Hey guys, welcome back to Skin Anarchy. I am so excited to share this episode with you guys because we're gonna be diving really deep into microbiome science, understanding more in depth. I know we've discussed the topic before on the podcast um in different ways, right? Whether it's like topical skincare or just trying to understand the microbiome at large, but I think our guest today is truly an expert. I've been uh meaning to interview someone like her for a long time, and I can't wait to really kind of pick her brain. So without further ado, please welcome Dr. Stephanie Culler, who is the co-founder and CEO of Persephone Biosciences, and also she is incredibly talented and has so much you know education in this field. So welcome, Dr.
Culler. I'm so excited to talk to you.
SPEAKER_00Thank you.
SPEAKER_01Yeah, I'm excited to dive in. I I want to learn more about your background because it's very impressive and you've done research in the field for so many years. Um can you kind of walk us down memory lane and tell us, you know, like your background and what got you interested in wanting to start your own company and all that great stuff?
SPEAKER_00Yeah, thank you. So um, yeah, I I'm a scientist by training and did my PhD at Caltech, um focused in gene therapy for new cancer therapies, and um became a scientist um really because I lost both my grandmothers to cancer when I was a young teenager. Um, inspired a personal passion for cancer research, but also how could we prevent disease? It was something on my mind. And, you know, I've always wanted to be an entrepreneur, and everybody in my family is, but nobody's a scientist. So I had to really kind of figure out my own path. And after Caltech, I wanted to embark on that journey, actually translating what I had developed there, but
um I quickly realized that I really didn't know anything about starting a biotech company, um, nor how to commercialize products. And so um I came down to San Diego, where our company is based, and I joined a company in industrial biotech where I met my co-founder working with microbes, like what's in our microbiome. And after our success of commercializing microbe-based products, really wanted to move on and start that entrepreneurial journey. And during that time period, became truly fascinated by the gut microbiome. Those microbes that line our GI track help us prevent disease and fight disease, um, and where 80% of our immune system is connected. You know, most disease that we know of is connected to the gut microbiome. And in focusing on the microbiome kind of married my two passions, you know, human health, but also, you know, this deep, deep expertise that I had developed in microbes, their metabolism, how to manufacture them through fermentation, et cetera, and using the latest cutting-edge machine learning AI tools to develop products. And so we founded Persephone eight and a half years ago to develop a technology platform that essentially unlocks the potential of the gut microbiome. Can we develop products, both therapeutics, but also consumer-facing products that can help treat disease but also potentially prevent it?
SPEAKER_01That's really fascinating because I think the microbiome and the science side, right? All of us have been kind of, we've known about it for a long time. I remember many, many years ago, I think it was like over a decade ago, my father, because he's an he's a microbiologist and he came to me and was talking to me about the microbiome. And then I started my podcast, and then everybody started talking about the microbiome. And I was like, oh wow, we're doing this, you know, we're we're catching up as a society. And I think it's so exciting because exactly what you said, where it's like the immune system is so heavily rooted in the normal, like just everyday balance of our microbes, you know? And so I really want to dive more into that. I know you have an incredible background in synthetic biology. You mentioned oncology. Can you talk to us a little bit more about this? You know, in terms of like where are some of the biggest, I guess, white spaces or like question marks that you've noticed when it comes to the microbiome and understanding its true role?
SPEAKER_00Yeah, so you know, been in the space for, you know, nearly a decade now, and in my scientific career for more than two decades, don't want to date myself. But, you know, in in and really where the white space and why we started the company was just the lack of real scientific rigor being applied to how do we develop products around the microbiome? How do we understand it? And really the key, you know, white pace, white spaces that we have today is is translation. How do we go from data mapping the gut microbiome to actually developing a product that manipulates it? And when we started 10 years ago, um, and it really took us the first few five years of the company, and
and us around and and global research around the world, we couldn't really understand the entire microbiome, meaning um 50% of the microbiome for a long time was like actually like dark matter. We didn't know what was in the gut, right? And um, you know, today we're at 99.9% accuracy identifying the microbes. So I would say a large part of the challenges in microbiome have been one, you know, we got through identifying. That was the first hurdle. What is in the gut? But now the key challenge is how is the microbiome functioning? And if it's dysfunctional, how do we repair it? That is the big leap today, right? And many companies have tried to get into the clinic for therapies in oncology, in clustering difficile, in Crohn's, IBD. Many, many have failed because of that huge gap. It's one thing to understand what microbes are there, but we'll still several years away from being understanding how we translate that in a routine way.
