Global Chemistry, Manufacturing, and Controls Manager at Wacker Biotech
Dr. Moira Monika Schuler is an expert in the field of microbiome-based therapeutics, discussing the challenges and potential of using live microbes as drugs to treat diseases, including antibiotic-resistant infections.
This Transcript is AI-Generated
Moira Monika Schuler: And if we look at it, there are currently about 130 trials, clinical trials that are ongoing with Box S drugs that are very often looking at harnessing a cultivation of different strains that we can use in therapeutics.
Chai: What are bugs as drugs? They're live microbes used as powerful therapies designed to help your microbiome fight back and even take down antibiotic resistant infections.
Micah: However, every person's microbiome is unique to them. The result, working with these tiny organisms can be a little complicated.
Moira Monika Schuler: If we can overcome these challenges of manufacturing, analytics, release, and regulatory aspects, we can really benefit.
Micah: In this episode, we're diving into the fascinating world of the microbiome.
We'll uncover how it shapes our health. Explore therapies that could tackle everything from gut issues to chronic disease, and dig into what this all could mean for the future of medicine.
Chai: I'm Chai Nussbaumer News Palmer.
Micah: And I'm Mike Sweitzer. This is Balancing the Future from METTLER TOLEDO.
Chai: On this show, we delve into the world of science and technology and explore its transformative impact on our lives.
Moira Monika Schuler: I think indeed, the microbiota, which is that whole collection of organisms that are on our surface, inside our body, et cetera, is. Way bigger than what we are. And it's essential both to our healthy state and helping us also understand some of our diseases or help influence some of these disease. And I have to admit, even though it's a topic that has been researched for quite a long time already, I think we are just scratching the surface of it.
Micah: To help us navigate this complex subject, we're joined by Dr. Moira Monika Schuler Monica Schuler, global Chemistry, manufacturing, and controls manager at Wacker Biotech.
Moira Monika Schuler: We have here in the US people spending decades of research on the topic and still we do not understand everything about it. But indeed, understanding how all these cells that populate us are both influenced by what we eat, how we live, but also how they influence, for instance, how drugs act upon our body, how our.
Mood can be influenced by them. How our hormones are balanced is a field that will be with us for the next decades to come.
Chai: So it sounds like the microbiome is hugely important for human health and that it's a topic that's just not gonna go away. It's not just the trend topic, but what exactly is the microbiome?
Can you explain?
Moira Monika Schuler: Yeah, it's a good question and maybe even a controversial one in the sense that sometimes people do not even fully agree on, on all of the terminology, and maybe even people might disagree with the way we will present it here even. But I think generally speaking, indeed, we can say that the microbiota is the collection of the microorganisms in our body.
On our body. And then we have the microbiome, which is really the collection of microbial cells and genes in our intestinal tract. And then there is either the microbiota or sometimes the microbiome, because some people still call it also like this, that is in our lungs. In, for instance, our mouth on our skin in particular.
And those are. All kind of niche environments that also are part at least of the microbiota and sometimes are called lung microbiome by extension.
Chai: So what are the direct impacts that a healthy or rather possibly even unhealthy microbiome have? So when we are talking
Moira Monika Schuler: about this, uh, dysbiosis, when the microbiome or the microbiota is diseased in a certain sense, what we very often see is that there is a lower diversity in the cells that are populating, for instance, the intestinal tract.
And by having this lower diversity, there are all these secondary metabolites. Uh. All the interactions that are happening that create a very imbalanced and dysfunctional environment altogether. And unfortunately, it's a bit of a vicious circle because by having this decreased diversity of microbiomes, we then also have the symptoms or or symptoms of disease that we experience that will trigger then in consequence.
Also, the fact that we are, for instance, taking painkillers, but maybe also even antibiotics will then. Decrease further, actually this diversity, hence really accelerate the vicious circle of imbalance.
Micah: And you mentioned antibiotics, I mean it's there in the name Antibio, right? Anti biome. Anti-biotic.
Exactly. What happens to our microbiome or to, I suppose to one of our microbiomes when we take antibiotics?
