[00:30] Welcome to another episode of Progress, Potential, and Possibilities, discussions with fascinating [00:58] people designing a better tomorrow for all of us. I'm your host, Ira Pastor. [01:02] Welcome everybody again to another episode of our show, bringing in another really awesome guest today involved in creating a better tomorrow. [01:12] Today we have the honor of being joined by Dr. Andrea Cho, who is the chief executive officer and co-founder of Holoclara, which is a really interesting biotech company. [01:23] They're focused on creating these novel, safe, orally bioavailable worm divide therapies, ultimately with a focus on therapeutic indications like allergies and autoimmune disorders. [01:35] While she was pursuing her doctorate at California Institute of Technology, Dr. Cho was involved in uncovering this really unique science around pharma languages that, you know, shared by roundworms that have evolved over hundreds of millions of years. [01:52] And ultimately her research and her discovery led her in the direction of really interesting novel molecules derived from these worms that can block the formation of various diseases in animal models of allergies, autoimmune disorders. [02:05] And this ultimately has led not just to the formation of Holoclara, but really some really interesting advances in the fields of both evolutionary biology as well as extreme biology. [02:15] And that's that Holoclara is focused on ultimately taking this technology and the mission to develop an entirely new class of therapeutics that can provide relief for millions of patients that live with these chronic debilitating disorders. [02:27] Dr. Cho is a winner of the Emerging Women's Founders Award in Biotech. [02:32] She did her medical degree at USC Keck School of Medicine, her PhD at Caltech, and is recently, as just a couple weeks ago, coming off a very impressive $16 million series financing to move the company's initiatives forward. [02:46] We're honored to have with us a lot of exciting themes to get into today. Dr. Andrea Cho, welcome to our show. [02:54] Ira, thank you so much for having me. I'm excited to be here and I'm excited to chat with you. [02:59] I'm excited you're here. I really enjoy what you're doing in this topic. [03:04] I would love to start off by handing you the floor for a little bit to talk a little bit more about you. [03:11] And ultimately, I spent a lot of time reading about you. [03:15] Clearly, you were doing the medical degree and the PhD at the same time. [03:19] I would love to hear about how you sort of migrated from, well, obviously, human work to, I know you work with mice to flies and ultimately how you ended up in Dr. Sternberg's lab working with nematodes. [03:30] I think that'd be a great way to start things off. [03:34] Yeah, I would love to tell you about, I'm trying to figure out where the best place to start in the story because you're right, there was this MD PhD component. [03:44] And it is split up in an interesting way when you do your MD PhD in the US, you do your first two years of medicine, which is a lot of in classroom learning. [03:55] That's where it's a lot of books. And that's where I became a hypochondriac. [04:00] You know, you're just reading about what are these diseases and do I have them? And then you do your PhD. [04:07] And then you go back and you do your two clinical years where it's solely looking at patients. [04:12] So that was a really interesting split for me because I gained a lot of insight into human health and these diseases that we're suffering from and then went straight into my PhD. [04:26] And at the time that I went to Caltech, I was naturally kind of looking at labs that might be studying human disease. [04:36] And then simultaneously, we had just finished human genome project and people were asking all these questions like, well, now we have this list of really interesting genes. [04:45] How do we study them? [04:47] Enter the roundworm. That's where C. elegans, this round, really simple roundworm crossed my path. [04:57] And I thought it was so interesting that you could study so many genes in this roundworm. [05:04] You could take a gene out. You could take a knock in a gene. You could do anything in any part of the life of this worm. [05:13] Like you could take a worm that's, you know, a partial juvenile versus an adult versus an egg and knock out a gene at that time and see what happens. [05:22] So I was just really fascinated with that. And like you said, I had done a rotation in flies. [05:29] I'd also worked with mice and just the simpler things got, the more I felt like we could explore something really deep and interesting about life. [05:40] So that's what brought me to the worms. [05:44] I'll just stop there for a second because I know that that was already kind of a lot to take in. [05:50] No, no, no. It's spot on. And obviously it leads up to my sort of my next talking point because, you know, we have this class, you know, that is sort of of the nematodes. [06:04] I've seen some of the figures here. So I know there's some debate on whether there's like 10,000 different species or potentially I have seen figures of upwards of a million. [06:14] They have adapted very successfully to every ecosystem, even those that put them in the category of extremophile. [06:22] The coolest number I saw is this 500 quintillion. [06:26] There's quite a few of them on the planet. And with 500 million years of evolution behind them, they're really good at producing chemistry, communicating with chemistry, defending with chemistry. [06:39] And we got no one's really ever tapped into that. So I think that's an extremely exciting thing that you're doing. [06:44] Before we get to the company, though, I'd love to stop at your your PhD. You published in 2012 