The gut microbiome, which consists of trillions of bacteria, viruses, and fungi, plays a crucial role in our health. However, there is still much to learn about this complex ecosystem. On this episode we talk with experts who tell us where the science is—how much we know, and how much we don’t. Two companies, Bloom Science and Seres Therapeutics, are leveraging the microbiome to develop new therapeutics. The potential of the microbiome is vast, and further research and technological advancements will continue to unlock its benefits.
The gut microbiome, which consists of trillions of bacteria, viruses, and fungi, plays a crucial role in our health. However, there is still much to learn about this complex ecosystem. On this episode we talk with experts who tell us where the science is—how much we know, and how much we don’t. Two companies, Bloom Science and Seres Therapeutics, are leveraging the microbiome to develop new therapeutics. The potential of the microbiome is vast, and further research and technological advancements will continue to unlock its benefits.
Theresa Brady: Interest in the microbiome, especially within the gut, has taken off over the last couple of decades. A wave of consumer products claiming to support and improve the gut microbiome has hit the market. Probiotics are all the rage. But how much do we really know about this complex world of trillions of microbes living within and on us? [00:01:00] Along with the interest in and the hype around the microbiome is a growing scientific exploration of microbiome communities, whether in water, soil, air or the human body. Today, we talk with experts who tell us where the science is, how much we know and how much we don't. And we'll meet two companies leveraging the microbiome to develop new therapeutics. I'm Theresa Brady and you're listening to I am BIO.
Spencer Diamond: Microbiomes [00:01:30] are really just collections of microorganisms that interact and live pretty much everywhere and all of these microorganisms interact [00:02:00] in different ways that either are beneficial or negative or neutral to our health, but microbiomes are basically all over our planet and they're essential for our survival.
Theresa Brady: This is Spencer Diamond, a principal investigator at the Innovative Genomics Institute at UC Berkeley, which was founded by Jennifer Doudna. Doudna, as you may know, shared the Nobel Prize in Chemistry for discovering the tool CRISPR/Cas9, [00:02:30] which is essentially genetic scissors. Later, we talk with Spencer about the fascinating application of CRISPR to the study of the microbiome. But first, Spencer gives us a crash course on the microbiome.
Spencer Diamond: Microbiomes are extremely important for our health. We've correlated a lot of human diseases and conditions to the proper functioning of the human microbiome. We can make these correlations like we can see, Oh, people who [00:03:00] end up having diabetes or that have anxiety, their microbiomes look different. They have different species in them than people who don't. But we don't necessarily know for certain whether the differences in those microbiomes are actually the cause always, and this is kind of where we also started with the human genome project. When people thought once we sequence the human genome, we're going to know all of the genetic problems that are bad and we're going to be able to fix them, but ultimately, [00:03:30] that just led to a lot of studies initially where people correlated certain genes with certain conditions and it took a lot more experimentation to show that those genes were the cause of various maladies or- or differences between us.
And so the microbiome, we're kind of at that stage at this point, we're seeing differences between cohorts of people that are sick or healthy and then we can say, Oh, well, there's a difference in their microbiomes, but we don't necessarily know exactly what those differences are [00:04:00] causing or if they are causal or if they're just a result of having a condition.
Theresa Brady: Correlation does not equal causation. Spencer explains that while this is true, there is growing evidence connecting the microbiome to immune development.
Spencer Diamond: One of the things that we're studying closely here at the IGI is how the human microbiome when we are very, very young, when we're infants just born, how it develops and how that development is influencing our immune function. [00:04:30] And one of the things we do know is that if you're breastfed or not breastfed, that your microbiome will develop differently and also that when your microbiome doesn't develop properly, you can have various immune dysfunctions, things like asthma and atopic disease which are caused by generalized inflammation through the microbiome or the fact that essentially, to boil it down, like your microbiome, if it doesn't develop properly, your immune system's not learning what is friend and foe. Your immune system is [00:05:00] reacting to things that are in your microbiome in a poor way es- essentially and you're not going to develop the proper immune responses that people should have if they're healthy.
