Using Viruses to Fight Disease

This is an iHeart podcast. Guaranteed Human. Did you ever notice how you spend hours shopping online only to pause it, check out because you wonder if you trusted enough to hit buy now? Agente Commerce is testing that moment more than ever. That's where PayPal comes in. With 25 years of checkouts, 400 million consumer accounts globally, and the benefit of fraud protection. So no matter where a purchase starts, it ends with trust. Built for payments, growth, and agentic. PayPal Open. Built for all business. Visit PayPalOpen.com. This is Jacob Goldstein from Business History. When the internet arrived, most people used it to look things up. Others saw what it could really do. The same is true with ChatGPT. ChatGPT work goes beyond answering questions. Give it a goal plus things like notes, files, feedback, data, or project plans, and it can help create a brief analysis, deck outline, tracker, or workflow. You stay in control, reviewing the work, and choosing the final result. Put ChatGPT to work on your most ambitious ideas and projects. Get started at ChatGPT.com by selecting Work Mode. Available on plus and pro plans. Working as a dedicated fidelity advisor, I always ask, what's important to you? I'll look at those priorities and goals alongside your full financial picture to build a comprehensive plan designed to help grow and protect your wealth. With proactive portfolio insights and an eye in taxes, I'm here to help you make the most of your money. I'm Laura Maxwell, and I'm a dedicated fidelity advisor. Learn more at fidelity.com/wealth. Investment minimum supply, Fidelity Brokage Services, LLC, member NYSE SIPC. Pushkin. I love Fages. Fages are viruses that attack bacteria. Fages are unimaginably abundant. A trillion Fages for every grain of sand on Earth, according to one estimate, which what does that even mean? Qualitatively, it means Fages are all around us. They are inside of us. They're essential to life on Earth. And they may help to improve human health in a profound way. I'm Jacob Goldstein. This is what's your problem. And my guest today is Paul Garafolo. He is the co-founder and CEO of a company called Locust Biosciences. Paul's problem is this. Can you use genetically engineered Fages to cure disease? People have been trying to use Fages to cure infections for over a hundred years now. But in most cases, naturally occurring Fages just don't work as well as antibiotics, as drugs. Fages reduce infections, but they often don't wipe them out entirely. So Paul and his colleagues are taking a different approach. They are genetically engineering Fages to make them better at killing bacteria. For now, the company is testing its first Fage-based drug in patients in combination with antibiotics. But Paul says the long-term dream is bigger than that. - So we actually have been trying to figure out how to selectively remove bacteria from the human body without touching any of the good bacteria that's in there. And we believe that that is a key to longevity of human life. We're starting with trying to replace antibiotics, but we believe that any number of diseases in the human body are actually the body's reaction to inflammation from bad bacteria getting in there and not leaving. And so that's what Locust is trying to do. - That's the big dream. - There's a narrower dream that I'm also interested in. - Yes. - And maybe a question that gets at the narrow dream is, what are the limitations of antibiotics that you're trying to address? - I think there are two things that are wrong with antibiotics. So one that most people are very, very familiar with is resistance is now everywhere. And so effectively, we're beginning to see exponential increases in drug resistance from almost all mainstream antibiotics, if not all. So there's sort of a math problem from here. At some point, none of them work. And the further up in strength, you move in antibiotics, the more toxic they are to your body. And so if you're really sick, and you have to go on a really strong antibiotic, the antibiotic itself can be your demise. So that's one thing. Another example might be people with recurrent ear infections or recurrent bladder infections, end up going on to frequent batteries of antibiotics, say, you know, starting at 15 days, but eventually getting the things like 30 days or 45 days of low volumes. And that can wreak havoc on your body. You know, it could basically destroy the balance in your microbiome. And you can have things that are long-ranging side effects like having to go on substantially simplistic diets for a long period of time, because you're in testimonial tract, can't handle the variety of food that it likely needs for longevity. So those are just a couple of examples. - Why might phages help to solve this problem? - So we think that phages are one of the most unique and creative ways of getting into the human body to selectively attack a very specific bacterial, pathogen or pathobion of interest, and only that particular target. So I'm sure you've heard about precision medicine on the gene editing side for human cells that might be able to fix some of the world's roughest diseases, but on the bacterial side, precision medicine is quite new. And the idea of using phages as a delivery vector is essentially centering around the fact that they're exquisitely unique to the bacteria that they've evolved to