Moira Monika Schuler: It can really wipe out the diversity of the microbial cells that are in particular in our intestinal environment. And I mean, we have heard it in one of the previous podcasts as well. What can be the devastating effects of taking antibiotics on the person, like on the individual that takes them, their microbiome, but then also.
Overall, having that influence on generating that anti-microbial resistance that is appearing over time.
Chai: If you want to dive deeper into the topic of anti-microbial resistance, check out season one, episode eight. We've linked to it in the
Micah: show notes. Restoring the gut microbiome could be a key weapon against antimicrobial resistant bacteria. It's a promising frontier. The idea fecal microbiota transplantation or FMT can shift an imbalance microbiome closer to that of a healthy donor harmful bacteria fade and the ecosystem starts to rebalance, but it's not instant.
It can take months for the gut to fully reset.
Chai: In contrast, the science of these therapies is moving pretty fast. In 2023, the American Food and Drug Administration approved two drugs aimed at treating anti-microbial resistance in the microbiome.
Micah: Here's Moira Monika Schuler again to explain. I.
Moira Monika Schuler: The one is, uh, Reta and the other one is Vost.
And what they both are is a kind of first step into harnessing microbiome related therapeutics. And we have there also to kind of differentiate because there are several categories. So those two are really the kind of more basic one. They are very much related to what we would call FMTs. Fecal microbial transplants, where the initial thought was to harness like a healthy microbiome and kind of reimplant this within the human body.
So very often that's done via an anima, but nowadays, the second company has brought out is to really have it in a capsule so that it can be. Swallowed and it can kind of start populating the gut again and thereby really fighting. So providing the gut with the microbiomes that have been eradicated by antibiotic treatments that have then been kind of populated by these c diff infections and giving the gut
Chai: what it needs to go further.
C Diff is a bacterium that can cause serious diarrhea, especially in people taking antibiotics. C diff normally lives quietly in our gut, but when antibiotics disrupt the balance, it can cause problems. But these two drugs
Moira Monika Schuler: are only kind of two example of a whole field that is expanding. And if we look at it, there are currently about 130 trials, clinical trials that are ongoing with box S drugs that are very often looking at harnessing a cultivation of different strains that we can use in therapeutics, but even more.
Looking into how we can engineer a single strain to kind of be living inside us for a very short amount of time, having a specific impact, a specific therapeutic application, an application window, and then, uh, kind of disappear from this environment. And I'm happily maybe digressing on this part in a little moment.
But maybe to start with, the first part is that the initial idea was indeed just that combine the different strains that are needed to kind of recreate a healthy environment. But that comes with challenges by themselves. I mean, it is very difficult to actually grow these strains separately.
Characterize them in a way like we would. Characterize a biologic or a small molecule or an aspirin like saying, okay, it's free of this. It does not have that, because in the end, it's not just a tiny molecule or a more complex biological molecule. It's a whole cell with its whole set of proteins inside on the outside of the cell, and then it's formulated.
In a consortia. So we have several of these strains being together, and because they're alive, at least partially, I mean, when they are formulated in this capsule form, they are usually what is called lyophilized. So they are kind of freeze dried and they will kind of reactivate when they get in contact with the water within our body and kind of get healthy again and start to live and strive again.
But because they will live again, they will produce secondary metabolites. They will start taking up things in the environment and hence having a control over what is happening. Once the capsule is inside us and the box start to multiply is actually also very difficult.
Micah: So you're looking at the fact that you're working with a living organism.
Yes. You're not just looking at some isolated part or a compound, like you said, you're actually working with, and in this case, you're not just working with a living organism. You're probably working with what, how many of them?
Moira Monika Schuler: With several.
Micah: Several and, and multiples of those? Several. Right.
Moira Monika Schuler: Yes, exactly.
Exactly. That's actually a very good point that you're pointing a multiple of the severals. That's exactly true, because very often what is looked at is maybe to have eight strains that's already not representative of what our microbiome is. But if we are combining eight or 10 or maybe six or 12, and then we have.