SPEAKER_01Yeah, no, that's an incredible insight because I think also some of the more, I guess more on the clinical side, the only techniques we had ever learned about, right? Even in medical school and like anything was like, for example, if someone gets C. diff and then they have crazy antibiotic usage, the only thing we can do is like a fecal transplant to get their, you know, the normal microbes back in there. And like that is, in my opinion, the most barbaric level of treatment. You know, like we we have to evolve from that point and really start discussing, you know, not only is it a big problem in people taking antibiotics, but these days, especially, I'm sure you know much more about this, is that the foods that we're eating, the foods that we're consuming over time, over our entire lifetime, what that does to us, and then what that does if we end up, you know, as women, especially when we're pregnant, we're passing that on to our kids. Like, you know, there's a lot here to unpack. So I want to kind of walk down this road with you, you know. Um, talk to us about, you know, what is the role of the microbiome for women, especially, for us understanding, you know, how it gets passed on to kids and all that kind of stuff.
SPEAKER_00Yeah, and that's been actually the topic of our in an area of focus of for our for us for at least the last four to five years. And prior to that was actually cancer, how the microbiome shapes treatment response for cancer patients. Um, and something and and there's some similar and commonalities, I would say, you know, for for women, especially those that are of childbearing age, and even through through menopause, the microbiome plays an incredible role in our metabolism and immune function.
But for women that are pregnant, um, really the role of the microbiome is to be passed on to the child through vaginal birth, right? And through breastfeeding, um the growth of the microbes, and I'll talk more about that. And really, modernization has impacted women's abilities to pass those microbes on. It has nothing to do with, you know, what we as parents are choosing to do. It's really modernization. So, where we see that impact and that disconnect, because babies today are born deficient in the right bacteria that trains their immune system. That's actually the role of the early microbiome is that training. And if you are missing those key bacteria, the wrong bacteria are essentially in its place, and the immune system doesn't get that training. And what that means for the child long term is that the immune system develops errors, and it's much more prone, or I would say at risk for getting what we call atopic disease conditions, which I know you've talked a lot about on your podcast. It's the eczema, atopic dermoditis, food allergies, asthma, and we think it's connected to many conditions. And what has broken that for women and for our children is antibiotics. You just mentioned that. Um, C-section births, because babies are getting the microbiome from the hospital, from skin, instead of the right gut microbes. Um, it is in some cases infant formula because breast milk provides the right prebiotics for the gut microbiome or the full repertoire. Um, in many cases, it is poor diet. And what that leads to over generations is to moms not having that bacteria anymore. And so baby doesn't get it, or family members don't have it. And so the child's just not getting the right microbiome that fosters the right immune development, and it can be permanent. That's when the immune system is developing in those first few years of life.
SPEAKER_01That's very fascinating because I know like I've looked into it like in myself in terms of like infant gut microbes that you know the most common species and stuff, and we don't know much. Like, at least I didn't find much when I first like was digging. And I would love for you to kind of educate us here. I know that um Bifidio bacterium comes up a lot, you know. That's I think the main big one that is like kind of the poster child here, you know. But tell us more about this. You know, what are babies actually like once they go through a normal vaginal birth, what are they seeded with to begin with? And where does it kind of go or you know, awry in terms of like not developing properly or anything that you found through your research?
