We are defined in large part by the genomes that we happen to come to the table with. So what does it mean when we can edit our own genomes? What does this have to do with viruses or copy pasting, or whether we are going to modify the story of our own species. This is in our cosmos, and I'm David Eagleman. I'm a neuroscientist and author at Stanford And in these episodes we sail deeply into our three pound universe to uncover some of the most surprising aspects of our lives. Today's episode is about the remarkable situation we find ourselves in, which is that we now know how to read our biological inheritance. Now, this is very easy to take for granted because for most of us this has been true for our whole lives. But it's a very recent ability for our species. It only began in the second half of last century. In my postdoctoral fellowship, I worked with Francis Crick, who was the co discoverer of the structure of DNA. In April of nineteen fifty three, he and James Watson published a paper in Nature, and in just over a page they proposed the double helix structure of DNA, explaining how genetic information is stored and copied. Now, there's something about this paper that always makes me tear up when I read it, because the insight changed our world and almost certainly the future of our species. What they realize is that DNA is made of two complimentary strands wound around each other, and the bases are which just means A on one strand always links with T on the other, and C with G. And this gives a mechanism for making a xerox copy of the whole thing, because you just unwind the two strands and then each serves as the template for sticking on new bases in the right spots. But what I want to emphasize is how new this is. Nineteen fifty three, isn't that long ago? World War Two was over, Eisenhower was president of the US, and by this point we already had automatic transmission in cars and color television and microwave ovens. But we had no idea why your ears look like your father's ears, or your eyes look like your mother's eyes. Just imagine this, before the discovery of the DNA code, how difficult it was to understand how inheritance actually happens biologically. People floated all kinds of wacky hyppods disease about it, like maybe each sperm cell contained a super tiny embryo. But everyone knew these models didn't work. And even while people were driving cars and watching TV and microwaving, they knew that inheritance was a total unknown in science. And then that all changed with that very short paper that laid the foundation for modern genetics and molecular biology and ultimately technologies like gene editing, and so that puts us where we are now. For as long as animals have walked this earth, we have been shaped by forces beyond our control, by the slow hand of evolution, by the accidents of mutation, by the blind winnowing of natural selection. The twisting helix of our DNA has been sculpted by nature's chisel. But now, for the first time, we are holding the chisel in our own hands. Just in the last nanosecond of evolutionary time, we now command gene editing technologies, things like crisper and single base pair editing tools and epigenetic editing tools and tools yet to be imagined, and these give us the power to rewrite the code of life itself. We can correct genetic disorders, we can eliminate inherited diseases, and we can presumably even enhance ourselves, pushing beyond the biological boundaries that we would have recently assumed are fixed. The rules of genetic inheritance were once immutable, but now they are revisable. So obviously, with this power comes deep questions. If we can edit our genetic destiny, what should we choose to become? Do we cure only what ails us? Or do we optimize ourselves enhancing features like intelligence and strength and longevity. How close are we to doing any of this? Does anything happen to the meaning of human struggle? When suffering can be edited away? Will we remain the same species once we begin sculpting ourselves? And who decides is it the scientists at the lab bench, the policymakers and government, the parent holding their newborn in their arms. What are the ethical and social and existential questions of putting our genetic future in human hands? So in today's episode, we're going to step into the frontier of gene editing. What does it mean to be human when we are no longer bound by the limits of our biology. What stories will future generation tell about the choices that we make? Now the code of life is no longer written in stone, so what will we write? So I called my friend Trevor Martin, who is the co founder and CEO of Mammoth Biosciences, which is based here in the San Francisco Bay area. They are building the next generation of Crisper products for editing the genome. If you've never heard of Crisper or aren't sure what it is, hangtight because we'll get to that in a minute. But the quick preview is, how do you build a platform to read and write the code of life? How do you make tools? So you get something like a word processor for the genome where you say, look, I just want to hit control X to cut a piece of the genome, or control V to paste it, and control F to find some sequence inside the genome. So here's my conversation with Trevor Martin. Technology is some of the most amazing technology we have, but it wasn't actually invented by humans. It was merely discovered by us. So tell us about that, tell us about Crisper.

We are defined in large part by the genomes that we happen to come to the table with. So what does it mean when we can edit our own genomes? What does this have to do with viruses or copy pasting, or whether we are going to modify the story of our own species. This is in our cosmos, and I'm David Eagleman. I'm a neuroscientist and author at Stanford And in these episodes we sail deeply into our three pound universe to uncover some of the most surprising aspects of our lives. Today's episode is about the remarkable situation we find ourselves in, which is that we now know how to read our biological inheritance. Now, this is very easy to take for granted because for most of us this has been true for our whole lives. But it's a very recent ability for our species. It only began in the second half of last century. In my postdoctoral fellowship, I worked with Francis Crick, who was the co discoverer of the structure of DNA. In April of nineteen fifty three, he and James Watson published a paper in Nature, and in just over a page they proposed the double helix structure of DNA, explaining how genetic information is stored and copied. Now, there's something about this paper that always makes me tear up when I read it, because the insight changed our world and almost certainly the future of our species. What they realize is that DNA is made of two complimentary strands wound around each other, and the bases are which just means A on one strand always links with T on the other, and C with G. And this gives a mechanism for making a xerox copy of the whole thing, because you just unwind the two strands and then each serves as the template for sticking on new bases in the right spots. But what I want to emphasize is how new this is. Nineteen fifty three, isn't that long ago? World War Two was over, Eisenhower was president of the US, and by this point we already had automatic transmission in cars and color television and microwave ovens. But we had no idea why your ears look like your father's ears, or your eyes look like your mother's eyes. Just imagine this, before the discovery of the DNA code, how difficult it was to understand how inheritance actually happens biologically. People floated all kinds of wacky hyppods disease about it, like maybe each sperm cell contained a super tiny embryo. But everyone knew these models didn't work. And even while people were driving cars and watching TV and microwaving, they knew that inheritance was a total unknown in science. And then that all changed with that very short paper that laid the foundation for modern genetics and molecular biology and ultimately technologies like gene editing, and so that puts us where we are now. For as long as animals have walked this earth, we have been shaped by forces beyond our control, by the slow hand of evolution, by the accidents of mutation, by the blind winnowing of natural selection. The twisting helix of our DNA has been sculpted by nature's chisel. But now, for the first time, we are holding the chisel in our own hands. Just in the last nanosecond of evolutionary time, we now command gene editing technologies, things like crisper and single base pair editing tools and epigenetic editing tools and tools yet to be imagined, and these give us the power to rewrite the code of life itself. We can correct genetic disorders, we can eliminate inherited diseases, and we can presumably even enhance ourselves, pushing beyond the biological boundaries that we would have recently assumed are fixed. The rules of genetic inheritance were once immutable, but now they are revisable. So obviously, with this power comes deep questions. If we can edit our genetic destiny, what should we choose to become? Do we cure only what ails us? Or do we optimize ourselves enhancing features like intelligence and strength and longevity. How close are we to doing any of this? Does anything happen to the meaning of human struggle? When suffering can be edited away? Will we remain the same species once we begin sculpting ourselves? And who decides is it the scientists at the lab bench, the policymakers and government, the parent holding their newborn in their arms. What are the ethical and social and existential questions of putting our genetic future in human hands? So in today's episode, we're going to step into the frontier of gene editing. What does it mean to be human when we are no longer bound by the limits of our biology. What stories will future generation tell about the choices that we make? Now the code of life is no longer written in stone, so what will we write? So I called my friend Trevor Martin, who is the co founder and CEO of Mammoth Biosciences, which is based here in the San Francisco Bay area. They are building the next generation of Crisper products for editing the genome. If you've never heard of Crisper or aren't sure what it is, hangtight because we'll get to that in a minute. But the quick preview is, how do you build a platform to read and write the code of life? How do you make tools? So you get something like a word processor for the genome where you say, look, I just want to hit control X to cut a piece of the genome, or control V to paste it, and control F to find some sequence inside the genome. So here's my conversation with Trevor Martin. Technology is some of the most amazing technology we have, but it wasn't actually invented by humans. It was merely discovered by us. So tell us about that, tell us about Crisper.

