1 00:00:00,000 --> 00:00:03,240 Textbooks have always lied to us about what neurons are. 2 00:00:05,800 --> 00:00:08,120 The human brain is the most complex structure 3 00:00:08,120 --> 00:00:09,280 in the known universe. 4 00:00:09,280 --> 00:00:11,760 And we are in the middle of a scientific revolution 5 00:00:11,760 --> 00:00:13,840 to understand its inner workings. 6 00:00:13,840 --> 00:00:15,280 Join us for a conversation 7 00:00:15,280 --> 00:00:16,960 with world renowned neuroscientists 8 00:00:16,960 --> 00:00:18,580 as they visit Rochester. 9 00:00:18,580 --> 00:00:21,560 I am Dr. John Foxe, director of the Del Monte Institute 10 00:00:21,560 --> 00:00:24,000 for Neuroscience at the University of Rochester. 11 00:00:24,000 --> 00:00:26,840 And you are listening to Neuroscience Perspectives. 12 00:00:26,840 --> 00:00:31,440 So Jeffrey Matlas, it's great to have you here in Rochester. 13 00:00:31,440 --> 00:00:33,200 I know you've been a repeat visitor 14 00:00:33,200 --> 00:00:36,200 to the University of Rochester over the years. 15 00:00:36,200 --> 00:00:38,180 So I have a few questions for you about your work 16 00:00:38,180 --> 00:00:41,240 and your thoughts about the field and where we're going. 17 00:00:41,240 --> 00:00:44,120 And I mean, let's kick off with stem cells. 18 00:00:44,120 --> 00:00:48,240 When can a person out there with neurological disease, 19 00:00:48,240 --> 00:00:50,720 when do you think we'll be at a point 20 00:00:50,720 --> 00:00:53,880 where stem cells will be transfected 21 00:00:53,880 --> 00:00:55,320 or inserted into the brain 22 00:00:55,320 --> 00:00:58,720 and be providing effective therapy? 23 00:00:58,720 --> 00:01:00,640 For the general audience, 24 00:01:00,640 --> 00:01:02,080 we'll take this opportunity 25 00:01:02,080 --> 00:01:04,200 to do a little bit of education that I think. 26 00:01:04,200 --> 00:01:08,040 I think the very term stem cell in the nervous system 27 00:01:08,040 --> 00:01:13,040 has been misused to great loss and confusion 28 00:01:13,920 --> 00:01:18,920 because those of us in the field from the mid late 90s, 29 00:01:19,120 --> 00:01:23,620 when progenitors were identified in the nervous system 30 00:01:23,620 --> 00:01:25,440 used to call them progenitors. 31 00:01:25,440 --> 00:01:28,160 And we call them by where they are 32 00:01:28,160 --> 00:01:31,880 of what molecular origin they are, 33 00:01:31,880 --> 00:01:35,280 of what neuron types they can become 34 00:01:35,280 --> 00:01:37,960 or glial types they can become. 35 00:01:37,960 --> 00:01:41,680 And then there's this totally parallel field 36 00:01:41,680 --> 00:01:45,360 of embryonic stem cell and IPS stem cell biology. 37 00:01:45,360 --> 00:01:50,360 And I think it's only been because of companies 38 00:01:50,380 --> 00:01:52,000 and intellectual property, 39 00:01:52,000 --> 00:01:55,640 and frankly, a lot of bad behaviors in the field 40 00:01:55,640 --> 00:01:58,720 where the very term stem cell is thought to be 41 00:01:58,720 --> 00:02:01,400 by the general public, a thing. 42 00:02:01,400 --> 00:02:05,040 So I'll declare right now, there is no such thing. 43 00:02:05,040 --> 00:02:06,160 It's not a thing. 44 00:02:06,160 --> 00:02:07,840 It's a range of things. 45 00:02:07,840 --> 00:02:12,120 It's like, it would be the equivalent of going to a doctor 46 00:02:12,120 --> 00:02:16,600 and saying, my friend had his cancer treated 47 00:02:16,600 --> 00:02:18,320 with liquid nitrogen. 48 00:02:18,320 --> 00:02:20,660 And that would be true on the scalp 49 00:02:20,660 --> 00:02:25,120 by the dermatologist of a dermatologic cancer. 50 00:02:25,120 --> 00:02:30,120 And then ask if their lung cancer or colon cancer 51 00:02:31,200 --> 00:02:34,260 couldn't be treated since it's cancer after all. 52 00:02:34,260 --> 00:02:38,760 So I think that imprecision has been purposefully used 53 00:02:38,760 --> 00:02:39,820 to mislead. 54 00:02:40,680 --> 00:02:44,240 That said, I think there's a huge amount 55 00:02:44,240 --> 00:02:47,480 of developmentally guided biology 56 00:02:47,480 --> 00:02:50,920 by which many of us in the field 57 00:02:50,920 --> 00:02:54,880 are learning the molecular pathways 58 00:02:54,880 --> 00:02:59,080 that build individual neuron types or astrogalel types 59 00:02:59,080 --> 00:03:01,980 or oligodendrogalel types of the brain. 60 00:03:01,980 --> 00:03:06,980 So I would say for certain human illnesses 61 00:03:07,120 --> 00:03:12,120 in which a specific cell type might want to be replaced 62 00:03:12,120 --> 00:03:15,440 and in which a couple of decades 63 00:03:15,440 --> 00:03:18,920 of precise developmental knowledge has advanced 64 00:03:18,920 --> 00:03:21,840 to the point where one can now try to make 65 00:03:21,840 --> 00:03:26,280 that kind of cell type, that one could do that. 66 00:03:27,400 --> 00:03:32,400 And that I'd say we already know that hematopoietic 67 00:03:32,400 --> 00:03:37,400 stem cells can repopulate the blood system. 68 00:03:37,400 --> 00:03:39,920 But we have no such thing in the nervous system. 69 00:03:39,920 --> 00:03:42,920 Hematopoietic stem cells are those that can make 70 00:03:42,920 --> 00:03:47,920 all the lineages and that can engraft in bone marrow. 71 00:03:48,480 --> 00:03:52,320 And in the nervous system, we have no such thing 72 00:03:52,320 --> 00:03:56,320 as a stem cell that can make all the nervous system lineages. 