Millions of those cells and they should be identical. They should be in a certain ratio. So balancing all of that in a formulated drug is actually extremely, um, difficult. And it comes along with all sorts of manufacturing challenges, but also with analytical challenges because in the development of drugs it is.
Crucial to characterize your drug to, to test it in the end prior to release. But it's not as straightforward as saying, okay, yeah, we do a mass spec of this molecule and we know that we have exactly, uh, what we claim we have in the drug.
Micah: I want to hear more about the manufacturing challenges, of course, but first.
We can't assume that my microbiome and your microbiome are identical, right? So yes. Now we're introducing living cells into different individual microbiomes, and maybe they have different outcomes. I.
Moira Monika Schuler: Exactly, and I think there you're touching a crucial point about the difficulties to setting up the right trials, to have also the right readouts and the importance of the fundamental research that still needs to happen also, or needs to continue to happen in the field.
So for instance. There is one university in Ireland, for instance, that is also really big into just assessing healthy and diseased microbiomes and kind of using the power of AI and the power of computation to kind of get a better understanding of what is a healthy microbiome, how differences in the microbiome.
Can still be differences, but being healthy, where does the difference start to lie between diseased and healthy and how all kind of factors are influencing also the microbiome. So we also know that, for instance, the menstruation cycle is influencing the microbiome. So it's always this kind of circle and interaction.
Chai: The program Moira Monika Schuler referring to is a PC Microbiome Ireland based at University College Cork.
Micah: They're not just studying how the microbiome works, they're diving deep into other topics like how processed foods affected and how the gut microbiota might play a role in cognitive decline in age-related diseases like Alzheimer's and Parkinson's.
Chai: They're doing groundbreaking work and we've included a link to their website in the show notes. Hence we are just
Moira Monika Schuler: scratching the surface also in terms of research because having a once off picture is very often not enough to indeed say is it right enough? And then to come back to the clinical trials, what is read off the clinical trial?
What are the samples that are taken? And what is analyzed is maybe also not sufficient to show the efficacy or, or to ensure that we are actually really capturing the small differences that are happening And. We cannot really control what is happening once the drug is delivered in a certain sense, uh, indeed how they interact with the existing microbiome, how they interact with themselves, and how, how it influences the progression of the disease in the end.
Chai: Now given the complexity of the microbiome, how can regulatory bodies such as the F-D-A-E-M-A assess the effectiveness of of the treatments that are available in the market?
Moira Monika Schuler: This is actually also a very big topic in the industry and in research at the moment. So for instance, the FDA has at least some kind of guideline that, for instance, talks about what we call the life Biotherapeutics, the LBP guideline, but it's also just a guideline, not a real policy document.
The European Union, on the other hand, has a monograph that kind of touches upon. Parts of it, but might not cover all different aspect of this particular niche. And in particular in Europe, there are several institutions that are quite active in saying that we need to kind of come together to define a regulatory framework for this particular part.
And we are probably gaining quite. A bit of traction, hopefully also from the advanced therapy field that requires their own set of regulations beyond what we know from the small molecule world or the biologics world. And we can maybe benefit from tagging along on on expectations along this side. And one particular challenge that is there is that, for instance, for a drug that is orally taken like a capsule, there are some guidelines and that's kind of okay to work with, but.
And that's where maybe I want to come back to a previous point in a certain sense, is there will be, and there are clinical trials with single engineered bacterial strains that are. Taken alive and are injected, for instance, in the bloodstream, or most likely currently in solid tumors, but they're injected.
And usually when we are talking about drugs that are injected, we need to really comply. I. With in the Europe, what is considered the annex one of Rol X volume four, so being sterile, but that's already mutually exclusive. How can we have a mono septic, uh, or a multi septic living thing on one hand and claiming sterility on the other?
It is not possible.
Micah: Do you have solutions to that? Uh, contradiction.
Moira Monika Schuler: Uh, only partial solutions and definitely, uh, not me, but all the people that are in these ongoing clinical trials and that working towards this, they really need to work on combined analytical methods. And we cannot just rely on the typical, we do a sterility test, but it needs to be a combined test of we can.