Yeah, So, similar to how we have immune systems, actually bacteria and small microbes and just teny little organisms. They have to defend themselves against invasion as well. Typically viruses actually much like us, and one of the ways that they evolve to do this is this thing called crisper that has become famous, of course for its ability to do genetic editing. But fundamentally nature has used these crisper type systems to protect themselves from viruses, very similar to how our adaptive immune system protects us from viruses.

Yeah, So, similar to how we have immune systems, actually bacteria and small microbes and just teny little organisms. They have to defend themselves against invasion as well. Typically viruses actually much like us, and one of the ways that they evolve to do this is this thing called crisper that has become famous, of course for its ability to do genetic editing. But fundamentally nature has used these crisper type systems to protect themselves from viruses, very similar to how our adaptive immune system protects us from viruses.

And we've kind of ripped that out.

And we've kind of ripped that out.

Of nature and done a ton of engineering on top of it to turn it into these technologies that can do genomic engineering. But that's kind of fundamentally where it came from. And I think it's this beautiful example of leveraging billions of years of evolution and combining that with human ingenuity and a lot of hard work from a lot of scientists.

Of nature and done a ton of engineering on top of it to turn it into these technologies that can do genomic engineering. But that's kind of fundamentally where it came from. And I think it's this beautiful example of leveraging billions of years of evolution and combining that with human ingenuity and a lot of hard work from a lot of scientists.

So let me get straight. So, so crisper if fits in, Let's say a single cell organism, a virus injects some DNA and it's got to figure out, hey, that's not mine, and then it cuts it up exactly.

So let me get straight. So, so crisper if fits in, Let's say a single cell organism, a virus injects some DNA and it's got to figure out, hey, that's not mine, and then it cuts it up exactly.

So there's a bunch of complicated steps there. First, it has to recognize Hey, that's not mine. Then it has to cut it up. And then actually there's a third step, which is, hey, I should remember this came and i'd want to make sure I protect against it in the future. And it's actually funny, that's where the name crisper itself comes from, is that I want to protect against the future. So CRISPER is actually an acronym stands for clustered regulatory interspace short palindromic repeats and this is actually kind of the memory of the cell that the crisper systems used to say, Hey, these are viruses that have invaded me before, and I want to make sure they don't do it again.

So there's a bunch of complicated steps there. First, it has to recognize Hey, that's not mine. Then it has to cut it up. And then actually there's a third step, which is, hey, I should remember this came and i'd want to make sure I protect against it in the future. And it's actually funny, that's where the name crisper itself comes from, is that I want to protect against the future. So CRISPER is actually an acronym stands for clustered regulatory interspace short palindromic repeats and this is actually kind of the memory of the cell that the crisper systems used to say, Hey, these are viruses that have invaded me before, and I want to make sure they don't do it again.

And this happens in unicellular organisms. That's so incredible, Okay, And so you started this company Mammoth with the idea to take these crisper systems and I prove them from what nature has done or search for other ways of doing it. So give me a sense of how you do that. Yeah.

And this happens in unicellular organisms. That's so incredible, Okay, And so you started this company Mammoth with the idea to take these crisper systems and I prove them from what nature has done or search for other ways of doing it. So give me a sense of how you do that. Yeah.

So probably the most famous Chrisper system is this thing called CAST nine. And this was what one of my co founders, Jennifer Dalna, won the Nobel Prize for a few years ago. Was the work in terms of really characterizing and developing this into a geneomic engineering technology. And CAST nine was just one example from a certain class of bacteria of this type of crisper technology. And one of the fundamental insights of Mammoth is that actually, there are all sorts of Christopher technologies out there, because these are present and all sorts of microorganisms, bacteria, even large viruses archaea. And our insight was, hey, we should look through all of these alternative versions of crisper that are not CAST nine and do a lot of work to develop those, and that could actually have a huge benefit for building genomic medicines, for building diagnostics, for improving agriculture. And that was kind of a fundamental insight that was maybe obvious today, but at the time people were so focused on CAST nine that people weren't really looking beyond that.

So probably the most famous Chrisper system is this thing called CAST nine. And this was what one of my co founders, Jennifer Dalna, won the Nobel Prize for a few years ago. Was the work in terms of really characterizing and developing this into a geneomic engineering technology. And CAST nine was just one example from a certain class of bacteria of this type of crisper technology. And one of the fundamental insights of Mammoth is that actually, there are all sorts of Christopher technologies out there, because these are present and all sorts of microorganisms, bacteria, even large viruses archaea. And our insight was, hey, we should look through all of these alternative versions of crisper that are not CAST nine and do a lot of work to develop those, and that could actually have a huge benefit for building genomic medicines, for building diagnostics, for improving agriculture. And that was kind of a fundamental insight that was maybe obvious today, but at the time people were so focused on CAST nine that people weren't really looking beyond that.

So you're looking for things that have already been discovered by nature elsewhere, and you're looking for versions of that that do what you want in terms of gene editing.

So you're looking for things that have already been discovered by nature elsewhere, and you're looking for versions of that that do what you want in terms of gene editing.

So the trick there is that you use nature as a starting point. And the unfortunate truth is that when you take these things and you rip them out of nature, actually usually they don't work at all, but they give you a starting point. And one of the fundamental insights we had was it's not enough just to go into nature and to say, ah, okay, what other alternative crispers are there? You have to do that, and then you have to do a ton of engineering. And we actually have a whole floor of our building that has these liquid handling robots. They're just running tens of thousands of experiments at a time and you just kind of grind away and you can use the latest AI techniques combining it with the latest and microfluid candling is what those robots are called. And it's only with that combination of all of that, with this kind of usually very wacky, kind of natural starting point. That's the secret sauce one or the other is not enough. You have to really have both together. And that was the unique insight as well.

So the trick there is that you use nature as a starting point. And the unfortunate truth is that when you take these things and you rip them out of nature, actually usually they don't work at all, but they give you a starting point. And one of the fundamental insights we had was it's not enough just to go into nature and to say, ah, okay, what other alternative crispers are there? You have to do that, and then you have to do a ton of engineering. And we actually have a whole floor of our building that has these liquid handling robots. They're just running tens of thousands of experiments at a time and you just kind of grind away and you can use the latest AI techniques combining it with the latest and microfluid candling is what those robots are called. And it's only with that combination of all of that, with this kind of usually very wacky, kind of natural starting point. That's the secret sauce one or the other is not enough. You have to really have both together. And that was the unique insight as well.

Oh great, okay, And so they're looking for these smaller systems, and what's the reason to have them smaller?

Oh great, okay, And so they're looking for these smaller systems, and what's the reason to have them smaller?

