Ethics Seminars

Understanding the ethical, legal and social questions raised by research with human tissue

We hold ethics seminars which provide regular opportunities for HDBI researchers to consider the wider implications of their work

Our research involves human embryonic and fetal tissues that are voluntarily donated to research. These sensitive tissues, along with the potential future implications of HDBI research, raise important ethical, legal and social questions. Many of these topics are discussed in these ethics seminars.

click for a playlist of all our ethics seminars

Research with human embryos and fetal tissue: bioethical perspectives (May 2022)

Dr Insoo Hyun (Harvard Medical School) and Prof. Bobbie Farsides (Brighton and Sussex Medical School) discuss moral status and moral considerability of human embryos and fetuses, and how the complexity of these moral questions has led to a legacy of careful regulation of research with these sensitive human tissues in the UK.

  • The first thing I wanted to say is just to thank Pilar and Naomi for organizing this event. I think it's going to be the first of many and they've done a really great job so thank you both to both of you. So I think it's very exciting that in parallel with our developmental biology research in the HDBI we're going to also examine various bioethical aspects of using human embryos and fetal tissue. And as I say we hope that this will be the first in a series of seminars looking at various different issues and please do make suggestions. You know today or anytime really send an email to Pilar, or Naomi, or myself so that we can plan future events as well and and cover different areas. Now we do realize that some people may find these topics, that we're going to discuss, contentious and so because of this I really would ask everyone to help make the seminar an open and inclusive and safe environment where everyone will feel welcome and able to participate, you know verbally if they wish, or just to listen. We're going to have two speakers and so they will make their presentations to begin with, and we'll keep our questions and discussions until afterwards at the end, and we're going to finish promptly after an hour. I think the best thing is if people can post questions in the chat if they wish but please wait until the end of the presentations before you do that. Naomi and Pilar will then scan those and read some of those out we'll also keep an eye out for people who've got raised hands who wish to say something as well. Okay so we've got two great speakers today the first is Insoo Hyun and we're really grateful to him for joining us, it's the morning where he is not the afternoon. Insoo is has a a very long and distinguished career in research ethics. He's director of research ethics and also member of The Faculty of the center for bioethics at Harvard Medical School and he's also director at the center for life sciences and public learning at Boston Museum of Science. He's a Fulbright scholar, Hasting Center fellow, and he has longstanding interests in various ethical and policy issues particularly around stem cell research and around new biotechnologies. He's been very much involved with the international society for stem cell research and he helped draft its International guidelines. And he served as chair of the ethics and public policy Committee of that organization. He's also served on various National commissions for example the Institute for medicine and the National Academy of Sciences in the USA and last but not least Insoo is a member of the HDBI's scientific advisory board. So we're really grateful to him for taking the time to help us mould our future as an organization. So Insoo over to you if you'd like to share your screen we'll look forward to your presentation.

    Thank you for that introduction Andrew and thank you Pilar and Naomi for inviting me and for organizing this session today. All right so.

    So I am going to start us off by thinking about moral status and the complexities the moral status. Now I'm going to try to make this as user friendly as possible. I'll only use philosophy when I absolutely need to and I hope that my discussion with you this morning is going to help your thinking about moral status and the use of embryos and fetal tissue for research. So moral status is a very complex notion.

    I'm going to start off with the broadest simplest definition of it. Moral status is basically when an entity has interests that matter morally to some degree, for that entity's own sake not for someone else's sake. Such that the entity can be wronged. And I'm going to unpack a little bit of where I've highlighted in red those aspects of the definition.
    So what you first see is that actually moral status comes in degrees. We talk about animals as having moral status maybe based on their sentience. But maybe the life of a mouse is not equal to let's say the life of a dog, or the life of a chimpanzee, or the life of a human being. Already there we're talking about degrees of moral status where you can go all the way up to full moral status if you keep going along that chain. Now I'm gonna, on the next slide, summarize what I'm talking about here. But just to continue on why do we think moral status could come in degrees? Because they are maybe based on different grounds of moral status what's required? I already hinted at one of them one might be sentience.
    Now what's interesting about this next point is it just that the entity has a potential for having these grounds for moral status or or do they actually have to have these grounds for moral status? Whatever they may be, whatever constitutes the reasons for giving something moral status. And finally what about just being a member of a group that includes some members who are actually, they actually have, moral grounds. Right so people say things like: 'human beings have social moral status because they're capable of great art'. Well I'm not capable of great art! But maybe I'm a member of a group, that group is human beings, for which some people are capable of great art. So maybe just being a part of that group, even though I don't have those grounds, is enough. So that's just an example of that third category.

    So here's a summary. Right so moral status comes in degrees. All the way up the 'full moral status' that's the most you could possibly have, most people put human beings up there, persons. And then we have all the way at the bottom 'minimal moral status'. And this is why animal research committees demand the review of research with animals because even a mouse, or zebra fish, or amphibian, may have some minimal amount of moral status, grounded in their capacity to feel pain. Now just the research entity examples will suggest to you that there's going to be at some point a threshold for non-interference, or maybe non-use in invasive research. Right it's not just because you have moral status that you can or cannot use the, let's say in this case animal, for research. Moral status doesn't give you that much that much protection. You could have some moral status but still be used for research. So you can still use mice that are fully sentient, you can still use, in some cases, canines for invasive research, and up until recently in the US you could use chimpanzees for invasive research. So the question here is not whether or not something has minimal moral status. The more interesting question, for me, is where is that threshold for non-interference.

    Now to further summarize my previous slide, it's really fascinating that there're actually three different views of when something actually has moral status. One is that it actually has the grounds for moral status. So maybe a blastocyst, might, you might say blastocyst has full moral status because it's the product of fertilization. So maybe being a unique genome in an organism built around a unique genome is sufficient, right necessary and sufficient for moral status. Others have said in the embryo debate, for example, that it's just having the potential to become a full human being that gives you moral status. So potentiality gets you there. And others might say even if we're talking about anencephalic newborns or those individuals who, don't actually have, or don't even have the potential for the grounds for moral status, let's say self-awareness and consciousness. That just there being a member, of a group, of a species for which some of those members have the grounds for moral status is sufficient. So whichever entry point you use. Whichever you know of those three entry points for moral status you use. There's always going to be that question of threshold. And as you know for embryo research in the UK many have said that, of course, the human blastocyst, the human pre-implantation embryo, has the potential, under the right circumstances, to become a full human being, and that gives it some degree of moral status. But not enough for it not to be used for research purposes. Right so I think the threshold question is really kind of the hidden key question that always lurks in the background.

    Now, I suggested that many people get the entity up on the moral status ladder by some kind of single Criterion like there's going to be some property that kind of gets it on that list. Whether it's sentience, whether it's conception, ensoulment etc. So I'm going up the greater and greater complex single criteria: Viability, consciousness, self-consciousness.

    I think that the issue here, let's say, for embryo research is that some have said that primitive streak formation is that key single criterion. It's interesting to me that, well all mammals have primitive streaks, so it's nothing uniquely human. All mammals are products of conception. Right so it has to be something like a single criterion that's uniquely human, that other animals don't have. And this is kind of a favorite approach for moral metaphysicians in philosophy to kind of say: 'well what separates us from all the other animals? what makes us unique?'. And of course the single criteria that typically comes up is rationality, or even a reflective self-consciousness and autonomy. But yeah I mean just getting back to the Primitive streak issue. I don't know of any ethical theory in western philosophy that says that the Primitive streak is determinative of moral status. I've never heard a Kant scholar, or Aristotelian scholar, say oh: 'it's when the Primitive streak appears in the human embryo that you have full moral status'.

    And I think the real question here is why should any single, in this case biological, property be determinative? I think one of the concerns in philosophy, or at least concerns I have. Is a single criterion view is always going to leave somebody out. Right, you can always find a counter example whatever single property you think is a touchdown for full moral status. You can think of a counter example where some human being that we would want to protect lacks that property, whether it's reflective self-awareness, whether it's, you know even in the case of newborn's consciousness.
    So it's a little bit dangerous to you look for that single touch stone. You're always going to find counter examples and there's always the question lurking in people's minds of well why exactly is that property so so so important for moral status.

    I think a different way to go, and I think a way that many people in the research settings go, is what's called a 'pluralistic properties' view a full moral status. So your moral status is going to be based on a variety of distinct but intersecting factors. The way I like to explain this difference is sort of you know on the basis of classical set theory versus fuzzy sets. Classical set would be like all those necessary sufficient conditions that will make x what it is. But a fuzzy said will be you know that, there are actually several different types of properties for which if you just have enough of them, if you have enough of a cluster of those properties, and they could be interchangeable, then you get full moral status. So it might be: member of a human community, it might be, you know, capacity for empathy, you can sort of pick and choose among a very big menu of things that make human beings distinctively human and when you get enough of those then you get full moral status. So I kind of like the fuzzy set approach that's definitely the way that we typically talk about biological categories and entities, even things like proteins, they kind of come in these fuzzy sets. But in any case if you take a pluralistic view, then that's definitely going to be consistent with the gradualist approach to moral status. Right and the way that maybe people will say things like: as the fetus continues to develop in the womb and gets to the point of viability. or as the child gets older and becomes a more self-aware and has has actual autonomy that their moral status grows, as these capacities, and as these, kind of you know elements in the fuzzy set, get added. So again the question here is at what point does something have enough moral status such that instrumental use would be prohibited?

    I want to make a distinction though between moral status and moral considerability. I think this is going to be probably the most important distinction I'm going to make for you today. And to draw this distinction, I have a picture of my dog here Rufus. Now suppose that I'm traveling and I ask you, my neighbor, to watch my dog Rufus for me while I'm gone. Suppose, and I don't think anybody on the call thinks this, but suppose that you think Rufus has no moral status. So like you don't think that my dog could be wronged. You don't think that it has interest for its own sake, not for other people's sake, you just think it's purely instrumental. But you're going to take really good care of Rufus while I'm gone. Why? because you might reason: well I really care about Insoo and I care about our relationship, I know that he cares a lot about this dog and that he's going to be very hurt if anything happens to Rufus, so I'm gonna take really good care of it, because, not for Rufus's own sake. Remember back to my original definition, the very broad one, it's not for his own sake, and it's not because I think I can wrong him, as the neighbor, but because he's important to my friend. So he's morally considerable. I have to take care of him. And there are many categories where it's not the moral status that's the questions more like the moral considerability.

    So you might say: Well where else does moral consider considerability come with bioethics? Well in stem cell research, human embryonic stem cells. You might say: well I don't think that human embryonic stem cells could be wronged. Like if they die in culture I don't have to apologize to them for wronging them. Of course they could die, they could be harmed, but they can't be wronged. Like there's nothing I'm doing for their own sake. But I have to use them very carefully in research, why? Because of, you know, the social sensitivities around them. Because of the the donor interest in making sure that their research materials, that have been donated, are being put to very good use, and justifiable scientific use. There all these other practices that we have because these entities are morally considerable but they're not in themselves the kind of thing that enters into that chain of moral status. That I put up there earlier. Another example will be whole organs for transplantation, right. If you drop a heart during the transfer from donor to recipient and it becomes damaged, that's a terrible thing that happened you don't apologize to the heart. You don't say: 'oh my gosh I wronged this heart', but certainly there were all these other human interests wrapped around this scenario that are of great importance. So please keep in mind whether or not you're talking about the moral considerability of your research entities, whether they're embryos or fetal tissue, and whether really you know you're mixing that up with a moral status and moral considerability. So I think moral considerability is really the more relevant category for everybody on this call rather than moral status.

    I just want to just close by raising one final observation and that is getting back to the human embryo debate. I'm finding that the human embryo, the definition of that, has been shifting. And more and more it's been defined by what it could become and less and less by how it was created. So I along with Megan Munsie, Martin Pera, Nicolas Rivron, and Janet Rossant wrote this paper a couple of years ago, where we tried to give some guidelines for research on what are called human embryo models. So as many of you know this is an exploding area of research. But what we found was that there are countries for which the legal definition of a human embryo is leaning very heavily toward what these entities can do and what they can become, if transferred into the uterus, and less about how they were created.

    So just for example, really quickly, in the Australian definition: 'An embryo is a discrete entity that has arisen either from first myotic division when fertilization of the oocyte by human sperm is complete'. Right, that's the traditional definition of how it was created, but look at the second one here: 'Any process that initiates organized development of a biological entity with a human nuclear genome or altered human nuclear genome that has the potential to develop'. So here we got the potentiality of criterion: 'To develop up to or beyond the stage at which perimeter streak appears and has not yet reached eight weeks devel' blah blah blah. Right, so: 'what it could do?'. A biological entity that has a human nuclear genome. In Japan 'An embryo is', and just to skip ahead 'it could be considered a cell group which has a potential to grow into an individual through the process of development in utero of a human or an animal, it remains at a stage prior to placental formation'. In the US, the US definition of a human embryo, just skipped down to this latter part B: 'For the purposes of the section the term human embryo, or embryos, includes any organism' ... ' that is derived by fertilization', look at this, 'parthenogenesis, cloning or any other means from one or more human gametes or, human diploid cells'. Looking at these in these three countries where embryo modeling research is is active one might think that we are heading towards some ambiguity and some trouble.

    Because for example human blastoid models that are fully integrated and can recapitulate not only the embryonic tissue lineages but also the extra embryonic tissue lineages are not, obviously, the products of fertilization.

    But the question remains what could they eventually become in the future with further technological work. Right so there I have two methods one from Jose Polo's team in Melbourne and one from Jun Wu's team in Texas in the United States. And in both cases they started with human pluripotent stem cells whether they were IPs or ES cells and the reprogrammed them put them into wells and just in a very short period of time recapitulated the human blastocyst, or what seems to be a blastocyst-like in structure. And it would be really interesting to see in the future whether blastoids, whether human or mouse, or other species, are in fact capable of giving rise to new life with that species. Now again these are not the products of fertilization what's fascinating to me is that uh you could have cells either from an ES cell line or somatic cell and end up with the blastoid.

    So this is certainly an area that's moving ahead quickly and we need to keep an eye on that. I'm going to stop here. I'm looking forward to the discussion. I just basically laid out several categories for you to think about and I'll be curious to know what you guys think in our chat.
    Thanks

    Thank you very much Insoo that was great I'm sure you've you've raised lots of issues which people will maybe thinking about and hopefully planning their questions and discussion points. Okay so now we're going to move straight on to our second speaker and then as I said at the beginning for those of you who join later we're going to take questions and discussion after both presentations.
    So our second speaker is Bobby Farsides. So we're delighted that she's been able to join us some of us saw her video when we did the public engagement training session a month or two ago, so that was very enjoyable. So Bobby has over 30 years of experience in the biomedical ethics field. She is Professor of clinical and biomedical ethics at Brighton Sussex medical school where she's been in that role since 2006. And she's particularly interested, in her research, in the experiences of healthcare professionals, particularly in areas where there are significant ethical issues. So stem cell research, like Insoo, but also assisted reproduction, pre-implantation genetic diagnosis, organ transplantation, and I'm sure a number of others. She is a past board member of the human fertilization and embryology authority the HFEA and she was deputy chair of that organization's statutory approvals committee. And she's also trustee of the BPAS the (british pregnancy advisory service) and has been chair of BPAS's research ethics committee. And I know of her role there from personal experience having been up before her on one or two occasions. She advises on a large number of, large, uh sorry, on a number of large scale International studies on ethical issues. So we're very pleased that she's able to give us our second presentation today and over to you Bobby.

    Thank you very much, and my apologies for those of you had two doses of Farsides in recent times. I hope I can add something to the fascinating discussion I had with Sarah on the training video. I'm really grateful to Insoo for setting us up so well today because with beautiful clarity he's, nonetheless shone a light on the complexity of thinking about moral status when we talk about human embryos and fetuses. And I think that, that complexity, is one of the reasons why it's very unlikely, even in a group as relatively small and cohesive as this one, we would, if we devoted the rest of the afternoon to discussing it, all come up with the same understanding of what we thought of the moral status of either a human embryo or a fetus. Or as Insoo pointed out, an early embryo, a later embryo, an early fetus a later fetus. And I would also ask you to keep in mind this question of considerability that he's he's offered you as an alternative to that. But I don't want to treat it as an easy solution for the moment because I want to sit and rest with this idea of complexity and the possibility of not being able to resolve moral disagreements. Because when that happens our ordinary intuition sometimes is to park the issue, to avoid it, or maybe to even prohibit things that touch upon those difficult questions. But then something happens societally, historically, or maybe for some of us at an individual level, which means we have to move into action we have to think about doing things which will in some way relate to the morally complex questions we've been troubled by and have yet to resolve. And if you look back to the late 1960s when David Steel, then a young liberal MP in the British Parliament put forward a bill to, legalize or decriminalize I should say, abortion in very specific situations, it was not driven in any way, by claims on his part about the moral status of the fetus. It was a response to a public health emergency where women were suffering terrible morbidity and mortality through backstreet abortions. And it was the commitment to trying to save life that led us to step into the politically fraught and challenging area of abortion legislation. And the shape of the legislation that arose, was in many ways a product of the acknowledgment that we were still dealing with something that many people found morally challenging, some people would find morally abhorent, and therefore the controls, and the limits, and the way in which we kept this as a very clearly circumscribed medical procedure, spoke to what was happening morally at that time.

