147: "Shhh…They’re Talking: Holoclara's Dr. Andrea Choe Tunes Into Worm Signals for Health”

[00:00:00] GE - Ep.147 Andrea - Karl: All right, Dr. Andrea Cho, welcome to the Grow Everything podcast. We are so happy to have you here today.

[00:00:06] GE - Ep.147 Andrea - Andrea: Thank you so much for having me. I am really excited to be here and talking with you guys.

[00:00:11] GE - Ep.147 Andrea - Karl: You have such an interesting background. The work you're doing is so fascinating. you have gone from evolutionary biology research to building a biotech startup around. Get this audience worm derived therapeutics. That's not what you've done is anything but typical. What was a moment that convinced you to go on this trajectory?

[00:00:34] GE - Ep.147 Andrea - Andrea: Oh man. Great question. I would say that once I made the discovery, which we'll get into, at some point in this conversation, but once I made it, I actually went back to finish my last years of medical school. For anyone that knows the MD PhD program, you do your PhD and then in the last two years of the program, you're in the hospitals, right?

[00:01:00] GE - Ep.147 Andrea - Andrea: So you wake up. You get to the hospitals 4:50 AM you talk to patients and you help with their care. And I would say while I was talking to them for those two years, sharing my story and what I had found, they had all just made the assumption that I would take this forward. They're like, oh, when are you gonna bring this forward?

[00:01:20] GE - Ep.147 Andrea - Andrea: When are you going to bring this to market? And then it wasn't. Like they persuaded me or I was coerced to, but every time I heard it, it had this resonance of truth, like, yes, that actually is my path, right? So at some point when I finished my medical degree, I thought, okay, I've got to do this. And I just saw no other way.

[00:01:43] GE - Ep.147 Andrea - Andrea: And one of my earliest angel investors said that, he invested in me because he got to witness seeing the phone ring and seeing me answer the call. So I don't know if that's too philosophical an answer, but really that was how it happened.

[00:01:58] GE - Ep.147 Andrea - Erum: No, it's amazing. It sounds like there was a demand, right? And Carl teed it up, worm derived therapeutics. So tell us about your discovery. what happened?

[00:02:08] GE - Ep.147 Andrea - Andrea: where do I even begin? I would say that I walked into a worm lab. Let's start there. when you start your PhD, you walk into a variety of labs. I actually. Originally worked in with mice, I worked with flies, and then I walk into a worm lab, and then from there you can study anything that you're curious about in life.

[00:02:28] GE - Ep.147 Andrea - Andrea: think about all of the Nobel prizes that have gone to worm scientists. It's because they can extract so much incredible detail about how life is programmed. So that's what originally brought me into the Worm lab. Then from there I just saw them engaging, interacting with each other, and I became deeply curious about them from, like a behavioral animal, behavioral perspective.

[00:02:55] GE - Ep.147 Andrea - Andrea: And,it's interesting 'cause I,I once met. Jane Goodall and she said the very first animal she ever had, her first pet was a worm. And by the way, my friends thought that I made up this story for years until like last month. She went on the call her daddy podcast and shared this story.

[00:03:11] GE - Ep.147 Andrea - Andrea: there you

[00:03:11] GE - Ep.147 Andrea - Andrea: go.

[00:03:12] GE - Ep.147 Andrea - Andrea: Butimagine you are a young Jane with worms in your hand. you become deeply curious about them. You have the patience to ask questions about them and how they might communicate with each other, which by the way, you normally wouldn't think that because your experience is probably, one worm on a sidewalk at a time.

[00:03:32] GE - Ep.147 Andrea - Andrea: You don't see them engaging. But when you work or you walk into a worm lab, you do see that. You do see them engaging with each other, and I could not help but become curious about how they're communicating without eyes, right? They. We don't have ears. It's gotta be sensory or chemical. So I embarked on a journey to understand their molecular language and how they communicate with each other.

[00:03:57] GE - Ep.147 Andrea - Andrea: from there, I'll just stop for a second because I know I just said a mouthful.

[00:04:01] GE - Ep.147 Andrea - Erum: Yeah. wait. Before we get into that, I just have two comments. Last questions. One is Nobel Prize winners, for worm research. I had no idea. you mentioned that, and so clearly there have been, Nobel Prize winners that have studied worms. Can you maybe tell us about one or two of those before we get into your discovery?

[00:04:19] GE - Ep.147 Andrea - Andrea: Yeah, understanding how RNA, how DNA is programmed in the worm, understanding the application of fluorescence protein, which was a tool that was then developed in the worm, helped us to understand a lot about how life is encoded and. Also how worms can be used as tools to understand science that you can now code encode any gene to glow, right?

[00:04:46] GE - Ep.147 Andrea - Andrea: So then if you become deeply curious about What is this gene that we found in the Human Genome Project? What does it do? You can actually tag it to a glowing protein. That was derived from jellyfish and programmed in the worm to light up, which is a transparent organism. So now you could see where it lights up at any point in its life.

[00:05:05] GE - Ep.147 Andrea - Andrea: So those are some of the discoveries that were made in worms. there's so many other discoveries that were made in worms too. Not yet. Nobel Prize winners.

[00:05:15] GE - Ep.147 Andrea - Karl: And one other just kind of comment, diary of a worm. have you seen this book? It's a kid's book, probably aimed at like pre-reads. Iam, you're probably at the point where Autumn is ready for Diary of a Worm and there's a couple of them and it tells the worm story from

[00:05:31] GE - Ep.147 Andrea - Karl: their point of view. and it's hilarious. but let's get into your discovery. I digress. I'm sorry.