pheromones and free living and parasitic nematodes. [06:53] And, you know, you go into, you know, you learn about, you know, you talk about this really interesting class of small molecules, the ascarasides, which we getting into the fact that these compounds can do many things in terms of attraction or delaying growth in an enemy. [07:08] And then some other interesting similarities of the chemistry's in terms of bacteria quorum sensing, which we'll talk about a little later in the show. [07:17] Talk a little bit about your dissertation. I mean, it's just a little body of cool work that I'd love to just have you reminisce on because it was, you know, 12 years ago. [07:26] Yeah, thank you so much for actually reading that and being interested in that. I guess where I would love to, you know, actually, so I was thinking about it. My husband is a musician. [07:39] I would Ferguson. I've been listening to his music for about a decade. And the other day, he told me something. One of his central themes is, you know, he likes to explore ways to reveal the unseen. [07:54] And he said that that's been his theme, his theme for a while now. I thought, well, that's so interesting because as scientists, that's really what we're trying to do to we're trying to reveal the unseen. [08:04] Our goal is to try to reveal something about us or the universe that we just didn't know before. And so, you know, when you're looking down at a worm on an agar plate, you know, we actually had this week. [08:18] You can track anything about this worm, whether it's going left or right or decides to go to sleep. We actually had this robot on the microscope that would follow it so that when you went home at night, it would continue. [08:33] The light would stay on and it would continue to track it. You would create mathematical algorithms for every single decision a worm has made, perhaps even over its entire lifetime. [08:42] But whether it goes left or right or whether it decides to do one thing or another was always kind of a mystery. What are those things that are driving those decisions? [08:53] That's what was really interesting to me. That sort of and then at the same time, you know, I was a kid, you go to these aquariums, you see the sardine, you know, the Monterey Bay Aquarium. [09:04] You see that sardine tank where they're all going in one direction or you see starlings in the sky and they're all going in one direction. How are they navigating those things? [09:14] What are those unseen forces? What are the unseen molecules that are guiding that sort of behavior as a group? So that was another piece that was really interesting to me. [09:25] And when you're looking down in your hand and you're holding this agri plate with the worm, that now you have a whole algorithm that you've just gathered about its entire life decisions. [09:36] I remember looking up from the microscope and someone had printed out this phylogenetic treat and cut it out and taped it on the wall. It might actually still be there. [09:47] I once was walking down the hall with Caltech and I saw in a freezer like a 20 faded paper that said human genome freezer project freezer. [09:56] I was like, you know how long that's been there? So looking at this tree, it was really interesting because I saw the worm that was in my hand. [10:05] It had been first evolved 500,000 years ago. I was like, wow, that is really interesting. Wait, how is that possible? I'm holding this worm in my hand. [10:14] It evolved half a million years ago. And then when it was discovered some early on, like a couple of decades ago, someone made this great decision to freeze as many as possible of this strain of this generation and then chip away at it and send it to any scientists around the world so that they can study this generation of worm and have a mutual understanding about that. [10:40] Now, you know, you've seen there's all these Nobel prizes that have been awarded to C. elegans researchers. [10:45] So then that really was interesting to me to look at this tree and say, okay, wow, there's a whole field of scientists that are studying this one worm, but there's all these lines before and after it, but he evolved 600,000 years ago or sooner than that. [11:04] And the natural question became, well, where are those worms? Where are they? I want to see them. How are they different? And so I took on this project where I would find them and I would sort of study how are they moving differently? What's different about them? [11:22] And I took on this project ultimately of pheromones because they were attracting the worms. They were making, they were guiding them to either go into diapause or this diapausal life stage where they can go into hibernation, live for a long time, or meet, find, or choose not to. [11:41] And then I realized, oh, they're actually secreting things. Now we can get all of these different worms that had evolved hundreds of thousands of years. [11:51] And how amazing is it that there are scientists around the world that have frozen them and are willing to send them to me and I can revive them. Actually, they come in the mail. [12:01] Well, they send them to you in a mail and you rip open your little package and there's a little agar, like maybe a five centimeter agar plate that's been taped around so no worms can escape. [12:11] You open it up and they're already moving around and you just take, take that awesome present. You go to the microscope and you see how different they are. You start collecting their pheromones. [12:22] You start asking, how is it, how can, if I divide this pheromone into a couple of fractions, what is it going to do to this worm? So that's sort of what led into this interest of, of pheromones. [12:36] So from there, the interesting discovery was no matter how far