1 00:00:15,356 --> 00:00:24,996 Speaker 1: Pushkin. Pain is terrible, obviously, it's kind of the classic 2 00:00:25,236 --> 00:00:30,716 Speaker 1: terrible thing, and having medicine to treat pain is great. 3 00:00:31,156 --> 00:00:35,156 Speaker 1: But the strongest drugs we have for pain, opioids, are 4 00:00:35,236 --> 00:00:40,796 Speaker 1: infamously addictive, deadly. Even more than ten thousand people die 5 00:00:40,916 --> 00:00:46,076 Speaker 1: every year in the US from prescription opioid overdoses. Opioids 6 00:00:46,076 --> 00:00:49,116 Speaker 1: are addictive because they act on the brain to blunt 7 00:00:49,116 --> 00:00:53,116 Speaker 1: our sensation of pain. But pain doesn't start in the brain. 8 00:00:53,756 --> 00:00:56,036 Speaker 1: It starts in the nerves in other parts of the body, 9 00:00:56,156 --> 00:00:59,236 Speaker 1: and then it gets relayed to the brain. So for 10 00:00:59,316 --> 00:01:03,156 Speaker 1: decades scientists thought it would be amazing if we could 11 00:01:03,156 --> 00:01:06,396 Speaker 1: find a molecule that was really good at blocking pain 12 00:01:06,436 --> 00:01:08,516 Speaker 1: in the nerves before it gets sent to the brain. 13 00:01:09,196 --> 00:01:11,396 Speaker 1: That way, we could make a pain drug that is 14 00:01:11,436 --> 00:01:15,556 Speaker 1: as strong as opioids but is not addictive. And earlier 15 00:01:15,596 --> 00:01:19,236 Speaker 1: this year, for the very first time, the FDA approved 16 00:01:19,476 --> 00:01:28,636 Speaker 1: exactly that kind of drug. I'm Jacob Goldstein and this 17 00:01:28,716 --> 00:01:30,556 Speaker 1: is What's Your Problem, the show where I talk to 18 00:01:30,556 --> 00:01:34,076 Speaker 1: people who are trying to make technological progress. My guest 19 00:01:34,156 --> 00:01:38,516 Speaker 1: today is Stephen Waxman. He's a professor of neurology, neuroscience, 20 00:01:38,556 --> 00:01:42,956 Speaker 1: and pharmacology at Yale. Stephen's research helped to pave the 21 00:01:42,996 --> 00:01:45,756 Speaker 1: way for that newly approved pain drug. It's a drug 22 00:01:45,796 --> 00:01:51,076 Speaker 1: called suzettrogene, and in particular, Stephen has spent decades studying 23 00:01:51,156 --> 00:01:54,756 Speaker 1: ion channels. Ion channels are these little gaps in nerve 24 00:01:54,836 --> 00:01:58,516 Speaker 1: cells that let charged particles ions in and out of 25 00:01:58,556 --> 00:02:03,236 Speaker 1: the cell. Suzettrogene works by blocking one particular ion channel. 26 00:02:03,836 --> 00:02:06,916 Speaker 1: As you'll hear later in the show, Stephen thinks suzetrogene 27 00:02:07,036 --> 00:02:10,316 Speaker 1: is a promising start, but he also thinks there's still 28 00:02:10,356 --> 00:02:12,596 Speaker 1: a lot of work left to do to develop better 29 00:02:12,676 --> 00:02:15,516 Speaker 1: pain drugs, and the story of how we got to 30 00:02:15,516 --> 00:02:19,236 Speaker 1: cizetrogene reveals a lot about how science works, and how 31 00:02:19,356 --> 00:02:23,916 Speaker 1: drug development works, and ultimately about how the body works. Well, 32 00:02:23,956 --> 00:02:25,116 Speaker 1: how did you get into pain? 33 00:02:26,116 --> 00:02:29,676 Speaker 2: You know? When I was an mdphd student, I had 34 00:02:29,716 --> 00:02:34,676 Speaker 2: the privilege of doing a four month stint at University 35 00:02:34,716 --> 00:02:39,836 Speaker 2: College London with Patrick Wall. Wall was the father of 36 00:02:39,956 --> 00:02:43,236 Speaker 2: modern pain research, and so I spent four or five 37 00:02:43,276 --> 00:02:46,436 Speaker 2: months with him. So I got to work at his side, 38 00:02:46,836 --> 00:02:49,716 Speaker 2: and I realized that pain is not only a very 39 00:02:49,716 --> 00:02:55,236 Speaker 2: important challenge, but also a puzzle box that presents intellectual challenges, 40 00:02:55,276 --> 00:02:56,556 Speaker 2: but that could be solved. 41 00:02:56,836 --> 00:03:00,676 Speaker 1: Huh. Tell me a little more about what you experienced 42 00:03:00,716 --> 00:03:03,476 Speaker 1: in those four months, Like, was there a particular moment 43 00:03:03,636 --> 00:03:06,436 Speaker 1: or some particular problem that was intriguing to you. 44 00:03:07,276 --> 00:03:11,156 Speaker 2: Well, what became clear to me is that pain is 45 00:03:11,196 --> 00:03:16,196 Speaker 2: a hierarchical experience. You may experience it peripherally through your 46 00:03:16,196 --> 00:03:20,876 Speaker 2: peripheral nerves, but that the pain messages are then processed 47 00:03:21,116 --> 00:03:25,156 Speaker 2: and modulated in the spinal cord, relate upwards to the 48 00:03:25,196 --> 00:03:28,276 Speaker 2: lower brain than to the cortex, and so it's an 49 00:03:28,316 --> 00:03:33,196 Speaker 2: experience that is processed at many levels, and at each 50 00:03:33,316 --> 00:03:36,436 Speaker 2: level if you take a reductionist approach, it seemed to 51 00:03:36,476 --> 00:03:39,436 Speaker 2: me that you can take it apart and understand it. 52 00:03:39,876 --> 00:03:43,716 Speaker 1: Huh. So you start thinking of pain as this sort 53 00:03:43,716 --> 00:03:49,996 Speaker 1: of hierarchical phenomenon, and is there a particular level of 54 00:03:50,036 --> 00:03:52,516 Speaker 1: the stack that you decide to focus on. 55 00:03:53,196 --> 00:03:56,756 Speaker 2: That's a great question, you know, Jacob. When I was 56 00:03:57,596 --> 00:04:02,756 Speaker 2: a young new scientist, an mdphd student resident then a 57 00:04:02,796 --> 00:04:06,356 Speaker 2: new assistant professor at MIT and Harvard, I wanted to 58 00:04:06,396 --> 00:04:10,876 Speaker 2: study grand philosophical problems at the mind interface. 59 00:04:11,196 --> 00:04:13,356 Speaker 1: What is consciousness? That sort of thing. 