WEBVTT - Inventing a Better Pain Pill 0:00:15.356 --> 0:00:24.996 Pushkin. Pain is terrible, obviously, it's kind of the classic 0:00:25.236 --> 0:00:30.716 terrible thing, and having medicine to treat pain is great. 0:00:31.156 --> 0:00:35.156 But the strongest drugs we have for pain, opioids, are 0:00:35.236 --> 0:00:40.796 infamously addictive, deadly. Even more than ten thousand people die 0:00:40.916 --> 0:00:46.076 every year in the US from prescription opioid overdoses. Opioids 0:00:46.076 --> 0:00:49.116 are addictive because they act on the brain to blunt 0:00:49.116 --> 0:00:53.116 our sensation of pain. But pain doesn't start in the brain. 0:00:53.756 --> 0:00:56.036 It starts in the nerves in other parts of the body, 0:00:56.156 --> 0:00:59.236 and then it gets relayed to the brain. So for 0:00:59.316 --> 0:01:03.156 decades scientists thought it would be amazing if we could 0:01:03.156 --> 0:01:06.396 find a molecule that was really good at blocking pain 0:01:06.436 --> 0:01:08.516 in the nerves before it gets sent to the brain. 0:01:09.196 --> 0:01:11.396 That way, we could make a pain drug that is 0:01:11.436 --> 0:01:15.556 as strong as opioids but is not addictive. And earlier 0:01:15.596 --> 0:01:19.236 this year, for the very first time, the FDA approved 0:01:19.476 --> 0:01:28.636 exactly that kind of drug. I'm Jacob Goldstein and this 0:01:28.716 --> 0:01:30.556 is What's Your Problem, the show where I talk to 0:01:30.556 --> 0:01:34.076 people who are trying to make technological progress. My guest 0:01:34.156 --> 0:01:38.516 today is Stephen Waxman. He's a professor of neurology, neuroscience, 0:01:38.556 --> 0:01:42.956 and pharmacology at Yale. Stephen's research helped to pave the 0:01:42.996 --> 0:01:45.756 way for that newly approved pain drug. It's a drug 0:01:45.796 --> 0:01:51.076 called suzettrogene, and in particular, Stephen has spent decades studying 0:01:51.156 --> 0:01:54.756 ion channels. Ion channels are these little gaps in nerve 0:01:54.836 --> 0:01:58.516 cells that let charged particles ions in and out of 0:01:58.556 --> 0:02:03.236 the cell. Suzettrogene works by blocking one particular ion channel. 0:02:03.836 --> 0:02:06.916 As you'll hear later in the show, Stephen thinks suzetrogene 0:02:07.036 --> 0:02:10.316 is a promising start, but he also thinks there's still 0:02:10.356 --> 0:02:12.596 a lot of work left to do to develop better 0:02:12.676 --> 0:02:15.516 pain drugs, and the story of how we got to 0:02:15.516 --> 0:02:19.236 cizetrogene reveals a lot about how science works, and how 0:02:19.356 --> 0:02:23.916 drug development works, and ultimately about how the body works. Well, 0:02:23.956 --> 0:02:25.116 how did you get into pain? 0:02:26.116 --> 0:02:29.676 You know? When I was an mdphd student, I had 0:02:29.716 --> 0:02:34.676 the privilege of doing a four month stint at University 0:02:34.716 --> 0:02:39.836 College London with Patrick Wall. Wall was the father of 0:02:39.956 --> 0:02:43.236 modern pain research, and so I spent four or five 0:02:43.276 --> 0:02:46.436 months with him. So I got to work at his side, 0:02:46.836 --> 0:02:49.716 and I realized that pain is not only a very 0:02:49.716 --> 0:02:55.236 important challenge, but also a puzzle box that presents intellectual challenges, 0:02:55.276 --> 0:02:56.556 but that could be solved. 0:02:56.836 --> 0:03:00.676 Huh. Tell me a little more about what you experienced 0:03:00.716 --> 0:03:03.476 in those four months, Like, was there a particular moment 0:03:03.636 --> 0:03:06.436 or some particular problem that was intriguing to you. 0:03:07.276 --> 0:03:11.156 Well, what became clear to me is that pain is 0:03:11.196 --> 0:03:16.196 a hierarchical experience. You may experience it peripherally through your 0:03:16.196 --> 0:03:20.876 peripheral nerves, but that the pain messages are then processed 0:03:21.116 --> 0:03:25.156 and modulated in the spinal cord, relate upwards to the 0:03:25.196 --> 0:03:28.276 lower brain than to the cortex, and so it's an 0:03:28.316 --> 0:03:33.196 experience