WEBVTT - Ep 97 "Can we rewrite the human code?" (with Trevor Martin) 0:00:05.120 --> 0:00:08.240 We are defined in large part by the genomes that 0:00:08.280 --> 0:00:11.280 we happen to come to the table with. So what 0:00:11.320 --> 0:00:15.440 does it mean when we can edit our own genomes? 0:00:15.480 --> 0:00:19.360 What does this have to do with viruses or copy pasting, 0:00:19.920 --> 0:00:23.200 or whether we are going to modify the story of 0:00:23.239 --> 0:00:29.040 our own species. This is in our cosmos, and I'm 0:00:29.120 --> 0:00:32.400 David Eagleman. I'm a neuroscientist and author at Stanford And 0:00:32.440 --> 0:00:36.000 in these episodes we sail deeply into our three pound 0:00:36.120 --> 0:00:40.000 universe to uncover some of the most surprising aspects of 0:00:40.040 --> 0:00:54.800 our lives. Today's episode is about the remarkable situation we 0:00:54.880 --> 0:00:58.840 find ourselves in, which is that we now know how 0:00:58.880 --> 0:01:03.480 to read our biological inheritance. Now, this is very easy 0:01:03.520 --> 0:01:05.760 to take for granted because for most of us this 0:01:05.800 --> 0:01:08.640 has been true for our whole lives. But it's a 0:01:08.959 --> 0:01:13.319 very recent ability for our species. It only began in 0:01:13.360 --> 0:01:17.640 the second half of last century. In my postdoctoral fellowship, 0:01:17.720 --> 0:01:21.520 I worked with Francis Crick, who was the co discoverer 0:01:21.920 --> 0:01:26.040 of the structure of DNA. In April of nineteen fifty three, 0:01:26.160 --> 0:01:29.840 he and James Watson published a paper in Nature, and 0:01:29.880 --> 0:01:34.400 in just over a page they proposed the double helix 0:01:34.520 --> 0:01:41.880 structure of DNA, explaining how genetic information is stored and copied. Now, 0:01:41.880 --> 0:01:45.000 there's something about this paper that always makes me tear 0:01:45.160 --> 0:01:48.680 up when I read it, because the insight changed our 0:01:48.760 --> 0:01:52.960 world and almost certainly the future of our species. What 0:01:53.000 --> 0:01:55.960 they realize is that DNA is made of two complimentary 0:01:56.120 --> 0:02:00.640 strands wound around each other, and the bases are which 0:02:00.680 --> 0:02:03.280 just means A on one strand always links with T 0:02:03.520 --> 0:02:06.400 on the other, and C with G. And this gives 0:02:06.440 --> 0:02:10.040 a mechanism for making a xerox copy of the whole thing, 0:02:10.080 --> 0:02:13.360 because you just unwind the two strands and then each 0:02:13.480 --> 0:02:16.240 serves as the template for sticking on new bases in 0:02:16.280 --> 0:02:19.120 the right spots. But what I want to emphasize is 0:02:19.200 --> 0:02:24.240 how new this is. Nineteen fifty three, isn't that long ago? 0:02:24.440 --> 0:02:28.200 World War Two was over, Eisenhower was president of the US, 0:02:28.240 --> 0:02:32.240 and by this point we already had automatic transmission in 0:02:32.360 --> 0:02:37.079 cars and color television and microwave ovens. But we had 0:02:37.200 --> 0:02:41.799 no idea why your ears look like your father's ears, 0:02:42.160 --> 0:02:46.520 or your eyes look like your mother's eyes. Just imagine this, 0:02:46.639 --> 0:02:50.720 before the discovery of the DNA code, how difficult it 0:02:51.120 --> 0:02:58.000 was to understand how inheritance actually happens biologically. People floated 0:02:58.280 --> 0:03:02.160 all kinds of wacky hyppods disease about it, like maybe 0:03:02.400 --> 0:03:07.000 each sperm cell contained a super tiny embryo. But everyone 0:03:07.080 --> 0:03:10.560 knew these models didn't work. And even while people were 0:03:10.960 --> 0:03:15.560 driving cars and watching TV and microwaving, they knew that 0:03:15.720 --> 0:03:20.560 inheritance was a total unknown in science. And then that 0:03:20.720 --> 0:03:24.800 all changed with that very short paper that laid the 0:03:24.880 --> 0:03:31.000 foundation for modern genetics and molecular biology and ultimately technologies 0:03:31.320 --> 0:03:35.160 like gene editing, and so that puts us