 Hello everyone, welcome to this third session of the Life and Health seminar series in the CEPISA seminar. Our speaker today is Andrew Barnett, he's a PhD student in KU11 and he is an expert on organoid ethics. He has published a couple of papers, articles on organoid ethics and he's going to present an overview of the ethical issues in the field. Thanks Maxence, it's a privilege to be here, I'm very happy to be here so thank you all for having me and giving me this opportunity to share some of my work. It's really fun for me to share all this sort of stuff. Before we begin, I have to give some shout outs to folks, of course first and foremost to you all for having me here and giving me the opportunity to speak to my consortium, organoids for virus research, an international training network I'm a part of, PUSTIV, it's the Dutch society for the replacement of animal testing, RIVM in the Netherlands, I'm really curious of your permission for helping fund this work. So as I mentioned before, as was mentioned before, I'm presenting a paper that was published a while ago just this last year titled the Many Moral Matters of Organoid Models and it is a systematic review of reasons. So I'm going to begin this little chat with you all by assuming that you don't really know what an organoid is, I'm sure, because every time I try to explain to folks that I work on ethics of organoids, their first question is what's an organoid? I have no idea what that is. So an organoid is an organoid. So it's a term that just means resembling an organ or they are organ-like. Organoids, well, there's many, many, many varieties of organoids. So sometimes in the literature, the scientific literature, instead of seeing organoid, you will see something like cardioid, like cardiac organoid or something like that, or cerebrooid, like a cerebral organoid or embryoid, an embryo-like thing. So there's a bunch of these different kinds of oids and I'm sort of exploring the morality and the ethics of all of these different kinds of organ oids. But organoids are generally defined by a few different things. One is first this self-arrangement and self-development characteristic in vitro. So these cells will, if you give them the right kind of medium in a petri dish, they'll naturally sort of evolve or transform themselves into a kind of structure. Usually it's three-dimensional in structure, so it's kind of a spherical entity. And early iterations of organoids were first called spheroids, before the fact that they would just self-arrange into this three-dimensional, spheroid-like structure. And then of course the third characteristic of the organoid, generally speaking, is that the organoid has features and functions and some structures that are similar to their in vivo organ counterparts. So I were to try and make a cardiac organoid in a petri dish, you would see a three-dimensional ball of tissue that resembles features and functions of a heart. So it would have cardiac tissue made up and it would beat in a similar fashion as a heart would. I should note that organoids are not like miniaturized versions of the organ itself. It's not like someone took a shrink ray to a heart or a brain and just shrunk it down and made like a little mini version of it. The best way I can kind of describe more or less what an organoid is like is that they're kind of like jumbled up versions of what you would see in vivo. So if you have something like a car, an organoid is like a smaller version of that car, but the parts are there, it's sort of jumbled up. So like the windows are on the floor, the engine is in the back, the exhaust pipe is sticking out the front. You might be able to roll the windows up and down and you might be able to get, there's a radio but the radio knob is like over on the side. You might be able to get like a station here or there and you might maybe be able to turn the engine over. You can hear like a click-click sound, but the engine isn't running so to speak. So it's kind of like this sort of real jumbled up version of it, but you can still sort of identify these features and functions of the car within this caroid, right? If that makes sense. Yes? What I don't see in the definition, I guess it's understood, should they be man-made and purposefully man-made? Or maybe accidentally man-made or just in nature somewhere? Yeah, generally speaking, this is kind of the overarching definition that is used in the scientific literature. They don't normally include like the man-made part, but they are man-made. You don't see organoids typically in nature. The only maybe possible exception to that would be something like a teratoma. But even then, no scientist would really call a teratoma an organoid. That's kind of the only sort of definition that would be sort of excluded for something like that. If there's any other questions, please feel free to interrupt me at any point in time. But to give you some pretty, pretty pictures of what these things look like, just to give you some examples and some more clear ideas of what these things are. What you can see here are again some examples of what organoids sort of look like. You have here in A a brain organoid. So you can kind of see like the folding of the brain here. If you know anything like about brain structure, you can see various cerebral layers forming here. But it's not, of course, like a complete brain or anything like that. And the folding is not super extreme. Again, I mentioned like the cardiac organoid. This is a liver organoid. This is a liver organoid. So it's again spherical. It has pieces of liver tissue there. And then the number C or letter C over there is a human airway organoid. So it's kind of like a lung organoid, so to speak. Or like an esophageal organoid. Some more pretty, pretty pictures of what they can look like. This is a typical render of a brain organoid. It's again spherical ball-like structure. This is also a rather famous image of a brain organoid from Madeline Lancaster. Sort of the godmother of brain organoids, so to speak. So again, you can see how it sort of looks like a brain. But if you know anything about neuroscience and brain biology, you can see some elements of the brain there. But this just doesn't look quite right in terms of what they're supposed to look like. Sometimes you get some interesting little organoids. Like this is another image of a brain organoid. But you can see these two spheres alongside. So they fuse in with the overarching brain organoid itself. Those black spheres are eyes. They are proto-eyes that just sometimes will naturally form when you grow a brain organoid in a dish. And yes, sometimes they will work. Sometimes they will send signals to the brain itself. So whenever I show this image to people, sometimes they immediately begin to think, oh, so this is getting some environmental inputs and this looks like a brain. Does this thing think? Some possible areas of ethical exploration. But why would you want to rather... Like I said, this is a little snapshot of all the different kinds of organoids that you can sort of make. Again, it's not a complete list, but you can make pretty much any kind of organoid these days. You can make a brain organoid, a pituitary organoid. You can make cardiac organoid, lung organoid, pancreas, gut, bone. I've seen researchers grow teeth organoids. You can make skin organoids, tumor organoids, or rather tumor oids. You can make gonad organoids, all different kinds. So there's all different kinds and they're used for all different kinds of research. Sometimes you can fuse organoids. You can fuse them all together. You can take a brain organoid with a spinal cord organoid and a muscle organoid and fuse them together to make something called an assembly and make this kind of entity. I say all these different oids, right? There's so many of these different oids that it gets jumbled up sometimes. But this is experimental, something that's sort of coming out more and more now that says in the future, but it's sort of present day. So why would researchers do this? Why would they make these little jumbled-up pieces of tissue? Why would they make an organoid? Well, they do it for a bunch of different kinds of reasons, including but not limited to regenerative medicine research, toxicology research, drug discovery research, host microbe interactions, gene editing research, omics studies, phylogenetic studies, developmental model, disease modeling. In fact, some of the research that was used to help develop the COVID-19 vaccine would utilize organoids, specifically human airway organoids, to try and see the mechanisms of infection for COVID. We also argue that they are nice alternatives to animal models. In fact, an organoid in a way has better representation, even if it's perfect. It is somewhat of a better representative model of what's happening in the human body than an animal model, for instance. So they're considered as this kind of alternative to animal models and perhaps as a way of better practicing medicine. If we're talking about using organoids for precision medicine or for personalized medicine, researchers can take, say, your skin cell, turn it back into an induced pluripotent stem cell, and then turn those stem cells into a brain organoid that represents elements and features of your brain and do a whole variety of tests surrounding that brain organoid and then, based on those results, they could figure out an appropriate treatment for you. We see this in cancer research, where researchers will take tumor oids, well, they'll take a piece of tumor tissue and they'll grow a bunch of these different tumor oids, hit them with different doses of chemo, and then, based on the results, they will fine-tune the dosage and the timing of the chemotherapy to that particular cancer patient. So it's used in precision medicine purposes. We have living biobanks now, where all of these sort of banks of these living tissues can be used for all different kinds of research and giant data sets for all different kinds of basic research or innovative research. Developmental modeling. We can do a lot more for making an embryo-like entity, for instance. We can do a lot more studies in embryo development than we could previously with just embryos, right? Because we're limited in how far we can allow an embryo to develop. With an embryoid, the limitation may or may not apply the same way, because it's a non-viable entity. And we go on and on and on, like transplantation and so on and so forth. So there's a lot of contexts and a lot of different things that you can do with these organoids. In a way, they're sort of method or both model and medicine. So let me get into a little bit just quickly of the methods of this review, right? Because what I wanted to do was sort of explore what are all these different ethical issues associated with organoid models in research and medicine, right? So here I've performed a systematic review of reasons. So going through all the ethics literature on organoids to see what reasons actually occur in the literature, what arguments occur in the literature. And then sort of