ERP048 - Genetic Engineering with Michael Seiler

Welcome to Evolve Radio where we explore the evolution of business and technology. Today on the podcast, we're diving into the evolution of biosciences and genetic engineering. I'm speaking with Michael Siler with Taconic. Michael is an expert in genetic engineering and at Taconic, they help researchers to test drug therapies and even gene therapies with highly controlled animal models. The field of biosciences is evolving fast, and Taconic is basically at the cutting edge of providing what is a more modern test tube. On the podcast, Michael and I discuss gene therapy and the science of genetic engineering. We also discuss the quickly advancing field of the microbiome. If you enjoy the show, be sure to subscribe on iTunes, Stitcher, or wherever you get your podcast from. Also, be sure to check out the webpage evolvedmt.com/podcast for show notes, links to my guests and to check out previous episodes. Now, let's get started. Joining me on the podcast today is Michael Siler, VP of commercial product with Taconic. Welcome, Michael. Thanks for having me. Really interesting discussion today. Uh a bit off the the typical path for uh for the podcast, but an area of particular interest for me. And um really looking forward to to diving into this. The the area that you work in, I guess would largely be described as uh research and genetic engineering. And you want to give us a a bit of background on the the work that you guys do and and fill us in on your role? Sure. Um my background goes back probably 15, 20 years in the research space studying how we can modify DNA for therapeutic purposes. Um the my personal research background goes back to engineering viruses for gene therapy back into the late 90s when this was um a really a really novel concept on how we can treat some of the underlying mechanisms of disease uh related to um monogenic gene dysfunction. Single genes cause a cause a specific disease and how could we go in and repair that? Um as I've kind of transitioned through my career from a research setting to now leading uh the commercial activities at Taconic, uh we basically take these tools and understand how a tool is used by scientists. How do we take the power that we have to manipulate the genome of living things and create or increase the potency of research tools, unlocking the creativity of scientists that uh are operating all over the the university research landscape and in the biotech space and in and and now transitioning into greater acceptance in large pharma. Very cool. And you you mentioned something that I think is important for people to understand uh when it comes to I guess uh this be the field of gene therapy. where you're doing research on monogenetic uh abnormality. I think that's an important piece to understand of what the capability of those systems are is that we only really have the capability to fix something if we know a very specific gene that causes a very specific function, which is not really typical of you think what you think of as most diseases and things. They typically are uh cascading effects of multiple genes. Is that right? Absolutely. And when you think of when we kind of break in sort of bifurcate these diseases into specific categories on ways that we can approach them therapeutically. Um you have lots of options. And and and clinicians have these in their toolkit, whether it's a small molecule therapy or something more creative uh in in the recent sort of success pattern in in cancer therapy with with designing a monoclonal antibody to to to act on a specific pathway and impede the ability of for cancer to develop. Gene therapies act somewhat differently, right? Gene therapy basically identifies a specific abnormality in the genome and attempts to correct it. And scientists are pure pragmatists. This can be a really big challenge if you figure that the the genes are not always expressed the exact same level in every tissue, they're not expressed in the same place. Sometimes those places are very hard to reach with a genetic intervention. Um these become challenges to the researcher to understand what are the pragmatic limitations to introducing a new gene to introduce a new function. And the long the long-standing history in genetic engineering is to understand the difference between gain of function and loss of function. If you if you neutralize a gene, you lose the functionality of that specific gene or pathway, the protein it makes, um the the the process and physiology that it affects. Gaining a function is a very separate thing. And most commonly in gene therapy, we we understand the specific diseases where there's a there's a hereditary mutation that leads to a loss of function of a critical gene and consequently a critical pathway. Losing that function yields us an ability to go to understand how if we correct that, if we correct it at 1% or 5% or 100%, what's the necessary threshold to intervene therapeutically? Um greatest example, um sort of the most historical example of this is hemophilia. We know that hemophilia is a monogenic disease. It's caused by a single gene lesion on uh factor 8 or factor 9 and several other of the blood clotting factors. Uh this leads people to have an inability to to properly clot after a cut or after a wound or an internal uh lesion. Replacing 1% or 5% of factor 8, the factor 8 gene will completely correct the adverse pathology of hemophilia. And so that gives us a lot of potential to understand us as as uh researchers in this space, how could we think about this disease? And how could we supply that 1 to 5% that's therapeutically corrective and prevents the majority of pathologies and uh and comorbidities associated with hemophilia through some genetic intervention. That's really interesting. That's really interesting. Let me let me uh underline if I understand correctly what you're saying that um when you correct the gene in hemophilia, it actually only has like a 1 to 5% effective rate on sort of the the total genetic map within the body, but it's enough that it actually corrects the disease