where we 0:03:35.200 --> 0:03:39.400 are now. For as long as animals have walked this earth, 0:03:39.480 --> 0:03:43.280 we have been shaped by forces beyond our control, by 0:03:43.320 --> 0:03:47.640 the slow hand of evolution, by the accidents of mutation, 0:03:48.240 --> 0:03:53.400 by the blind winnowing of natural selection. The twisting helix 0:03:53.480 --> 0:03:59.360 of our DNA has been sculpted by nature's chisel. But now, 0:03:59.720 --> 0:04:03.320 for the first time, we are holding the chisel in 0:04:03.360 --> 0:04:08.440 our own hands. Just in the last nanosecond of evolutionary time, 0:04:08.960 --> 0:04:14.760 we now command gene editing technologies, things like crisper and 0:04:15.040 --> 0:04:19.640 single base pair editing tools and epigenetic editing tools and 0:04:20.120 --> 0:04:23.400 tools yet to be imagined, and these give us the 0:04:23.560 --> 0:04:28.719 power to rewrite the code of life itself. We can 0:04:29.080 --> 0:04:34.760 correct genetic disorders, we can eliminate inherited diseases, and we 0:04:34.839 --> 0:04:41.520 can presumably even enhance ourselves, pushing beyond the biological boundaries 0:04:41.560 --> 0:04:46.359 that we would have recently assumed are fixed. The rules 0:04:46.440 --> 0:04:52.440 of genetic inheritance were once immutable, but now they are revisable. 0:04:52.800 --> 0:04:57.720 So obviously, with this power comes deep questions. If we 0:04:57.760 --> 0:05:03.120 can edit our genetic destiny, what should we choose to become? 0:05:03.640 --> 0:05:06.240 Do we cure only what ails us? Or do we 0:05:06.320 --> 0:05:11.560 optimize ourselves enhancing features like intelligence and strength and longevity. 0:05:12.200 --> 0:05:15.000 How close are we to doing any of this? Does 0:05:15.040 --> 0:05:19.200 anything happen to the meaning of human struggle? When suffering 0:05:19.279 --> 0:05:23.440 can be edited away? Will we remain the same species 0:05:23.560 --> 0:05:28.280 once we begin sculpting ourselves? And who decides is it 0:05:28.360 --> 0:05:32.719 the scientists at the lab bench, the policymakers and government, 0:05:33.400 --> 0:05:37.680 the parent holding their newborn in their arms. What are 0:05:37.720 --> 0:05:42.520 the ethical and social and existential questions of putting our 0:05:42.640 --> 0:05:48.520 genetic future in human hands? So in today's episode, we're 0:05:48.560 --> 0:05:52.280 going to step into the frontier of gene editing. What 0:05:52.360 --> 0:05:54.279 does it mean to be human when we are no 0:05:54.400 --> 0:05:58.800 longer bound by the limits of our biology. What stories 0:05:58.800 --> 0:06:02.520 will future generation tell about the choices that we make? 0:06:02.640 --> 0:06:06.640 Now the code of life is no longer written in stone, 0:06:07.120 --> 0:06:10.920 so what will we write? So I called my friend 0:06:10.920 --> 0:06:13.840 Trevor Martin, who is the co founder and CEO of 0:06:14.120 --> 0:06:18.040 Mammoth Biosciences, which is based here in the San Francisco 0:06:18.080 --> 0:06:22.159 Bay area. They are building the next generation of Crisper 0:06:22.240 --> 0:06:25.200 products for editing the genome. If you've never heard of 0:06:25.279 --> 0:06:28.160 Crisper or aren't sure what it is, hangtight because we'll 0:06:28.160 --> 0:06:30.440 get to that in a minute. But the quick preview is, 0:06:30.880 --> 0:06:34.560 how do you build a platform to read and write 0:06:34.800 --> 0:06:38.120 the code of life? How do you make tools? So 0:06:38.160 --> 0:06:41.680 you get something like a word processor for the genome 0:06:41.880 --> 0:06:44.240 where you say, look, I just want to hit control 0:06:44.480 --> 0:06:46.840 X to cut a piece of the genome, or control 0:06:46.920 --> 0:06:50.159 V to paste it, and control F to find some 0:06:50.360 --> 0:06:55.080 sequence inside the genome. So here's my conversation with Trevor Martin. 0:07:00.160 --> 0:07:02.920 Technology is some of the most amazing technology we have, 0:07:03.040 --> 0:07:05.880 but it wasn't actually invented by humans. It was merely 0:07:05.880 --> 0:07:07.600 discovered by us. So tell us about that, tell us 0:07:07.600 --> 0:07:08.240 about Crisper. 