I went on this evolutionary tree, we found this class of molecules that had been conserved, meaning that they were all secreting a similar language. [12:50] So that's where things get really interesting because I thought, wait, how is that possible? You know, in insects, you really try to avoid using the same pheromones because you don't want to get confused and mate with the same pheromones. [13:02] I don't know, moth, if you're one moth, but the worms were you secreting a lot of the same language and they had this unique sugar moiety not made by any other animal in the world and different links of the carbon tail were like different letters of the alphabet. [13:15] Different combinations would make them the different things. I mean, that's to any scientist, such an interesting thing to study is trying to decode the different things that you can see in the same pheromones. [13:29] Such an interesting thing to study is trying to decode this language that's been here under our nose this whole time for millions of years. [13:42] And I thought that was really interesting. Actually, it just, I have been saying hundreds of thousands of years. I actually meant hundreds of millions of years. So C. elegans was actually evolved a couple hundred million years ago. [13:53] And it's funny I made that mistake because it's so hard to think about something that was that long ago. Like it kind of, I still can't think about what life could be like before the Egyptians, right? [14:05] It's quite intriguing whether we talk about worms or plants or any of these organs. Been here a long time, survived many extinctions. A lot of stuff has gone bye bye and they're still hanging out. [14:25] And yeah, I mean, they do it with chemistry and really good at evolving and figuring out what works, what doesn't, finding out interesting combinations. So no, it's extremely exciting. [14:37] And then, you know, just as a, you know, after your PhD, because, you know, we're talking about, you know, obviously this, this evolutionary perfected toolkit that whether it's C. elegans or some of these other ones that you published about Panagrellus redivivus. [14:54] There's all sorts of cool names, but these chemicals you've not just published on the interaction between the different nematodes, but you followed up with a variety of really interesting papers. [15:07] There's one on nematode signaling in the metabolism of animals, plants and microorganisms. Another cool one on the way they elicit all sorts of interesting plant defense and pathogen resistance. [15:18] Talk about the cross species component here because clearly the species will be getting up to humans. You know, is what we're most interested in. [15:27] And then in addition to how the nematodes play their chemical game with plants and everything else out there, you also talk a little bit about in your publications, the hygiene issue. [15:38] And we talked a little bit about this before on the show that, hey, we used to we've been co evolving with them as you know, we haven't been there that long, but nonetheless, you know, we've done a lot to kill off and get a lot of these things out of our ecosystem. [15:53] Maybe that hasn't been the greatest thing because tremendous uptick in allergies and autoimmune disease following these technologies. Say a few words about the hygiene hypothesis connection here as well, if you would. [16:04] Yeah, I mean, I think to go. [16:07] Well, I have to confess then in telling this whole story that when I picked my PhD, I really took on this pheromonal language. I truly just wore the hat of evolutionary biologist. [16:20] And I don't know if my my MD PhD program at the time knew that I just took on this really evolutionary project. And that's that's honestly because I have an interest in both human health and also just life and the world and Earth. [16:35] So then I didn't know that at that time that there could be this cross species and therapeutic potential that I heard this radio lab podcast where some guy with terrible asthma, nothing worked for him. [16:50] He walked. He went to Africa to walk barefoot to get hookworms on purpose to treat his disease. And it works for him. And he came back and he tried to sell it. [16:59] So that was very interesting to me because I thought, what? What is why would he do that? And what is going on? And that's when I started realizing that the hygiene hypothesis expanded into worms and that they're not just the case of this really interesting individual. [17:17] But as I was diving into the literature, I saw that there were all of these findings where even people that with Crohn's disease that took worms would go into remission. [17:31] And then there were all these decades of preclinical studies in animal models of diseases showing that when they returned got hookworms that the disease would be eradicated or blocked. [17:44] And so I thought that was really interesting. So I started with that and I started exploring why is that. [17:51] And so there's this whole study where we actually if you look at mummies that they have had got roundworms from a very long time ago, the oldest mummy that you could find, odds eat a Iceman. [18:04] Remember when they found him? King Richard the third when they found his body under the parking lot. There was there was worms. [18:12] So I think that there has been a long history of worms. And the further you go into the literature, you realize, oh, they've actually been here before we were homo sapiens. [18:22] They were here back when we were in the grasslands like Lucy and australopithecus, and they've co evolved with all of our human ancestors to this point. [18:33] So now it makes sense that actually they're a part of our immune system the same way that gut bacteria are a part of our immune system. [18:40] And