Precision Care for Acne and Eczema with Oliver Liu of Hypothesis

0:00Hey guys, welcome back to Skin Anarchy. This is a very special episode because we're going to be covering a topic that I think we rarely get to sit down and speak about in detail and in full fullness in terms of the science. And so for decades, I know a lot of you have heard about acne, eczema, kind of the same way when it comes to the bacteria that are involved, the microbiome that's involved, but nobody dives into like what that actually means. I feel like we keep having this conversation and going in circles and not really getting to the nitty gritty of all of it. So our guest today is going to do exactly that and really talk to us in depth about the microbiome and really what that means for these different skin conditions.

0:41So without further ado, please welcome Dr. Oliver Liu, who is the co-founder and CEO of Hypothesis. Welcome, Dr. Liu. I'm so excited to host you. Yeah, thanks for having me. Really excited to have this conversation. Yeah, I'm really excited to dive in. I would actually love to start off with learning more about your background. I know you have such extensive experience in biochemistry, genetics, metagenomics. I mean, I would love for you to dive into that and kind of walk us down memory lane and tell us about your background. Yeah. As you mentioned, the bulk of my career since my PhD has been in what's called metagenomics.

1:13Metagenomics is the study of communities of microorganisms, whether that be in the soil, in a hot spring, or on your body, like with the skin microbiome. The thing that makes metagenomics so interesting is that we honestly have barely scratched the surface of natural diversity. It's estimated that 99.9 % of microbial diversity in the world has never been studied, primarily because we don't know how to grow them in the lab. That means almost everything we've learned, all these huge databases of species and genomic information, all these things, come from just a small sliver of natural diversity.

1:46And the thing that I and my fellow co-founders at Hypothesis have learned, both at Hypothesis as well as at Radiant Genomics, the previous company I co-founded, is that if you do have a biological challenge, nature has almost always come up with a more elegant and effective solution than anything scientists can come up with in the lab. The answers are out there, often in those huge swaths of natural diversity that no one has looked at before, and metagenomics is a way for us to uncover those solutions. When it comes to the skin microbiome, we have been following that field for a while. So we know now that a well-balanced, diverse skin microbiome is critical for skin health.

2:26It helps to strengthen the skin barrier, train the immune system, prevent pathogens from colonizing. And over the past 15 years or so, the tools that researchers have to study and characterize the skin microbiome have improved tremendously. And so now we can not only look at someone's skin microbiome and see the specific species of microbes that make up the skin microbiome and their relative percentages in different parts of the body, we also have a much better understanding of what can go wrong in the skin microbiome, particularly when you have skin conditions like acne or eczema. And what we see in both those cases is that specific species of bacteria can overgrow in the skin microbiome and cause or worsen these conditions.

3:06In the case of eczema, that bacteria is called Staph aureus. In the case of acne, this bacteria is called C. acnes. That's really interesting. And it really stood out to me what you said about how we don't know about a lot, most of what's out there in the world of microbes. I mean, that's really fascinating. I think that really hits home for, I think, a lot of us. Because we often think that now that science is diving into the gut skin access, the microbiome, It feels like we have it all figured out, but clearly there's so much to explore there. I would love for you to dive into where did you see the biggest disconnect between what the science already knows, which I think you were talking about just now, about the microbiome and what's actually available to consumers?

3:50Yeah, so as I mentioned, on the one hand, we increasingly have this kind of very detailed mechanistic understanding of how specific bacteria can drive conditions like eczema or acne. These bacteria not just happen to be growing more, they are actually playing a central role in disease progression. On the other hand, the products that we have to treat these conditions haven't changed in decades. We're still using the same ingredients we always have. And they either don't really address the skin microbiome, things like colloidal oatmeal or steroid creams, or you have ingredients like benzoyl peroxide, antibiotics, disinfectants like hypochlorous acid that are meant to kind of try to control some of this causal bacteria, but they're broad spectrum, right?

4:34And they indiscriminately kill all bacteria, including the good bacteria your skin needs to stay healthy. So that's the gap that we saw when we founded Hypothesis. You have these skin conditions that are crying out for a precision approach that's more than simply, you know, carpet bombing your skin microbiome. And importantly, we also thought we had the solution. We were inspired by a class of high-specificity enzymes that are found in nature. And with these enzymes, we believed we could usher in what could truly be called precision skincare. And so over the course of two, three years of R &D, that's what we worked on.