[00:05:37] GE - Ep.147 Andrea - Andrea: Oh, that's great. I have a five-year-old son and I haven't, if there's anyone that should be reading it to their child, it should be me, so I will find it on my Amazon list later today.

[00:05:49] GE - Ep.147 Andrea - Karl: yeah, so tell us about your discovery and how that has led to Ola Clara, and what you guys are doing.

[00:05:54] GE - Ep.147 Andrea - Andrea: Yeah, so where we left off was that I became interested in studying how the worms were communicating. And the other thing is when you open the worm freezer, so there's a minus 80 freezer where you open it and the cold fog kind of drifts out, and then there are shelves in there like at a library, and it's organized like the dewy decimal system.

[00:06:15] GE - Ep.147 Andrea - Andrea: And so then you can look for the worm species that you want. Pull it out. And then it's a little tube that you can flick the lid open, scrape a tiny piece out, put it on a Petri dish, and then you see them crawling within hours.

[00:06:30] GE - Ep.147 Andrea - Andrea: And that could be any mutant strain, right? Or some species that you gathered from some other part of the world. and then someone, I could actually print it out and paste it in the room, an evolutionary tree of all these worms and how long ago they evolved, which blew my mind. I was like, wait a minute.

[00:06:46] GE - Ep.147 Andrea - Andrea: This worm evolved a hundred million years ago. This one was 200 million years ago. This one was 300 million years ago. How do we even know? And it turns out that because Sea Elgan, one of the organisms was so well studied, people thought to study all of these worms around it and say, this is how far away it's diverged from Sea Elgan.

[00:07:05] GE - Ep.147 Andrea - Andrea: And you could tell that by looking at the RNA. And the DNA. So I thought that by itself was fascinating. So then I thought, wait a minute, I actually have these worms at my fingertips and the ones that I cannot get, I'm gonna email and introduce myself and say, I'm a scientist from Caltech. Will you send me your worms?

[00:07:24] GE - Ep.147 Andrea - Andrea: and it worked. People sent me their worms from all over the world. People would gift me worms. I would come to work, I would see it on my bench. here's some worms for you. And then what you could do is you could either watch them move around, but what I became interested in was collecting their secretions and then partnering.

[00:07:42] GE - Ep.147 Andrea - Andrea: With a chemist at Cornell who could do Mass Spec and NMR and tell me what was in them. So then from there, I originally intended to, I don't know, publish like a worm book with chapters of it. Like, here's what this one did and secreted, and this one secreted and this one secret. But ultimately what we accidentally found was that they were all secreting something similar.

[00:08:05] GE - Ep.147 Andrea - Andrea: There was some common denominator between all of them. And then when we found it, we said, wait a minute. We knew about this already. This is something that puts sea elegance into hibernation. This was what helps launch this whole field of longevity in sea elgan in aging. How could it be that such an important pheromone is used by other species?

[00:08:27] GE - Ep.147 Andrea - Andrea: So then we started mapping it out and we saw these other patterns. Wait a minute, there is this one sugar chain that's not found in any other animal in the worm. It's like a world. It's not found in any other animal in the worm. See now I'm just using the word worm to replace any word that starts with the letter

[00:08:44] GE - Ep.147 Andrea - Andrea: W.

[00:08:45] GE - Ep.147 Andrea - Andrea: S and then we saw that different lengths of the tail, like three carbons versus four versus one with the carboxylic acid, they were like different letters of the alphabet, and then they all spoke the same language, which to me is mind blowing because it's been this secret, invisible language that we didn't know that they were using, that they could communicate with each other around the world without us even knowing.

[00:09:11] GE - Ep.147 Andrea - Andrea: So then that became my thesis was the discovery of this sort of universal worm language. So that's also a whole thing on its own. And I could get to part three of where this brings us to biotech, but any questions there?

[00:09:26] GE - Ep.147 Andrea - Erum: Yeah, and this is, fascinating. So you have this worm pheromone language, when we first were introduced to you, I'm like, okay, I'm curious and I'm like, I wanna learn more. And I was like, okay, what are you doing? You're in the lab and I wanna go more into the science, but maybe we just go into, how you started your company, halo Clara.

[00:09:46] GE - Ep.147 Andrea - Erum: so tell us the work that you do. What would someone see, touch, experience if they were in your lab or holding one of your. Therapies that are in development, how did you make that leap from worm pheromone language to therapies?

[00:10:01] GE - Ep.147 Andrea - Andrea: Yes. So I would say the walking into the lab back then is a very different experience than to walking into our lab today, walking into the lab. Back then you would see all of these flasks shaking with different species in them. Me collecting all of those secretions. And then over there was mosquitoes infected with larva.

[00:10:21] GE - Ep.147 Andrea - Andrea: You could see the worms explode out of them, and then you would see I had roses growing on the window sill and I,I actually planted them there when my lab mate left town, he came back. He's like,oh, nice roses. I'm like, oh, they're infected. They're infected with parasitic worms. So it was a zoo, it was for sure a zoo.

[00:10:42] GE - Ep.147 Andrea - Andrea: And that's chapter one. Then after I just discovered, along with our collaborators, this worm language, then I heard this radio lab podcast about how there was this guy who had terrible asthma. he went to Africa to get hookworms on purpose. He walked around barefoot and he said, I'm gonna get hookworms because I've heard that they can treat allergic disease.

