
  91. eating
  92. edit
  93. editing
  94. electricity
  95. emotional
  96. emulation
  97. engage
  98. engineered
  99. entered
  100. entire
  101. environment
  102. erase
  103. ethical
  104. ethics
  105. evocative
  106. excited
  107. exciting
  108. exist
  109. experience
  110. experienced
  111. experiment
  112. experimental
  113. exploring
  114. eye
  115. eyes
  116. fact
  117. false
  118. falsely
  119. fast
  120. fear
  121. fearing
  122. feeling
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  124. female
  125. fiction
  126. finally
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  130. fingers
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  132. fleeting
  133. flipping
  134. follow
  135. foot
  136. footprint
  137. form
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  140. forming
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  142. freezing
  143. fry
  144. future
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  150. good
  151. grad
  152. green
  153. ground
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  156. hand
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  159. haystack
  160. heard
  161. hell
  162. hippocampus
  163. hmm
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  167. hours
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  172. ideally
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  176. imagination
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  178. impact
  179. implicated
  180. importantly
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  182. inactive
  183. incapacitate
  184. inception
  185. incorporate
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  187. inject
  188. injected
  189. installed
  190. installing
  191. intact
  192. interesting
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  195. journal
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  203. laser
  204. lasers
  205. laughter
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  211. light
  212. lights
  213. limits
  214. listening
  215. living
  216. lofty
  217. long
  218. longest
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  220. luckily
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  222. male
  223. manipulation
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  225. mediated
  226. meh
  227. memories
  228. memory
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  231. methods
  232. mice
  233. mild
  234. mildly
  235. milliseconds
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  240. mode
  241. modern
  242. moment
  243. morgan
  244. mouse
  245. move
  246. movement
  247. movie
  248. mysterious
  249. nah
  250. nature
  251. nauseating
  252. needle
  253. negative
  254. neural
  255. neuroscience
  256. neuroscientist
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  258. night
  259. north
  260. notice
  261. nowadays
  262. number
  263. numerous
  264. ocular
  265. opinion
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  267. optimism
  268. optogenetics
  269. original
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  272. people
  273. peoples
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  275. period
  276. person
  277. personal
  278. personally
  279. pharmacological
  280. philosophically
  281. physical
  282. physically
  283. place
  284. plant
  285. play
  286. pleasurable
  287. pluck
  288. positive
  289. possibility
  290. possibly
  291. posture
  292. potential
  293. present
  294. pretend
  295. pretty
  296. principle
  297. processes
  298. processing
  299. project
  300. properties
  301. publication
  302. published
  303. pulses
  304. push
  305. put
  306. questions
  307. quote
  308. ramifications
  309. reactivate
  310. reactivated
  311. real
  312. reality
  313. realized
  314. reason
  315. reasoned
  316. recall
  317. recalling
  318. receiving
  319. red
  320. region
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  322. remain
  323. remember
  324. remembers
  325. remind
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  327. remix
  328. remotely
  329. represent
  330. resembles
  331. respond
  332. response
  333. rid
  334. river
  335. robustly
  336. room
  337. rumor
  338. run
  339. scale
  340. scares
  341. school
  342. science
  343. screen
  344. sea
  345. seconds
  346. seemingly
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  348. sensor
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  350. separate
  351. shake
  352. shock
  353. shocked
  354. shocks
  355. shoot
  356. show
  357. silence
  358. similar
  359. simple
  360. simplicity
  361. simply
  362. single
  363. sit
  364. slice
  365. small
  366. sniffing
  367. sophisticated
  368. sort
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  370. sox
  371. speaking
  372. specific
  373. speed
  374. spirit
  375. spotless
  376. spread
  377. spring
  378. stars
  379. start
  380. stayed
  381. staying
  382. steps
  383. steve
  384. straws
  385. street
  386. strong
  387. stuff
  388. sudden
  389. suddenly
  390. sunshine
  391. swift
  392. switch
  393. system
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  396. talk
  397. talking
  398. tape
  399. target
  400. task
  401. taylor
  402. team
  403. technically
  404. technique
  405. technology
  406. temporarily
  407. terrifying
  408. test
  409. thinking
  410. thought
  411. thoughts
  412. threats
  413. time
  414. tinker
  415. today
  416. told
  417. trashy
  418. travels
  419. tree
  420. trick
  421. true
  422. turn
  423. turned
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  425. tv
  426. typical
  427. understand
  428. undertones
  429. undetected
  430. unwanted
  431. video
  432. virtual
  433. virus
  434. visceral
  435. visual
  436. voice
  437. walking
  438. watching
  439. windowless
  440. windows
  441. wishing
  442. won
  443. work
  444. working
  445. works
  446. world
  447. xu
  448. yeah
  449. year
  450. years
  451. yep
  452. zap
  453. zoom