    Move forward to the 1980s when people were beginning to understand much more scientifically about embryology. We have the development of assisted reproductive techniques, they're becoming successful and of course a growing demand for those techniques. And Mary Warnock was charged, some would say rather late in the day, with finding a way of regulating this area of science and medicine. Again acknowledging and and who better to know than Mary Warnock a moral philosopher that we were not going to solve and agree on the issues of moral status. and Mary Warnock very early on in her reckoning, said what we could agree on, perhaps, is the extent to which we all share an idea, that human embryos, and I'll extend that to fetuses, are in some way special. They are different to other collections of cells forms of life, and Insoo has touched upon some of the ways in which philosophers might then choose to unpick that specialness. But again Mary Warnock on this occasion was willing to park that, and say if we simply accept, that how we treat these entities will matter in some way to most people. Matter very much to some, matter less to others, matter, particularly, perhaps to those who get caught up in a personal way, be that as scientists, or doctors, or be that as patients. We can start there with our regulatory framework and we can think about the things that matter to people, and try and protect those things. Whilst at the same time promoting what we know is the promise, and the use to which embryonic and fetal material can be put.

    Now as soon as you give up on that idea of parking, or avoiding, or working round a tricky ethical area, you will have people coming to warn you of the slippery slope that you are stepping on to. Because if you don't allow, say, anything at all things stay pretty stable, at least at an official level, although we know that unofficially going back to the example of abortion things do still carry on. But I'm going to suggest to you, and I'd be interested in Insoo's response to this later, that slippery slopes are a more useful rhetorical tool, than a philosophical tool. Because sometimes the things that people fear will happen, logically because you've allowed something to happen at a limited level such as, the very carefully regulated use of early embryos, does not follow on. It does not necessarily, logically, lead us to a position where we would have to accept as morally acceptable widespread eugenics or some of the fears that people evoke. Furthermore there's another sort of slippery slope, which we call an empirical slippery slope, which tries to suggest that the minute we move away from a prohibition and allow limited things to happen it's necessarily the case that people will want to do more, and more, and more, and it will become irresponsible and we can't stop it. We have shown I think in the UK that you can stay true to the fundamental principles and values behind a piece of regulation. Such as the human fertilization and embryology act whilst not remaining stuck in time and thereby losing out on scientific and medical advantages that society could enjoy. And we've done this through, careful, cautious revisiting of the act. Introduction of new regulations and very much doing that in consultation with the public. Because I think this is where Insoo's point about considerability is so important, because if we wish to, not just allow but maybe encourage and support, activities that touch upon ethically sensitive matters we need to understand what matters to people and how we can reassure them. How we can build trust, and how we can set a pace, that means that this thing we sometimes call public morality, and the law, and the regulation, and the activities of scientists stay somehow in step. And it used to be that philosophers would say: 'oh well what I'm interested in is only what people ought to do'. But I think we've become much more part of the real world in recent decades, and we know that in talking to people about what they ought to do, we also need to understand what they do and don't want to do. How their values operate in relation to particularly important issues. And at a very basic level how people behave when they are given permissions to do things that some others would prefer remained prohibited.

    And that's where, the work, the empirical work that I've done in stem cell laboratories talking, to assisted reproduction teams, etc. is so encouraging. And the fact that so many people have come this afternoon to listen, not to the latest scientific breakthrough in the world that you work in, but listen to the knotty ethical issues that that might arise as a result of that, I think it is again a rhetorical tool that is sometimes used that science has this momentum that means it attempts and often does race ahead of of moral considerations. My own experience is that the scientists I've worked with over the years are thirsty to reflect upon the ethical issues in their own work and that that of those around them. And their practices acknowledge not just the fact that a human embryo or a human fetus becomes a valuable resource to them in conducting their scientific research, but also that that entity had a different meaning and probably a different intention attached to it at some time in the past. And so you meet the embryologist who, before discarding any spare embryos, says a Buddhist prayer. Or you meet the team who discuss very carefully in the context of their early work on stem stale research how comfortable they felt utilizing embryos that had been pronounced spare, in the context of reproductive technology, as opposed to embryos that had been discarded as unsuitable for that. A fine distinction that many people from the outside might not expect to be being discussed and rehearsed. People have pride in their science, but I think they also have pride in how they do their science. And again it unpacks in different ways. I met scientists who were far more exercised by the animal research they'd done earlier in their careers than the research that they were conducting with human embryos. Because they felt secure in the consent that had been given to donate those embryos, and that the purposes to which they were putting them. And the issue of sentience was nowhere in there, in the way that it had been with their animal work.

    So I'm trying to cast a cheery note and some of you might think I'm being being somewhat naive, because we cannot pretend that the areas around the issues of the moral status of fetuses and embryos is anything other than highly, and some might say dangerously politicized, at the moment. And 20 years ago, when I first started my research in this area, people were sometimes worried to mention, at a dinner party exactly, what they did, and the human materials that enabled them to do their work. One can only imagine in the current context when you have people making wild, and dangerous, and provocative claims, about the use of human embryos and fetuses. How compromised and endangered some people might feel. But I'm going to make a plea to proceed with pride. Because as Andy says in my role as the chair of the BPAS ethics Committee I received four times a year reports from the project the HDBI project, that's right have I got the right initials, yes? HDBR. HDBR, yes sorry I knew I'd get it the wrong way. HDBR and at the end of that report would be a list of all the publications that had gone out in that time frame of important scientific work many of it relating directly to the interests of people who might initially have donated the fetal material that had been used. And whilst if you find yourself in an ethical minefield it might sometimes be very tempting to try and acquire a cloak of invisibility. I think one of the things we should be thinking about doing is amplifying this sense that science can make use of, and put value, additional value into embryos which may have been discarded, but may have also been donated, or may have come to the end of a legally sanctioned time limit of storage. Fetuses that may have been through tragic and spontaneous abortion, miscarriage, or may have followed on from a difficult choice for social reasons. And amazingly, I think Andy would agree, from people who've had to face the terribly difficult decision of terminating a pregnancy due to fetal anomaly. These are all human stories that shouldn't be forgotten, but we should allow for the fact that those stories have gone on, and translated into something socially, and scientifically valuable and I've certainly in the past felt very pleased to have been a very small part of that process.
    Thank You.

    Thank you very much Bobby. That was tremendous.

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Human embryo research from Carnegie Department to HDBI (September 2022)

Prof. Nick Hopwood (University of Cambridge) speaks about human developmental biology over the last 100 years, exploring what makes this field of research distinctive and investigating how it is related to past research.

  • So my name is Kate Storey. I'm a professor of cell and developmental biology at the University of Dundee and I'm going to chair today's seminar. So this is one of, this is the second HDBI seminar on human embryology and ethics. We set up these sessions so they're intended to be facilitating a respectful discussion about, this is, what is sometimes a contentious topic, related to developmental biology research and what we're aiming for here is, an open, and inclusive, and safe environment in which we can explore ideas and understand, come to new understandings. So we encourage active participation and we've allowed plenty of time for questions and discussion at the end

    There are going to be two speakers today on our topic of human embryos and developmental biology history and ethics. Our first speaker is Professor Nick Hopwood who's professor of the history of science and medicine at the University of Cambridge and Dr Sarah Chan is our second speaker and she's a reader in bioethics at the Usher Institute at the University of Edinburgh so Nick's going to speak first for 20 minutes and then Sarah will follow on and speak for a further 20 minutes and then we'll open the floor for discussions.

    So I want to begin by just introducing briefly Nick and then handing over to him to give his talk. So Nick began his career actually as a developmental biologist and then he progressed to researching the history of, the history of embryology. He's written numerous books on this topic including: ''Haeckel’s Embryos: Images, Evolution, and Fraud" which won the Levinson prize from The History of Science Society. He recently co-edited: "Reproduction: Antiquity to the Present Day" which is now out in paperback if you're interested. And he is currently working on a further book "Dramas of Development: Imaging life Before Birth - A History of Visualizing Human Embryos". Nick holds a Leverhulme major research Fellowship which supports his research for and writing of a new book "The Many Births of The Test-Tube Baby: A History of Claims of IVF" he's going to talk to us today about "Human embryo research: from Carnegie Department to the HDBI".

    Thanks very much Kate I hope you can hear me and see my screen okay and thanks very much to all of you for coming.

    Have you ever wondered, how come there was such a field as human developmental biology? Why are there people like you doing what you do? That's what I'd like to explore today. To see what we can learn from the answers and the comparisons that they draw between the present and the past. Now research on human embryos goes back a few centuries but for the 20-minute version I'm going to focus on the last 100 years.

    I'm going to divide this into three periods. A period of dominance of the Department of embryology of the Carnegie institution of Washington, a period of marginalization of human embryology, and the Revival of this field as something different human developmental biology. And I'm going to suggest that we get a stronger sense of human developmental biology by comparing and contrasting it with what went before. By thinking about collecting, image making, staging, communicating the results, relations with donors, and audiences, and thinking about the infrastructures that have made those possible. And we'll see that a lot has changed but that much of what you're doing builds on what went before. That's not always acknowledged, I mean we all need to claim novelty, and we don't all like old books. But in reflecting on what you're doing I hope I can persuade you that the past is a fantastic resource.

    So I want to start with the Carnegie era. The department that institutionalized the approach to human embryology that had been developed in late 19th century Germany.

    Above All by the anatomist Wilhelm His. A normal plate provided a framework for ordering new specimens collected mostly from miscarriages and abortions though also the occasional postmortem, and increasingly gynecological operations. The more important preparations were serially sectioned and reconstructed as commercially sold wax models, and the anatomists who did this human embryology they really prided themselves on studying human embryos. They were reacting against what they saw as the the excesses of comparative evolutionary embryology and rather disparaged the use of the chick and domestic mammals to fill in the gaps.

    His' American student Franklin Mall got the money from the Carnegie institution of Washington, a major private funder before the federal government got much involved in science, Mall got the money to set up this department of embryology at the Johns Hopkins University in Baltimore. Mall promised medical benefits in relation to the causes of miscarriages, infertility, malformations, and other pathologies. He also wanted a more rational anatomy, as he put it: 'Gross human anatomy is bankrupt, it is made solvent through embryology'. And there was also an impetus simply to know ourselves unborn. Now what we're seeing in this rather staged photograph I don't think they wore bow ties every day, even in those days. What we're seeing is the fireproof vault where the Carnegie embryologists amassed some 10,000 specimens. Those that have been sectioned in the cabinets on the left, and the records on the right. Now they collect from medical school alumni, clinical colleagues, fairly transparently among the professionals but the patients were largely unaware of what was going on. Most of the preparations still came from miscarriages or induced abortions but the best from operations.

    This is the record for one of those. We have it because it was reproduced in an article. They were proud of this one in particular because they had obtained the preparation live from an operation and injected it with the heart still beating with India ink. Now you might notice that under nationality of mother, towards the top here it says, in the language of the time: "negro". The department did have a project in "racial embryology" as they called it but that was a fairly minor strand. They mostly worked blind as to race and sex.

    Now they serially sectioned and reconstructed many hundreds of embryos. Here we're seeing four views of one model, stage 10. So they photographed sections on the cut surface of the block, magnified those on wax plates, cut them out, stacked them up, and filled the hole with plaster, and then removed the wax. You can see they left the models unsmoothed, and this produced a lot of information about development, also of organ systems. But there was a lot they couldn't do.

    So in the 1920s they developed a side project which turned monkeys, rhesus macaques, into laboratory organisms for studies of embryology and the menstrual cycle. They became adapt at what they sometimes called: "monkey gynecology". Which was really very invasive, it's almost more disturbing than what they did to the women patients. But it did provide the first direct evidence for mid-cycle ovulation and let them film the early stages. They could do nothing like this for human embryos. They'd still never seen those between fertilization and the end of the second week. How to emulate the monkey work when they couldn't treat women quite like monkey, even then? Answer: Take advantage of routine gynecological surgery to take more control.

    So this is the so-called Boston egg hunt. Between 1938 and 1954 the pathologist Arthur Hertig and the gynecologist John Rock, they were at Harvard Medical School, they collaborated with the Carnegie Department to retrieve human specimens through the first two weeks. Rock selected women of known high fertility who were waiting for non-urgent hysterectomies. Operations to remove the uterus. Women who menstruated regularly and who lived with their husbands, and as he put it: "were willing and intelligent enough to cooperate". The decision on the operation was separate from the research project though some of the same surgeons were involved. Now 'cooperation' meant reporting each menstrual period during the months of waiting, using postcards, and then having unprotected sex on a particular day in the run-up to the operation. Rock's assistant Miriam Menkin, explained the project and encouraged the patients. Now that would of course be unethical today and it was tricky then, especially since Rock and most of the patients were catholic and abortion was illegal. But medical power was then at its peak and this was before informed consent. It did give them the chance of finding something real.

    This is a photograph and a drawing of 'the Harvard egg' at 12 days, there's a whole history of how they named these these embryos. Researchers today sometimes dismiss all this as grainy photos, but this was high quality printing in the journal: 'contributions to embryology' with drawings by one of the best medical artists. It wasn't secret. There was some reporting of it but Hertig called the: "more or less planned approach" what he called that. It it was somewhat ethically delicate at the time and by the 1970s had become very hard to justify in retrospect. In their defense they said they didn't know whether or not the women were actually pregnant so it wasn't like they were performing abortions to order.

    Meanwhile the former director George Streeter set up: 'Horizons', initially for later embryos what become the Carnegie stages. Now the term 'Horizon' reflected his wariness of the term 'Stage' because of the problem of normal variation. Which meant that there was no single seriation that could, no single series, that could be set up. Street decided to side step this by defining age groups based on points scores, often for internal criteria like you can see here in the development of the eye. He later decided that 'Stage' was okay because there was enough correlation in the development of the different organ systems. Streeter took the timings from the macaques. That became controversial, by the 1960s it seemed they were they were rather too fast. Which is one of the things that was revised when Ronan O'Rahilly and Fabiola Müller competed the staging project in 1973.

    Now the primary audience for all this were fellow researchers and medical students. But they put effort also into, diffusion and popularization, as they called it. Including providing photos for reproduction in leading magazines. So here some of the Rock and Hertig embryos along the bottom and a prize-winning photo of 40-day embryo at the top.

    Even while this work was going on though research on human embryos was already starting to be marginalized at the Carnegie department.

    And we can see that if we look at the director's annual reports so one is referring, already 1941, to diminishing returns because traditional descriptive morphology of human embryos was seen as basically finished. So even at the department founded to research them, this was de demoted to an 'ancillary position'. More positively I suppose one might say, that James Ebert saved the department from closure by completing a refocusing onto experimental, cellular, molecular, and genetic studies, that were better pursued in more accessible species. In 1973 the human embryo collection was hived off to the University of California at Davis.

    And this was part of making developmental biology as a new field in the 1950s.
    A field that intended to expand the scope of experimental embryology across the whole living world. Though it increasingly concentrated on a few organisms, especially mice which were only now established as The model mammal. I should say that developmental biology wasn't the only game in town. Anatomists carried on with descriptive human embryology. There was clinical work on fetuses, including now using ultrasound, and in vitro fertilization was made a line of research. As I'll say a bit more about in the minute, but human embryology overall spent much of the post-war period in decline. Now fortunately that isn't the end of the story, as you know. The history of studying human embryos directly is almost cyclical, with rise then decline and then with new opportunities, a rise again and human developmental biology is the latest Incarnation. And a new one, at least that's my argument. I should say that, like science history isn't done, once and for all, it needs improvement and revision. I'm giving you a first stab at one that hasn't been written yet, and I'm hoping that you can help me improve it. Anyway, what I think is that one of the things that promotes change is because developmental biology changes in the 1990s with critiques of over-reliance on model organisms and genomics opening other organisms up for analysis.

    Another context is new pressure in the 1990s for 'translation' or medical benefits. This went along with the rise of external regulation and stakeholder involvement which which accompanied the decline of medical power. There's also a diversification of personnel, especially as a result of of feminism, and other general changes.

    The two main strands of technical Innovation, I think, are in vitro culture systems for embryos and stem cells and post-genomic methods for mapping gene expression. Part of a larger visual term in biomedicine. And all that means that human developmental biology is not just human embryology by another name. It builds on Carnegie embryology, makes similar arguments, uses related techniques, but it's different because, well, the world has changed.

    So looking at first at culture pre-implantation embryos could now be obtained from IVF clinics. Following the achievement of a live birth from IVF in 1978 the UK government set up the Warnock committee which recommended allowing research, under a strict licensing regime up to 14 days. And after a lot of parliamentary and public debate this was enshrined in the human fertilization and embryology act 1990 with a 14-day limit that as you'll know is now under some pressure.

    I would just mention stem cell models as another dimension of innovation in culture systems. I'm sure you're familiar with embryoids and organoids and so on.

    The other set of Innovations is in mapping, and initially anatomists digitized old slides. The first projects in the 1990s were at the national museum of health and medicine in Washington DC. that's where the Carnegie collection had moved from UC Davis. And they obtained NIH contracts that looked forward to a world of cooperation between what they called 'institutions using wide bandwidth image transmission technologies'. So I suppose you know the kind of thing that we're rather used to in the age of the internet. And these visible embryo projects digitize some of the old slides they produce 3D images, videos, fly-throughs, using technology from the animation and gaming Industries. You may be more familiar with the later Dutch 3D digital atlas also produced in part using the Carnegie slides, and there's now an international digital embryology consortium. But for gene expression studies you need fresh or frozen material.

    And this is really I think where human developmental biology, as a project as well as a name, really comes from. Human geneticists in Newcastle were interested in congenital malformations and wanted to study gene expression by in situ hybridization immunocytochemistry and 3D reconstruction. Now they had to make a case against Skeptics.

    This is what a referee of an early grant application is supposed to have said: "Why bother studying gene expression in human embryos when they're difficult to obtain and can't tell us anything we couldn't learn from studying plentiful Mouse embryos?"

    Responding to that the Newcastle group tried to set up a win-win. If gene expression is the same in human and mouse that's very important, as they said, because it confirms the relevance of the mouse model, and if the expression is different well it's also very important because it shows that you have to study humans to understand what makes us human, or at least not mice. Now for a systematic approach they needed an infrastructure to secure the embryo supply and pool results.