Yeah, So one of the giant challenges of the field is how do you deliver these systems to the cells that need it the most. So when you and I think about genetic medicine, what comes to mind, it's going to be things like Alzheimer's, Parkinson's, Huntington's, you know, these really debilitating disorders where they can be basically a death sentence and you something that's kind of known in your genome from birth. And the big problem though, has been what the genetic medicine, the crisper field has been focused on is a tiny subset of diseases that are typically not that and that's amazing for those patients that have diseases that are like blood disorders or like certain liver disorders, and there's amazing progress in this field, like for example, there's now an approved therapy using Crisper for sickle cell disease in beta talasmia. Those are overlook diseases with underrepresented populations and that's a huge win for the field. But the proms of genetic medicine is not just blood disorders and liver disorders. The promise is to go to any cell in the body and do any kind of edit. And that really is what guides us at Maamath that means you need to go to the muscle, you need to go to the brain, you need to get to the heart. And that has been a gigantic challenge, and it's because CAST nine is actually a big protein. So obviously it's small relative to us, like all proteins, but it's really really big on a kind of molecular scale. And one of the things that we did is we said, hey, could we create a crisper system that's not just a little bit smaller than CAST nine, but it's way smaller. And that resulted in a thing we called nanocasts nano and that was really exciting and there's a lot of skepticism in the field, which is great for our patents, people like, oh, these will never work. And it required a ton of work and a lot of these robots doing a lot of work overtime with our scientists. And what's cool though, is that now we actually have data showing that in monkeys, which is a really high bar. It's not you know, cell lines or mice, we actually get extremely good editing either equivalent or better than CAST nine with these really really tiny systems. And these really tiny systems, unlike CAST nine, can actually be delivered anywhere in the body, so that's a seed change in terms of what's possible.

Yeah, So one of the giant challenges of the field is how do you deliver these systems to the cells that need it the most. So when you and I think about genetic medicine, what comes to mind, it's going to be things like Alzheimer's, Parkinson's, Huntington's, you know, these really debilitating disorders where they can be basically a death sentence and you something that's kind of known in your genome from birth. And the big problem though, has been what the genetic medicine, the crisper field has been focused on is a tiny subset of diseases that are typically not that and that's amazing for those patients that have diseases that are like blood disorders or like certain liver disorders, and there's amazing progress in this field, like for example, there's now an approved therapy using Crisper for sickle cell disease in beta talasmia. Those are overlook diseases with underrepresented populations and that's a huge win for the field. But the proms of genetic medicine is not just blood disorders and liver disorders. The promise is to go to any cell in the body and do any kind of edit. And that really is what guides us at Maamath that means you need to go to the muscle, you need to go to the brain, you need to get to the heart. And that has been a gigantic challenge, and it's because CAST nine is actually a big protein. So obviously it's small relative to us, like all proteins, but it's really really big on a kind of molecular scale. And one of the things that we did is we said, hey, could we create a crisper system that's not just a little bit smaller than CAST nine, but it's way smaller. And that resulted in a thing we called nanocasts nano and that was really exciting and there's a lot of skepticism in the field, which is great for our patents, people like, oh, these will never work. And it required a ton of work and a lot of these robots doing a lot of work overtime with our scientists. And what's cool though, is that now we actually have data showing that in monkeys, which is a really high bar. It's not you know, cell lines or mice, we actually get extremely good editing either equivalent or better than CAST nine with these really really tiny systems. And these really tiny systems, unlike CAST nine, can actually be delivered anywhere in the body, so that's a seed change in terms of what's possible.

And they can be delivered by a virus for example.

And they can be delivered by a virus for example.

Yeah, So a classic way that you can deliver to muscle or brain, for example, would be with a thing called AV which is another acronym that stands for adno associated virus. And one of the big limitations of this is that it has a very strict size limit. Like you can think of it as like a semi trailer truck where you can only fit so much in the back and cast nine is just way too big to fit inside it. But these nanocast style systems don't just fit, but they actually have a ton of room to spare. And the room to spare is really important as well, because when you're a scientist you can start to think really creatively about how do I use that. And one of the key ways that we use that is to fit in the machinery to do different types of edits. So people may have heard of things like base editing or writing or epigenetic editing. These are all techniques that take the fundamental Chrisper system and say, hey, what if instead of editing the genome as this like word document and only being able to delete sentences, what if we could add a paragraph, What if we could spell check a word? What if we could italicize a sentence. These are all kind of different types of edits you can do in the genome, and they require delivery have even more machinery, and that means that Mammoth has really been the only company that's been able to actually deliver not just anywhere in the body, but also deliver any kind of edit anywhere in the body. And I think it's you have to do both of those if you really want to address all genetic.

Yeah, So a classic way that you can deliver to muscle or brain, for example, would be with a thing called AV which is another acronym that stands for adno associated virus. And one of the big limitations of this is that it has a very strict size limit. Like you can think of it as like a semi trailer truck where you can only fit so much in the back and cast nine is just way too big to fit inside it. But these nanocast style systems don't just fit, but they actually have a ton of room to spare. And the room to spare is really important as well, because when you're a scientist you can start to think really creatively about how do I use that. And one of the key ways that we use that is to fit in the machinery to do different types of edits. So people may have heard of things like base editing or writing or epigenetic editing. These are all techniques that take the fundamental Chrisper system and say, hey, what if instead of editing the genome as this like word document and only being able to delete sentences, what if we could add a paragraph, What if we could spell check a word? What if we could italicize a sentence. These are all kind of different types of edits you can do in the genome, and they require delivery have even more machinery, and that means that Mammoth has really been the only company that's been able to actually deliver not just anywhere in the body, but also deliver any kind of edit anywhere in the body. And I think it's you have to do both of those if you really want to address all genetic.

Disease, and any kind of edit means reading or writing. Yeah.

Disease, and any kind of edit means reading or writing. Yeah.

So we also had a lot of work we did on diagnostics as well, and during the pandemic we actually got emergency use authorization for a Chrisper based COVID test. So we're super proud of the work we did there. The focus of the company today is very much on the writing side, but definitely I think there's huge potential on the reading side.

So we also had a lot of work we did on diagnostics as well, and during the pandemic we actually got emergency use authorization for a Chrisper based COVID test. So we're super proud of the work we did there. The focus of the company today is very much on the writing side, but definitely I think there's huge potential on the reading side.

As well. Give us an example of the reading side.

As well. Give us an example of the reading side.

Yeah, so basically there, instead of using the Chrisper systems to change the DNA, you can use the Chrispher systems to send out some signal that there's a certain sequence present, so to say, hey, I found the word potato and it'll glow green if it finds potato, and it won't show any color if it doesn't. And that's a very powerful kind of concept, and that means you could do really low cost, high accuracy style molecular testing, and that's something that we're very bullish on long term. But as a company, obviously you have to focus on a certain area, and already, you know, trying to tackle all genetic diseases a limited set of focus to begin with, So that's kind of kind of where we're focusing our efforts otherwise.

Yeah, so basically there, instead of using the Chrisper systems to change the DNA, you can use the Chrispher systems to send out some signal that there's a certain sequence present, so to say, hey, I found the word potato and it'll glow green if it finds potato, and it won't show any color if it doesn't. And that's a very powerful kind of concept, and that means you could do really low cost, high accuracy style molecular testing, and that's something that we're very bullish on long term. But as a company, obviously you have to focus on a certain area, and already, you know, trying to tackle all genetic diseases a limited set of focus to begin with, So that's kind of kind of where we're focusing our efforts otherwise.

Right, So let me come back to something you said. So, as far as the writing goes, you can write single base pairs, you can write something longer. You can write whole genes or collections of genes. Ice.

Right, So let me come back to something you said. So, as far as the writing goes, you can write single base pairs, you can write something longer. You can write whole genes or collections of genes. Ice.