73 00:03:56,320 --> 00:04:00,320 So all of those clinics in Mexico and the Caribbean 74 00:04:00,320 --> 00:04:02,600 and other places that I won't mention 75 00:04:02,600 --> 00:04:05,680 that promise the therapy that you offered 76 00:04:05,680 --> 00:04:09,200 of putting a stem cell in the nervous system 77 00:04:09,200 --> 00:04:14,200 to treat something, either are performing, 78 00:04:14,760 --> 00:04:16,600 and I'm not gonna use this term, 79 00:04:16,600 --> 00:04:20,080 but as many of my colleagues term charlatans, 80 00:04:21,400 --> 00:04:24,720 or we're talking about those stem cells performing 81 00:04:24,720 --> 00:04:27,280 things like immune functions. 82 00:04:27,280 --> 00:04:32,280 Because there's no way to think of an undifferentiated cell 83 00:04:32,280 --> 00:04:34,440 just being placed in the nervous system 84 00:04:34,440 --> 00:04:37,120 and knowing what it should become. 85 00:04:37,120 --> 00:04:39,760 Knowing what it should become. 86 00:04:39,760 --> 00:04:42,200 You know, when I'm out of my travels around the country 87 00:04:42,200 --> 00:04:44,720 and talking to people, particularly we were talking, 88 00:04:44,720 --> 00:04:47,600 you and I, about autism spectrum disorder and that, 89 00:04:47,600 --> 00:04:52,360 and the number of parents and caregivers 90 00:04:52,360 --> 00:04:56,040 who are being drawn into this, who are looking for hope 91 00:04:56,040 --> 00:04:58,640 and being provided very unrealistic answers. 92 00:04:58,640 --> 00:05:00,480 And it's important that there's a corrective. 93 00:05:00,480 --> 00:05:04,040 Now I'll give you the optimistic answer. 94 00:05:04,040 --> 00:05:09,040 The optimistic answer is within certain human illnesses 95 00:05:09,800 --> 00:05:14,800 where pathology of a single cell type at a time 96 00:05:16,400 --> 00:05:21,400 is so centrally causal that even partial reversal of that 97 00:05:24,080 --> 00:05:28,760 could bring huge, immense impact to humans. 98 00:05:28,760 --> 00:05:31,880 I think stem cell biology is going to be 99 00:05:31,880 --> 00:05:33,080 exceptionally important. 100 00:05:33,080 --> 00:05:35,000 But those illnesses, for example, 101 00:05:35,840 --> 00:05:37,480 are gonna be very difficult. 102 00:05:37,480 --> 00:05:42,480 They're gonna range from illnesses where demyelination 103 00:05:43,120 --> 00:05:48,120 happens and there's not simply a dysregulation 104 00:05:48,200 --> 00:05:51,360 of the myelinating cells already in the brain. 105 00:05:51,360 --> 00:05:53,960 Because we know there are already progenitors. 106 00:05:53,960 --> 00:05:58,960 There are already oligodendroglio progenitor stem cells 107 00:05:59,280 --> 00:06:00,880 in the nervous system. 108 00:06:00,880 --> 00:06:03,480 So we're gonna have to find out if those guys 109 00:06:03,480 --> 00:06:07,120 are not operating right, then one might bring in 110 00:06:07,120 --> 00:06:11,120 oligodendroglio progenitors or stem cells 111 00:06:11,120 --> 00:06:15,720 that are functioning correctly to be therapeutic. 112 00:06:15,720 --> 00:06:17,440 Same thing with astroglia. 113 00:06:17,440 --> 00:06:21,360 And in the nervous, in the neuron systems, 114 00:06:21,360 --> 00:06:25,640 I think for disorders like spinal cord injury, 115 00:06:25,640 --> 00:06:30,640 where it's not replacement of some kind of spinal cord 116 00:06:30,640 --> 00:06:35,640 tissue, but rather it's connections from the cerebral cortex 117 00:06:35,880 --> 00:06:40,840 to the spinal cord or from sensory system up, 118 00:06:40,840 --> 00:06:45,840 one might imagine very careful cellular engineering 119 00:06:46,320 --> 00:06:51,320 to build new developmental embryonic-like neurons 120 00:06:51,780 --> 00:06:55,520 that will grow past lesions and provide recovery. 121 00:06:55,520 --> 00:06:58,800 That all said, I think what many clinics 122 00:06:58,800 --> 00:07:02,080 around the world are doing in the orthopedic, 123 00:07:02,080 --> 00:07:06,680 rheumatologic, cerebral palsy nervous system 124 00:07:06,680 --> 00:07:11,680 in certain countries is setting back 125 00:07:11,980 --> 00:07:14,160 that progress by decades. 126 00:07:14,160 --> 00:07:17,640 Right, because failure, because of failures to really. 127 00:07:17,640 --> 00:07:18,760 Well, it's not just failure. 128 00:07:18,760 --> 00:07:21,760 I think it's no rational basis. 129 00:07:21,760 --> 00:07:26,760 And by using this confusing term of saying stem cells 130 00:07:26,760 --> 00:07:31,760 rather than we are using carefully designed 131 00:07:31,760 --> 00:07:36,240 progenitor derived cells to do X, 132 00:07:36,240 --> 00:07:41,240 there's almost like the Wild West of snake oil 133 00:07:41,560 --> 00:07:44,880 and cure-all disease potions. 134 00:07:44,880 --> 00:07:48,000 You and I are too young to remember that in the 1920s, 135 00:07:48,000 --> 00:07:53,000 radiothor, radiation was claimed to cure all ills. 136 00:07:53,720 --> 00:07:55,360 Right, right. 137 00:07:55,360 --> 00:07:58,640 I'm gonna read, I quote, I read of yours. 138 00:07:58,640 --> 00:08:00,920 It'll get us into some of the work 139 00:08:00,920 --> 00:08:04,960 that your lab is directly famous for really. 140 00:08:04,960 --> 00:08:07,640 And you were talking about neurons, 141 00:08:07,640 --> 00:08:10,400 it's like a federal system with both central 142 00:08:10,400 --> 00:08:12,800 and independent local government 143 00:08:12,800 --> 00:08:14,560 when you're talking about the growth cone. 144 00:08:14,560 --> 00:08:19,360 Can you help people understand that distinction 145 00:08:19,360 --> 00:08:23,160 between the cell body and its emanations? 