they're communicating with all of the molecules, the pheromones of our body. [18:47] And when we take them out, what happens? Well, we know what happens. [18:52] And then suddenly there's a spike in allergic and autoimmune disease. Is that a coincidence? [19:04] And epidemiologically, you know, sure, you can always ask yourself if that's a question. [19:09] But if you look up, you know, if you go to chat, GPT right now and you ask what's the country with the most allergic and autoimmune disease? [19:16] It's sub-Saharan Africa. And what's the country that has the least, I'm sorry, the least amount of allergic and autoimmune disease that's sub-Saharan Africa. [19:26] What is the country that has the most amount of gut dwelling brown worms? Sub-Saharan Africa. [19:34] So that's really interesting because they didn't take out their worms. They're also not industrialized. [19:41] They're not they don't have a bunch of microplastics in all of their food and all of these components. [19:48] So then I thought, let's get into the worm piece there. Let's tie this now. [19:53] Now people are looking for what could it be that these worms are secreting that could be responsible for protecting them? [20:01] And then that's where I thought, oh, I think I have that right. I've tapped into this secret language of worms. [20:07] Could it be that something from there is capable of doing that? And lo and behold, that's what we found. [20:13] So then that's what changed my trajectory in becoming a physician scientist, which was just my plan for the longest time. [20:24] And when you suffer through that many standardized tests, you're like, I'm doing it no matter what. [20:31] So it really wasn't my plan initially to be an entrepreneur. It's not a necessity because I knew that there was a lot of potential here in the discovery that we made that we could actually turn the tides on allergic and autoimmune disease. [20:47] No one had actually tested this before. We've been trying putting back bacteria for decades now, right? It hasn't turned the tides yet. [20:55] Could it be that the missing piece is actually worms? And can we return that without having to return gut roundworms? [21:04] Can we encapsulate some of the key therapeutic secretions that they're utilizing and then return that back into mankind? What would happen? [21:16] And so I just really need to know the answer to that. [21:21] And, you know, I mean, you might have wanted to be an entrepreneur, but you turned out to be a pretty good one. [21:26] And so, I mean, you know, it leads us up to Hola Clara. [21:31] We'd love to hear a little bit. Well, I love to hear where the name comes from. [21:35] But, you know, clearly you've been on a roll. [21:39] There's, you know, you've been publishing on a lot of the sort of the the pharmacology as of late. [21:48] It was an interesting paper that you did in PNAS on mammalian type two inflammatory responses, interesting models of asthma, [21:59] even patented on all sorts of interesting mechanisms of these substances. [22:05] I'll six, I'll one disease, the oceanophilic esophagitis. [22:10] Talk about the company, sort of what goes on on any day. [22:14] And what do you have? I have a lot of worms and assays. [22:18] But what typically happens in your discovery process? [22:22] And, you know, how do you choose which of these interesting diseases to go after? [22:27] Walk us through a little bit of sort of the day to day of Hola Clara, if you would. [22:31] Yeah, I think in making those sorts of decisions about where we go, which molecules we choose, [22:38] we've really pulled in a lot of great advisors and people that are here to help with that process. [22:47] So, you know, early on, I thought, OK, how first of all, how are we going to do this? [22:52] Are we going to put this into a powder and sell it at GNC? [22:57] Or are we going to formulate this into a drug and go to the FDA? [23:02] And that's for anyone that's an academic. That's a little daunting. [23:07] Right. Because you just think, oh, hundreds of millions of dollars, huge failure rate. [23:13] But when I did the analysis, here's what I came to that really drove that decision, which is I impact. [23:21] I think this could truly change the world. What is the greatest impact? [23:25] And that really is FDA approval on clinical trial. [23:30] The other reason is of not going into a supplement or medical food, which I've explored all of those, [23:36] is that I read this study that if someone changes your copayment by even a couple of bucks, [23:44] people don't want to take that medicine, even if it leads to morbidity, mortality, [23:51] because there's something about when you when you start paying two dollars fifty cents for your medication, you get used to that. [23:58] You really get used to that. And I get it. [24:01] People can't afford expensive medication. [24:04] So if I'm trying to sell my supplement for 100, 200 dollars out of pocket, then my reach is going to be pretty limited. [24:14] So that's how I thought about, OK, we're going to do FDA approved trots. [24:21] So that's number one. Number two is the molecule. [24:24] And we chose a potent molecule that not only worked for allergic disease, which is TH2, but also autoimmune disease, [24:36] which is TH1, T helper type two and T helper type one. [24:40] And so that was really interesting because then we realized this is not working like your typical drug. [24:47] Nowadays, we look in drug as modern day drug developers. [24:52] Look at the history of how we've been doing it. [24:54] You know, we started with nature to try to find things like that could just naturally affect, you know, [25:01] help people with with antibiotics or natural chemo drugs. [25:07] And then we moved into this era of targeting things to