SPEAKER_00Absolutely. Um, and so you we've conducted the biggest study in the United States called My Baby Biome to map the microbiome of babies today. And what we found is, you know, when a baby is born vaginally, they get their gut microbes from their mother essentially. Um, the mom's stool essentially seeds the baby. So there are some microbes through that they get through the birth canal. Um, but by and large, their gut microbiome is seeded by their mom's microbiome, their stool that's coming out during that birthing process. And what we find that's really important in that initial stage, in the newborn stage, but actually through the
first few years, are key species of bifidobacterium. Well, bifidobacterium are very common probiotics, but they're a key species that the babies need that have the ability to thrive in the presence of breast milk. Um, over the last two decades, it was determined that there's a major component of breast milk called human milk oligosaccharides. It's actually the third largest component of breast milk. They're basically oligosaccharides or carbohydrates. And they don't feed the child. Um, they actually feed the microbiome. This was a big, you know, surprise to researchers because for the longest time they're like the babies are not, you know, absorbing this. Where is it going? It's going to the gut microbes. And they feed specific types of bifidobacterium. One of the most important species of bifidobacterium for babies is called bifidobacterium infantis. Go figure. Um, and it is the only species of gut bacteria we know that can consume all of the breast milk prebiotics, all of those HMOs. Um, and so it's really that baby strain that's important. Um, but what's been found most recently, and I would say in the last few decades, is that this strain, while it used to be common, it's common in non-industrial populations like the Amish, the old order Mennonites in the US, or the hunters and gatherers of Africa. Those babies have high levels of bifidobacterium infantis. It's become rare in Western populations. Um, we found in our study that only 8% of US babies have it. 8%. It's become, you know, it used to be at maybe 80, 90%, and now it's at 8%. You know, other strains of bifidobacterium are very important as the child develops into toddlerhood. Bifidobacterium longum and brevade. And that's what we found from our research. And how we know these are critical for health and development is that babies who don't have these bifidobacterium or at very low levels, they end up getting um food allergies and eczema or at least three to four times more at risk. That's what we found in our research. By age two, if they had low amounts of these um key species of bifidobacterium, they were at elevated risk, right? And if they had these bifidobacterium, they were at reduced risk. And we see that this is similar to what is observed globally in other longitudinal studies.
SPEAKER_01It's interesting because I'm just trying to figure out what is the risk that you're quantifying? Like what is the real risk for babies?
SPEAKER_00I mean, the real risk is immune system development. Um, you know, atopic dermatitis, food allergies, these are all errors of the immune system, that the immune system isn't functioning properly. And so that's really the inherent risk. What is what is it long-term? That's something we're looking into. You know, there is emerging data in some studies that we're also partnering on that suggests the microbiome may even be connected to cancer, um, early onset of cancer. You know, we're seeing colorectal cancer in people who are in their 20s and 30s now and early 40s. Um, this is at a rate that's increasing. It's one of the cancers that seems to be increasing as you know, in comparison to others that are decreasing in this younger population. This is emerging data, we don't know yet, but we're starting to see some associations between these earlier onset of disease and that early microbiome if it's not shaped properly.
SPEAKER_01So this is interesting because I'm just trying to figure out for all of the the mothers, you know, in the audience, like, you know, if you're, I'm sure a lot of you have gone through like trying to figure out what's the best form. Like, you know, do you do you use formula, do you breastfeed? Like there's a lot of questions, right? Especially if it's your first time in in motherhood, you know. Like I would love to get a more clear understanding here, you know, for that audience, because you spoke about this, I think, briefly earlier, about how you like the microbiome is shaped by multiple factors for infants, you know, and breast milk and formula milk being one of those components. Where is it that you think the education is needed for first-time moms when it comes to understanding what I can really do for my baby? So I'm setting them up for success to normally develop. Not so much, I guess I'm more interested in that normal development. You know what I mean?