0:07:08.720 --> 0:07:12.160 Yeah, So, similar to how we have immune systems, actually 0:07:13.520 --> 0:07:17.440 bacteria and small microbes and just teny little organisms. They 0:07:17.480 --> 0:07:21.120 have to defend themselves against invasion as well. Typically viruses 0:07:21.160 --> 0:07:23.920 actually much like us, and one of the ways that 0:07:24.000 --> 0:07:26.880 they evolve to do this is this thing called crisper 0:07:27.120 --> 0:07:30.560 that has become famous, of course for its ability to 0:07:30.600 --> 0:07:35.480 do genetic editing. But fundamentally nature has used these crisper 0:07:35.560 --> 0:07:39.440 type systems to protect themselves from viruses, very similar to 0:07:39.480 --> 0:07:42.280 how our adaptive immune system protects us from viruses. 0:07:42.720 --> 0:07:44.160 And we've kind of ripped that out. 0:07:44.040 --> 0:07:46.040 Of nature and done a ton of engineering on top 0:07:46.080 --> 0:07:49.640 of it to turn it into these technologies that can 0:07:49.680 --> 0:07:53.600 do genomic engineering. But that's kind of fundamentally where it 0:07:53.640 --> 0:07:55.640 came from. And I think it's this beautiful example of 0:07:56.320 --> 0:07:59.600 leveraging billions of years of evolution and combining that with 0:07:59.720 --> 0:08:03.200 human ingenuity and a lot of hard work from a 0:08:03.240 --> 0:08:04.080 lot of scientists. 0:08:04.120 --> 0:08:06.720 So let me get straight. So, so crisper if fits in, 0:08:06.800 --> 0:08:09.800 Let's say a single cell organism, a virus injects some 0:08:09.920 --> 0:08:12.280 DNA and it's got to figure out, hey, that's not mine, 0:08:12.320 --> 0:08:13.960 and then it cuts it up exactly. 0:08:14.000 --> 0:08:15.920 So there's a bunch of complicated steps there. First, it 0:08:15.920 --> 0:08:19.120 has to recognize Hey, that's not mine. Then it has 0:08:19.200 --> 0:08:22.320 to cut it up. And then actually there's a third step, 0:08:22.360 --> 0:08:24.680 which is, hey, I should remember this came and i'd 0:08:24.680 --> 0:08:26.679 want to make sure I protect against it in the future. 0:08:27.040 --> 0:08:29.679 And it's actually funny, that's where the name crisper itself 0:08:29.720 --> 0:08:32.080 comes from, is that I want to protect against the future. 0:08:32.360 --> 0:08:35.840 So CRISPER is actually an acronym stands for clustered regulatory 0:08:35.880 --> 0:08:39.680 interspace short palindromic repeats and this is actually kind of 0:08:39.679 --> 0:08:43.760 the memory of the cell that the crisper systems used 0:08:43.760 --> 0:08:45.960 to say, Hey, these are viruses that have invaded me before, 0:08:46.000 --> 0:08:47.520 and I want to make sure they don't do it again. 0:08:48.120 --> 0:08:52.720 And this happens in unicellular organisms. That's so incredible, Okay, 0:08:52.960 --> 0:08:56.760 And so you started this company Mammoth with the idea 0:08:57.440 --> 0:09:01.400 to take these crisper systems and I prove them from 0:09:01.400 --> 0:09:04.360 what nature has done or search for other ways of 0:09:04.480 --> 0:09:06.000 doing it. So give me a sense of how you 0:09:06.040 --> 0:09:06.920 do that. Yeah. 0:09:06.960 --> 0:09:09.480 So probably the most famous Chrisper system is this thing 0:09:09.520 --> 0:09:12.240 called CAST nine. And this was what one of my 0:09:12.240 --> 0:09:14.840 co founders, Jennifer Dalna, won the Nobel Prize for a 0:09:14.880 --> 0:09:18.679 few years ago. Was the work in terms of really 0:09:18.760 --> 0:09:23.240 characterizing and developing this into a geneomic engineering technology. And 0:09:23.360 --> 0:09:26.560 CAST nine was just one example from a certain class 0:09:26.559 --> 0:09:30.080 of bacteria of this type of crisper technology. And one 0:09:30.120 --> 0:09:33.559 of the fundamental insights of Mammoth is that actually, there 0:09:33.559 --> 0:09:35.959 are all sorts of Christopher technologies out there, because these 0:09:36.000 --> 0:09:40.720 are present and all sorts of microorganisms, bacteria, even large 0:09:40.760 --> 0:09:44.920 viruses archaea. And our insight was, hey, we should look 0:09:45.000 --> 0:09:48.360 through all of these alternative versions of crisper that are 0:09:48.360 --> 0:09:50.760 not CAST nine and do a lot of work to 0:09:50.920 --> 0:09:53.600 develop those, and that could actually have a huge benefit 0:09:53.679 --> 0:09:58.360 for building genomic medicines, for building diagnostics, for improving agriculture. 