Proof that we have our microorganisms proof that still in presence of these microorganisms, all those that we don't want to be present, do not grow. Plus maybe more advanced technologies that are less used on the typical release panel in the biologic industry. So maybe more going into the PCR techniques, but also, yeah, sequencing in general.
That might help. And definitely it needs always to be a combined panel of analytics that help fulfill that. That's also to come back to your initial question a few moments ago, that's where there is that need for more clarity in the regulations, but also for every sponsor in the clinical trial to have that engagement with the regulatory bodies to actually discuss, okay, is this strategy good enough?
Do you have the feeling that we are not putting the patients at risk? Do you have enough information to be able to make the judgment call that this will be both a safe drug but
Chai: also a, an effective one. This contradiction is a tough one to crack, but scientists have managed to bridge this sterilization gap before
Micah: take CAR T-Cell therapies, for example.
They've been approved for treating lymphomas and some forms of leukemia.
Chai: T-cells are taken from the patient, genetically engineered, and then put back into the body. Because these are living cells, this process can't be sterile, at least not in the traditional sense.
Micah: Instead of testing for living cells, these therapies check for contaminating microorganisms.
They also assess the purity of the final product by testing for residual DNA and chemicals leftover from the purification process.
Chai: So yes, it is possible, but we have to change how we approach sterilization and a big part of the challenge how this all fits into the manufacturing process.
Moira Monika Schuler: Interestingly enough, I mean, if we are trying to produce a biologics or even more a small molecule, we want to kill any bacteria that is in a manufacturing stream alongside.
So knowing how to keep them out is probably easier. And here we are really trying indeed to grow, grow them. I mean, that's still part of what we are doing for monoclonal antibodies or so on. So growing cells. So that's, uh. Occasion enough, but maintaining an environment where only those microorganism grow, in particular microorganisms that are very often anaerobic because I mean, they are very often the ones that we are taking from our guts or that are related to the ones that we have in our gut.
So they are. Anaerobic. We really need to maintain that anaerobic environment in the manufacturing condition. So that's rather difficult actually when you're thinking about it. Large scale, where we usually would have a fermentor blow in oxygen to make them grow here. We need to ensure that there is no ingress of oxygen.
We need to keep that through the harvesting step, which makes it even more difficult. And then. Comes the most crucial part is that formulation and very often lyophilization where we freeze dry the cells and, uh, need to ensure that we kind of kill them off, but in a way that allows them to be reconstituted as soon as they hit the place where they need to be active for some of them.
So the injectable ones that are kind of in the clinical study, we see that very often. That part is not even attempted because it's too difficult. So those cells would then very often be formulated in a liquid way and frozen away. But even there, freezing and thawing, we, we all know as scientists, is very difficult and challenging for cells because, uh, if they don't have the cryo protectants around them, we have half of them dying.
And then it's very difficult to even ensure that. We have the right amount of cells later on. And if we combine that then with the fact that we want to have actually not only one strain, but several strains in the end, we need to aid to grow them together, which is a challenge in itself. And I have not seen a clinical trial yet out there where such true co cultivation has been really successfully used.
So very often, strains are grown apart and then formulated together in the end, and not knowing maybe how they really react upon. Reconstitution, whether it's from free storying or from Yeah, the Lyophilized state, yeah. Has another challenge in itself.
Micah: So you've talked a lot about challenges involved with microbiome based therapies. Why is it worth trying to find answers to all of these issues?
Moira Monika Schuler: It's a good part. Indeed. It might come across, uh, very, uh, negative talking about all of these challenges, but indeed, I mean, for instance, to come back to the c diff infections, there is not much in terms of alternatives out there.
I mean, we have had these initiatives for the next generation antibiotics, and truly those are also. Coming along, but very slowly, probably not at the rate that we are expecting and being able to use something that is inherent to what we have in a better understand and controlled way. If we can overcome these challenges of manufacturing, analytics, release, and regulatory aspects, we can really benefit also there.