I would say we're rather certain the development of our microbiomes has a significant impact on our immune function and immunity development. The exact mechanisms by which that occurs, we're less certain about.
Theresa Brady: Spencer says that despite scientific progress and continued [00:05:30] research, we are a long way from understanding the complex ecosystem of the microbiome.
Spencer Diamond: We don't really know exactly what a healthy microbiome looks like. Humans are incredibly diverse, right? And we're also not lab rats. We do as we please, right? We eat what we want. We also live in very different places, have different life experiences, different exposures to other microbes from the environment. [00:06:00] If you live in California in the United States or if you live in Spain, you might encounter very different microbes in your environment, in your water, in your food. You eat very different food. And due to all of these things, our microbiomes develop differently. Additionally, our genetics play some role. And so because of that, it's been extremely difficult to get a good understanding of what a healthy microbiome is for different types of people. The microbiome is a very individualized [00:06:30] thing and I would suspect that, you know, it's somewhat of a fingerprint and so ultimately, the treatments that are going to be developed for microbiomes are likely going to be somewhat individualized.
Theresa Brady: DNA sequencing has transformed our understanding of the microbiome, but it has its limitations according to Spencer.
Spencer Diamond: Ultimately, what sequencing is doing is it's giving you a snapshot of what is there. It's giving you basically a- [00:07:00] a single picture. It's like if we said we wanted to know what's happening on the Serengeti and we went there and we were able to take one picture, and then we had to take that picture home and then look at it and say, Okay, this looks like what animals are there and it looks like these two animals might be interacting with each other, and try to infer kind of what's going on from these singular snapshots. And again, that doesn't really give us any ability to test what's going on in the Serengeti [00:07:30] for instance. It's very observational. So we can learn a lot from observing, but we can't really learn very much if we can't set up something in the lab and test it.
Theresa Brady: Spencer uses a car analogy to explain why it's important to go beyond a snapshot of the microbiome and view it functioning in a community with different types of stresses.
Spencer Diamond: You can think about that is imagine you had a car and you didn't know what any of the parts on the car did, [00:08:00] right? And so you could see, Well, if I remove the carburetor, for instance, now the engine doesn't function, so that- that's an essential part. But if you broke one of the headlights, let's say, you would be driving during the day and you say, Well, doesn't seem to have any function, but then it would be nighttime and you would actually see that it's conditional, like there are certain parts that are conditionally important. And then maybe you scratch the roof and that doesn't do anything, it's just cosmetic, has some other kind of ancillary or it's beneficial to have a [00:08:30] nice looking roof, but it (laughs)... you know, it's not really essential or- or conditionally essential for the function of the car.
Theresa Brady: Enter CRISPR.
Spencer Diamond: So to understand what genes do in a microbial genome, we use genetics to break them. And we see some genes you break and the microbe can't live at all, it's essential for its life. Some genes you break and they're essential only under certain types of condition.
Theresa Brady: In 2022, Spencer and two of his colleagues released a study that demonstrated the first [00:09:00] proof of concept editing an individual microorganism while it existed in the microbiome.
Spencer Diamond: One of the experiments that we performed was we took some microbiome matter from a human, an infant human, we put it in a test tube and we grew it and like we just whatever grew, you know, was what grew. And so there was about 20 or 30 different microbial species that ended up growing in there, and we understood also what their [00:09:30] genomes looked like.
So we're able to design a very, very specific and targeted CRISPR editing machinery that could go after a single one of those species and make an edit and then, we could show that that edit occurred and we never isolated any of those organisms so it occurred in- in situ in the community. And so that was a big step forward in just the ability to be able to do this. And essentially, that opens up [00:10:00] the possibility that if we can do this in a very contrived system, then in theory, we can do this is a- a wide variety of microbiomes. There's really no limit to the theoretical possibilities for where this could be applied. I think I should also say that what we did was quite contrived. It showed that it's possible and it painted kind of a roadmap for how to do it.
Theresa Brady: While we have so much more to learn about microbiome communities, the science march is on. Scientists like Spencer and his colleagues are starting to [00:10:30] probe very complex systems and understand how they function, and they are working to overcome hurdles that prevent applying the technology in a beneficial way for people and the planet.