5:10We developed these high-precision enzymes that can specifically target either staph aureus or C acnes without damaging or affecting the broader beneficial microbiome. One of the things you see is if some of these acne treatments aren't working for you, So the suggestion often is to use higher and higher concentrations of these treatments and harsher and harsher things. And you're really starting to make a lot of tradeoffs in terms of kind of collateral damage you're doing. Right, right. No, that's exactly it. Just keep upping it. And that's never the solution. But I want to actually go back to what you were talking about.

5:44You were mentioning this new approach, this precision-based approach. Can you dive a little deeper into that? I mean, what enzymes? And just tell us more about that. Yeah. So when we started Hypothesis, we got really interested in a class of naturally occurring enzymes found in bacteria and bacteriophages called lysins. They're interesting for a couple of reasons. First is these enzymes are designed to bind to bacterial cell walls and chew them up very rapidly, causing the bacteria to burst and die. So it's a kind of really rapid bacterial killing activity. It's like popping a balloon with a pin.

6:18The really interesting thing about lysins, though, is that because the structure of the cell wall can differ pretty significantly from species to species, depending on how an enzyme binds to that cell wall, it has the potential for very high specificity down to a single genus, species, or sometimes even a subspecies. And so that means potentially one of these enzymes could specifically target a single species of bacteria within a community of many different types of bacteria. And that potential for very high selectivity struck us as an incredibly powerful property. As we've talked about, most ingredients with these antibacterial properties like antibiotics, hypochlorous acid are broad spectrum.

7:00They kill all bacteria. And so the idea of being able to target a single species within the community seemed like, you know, honestly, like a superpower. And in particular, we thought the skin microbiome would be the perfect application. Yeah, that's, I mean, that's incredibly fascinating that you can really narrow it down to that level. I mean, I hope we can go in that direction with everything now that I'm thinking about it when it comes to skin health. Now, I want to dive a little bit deeper because we started the conversation talking about acne and eczema. And I think it's important for all of us to kind of revisit like eczema and really understand what's happening here.

7:32Can you break down the three-driver model for eczema so we can just kind of get our brains around this? Yeah, sure, absolutely. I think the best way to understand eczema is through what dermatologists call the itch-scratch inflammation cycle. So if you have eczema, that term sounds familiar, and this process sounds familiar, right? It starts with you have a patch of irritated skin. It might be a bit inflamed. It itches. is you scratch it, and that scratching ends up causing more damage to the skin, which unfortunately triggers more inflammation, which triggers more itching, and then more scratching, and you have that cycle that repeats getting worse each time.

8:11And once it gets going, it can be really hard to stop, and before that initial itch has turned into a full-blown flare-up. So we now know that three interconnected factors really drive that cycle and keep it going. The first factor is a weakened skin barrier. The outermost layer of your skin is supposed to act like a seal, right? It keeps moisture in and irritants, allergens, bacteria out. In people with eczema, this barrier is often compromised. Sometimes it's genetic. A lot of people with eczema have a mutation in a protein called filagrin that's important for building a strong barrier. But the barrier can also be damaged by things like physical irritation, inflammation, and even bacterial activity.

8:53So that's one factor. The second factor is an overactive immune system. Eczema-prone skin tends to overreact, tends to overreact to things that generally should be safe. And so it's prone to inflammation that can damage the skin and drive itch. This inflammation also makes the skin more hospitable to harmful bacteria like Staph aureus. And finally, the third factor, which is the piece that's really been uncovered over the past 5-10 years and has been generally overlooked in eczema care previously, which is the microbiome imbalance, specifically an overgrowth of staph aureus. Staph aureus produces toxins and factors that break down the skin barrier, increase inflammation, increase itching, and you can see how this directly feeds into the other two drivers.

9:43And so that's what's so challenging, right? These three drivers don't exist in isolation. They feed on each other to drive that itch-scratch inflammation cycle. And once that's established, it tends to start reinforcing itself. So what is this like with staph or specifically, like you said, this is a really, like, this is the critical one, the bacteria and eczema. Can you dive deeper into that? Like, what about it exactly is making things worse? Yeah. So this is a great example of how we have learned so much about the skin microbiome over the past 10 years. Dermatologists have long known that staph aureus is more likely to be found on individuals with eczema.