SPEAKER_00Yeah, I I think, you know, and that's why I'm here. You know, I'm a mom to a four-year-old. I got on this path when my daughter was six months old and finding out that this was a problem. I'm a leading microbiome researcher, and I I didn't even know about this problem, right? I didn't even know what to do. I had to figure it out and do the science around it to help others. I think it's very early on. I think it's when mothers are expecting, I think it's through communication with OBGYN, um the pediatricians, lactation support, doulas, this community needs to bring awareness to it. Um, you know, you can't start focusing on your microbiome early enough, you know, as women when they are thinking about getting pregnant or are pregnant should really be thinking about how do I feed my microbiome best? You know, how do I make it as robust as possible? Fiber is a great, you know, way to do that, fermented foods, but um it's really that we start to share this education. And and I think
what was striking about our research that we published was that even vaginally born breastfed babies have a compromised microbiome, right? So the ideal situation now, and it's again, it's not anything we as parents are doing, it is just the babies born in modern times, and this is how modern life has impacted us, you know, you know, brought cures, but also had unintended consequences that is happening today.
SPEAKER_01Interesting. Yeah, that's very interesting because I yeah, I think for me, whenever I think about this, and I know I have a few friends who are in pediatrics and they're always very cautious, you know, when it comes to making any any claims about children, you know, because like you know, I've always heard, and this is that's why this is conversation is so fascinating for me, because I've always heard them say like less is more with infants, you know, like you you want to let them kind of grow up and you want to, but I mean at the same time, like the point also stands of like, well, if we don't know, you know, if we don't know what's missing, then how do you know if it's actually something that we don't need to intervene? You know, so it's like the knowledge is power at the end of the day.
SPEAKER_00Um absolutely.
SPEAKER_01Yeah. So I want to dive into Persephone because I think it's really unique. Um, your your approach is unique, and I want you to actually explain to us, like, you know, what was the the what were you trying to accomplish here with the product and just kind of walk us through that.
SPEAKER_00Yeah, yeah. And and you know, our vision here to thinking about pediatricians in that adoption, we are trying to create what we call standard of care, right? The data, there's over 10,000 academic scientific publications on the infant gut microbiome. So quite a bit of data from around the world suggesting this is a problem and it's getting worse, right? And it correlates with the increase in chronic disease that
we see across the world. So our goal here is to repair that infant microbiome so that all children can live life, you know, great, great health for their life, essentially, put them on that right track. And so, you know, our My Baby Biome study, as I mentioned, just you know, discovered that there were three key bifidobacterium that were missing. And so we wanted to create a product that put back those those key species, um, but also provided the right nutrients to feed them those breast milk prebiotics. And so in our lab, um, I'm speaking today from San Diego, um, our lab is here. Um, in our lab, we went to um, since we bank stool samples for our research, we isolated many strains of those three key species of bifidobacterium, infantis, breve, and longum, and formulated a product that um when when given um to the infant microbiome can basically colonize and engraft in the gut. Um and we launched this product commercially about five months ago, direct to consumer. We have two two products essentially for infants. There's a 12 months, toddlers, 12 to 36 months plus, I would say. And what's key here, this is really a first of its kind product. It's precision medicine essentially, all based on this research, right? And strains coming from the babies in the study. We include the three key species of bifidobacterium, but two strains of bifidobacterium infantis, that superhero of the infant gut, we found that there were two strains that were very dominant in the United States. I know it's rare, but these were the rare species that are left, and that's what's dominating. And so we have a first of its kind product that includes that, as well as a blend of the HMOs or those prebiotics from breast milk, and then vitamin D, which is at the American Academy of Pediatrics recommended level. What's important here is that this has been clinically validated. We've conducted a study, shared the results. We have a manuscript and review demonstrating, of course, safety and tolerability in infants, but also how it gets into the gut and colonizes. And we're very excited about the product and its potential. Um, you know, future clinical studies, we've seen some, you know, results with children who have been impacted by eczema and food allergies, and we aim to do some clinical research in that area moving moving forward.