146 00:08:23,160 --> 00:08:27,560 The idea is where the motivating truths are 147 00:08:27,560 --> 00:08:30,520 that textbooks have always lied to us 148 00:08:30,520 --> 00:08:32,280 about what neurons are. 149 00:08:32,280 --> 00:08:36,440 And they will show a cell in the kidney 150 00:08:36,440 --> 00:08:41,440 as my hand with its nucleus and its membrane, 151 00:08:42,640 --> 00:08:43,800 and it's that big. 152 00:08:43,800 --> 00:08:47,440 And then they'll show a neuron with its nucleus 153 00:08:47,440 --> 00:08:48,920 and its membrane, and then I'll say, 154 00:08:48,920 --> 00:08:52,280 and that's the axon and that's its synapse. 155 00:08:52,280 --> 00:08:54,000 But that's not true at all. 156 00:08:54,000 --> 00:08:58,800 If a neuron had a cell body the size of my hand, 157 00:08:58,800 --> 00:09:03,800 its axon would be the size of my pinky in diameter 158 00:09:03,800 --> 00:09:08,400 and would extend that same cell 159 00:09:08,400 --> 00:09:13,400 on the order of two to three to seven to 10 kilometers. 160 00:09:13,440 --> 00:09:18,440 So one and a half to three to five or six miles 161 00:09:18,440 --> 00:09:23,440 with precision and would find a target with accuracy 162 00:09:24,640 --> 00:09:27,560 of our two chairs talking to each other. 163 00:09:27,560 --> 00:09:30,440 And that's extraordinary. 164 00:09:30,440 --> 00:09:33,400 And it's never been at all clear 165 00:09:33,400 --> 00:09:38,400 how the control center nucleus of such a neuron 166 00:09:40,880 --> 00:09:42,880 can actually control things 167 00:09:42,880 --> 00:09:46,440 that are happening that far away. 168 00:09:46,440 --> 00:09:50,040 And it turns out we know a lot about neurons 169 00:09:50,040 --> 00:09:52,360 over the last 30 or 40 years, 170 00:09:52,360 --> 00:09:56,240 the fastest signaling method 171 00:09:56,240 --> 00:09:59,360 for the tip of this growing pinky 172 00:09:59,360 --> 00:10:03,000 two miles down the road with precision 173 00:10:03,000 --> 00:10:06,280 would be almost like an old stagecoach. 174 00:10:06,280 --> 00:10:09,160 And it would take between eight and 15 hours 175 00:10:09,160 --> 00:10:12,040 in each direction to signal back. 176 00:10:12,040 --> 00:10:16,040 Well, I've gotten to this sign post eight hours later, 177 00:10:16,040 --> 00:10:17,280 what do I do? 178 00:10:17,280 --> 00:10:20,200 And then eight hours later, turn left. 179 00:10:21,200 --> 00:10:22,800 And that doesn't work. 180 00:10:22,800 --> 00:10:26,240 So the work that you're alluding to 181 00:10:26,240 --> 00:10:28,560 has taken an approach of asking 182 00:10:28,560 --> 00:10:32,160 now that there are extremely powerful methods 183 00:10:32,160 --> 00:10:37,160 in molecular biology to look at every coding RNA 184 00:10:40,080 --> 00:10:44,640 or non-coding RNA molecule and every protein, 185 00:10:44,640 --> 00:10:49,640 we asked what is the actual molecular machinery 186 00:10:49,880 --> 00:10:54,880 out at those growing tips compared to the same cell. 187 00:10:56,280 --> 00:11:00,320 And neurons have long been viewed like that kidney cell. 188 00:11:00,320 --> 00:11:03,000 It's one cell, it does a thing. 189 00:11:03,000 --> 00:11:05,760 But in fact, what we found is that 190 00:11:06,800 --> 00:11:09,800 what we term subcellular compartments 191 00:11:09,800 --> 00:11:12,920 have entirely independent control mechanisms 192 00:11:12,920 --> 00:11:16,600 as if they're their own operating cell. 193 00:11:16,600 --> 00:11:20,400 They have not just a subset of what's happening back 194 00:11:20,400 --> 00:11:23,720 in my hand, but things that you don't even see back 195 00:11:23,720 --> 00:11:24,560 in my hand. 196 00:11:24,560 --> 00:11:29,560 And I actually liken these things more to NASA 197 00:11:30,200 --> 00:11:32,480 designing deep space satellites 198 00:11:32,480 --> 00:11:36,360 that are going out past the solar system or into the sun. 199 00:11:36,360 --> 00:11:39,960 And they have to go out and be pretty autonomous. 200 00:11:39,960 --> 00:11:41,200 They can't radio back. 201 00:11:41,200 --> 00:11:45,080 Turns out from Pluto, it takes about eight to 15 hours 202 00:11:45,080 --> 00:11:46,120 for radio signals. 203 00:11:46,120 --> 00:11:47,800 It's a remarkable coincidence. 204 00:11:49,720 --> 00:11:54,080 So these things appear to be one cell 205 00:11:55,000 --> 00:11:59,160 functioning without a single command structure, 206 00:11:59,160 --> 00:12:04,160 but rather for decisions based on local context 207 00:12:05,520 --> 00:12:07,800 and local needs for decision-making, 208 00:12:07,800 --> 00:12:09,880 if that makes sense to your question. 209 00:12:09,880 --> 00:12:12,400 I think that was an absolutely elegant explanation. 210 00:12:12,400 --> 00:12:13,640 That was really wonderful. 211 00:12:14,560 --> 00:12:15,880 Let me switch gears a little bit. 212 00:12:15,880 --> 00:12:17,440 Maybe I can add in. Please. 213 00:12:17,440 --> 00:12:22,080 To connect to you, who's a world expert in autism 214 00:12:22,080 --> 00:12:24,960 and intellectual disability and abnormalities 215 00:12:24,960 --> 00:12:29,240 of the human intellect developing brain. 