0:09:58.800 --> 0:10:01.400 And that was kind of a fundamental insight that was 0:10:01.600 --> 0:10:03.600 maybe obvious today, but at the time people were so 0:10:03.640 --> 0:10:06.240 focused on CAST nine that people weren't really looking beyond that. 0:10:06.800 --> 0:10:10.000 So you're looking for things that have already been discovered 0:10:10.040 --> 0:10:14.199 by nature elsewhere, and you're looking for versions of that 0:10:14.200 --> 0:10:16.760 that do what you want in terms of gene editing. 0:10:17.600 --> 0:10:20.120 So the trick there is that you use nature as 0:10:20.120 --> 0:10:23.760 a starting point. And the unfortunate truth is that when 0:10:23.840 --> 0:10:25.520 you take these things and you rip them out of nature, 0:10:25.520 --> 0:10:27.480 actually usually they don't work at all, but they give 0:10:27.480 --> 0:10:29.880 you a starting point. And one of the fundamental insights 0:10:29.920 --> 0:10:32.160 we had was it's not enough just to go into 0:10:32.240 --> 0:10:34.680 nature and to say, ah, okay, what other alternative crispers 0:10:34.679 --> 0:10:37.160 are there? You have to do that, and then you 0:10:37.160 --> 0:10:39.240 have to do a ton of engineering. And we actually 0:10:39.280 --> 0:10:41.040 have a whole floor of our building that has these 0:10:41.080 --> 0:10:43.680 liquid handling robots. They're just running tens of thousands of 0:10:43.679 --> 0:10:45.959 experiments at a time and you just kind of grind 0:10:46.000 --> 0:10:48.480 away and you can use the latest AI techniques combining 0:10:48.520 --> 0:10:50.880 it with the latest and microfluid candling is what those 0:10:50.920 --> 0:10:53.880 robots are called. And it's only with that combination of 0:10:54.000 --> 0:10:57.160 all of that, with this kind of usually very wacky, 0:10:57.240 --> 0:11:00.200 kind of natural starting point. That's the secret sauce one 0:11:00.320 --> 0:11:01.800 or the other is not enough. You have to really 0:11:01.800 --> 0:11:04.480 have both together. And that was the unique insight as well. 0:11:04.559 --> 0:11:08.439 Oh great, okay, And so they're looking for these smaller systems, 0:11:08.480 --> 0:11:10.920 and what's the reason to have them smaller? 0:11:11.440 --> 0:11:14.040 Yeah, So one of the giant challenges of the field 0:11:14.120 --> 0:11:16.640 is how do you deliver these systems to the cells 0:11:16.640 --> 0:11:18.280 that need it the most. So when you and I 0:11:18.440 --> 0:11:20.760 think about genetic medicine, what comes to mind, it's going 0:11:20.800 --> 0:11:23.640 to be things like Alzheimer's, Parkinson's, Huntington's, you know, these 0:11:23.679 --> 0:11:28.040 really debilitating disorders where they can be basically a death 0:11:28.080 --> 0:11:30.360 sentence and you something that's kind of known in your 0:11:30.400 --> 0:11:34.360 genome from birth. And the big problem though, has been 0:11:35.120 --> 0:11:37.559 what the genetic medicine, the crisper field has been focused 0:11:37.559 --> 0:11:40.680 on is a tiny subset of diseases that are typically 0:11:40.720 --> 0:11:43.880 not that and that's amazing for those patients that have 0:11:44.000 --> 0:11:47.280 diseases that are like blood disorders or like certain liver disorders, 0:11:47.280 --> 0:11:49.600 and there's amazing progress in this field, like for example, 0:11:49.840 --> 0:11:53.280 there's now an approved therapy using Crisper for sickle cell 0:11:53.320 --> 0:11:56.319 disease in beta talasmia. Those are overlook diseases with underrepresented 0:11:56.320 --> 0:11:59.280 populations and that's a huge win for