SPEAKER_01That's interesting. Yeah, I have um a few people that have spoken to me about this idea of like, you know, we need to start looking at the microbiome very, very early on, especially for eczema patients, because you know, it is some it is a disease that develops in life. It's not always that you're born with it, you know what I mean? You're not born with it, and you will develop. And so that is a very fascinating area, I think, because you know, it really shows, and I think it speaks to your point earlier when you were going into how like the immune system is so closely tied with the microbiome and like you know, its stability. And so I think there is a question here that needs to be asked for sure. You know, I think every parent, every person needs to ask that question of like, what are we doing now in society that's leading to like, you know, we have more autoimmune diseases now than ever before, you know? We have more like atopic, you know, conditions going on than ever before. Like it's it's a it's really turning into the snowball effect that I see every day on the clinical side, you know, and I and I don't know when we're going to pause a society and go, well, where is that intervention supposed to take place? And when, you know, like when is that when is the right time for us to become preventative in our thought process rather than just okay, you know, we'll deal with it when we get there. So I think from that angle, I'm very intrigued by your research because it's it's really, I think it's ahead of its time, you know, and I think there's a lot here that can be unpacked if you're really somebody who is, you know, trying to understand this better. I know a lot of my friends have children that they're like, you know, I wish I could have done something to prevent what has happened, you know, and like whether it's eczema, whether it's an autoimmune condition. And it just makes you wonder as a scientist, like, where is the microbiome's role in all of this? You know what I mean? And where are those studies? So yeah, I mean, I think it's very fascinating, um, to say the least.
SPEAKER_00Thank you. And then that that's that's really what our focus is, is to continue to do rigorous clinical research to demonstrate that. Um, again, every parent should be aware of this. And I do think we're getting close as a society. We're not quite there, but we're, you know, as as a biotech company, that is, that is our focus, is is doing the groundbreaking research to share that and to have thoughtful conversations on it. You know, obesity is at an all-time high in children. 20% of children are obese, whereas in the 1970s, that statistic was around 5%, right? And so I think there's a lot that we can do here. Um, but it's everybody kind of coming together. It's parents and it's healthcare practitioners, but it's also um, you know, through regul regulations.
SPEAKER_01Yeah, yeah. And that's the I think that's my biggest thing is like we need to like one, obviously understand this this area, but we need to really like push regulatory stuff in this area because like there, if there is true value here, which I know there is, like there needs to be somebody who stamps it and says this is needed, you know what I mean? And and really does that because I think that's when it just it's something that we've been talking about. Like we just we said that in the beginning, you know, it's been over 20 years. We've been talking about the microbiome, I think, in a more public-facing format. But like, when is somebody like the FDA gonna come in and be like, yeah, okay, this is legit, you know, we need to like really focus here. So that's always my question.
SPEAKER_00Yeah.
SPEAKER_01Um, so I want to actually, you know, I want to dive a little bit deeper into this because you've, you know, you spoke a little bit about oncology, and I think oncology is so fascinating because I see every day that we have, like, for example, in skincare, so many things, right? Like that are translated over into like topical solutions, right? And a lot of it comes from oncology research. And I'd love for you to speak on this a little bit, you know, just to kind of educate our listeners about where you think oncology really ties into understanding the more advanced level of science when it comes to our health overall, and what should we be, you know, kind of what should we know as consumers about this field?