216 00:12:30,480 --> 00:12:34,840 It turns out that if we think about all of these 217 00:12:34,840 --> 00:12:39,840 disabilities, you and I know that there is evidence 218 00:12:40,880 --> 00:12:44,200 in different subgroups of humans 219 00:12:44,200 --> 00:12:49,200 for not only misrouting circuit abnormalities, 220 00:12:49,480 --> 00:12:51,320 but as your work has shown, 221 00:12:52,800 --> 00:12:57,800 dysfunction of the actual computations at synapses. 222 00:12:59,040 --> 00:13:02,400 Well, the growing ends of those axons, 223 00:13:02,400 --> 00:13:04,520 now I'm gonna blow up as if we're going 224 00:13:04,520 --> 00:13:06,080 in a big microscope. 225 00:13:06,080 --> 00:13:09,760 Now, if my body is the cell body, 226 00:13:09,760 --> 00:13:12,840 my axon would be the size of my arm, 227 00:13:12,840 --> 00:13:16,200 six feet more or less and six inches. 228 00:13:16,200 --> 00:13:20,960 And this would then go 20 to 30 to 50 to 70 kilometers. 229 00:13:20,960 --> 00:13:23,240 It would take me beyond Canandaigua. 230 00:13:23,240 --> 00:13:24,080 I don't know where that would take me. 231 00:13:24,080 --> 00:13:25,800 It's pretty close to Buffalo. 232 00:13:25,800 --> 00:13:27,080 Oh, so close to Buffalo. 233 00:13:27,080 --> 00:13:28,760 And that's quite remarkable. 234 00:13:28,760 --> 00:13:31,360 But at the end of my growing axon, 235 00:13:31,360 --> 00:13:34,600 making all the decisions to turn on the whatever it is, 236 00:13:34,600 --> 00:13:38,080 the 490 and then on the this and then on route 90 237 00:13:38,080 --> 00:13:43,080 and then it will then transition and develop into synapses. 238 00:13:43,720 --> 00:13:45,760 So everything I just told you about, 239 00:13:45,760 --> 00:13:50,200 I think of not just about building the circuits, 240 00:13:50,200 --> 00:13:54,480 but that means the decisions of whether I'm going to be 241 00:13:54,480 --> 00:13:59,480 bolted with steel or with Velcro so I can be plastic 242 00:13:59,480 --> 00:14:04,480 and learn to change are all coded 243 00:14:04,800 --> 00:14:08,320 in the subcellular organelles of neurons. 244 00:14:08,320 --> 00:14:13,320 And that means that subtle dysfunction of those mechanisms 245 00:14:14,640 --> 00:14:17,600 might account for what goes wrong 246 00:14:17,600 --> 00:14:22,280 and the relatively subtle dysfunctions of humans 247 00:14:22,280 --> 00:14:26,200 with certain forms of social behavioral 248 00:14:26,200 --> 00:14:27,880 autism spectrum disorders. 249 00:14:27,880 --> 00:14:31,360 And if that was just a speculation, it would be one thing. 250 00:14:31,360 --> 00:14:35,320 But if we look at most of the candidate genes, 251 00:14:36,800 --> 00:14:38,080 guess what? 252 00:14:38,080 --> 00:14:42,880 Many of them are actually differentially localized 253 00:14:42,880 --> 00:14:46,560 with splice variants and various variant forms 254 00:14:46,560 --> 00:14:48,720 between cell body and growth cones 255 00:14:48,720 --> 00:14:50,680 now that we're looking at these things. 256 00:14:50,680 --> 00:14:55,680 So I think this basic cell biology that you asked me about 257 00:14:55,680 --> 00:14:59,480 is quite relevant to the immensely complicated 258 00:14:59,480 --> 00:15:00,880 human biology of the brain. 259 00:15:02,120 --> 00:15:03,880 I have a colleague in New York, Charlie Schroeder, 260 00:15:03,880 --> 00:15:05,320 who obviously he always says this term, 261 00:15:05,320 --> 00:15:08,160 he says, wiring is computation. 262 00:15:08,160 --> 00:15:10,200 When it comes to the brain, exactly the routing 263 00:15:10,200 --> 00:15:12,160 of the wiring systems is incredible, 264 00:15:12,160 --> 00:15:14,320 massively complex system. 265 00:15:14,320 --> 00:15:16,200 It's important that things end up 266 00:15:16,200 --> 00:15:18,240 where they need to end up. 267 00:15:18,240 --> 00:15:21,280 We start out life though as an infant 268 00:15:21,280 --> 00:15:25,360 with massive over exuberance of neuronal development. 269 00:15:25,360 --> 00:15:26,520 Is that part of the process? 270 00:15:26,520 --> 00:15:29,000 So that we have, when we talk about pruning, 271 00:15:29,000 --> 00:15:31,560 so we lose cells, it's because many of these things, 272 00:15:31,560 --> 00:15:34,680 maybe there's an imprecision that's in the system 273 00:15:34,680 --> 00:15:38,800 that can be tolerated because as long as most of the, 274 00:15:38,800 --> 00:15:42,760 or substantial number of these neurons 275 00:15:42,760 --> 00:15:45,280 end up where they're targeted so you can function. 276 00:15:45,280 --> 00:15:47,400 So I'll give you two or three answers on that. 277 00:15:47,400 --> 00:15:50,400 And I don't mean to be argumentative on this. 278 00:15:50,400 --> 00:15:51,240 Please feel free to be argumentative. 279 00:15:51,240 --> 00:15:54,960 But you and I grew up being taught that. 280 00:15:54,960 --> 00:15:58,320 But I think over the last 20 years, 281 00:15:58,320 --> 00:16:01,480 the evidence has become vanishingly small 282 00:16:01,480 --> 00:16:04,000 for the two to one dying out. 283 00:16:04,000 --> 00:16:05,720 In fact, one doesn't see that at all 284 00:16:05,720 --> 00:16:08,200 during the development of cortex. 285 00:16:08,200 --> 00:16:11,640 What one does see, and I think that those data 286 00:16:11,640 --> 00:16:14,760 came from the 70s and 80s, where there were 287 00:16:15,760 --> 00:16:20,320 fewer and fewer connection axons seen. 288 00:16:20,320 --> 00:16:23,920 And there used to, I think, be a textbook view 289 00:16:23,920 --> 00:16:27,680 that a neuron sends an axon. 290 00:16:27,680 --> 00:16:29,520 But now it's increasingly clear, 291 00:16:29,520 --> 00:16:32,600 and my lab was the first to discover these in rodents, 292 00:16:32,600 --> 00:16:34,560 but they've been hinted about in 293 00:16:34,560 --> 00:16:36,640 non-human primates and humans. 