Yeah, you could have all insert an entire gene. You could kind of change a single base pair out of all the billions of base pairs in your genome. And that's an important philosophical point as well, because I think in biotech we often get so enamored with technology, so we always think in terms of like, ah, this is a base editing technology, or this is a gene writing technology, This is like Deuvile's trand break if you're patient. You don't care, Right, I have a disease and I don't care how you're doing it. I just want you to cure or treat my disease. In our case, we can actually cure it. And I think that's where our philosophy is. Will actually develop many techniques, all the techniques, and actually be able to deliver them. And then for any disease, we might try a couple of different ways of doing it. We might say, ah, there's like a way to do it by base editing, there's a way to do it by epigenetic editing. We're not sure which one's gonna be the best, but we'll try both and see which one actually works well. And that's very different from philosophy from typical biotech, where you try and create like ten companies whe each company is doing a different method and I think that's all fine and well in some ways, maybe also from like how do you maximize like investor involvement in different companies, But from a I think long term company building and from a patient perspective, I think that's very much like the wrong way to go about it.

Yeah, you could have all insert an entire gene. You could kind of change a single base pair out of all the billions of base pairs in your genome. And that's an important philosophical point as well, because I think in biotech we often get so enamored with technology, so we always think in terms of like, ah, this is a base editing technology, or this is a gene writing technology, This is like Deuvile's trand break if you're patient. You don't care, Right, I have a disease and I don't care how you're doing it. I just want you to cure or treat my disease. In our case, we can actually cure it. And I think that's where our philosophy is. Will actually develop many techniques, all the techniques, and actually be able to deliver them. And then for any disease, we might try a couple of different ways of doing it. We might say, ah, there's like a way to do it by base editing, there's a way to do it by epigenetic editing. We're not sure which one's gonna be the best, but we'll try both and see which one actually works well. And that's very different from philosophy from typical biotech, where you try and create like ten companies whe each company is doing a different method and I think that's all fine and well in some ways, maybe also from like how do you maximize like investor involvement in different companies, But from a I think long term company building and from a patient perspective, I think that's very much like the wrong way to go about it.

Yeah, So tell us about diseases in the brain and what you're thinking of, is the future of those maybe in give me a sense of three years, ten years where we'll be with that. Yeah.

Yeah, So tell us about diseases in the brain and what you're thinking of, is the future of those maybe in give me a sense of three years, ten years where we'll be with that. Yeah.

So to start with a specific example of one that I think kind of is frankly a condemnation of the genetic medicine space is Huntington's disease. So this is a disease that was mapped, Oh my god, not just decades ago, like half a century ago, like I think in like the late eighties, and it was mapp They mapped it with microsatellites, I believe, on giant gels that were in the lab. Right, this is like, you know, not pre computer, it's like Wexler, right, Yeah, but you know, very very early technologies, and we have understood, you know, fundamentally kind of the genetic base of Huntington's for a very long time, and still today people die from this every single year, and it's a horrible disease where basically, if you have a certain genomic sequence, then you know, typically in your thirties, you'll have the accumulation of a certain protein and you'll pass away. And it's infuriating, honestly that we understand the genetic cause of this and we can do nothing about it. So I think the genetic medicine space and Crisper in particular will have arrived and will have really I think, done a hallmark deliverance of like what the true potential is the day the last Huntington patient dies?

So to start with a specific example of one that I think kind of is frankly a condemnation of the genetic medicine space is Huntington's disease. So this is a disease that was mapped, Oh my god, not just decades ago, like half a century ago, like I think in like the late eighties, and it was mapp They mapped it with microsatellites, I believe, on giant gels that were in the lab. Right, this is like, you know, not pre computer, it's like Wexler, right, Yeah, but you know, very very early technologies, and we have understood, you know, fundamentally kind of the genetic base of Huntington's for a very long time, and still today people die from this every single year, and it's a horrible disease where basically, if you have a certain genomic sequence, then you know, typically in your thirties, you'll have the accumulation of a certain protein and you'll pass away. And it's infuriating, honestly that we understand the genetic cause of this and we can do nothing about it. So I think the genetic medicine space and Crisper in particular will have arrived and will have really I think, done a hallmark deliverance of like what the true potential is the day the last Huntington patient dies?

Agreed? When is that? Do you think?

Agreed? When is that? Do you think?

Yeah? So, I think it's definitely within sight. I'm not going to give a specific.

Yeah? So, I think it's definitely within sight. I'm not going to give a specific.

Three years or five or ten.

Three years or five or ten.

Yeah, it's probably not three, but it better not be ten. Okay, Yeah, I think in general, like you can kind of see the steps that you need to take and it's a matter of walking down the path.

Yeah, it's probably not three, but it better not be ten. Okay, Yeah, I think in general, like you can kind of see the steps that you need to take and it's a matter of walking down the path.

Got it? And what has been the problem? Given that we have Chrisper cast technology and that we have known the gene for Huntington's it's monogenetic, what has been the hold up? Yeah?

Got it? And what has been the problem? Given that we have Chrisper cast technology and that we have known the gene for Huntington's it's monogenetic, what has been the hold up? Yeah?

So I think there's a lot of things you have to think about. One is what type of edit are you going to do? Like can you just knock out the whole Huntington gene or do you have to think more creatively about modifying it in a more subtle way. Then the second one is can you actually get the editing machinery to the cells of interest? Can you actually get this into the brain, and those are two of the most obvious problems. I think that we've really thought deeply about mammoth and like the general sense, not just running to the before any brain disease. And I think that's where the technologies we've developed, like these ultracompact systems and having all these different editing modalities I think can make a huge difference.

So I think there's a lot of things you have to think about. One is what type of edit are you going to do? Like can you just knock out the whole Huntington gene or do you have to think more creatively about modifying it in a more subtle way. Then the second one is can you actually get the editing machinery to the cells of interest? Can you actually get this into the brain, and those are two of the most obvious problems. I think that we've really thought deeply about mammoth and like the general sense, not just running to the before any brain disease. And I think that's where the technologies we've developed, like these ultracompact systems and having all these different editing modalities I think can make a huge difference.

Potentially got it and so it sounds like you've got the can we get it to the right cells? It sounds like you've got a beat on that. But as far as what edit to make is that something you're experimenting with, well, I.

Potentially got it and so it sounds like you've got the can we get it to the right cells? It sounds like you've got a beat on that. But as far as what edit to make is that something you're experimenting with, well, I.

Think that's definitely something where we have a lot of great ideas for any about like different types, and that's where we're very unique because we can actually try different methods and we can say, hey, this is our hypothesis, prove it out or not, but not have a hammer and everything else to look like a nail, which is very very classic not just a biotype but a deep tech in general. And you know the classic startup advice of like find the problem first and then figure out the solution. There's a lot of reasons why that doesn't work in deep tech right, Like, sometimes you really do have to kind of build the thing and then figure out what the best application is. But that being said, the more you can mitigate that, that's a very powerful idea to get away from hammer, you know, squint at everything until it's a nail.

Think that's definitely something where we have a lot of great ideas for any about like different types, and that's where we're very unique because we can actually try different methods and we can say, hey, this is our hypothesis, prove it out or not, but not have a hammer and everything else to look like a nail, which is very very classic not just a biotype but a deep tech in general. And you know the classic startup advice of like find the problem first and then figure out the solution. There's a lot of reasons why that doesn't work in deep tech right, Like, sometimes you really do have to kind of build the thing and then figure out what the best application is. But that being said, the more you can mitigate that, that's a very powerful idea to get away from hammer, you know, squint at everything until it's a nail.