60 00:04:13,876 --> 00:04:17,636 Speaker 2: Yeah, and I published some papers in the cybernetics literature 61 00:04:17,676 --> 00:04:20,556 Speaker 2: and got awards for them. But I came to the 62 00:04:20,596 --> 00:04:26,316 Speaker 2: conclusion that while that was a very important challenge, that 63 00:04:25,916 --> 00:04:28,316 Speaker 2: it was those issues were not going to be resolved 64 00:04:28,756 --> 00:04:33,596 Speaker 2: during my professional lifetime, and so I retreated from grand 65 00:04:33,596 --> 00:04:40,116 Speaker 2: philosophical questions to much more soluble, concrete questions that could 66 00:04:40,116 --> 00:04:44,436 Speaker 2: be solved during my professional lifetime. So that's what I did. 67 00:04:44,436 --> 00:04:48,476 Speaker 2: When I talked to students trainees, I relay this story 68 00:04:48,516 --> 00:04:50,836 Speaker 2: to them because they have a choice. Do they want 69 00:04:50,876 --> 00:04:56,236 Speaker 2: to attack large, philosophically grand questions or work at a 70 00:04:56,236 --> 00:05:00,476 Speaker 2: more fundamental, reductionist level. There's no right answer. This was 71 00:05:00,596 --> 00:05:03,916 Speaker 2: right for me, and they have the opportunity to make 72 00:05:03,956 --> 00:05:04,676 Speaker 2: your own choice. 73 00:05:05,316 --> 00:05:10,956 Speaker 1: So you go from big consciousness ultimately to very small 74 00:05:11,116 --> 00:05:15,956 Speaker 1: right like ion channels, which about as small as you 75 00:05:15,996 --> 00:05:19,756 Speaker 1: can get in medicine, right, and ion channels obviously mostly 76 00:05:19,796 --> 00:05:22,276 Speaker 1: what we're going to talk about here, right, a tremendous 77 00:05:22,276 --> 00:05:22,996 Speaker 1: amount of your work. 78 00:05:23,036 --> 00:05:24,036 Speaker 2: So that's correct. 79 00:05:24,476 --> 00:05:26,196 Speaker 1: How did you get into ion channels? 80 00:05:26,356 --> 00:05:28,996 Speaker 2: Well, I got into ion channels because of my interest 81 00:05:29,076 --> 00:05:32,636 Speaker 2: in axons nerve fibers. While I was an undergraduate, I 82 00:05:32,676 --> 00:05:36,156 Speaker 2: spent nine months at University College working with a man 83 00:05:36,276 --> 00:05:40,956 Speaker 2: named Jays zed Young. He discovered the giant axon in 84 00:05:40,996 --> 00:05:44,436 Speaker 2: the squid, and so I became interested in how axons work. 85 00:05:44,796 --> 00:05:46,716 Speaker 1: And the axon is part of the nerve cell. 86 00:05:46,996 --> 00:05:49,756 Speaker 2: The axon is the long nerve fiber that extends from 87 00:05:49,756 --> 00:05:54,156 Speaker 2: the nerve cell. Our nervous system consists of one hundred 88 00:05:54,276 --> 00:05:58,116 Speaker 2: billion nerve cells in every one of us. It's the 89 00:05:58,116 --> 00:06:02,796 Speaker 2: world's most complex computer. And each of the nerve cells 90 00:06:02,796 --> 00:06:05,996 Speaker 2: has an axon that connects it to other nerve cells. 91 00:06:06,236 --> 00:06:09,036 Speaker 2: So I was interested in axons, and it rapidly became 92 00:06:09,196 --> 00:06:11,436 Speaker 2: clear to me that I had to understand how axons 93 00:06:11,476 --> 00:06:16,916 Speaker 2: work and the driver of activity in axons nerve impulses bup, bup, up, 94 00:06:16,996 --> 00:06:20,716 Speaker 2: up up up up is ion channels, sodium channels that 95 00:06:20,756 --> 00:06:25,636 Speaker 2: act as molecular batteries, potassium channels that act as molecular breaks. 96 00:06:26,356 --> 00:06:30,836 Speaker 1: Huh. So these are basically channels in the membrane of 97 00:06:30,876 --> 00:06:34,556 Speaker 1: the cell through which ions charge particles move, causing the 98 00:06:34,596 --> 00:06:37,316 Speaker 1: nerve cell to fire or not fire more or. 99 00:06:37,356 --> 00:06:40,156 Speaker 2: Less, that's right. And when they fire, a nerve cell 100 00:06:40,196 --> 00:06:43,436 Speaker 2: produces what's called an action potential or a nerve impulse, 101 00:06:43,876 --> 00:06:47,076 Speaker 2: and it's the pattern of firing of nerve cells that 102 00:06:47,156 --> 00:06:48,836 Speaker 2: they use to communicate with each other. 103 00:06:49,196 --> 00:06:52,036 Speaker 1: So you're doing work on ion channels as a way 104 00:06:52,036 --> 00:06:54,436 Speaker 1: to understand the behavior of nerve cells. You're also doing 105 00:06:54,476 --> 00:06:57,596 Speaker 1: work on pain, right, And there has been, by the 106 00:06:57,636 --> 00:07:00,196 Speaker 1: time you get into the field a history of work 107 00:07:00,276 --> 00:07:03,436 Speaker 1: on the relationship between ion channels and pain. Right, So 108 00:07:04,796 --> 00:07:06,716 Speaker 1: when you get into the field, what do we know? 109 00:07:06,796 --> 00:07:10,236 Speaker 1: What does humanity know already about that relationship? 110 00:07:10,876 --> 00:07:15,316 Speaker 2: Actually, when I got into the relationship between ion channels 111 00:07:15,316 --> 00:07:17,836 Speaker 2: and pain, not much at all was known. 112 00:07:18,276 --> 00:07:21,276 Speaker 1: I mean, we had lytocane and novacane, right. 113 00:07:21,436 --> 00:07:27,236 Speaker 2: So lytacane and novacane are sodium channel blockers. We all 114 00:07:27,276 --> 00:07:29,796 Speaker 2: know that when they're injected locally, no pain. 115 00:07:30,076 --> 00:07:31,876 Speaker 1: That's what you get when you get a cavity filed. 116 00:07:31,956 --> 00:07:34,556 Speaker 2: Right, that's correct. But if you put those drugs in 117 00:07:34,556 --> 00:07:38,756 Speaker 2: the form of a pill and administer them systemically, they 118 00:07:38,756 --> 00:07:41,716 Speaker 2: would affect sodium channels in the brain. So there is 119 00:07:41,796 --> 00:07:48,116 Speaker 2: double vision, impaired balance, sleepiness, and confusion. And so that 120 00:07:48,156 --> 00:07:52,236 Speaker 2: doesn't work. And so this is a really interesting arc 121 00:07:52,356 --> 00:07:56,956 Speaker 2: of science. Sodium channels were discovered by Hodgkin and Huxley. 122 00:07:57,516 --> 00:07:59,796 Speaker 2: They did the work right after World War two and 123 00:07:59,836 --> 00:08:03,716 Speaker 2: published it in nineteen fifty two, and their studies were 124 00:08:03,716 --> 00:08:06,476 Speaker 2: in the giant axon of the squid. And then fast 125 00:08:06,516 --> 00:08:10,116 Speaker 2: forward to our lab in around nineteen eighty five, we 126 00:08:10,116 --> 00:08:15,076 Speaker 2: were able to record similarly from axons from rats and 127 00:08:15,116 --> 00:08:18,836 Speaker 2: then humans. They're one fiftieth the size of the squid 128 00:08:18,836 --> 00:08:22,516 Speaker 2: giant axon, and we were able to see that not 129 00:08:22,556 --> 00:08:27,156 Speaker 2: only were sodium channels there, but that the abnormal firing 130 00:08:27,476 --> 00:08:33,276 Speaker 2: of peripheral nerve that underlies pain was caused by a 131 00:08:33,316 --> 00:08:35,156 Speaker 2: particular type of sodium channel. 