0:00:15.186,0:00:20.751 My beloved grandmother passed away[br]earlier this year on February 28th 0:00:20.751,0:00:25.704 after suffering for a very[br]long time from a stroke. 0:00:25.704,0:00:28.139 One day, she collapsed. 0:00:28.139,0:00:30.837 A few days later she woke up[br]in the hospital 0:00:30.869,0:00:35.818 to find herself completely paralyzed[br]on the right side of her body. 0:00:35.838,0:00:39.682 It was just a small little vessel[br]that burst inside her head, 0:00:39.697,0:00:43.060 but it had a life-altering[br]implication for her 0:00:43.089,0:00:48.445 where now she could[br]no longer move her own body. 0:00:48.493,0:00:53.406 For the next three-and-a-half years[br]she was hospitalized, 0:00:53.406,0:00:56.798 and went through extensive[br]rehabilitation therapy, 0:00:56.798,0:01:00.090 at the end of which she could barely walk 0:01:00.090,0:01:04.558 on her own with an extensive[br]help of a walker. 0:01:04.592,0:01:10.349 Then, she returned home and stayed[br]bed-bound for another eight years 0:01:10.388,0:01:12.949 before she passed away this year. 0:01:13.618,0:01:19.582 Watching her suffer through this very[br]painful and devastating disease, 0:01:19.582,0:01:23.943 the most difficult thing,[br]the most painful thing for me, 0:01:23.943,0:01:29.182 was the fact that there was nothing[br]that any of us could do 0:01:29.182,0:01:32.039 to give her back what she had lost 0:01:32.039,0:01:36.607 when the small blood vessel[br]burst in her head 0:01:36.624,0:01:41.671 so that she can have control[br]over her own body again. 0:01:41.930,0:01:47.111 When we have a device broken,[br]like a computer or a cellphone, 0:01:47.111,0:01:48.723 what do we do? 0:01:48.723,0:01:52.372 Do we just put it on a place,[br]comfortable somewhere, 0:01:52.372,0:01:58.278 and just press the button repeatedly[br]until maybe it starts working again? 0:01:59.178,0:02:01.230 Well, yes, I sometimes do that. 0:02:01.230,0:02:06.603 But if we really want it fixed,[br]that's not what we should do. 0:02:06.653,0:02:11.662 When we have a device broken,[br]what we do is we directly go in. 0:02:11.669,0:02:14.897 If there is a broken software,[br]we reprogram it. 0:02:14.928,0:02:18.108 If there is a broken wire, we rewire it. 0:02:18.123,0:02:23.217 If there is a worn out[br]or broken part, we replace it. 0:02:23.222,0:02:29.513 The question is: Can we do[br]something like this for our own brains? 0:02:31.615,0:02:35.361 There are many different forms[br]of brain diseases. 0:02:35.368,0:02:38.044 Some of which includes the following. 0:02:38.078,0:02:43.880 It includes stroke, where your blood[br]vessel bursts and damages your brain. 0:02:43.929,0:02:47.103 There's also a disease called epilepsy, 0:02:47.122,0:02:49.649 where you suddenly have[br]uncontrollable activity 0:02:49.669,0:02:52.975 that happens inside your brain[br]without any warning, 0:02:53.007,0:02:55.996 where you are no longer able to[br]control yourself. 0:02:56.018,0:02:59.149 And this seems like a very foreign[br]concept to most of us, 0:02:59.295,0:03:01.837 but this is something[br]that can happen to any of you 0:03:01.868,0:03:05.886 by simply hitting your head[br]in the wrong place at the wrong time. 0:03:06.418,0:03:09.557 Another important brain disease,[br]psychiatric disease, 0:03:09.566,0:03:14.735 includes depression, where you feel[br]hopelessness and sadness. 0:03:14.946,0:03:17.483 There is also a form called autism, 0:03:17.494,0:03:22.795 where children find it difficult[br]to relate to other people. 