Yeah, let me make sure I understand. What's the way that you can test out these different hypothesies. Do you have an animal model of Huntington's.

Yeah, let me make sure I understand. What's the way that you can test out these different hypothesies. Do you have an animal model of Huntington's.

Yeah, it's gonna so not speaking specifically about Huntington's, but just generally in terms of different diseases. Some diseases you'll have an animal model that's really good, and that means you can actually try it out like in mice or maybe even monkeys, and like really get a lot of confidence for others. Honestly, you don't have anything. Maybe there's no animal models, so like you have to try it out in cell lines and then kind of make your best guess about what's going to work.

Yeah, it's gonna so not speaking specifically about Huntington's, but just generally in terms of different diseases. Some diseases you'll have an animal model that's really good, and that means you can actually try it out like in mice or maybe even monkeys, and like really get a lot of confidence for others. Honestly, you don't have anything. Maybe there's no animal models, so like you have to try it out in cell lines and then kind of make your best guess about what's going to work.

Well.

Well.

So it's very varied, i'd say, across different diseases and across different tissues, but you want to have as many shots on goal I think as possible because then when you go to humans, maybe you'll find something surprising, Like you only had cell line work and then it doesn't work in humans. And if you only have one technique, you're kind of out of luck. But if you have, like you know, a backup or a backup to the backup, that means you can actually go in and you know, do something for patients after that.

So it's very varied, i'd say, across different diseases and across different tissues, but you want to have as many shots on goal I think as possible because then when you go to humans, maybe you'll find something surprising, Like you only had cell line work and then it doesn't work in humans. And if you only have one technique, you're kind of out of luck. But if you have, like you know, a backup or a backup to the backup, that means you can actually go in and you know, do something for patients after that.

Got it. So that gives us a good sense of what the challenge is with something like Huntington's. Now, Huntington's is one gene. If you got it, you're getting Huntington's. But what about other diseases, whether it's Alzheimer's or schizophreny or whatever, that are polygenic, I can involve lots of machines. Does that make the problem exponentially harder.

Got it. So that gives us a good sense of what the challenge is with something like Huntington's. Now, Huntington's is one gene. If you got it, you're getting Huntington's. But what about other diseases, whether it's Alzheimer's or schizophreny or whatever, that are polygenic, I can involve lots of machines. Does that make the problem exponentially harder.

Yeah, so that's a really really good question. So kind of building on your point about monogenic disease, the diseases where there's a single gene that causes it, there's depending on how you count, let's say about four thousand of those that we kind of are well understood, and that means you have a lot of you have your work cut out for you just in monogenic disease, and you know, there's a lot of work to be done there. And the one thing I'll mention before moving on to the polygenic is that one of the beauties of the kind of crisper technology is that, unlike a lot of previous things that have happened in biotech, the first therapy you build with a crisper technology is the hardest, and then the second one gets easier, and the third one gets easier, and the fourth one gets easier. And that's very different from a lot of things, like you know, small molecule development, where every drug you kind of go back to the starting board and you're like, Okay, well I got to kind of go through the whole process again, and I haven't you know, obviously I've learned something, but I'm not going to like shorten the process for the second small male the third small molecule I make. And with Christopher, that's very very different because you're using the same technology and you're switching out this thing that's called a guide RNA. You can kind of think of it as like you go to Google and you type into the search engine and the guide RNA is what you're typing. So it's very kind of facile to switch these things out. And I think that means that even though there are four thousand, you know where monogenetic diseases, I think we have a real shot at tackling them all because the first one is the hardest and it only gets easier from there. And that's very different from classic biottech.

Yeah, so that's a really really good question. So kind of building on your point about monogenic disease, the diseases where there's a single gene that causes it, there's depending on how you count, let's say about four thousand of those that we kind of are well understood, and that means you have a lot of you have your work cut out for you just in monogenic disease, and you know, there's a lot of work to be done there. And the one thing I'll mention before moving on to the polygenic is that one of the beauties of the kind of crisper technology is that, unlike a lot of previous things that have happened in biotech, the first therapy you build with a crisper technology is the hardest, and then the second one gets easier, and the third one gets easier, and the fourth one gets easier. And that's very different from a lot of things, like you know, small molecule development, where every drug you kind of go back to the starting board and you're like, Okay, well I got to kind of go through the whole process again, and I haven't you know, obviously I've learned something, but I'm not going to like shorten the process for the second small male the third small molecule I make. And with Christopher, that's very very different because you're using the same technology and you're switching out this thing that's called a guide RNA. You can kind of think of it as like you go to Google and you type into the search engine and the guide RNA is what you're typing. So it's very kind of facile to switch these things out. And I think that means that even though there are four thousand, you know where monogenetic diseases, I think we have a real shot at tackling them all because the first one is the hardest and it only gets easier from there. And that's very different from classic biottech.

Now, how about the polygenetic diseases.

Now, how about the polygenetic diseases.

Right So on the polygenic side, I think the main challenge there is in an exciting way, going to become what to edit. So there are limitations to what we call multiplex editing. Right now, I think the state of the art would be, you know, you could reasonably do maybe three to five edits in one go, depending on which lab you want to kind of take a queue from, And there's a lot of progress that can be made there, of course, But even for these things where you're trying to edit multiple genes, it's often very unclear. Even if you want to edit five things and you said, hey, I can go edit five things, like which five you should edit can be very very tricky, like schizophrenia being a classic example, even things like type two diabetes, and there I think there's a lot of progress that could potentially be made in terms of mapping these diseases and really understanding even like are these edits additive, Like if I edit five things, am I getting just the full benefit of every edit? Or maybe is there a sequence of edits that's going to be more beneficial if I do them in a certain kind of cohort together. And these are very complicated statistical questions, right, and it's very non obvious kind of what the answer is for many of these diseases. And that's where I think there's a lot of additional kind of statistical work that could be done.

Right So on the polygenic side, I think the main challenge there is in an exciting way, going to become what to edit. So there are limitations to what we call multiplex editing. Right now, I think the state of the art would be, you know, you could reasonably do maybe three to five edits in one go, depending on which lab you want to kind of take a queue from, And there's a lot of progress that can be made there, of course, But even for these things where you're trying to edit multiple genes, it's often very unclear. Even if you want to edit five things and you said, hey, I can go edit five things, like which five you should edit can be very very tricky, like schizophrenia being a classic example, even things like type two diabetes, and there I think there's a lot of progress that could potentially be made in terms of mapping these diseases and really understanding even like are these edits additive, Like if I edit five things, am I getting just the full benefit of every edit? Or maybe is there a sequence of edits that's going to be more beneficial if I do them in a certain kind of cohort together. And these are very complicated statistical questions, right, and it's very non obvious kind of what the answer is for many of these diseases. And that's where I think there's a lot of additional kind of statistical work that could be done.

Okay, got it, But you've got the technology now to go in there and do these experiments. What do you see as the ethical issues about a society that knows how to edit genes? As we move forward, Let's say we're thinking ten years in the future, two twenty years, what do you see is the issues there? Yeah?

Okay, got it, But you've got the technology now to go in there and do these experiments. What do you see as the ethical issues about a society that knows how to edit genes? As we move forward, Let's say we're thinking ten years in the future, two twenty years, what do you see is the issues there? Yeah?