132 00:08:35,716 --> 00:08:39,196 Speaker 1: So at some point, as I understand it, you get 133 00:08:39,236 --> 00:08:43,636 Speaker 1: a call about a neighborhood in Alabama where a lot 134 00:08:43,676 --> 00:08:48,516 Speaker 1: of people have an unusual experience of pain. Is that true? 135 00:08:48,796 --> 00:08:50,756 Speaker 1: Did somebody call you on the phone? Is that how 136 00:08:50,756 --> 00:08:52,036 Speaker 1: that starts? 137 00:08:52,596 --> 00:08:56,036 Speaker 2: That's correct. We were taking two approaches. One was a 138 00:08:56,076 --> 00:09:01,196 Speaker 2: mechanistic approach from ground up, looking at pain signaling neurons 139 00:09:01,396 --> 00:09:04,116 Speaker 2: that we could study in a dish and dissecting them 140 00:09:04,516 --> 00:09:07,676 Speaker 2: channel by channel, asking what did the various channels do 141 00:09:08,156 --> 00:09:10,996 Speaker 2: to cause abnormal firing and pain. You can think of 142 00:09:10,996 --> 00:09:15,356 Speaker 2: a neuron a symphony of multiple ion channels working in 143 00:09:15,396 --> 00:09:18,356 Speaker 2: a highly orchestrated way, and so at that point, we 144 00:09:18,396 --> 00:09:24,716 Speaker 2: had identified three sodium channels as potential very very important 145 00:09:25,156 --> 00:09:29,996 Speaker 2: participants in pain signaling NAV one point seven, NAV one 146 00:09:29,996 --> 00:09:32,836 Speaker 2: point eight, and NAV one point nine. 147 00:09:32,916 --> 00:09:36,076 Speaker 1: So these are just the names of different ion channels 148 00:09:36,076 --> 00:09:39,476 Speaker 1: that behave differently under different circumstances that we have in 149 00:09:39,516 --> 00:09:40,716 Speaker 1: our nerve cells. 150 00:09:41,036 --> 00:09:44,556 Speaker 2: That's exactly right. Yeah, So that's the sort of ground 151 00:09:44,636 --> 00:09:48,316 Speaker 2: up mechanistic work that we were doing. But there's another 152 00:09:48,476 --> 00:09:53,156 Speaker 2: top down approach beginning with whole human beings and trying 153 00:09:53,196 --> 00:09:58,396 Speaker 2: to see using genetics as there are there particular genes, 154 00:09:58,516 --> 00:10:02,316 Speaker 2: particular proteins related to a disease, in this case, the 155 00:10:02,396 --> 00:10:05,356 Speaker 2: disorder of pain. And let me back up a bit. 156 00:10:05,876 --> 00:10:08,836 Speaker 2: If you think about the history of modern drug development, 157 00:10:09,516 --> 00:10:13,356 Speaker 2: why look around the world for families with rare inherited diseases. 158 00:10:14,676 --> 00:10:19,196 Speaker 2: The answer is that rare diseases, inherited diseases often teach 159 00:10:19,276 --> 00:10:23,636 Speaker 2: us important lessons about more common disorders. And a good 160 00:10:23,636 --> 00:10:27,636 Speaker 2: example is the statin drugs. The statin drugs which have 161 00:10:27,716 --> 00:10:29,676 Speaker 2: revolutionized cardiovascular medicals. 162 00:10:29,676 --> 00:10:31,716 Speaker 1: I'm a fan, I take one every day. 163 00:10:32,396 --> 00:10:36,196 Speaker 2: Many of us do, and they were developed on the 164 00:10:36,236 --> 00:10:40,596 Speaker 2: basis of the discovery and then study of incredibly rare 165 00:10:40,636 --> 00:10:43,996 Speaker 2: families where everybody who was having heart attacks in their twenties. Huh, 166 00:10:44,036 --> 00:10:49,396 Speaker 2: those families had inherited hypercholesterolemia. Their genes pointed the way 167 00:10:49,636 --> 00:10:53,996 Speaker 2: at the relevant molecules and informed of drug development. 168 00:10:54,116 --> 00:10:56,876 Speaker 1: So it's basically like, if there's some family of people 169 00:10:56,916 --> 00:11:00,556 Speaker 1: that has a strange version of a common malady, let's 170 00:11:00,556 --> 00:11:02,556 Speaker 1: look at their genes and maybe that'll point to a 171 00:11:02,596 --> 00:11:05,556 Speaker 1: way to treat that malady in people without the mutation. 172 00:11:05,756 --> 00:11:07,396 Speaker 1: That's the basic hypothesis. 173 00:11:07,476 --> 00:11:09,756 Speaker 2: That's exactly right. You just did it. 174 00:11:09,916 --> 00:11:13,156 Speaker 1: Yeah, so you want that, but for ion channels, that's 175 00:11:13,156 --> 00:11:15,436 Speaker 1: what you're looking for as you're doing your lab work. 176 00:11:15,476 --> 00:11:19,036 Speaker 1: You want this sort of genetic mutation that might show 177 00:11:19,076 --> 00:11:20,116 Speaker 1: a clinical application. 178 00:11:20,596 --> 00:11:24,836 Speaker 2: That's correct. So we launched a worldwide search for families 179 00:11:24,876 --> 00:11:29,116 Speaker 2: with inherited neuropathic pain pain due to inappropriate firing of 180 00:11:29,156 --> 00:11:33,396 Speaker 2: peripheral nerves. Neurologists see patients with neuropathic pain all the time, 181 00:11:33,836 --> 00:11:37,196 Speaker 2: our clinics are filled, but we never see families. 182 00:11:37,276 --> 00:11:40,876 Speaker 1: So it's typically not a genetic problem. Right, It's like 183 00:11:40,956 --> 00:11:43,436 Speaker 1: you have diabetes or something. It's not you inherited it 184 00:11:43,476 --> 00:11:44,356 Speaker 1: from your mother. 185 00:11:44,716 --> 00:11:48,636 Speaker 2: That's correct. So we launched this search and what happened 186 00:11:48,796 --> 00:11:52,316 Speaker 2: was interesting. In the beginning of two thousand and three, 187 00:11:52,916 --> 00:11:56,436 Speaker 2: February or March, a colleague member of my team brought 188 00:11:56,476 --> 00:12:00,076 Speaker 2: me the latest issue of the Journal of Human Genetics. 189 00:12:00,716 --> 00:12:05,516 Speaker 2: There was an article out of Beijing, China on two 190 00:12:05,596 --> 00:12:10,596 Speaker 2: families with men on fire syndrome inherited from lalgia, each 191 00:12:10,916 --> 00:12:14,996 Speaker 2: with a mutation of navy one point seven. The man 192 00:12:15,036 --> 00:12:19,716 Speaker 2: on fire syndrome inherited erythrommelalgia is a really interesting disease. 