try and do a bit of thematic analysis of these reasons, right? First pulling out very sort of narrow basic reasons from the literature and then categorizing them into broader reasons and then further categorizing them into topics and then into themes, right? So I have my little search string here looking for organoids, ethics, and trying to cover my basis in terms of which databases I'm hunting through. So I'm hunting through, of course, the classic Google Scholar, looking through JSTOR, more humanities papers, fill papers, and then, of course, PubMed and Web of Science, right? Because sometimes science publications will, or science journals will publish ethics papers relating to something scientific there, right? And based on my inclusion criteria, we found about 23 papers including snowballing and looking through references. So this is sort of my first attempt, oh, this is really hard to read, sorry. So this is sort of my first attempt at this systematic review. And basically, when reading through these papers, I pulled out and coded, nearly line by line, or a few sentences at a time, these particular reasons, unique reasons within the literature, and identifying them as either a positive reason or a neutral descriptive reason, or a negative reason, or a reason against a particular position. Then you have, of course, things like call to action, like more research is needed, or we need to do more ethical research in this area. Yeah. Yeah, sorry, what were your inclusion criteria and which papers? Which papers, right. So they had to be published and peer reviewed. They had to be in English, mostly just because I am not a Dutch or a French speaker, or in any way I can, I only speak English. And basically, they had to be published within, from basically, at least 2020, and back to around the first time in Organoid, came onto the scene, which is around 2010 or so, right. So we were looking for papers in that category. So we also had some exclusion criteria, including things like grade literature. So we excluded any kind of national guidelines, for instance, or any kind of regulatory policies and things like that. So we were just really focused on ethics papers. And also part of the criteria is that the paper itself, or the publication itself, had to be primarily focusing on ethical issues relating to organoids. It couldn't just be sort of like a paragraph at the end of a paper that says, we need to think about ethical issues like this, that, and the other. So we had to sort of pull those aside. So that's basically the inclusion criteria here. And so basically, the way this kind of function is we go through these papers, pull out these reasons, and then categorize, basically summarize these reasons into the narrow reason category. And then from there, we sort of inductively group them into bigger groups and groups that sort of make sense going up. So here, you can kind of see it in play with the narrow reasons here. And then the broad reasons seem like, say, we have a reduced refiner placement as a broad reason for these narrow reasons, which all of these reasons are grouped within the topic of animal models, and all of this topic of animal models is grouped within the broader theme of animal experimentation. So we go through this for all 23 of these papers and try and pull out all these reasons and categorize them in various ways. And so here is the kind of end result of it all. We ended up with five broad themes, generally speaking, for organoid ethics issues. We have animal experimentation, of course. We have commercialization and consent grouped together. And I'll explain why those two are grouped together, because it doesn't seem so obvious like why they are. Research ethics and research integrity as one. Clinical applications and experiments and organoid ontology and organoid moral status. Some of these are somewhat divided into sort of sub-topics or sub-themes, rather like research ethics and research integrity is sub-divided into research ethics and research integrity, because they're slightly different things. Same thing with some stuff like with moral status. With organoid ontology and moral status, there's a sort of special category of moral status within there, because it just seems to make sense to make some slight divisions here. And of course then these topics come into play, and these topics of course go into the broad reasons and the narrow reasons further on. So this is a kind of simplified tree of all these different ethical issues and ethical reasons that are found within organoid ethics. This is a much more complicated version of it. This is something that was plastered on my wall at work, and I would be like drawing lines everywhere and having like red string all over the places. My colleagues lovingly referred to this as my conspiracy theory. So I would be on the wall just basically saying like these are connected in this way, but these are also similar. It drove me mad for a while. So let me go on a little bit about the theme of animal experimentation first. I didn't include the number of reasons in this presentation specifically, but basically animal experimentation was one of the smaller categories that didn't have as many reason mentions as the other categories. So one of the topics within the theme of animal experimentation was of course animal laws. And a question you can think about here for something like this is, what should happen with lab animals given new organoid research? I mentioned before that organoids are sometimes presented as this sort of animal model alternative as a way of doing research without so many animals. So there are some reasons that you can see here. I have some reasons up below this. Maybe it's a little bit hard to read if you're in the back, but here we have say animal use is permitted. So some folks will say well while organoids are nice, they're not necessarily so perfect as an alternative. So animal use is permitted still. Some will argue that organoids are actually a pretty decent model and we should move towards more a kind of comply or explain model. Where you have to comply by using organoids first within your research and if you can't use organoids in your research for some reason or another, you have to explain why you need to use animal models. So this is a reason that sometimes pops up within the literature here. We have this idea that with organoids should come increase in animal ethics standards for journals. Some think that journals themselves have a responsibility towards animal welfare and should demand higher standards of ethics in animal welfare given that organoids are perhaps a viable alternative for a bunch of different kinds of research. We have of course lower animal interests meaning that now with organoids maybe we can start to consider the interests of animals that are saying non mammalian. Maybe we need to start thinking more heavily about the interests of say lizard species or snakes or fish species and so on and so forth. And then of course there is the classic paradigm that still pops up of the reduced refined replace. And the idea here is that oftentimes researchers will say organoids are a great way to in a way reduce the number of animals that are needed for research and to demand more refinement within animal experiments but most think that it's not going to totally replace animal research altogether although various organizations will argue that and various ethicists might argue that yes this can be a replacement, perhaps one of many. But then we move on to chimeras. In a way organoids are a bit strange in how they're presented somewhat in this space because organoids are often presented as this possible viable alternative to animal models and yet researchers are now and have been for some time transplanting organoids into animal models for research purposes. So for instance in the case of chimeras, there's in the case of here Cerepochimeras researchers are transplanting human brain organoids into the brains of animal models, rats, macaques. No study I know of looks at even higher order non-human primates than macaques. So no chimpanzees, no gorillas as far as I am aware though they are heavily protected still. So given this there's this question that often sort of comes up is should cerebral chimeras be created with human brain organoids? Because one of the concerns here might be say like humanizing the chimera but then there's this sort of question of what does humanizing an animal really mean or really entail? Then there's of course this question of a need for measuring consciousness because if we're thinking of humanizing often we're sort of thinking about it in a kind of cognitive capacity context and so if we're talking about this in a kind of cognitive capacity context or consciousness context we need some kind of way of measuring consciousness and higher order forms of consciousness if we are advancing or generating higher forms of consciousness or possible higher forms of consciousness within the animal model itself. But there's also this question of how do we assess ethically assess cerebral chimeras? That's also a bit of a question here too. But maybe this is also a bit of a continued discussion of prior debate. Maxons and I were talking a little bit before this and saying like well you know researchers have been transplanting stem cells into animal model brains for some time now right? Isn't this in a way just sort of a continuation of what's been going on before organoids have come on the scene? Possibly. Then of course there's this question of how do we actually treat cerebral chimeras? Do we have to give them special considerations as opposed to other kinds of animal welfare considerations? There's also questions about important transplant variables, questions about policy guidance, how do you create effective policy surrounding this? What are the actual scientific benefits from creating cerebral models? Are these benefits like say actual benefits that can be implemented? It's kind of murky I think. The science is a little bit murky in terms of the direct translatability of some of this chimeric research to human beings. It's not exactly clear and in a way it might be similar to say other forms of animal model research in the murkiness of its translatability into clinic. And then of course more special considerations for chimeric models. But what I've been talking about here has been primarily about cerebral chimeras, right? Because there are other kinds of chimeras than just cerebral chimeras. So researchers will sometimes transplant other kinds of organoids into animal models to again look at like say transplantation techniques and so on and so forth. So for general chimeras what we're talking about is what I'm sort of defining here as say transplanning a liver organoid into a human liver organoid into a mouse or a macabre or something like that. There's questions still about say chimeric research design and whether or not this research design is ethically appropriate, right? And that chimeric research is still sensitive generally speaking, right? It's not something that isn't