After the break, we'll talk to the heads of two companies who are at the forefront of microbiome science. One company is working on the gut-brain connection and the other has an FDA-approved product.
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We've talked a lot about the research around discovering how the microbiome functions and how we can apply what we learn to potentially improve our health and the environment. Our next [00:12:00] guest heads a company that is already developing therapeutic approaches based on microbiome science.
Christopher Reyes: My name is Christopher Reyes. I'm CEO and co-founder of Bloom Science.
Theresa Brady: At Bloom Science, instead of focusing on a faulty or unhealthy microbiome, they're discovering what properties of the microbiome are responsible for a healthy immune system.
Christopher Reyes: Just taking a step back, a lot of the microbiome research has traditionally been focused on looking at the differences between say [00:12:30] a patient population's microbiome and kind of a healthy population's microbiome, and looking at the differences and asking the question do those differences drive anything related to the disease, the pathology of the disease. Do they drive symptoms? Is this actually the cause of the disease? For a lot of GI-focused conditions, the answer is yes. The microbiome itself, those disruptions oftentimes are a big driver.
Bloom takes a very different approach from this in the perspective that we're really focused on is, you know, understanding [00:13:00] how the microbiome as a process [inaudible 00:13:03] for our nutrition really delivers key metabolic intermediates and again, really interfaces with the immune system to regulate immune response.
Theresa Brady: Christopher explains how the microbiome provides the basis for a different approach to drug development.
Christopher Reyes: So Bloom, we think where our drug discovery platform, IrisRx, is very different from traditional drug discovery. Traditional drug discovery is really driven by a linear process, right? It's a... You select a target. We have a target [00:13:30] hypothesis. Then we do target validation and we work our way out to a candidate. And you can have a really good candidate, could be some great small molecule or- or a monoclonal antibody that has the exact effective profile. But you may have got the basic thesis wrong and so you don't see that translate in the clinic or that hypothesis was just a little off and so, you're just... you don't see the effect in the clinic. And so what Bloom does is very much a reverse engineering approach. We take real world data [00:14:00] from clinical interventions that we see positive efficacious benefit and we reverse engineer that.
Theresa Brady: If you were around in the early 2000s, you will remember the Atkins Diet craze, which at its height was followed by 30 million Americans. It was a low-carb, high-protein diet that promised rapid weight loss and improved health. Although the fad quickly declined as a weight loss remedy, Christopher explains that it was based on a diet developed many years ago [00:14:30] for a very different purpose.
Christopher Reyes: Our lead program is actually a reverse engineering of the ketogenic diet. And the ketogenic diet is a diet that was developed roughly a hundred years ago specifically to treat seizures in epilepsy. It's a diet that in its most strict form is 90% of your calories come from fat and like 5, carbohydrates, 5, protein. The idea is it shifts the energy utilization from sugar essentially to fat. And it's actually goes back even further, this was kind of like a- the heyday [00:15:00] of biochemical research and so, this was a way to try to replicate in none of the extreme manner intermittent starvation, which was how seizures were treated in like ancient Greek times where they really starve these epilepsy patients and get a reduction of seizures. So this is kind of this attempt to like let's alter the whole metabolic system and it works quite effectively. Again, if it was a pharmaceutical, it would be a multiple blockbuster because 90% of patients respond [00:15:30] with a reduction of seizures.
Theresa Brady: An effective solution to reducing seizures, but not necessarily practical.
Christopher Reyes: As you can imagine, the challenge is it's compliance. It's a very challenging diet. So we started with this diet and we thought okay, but you know, you're going to have big changes in your microbiome when you have such a radical change in your diet. Do those changes in the microbiome related to the diet contribute to the efficacy? Are they essential? If they contribute or are essential, what factors are essential? [00:16:00] And this is really where we built up our platform and so we can identify the specific species of bacteria that gets selected for by the diet. We can then screen through those and say, Well, these are the specific species of bacteria that are driving that functionality. Go even further and say, Well, what are they producing? What are the interactions with the host?