    So they got together with the group at the institute of child health in London to found the human development biology resource, funded by a series of welcome and MRC grants from 1999. They called it 'human developmental biology', perhaps to avoid the connotations of 'embryo research', which could be controversial, and it perhaps appealed that this assimilated the field to developmental biology rather than developmental anatomy. So this is now ethical collecting from gentle ultrasound guided terminations or medical abortions within the framework of the abortion act 1967, informed consent, and the separation of clinical procedure from research. It's also a new way of making material available and sharing results. In the Carnegie era researchers had traveled to central collections. Now material is distributed and results are uploaded, but the techniques still rely on the 19th century principle of serial sectioning and reconstruction. But using light-sheet microscopes and all the rest, and this paves the way for the HDBI that you know.

    Now I'm showing this, and many of you know it far better than me, to highlight a final contrast to the Carnegie era, how public engagement, not just unidirectional popularization, is built into the project to secure donor consent and wider public support. And how ethics is not about just legal requirements but also researcher education. I hope it's not presumptuous to suggest that history might have more of a role to play. Why do I say that?

    Coming to my last slide. I promised that comparing and contrasting human developmental biology with what went before would give a clearer sense of what human developmental biology is. And here's what strikes me from comparing two periods, when. they are two periods, when the argument succeeded for studying human embryos directly, rather rather than via surrogates. Collecting remains limiting of course but it's importantly different, in sources and organization. The resources are not concentrated in one collection but distributed, and collecting is within a regulatory framework which means that engagement work. By the 1950s people at the Carnegie are wondering if descriptive human embryology was finished in the 80s O'Rahilly would say well you know there's actually still quite a lot more to do on the fetus. In human developmental biology there's perhaps most talk about the 'black box' around and after implantation, as a gap in knowledge. Both eras have their surrogates which are also used though those have changed. Imaging techniques are still fundamentally about sections and reconstruction as developed in the mid-19th century but transformed by molecular biology, new microscopes, and digital infrastructure. And I suppose the Carnegie stages could be the most frequent reminder of the past of the field. Now I've just scratched the surface today, but I hope I've done enough to persuade you that a historical perspectives sharpens our sense of what is distinctive about human developmental biology. Thanks very much.

    Thank you very much Nick.

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Human embryo research and regulation: ethical and sociological perspectives on the past and future (May 2023)

Prof. Sarah Franklin (University of Cambridge) gives a sociological account of the development of the 14-day rule and Dr Sarah Chan (University of Edinburgh) discusses potential futures of regulation for human embryo research with an ethical perspective.

  • So I'm Andrew Copp, I'm very pleased to welcome you all to the third in the HDBI ethics seminar series. So on bioethical and social aspects of human embryo research today. And for those of you who've been to these before we you you'll remember that we have two speakers so I'm delighted to to have Sarah Chan and Sarah Franklin here to speak to us today.

    And then we're going to have, we hope, quite a long period, because they'll probably talk for about 15 minutes each, and then we'll have quite a long period for questions and discussion and so on. And we realize that that the discussion of these topics is some sometimes covers contentious issues, particularly in relation to human developmental biology research which the HDBI is involved with. And so we hope that we'll be able to have a completely open inclusive and safe sort of environment for this discussion everybody will feel welcome and able to participate.

    As we go along please do write any comments or or questions in the chat and then we can return to those towards the end. But we'll take questions and discussion at the end of the of both the talks, I think that will be the best way.

    So let's get started then. So our first speaker is Professor Sarah Franklin so I'm delighted that she's able to join us so Sarah's a professor of Sociology at Cambridge where she's been since 2011 or at least in that role since 2011. She's extremely well known in the area of of sociology in relation to new reproductive technologies. She's established two initiatives that have been very influential the 'IVF histories and cultures project' and the 'reproductive sociology research group' and so she's really been a Pioneer in considering social change in relation to new reproductive technologies. She's published extensively on many different aspects of this including cloning, and pre-implantation genetic diagnosis, and human embryonic stem cell derivatives. So without further ado then I'll ask Sarah to give us her talk. I think she's probably going to cover the 14-day rule as part of her presentation, I hope so anyway. And we'll look forward to hearing what she has to say, so Sarah over to you.

    Thanks so much Andy it's really great to be here today and obviously I'm not an ethicist, but I would like to talk about the UK legislation of human embryo research and in particular the 14-day rule. Because this is an obviously very important ethical area. But it is what we might call a kind of hybrid ethical area in the sense that the UK legislation has been based on very strong ethical principles but formulated with a great deal of input from scientists, social scientists, public engagement, initiatives, policy people. And so I really want to talk about the 14-day rule as a case in point about what kind of social contract the UK has around human embryo research. And this is of course very important because this legislation is now up for review. So it may be that some of this is quite familiar to some of you and, if so, apologies for telling you things you already know. But I think this is a story that really shows us what's at stake in this area not only for ethicists but for as I say scientists and social scientists as well.

    So the birth of Louise Brown 1978 was widely seen to have created what was often referred to as a legal vacuum. You know there was no ethical oversight, no legislative infrastructure for the clinical practice of of IVF when it first appeared in 1978. And the establishment of the Warnock committee here in the UK was established to provide legislative guidance for what was termed human fertilization and embryology. The UK is the only country that has ever had had extensive regulation in this area. So the achievement of the Warnock committee in first writing their report in 1984 and eventually passing legislation in 1990 was exceptional. It was a highly exceptional achievement and so it's worth keeping that in mind when we think about what might be the successor to the human fertilization and embryology act. Which would be the regulatory instrument for the next phase of human embryo research.

    Following the publication of the report there was a very long period of legislative, parliamentary, and public debate culminating in the passage of the first HFEA. This was then revised in 2008 and is now, as I said, being revised again to take into account things like embryo models. Which is something that we might want to talk about later. So the 14-day rule is particularly important because it's the centerpiece of the human fertilization and embryology act. And the way it works is along a principle we could describe sociologically as a reciprocal principle in the sense that the 14-day rule instituted a kind of social contract based on an exchange. So that in exchange for allowing controversial scientific research, research on human embryos would be allowed but subject to the very strictest regulations including a time limit, a strict enforceable time limit, and criminal sanctions backed up by parliament. So that was really the sort of principal basis for the legislation.

    And this was devised largely by Mary Warnock and Anne McLaren. And so the principle of the 14-day rule, the reciprocal principle for the 14-day rule, could also be considered the foundation for much of the legislation around biotranslational science here in the UK. And that model, the model of a reciprocal social contract, underlying biotransational research is at once a very general model, but in the case of the 14-day rule also a very specific one.

    And I want to tell you a little bit about its specificity in order to make some suggestions about what might be needed in order to have a new time limit, a new regulatory centerpiece as it were, for human embryo research.
    So the Warnock principles were, I think you could say, not strictly ethical they were also somewhat anthropological or sociological. For example Warnock argued that if the 14-day rule, or whatever other regulation of embryo research was devised, wasn't 'right' in the strict ethical sense then it would be at least 'all right' to the largest number of people because some limit, or indeed any limit, would be better than none which as she put it: 'nobody wants'.
    She also argued along with Anne McLaren that consensual limits don't need to be non-arbitrary to be effective. She didn't like using the 'ar' word arbitrary and the rule was often criticized for being arbitrary, but for Warnock it was sufficient that it be workable and consensual, and it could still also be a rule that could be changed. She therefore argued that such limits are more likely to win support if they don't appear to be entirely arbitrary. But they can be somewhat arbitrary and we'll come back to that. She argued the limits were both literal and also in a sense symbolic and, as I noted, she argued the limits could be changed.

    So the 14-day rule is a literal limit it's a 14-day limit but it's based on a biological fact that may or may not take place exactly at 14 days. So this represents the idea that there should be some limit even if the limit isn't entirely clear, and we'll come back to this. They argue that IVF and human embryo research should be allowed for the greater good of society. They argued that if IVF were to be allowed embryo research had to be allowed in order to ensure it was safe and to and could be improved. They argued that if these were allowed there had to be a firm line, beyond which the research couldn't go. They argued the line had to be credible and enforceable, it had to be clear precise and pragmatic, and it had to be based on robust scientific evidence. And it had to stand as a means of ensuring that there would be a moral expression of social limitation on research, as well as a legal one.

    So that was a lot to try to put together and here to cut to the chase is exactly how they did it. This is one of the drawings from one of the most important documents that was distributed at the key meeting on the 9th of November in 1983. The penultimate meeting of the committee. Where a linear illustration of the very precise process of implantation, embryonic implantation, is Illustrated. And as you can see there is really an actual line. Which for some is understood as the formation of the embryonic disk, for some is understood at the formation of the primitive streak, but is in either interpretation a physical developmental landmark as it was often described. However that wasn't quite sufficient and so the two week limitation was also argued to be necessary in order to make the law enforceable.

    So let's just consider for a second what the 14 day rule is not. It's not a measure of the moral status of the human embryo, in fact it doesn't really address the moral status of the human embryo at all. It's not a line that establishes when human life should be protected, it's not a line that applies to any other issues, in particular abortion. It's not importantly, strictly speaking, technically purely a line based on biological development or scientific evidence. It's not an entirely arbitrary line and it's not a permanent line. it's none of these things so what is it?

    Well actually technically it's a bit of a mishmash. It's Loosely based on scientific facts and on highly specific biological landmarks such as the formation of the embryonic disk, which makes it not entirely arbitrary. It's it's indeed tightly based on a detailed map of early embryonic development but equally on an overarching sociological principle of reciprocity, of exchange. The act which eventually emerged in 1990, is a legal document that enforces a social contract for biological research overseen by a statutory body, charged with enforcing the will of parliament. So the 14-day rule is at once a sort of hybrid ethical marker, a sociological process, a social contract, a legal process, a policy process, and of course a scientific process. And it results in the 14-day rule which is at once arbitrary and non-arbitrary.

    So another interesting fact about the 14-day rule is how long it has lasted. It has now lasted into its fourth decade. It has now endured as the anchor for the unique system of governance of research in the UK and it has withstood number of substantial amendments over time. The 14-day rule is the most emulated feature of the HFEA, and remember no other country has ever managed to have comprehensive legislation of this kind. And it has become the default standard for all of the other countries that don't have laws. It's been singled out out by policy makers and legislator legislators worldwide as quote unquote 'a textbook case' for successful regulatory policy in this area. And it's continued to uphold, and indeed to help to build, public confidence in bio-innovation, creating a unique climate for translational bioscience in the UK.

    And this has been noted by a number of commentators including in this 2019 article by Sheila Jasanoff and Ingrid Metzler two of the world's most prominent political scientists, who work in this area.

    Who describe the Warnock consensus, as it's known, based in large part on the 14-day rule. As a legislative framework that 'has enabled controversial bioinnovation to proceed markedly more smoothly than in any other Western Nation. One by one The HFA has approved an array of practices and entities, [from] derivation of human embryonic stem cells ... to somatic nuclear transfer, ... to human admixed human embryos ... to mitochondrial donation' and so forth. Nevertheless, they say, sorry: 'all of these Innovations were subjected to extensive public consultation. [and]. Nevertheless, or perhaps precisely for this reason, none produced the public uproar or political deadlock that characterized comparable debates in Germany and the United States'. They suggest.

    Okay so all of this really began to become the subject of more intensive public engagement and discussion when it became physically possible to culture embryos for longer than 14 days. And the possibilities of the scientific and potentially clinical benefits that would result emerged as a subject of of more concerted discussion.

    And alongside a progression of research developments, which has continued since 2016, have emerged a number of new questions about the 14-day rule. Whether it should be changed, whether it should be extended, whether the governance of human embryos should be removed from the human fertilization embryology act and become subject to a new act. That's more specific to fertility research, with a different set of legislation that's designed for science including embryo models?

    Should there be in effect a new social contract in this area? This is the big question on the table right now for which the history of the 14-day rule is a very important guide. If there were to be a new new social contract what would it involve, I'd be very interested to hear the thoughts of people here. Obviously the new social contract also has to be a new ethical contract, a new legal contract, a new kind of bridge between the scientific community and the wider public. Would it be important, I'd be very interested to know what you think of these questions, would it be important to take into account that fertility care is now in some ways a greater cause of public concern than embryo research in the post IVF era? Could a new social contract be orientated towards regulating research, but also towards enabling transparent equitable access to high quality health care, including fertility care? Or should it be? Would it be be advisable, or not advisable, to introduce a more graduated system of enforcement. Where some types of embryo research are more subject to higher levels of oversight or indeed of legal protection? Would it be possible to have this be based on many of the same Warner principles or or should the 14-day rule remain? Or should it remain with the proviso that there could be exceptions to this rule and if so how would they be regulated? These are the questions that are on the table at the moment.

    So what are we going to need to answer them? Well I would say we need, importantly, to look at the history of how we got to where we are. But secondly we will need new public engagement and outreach, and some of you here may already be engaged in some of the extensive public engagement and outreach activities orientated around the prospective new regulation in this area. There will be a need as there was in Warnock for excellent scientific communication, for a real dialogue between the scientific community and the general public. There will need to be the ability to build on the very significant history of existing consensus around legislation in this area. There will obviously need to be high public trust in scientific credibility, transparency in the legislation or regulatory apparatus that succeeds the current arrangement. And I would argue there will need to continue to be a very strong sense of reciprocity that this legislation is facilitating work that is in the public good. And of course that will need to be credible, which was a crucial part of the 14-day rule. So I'm just going to leave it there. Looking forward to your responses, questions, and comments. And I will stop sharing my screen.

    Thank you very much thank you Sarah that was tremendous very thought-provoking and made me feel quite excited but also daunted that we're really at a position in a similar way to Anne McLaren and Mary Warnock all those years ago and trying to sort of Blaze the trail towards some new system. So I'm sure we'll return to this in due course. Okay so our second speaker this afternoon is Sarah Chan. and Sarah apart from anything else has the dubious, uh she she she's actually, attend, she's actually been a speaker at two of these seminars, last time she was on the agenda for our second seminar and was forced to leave the seminar within minutes of starting because of a fire alarm. So I'm really delighted that she's now here without any fire alarm going on in her Department. Sarah's reader in bioethics at the Usher Institute in the University of Edinburgh and she's associate director of the center for biomedicine, self and society. And she has done a great deal of research on the ethics of new biomedical technology. So very relevant to the topic that Frankin's just addressed as well. So this has included gene therapy, genetic modification, stem cell and embryo research, various different aspects of reproductive medicine, synthetic biology, and also human and animal enhancement as well. So I'm very much looking forward to hearing Sarah's presentation which is going to be on 'the future of human embryo research regulation'.

    Okay so having, I think, been presented with a very convincing case that now might be the time to revisit the regulation of human embryos, not just for research but for reproduction, I want to spend my talk thinking about what that future might look like.

    Specifically what I want to walk us through is why might we want to change the rules on human embryos. How might we go about doing so, and what some of the challenges and issues are that we might face along the way.
    And I'm going to argue overall that changing the rules is going to require us to understand both what the rules are but what their role is in public bioethics and policy. So as you've already heard from Professor Franklin the regulation of both human embryo research and assisted reproduction in the UK is generally a permissive one. We're allowed to do many activities but we're allowed to do this under a complex and comprehensive system of regulation that sets out what may and may not be done with embryos. And in particular some activities involving human embryos are permitted when those embryos are to be used in research but not currently for reproductive use. And we've heard that developments in science and medicine are now posing challenges to this regulatory framework.

    The key elements, so I won't go through the historical background because again Professor Franklin has has done that very comprehensively. But the key regulatory elements that I want to focus on, in terms of what we might want to change, or we might need to change in the future, are that, as we know, use of embryos whether for research or reproduction is regulated by the human fertilization and embryology Authority. Uses of embryos and gametes are controlled under a licensing system. In particular we have the 14-day rule, or the 14-day limit, for how long embryos can be maintained in culture. And we also have this distinction between embryo research versus their reproductive use. And as I said there are particular things that may be done to embryos that render them, what's called for the purposes of the act as it stands in its modified form, a non-permitted embryo. That is an embryo that is no longer permitted to be used in reproduction. So genetically modified embryos, hybrid embryos, so inter-species embryos, are embryos that now fall under the non-permitted distinction. With a very specific exception that allows for embryos that have had their mitochondrial DNA modified for the purposes of treating mitochondrial disease, can be permitted embryos under the human fertilization and embryology mitochondrial donation regulations passed in 2015. And as we've heard the development of this regulation has established a sort of model for how public bioethics can be enacted in the policy sphere when it comes to controversial areas of research.

    So we have a system, it works well, why might we want to change it? Well first of all as we've just heard there are scientific prospects that might challenge the current regulatory system. We now have the technical ability to grow embryos potentially Beyond 14 days and doing so might help us to understand mechanisms of development that happen at this crucial stage of embryonic development. We also have the prospect of what has been called synthetic embryos, or gastruloids, or embryoids, the self-organizing entities assembled from pluripotent cells that seem to recapitulate the embryo at that stage of development and don't have a clear 14-day limit from when we should start counting. So what do we do with these scientific challenges to the 14-day rule? But there are also therapeutic prospects that under our current system of regulation would not be possible. In particular human reproductive genome editing. So we can perform genetic modification, genome editing, on embryos for research but at the moment we can't use it in reproduction for example to try to cure genetic disease. So these scientific and therapeutic prospects together give us reasons to say well we might want to change the law. Now of course just because we can do something doesn't mean we should. So we can grow embryos Beyond 14 days, we can genetically modify embryos and use them reproduction, but that doesn't mean that we ought to do this. Gulia Cavaliere calls this: 'the argument from technical feasibility', well we can do it now so we should be allowed to do it. That's not necessarily the case, but if we can do good, on balance, all things considered. Then we should do that. And so the question for us becomes, what benefits might be made possible possible if we were to change the regulation to allow embryos to grow past the 14-day limit? To allow reproductive genome editing. So not only can we do it, but can we do good with it, can we realize the benefit? And of course because that question is on balance and all things considered, we also need to take into consideration what the risks might be of doing so, and these might include both scientific and medical risks. The discourse around the use of genome editing in human reproduction has concentrated very much on what might be the risks of this still largely untested procedure, for future children, for future Generations. But we also need to think about what we might call 'social risks' to science. So would for example a change in regulation that somehow breached the social contract that we've talked about, that engendered a lack of public trust in science, what risks might that pose to the good that science is able to achieve?