the field. But 0:11:59.400 --> 0:12:03.160 the proms of genetic medicine is not just blood disorders 0:12:03.320 --> 0:12:06.520 and liver disorders. The promise is to go to any 0:12:06.520 --> 0:12:08.360 cell in the body and do any kind of edit. 0:12:08.720 --> 0:12:11.040 And that really is what guides us at Maamath that 0:12:11.120 --> 0:12:12.320 means you need to go to the muscle, you need 0:12:12.360 --> 0:12:13.440 to go to the brain, you need to get to 0:12:13.440 --> 0:12:16.080 the heart. And that has been a gigantic challenge, and 0:12:16.120 --> 0:12:19.080 it's because CAST nine is actually a big protein. So 0:12:19.400 --> 0:12:23.000 obviously it's small relative to us, like all proteins, but 0:12:23.120 --> 0:12:25.640 it's really really big on a kind of molecular scale. 0:12:26.080 --> 0:12:28.640 And one of the things that we did is we said, hey, 0:12:28.920 --> 0:12:30.880 could we create a crisper system that's not just a 0:12:30.920 --> 0:12:33.240 little bit smaller than CAST nine, but it's way smaller. 0:12:33.800 --> 0:12:37.679 And that resulted in a thing we called nanocasts nano 0:12:38.640 --> 0:12:40.400 and that was really exciting and there's a lot of 0:12:40.400 --> 0:12:42.800 skepticism in the field, which is great for our patents, 0:12:42.840 --> 0:12:46.040 people like, oh, these will never work. And it required 0:12:46.080 --> 0:12:47.560 a ton of work and a lot of these robots 0:12:47.640 --> 0:12:50.199 doing a lot of work overtime with our scientists. And 0:12:50.360 --> 0:12:52.559 what's cool though, is that now we actually have data 0:12:52.640 --> 0:12:56.160 showing that in monkeys, which is a really high bar. 0:12:56.200 --> 0:12:59.240 It's not you know, cell lines or mice, we actually 0:12:59.280 --> 0:13:04.640 get extremely good editing either equivalent or better than CAST 0:13:04.720 --> 0:13:07.320 nine with these really really tiny systems. And these really 0:13:07.360 --> 0:13:11.120 tiny systems, unlike CAST nine, can actually be delivered anywhere 0:13:11.120 --> 0:13:12.920 in the body, so that's a seed change in terms 0:13:12.920 --> 0:13:14.200 of what's possible. 0:13:14.120 --> 0:13:17.120 And they can be delivered by a virus for example. 0:13:17.360 --> 0:13:19.400 Yeah, So a classic way that you can deliver to 0:13:20.120 --> 0:13:23.240 muscle or brain, for example, would be with a thing 0:13:23.320 --> 0:13:26.240 called AV which is another acronym that stands for adno 0:13:26.280 --> 0:13:29.200 associated virus. And one of the big limitations of this 0:13:29.360 --> 0:13:31.000 is that it has a very strict size limit. Like 0:13:31.040 --> 0:13:33.440 you can think of it as like a semi trailer 0:13:33.480 --> 0:13:35.120 truck where you can only fit so much in the 0:13:35.160 --> 0:13:38.080 back and cast nine is just way too big to 0:13:38.120 --> 0:13:42.480 fit inside it. But these nanocast style systems don't just fit, 0:13:42.520 --> 0:13:44.160 but they actually have a ton of room to spare. 0:13:44.760 --> 0:13:46.480 And the room to spare is really important as well, 0:13:46.520 --> 0:13:48.480 because when you're a scientist you can start to think 0:13:48.520 --> 0:13:51.040 really creatively about how do I use that. And one 0:13:51.080 --> 0:13:53.760 of the key ways that we use that is to 0:13:53.920 --> 0:13:56.640 fit in the machinery to do different types of edits. 0:13:56.760 --> 0:13:59.679 So people may have heard of things like base editing 0:13:59.760 --> 0:14:03.120 or writing or epigenetic editing. These are all techniques that 0:14:03.360 --> 0:14:06.480 take the fundamental Chrisper system and say, hey, what if 0:14:06.840 --> 0:14:09.720 instead of editing the genome as this like word document 0:14:09.760 --> 0:14:12.280 and only being able to delete sentences, what if we 0:14:12.320 --> 0:14:14.439 could add a paragraph, What if we could spell check 0:14:14.480 --> 0:14:18.679 a word? What if we could italicize a sentence. These 0:14:18.720 --> 0:14:20.960 are all kind of different types of edits you can 0:14:21.000 --> 0:14:23.920 do in the genome, and they require delivery have even 0:14:23.920 --> 0:14:27.240 more machinery, and that means that Mammoth has really been 0:14:27.280 --> 0:14:30.080 the only company that's been able to actually deliver not 0:14:30.120 --> 0:14:32.720 just anywhere in the body, but also deliver any kind 0:14:32.720 --> 0:14:34.760 of edit anywhere in the body. And I think it's 0:14:34.920 --> 0:14:36.360 you have to do both of those if you really 0:14:36.360 --> 0:14:38.040 want to address all genetic. 