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Welcome to this episode of the ELSI Dialogues. My name is Melanie Goisauf and I am senior scientist and a member of the ELSI Services and Research Team. I will be moderating this discussion which will be recorded and made available online. Today we have a panel of multidisciplinary experts who will be telling us something about the ethical, regulatory and scientific aspects of organoid technology.

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But first, I want to say a few words about BBMRI-ERIC, which is the European research infrastructure for biobanking, with the primary mission of promoting biomedical research benefiting European citizens. It achieves this by providing access to sample and data collections across Europe and to fulfil its objectives BBMRI-ERIC relies on a network of national nodes with member countries and an interdisciplinary team of experts from various fields, all sharing the common goal of advancing health care and disease prevention through facilitated access.

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Established in 2013 BBMRI-ERIC is now a distributed research infrastructure and it is one of the largest health research infrastructures in Europe. The ELSI services and research department of BBMRI-ERIC provide support on ethical, legal and societal issues through a federated model, collaborating with experts from academia and practice across our national nodes and with project partners.

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And this support is built on three key pillars, which is research service and training. And these pillars work in synergy to ensure that our community receives state of the art support. Today's webinar is a collaborative effort between BBMRI-ERICS's ELSI team and the Stakeholder Forum Patient Pillar of BBMRI-ERIC. The Stakeholder Forum is the main interface for European patients, organisations, civil society, industry and academia to interact with the biobanking universe.

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It is an integral part of BBMRI-ERIC's governance and was put in place at the very inception of BBMRI-ERIC in 2009. Through the Stakeholder Forum, we are building a sustainable, egalitarian relationship between the Biobanking community and its stakeholders. The objective is to increase each other's awareness of needs and expectations on key issues related to biobanking, such as data protection, informed consent in health research, health research priorities and other ethical, legal and societal issues.

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And please visit the BBMRI-ERIC's website for more information.

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Now, let's begin with our with today's topic, which is organoids and their scientific, ethical and regulatory aspects. organoids are advanced three dimensional cell culture systems designed to replicate essential characteristics of real organs, making them invaluable for clinical research where they serve as ethical alternatives to animal models. However, this technology presents a spectrum of ethical, legal and social issues. These encompass questions about the moral status of the type of organoids models, cell sources, informed consent, issues of ownership and the development of regulatory frameworks.

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Furthermore, the creation of human animal chimeras through organoid research raises complex ethical questions. Biobanks which are an integral part of organoids research, are additionally faced with these challenges along with issues related to donor participation in Biobank governance. Adding to the complexity of this evolving field to address these issues, an open and inclusive dialogue among researchers, institutions, policymakers and society is essential for establishing responsible and ethical guidelines and regulations for the advancement of organoid research.

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And I'm delighted to host this webinar as a contribution to this ongoing discourse. Our panel comprises experts from various fields who will guide our webinar with insightful discussions about the ethical, regulatory and scientific dimensions of organoid technologies. And we welcome today Dr. Maria Berdasco Menendez who is a molecular biologist with over 20 years of experience in the field of clinical epigenetics.

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Previously, she was the principal researcher at the Spanish National Cancer Research Centre in Madrid and of the Research Institute in Barcelona. She is currently the head of Epigenetic Therapies Research Group at Josep Carreras Leukaemia Research Institute. Dr. Zisis Kozlakidis is a virologist with a Ph.D. in microbiology from the Imperial College London. Until recently, he served as the president of ISPR, the International Society for Biological, Biological and Environmental Repositories.

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He is currently the head of Laboratory Services and biobanking at the International Agency for Cancer Research on Cancer. Dr. Signe Mežinska is a bioethicist and sociologist by training. She is affiliated at the University of Latvia Faculty of Medicine as an associate professor and holds a PhD in sociology and a masters in bioethics. She has been teaching medical ethics, bioethics and research ethics for more than 20 years.

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She serves as a member of the UNESCO International Bioethics Committee, as well as an ethics expert for the WHO, BBMRI-ERIC, the European Commission, and several national bodies in Latvia. Dr. Mike Lensink was trained in philosophy and technology ethics, specialising in the ethical aspects of biomedical innovations. He has worked as an academic researcher at the Medical Humanities Department at the University Medical Centre in Utrecht in the Netherlands, where he studied the ethical aspects of organoid research.