that is processed at many levels, and at each 0:03:33.316 --> 0:03:36.436 level if you take a reductionist approach, it seemed to 0:03:36.476 --> 0:03:39.436 me that you can take it apart and understand it. 0:03:39.876 --> 0:03:43.716 Huh. So you start thinking of pain as this sort 0:03:43.716 --> 0:03:49.996 of hierarchical phenomenon, and is there a particular level of 0:03:50.036 --> 0:03:52.516 the stack that you decide to focus on. 0:03:53.196 --> 0:03:56.756 That's a great question, you know, Jacob. When I was 0:03:57.596 --> 0:04:02.756 a young new scientist, an mdphd student resident then a 0:04:02.796 --> 0:04:06.356 new assistant professor at MIT and Harvard, I wanted to 0:04:06.396 --> 0:04:10.876 study grand philosophical problems at the mind interface. 0:04:11.196 --> 0:04:13.356 What is consciousness? That sort of thing. 0:04:13.876 --> 0:04:17.636 Yeah, and I published some papers in the cybernetics literature 0:04:17.676 --> 0:04:20.556 and got awards for them. But I came to the 0:04:20.596 --> 0:04:26.316 conclusion that while that was a very important challenge, that 0:04:25.916 --> 0:04:28.316 it was those issues were not going to be resolved 0:04:28.756 --> 0:04:33.596 during my professional lifetime, and so I retreated from grand 0:04:33.596 --> 0:04:40.116 philosophical questions to much more soluble, concrete questions that could 0:04:40.116 --> 0:04:44.436 be solved during my professional lifetime. So that's what I did. 0:04:44.436 --> 0:04:48.476 When I talked to students trainees, I relay this story 0:04:48.516 --> 0:04:50.836 to them because they have a choice. Do they want 0:04:50.876 --> 0:04:56.236 to attack large, philosophically grand questions or work at a 0:04:56.236 --> 0:05:00.476 more fundamental, reductionist level. There's no right answer. This was 0:05:00.596 --> 0:05:03.916 right for me, and they have the opportunity to make 0:05:03.956 --> 0:05:04.676 your own choice. 0:05:05.316 --> 0:05:10.956 So you go from big consciousness ultimately to very small 0:05:11.116 --> 0:05:15.956 right like ion channels, which about as small as you 0:05:15.996 --> 0:05:19.756 can get in medicine, right, and ion channels obviously mostly 0:05:19.796 --> 0:05:22.276 what we're going to talk about here, right, a tremendous 0:05:22.276 --> 0:05:22.996 amount of your work. 0:05:23.036 --> 0:05:24.036 So that's correct. 0:05:24.476 --> 0:05:26.196 How did you get into ion channels? 0:05:26.356 --> 0:05:28.996 Well, I got into ion channels because of my interest 0:05:29.076 --> 0:05:32.636 in axons nerve fibers. While I was an undergraduate, I 0:05:32.676 --> 0:05:36.156 spent nine months at University College working with a man 0:05:36.276 --> 0:05:40.956 named Jays zed Young. He discovered the giant axon in 0:05:40.996 --> 0:05:44.436 the squid, and so I became interested in how axons work. 0:05:44.796 --> 0:05:46.716 And the axon is part of the nerve cell. 0:05:46.996 --> 0:05:49.756 The axon is the long nerve fiber that extends from 0:05:49.756 --> 0:05:54.156 the nerve cell. Our nervous system consists of one hundred 0:05:54.276 --> 0:05:58.116 billion nerve cells in every one of us. It's the 0:05:58.116 --> 0:06:02.796 world's most complex computer. And each of the nerve cells 0:06:02.796 --> 0:06:05.996 has an axon that connects it to other nerve cells. 0:06:06.236 --> 0:06:09.036 So I was interested in axons, and it rapidly became 0:06:09.196 --> 0:06:11.436 clear to me that I had to understand how axons 0:06:11.476 --> 0:06:16.916 work and the driver of activity in axons nerve impulses bup, bup, up, 0:06:16.996 --> 0:06:20.716 up up up up is ion channels, sodium channels that 0:06:20.756 --> 0:06:25.636 act as molecular batteries, potassium channels that act as molecular breaks. 0:06:26.356 --> 0:06:30.836 Huh. So these are basically channels in the membrane of 0:06:30.876 --> 0:06:34.556 the cell through which ions charge particles move, causing the 0:06:34.596 --> 0:06:37.316 nerve cell to fire or not fire more or. 0:06:37.356 --> 0:06:40.156 Less, that's right. And when they fire, a nerve cell 0:06:40.196 --> 0:06:43.436 produces what's called an action potential or a nerve impulse, 0:06:43.876 --> 0:06:47.076 and it's the pattern of firing of nerve cells that 0:06:47.156 --> 0:06:48.836 they use to communicate with each other. 