overall in the body. slightly slightly different twist on that. What we've learned through studying the pathways of hemophilia is that the the factor 8 gene creates a protein that if you were to re in a person that's that is factor 8 deficient, if you were to re if you were to resurrect 1 to 5% of that total amount of factor 8, you would completely correct the the major pathophysiology, the major issues with the disease. And so while normal uh high functioning factor 8 individuals in the population may make 100%, let's call it 100%, 5% of that would be sufficient to correct the majority of catastrophic consequences for people that are completely deleted for that gene. Interesting. And so, so the the bar for success for for genetic therapies in that space uh is achievable. And that means that when we think of the pragmatic aspect of gene therapy, how are you going to correct 1 to 5%? Does it have to come from the actual cells and tissues in the body that make factor 8? Or could it come from somewhere else? Could it come from the muscle? Could it come from a different tissue that's more uh prone to genetic manipulation so that you could resurrect that same circulating amount of factor that corrects all the all the downstream consequences of lacking it. Very cool. So hemophilia being one of the the diseases that's obviously treatable with the gene therapy. What are some of the others just quickly on that are top of the list areas of of uh what we feel are practical research for that? Yeah, so, so uh different um uh cystic fibrosis is sort of the other most commonly recognized potential target for gene therapy. Uh this is a this is a single gene mutation where we know an extensively about the biology on what is uh what the mutation leads to and how to we could correct it. Um there's been massive advances uh with companies like Vertex and others that have addressed some of the common limitations with cystic fibrosis and created inordinate clinical success in prolonging the lifespan of people with CF. Um but what if you could have a longer-term therapy where it's a single intervention that results in uh in course correction over a significant amount of time. So what are some other capabilities that you hope to see in the future that are not maybe entirely practical today with gene therapy? Well, I think where we've seen the field transition to is to understand how our ability to manipulate the genetic code can be leveraged in several ways. One is to directly intervene in a therapeutic pathway, and that's and we kind of generally refer to that as somatic gene therapy. We're going to take for for hemophilia for instance or for cystic fibrosis, we're going to target the tissue where the protein is absolutely required and try to modify the genome there, whether it's gain of function or loss of function uh by intervening specifically. Uh but what has been the biggest pivotal moment in gene therapy, I think has been the recognition that you can take a patient's own immune cells out of their uh by by electrophoresing the blood and collecting their T cells and modifying them for a different therapeutic purpose. And that gives us a new power and that lets us unlock much of the much of the new potential with CRISPR Cas9 genome editing that gives it an immense amount of uh bandwidth to the capabilities of genome of genome modification. How do you take a these cells are terminally differentiated, right? So you're not going to get a lot of propagation out of a T cell uh beyond its clonal its clonal expansion. But you are going to be able to affect a certain specific function in a in a short window of therapeutic opportunity where by unlocking that capability, you may treat a growing tumor or you may treat another infectious process, infectious disease process. And that power is is really at the forefront of the of the field. More sort of generally, would you think of that as kind of retargeting the T cells directly? Like kind of like taking them out, reprogramming them to look for something specific and then popping them back in? Is that is that a way to think of it? That that's that's generally how that's generally how the field has moved and we've seen that work in some settings and in it can be challenging because all tumors are different. Every tumor is in some ways unique, but it shares a lot of characteristics of past history. So how do we how do we best re-engineer those those specific effectors of the immune system so that they're so that they're sufficient to fight specifically what we want them to fight, whether it's a growing tumor, but also make sure that they're not able to fight something that we don't want them to, some other natural function. Like autoimmunity. Exactly. Yeah. Autoimmunity is one of the one of the common consequences uh for these immune therapies that are that are basically T-cell extraction, modification and reimplantation into the patient. Um but going back to the concept of of pragmatic approach to the science, in hemophilia and in in cystic fibrosis, other like commonly germ line codified uh genetic issues, in T-cell therapies, you get to take the cells out of the patient and then modify them. You don't have to modify them inside the patient or inside the research animal. That creates an additional tool for the researcher and for the clinician to understand how we can mitigate some of the side effects of genetic intervention. All right. Um you mentioned CRISPR CRISPR Cas9. Um obviously a a huge revelation in in gene editing and gene therapy, the the tool now being used. So we won't get too deep into this. There's lots of other resources that I'll link to in in show notes if people want to check out what it is. But the the basic summary that I I would say is it's a basically basically copy and paste for genes. Like you you guys now have a function to say, if you find this gene, you pull this out and you replace it with this. So it's a pretty revolutionary thing around how to more specifically target in a surgical fashion how what what genes you're editing and what you want to put in place. Absolutely. CRISPR