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He currently works as an adviser to governmental organisations to facilitate the ethically responsible use of technology, Big Data and AI. Welcome to the webinar everyone, and thank you for giving your time and expertise on this important topic for our audience today. Please use the chat box to write your questions and I will read them later on your behalf.

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Well, first of all, I want to hand over now to Maria to give us an introduction to the scientific perspective. So to the question, what are organoids?

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Okay.

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Okay. Good afternoon. I'm sorry. Can you hear me? Okay? Good afternoon. I'm glad to be part of this of this webinar. Well, before starting the discussion, we need to know very basic concepts. We need to define what is an organoid, what especially why we are using them. If you want to understand human development, how a human develops, and also human diseases, you need to have one

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of these things. You need to have human samples. You need to have human laws. But primary samples such as pieces of tissues or blood, they are very limiting quantity, and especially they did not reproduce what happen in a whole body. So we need to develop more this the organoids or the mini organs, and especially the advanced type of cell culture that follows these through the structure.

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It is also important to notice it is a mixed population of cells. For example, if you are trying to produce how many kidney you need to put renal cells they are but also vascular system. The immune system is a [...] and so on. So trying to create something as possible, as a as as closer as possible to what happens in the natural situation.

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So next slide please. Organoids are not the unique alternative that we have in the lab. We have been using models for a long time in your experiments, but organoids have a very good properties for research. For instance, if you compare with the [...] models trying to develop the then in the lab is cheaper. You can also manipulate genetically and in a mouse is more difficult.

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And especially they are humans, they are [...] properties that nowadays made organoids as the best tool for biomedical research. One of the best. At least Next slide. How can we generate organoids? Organoids organoids are created for a specific population of stem cells, but we have too many different stem cells in our body. The best are these ones pluripotency cells. These are may are found in very early stages of development these days, five or six after embryo development.

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We have a small population of cells that we can culture in vitro and this is the embryonic stem cells. So they are several embryonic cell lines that can be used for generating the organoids. These are pluripotency, that means pluripotent. That means that they can generate all of all of that [...] of our body. But we have more cells.

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We have also this other population of the stem cells, they have a limited potency. Such as cells, progenitor cells from the blood or from the bone marrow. So our best candidates are these pluripotent stem cells, embryonic stem cells. But there is a big ethical question. You are destroying an embryo. So next slide. So in 2007, it was established the first human induced pluripotent stem cell.

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This was possible due to the work of these Japanese men, Yamanaka and team, that they were able to induce pluripotent stem cells from somatic [...] This is something artificial maybe in the lab, but are then you have the same result, you have pluripotent stem cells, you have the full potential to differentiate in many diseases, but you are not destroying.

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an embryo, a human. So next slide, please. We have we have more cellular sources for organoids. So as I mentioned, the embryos, but also the stem cells. But one of the one of the tissues that are that are used to to be useful in the organoid generation uses cancer stem cells because cancer stem cells that are specific says that that inside the tumours and they also have this high proliferation rate.

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So using this different resources, next slide, we have created several organoids Yes. Here you have just a representation of some of the organoids that we already are able to produce in a lab. We have a brain organoids lung organoids organoids from the blood mammary, liver, kidney and so on. We have here also they all [...]

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at stem cells [...] etc. So this is the catalogue that we already have in the, in the, in the lab. So next slide please. If you are wondering how yes if you are wondering how an organoid looks this is a brain organoid on a plate. Okay. And of course something is missing here because the brains are not working alone.

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They are not working in an independent manner. You need to put this into our body. You need to communicate this brain with the rest of the of the of the of the organs. So one way of doing this is, as we mentioned before or Melanie mentioned before, through the use of chimeras to try to put these organoids into animal models, for instance.

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But a second way of doing this, next slide, is trying to use these devices, this organoid chip are the next generation type of organoids in this way you can put several organoids and communicating. How do you say, these vessels, that's adding to the communicating the the the organoids. So these canals can carry nutrients, drugs, cellular signal signals.

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etc. so it's a way of doing more heterogenous and more reproducible to what happens in a body. We still have some methodological limitations but this is the way this is how organoids are going to be developed. So next slide. So regarding the applications, the present is mainly here. The present is mainly for basic research, but the future, the future application, an approach of course to therapy because they can be used for by artificial organs, for instance, and also for therapy as models of diseases, because it is so easy to to check how the drugs can work on these diseases.