[00:11:06] GE - Ep.147 Andrea - Andrea: And then he treated himself and got better, which I thought was. Bizarre, right? Why would he do that? And then I just started looking online and finding that actually a lot of people with these severe diseases are taking dis round worms, parasitic worms to treat their disease. So then that led me to try to figure out why is that and why would worms do that?

[00:11:30] GE - Ep.147 Andrea - Andrea: And it led me down this whole path of realizing that worms are actually secreting something. Immunomodulatory. And then I thought, I actually think I have that. people are trying to figure out how do we get that therapeutic effect without having to eat worms? Do people know what worms are secreting and.

[00:11:48] GE - Ep.147 Andrea - Andrea: My answer was yes. I think we found the rose outta stone of worms. So why don't we look there and try to decode this? So from there we tested our molecules and animal models of disease, blocked a couple of diseases, and then everybody that I was working with was like, wait, when This should be become a therapy?

[00:12:05] GE - Ep.147 Andrea - Andrea: You should start a company. And so how the company arose. We took a molecule that we found out of worm, started synthesizing it from scratch. So now part two is without the worm, son's worm, the molecule in its purity, right? And then the cells that you're seeing mostly in the lab.

[00:12:28] GE - Ep.147 Andrea - Andrea: Are mostly human cells because now we're testing them in that context. So now if you walk into our lab today, it's mostly, like here are our T cells or our B cells, or our dendritic cells or macrophage that we're growing and testing how our worm derived molecule interacts with the human system.

[00:12:46] GE - Ep.147 Andrea - Erum: Yeah, I have two comments. First of all. You said macrophage in,such a classy way. 'cause we've been talking about it and we say phage like just like hunky donkey people like, Hey, phages, Fages. Okay, moving forward we're saying fages.

[00:13:01] GE - Ep.147 Andrea - Karl: Forever

[00:13:02] GE - Ep.147 Andrea - Karl: It sounds like the yogurt. It's that Greek I was just gonna say, my husband Issa Yogurt, and he was like, I'm gonna get my F or fa. I was like, what is he

[00:13:12] GE - Ep.147 Andrea - Andrea: saying?

[00:13:13] GE - Ep.147 Andrea - Karl: Yeah. He is talking about Fs.

[00:13:15] GE - Ep.147 Andrea - Erum: and then that story about the guy who went to Africa, and got the hookworms. I first read that in a book, by Rob Dunn, who is, a amazing biologist and his book is called Wildlife of Our Bodies, and his approach was that. maybe like hundreds of years ago, I don't know the correct timeline.

[00:13:34] GE - Ep.147 Andrea - Erum: We didn't have shoes. We were walking around the earth and worms were always around us and they were a part of our ecosystems and had. Effects on us. And so,whether they're in and or on us, our bodies, our immune systems and other systems became acquainted with these other organisms. And, we had talked about it several episodes ago, 'cause I was reading the book and I always like to like, recap some things I'm reading to make myself sound smarter.

[00:14:03] GE - Ep.147 Andrea - Erum: but it's really incredible to be able to see it because we live in such sterile. Worlds now that there's no way people are walking out barefoot, near like a latrine, which we don't have here in our Western world, in the United States, 'cause that's you're in the us. Maybe we need to, and this guy did and he cured a disease.

[00:14:23] GE - Ep.147 Andrea - Erum: It's like,how much of our bodies today are these autoimmune disorders are caused by our sterile environments? And I thought, it's a very interesting thought, which I am so curious to know if this is something that you and your team have been thinking about.

[00:14:39] GE - Ep.147 Andrea - Andrea: I think you've nailed it. the key there is to go back in time. Let's go back in time a little further from that turn of the century, right? from the 19 hundreds, let's go back further to the earliest human ancestors. So now we pretend that you are an APHAs, you're friends with Lucy, you're on the grasslands of Africa, right?

[00:15:01] GE - Ep.147 Andrea - Andrea: And there, you and all primates are constantly getting. Roundworm infections from birth to death. So that's number one is you are right. You're acquainted with, you said that they're acquainted with these roundworms for your whole life. Now, so were your ancestors and so are your progeny. So now let's do another shift in perspective.

[00:15:28] GE - Ep.147 Andrea - Andrea: Now imagine, pretend you are the gut worm and you're in the gut. Okay? So let's just stick with, still being in the grasslands of Africa at the time, and you're sitting in the gut and you see a hole in the wall, you know that's a problem because you are there. You wanna live in the intestines for not.

[00:15:46] GE - Ep.147 Andrea - Andrea: Months, years to possibly decades. Okay? So you need to patch that up. Although there is no Home Depot for worms in the human body, right? You can't go buy a bucket of spackle and paint, right? So what you do know is that the human body already has their versions of that, and you can start secreting things and seeing if you could lure them in.

[00:16:09] GE - Ep.147 Andrea - Andrea: So let's say you're a worm and you're sitting by this hole, okay? So then you start secreting things and then lo and behold, one of those compounds. Ends up recruiting neutrophils to come eat up the debris and then another. molecule or maybe even the same molecule, better if it's the same molecule, for efficiency's sake, can then also attract these epithelial cells to start laying down and replacing what was lost and also stem cells to do that.