We have a virtuous cycle or circle in a certain sense because the more we work into this direction, the more we also understand about. What is a healthy microbiome? How can we maintain it before it becomes diseased? Because all of the fundamental research is also around this, and we have plenty of evidence that, uh, certain type of diets will help, even enough sleep, might help, et cetera, that we can already take care of it upfront.
So working on the therapeutics may help the understanding. And get in a better way there. But also, I mean, sometimes these are the only way maybe to approach such diseases such as these recurrent infections that may not have an alternative. And then there is that other way of sometimes using the bug as a vehicle, as a vector to deliver a payload to something particular.
And this is fascinating to me because inherently we know that. Some of the box that are actually more on the bad side, we could see, so for instance, the salmonella or so on, they have this inherent way of targeting particular cells also within our body. So harnessing their own way of working for us is also something that while presenting its own set of challenges can help us actually working in these cancer therapies that need also still.
Advances because we are, they're also stuck with what we can do currently.
Micah: And given that the microbiome, I mean, obviously there are generalities that you can draw about the microbiome for humans, broadly speaking. But given that there are variations from person to person, do you see microbiome treatments and personalized medicine converging at some point in the future?
Moira Monika Schuler: It's a good point that you're mentioning that, uh, forgot about that. Sometimes I'm too stuck in the present challenges as you, as you've seen, but it is true in particular, seeing the advances also in computations, in ie, in the use of IE to kind of understand data sets better and correlate better.
Chai: Here IE means information extraction.
This is using computer power to automatically find and organize the important stuff hidden in the messy data.
Moira Monika Schuler: And the combination with the next generation sequences, uh, devices, analytics services that are provided in the field, the combination thereof can really maybe lead to understanding not what is a healthy microbiome versus a diseased microbiome in general, but really also understanding it on a personal level and hence tailored and, uh, medicines as we go along both.
Medicines in a broader sense. I mean, other than, uh, microbiome based ones, but then maybe in the future, also really developing tailor made
Chai: medicines. So I just wanted to sneak in a question because probiotics are so popular in the marketplace Oh, yeah. In grocery stores and just, it's a buzz topic for a few years now.
Yeah. So what about the probiotic rich foods and supplements? Is that something that is a part of the therapeutic aspects that you mentioned, or is that really just kind of small things that may help your gut? Can you make a distinction between the two and especially for the future of where the market is going for probiotics?
Moira Monika Schuler: And it's also a big topic in itself. First of all, there is indeed that distinction that probiotics, they have a kind of health claim versus therapeutics really addressing a medical need and being trialed in that sense. But by having looked at the clinical trial field that we see at the moment, there is a kind of a blurred line also between this because we see very often, let's say.
Formulations based on living cells are trialed, for instance, in combination with a cancer therapy and so on. And then the line starts also to be blurred between what is just the health claim or what is then actually also a therapeutic aspect of it. And to be very honest. Some of the probiotics, it's always very difficult to judge it all.
They are manufactured in a very similar way to some of the microbiome based therapeutics that we are talking about. So they're also grown in bioreactors, harvested in a very clean and safe environment. Lyophilized calculated and are available as such or added, uh, to food in particular, and sure there as well.
There is something that is happening and can definitely have a benefit on the body, except that it's not studied in the same way because it's indeed that health claim administered to a healthy or considered healthy individual in the first place.
Micah: We've talked, I think, almost exclusively about the gut, but earlier in the show you mentioned that we have microbiomes in other parts of our bodies too.
Moira Monika Schuler: The lungs. I have been personally very interested in hearing how this is, and that's where I mentioned, for instance, studies done by some of the universities in Belgium. They're really focusing on that aspect and it's incredible to see that the microbes that are part of our lungs are also essential. And I guess there we will also see.
Evolution in the future happening in the sense that with, uh, all these respiratory viral infections and the effects that we are seeing there, this is surely a topic in the field that will attract interest in the future as well. And, uh, vaginal microbiome is also in particular. Of importance and actually quite a lot of the clinical trials that are ongoing right now are focusing on that aspect as well.