0:03:22.809,0:03:26.449 And there's also a category of[br]neurodegenerative diseases, 0:03:26.466,0:03:30.198 which includes Parkinson's[br]and Alzheimer's disease, 0:03:30.207,0:03:32.625 where in the Parkinson's disease case 0:03:32.648,0:03:37.078 you start to tremor and you can no longer[br]control your body movements, 0:03:37.093,0:03:39.332 and in the case of Alzheimer's disease, 0:03:39.332,0:03:45.221 you have memory loss, where ultimately[br]you forget even who you are. 0:03:46.931,0:03:50.916 While there are these many forms[br]of neurological diseases, 0:03:50.916,0:03:53.807 there is one thing that is[br]common to all of these. 0:03:53.807,0:03:58.165 Despite the increasing[br]prevalence and cost, 0:03:58.165,0:04:03.987 there is one common thing[br]which is that there is absolutely no cure. 0:04:03.987,0:04:06.859 You see all of these numbers[br]on the screen? 0:04:06.859,0:04:09.390 These are very, very large numbers. 0:04:09.431,0:04:12.235 For example,[br]in the Alzheimer's disease case, 0:04:12.270,0:04:18.725 we are expected to spend[br]about 1.1 trillion dollars by 2050 0:04:18.738,0:04:20.512 on treating Alzheimer's disease 0:04:20.531,0:04:23.479 if we go at the current rate[br]where we can't cure anything 0:04:23.502,0:04:25.617 and we just keep providing support. 0:04:25.660,0:04:30.205 This is over 6% of the US GDP. 0:04:30.222,0:04:32.839 This is not a sustainable number. 0:04:32.857,0:04:36.878 In addition to the fact that we have[br]the need to treat our loved ones, 0:04:36.897,0:04:40.149 we also need to have a solution for this 0:04:40.160,0:04:46.796 in order to not get completely bankrupt[br]by our need to treat our patients. 0:04:46.824,0:04:53.665 So the question is: Why do we not know[br]how to treat any of these diseases? 0:04:53.715,0:04:59.012 The answer to that boils down[br]to this one question: 0:04:59.012,0:05:01.381 How does the brain work? 0:05:01.381,0:05:04.402 Does anybody have an answer to that? 0:05:04.402,0:05:07.565 Unfortunately, none of us do. 0:05:07.565,0:05:11.735 And so because we do not know[br]how the brain works, 0:05:11.749,0:05:16.936 the task of trying to fix it[br]becomes impossible. 0:05:16.964,0:05:19.575 Well, it's too early to give up. 0:05:19.585,0:05:23.917 Let's think about what we know[br]and what we can do 0:05:23.932,0:05:27.111 to perhaps fix this situation. 0:05:28.032,0:05:31.085 First thing that we know about the brain 0:05:31.085,0:05:35.643 is the fact that it consists[br]of this unit called the neurons. 0:05:35.658,0:05:38.257 This is a very special kind of cell. 0:05:38.273,0:05:44.740 It has inputs that come in with a signal[br]through what's called the dendrites. 0:05:44.772,0:05:47.915 And these inputs are[br]processed inside the cell, 0:05:47.930,0:05:52.712 where it produces an output,[br]an electrical signal in a digital form, 0:05:52.728,0:05:55.668 what's called an action potential, 0:05:55.682,0:06:01.627 that is sent throughout the axon[br]to send this message to the next neuron. 0:06:01.627,0:06:04.860 It's a little device[br]that does this simple processing. 0:06:04.860,0:06:10.757 And many of these neurons[br]are put together in our brain 0:06:10.779,0:06:13.395 forming a brain circuit. 0:06:13.973,0:06:18.046 And this brain circuit[br]does dynamic electrical signaling 0:06:18.055,0:06:23.500 to control all of the things that we do,[br]all of our behaviors. 0:06:23.660,0:06:26.876 So, then the task is pretty simple now. 0:06:26.916,0:06:29.493 What we need to do is to understand 0:06:29.508,0:06:34.553 how exactly these neuronal circuits work[br]to elicit our behaviors 0:06:34.579,0:06:38.240 and perhaps fix it when it goes wrong. 