Well, I think the exciting thing is that we're quickly going to live in a society where we're better at making edits in any cell in the human genome than we are understanding what to edit, which also has to read out on. Yeah, your question about the ethics of like, Okay, let's move beyond monogenetic disease. Let's even move beyond like the classic polygenetic diseases like schizophrena, type two diabetes. I think these are relatively non controversial things where of course, if you have an ability to cure people, yeah, you probably should, or at least I feel very strongly personally that you should. And then it gets into the realm of I think, you know, people like to think about, oh, well, what about things that are not necessarily diseases, but maybe you want to improve, like whether that's uh, you know, kids, athleticism or intelligentism and intelligence.

Well, I think the exciting thing is that we're quickly going to live in a society where we're better at making edits in any cell in the human genome than we are understanding what to edit, which also has to read out on. Yeah, your question about the ethics of like, Okay, let's move beyond monogenetic disease. Let's even move beyond like the classic polygenetic diseases like schizophrena, type two diabetes. I think these are relatively non controversial things where of course, if you have an ability to cure people, yeah, you probably should, or at least I feel very strongly personally that you should. And then it gets into the realm of I think, you know, people like to think about, oh, well, what about things that are not necessarily diseases, but maybe you want to improve, like whether that's uh, you know, kids, athleticism or intelligentism and intelligence.

These are the classic ones.

These are the classic ones.

And as someone that did a lot of work on the kind of genetic side of the equation, I think one thing that's often lost here is that there's no intelligence. Just to be clear, Like the gains you can get even from doing a lot of it, it's on the intelligence side are kind of shockingly minimal.

And as someone that did a lot of work on the kind of genetic side of the equation, I think one thing that's often lost here is that there's no intelligence. Just to be clear, Like the gains you can get even from doing a lot of it, it's on the intelligence side are kind of shockingly minimal.

Agreed. Although, although if we fast forward twenty years and you've figured out, hey, polygenetically, here's some very clever AI way to test this and try that, maybe we'll find out Oh it's.

Agreed. Although, although if we fast forward twenty years and you've figured out, hey, polygenetically, here's some very clever AI way to test this and try that, maybe we'll find out Oh it's.

Yeah, it's definitely definitely possible. I think there's a bit of a holy war in terms of, you know, the environmental component versus the innate genetic component.

Yeah, it's definitely definitely possible. I think there's a bit of a holy war in terms of, you know, the environmental component versus the innate genetic component.

But the innate genetics doesn't hurt right.

But the innate genetics doesn't hurt right.

Right, So let's put that aside for a second and say, okay, let's just same. There's been progress made, and we have some better understanding maybe of at least what are the best possible dits you could make. I think there it's going to be really interesting because if you zoom out, I feel like this is, first of all, this is a question beyond any individual and beyond any company. It's really kind of a society level question where there's you know, religious and you know, ethical and kind of personal and of course corporate kind of viewpoints here. But I think you've seen this in other deep tech areas. You see it with AI right now, every country is going to have kind of a different view on this. And I think the really interesting thing when you start thinking about human biology, which we all share, of course, is that these decisions very much are not in isolation, right, And it does make you wonder if one country is more willing to kind of go down some of these paths that other countries might find less ethical, does that create an imperative for other countries just to fall along to stay competitive. And I don't know what The answer to that is, but I think that's the part that seems like it might be most complicated, honestly, is different countries will come to different conclusions, and there's definitely been a lot of work to try and come to like international consensus around these things. But in general, I think that's going to be the trickiest pressure is that even if let's say in the United States, we make, you know, certain decisions around this is the line, We're not going to do edits for intelligence, but we are going to do edits for anything that's you know, classified as a disease. Maybe another country decides, hey, actually I want to give my population super charging powers to whatever extent I can, and maybe it's a minimal extent, but we're going to try our vest I think that creates a pretty interesting situation geopolitically about like how do you handle that?

Right, So let's put that aside for a second and say, okay, let's just same. There's been progress made, and we have some better understanding maybe of at least what are the best possible dits you could make. I think there it's going to be really interesting because if you zoom out, I feel like this is, first of all, this is a question beyond any individual and beyond any company. It's really kind of a society level question where there's you know, religious and you know, ethical and kind of personal and of course corporate kind of viewpoints here. But I think you've seen this in other deep tech areas. You see it with AI right now, every country is going to have kind of a different view on this. And I think the really interesting thing when you start thinking about human biology, which we all share, of course, is that these decisions very much are not in isolation, right, And it does make you wonder if one country is more willing to kind of go down some of these paths that other countries might find less ethical, does that create an imperative for other countries just to fall along to stay competitive. And I don't know what The answer to that is, but I think that's the part that seems like it might be most complicated, honestly, is different countries will come to different conclusions, and there's definitely been a lot of work to try and come to like international consensus around these things. But in general, I think that's going to be the trickiest pressure is that even if let's say in the United States, we make, you know, certain decisions around this is the line, We're not going to do edits for intelligence, but we are going to do edits for anything that's you know, classified as a disease. Maybe another country decides, hey, actually I want to give my population super charging powers to whatever extent I can, and maybe it's a minimal extent, but we're going to try our vest I think that creates a pretty interesting situation geopolitically about like how do you handle that?

Yeah, agreed, once we're a species that knows how to modify our code. Yes, So the geopolitical things, what do you think it means just in terms of what it means to be a human? How does that change? I mean, let's say we're thinking fifty years in the future here, and you get to choose everything about your kids and perhaps yourself in some ways. But how does that change society?

Yeah, agreed, once we're a species that knows how to modify our code. Yes, So the geopolitical things, what do you think it means just in terms of what it means to be a human? How does that change? I mean, let's say we're thinking fifty years in the future here, and you get to choose everything about your kids and perhaps yourself in some ways. But how does that change society?

Yeah, I think it brings to mind one of my favorite movies, Gatica. I'm sure you've seen it.

Yeah, I think it brings to mind one of my favorite movies, Gatica. I'm sure you've seen it.

I have seen it, but I thought that was it was silly in the sense that, just as a reminder to the listeners, your genes predispose you to some particular career in that movie, and if you have these genes, are going to be this kind of janitor or whatever as opposed to the astronaut. And of course, with the nature nurture debate, that's totally dead because it's always both so, but yeah, tell me why it reminded you of Ghika.

I have seen it, but I thought that was it was silly in the sense that, just as a reminder to the listeners, your genes predispose you to some particular career in that movie, and if you have these genes, are going to be this kind of janitor or whatever as opposed to the astronaut. And of course, with the nature nurture debate, that's totally dead because it's always both so, but yeah, tell me why it reminded you of Ghika.

Yeah, because the part there was most salient to me, I think was this idea that let's say one child was kind of quote unquote natural born, the other child was given these certain advantages to whatever degree at birth, and more to the point, being natural born was just a disadvantage you weren't allowed to apply to be like an astronaut, like doors were just closed to you, basically, And I think that is a very kind of concerning world to live. I don't want to live in that world in all honesty and I think you could maybe have like some rationalist argument about why maybe you should do that, but I think just morally and ethically, that feels just really horrible to me. And the whole point of the movie was that actually, no matter how good the sciences at that point, there's just certain factors that make that a silly choice, just the resilience of the individual and their ability to overcome the challenges they had genetically. And I think that's a very that's a message that really resonates with me, because I think even fifty years from now, there's gonna be many things we don't understand about our biology. And I think if you try and overrationalize these things and shut doors because like oh, someone had this genotype and not that one, just inherently you're going to be missing things and you're not going to be actually as rational as you think.