Because I mean, we see also with things such as fertility issues, et cetera, that there is research leading back to ensuring that a healthy state is relevant there as well. So I think those are the two important ones. But there are more, I mean, our ears, uh, our mouth, our skin, they're everywhere. I mean, we are the smaller part of, of the individual that we are.
Right. If we compare it to the number of, uh, other cells that we are carrying around, I think there is still a lot to discover.
Chai: So what advice would you give to researchers who would like to go into discovering more about the microbiome field or people who are currently in the same field? Is there something that you would say to them for advice or, or just to share your excitement?
Moira Monika Schuler: Maybe One of the things that I would like to share is that it is a bit of a niche. It's not as big as the big pharma and the big research about, or the big buzz around advanced, uh, medicinal therapeutics or. Gene therapy, or even in the field of pharma, the antibody drug conjugates or these kind of things.
But it's hence also maybe easy to, to kind of integrate that niche. So there are a few institutes in Europe that are kind of advocating for the use of microbiome based therapeutics, and I think it is an interesting field to get into, and it's, as I said, a bit of a niche, but, uh, an interesting and very diverse to explore.
Micah: Given the amount of potential that you've talked about, do you see this niche expanding?
Moira Monika Schuler: I think prior to COVID I would have said it is extremely striving and it's expanding and we have indeed seen clinical trials going up over those years. But then, uh, during that COVID part, a lot of focus of the industry and of research has indeed pivoted.
And I think we still feel that in that niche. And I think the bigger advances in cell and gene therapy are. Shadowing or overshadowing this part. So I think right now getting funds for fundamental research in the field is difficult. Also, industry investing in startups in this field is, is maybe not as evident as it was prior to the COVID part, but I think it cannot be overlooked.
And I also feel that it is slowly taking up. Again, we see that with. More and more conferences that are happening around the topic again. And indeed, I think the approvals of these two products by the FDA two years ago, or almost two years ago, really kind of sets the pace and, uh, we see more publications happening again.
So I think it's slowly picking up, but because it represents a niche, it's uh, yeah, it's probably still underestimated.
Chai: We. I've been speaking to Dr. Moira Monika Schuler, Monica Schuler, global Chemistry, manufacturing and controls manager at Wacker Biotech. So Micah, what are some of the key takeaways from this conversation?
Micah: Well, the big one obviously is what a significant effect the microbiome has on our human health. I mean, it's amazing to think that our mood, our memory, all kinds of aspects of our health are affected by the microbiome.
And as we look at how to. Bring this into, into the world of therapies. It's fascinating to me that this is such a different way of approaching medicine where you know, instead of a traditional therapeutic where you sort of take something that does something to or for your body, this is about an approach that cultivates something that's already inside of you and works with that to help improve your health.
Chai: Yeah, I mean, it's definitely a unique way to think of medicine and improving your life, and it's really clear that there are some challenges in scientific terms. It's really impossible to create a completely sterile environment for manufacturing these treatments, especially using traditional methods. So it really highlights the need for complex regulatory frameworks to support innovation in this space.
Micah: And I think the need for these changes and ways of thinking about how we produce these therapeutics and how we regulate them goes to show what a fundamental shift this is in an approach to medicine. That this is really a working with the body approach and that it. Creates quite a number of challenges and new definitions, but it's also very interesting to hear all the ideas there are for addressing these.
I mean, it's not like these are roadblocks, it's they're inviting new ways of structuring our approach to medicine.
Chai: Yeah, and there's just so many opportunities here. But it's also not a trend. I don't think this is going anywhere. You know, it's very clear that this is something that is good for improving human health and it's sticking around.
More and more discoveries will be happening each and every week, month, or maybe even a yeah, year.
This has been Balancing the Future from METTLER TOLEDO.
Micah: What questions about science and technology would you like answered in a future episode?
Chai: Let us know by leaving a review or if you listen on Spotify, leave us a message in the comments section
Micah: and be sure to subscribe wherever you get your podcasts.