10:18So studies show that 70 to 95 % of individuals with eczema are colonized with Staph aureus, while only about 10 to 30 % of the general population is. The question has always been, what does this mean? Is this correlation or is this causation? In 2012, there was this great paper that came out of the NIH that looked at how the levels of staph aureus change in people with eczema as they go through flare-ups. And what they found was that the level of staph aureus on the skin is not static. Instead, the amount of staph aureus actually spikes dramatically right before and during flare-ups. And the more staph aureus that you have, the worse your symptoms tend to be.

11:00And so this finding was really important. It kind of indicated that staph aureus isn't just this bystander on the inflamed skin, but is actually an active participant is actually one of the big drivers and triggers that amplifies these flares. Since that study, other researchers have not only confirmed those results, they begin to uncover exactly how staph aureus drives that itch-scratch cycle. It actually produces toxins, enzymes, molecules that break down the skin barrier, drive inflammation, crowd out other microbes. There was a paper that came out a couple years from Harvard Medical School that actually identified the specific enzyme that staph aureus produces that can activate a nerve cell that drives itch.

11:45And so this is the first time actually that they found a microbe that could directly trigger itching. And so it basically accelerates all the drivers of this itch-scratch inflammation cycle. So it turns out staph aureus is really like the fuel on the fire, right? It's really what's revving up the itch-scratch inflammation cycle. It turns that initial trigger into that full-blown flare-up. That's so fascinating. I mean, especially with the nervous system integration that you just explained, that's really interesting. Now, in terms of like, now, I mean, staph, that's very interesting for example, but I know with acne, we hear about bacteria a lot more, especially with sea acne.

12:22It's like, can we dive into acne as well and talk about what we've been told about acne thus far, right? It's caused by bacteria, but you say it's actually about balance. So can you kind of walk us through that? Like, what does that mean for acne? Yeah, no, absolutely. As you mentioned, in the case of acne, most people know that bacteria play a role, right? It's why you do see things like benzoyl peroxide or why dermatologists prescribe antibiotics, why you see a lot of antibacterial being a selling point. But just as with eczema, it's not all the skin bacteria that's involved in acne. It's driven by imbalance of a specific bacteria called QD bacterium acnes or C acnes.

13:01And actually, even in the past five years, our understanding has gotten even more nuanced than simply saying you have too much C-acnes. In the past, it was thought that acne was caused simply by an overgrowth of C-acnes. But now that we have much more detailed genetic studies of the skin microbiome, we know that people with clear skin often have just as much C-acnes as those with acne. And C-acnes is a normal permanent resident of your skin. It's actually one of the more abundant bacteria to face. We now know the problem is not necessarily how much C-acnes you have in the skin, but instead what subtypes or phylotypes of C-acnes dominate the population.

13:42In people with clear skin, these subtypes exist in kind of a relatively balanced distribution. They kind of keep each other in check. There's a lot of strains that are less inflammatory. But in acne-prone skin, that balance shifts. And so there's one subtype in particular known as 1A1, which becomes dominant. And so it can make up 95 % of the sea acne's population on acne-prone skin versus 30 % to 40 % in non-acne skin. And this inflammatory subtype produces more lipases that break down sebum into irritating fatty acids. They generate more inflammatory metabolites. They're more likely to form biofilms.

14:25And so it's not necessarily, in the case of acne, it's not necessarily that sea acnes as a species is overgrowing. In general, it's more that there's a specific subtype of sea acnes that has taken over the population. That's really fascinating to learn about because it really makes you then question this whole idea of what we were originally talking about, where it's like the whole kill everything model, like just nuke everything. Can you talk to us a little bit more about that now in terms of why that doesn't really make sense then, now that we know this? So as we mentioned, most molecules that kill bacteria, treatments like benzoyl peroxide, antibiotics, they indiscriminately kill all bacteria, including the good bacteria.

15:05So obviously you're losing out on the benefits of a diverse, well-balanced skin microbiome. All the good bacteria that your skin needs to stay healthy are being wiped out. I think it's also worth noting that wiping out large portions of your microbiome has other downstream effects. you're actually removing a lot of the healthy competitors that keep bad bacteria like staphores in check so once you stop using these treatments the bad bacteria can actually come back even stronger because their their natural competitors are are gone and so and then i think we talked about uh about the harshness of yeah it's like uh benzoyl peroxide one other thing to note around antibiotics is that there's a lot there's also a lot of issues with antibiotic resistance, right?