ethically neutral if it's not cerebral chimeric research, right? There's of course concerns about chimeric reproduction if we're talking about transplanting say human gonad organoids into animal models, right? So there's some possible, maybe some possible concerns there even if scientists say what are you talking about? It's not really going to affect anything, right? There's concerns over chimeric organoid transplantation. Again another question about humanizing chimeras here as well, right? Because if we're thinking about humanizing chimeras maybe humanizing doesn't necessarily mean just something cerebral. Maybe there's also other kinds of biological components that are related to humanizing an animal, right? Of course policy guidance and then there's this tricky question of unknown outcomes for thinking about chimeric research in general. So this is sort of what has been found in the animal experimentation space of organoid ethics thus far. Are there any, what questions do you have for me about this so far? It seems kind of clear I guess, right? Yeah. I tried my best to also add something to this space in my other work outside of this review where even if we're looking at two different kinds of say human cerebral organoid transplantation into animal models and looking at two different kinds of experiments, there might be relevant ethical considerations that need to be looked at in certain ethical contexts. Like does it matter if we're say transplanting a Down syndrome human brain organoid into an animal model versus a neurotypical brain organoid into an animal model? And is something like say genetic research on Down syndrome which is the purpose that's often the intention behind some of these chimeric experiments with Down syndrome brain organoid transplantations is the science that comes out of that research actually going to benefit the Down syndrome community and does the Down syndrome community actually even want this kind of research and the creation of new genetic interventions for their community, right? So moving on then to clinical applications and experimentation. So here is one of the more populous ones as you can see there's more variety of topics within this particular space on it. One is ethics within drug development with organoid ethics here. So for one is there's this question about line blurring in precision medicine and personalized medicine. I'll talk a little bit more about that in just a bit and explain what exactly do I mean by line blurring, what's often meant by line blurring in precision medicine. But there's also again questions about the usefulness of organoids in drug development too because they are imperfect models in a variety of ways. One of the two main problems with organoid models in terms of their use in either pre-clinical applications or clinical applications as a model is that they have what's sometimes referred to as a plumbing and scaffolding problem. So if you think about what an organoid is, it's a sphere of tissue that's sitting in nutrient medium. And so that means that the sphere is getting appropriate nutrients on its surface from the outside but the core is not getting any kind of nutrients at all or at least not enough of what it really means. And so what happens is when that core doesn't get enough of the nutrients that it needs, the core begins to undergo necrosis, means the core begins to die and the organoid begins to kind of fall apart from the inside out, begins to run from the inside out. So the plumbing problem is how do you get nutrients into that core so that the organoid can maintain its structure. And the scaffolding problem is kind of similar but as a sphere organoids can't really grow really big. So it's not a fully stable structure for them. So it's this plumbing and scaffolding problem that makes them somewhat imperfect. And that's also one of the reasons why researchers will transplant organoids is a way to solve the plumbing and scaffolding problem. So there's this question about their usefulness within drug development for those particular science reasons. But there's also questions about say well who is going to reimburse for the experiments of drug development and care that comes with like say the drug discovery for this stuff. Who pays for this? And then of course there's questions of safety and efficacy if you're using organoids for drug discovery. How do you know that it's going to be safe and effective to move to clinical trials? And that's also one of the reasons why some will argue that animal models will sort of in a way always be necessary and that organoids may be just an extra preclinical step. You have some applications when it comes to embryonic and embryoid research. A question here might be do organoids further require the reduction of embryonic stem cells for research? Because there's this question about embryonic stem cell use and you can make various kinds of embryoids embryo like entities without the use of embryonic stem cells. Most of the time though right now there is a mixture of use of embryonic stem cells and induced pluripotent stem cells to make embryoid models. However there are various advancements that have come forth to show that you can make certain kinds of embryo and embryoid like models with just induced pluripotent stem cells. In fact there was an experiment that came out of Australia recently where they created blastoids, blastocyst like models solely from induced pluripotent stem cells and they did it by accident and they called it the eye blastoid. And of course when they did this by accident they immediately rang their ethics committee and said hey this thing is turning into a blastocyst kind of like entity what should we do? And they basically said probably should cancel the experiment and put a stop to it further developing if it might continue down that developmental path. So I will say that this question about does it require embryonic stem cell reduction is an important ethical issue but that doesn't eliminate the ethical problems that are associated perhaps with embryoid models. There are also ethical questions about first in human trials. What happens in terms of ethics and how do we ethically assess transplanting organoids into people or even say utilizing drugs that have been developed solely from organoids? And then moving to the clinical trial stage. There's this question there in terms of the first in human trials in that front. And then there's questions of well what about first in children trials? Some have argued that yes we should advance to first in children trials as so long as various safety assessments have been done and as long as everything we've done our best to our ability to ensure the safety and efficacy of this treatment for children. Talks about you know from moving bench to bedside here. There's also questions about choosing study populations. Can you kind of refer to the first on child's argument? The what? The first on children argument. You're going to repeat the first in children argument? Yeah, I didn't have time to. What are they actually arguing that we should. Primarily because it's about trying to reduce suffering and if it seems that based on various kinds of studies including say some animal studies or based on if it's say drug development. If the drugs after numerous sort of testing especially if we're talking about say personalized medicine. If it seems that the organoids are responding well to a particular kind of drug treatment. Then it seems and we undergo other kinds of various safety and precautionary procedures. Ensuring and have extreme kind of like a hawkish watchful gaze over the children and intervene if anything might go wrong. Then yes it seems like this could be a viable solution for certain kinds of conditions for children. So the argument goes that is basically sort of saying culminating into the position of yes we should advance the use of organoids into first in children trials. Because ultimately and basically the argument sort of goes that ultimately that's what we will have to do eventually if the whole point of using organoids is for medicine. We will eventually have to go to a clinical trial with them at some stage. Some argue that the stage is now. Others would say no there's still more stuff to try and sort out here scientifically and sort of safety and efficacy wise before we can really go to first in children trials. Let alone maybe first in first in human trials. But of course as I mentioned some of the concerns might be something like say complex translational trials. This might be sort of complicated in terms of how you are setting up the clinical trial. Because a lot of the times when you're doing say drug trials there's a double blind study that's done. But in the case of say like organotransplantation you can't really have something like a kind of double blind study. So you have to set up the trials in different ways. There's also of course the concern about protecting children. As I mentioned before we shouldn't go to first in children trials because we want to make sure that the children are protected to an extreme high degree because they are a vulnerable population. Then there's more like say risk benefits argument here where if we do a risk benefit assessment we will probably see that the benefits outweigh the risks or maybe vice versa. Safety and efficacy but we also want to ensure that first in human trials are for therapeutic purposes only and not for say enhancement purposes. So this ethics of being sort of drawn on the lines of therapy versus enhancement. There's also questions about gene editing here too. Could gene editing organoids further complicate ethical issues with gene therapy? Because if we're using organoids as say a tool on the one hand for medicine in terms of transplantation we can also think about that in terms of a tool for helping with trying to develop some sort of gene therapy. Or a model to help with the gene therapy. So in a way I like to think about the ethical quandary of gene editing and gene therapy with organoids is if you were to go to an American and say hey imagine a pharmaceutical company in the United States has CRISPR-Cas9 a gene editing pair of scissors in one hand and then your organoid in another. Would you want a pharmaceutical company in the United States to have that? And I think a lot of Americans would say maybe because they distrust the companies in the United States for having both of these tools in hand. So there's questions there in terms of risk benefits but not a lot has been discussed in this space about it. So that's why there's so few there. I mentioned organoid transplants as this first in human trials is mostly somewhat in the context of organoids transplantation. But organoid transplants here are thinking about this is the best possible option. We have to have a lot of cautiousness about this. Maybe there's also the idea is that full organ transplant delays are not problematic. Also this might be a less invasive alternative so maybe the idea here is that well someone who needs a liver transplant maybe we can give them a liver organoid