193 00:12:19,796 --> 00:12:23,356 Speaker 2: Most physicians have never seen a case, never will, but 194 00:12:23,676 --> 00:12:26,716 Speaker 2: if you see it, you remember it because it's so striking. 195 00:12:27,036 --> 00:12:32,836 Speaker 2: These people feel that they're on fire. They describe searing, scalding, 196 00:12:32,996 --> 00:12:36,836 Speaker 2: burning pain that's triggered by mild warmth, putting on shoes, 197 00:12:37,396 --> 00:12:41,756 Speaker 2: wearing a sweater, going outside when it's seventy two degrees fahrenheit. 198 00:12:41,876 --> 00:12:44,476 Speaker 2: The pain is so bad some patients ask for limbs 199 00:12:44,516 --> 00:12:49,156 Speaker 2: to be surgically amputated, which does not help. But it's 200 00:12:49,236 --> 00:12:53,436 Speaker 2: excruciating pain. So here was an article out of Beijing 201 00:12:53,876 --> 00:12:58,796 Speaker 2: by a very good group of academic dermatologists and geneticists saying, 202 00:12:58,836 --> 00:13:01,436 Speaker 2: we have two families with the man on fire syndrome, 203 00:13:01,756 --> 00:13:04,636 Speaker 2: each with a mutation of Navy one point seven. And 204 00:13:04,676 --> 00:13:08,716 Speaker 2: my initial response to my colleagues my research team was 205 00:13:08,796 --> 00:13:11,836 Speaker 2: to say, think, gee, we've been scooped. This is not 206 00:13:11,956 --> 00:13:14,596 Speaker 2: a good day. And I said to my colleagues, stay 207 00:13:14,636 --> 00:13:15,196 Speaker 2: away from me. 208 00:13:16,436 --> 00:13:18,716 Speaker 1: It's a good day for humanity, but not a good 209 00:13:18,756 --> 00:13:20,636 Speaker 1: day for your lab because somebody beats you. 210 00:13:21,036 --> 00:13:25,916 Speaker 2: Yeah, exactly. And my initial response was stay away from me. 211 00:13:26,156 --> 00:13:27,476 Speaker 2: I'm going to be pretty grumbly. 212 00:13:27,956 --> 00:13:30,276 Speaker 1: And just as a reminder any of you one point seven, 213 00:13:30,436 --> 00:13:33,636 Speaker 1: that's the that's the ion channel that you had identified 214 00:13:33,676 --> 00:13:36,436 Speaker 1: as associated with pain in the lab. And here's a 215 00:13:36,516 --> 00:13:40,236 Speaker 1: kind of clinical validation of that, but coming not from 216 00:13:40,316 --> 00:13:42,036 Speaker 1: you but from some other scientists. 217 00:13:42,116 --> 00:13:46,756 Speaker 2: Yeah, from Beijing, China. But when I closed the door 218 00:13:46,956 --> 00:13:49,596 Speaker 2: and read the paper over a cup of coffee, I 219 00:13:49,716 --> 00:13:52,916 Speaker 2: realized they had not told the full story. They had 220 00:13:52,956 --> 00:13:55,476 Speaker 2: told just the first chapter. And the reason is this. 221 00:13:56,276 --> 00:14:01,196 Speaker 2: When you when a neuroscientist finds a or an ion channel, 222 00:14:01,196 --> 00:14:05,036 Speaker 2: biologist finds a mutation of an ion channel, that's just 223 00:14:05,116 --> 00:14:08,356 Speaker 2: the beginning of the story. Because the presence of the 224 00:14:08,436 --> 00:14:12,956 Speaker 2: mutation doesn't necessarily establish that the mutation is causing disease. 225 00:14:14,036 --> 00:14:17,396 Speaker 2: What you need to do and what's industry standard is 226 00:14:17,676 --> 00:14:20,436 Speaker 2: you make the mutant channel, you put it in cells, 227 00:14:20,836 --> 00:14:23,956 Speaker 2: and you find out does the mutation cause a change 228 00:14:23,996 --> 00:14:27,316 Speaker 2: in activity of the mutant channel, and then hopefully you 229 00:14:27,356 --> 00:14:29,716 Speaker 2: can then take the mutant channel, put it in cells 230 00:14:29,716 --> 00:14:32,596 Speaker 2: where it normally is expressed, and ask does it change 231 00:14:32,636 --> 00:14:35,436 Speaker 2: their behavior. They hadn't done any of this stuff. 232 00:14:35,716 --> 00:14:38,756 Speaker 1: So essentially they had identified a correlation, but they had 233 00:14:38,756 --> 00:14:40,756 Speaker 1: not demonstrated that causation. 234 00:14:41,436 --> 00:14:44,516 Speaker 2: Right, yeah, and they hadn't done it. These were very, 235 00:14:44,596 --> 00:14:49,156 Speaker 2: very fine academic dermatologists. We've subsequently become friends. One of 236 00:14:49,196 --> 00:14:51,956 Speaker 2: them spent the sabbatical in my lab. But so what 237 00:14:52,036 --> 00:14:54,636 Speaker 2: needed to be done was what I just said, to 238 00:14:54,836 --> 00:14:58,956 Speaker 2: make the channel and study its physiology. And we had 239 00:14:58,996 --> 00:15:01,396 Speaker 2: the channel in our freezer because we had done all 240 00:15:01,436 --> 00:15:03,756 Speaker 2: the work on the normal channel. So what would have 241 00:15:03,796 --> 00:15:06,316 Speaker 2: taken anyone else a year took us a few months. 242 00:15:06,636 --> 00:15:09,956 Speaker 2: We made the mutant channel, we found that in the 243 00:15:10,516 --> 00:15:14,356 Speaker 2: mutation causes the channel to be overactive, and at that 244 00:15:14,556 --> 00:15:17,916 Speaker 2: point we published it and shortly thereafter got a call 245 00:15:18,036 --> 00:15:22,556 Speaker 2: or an email from the Erythrum Lalgia Association. This is 246 00:15:23,196 --> 00:15:26,716 Speaker 2: a small group of patients with erythrumlalgia. 247 00:15:26,236 --> 00:15:28,116 Speaker 1: Which is man on fire syndrome. 248 00:15:28,476 --> 00:15:33,276 Speaker 2: Yeah, and the large family is in Alabama, Okay, and 249 00:15:33,916 --> 00:15:37,436 Speaker 2: I sent the team down to Alabamas. We spent a 250 00:15:37,476 --> 00:15:41,716 Speaker 2: week examining these patients, getting detailed histories, and most importantly, 251 00:15:41,756 --> 00:15:46,316 Speaker 2: getting blood for DNA analysis. The Erhythmologia Association gave us 252 00:15:46,316 --> 00:15:49,876 Speaker 2: a gift to support our research, but much more important 253 00:15:49,876 --> 00:15:53,876 Speaker 2: than the funding gift, the monetary gift was the gift 254 00:15:53,916 --> 00:15:58,156 Speaker 2: of DNA and these precious histories for correlation with it. 255 00:15:58,236 --> 00:16:02,556 Speaker 2: And it's been a very, very a warm relationship. It's 256 00:16:02,596 --> 00:16:05,316 Speaker 2: taught me a lot about how patients really are, are 257 00:16:05,356 --> 00:16:08,356 Speaker 2: more than patients their partners in our research. 