0:06:39.395,0:06:42.428 As easy as that sounds,[br]it's actually quite complicated. 0:06:42.443,0:06:46.833 There is a very good reason[br]why we do not have a solution to this. 0:06:47.032,0:06:50.435 Let's look at some of these reasons. 0:06:50.435,0:06:53.489 Some of these reasons are quite obvious. 0:06:53.489,0:06:58.456 One is the fact that our brain[br]is surrounded by a skull. 0:06:58.456,0:07:00.892 This is there to protect our brain. 0:07:00.892,0:07:05.379 But for those of us who are trying[br]to figure out what's going on inside, 0:07:05.379,0:07:07.566 it makes it extremely difficult. 0:07:07.570,0:07:12.496 All of our fancy microscopic imaging tools[br]cannot be really used to look inside 0:07:12.511,0:07:15.139 because of the fact that[br]it's surrounded by the skull. 0:07:15.139,0:07:19.755 Once you go inside the skull[br]you have an even greater problem, 0:07:19.755,0:07:22.797 which is that it has extreme complexity. 0:07:23.747,0:07:29.763 The number of neurons inside your brain[br]are about a hundred billion. 0:07:29.763,0:07:32.828 To give you an idea of what[br]a hundred billion means, 0:07:32.828,0:07:35.479 you can think of the world's population. 0:07:35.479,0:07:41.074 A hundred billion is an order of magnitude[br]larger than the whole world's population. 0:07:41.074,0:07:45.727 We talk about big data,[br]network of all of these different people, 0:07:45.727,0:07:51.249 but in fact we have something that's much[br]more complex sitting inside our skull. 0:07:51.659,0:07:55.438 On top of that, I told you about a neuron, 0:07:55.438,0:07:58.227 but there are also many different[br]kinds of neurons. 0:07:58.227,0:08:00.706 They're not all the same.[br]They do different things. 0:08:00.706,0:08:03.182 And they are densely[br]intermingled inside your brain, 0:08:03.182,0:08:04.447 where you can't really say 0:08:04.456,0:08:06.736 this part of your brain[br]has this type of neuron, 0:08:06.742,0:08:10.570 and the other part[br]has another kind of neuron. 0:08:11.531,0:08:13.928 To make matters worse on top of that, 0:08:13.928,0:08:16.027 every one of your neurons, 0:08:16.027,0:08:19.483 they don't just talk to[br]neighbors surrounding them, 0:08:19.483,0:08:23.759 they have connections going all the way[br]to different sides of the brain, 0:08:23.766,0:08:26.365 making very large-scale connections, 0:08:26.373,0:08:29.859 which means that if you just go in[br]and look at one part of your brain, 0:08:29.926,0:08:34.392 there is no way to understand[br]what this neuron is doing. 0:08:34.607,0:08:36.542 And so all of this combined, 0:08:36.542,0:08:41.870 it makes the task of understanding[br]how the brain works extremely difficult. 0:08:43.080,0:08:46.016 However, given this situation, 0:08:46.028,0:08:49.572 we need to start thinking about[br]how we might fix this situation 0:08:49.578,0:08:51.578 of understanding this brain. 0:08:52.235,0:08:55.298 If you want to understand[br]a complex system, 0:08:55.348,0:08:57.909 there are many different approaches. 0:08:57.938,0:09:00.411 But let's think of two different ones. 0:09:00.411,0:09:04.836 Let's say I gave you a new device[br]that was given to you on your hand. 0:09:04.836,0:09:06.903 Let's say this is a cell phone. 0:09:06.903,0:09:10.102 One way you can try to figure out[br]what this device is, 0:09:10.121,0:09:13.871 is to sit there and passively[br]observe what happens. 0:09:13.885,0:09:16.626 Depending on whose cell phone I gave you, 0:09:16.626,0:09:19.261 you might sit there for hours[br]and nothing happens, 0:09:19.261,0:09:21.862 and conclude that it's actually a clock. 