take them down. [25:11] Like a biologic is a targeted monoclonal antibody that will take something down. [25:15] And so we get used to this mentality of let's inhibit, let's block, let's take the disease pathways and block them. [25:21] So now we have a technology that's in different contexts of disease able to block either a allergic disease or not immune disease. [25:30] So what that means is it's actually not blocking anything. [25:34] It's promoting something. It's promoting the good cells of the immune system. [25:40] It's promoting the regulatory elements that are now able to block disease. [25:46] And I thought that was really incredible because of course, nature evolves something to work with the immune system, not against it. [25:55] And then how can we continue to understand that? That's really compelling to me. [26:00] So for our first molecule, we're starting with an allergic disease. [26:05] The plan for it to quickly follow on to the autoimmune space as well. [26:11] And I can share more about that indication later this year. [26:15] We are entering clinical or phase one clinical trial this year. [26:19] And so that is with healthy volunteers where we'll be able to get pharmacokinetic data in humans that will be orally ingesting this molecule and returning it back to mankind for the first time, which actually is where the name Holoclara comes from. [26:35] Holoclara comes from the Greek word holoclaros, which means to complete the missing piece, to complete. [26:41] And I think that this is actually the one thing that we've been missing and we haven't yet returned. [26:47] So this will be the first time in the history of mankind that we're going to replace and return this missing piece now that it had been removed. [27:00] Andre, you mentioned early on, you know, you're talking a little bit about sort of the novel structures that you were finding in the pheromones when you're doing this work. [27:13] And, you know, for my own a couple of careers ago, I was involved in the in the in the fight of chemistry space. [27:20] And I was always amazed by the the complexity of which plants and these other organisms created their chemistry. [27:28] It was it went beyond how sort of the chemist in the lab thinks about stuff. [27:32] And I was just wondering if we're getting into confidential stuff, we can we can go right by it. [27:36] But how complex are some of these moieties that the nematodes make? [27:42] Because you mentioned sugars and fatty acid chains and stuff. [27:45] And do you have to do much in terms of modifying them? [27:50] Not just not for activity, but in the sense that sometimes it's hard to get patents around things that pop out in nature. [27:59] Yeah, so that's actually was one of my initial worries was what are we going to do with this natural molecule? [28:07] And so then I went to this chemist at Caltech, Brian Stoltz, who's well known for one of the best chemists in the world, [28:15] but also really interested in synthetic pathways from nature. [28:19] And I said, will you help me modify this molecule if we need to? [28:25] But I really don't want to change it because I don't want to change nature. [28:30] If there's something that's going to keep me up at night, it's that nature has spent millions of years innovating this great molecule and I just muck it up somehow. [28:40] And, you know, he was a great thought partner in thinking about how we could be really intentional about ways that we could modify it if need be. [28:50] Well, gee, you're trying to return this molecule, but now you're going to swallow it instead of it being secreted by a worm that's living in your gut. [28:58] So how can we help that process? How can we improve that and only modify things there? [29:04] So ultimately, we ended up doing a lot of medicinal chemistry and we did find things that worked well. [29:11] And our top modified compound, funny enough, we were going to go forward with that one. [29:18] And it ended up turning right back into the natural molecule, which I thought was so spectacular that we thought that we could iterate and make it better. [29:27] And then in the end, it was just going back to the nature's nature's active molecule. [29:34] So in that sense, there are actually a lot of ways to protect that natural molecule. [29:40] And there's formulation patents, there's method of use, and the method of use can be quite broad. [29:46] It doesn't need to be in by indication. It could be methods of modifying a whole categories of disease. [29:53] So we were very excited to move forward with our natural molecule. [29:58] Continuing along that, one of the one area that worms were not your worms, but another worm, namely the leech has had success in has been this [30:19] Herodin combos. It was, you know, this is back in whatever 20 years ago now, but, you know, they found this anticoagulant and the saliva of leeches. [30:28] It was turned into a drug. But back in the day when they were doing that research, you know, the leech, as most of these ancient organisms, didn't just secrete that one thing. [30:39] They secreted really these complex combinatorial libraries of stuff to do their leeching or whatever they needed to do. [30:47] Hey, I'm going to fight. I want to suck this blood. I don't want it to coagulate. [30:51] I'm going to pop out all sorts of anticoagulants to make sure that doesn't happen. [30:56] Single molecules developed, but obviously a lot more stuff there. And I'm just I was quite interested. [31:01] I looked at one of your patent publications and then, you know, I see much recent one utility of nematodes, small molecules. [31:08] You do mention not just compounds, but mixtures of compounds. And I know this is early in the process, but any interesting findings along the way as you're doing your