[00:16:39] GE - Ep.147 Andrea - Andrea: And then now don't forget about the plumbing, right? So then you need to call in the endothelial cells to lay in new pipes, the vessels to bring in oxygen and nutrients. Bingo. So that's what you do and you have all of time to figure that out. Then the other side of that is now you're sitting in your home and you're like, okay, job well done, worm job well done,

[00:17:01] GE - Ep.147 Andrea - Andrea: right? And then suddenly you see that the police force of that human ancestors starting to come detect you, and it's blowing. Like shots at you, bazooka is at you, and you're like, oh no, this is not good. And by the way, if it misses, it's actually creating another hole in the wall. So you're like, oh no, I have to deal with this again.

[00:17:25] GE - Ep.147 Andrea - Andrea: So the easiest thing to do is now to secrete something. To tell it to just chill out, quiet down, put away the bazooka. So that's their incentive. They need to do that to survive. So then you and I are sitting there thinking, oh my gosh, if we were playing this video game, I don't know how we figure this out, but they have time.

[00:17:45] GE - Ep.147 Andrea - Andrea: They can secrete whatever they want for years, decades, hundreds of years. Thousands of years. Millions of years. So they've really dialed it in. To do that. So then now with we are acquainted and we rely on that dynamic, and then we fast forward to the 19 hundreds, suddenly the global North, the North America, Europe, we decide this is gross.

[00:18:10] GE - Ep.147 Andrea - Andrea: We begin implementing an aggressive hygiene routine. We start removing worms. And lo and behold, we get all of these diseases. Allergic disease, autoimmune disease. So is that a coincidence? Probably not right.

[00:18:24] GE - Ep.147 Andrea - Karl: Yeah.

[00:18:25] GE - Ep.147 Andrea - Karl: I mean it's super interesting because parasitic worms is something that people maybe think about if they're traveling to a developing country. And maybe what people don't know is like worms are, there's thousands of species. K correct me if I'm wrong, Andrea, and they range from, microscopic, millimeter size to like a hundred, I don't know, a meter long sea worms.

[00:18:47] GE - Ep.147 Andrea - Karl: So there is like this range of worms and maybe the ones that most people are familiar with are the ones that you see on your sidewalk that come up after the rain. And these are incredibly important for the soil. So we need them to churn the soil, digest the soil, keep the soil alive. And there is an issue with over fertilizing and trying to create these aseptic environments to grow food in.

[00:19:11] GE - Ep.147 Andrea - Karl: But when it comes to our own living systems, they're incredibly complex. And it seems like you guys have figured out like this language, but now you're working with these. Living systems that can be very unpredictable. what has been, a setback or something that you've seen that has allowed you guys to leap forward.

[00:19:28] GE - Ep.147 Andrea - Andrea: Wow. You just said a lot there. there's so many interesting facets to your question that let's just un unpack that. One is the un unpredictability piece. I think that it's such an interesting word because it's really in the eye of the beholder.

[00:19:42] GE - Ep.147 Andrea - Andrea: I in some ways think that this longstanding relationship between worm and human has made this the most predictable relationship. Then we suddenly remove something and the problems happen. To me, the obvious solution is put it back. And then, On the other side, we are so accustomed to wanting things to work in some unique one way that we have control over as humans.

[00:20:07] GE - Ep.147 Andrea - Andrea: And then we get really comfortable with it because there's something about how that story is told that now it's like,okay, I've never had an mRNA vaccine before, let's do it so that it is just that. That uncertainty is really interesting to me because I find that a lot of things that we do today, as modern humans are uncertain and unpredictable. And then I guess the other side of your question is, what did we learn? I think I learned to navigate that truly is, went into this as a scientist, as a physician scientist, right? I didn't go to business school.

[00:20:38] GE - Ep.147 Andrea - Erum: You saved your money. What a waste of time. That's my personal thought. Not a thought of everyone. So sorry for everyone that's spent the money.

[00:20:48] GE - Ep.147 Andrea - Erum: I'm sure you have a great network of people.

[00:20:51] GE - Ep.147 Andrea - Karl: Yeah,

[00:20:51] GE - Ep.147 Andrea - Karl: no shade on our friends. who went to business school.

[00:20:54] GE - Ep.147 Andrea - Andrea: Not at all. But I think my only reason for saying that is I didn't go into this knowing originally how this worked, that you have an idea that there are milestones and venture capitalists and they have expectations. So then learning that whole infrastructure and then having to slot into that was very interesting to me.

[00:21:15] GE - Ep.147 Andrea - Andrea: And learning how this whole world functioned, which is, primarily. Money driven rather than trying to, a lot of times it tries to go hand in hand with unmet need, right? But it's primarily profit driven. What is it that you are gonna do that gives us this extra turn in this many years?

[00:21:34] GE - Ep.147 Andrea - Andrea: It's not about a certain disease. It's like,do you know that those patients are suffering? Do you know that they only have, two FDA-approved drugs? Sometimes I hear like,oh, they're not really orphan anymore. So I don't know that we would get the extra incentive to make the extra capital to go into that.

[00:21:49] GE - Ep.147 Andrea - Andrea: And then just being able to hear that time and time again. I will say. It still surprises me every single time because where is the human curiosity to have discovered something that could potentially reverse the tides of disease, that's actually sitting in the hands of a funding framework that was.

[00:22:10] GE - Ep.147 Andrea - Andrea: Very non-intuitive to me. Very, very non-intuitive to me. So I think that the learning was that one, I cannot rely on finding like billionaires that wanna come find me and drink a glass of wine and talk about worms, right? I can't be in my own silo drinking a glass of wine thinking like, oh, that's that.

[00:22:31] GE - Ep.147 Andrea - Andrea: I have to learn the model and I have to find a place for them to coexist. So I think that was just the greatest learning and probably is the greatest learning for any scientist turned entrepreneur.