0:06:49.196 --> 0:06:52.036 So you're doing work on ion channels as a way 0:06:52.036 --> 0:06:54.436 to understand the behavior of nerve cells. You're also doing 0:06:54.476 --> 0:06:57.596 work on pain, right, And there has been, by the 0:06:57.636 --> 0:07:00.196 time you get into the field a history of work 0:07:00.276 --> 0:07:03.436 on the relationship between ion channels and pain. Right, So 0:07:04.796 --> 0:07:06.716 when you get into the field, what do we know? 0:07:06.796 --> 0:07:10.236 What does humanity know already about that relationship? 0:07:10.876 --> 0:07:15.316 Actually, when I got into the relationship between ion channels 0:07:15.316 --> 0:07:17.836 and pain, not much at all was known. 0:07:18.276 --> 0:07:21.276 I mean, we had lytocane and novacane, right. 0:07:21.436 --> 0:07:27.236 So lytacane and novacane are sodium channel blockers. We all 0:07:27.276 --> 0:07:29.796 know that when they're injected locally, no pain. 0:07:30.076 --> 0:07:31.876 That's what you get when you get a cavity filed. 0:07:31.956 --> 0:07:34.556 Right, that's correct. But if you put those drugs in 0:07:34.556 --> 0:07:38.756 the form of a pill and administer them systemically, they 0:07:38.756 --> 0:07:41.716 would affect sodium channels in the brain. So there is 0:07:41.796 --> 0:07:48.116 double vision, impaired balance, sleepiness, and confusion. And so that 0:07:48.156 --> 0:07:52.236 doesn't work. And so this is a really interesting arc 0:07:52.356 --> 0:07:56.956 of science. Sodium channels were discovered by Hodgkin and Huxley. 0:07:57.516 --> 0:07:59.796 They did the work right after World War two and 0:07:59.836 --> 0:08:03.716 published it in nineteen fifty two, and their studies were 0:08:03.716 --> 0:08:06.476 in the giant axon of the squid. And then fast 0:08:06.516 --> 0:08:10.116 forward to our lab in around nineteen eighty five, we 0:08:10.116 --> 0:08:15.076 were able to record similarly from axons from rats and 0:08:15.116 --> 0:08:18.836 then humans. They're one fiftieth the size of the squid 0:08:18.836 --> 0:08:22.516 giant axon, and we were able to see that not 0:08:22.556 --> 0:08:27.156 only were sodium channels there, but that the abnormal firing 0:08:27.476 --> 0:08:33.276 of peripheral nerve that underlies pain was caused by a 0:08:33.316 --> 0:08:35.156 particular type of sodium channel. 0:08:35.716 --> 0:08:39.196 So at some point, as I understand it, you get 0:08:39.236 --> 0:08:43.636 a call about a neighborhood in Alabama where a lot 0:08:43.676 --> 0:08:48.516 of people have an unusual experience of pain. Is that true? 0:08:48.796 --> 0:08:50.756 Did somebody call you on the phone? Is that how 0:08:50.756 --> 0:08:52.036 that starts? 0:08:52.596 --> 0:08:56.036 That's correct. We were taking two approaches. One was a 0:08:56.076 --> 0:09:01.196 mechanistic approach from ground up, looking at pain signaling neurons 0:09:01.396 --> 0:09:04.116 that we could study in a dish and dissecting them 0:09:04.516 --> 0:09:07.676 channel by channel, asking what did the various channels do 0:09:08.156 --> 0:09:10.996 to cause abnormal firing and pain. You can think of 0:09:10.996 --> 0:09:15.356 a neuron a symphony of multiple ion channels working in 0:09:15.396 --> 0:09:18.356 a highly orchestrated way, and so at that point, we 0:09:18.396 --> 0:09:24.716 had identified three sodium channels as potential very very important 0:09:25.156 --> 0:09:29.996 participants in pain signaling NAV one point seven, NAV one 0:09:29.996 --> 0:09:32.836 point eight, and NAV one point nine. 0:09:32.916 --> 0:09:36.076 So these are just the names of different ion channels 0:09:36.076 --> 0:09:39.476 that behave differently under different circumstances that we have in 0:09:39.516 --> 0:09:40.716 our nerve cells. 