    What sorts of issues might we face when it comes to thinking about how we how we might go about changing the rules? First of all, how can and how should, regulatory change be achieved? Now as we've heard regulating the human embryo in the UK has established a history, if you like, of public bioethics as a mode of policy making. And I think we've learned a lot along the way about what effective ethical policy making looks like. First of all from the IVF era and the Warnock report, through the major changes to the act that happened in 2008, and then the mitochondrial donation regulations in 2015. And so the lessons that we can learn from the way in which this process has been achieved each time, show that certain key aspects have been important in the successful establishment and maintenance of regulation and in regulatory change. These include public discourse and consultation they include the involvement of scientists alongside experts from other disciplines and lay representatives. So the at the time unique feature of the Warnock committee, was that it brought together this diverse group of individuals to represent different perspectives. The modes of discourse and of public involvement have evolved and changed at each step. So the consultation around the changes to the act in 2008 was a little different. The consultation and the public involvement, when we, when the mitochondrial donation regulations were enacted. Again different, and the involvement of scientists as well has evolved over time. So for example in relation to the mitochondrial donation regulations. There were a series of steps of proofs of safety and efficacy. There was a scientific committee that was specifically tasked with examining the these aspects. But the other component that it has been shown that we need for this for regulatory change to be effective and to maintain that that social license around research it takes time. So Louise Brown born in 1978, Warnock committee took another six years to report back 1984, took another six years after that for the human fertilization and embryology act 1990 to be made into legislation. Similarly the consultations and discourse around the 2008 changes to the law, the 2015 changes to the law, started years before any reform went into the legislation. And so we need to be starting to think now about how we might change the regulation in the future, and to be aware that it's not going to happen tomorrow, or next year, it will take time for this to happen. And so that's why now is the time to start thinking about the changes we want to see in the future.

    Okay I want to address two challenges in particular that I think we need to consider when we talk about changing regulation. One of these is, if you like, an ethical objection, or an argument about moral consistency and the role that regulation plays in expressing a moral position. So the 14-day limit has often been described as a 'bright line'. Certainly it was a clear limit it was something that was, as Mary Warnock said, was countable, everyone can count to 14 and it provided that sort of certainty that here is a limit. And, as we've heard, that clear, not necessarily non-arbitrary, but at least justifiable limit, provided the cornerstone of our regulatory system and remains so to this day. So the first question is, can we think about moving that 'bright line' without falling foul of what we might call 'slippery slope' objections. Now let me explain this, this is tending towards the sort of ethical philosophical side. The slippery slope argument is often used to object to advances in technology and changes in what are we doing in these controversial areas. So the argument would go that: Allowing research on human embryos is the first step on a path that will inevitably lead to: Something obviously impermissible such as, destructive research on adult humans, or so forth. And that would have been the argument at the time when we were considering, will we allow research on human embryos. And in some ways the 'bright line' may have been perceived as a response to a slippery slope. So if we draw a line and we say you cannot cross this line it will prevent us from slipping. So there's a question about whether willingness to consider crossing the line, crossing the 14-day line, or moving the limit. Would that be evidence of the slopes slipperiness, giving weight to arguments that say: 'look we told you so we've allowed research on human embryos and now we're going to start growing them in culture up to 28 days, 2 months, 3 months, we're going to grow human babies in culture. The slope is slippery and this proves it.' Is that a consistent moral position? Is that correct?

    And I'm going to say it's not because the 14-day limit, I think we should view more as a regulatory fence. So with slippery slope arguments we need to argue, we need to question, what lies at the bottom of the slope, and how bad is it actually, and how likely are we to slip. Now the slippery slope argument seems to imply that there is one single way down the slope and at the bottom of the slope lies something very bad, such that we must not even start to go there. But research as we know, is not a singular route from A through, B, C, D, all the way to Z. It's more like what I would describe as a garden of forking paths. Each development in science, it's true might, if allowed to slip, lead to a very bad consequence but we also need to take those steps to get to the good consequences that we want to see. There's not a single route down the slope. What we need to do is navigate the slope rather than close the gate to to the garden. And so the 'bright line' we need to see not as a line that may never be crossed, but something that exists for the time being as a regulatory fence. It gives us a place of security from which we can look at what's on the other side of the fence and see whether or not we want to go there. So I've been willing to revisit our rules, and think about the moral basis on which they were enacted, and whether it's time to move on from those is actually a necessary part of ethical policy. I won't go through, I wanted to draw a sort of comparison in terms of moral consistency from an argument in the early days of stem cell research about whether the time limit that used to exist on human embryonic stem cell funding was, could be moved. I won't go through the argument in detail, but suffice to say that, as you heard Professor Franklin explaining. The 14 day rule isn't in itself a moral boundary. I think of it as a boundary object. So it's not that before 14 days embryos have no moral status and after 14 days they suddenly acquire it. The 14-day limit instead is representative of the special status of the embryo. The idea of, as we heard, the symbol of, a moral idea of society not a moral limit in itself. And so therefore the 14-day rule has enabled discourse among different perspectives, amongst different views of embryos as being reproductive futures, and repositories of reproductive choice, resources for research, and resources for therapy. Moving where that boundary object is, or being willing to move it, signals not a moral step change, not a step down the moral slippery slope, but an evolution in the discourse.

    The second issue that I want to mention um is around the global context for regulation and what scientific responsibility requires. Now in thinking about how we regulate cutting-edge research an argument that sometimes comes up is: 'well if we don't allow it somewhere else will'. If we don't permit this in the UK, UK scientists might go to other countries where regulation is more permissive. or more lax, we will lose the benefits of the research being done in this country, we'll lose our position as world leaders in the field. So there are concerns there about, missing out, losing ground, due ... [faint barking] sorry not a fire alarm only a dog ... Due to overly restrictive regulation. And you know I want to ask whether is this a sound argument to say: 'well we need to we need to relax our regulation otherwise we're going to miss out'. But regulation is not just about stopping science, although I think it does have that role, of an exchange, of reciprocity, as Margot Brazier described it as: 'regulation being the price of assuring research'. But it's not a strict social contract in the, the sort of Hobbesian sense of: 'you agree to something you otherwise wouldn't agree to', just to to stop being nasty and brutish to each other. Scientists don't want to do bad things anymore than publics want them to be able to do bad things. Regulation can also facilitate research especially in controversial areas, it provides scientists with the certainty to operate and it provides that social license, it ensures support well-governed research.

    So what does it mean if scientists then go about escaping that regulatory system through scientific tourism. What does it mean for scientific responsibility when scientists exploit regulatory gaps, or lacunae, in order to do something that the rest of the scientific community deems to be irresponsible. And there are two obvious examples of this within recent years in the reproductive research field. The first obviously the creation of genome edited babies, three four years ago yeah four four years ago now. And about seven years before before this. The creation of children using mitochondrial replacement therapy at a time when this had not yet fully been approved in any of the countries concerned. And the scientist who did this he was a, he US scientist, carried out the procedure and did the embryo transfer in Mexico because he said: 'in Mexico there are no rules'. Similarly when the genome medic babies were created in China, many of the world's scientists commented: 'well in China there are no rules'. In fact neither of those things are true, but the perception that in certain countries there are no rules and the actions of scientists in taking advantage of that perception have consequences. Decisions about where and when to conduct research affect the global politics of science. The mitochondrial tourism incident in Mexico had a number of consequences. In the first place it fueled a regulatory push back and a disruption to the delicate evolving process of regulation in the country. More restrictive regulation being being introduced as a sort of knee-jerk response to this. This then hampers scientific development in these under-resourced countries and it increases to burden on local oversight mechanisms. But it also reveals a deep, what I call scientific chauvinism, and an underlying political hegemony in terms of who sets standards of good science, who says what constitutes good governance, in which countries does good science get done. When it comes to ethically questionable research who do we blame? And if you look at the cases in Mexico, in China, people said well of course it would happen in places like that where there are no rules. By contrast there was a very high-profile case of a stem cell clinician conducting ethically questionable research in Sweden. Nobody said in Sweden there are no rules. So blaming the destination countries both allows scientists to escape individual responsibility but also reinforces these hegemonic power structures within global science that disadvantage countries that are already lower in scientific capital, lower in resources.

    It reinforces the systemic power disadvantages that exist within science, and it creates a problem of justice with respect to regulatory resources and capacity because it increases the burden of oversight in countries where ethics and governance structures are already struggling to develop. So scientific tourism is an unjust appropriation of human resources and scientific capital. And so the moral of the story, and where I'm going to finish, is that responsible science requires that we not go elsewhere and we try and make things better here.

    Thank you very much.

    Thank you very much Sarah. Another very thought-provoking talk. I guess most of us are interested in making things better here and carrying on our research which is exactly what you're saying.

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Fetal tissue research in Japan and the Dutch advice to extend the 14-day rule (January 2023)

Prof. Misao Fujita (Kyoto University) speaks about issues regarding the regulation of research with fetal tissues in Japan and Dr Hafez Ismaili M’hamdi (Maastricth University) discusses the recommendation from the Health Council of the Netherlands to extend the 14-day rule to 28 days (advisory report can be found here).

  • Hello my name is Kate Storey I'm a developmental biologist based in the University of Dundee part of the HDBI and I'm going to chair this session so welcome to everybody. This is a seminar which is part of a series organized by the human developmental biology initiative and it's intended to facilitate a respectful discussion about sometimes contentious subjects related to developmental biology research in organizing this session we want we aim to create an open and inclusive and safe environment where we all feel welcome and able to participate and indeed we encourage participation actively there'll be plenty of time for discussions after each speaker and also more broadly at the end. Please feel free to write in the chat at any point and we'll pick this up later in the discussion and if you want to do this anonymously you can submit your questions through slido and and Pilar will provide a link in the chat which will allow you to do that. So please be aware that only the talks are going to be recorded not the discussions and so we'll proceed on that basis. So we're fortunate to have two fantastic speakers with us here today. The first speaker is Professor Misao Fujita, Misao Professor of bioethics at the center for iPS research and application and also the institute for advanced study of human biology at Kyoto University she's a member of the UNESCO International bioethics committee the ISSCR Ethics Committee and the expert panel on bioethics of the Council for science technology and Innovation for the cabinet office in Japan. Her research group is is committed to investigating issues concerning unproven cell-based interventions, the use of human IPS cells to create climic animals and also to make germ cells, and related questions about domestic and international ethical regulation, government policy and public attitudes and current practice. The title of her talk is: 'An initiative to establish guidelines for fetal tissue research in Japan'. She'll be followed, I'm going to introduce now also our second speaker so we can move smoothly through the seminar. Our second speaker is Professor Hafez Ishmaili M'hamadi. He is an associate professor of Ethics at Maastricht University. He's Vice chair at the center for ethics health and a member of the Council of Public Health Society in the Netherlands and Hafez has a background in philosophy and in music in fact he's a jazz guitarist but perhaps not today his Fields expertise additionally include Health and Social Justice justification of Health policy ethical issues surrounding pregnancy and ethics of reproduction and the moral status of the embryo. His title today is: 'A fortnight away: on the Dutch advice to extend the 14-day rule to 28 days' So we will begin with Misao and she will present her talk and as again I've said her title is: 'An initiative to establish guidelines for fetal tissue research in Japan'. Thank you Misao. Ok thank you for the introduction Kate. I'm very honored to be invited to this prestigious meeting and thank you very much for giving me such a precious opportunity. Today I'd like to talk about our project to develop guidelines for fatal tissue research in Japan but before starting my talk let me explain this picture this box contains my umbilical cord. This Chinese character crane and turtle all mean celebration and long life. In Japan when a baby is born there is a custom of placing the umbilical cord in a wooden box and giving it to the parents this comes from the ancient belief that the umbilical code which used to be called Ena has special powers to protect the baby. I'd like to talk later about the influence of such Japanese culture regarding Ena on cutting edge science. Studies on early human development often use aborted fatal tissue, for example to generate more mature germ cells from pluripotent stem cells we need to co-culture them with aborted fetal cells. There's also a growing need for fetal tissue in basic research on genetic and infectious diseases and for the development of treatment. However, to procure such tissues it is necessary to obtain consent from a woman who goes through an abortion. Therefore consideration of the physical and emotional burden on the woman and respectful handling of the aborted fetus are also required

    For this reason the international society for stem cell research issued an informed consent standard for human fatal tissue research in 2022 and I was on the task force that develop this standard and I cannot give you the full story but the basic principles for obtaining consent from donors are as follows: First respect for women's autonomy goes without saying in addition the decision to donate tissue must be made after the decision to have an abortion to avoid an abortion for the sake of tissue donation. Other principles include the prohibition prohibition of monetary reward for tissue donation prioritization of medical care for women over tissue collection and exclusion of anyone involved in the research from the abortion.

    This standard is especially useful for researchers in Japan where there are no clear rules for fetal tissue research. Therefore our research team translated this into Japanese and there is now available on the website of ISSCR. However, this standard cannot be implemented as is because existing relevant regulations and situation must be taken into account. The standard also says regardless of what is in this ISSCR informed consent standard any donation must also meet all applicable local legal requirements

    Therefore we decided to organize a multidisciplinary research group including scientist, philosophers, jurists, and bioethicists to develop guidelines for conducting fetal tissue research and to compile an academic report that can be the basis for the guidelines. The guideline is not the national guidelines or anything like that but at least for local institutional guidelines so that researchers at our institution can follow. But today I'd like to introduce some Japan specific issues that were identified in the course of discussion at our research group. I hope this will serve as a reference for implementing the ISSCR standard in other countries.

    So what are the issues unique to Japan. They are the lack of rules directly regulating fetal tissue research. The relatively heavy burden on women who have abortions the possibility of male consent being required and ambiguity of the legal status of the fate of the fetus. So let me explain each in turn.

    The first issue is a lack of rules uh regarding fatal tissue research in Japan. In 2002 the Ministry of Education culture Sports Science and Technologies expert committee on human stem cell based clinical research began developing guidelines on clinical research using human stem cells. At that time procedures for handling fetal tissue were to be included in that guidelines because transplantation for patient with Parkinson's disease were highly expected. However in 2004 after a scandal like here involving a clinic that illegally disposed of aborted fetuses as household waste. The committee suddenly decided to exclude the procedures from the guidelines which meant that the clinical research with this tissues were banned. One reason for this was that the politicians and pro-choice groups opposed it because the reality of abortion clinics and the burden on women having abortions were unclear. Basic research using fetal tissue was outside of the scope of the committee discussion from the beginning therefore it is neither explicitly permitted nor prohibited. This situation persisted even after 2014 when the act on the safety of regional medicine took over these guidelines.

    Conversely some countries have permitted fetal tissue research through regulations for example as you know in the UK a national overseeing body called the Human Tissue Authority issued its guidelines in 2006. Which defined the fetus less than 24 weeks old as the mother's tissue so the mothers can donate a fetus that is her own tissue for research. In the US The Uniform Anatomical Gift Act of 1968 allows family members to donate the body of the diseased person. This is the law governing organ transplantation and in 1975 medical research guidelines stipulated that activities involving deceased fetuses fetal samples or placentas are permitted only in accordance with the state or local law. This has allowed states to permit or prohibit research through the Uniform Anatomical Gift Act or through their own rules. In France the bioethics law was introduced in 1994. One of its feature was to set the category for human body which means the special entity that was neither a person nor a thing but should be respected. Fetuses less than 22 weeks old were categorized as human body in 2004 and research use was allowed with the woman's consent. These regulations clearly define the donor and the fetus but in our case Japan doesn't have such a legally clear definition of the donor and aborted fetus. This fact is related to the remaining issues that I'm going to talk about.

    But even so in general a donor of fetal tissue would be considered woman who goes through an abortion. The abortion rate in Japan is not as high as um other countries as this graph shows. and in 2021 there are more than 120,000 abortions in Japan. Most abortions are performed in the early stage of pregnancies at less than 12 weeks the W.H.O. recommends the use of vacuum aspiration and abortion pills for early abortion.

    However, in Japan the W.H.O recommended abortion bill was approved just last spring just last April, and vacuum aspiration is used but the 80% of this procedures are either Curettage or a combination of these two which are physically invasive and cost from 540 to more than 1000 pounds, which is not covered by National Insurance. Since child birth fertility treatment and abort are often performed in the same Hospital there is also an emotional burden on the woman having the abortion, therefore it is important to select medical institution that are attentive to women who have abortions so as not to place an undue burden on them due to tissue donation.

    Furthermore as this map shows Japan is one of the few countries where spousal consent is still required for abortion. The maternal Health act requires doctors who perform abortions to obtain consent from the woman and her spouse this is problematic for women's rights. However, regarding fetal tissue research if consent for abortion is obtained from both men and woman in accordance with the role whereas consent for tissue donation is obtained only only from women that rationale is unclear.

    Moreover when dealing with genomic information of fetal tissue especially for germine research it may fall under the legal category of personal information we call it personal identifiers of parents. According to the guidelines for the act on the protection of personal information the personal identifiers here refers to the base sequence making up the DNA such as whole nuclear genome sequencing data, whole exome sequencing data, and whole genome snip data, and so forth. So when addressing this information parents even if the information is anonymized Japanese regulations requires researchers to specify the purpose of use and obtain consent from both women and

    men.