infect. And so I think the largest, most abundant and oldest biological organism on the planet besides bacteria is phage. - Yeah, it's amazing, right? Like the earth is full of phages. Some in the sea, when every day half of the bacteria in the sea get killed by phages or something, like it's wild, right? It's like, it's incredible. - Yeah, they say that half the bacteria on the planet, so I'll see in you every day. - Like it's happening all around us. It's happening inside our bodies, right? There are phages that naturally occur inside our bodies. - Yes, and bacteria actually double at a very similar pace, right? So this is one of nature's oldest and most established ecosystems. - And this is an old idea. It's super exciting when you hear it. And they're like, oh wait, people have been trying to attack bacterial infection with phages for literally like a hundred years, right? And they haven't got that far with it. It sounds perfect. Why hasn't it worked that well so far? - I think there are probably two or three reasons of note. One is that people essentially, since I'd say a century ago, when they were discovered, they use wild type phages. Meaning they don't do any type of enhancement to that virus. They don't change the genome in any way. They simply search for one that is effectively a good killer in an academic lab. And then they take that killer and they put that into the human body, expecting similar results. And you can see efficacy levels of those types of what we call wild type phase treatments in anywhere from 50 to maybe even 65, maybe even in best cases, 70% range. Which you would say, well, that sounds decent, pretty good. But antibiotics have traditionally up until when resistance has started to come into fray. Those typically work around or above 95%. So the efficacy difference between those two wild type phages and antibiotics is just so stark. In the days of the Cold War, antibiotics were not really available to people that were behind the Iron Curtain. And so phage there be actually continued in many places inside Georgia, Russia, et cetera, and advanced into treatment centers that really were geared around a single phase for a single bacteria. And what that leads me to this sort of the second, I think not shortcoming, but just natural component of phage, which is an individual phase. phage to go after, let's say, a large population of bacteria in the human body will begin to see resistance. So, that's the story of, as you said, wild-type phages, naturally occurring phages. You're doing something much more 21st century, right, in a few ways. So we should introduce another sort of idea of a slash piece of jargon now, right, which is CRISPR-Cas III. People are used to think of CRISPR as like the gene scissors, right? I think people are relatively familiar with that. But this is a variant that is like the gene shredder, right, as opposed to a scissors. Yes. It works like essentially a Pac-Man if you remember the old arcade game. So it essentially makes a small nick in one strand of the DNA of the double helix and then it choose that strand back by hundreds of not thousands of base pairs to the point where it renders that cell dead. And by no means, and I think this is an evolution of our company and perhaps many others, CRISPR systems are not the only thing that you can engineer into a phage, peptides, other enzymes, all kinds of things. Oh, interesting. But that's, I mean, just to be clear, like the, the, I call them drugs, they're drugs, right? They're drugs. The drugs that you have in clinical trials are combining CRISPR-Cas III with a phage, right? Yes, our lead asset is an E. coli-based product. It has six phases inside of that product. So it's a cocktail of phages and the majority of those phages are engineered to carry the entire CRISPR-Cas III construct inside. So it's basically six different phages, each of which you've engineered to put on this gene shredder, gene Pac-Man. So the ideas, the phages go into the, the infecting cells, the E. coli, the bacteria. And then the CRISPR eats up the DNA of those bacteria, thus killing the bacteria. That's the basic idea. So basically, the ideas, if you do a bunch of different phages and be add to them, something like CRISPR-Cas III that makes it extra deadly, then you can clear the infection rather than just reducing. Correct. And so now you are running a clinical trial on, is it women with recurrent urinary tract infections? Is that right? Correct. So tell me about that trial, like where is it, what's happening, what's the, you know, what's the outcome? Yeah. So we just dose patient 229 yesterday. We've got probably 288 to maybe 308 patients that we're going to dose. And the idea is that it would not only deal with the acute infection that you're getting hit with right now, but it actually either eliminates or dramatically reduces the number of recurrent infections that you'll see in the future. Yeah. So tell me about like recurrent UTI as a problem. At the United States alone, over 10 million people get recurrent infections of which two million of that patient block get multiple recurrences. Once you get into a pattern of having multiple recurrences, it's very difficult to get rid of those. Many patients evolve through decades into a state of colonization, which just simply means that that bacteria embeds itself somewhere in your body and re-infections occur, you