transplant to help them along until maybe there is a viable full liver transplant alternative. Maybe so we can do a bit of a partial transplants here that might help. Maybe organoids could be used in terms of transplantation as a way of alleviating the organ donor crisis because there are too few organs to go around. So that's one argument sort of in favor of organoid transplantation as it means to mitigate the issue with organ donation. Promising applications are sometimes mentioned. Of course again with organoids they have similar mechanisms to their in vivo counterparts, transplant for repairs, generally speaking and not for enhancement purposes so on and so forth. I mentioned personalized medicine precision medicine a little bit before. There's kind of a big ethical question here which is will organoids further blur the line between research and care because in medical ethics research ethics and clinical care ethics are treated as separate things and you have different ways of doing ethics within ethics of clinical care versus ethics of research. If we're sort of combining research with medical care more and more with something like say organoids for personalized medicine then what's happening in the research is going to more directly impact the care that the patient is receiving and this puts even more pressure on something like say research integrity for instance because if you mess up with the research on the organoid and it's being used for medical care then you are also possibly screwing up the care and treatment that a particular patient is receiving so there might be a lot more responsibility now on researchers when it comes to this blurring of research and medical care. Furthermore there's also issues of building the infrastructure because at the moment there's not really good enough infrastructure for this to really happen very well and if you don't have a good enough infrastructure for something like precision medicine it's not going to be effective and maybe harmful to patients. Then of course there's this issue of something like clinical validation challenges like say you have an N of 1 trial where you have a trial that consists of a population of just one and what you can do is you can generate a bunch of different organoids from this one patient but nevertheless the trial study and the trial population is just one and statistically speaking that's a bit complicated when you just have one patient in the study. So that's kind of the idea here is this question. And then of course organoids are considered as promising applications they are referred to as promising applications generally speaking and so we have to sort of consider similar ethical issues as other promising applications within the clinic as well. There are also human development models and we may want to consider ethical issues to other kinds of human development models that might be similar in ways. I've made some have argued that as a promising application we have a moral imperative to pursue organoid research to the furthest extent possible. There's also of course practical implementations that we need to consider in terms of the ethics there. We have to consider some ethics about regenerative medicine for instance more risk benefit questions and questions about their use as a reductionist model because if we're talking about organoids being used as models for in vivo counterparts in certain ways they are a reduction of what is actually happening in vivo. And of course we have to consider their variety of applications. So that's kind of what we see in the ethics literature about clinical applications and experiments. Any questions for me about this? Yeah, I'm not very sure about the precision aspect of personalized medicine. What is the specificity of organoids there? Does that they allow personalized medicine? Or is there something more specific going on with respect to organoids? What do they have to do with care? Right, so with organoids they could be used as a form of personalized medicine. That's kind of one of the hopes of them. So I gave the example earlier like say for cancer. What you can do is something like a tumoroid. You can take the tumor tissue from the cancer patient, turn it into say a variety of tumor oids and hit these tumor oids with different doses of chemo to see then how the patient might best respond to particular dosage of chemo and for a duration of them. So that's an example of personalized and precision medicine that organoids could be used for there. Now in that example again there's a blurring of research and care because the care, the treatment of the patient is going to be more and more heavily based on the experimental research and the experimental research and clinical care. The ethics of these areas have typically been considered primarily in separate silos. Research ethics has a variety of ethical questions that you won't really see in clinical care. And when you blur this line of research and care, the ethics can then become kind of muddled. Organoids are probably an example of this. I would argue this. Organoids are an example of this. They're an extension of a kind of consequence that you would see within precision medicine and personalized medicine. But in a way they're not, they might not necessarily bringing something completely new. I think they would be bringing some slightly different contexts that are probably relevant to consider. But I would argue that the overarching question, the overarching questions are quite the same. But will organoids further blur this line between research and care? Do they blur the line between research and care? I think you can make a case for the fact that they can and will blur that line. And whether or not this is problematic is perhaps up for debate because some researchers say, yeah, this is what we want. Of course we want more precision medicine and personalized medicine. Of course we want research to be more directly involved in the care of the patient. So whether or not that's a good thing is, I think, the big debate here. No worries. Yeah, it's really fascinating. And already just for two themes here, this stuff is getting really complicated. And there's a lot of variety of contexts here that need further exploration. I didn't bother putting the numbers up here in terms of how many times these reasons or topics are popped up. But a lot of times these reasons, even the broad reasons, the number of times they pop up in the literature is like once. So this doesn't necessarily give you, I think, the best impression of how in depth or how shallow the conversations are and how much more we really need to talk about this sort of stuff. This is really just sort of trying to tell you there's some of this out there, but a lot of this stuff is actually quite underdeveloped. So if you're asking me, sometimes if you might ask me, well, what's the argument? I might say there really isn't any because the argument isn't really that in depth. It's really just kind of like we ought to consider this aspect. We ought to consider this reason, right? But there's nothing really like in depth or substantial. Sometimes there is, and sometimes there is. The example, for instance, of sometimes there's a lot of in depth conversation, though. It comes from this particular theme, for instance, about commercialization and consent. A lot of stuff, though, surrounding commercialization and consent falls into the topic of organoid biobanking. So you can think of biobanks as like banks where you have any kind of tissue. Sperm banks are a form of biobanking as an example, or an egg bank, a fertility bank is another example of a kind of biobank. But instead of thinking of something like a sperm bank or an egg bank, you can think of an organoid biobank as just a biobank full of different kinds of organoids and tissue, basically. So there are ethical quandaries, perhaps, when dealing with organoid biobanking. Some might be benefits sharing in biobanking. Who should get the benefits when it comes to biobanking? Or how do you share the benefits of biobanking generally? And benefits can mean both scientific benefits, like, say, data, financial benefits, of course. You can think about medical benefits, who should get the medical benefits there. Benefits sharing is something that needs to be considered within an organoid biobank. Questions about biobanking infrastructure. What's the best form of infrastructure to set up for something like an organoid biobank? There's also complex donor relations when it comes to, you know, you have to get the material for an organoid biobank from somewhere, right? It's going to come from people, right? And so if people are going to donate their tissue, what is the relation between the donor and the organoid within the organoid biobank? So, for instance, does the biobank own the organoid, or does the donor own the organoid, right? And maybe they do, and maybe they don't. There's questions there. Consent for biobanking. What form of consent is best for biobanking here? Do you give, you know, say, a broad opt-in consent, opt-out consent, for instance? Questions about data sharing, and then there's also this question of what sorts of future goals should biobanks have as well, right? Broadly speaking, there is a question about commercialization and organoids, right? How should organoids be ethically commercialized, if at all, right? Are organoids kind of more like organs, and commercialization of organs is generally frowned upon, right? Or there might be some arguments, maybe we should think of organoids like organs in that fashion, but organoids are not organs, right? They're only organ-like. And so maybe we have to think about this special category for organoids and say, well, maybe organoids can and should be commercialized, but not full organs, right? So there is this idea that, yes, maybe if we are going to commercialize, caution is, of course, required for this, right? Because for one thing, organoids, of course, contain human DNA, right? And if they contain human DNA, you're selling an organoid, you are effectively giving somebody, you know, your DNA, right? Maybe there's some arguments against commercialization, which is that commercialization of organoids doesn't necessarily lead to innovative therapies or innovative techniques. Sometimes, of course, the other way around is sometimes argued that commercialization will, of course, lead to innovation in medicine, right? So you have arguments a little bit on both sides here, right? The question of the role of commercialization itself, right? There's concerns over the lack of reciprocity here, right? Because if you are commercializing an organoid, who is getting the money, right? Should we actually pay donors for their tissue when we're commercializing organoids? Or should we not? Should it be a totally altruistic thing and, say, commercialize biobanks being able to receive the money itself, right? There's also a question over control over the organoids. Who has the final say in control over what happens to the organoid, right? Is it going to be the researcher? Is it going to be the