0:14:37.640 --> 0:14:42.120 Disease, and any kind of edit means reading or writing. Yeah. 0:14:42.160 --> 0:14:43.800 So we also had a lot of work we did 0:14:43.960 --> 0:14:47.320 on diagnostics as well, and during the pandemic we actually 0:14:47.320 --> 0:14:50.800 got emergency use authorization for a Chrisper based COVID test. 0:14:51.160 --> 0:14:52.760 So we're super proud of the work we did there. 0:14:52.840 --> 0:14:54.640 The focus of the company today is very much on 0:14:54.680 --> 0:14:58.520 the writing side, but definitely I think there's huge potential 0:14:58.520 --> 0:14:59.760 on the reading side. 0:15:00.960 --> 0:15:03.960 As well. Give us an example of the reading side. 0:15:04.240 --> 0:15:07.280 Yeah, so basically there, instead of using the Chrisper systems 0:15:07.320 --> 0:15:10.480 to change the DNA, you can use the Chrispher systems 0:15:10.520 --> 0:15:14.160 to send out some signal that there's a certain sequence present, 0:15:14.240 --> 0:15:18.360 so to say, hey, I found the word potato and 0:15:18.640 --> 0:15:21.600 it'll glow green if it finds potato, and it won't 0:15:21.640 --> 0:15:24.720 show any color if it doesn't. And that's a very 0:15:24.760 --> 0:15:27.400 powerful kind of concept, and that means you could do 0:15:27.480 --> 0:15:33.080 really low cost, high accuracy style molecular testing, and that's 0:15:33.080 --> 0:15:35.560 something that we're very bullish on long term. But as 0:15:35.560 --> 0:15:38.960 a company, obviously you have to focus on a certain area, 0:15:39.000 --> 0:15:42.040 and already, you know, trying to tackle all genetic diseases 0:15:43.360 --> 0:15:45.520 a limited set of focus to begin with, So that's 0:15:45.560 --> 0:15:48.400 kind of kind of where we're focusing our efforts otherwise. 0:15:48.520 --> 0:15:50.240 Right, So let me come back to something you said. So, 0:15:50.320 --> 0:15:53.400 as far as the writing goes, you can write single 0:15:53.440 --> 0:15:57.240 base pairs, you can write something longer. You can write 0:15:57.320 --> 0:15:59.920 whole genes or collections of genes. Ice. 0:16:00.720 --> 0:16:03.600 Yeah, you could have all insert an entire gene. You 0:16:03.640 --> 0:16:06.880 could kind of change a single base pair out of 0:16:06.920 --> 0:16:09.200 all the billions of base pairs in your genome. And 0:16:09.200 --> 0:16:12.280 that's an important philosophical point as well, because I think 0:16:12.600 --> 0:16:14.960 in biotech we often get so enamored with technology, so 0:16:14.960 --> 0:16:17.120 we always think in terms of like, ah, this is 0:16:17.160 --> 0:16:20.040 a base editing technology, or this is a gene writing technology, 0:16:20.040 --> 0:16:22.320 This is like Deuvile's trand break if you're patient. You 0:16:22.360 --> 0:16:25.840 don't care, Right, I have a disease and I don't 0:16:25.840 --> 0:16:27.920 care how you're doing it. I just want you to 0:16:28.120 --> 0:16:30.520 cure or treat my disease. In our case, we can 0:16:30.560 --> 0:16:34.400 actually cure it. And I think that's where our philosophy is. 0:16:34.440 --> 0:16:38.800 Will actually develop many techniques, all the techniques, and actually 0:16:38.800 --> 0:16:40.640 be able to deliver them. And then for any disease, 0:16:40.680 --> 0:16:42.600 we might try a couple of different ways of doing it. 0:16:42.640 --> 0:16:43.920 We might say, ah, there's like a way to do 0:16:44.000 --> 0:16:45.240 it by base editing, there's a way to do it 0:16:45.280 --> 0:16:47.160 by epigenetic editing. We're not sure which one's gonna be 0:16:47.200 --> 0:16:48.760 the best, but we'll try both and see which one 0:16:48.800 --> 0:16:52.320 actually works well. And that's very different from philosophy from 0:16:52.320 --> 0:16:55.240 typical biotech, where you try and create like ten companies 0:16:55.240 --> 0:16:57.720 whe each company is doing a different method and I 0:16:57.720 --> 0:17:00.960 think that's all fine and well in some ways, maybe 0:17:00.960 --> 0:17:06.960 also from like how do you maximize like investor involvement 0:17:06.960 --> 0:17:09.960 in different companies, But from a I think long term 0:17:09.960 --> 0:17:12.400 company building and from a patient perspective, I think that's 0:17:12.480 --> 0:17:14.120 very much like the wrong way to go about it. 0:17:14.240 --> 0:17:17.600 Yeah, So tell us about diseases in the brain and 0:17:17.760 --> 0:17:20.639 what you're thinking of, is the future of those maybe 0:17:20.720 --> 0:17:23.840 in give me a sense of three years, ten years 0:17:23.880 --> 0:17:25.679 where we'll be with that. Yeah. 0:17:25.720 --> 0:17:28.399 So to start with a specific example of one that 0:17:28.480 --> 0:17:32.080 I think kind of is frankly a condemnation of the 0:17:32.080 --> 0:17:35.280 genetic medicine space is Huntington's disease. So this is a 0:17:35.320 --> 0:17:38.320 disease that was mapped, Oh my god, not just decades ago, 0:17:38.320 --> 0:17:40.840 like half a century ago, like I think in like 0:17:40.880 --> 0:17:44.200 the late eighties, and it was mapp They mapped it 0:17:44.280 --> 0:17:46.800 with microsatellites, I believe, on giant gels that were in 0:17:46.880 --> 0:17:48.960 the lab. Right, this is like, you know, not pre computer, 0:17:49.280 --> 0:17:52.240 it's like Wexler, right, Yeah, but you know, very very 0:17:52.240 --> 0:17:56.480 early technologies, and we have understood, you know, fundamentally kind 0:17:56.480 --> 0:17:58.720 of the genetic base of Huntington's for a very long time, 0:17:59.160 --> 0:18:01.720 and still today people die from this every single year, 0:18:02.440 --> 0:18:06.600 and it's a horrible disease where basically, if you have 0:18:06.680 --> 0:18:10.040 a certain genomic sequence, then you know, typically in your thirties, 0:18:10.080 --> 0:18:13.520 you'll have the accumulation of a certain protein and you'll 0:18:13.800 --> 0:18:19.320 pass away. And it's infuriating, honestly that we understand the 0:18:19.359 --> 0:18:22.640 genetic cause of this and we can do nothing about it. 0:18:23.040 --> 0:18:25.800 So I think the genetic medicine space and Crisper in 0:18:25.840 --> 0:18:29.760 particular will have arrived and will have really I think, 0:18:29.920 --> 0:18:33.080 done a hallmark deliverance of like what the true potential 0:18:33.200 --> 0:18:35.240 is the day the last Huntington patient dies? 0:18:35.440 --> 0:18:37.000 Agreed? When is that? Do you think? 0:18:37.520 --> 0:18:40.800 Yeah? So, I think it's definitely within sight. I'm not 0:18:40.840 --> 0:18:42.479 going to give a specific. 0:18:42.960 --> 0:18:44.360 Three years or five or ten. 0:18:44.800 --> 0:18:49.240 Yeah, it's probably not three, but it better not be ten. Okay, Yeah, 0:18:49.440 --> 0:18:52.040 I think in general, like you can kind of see 0:18:52.040 --> 0:18:53.760 the steps that you need to take and it's a 0:18:53.800 --> 0:18:55.080 matter of walking down the path. 0:18:55.280 --> 0:18:58.040 Got it? And what has been the problem? Given that 0:18:58.119 --> 0:19:01.359 we have Chrisper cast technology and that we have known 0:19:01.440 --> 0:19:04.879 the gene for Huntington's it's monogenetic, what has been the 0:19:04.880 --> 0:19:05.720 hold up? Yeah? 0:19:05.760 --> 0:19:07.280 So I think there's a lot of things you have 0:19:07.320 --> 0:19:09.959 to think about. One is what type of edit are 0:19:09.960 --> 0:19:12.480 you going to do? Like can you just knock out 0:19:12.480 --> 0:19:14.280 the whole Huntington gene or do you have to think 0:19:14.359 --> 0:19:18.000 more creatively about modifying it in a more subtle way. 0:19:18.840 --> 0:19:21.360 Then the