know, maybe for some a few times a year, but for many five, six times a year. And how are you delivering the face treatment? So we have an intraerethral delivery into the bladder. So we use a catheter when we avoid the bladder of its content and then we reverse flow the drug product into the bladder. And in the process, we also expand the bladder to make sure that the bladder wall is coated and we hold the drug product there for about 40 to 50 minutes before the patients void again. We do that on the first day and the second day. And then simultaneously, we have an intravenous backdrop that really is meant to try to get to the kidneys and we do that on day one, two, and three. So the total time and duration is three days. So this is an intense treatment. This is like your UTI would have to be extremely bad to want to do this, Franklin. You're in that two million patient population. And you know, if you had, just think about it this way. If you had a urinary tract infection, that was so bad that you had to stay home from work for three or four days until the antibiotics that you got called in for you kicked in. And then you were still under the weather for another six or seven days. And at the end of that period, within a month to two months, you got another one. And those infections, just in fact, when we talk to urologists and we talk to urogynecologists, they say that this particular infection is the one that they feel the worst about for their patients over anything that they deal with because there's nothing that they can really do about them except for treat them with antibiotics as the occurrences happen and just keep giving them antibiotics every time that happen. One of the risks, what are the risks associated with the fist treatment? So we have not seen any crazy adverse events, but the amount of viral particles that we put into the body, some patients can get low grade fever, some patients can get a little nauseous. You're giving people a virus, right? You're giving a lot of virus. So when are you going to know if phage plus antibiotic works better than antibiotic alone? So we should be finished dosing. We believe we'll be finished dosing sometime in the late fall to early winter. And then within 90 days from that last dose, we'll have the data. So next, less than a year, you should know, definitely less than a year. So this UTI study is the one that's farthest along for you. What else do you have in clinical trials? So we have applied for an IND for a Crohn's asset to try to essentially have an oral product that is similar to the UTI product, but works more towards adherent invasive E. coli, which is in many areas of medicine considered to be at worst associated with best causal of Crohn's disease. In addition to that one, we're very close to being able to submit an IND for this hospital acquired pneumonia asset. And that should be, if we're on time, that one should get approved before the end of the year. In theory, by the end of this year and the beginning of next year, we would have three to four assets that we're moving through the clinic. And an asset is a drug. An asset is a drug. A drug that you own, that's why it's an asset for you. Well, in some cases, partnered, but yes, one that we own. Or co-own. Yes, somebody owns. We'll be back in just a minute. With proactive portfolio insights and an eye on taxes, I'm here to help you make the most of your money. Investment minimum supply, fidelity brokerage services, LLC member NYSE SIPC. Imagine Henry Ford trying to create the assembly line. He had factory plans, production schedules, supply information, research, and ideas coming from all directions. His team spent years studying how to make the process work. Now imagine having chat GPT work. Chat GPT work can help with big projects that have lots of steps. You give it the goal, along with real information like notes, files, reports, feedback, and project plans. It can use approved apps, connected tools, and files to help turn all of that into something useful. A plan, an analysis, a tracker, a presentation outline, or a workflow you can keep improving. And you stay in control, you give direction, review the work, approve actions, and choose the final result. With Henry Ford have built the assembly line faster with chat GPT, we'll never know. Ford didn't have chat GPT, you do. Put chat GPT to work on your most ambitious ideas and projects. Get started at chat GPT.com by selecting work mode, available on plus and pro plans. Did you ever notice how you spend hours shopping online, only to pause right before you hit buy now? That tiny hesitation, the one where you wonder if it's trustworthy, can make or break the sale. Now with AI changing the way we discover and compare things, that split second trust question matters more than ever. For more than 25 years PayPal has been a leader in online payments. And now they're at the forefront of agentic commerce, making it work for businesses, letting them maintain control of their brand and their customers. customer relationships. So even as the way we shop changes, the moment that matters most still feels familiar and deeply dependable. Built for payments, growth and agentic, PayPal Open, built for all business. Visit PayPalOpen.com to get started. Tell me about how you're using AI at your company. So we use what we call AI-driven robotics. And so we discover phase at a volume. I