258 00:16:09,796 --> 00:16:14,396 Speaker 1: What did you learn from those patients in Alabama that 259 00:16:14,476 --> 00:16:15,556 Speaker 1: you didn't know already? 260 00:16:17,156 --> 00:16:21,076 Speaker 2: What we learned was now we had a pedigree of 261 00:16:21,116 --> 00:16:26,316 Speaker 2: around sixty individuals in five generations. Half of them had 262 00:16:26,356 --> 00:16:28,556 Speaker 2: the mutation. That's what you expect for a mutation of 263 00:16:28,596 --> 00:16:32,036 Speaker 2: this sort. Every patient you had the mutation had the 264 00:16:32,076 --> 00:16:35,356 Speaker 2: man on fire syndrome. None of the patients without the 265 00:16:35,436 --> 00:16:38,636 Speaker 2: mutation had it. And now putting it together, this was 266 00:16:38,756 --> 00:16:41,756 Speaker 2: rock solid. This is as good as it gets in 267 00:16:41,876 --> 00:16:44,036 Speaker 2: terms of genetic validations. 268 00:16:44,316 --> 00:16:49,076 Speaker 1: So this mutation that all of these people have effects 269 00:16:49,756 --> 00:16:53,556 Speaker 1: the sodium channel in AV one point seven, right, one 270 00:16:53,596 --> 00:16:56,396 Speaker 1: of the ones you had identified, and is it right 271 00:16:56,476 --> 00:17:02,316 Speaker 1: that that inspires you or other researchers to think reasonably, Okay, 272 00:17:02,396 --> 00:17:05,156 Speaker 1: let's try and make a drug that blocks that channel 273 00:17:05,236 --> 00:17:08,916 Speaker 1: and see if it will treat pain or Jacob. 274 00:17:08,996 --> 00:17:12,316 Speaker 2: This is really interesting and it speaks to sort of 275 00:17:12,316 --> 00:17:16,836 Speaker 2: the sociology of science and the way science moves forward 276 00:17:17,156 --> 00:17:20,356 Speaker 2: given the fact that it's very expensive. So we had 277 00:17:20,436 --> 00:17:25,436 Speaker 2: mechanistic validation from studies in a dish for a strong 278 00:17:25,556 --> 00:17:29,316 Speaker 2: strong role of both NAV one point seven and NAV 279 00:17:29,436 --> 00:17:33,516 Speaker 2: one point eight in pain, and we argued that both 280 00:17:33,596 --> 00:17:36,996 Speaker 2: were good targets. In some ways NAV one point eight 281 00:17:37,036 --> 00:17:39,876 Speaker 2: could have been regarded as a stronger target, but what 282 00:17:39,956 --> 00:17:44,196 Speaker 2: we had for NAV one point seven was this very 283 00:17:44,316 --> 00:17:48,596 Speaker 2: very remarkable picture of genetic validation. And in addition to 284 00:17:48,636 --> 00:17:51,476 Speaker 2: our patients with men on fire syndrome, there were other 285 00:17:52,076 --> 00:17:55,356 Speaker 2: families found a few years later with loss of function 286 00:17:55,596 --> 00:17:58,516 Speaker 2: of NAV one point seven. These families don't make NAV 287 00:17:58,636 --> 00:18:02,196 Speaker 2: one point seven, and those people don't feel any pain, 288 00:18:02,316 --> 00:18:07,916 Speaker 2: painless childbirth, painless tooth extractions, painless bone fractures. 289 00:18:07,956 --> 00:18:10,276 Speaker 1: We basically, if you have two much action in NAV 290 00:18:10,356 --> 00:18:11,956 Speaker 1: one point seven, you have a lot of pain, and 291 00:18:11,996 --> 00:18:14,716 Speaker 1: if you have no action there, you have no pain. 292 00:18:15,116 --> 00:18:17,676 Speaker 1: That's correct, very compelling set of evidence. 293 00:18:18,316 --> 00:18:22,916 Speaker 2: It is compelling, and most of the biopharma industry followed 294 00:18:22,916 --> 00:18:26,276 Speaker 2: that evidence and studied one point seven or tried to 295 00:18:26,276 --> 00:18:30,196 Speaker 2: develop drugs that block NAV one point seven. It was 296 00:18:30,316 --> 00:18:35,116 Speaker 2: harder to convince biopharma to study NAV one point eight. 297 00:18:35,396 --> 00:18:40,436 Speaker 2: The physiological evidence was there, but the genetic validation wasn't. 298 00:18:43,596 --> 00:18:55,396 Speaker 1: We'll be back in just a minute. Back in the aughts, 299 00:18:55,956 --> 00:18:59,556 Speaker 1: Pfizer and other pharmaceutical companies started trying to develop drugs 300 00:18:59,556 --> 00:19:03,436 Speaker 1: to treat pain by blocking NAV one point seven, that 301 00:19:03,596 --> 00:19:07,476 Speaker 1: key channel that Stephen and other researchers had identified both 302 00:19:07,516 --> 00:19:10,636 Speaker 1: in the lab and in pall with man on fire syndrome. 303 00:19:11,396 --> 00:19:15,556 Speaker 1: The preliminary results were promising, but kind of shockingly, in 304 00:19:15,676 --> 00:19:19,396 Speaker 1: larger trials, the drugs targeting NAV one point seven did 305 00:19:19,436 --> 00:19:22,516 Speaker 1: not seem to be effective in treating pain. It's not 306 00:19:22,676 --> 00:19:26,116 Speaker 1: entirely clear why the drugs didn't work, but this kind 307 00:19:26,156 --> 00:19:28,836 Speaker 1: of thing in fact happens all the time. Drugs that 308 00:19:28,876 --> 00:19:31,916 Speaker 1: seem perfectly designed just don't end up panning out in 309 00:19:31,956 --> 00:19:36,516 Speaker 1: the real world. But remember NAV one point seven wasn't 310 00:19:36,556 --> 00:19:40,676 Speaker 1: the only key channel involved in pain. There's also NAV 311 00:19:40,836 --> 00:19:43,956 Speaker 1: one point eight, and one drug company decided to bet 312 00:19:43,996 --> 00:19:44,876 Speaker 1: on one point eight. 313 00:19:45,276 --> 00:19:47,916 Speaker 2: The company that's taken this across the goal line as 314 00:19:47,956 --> 00:19:52,876 Speaker 2: a company called Vertex. I'm now advising them. They looked 315 00:19:52,876 --> 00:19:56,156 Speaker 2: at one seven, and they looked at one eight. They 316 00:19:56,196 --> 00:20:00,236 Speaker 2: had a number of failures, and they kept going. They 317 00:20:00,276 --> 00:20:04,636 Speaker 2: invested an immense amount of money when we worked with Pfizer. 