15:47So studies show anywhere from like 60 to 90 % of C-acne strains are resistant to some antibiotic. So, you know, that's both a public health problem and a practical problem for patients when their antibiotics aren't working. What is your opinion on why the industry hasn't been able to embrace this more precision-based model so far? Like, why have we been stuck in this like nuke everything mode? Yeah, honestly, it's because In my opinion, and I think it's because creating precision ingredients that actually can be highly selective for a single species of bacteria is actually a really hard biological challenge.

16:26You need an ingredient that somehow can tell the difference between different bacteria, can kind of distinguish between one bacteria from another, or you need to find some vulnerability that only your target bacteria has. And that's not easy to do, particularly with simple chemicals like benzoyl peroxide or hypochlorous acid. It's not even easy to do with more complex molecules like antibiotics. And so this is where we really took inspiration from nature because, of course, nature has solved this biological challenge in the form of these high specificity enzymes. and you really do need the biological complexity of a large molecule like an enzyme that can actually distinguish between different bacteria.

17:14And so when we learn more and more about Lysense, the more we thought, yeah, this would be the key to precision microbiome skincare. Yeah, I mean, it makes a lot of sense, honestly. And I like that you brought up the point about how there isn't a vast amount of resources required to create technologies like this. I mean, this is really worth noting is that it takes a lot of dedication and years and decades of science to come to this kind of understanding. So, I mean, that's huge. And I'm glad that you guys are doing it, honestly, because we need this approach. And now, how are technologies like TPZ01 and Cut02 different from traditional actives?

17:50Right. So TPZ01 and Cut02 are our two patented and proprietary precision enzymes. TPZ1 is designed to specifically target staph aureus, while CutO2 is designed to specifically target C acnes. We spent two to three years developing these enzymes. I mentioned they're based on enzymes that are found in nature that we discovered in our research. We tested over 800 variants of these enzymes to find ones that kind of met the criteria and specificity that we wanted. So in our laboratory testing, both of these enzymes kill 99.99 % of their target bacteria, while having no measurable impact on a broad panel of beneficial skin bacteria.

18:36So they have very strong and very selective activity. And because they only bind to their target bacteria and don't really interact with human cells, TPZO1 and CutO2 are incredibly gentle. They don't cause irritation or affect the skin barrier. We have done both tests on panels of people with sensitive skin or looked at 3D models of human skin tissue. And what we see, we confirm the enzyme has no effect on human skin cells at all, even at really high concentrations. And so these have very few side effects. They're non-irritating. And our clinical testing backs that up. 95 % of participants that use our acne serum for eight weeks said it was non-irritating.

19:21They had no issues. Wow, that's amazing. And that's really amazing that they're so precise. They're not interacting with the skin in any negative way. That's really, that's very fascinating. Now, I'm curious though, what is the biggest challenge? Because I always wonder, right, with proprietary ingredients, it's got to be hard bringing that to mass scale and putting in skincare. So what were some of the biggest challenges that you faced bringing these enzymes over into skincare products? Yeah, it wasn't easy. So we're not the first group to think about using license to manipulate the skin microbiome.

19:50other labs, other groups, other companies have looked into it. I think historically, there have been three kind of big challenges in turning these enzymes into effective products. The first is that specificity. And there are a lot of license, you know, you can find license, and while license have the potential for specificity, it can be really hard to find one that actually has a specificity you want, right? So for example, there are a number of enzymes that have been found that target the genus Staphylococcus broadly. But finding an enzyme that can distinguish between Staph aureus and its closely related species, Staph epidermidis, which is actually a good bacteria, is really hard.

20:32And so finding that specificity and figuring out ways to distinguish between those can be quite challenging. In the case of acne, no one has previously been able to find an enzyme that effectively targets C acnes. So CutO2 is really the first enzyme that even really targets C acnes in this class. So specificity is the first challenge. I think the second challenge is that even if you can find an enzyme with the right specificity, you still need more from that enzyme, right? You need an enzyme that has high activity. It works that you want it to work at the right pH. You know, skin is ideally slightly acidic and most importantly is highly stable.