[00:22:43] GE - Ep.147 Andrea - Erum: yeah, exactly. Oh my gosh. It's such a, amazing point because You're not talking about a setback. That's scientific. there're setbacks. You learn and then you adjust and you continue to move forward. The setbacks and the current, capitalistic institution in which you have to operate and something that we talk about and can continue talking offline, but just like what are new financial models to support science and entrepreneurship?

[00:23:06] GE - Ep.147 Andrea - Erum: Venture capital. Is it the only way? it's the way that's been tested in other industries. Can we have new ones? but back to the work that you're doing. I wanna get back to this idea of worm derived molecules and how they can help with allergies and autoimmune disease.

[00:23:24] GE - Ep.147 Andrea - Erum: Clearly have discovered some molecules. you're testing in animal models. Now. you're testing worm derived molecules in worms, or you're going to mice. and tell us what discoveries you made, like specifically, like what specific autoimmune disease maybe are you targeting?

[00:23:40] GE - Ep.147 Andrea - Erum: We'll just love to know some of the progress on the science side at Hall Clara.

[00:23:44] GE - Ep.147 Andrea - Andrea: For sure. So we actually tested them in animal models, some of our molecules in IBD asthma. And, for anyone that's trying to discover something, you usually stop at that point. You're like, oh, let's start a company. and I, I felt like there was something in me that was driving me. To find another indication in that world.

[00:24:11] GE - Ep.147 Andrea - Andrea: They call it indication is like the disease that you first go into. That's what you're asked. It's likewhat is your first indication? And I do not know what compelled me to do this. Like I sometimes look back at my own journey and I do not know what compelled me to do certain. Things like, I just imagine that hand from the Adams family, like this hand on my shoulder.

[00:24:32] GE - Ep.147 Andrea - Andrea: Like just saying like, join the worm love, abandon your project and study worm communication. abandon the MD PhD H program. And I think there was this hand that told me to find this other disease. And that disease was eosinophilic esophagitis, which is a really interesting one because it's a little newer.

[00:24:54] GE - Ep.147 Andrea - Andrea: It was, I think maybe 15, 20 years ago was characterized a lot of people that had trouble swallowing food thought, oh, I must have gerd, or, I should just be chewing my food more. But then now they do biopsies and they look in their throats and they realize no, you actually have a lot of inflammation that's making it hard for you to swallow because your esophagus is now narrow.

[00:25:15] GE - Ep.147 Andrea - Andrea: And now they know that children get this and adults get this. And I've gone to these conferences. Which, by the way, for newer diseases, right? I just said that this one was more new. I'm so inspired by the people that come out. It's the parents that come out. They're asking questions that wanna understand how this works.

[00:25:36] GE - Ep.147 Andrea - Andrea: They're driving this forward. So the patient advocacy groups for this disease, it's super inspiring. Have you ever seen, what was Lorenzo's Oil? That movie? Do you remember that

[00:25:46] GE - Ep.147 Andrea - Andrea: movie Back in

[00:25:47] GE - Ep.147 Andrea - Andrea: the day?

[00:25:48] GE - Ep.147 Andrea - Karl: Yeah.

[00:25:48] GE - Ep.147 Andrea - Andrea: It was the parents that found the solution for their child. going to these meetings, I was just really pumped to try to help this group of people.

[00:25:57] GE - Ep.147 Andrea - Andrea: they would tell me stories about how their kids can't have cookies, and then their sibling gets a cookie and then they feel so guilty they go to the bathroom to try to eat it. Privately, but then they come out and they start crying because they did something that, it's just like the stories of how these families are affected.

[00:26:13] GE - Ep.147 Andrea - Andrea: It's not just kid that has the disease, it's the whole family. So that one I felt really pumped to try to find a solution for them, because also the kids don't have that many solutions. There's only two FDA-approved drugs and one of them is a steroid, which kids cannot. Take, so then they have to get an injection every single week.

[00:26:33] GE - Ep.147 Andrea - Andrea: So can we find an alternative for them? And when we, actually went up to, Glenn Farda, who's one of the amazing, they call him one of the godfathers of eoe. And I asked if he would study this in his laboratory. we studied in his lab and was able to block the disease there.

[00:26:52] GE - Ep.147 Andrea - Andrea: And so,that's part of the journey that we're at now is, okay, let's help these people. And our first molecule, we've already taken it through phase one clinical trials. It's clear safety hurdles. People have ingested it. it's that we found no significant adverse events. We've given rodents 10,000 times the therapeutic dose and could not find tox.

[00:27:16] GE - Ep.147 Andrea - Andrea: I think it's just about getting it now to patients.

[00:27:19] GE - Ep.147 Andrea - Karl: Let me just ask,let's also put this into a different kind of perspective. when you've gone to these meetings, this is a relatively. A new disease, like how many people show up at these meetings? You said a lot of it is the parents, is it a hundred, is it a thousand?

[00:27:32] GE - Ep.147 Andrea - Karl: Is it 10,000? just give our listeners a sense of the scale.

[00:27:35] GE - Ep.147 Andrea - Andrea: I would say it's around a thousand people. There is a West Coast one and there's a East coast one. There's two advocacy groups. So I would say, it's cozy and. I actually like this because I've been to a lot of conferences where there's like Society for Neuroscience, right? There's just tens of thousands of people.