0:09:41.036 --> 0:09:44.556 That's exactly right. Yeah, So that's the sort of ground 0:09:44.636 --> 0:09:48.316 up mechanistic work that we were doing. But there's another 0:09:48.476 --> 0:09:53.156 top down approach beginning with whole human beings and trying 0:09:53.196 --> 0:09:58.396 to see using genetics as there are there particular genes, 0:09:58.516 --> 0:10:02.316 particular proteins related to a disease, in this case, the 0:10:02.396 --> 0:10:05.356 disorder of pain. And let me back up a bit. 0:10:05.876 --> 0:10:08.836 If you think about the history of modern drug development, 0:10:09.516 --> 0:10:13.356 why look around the world for families with rare inherited diseases. 0:10:14.676 --> 0:10:19.196 The answer is that rare diseases, inherited diseases often teach 0:10:19.276 --> 0:10:23.636 us important lessons about more common disorders. And a good 0:10:23.636 --> 0:10:27.636 example is the statin drugs. The statin drugs which have 0:10:27.716 --> 0:10:29.676 revolutionized cardiovascular medicals. 0:10:29.676 --> 0:10:31.716 I'm a fan, I take one every day. 0:10:32.396 --> 0:10:36.196 Many of us do, and they were developed on the 0:10:36.236 --> 0:10:40.596 basis of the discovery and then study of incredibly rare 0:10:40.636 --> 0:10:43.996 families where everybody who was having heart attacks in their twenties. Huh, 0:10:44.036 --> 0:10:49.396 those families had inherited hypercholesterolemia. Their genes pointed the way 0:10:49.636 --> 0:10:53.996 at the relevant molecules and informed of drug development. 0:10:54.116 --> 0:10:56.876 So it's basically like, if there's some family of people 0:10:56.916 --> 0:11:00.556 that has a strange version of a common malady, let's 0:11:00.556 --> 0:11:02.556 look at their genes and maybe that'll point to a 0:11:02.596 --> 0:11:05.556 way to treat that malady in people without the mutation. 0:11:05.756 --> 0:11:07.396 That's the basic hypothesis. 0:11:07.476 --> 0:11:09.756 That's exactly right. You just did it. 0:11:09.916 --> 0:11:13.156 Yeah, so you want that, but for ion channels, that's 0:11:13.156 --> 0:11:15.436 what you're looking for as you're doing your lab work. 0:11:15.476 --> 0:11:19.036 You want this sort of genetic mutation that might show 0:11:19.076 --> 0:11:20.116 a clinical application. 0:11:20.596 --> 0:11:24.836 That's correct. So we launched a worldwide search for families 0:11:24.876 --> 0:11:29.116 with inherited neuropathic pain pain due to inappropriate firing of 0:11:29.156 --> 0:11:33.396 peripheral nerves. Neurologists see patients with neuropathic pain all the time, 0:11:33.836 --> 0:11:37.196 our clinics are filled, but we never see families. 0:11:37.276 --> 0:11:40.876 So it's typically not a genetic problem. Right, It's like 0:11:40.956 --> 0:11:43.436 you have diabetes or something. It's not you inherited it 0:11:43.476 --> 0:11:44.356 from your mother. 0:11:44.716 --> 0:11:48.636 That's correct. So we launched this search and what happened 0:11:48.796 --> 0:11:52.316 was interesting. In the beginning of two thousand and three, 0:11:52.916 --> 0:11:56.436 February or March, a colleague member of my team brought 0:11:56.476 --> 0:12:00.076 me the latest issue of the Journal of Human Genetics. 0:12:00.716 --> 0:12:05.516 There was an article out of Beijing, China on two 0:12:05.596 --> 0:12:10.596 families with men on fire syndrome inherited from lalgia, each 0:12:10.916 --> 0:12:14.996 with a mutation of navy one point seven. The man 0:12:15.036 --> 0:12:19.716 on fire syndrome inherited erythrommelalgia is a really interesting disease. 0:12:19.796 --> 0:12:23.356 Most physicians have never seen a case, never will, but 0:12:23.676 --> 0:12:26.716 if you see it, you remember it because it's so striking. 0:12:27.036 --> 0:12:32.836 These people feel that they're on fire. They describe searing, scalding, 0:12:32.996 --> 0:12:36.836 burning pain that's triggered by mild warmth, putting on shoes, 0:12:37.396 --> 0:12:41.756 wearing a sweater, going outside when it's seventy two degrees fahrenheit. 