Cas9 and and, you know, when I if I draw it back to what Taconic focuses on as a company, we focus on the tools and unlocking the potential for researchers more on the pre-clinical side of discovery, on the discovery side of new therapeutics, um and and providing those tools at a high integrity so that so that researchers can then go in and then ask these probing questions about what is given given this context, what is an appropriate therapy I could come up with to address a specific problem. Um when we think about CRISPR Cas9 as a tool, it has inordinate potential. And CRISPR itself is is was not was a was an identification of a of a primordial, a bacterial immune system essentially, a way for the for bacteria to detect invading DNA and eliminate it. And it did so in a way that was uh very specific and that was harnessed to now say maybe we can we can hot wire that exact system for intervention and modification of genomes in eukaryotic cells, in living systems. And it started in cell lines and progressed into animal models and and now it's been shown that you can actively intervene in human cells to modify the genome in a very scripted specific way. Um it's not without limitations, however, and that's and that's where the scientist uh have to focus much of their energy is the capability to drive that that sort of Microsoft Word version of function where you can find and replace, it's really at the fine and efficiently modified. The extent of that modification, the ability to introduce a copy and paste of a paragraph or a two pages of text, those are still at the boundaries of success for CRISPR Cas9. Right. Yeah. Okay. Um what you mentioned around what Taconic does, I I think um just to underscore uh sort of the one of the elements that I didn't really think about when when we talked about this is um in order for you guys to provide a product that um produces uh consistent results for research and is sort of is uh impure uh from other influences is was a really interesting aspect of what you do. You guys provide uh basically lab specimens that are are engineered in a certain fashion to either have a a dysfunction or a certain um uh gene line that the creates basically a pure Petri dish for a researcher to work from. So rather than just sort of uh a a bred uh animal or something like that, you guys use use mice for the most part as as your products is what I understand. But having them built basically with with a sort of a gene sequence that is understood and is essentially clean because the part I didn't think about in this is that if you're trying to research sort of a very specific function from a gene and it has other influences that may or may not be there, that could produce sort of offside results and influence what the researcher sees when they're actually trying to research any gene therapy that they're working on. Yeah, it's a this this is sort of the the modern day test tube, right? How do you build how do you build the most potent environmental test system to learn as much as you can as quickly as you can. And when we think of when we think of disease context, we can think of things like obesity or Alzheimer's and they're multifactorial. There's a million things that that uh in if we think about the end game is a clinical intervention to improve human the the human condition, we have to understand that humans are multifactorial and there's many things that contribute to the onset of specific diseases. How do we take and distill in a research setting those most appropriate conditions so that when a researcher is attempting to develop a new drug, that that will target specifically the thing that is at the common consequence for most of the people with that experiencing that pathology. And that reproducibility can take a lot of different facets. It can be the the constant and consistent diet conditioning in a liver disease where we're giving them a a fancy diet so that they develop a specific pathology that is commonly shared across many of the people that are experiencing this liver disease. And and then documenting how consistent and how frequently that liver disease onset happens in a rodent system, so that when a therapeutic intervention is designed, you will know when and how to go into that system to test whether or not it has an effect on that common consequence that we that that invariably will happen based on based on the conditioning of the model. When it comes to Alzheimer's, it it it's much more nebulous because Alzheimer's is not a predictable disease. There's not a single gene we can identify. There's lots of different pathways. There's certain commonalities we understand, but if we can recreate some of those commonalities through either gain of function or loss of function through genetic engineering of the mouse, we can provide a testable unit that gives certainty to the researcher that when they go to do a specific experiment, they have a known consequence for no intervention or a placebo intervention. And that gives them that yields them the ability to test uh the the outcomes of the the therapeutic intervention that they're developing. So, all certainly volunteer myself as one of the people that is on side with what you guys are doing here. Uh I think I think it's incredible um sort of uh a use case for what is required and and the diligence uh necessary to do this type of research. But I I'm sure you guys are met with some resistance around, you know, the the people, the naturalists essentially suggesting that, you know, we shouldn't be manipulating the genes and this is playing God and those types of things. What would you suggest sort of say to to the the people that are a bit sensitive around this type of technology? Well, I think that I think that tightly controlled this technology is incremental advancements, right? We take and we we can modify a single gene and we can yield an outcome and we can characterize what happens with that outcome. And that takes a lot of not once you've done the modification at least in a rodent system where you've actively intervened to gain or lose a function, you