Yeah, because the part there was most salient to me, I think was this idea that let's say one child was kind of quote unquote natural born, the other child was given these certain advantages to whatever degree at birth, and more to the point, being natural born was just a disadvantage you weren't allowed to apply to be like an astronaut, like doors were just closed to you, basically, And I think that is a very kind of concerning world to live. I don't want to live in that world in all honesty and I think you could maybe have like some rationalist argument about why maybe you should do that, but I think just morally and ethically, that feels just really horrible to me. And the whole point of the movie was that actually, no matter how good the sciences at that point, there's just certain factors that make that a silly choice, just the resilience of the individual and their ability to overcome the challenges they had genetically. And I think that's a very that's a message that really resonates with me, because I think even fifty years from now, there's gonna be many things we don't understand about our biology. And I think if you try and overrationalize these things and shut doors because like oh, someone had this genotype and not that one, just inherently you're going to be missing things and you're not going to be actually as rational as you think.

Well, that's true, but maybe one hundred and two years from now will be less bad at that. It would be just by Devil's advocate. It would be like saying, you know, athletes are on anabolic steroids won't ever be better than natural athletes, but they will be they can lift more and so on. Well, yeah, now, there's gonna be the Enhanced Olympics. I suppose, yeah, exactly so. But but that doesn't affect the career choices like in Gatica.

Well, that's true, but maybe one hundred and two years from now will be less bad at that. It would be just by Devil's advocate. It would be like saying, you know, athletes are on anabolic steroids won't ever be better than natural athletes, but they will be they can lift more and so on. Well, yeah, now, there's gonna be the Enhanced Olympics. I suppose, yeah, exactly so. But but that doesn't affect the career choices like in Gatica.

Yeah, I think it's where I think where I get missed squeamashes when it comes down to like the individual choice, because going on the athletics example, you can choose to take performs enhancing drugs or not, right, and that either shuts through a pensors for you. I think the thing that's more human to me is you don't choose how you're born, right, That's a choice that's made for you in a lot of different ways. And I think that's where the type of world that I don't want to live in is where things that are truly outside of your control in terms of like your your genome before you even born, determine kind of how you live. And that's that's not something where I can reconcile personally.

Yeah, I think it's where I think where I get missed squeamashes when it comes down to like the individual choice, because going on the athletics example, you can choose to take performs enhancing drugs or not, right, and that either shuts through a pensors for you. I think the thing that's more human to me is you don't choose how you're born, right, That's a choice that's made for you in a lot of different ways. And I think that's where the type of world that I don't want to live in is where things that are truly outside of your control in terms of like your your genome before you even born, determine kind of how you live. And that's that's not something where I can reconcile personally.

I mean, interestingly, we're already in that situation, right, which is that there's a genetic lottery and you show up in the world with advantages or disadvantages. But now it's just a matter of whether your parents did the right payments and edited.

I mean, interestingly, we're already in that situation, right, which is that there's a genetic lottery and you show up in the world with advantages or disadvantages. But now it's just a matter of whether your parents did the right payments and edited.

Well and I think that's an important point as well. I don't want to live in a world where there's a massive stratification between the rich and the poort, not just from like a starting point of like, okay, these are the opportunities available to you in terms of schooling, but oh, this is the starting point for you in terms of your genome. Yeah, and that's something that we talk about the inheritance of wealth. Well, you literally inherit your genes. Yes, So that's something that could be a very durable advantage in some ways if it's not, you know, something that we think about very deeply before we go down that path. If we go down that path.

Well and I think that's an important point as well. I don't want to live in a world where there's a massive stratification between the rich and the poort, not just from like a starting point of like, okay, these are the opportunities available to you in terms of schooling, but oh, this is the starting point for you in terms of your genome. Yeah, and that's something that we talk about the inheritance of wealth. Well, you literally inherit your genes. Yes, So that's something that could be a very durable advantage in some ways if it's not, you know, something that we think about very deeply before we go down that path. If we go down that path.

So following up on that, can we change features in adults as in you make a change again in the future where you decide, hey, now I want to be like the equivalent of performance enhancing drugs and do that at any age.

So following up on that, can we change features in adults as in you make a change again in the future where you decide, hey, now I want to be like the equivalent of performance enhancing drugs and do that at any age.

Yeah, And I think that's kind of where the most of the focus is now, is like, well, first of all, for disease, of course, you know, let's say someone was born with Huntington's and now they're in their twenties, like you want to help them out and really, you know, prevent them from how any problems in their thirties. I think for a lot of diseases, one of the key questions you have to answer is like when do you have to intervene For some diseases, maybe it could be very early in life. Maybe there's certain biological processes that just take place early in life and you need to do the edit before then, or else maybe you have to come up with some other way of reversing the disease. I think, fortunately for seems like maybe most diseases you can edit an adulthood and that can actually have a very material effect on the disease. But that isn't going to necessarily always be true.

Yeah, And I think that's kind of where the most of the focus is now, is like, well, first of all, for disease, of course, you know, let's say someone was born with Huntington's and now they're in their twenties, like you want to help them out and really, you know, prevent them from how any problems in their thirties. I think for a lot of diseases, one of the key questions you have to answer is like when do you have to intervene For some diseases, maybe it could be very early in life. Maybe there's certain biological processes that just take place early in life and you need to do the edit before then, or else maybe you have to come up with some other way of reversing the disease. I think, fortunately for seems like maybe most diseases you can edit an adulthood and that can actually have a very material effect on the disease. But that isn't going to necessarily always be true.

Okay, got it. And so coming back to this conversation about what society will become, it may be that some of it is not an issue that you're born with and you have to deal with, but that you make a choice, just like anibolic steroids, that people are doing it that way. Do you suppose that people are going to be looking for things that involve longevity as one of their first aims with this.

Okay, got it. And so coming back to this conversation about what society will become, it may be that some of it is not an issue that you're born with and you have to deal with, but that you make a choice, just like anibolic steroids, that people are doing it that way. Do you suppose that people are going to be looking for things that involve longevity as one of their first aims with this.

Yeah, I mean, obviously there's a huge amount of interest in longevity. I have a personal interest in living a healthy life. For a long time anyway. I think I'm definitely fall more on the spectrum of like health span versus life span. If I'm living to be two hundred, but i'm you know, de crefit and can't remember my kids, that's not a life I personally wanted to live. But if I live to a very healthy one hundred and ten and where you know, I die in my sleep, that sounds great to me. So I think longevity is definitely an area where gene editing could play a huge role in terms of you know, what are the processes is like, you know, some sort of mutation accumulation in certain areas that's like causing these cells to age in the way they are, and could we reverse that with genetic editing approaches. I think that is a very reasonable and potentially promising line of research. I think that in general, some of the biggest longevity things we can do though today is like, you know, heart disease like cancer obviously being a big one, and those are of course directly addressable by genetic editing as well. And it goes to interesting questions of like, should we edit millions of people in the US to reduce their risk of heart disease by thirty percent. That could say tons and tons of lives. It's a relatively large in invention for them. So obviously you'd have questions about safety. So far, crisper seems to be very very safe at least based on the trials and humans so far. So that's something we could do. Is that something we want to do as a society?