don't think anybody in the past has used. And then when we get those phase isolated, we sequence them, we run full characterization on them and then we start running them through prediction engines that help us figure out what payloads to put into their genomes and which ones of those should go together into a fixed drug. So let me just take a sec to understand that. The prediction engines part, that second part, that sounds like AI. But what's the robot part? And how is it different than, you know, what happens in a normal lab? Well, in a normal lab you have a pipette, you know, kind of like a, you're holding up your hand. Yeah, you have a little thumb thingy that you're like depressing. Yeah. So, you know, discovering phases, using sort of your regular road, run of the mill. So what, so, okay, what are you doing? Well, we're using hundreds of not thousands of 96 well plates with the robot running 24 hours a day, essentially, looking at waste water that we pull from all 50 states outside of international airports. Oh, you do it outside of international airports because it's a more biodeiverse sample, like 100% are flying in from all over the world in people's bodies and you're sampling them. 100%. I love that. Yeah, it's really cool. When you say waste water, like you just go to like the sewer, like, how do you actually do this? You reach out to the municipalities and you set up opportunities to pull them in, I mean, in the early, early days, we would go out there and we'd knock on the door and we'd ask for like, hey, can we get this? And in a lot of cases, you can. And what's the order of magnitude of like how many different phases your, your system is going through? So we have found it probably 8,500 uniquely identified, fully characterized phases against 99 different bacterial targets. So the size and scale that most academic labs, if not any academic lab, could ever match. So then, so that's, that's the robot stage. And then you were saying you move on to the, yeah, to the kind of AI stage. What's that? So you, maybe the best way to think about is it can work a little bit like Netflix. So if you're, you know, you watch a particular type of movie and there's a little algorithm behind the scenes that tries to figure out, well, what's the next best movie that's like that that you might want? And so we essentially apply very similar models to the sequenced information that we have on each of these unique phases. And we start to try to figure out really by evaluating quadrillions of different options of pairing hundreds of not thousands of phased together, which one, which four, five, six or seven of these go best together. So you want them to be complimentary. You're targeting, you're targeting some particular bacteria. And you're like, okay, give me the best cocktail. Correct. AI. Yep. And then once it says try these top three, we go make them. And then we, we grow it up and, you know, manufacture small quantities of it. And then we test them out. And is that how you got the cocktails that are in trials now? The one that we have that's in trial now, probably was a bit more manual because this is the first asset. And it's probably built like seven years ago, the two, the three that we have that are coming this year, we're all built using that approach. So we're excited about the second generation assets that are going in. So, so let's talk more long term like let's talk about the sort of phase dream. I've heard you talk about, you know, the potential that the kinds of things you're working on might go beyond what we think of as infectious disease someday. Tell me about this sort of big, big dream for, for phase dream. I think Crohn sits in that arena for us. So Crohn's disease is a immune disorder that essentially your body's immune system mistakes something in your intestinal track for an infection. And it targets your own intestinal organs and eats away at them to the point where you have small lesions that are actually in your intestinal lining. And what we know how to do in the field of the medicine is essentially turned down the intensity of the attacking. So it's an autoimmune disorder. It's not thought of as a infectious disease. So what, where does, where does phase therapy come in? In many circles of, of IBD, it's thought that bacteria is what the immune system is attacking. And IBD is inflammatory bowel disease. Correct. Like that Crohn's is one of, yeah. Crohn's colitis variant forms of those anything that essentially diverticulated these types of things that are essentially in intestinal organ disorders. There's a big umbrella term for IBD. And so many scientists believe that there are bacteria that get stuck in there and are nontransient. And it's those bacteria that get stuck in there and somehow adhere to the intestinal walls. That is what the immune system is attacking. And that makes your immune system freak out and start attacking not just those cells but the body's own cells. Correct. And so our drugs and what we think is the holy grail of medicine is to be able to use phage encoded with payloads that can eat through either the biofilms, mucle layers or macrophage layers that protect those intracellular pathogens that our drugs would be able to get there precisely and kill just those pathogens. Thereby causing the immune system to calm down and to potentially heal that patient with something that's curative. And