294 00:16:36,640 --> 00:16:41,080 There are many neuron types that send from the same nucleus 295 00:16:41,080 --> 00:16:45,200 and cell body two or three distinct axons 296 00:16:46,080 --> 00:16:50,920 that precisely target different targets. 297 00:16:50,920 --> 00:16:53,000 And then the question you ask, I think, 298 00:16:53,000 --> 00:16:55,560 becomes really insightful and important. 299 00:16:55,560 --> 00:16:59,640 And it's clear during development that many of them 300 00:16:59,640 --> 00:17:03,560 will prune one of these axons. 301 00:17:03,560 --> 00:17:08,560 And in fact, some of the human autism associated genes 302 00:17:10,000 --> 00:17:14,000 we have identified are responsible for 303 00:17:14,000 --> 00:17:18,040 inaccurate pruning of such axons. 304 00:17:18,040 --> 00:17:20,240 So it's another version of your question, 305 00:17:20,240 --> 00:17:23,720 but rather than it being, I think, 306 00:17:23,720 --> 00:17:26,280 it's not just that we have so many extra cells, 307 00:17:26,280 --> 00:17:27,920 it can be sloppy. 308 00:17:27,920 --> 00:17:32,920 It's that the nervous system has even more elegantly evolved 309 00:17:34,040 --> 00:17:38,120 to precisely pull back certain connections, 310 00:17:38,120 --> 00:17:40,800 and when those are not pulled back, 311 00:17:40,800 --> 00:17:43,520 or when they're pulled back too much, 312 00:17:43,520 --> 00:17:46,960 that's, to your friend's point, 313 00:17:46,960 --> 00:17:50,200 bad circuitry and bad computation. 314 00:17:50,200 --> 00:17:52,280 Let's take a switch in direction here, 315 00:17:52,280 --> 00:17:54,520 because one of the things, 316 00:17:54,520 --> 00:17:57,800 noticing your extraordinary CV and all the prizes, 317 00:17:57,800 --> 00:18:01,240 you're trained as a medical doctor, first and foremost, 318 00:18:01,240 --> 00:18:03,560 and indeed you kept, is that correct? 319 00:18:03,560 --> 00:18:06,400 Well, I don't know what first and foremost means. 320 00:18:06,400 --> 00:18:10,800 I was trained in science, and I have an MD, 321 00:18:10,800 --> 00:18:13,960 and I'm fully trained as a neurologist, and as a scientist. 322 00:18:13,960 --> 00:18:17,760 I was in a combined medical school, graduate school program 323 00:18:17,760 --> 00:18:22,760 at Harvard and MIT, and I expected to have a dual career 324 00:18:24,360 --> 00:18:27,200 in the Boston, New York, Baltimore, 325 00:18:27,200 --> 00:18:29,960 San Francisco style of 90-10, 326 00:18:29,960 --> 00:18:33,400 and I have not seen patients for many years. 327 00:18:33,400 --> 00:18:34,480 That's my question. 328 00:18:34,480 --> 00:18:37,720 Right, so, I mean, because this is quite a tension, I think, 329 00:18:37,720 --> 00:18:40,600 for many, there'll be trainees, MD, PhDs, 330 00:18:40,600 --> 00:18:44,320 we train a lot of people with MDs and PhDs 331 00:18:44,320 --> 00:18:46,560 who spend a large chunk of their career 332 00:18:46,560 --> 00:18:49,600 then really feeling these two things 333 00:18:49,600 --> 00:18:51,080 in somewhat in competition. 334 00:18:51,080 --> 00:18:52,280 Was that your experience? 335 00:18:52,280 --> 00:18:54,480 And when did you make the decision 336 00:18:54,480 --> 00:18:58,160 to be completely in basic science? 337 00:18:58,160 --> 00:19:00,400 Well, so I'm gonna push back on that. 338 00:19:00,400 --> 00:19:02,520 We're doing this in a friendly way, 339 00:19:02,520 --> 00:19:05,400 only because I like to be provocative on these things. 340 00:19:05,400 --> 00:19:08,760 I don't find binary choices 341 00:19:08,760 --> 00:19:10,880 as illustrative as gradation. 342 00:19:10,880 --> 00:19:15,880 So my view is that my lab is large enough 343 00:19:16,760 --> 00:19:21,360 that some folks are thinking about the questions 344 00:19:21,360 --> 00:19:24,340 we were just discussing as the basic building 345 00:19:24,340 --> 00:19:27,640 of this amazing processing unit, the brain, 346 00:19:27,640 --> 00:19:29,960 its organization, its cellular structure, 347 00:19:29,960 --> 00:19:33,360 its molecular development and function, 348 00:19:33,360 --> 00:19:38,360 but all of them are also interested in the fact 349 00:19:39,440 --> 00:19:44,440 that leads to insights into neurodegenerative disease, 350 00:19:44,800 --> 00:19:48,480 ALS in particular, the regeneration of spinal cord injury, 351 00:19:48,480 --> 00:19:50,440 autism and intellectual disabilities. 352 00:19:50,440 --> 00:19:54,240 So to me, my clinical training, 353 00:19:54,240 --> 00:19:58,840 though I took care of patients as a primary, secondary 354 00:19:58,840 --> 00:20:03,840 and tertiary neurologist for, well, altogether, 355 00:20:04,480 --> 00:20:07,320 including residency about 15 years, 356 00:20:08,480 --> 00:20:11,120 I still think about patients centrally. 357 00:20:11,120 --> 00:20:16,120 And what I'm struck by is that so many folks 358 00:20:17,160 --> 00:20:20,800 see the two as distinct. 