We do this with combination of AI and brute force screening, and we're able to arrive at these basic building blocks. And so it's a very different way of approaching [00:16:30] drug development where we're really trying to replicate something we already know works. And so it gives us a really nice what we think is a de-risked pathway to a therapeutic. It tells us what we can do in terms of the clinical development. We know the underlying pathways to target and screen for. And so this is why we take a very different view of the microbiome as kind of this rich area for drug development because if we already know something works, let's just really figure out what those essential components are.
Theresa Brady: Bloom [00:17:00] Science's initial focus is on Dravet syndrome, a form of epilepsy that is resistant to available treatments and is characterized by seizures starting between the ages of 4 and 12 months.
Christopher Reyes: Ninety percent of Dravet patients do not have adequately controlled seizures, significant GI issues, a lot of other symptoms that really characterize these patients, so very debilitating pediatric, I should also say, rare epilepsy. And so that is our primary focus. We're beginning [00:17:30] to see clinically evidence or support of our treatment hypothesis, our mechanistic hypothesis from our preclinical work. Looking at a difference of how we approach drug development so instead of pharmacokinetics, which is the measure of- of movement of that drug through the host, we're looking at strain kinetics, which is again, measuring the movement of these strains through the host. And so we're able to see really nice strain kinetic, pharmacodynamic effects or we can correlate [00:18:00] the increases of our strains with changes in very key tab lights that we've already shown are major drivers of the disease treatment or pathways, you know, related to the ketogenic diet. And we do that pre-clinically and now we're seeing that in our clinical data. To me, that's the most exciting, uh, thing is that we can really see what we were expecting to see, but now, we're actually seeing it in the human population. So I think that's really exciting.
Theresa Brady: [00:18:30] Of course, Bloom Science hopes its approach to reverse engineer the ketogenetic diet will produce an effective and life-changing therapeutic for Dravet sufferers. The company is also expanding into potential treatments for other diseases with similar profiles such as ALS.
Now let's turn our attention to a company that is also focused on the gut microbiome and started its mission around a decade ago when the idea that bacteria [00:19:00] was essential to human health was somewhat of a revolutionary concept.
Eric Shaff: My name is Eric Shaff. I'm president and chief executive officer of Seres Therapeutics that's based in Cambridge, Massachusetts.
Theresa Brady: Eric says that when his company was founded in 2010, scientists were not heavily involved in researching the connection between bacteria produced in microbiome and human health.
Eric Shaff: If you think back about 10 plus years, there was a notion that there was harmful bacteria. There certainly was a notion that there was perhaps [00:19:30] neutral bacteria, but the idea or the notion that bacteria or the ecosystem of bacteria in our bodies is absolutely essential for human health and disruptions to that healthy ecosystem or what we call a- a dysbiosis of that ecosystem, that those disruptions could be correlated or connected to disease, that was kind of a novel concept.
Theresa Brady: At the time, fecal transplants were the most common procedure to control Clostridium difficile [00:20:00] or C. diff. It works by adding healthy bacteria into a recipient's intestines.
Eric Shaff: Specifically, Seres was founded around the idea that fecal transplants, and fecal transplants are exactly what they sound like, you could potentially use a fecal transplant to interdict into a- a serious disease like C. difficile infection. And the idea was you could potentially impact someone's microbiome and have an impact on this terrible, devastating, debilitating [00:20:30] disease, but the founders of Seres said, you know, there's got to be a better way of helping patients, right? If you could take the idea of a fecal transplant, but if you could elevate the science and understand how the bacterial organisms interact with each other and the human host, that would create value. If you could manufacture drug under GMP conditions, that would create value. If you could study patients under rigorous FDA oversight, you know, that would create value [00:21:00] and, of course, hugely important, if you could make it oral, if you could deliver bacteria in an oral pill, that would be of substantial value for not just patients, but all stakeholders.
Theresa Brady: And sure enough, Seres did just that. Last year, their drug, VOWST, was approved by the FDA. It treats patients with C. diff infection and is delivered orally. Eric explains why C. diff can be so debilitating.