have you have a standard playbook that we must follow and that's to make sure that the pedigrees, the the follow on breeding is appropriate so that that's always going to be the thing that you're testing. And that's part of that clean test tube hypothesis that if you if you're testing a pure system, you can recognize the results based on whatever variable you choose to manipulate and it's not going to be the system that's going to be the moving target. It's going to be the it's going to be the therapeutic intervention. Um that's absolutely required for us to to advance these therapeutics through a drug development pipeline. And for us to yield the benefit on on these specific human common consequences of whether it's a a western diet or um uh uh genetic propensity for a specific disease, we're obligated to build the right tools to unlock the creativity of the of the researchers downstream and provide those in a high integrity way. And that that's where we focus on is what's the what's the highest integrity, most information packed system we can provide to the research community. So, would that include systems like like gene drives? Because I know that there's there's probably a higher sensitivity to that type of technology where you're making germ line changes and those would be passed on to future generations and potentially have sort of influential effects on basically the entire uh gene line of a of a of a species, for example. Yeah. Um so we generally don't participate that broadly with the with that overall core concept of of gene drives. It's a fascinating topic um to to understand how could one manipulate external populations. Um in our industry, we're very tightly controlled on how we keep things specifically within the research paradigm. They're not really made to to wind up in a in any other setting, um other than a research laboratory where scientists are actively intervening. Uh when we when we address the concept of gene drives, it's profound and fascinating to think that our ability to manipulate the genetics of living things that live externally, uh will have downstream consequences, whether it's introducing, you know, pesticide resistance in crops or or or um or some some uh susceptibility to a uh uh uh pesticides for for controlling malaria outbreaks. These are these are these are fascinating concepts, but what is important for the researchers is to have the incremental advancements in understanding of the cause and effect of a manipulating an organism and be the downstream outcomes. Um one thing we touched on earlier was that genes don't operate in isolation. So when we manipulate the genome, we are creating a lot of downstream consequences. Some of them are easy and and they're very severe like hemophilia. If we intervene in that disease, we may correct the the thing that is most likely to cause a negative outcome for a patient that's that's deficient in a factor of one of the blood clotting factors. When you start moving into other areas, the gain and loss of function of specific genes has a myriad effect that may not be easily predictable, but having that testable system to scenario plan what are what are the things that could happen are necessary for researchers to to really advance the development of these medications. Right. So, uh the the gene drive functions um appropriately scary, not necessarily something that you guys uh sort of participate in and and it's just sort of an externality of this capability to be able to make these these changes. But as you said, you know, uh appropriate caution because uh we're not as humans, we're not terribly good at understanding the larger impacts of of manipulations or changes that we make to the environment and not really having a capacity to understand the downstream effects is is why people are could get appropriately nervous around that that that type of intervention, right? Sure. I think that that that's sort of where um when you when you have scientists with a healthy amount every scientist sort of inbred with this healthy amount of skepticism on on tools. I I remember when CRISPR Cas9 came out before that we had zinc finger nucleases and talons and other ways to modify the genome that were giving us these indicators of potential to to actively intervene in specific genetic pathway and our control at this point is is pretty good, but the downstream consequences when you factor in how many genes are expressed and the constellation of interactions that those proteins encoded by those genes have in executing a physiologic outcome, uh a specific pathway, a metabolic pathway or a or an immunologic pathway. How do we factor in the the downstream consequences of loss of function? It's it's a it's an important provocative question that that without the appropriate tools, scientists can't ask. Right. And and what we try to do at Taconic is provide a testable living system capable of answering some of those questions. Right. So the other side of this uh that I think is more, I guess more of a recent uh application of of the sciences would be the microbiome. And this, you know, the microbiome has become the superstar of uh biological research and just general biological interest. Like the level that we've learned of how influential the microbiome is to the overall system and its uh its direct integration to brain function and all kinds of stuff has been absolutely fascinating over the last few years. Do you want to comment a bit on on sort of the expansion of the microbiome research? Yeah, this is a major focus for us in our company. Um you can imagine that that if the microbiome, if we assume the microbiome is important. And when we when we properly define the microbiome, it's the bacteria that lives in our gut and on our skin. That's that's the most general way to think about it. But what that what those bacteria do is they live in a state of symbiosis. with that create a holistic organism. And their function is important for our function. And when we think that in a in a typical in vivo model system, we are discreetly controlling the microbiome by eliminating the