work on how some of these synergies that may pop up in the sense that evolution probably says, [31:25] I'm not just going to make this one thing because of whatever I'm going to make combinations because it's probably a more efficient way of if one molecule doesn't work, this one might and so forth. [31:36] Any interesting stories, anecdotes as you're studying these compounds? Hey, you know, if we put A, B and F together, well, that's even it does something to pharmacokinetics, pharmacodynamics. [31:49] You see where I'm going. I'm just I do. And that's actually where I started. But we ended up finding individual molecules are actually quite potent on their own. [32:01] You know, when you're imagine you're an alchemist and you have every, you know, this lab alchemy, right? Imagine you have this great alchemy lab with all these things bubbling over when you're studying them. [32:12] The best place to start is to really characterize one thing at a time and then add a different spice. [32:19] Once you add that spice, you can't add that spice. So I think we really tried to focus on which of these molecules actually is strong on its own. [32:30] And we can always go back and study these other things that work in combination. But for our first shot over the bow, going into a trial, we don't want to make this complicated. [32:40] We want to make this as simple as possible and then go from there. [32:46] Makes complete sense. And I appreciate that. And I think I know what you're going to say. The next question I was going to ask anyway. [32:54] Back in the early 2000s, both leeches and maggots were approved in the United States by FDA as medical devices, living medical devices. [33:05] I don't know if the FDA has yet approved any living nematode products in the United States. I think there's some in Israel or some other countries. [33:13] Again, early days, you're focusing on small molecule drug development. If you came up with a really cool nematode that did something, if you kept it alive, [33:24] any interesting discussions going on in-house about FDA is open to these other types of therapies? [33:32] You can be a drug company, you can be a consumer product company, you can be a medical device company. [33:38] Hold on, hold on, hold on. Let's talk about leeches for a second because this is the second time you've brought it up. [33:43] I trained at County Hospital and it's great because you see everything and there's no treatment that's off the table. [33:52] I remember writing a script for leeches from the general pharmacy and I just could not believe when they arrived in a little saline bottle and they were looking around, [34:05] what in the world? Are we really going to do this? And there was a girl that came in with diabetic foot and there was some necrosis. [34:13] As you know, when you have necrosis, the treatment can't really, when you take it orally, it can't really reach there because it's not vascularized in that tissue as well. [34:21] So the leeches were great in that you could put them topically on and it could de-bride, it could remove some of that tissue. [34:28] So that's if you're, you just have to pretend, always ask yourself, if I am the worm, what am I doing? With a leech, that's its perspective. [34:38] And so if I were to tap the leech for more therapeutics, it would probably be, you know, like you said, okay, if it wants to take some of the tissue, [34:49] it's probably releasing something that can help numb the tissue. So then I would mine that worm for numbing agents. [34:56] Not all worms make all therapeutic things. You just have to look at it from the point of view like, if I were this worm, what would help me? [35:03] What would be beneficial for me to secrete? So then going to gut worms, that's where I'm really interested in because those are the ones that have co-evolved with the ancestors. [35:16] What is their end game? It's to promote the best environment for their host, which is their home, right? [35:23] So you want to influence things that are not just inflammation. When you're inflamed, you know, your body is sending angry, patrolling molecules. [35:31] It's the worm doesn't want any, they don't want the police force breathing down their neck, right? So they're just trying to create a balanced, happy home. [35:39] And if there's a wound, it's trying to send reparative molecules to help promote repair. You don't want a hole in your home. [35:46] So that's really where our focus is, those families of worms. And so with them, I don't want to return the actual living worm back into the human body. Why? [35:59] Because of variability. And there's always, it's so funny, someone once asked me like, what kind of, what do you, what do you have nightmares about? [36:09] And sometimes I'm like, just math, like just signal the noise. And I think that's really where this variability nightmare is. [36:18] When you give a living worm to somebody, I think you swallow it. You don't know what's going to happen to that worm. [36:25] It's it's first of all, definitely not studying the worms that go to your eyeball and all of that. [36:30] Those those ones are off the table. We're not, we're not even messing with those. I'm talking about the ones that have led to better health of those worms. [36:40] I don't want to be, I can't, I can't account for that worm. I'm not going to sit down and have a talk with it. All right. [36:46] You go into the intestine, you stay there, you have exactly 100 progeny and then you're out. Okay. [36:51] There's no way to do that. So I think that we really want to focus on removing the worm and finding ways of just taking a therapeutic and be making it measurable, understanding the pharmacokinetics of that. [37:05] And so that's why I'm moving away from live worm administration. And