359 00:20:20,800 --> 00:20:25,240 So I have a new form of translation for them. 360 00:20:25,240 --> 00:20:28,620 My form of translation is to say that all the time 361 00:20:28,620 --> 00:20:33,620 that I spent with patients understanding human biology, 362 00:20:35,180 --> 00:20:39,000 some people who call themselves basic scientists, whatever, 363 00:20:39,000 --> 00:20:44,000 I did a second postdoc in the neuropharmacology drugs, 364 00:20:45,340 --> 00:20:50,340 neurobehavior, neuroanatomy, pathobiology, circuit biology 365 00:20:52,740 --> 00:20:56,220 of non-non-human primates. 366 00:20:56,220 --> 00:20:59,580 So for those out there, that would mean humans. 367 00:21:00,660 --> 00:21:03,760 So I think actually understanding what happens 368 00:21:03,760 --> 00:21:07,680 in human disease and knowing which systems 369 00:21:07,680 --> 00:21:12,680 and which neurons and which pathologies happen, 370 00:21:13,640 --> 00:21:18,640 which don't actually enable in many ways a deeper insight 371 00:21:19,480 --> 00:21:23,480 that we've been able to take to attack fundamental problems 372 00:21:23,480 --> 00:21:26,520 of molecular and cellular neuroscience. 373 00:21:26,520 --> 00:21:31,240 But to me, it was not a switch anymore than someone 374 00:21:31,240 --> 00:21:35,000 who was an attorney, because they went to law school 375 00:21:35,000 --> 00:21:40,000 and were in a firm and are now being a judge. 376 00:21:40,600 --> 00:21:42,600 That's not a switch. 377 00:21:42,600 --> 00:21:47,040 That's a different form of the same field. 378 00:21:47,040 --> 00:21:50,240 And I always wanted to understand 379 00:21:50,240 --> 00:21:54,940 why do humans get these remarkable diseases? 380 00:21:54,940 --> 00:21:59,820 And when I first asked in about 1983 as a graduate student, 381 00:21:59,820 --> 00:22:03,100 why are these genes being discovered that are mutant 382 00:22:03,100 --> 00:22:06,700 in every cell in the body and in every neuron in the brain? 383 00:22:06,700 --> 00:22:10,580 And why do only two neuron types die in this disease? 384 00:22:10,580 --> 00:22:13,780 Professor, all the professors would say, 385 00:22:13,780 --> 00:22:18,020 and they still do today, we don't have the foggiest idea. 386 00:22:18,020 --> 00:22:20,140 And I thought that that was a problem. 387 00:22:20,140 --> 00:22:25,140 So I set a career goal of defogging that problem, 388 00:22:26,300 --> 00:22:29,100 which I think might bring us right back to patients, 389 00:22:29,100 --> 00:22:31,780 which is the career goal for the rest of my career. 390 00:22:32,860 --> 00:22:36,020 So a medic at heart, basic science is not, 391 00:22:36,020 --> 00:22:39,020 you just don't see them as a distinction there at all. 392 00:22:39,020 --> 00:22:41,180 I think if we go back a century, 393 00:22:41,180 --> 00:22:45,980 Santiago Ramon y Cajal, who discovered about 95% 394 00:22:45,980 --> 00:22:48,080 of what we know in the nervous system, 395 00:22:48,080 --> 00:22:52,060 was originally trained, not even as a physician, 396 00:22:52,060 --> 00:22:54,620 because that was a higher form, but as a surgeon, 397 00:22:56,100 --> 00:22:58,380 sent off to Cuba as a military surgeon, 398 00:22:58,380 --> 00:23:00,920 came back retrained as a physician. 399 00:23:02,100 --> 00:23:02,900 What does that mean? 400 00:23:02,900 --> 00:23:06,380 He wasn't a keen scientist? 401 00:23:06,380 --> 00:23:10,600 My mentors at Harvard Medical School, 402 00:23:10,600 --> 00:23:12,860 Torsten Wiesel and David Hubel, 403 00:23:12,860 --> 00:23:15,860 were trained as physicians. 404 00:23:15,860 --> 00:23:18,500 I think their Nobel Prize discovering 405 00:23:18,500 --> 00:23:21,900 the understanding of computation in the cerebral cortex 406 00:23:21,900 --> 00:23:23,820 was not to that deficit. 407 00:23:23,820 --> 00:23:25,540 So I actually find that the reason I'm giving you 408 00:23:25,540 --> 00:23:29,780 such a long answer is I find within our progressive world 409 00:23:29,780 --> 00:23:34,500 of science, the siloing and almost xenophobia 410 00:23:34,500 --> 00:23:35,740 between the two. 411 00:23:35,740 --> 00:23:38,720 Now to get to your point more pointedly, 412 00:23:40,060 --> 00:23:42,800 I don't think it's an easy decision for students 413 00:23:42,800 --> 00:23:46,180 deciding whether they should train duly as physician 414 00:23:46,180 --> 00:23:47,380 scientists or not. 415 00:23:47,380 --> 00:23:52,380 And I think too many don't have that clarity 416 00:23:56,060 --> 00:24:01,060 of what that means and end up doing one or the other, 417 00:24:02,060 --> 00:24:03,260 but not both. 418 00:24:04,140 --> 00:24:08,220 And if it hasn't actually benefited the one they do, 419 00:24:08,220 --> 00:24:12,740 it's unclear whether the training has been fully worthwhile. 420 00:24:12,740 --> 00:24:17,340 But when it does, I don't think it gets measured 421 00:24:17,340 --> 00:24:21,660 on the axes that you laid out, if that makes sense. 422 00:24:21,660 --> 00:24:26,420 I think some of my very clinically focused 423 00:24:26,420 --> 00:24:30,660 hematology oncology colleagues who are deeply 424 00:24:30,660 --> 00:24:35,100 scientifically trained think about cell cycle dynamics 425 00:24:35,100 --> 00:24:38,420 and how to disrupt cancers in elegant ways 426 00:24:38,420 --> 00:24:40,580 that are not cookie cutter recipes. 427 00:24:40,580 --> 00:24:45,580 And some of my colleagues who are working purely 428 00:24:46,300 --> 00:24:51,300 on fly visual system, ask questions that will inform 429 00:24:52,420 --> 00:24:54,740 what they know from their medical training 430 00:24:54,740 --> 00:24:56,260 about the human visual system. 