0:09:22.188,0:09:25.943 A much better way to try and understand 0:09:25.943,0:09:29.093 and get meaningful information[br]out of a system 0:09:29.120,0:09:32.555 is to try and play with them. 0:09:32.587,0:09:36.349 Press the button, give it input,[br]and see what happens. 0:09:36.349,0:09:39.196 Even if this is a cell phone[br]that never receives any calls, 0:09:39.196,0:09:41.306 if you press a button[br]and see what happens, 0:09:41.306,0:09:44.268 you will know that it makes calls[br]and that it is a cell phone. 0:09:44.286,0:09:46.766 So to do something like that[br]for the brain, 0:09:46.780,0:09:48.544 what we need to be able to do, 0:09:48.556,0:09:53.228 is to provide test inputs[br]to specific parts of the brain circuit 0:09:53.256,0:09:58.475 and measure its dynamic activity[br]across this whole intact system. 0:09:58.566,0:10:02.175 So, to do this task, what do we need? 0:10:02.192,0:10:04.023 We need two components. 0:10:04.034,0:10:10.109 One is to be able to stimulate every[br]circuit elements with high specificity. 0:10:10.109,0:10:15.076 I just told you earlier that the circuit[br]consists of many different types of cells, 0:10:15.076,0:10:17.642 and that they communicate[br]with electrical signal. 0:10:17.642,0:10:19.660 If you put an electrode 0:10:19.660,0:10:23.148 - that's one strategy that you can use[br]to perturb the system - 0:10:23.148,0:10:26.180 and put an input into this brain. 0:10:26.180,0:10:28.717 But because there are[br]many different cell types, 0:10:28.717,0:10:32.233 it is very difficult[br]to decipher what that means. 0:10:32.233,0:10:34.863 For example, if you are trying[br]to figure out 0:10:34.863,0:10:37.495 the volume up and down button[br]on your cell phone, 0:10:37.495,0:10:42.588 if you press both buttons[br]at the same time, what would you see? 0:10:42.604,0:10:44.536 It might not do anything. 0:10:44.539,0:10:46.302 It might go up, it might go down. 0:10:46.317,0:10:49.416 You'll be very confused[br]as to what this button does. 0:10:49.416,0:10:53.015 What you need to be able to do[br]is to press these buttons separately 0:10:53.015,0:10:55.374 and see that one button increases volume, 0:10:55.374,0:10:57.247 the other one decreases the volume, 0:10:57.247,0:11:00.072 which gives you a clear idea[br]of what that does. 0:11:00.072,0:11:03.200 And so to have something[br]similar for the brain, 0:11:03.200,0:11:09.321 there is a novel technology that[br]allows us to do that called optogenetics. 0:11:09.321,0:11:14.840 What this does is genetically engineer[br]the cells inside the brain 0:11:14.840,0:11:19.996 so that only a specific cell type,[br]only the volume up button, 0:11:19.996,0:11:23.046 responds to light upon stimulation. 0:11:23.054,0:11:25.093 That way, now we have a tool 0:11:25.107,0:11:27.816 to specifically press[br]a button in our brain 0:11:27.845,0:11:30.795 so that we might understand what it does. 0:11:31.693,0:11:34.961 To give you an example of what this means, 0:11:34.994,0:11:36.707 we'll look at an experiment 0:11:36.712,0:11:40.611 where we stimulate[br]two different types of neurons 0:11:40.626,0:11:44.749 that are placed in the same location[br]within the brain. 0:11:44.761,0:11:47.148 These are called medium spiny neurons. 0:11:47.148,0:11:50.876 One is a D1 receptor type,[br]the other is a D2 receptor type, 0:11:50.876,0:11:53.909 but these two neurons[br]are placed in the same location, 0:11:53.909,0:12:00.960 and have very important implications[br]for things like Parkinson's disease. 