just to be clear, is it the case that antibiotics just don't work for the particular, the bacteria in the, in the setting that you're describing? Any biotics are known to not be able to kill intracellular pathogens. They can't transit into the human cells to kill the human cells. Which is why they don't kill us, presumably. Why antibiotics don't kill us? Yeah, presumably. I mean, that's, that's one way to look at it. Absolutely. Yeah. And this is a trial that you're hoping, you're hoping to sort of start a clinical trial based on this hypothesis. You said in the next year or so. We hope to. We hope to. We still need to raise funds specifically for that one. I believe it less the way you say we hope to. Yeah, that when you're running a company like this, you tend to go where your contracts and partnerships are. And right now we have contracts in three of four areas. And so of course, we're busy working on all three of those. Yeah. And we hope to add the fourth. So what's the bigger idea here? Like we kind of went far into the, the weeds on crumbs. What is the bigger idea for, you know, if you're right, like what is the big hope for phased therapy and whatever, 10 years or something? So I'll, I'll start high level and go down into that. Yeah, inflammation in the human body is not good. It causes many diseases without question, things like rheumatoid arthritis, potentially neuro diseases, things related to dementia, Parkinson's, etc. Like when inflammation occurs in certain sections of the body, bad things happen. Our hope for this platform is that it can reach into the human body via precision medicine and pull those pathogens or pathogens out. Is the underlying hypothesis that this sort of mysterious systemic inflammation is caused by particular kinds of bacterial infection? Yes, many pathogens that are in the body are bad actors, they're non transient. And the immune system is likely attacking those non transient bad actors. And so if you have a platform that can remove those bad actors, you likely also get the benefits of being able to improve the health of the human body. And that we believe will do things like increase the lives of most people in society or if you're genetically predisposed to a disease, you may be able to prevent the onset of that disease for a longer period of time. If you're genetically predisposed to a disease, you might be able to lessen the severity of that disease on your life. A good example might be rheumatoid arthritis. So if you remove pathogens that either aggravate or cause rheumatoid arthritis, can you help that patient with their symptomology? Can you decrease the pain that's associated in your joints with that disease by decreasing the amount of pathogens that you actually have in the body? We believe that that is a theory that is absolutely worth going after trying to figure out. And many people don't really realize this, but a lot of medicine is built on suppression, GLP-1s, autoimmune drugs. These things are basically shutting something down in the body to help a patient. They're not actually dealing with causes and so hopefully also then we can start to talk about cures. But certainly if we're able to show direct causal relationships between certain pathogens that are in the body and improvement in disease symptomology, I think we're onto something really really big. We'll be back in a minute with the lightning round. Working as a dedicated fidelity advisor, I always ask, "What's important to you?" I'll look at those priorities and goals alongside your full financial picture to build a comprehensive plan designed to help grow and protect your wealth. I'm Laura Maxwell and I'm a dedicated fidelity advisor. Investment minimum supply, Fidelity Brokage Services LLC member NYSE SIPC. You give it the goal along with real information like notes, files, reports, feedback and project plans. It can use approved apps, connected tools and files to help turn all of that into something useful. And you stay in control. You give direction, review the work, approve actions, and choose the final result. Would Henry Ford have built the assembly line faster with chat GPT? We'll never know. Ford didn't have chat GPT. You do. Get started at chatgpt.com by selecting work mode, available on plus and pro plans. Now, with AI changing the way we discover and compare things, that split second trust question matters more than ever. For more than 25 years, PayPal has been a leader in online payments. And now they're at the forefront of agentic commerce, making it work for businesses, letting them maintain control of their brand and their customer relationships. Vote for payments, growth, and agentic. PayPal open, built for all business. What's your favorite phase? My favorite phase? Yeah. Actually, I really enjoy thinking about macrophages. Oh, the giant ones, that they didn't even know where virus is because they're so big. Yeah, they tend to evolve really fast and move around on you, so it makes it a little bit interesting to figure out how to actually pin one down and keep it from doing that when you don't want it to. But the possibilities of what you can load into a phase, the size of the payload that you could get in there if you could replicate it, that's pretty exciting. So as a phase engineer, you're like, if we could tame that guy, we could stick anything in there. Yeah, I guess it'd be like taming a really