318 00:20:05,196 --> 00:20:08,316 Speaker 2: My estimate is that they invested well over two hundred 319 00:20:08,356 --> 00:20:11,916 Speaker 2: and fifty million dollars in their one seven blocker before 320 00:20:11,916 --> 00:20:17,756 Speaker 2: abandoning it. Vertex has studied many compounds, they have very 321 00:20:17,756 --> 00:20:21,756 Speaker 2: gifted scientists, and they made the decision to stay with it. 322 00:20:21,956 --> 00:20:24,596 Speaker 2: They invested much more than that, and they stayed with 323 00:20:24,676 --> 00:20:29,276 Speaker 2: it over over twenty plus years. So I don't know 324 00:20:29,916 --> 00:20:33,156 Speaker 2: who the decision makers were, but they made the right decision. 325 00:20:33,476 --> 00:20:38,636 Speaker 1: So they decided to work on compounds that blocked this 326 00:20:39,116 --> 00:20:42,716 Speaker 1: channel one point eight, another one that you had identified. 327 00:20:44,036 --> 00:20:46,076 Speaker 1: I know you weren't involved in all of it, but 328 00:20:46,596 --> 00:20:50,556 Speaker 1: more or less, what is the story of developing that drug. 329 00:20:51,676 --> 00:20:55,396 Speaker 2: So what this company did and others did is they 330 00:20:55,436 --> 00:20:59,396 Speaker 2: had their target molecule. The question is can you identify 331 00:20:59,836 --> 00:21:03,556 Speaker 2: a molecule potential drug that blocks it, and you can 332 00:21:03,596 --> 00:21:07,836 Speaker 2: put those molecules into a cell. There are robots that 333 00:21:07,916 --> 00:21:11,396 Speaker 2: will look as you screen hundreds of thousands of compounds, 334 00:21:11,436 --> 00:21:15,796 Speaker 2: asking is there something that silences that molecular battery one 335 00:21:15,916 --> 00:21:16,636 Speaker 2: seven or one. 336 00:21:16,516 --> 00:21:20,036 Speaker 1: Eight and you wanted to silence that and nothing else, right, 337 00:21:20,116 --> 00:21:22,756 Speaker 1: that's correct part of that and not have some weirdo 338 00:21:23,076 --> 00:21:24,996 Speaker 1: side effect that's gonna make people sick. 339 00:21:25,436 --> 00:21:31,236 Speaker 2: That's absolutely crucial. But with using these robotic technologies, it's 340 00:21:31,276 --> 00:21:34,596 Speaker 2: possible to find one or two that work. And then 341 00:21:34,636 --> 00:21:37,356 Speaker 2: you say to your chemists, Okay, this is our lead compound, 342 00:21:37,556 --> 00:21:40,996 Speaker 2: make it better, make it orally available, give it the 343 00:21:41,076 --> 00:21:46,036 Speaker 2: right absorption and excretion compounds properties, et cetera, et cetera. 344 00:21:46,476 --> 00:21:49,676 Speaker 2: And so that's how it goes. And then you still 345 00:21:49,676 --> 00:21:51,836 Speaker 2: have a lot of work because you need to demonstrate 346 00:21:51,916 --> 00:21:55,716 Speaker 2: in a dish that the compound silence is the activity 347 00:21:55,876 --> 00:22:00,356 Speaker 2: of pain signaling neurons. Then usually go to rodent models, 348 00:22:00,516 --> 00:22:03,796 Speaker 2: sometimes non human primates, and then the human trials. It's 349 00:22:03,836 --> 00:22:06,596 Speaker 2: a long, long process and they. 350 00:22:06,436 --> 00:22:08,596 Speaker 1: Managed to get through this process, right. So there is 351 00:22:08,636 --> 00:22:15,116 Speaker 1: this drug suzetragene. Yeah, it got FDA approval for at 352 00:22:15,196 --> 00:22:18,156 Speaker 1: least some indications this year, correct. 353 00:22:18,476 --> 00:22:20,476 Speaker 2: Yeah, I think there were a couple of milestones. 354 00:22:20,716 --> 00:22:20,916 Speaker 1: Yeah. 355 00:22:21,036 --> 00:22:24,676 Speaker 2: One was the demonstration even prior to FDA approval that 356 00:22:24,756 --> 00:22:29,996 Speaker 2: it produced a statistically significant reduction in pain in humans. 357 00:22:30,396 --> 00:22:33,316 Speaker 1: So let's talk about that moment. So, you know, it's 358 00:22:33,316 --> 00:22:35,876 Speaker 1: this incredible long road and they have to find the 359 00:22:35,876 --> 00:22:37,836 Speaker 1: compound in testing animals, and they do phase one and 360 00:22:37,836 --> 00:22:40,596 Speaker 1: face two, and then finally there's the giant phase three trial. Right, 361 00:22:40,596 --> 00:22:42,676 Speaker 1: so you're a phase three trial with hundreds of patients 362 00:22:43,116 --> 00:22:46,196 Speaker 1: and then the results come out, Like when did you 363 00:22:46,276 --> 00:22:49,036 Speaker 1: learn the results of this pivotal trial. 364 00:22:52,796 --> 00:22:56,636 Speaker 2: I learned of the results of this pivotal trial when 365 00:22:56,636 --> 00:23:00,356 Speaker 2: a medical journal, the New England Journal of Medicine, said, Steve, 366 00:23:00,436 --> 00:23:03,996 Speaker 2: there's been this pivotal trial. You've done all the work 367 00:23:04,036 --> 00:23:07,916 Speaker 2: on one eight identifying it as a target, and when 368 00:23:07,956 --> 00:23:11,676 Speaker 2: we published the results of the trial, will you write 369 00:23:11,916 --> 00:23:15,316 Speaker 2: an accompanying article. We have a series of articles on 370 00:23:15,396 --> 00:23:18,716 Speaker 2: the science behind the clinical trial and they asked me 371 00:23:19,156 --> 00:23:19,676 Speaker 2: to do that. 372 00:23:19,916 --> 00:23:23,036 Speaker 1: You really didn't know until the New England Journal asked 373 00:23:23,076 --> 00:23:24,636 Speaker 1: you to write an editorial. 374 00:23:25,356 --> 00:23:27,836 Speaker 2: I didn't And what did you think when you saw 375 00:23:27,876 --> 00:23:28,436 Speaker 2: the results? 376 00:23:29,236 --> 00:23:30,676 Speaker 1: I thought, my. 377 00:23:30,836 --> 00:23:34,516 Speaker 2: God, we're getting there. We're not there, but we're getting there. 378 00:23:34,836 --> 00:23:38,436 Speaker 2: If this can be repeated, it's a very important step forward. 379 00:23:38,636 --> 00:23:41,516 Speaker 1: Tell me about both pieces of that. That's like two things, like, 380 00:23:41,556 --> 00:23:44,636 Speaker 1: we're getting there is something, but we're not there is 381 00:23:44,636 --> 00:23:47,036 Speaker 1: also something, So what is the we're getting there piece? 