0:12:41.876 --> 0:12:44.476 The pain is so bad some patients ask for limbs 0:12:44.516 --> 0:12:49.156 to be surgically amputated, which does not help. But it's 0:12:49.236 --> 0:12:53.436 excruciating pain. So here was an article out of Beijing 0:12:53.876 --> 0:12:58.796 by a very good group of academic dermatologists and geneticists saying, 0:12:58.836 --> 0:13:01.436 we have two families with the man on fire syndrome, 0:13:01.756 --> 0:13:04.636 each with a mutation of Navy one point seven. And 0:13:04.676 --> 0:13:08.716 my initial response to my colleagues my research team was 0:13:08.796 --> 0:13:11.836 to say, think, gee, we've been scooped. This is not 0:13:11.956 --> 0:13:14.596 a good day. And I said to my colleagues, stay 0:13:14.636 --> 0:13:15.196 away from me. 0:13:16.436 --> 0:13:18.716 It's a good day for humanity, but not a good 0:13:18.756 --> 0:13:20.636 day for your lab because somebody beats you. 0:13:21.036 --> 0:13:25.916 Yeah, exactly. And my initial response was stay away from me. 0:13:26.156 --> 0:13:27.476 I'm going to be pretty grumbly. 0:13:27.956 --> 0:13:30.276 And just as a reminder any of you one point seven, 0:13:30.436 --> 0:13:33.636 that's the that's the ion channel that you had identified 0:13:33.676 --> 0:13:36.436 as associated with pain in the lab. And here's a 0:13:36.516 --> 0:13:40.236 kind of clinical validation of that, but coming not from 0:13:40.316 --> 0:13:42.036 you but from some other scientists. 0:13:42.116 --> 0:13:46.756 Yeah, from Beijing, China. But when I closed the door 0:13:46.956 --> 0:13:49.596 and read the paper over a cup of coffee, I 0:13:49.716 --> 0:13:52.916 realized they had not told the full story. They had 0:13:52.956 --> 0:13:55.476 told just the first chapter. And the reason is this. 0:13:56.276 --> 0:14:01.196 When you when a neuroscientist finds a or an ion channel, 0:14:01.196 --> 0:14:05.036 biologist finds a mutation of an ion channel, that's just 0:14:05.116 --> 0:14:08.356 the beginning of the story. Because the presence of the 0:14:08.436 --> 0:14:12.956 mutation doesn't necessarily establish that the mutation is causing disease. 0:14:14.036 --> 0:14:17.396 What you need to do and what's industry standard is 0:14:17.676 --> 0:14:20.436 you make the mutant channel, you put it in cells, 0:14:20.836 --> 0:14:23.956 and you find out does the mutation cause a change 0:14:23.996 --> 0:14:27.316 in activity of the mutant channel, and then hopefully you 0:14:27.356 --> 0:14:29.716 can then take the mutant channel, put it in cells 0:14:29.716 --> 0:14:32.596 where it normally is expressed, and ask does it change 0:14:32.636 --> 0:14:35.436 their behavior. They hadn't done any of this stuff. 0:14:35.716 --> 0:14:38.756 So essentially they had identified a correlation, but they had 0:14:38.756 --> 0:14:40.756 not demonstrated that causation. 0:14:41.436 --> 0:14:44.516 Right, yeah, and they hadn't done it. These were very, 0:14:44.596 --> 0:14:49.156 very fine academic dermatologists. We've subsequently become friends. One of 0:14:49.196 --> 0:14:51.956 them spent the sabbatical in my lab. But so what 0:14:52.036 --> 0:14:54.636 needed to be done was what I just said, to 0:14:54.836 --> 0:14:58.956 make the channel and study its physiology. And we had 0:14:58.996 --> 0:15:01.396 the channel in our freezer because we had done all 0:15:01.436 --> 0:15:03.756 the work on the normal channel. So what would have 0:15:03.796 --> 0:15:06.316 taken anyone else a year took us a few months. 0:15:06.636 --> 0:15:09.956 We made the mutant channel, we found that in the 0:15:10.516 --> 0:15:14.356 mutation causes the channel to be overactive, and at that 0:15:14.556 --> 0:15:17.916 point we published it and shortly thereafter got a call 0:15:18.036 --> 0:15:22.556 or an email from the Erythrum Lalgia Association. This is 0:15:23.196 --> 0:15:26.716 a small group of patients with erythrumlalgia. 0:15:26.236 --> 0:15:28.116 Which is man on fire syndrome. 