that's not to disparage that there are people that do that. [37:15] There are people find me and talk to me about how they give their children with intractable diseases living around worms. And now they can they can thrive and they could do things they could never do before. [37:28] So I'm not, I certainly don't disparage all those brave people and parents that are doing that. [37:35] I just thought I'd get your perspective on it because, you know, and I was thinking as much about sorry, as leashes and maggots, but, you know, with with with fage therapy as well, when you think about giving viruses and stuff like that. [37:48] But no, I appreciate your insight on that. So I just thought I'd ask because you're at the epicenter of it all. So I. [37:54] But I know as you know, bringing up fage for a minute here, I'm getting into my next topic and I think this is kind of important. [38:04] Kind of important because you do have an interesting patent on in terms of these compounds and modification of the mammalian microbiota. [38:14] Going back to your PhD for a minute, there is this cool part where you talk about the similarities between these caricides and some of the compounds that we see in bacterial quorum sensing. [38:27] And, you know, antimicrobial resistance has been a really hot topic for the show. [38:33] And, you know, obviously we're in this realm where, hey, we're yes, we need to antibiotics for the same time. [38:39] It'd be cool to have other compounds that do other things like quorum sensing say, you know, bacteria, you know, go away, separate, do other, you know, go pay attention to other stuff as opposed to sort of the typical antibiotic strategy. [38:51] Any interesting stuff that you could talk about in terms of how some of these molecules, no doubt, you know, worms have had to develop their own antibiotics over the years as well to defend against disease. [39:04] But when I saw this, you know, patent of here, I was like, they're thinking about this as well. [39:09] So it's I yes, I love this question. [39:13] And there's something that you said that stuck with me, which is go away. [39:17] And I think that that's here's what I would love to propose to you and your listeners is to try to think about possible therapeutics in a different way where we don't have to tell something to go away or inhibit or block. [39:34] How can we work with them in synergistic ways? [39:37] And I know that sounds bizarre because you're like, oh, there's a bad bacteria. [39:41] They should be out. [39:42] Well, not all bacteria are bad. It's just when they're out of control. [39:47] So how are they communicating? [39:50] And for example, you know, if you if you take an if you take an antibiotic, your wife, you're wiping out a lot of your bacteria, then suddenly you're more prone to a fungal infection. [40:00] So wiping out one thing can cause all of these. [40:03] It's about balance, not having that balance can cause a different infection to come. [40:08] So then we're playing this constant game of wipe it out. [40:10] Now deal with the side effect. [40:11] Why fund this out? [40:12] Now deal with the side effect of that. [40:14] And we're just chasing our tails as humans because that's how we're programmed to think is you take something and you take it out. [40:23] But how can we start to study now the language of all of these microbes and how we communicate with them to and our cells are communicating? [40:32] How are they working together? [40:33] And how can we promote that? [40:35] Even in that example where I said I don't the worms don't want the police force coming. [40:39] It's not that they're going to I'm just imagining a cartoon in my head of like immune immune cells dressed up like bad or something. [40:48] And you're like catching the net and you you throw them down the drain. [40:52] But actually, it's like, how do you talk to that cell and promote it to do something better with its time and its life? [41:01] And again, I know that that sounds far from our current reality of understanding, but those are the types of therapeutics that I'm really compelled by. [41:10] And I think those are the types of things that we seek to explore. [41:13] Ultimately, is this Atlas of worm molecules and how they're commuting with with the microbes and with immune cells. [41:21] And what are the molecules that they're using that can promote synergy? [41:28] I in researching this stuff to prepare for our discussion, one of the things that I found quite interesting was that the nematode taxonomy or the taxonomic clade or whatever that they're involved in. [41:46] The tardigrades are there also. [41:49] And I did a show on tardigrades a couple of years ago, which are also an extremely resilient group of organisms. [41:58] And they have this really interesting ability to shut down and go into this extended state of suspended animation. [42:10] And I saw this little piece on how these ascaricides and you mentioned this earlier on this induction of long lived sort of the stress resistant dour state. [42:22] Obviously, aging is a very hot topic as well nowadays. [42:26] Longevity biotechnology is something we focused on. [42:30] Any interesting findings so far in terms of how or thoughts on how ascaricides or other interesting molecules from these organisms can potentially be applicable in the human resilience space that sort of compromises sort of longevity biotech today. [42:48] Yeah, I love that you chose the water bear the tardigrade because it is an extreme organism and those are the types of organisms that are being studied studied in extreme biology. [43:00] How are they doing that? [43:02] Someone outer space. [43:05] And also worms they sent them down our space. [43:08] I don't know if that's part of studying whether their extreme is can