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For instance, of course, generating these models is not something you see in the lab. It's not so simple as we can just summarise in a few slides. So what it is interesting from the scientific point of view is to make these models available for researchers, for scientific community. So biobanking of organoids aim to create this catalogue for research is really a very, very useful tool for for science.

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So this is what it is in a very fast way. So I think that now we have the main concepts to, to start a discussion on the ethical and legal issues.

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Thank you very much, Maria. And I want to ask now Zisis to give us an overview about the regulatory issues or organoids research. Yes,

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and thank you very much for the invitation.

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So if we look at the organoid field basically as a scientific field, we can say the development there's been a very rapid one and in particular in the last few years as new technologies are becoming available. That development is accelerating. What we can see if you, for example, take the 3000 papers that have been published on the subject and you try to map them out

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You can see that a few countries have emerged as frontrunners. Well, this is not particularly surprising because they represent from [...] a lot of scientific pursuits But what we can say is that it's a it's really a child of technological development because it correlates very, very highly with a very advanced technological geography. Next one.

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So if we take the last ten years and we focus on the published manuscripts, we can see there is an increasing shift in absolutely coming to the same words that Maria has used. We are going from a very technical publication, a very basic science pursuit of how do I do this to more translational publications, what do I do with this?

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So it's a slightly different question that we're trying to answer. Increasingly, the technical limitations are still there, so we don't necessarily we have all the component parts to bridge the gap from the basic science to the translation. But the direction of travel is very definitive, at least if you look at the publications as part of any systematic review.

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So from a regulatory perspective, it is at this point where the technological process becomes highly relevant because it shows the field is maturing and it's starting to have potential application into everyday life. Next one please. So what are the regulatory approaches that we've seen anyway? We haven't seen a common approach. It's a very fragmented regulatory approach in most countries.

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It's has been created ad hoc in response to something that has already happened, some technological development and different models have emerged. So we have models that are very prohibitive for for research and for example, Italy, and it's not prohibitive forever, but it's prohibitive for now. In the Netherlands, research can be conducted, for example, in vitro created embryos, but it follows a strict licensing process.

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And in other countries such as Portugal, Greece, but many others as well, these are just examples. The research is allowed in surplus embryos up until the fourteenth day of invitro development. This just how the law has been for some time and remains to this day. So the side effect of these is regulatory uncertainty because parts of the regular framework concerning the rights and duties of persons are now starting to merge with elements of regulations that deal with the stewardship of objects or things.

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So we start coming into this [...] and this forms a little bit of an uncertainty from a regulatory perspective, and that's why we see different interpretations in different parts of the world. Next one please. The other aspects from a regulatory perspective is the lack of specificity. Generally, when we talk about the regulatory frameworks, the more specific the cell types, the less likely it is that the regulation will be very specifically addressing.

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When we talk about regulation, we tend to try to group things together into big blocks to make life easier for the case to take place. So we observe two separate areas of coexistence on the global stage. We have some European countries that researchers are complaining over regulation. That means that the regulators, the regulatory framework is too specific for that particular line of work.

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And we have other countries to to graphical areas that are very defined regulatory gaps, for example, in Southeast Asia, where regulation for work on on different cells and cells by-products is not necessarily well defined. So continuing this discussion such as today is absolutely critical. At some point, the hope that we will get to some regulatory harmonisation or at least be on equal footing in terms of understanding, even with regulations differently what they mean and what the potential is so that we can avoid this fragmentation which at the end will probably be counterproductive for research as a whole.

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And. Okay, thank you very much. And I now want to hand over to Signe to address the ethical issues. Thank you. And thank you very much. And I will take my research Ethics Committee hat, I think in this case and I will try to look at the informed consent part and at the protection of donors rights. And here we come to several challenges.

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If we think about organoid research. First, there is this question how broad or narrow should the consent be for organoid research? Because as we saw from the introduction, the organoid research is quite a different type of research from from so-called classical biobank research. And the question is what information should be given to the donor and it's also quite clear that it's hard to predict all potential uses in organoid research.

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So if we think about traditional specific informed consent for one research study, it doesn't work well here because we cannot give the all necessary information and the potentially we should ask for recontact. Then we might think about broad or general or open consent forms. But in that case we have questions and challenges about about informing donors appropriately and about trust of of public and trust of donors in biobanks and the research ethics committees approving this type of research.

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So as far by by today into discussions about consent, informed consent to organoid research, it seems that the most acceptable answer is dynamic consent. Are lobbying to to be in contact with donor or at least giving this option to donor to follow in electronic system what is going on with his or her her cells and and how they are used in different projects.