0:15:28.476 --> 0:15:33.276 Yeah, and the large family is in Alabama, Okay, and 0:15:33.916 --> 0:15:37.436 I sent the team down to Alabamas. We spent a 0:15:37.476 --> 0:15:41.716 week examining these patients, getting detailed histories, and most importantly, 0:15:41.756 --> 0:15:46.316 getting blood for DNA analysis. The Erhythmologia Association gave us 0:15:46.316 --> 0:15:49.876 a gift to support our research, but much more important 0:15:49.876 --> 0:15:53.876 than the funding gift, the monetary gift was the gift 0:15:53.916 --> 0:15:58.156 of DNA and these precious histories for correlation with it. 0:15:58.236 --> 0:16:02.556 And it's been a very, very a warm relationship. It's 0:16:02.596 --> 0:16:05.316 taught me a lot about how patients really are, are 0:16:05.356 --> 0:16:08.356 more than patients their partners in our research. 0:16:09.796 --> 0:16:14.396 What did you learn from those patients in Alabama that 0:16:14.476 --> 0:16:15.556 you didn't know already? 0:16:17.156 --> 0:16:21.076 What we learned was now we had a pedigree of 0:16:21.116 --> 0:16:26.316 around sixty individuals in five generations. Half of them had 0:16:26.356 --> 0:16:28.556 the mutation. That's what you expect for a mutation of 0:16:28.596 --> 0:16:32.036 this sort. Every patient you had the mutation had the 0:16:32.076 --> 0:16:35.356 man on fire syndrome. None of the patients without the 0:16:35.436 --> 0:16:38.636 mutation had it. And now putting it together, this was 0:16:38.756 --> 0:16:41.756 rock solid. This is as good as it gets in 0:16:41.876 --> 0:16:44.036 terms of genetic validations. 0:16:44.316 --> 0:16:49.076 So this mutation that all of these people have effects 0:16:49.756 --> 0:16:53.556 the sodium channel in AV one point seven, right, one 0:16:53.596 --> 0:16:56.396 of the ones you had identified, and is it right 0:16:56.476 --> 0:17:02.316 that that inspires you or other researchers to think reasonably, Okay, 0:17:02.396 --> 0:17:05.156 let's try and make a drug that blocks that channel 0:17:05.236 --> 0:17:08.916 and see if it will treat pain or Jacob. 0:17:08.996 --> 0:17:12.316 This is really interesting and it speaks to sort of 0:17:12.316 --> 0:17:16.836 the sociology of science and the way science moves forward 0:17:17.156 --> 0:17:20.356 given the fact that it's very expensive. So we had 0:17:20.436 --> 0:17:25.436 mechanistic validation from studies in a dish for a strong 0:17:25.556 --> 0:17:29.316 strong role of both NAV one point seven and NAV 0:17:29.436 --> 0:17:33.516 one point eight in pain, and we argued that both 0:17:33.596 --> 0:17:36.996 were good targets. In some ways NAV one point eight 0:17:37.036 --> 0:17:39.876 could have been regarded as a stronger target, but what 0:17:39.956 --> 0:17:44.196 we had for NAV one point seven was this very 0:17:44.316 --> 0:17:48.596 very remarkable picture of genetic validation. And in addition to 0:17:48.636 --> 0:17:51.476 our patients with men on fire syndrome, there were other 0:17:52.076 --> 0:17:55.356 families found a few years later with loss of function 0:17:55.596 --> 0:17:58.516 of NAV one point seven. These families don't make NAV 0:17:58.636 --> 0:18:02.196 one point seven, and those people don't feel any pain, 0:18:02.316 --> 0:18:07.916 painless childbirth, painless tooth extractions, painless bone fractures. 0:18:07.956 --> 0:18:10.276 We basically, if you have two much action in NAV 0:18:10.356 --> 0:18:11.956 one point seven, you have a lot of pain, and 0:18:11.996 --> 0:18:14.716 if you have no action there, you have no pain. 0:18:15.116 --> 0:18:17.676 That's correct, very compelling set of evidence. 0:18:18.316 --> 0:18:22.916 It is compelling, and most of the biopharma industry followed 0:18:22.916 --> 0:18:26.276 that evidence and studied one point seven or tried to 0:18:26.276 --> 0:18:30.196 develop drugs that block NAV one point seven. It was 0:18:30.316 --> 0:18:35.116 harder to convince biopharma to study NAV one point eight. 0:18:35.396 --> 0:18:40.436 The physiological evidence was there, but the genetic validation wasn't. 0:18:43.596 --> 0:18:55.396 We'll be back in just a minute. Back in the aughts, 0:18:55.956 --> 0:18:59.556 Pfizer and other pharmaceutical companies started trying to develop drugs 0:18:59.556 --> 0:19:03.436 to treat pain by blocking NAV one point seven, that 0:19:03.596 --> 0:19:07.476 key channel that Stephen and other researchers had identified both 0:19:07.516 --> 0:19:10.636 in the lab and in pall with man on fire syndrome. 