    The last issue is the ambiguous legal status of fetuses that are less than 12 weeks old. The ethical guidelines for medical and biological research involving human subject include dead persons in the definition of research subject and do not prohibit research involving them. However, the postmortem examination and corps preservation act, and graveyard and burial act define a dead person to include a dead fetus who is older than 12 weeks. In other words a dead fetus less than 12 weeks old is legally not a dead person. Therefore it is not clear whether it should be treated as corps or as medical

    waste.

    As a result we may need to confirm the Ena ordinance before conducting fetal tissue research. Ena in Japanese usually refers to the placenta umbal code and omentum which are expelled after child birth. This was mentioned in my first title slide. The ordinances regulate the licensing or notification of companies that collect and dispose of Ena as well as the condition of established disposal facilities. Currently eight prefectures have Ena ordinances and some municipalities have their own ordinances. However their contents vary slightly from region to region. The definition of Ena may or may not include fetuses that are less than 12 weeks old, it may or may not refer to research use as well. So researchers medical institutions and ethics review committees involved in fetal tissue research in Japan are encouraged to check the Ena ordinances of their local governments. So why these Ena ordinances exist throughout Japan and this is closely related to ancient Japanese customs.

    The photo on the left shows the Ena mound of Michizane Sugwara, known as the god of study his umbilical code is buried in this red wall. The photo on the right show the Ena mound of the famous Japanese Samurai Yoshitsune Minamoto his umbilical cord is buried under this pine tree, and you can see both of these sights Kyoto where I am am now and I took these pictures by myself. In Japan there has been a custom to treat Ena with great care and bury them since ancient times. However since the end of the 19th Century people's idea of hygiene had changed especially after the Cholera pandemic and the burying of the Ena was forbidden by local ordinances. But as the method and location to bury Ena varied from region to region it is assumed that the different ordinances were created in the different regions and I found it really fascinating all the troublesome how these ancient practices have influenced on cutting edge science.

    So this is a summary of my talk. We identified several Japan specific issues that arise when conducting fetal tissue research. In order for fetal tissue research to be properly conducted existing relevant regulations and situation in each country need to be considered in addition to globally common principles. We are currently developing guidelines for fetal tissue research and also compiling the academic report which these guidelines are based on. And we hope that the discussion that emerged from this process will serve as a reference for similar effort in other countries.

    We are conducting this project with many collaborators. I would like to take this opportunity to express my gratitude in particular I'd like to thank Dr Saitou of ASHBi and Dr Takashima of CiRA who always provided valuable Insight from a scientific standpoint. Thank you very much for your kind attention.

    Thank you very much Misao that was a very interesting and informative talk telling us how distinct cultural practices in Japan actually impact the ability to use fetal tissue for research.

    Our next speaker is Hafez ishmaili M'hamdi and he's going to tell us about his talk: 'A fortnight away: On the Dutch advice to extend the 14-day rule to 28 days'. Go ahead please.

    Thank you so much for the invite thank you HDBI and Pilar in particular for giving me the opportunity to share with you the recently published Dutch Health Council advice on the extension of the limit of research with embryos from 14 days to 28 days. So the 14 day rule is a rule that stipulates that the in vitro culture of human embryos is not allowed to proceed beyond the equivalent of 14 days of embryonic development or so to say the approximate time at which the primitive streak appears. It is important to note that this rule applies to supernumerary embryos because at least in the Netherlands but as far as I know in most countries involved in embryologic uh in embryo research the creation of embryos for other other purposes than reproduction is prohibited. So the 14-day rule therefore only applies to supernumerary embryos and the question is whether this 14-day rule should be revisited more concretely whether we should extend the 14-day rules. So this advice specifically was requested by the Dutch minister of health and it was precipitated by all kinds of advances in human embryology and also by the creation of embryo models. These are models which recapitulated the development of human embryos. There are non-integrated models and integrated models so these non-integrated models they simulate the growth of parts of the embryo, So like they might be simulating an organ so there are brain organoids and liver organoids or they might simulate a process such as gastrulation those are the gastroids and then there's integrated models which is the blastoids which tries to recapitulate the development the full and integrated development of the human blastoid. Now given these scientific advances the minister wondered whether there would be reason to extend the 14-day rule and whether there should be a comparable limit for integrated embryo models or they're also called embryo-like structures. Now in order to answer this question and the committee was formed consisting of scientists legal scholars and ethicists. I had the privilege to join that group, and then we set off and tried to uh answer these questions. So here are the two questions sorry missed the slide yeah there we go. Now we conceived of that first question right the balance whether the 14 day should be 14 day rule should be extended as a question of balancing the moral worth or moral status of the embryo on the one hand and the importance and the benefits of scientific research on the other. And in order to determine the moral worth of that embryo we took what is known as a pluralistic stance that is to say that we recognized and respected the fact that there are more than one sensible and reasonable view on what makes an embryo worthy of protection. Common reasons for conferring moral worth to the embryo are because the embryo might become sentient or it might become aware or self-aware or that it's part of the human species and rather than selecting so to say for the strongest view in the eyes of the committee we tried to include as many views as possible as long as they were at least in our view, they met a minimal threshold of of of scientific soundness and and and ethical reasonableness, and I will discuss some of these views in the next slide. But one of these views and it's a view on which there exists I think strong International consensus is to view that the human embryo's entitlement to moral consideration is widely assumed to be gradual and progressive in time and relative what this means is that as the embryo develops biologically its moral value also increases, and its increasing moral value is relative, in the sense that there may be counterveiling values such as the importance of scientific research and possible clinical benefits which may outweigh the embryo's entitlement to protection. So this is to say that although the value of the embryo increase it is it never becomes categorical so that it always offsets other scientific or societal considerations.

    Now going back to that balancing act between the moral value of the embryo and the scientific interests and benefits if we focus on the left arm of the balance we'll find two types of considerations, and first type of considerations is what we may call intrinsic considerations which are considerations that matter for the embryo's own sake. So these are the considerations that ground the moral status of the embryo. Now what could these considerations be and analogously to the human adults the considerations the committee looked at included sentience awareness self-awareness personhood and species membership. Given that those are also the considerations that underpin moral protection for human beings. Now starting with sentient: to say that beings with sentience matter for their own sake is to say that these beings should in principle be spared from the experience of suffering. For self-awareness this entails that someone should not be frustrated in pursuit of their ends, and when it comes to personhood it entails that someone's Freedom should be respected and that interference with a person's Freedom should always be conditioned on some form of consent. Now these are typical moral considerations in the domain of humans and human conduct but when it comes to embryos none of these considerations seem to apply, since an embryo is not sentient, has neither awareness nor self-awareness and in their embryonic stage they lack the properties of personhood. So all those considerations fell away then there is species membership as a consideration which is to say embryos should matter for their own sake because they are a member of the human species, which automatically and by definition confers onto them moral status. You hear this argument a lot but this argument at least according to the committee, and I agree with that, I think that this argument is a form of unwarranted discrimination which is called speciesism, and what is speciesism well just like it is impermissible sorry just like it is in principle impermissible to discriminate on the basis of sex or race it is also and equally in principle impermissible to discriminate on the basis of species, because why should we as a species, of human ,the human species why should we matter more than apes, whales or elephants. There's, that seems to be an arbitrary distinction therefore species membership also did not make the cut. The only intrinsic consideration which according to the committee holds water is that of potentiality. That is the view that the embryo matters for its own sake because of their developmental potential. Their potential to develop all those properties which I just mentioned. So one could say an embryo's potential to develop sentience grounds moral value or the embryo's potential to develop self-awareness or personhood. Those are properties that ground moral value once someone actually acquires them and therefore that potentiality as such also deserves some form of of moral protection. Now this potentiality argument is ubiquitous and it's very controversial also we didn't reach consensus in our own group but given our pluralistic stand we did mention it as a valid argument in favor of protecting the embryo, and thus as a reason to be careful with extending the 14-day rule. So when it comes to thinking about reasons as to why we should not extend the 14-day rule and this reason pertaining, has to pertain, to the intrinsic value of the 14-day rule in view of the committee only the the argument from potential qualifies. Which I mean, I can definitely imagine that that's already quite a contentious claim to make.

    Now in addition to these intrinsic considerations there are also extrinsic considerations, and these are considerations that pertain the way that we are as a community of human beings with a sociocultural background, how we view and value embryos. Now one type of such an extrinsic consideration of a value is called the relational value of embryos and this value expresses that there are more and that there are less appropriate ways of standing in relation to an embryo. Which is to say that it expresses that it would be for example say, indecent or improper or or inappropriate to bring about an embryo to create it only to discard it or use it for all kinds of trivial needs. So the basis of the argument not is not that it's bad for the embryo itself but it's an undecent thing of human beings to bring about these creatures just for trivial needs. That's not the way we ought to relate to embryos, that's the idea, right, that these behaviors would be unethical even if the embryo has no interests or values for its own sake. Which is not to say that it doesn't but in addition to Intrinsic values, like that even if the embryo would have no moral status, right, these reasons hold. So there is something about the relation between human beings and their embryos which itself is worthy of moral concern and this relational value is at the very least in tension with an extension of the 14-day rule. Another extrinsic consideration is that of symbolic value, and to say that the embryo has symbolic value is to say that the embryo stands for something or it signifies something beyond itself, which is of ethical social or cultural significance. The most common example is that of a nation's flag. So the value of a flag does not reside in the colored cloth but rather what the flag stands for, it might be the nation's history, its culture, its victories, its losses or, what have you. This right because of the value we attach to Flags is why are to step on a flag or burn a flag is perceived as impermissible, or at least as offensive. What goes for flags also goes for graves or burial sites, or for sacramental texts, goes for the Bible or for old Sequoia trees or even the number 13. All these have meanings, all these things have value or disvalue not because of the itself but rather because of what it stands for. Now if we apply this idea of symbolic value to the embryo. The embryo might stand for a number of things such as the sanctity of human life, the mystery of conception and birth, or the miracle of life. What the symbolic value in the end stands for is something that has be has to be determined empirically by talking to people from all walks of life. But the committee did recognize that the embryo could have such a value for persons. And this brings me to an important endeavor of indeed discussing all these different values and views I mentioned with a broad audience and this is necessary to understand whether and to which extent people will accept the use of embryos for research and whether they think that an extension of the 14-day rule is permissible. This makes empirical research this makes public outreach not of derivative importance but it puts it at the heart of ethical reflection on embryo research in general and the extension of the 14-day rule in particular. So to summarize the method of the of the health council was to to make a distinction between the intrinsic value and the extrinsic value of the embryo. The committee did its best to identify and include as many of those values as possible but for the intrinsic value we identified potentiality to develop all sorts of moral features which people find important and which ground some form of protection. So it can be the potential to become sentient, self-aware, the potential to become a person, and so on, and so forth, and for extrinsic value we identified the importance of relational value and symbolic value. And we added that a broad discussion is necessary to gauge what people's views are on the instrumental use of embryos, making embryos in order to facilitate scientific research, as well as for the benefits in the clinical practice. Now we come to the other side of the balance which holds the reasons in favor of an extension of the 14-day Rule and well after that array of somewhat convoluted ethical considerations this is a merciful straightforward list of of of reasons.

    So first we know that there exists a gap in our knowledge on embryonic development beyond 14 days, and research with embryos beyond 14 days expected, at least to generate fundamental knowledge about for instance the gene expression behind the physiological changes in the embryo as well as the first steps towards the development of organs. And this in turn increases our understanding of human disease etiology, our understanding of how diseases develop, so to hopefully be able to prevent congenital diseases. Another reason to extend the 14 day rule is to improve fertility treatments. A better understanding of the causes of unsuccessful embryo transfer and of the stagnation in embryonic development could help to increase the success rate of IVF treatments. And lastly our understanding of human embryonic development relies mostly on human stem stem cell models and animal models. And although we might eventually recapitulate the entire embryo development with embryo-like structures validating their accuracy requires using human embryos as a benchmark. And this is a a big if, whether we can do this with embryo-like structures. I've talked to many scientists some are very optimistic others are more pessimistic. I do not have the expertise to make claims about which one is realistic but maybe we can discuss that. But the extension of the 14-day limit to 20 days would allow for the benchmarking of embryo-like structures against natural human embryos. And again according to the committee it's Paramount Paramount to also gauge whether and to which extent the scientific and clinical benefits uh resonate with a broad audience in order to create acceptance and trust.

    But based on the considerations on both sides of the balance the committee concluded that it is impossible to pinpoint a moment in time beyond which research with embryos would become unethical except except in a late stage of development. So pinpointing uh there's nothing about 28 or 14 for that matters which is ethically uh important as opposed to say 13 days or 27 days or 29 days, but nevertheless an important reason for the committee to propose a legal limit at day 28 is the societal perspective, which is closely tied to public interests that embryo research serves. So research up to 28 days in the development of an embryo can yield valuable knowledge that may be used to prevent all kinds of developmental disorders and treat fertility problems.

    Now almost done but I've not touched on the issue of embryo-like structures or embryo models yet. I'm sorry first this is a this is a visual representation of the arguments I just represented and you can find this and you can actually find the whole advisory report online and I can definitely send the URL so you can have a look for yourself.

    Now should there be a comparable developmental limit for so-called embryo-like structures, and the view of the committee here is that when it is the case that there are embryo-like structures which fully recapitulate the growth of the human embryo, which is to say that requires embryonic and extra embryonic tissue to be there so that there, are realistic, that there is a realistic likelihood that that model has the capacity to go through the embryonic stage and to go through the fetal stage and all the morally relevant features start to appear such as sentience such as awareness such as self-awareness, only in that case that basically they would be undistinguishable, the natural embryo and the embryo-like structure. In that case it is the view of the committee that they should fall under the ambit of the embryo act, and therefore that the 28 limit should also apply to these fully integrated embryo-like structures, and in all other cases they should be regulated but then they should be regulated as other biological material is regulated. We did not consider how, that specific, how that regulation should take shape, so I'm talking about all the other embryo like structures except for the embryo-like structure which has the full capacity and the active potentiality to develop into a full-blown human person. So we did not consider that but we just made the distinction between embryos which do have a capacity to develop into human persons and those which do not, and for the first class we think that it will be appropriate to subsume them under the embryo act and therefore that the 28 day limit should also apply to that class of embryo models and I think that's it so thank you for your attention.

    Thank you very much much that's very insightful telling us about how the different considerations were explored in the Dutch Health Council.

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Regulation of research with embryos and embryo models (May 2024)

Prof. Emily Jackson (London School of Economics) covers the UK’s history of regulation of embryo research and how embryo models fit in with that and Assoc. Prof. Rosie Isasi (University of Miami) gives the international perspective, including the International Society for Stem Cell Research (ISSCR) guidelines.

  • Well thank you very much everybody for um attending today. So this is the fifth in our HDBI ethics seminar series. We have two great speakers Emily Jackson and Rosie Isasi and so I'll introduce them in due course, and also my sincere thanks to Pilar for arranging this seminar and making such a great job of putting on these ethics seminars, which I think we're all finding really useful. So basically we realize that some of the topics that are discussed in these seminars can be contentious, people can have strong personal views on them and so really we hope that we will be able to create an open inclusive and a safe environment during this this next hour where everybody feels welcome and able to participate. And we really do encourage you to participate in this actively and we have plenty of time for questions and discussion. The way we'll do this is that both speakers will present in turn and then we'll have a question and answer session at the end, and as Pilar has said in the chat the talks themselves will be recorded but the Q&A will not be recorded. So everybody can feel free to say whatever they want. Please do feel free to write any questions or comments in the chat at any point and then we can pick them up during the discussion. I think we have a Slido link yeah so that's also in the chat so if you prefer to put your question anonymously there you can do that as well. So I think that's all I had to say as a sort of introductory remarks. And so we can begin. So our first Speaker I'm very pleased to introduce um first Emily Jackson uh Emily is Professor of law at the London School of economics and her research interest were in the field of medical law. She's served as a member of the BMA's medical Ethics Committee for quite a long period until quite recently and in the period 2008 to 2012 she was deputy chair of the Human Fertilization and Embryology Authority the HFEA. She's a Judicial appointments commissioner or she has been in the past. She's currently fellow of the British Academy and in 2017 she was awarded an OBE for services to higher education. So Emily thank you very much for speaking to us your title is "Regulating stem cell-based embryo models" and please do share your screen.

    Thank you so much um for that very, incredibly generous introduction and thank you very much for inviting me. So um I'm going to be focusing on UK regulation here I think Rosie is going to cover more the international dimension so hopefully the two will fit together.

    So before saying anything about embryo models I just thought I'd recap, very briefly, on what restrictions apply to research on embryos in the UK. There's a very very strict regulatory scheme which has been in place in the UK since 1991. So you can't do research on embryos in the UK without a license from the human fertilization and embryology authority. You also are not allowed to culture embryos in vitro after the formation of the Primitive streak or 14 days whichever happens sooner. So there's a very hard limit primitive streak or 14 days. The HFEA is only allowed to Grant a license for embryo research if the research proposal is necessary or desirable for one of the statutary purposes. So it has to serve a particular purpose, for example to improve fertility treatment, it also must be necessary to use human embryos. So the HFEA couldn't grant a license for research on embryos if you could do the result do the same research using animals or existing cell lines. One of the features of this regulator regulatory regime is quite how tough the sanctions are. So it's a crime to do anything these things without a license and it's a crime culture an embryo in vitro for more than 14 days and the maximum penalty, which is in some ways quite shocking is 10 years in prison. I mean nobody has gone to prison for 10 years, in this case in fact, I think one of the hallmarks of the regulation of embryo research in the UK, is there's been very very high levels of compliance. I think most people think it's very well regulated and the the HFEA has a good handle on what's going on and, and control is there.