431 00:24:56,260 --> 00:24:59,460 So, but I'm a troublemaker. 432 00:25:01,180 --> 00:25:03,420 The field needs troublemakers, people to start up 433 00:25:03,420 --> 00:25:07,540 and ask the tough questions and call out the nonsense 434 00:25:07,540 --> 00:25:10,240 where you see it and issue correctives 435 00:25:10,240 --> 00:25:12,820 and then if we can't rely on people like you to do that, 436 00:25:12,820 --> 00:25:13,860 we're lost, I think. 437 00:25:13,860 --> 00:25:16,100 The nicer answer to your question is, 438 00:25:16,100 --> 00:25:19,260 I think there are ranges of people who work 439 00:25:19,260 --> 00:25:21,760 across all kinds of levels. 440 00:25:21,760 --> 00:25:26,300 And in many ways, a deeply scientifically trained 441 00:25:26,300 --> 00:25:30,400 physician scientist can be somebody who thinks 442 00:25:30,400 --> 00:25:34,860 at a level of mammalian primate and human biology 443 00:25:34,860 --> 00:25:36,760 with keen insights. 444 00:25:36,760 --> 00:25:40,740 And that might be very diametrically opposed 445 00:25:40,740 --> 00:25:45,740 to somebody who thinks about bacteria or worms or flies, 446 00:25:45,980 --> 00:25:49,420 but that's a whole continuum that contributes 447 00:25:49,420 --> 00:25:51,820 to how we ultimately think about human disease 448 00:25:51,820 --> 00:25:52,700 and its treatment. 449 00:25:52,700 --> 00:25:53,620 Right. 450 00:25:53,620 --> 00:25:57,100 You're on the local bus going back into Rochester 451 00:25:57,100 --> 00:25:58,900 to get a bit of dinner. 452 00:25:58,900 --> 00:26:01,260 And you're talking to somebody who, 453 00:26:02,380 --> 00:26:04,860 conversation strikes up with somebody 454 00:26:04,860 --> 00:26:06,820 who doesn't know the scientific enterprise. 455 00:26:06,820 --> 00:26:09,060 And they ask you, what on earth, 456 00:26:09,060 --> 00:26:13,780 why are my tax dollars being spent to study 457 00:26:13,780 --> 00:26:16,700 the life cycle of a fly, of a fruit fly, 458 00:26:16,700 --> 00:26:19,220 or the sexual proclivities of a fruit fly? 459 00:26:19,220 --> 00:26:20,060 What do you say? 460 00:26:20,060 --> 00:26:22,580 How do you explain to somebody how important that is? 461 00:26:22,580 --> 00:26:25,820 When I was growing up, and I'm not sure 462 00:26:25,820 --> 00:26:27,980 if you and I grew up in the same place, 463 00:26:27,980 --> 00:26:31,460 so I'm not sure if you heard the same jokester, 464 00:26:31,460 --> 00:26:34,220 but there was a senator, 465 00:26:34,220 --> 00:26:38,820 William Proxmire, who, when I was a tiny child, 466 00:26:38,820 --> 00:26:40,060 I don't know why I remember this. 467 00:26:40,060 --> 00:26:44,360 I was probably three or four, used to come on television 468 00:26:44,360 --> 00:26:48,620 and give what he called the Golden Fleece Award 469 00:26:48,620 --> 00:26:51,460 for things like you just described. 470 00:26:51,460 --> 00:26:54,740 Why are we being fleeced as taxpayers 471 00:26:54,740 --> 00:26:59,740 to study the asexual reproduction of treponemes, 472 00:27:01,860 --> 00:27:03,460 worm or whatever? 473 00:27:03,460 --> 00:27:07,340 And it turns out, those basic studies 474 00:27:07,340 --> 00:27:12,220 of how bacteria replicate, or worms infect, 475 00:27:12,220 --> 00:27:17,220 or flies modulate pheromones and sexual attraction 476 00:27:18,560 --> 00:27:23,560 have led to countless thousands of human drugs 477 00:27:24,320 --> 00:27:29,320 that now have children that used to die of leukemia live, 478 00:27:29,320 --> 00:27:34,320 and people who used to die within two years 479 00:27:35,640 --> 00:27:39,960 with certain neurodegenerative diseases live, 480 00:27:39,960 --> 00:27:44,320 and people around the world having antimicrobials 481 00:27:44,320 --> 00:27:49,320 that cure hookworms and tapeworms and malaria 482 00:27:50,400 --> 00:27:52,200 and countless infections. 483 00:27:52,200 --> 00:27:57,040 And it's that we as scientists, the work should be funded, 484 00:27:57,040 --> 00:28:00,640 the public should know and want us to do 485 00:28:00,640 --> 00:28:03,500 because it's to the benefit of the public and health. 486 00:28:03,500 --> 00:28:07,280 There's a secondary benefit of discovery, 487 00:28:07,280 --> 00:28:11,700 but I think that's not really the strongest driving force, 488 00:28:11,700 --> 00:28:16,240 but I think it's in some ways the scientific system 489 00:28:16,240 --> 00:28:21,240 that forces us to describe things in very technical ways 490 00:28:21,240 --> 00:28:26,240 that our taxpaying public doesn't understand. 491 00:28:27,960 --> 00:28:31,240 So it's our job to translate for people. 492 00:28:31,240 --> 00:28:33,360 So when William Proxmire complained 493 00:28:33,360 --> 00:28:38,360 about the asexual replication in helmets, 494 00:28:38,600 --> 00:28:42,100 somebody should have said, or Senator Proxmire, 495 00:28:43,100 --> 00:28:48,100 how hookworms infect 85% of children in tropical areas 496 00:28:48,100 --> 00:28:53,100 from Mississippi and Georgia and Florida 497 00:28:53,580 --> 00:28:56,640 down through the central Congo. 498 00:28:56,640 --> 00:28:58,420 So it matters to all of us. 499 00:28:58,420 --> 00:29:00,780 And maybe Proxmire would have said, 500 00:29:00,780 --> 00:29:05,380 oh, now that you explained it to me, that's worthwhile. 