0:19:11.396 --> 0:19:15.556 The preliminary results were promising, but kind of shockingly, in 0:19:15.676 --> 0:19:19.396 larger trials, the drugs targeting NAV one point seven did 0:19:19.436 --> 0:19:22.516 not seem to be effective in treating pain. It's not 0:19:22.676 --> 0:19:26.116 entirely clear why the drugs didn't work, but this kind 0:19:26.156 --> 0:19:28.836 of thing in fact happens all the time. Drugs that 0:19:28.876 --> 0:19:31.916 seem perfectly designed just don't end up panning out in 0:19:31.956 --> 0:19:36.516 the real world. But remember NAV one point seven wasn't 0:19:36.556 --> 0:19:40.676 the only key channel involved in pain. There's also NAV 0:19:40.836 --> 0:19:43.956 one point eight, and one drug company decided to bet 0:19:43.996 --> 0:19:44.876 on one point eight. 0:19:45.276 --> 0:19:47.916 The company that's taken this across the goal line as 0:19:47.956 --> 0:19:52.876 a company called Vertex. I'm now advising them. They looked 0:19:52.876 --> 0:19:56.156 at one seven, and they looked at one eight. They 0:19:56.196 --> 0:20:00.236 had a number of failures, and they kept going. They 0:20:00.276 --> 0:20:04.636 invested an immense amount of money when we worked with Pfizer. 0:20:05.196 --> 0:20:08.316 My estimate is that they invested well over two hundred 0:20:08.356 --> 0:20:11.916 and fifty million dollars in their one seven blocker before 0:20:11.916 --> 0:20:17.756 abandoning it. Vertex has studied many compounds, they have very 0:20:17.756 --> 0:20:21.756 gifted scientists, and they made the decision to stay with it. 0:20:21.956 --> 0:20:24.596 They invested much more than that, and they stayed with 0:20:24.676 --> 0:20:29.276 it over over twenty plus years. So I don't know 0:20:29.916 --> 0:20:33.156 who the decision makers were, but they made the right decision. 0:20:33.476 --> 0:20:38.636 So they decided to work on compounds that blocked this 0:20:39.116 --> 0:20:42.716 channel one point eight, another one that you had identified. 0:20:44.036 --> 0:20:46.076 I know you weren't involved in all of it, but 0:20:46.596 --> 0:20:50.556 more or less, what is the story of developing that drug. 0:20:51.676 --> 0:20:55.396 So what this company did and others did is they 0:20:55.436 --> 0:20:59.396 had their target molecule. The question is can you identify 0:20:59.836 --> 0:21:03.556 a molecule potential drug that blocks it, and you can 0:21:03.596 --> 0:21:07.836 put those molecules into a cell. There are robots that 0:21:07.916 --> 0:21:11.396 will look as you screen hundreds of thousands of compounds, 0:21:11.436 --> 0:21:15.796 asking is there something that silences that molecular battery one 0:21:15.916 --> 0:21:16.636 seven or one. 0:21:16.516 --> 0:21:20.036 Eight and you wanted to silence that and nothing else, right, 0:21:20.116 --> 0:21:22.756 that's correct part of that and not have some weirdo 0:21:23.076 --> 0:21:24.996 side effect that's gonna make people sick. 0:21:25.436 --> 0:21:31.236 That's absolutely crucial. But with using these robotic technologies, it's 0:21:31.276 --> 0:21:34.596 possible to find one or two that work. And then 0:21:34.636 --> 0:21:37.356 you say to your chemists, Okay, this is our lead compound, 0:21:37.556 --> 0:21:40.996 make it better, make it orally available, give it the 0:21:41.076 --> 0:21:46.036 right absorption and excretion compounds properties, et cetera, et cetera. 0:21:46.476 --> 0:21:49.676 And so that's how it goes. And then you still 0:21:49.676 --> 0:21:51.836 have a lot of work because you need to demonstrate 0:21:51.916 --> 0:21:55.716 in a dish that the compound silence is the activity 0:21:55.876 --> 0:22:00.356 of pain signaling neurons. Then usually go to rodent models, 0:22:00.516 --> 0:22:03.796 sometimes non human primates, and then the human trials. It's 0:22:03.836 --> 0:22:06.596 a long, long process and they. 0:22:06.436 --> 0:22:08.596 Managed to get through this process, right. So there is 0:22:08.636 --> 0:22:15.116 this drug suzetragene. Yeah, it got FDA approval for at 0:22:15.196 --> 0:22:18.156 least some indications this year, correct. 