biobank? Is it going to be, you know, like the executive? Is it going to be the donor, right? Who has control over what happens to the organoid in the commercialization process? Should the government be involved in terms of control here? And how much? There's also this question about the creation of value. Does commercialization of an organoid in some way, shape, or form create more value within the organoid itself, right? Or does it maybe possibly destroy value? There's this idea about the disentanglement of organoid values, right? And the disentanglement of the relation between the donor of the organoid and the organoid itself within the biobank. How do you disentangle the value between the donor and the organoid? Because if in a way you could disentangle this complex relation between the donor and the organoid, it might make it easier to actually and ethically, more easier and more ethically, to commercialize organoids if you were able to disentangle the value between the donor and the organoid itself. There's this question, of course, a lot of this sort of comes under these sort of two different paradigms of, say, gift versus market paradigm when it comes to, say, like in organ commercialization, right? The main arguments within organ commercialization is like, no, you shouldn't commercialize selling organs, right? Because it should be a gift, right? If you are going to give somebody an organ, like, say, I'm going to give you a kidney, right? It should be just as an altruistic gift. That's the paradigm that it ought to fall under as opposed to, no, I'll give you my kidney for, you know, $10,000, right? That's the market paradigm here. The idea is that, well, here's the thing, though, right? Organoids, as in biomedical technology, are super expensive. They're really, really expensive to make. Really, really expensive to make. Commercializing them might be able to lower the costs to make and use organoids, and thus, you might be able to be able to reach more people with them. I'm being told it's time for discussion, but unfortunately I have a few more things to talk about here. But I'll run through these really quickly, just so that we have some time to discuss. Consents, of course, I already sort of talked about this, which forms of consent are the most appropriate for organoid research? Broad consent, opt-in consent, there's a form of consent out there, sometimes called consent for governance, where the donor is consenting to how the organoid will be governed as opposed to how it will be used. Of course, questions about ownership, questions about vulnerable groups here. And consent, of course, is deeply entwined within commercialization within organoid ethics here. Organonautology, unfortunately, this is probably the most complicated one out of them all. And unfortunately, since it's time for discussion, I can't really talk about this too much. I'll say this, like, in terms of this space, the biggest question, the one that's most talked about here is the cerebral organoid moral status, right? I showed you that picture of a brain organoid with eyes. And there's this question of, well, do brain organoids have consciousness? Can they develop consciousness? What are, if they have consciousness, should they then have moral status, right? And to what degree should we give the moral standing if they have consciousness, right? There's also, of course, similar questions with something like embryoid and gastroloid bodies. Since they're embryo-like entities, should they have moral status kind of similar or not to embryos themselves? So that's an interesting question to explore there. And the last thing I will try to hurriedly talk about and just mention is this theme of research ethics and research integrity, where within research ethics you can see that there are these layers of ethical complexity within organoid ethics on its own, right? So maybe we need more time to unpack the ethics of organoids. Given the fact that I'm forced to go into discussion mode with you right now, I think we really do need more time to unpack the ethics of organoids. And of course we need further justifications of use. There's a lot of different frameworks out there for this. And one last thing I think I'll say really quickly and then we can go into discussion is this area of research integrity, which is really talking about things like communication and guidance and oversight for all of this research. With communication we have to ask this question of how do we ensure scientists don't overhype organoids and organoid frontier technology, right? So how do we ensure that scientists don't go overboard and say these things are the next best things since sliced bread, right? They are the next best thing in medicine, right? And you know, they can do all different things. They can help with regenerative medicine, precision medicine, disease modeling, you know, it slices, it dices, it makes Julian fries, right? How do we ensure that researchers don't overhype it and how can we ensure that media communication accurately portrays what these things are and what they can do? And who, in terms of guidance, how should we formulate our guidelines and also for oversight, who should be responsible for oversight of this stuff? Should it be existing stem cell ethics committees? Should we make new ones? It's unclear exactly who should have exact oversight and control over this form of research. So with that, I will end it there and open it up for discussion. You know, you need a break? I don't think so. Okay, no break, no break. I'm happy to keep going. Yeah, sure. Maybe this question, you made a review of all the sort of arguments and ethics issues that people have brought up, people have studied or not. What would you say are the issues, the ethical issues that are under-talked or omitted, that scientists, that practitioners, that philosophers should be, actually, you mentioned the personalized medicine, the Brewery Division, I think it's interesting, I don't know if you wanted to, if you have some ideas of things like, okay, we are talking too much about this and we're forgetting a lot about this. Yeah, so I can give you a couple of examples of this that are slightly different from what you, a little bit different from what you're asking. So for instance, I mentioned with commercialization and consent. That was, in this review, one of the largest, theme in terms of the number of reason mentions that occurred. But all the papers and all the arguments that came from commercialization and consent came from one research center in the Netherlands. So there was a lot of in-depth argumentation that was happening, but there wasn't really any kind of response that was occurring with this commercialization and consent. Discussion. So a lot of what we're thinking about when we see when it comes to, say, consent with organoids, it's dominated by something like, say, the Consent for Governance idea, wherein, you know, the patient isn't opting into particular kinds of experiments or giving a kind of broad consent where it's like, do whatever you want. They're saying, no, I will consent to you being able to govern over my organoids within a kind of governance structure. That idea, again, comes from one particular research group and dominates that theme. And there's not really any other kind of ethics literature in ethics of organoids that says, that's a great idea. No, that's a bad idea. So it's a standalone sort of thing. I personally think that that's also an area where ethicists ought to continue working and continue to develop more in-depth conversations around. Another one, even though I didn't really get to talk about it a lot, was the brain organoid ethics debate. Because a lot of the brain organoid ethics debate sort of centers around this question of, what's the moral standing of a brain organoid? And usually there's this question about, well, can brain organoids think? Do they have consciousness? Do they have a moral minimum of kind of consciousness? How do you measure it, et cetera, et cetera? That I particularly think, while that's an important debate to probably have, in a way, if ethicists are focusing on that so much, they might overlook other relevant ethical issues relating to brain organoids and brain organ research. So one way I've tried to help with that has been a couple of ways. One sort of is to show, hey, this is perhaps going to be a growing issue and we don't want to turn this brain organoid debate or an embryoid debate into something similar as, like say, the abortion debate, where it's in a way often reduced to this question of personhood and fetal ontology and all this sort of stuff. And there's other relevant ethical questions relating to abortion that don't necessarily center around fetal personhood. So that's one thing I've done in my work and the other thing has been to sort of give an instance of this, where I talk about, say, the value conflict between using human brain organoids for autism research and that may be in contrast with an conflict with the values found within the neurodiversity movement. And so you can see the ethical discussion that could happen there without this need for going into, well, kind of brain organoid thing and grounding the ethics within this question of, well, brain organoid personhood or something along those lines. So that's kind of another area where I think we ought to sort of focus our attention a bit more there. So, yeah. Hope that answers your question. Yeah, totally. Maybe I missed it because there was a lot to that. An issue that I wonder whether it is being researched or whether you think it should be researched is about the controllability or getting out of control like the sort of arguments you see a lot in AI research or virus research but you can work on these things but at some point you cannot foresee the consequences. It gets a lie of its own. I don't know whether this is your possible given that you're in a better condition and so on but can something escape the life of the laboratories somehow, I mean, or via a virus, you know, like I guess these living materials they can get certain diseases too that are new and then accidentally get out of the lab or maybe in sort of more satisfaction that they would become bigger and then they can transport themselves somehow. I mean, these kinds of considerations are in any way taken into account. You see it a little bit but it's not really a major concern. The areas where it is of the most concern are really with, first and foremost, the embryoids. So I mentioned that experiment from Australia where they had accidentally created a blastoid, a blastocyst like entity from induced plant stem cells. They had no intention of making that complex of an entity. It's just what the stem cells wanted to do. And they were concerned that it was going to further develop within the embryogenesis phases, right? They were concerned that, ooh, well, if it's at a blastocyst stage maybe it's going to develop into a gastrolyte. You can get to the stage of gastrulation. And in embryogenesis, we typically don't allow embryos, full-fledged embryos