382 00:23:47,836 --> 00:23:52,436 Speaker 2: We're getting there was why I regard their study as 383 00:23:52,476 --> 00:23:56,596 Speaker 2: a milestone. It was proof of concept that by targeting 384 00:23:56,596 --> 00:24:01,796 Speaker 2: a peripheral sodium channel, which is a step toward non addictive, 385 00:24:02,036 --> 00:24:05,516 Speaker 2: non opiate pain therapy, one can reduce pain in humans. 386 00:24:05,556 --> 00:24:07,956 Speaker 2: That in itself is a real milestone. 387 00:24:08,156 --> 00:24:10,876 Speaker 1: And just to be clear, what was the finding specifically 388 00:24:10,916 --> 00:24:12,996 Speaker 1: of this trial, what was the outcome? 389 00:24:13,356 --> 00:24:18,356 Speaker 2: These were two groups of patients with abdominoplasty that's tummy 390 00:24:18,396 --> 00:24:22,756 Speaker 2: tuck surgery and bunyan ectomy, and the reduction in pain 391 00:24:23,356 --> 00:24:28,956 Speaker 2: was statistically significant, about as large as was seen with opiates. 392 00:24:29,756 --> 00:24:32,076 Speaker 1: It was vicd in right, it was some fairly standard 393 00:24:32,396 --> 00:24:34,916 Speaker 1: h yep. So it's like this basically is like for 394 00:24:34,996 --> 00:24:37,636 Speaker 1: these patients, this is about as good as vicotin, which 395 00:24:37,676 --> 00:24:42,836 Speaker 1: is actually great because as we know, opioids are addictive 396 00:24:42,916 --> 00:24:45,996 Speaker 1: and it's a huge problem. And so if you can 397 00:24:46,076 --> 00:24:48,796 Speaker 1: reduce pain in a non addictive way, that seems like 398 00:24:49,436 --> 00:24:50,436 Speaker 1: quite a happy finding. 399 00:24:50,956 --> 00:24:53,596 Speaker 2: So that is a happy finding. It's a contribution to 400 00:24:53,716 --> 00:24:57,596 Speaker 2: clinical medicine. But for me, as a researcher, it's also, 401 00:24:57,676 --> 00:25:00,956 Speaker 2: as I said, proof of concept, and it raises the question, Okay, 402 00:25:01,276 --> 00:25:03,436 Speaker 2: we have proof of concept. Now we build on it 403 00:25:03,636 --> 00:25:06,516 Speaker 2: and build even better drugs. And that gets to the 404 00:25:06,556 --> 00:25:10,556 Speaker 2: issue of that you asked, why still more work to do? 405 00:25:11,196 --> 00:25:14,276 Speaker 2: And the point is that the drug was as good 406 00:25:14,316 --> 00:25:17,796 Speaker 2: as vicodin. It reduced pain by two points on the 407 00:25:17,836 --> 00:25:21,596 Speaker 2: ten point scale, but it did not totally abolish pain, 408 00:25:22,876 --> 00:25:26,836 Speaker 2: and so why did it not work better? So we're 409 00:25:26,916 --> 00:25:30,596 Speaker 2: working and I'm assuming that within the biopharma industry there 410 00:25:31,396 --> 00:25:34,596 Speaker 2: is great effort to We're working on the question of 411 00:25:34,676 --> 00:25:37,276 Speaker 2: can you do better? And if so, how would you 412 00:25:37,316 --> 00:25:40,476 Speaker 2: do it? So the first question is when you see 413 00:25:40,596 --> 00:25:44,556 Speaker 2: less than full pain relief, is it because the drug 414 00:25:44,836 --> 00:25:49,916 Speaker 2: to in this particular drug is less than optimally designed 415 00:25:49,956 --> 00:25:54,396 Speaker 2: in terms of its pharmacokinetics, pharmacodynamics, distribution through the body. 416 00:25:54,756 --> 00:25:58,316 Speaker 2: And if so, then it should be possible to build 417 00:25:58,356 --> 00:26:03,716 Speaker 2: a better drug, or is there a biological ceiling. This 418 00:26:03,876 --> 00:26:07,436 Speaker 2: is the best you can do by targeting that particular 419 00:26:07,516 --> 00:26:11,076 Speaker 2: molecule at a one point eight. So we're looking at 420 00:26:11,076 --> 00:26:12,796 Speaker 2: that right now in the lab. 421 00:26:12,876 --> 00:26:15,036 Speaker 1: Right now, is there a notion that there are other 422 00:26:15,236 --> 00:26:19,556 Speaker 1: channels that might be complementary. If you target more than 423 00:26:19,596 --> 00:26:23,356 Speaker 1: one channel at once, you might get improved outcomes. So 424 00:26:23,396 --> 00:26:26,236 Speaker 1: anybody trying one point seven and one point eight, that's 425 00:26:26,236 --> 00:26:28,876 Speaker 1: an obvious question, would you like a job? 426 00:26:30,596 --> 00:26:35,196 Speaker 2: So we're going through the exercise of doing that in 427 00:26:35,236 --> 00:26:38,716 Speaker 2: a dish in a very quantitative way. Let's block one 428 00:26:38,916 --> 00:26:41,916 Speaker 2: point eight plus one point seven. We could do it 429 00:26:41,956 --> 00:26:45,076 Speaker 2: with one point nine. There's a channel of interest. It's 430 00:26:45,116 --> 00:26:47,796 Speaker 2: a break on the firing of these sales called kV seven. 431 00:26:48,676 --> 00:26:52,116 Speaker 2: These are very, very challenging experiments, but we're doing it 432 00:26:52,236 --> 00:26:55,316 Speaker 2: very systematically, and so in a year I hope we 433 00:26:55,396 --> 00:26:59,276 Speaker 2: have an answer for that. My prediction is number one, 434 00:26:59,556 --> 00:27:03,316 Speaker 2: there will be next generation drugs that are more effective. 435 00:27:04,116 --> 00:27:07,596 Speaker 2: But my caveat to it is they may involve a 436 00:27:07,636 --> 00:27:12,996 Speaker 2: combinatorial approach, blocking several channels or modulating several channels, and 437 00:27:13,036 --> 00:27:14,836 Speaker 2: we have a lot of work to do to get there. 438 00:27:15,676 --> 00:27:18,756 Speaker 1: If you think about that future, whenever it is five 439 00:27:18,836 --> 00:27:21,996 Speaker 1: years from now, ten years from now, twenty years from now, like, 440 00:27:22,956 --> 00:27:23,956 Speaker 1: what's that world look like? 441 00:27:26,596 --> 00:27:27,836 Speaker 2: What's that world look like? 442 00:27:28,516 --> 00:27:28,716 Speaker 1: You know? 443 00:27:30,436 --> 00:27:37,076 Speaker 2: Weekly daily, I receive letters more frequently emails from patients, 444 00:27:37,196 --> 00:27:42,156 Speaker 2: or more frequently from their loved ones, particularly parents, concerned doctors. 445 00:27:42,916 --> 00:27:48,676 Speaker 2: I have a patient with whatever, and their pain is untreatable. 446 00:27:48,796 --> 00:27:53,116 Speaker 2: There's just nothing for them. And I envisioned a world 447 00:27:53,316 --> 00:27:56,636 Speaker 2: where we can treat these people. It's an important goal. 448 00:27:57,196 --> 00:28:00,556 Speaker 2: It's hard to quantitate it. I certainly can't put a 449 00:28:00,596 --> 00:28:05,196 Speaker 2: timescale on it, but there's an immense need and I'm encouraged. 