Enjoy. Kieran, hello. How are you doing? I'm

doing great. How are you? I'm

very well. And you are coming to me from the that I went to preschool in Chicago. It's lovely to have you on the show. I want to dive right in and ask you the first question I want to ask, which is of all scientists, why microbiome for you? Where did that torch get lit in your scientific mind that you wanted to go down that rabbit hole.

Yeah, you know, well, funny enough, when I chose the path of science in general, the microbiome did exist, at least it existed, but we didn't know it existed, right? I was fortunate enough to choose to study microbiology, which I knew I was going to go into the biological sciences. I wasn't quite sure which one, but having watched a very exciting movie in the first week of college, a movie called Outbreak, I decided like, wow, that is really exciting. I wanted to chase pathogens and figure out cures for them and so on. So that's why I went into microbiology and virology. And then once in the world of microbiology, I did research on a number of topics, including lots of pathogenic organisms. And what I came to realize fairly quickly is that so much in the area of clinical microbiology, which was the part that was most relevant to me, because this microbiology of lots of different things, right, you're microbiologists that study soil and wastewater treatment and biodegradation, all kinds of wonderful things, but I wanted to do clinical microbiology. That was my interest. The vast majority of focus in clinical microbiology was around pathogens. And when I started looking at all of the microbes discovered, such a small percentage of them are actually pathogens, right? It's like less than 0 .1 % under best case scenarios are actually pathogenic. The rest of them are either benign or useful in some way. But at that time, when I was starting off in research and industry and things like that, there was no real impetus to study the benign or the potentially even beneficial microbes. It was all around disease causing microbes, right? And so then I went into the nutrition space, I started doing clinical trials and arranging clinical trials for in the nutrition space. And then the NIH kicked off this project of the human microbiome. And the main reason they kicked it off is to understand this massive universe of benign and beneficial organisms that we knew nothing about. And so to me, that was like, aha, that's where I want to go. You know, that is the treasure trove of healing opportunities, of discoveries, of understanding the human system. That's where it is. So I wanted to dive headfirst into that because to me that was the frontier, the new frontier of biology.

And is it as it has turned out to be? Absolutely. And the first pathogen you made me think of as you were talking there is something like E. coli, right? Because it's like it gets all this bad press because yes, in too much of an amount, it becomes a big problem. But it actually serves a purpose in a role of a happy microbiome as well. And so how in science do you guys figure do, I think with probiotics, which of course we're going to unpack, we then like push things a big way one other way and then like are we getting everything else out of balance? It's it can be really confusing.