[00:27:55] GE - Ep.147 Andrea - Andrea: But this one, you see everyone, you know their names. you know the players. You stop them in the hallways. You talk to them about their research. you seepatients that ask questions. You can go up to them afterwards and you go on a walk with them through a park.

[00:28:10] GE - Ep.147 Andrea - Andrea: And, talk about the disease and their family and everything. So would say it's in that range.

[00:28:15] GE - Ep.147 Andrea - Karl: I think that's great For me, it says two things. One is like you get to know this community where you're making a difference, and two, because this is a new disease, it's probably still considered a rare disease and it only has two approved therapies, one that children can't take.

[00:28:29] GE - Ep.147 Andrea - Karl: It means that the impact that you can make can happen a lot faster.

[00:28:33] GE - Ep.147 Andrea - Erum: Yeah, it's like a

[00:28:34] GE - Ep.147 Andrea - Erum: pilot indication.

[00:28:35] GE - Ep.147 Andrea - Karl: exactly. Then the other question is, when you think about the community of. People who are doing worm pheromone research, like how big is that community? Is that

[00:28:47] GE - Ep.147 Andrea - Karl: also a hundred thousand?

[00:28:49] GE - Ep.147 Andrea - Andrea: that is something that I have. Wondered about for a long time because,after I heard the Radiolab podcast, I actually went into the literature to figure out who's studying this kind of stuff. It's a whole field called helminthic Immunomodulation. And most of them are in Europe, and I do not know why.

[00:29:07] GE - Ep.147 Andrea - Andrea: And then also they discover these interesting compounds from worms, from different species that do amazing things, and then they don't do anything with it.

[00:29:15] GE - Ep.147 Andrea - Karl: That's crazy. Oh my God. VCs listening. we've got several dozen company ideas coming.

[00:29:21] GE - Ep.147 Andrea - Erum: yeah, absolutely. And our friend Benji, who does like longevity, drug. not discovery, but, experiments and has a whole, I don't even wanna say like patent coins. We just interviewed 'em. and basically they do experiments like that's, you can watch and then people can put money into getting these, drugs validated to animal studies and then when they sell the drug, the people that put money in will get money back.

[00:29:44] GE - Ep.147 Andrea - Erum: That's all I'm gonna say if that's how it works. But I don't wanna get too crazy.

[00:29:47] GE - Ep.147 Andrea - Karl: Yeah, but Andre, I think it's so fascinating. what did you say, Hillman? What's the field called?

[00:29:52] GE - Ep.147 Andrea - Andrea: IC Immunomodulation.

[00:29:54] GE - Ep.147 Andrea - Karl: Hellthe. Immunomodulation, okay. Everyone listening to grow everything. This is probably the heaviest part of this podcast, just knowing that name,

[00:30:03] GE - Ep.147 Andrea - Andrea: there are incredible scientists out there that are studying these species, which by the way, now we go and get the species sometimes from those authors, right? We find them, we partner with them, and then we bring them in and we study them. And one of those is Rick Maisels and he's in Glasgow.

[00:30:21] GE - Ep.147 Andrea - Andrea: And I have looked up to his work for a very long time and asked him to help in, what we're doing, join us in our efforts. So he does work with us and he is a part of Hall Clara. So that's an example. And he's in Glasgow, right? So there are people around the world that are doing this.

[00:30:40] GE - Ep.147 Andrea - Karl: Yeah. the other, message that is coming loud and clear, and we say this a lot on the podcast, is that all the answers are in front of us. We just haven't uncovered 'em, and there's a lot of 'em. And so you're an example of. looking at something that most people wouldn't ever think has any kind of therapeutic effect, and yet all of a sudden it's like there's this evolution, this co-evolution, this symbiotic relationship that developed between these organisms and humans that we've just ignored and have actually, antagonized, But right now where you are in this business. Give us a picture of where the business is. Where's for La Clara, and what's the biggest challenges you're facing? Are they scientific, regulatory, cultural? You've given us a broad picture.

[00:31:21] GE - Ep.147 Andrea - Andrea: I think that right now we are really focused on advancing our lead molecule into a patient population. So that's, we're looking forward to and we're. Really excited about our safety data, just clearing that path for us to move forward. The hurdles, I would say, I don't have any regulatory hurdles because like I said, we gave rodents 10,000 times.

[00:31:45] GE - Ep.147 Andrea - Andrea: The active docent didn't find any talks, so as long as you're. Safe. You're good. I think the cultural hurdles for sure they are there because again, you just need to fit into that model. There's not a lot of people that are discovering natural molecules and pushing them through. What people typically do is you have a target in a cell that glows and then you're put in a Petri dish and then you screen thousands of manmade drugs to say.

[00:32:14] GE - Ep.147 Andrea - Andrea: Did that tinker with that signal, right? and then you take it forward and pray that there's no talks. And a lot of times there is, and you don't find that out until you're in your patient population. And that to me is really interesting because you're not looking at everything else that it's touching upon because you only tag that one protein with a glowing, signal.

[00:32:34] GE - Ep.147 Andrea - Andrea: So it's almost like I just know that it's working on this target. I'm not gonna look at anything else. And that, for some reason gives people the sense of safety that they can go to sleep at night. But that's a myth, right? That's not how things work. So now that we find natural molecules, instead of just marching forward with it into clinic, people expect you to backfill every single thing from the beginning, right?

[00:32:57] GE - Ep.147 Andrea - Andrea: And then for people like me, you have to do both simultaneously with half the money because then you've raised money to go into trial, and then the expectation is, but just magically figure everything else out at the same time. Based on these milestones in front of you. So I think that those are, it's easier to do all of that than change someone's mind.