Eric Shaff: What's really important to understand about the nature of the disease [00:21:30] is that certainly, there's a bad actor, which is the C. diff bug itself, but your likelihood of getting C. diff really relates to the susceptibility of the system or the vulnerability of the system to get C. diff. So in other words, when let's say we go in for knee surgery, you get antibiotic therapy. Antibiotics tend to be very effective in knocking back infections, but they tend to be indiscriminate in terms of what they kill, that they kill all the bacteria in- in the microbiome, and what you hope is that you naturally [00:22:00] reconstitute or rebuild that healthy ecosystem of bacteria that constitutes a, you know, a healthy microbiome.
But if you are unlucky, there is a niche that C. diff can infiltrate and tap the nourishment sources and- and begin to replicate, then you can be susceptible to an infection. What we know about the disease is if you have C. diff, you're more likely to get it again. And once you've had C. diff three, four, five times, unfortunately, you become marked and you become someone that's ultimately eventually [00:22:30] will become more likely to recur than not recur. So the idea or the premise behind microbiome therapy is to say replenish, repair the microbiome and outcompete the bad actor from infiltrating, which ultimately can result in a recurrence.
Theresa Brady: Eric talks to us about the journey from concept to approval and explains why this breakthrough addresses a huge unmet need.
Eric Shaff: So the story of VOWST is a journey of going from an idea on a whiteboard [00:23:00] to an approved product that is making a different for patients today, it's an incredible story. It's one that I and others are incredibly proud of and I think it's a great illustration of some of the complexities, but also some of the triumphs of pioneering in a new space. VOWST is a consortium of bacteria that's delivered in spore form. So we deliver a cocktail of bacteria that's intended to replenish and repair the microbiome and prevent future recurrences of- of- of C. diff infection. VOWST or what was then [00:23:30] SER-109 went through a journey where we had interesting, encouraging early phase I results.
We actually had surprising and disappointing phase II results and as a company, we are immensely proud of how we dealt with that setback. So we took a rigorous objective scientific approach in thinking about why the phase I was successful and why the phase II was less so. We considered and rejected [00:24:00] dozens of different ideas before we came up with two hypotheses that we felt we could change the nature of the study and the drug, the diagnosis that was used as well as the formulation of the dose that was used. I think when you're pioneering a new space, you have to accept that it may not be a straight line from point A to point B, and the team at Seres I think a, um, it's part of our DNA of not being daunted by complexity, embracing adversity and, uh, doing so with an eye towards patients. And ultimately, we [00:24:30] hoped that with those changes, we might end up after our phase III result with a positive result.
The phase III results were, um, stunning, 88% reduction in recurrence as compared to significantly lower with placebo. And in an oral form, in a pill that was well tolerated and the effects were actually quite durable. So in a field in which there has been, I would argue, limited innovation in a number of decades, actually since Vancomycin was approved, this [00:25:00] is a new solution for patients. It's a new solution for providers, for physicians. Ultimately, what matters most is preventing a recurrence of the disease and VOWST, we believe, is highly effective in doing that. So it's a great story of pioneering, of perseverance, of a team that faced with a lot of adversity over the last couple of years really faced it head on and pioneered and persevered on behalf of patients that we're looking to serve.
Theresa Brady: [00:25:30] Exploring the microbiome's potential is vast and we are only at the beginning. As we've learned today, deep understanding of microbial communities and their interactions will advance science and create a better future for patients. As research advances and technologies evolve, the microbiome is poised to become a cornerstone of future breakthroughs.
[00:26:00] I want to thank Spencer for pulling back the curtain on the complexities of microbiome communities and Christopher for demonstrating what it means to think outside the box and, finally, Eric for not giving up until they had an effective, safe and well-tolerated medication for patients suffering from C. diff. And thank you all for listening.
I'm Theresa Brady and I produced this episode with help from Lynne Finnerty and Kourtney Gastinell. [00:26:30] It was engineered and mixed by Jay Goodman with the music created by Luke Smith and Sam Brady. Make sure to subscribe, rate and/or review this podcast and follow us on X, formerly Twitter, Facebook and Instagram @ iambiotech and subscribe to Good Day BIO at bio.org/goodday.