Yeah. Well, you know, we can relate this to humans to a certain degree, right? So if you think about let's just take bacteria. Bacteria, you can really think about them in three categories. So category one are what we call a pathogenic organism. So these are direct pathogens, meaning their whole purpose is to be pathogenic. They have a ton of genes that code for things like virulence factors. Virulence factors are any genes that help them cause infection or problem or tissue damage. So they code for toxins, they code for things that help them evade the immune system, they code for things that kill other microbes in a dismantling way. So their whole world is being a pathogen. And a great example of this is like, you know, let's say Salmonella typhimirium, right? Salmonella typhimirium is a direct pathogen, or you take the microbacterium that causes tuberculosis. So mycobacterium tuberculosis is a pathogen, a direct pathogen that if you get exposed, you can live with it for a period of time, but it's trying to cause an infection in your system. And I would say actually in the world of evolution, these are the least evolved pathogens, the least evolved microbes. And the reason for that is it doesn't really help a microbe to kill its host. Ultimately, what the microbe wants to do is be able to live within the host for a long, long period of time. So the pathogens that show up, like Ebola, for example, shows up and kills its host in a matter of weeks or months, that's a terrible microorganism because it's basically wiped out its home. It's like an Easter Island kind of situation. Yeah, exactly. Yeah, they overuse resources. They go a little bit crazy in haywire. And what tends to happen with pathogens over time, and this happens with viruses as well, and we can give examples of this, is they start to become more and more and more benign. The best viruses are the that can live within you forever, not kill you, they might be very annoying, but they can live with you forever and not kill you and they themselves have a home forever. So Epstein -Barr virus, for example, cytomegalovirus, right? Or you even look at herpes virus, right? They can live within the host forever, not actually killing the host. They found ways to evade the immune system indefinitely. But they don't harm the host because they need us they need our cellular machinery to replicate themselves. So you take the direct pathogens, these are microbes by all accounts in their nature, they're here to harm. Then you've got opportunistic microbes. So these are microbes that have toxicgenic tendencies, meaning they have genes within their system that code for toxins or that code for virulence factors, but they don't express those genes until certain conditions are met, right? A example of that is like a transmissible pathogen called listeria monocytogenes. So listeria is interesting because it is a pathogen, but it only infects once it reaches a certain threshold of its own population in the body. And if it doesn't reach that threshold, it's not going to upregulate its virulence factors. There's lots of E. coli's that are similar to that. So and Staphylococcus, streptococcus, many of those that tend to live in our system for long periods of time, they tend to be opportunistic like that, where you might have, you know, a staff sitting on one part of your skin, and it's totally fine. It's benign, not doing anything bad, but then another part of your skin and there's a break in the skin, all of a sudden it has the opportunity to express its virulence factors and it may cause a massive infection there. So these organisms sit down and often they can have beneficial effects when they're not acting as pathogens, but given the right conditions, they will express their virulence factors and they will cause a problem. More often than not, the right conditions are if other pathogens in the area are also expressing virulence factors or their numbers reach a certain threshold or the host immune system seems to be Right? They measure things like your stress hormones and other things to understand what is going on with the host immune system, or they can even measure inflammatory cytokines to understand what the inflammatory state is. And if the inflammatory state is high, then they may express their virulence factors. Now the third category are completely benign and or beneficial microbes. Now the big difference between these types of microbes is that they don't contain any virulence factors. So even if they wanted to, they can't actually be pathogenic because they don't code for any toxins, they don't code for antibiotic resistance, they don't code for any other virulence factors. They don't have it in their genome at all. Right now in some cases they can pick up some of these genes from pathogenic organisms. But the ones that are commensal within our body that we've developed this symbiotic relationship with, they tend not to do that because they do know that maintaining this homeostasis is better for them, right? They don't want the host to actually get ill. So those are the three categories of microbes. Now, I would say that in most humans, when we think about dysbiosis, in the gut, on the skin, in other parts of the body, and we think about like, okay, pathogens causing a problem, everything from creating a frank infection or illness where you feel it, you're sick, you have fevers, whatever the symptoms are, to the poor, causing disruption like in your digestive system, immune dysfunctions, all of those things. Most of the time, those are the opportunistic, right? It's not as common for us to have exposure and get ill from a direct pathogen. That's the most common version of that is when people get foodborne illnesses, right? You eat a you eat a contaminated burrito or something and you're vomiting and feeling like you're dying for the next two, three days, but then your body clears that your immune system clears that, or maybe you took a medication to clear it, and it's gone. That's the acute illness that's often associated with direct pathogens. Most of the chronic issues that are credited to microbes come from the opportunistic ones. Yeah.

Wow. Well, that was quite a tour there, Karen. Thank you. It's so important for people to understand. It is so important. Yeah, I want people

to know that the terrain really matters, right, whether a bacteria, or even to a certain degree of virus is going to act in a pathogenic way is dependent on the terrain and the ecosystem. The ecosystem dictates what they do. And so if you have an ecosystem that tends to allow for the manifestation of the expression of virulence genes, then you're gonna be somebody that's constantly dealing with toxin producing microbes that are causing inflammation, illness, chronic issues and so on, right? So managing your terrain really important. And a lot of that management can be done through improving the benign and beneficial microbes. Yeah.