    So that's restrictions on embryos but what about embryo models? Are they included in this incredibly intense regulatory regime? Well if we look to the legislation to tell us whether they're included, it's actually not really very helpful, that the first section of the statute says, in this act: "embryo means a live human embryo". Now as you probably completely obvious to all of you that's a very weird definition, because we don't usually use a word um that we're trying to define in defining what it is. So just as an example it would be like saying: "a table is a round wooden table". That doesn't tell you what a table is, it just tells you what type of table you're talking about. So the highest court in the country which was then, at that point, the House of Lords rather than the Supreme Court. It was faced with this question in a case about cloning at the beginning of this century and it's conclusion, which I think has to be the right one, is that: the act assumes we know what an embryo is, therefore "embryo" has its ordinary language meaning in law and on that basis, the basis that it has its ordinary language meaning, the HFEA's current working assumption is that embryo models are not embryos, and so they're not included. That means, aside from the rules that apply to stem cell research or other kind of human tissue research, research on embryo models is pretty much unregulated in the UK. Now there is a mechanism within the statute for the Secretary of State for Health and Social Care to change that with regulations. Regulations could be passed to say that for the purposes of of the act embryo models were included. But I'm not sure that that would be a helpful solution here. It would be a real Sledgehammer of a solution. It would have an immediately chilling effect, all research would have to stop immediately while scientists applied for licenses, but it would also result in a hugely more restrictive environment for research and embryo models than, than exists at the moment. So though there's a mechanism to bring them within regulation very quickly I'm not sure anybody thinks using that would be a good idea.

    Now some people have suggested that embryo models could replace embryos in research. And currently, something I mentioned just then, which is often described as a necessity principle, does mean that if you can't get a license to use embryos, if you could use something else, the statute therefore already contains an inbuilt statutory presumption that you should use embryo models if you can. So if you can use embryo models you should, but I think everybody accepts that, they're not, embryo models aren't going to replace embryos entirely. In part because you also need to validate embryo models in terms of seeing how they're developing. And to that end I think lots of people think it might be a good idea to actually extend the 14-day rule. But in addition I think the argument that's sometimes made that we could have a kind of three Rs approach to embryos, in the same way as we do to animals where we try to reduce their use, that that actually isn't necessarily a sensible thing to do because what we know about IVF patients is that for lots of them donating leftover embryos to research is really something they want to do. And Kathy Niakan has spoken incredibly movingly about the lengths some patients go to to try to find a research project as a home for their embryo. So it's not self-evident that discarding embryos is better than using them in research. The key difference of course, I'm sure you're all aware, is scale that you could make millions of embryo models and that that enables things like high throughput toxicology testing which would be impossible, as well as illegal, on human embryos.

    If we were to ask instead what the moral status of an embryo model is, what our obligations might be towards it, this is a complicated question as well. There are some people who have said well is there a point at which something is so much the same as something else that it becomes that something else and obviously you could go around in circles with this sort of this this sort of discussion. But in trying to think about moral status it might worth trying to think about where the special moral status of the embryo comes from. Is it because it derives from human eggs and human sperm or is it from its potential. Now potential is quite a complex and confusing concept here. In part because IVF embryos don't have any potential at all unless they're gestated in a uterus for at least five months. But also if you can make pluripotent stem cells, that rather disrupts any arguments that you might have grounded in potential because anything has the potential to become anything else. The skin cell can become almost anything. If we're instead interested in the question of whether it could implant we in at bit of an impasse there as well because the research necessary to answer that question would be very dangerous and unethical, and no one wants to carry out those sorts of experiments. So I think in terms of what the potential of embryo models are is we really really don't know.

    So you can go around in circles about moral status and I think here at this point it's quite helpful to look back to the Warnock report which considered groundbreaking, at that point in the 80s, the completely groundbreaking possibility of fertilizing an egg outside of a woman's body. Which was revolutionary in the 70s. 60s 70s and 80s, 70s obviously the first birth, and Warnock obviously reported in 1984. But the thing that I think is useful from Warnock is that they accepted they were dealing with similarly intractable questions about when life, when personhood, began and there was never going to be agreement on them. So the better approach, the simpler approach, was go straight to the Practical question of how the embryo should be treated. So rather than think about what its status is, how would would we want an embryo model to be treated?

    Also the other thing that I think is quite useful from Warnock is that though the Warnock committee itself disagreed on the of embryos, there was a dissenting minority opinion, there was one thing on which the Warnock report did agree and that's that some legislation here is better than none. That there should be some limits that should not be crossed.

    Mary Warnock herself, I think, also recognized that regulation was not only needed in order to allay public concerns but that actually it was also positively helpful for scientists to know where the boundaries are so that they can get on with their work, and it was very helpful for scientists for Parliament to be taking responsibility for deciding where those boundaries should lie.

    The Warnock committee was also I think ahead of its time in recognizing the need for public engagement in relation to novel scientific developments. And Anne McLaren the incredibly influential developmental biologist who played an absolutely pivotal role on the Warnock committee. She was interviewed by Jane Denton shortly before she died, and I love her quote about just "the more consultation the better", she was all for public consultation. But also I think what she's saying here is it's not public dialogue, here, is not just top down public education, telling people things, it's also genuine two-way dialogue with the public. At the same time obviously we must admit public understanding of embryo model research is currently pretty low. So it's also important to be able to explain clearly, and accessibly, what this research involves and what it hopes to achieve. And in doing so it's important not to over-promise that the cure for miscarriage is imminent. But also not to under-promise by making claims that embryo models could never develop into a full baby, if they were to be carried to term, because we simply don't know the answer to those questions. We don't think they can from mice but there were no certainties here.

    So there has been some public engagement published recently, in relation to embryo models, which is incredibly interesting and helpful. And I think predictably perhaps the public are surprised about the lack of regulation. They view governance as vital here and see the fact that actually what we need is legislation, that voluntary codes of practice, which we hope that one will be out relatively soon, are important but legislation needs to follow up. But also recognizing that legislation shouldn't be impeding research by being too inflexible, and the need for regulation to keep up to date, to be regularly reviewed, because obviously the science is moving very fast.

    So if we think about how this sort of research should be regulated in the future well we do need a regulator here, the International Society for Stem Cell Research guidelines suggests that there should be some sort of oversight and we're currently not fulfilling that in the UK. And I think most people would agree that the HFEA is probably the appropriate regulator here. It's well respected, lots of experience of dealing with novel issues. I think an initial red line, I think again there's widespread agreement on, would be that these shouldn't be put back into a uterus. And the act in fact tries to accomplish that by saying you mustn't put back an embryo other than the permitted embryo, which is made with human eggs and human sperm. But of course the form of words is a bit unfortunate because it says you mustn't place an "embryo" other than the permitted embryo so if these things aren't embryos are they covered by that prohibition? I think you would, so even though no scientist want to do this, I think this is a legal loophole potentially that needs to be plugged. You would want a prohibition on putting them back into an animal host, and I think you would also want some kind of time or developmental limit. Now the 14-day limit doesn't work because embryo models don't develop in a linear way, from day one, day two, day three, et cetera, you can jump forward and make an embryo that starts off at, an embryo model, that starts off at a later point. So ISSCR suggest: "minimum time necessary to do the research" which is helpful but potentially infinitely expandable, so you might need to supplement that with some kind of developmental landmark. I think the statutory purposes that we have for embryo research would be too restrictive here and I think probably we don't need to have on the face of any legislation what the purposes should be. But I think it's an open question about whether there might be a preference, or an obligation, on scientists to use the least complex model necessary to do the research. Clearly you need consent from the tissue donor who provided the original tissue for the stem cell. And again open questions there about whether that consent needs to be specific or generic, whether generic or broad consent is appropriate. And finally I think you need to decide what penalties should be appropriate. Would a, would the, sort of criminal penalties that attached to embryo research be appropriate. Well possibly for putting back into a woman's body, but perhaps not for some other things. Final thing I just wanted to say really really briefly is I really hope, that it's obviously not going to be this government that tackles this, probably the next one. I really hope it takes it's time in so far as there is time, to produce properly well thought through legislation, because I think one real danger that we all need to be really aware of, is that there's some scary headline followed by knee-jerk legislation which ends up imposing restrictions on research which in the future I hope will transform all of our lives. And I'll stop there.

    Thank you very much Emily that was really nice and very thought-provoking. I'm sure there'll be plenty of questions in due course on what you've said, some of the different aspects. Okay so now on to our second speaker. If I can just sort out my screen a little bit. Okay, so I'm very pleased to introduce Rosie Isasi who is associate professor of human genetics and adjunct professor of law in the John T. MacDonald foundation department of human genetics at University of Miami Miller School of medicine. Rosie is researching various aspects of the social, ethical, and policy dimensions of technologies, which she calls disruptive technologies. I hadn't really heard that term before but, by that she means technologies that challenge us, I guess to change the way we do various things, so genomics, precision medicine, regenerative medicine, are examples of that. She, Rosie, holds many leadership roles both nationally and internationally. So for example she is ethics policy advisor of the European Commission's European Human Pluripotent Stem Cell Registry, she's co-chair of the American Society of human genetics' professional policy practice and social implications committee, and she's a member of the ethics and policy committee of the ISSCR, which Emily has already mentioned, the International Society of Stem Cell Research. So Rosie thank you very much for agreeing to speak to us today. The title of your talk is: "Charting the governance of stem cell-based embryo models" and so please take it away.

    Thank you and appologies I will stop the video while I present it because I find myself distracted by looked at myself.

    So I want to talk about the regulation of stem cell embryo models at both International and National level.

    But let me start with some conceptual issues to just frame the discussion.

    There's a definition, almost universally accepted, of what is and what is not an stem cell based embryo model. It's not a human embryo, as Professor Jackson was explaining to us. These three dimensional structures that derive from pluripotent stem cells and the idea is that they will model mimic or recapitulate the developmental process that occurs in early human embryo. The different countries have adopted different criteria to further define what is an embryo and what is a stem cell embryo model, maybe. The ISSCR's new approach is non inte..., is distinguishing between integrated and non-integrated stem cell models. The difference being whether they contain extra-embryonic structures and / or the ability to undergo further integrated development in vitro. So the more they can really resemble, and feel like, and be like like, a real human embryo. Other countries have looked at the potentiality criteria, so the potential to develop in a full structure human embryo, with all the extra layer characteristics, and others have look at developmental stage or the method of creation. Why this is important. Definitions, as Professor Jackson was saying, are the source of an entity's legal status, but also they provide a moral or an ethical justification for the purposes which is that entity can be created, can be a studied, can be used, in research and even in eventually clinical therapies.

    When we talk about the governance model there's several approaches, just want to remind the audience that, there's not only the typical legislative approach where there's laws regulations. There is also this important level of self-regulation, how professional guidelines, like the ones from ISSCR and other entities, and best practice establish what are the goal golden startup for scientific and ethical Integrity in conducting this type of research. There's International treaties and conventions, the European Union has some of them; not applicable, yet, to stem cell embryo models. And also as you know from the UK example, and others, sometimes precedent jurisprudence, can fill those gaps in legislative or in the governance approaches.

    Another terminology that I want to clear, when I talk about a governance and oversight. Governance, what we are talking about is that the HFEA is an entity that have the authority to provide oversight. To actually, to make individuals accountable through respecting the set of rules, and oversight is this level of regulatory supervision that has twofold purposes: Safeguard the rights and the welfare of research participants, or their interests, such as donor of embryos or somatic tissues, but also to ensure that research is conducted with ethical Integrity.

    Now let me navigate you to the International Society for Stem Cell Research and the guidelines. They are based into two premises: Scientific integrity and is interpreted in the principle of transparency, integrity of the research enterprise; and the second one, is ethical Integrity, this is respect for patients and research subjects, put the their welfare first, but also we attend to social and distributed justice issues that might arise as a course of research.

    The guidelines for the conduct of human embryonic stem cell research have evolved over time, trying to keep pace with scientific developments. The early ones very embryo-centric, given the time 2016 in er 2006 I'm sorry. 10 years later with the scientific developments it starts the guidelines addressing stem cell embryo models. At that time they were calling "embryonic like structures". And they were trying to establish with the guidelines a pathway for oversight, for the assembly, the differentiation, the aggregation, of cell populations in a manner that mimics or recapitulates key stages of embryonic development. And this is important, they talk about "key stages", but overall they talk about this human organismal potential, this potentiality criteria. What happened? Six years later, and I was part of the ISSCR guidelines committee revisions, we realized that the potentiality criterion whether it's sound on a theoretical basis it's very impractical in because it cannot be measured or validated for a stem cell basis embryo models, due to ethical concerns and incomplete knowledge about embryonic development. So the criterion became being useless for regulatory purposes, right. If we cannot culture an embryo beyond the 14 days if you cannot mimic embryonic stem / embryo models beyond that stage it will be very difficult to even assert what they're like.

    I just wanted to remind what the guidelines, what they meant to be, is to provide this golden best practice, or these standards, that are aimed to be reconciled or harmonized with national law. Scientific and ethical rigor, independent oversight, transparency are, at the core, one of the core values. And an aspect that is very important is the highlights how scientific and meritorious purposes for novel stem cell research projects and different levels of oversight, which I will address.

    In terms of the regulation on stem cell embryo models, this is a statement in June 2023 as a reaction of many scientific developments that were headline news, and just reiterates what the guideline said: There's a distinction between integrated and un-integrated embryo models, and just calling into attention that the basic criterion is there have to be a compelling scientific rationale. There has been to be a careful review by a specialized oversight process, and a call for scientists to maintain in culture these entities for the minimum necessary time to achieve the scientific objective. And of course this opens to many questions. The guidelines reiterate that is prohibited, the transfer of any embryo model to the uterus, of a human or an animal.

    So when we talk about oversight what are the guidelines, the new revision of the guidance establish? They establish different categories of oversight depending on the type of Science and the ethical issues that arise. In the category one are those experiments that are reportable to an oversight body but are not typically reviewed or call for a specialized oversight process. And here we have non-integrated stem cell embryo models. So they have to go a level of ethical and scientific review but it doesn't call for this extra layer. If we move to category two, and this categorization is new in the 2021 guidelines, it just creates another layer of protection for scientific and ethical integrity and moves here integrated stem cell embryo models. Finally the third category is divided in two, and almost you can criticize that it can be a fourth-, three B might be a fourth category. What it means is that research that in three A - that it could - there is a scientific rationale for conducting this type of research but is currently deemed unsafe by the scientific Community, and also there's a level of ethical sensitivity about that research. And three B is a category that is prohibited it's not allowed because it lacks this compelling scientific rationale but it's also very ethical concerning and here is where gestating human stem cell embryo models within in human and animals is. I must mention to you that all the regulation about stem cell embryo models, establishing the guidelines, are now being reviewed. I'm part of a working group committee that are trying to revise the guidelines. Because scientific developments have happened so fast in the last three years that we feel, we, talking collectively as all the members of ISSCR that doesn't longer reflect the state of the science, and also that we can do a better job in explaining how the, this, complex different varieties of stem cell models will fit better with these categories.

    When I talk about specialized oversight, when the guidance refer, because when it people said well, what it means by the specialized oversight? what it means it's just basically see criterias. They, they have to be. First the project must include scientific rationale. What is the Merit of a research proposal? And they have to be relevant expertise of their researchers. So here the guidelines come for researchers that will be capable of evaluating this complex unique aspects of this science, but also to have enough knowledge and be attentive to the associated ethical issues. You might be familiar in embryo research policies also, that always have this criteria, that it have to be a lack of a justified alternative, have to be ethical and legal permissible and they have to be a strong justification for research. When we talk about how this oversight process look like and how an oversight body must be must be composed or integrated. It calls, the guidance, for membership to be highly multidisciplinary with Scientists, Ethicists, Legal and Regulatory experts, but very importantly it also calls for community members who are not necessarily directly engaged in the research under consideration. So this the, the wisdom of society reflected here, of the public. The updated guidelines also provide some more flexibility in terms of how this requirements, or this calls for special oversight, be harmonized with ethical, for legal norms.

    I want to quickly talk about another aspect that is also germain about the creation and regulation and stem cell embryo models, that Professor Jackson also mentioned. Which is how we culture those human embryos and one of the guidance that is provocatively called to extending the 14-day limit role of culturing embryos in vitro and and to say well maybe that limit it was too arbitrary, and it could, might, might be extended. If there's a robust process for governance and specialized oversight, with the criteria that I mentioned before the scientific justification, this and ethical merit. And finally another important aspect of the guidelines that is, reminds scientists, reminds the whole scientific community, and us, that public dialogue is essential and then establish a new recommendation to encourage public dialog not only beyond issues of how to culture embryos between the 14-day rule, but also to engage them as truly participatory in creating this governance structures.

    The last part of my presentation. I just want to give you just a quick overview to flesh out how that it looks like, how embryo, stem cell embryo models or embryos are defined, are subject to oversight, and, and, and how there's a level of permissibility in the countries. I'm not going to in detail, really I'm just going to post a publication we have some years ago. And would you look at just a sample of countries that cross the spectrum for very restricted approaches to stem cell and embryo research, particularly, to very liberal. And we just look at how the criteria of: potentiality of embryo, developmental stages, and others, were included and how also, according to Prof Jackson, how in many countries there's this loophole and, and this uncertainty of where stem embryos fit within the existing regulatory framework.

    So it had got by surprise to many regulators to see that, well these are embryo like entities, but they're not embryos, and should never be treated as an embryo, unless we go to very complex integrated stem cell embryo models. And, and then these regulatory gaps raise concern about giving proper governance, and oversight, and respecting also societal, moral, and ethical perspectives of how we should look at, how we should regulate, these entities.

    So I'm going to stop share here and just acknowledge my institution and contributions.

    Thank you very much for your attention, I'm trying to put my camera back, Okay.