to develop beyond the stage of gastrulation or the development of the primitive streak or 14 days after conception, whichever comes first. So that is probably where you see most of that kind of concern pop up. Some of it is also true for brain organoids. If somehow a brain organoid were to, say, further develop in a way, it's not necessarily a big concern there, primarily because of what I mentioned before with the plumbing and scaffolding problem, right? So it's not the biggest concern there. But I think you see some associations with something like, say, Frankenstein, for instance, when we're talking about something like assembloids where you're fusing, say, two different kinds of brain organoids together or you're fusing, say, a brain organoid with a spinal cord organoid and a muscle organoid, that is a bit sort of Frankenstonian where people sort of get concerned. You see this with sort of these on a chip systems where you'll take an organoid, put it within a kind of plastic case that allows for microfluidics to run through the way of trying to get around that plumbing and scaffolding problem. And then you connect that this plastic case with, say, like a brain organoid in it and run tubes through it. And then you connect that tubing to another case with, like, say, a cardiac organoid. Then you connect it to another case with, like, a liver organoid. And then you start to create these kind of body-on-a-chip systems. That's where people start to say, like, starting to, like, kind of take a life of its own, maybe. But that's not really induced from the organoid itself. It's from the researcher perspective. So it's more, like, again, a little bit more like Frankenstonian kind of concern rather than, like, oh, well, these things can take on a life of their own. When it comes to, like, something like, say, virology and trying to develop, say, viruses, like, normal safety concerns will apply when it comes to virus research there. Same thing with, like, bacterial research if you're doing something like that. So that's kind of the way where all that sort of is. Yeah. Come. I had a question about the design of your research and more frequently having defined reasons and material inclusion criteria work. Because a lot of them strike me more like topics or something like that than me as reasons. Yeah. So I was just wondering how did you decide what should be in this and why did you call it reasons? Right. So this is based off of a review methodology by Sofair and Sketch. And they called us a systematic review of reasons. In their particular review, it's also kind of, reasons is slightly a bit of a misnomer. And furthermore, given that I was building this review off of their work, they also don't give any definition for what a reason is. Right. So a reason for a reason included maybe concepts of things like concerns. So it's not necessarily just like a structure or a piece that you might find in a formal argument. So it's not necessarily just building blocks of arguments which some folks might think of as what reasons are. They are these building blocks within a grander argument of scheme. I really just kind of went down into this and looked for anything that might be used as a way of thinking about an ethic. So it might be an ethical consideration and ethical concern that might be part of this. And basically trying to piecemeal these slightly smaller different concepts apart from each other and then sort of regroup them together within topics. Right. So it is true that like these reasons, as I cluster them together, they become more and more topic related. But as you get further and further down, they become a bit more normative. Sometimes though the other is that I don't make any distinction between say normative reasons and descriptive reasons. Right. So that's another thing here too is why you might see some top or some reasons in here that seem to be more like topics is that they are more descriptive reasons and descriptive rationale than they are say parts of normative arguments arguing one way or another. Because a lot of the ethics literature in ethics of organoids is really descriptive or even talking about this could be a position or that can be a position. So that's kind of what I'm sort of going off of here for that. And again for the inclusion criteria, it really was kind of just sort of basic simple inclusion criteria where the articles had to be peer reviewed. I mean for the reasons. Oh just for the reasons. Okay. Yeah for the reasons that's really kind of it. But I also made distinctions in terms of say what might be background information. So there were some stuff like say within an introduction that is background information and scientific information. Sometimes though the scientific information is relevant to the reason and so sometimes it blends together. But anything that was purely scientific I put as sort of background and it's not really relevant. Other things like call to actions I had coded for but basically again did not code as reasons. They are calls to action. And further kinds of ethical questions that are raised. Again questions not necessarily reasons in of themselves. So there's a few different kinds of reasons that are in there. And given the fact that most of the ethics literature is descriptive literature and not necessarily normative. It kind of gets weird in terms of blurring together because you normally treat those two things separately and distinct. But if I had just done descriptive ethics or normative ethics literature and normative reasons or versus descriptive reasons I would have very, very much fewer dynamics or themes that you would see here. So yeah. I hope that answers your question. Yeah. Yeah. Yeah. So my question perhaps needs a little bit away from the ethics side of it. I apologize for that. No actually like some of this too is like some beneficial questions are in here too. Yeah. No I mean I'm specifically interested in this representational relations between organizing the body that you mentioned at one point and their potential for being alternatives to animal models. Because it seems to me, so I don't know much about the issue, but it seems to me that this representational relation is somewhat different from the model target relation. In that if I take pro in organoids I need to have a donor so that in a sense what this organoid then is, so it is a representation of that very particular individual. And so generalizations based of these organoids seems to be more like a transformation than being a representation for a target system. So I wonder whether the claim that this could make animal models obsolete is somehow exaggerated or I don't really see the... So is the concern that we need more donors in order to make this model an accurate representative model? Yeah that would be the question. Yeah so I'll say that I'll say that a lot of source material for growing an organoid comes from bio banks themselves and bio banks have a variety of donors including both living and dead. So bio banks try to gather as much biomedical material as possible as much material as possible so that they can send the material to researchers and researchers will grow organoids from that material for basic research purposes. And again, if you want to think about organoid research you can think about it in a way of like say this context of basic research where you might want to study some developmental model for instance or you want to do just some basic biology research. Maybe you can and that is a slightly different than say if you're using organoids in terms of precision medicine and personalized medicine as an example there. So yeah and actually like some of this concern of like well the material in terms of precision medicine and personalized medicine where's the material coming from? It's coming just from one person and that's kind of a validation concern when it comes to that research and if we're going to actually sort of apply this research to care especially for that one person who gave us the original source material. So what you're saying is exactly true in terms of like say precision medicine like is this really a valid model for this? And don't we still need to do like some like say animal models and use animal models like to help validate this sort of thing? That's why like what you're saying exactly is exactly the argument that a lot of people make that organoids are great models but they're imperfect for a variety of different reasons. Not just that you know there's a lot of these organoids are coming from maybe a few different biobanks and while they have a variety of donors you know that's still a small sample pool and maybe organoids can be used as a stage of pre-clinical trial that comes before an animal model and then you go to the clinical phase and if we're talking about translational purposes. So this is why the argument when we're talking about like the arguments of like say reduce, refine, replace for animal models a lot of people will say well organoids are great for reducing animal models and refining animal models or demanding for the reduction demanding for the refinement but they won't ever replace animal models because animal models will always have some benefits that organoid models won't because organoid models if you want to study the immune system you can't do that with an organoid right? It's not a full fleshed out system you need a full system like an animal to study something like the immune system right? So that's why folks will say well we still require animal models for some things like that but others will say well no we're on the verge of being able to do things like say these body on a chip systems right? And we can do these immune studies very effectively and they have much more representative and translatability it's an ongoing scientific debate basically so what you're pinpointing is stuff that's kind of an ongoing debate at this very moment and unfortunately I don't really have an answer for you in terms of which way is correct I would like to continue this question but on the ethical side so at least organids are of the same species than us so which is one of the problems with animal models so it seems to be very tempting for the researcher to try to improve organoids to overcome their imperfection to have better models but to overcome the imperfections to make them more like real organ or to have body on a chip so to have a system which is what would you say about the ethical problem because you seems to claim that they are okay because they are not like us but the more we transform them like us to overcome animal models the more problematic it is you know I don't worry about consciousness of a bunch of cells of a petri dish but a complete physiology is trickier than we mean I'm asking you so basically what I've been doing here is mostly just trying to give an accurate description of what the current ethical literature is my own personal take on all of this when it comes to something like what you're talking about there one way I like to try and think about it is if we're thinking about this from a kind