adverse consequences of specific bacteria that can lead the animals to get sick or they can that that can erode the confidence in specific results. Um we're basically we're basically producing our animal models in a clean room. And as a and and so the next question is, is a clean room reflective of what happens in the population? Because we know humans aren't living in a clean room. So when we think about the impact on an in vivo model and how it translates to what is the the for lack of a better term, the messy situation that happens for normal human behavior and human life and human activity, how do we start to better model what the microbiome impact is on um physiology and drug metabolism? Uh what we know about what we've learned in the last four or five years is that drugs don't always respond the same way in the in every person that they're given to. And we can then go back and model that in in uh in vivo systems like our models where we change the we manipulate the microbiome, and the drugs don't behave the same way. In that very well controlled testable system, the drugs don't behave the same way and it's more reflective of a human population. That tells us that the microbiome itself is an acting contributor to what the success or failure of not only whether a drug works in humans when it makes it to the clinic, but whether it worked in the pre-clinical space when someone was testing something that otherwise looked really important to move move through a pipeline. Perhaps the the in vivo model used had a microbiome that was actively intervening blind to the scientists whether or not that was important. And that's that to me is a very disruptive element of uh what we do and an active area of investigation for our uh what we call our sort of our disruptive innovation uh strategy. That's that's so fascinating. Like I've I've heard some reports of um people that get fecal matter transplants and they report uh personality changes, even sort of their ability to lose weight or gain weight is a function of the micro the microbiome and what exists inside them. It sort of has this this knock-on effect of this direct correlation to their physiology. It's such a wild thing to think of. Yeah, it's it for us it's it's of critical importance to understand. Because if we take if we take the way that just those those anecdotal responses point are an indicator to us that the microbiome itself is going to be a new criteria for evaluating the success or failure of specific drugs and compounds. And that's that's not even addressing whether the microbiome itself can be an active therapeutic. It's another area of active of um significant, it's an active area of investment in in the venture capital space where we're seeing a lot of activity in companies that are making bugs as drugs. And maybe you can re-engineer the microbiome combining both the capabilities uh of our of our ability to manipulate the genome in a bacterial setting, reintroduce those to have some positive function or to have some insulating function in in preserving uh a status quo or a therapeutic uh in a therapeutic intervention. So there's lots of places where this microbiome aspect of our uh of what we do to build tools for researchers uh can take us. So what would be your feeling of uh sort of the state of research around more the public commercial space of this? There's there's companies that uh like Ubiome and Viome that do uh the analysis of the microbiome, but a lot of people suggest that our understanding of what's actually in there is so infantile that it's not really that useful. What's your feeling on that? Uh so, so that is the exact same perspective that uh that Gregor Mendel, Watson and Crick were confronted with, right? There is this idea of heredity in the genome. And going back hundreds of years, you can say that there is there must be something hereditary to the way to the way genes are propagated through a typical species. That's a that's a point that we had no clear understanding until Watson and Crick solved the structure of DNA. And it wasn't until Carrie Mullis solved the the ability to do polymerase chain reaction where we could start really examining base by base the genetic integrity of a specific modification. And as that carried forward, I think that's what we're looking at with the microbiome. As we with our ability to do next gen sequencing, we have a greater level of granularity to understand how the microbiome itself is characterized, codified and differentiating across geographic regions, specific ethnicities, populations, dietary patterns, um physiologic conditions that once we start aggregating this information, we can start harnessing it uh for that therapeutic outcome. And and so I think we're really in the early days of understanding it, um which creates a really exciting time because we're back to uh we're back to that setting where, you know, back when the the genome was originally sequenced, we had a billion base pairs in the genome. We now know there's maybe give or take 30,000 genes that are actively expressed in any given uh any given cell in the human in the human. Um now move into the microbiome. There are 14 trillion variables in every single mouse that we produce. Wow. You know, you think about the when you think about the magnitude of variable introduction, unappreciated variables. And these come in lots of different ways. We know that they come directly when you take an oral medication, they connect directly on that medication to change the way that it's metabolized, creating a a positive or a negative outcome. Or the bacteria itself can create a system where the immune system doesn't recognize a specific therapeutic. So, so understanding the myriad ways, characterizing, cataloging, understanding the the the different conditions that drive these outcomes and tying that back to what specific interventions could we make to either improve our testable system or improve our uh our therapeutic decisions. I think is going to be uh is going to be a game changer for the way we think about the microbiome and therapeutics going forward.