    Thank you very much Rosie for very interesting talk. So I think we've had two really great presentations very complimentary to each other raising lots of extremely difficult issues but ones that I know many of us on this call are involved with in some way or another.

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Governance and regulation of stem cell-based embryo models (October 2024)

Dr. Ilke Turkmendag (Newcastle University) addresses the issues of exploitation and control presented by biomedical intervention on pregnant bodies seeking to effect the health of their offspring. As well as the challenges of effective communication of scientific findings in this field, including their limitations, in a complex media landscape.

Dr. David Lawrence (Durham University) addresses the ethical and regulatory challenges of neural organoids, advanced three-dimensional models mimicking aspects of human brain development. What moral status, if any, should be afforded to these models as their complexity increases in the future and what should be done now in anticipation of this?

  • [Kate Storey] So hello my name is Kate Storey I'm part of the HDBI, the human developmental biology initiative, and today I'm going to introduce you to the, welcome you to our ethics seminar. So these seminars are part of a series that are intended to facilitate respectful discussion about sometimes contentious subjects related to developmental biology research. In organizing this session we aim to create an open inclusive and safe environment where everyone should feel comfortable to participate and indeed we encourage active participation. And we've also allowed plenty of time for discussion afterwards, after both of our two speakers who are presenting today have given their talks. So please feel free to write things in the chat as questions and comments as, as we go along. And be aware that only the talks and not the discussions are going to be presented, are going to be recorded during the seminar.

    So our first Speaker today is is Dr Ilke Turkmendag, hello Ilke. Ilke is a reader in biomedicine and society and law and, er biomedicine and Society at the law school at the University of Newcastle. She's a legal-medical scholar working in the intersection of science technology and she studies bioethics, sociology with an expertise in human reproductive technologies. Her research has addressed human egg provision for stem cell research, mitochondrial replacement techniques, and maternal epigenetics. As well as human genome editing and most recently longevity technologies. In the law school she's the director of the 'law and futures' research group and at the faculty level she's the lead for the biomedical engineering research center. Ilke is also a member of the Wellcome trust 'social sciences discovery advisory group' and the AHRC peer review college, she serves on executive committees of the socio-legal research association and the north of England medico-legal Society. So welcome Ilke, thank you for agreeing to give a talk.

    Um I think what do is is is do your talk first, and then follow on with David Lawrence's talk afterwards. So the title of your talk: 'Maternal epigenetics: Sins of women of childbearing age' Thank you very much.

    [Ilke Turkmendag] Thank you. Okay hello everyone and thanks for logging on. Today I will talk about transgenerational epigenetics and I know this is a tough audience because I'm not a scientist so I might make some mistakes, please bear with me. So I will talk about how some findings from transgenerational epigenetics especially the ones on maternal effects are presented on social media and in policy, by the policy makers. And so how does this findings find themselves in the public sphere, and what are the ethical legal implications of public discourse on maternal effects. But before doing that I'm going to take you to the world health organization's warning in published in 2021. So they said that: "appropriate attention should be given to prevention of the initiation of drinking among children and adolescents. Prevention of drinking among pregnant women and childbearing age, and protection of people from pressures to drink, especially in societies with high levels of alcohol consumption where heavy drinkers are encouraged to drink even more." Now this was a statement about alcohol, reduction, to reduce the harms in society of course, and I would believe that it was a well-intentioned statement. But the statement was met with immediate backlash on social media because of the definition of the vulnerable group here as 'women of childbearing age' which is according to WHO from 15 to 49 years old that means that any women in childbearing age cannot and should not drink because it will harm potentially the baby that she, they, might have regardless of their plans of having a baby or not. Now I'm going to leave it there because this talk is not about it but about how women's bodies are policed and monitored.

    Now this kind of risk messaging that targets women of reproductive age and pregnant women in particular is not new. For example I don't know if you're familiar with Meloni and Muller's work, they looked at the ways in which maternal impression was used in scientific studies and they say that: "The notion that the thoughts, behaviors, emotions and experiences of a pregnant woman could 'imprint' on her offspring ... has stubbornly crossed different cultural and medical frameworks from ancient and early modern biology into the early 20th century". So the idea about controlling maternal body to shape the best possible baby is not new. But what is new is now these kind of notions can be backed up by science, of course this depends on who is interpreting the scientific findings, but there's a place for the scientific evidence to support these claims.

    The findings in epigenetics suggesting a link between behavior and experiences of women during pregnancy and after birth and subsequent well-being of their children and even the future generations. Now this is a little bit scary scene if you look at it, apart from alcohol intake before conception and during pregnancy there are other examples including: poor prenatal diet, prenatal exposure to domestic violence, or maternal distress, Cesarean delivery, and also emotional problems, symptoms of attention deficit hyperactivity disorder, or impaired cognitive development, is also explained by epigenetic changes. I am usually using the 'maternal epigenetics' so I just wanted to clarify that term: I mean that the environment that the mother is exposed to may affect the offspring and the, even can be passed to the next generations. So I'm looking at maternal effects in transgenerational epigenetics. But this body of women, or the pregnant woman, is not isolated, so this is a problematic part of this kind of discourse because experiments in epigenetics do not address genetic influences in isolation but also take environment into an account. Now this is a positive thing because it departs from the genetic determinism. Therefore it is embraced by some feminists, for example Malubu and Davis thought that this challenge the anatomic essentialism and gender or genetic determinism. But by contrast a number of studies conducted by feminist science studies scholars suggest that maternal epigenetics not only reinforces anatomic essentialism, but also creates a powerful new discourse to control pregnant women and their bodies.

    I'd like to show you video from the former begin before birth foundations website. Please note that the foundation is no longer in operation and the website is closed down, so if if you Google it you may not find it, although there's a link on the slide to find the former pages, and it's no longer operated by a legitimate entity. So on these pages Professor Vivette Glover who is a psychobiologist at Imperial College shares lots of information to help pregnant women, for their pregnancy journey and for the early development, and I think it's a well intentioned foundation to help women, to, benefit from some mental health support during the pregnancy. But there are also lots of materials and videos here, and one of the videos Charlie's story as you can see on the right side of the screen is quite an interesting one. The motto of the foundation was that: 'what happens in the birth' um or: 'what happens in the womb can last a lifetime', and this video is about Charlie, who is wearing a hoodie, Charlie committed criminal offenses and the reason was because his mother was quite stressed during the pregnancy, and she didn't get enough support from her family and friends and also the partner rejected this pregnancy. So she was under a lot of stress and the video suggests that Charlie's criminal tendencies can be explained by this fact.

    So I'm going to show you the video, but before I go on to that it's a worth mentioning that Glover says: 'prenatal anxiety or depression May contribute 10-15% of the attributable load for emotional and behavioral outcomes'. So the problem with this is although this is an interesting observation and worth taking into account, that 'what happens in the womb can last a lifetime', is a quite deterministic approach. And it doesn't give any agency to the people, and the babies' future actions. Which might actually change their mental health or potential criminal tendencies. So the video is here, I'm going to turn it on and it will take only two minutes.

    [Charlie] I'm Charlie I'm 19 and I spent the last last year of my life in prison. I got caught looting during the riots. [Narrator] like many arrested that night Charlie had previous convictions for theft and was known for his aggressive behavior. [Charlie] You probably think I deserve to be locked up. [Narrator] You may have little sympathy for Charlie but perhaps there is another side to his story perhaps his problems stretch right back to the womb. Charlie's mother was very stressed when she was pregnant and had no support from her family or friends. Charlie's father soon left her. [Charlie] My dad was never around when I was growing up. Mom didn't show me much warmth either. [Narrator] Charlie was a very difficult baby often crying for hours on end. [Baby Crying]. His mother soon became depressed and found it increasingly hard to relate to him. [School Bell Ringing]. [Charlie] I didn't do well at school. I'm [words echoed] a slow learner, easily distracted, a rule breaker. I stopped showing up in the end. Then I was excluded, which was sort of what I wanted anyway. [Narrator] It didn't take Charlie long to turn to Crime. Charlie wasn't born a criminal but research suggests that his time in the womb and his early life could have made his behavior more likely. His mother's stress during pregnancy could have led him to be a difficult baby, and even to his ADHD and behavioral problems in later life. The risk of these problems developing are doubled. So could better care of pregnant women be a new way of preventing crime? Research in the US is showing that supporting vulnerable women during pregnancy and the following 2 years can halve the number of crimes committed by their children. Maybe if Charlie's time in the womb had been different he'd have been different too.

    [Ilke Turkmendag] But the annoyingly deterministic motto that 'what happens in the womb can last time', 'can last a lifetime' is surely problematic and I understand the well intention behind that. This, but, in most cases the stress during pregnancy could be caused by lots of different reasons: economic, food insecurity, unemployment, losing someone. So there is really not easily, easy way, to address that and give fetus a safe environment, in the UK where access to mental health care gets increasingly difficult. With waiting times up to six months, that help will not be always available. And If a mother feels that her emotional state is causing detrimental and irreversible harm to the child, like they mentioned in the video, ADHD for example, she's not going to feel any better, will she? So this is a problematic part of translation of epigenetics in the public sphere. And this is another example from social media. Don't worry there's no videos here, this study was presented by Menno Henselmans in August this year. And the study he's talking about suggests that pregnant Mother's diet influences the child's taste preferences. So here he says that: "This begs the question of how acceptable it should be for pregnant women to eat junk food, as this will predispose the child to like those foods, and probably not healthy 'whole foods'." And he also, as you can see in the screen he referring to: "Currently the social norm is that smoking and drinking during pregnancy make you a bad mother. Yet gaining lots of weight, far more than necessary for a healthy pregnancy, and eating unhealthy foods are socially very accepted, sometimes even encouraged." So is actually criticizing so we should not only police women for smoking and drinking during pregnancy but also their food choices.

    These examples, I mean I have many and I don't have time to show you. But they all show that, the pregnant body is considered a closed system. A micro environment for fetal development that we can control. And yes we all wish that we can have a happy pregnancy and, not exposed to stress, and we have the sources, so that we can have the best kind of diet and nutrition but that's not the fact for many people. They're also exposed to lots of environmental pollution and hazards, and stigmatizing women, or responsibilizing women, for doing the right things during the pregnancy is a little bit problematic. But what we are going to look at here is the legal process. This is because in the legal process, the social understanding of the normative values around parentage holds a big value. I mean if you think about the debates on abortion and how there is a desire to control the woman's reproductive body, in the US at the moment, this actually gives a lot, a little bit, wider context to this: "Claims associated with epigenetics may influence public notions of maternal responsibility towards future generations and also raise novel challenges for law particularly for transgenerational justice."

    Some lawyers talked about this and bioethicists as well they say that for example: when epigenetics research focuses excessively on the maternal effects women may be constituted as hostile, or as potentially hostile, environments for future people and that might have legal consequences. She rightly warns it's not hard to imagine a solution in the form of more regulatory and social constraints on women. And there are lots of examples of that. If you're interested you can read Fentiman's book, she has a book about this kind of interventions on women's bodies and pregnancy, so it's not unheard of or unprecedented. Given the causal relations that may be established in epigenetic studies legal thinkers already started speculating how epigenetics can be used in the court. For instance, Robison notes if: "Connections between present actions and future consequences can be established scientifically via epigenetics a tidal wave of legal claims would potentially arise of children against parents, grandchildren against grandparents, and so on", and actually I saw some news coverage of, you can sue your grandparents for what they ate during pregnancy, this is not, ur, this is already in the social media and news. Furthermore as epigenetic changes can be transmitted to subsequent generations concerns arise as to whether transgenerational claims could be successfully established in the courts. There's also example of this, for example cases relating to diethylstilbestrol (DES) in the US illustrates how the courts were faced with claims as to epigenetic imprints from multiple generations. The initial claims were successful, made by mothers and daughters exposed to DES against manufacturers. So there are, the third generation claims were not successful, but there is also precedent in the law that this might happen.

    I have conducted some interviews, this was funded by British Academy and the leverhulme trust, I spoke to legal thinkers and the bio-ethicists to see if these, the, discourse available in the public sphere can rise to legal and moral obligations and whether this can be even used in the court.

    Well actually it does look like that there is a risk of that, for example one of the bio-ethicists says that: "We need to be careful we need to put safeguards against bad interpretations and discrimination ... but it is going to be difficult to an anticipate those issues". Another bio-ethicists said that: "The way epigenetic findings are interpreted by policymakers are deeply influenced by the ethical and ideological views of the policy makers". So for example someone who is also have a policy to avoid abortions might have different ideas about how to control that pregnant body, or how to discriminate women for example, when they didn't take care of themselves as much as it was asked by the policymakers.

    There are also, there was also, talk of gender biases for example this bio-ethesis says that: "There are ways to articulate epigenetics that are compatible with classic neoliberal logics of responsibilizing the individual. It still makes intuitive sense right can have this kind of idea of the very importance of the mother because we were all raised at this point in some kind of dysfunctional version of nuclear family. We grow up in a society where a lot of women, in one way or another, raise children and in some kind of level of isolation, right?" So the bioethicist here is talking about that there's already that idea of women as carers of the children, and this this might actually affect the ways in which gender biases play out in the court.

    A lawyer said that: "I would give very little credence to these victim blaming schemes", So he referred it as 'victim blaming schemes' and he said that: "Start out telling me you are going to now blame men as well as women and their role in this and then I'll pay attention to you". And also he reflected on his work in the past: "In terms of blaming mothers, one issue that I've worked on for many years is policies in the US that excluded from the workplace", excluded women from the workplace, "who not only were pregnant but they were fertile, so they were potentially pregnant." and therefore they weren't given jobs, and it went to the Supreme Court. "so it's the same kind of issue that we've been seeing"

    And there is also some concern about the stigmatization of women, especially pregnant women, this lawyer, another legal thinker says that: "It is a well-known fact [women] are already under pressure for their behavioral and other life choices during pregnancy and if you can propagate this idea, well, then it's not only you will be responsible of how the child turns out like, but also for your behavior six generations after. {...} This will kind of drill down even more pressure on women".

    So overall, the scientific findings in epigenetics and maternal environment are too preliminary at the moment to provide a solid evidence in courts. But but we don't know how it will play out in the next for example 10 years, and even if the evidence is good science, because it's not always translated in the accurate way. But even if the evidence is good science, it will almost impossible to isolate epigenetic mechanisms from the social context. So you can see the causality between, for example Charlie's, criminal behavior and his mother's exposure to stress, but that that's isolated environment, what's important is where she was living, why she was stressed, and those are the um environmental facts that we cannot control and also this relationship is a very private one, as held in Stallman v. Younquist the relationship between a pregnant woman and her developing fetus was: "unlike the relationship between any plaintiff and defendant". So putting them against each other is very problematic. Almost all bio-ethicists and legal thinkers agree that gender biases play a big role in our understanding of moral responsibility, but also how we understand and translate the epigenetic findings. There's also a lot of evidence coming from transgenerational epigenetics that showing the, for example a father's exposure to bad environmental hazards can cause problems in the sperm quality, of the sperm, but that's not we are picking up in the social media. So finally while the findings from epigenetics research can generate useful insights to enhance people's lives, and of course the pregnant women's lives, by tackling with social inequality they might also bring an undesirable effect of discriminating and stigmatizing certain groups of people, and that's probably something that we have to think about when translating findings from epigenetics to public. So I think that will be all. I welcome all your questions and thanks for listening.

    [Kate Storey] Thank you very much Ilke. It's, it's fascinating to think about how advances in science can change the way we perceive our own bodies as women, but also how, how we also framing that in terms of a wider society, and, and the responsibility women have for their for their developing child. So we'll come back with discussion about that after, after David Lawrence has given his talk. So I'll briefly introduce you David, as we I think we're probably running a little bit short on time, I'll try and be quick. [Ilke Turkmendag] Sorry. [Kate Storey] Yeah never mind it's okay. David is a bioethicist researching ethical legal and policy implications of emerging biotechnologies including neurotechnologies, implantable devices, and human enhancement. He has other interests in bioethics and medical law more generally, with a current project focusing on the creation of new life forms through synthetic biology. He's an editor of the clinical journal of neuroethics and the Cambridge quarterly for healthcare ethics. And David's talk today will explore ethical and legal challenges posed by neural organoids and related technologies, particularly the moral and sentience related risks posed by advanced neural models and consider whether these need new forms of regulatory Insight. So a very different topic. Thank you very much.

    [David Lawrence] Thank you, I also, just to say there's a lot of people here thank you for coming to listen to this, far more than I perhaps anticipated. I want to preface just by saying um this is a a fairly broad overview. I thought the thing to do would be to discuss kind of what issues are being discuss, what ethical issues and sort of policy related issues, are being discussed, in the places that such things are discussed. So there won't be a huge amount of depth on, on most of the things that are mentioned but I just thought it was important to highlight what is being talked about. Conveniently for me that includes the thing that I most interested in, which is the sort of moral status related, ur thing, we'll come to that in a moment. So yeah this will just be a kind of an overview of the what are probably the more pressing ethical and regulatory questions coming out out of neural organoid research. Specifically thinking about things how these structures are forcing us to rethink some of the fundamental issues in the frameworks that we use to govern them. But my point is that this, you know, this isn't theoretical, as these technologies, or things like neural organoids and related technologies develop, there is a need for a kind of much more nuanced ethical oversight, and this is becoming sort of increasingly urgent. Just trying to start my stopwatch so I don't go over time sorry. There we go.