21:12You're probably familiar. Enzymes are notoriously fragile. They're sensitive to heat. They can be damaged. They can be degraded. They just fall apart over time. And of course, when it comes to skincare products, shelf life is really important, right? So you want a long shelf life at room temperature so that it's both convenient for customers. Also, you need that long shelf life to let you sell through different channels like retail or Amazon. So we had to work really hard to develop enzymes with very high stability and develop formulations that really protected these enzymes so we could achieve that two-year shelf life.

21:52Third challenge I think you alluded to is that you need to be able to produce these enzymes at large scale and cost effectively. We worked really hard to increase the production yields of our enzymes so that we can sell at accessible price points. Well, no, that sounds incredibly like a true feat to be able to accomplish this. Yeah, I mean, it's really, I think that's one of my biggest, I'm always like in awe of that when you look at innovation in the space and how it's brought to life. In skincare, like it's always very inspiring to see how much work goes into that because scaling is, yeah. I mean, this is one of the reasons we also wanted to found hypotheses is that we did feel like we had, with our experience with metagenomics, with harnessing natural diversity, with our background in engineering biology, we felt like we had a new way and a new approach to try to overcome these historical hurdles.

22:48And so, as you can imagine, a lot of the ways we've been able to overcome these challenges by looking to find better enzyme candidates and better starting points, kind of by looking broadly in natural diversity where no one else has looked before. Yeah. No, I mean, I think that's very fascinating. I'm glad you're also highlighting that there is so much in nature that we can still use. I think that gets lost a lot of times is that we can really go there and find solutions still. We just have to do the science. Like you got to do the work. You got to look into technologies that can bring that out.

23:22But I want to dive deeper into your clinical results. I know you have an immense amount of clinical data really backing up what you're doing. Can you dive into the clinical studies and what they revealed about how effective this approach actually is? Yeah, so I think this is where the kind of proof is really in the pudding, right? It's great to be able to show specificity and activity in the lab, but the question really is what happens when you apply it to the skin? So we have run a number of clinical trials. In the case of eczema, we ran what's called a dual-arm formulation-controlled clinical study.

23:54So we split our participants into two groups. One group used our eczema precision hydrogel, which contains our TPZO1 precision enzyme. They used it twice a day for two weeks. We also had a second group, which is our control group, which used an identical formulation, contained kind of same OTC levels of colloidal oatmeal, same provitamin B5. The only difference is that it did not contain the enzyme. Again, that control group used that control formulation twice per day. We looked at eczema symptoms. We had them clinically scored by experts using the SCORAD rubric at baseline one week and two weeks.

24:35After two weeks, the control group saw a 25 % decrease in eczema symptoms on average. The group that used the eczema precision hydrogel saw a 61 % decrease in symptoms. So simply adding TPZO1 to the formulation improved results over two and a half times. Importantly, when we looked at the microbiome, the amount of staph aureus decreased by 85 % in the group using our hydrogel, while there was no significant change in the control group. So we think this study was really a nice set of data that ties and demonstrates the performance of TPZ1 with its benefit. Yeah, that's really huge. That's really, really good.

25:21Yeah. Yeah. In the case of acne, we ran longer eight-week trials. So improvement in acne is generally more gradual. And actually, a lot of trials go out even longer, 16, 24 weeks. So we had participants use our acne precision serum, which contain cut O2 once per day, nightly for eight weeks. In these trials, we saw that 93 % of participants saw improvement by week two, but with the most kind of substantial improvements accruing over kind of weeks four through eight. We saw significant groups in all the symptoms that we tracked, including lesion count, redness, tenderness, skin tone. We didn't do a head-to-head with traditional treatments, but when we compare our clinical trial results to clinical trials in the literature that are testing first-line treatments like combinations of antibiotics, benzyl peroxide, and retinoids, the magnitude and pace of improvement we see with the acne precision serum is comparable.

26:19So comparable, good efficacy, but with much less irritation, much better tolerance. Wow. That's really fascinating because, yeah, because the protocol for acne just feels so daunting. So that's really, really promising to hear that. Now, in terms of like, I want to really put this in context for our listeners in terms of routines, because I think that's where a lot of us get stuck, right? Is like figuring out how to incorporate novel tech into our routine. So if somebody is using hypothesis products, what is a realistic routine that they can follow? Yeah, great question. I think this is really where science becomes kind of really practical for people, right?