0:12:00.960,0:12:05.220 And what this does is, upon stimulation, 0:12:05.235,0:12:08.752 even though these are[br]neurons in the same location, 0:12:08.768,0:12:12.389 when you stimulate one of the neurons[br]on the left side, 0:12:12.428,0:12:16.626 you will see that the mouse starts[br]to rotate in the clockwise direction, 0:12:16.703,0:12:19.200 and generally increases activity. 0:12:19.220,0:12:20.951 And in the other case, 0:12:20.971,0:12:24.538 you will see that the mouse[br]starts rotating in the opposite direction, 0:12:24.558,0:12:26.414 and it will stay generally still, 0:12:26.422,0:12:30.769 where you might even think that the video[br]has stalled but it actually hasn't. 0:12:30.769,0:12:35.689 And so these are two different cell types,[br]exactly in the same location, 0:12:35.689,0:12:39.915 but because we have this new genetic tool,[br]we could manipulate them separately, 0:12:39.915,0:12:42.516 have volume up and down buttons separately 0:12:42.516,0:12:45.952 so that we might understand[br]what this does. 0:12:46.499,0:12:47.847 That's great! 0:12:48.036,0:12:49.301 We have one problem solved 0:12:49.318,0:12:55.065 of being able to specifically manipulate[br]important buttons of the brain. 0:12:55.102,0:13:00.978 Next, what we need is to be able to read[br]out what is happening inside the circuit. 0:13:00.978,0:13:06.402 We want to press this button and[br]see what happens in the overall system. 0:13:06.402,0:13:11.191 To do that, we combine[br]this optogenetics stimulation technology 0:13:11.191,0:13:13.952 with the functional MRI methods, 0:13:13.952,0:13:17.975 where we can now selectively control[br]specific cell types 0:13:17.975,0:13:21.243 with temporal precision in a live subject. 0:13:21.243,0:13:23.636 You want to monitor this in a live brain 0:13:23.636,0:13:27.506 - once you take out the tissue [br]it doesn't do what it was designed to do - 0:13:27.527,0:13:30.733 and monitor its brain wave[br]activity responses. 0:13:30.742,0:13:34.170 And so here is an example[br]of an experiment 0:13:34.178,0:13:37.760 where we can now stimulate - 0:13:37.783,0:13:40.378 You see the blue line in the image there? 0:13:40.378,0:13:44.534 This is where we specifically target[br]a set of neurons 0:13:44.556,0:13:50.274 that are called excitatory neurons[br]of the hippocampus. 0:13:50.344,0:13:52.422 This is a very special area of the brain 0:13:52.442,0:13:55.188 that is implicated[br]in Alzheimer's disease and epilepsy 0:13:55.199,0:13:57.494 and other important neurological disease. 0:13:57.541,0:14:01.800 And now by stimulating them specifically[br]and monitoring what happens throughout - 0:14:01.800,0:14:05.496 these are brain images from the front[br]to the back of the brain, 0:14:05.496,0:14:06.789 all the way throughout. 0:14:06.789,0:14:10.146 And you can now see what happens[br]in every part of the brain 0:14:10.146,0:14:16.388 as a result of provoking[br]this particular type of neuron. 0:14:16.401,0:14:21.442 What this means for us [br]is that now we have tools 0:14:21.457,0:14:24.016 to start and investigate, see, 0:14:24.028,0:14:28.547 have access to the data[br]of what goes on inside the brain. 0:14:28.665,0:14:32.874 What this means is[br]that we now can perhaps open 0:14:32.882,0:14:37.056 a new era of neuro-[br]information technology. 0:14:37.056,0:14:41.237 We no longer have to wonder about:[br]What is it that the brain does? 0:14:41.237,0:14:44.067 Is this a property of the brain?[br]Is that the property? 0:14:44.067,0:14:47.953 Instead, we can have direct access[br]to the information there. 0:14:47.953,0:14:50.291 Where in the case of diseases, 0:14:50.291,0:14:55.763 we might attempt to directly restore[br]what has gone wrong inside the brain. 