And can it end up being a little bit chicken or the egg? Like if the immune system's down, then that affects the gut. If the gut's down, then that affects the immune system. Like, I mean, part of the chronic illness picture for so many people is like that silver bullet root cause, but then in fact finding a holistic approach ends up being the best because it's very hard to find out which one went out first. It's better to just try and build a healthier person. It's

true. So when it comes to the immune system and the gut microbiome, and we can talk a little bit deeper about the relationship between the two, one affects the other quite dramatically, right? So a messed up immune system will cause a dysfunctional gut microbiome, and then thereby a dysfunctional gut microbiome will cause even more problems with the immune system, and it becomes a self -perpetuating cycle. And often what the people who are experiencing this cycle feel like is it may start off with, you know, I get sick quite a bit, maybe more often than my peers, right? Like, oh, every time there's a cold or flu thing going on, I pick it up. Or they might be more, less resilient to things like lower sleep amounts or, you know, you know, being exposed to things all the way to like, all of a sudden they're getting food sensitivities and they're getting more autoimmune type responses like eczema, psoriasis, they're seeing more inflammatory conditions like acne popping out or indigestion and chronic indigestion. And then it goes all the way to more serious conditions. But that is a self -perpetuating cycle that then needs to be arrested.

Yeah, absolutely. And how does one decide to approach improving one's gut health best in your view? I mean, you've obviously explored this to the point where you decided to start a company and it's by no means an ad for microbiome labs, but it's a very interesting take, if you like, in the microbiome space. And I'm curious to see how you arrive at, I think this is missing.

