From Infant Immunity to Cancer Therapy: The Power of the Microbiome with Dr. Stephanie Culler of Persephone Biosciences

0:00Hey guys, real quick. Have you checked out Droplet? It is by far the most revolutionary skincare device on the market. Basically, it takes those harder to penetrate ingredients and pushes them deeper into the skin layers. They're actually getting to the cells that can utilize those ingredients. Recently, they just launched their ExoSome Serum Mist, which is a phenomenal product because it's using real exosomes that are shipped to you on ice. So you don't have to worry about them being degraded by the time you use them. And so when you put the capsule of exosomes into your Droplet device, it creates a fine mist.

0:25That mist is allowing those exosomes to be pushed into the layers where they're going to actually be able to interact with the cells. that can use them for signaling. If you want to check out the device, go to droplet.io, use our code ANARCHY, A-N-A-R-C-H-Y, to get a very special bundle deal on this exosome and droplet device duo. Hey guys, welcome back to Skin Anarchy. I am so excited to share this episode with you guys because we're going to be diving really deep into microbiome science, understanding more in depth. I know we've discussed the topic before on the podcast in different ways, right?

0:54whether 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 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 education in this field. So welcome, Dr. Culler. I'm so excited to talk to you. Thank you. Yeah, I'm excited to dive in. I want to learn more about your background because it's very impressive.

1:27And you've done research in the field for so many years. 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? Yeah, thank you. So, yeah, I am a scientist by training. I did my PhD at Caltech, focused in gene therapy for new cancer therapies and became a scientist really because I lost both my grandmothers to cancer when I was a young teenager. 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.

2:11So 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 I quickly realized that I really didn't know anything about starting a biotech company, nor how to commercialize products. And so 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 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.

2:52Those microbes that line our GI tract help us prevent disease and fight disease. And where 80 % of our immune system is connected. You know, most disease that we know of is connected to the gut microbiome. And 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.

3:36Can we develop products, both therapeutics, but also consumer facing products that can help treat disease, but also potentially prevent it. That's really fascinating because I think the microbiome on 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 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 catching up as a society.

4:08And 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? Yeah. So, you know, been in the space for, you know, nearly a decade now and in my scientific career for more than two decades.

4:45Don't want to date myself. But, you know, 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 white spaces that we have today 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, and it really took us the first few five years of the company and us around and global research around the world, we couldn't really understand the entire microbiome, meaning 50 % of the microbiome for a long time was actually like dark matter.

5:32We didn't know what was in the gut, right? And, 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 clostridium 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're still several years away from being understanding how we translate that in a routine way.

6:25Yeah, no, that's an incredible insight because I think also some of the more, I guess, 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 neural microbes back in there. And like that is, in my opinion, the most barbaric level of treatment, you know, 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.

7:09And 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, 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. Yeah. And that's been actually the topic of our area of focus 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.

7:44and there's some similar uncommonalities, I would say, you know, for women, especially those that are of childbearing age, and even through menopause, the microbiome plays an incredible role in our metabolism and immune function. But for women that are pregnant, really the role of the microbiome is to be passed on to the child through vaginal birth, right, and through breastfeeding, 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.

8:26It's really modernization. So where we see that impact and that disconnect, because babies today are born deficient in the right bacteria that It 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.

9:05It's the eczema, atopic dermatitis, 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. C-section births because babies are getting the microbiome from the hospital, from skin instead of the right gut microbes. It is, in some cases, infant formula because breast milk provides the right prebiotics for the gut microbiome or the full repertoire. 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.

9:55And 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. That's very fascinating because I know, like, I've looked into it, like, in myself in terms of infant gut microbes, 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 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.

10:32But 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 awry in terms of like not developing properly or anything that you found through your research? Absolutely. And so 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. The mom's stool essentially seeds the baby. So there are some microbes that they get through the birth canal.

11:12now, 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. 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.

11:57They're basically oligosaccharides or carbohydrates. And they don't feed the child. 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. And it is the only species of gut bacteria we know that can consume all of the breast milk prebiotics, all of those HMOs. And so it's really that baby strain that's important.

12:42But 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 U.S., or the hunters and gatherers of Africa. Those babies have high levels of Bifidobacterium infantis. It's become rare in Western populations. We found in our study that only 8 % of U.S. 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 brevet.

13:26And 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 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 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. It's interesting because I'm just trying to figure out what is the risk that you're quantifying?

14:08Like, what is the real risk for babies? I mean, the real risk is immune system development, 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 it long term? That's something we're looking into. You know, there is emerging data and some studies that we're also partnering on that suggests the microbiome may even be connected to cancer. early onset of cancer. We're seeing colorectal cancer in people who are in their 20s and 30s now and early 40s. This is at a rate that's increasing.

14:53It's one of the cancers that seems to be increasing 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. So this is interesting because I'm just trying to figure out for all of 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 use formula? Do you breastfeed? Like, there's a lot of questions, right?

15:27Especially if it's your first time in motherhood, you know, like, I would love to get a more clear understanding here, you know, 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 can I 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.

16:00You know what I mean? Yeah, 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 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 gets through communication with OBGYN, the pediatricians, lactation support, doulas, this community needs to bring awareness to it.

16:39You 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 way to do that, fermented foods. But it's really that we start to share this education. 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.

17:18It 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. Interesting. 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 that's why this 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 absolutely yeah so I want to dive into Persephone because I think it's really unique.

18:17Your approach is unique. And I want you to actually explain to us, like, you know, what were you trying to accomplish here with the product and just kind of walk us through that. Yeah, yeah. 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.

18:55So 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 key species, but also provided the right nutrients to feed them those breast milk prebiotics. And so in our lab, I'm speaking today from San Diego, our lab is here. In our lab, we went to, since we bank stool samples for our research, we isolated many strains of those three key species of Bifidobacterium infantis brevain longum and formulated a product that when given to the infant microbiome can basically colonize and engraft in the gut.

19:57And we launched this product commercially about five months ago, direct to consumer. We have two products essentially for infants, 0 to 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 this 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.

20:45And 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 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. Future clinical studies, we've seen some results with children who have been impacted by eczema and food allergies.

21:28and we aim to do some clinical research in that area moving forward. That's interesting. Yeah, I have 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 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 it. 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.

22:06And 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 a topic, you know, conditions going on than ever before. Like 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, OK, you know, we'll deal with it when we get there.

22:50So I think from that angle, I'm very intrigued by your research because 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, 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?

23:17So, yeah, I mean, I think it's very fascinating, to say the least. Thank you. And that's really what our focus is, is to continue to do rigorous clinical research to demonstrate that. 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 a biotech company, 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?

23:59And so I think there's a lot that we can do here, but it's everybody kind of coming together. It's parents and it's healthcare practitioners, but it's also, you know, through regulations. Yeah. Yeah. And that's, 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, 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 really does that. Because I think that's when it just, it's something that we've been talking about.

24:38Like 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 going to 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. 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.

25:12And 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? Yeah, 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, you know, we've really improved over the last 20, 30 years.

25:55And, you know, it's the trickle down of that those capabilities apply to other diseases, but also prevention that I think can have a huge impact. And you're starting to see that 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 K-Truda is the most famous of them, an anti-PD-1 checkpoint inhibitor.

26:57These are incredible drugs that allow a patient's immune system to recognize and attack cancer. They take the brakes off the immune system to do that. 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 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, 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.