0:14:55.763,0:14:59.928 One of the most promising therapies[br]that are being tested right now, 0:14:59.928,0:15:03.636 and some are being used in[br]the clinic for brain disease, 0:15:03.636,0:15:06.383 is called neurostimulation therapy. 0:15:06.383,0:15:09.124 Because the brain is[br]an electrical circuit, 0:15:09.124,0:15:15.709 by putting an electrode inside the brain[br]and disrupting the erroneous signal, 0:15:15.709,0:15:18.807 we attempt to get rid of the symptoms, 0:15:18.807,0:15:21.501 such as tremoring in[br]the Parkinson's disease, 0:15:21.501,0:15:24.563 and restore its normal function. 0:15:24.563,0:15:28.097 The keyword here is "disrupt." 0:15:28.097,0:15:32.696 We call it disrupt because we really[br]don't know what we're doing. 0:15:32.696,0:15:34.921 It was doing something[br]that we didn't like. 0:15:34.921,0:15:36.780 We put it there and zapped it, 0:15:36.780,0:15:41.832 and somehow it gave us[br]a desirable result - sometimes. 0:15:41.832,0:15:47.186 But now that we have access to[br]information directly inside the brain. 0:15:47.186,0:15:50.252 What this means is[br]that, instead of disrupting, 0:15:50.264,0:15:54.487 we can reprogram what our brain can do. 0:15:55.207,0:15:56.614 On top of that, 0:15:56.614,0:16:02.100 if the damage was more extensive,[br]where you actually need to replace parts, 0:16:02.100,0:16:05.141 which is what stem cell[br]therapy promises us, 0:16:05.144,0:16:09.228 despite the fact that we have[br]the powerful stem cell therapy option, 0:16:09.228,0:16:12.464 one of the reasons[br]why we could not make progress 0:16:12.491,0:16:15.711 in treating brain disease[br]with the stem cell therapy 0:16:15.735,0:16:19.004 was the fact that there was[br]no way to know exactly 0:16:19.013,0:16:22.148 what it does once it enters the brain. 0:16:22.172,0:16:25.401 And by having programmable stem cells 0:16:25.401,0:16:29.451 that we can put in and look at with[br]access to all the information, 0:16:29.451,0:16:35.616 we might be able to also enter an era[br]where we can replace parts. 0:16:35.616,0:16:37.502 And so with all of these technologies 0:16:37.514,0:16:41.515 that allows us to get into the realm[br]of neuro-information technology, 0:16:41.590,0:16:43.796 we might be able to open a new era 0:16:43.796,0:16:46.015 where we no longer need to be frustrated 0:16:46.037,0:16:49.072 with our inability[br]to control our own brains. 0:16:49.594,0:16:53.656 Beyond being able to fix diseases, 0:16:53.656,0:16:58.930 the future of being able to have access to[br]neurological information and data 0:16:58.955,0:17:03.538 promises much more[br]than just treating diseases. 0:17:03.566,0:17:07.323 This is one of my favorite scenes[br]from the movie "Avatar" 0:17:07.345,0:17:11.771 where you have the human brain and[br]the avatar brain that is being synced up. 0:17:11.799,0:17:18.422 In this particular scene,[br]the syncing is 40.665% complete. 0:17:18.425,0:17:23.276 This is just a fantasy, a movie,[br]for us right now, 0:17:23.276,0:17:27.521 but by having the ability to access[br]your neurological information, 0:17:27.521,0:17:32.127 the power of what we can do[br]with that is limitless. 0:17:33.445,0:17:37.951 It deeply saddens me to think[br]about the fact that 0:17:37.974,0:17:44.701 I could not help my grandmother[br]in the time of her desperate need. 0:17:44.745,0:17:47.681 However, it is my hope and dream 0:17:47.713,0:17:50.018 that she will live on in our memory 0:17:50.049,0:17:57.112 as we make bold and brave steps towards[br]this new era of information technology. 0:17:58.932,0:18:00.210 Thank you very much. 0:18:00.210,0:18:02.210 (Applause)