So when I looked at it, I really am, as a microbiologist, I follow a lot of evolutionary biology cues, right? Because the thing is our microbiome, our digestive system, our immune system didn't occur overnight. These are products of hundreds of thousands of years of evolution, right? And you have to look at the pattern of evolution and how we co evolved with microbes in the environment and all that to understand how a lot of this may work. my thinking and my investigation, but then from lots and lots of studies that have been done on this topic, what becomes clear is that we have a very intimate relationship with microbes, not only in us, but in our environment as well, right? And constant and continuous exposure to a large variety of microbes in our environment and between each other, between individuals itself, is a very important aspect of maintaining diversity and resilience within the gut microbiome. That's also arguably one of the most important things that occurs for your immune system in terms of maintaining robustness and proper functionality of the immune system. And so when we looked at, okay, so if we're gonna people a tool, there's a lot of things they need to be doing themselves because there's no silver bullet in fixing the gut, right? But we wanna give them a tool that helps mimic what our ancestors did to evolve and create this amazing robust microbiome. And so we honed in on microbes that acted as what you call quorum sensing agents, right? So think about it this way, we've got this diverse and complex microbiome in our gut and on our skin and everywhere else in our body. And there's tons and tons and tons of microbes in the environment, right? And for the vast of human evolution, for 99 .999 % of the time that we've been here, we've been in concert with the dirt, right? We've lived in the dirt, ate off the land, we drank water, some rivers and streams, we dug for roots and tubers and foraged, and so we got a lot of exposure on a regular basis to the environment around us. And as a consequence of that exposure, we also get a lot of exposure to microbes. And as it turns out, that constant osmosis of us putting microbes back out into the environment, through shedding it through our skin, through breathing, through sputum, through sneezing, and then of course, through defecation, which is a huge part of it, and then bringing in microbes through food and diet and exposure and all that, that constant exchange seems to be incredibly important, not only to maintain a measurement of what the environment is like for our immune system to understand where we live and what we live amongst, but also to maintain a certain diversity and cohesiveness to our gut microbiome. And so we said, okay, how do we mimic that? Right? And so we started looking for organisms that exist naturally in the environment that also can colonize and play a role in the gut microbiome. And that's where we found these bacillus endospores. And the endospores are very unique because they've been around for millions of years. They were possibly some of the earliest cellular life form on earth itself. There's some really interesting documented studies on the ability of these spores to survive interstellar travel on meteorites and possibly be... Yeah, this is the theory. If people really want to nerd out, there's this amazing theory called the theory of panspermia. The theory of panspermia says this. It's like, okay, where did the building blocks of cells come from on Earth? So we know, early Earth, there was this massive bombardment period where Earth was basically being bombarded with rocks from outer space. Some of it coming off of other planets, some of it coming from Kuiper belts and all these other regions of space, but Earth is being bombarded. the bombardment era stopped and Earth continues to get hit by meteorites because we didn't have an atmosphere just yet, right? Right now, a lot of those rocks would be, you know, disintegrated in our atmosphere, but we before we had this thick atmosphere, we were getting hit by a lot of things. they found, scientists have found that on meteorites that have hit the earth in the more modern day, they find proteins and nucleic acids, which are the building blocks of cellular life, on these meteorites, right? So they're present on meteorites that are coming in from out of space. They even found some, if I'm not mistaken, on ones that are found on the moon, Right? And so the thinking is that, wait, so there, there may be microbes that live on earth today, that were part of the original seeding of cellular machinery on earth from outer space. So this is the idea of pan -spermia. And it sounds cuckoo, but it's not, right? It is great documentation this from a scientific literature standpoint. So for example, Mars had a completely different environment early on than Earth did, right? We now know that there was likely liquid water on Mars, there were likely microbes and other things on Mars. skipped off of surface of Mars and made their way to Earth. So it could have picked up microbes from Mars. This can something survive the interstellar travel from Mars to Earth, a microbe. They found that spores that live on the Earth today can survive up to seven years of interstellar travel on a rock. And then when they look at the genetic of Bacillus hematospores that are found today versus ones that are found in glacial ice cores that are six, seven million years old, they find that their genes don't hardly change. So these are very stable microbes have been the way they are for the vast majority of time. And could be at least they could be an answer to what seeded the earth with proteins, nucleic acids and all that in the early bombardment period, right? So it's pretty crazy when you think about it. But it also speaks to, you know, paying homage to where we all may have come from, and where cellular life, how all of that started, right? And of course, there's lots of different explanations that people can have, but as a microbiologist, this is where my brain goes, right? I go to the smallest of biological units and I look at the cell and I go, okay, where did these components come from? And microbes could have very well seeded it. And so we honed in on those microbes. We said, okay, those microbes have been here for billions of years. They have a very unique capability of surviving through the gastric system, living in the human gut, and also waiting in the environment for up to, you know, 200 million years before they get re -swallowed and go work in the human gut. And they have this unique ability of quorum sensing. And this part is really interesting because quorum sensing is the ability of microbes to read each other's chemical signatures, to understand who's in the environment. And then some of these microbes can take action as a result of that. No, it's like a little networking event. It is a networking event and it's the earliest language, right, that we know of. I mean, before it completely predates our ability to communicate with one another, right? And microbes are still doing this today. In the body itself, they're quorum sensing with each other and talking to each other. And in fact, we know that microbes in different sites of the body can talk to each other. don't exactly know how, right? How are they sending messages among each other within our body? So it's absolutely fascinating. So I'll give you a story of the earliest understanding of Bacillus quorum sensing, right? Yes, that's why they were so exciting to me. So it's well documented that in World War Two, the German army, in their campaign in North Africa, most of the German soldiers were dying of dysentery and food poisoning and so on, right, they couldn't drink the local water, they couldn't eat the local food. is when the locals got an upset stomach. One of the things that they would do is they would look for dried camel dung and they would chew on the dried camel dung and that would cure their digestive issues, right? And so they took back a bunch of this dried camel dung and a pharmaceutical company in Germany or in Europe in general worked on figuring out what is it in the dried camel dung that could heal dysentery, which is of course a terrible gut infection.