of organoid centered approach where we're beginning to think about our ethics from the organoid itself I like to sort of begin thinking about what is the level of complexity here right is it a simple entity where it's just like a couple of different kinds of tissue or is it something more like say an assembly where we have a frontal brain cortex and a hindbrain cortex and they're fused together and you see axonal migrations that are happening and there's much more intricate structures that are happening there's more features and functions and much more organized structure that's happening within that entity I think that level of complexity if we're focusing on the organoid itself requires us to have more ethical reflections about what this entity is and of course questions if it's something like a brain organoid questions about maybe developing some kind of morally minimal consciousness and what to do if that were to happen given this level of complexity and the same thing I would argue is also true for the embryoid models where the further you go into the stages of embryogenesis the more complex the entity you're making and the more kinds of ethical reflections that you would have to do now if we're thinking not necessarily from an organoid centered approach and we're looking at it in terms of their translation and we're looking at more either patient oriented approach or a society oriented approach I think that we have to again take in relevant contexts here what sort of lens are we looking at this through if we're looking at this say for like the example of I take like the brain organoid example of using brain organoids for personalized medicine research for autism I would argue that the research there lies in complete contrast and conflict with the values that are found within something like say the neurodiversity movement because the neurodiversity movement says autism isn't a disease a deficit or disorder it's not something that needs to really be fixed right by the way just for your information in this university the university hospital I can declare to you that autism is not considered as a disease for a university a center of autism our university does not consider autism any big body on the spectrum as having a disease that's the official position of this university that's good unfortunately when you look at organoid science on something like that what you see is you see a very medical model of disability that is integrated within the organoids right so when I think about the application side of things I want to I really want to focus more on things like the value of the of the design of the technology the value of the research aims themselves and the values that are found within the target population and trying to integrate the target populations values within the science of organoids itself so that's kind of my take on it and my take on a lot of organoid ethics is very much a kind of contextualist approach because as you can see here there's a variety of different contexts of organoids in terms of their research and also just a variety of different kinds of organoids and it necessitates focusing on the relevant context of the matter and even sort of demanding ethicists to take a kind of pluralist approach it's not appropriate to use say an animal ethics framework when we're talking about chimeras and transplanting grain organized into animal models it's not appropriate to use an animal an animal model framework there, ethical framework there and apply it to transplanting a brain organoid into a human being so you would require fundamentally different moral frameworks because those are fundamentally different contexts so that's kind of my take on it basically it's funny I want to do the same question but in a third sense we did the like sciencey sense we did the ethicsy sense I want to do the kind of sociological sense I want to make you really kind of speculator really just kind of hear your experience because I thought it was really interesting to see the logo of a research animal protection organization on your slide so my question this is kind of vague but I think it's really interesting and what's the discourse around that being like is there a chance to really interact with some of these folks what has that been like because again speaking of we're at the very end there speaking of worries about type cycles it's something that I've been concerned about in this space is you get too promising organoid results and people are going to start logging to close down the the research veterinary arm of the biology department and so I wonder what that's been like because I put it this way you're the first person I've had the chance to talk to who I think is really works on the ground perhaps with some of those folks so I'm really interested just to hear your kind of socio-cultural thoughts yeah you've worked with one of the protection that's cool yeah well I mean basically I mean for my project the only kind of socio the sociological quote-unquote research that I'm doing is asking researchers and clinicians who work with organoids what are their perspectives on all these different ethical issues so I don't have any kind of empirical evidence to kind of give you about this sort of stuff but from my experience working with Pustia Verag I was I stayed with them in The Hague for a few months on succumbent and doing research with them basically talking to them about what exactly it is they do how they function, how they've changed over time Pustia Verag is kind of an interesting organization in that they used to be a kind of like what you were describing a very radical animal rights and animal protection group but they would go free animals from lab cages and all that sort of stuff so they were very radical in when they first started but now they've since I would say like for the last 20 25 years or so they've changed their approach to be more policy and research oriented and they've also changed their approach in terms of providing funds to research that is hopeful or perspective in eliminating animal testing so they've changed their approach over time very drastically from their history and so right now they put on every year a kind of innovative contest where researchers will provide innovative new kinds of experiments or technologies that can be used as a replacement for animal models or another sort of example of reducing animal models or refining animal models in certain ways so that's kind of been the experience I've had with them and sort of talking with them about their history and those folks are very nice folks and they try and help with developing policy in the Netherlands to surrounding animal research so they've I don't want to necessarily sort of soften their stance so to speak because they still believe in the total replacement of animal models as a goal to which I also sort of like deeply sympathize as well with that aim but now they are trying to do it in a sort of less violent and radical way and more of a way of showing people genuinely speaking and scientifically speaking there is a genuine alternative to this as well as trying to help develop some moral arguments and positions to help further advance that along they help with like looking at innovative transition studies and some sociological work like what are the barriers that actually help prevent researchers from shifting to animal free alternatives right so that's kind of the stuff that I sort of focused on there my research or some of the stuff I was learning there was looking at things like behavioral science and innovative transition studies and things like that cool so the problem is not that epistemic values can impact on impact on research because we know it can be it can be the case but what we point to is that it can fuel the hype and actually we have a lot of hype currently on this individual models and all this is impacted as well by this looking forward alternatives and we try to reach out to others and so it's a very important move in December that the FDA modernization act actually in the past and then it's the first time in almost a century since FDA does exist that animal models are not required anymore for drug testing because for the medication and the impact on the better one is because we have all these individual alternatives it's mostly organizations and organizations across the picture organizations as well and when it goes into regulation why we still know that these models are very eco-active so we have a lot to do to confirm to validate before we can use this model even for pre-clinical use and so as a move for FDA it starts to get rid of animal experimentation right away but it opens a huge door and this door has been opened maybe because of this kind of push because it's political it has to pass by human and so on and so that's where we have issues of time yeah I mean it's also interesting with all this sort of stuff generally speaking because there is this in studying this there's been this kind of nagging question of is there really such a thing as organoid ethics or do organoids really just situate themselves in other ethical domains and I'm kind of of the opinion that it's a bit more of the latter but in a way I kind of look at almost as sort of like the ethics of multi-tools because multi-tools can be used in a variety of different contexts and you can think of multi-tools as being used in carpentry or being used in fishing or being used in whatever in all these different contexts but if you're focusing just on the multi-tool itself then you can kind of see the ethical domains in a slightly different angle and see how much more interconnected they all really are in a way so I think if we're thinking about organoid ethics in a way we're sort of thinking about the interrelation between all of these different ethical domains and the focal point of it all are these organoids because I kind of say at least with this PhD that I have studied pretty much anything in everything and I've also learned about all these different fields and the only things I've yet to have to dive into in some way shape or form has been astrophysics and quantum mechanics and I actually said that to somebody at a conference a little while ago and they said wait you know that they've grown brain organoids on the International Space Station right like what? yeah they sent organoids into space like what for? they're studying the effects of microgravity on the brain I'm like no now I have to figure out what microgravity is I have to go into astrophysics for this no and now I'm waiting for someone to hook up a computer like a brain organoid and do quantum computing with it I'm waiting for all that to happen yeah this stuff has become so much more complex than what I thought it would be going into it yeah it's much more complex than it seems on the surface just a little ball of tissue so strange one question would be since you did this review some of you have failed are there anything new that's in the literature recently since you did this scoping review like two years ago? yeah this systematic review happened