Yeah, I mean, obviously there's a huge amount of interest in longevity. I have a personal interest in living a healthy life. For a long time anyway. I think I'm definitely fall more on the spectrum of like health span versus life span. If I'm living to be two hundred, but i'm you know, de crefit and can't remember my kids, that's not a life I personally wanted to live. But if I live to a very healthy one hundred and ten and where you know, I die in my sleep, that sounds great to me. So I think longevity is definitely an area where gene editing could play a huge role in terms of you know, what are the processes is like, you know, some sort of mutation accumulation in certain areas that's like causing these cells to age in the way they are, and could we reverse that with genetic editing approaches. I think that is a very reasonable and potentially promising line of research. I think that in general, some of the biggest longevity things we can do though today is like, you know, heart disease like cancer obviously being a big one, and those are of course directly addressable by genetic editing as well. And it goes to interesting questions of like, should we edit millions of people in the US to reduce their risk of heart disease by thirty percent. That could say tons and tons of lives. It's a relatively large in invention for them. So obviously you'd have questions about safety. So far, crisper seems to be very very safe at least based on the trials and humans so far. So that's something we could do. Is that something we want to do as a society?

What would be the pros and cons?

What would be the pros and cons?

So the pro would be you reduce let's say hard tech and it all cause mortality essentially and a huge segment of the population. The con would be there's going to be some expense associated with that. Do we want to pay that expense as a society? Maybe it saves us money in the long term because both people are more productive and you're also spending less and kind of in stage care in the hospital.

So the pro would be you reduce let's say hard tech and it all cause mortality essentially and a huge segment of the population. The con would be there's going to be some expense associated with that. Do we want to pay that expense as a society? Maybe it saves us money in the long term because both people are more productive and you're also spending less and kind of in stage care in the hospital.

And then see that as a government program that's paid for as opposed to individuals saying, hey, I'm going to pay for this.

And then see that as a government program that's paid for as opposed to individuals saying, hey, I'm going to pay for this.

Well, I think that's a very interesting question as well, and I think you could see stratification there of maybe you know, frankly wealthier individuals choosing to get a lot of these types of technologies, whereas you know, is that available to everyone. That's the kind of choice for society. And then of course the big one would be safety. You only want to do that if it's extremely safe, right, because you're trying to prevent disease kind of an aggregate, so it needs to be extraordinarily safe for each individual.

Well, I think that's a very interesting question as well, and I think you could see stratification there of maybe you know, frankly wealthier individuals choosing to get a lot of these types of technologies, whereas you know, is that available to everyone. That's the kind of choice for society. And then of course the big one would be safety. You only want to do that if it's extremely safe, right, because you're trying to prevent disease kind of an aggregate, so it needs to be extraordinarily safe for each individual.

Do you think if you're interested in longevity, do you think you're going to see this in your lifetime where there are edits that can be made Let's say forty years from now, where you say, hey, this is great, I'm going to live longer. I'm going to expand this.

Do you think if you're interested in longevity, do you think you're going to see this in your lifetime where there are edits that can be made Let's say forty years from now, where you say, hey, this is great, I'm going to live longer. I'm going to expand this.

Yeah, it's an interesting question. I wouldn't be surprised if there's things that can maybe get you ten to twenty percent further along. Are we going to see like a doubling. I mean, that'd be great. Sure, I'm not going to be root against it. I would be surprised. Frankly, we've run a natural experiment. There's billions of humans on Earth with all sorts of genomes. No one seems to live over one hundred and ten hundred and twenty. Let's say that doesn't mean you know, it's not possible, but I think that one of the areas where I think we'll see way more progress on is like health span within that period. So like if you can live to an extraordinarily healthy one hundred ten where you're hiking mountains and you're having fun with your kids, that's already a huge extension of that's like a twofold extension of life relative to what a lot of people really kind of practically experience. And I think glip ones and things like that, the obesity drugs from the Lili and Novo and others, I think that that's also kind of u shown that there can be these kind of giant mass markets in biottech. And longevity is the other one that everyone always kind of thinks about, but there's others as well. You can imagine things that mitigate like alcohol consumption or you know, other areas. I don't I don't think glip ones are going to be the only kind of trillion dollar drug in biotech, but I think it's the first, and I think hopefully that kind of inspires everyone else in biotech, including us at Mammoth, to really think more broadly and more fundamentally about, Okay, what are the things we can do that actually change society for the better overall, not just necessarily for specifical you got to start with specific things and knock out rere diseases. But I think in terms of like the long term vision of Mammoth, I think that becomes very very exciting.

Yeah, it's an interesting question. I wouldn't be surprised if there's things that can maybe get you ten to twenty percent further along. Are we going to see like a doubling. I mean, that'd be great. Sure, I'm not going to be root against it. I would be surprised. Frankly, we've run a natural experiment. There's billions of humans on Earth with all sorts of genomes. No one seems to live over one hundred and ten hundred and twenty. Let's say that doesn't mean you know, it's not possible, but I think that one of the areas where I think we'll see way more progress on is like health span within that period. So like if you can live to an extraordinarily healthy one hundred ten where you're hiking mountains and you're having fun with your kids, that's already a huge extension of that's like a twofold extension of life relative to what a lot of people really kind of practically experience. And I think glip ones and things like that, the obesity drugs from the Lili and Novo and others, I think that that's also kind of u shown that there can be these kind of giant mass markets in biottech. And longevity is the other one that everyone always kind of thinks about, but there's others as well. You can imagine things that mitigate like alcohol consumption or you know, other areas. I don't I don't think glip ones are going to be the only kind of trillion dollar drug in biotech, but I think it's the first, and I think hopefully that kind of inspires everyone else in biotech, including us at Mammoth, to really think more broadly and more fundamentally about, Okay, what are the things we can do that actually change society for the better overall, not just necessarily for specifical you got to start with specific things and knock out rere diseases. But I think in terms of like the long term vision of Mammoth, I think that becomes very very exciting.

And I've been throwing out numbers like three years, five years, ten, But what you see, given your incredibly specific view on what is happening right now, what you're capable of doing, what is that time scale that we're talking about.

And I've been throwing out numbers like three years, five years, ten, But what you see, given your incredibly specific view on what is happening right now, what you're capable of doing, what is that time scale that we're talking about.

Yeah, so I mean, going back to the beginning of the conversation, Already, today people are being treated for sickle cell disease using crispers.

Yeah, so I mean, going back to the beginning of the conversation, Already, today people are being treated for sickle cell disease using crispers.

That's today.

That's today.

I think over the next five years, for the tissues that are kind of most easily accessible, like blood and liver, people are going to be shocked at how much progress is made at curing rare diseases in those areas. And these are kind of things where it's like it happens slowly and then it happens all at once. It's very much like that. And then I think over the next ten years, you're gonna, because of you know, Mammoth, be able to see us knocking out diseases and like muscle and brain and all the other tissues of the body, and I think it's going to take time, and there's a lot.

I think over the next five years, for the tissues that are kind of most easily accessible, like blood and liver, people are going to be shocked at how much progress is made at curing rare diseases in those areas. And these are kind of things where it's like it happens slowly and then it happens all at once. It's very much like that. And then I think over the next ten years, you're gonna, because of you know, Mammoth, be able to see us knocking out diseases and like muscle and brain and all the other tissues of the body, and I think it's going to take time, and there's a lot.

Of diseases to go through.

Of diseases to go through.

But I think if we're sitting here a couple decades from now and people are still suffering from rare disease, we've done something incredibly wrong, Like things have gone off the rail somewhere, and that's insane. Like to live in a world where genetic disease is really a thing of the past would be transformative for those patients, but also I think for society generally. And I think once you've done that, that's when you in parallel, because now you're showing the safety, Now you're showing that this is an effective technology. I think you can start to dream even bigger. You can start to think about, like, you know, how do you go after reducing cardiovascular risk, how do you go after even more esoteric things like thinking about health span, Like there's certain people that have short sleep and they actually only need to sleep like three to four hours a night, Like what if we could all do that?