450 00:28:05,276 --> 00:28:09,876 Speaker 2: I tend to use my words very conservatively and cautiously. 451 00:28:10,596 --> 00:28:15,436 Speaker 2: And there's one particular teenager whose father periodically emails me, 452 00:28:15,836 --> 00:28:18,836 Speaker 2: is there anything for my daughter? I used to tell 453 00:28:18,916 --> 00:28:22,636 Speaker 2: him that I hoped we would have a non addictive 454 00:28:22,716 --> 00:28:26,476 Speaker 2: treatment for chronic pain for people like his daughter. I 455 00:28:26,596 --> 00:28:29,636 Speaker 2: now can write back confidently and say I can't say 456 00:28:29,676 --> 00:28:31,756 Speaker 2: how long it's going to take, but there will be. 457 00:28:32,636 --> 00:28:35,236 Speaker 2: And so that's the way I look at things. And 458 00:28:35,596 --> 00:28:36,556 Speaker 2: we've come a long way. 459 00:28:40,716 --> 00:28:54,596 Speaker 1: We'll be back in a minute with the lightning round. Okay, 460 00:28:54,636 --> 00:28:56,556 Speaker 1: now we're going to finish with the lightning ground it's 461 00:28:56,596 --> 00:28:59,636 Speaker 1: going to be a little bit more random, but still 462 00:28:59,676 --> 00:29:02,436 Speaker 1: more or less on point. Is it possible to learn 463 00:29:02,516 --> 00:29:04,636 Speaker 1: to be more resilient to pain? Oh? 464 00:29:04,716 --> 00:29:10,276 Speaker 2: Absolutely, Look we send marines to Tampa June to toughen 465 00:29:10,276 --> 00:29:12,916 Speaker 2: them up, and they learn to be resilient to pain. 466 00:29:13,556 --> 00:29:17,836 Speaker 2: There are various types of monks who manage their pain beautifully. 467 00:29:18,516 --> 00:29:23,276 Speaker 2: Cognitive and behavioral therapy work. So there's no question that 468 00:29:23,316 --> 00:29:27,436 Speaker 2: there are psychological aspects to pain, and that provides an 469 00:29:27,436 --> 00:29:31,716 Speaker 2: important lever on pain. Having said that, here we are 470 00:29:31,756 --> 00:29:35,356 Speaker 2: in the year twenty twenty five. Those techniques have been 471 00:29:35,396 --> 00:29:39,156 Speaker 2: refined again and again, and we still have just a 472 00:29:39,276 --> 00:29:43,596 Speaker 2: highway of patients who have unrelieved pain, and so we 473 00:29:44,156 --> 00:29:45,676 Speaker 2: need pharmacological approaches. 474 00:29:46,476 --> 00:29:49,116 Speaker 1: Is there something I can do to be less angry 475 00:29:49,156 --> 00:29:52,836 Speaker 1: when I bang my head or stub my toe. It's remarkable. 476 00:29:52,876 --> 00:29:54,796 Speaker 1: I'm not generally an angry person, but I get so 477 00:29:54,916 --> 00:29:58,796 Speaker 1: angry for a moment when that happens. You know. 478 00:29:59,356 --> 00:30:02,556 Speaker 2: I follow a family with a man on fire syndrome, 479 00:30:03,156 --> 00:30:06,836 Speaker 2: and there are two children who have severe pain. They've 480 00:30:06,876 --> 00:30:10,076 Speaker 2: had a hard time dealing with it. But their mother 481 00:30:10,116 --> 00:30:13,156 Speaker 2: wrote to me some months ago and she said, one 482 00:30:13,196 --> 00:30:15,436 Speaker 2: of the children is having a very hard time because 483 00:30:15,476 --> 00:30:20,036 Speaker 2: he fights the pain, and her other child, through therapy, 484 00:30:20,116 --> 00:30:23,476 Speaker 2: has learned to quote, go with it, and there's a 485 00:30:23,556 --> 00:30:25,116 Speaker 2: lesson there go with it. 486 00:30:25,996 --> 00:30:27,916 Speaker 1: When I'm taking away from that is go with it. 487 00:30:28,436 --> 00:30:30,116 Speaker 2: Well, that's the word the mother used. 488 00:30:31,996 --> 00:30:37,076 Speaker 1: What is something about pain that is currently poorly understood 489 00:30:37,396 --> 00:30:40,876 Speaker 1: or entirely mysterious that you wish were better understood. 490 00:30:41,396 --> 00:30:47,156 Speaker 2: Well, one major problem is how pain becomes chronic. So 491 00:30:47,916 --> 00:30:51,676 Speaker 2: if you stub your toe or burn your finger, there 492 00:30:51,756 --> 00:30:56,676 Speaker 2: is hyperactivity of those sensory neurons that is appropriate and protective. 493 00:30:56,796 --> 00:30:58,196 Speaker 2: You withdraw your your finger. 494 00:30:58,316 --> 00:31:00,276 Speaker 1: That's good pain, that's the pain we need. 495 00:31:00,676 --> 00:31:04,396 Speaker 2: That's good pain. But if you have diabetic neuropathy and 496 00:31:04,436 --> 00:31:09,476 Speaker 2: develop a painful neuropathy or chemotherapy and doce neuropathy, or 497 00:31:09,516 --> 00:31:12,596 Speaker 2: if you have a nerve injury, those same nerve cells 498 00:31:13,116 --> 00:31:20,116 Speaker 2: generate barrages of impulses in the absence of a painful stimulus, 499 00:31:20,676 --> 00:31:25,716 Speaker 2: and the details of what drives cells to become chronically 500 00:31:25,836 --> 00:31:31,716 Speaker 2: hyperactive are still unknown, So that's something we need to understand. 501 00:31:32,076 --> 00:31:35,076 Speaker 2: We need to understand when that happens. Are their changes 502 00:31:35,116 --> 00:31:38,316 Speaker 2: also in the spinal cord, lower brain, and higher brain. 503 00:31:38,716 --> 00:31:42,116 Speaker 2: All these things are understudy, but they are important mysteries 504 00:31:42,156 --> 00:31:49,756 Speaker 2: and they will be solved. 505 00:31:51,956 --> 00:31:56,396 Speaker 1: Stephen Waxman is a professor of neurology, neuroscience, and pharmacology 506 00:31:56,916 --> 00:32:01,516 Speaker 1: at Yale. Please email us at problem at pushkin dot fm. 507 00:32:01,556 --> 00:32:04,316 Speaker 1: We are always looking for new guests for the show. 508 00:32:05,036 --> 00:32:08,796 Speaker 1: Today's show was produced by Trinamnino and Gabriel Hunter Chang. 509 00:32:09,236 --> 00:32:13,236 Speaker 1: It was edited by Alexander Garriton and engineered by Sarah Bruger. 510 00:32:13,636 --> 00:32:15,756 Speaker 1: I'm Jacob Goldstein and we'll be back next week with 511 00:32:15,836 --> 00:32:19,556 Speaker 1: another episode of What's Your prob