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So dynamic consent might be one quite acceptable answer. Another potential answer, which has been mentioned in discussions is the governance model, which means that the governance of organoid research might be given to some kind of public body or, I don't know, like representatives of of patient organisations or some specific body which would oversee the use of organoids. And that's how the rights of donors might be protected.

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So you see that the question about the the most most appropriate type of of consent is still open and as well as the types of information which should be given to the organoid, to the donors, It's also open how to how to collect donor preferences, how to know donors’ preferences, what kind of document to use to to ask about donors’ preferences.

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And there are several projects running right now in Europe which are developing suggestions how to do it. Then what is acceptable duration of the consent should it be unlimited or with certain limitations. A very, very important question is about right to withdraw consent, because when we think about withdrawing consent, then researchers, of course say that it's possible for sure until the moment when the cells enter processing.

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But when the scientific work starts and the and a lot of resources and efforts are are already spent for development of organoids or even more if the if organoids are already distributed to two users, it might be not possible to withdraw consent anymore and it should be explained in the informed consent form. And a very specific question is about minors as donors, because if we think about children, then we have additional questions about their assent and the reconsent in the future.

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Next slide, please, so we can look at at the rights of the donors also from the angle of privacy and there are many questions about decisional privacy, about informational privacy because of the distribution of of cells. In case of organoids, it's much broader than in cases when you have only one sample. So it's it's there are very specific questions about also bodily privacy in this case also intellectual privacy, especially intellectual privacy, is questioned in case of brain organoids.

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However, of course scientists are quite sceptical about the possibility that that brain organoids might develop consciousness. But but still, at least in philosophical discussions, this question is raised also. And next slide, please. So and and the last point from my my point of view is about the research ethics committees, because as in as with any new type of research, it raises also questions about competence of ethics committees.

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So therefore, there is a question, are ethics committees ready? And I mean, both sides are ethics committees ready to protect interests of donors, but also, are ethics committees ready to understand the needs of researchers? So there are several sides involved. What expertise is needed for research ethics committees? Are they ready to review this very specific type of research and what support is needed for research ethics committees?

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Do they need guidelines? Do they do they need better regulation? As mentioned by Zisis? Do they need any other type of of support? That's it. I think here I can hand over to the next speaker. Thank you very much for raising all these complex questions. And I want to hand over now to Mike to give us some insights into more ethics and also on the stakeholder perspective.

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Yeah, more ethics and yes, exactly that. I think when Signe said she was she was going to explain something about ethics and putting on the research ethics hat and I thought maybe I will then represent the social aspect of the of the ELSI abbreviation. And I I'm very glad to be talking to you today here because it's been two years since I wrote my since I wrote my PhD thesis.

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And I it's still a fascinating subject. So thanks, first of all, and I would like to add to all of the very important things that Signe already mentioned. And I thought maybe it's interesting also, and just for anyone wondering, I noticed that very much in my work as a researcher, people are asking me like, your ethics is that it's so vague and fluffy and how do you actually do that in a scientific way?

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I thought maybe to explain something about what I did. So you get a sort of idea for how that can be done. And so the image that you see is my dissertation. And it it has to be said that I did it from the medical humanist department in Utrecht, which has a really nice, I think, but also a typical approach to doing ethics, which involves a lot of going out into the social world and researching how people experience a certain technological innovation or a development like organoids.

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And they they call this ethics parallel research, which is also what I what I did. And so the idea is that you, while a technological development is is unfolding or is being innovated, you already start researching, you know, your ethical and social implications of what you're making so that you can actually add your findings into the innovation process.

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And that leads to hopefully a better, more ethical, more socially robust result. And what I did was I analysed, first of all, I needed to wrap my head around the technology. So I did a lot of desk research about all of the things that like technical aspects, but also the things that Signe mentioned. You know, how the how complex the debate is around consent and and privacy.

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But then also I interviewed lots and lots of people who had already provided their tissues to make organoids with, patients, but also professionals, clinicians, biobank managers, policymakers, all of them. I wanted to hear everything that was there, all the people's experiences with it, and then just the easy task of combining everything into a coherent view on how maybe responsibility to move forward.

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And that's what I did. If you want to read more about the method, there is an article there that you can consult. Next slide, please. And yeah, diving into the world of of people's experiences was such an eye opener to me. Is it's just to give you an idea of the diverse things that people say really blew me.