[00:33:18] GE - Ep.147 Andrea - Andrea: Like I will just, we will just go figure everything out with the fraction of the money, with a fraction of the time. That is easier to do than changing someone's cultural expectation of how to move forward.

[00:33:32] GE - Ep.147 Andrea - Erum: you've definitely touched on, my own personal frustration with the. Pharmaceutical industry as it is today. I worked in pharma in early in my career and I left because I was frustrated because it's like,wait, what is going on? And it's likeso stuck in its way. It's so rigid. but I sense a disruption happening.

[00:33:51] GE - Ep.147 Andrea - Erum: I said it before, think, pharma's rip for disruption, but there's also disruption happening whether we like it or not. Perhaps in, like in the world of FDA, there's a lot of question marks going on will be a good thing or a bad thing. And then there's the bridge, or not the bridge, it's just like two worlds of pharmaceutical versus nutraceutical.

[00:34:10] GE - Ep.147 Andrea - Erum: And it's like one's under-regulated and one's over-regulated. And so it's like,okay,

[00:34:16] GE - Ep.147 Andrea - Erum: like what gives? Right? Like can,you know? And then my whole thing is can we Just live in nature and eat fruits and vegetables that are grown. You know, like

[00:34:22] GE - Ep.147 Andrea - Andrea: Oh, I am with you. So I actually thought about going into the nutri. Suitable path, which is why I recruited Peter Barton hut to my board because he was former chief counsel to the FDA and he helped establish this whole generally regarded and safe pathway. What changed my mind though, was reading a study that a lot of people do not wanna take drugs unless they are insured.

[00:34:44] GE - Ep.147 Andrea - Andrea: FDA approved, covered. And that they can have a $2 copay instead of paying for a nutraceutical that might be $20. And to me, I think that's crazy. 'cause I would pay that amount of money for my life and my wellbeing. But it's also just an expectation, right? I am used to paying $10 for my drugs and a lot of people can't afford more either.

[00:35:06] GE - Ep.147 Andrea - Andrea: So then understanding that system, knowing that there was a study where the copay went up by likea couple of bucks and people just decided to get sick instead. So then I thought, okay, if I was really gonna make an impact, do need to go down this path and have an FDA approved, payer cover drug.

[00:35:23] GE - Ep.147 Andrea - Karl: But that doesn't preclude you from potentially, creating an ingredients company. separate, that is creating ingredients based on this research that could be added as a supplement to foods. I don't know whether what that looks like, I'm just throwing it.

[00:35:38] GE - Ep.147 Andrea - Andrea: Totally. That's like if I find that billionaire that wants to come drink wine and talk about worms, let's do it then. Then we start the whole. Pharmaceutical company based on worms, and it's a nutraceutical pharmaceutical company where we can help lots of patients in need, but also develop nutraceuticals too.

[00:35:57] GE - Ep.147 Andrea - Karl: let's jump to that question. if resources and technical limitations disappear tomorrow, what would your dream experiment or moonshot be for? Hola, Clara?

[00:36:08] GE - Ep.147 Andrea - Andrea: I think it would be exactly that as getting all of the species, which by the way, we do have a lot of them, but now having just the time, money, the team, the talent. To characterize the worm atlas of interesting molecules. take them forward into different indications, finding the people that need them and getting it in front of them.

[00:36:31] GE - Ep.147 Andrea - Andrea: it's so funny because the technical limitations is not what I lose sleep over at night. I feel like we can solve for anything. So as long as we have the time and money and team. So

[00:36:41] GE - Ep.147 Andrea - Andrea: I think that would be the goal.

[00:36:43] GE - Ep.147 Andrea - Karl: yeah, sorry. I was just gonna say, I just did a quick search 'cause I was like, how many worm species are there? And my AI says there's no definitive number, but it's at least 20,000 and potentially 250,000. So there's a lot of worms out there that we can study.

[00:36:59] GE - Ep.147 Andrea - Erum: Yeah,I have another question. Maybe we wanna put this up top 'cause it's like not the, vision question that you just answered. but. so worm derived molecules, you're finding these and like they're natural. And I think one of the things that, why pharma does manmade is 'cause they could patent those molecules.

[00:37:15] GE - Ep.147 Andrea - Erum: are there issues with patenting, naturally derived molecules? how do you navigate that? Or do they change them a little bit?

[00:37:22] GE - Ep.147 Andrea - Andrea: Yeah, so there's different ways to patent natural molecules. You could patent method of use, right? And you could patent formulation. You could patent the synthetic method, right? But also I like to deal with small molecules. So there's small molecules and there's proteins. And I like to deal with small molecules, which by the way, I.

[00:37:45] GE - Ep.147 Andrea - Andrea: Any brilliant chemist can modify those to create composition of matter. And sometimes we do need to because the drugs are not appearing from a worm that's living in your gut. Now you're taking it orally so you can make a small chemical modification for absorption and permeability, and then you have composition of matter.

[00:38:05] GE - Ep.147 Andrea - Andrea: So I think that there are solutions to that work for both

[00:38:08] GE - Ep.147 Andrea - Andrea: for everyone involved.

[00:38:10] GE - Ep.147 Andrea - Erum: Oh no. Thanks so much for clarifying. Oh my gosh. lot of different. Worlds we can go down in this conversation, but we can, it up because we have is Carl, I'm gonna go to the next round. Is there anything else?