SPEAKER_00Yeah, absolutely. I think, you know, oncology being one of the hardest diseases to tackle because everybody's cancer is so unique, it is so complex. The tools that we've developed, the scientific tools to holistically understand cancer for any individual, any type of cancer, um, you know, we've really improved over the last 20, 30 years. And, you know, you know, it's the trickle down of that, those capabilities applied to other diseases, but also prevention that I think can have a huge impact. And you're starting to see that in in consumer health. You know, you think about function health and the access to biomarker data. A lot of
you know, oncology is based on biomarker data. We're getting so much better with targeting disease because we know biomarkers. We know specific drugs that can target a specific mutation, for example. So that has been kind of the evolution in oncology. But from a microbiome perspective, I would say it's been now exactly about 10 years that microbiome and oncology have started to be very much recognized in the scientific field, initially in animal studies, when some large pharma companies were evaluating their immuno oncology drugs, checkpoint inhibitors. That um K. Truda is the most famous of them, an anti-PD1 checkpoint inhibitor. These are incredible drugs that allow patients' immune system to recognize and attack cancer. They take the breaks off the immune system to do that. Um, and they can be a cure for many patients. The problem with these drugs is while they work for many cancers, a lot of patients don't respond. Maybe at least 50%, if not for certain cancers, much, much higher. And over the you know, course of the, you know, about 10, 10, 15 years ago, started to be recognized that the microbiome seems to be impacting how in animal studies, at the very minimum, um, that they respond to these drugs. And if you give a mouse antibiotics, wipe out the microbiome, all of a sudden these drugs stop working. They don't work. And so immediately researchers started to realize wow, the microbiome is very much connected, makes sense because the immune system is meeting the gut. Um, 80% of our immune cells are in our gut. And if we wipe out the microbiome, it these drugs don't work. And about I would say nine years ago, it was demonstrated in cancer patients that the microbiome seems to very much impact how they respond to immunotherapy drugs. And there are certain types of microbes that seem to be beneficial to cancer patients to respond to treatment. So essentially, if a cancer patient has an unhealthy microbiome, one that is low in diversity, so not a lot of kinds of bacteria, but high potential and potential pathogens, infectious organisms, those that have toxins, antimicrobial resistance genes, they tend to be non-responders, not respond as effectively. And so, you know, for us as a company, we've been working for the last almost decade on trying to understand what is the key difference between those two microbiome states. One in which a cancer patient responds to treatment. Their microbiomes look more like a healthy individual, as opposed to those that don't respond. And how could we create a microbiome therapeutic that can fix the microbiome and allow a cancer patient to respond to treatment? And very recently, in the last few years, and in fact, about last week, actually, in Nature Medicine was a groundbreaking publication demonstrating when you do a fecal transplant from a healthy individual to a cancer patient that is a non-responder, you're able to really improve their response rates. Many of them have stable disease and some have partial, you know, cures. And so we know that the microbiome, if repaired, can have a tremendous impact on response. And so, to your point, you know, from earlier in the conversation, we have to get beyond fecal transplants. We get need to get to the bottom of what's exactly flipping the microbiome of these patients in order to create more cures for people.
SPEAKER_01Absolutely. No, I love that you shared that with us because I really do, you know, if somebody told me a long time ago about this exact, like not the exact science you've shared, but like the the idea was that, you know, it's not so much about what bacteria you have, it's about what they're doing for your normal physiology. And that's where it really, really, you know, I think for me, that was the first like mind-opening moment, you know, for understanding a little bit about the microbiome. And you've brought up such excellent points here about like actual drug metabolism. And I think for a long time, if you go into anything drug development related, you know, I have a background in drug development myself, and they teach you from the get-go, like, yeah, it's all about the vehicle, it's all about, you know, like bioavailability, and there's a lot of pharmacinetic stuff that's taught. But what's not taught is that there is a huge component when it comes to metabolism. And that metabolism is not always by your P for 50 enzymes. You know what I mean? It's a lot more than that. There's a, you know, I need to make sure my metabolism is working the way it should, you know. We talk about things like leaky gut all the time. Like I know, I'm sure you've heard it all over the place. Like leaky gut, leaky gut, but it's like, what does that even mean? You know, it's like we have to really quantify these terms and understand like leaky gut can mean, yes, you, you know, increase inflammation in your body because things are, you know, getting through the gut barrier, but it also can mean that you're not really utilizing what's you're eating or what you're putting in your body, you know. So it's like a lot of different things. And I think it really plays in everything you've shared.
SPEAKER_00Absolutely.
SPEAKER_01Yeah, it's very fascinating. No, I'm just I'm very intrigued and I think it's so wonderful that you're, you know, you're really like so forward thinking here in this space. I think we definitely need that. And like I said, I think you're definitely ahead of your time, you know, uh, with your innovation. And and so I'm very excited for our listeners to discover Persephone. Um, I would love for you guys to scroll down in the show notes right now if you want to check out the brand. But uh, Dr. Culler, thank you so much. This has been so eye-opening.
SPEAKER_00Thank you for having me.