0:22:18.476 --> 0:22:20.476 Yeah, I think there were a couple of milestones. 0:22:20.716 --> 0:22:20.916 Yeah. 0:22:21.036 --> 0:22:24.676 One was the demonstration even prior to FDA approval that 0:22:24.756 --> 0:22:29.996 it produced a statistically significant reduction in pain in humans. 0:22:30.396 --> 0:22:33.316 So let's talk about that moment. So, you know, it's 0:22:33.316 --> 0:22:35.876 this incredible long road and they have to find the 0:22:35.876 --> 0:22:37.836 compound in testing animals, and they do phase one and 0:22:37.836 --> 0:22:40.596 face two, and then finally there's the giant phase three trial. Right, 0:22:40.596 --> 0:22:42.676 so you're a phase three trial with hundreds of patients 0:22:43.116 --> 0:22:46.196 and then the results come out, Like when did you 0:22:46.276 --> 0:22:49.036 learn the results of this pivotal trial. 0:22:52.796 --> 0:22:56.636 I learned of the results of this pivotal trial when 0:22:56.636 --> 0:23:00.356 a medical journal, the New England Journal of Medicine, said, Steve, 0:23:00.436 --> 0:23:03.996 there's been this pivotal trial. You've done all the work 0:23:04.036 --> 0:23:07.916 on one eight identifying it as a target, and when 0:23:07.956 --> 0:23:11.676 we published the results of the trial, will you write 0:23:11.916 --> 0:23:15.316 an accompanying article. We have a series of articles on 0:23:15.396 --> 0:23:18.716 the science behind the clinical trial and they asked me 0:23:19.156 --> 0:23:19.676 to do that. 0:23:19.916 --> 0:23:23.036 You really didn't know until the New England Journal asked 0:23:23.076 --> 0:23:24.636 you to write an editorial. 0:23:25.356 --> 0:23:27.836 I didn't And what did you think when you saw 0:23:27.876 --> 0:23:28.436 the results? 0:23:29.236 --> 0:23:30.676 I thought, my. 0:23:30.836 --> 0:23:34.516 God, we're getting there. We're not there, but we're getting there. 0:23:34.836 --> 0:23:38.436 If this can be repeated, it's a very important step forward. 0:23:38.636 --> 0:23:41.516 Tell me about both pieces of that. That's like two things, like, 0:23:41.556 --> 0:23:44.636 we're getting there is something, but we're not there is 0:23:44.636 --> 0:23:47.036 also something, So what is the we're getting there piece? 0:23:47.836 --> 0:23:52.436 We're getting there was why I regard their study as 0:23:52.476 --> 0:23:56.596 a milestone. It was proof of concept that by targeting 0:23:56.596 --> 0:24:01.796 a peripheral sodium channel, which is a step toward non addictive, 0:24:02.036 --> 0:24:05.516 non opiate pain therapy, one can reduce pain in humans. 0:24:05.556 --> 0:24:07.956 That in itself is a real milestone. 0:24:08.156 --> 0:24:10.876 And just to be clear, what was the finding specifically 0:24:10.916 --> 0:24:12.996 of this trial, what was the outcome? 0:24:13.356 --> 0:24:18.356 These were two groups of patients with abdominoplasty that's tummy 0:24:18.396 --> 0:24:22.756 tuck surgery and bunyan ectomy, and the reduction in pain 0:24:23.356 --> 0:24:28.956 was statistically significant, about as large as was seen with opiates. 0:24:29.756 --> 0:24:32.076 It was vicd in right, it was some fairly standard 0:24:32.396 --> 0:24:34.916 h yep. So it's like this basically is like for 0:24:34.996 --> 0:24:37.636 these patients, this is about as good as vicotin, which 0:24:37.676 --> 0:24:42.836 is actually great because as we know, opioids are addictive 0:24:42.916 --> 0:24:45.996 and it's a huge problem. And so if you can 0:24:46.076 --> 0:24:48.796 reduce pain in a non addictive way, that seems like 0:24:49.436 --> 0:24:50.436 quite a happy finding. 0:24:50.956 --> 0:24:53.596 So that is a happy finding. It's a contribution to 0:24:53.716 --> 0:24:57.596 clinical medicine. But for me, as a researcher, it's also, 0:24:57.676 --> 0:25:00.956