while I was published back in 2022 but the collection happened in 2020 yeah it happened in 2020 so in the last couple of years there have been some advancements mostly some advancements have really occurred in relation to thinking about similarly related entities so I think for instance there's some stuff about out there a little bit about what I call organoids which are things like the on a chip systems I mentioned and also things like something called dish brain where researchers integrated neural tissue and like basically a neural organoid onto an electrode red which was able to translate the electro signals from that neural tissue and also give it some kind of sensory input and using artificial intelligence it taught the neural tissue how to play palm and so you'll see you'll see so you'll see on the video in the supplemental video of this experiment the paddle moving up and down and that paddle is controlled by that neural tissue and it's looking for where the palm will go and it's moving it accordingly and the palm will bounce off the paddle and based on the movement with artificial intelligence the input to that neural tissue and that neural tissue was giving that behavioral output of the paddle so dish brain is in a way that scientific advancement that isn't that's sort of I think now demanding ethicists like kind of putting the cards on the table for the ethicists saying oh hey you all were concerned about like creating about brain organoids having sensory inputs and behavioral outputs well now here's an instance of that and so I think we're going to see and it's actually some future research of mine I'm hoping will be on things like that like what is really what are these sorts of things now that you can do things like give some neural tissue like sensory inputs and they can have behavioral outputs so there's some philosophical questions there a lot of the stuff now a lot of the advancements and more discussions that have come out again it's been really centered around brain organoids mostly and some stuff has also come out looking at different kinds of perspectives about organoids so there have been some studies with patients of say who have cystic fibrosis and asking what do they think about using organoids for their treatments and those patients with CF seem to be okay with it so there's some evidence there that patients seem to be okay about this sort of thing even though they don't have a lot of working knowledge about what organoids are they're kind of fine with it as long as they trust that the doctor and the researchers are going to use their tissue and their DNA and their data responsibly so that is also kind of advancement I think who we're seeing more of is trying to understand other people's perspectives about this sort of thing you did that on so my question sorry for my question is I ask you for because you have this structure of things of topics or reasons are there any new topics that you think and then you also was it's kind of characteristic of this you have this new technology and we have this new technology that pushes boundaries further but in terms of topics or something is that something that from your list and that when you look at it after you I'll say oh we have not seen this topic or just everything fits in well I'll say in terms of themes pretty much all the literature that's come out now fits within the themes some in some form or another and the same is kind of true I think with most other yeah with all like the literature in terms of say the most of the topics there's some topics I think that have popped up and some of it has been like more discussions about say like Frankenstein like the association of Frankenstein is also something that's kind of that has sort of escaped this literature also the use of something called the six principles of animal ethics that goes to the use of the classic three R's framework of reduced refinement place a new animal ethics framework by David de Grazia and Tom Beecham came out in 2019 and 2020 they named it the six principles which divides these six principles into sort of two core values and they're trying to sort of fill it upon the three R's and fill in the gaps of the three R's that and so on and so forth so and that has been applied to say something like brain organ arts for instance so something like the use of a new framework has popped up the same thing with something like say the use of responsible research and innovation frameworks that was also something new responsible research and innovation frameworks are also something that's new within the urban or ethnic space that wasn't really captured here there's some other perhaps do you have to use somewhere do you have to use do you have to use no no but there are perhaps I think I imagine there are other topics that have popped up nowadays more of it has been about expanding upon more of the new stuff that has come out is more about expanding and deepening further discussions about these different kinds of topics because as I mentioned before a lot of these different topics are very much underdeveloped and require a lot more in depth discussion so most of the new stuff isn't really about trying to give something completely new here most of the new stuff is really more about alright we have all these different questions now we should really go more in depth about all of them there was something I didn't really understand in the discussion you said something about descriptive ethics saying that most of this is descriptive ethics do you mean that what you are doing is descriptive ethics or these papers you refer to are descriptive ethics and in which sense if that matters the case are they descriptive what makes them descriptive rather than normative? so a lot of what I'm doing is really kind of a bit more descriptive ethics and I see although some of what I do is also normal because in my work I've advocated for something I call the moral principle of complexity the more complex the entity is the more researchers ought to undergo certain processes like reflection anticipation and deliberation a lot of this is also like say descriptive work and so far as ethicists will sort of describe various problems and come to certain conclusions but they might give some recommendations at the end about we see a kind of problem arising here but then like they'll give some recommendations at the end of the paper about well we recommend that ethicists think about this in this way and we recommend they think about it in this other way and we recommend you know considering this aspect so a lot of the papers in a way are mostly a lot of them are like the paper will be mostly descriptive and then at the end there's a little normative piece of it how is describing a problem descriptive? well it's as a problem that's a normative blame does it take after all yeah it's it's describing it is describing the problem but it's not providing any kind of say like advocating for a particular kind of solution so it's kind of like like say I'll give like the within the commercialization or consent theme with Boers and Brethrenorns or the two ethicists who are primarily in the space what they do is they will say things like there have been certain arguments about these kind of strange fitting entities that others have argued to say that these entities require objective status or they require subjective status or they require a kind of hybrid status so they'll go through like some of the arguments that they will respond to that they're going to be responding to so that first bit where they're describing the position of something that they might be responding to is descriptive and then their arguments sort of for budding against it would be is what I'm sort of normative position where they're sort of saying okay so now that we've described this position within Orman with Ethics we're going to say why this is wrong and they also will sort of say they'll build a lot of their argumentation on like say like arguing why consent for governance is the best structure for Orman with Biopentki right but they'll also say here is sort of what's happening in some of the consent spaces within Biovex previously and they'll say like these are valid concerns but here's why our and these concerns also apply to Orgenways and Orgenway Biovex but here's why our position is best right so that's kind of the distinction I'm sort of making here where if someone is sort of advocating for a particular position or advocating maybe against a particular position outright I will label that as a kind of normative position and give it a kind of attitude coding whereas if they're not outrightly expressing advocacy for a position or opposition to a position I will sort of on the safe side label that as descriptive because I don't want to put words in the ethicist's mouth and saying like you are advocating for this position where I'm saying no but when they might say no no no I'm just describing the problem itself right so that's kind of that distinction that I would draw there and a lot of this is describing these different positions that are possible so there's a lot of ethicists will say this is a possible position that people could take and this is a possible position that people could take but they're not outright advocating for one or the other so if like I'll give an example of a mind where I'm talking about the value conflict between brain organ research for autism and neurodiversity and I'll describe in a way what the values are within the within the organ research and then I'll also describe the positions of the neurodiversity perspective but I will not outright claim that I am arguing in favor of the neurodivergent and neurodiverse perspective all I'm saying is that there's this perspective and here are the obvious values that you see in the research they do not converge they are conflicting with each other that is a problem and then I'll give some normative conclusions at the end and say here's a this is the problem but here's some quick possible areas where we can think about and further explore in terms of normativity where like say bringing neurodiverse people into the science as co-creators rather than as subjects of study allowing physicians to be open and honest about the negative aspects of autism but have them do so in a respective way rethinking about the ideas of what disability is what it means to be a person, what illness is what disease is those would be my normative positions but I'm not really outright arguing in favor of that neurodiversity perspective or the medical model perspective so that's again kind of what I mean with this a lot of this is sort of descriptive and it doesn't mean that most of this is descriptive I would argue is like 60% maybe is descriptive and 40% is more more if that makes sense I was more thinking like more sociological view on ethics or something like that descriptive ethics is usually something like that study people's views without any suggestions or even evaluation of these views but that's not what you're thinking of no okay we have 4 questions so we'll answer them