second one is can you actually get the 0:19:21.600 --> 0:19:24.720 editing machinery to the cells of interest? Can you actually 0:19:24.720 --> 0:19:27.320 get this into the brain, and those are two of 0:19:27.359 --> 0:19:30.320 the most obvious problems. I think that we've really thought 0:19:30.320 --> 0:19:33.199 deeply about mammoth and like the general sense, not just 0:19:33.320 --> 0:19:36.600 running to the before any brain disease. And I think 0:19:36.640 --> 0:19:40.080 that's where the technologies we've developed, like these ultracompact systems 0:19:40.080 --> 0:19:42.560 and having all these different editing modalities I think can 0:19:42.560 --> 0:19:43.440 make a huge difference. 0:19:43.480 --> 0:19:46.160 Potentially got it and so it sounds like you've got 0:19:46.200 --> 0:19:49.399 the can we get it to the right cells? It 0:19:49.400 --> 0:19:52.280 sounds like you've got a beat on that. But as 0:19:52.280 --> 0:19:54.440 far as what edit to make is that something you're 0:19:54.520 --> 0:19:55.760 experimenting with, well, I. 0:19:55.720 --> 0:19:58.439 Think that's definitely something where we have a lot of 0:19:58.600 --> 0:20:01.600 great ideas for any about like different types, and that's 0:20:01.640 --> 0:20:03.960 where we're very unique because we can actually try different 0:20:04.000 --> 0:20:07.400 methods and we can say, hey, this is our hypothesis, 0:20:07.840 --> 0:20:10.479 prove it out or not, but not have a hammer 0:20:10.520 --> 0:20:12.560 and everything else to look like a nail, which is 0:20:12.800 --> 0:20:14.800 very very classic not just a biotype but a deep 0:20:14.800 --> 0:20:17.399 tech in general. And you know the classic startup advice 0:20:17.400 --> 0:20:19.639 of like find the problem first and then figure out 0:20:19.640 --> 0:20:21.680 the solution. There's a lot of reasons why that doesn't 0:20:21.680 --> 0:20:23.720 work in deep tech right, Like, sometimes you really do 0:20:23.840 --> 0:20:25.960 have to kind of build the thing and then figure 0:20:25.960 --> 0:20:28.840 out what the best application is. But that being said, 0:20:28.840 --> 0:20:31.360 the more you can mitigate that, that's a very powerful 0:20:31.400 --> 0:20:35.280 idea to get away from hammer, you know, squint at 0:20:35.320 --> 0:20:36.400 everything until it's a nail. 0:20:36.520 --> 0:20:54.560 Yeah, let me make sure I understand. What's the way 0:20:54.600 --> 0:20:56.920 that you can test out these different hypothesies. Do you 0:20:57.000 --> 0:20:58.560 have an animal model of Huntington's. 0:20:58.600 --> 0:21:02.399 Yeah, it's gonna so not speaking specifically about Huntington's, but 0:21:02.520 --> 0:21:05.360 just generally in terms of different diseases. Some diseases you'll 0:21:05.359 --> 0:21:07.600 have an animal model that's really good, and that means 0:21:07.680 --> 0:21:10.000 you can actually try it out like in mice or 0:21:10.000 --> 0:21:12.119 maybe even monkeys, and like really get a lot of 0:21:12.119 --> 0:21:15.360 confidence for others. Honestly, you don't have anything. Maybe there's 0:21:15.400 --> 0:21:17.119 no animal models, so like you have to try it 0:21:17.160 --> 0:21:19.239 out in cell lines and then kind of make your 0:21:19.240 --> 0:21:20.680 best guess about what's going to work. 0:21:20.720 --> 0:21:21.040 Well. 0:21:21.119 --> 0:21:24.320 So it's very varied, i'd say, across different diseases and 0:21:24.359 --> 0:21:28.040 across different tissues, but you want to have as many 0:21:28.119 --> 0:21:30.440 shots on goal I think as possible because then when 0:21:30.480 --> 0:21:33.080 you go to humans, maybe you'll find something surprising, Like 0:21:33.119 --> 0:21:35.040 you only had cell line work and then it doesn't 0:21:35.080 --> 0:21:37.400 work in humans. And if you only have one technique, 0:21:37.400 --> 0:21:40.040 you're kind of out of luck. But if you have, 0:21:40.119 --> 0:21:42.880 like you know, a backup or a backup to the backup, 0:21:43.280 --> 0:21:45.040 that means you can actually go in and you know, 0:21:45.440 --> 0:21:46.800