you make it there and back. [43:14] The space station. [43:16] Exactly. [43:17] And I think that you just have to think about it from the perspective of that, that that organism. [43:26] So the in the example where you're talking about the worm going into hibernation state. [43:33] That's the worm itself going into hibernation state. Right. So those molecules are going to do diddly squat for the organisms around them, because it's using it for its own. [43:44] So, you know, just thinking about them turning into like Han Solo going into carbonite, you know, whatever they're they're helping themselves. [43:52] But what are the molecules where are the worms that really want to promote human health and longevity, where what what worms are those so then you're looking at hosts that have lived for a long time, or the worms that are there. [44:06] And actually, there are studies to show that they can increase stem cells and do that sort. [44:13] So I think that's where we start looking is what are the molecules from those worms that can increase stem cells and turn on these genes. [44:23] These that are so they're known as fetal genes, right, that's like, oh, wait a minute. They're able to turn those on me didn't. We haven't turned those on since you're a fetus. [44:32] How can we read how do we turn those back on. So people are finding that worms and specific worm species and think and and families of worms can do that. [44:43] So that's something that we are studying that I think is really interesting. [44:48] For sure. Yeah. Yeah, I saw that as well and thinking, you know, as we're in this really interesting era of cellular reprogramming, epigenetic rejuvenation things of that nature. [45:00] I think there's, there's a lot for you to uncover that space as well. I'm excited for you. [45:05] So that as well. [45:07] Epigenetics itself like what is that? That's the hand. That's the unseen hand, right? That's the unseen. [45:14] So I love people that are studying epigenetics because it's like the the DNA is like the the code. [45:22] The RNA is like the music and the epigenetics is like the conductor's hand. That's that's unseen. [45:28] And I think that the world right now is they're either really excited about it or really scared of what that looks like. [45:34] I think it's a really exciting time for epigenetics. [45:39] So, Andre, so I mean, awesome scientific story. You put together a great team, a really cool board. [45:47] And then, yeah, a couple of weeks ago, 16 million dollars, Series A. [45:52] What else is what else is happening that we should know about? Clearly, you're set up to do some amazing work headed towards the clinic. [45:59] What else should we know about for 2024 as we get into 2025 with regard to Huluklera? [46:06] I think it's really all about going towards the patients, right? That's our mission is ultimately to help people. [46:13] I mean, that's what your three and four med school showed me is the tremendous need of people that are looking for something outside of steroids will shut everything down or biologics will take something down. [46:25] But it's like, how can we what are the other options? So, I mean, that is always going to be a carrot at the end of my stick. [46:33] So the fact that we're going into this phase one trial is just really exciting for us at the company. [46:41] Really excited for me. Really exciting time for all of our co-founders and advisors, all the great people that are part of the Worm mission, so to speak. [46:52] All eyes are on this launch. And I think that's really where our eyes are on going into the end of this year. [47:02] And we'll be really excited to announce that more details around that and more details around the first indication that we've had our eye on that we've been really exploring, getting to understand the KOLs in the space, the patients I've been interacting with for years in that space. [47:20] So I think that that's all where my focus is going to be going into this year. [47:27] Well, it's a great focus. I'm excited for you. I'm excited for the company. I love these stories that merge, you know, hundreds of billions of years of evolutionary power with modern biopharmaceutical technology. [47:42] And I think you're on the right path. I think, you know, not to put down any of the artificial intelligence and all the other tools that we profile on the show, but nature, you know, the species have been here for a long time and still have a lot to teach us. [47:55] So I'm really looking forward to continue to follow you or your journey, the company's journey and really wishing you the best with all of it as you get close to humans. [48:04] Again, for everybody that is going to be listening to this episode of our show across the various podcast networks or who will be watching on our YouTube channel. [48:18] Again, you've been spending time with Dr. Andrea Cho, Chief Executive Officer and co-founder of Holoclara, doing really amazing things to develop novel, safe, orally bioavailable, worm-derived therapeutics for a range of unmet mental conditions. [48:32] Andrea, I really want to thank you for the talk, the discussion. I really enjoyed everything. I appreciate you taking the time out of your schedule to educate us on all these topics. [48:42] And again, we'd like to say on our show, thanks for creating a better tomorrow for a lot of people via what you're going to be creating here. Really great story. [48:50] Thank you so much for having me and having this platform where you really help to support all of these ideas for a better tomorrow possibility. [48:59] I've been listening to your podcast for years. So, you know, thank you for just doing all of this and bringing these stories out there. [49:08] I appreciate the kind words. It was really a lesson having.