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It blew me away also because I had an expectation of what people would say, and sometimes that people just said something completely different, which made me think like, Oh, maybe there is a way that we scientists speak about things, but people have experienced it very differently. And so one example is one of the patients who had already signed up for the organoid program.

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This is a cystic fibrosis patient. For those interested said, as long as I live, I would like to receive yearly or two yearly reports about which studies have been done with my cells because I still feel partly connected to the cells that are there. And I just want to know what happens with them because I still feel sort of owner because it is my bodily material.

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It kind of blew me away. How people see these cells as part of their body still. And then if it is a body part, then what does that mean? And then the researcher said about working with these patient cells, with these living tissues, they say, yeah, we do research in the lab, but we also are sort of in a clinical care kind of space and we need to think about how what we do impacts patients, how do we manage the hope and expectations that they have about receiving treatments, but also what do you do when you find something that is relevant maybe to their health?

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Do you then go back? But the cells are anonymised? What is my duty here? What is my responsibilities? Next slide, please. So I actually interestingly found a few things. I mean, it's too short here to go over everything, but a few things that I thought were interesting. And what I saw with people talking about this, this whole field was that there was a really strong connection between people and their cells.

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And it seemed to me like the whole paradigm in which we speak about, you know, banking and donor and consent there is, I don't know, for me it didn't really fit well. It seemed to me more like data where people, you know, have a sort of idea of like, I want to know where my data goes, I want to be able to control it.

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It's part of me I have a right of say about it. So then I started I started moving from the whole idea of consent and and privacy as the main sort of Yeah, almost like moulds to to, to put the ethical debate in, but also to look broader than that and to maybe problematise also the fact and that is how is that is what is most focused on.

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So what do you do with with this question of what does it mean that your stem cells are there, your body part, you have the fundamental right to bodily integrity. Does that mean that you can no longer say what people use your living tissue for as soon as you give it away? And how should that control look? And consent is a way to to shape that form of control.

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But maybe there are other ways that are more appropriate. And also, what is the moral status of a brain organoid or, you know, at what point does it have to start to have certain rights? Like most like lots of cultures think about embryos as well. If it's before 14 days is fine and then after 14 days, suddenly we have all these moral rights that appear out of nowhere.

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And how does that for organoids and what does that mean and how does that relate also to the sensitive use cases that you can use organoids for? You can give your organoids up for research and donate them, but does that mean that you that you didn't have to accept, you know, certain use cases that you're not happy with from a personal principle perspective?

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Maybe. But also, how do you envision this is also what Signe said. How do you envision this communication between the users of the tissue and the providers of the tissue? How can you how can you make these preferences known? Right. Maybe through consent, but maybe something completely different needs to happen. And that's also why this I brought up the second point.

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Maybe we need to go beyond consent and think about just ways of cooperation that make more sense in this in this, in this as theme. Right. But because it maybe it's so it's such a personal thing that maybe we need to actually involve people in in a certain way in the governance or in how research is set up and how profits are divided as well.

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Because people like, for example, in cystic fibrosis, they give their material for research and then it turns out that they first of all, they don't get their treatment reimbursed but second of all, the pharmaceutical company is making loads and loads of money because of the tissue that they provided, you know, with the hope of getting some treatment and how to navigate this as well.

00:37:55:04 - 00:38:16:15

And a third thing maybe that I would like to give to you also as a maybe as a as a thing to spark your ethical sixth sense, maybe is I. At the end of my PhD I started to really think about the word donor and whether that is actually an appropriate way to describe people that provide their cells for research.

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Because if you think about the organ donor context, we created that word so that you can no longer say anything about that liver that you gave away or kidney that you gave away. Because otherwise you can’t say that you want it back, so you donate it. And so there's no reciprocity. But with organoids, it's a vastly different thing. I think we as providers of the tissue are, you know, we can expect something in return, you know, being informed, being treated with respect, being involved and which means that as soon as you call it, donate, people think that there should be nothing in return because that is what's in the word.

00:38:57:03 - 00:39:15:05

And I wonder if that is still the most appropriate word to use. So that is not to criticise anything that Sigma said, but more to add on top of what she already described is also really fundamentally important. And yeah that's it.

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Thank you very much. To add more complexity to an already a very complex question to our audience, feel free to ask your questions and put them in the Q&A box and we will then read it to the to the panel.