[00:38:20] GE - Ep.147 Andrea - Karl: No, I don't think so. Unless, Andrea, before we go to quickfire, was there anything we haven't covered yet that you think we should have?

[00:38:26] GE - Ep.147 Andrea - Andrea: Oh, I think that's just what a wonderful conversation so far. You guys have really thoughtfully covered every part of the worm corners here.

[00:38:37] GE - Ep.147 Andrea - Erum: Exactly. All right, here we go. we don't have, like,a sound yet. Maybe we should get a sound that goes like BPB quickfire questions. Here we go. All right. All right. So most surprising fact you've learned about worms that blew your mind.

[00:38:51] GE - Ep.147 Andrea - Andrea: similar to what Carl mentioned about the many species, they are actually the most abundant animal in the world by number. So you can look it up right now. Anywhere you're like, what is the most abundant animal in the world? By number? It is roundworms. There are 10 to the nine.I can't remember the word for that.

[00:39:10] GE - Ep.147 Andrea - Andrea: It's I can't remember the mathematical number for 10 to the 19th, but that many worms, if you erase everything in the world, you would see an outline of worms. So they actually do dominate this world, and I know that makes us uncomfortable,

[00:39:23] GE - Ep.147 Andrea - Andrea: but they do.

[00:39:23] GE - Ep.147 Andrea - Erum: Wow.

[00:39:24] GE - Ep.147 Andrea - Karl: Holy cow. Yeah, that's crazy. Okay. What's one immune related myth you wish would disappear forever?

[00:39:32] GE - Ep.147 Andrea - Andrea: I think this concept of it's like,okay, if you understand the one target, then you understand what it does, and I can go to sleep at night. That's not at all true. This. Control driven way of viewing drug developments. Like it's mythical, the drugs are doing all these other things. if we can just try to really accept that we've co-evolved with worms and they're secreting molecules and your ancestors have already been exposed to them, you need them.

[00:39:59] GE - Ep.147 Andrea - Andrea: those would probably go hand in hand with how I think about in immunology.

[00:40:04] GE - Ep.147 Andrea - Erum: Amazing. Amazing. Okay. you could borrow one superpower from the worm world, what would it be?

[00:40:10] GE - Ep.147 Andrea - Andrea: Hibernation, don't you? Wouldn't

[00:40:14] GE - Ep.147 Andrea - Andrea: you wanna just go to sleep until things are better?

[00:40:17] GE - Ep.147 Andrea - Erum: Oh yeah.

[00:40:18] GE - Ep.147 Andrea - Andrea: let's just go to sleep for four years and then wake up.

[00:40:22] GE - Ep.147 Andrea - Erum: I would be like, I would wanna dig into the ground and go like far underground and see what's going on.

[00:40:29] GE - Ep.147 Andrea - Andrea: I love that. That's the opposite of flying, right? It's like people are like, oh, I want the superpower of flight. You're like, no, I just wanna dig.

[00:40:38] GE - Ep.147 Andrea - Erum: Yeah, I wanna go and see the different layers of the earth.

[00:40:41] GE - Ep.147 Andrea - Karl: You can do that in Minecraft today. you don't need a worm superpower.

[00:40:44] GE - Ep.147 Andrea - Erum: Okay. Well, I'll have to play that when my son's a little older.

[00:40:46] GE - Ep.147 Andrea - Karl: Okay. So, Andrea, one word to describe the future of worm inspired medicine.

[00:40:52] GE - Ep.147 Andrea - Andrea: Oh, that's a good one. I would say balance because we live in a world today where we just wanna wipe everything down to zero, get rid of all the eosinophils down to zero, or this cytokine down to zero. But really it's about living in harmony. And I balance, and I think that we have been in balance.

[00:41:10] GE - Ep.147 Andrea - Andrea: With worms for a very long time, and then removing them created an imbalance. So how do we restore that balance? I think that we could do that.

[00:41:19] GE - Ep.147 Andrea - Erum: Beautiful.

[00:41:19] GE - Ep.147 Andrea - Erum: Beautiful. I also just wanna acknowledge that I said Worm World very perfectly.

[00:41:25] GE - Ep.147 Andrea - Karl: You did. I was gonna congratulate you on that in the commentary.

[00:41:28] GE - Ep.147 Andrea - Karl: yeah. Andrea, this has been such a great conversation because we touched on so much. first of all, talking about worms, not something that we do every day, but now I think it's been added to our vocabulary. Two, what you're doing is inspirational and just opened my mind to so many possibilities and just reinforces to me again that every answer that we seek.

[00:41:51] GE - Ep.147 Andrea - Karl: Is right in front of us. We just have to uncover that. And,this whole, I mean like drug development is extremely complicated and you're, challenged with that, but also overcoming it. So, congratulations. We're so happy you came on the podcast.

[00:42:05] GE - Ep.147 Andrea - Andrea: Oh, thank you so much. I really appreciate the thoughtful conversation. I know we don't have wine right now, but it does feel like we sat around the fireplace with a nice glass of. Malbec and was able to just explore all of these really interesting topics about past, present, future. So thank you so much for having me and joining me at that level of conversation.

[00:42:29] GE - Ep.147 Andrea - Erum: Yeah, it was great. you're also very easy to speak with, and I will say if there's any billionaires out there, we have a glass of wine waiting for you. Call Andrea.

[00:42:39] GE - Ep.147 Andrea - Andrea: yes. There you go. I love it.

[00:42:42] GE - Ep.147 Andrea - Karl: Thank you. Thank you.