big bull, right? Like what was your death from that? I think the idea of being able to put all kinds of different peptides or other enzymatic tools into a phase and getting it very specifically into a certain part of the body and then having it in C2 manufacturer that payload right at the site where you want it is pretty fascinating. As someone who's been in the industry for a number of decades, there's tons of good drugs that are on the shelf because of things like half-life considerations where it just doesn't stay alive and active long enough. But if you're manufacturing it in the body right where you need it with a phase, what can you do with those peptides that have long since been on the shelf. So I think there's some really cool things you can do with phases that are larger that might be able to carry some cool stuff. I heard you say that part of the reason you started a company was because you don't have a PhD and you realize that in bigger companies, there was just a ceiling on what you could do without a PhD. And I'm curious, have you found any advantages of not having a PhD? Does it give you any kind of insight or edge that you might not have if you did have one? I mean, you can ask dumber questions of your team and get away with it. The sort of like, why do you think that? I don't understand, explain that to me. That's actually, I will say, that's my whole game. That's like my job is saying, I don't understand that, explain it to me. I also think that it gives us, it gives our culture inside of our company and bias towards more execution and not that we're any less curious about scientific discovery, but once you pass a certain point where you're moving into the clinic and through the clinic, it's time to execute. And so you can stay focused a little bit better. Right. You're an engineer by training, right? That's a very engineering mindset, right? Let's build a thing. Yeah, I have a project manager. My background in a project manager, that's what I was, I guess, raised doing is running huge projects. So you've been in biotech for what, 30, more than 30 years, right? Which is a long time. And I'm curious if you sort of look over the art. If you go back to when you were starting, I'm curious what's surprising to you, like what has done better than you expected, what has done worse? That's a really, no one's ever asked me that one before. Okay. I mean, I think on the better side, I really have been in awe and excited about cures. When I started, if you said, hey, we're working on a cure, people would look at you and you'd immediately be discredited. So what can we cure now that we couldn't cure when you started? I don't think you necessarily have all of the cures for things like doucheins or Parkinson's or Alzheimer's that are definitely not for those, but what can we cure? I think they're, I think they're coming and that's my answer to your question of what's really cool about biotech. The hard parts, the parts that maybe aren't so fun is I think we had just a huge bolus of garbage ideas that flooded into the industry post-COVID, the amount of money that came into the industry post-COVID, the craze around SPACs, it basically drained all the talent into a bunch of BS companies and it took a couple years for that to flood out. The curse of too much money, it's funny. People mentioned that more often than I would have thought. In an industry that's used to creating 400 companies per year, you don't want to create 4,000 for two and that's not, you just don't have the talent enough in executive and leadership ranks to hold that and where you get that from is your service partners, your vendors and then your vendors don't know what they're doing and so we had to live through that. I think we're through that. I actually think we're on the other side of that which is I guess time will tell as we see what actually breaks through. Paul Garafolo is the co-founder and CEO of Locust Biosciences. Please let us know what you think of the show, which we want to hear more of, which we want to hear less of, particular guest ideas. You can email us at [email protected], I read all the emails. You can also find me on X, or on LinkedIn, really do appreciate all the messages that we get. Today's show was produced by Gabriel Hunter Cheng and Trina Manino. It was engineered by Hans Dail She and edited by Lydia Jean Cot. I'm Jacob Goldstein and we'll be back next week with another episode of What's Your Pronto. A look at those priorities and goals alongside your full financial picture to build a comprehensive plan designed to help grow and protect your wealth. Learn more at fidelity.com/wealth, investment minimums apply, fidelity brokerage services, LLC member NYSE SIPC. Before you sign off, you tuned in for ways to help teams move faster, make sharper decisions, and turn scattered contexts than to work they can use. Chatchy PT for Business gives teams a shared workspace with admin controls, permissions, and access to work and codex in Chatchy PT. This means your business can move from question to answer and code to rollout quicker. Join over 10 million business and enterprise users worldwide. already using chatGPT for work. Download the chatGPT desktop app or contact sales to learn more. Running a business is hard enough. Don't make it harder with a dozen apps that don't talk to each other. 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