501 00:29:05,380 --> 00:29:10,380 So, Jeffrey, you know, the public have sort of a notion 502 00:29:10,460 --> 00:29:14,200 of scientists beavering away in the lab, 503 00:29:14,200 --> 00:29:17,460 maybe not eating, forgetting for a few days to eat. 504 00:29:17,460 --> 00:29:19,980 Speak to this business of work-life balance. 505 00:29:19,980 --> 00:29:23,060 Now, I happen to know that you were a really excellent 506 00:29:23,060 --> 00:29:24,620 squash player before sports. 507 00:29:24,620 --> 00:29:26,940 I was a mediocre competitive squash player. 508 00:29:28,740 --> 00:29:33,380 But how do you keep the balance, the work-life balance? 509 00:29:33,380 --> 00:29:35,000 Well, it depends on whether you ask me 510 00:29:35,000 --> 00:29:38,580 or whether you ask my wife and our two children. 511 00:29:38,580 --> 00:29:43,580 It might be imbalanced, but I think the public sometimes 512 00:29:43,660 --> 00:29:46,620 was led astray by television shows 513 00:29:46,620 --> 00:29:49,060 and movies of the 60s and 70s, 80s, 514 00:29:49,060 --> 00:29:52,540 showing scientists of being some odd form. 515 00:29:52,540 --> 00:29:57,540 But I garden, I move rocks around in the yard, I rake, 516 00:30:00,100 --> 00:30:03,900 I ski, I work out every morning, 517 00:30:03,900 --> 00:30:08,900 I've played multiple sports, even growing up in Pennsylvania, 518 00:30:10,020 --> 00:30:12,420 the quintessential Pennsylvania sports 519 00:30:12,420 --> 00:30:14,700 of football and wrestling. 520 00:30:14,700 --> 00:30:19,180 So I think scientists can have balance in life. 521 00:30:19,180 --> 00:30:21,480 I think a more pointed answer is, 522 00:30:22,580 --> 00:30:26,660 my lab is my second family, we're quite active together, 523 00:30:26,660 --> 00:30:29,660 we hike together, we ski together. 524 00:30:29,660 --> 00:30:34,060 These kinds of activities often lead to the most informal 525 00:30:34,060 --> 00:30:37,180 of brainstorming and of thinking 526 00:30:37,180 --> 00:30:41,420 and are quite useful distractions 527 00:30:41,420 --> 00:30:45,140 because scientists don't just go to a lab and pipette. 528 00:30:45,140 --> 00:30:47,660 It's ultimately a creative discipline 529 00:30:47,660 --> 00:30:49,780 or at least at the highest forums, 530 00:30:49,780 --> 00:30:51,980 thinking of new ways to ask questions 531 00:30:51,980 --> 00:30:56,240 and to sculpt the discovery of new knowledge. 532 00:30:57,460 --> 00:31:00,100 Students out there working away in labs 533 00:31:00,100 --> 00:31:01,340 and the neuroscience labs 534 00:31:01,340 --> 00:31:03,300 and the cell and molecular biology labs 535 00:31:04,280 --> 00:31:05,780 with their eye on the prize, 536 00:31:05,780 --> 00:31:08,820 as somebody who's really had a fantastic career, 537 00:31:08,820 --> 00:31:10,340 what's that one pearl of wisdom? 538 00:31:10,340 --> 00:31:12,180 What do you say to them? 539 00:31:12,180 --> 00:31:13,680 What's gonna get them through? 540 00:31:15,540 --> 00:31:19,180 Yeah, so single pearls are always a problem for me. 541 00:31:19,180 --> 00:31:21,060 We have one minute, you can do five. 542 00:31:21,060 --> 00:31:26,060 But I think one might be to identify 543 00:31:26,940 --> 00:31:30,180 not a problem right this moment 544 00:31:30,180 --> 00:31:33,320 that you wanna attack that's important, 545 00:31:33,320 --> 00:31:36,620 but what would give your entire career 546 00:31:36,620 --> 00:31:41,620 in its inevitable arc meaning and importance 547 00:31:43,180 --> 00:31:45,340 so that if you got there, 548 00:31:47,840 --> 00:31:51,620 you would have felt fulfilled. 549 00:31:51,620 --> 00:31:55,820 And to some of us, that has some sort of highfalutin 550 00:31:55,820 --> 00:31:59,300 kinds of words like changing the world 551 00:31:59,300 --> 00:32:04,220 or discovering things that will help large classes. 552 00:32:04,220 --> 00:32:07,700 To some people, it might be equally important, 553 00:32:07,700 --> 00:32:12,700 but to answer this question that's always been unknown. 554 00:32:14,420 --> 00:32:19,040 And if you have that, I think the complexities of life 555 00:32:19,040 --> 00:32:24,040 become just steps toward that fascinating goal. 556 00:32:25,520 --> 00:32:28,380 And that might be toward human health, 557 00:32:28,380 --> 00:32:29,940 toward the betterment of the world, 558 00:32:29,940 --> 00:32:33,860 or maybe just discovering the subatomic forces 559 00:32:33,860 --> 00:32:35,680 that explain black holes. 560 00:32:36,860 --> 00:32:37,680 Just that. 561 00:32:37,680 --> 00:32:39,220 Just that. 562 00:32:39,220 --> 00:32:42,820 I do think sometimes to describe that moment, 563 00:32:42,820 --> 00:32:45,060 and all scientists who've been in the business 564 00:32:45,060 --> 00:32:49,740 will know this, where you, for just a brief moment 565 00:32:49,740 --> 00:32:52,260 when a discovery's been made in the lab, 566 00:32:52,260 --> 00:32:53,820 you and your colleagues, 567 00:32:53,820 --> 00:32:55,780 whoever happens to be there at that moment, 568 00:32:55,780 --> 00:32:57,940 are the only people on the planet 569 00:32:57,940 --> 00:33:00,420 to ever have known this piece of information. 570 00:33:00,420 --> 00:33:02,740 It's rather an extraordinary thing. 571 00:33:02,740 --> 00:33:06,380 The idea, of course, is to share it afterwards. 572 00:33:06,380 --> 00:33:07,220 Thank you so much. 573 00:33:07,220 --> 00:33:08,700 That was really fantastic. 574 00:33:08,700 --> 00:33:09,780 Thank you very much. 575 00:33:09,780 --> 00:33:33,120 Where you are connected.