    So look I realize that there are those in the room, there's names that I recognize in the list who are, who are going to be vastly more familiar with some of these concepts, particular the sort of scientific side of things, so I will try to keep this brief. For those less acquainted neural organoids are essentially 3D 'brain-like', and I use that term advisedly, structures grown from pluripotent stem cells. What's gaming about these is that they will help us overcome some of the limits of older models, like 2D cell cultures and animal, excuse me, animal models. They kind of give us a window into, direct window, into human brain development and neurological, the development of neurological conditions. So for example models are being used to better understand diseases like Alzheimer's, Autism, the impact of the Zika virus, I know was, has, been the subject of some research on fetal brain development with organoids. And this is where the, these, things come into their own. They go way beyond what we've been able to... Whoops sorry I've skipped ahead there, they've, they kind of go way ahead what we've been able to achieve with, um you know, traditional cultures. They let us track, you know, human specific neural activity in a, you know, a perhaps a more realistic context, if you like. And lately there have been a number of really exciting developments things like assembloids. These are a step forward, they're combining different regions of the brain to create more comprehensive models. More recently 'organoid on a chip' where these are systems by which we're able to keep these cultures alive longer, provide them with steady steady and directly controlled nutrient supplies, which opens up the possibility for much more detailed, much more extended, studies. But, and it's a big but, there are a lot of limitations. Despite advances, you know, neural organoids are a very long way from replicating anything close to a functioning human brain which if you read, I don't know the Daily Mail, is what they would have you believe. They lack vascular systems, for the most part, which limits their growth, their structure, again for the most part, it's very disorganized compared to, you know, actual human brain tissue. So understanding these kinds of limitations is really important when you are thinking about the ethical implications. I know that that was a very potted version, possibly incorrect In some instances, of the science so please hold your excoriation until the end. So what I'm going to do is just outline a couple of the kind of pressing concerns that stem from this, and then we'll go into a little bit more depth on what I think are the more complex issues on the horizon.

    So one of the core ethical dilemmas, perhaps a more prosaic one admittedly, is ensuring truly informed consent, right to to tissue donors. The pace of advancement in this field is giving kind of quite unique challenges. How can you expect, like really expect, a donor to kind of fully grasp how their cells might be used in future research in this area? Because the fact of the thing is, that we, I say we as a research community, we, don't necessarily know what direction things are are going to take, you know, in a year or two years. The kind of traditional... done that again sorry... The kind of traditional consent module, uh model, traditional forms of consent, informed consent, they might not be enough anymore. And I mean this is not just limited to neural organoids, this is true in a lot of, kind of, fast moving areas of of scientific research. But in this context people who are donating tissues, donating cells today might not realize that their cells could end up forming, you know, these brain-like structures and so the question is are they really providing inform consent for that outcome? And the question is that even if we are to try to explain these things, as I say, we don't know exactly what direction the research is going to be taking and it's quite hard to ensure that people fully understand the implications of this in when we're talking about brain related things. There is a tendency, there's some good kind of socio-, medical sociology on this, of people being um sort of overawed by discussion of brain related things and kind of willing to uh so non-critically accept what they're told. So it's actually quite difficult to ensure a full understanding, in some instances, when you're talking about this type of thing. I mean that, actually I say that research is, actually, that's largely been used in neuro-evidence, the use of neuro-evidence in the courtroom, where it's even more crucial, or could be more crucial. So anyway, this issue of content becomes all the murkier when you think about the long-term, right, these unforeseen uses of organoids. We're all aware of, you know, the Henrietta Lacks thing. So you can imagine a donor's cells being created, used to create, an organoid that be could be kept alive and studied for months, for years, a new cell line... These are levels of complexity that most people just don't anticipate when they're giving consent. And there isn't really a clear or particularly great solution for this at the moment. It's something that is currently under discussion. One proposal that has gained a lot of traction is the idea of 'dynamic consent', right. So a model of ongoing communication with donors where they're updated and they, kind of, give fresh consent as new research possibilities arise. Which sounds great in theory but in practice that's so difficult, keeping track of donors over the long term, especially as the research changes unexpected ways, this is a logistical nightmare. And so as researchers, you know, we've got to think about how to find the right balance. We want to be able to move forward with critical scientific research, but you, we, need to be able to continue to respect the autonomy of those who donate cells. If we don't do that then we can kiss goodbye to people donating in the future. So this might just mean being more upfront about the potential and the sort of known unknowns, or it might be you know developing these new consent models that allow for flexibility and finding ways to make those those work as research evolves in unpredictable ways.

    A somewhat related further important set of concerns revolves around data protection and issues around commercial commercialization. So neural organoids will often carry genetic information from the individual whose cells we used to create them. There are corresponding, sort of, serious privacy concerns there. How do you respect the the confidentiality of that genetic data? Especially when organoids can be kept alive and studied for extended periods, or that is the goal. So it's not just about privacy in the short term, it's about safeguarding data over months and even years of research. And the further question of commercialization, you know, as neural organoid technology progresses we are likely to see commercial opportunities arise. Which raises all kinds of thorny questions about ownership and profit sharing, which is something that's been faced in other areas of sort biomedicine/biotechnology lately. You know, should the individuals who provided the cells have any claim to profits generated from organoids that become commercially valuable? That's a sticky question. So striking a balance between the interests of donors, researchers, and companies who might be involved is a significant challenge. You also have, kind of, a more, related this as a more broad concern about the commodification of you know brain-like structures. Some people are worried that creating, you know, neural organoid as commercial products might undermine human dignity, they might blur ethical boundaries that we consider to be fundamental to you know biotechnology work and tissue research in particular. And those sort of issues don't exist in isolation, right. They intersect with debates that are, have been, going on for years about genetic privacy, commercialization of human tissue, broader biotechnological ethics questions, so for us it's essential that we remain aware of those concerns and how those conversations are developing in these, like, slightly different fields, or slightly different areas, in order to consider how work on organoids, or indeed whatever, you know, your focus is, fits into that, sort of, larger ethical and societal framework. So that's the more prosaic issues I wanted to touch.

    So let's talk about what's maybe a bit more provocative and more comp, more complex, in some ways, the question of moral status and consciousness and like, I can already see some of you in the room rolling your eyes at this. So I want to just preface by putting a couple of words on my position here. This is kind of my core area of Interest more generally, throughout biotechnology. But I don't want to give the impression that I think we're currently in a position where we, you know, have this concern, where we have organoids that are sentient, might suffer, possess sapience, anything like that. I'm fully aware that we're not. That organiods are, you know, not that well developed, and they may never be so well developed. Because of, you know, things about their structure which we'll mention a little bit later, but I have two thoughts on this. Two very brief versions of thoughts on this: One is that, well my intent here is to give an overview of what's been discussed in the kind of ethics and policy sphere around neural organoids, every room that I've been in where we've been having these discussions, at whatever level, this issue has come up. If it, and if not been, the kind of, the core focus of the discussion. And secondly I'm of the opinion that with biotechnology we ought to think proactively. Should this situation never arise then okay well we wasted a little bit of time talking, but if it were to arise, as we'll discuss a little bit later, as well; setting up any kind of regulatory regime will take an awfully long time, decade maybe. And it is taking a long time, and taking a lot of work, and if it needs to account for a scenario with moral status kinds of issues then it will take even longer, because these are difficult to parse out. So it kind of behooves us, in my view, to start thinking about it early. So I'm just going to outline the very basics here. As these organoids become increasingly sophisticated they exhibit more brain-like, or more akin to brain activity, we are forced to think about these challenging questions about the moral status. You know, at what point, if any, might an organoid deserve moral consideration in its own right? And this is not just an academic question, right, it has profound implications for how we conduct research, what limits we place on experimentation, and so on. When we are thinking about moral status, you know, it's sort of the intrinsic value of things. This is in inextricably linked to questions of consciousness. We've seen, you know, reports that have been heavily criticized, studies reporting patterns of electrical activity, there was that paper from 2019 the name of, names of the authors I forget, but that purported to show electrical activity resembling those seen in, you know, like a premature human fetus neural tissue. I believe that that was sort of largely debunked, but these are concerns that people have. You know, there was supposedly showing coordinated waves of activity, which I know does happen. The thing that was in question was, like, whether this was actually representative of something that might happen in a pre-term fetus. So, you know, while it's crucial to emphasize that, you know, current organoids are far too simple to possess anything resembling what we might think of as human consciousness. Then these findings, kind of, raise really important questions about the future trajectory this technology is going to take. And so I feel like I should say what we mean when we talk about consciousness in this context then. Within bioethics more generally consciousness could refer to a range of capacities, and it's you know, this is something that is a constant argument. But for my purposes at it is most basic it might mean the ability to have, you know, any kind of experience, even if it's not something self-reflective. You know I, this is all as I say, this is not widely agreed, everyone has their own interpretations, so every paper that talks about this will set it out at the beginning. But for my purposes I tend to divide like this: Sentient beings can experience positive and negative sensations, right. That we can think of as representing the, sort of, most basic level of consciousness. Above this we might think of beings that are self-aware, or to different extents capable of experiencing like a wide range of subjective mental states, and that might encompass a broad spectrum of cognitive abilities. And within that category there's, there's you know, significant variation as the kind of complexity and richness of conscious experience can differ greatly between between the sort of subjects. Beyond that we have what we might think of as sapient entities. Things that are in possession of advanced cognitive abilities, reasoning, abstract thinking, moral agency. These are things that we would, you know, associate with personhood, and what we sometimes call 'full moral status'. The kind of thing that, you know, we like to think that we possess. Obviously not an issue for organoids just yet. There are also of course various kind of competing theories of consciousness that we we have to throw into the mix in these discussions, we might think about things like 'Higher Order Theory' where it's arguing that consciousness requires the ability to reflect on your thoughts, which you know organoids don't have obviously. Things like integration, uh excuse me, 'Integrated Information Theory', it's quite popular, on the other hand, suggests that, you know, even simple neural networks might have basic awareness. There's other things like 'Global Workspace Theory' which I'm personally less familiar with, but you know, these see consciousness as the product of widespread neural activity right which is maybe a level of complex that organoids haven't yet reached. This is something that goes hand in hand with complexity science, which is something I'm starting to try and learn about myself, but because there's this big range of interpretations it becomes quite challenging to pinpoint exactly what constitutes sort of morally relevant consciousness in organoids.

    But I like to be pragmatic right, this is kind of my my thrust in a lot of what I write. I think that we can cut through a lot of this to get to the heart of the matter and the lawyer Hank Greely did this really nicely he asked: "If it looks like a human brain and it acts like a human brain at what point do we just treat it like a human brain?" and I think that encapsulates the core of the ethical quandary, like, quite nicely, it's like a nice little nutshell. It's a bit sound bitey, it makes some assumptions, but I think the thrust of it, yeah I'm on board. So to kind of address that some ethicists really go for a precautionary approach, right. They argue that given the uncertainty the high stakes that could be involved here, then we should err on the side of caution, and that might mean treating organoids like they have a, you know, a degree of moral status worth protecting, once they reach a certain level of complexity, even if we're not actually certain that they do possess sentience or consciousness of any kind. The rationale being that if we're wrong, because we don't really understand consciousness, if we're wrong about them lacking it, then the moral cost of causing that kind of suffering, or the potential kind of suffering, is a severe moral cost. On the other hand some researchers, ethicists, kind of contend that ascribing moral status to organoids is premature, right, and doing so would unnecessarily hinder really valuable, really important, research. Some of they, some of these, kind of, argue further that without the broader context of a body sensory inputs, interactions with an environment, an organoid no matter how complex it is, can't meaningfully be said to have experiences that, you know, some people consider to be vital for the granting moral status. So they would tend to emphasize the sort vast difference between even the most advanced organoids, organoids excuse me, and, you know, a functioning piece of human brain tissue. At the moment they simply lack structures that are considered to be fundamentally necessary for things that, you know, cognitive processes that we think are necessary for consciousness. So lacking the cortical plates for instance. And then there's another level of complexity, which we'll come to a moment, the, kind of, question of moral status within chimeric models, you know, where um, transplanting neural organoids into animal brains. But as we, sort of, navigate these sorts of questions it's worth, sort of, thinking about the concept of moral status as a continuum rather than a binary state. You know, maybe as organoids develop more sophisticated neural activity they could be granted increasing levels of moral consideration. Mirroring in some ways how we often can afford different levels of moral status to various forms of life that we're familiar with. This is, you know, shamelessly, this is the subject of a book I'm working on the minute, so you know look out for that in, who knows how long sometime. Ultimately as researcher is pushing the boundaries of what's possible with with neural organoids, you know, you'll need to think about these profound questions I think. It's crucial, in my view, to remain informed about the the latest ethical discussions, what's going on in the policy sphere, in the area and to be prepared to justify the moral considerations in your research designs. It might be that we need to develop new ethical frameworks and guidelines that can evolve alongside this kind of technology. You know, that can ensure that our moral reasoning keeps pace with the science, which, you know, it doesn't always do.

    I mentioned another issue here, sort of a growing concern, that you, around neural organoid research, the use of human animal chimeras. The ethical questions here are not new, particularly, but in this instance, you know, you're transplanting neural organoids, or organoid tissue, into animal brain tissue. Primarily to side step, or my understanding is primarily to side step, the sort of size and vascularization limitations that we have in in vitro models. I could be mistaken about that. Which is exciting, there's exciting research opportunities there, but it opens up the door to a number of significant ethical questions that, kind of, have been going on in the chimeric sphere for a while. The first being, more obviously, animal welfare. How does introducing human neural tissue impact on the host animal? Or suffering?, could it change the animals cognitive behavior in ways that might raise serious, sort of, welfare issues? There's a broader question about humanization, you know, if part of an animal's brain is made up of human neural cells, like, at what point do we need start reconsidering its moral status, right? You know, could they, could chimic animals, be developing cognitive capacities that are in some way resemblant of those of humans? And if so what ethical obligations do we then have to these strange new creatures, you know in, in how they're treated? And we could push it even further and say, you know like, or we push that last idea further rather, there's a really tricky issue is the potential of the development of you know mental states that we might recognize, or cognitive abilities that we might recognize, from humans. Whilst we are not at that stage of research it's an incremental risk that we can't afford to ignore. You know, experiments as I understand it, have already shown, sort of, some degree of integration between human animal neural tissues and there are suggestions, again as I understand it, I could be mistaken, of behavioral impacts. So these questions, as I say, they connect to, like, larger debates that have been going on for since the year dot about the ethics of animal research, the moral states of non-human animals. But, you know, we need to weigh the benefits of chimeric research against the ethical concerns and we need to think about what our safeguards ought to be.

    So with all that in mind as this kind of research advances one of the biggest challenges that we face is how to regulate the, sort of, science around these kinds of models, or the development, of these kinds of models. You know, the pace of the technological development, kind of, outstrips the ability of regulatory frameworks to keep up, right. A the moment, to my belief, no country has any kind of dedicated agency or body that's, you know, specifically overseeing neural organoids. In many places they do fall under the jurisdiction of broader regulatory agencies but these agencies by their own admission are largely not equipped to handle the kind of unique ethical and legal issues that arise from this kind of research. You know, I realize this is sort of an international audience, and I'm forgive me for only addressing the UK, but that's my my chief familiarity and also time constraints. In the UK we have the, um I've done it again, the HFEA, the human fertilization and embryology authority, which regulates research on human embryos and we have the human tissue authority, the HTA, overseeing the sourcing and the use of human cells. But neural organoids fall outside of their jurisdictions once the cells have been dissociated, disaggregated, or developed in the lab, since the organoids are lab grown structures the HFEA's oversight ends after that dissociation and the HTA only covers the sourcing of the initial tissue. So that means that neural organoids are not regulated, they don't come under what's known as the category of "relevant material", and so they occupy this strange unregulated space, despite showing complex, you know, neural activity. And this is a significant, kind of, ethical / legal gray area that existing frameworks just don't address. You know, the issue is then compounded by, as I say, the glacial pace of regular development when compared to the rate of scientific advancements.

    And this problem is not limited to the UK. to mention a couple of things very briefly, Globally the situation is is very inconsistent. A lot of countries, the US, Japan, China, The collective countries of the EU, have a variety of regulations on chimeric work, on embryo research, on stem cell research of various types, but, to my knowledge, and again this this could be somewhat out of date because this is moving quickly, none of them have specific regulation pertaining to neural organoids just yet. There've been a number of white papers, major reports, come out over the last few years: The US National Academy consensus study from 2021, The German leopoldina white paper from 2023, both very interesting. The Nuffield Foundation UK has recently had a briefing come out on this, but there there's no action that's been forthcoming based on those, in those countries, or or elsewhere. The international society for stem cell research, the ISSCR, gives us some, kind of, general guidelines on stem cell research, but they don't directly tackle the ethical challenges posed by neural organoids. They have the quote that's there on the slide: [(Researchers) should be aware of any ethical issues that may arise in the future as organoid models become more complex through long-term maturation or through the assembly of multiple organoids]. And it should be noted that, you know, this guidance is being updated and is due to come out in the not too distant future, so hopefully that will have something, kind of a little bit more meaty on it. As I say countries have laws on animal-human chimeras but, you know, they don't really apply to organoids. I'm sorry I don't know why that keeps flicking forward um, so anyway: What I think we need, urgently, is forward thinking guidance, even regulation, that can anticipate the ethical challenges on the horizon, right, these models are only going to become more complex and as they do our current frameworks will become, sort of, increasingly insufficient, they're insufficient already. We might need to think about creating, kind of, new legal categories for things like neural organoids, entities that exist somewhere between, you know, traditional tissue models and those with, you know, the potential for moral status, sentience. But we're at this kind of tricky phase, this critical phase, in the research where you know regulatory oversight needs to be flexible, it needs, to be interdisciplinary, and it needs to be proactive. You know, the major challenge is to ensure that any regulation that's put in place, guidelines put in place, don't stifle innovative research, but at the same time protect the, kind of, ethical, legal, social, rights of all parties involved. And then, I'm conscious of the time, I'm coming towards the end.

    As we look ahead, it's pretty clear that neural organoid research is moving into, like, this this critical phase, I say, and one that really places, places us, at a crossroads of innovation and ethical responsibility. These models have already shown us all kinds of massive potential in helping us understand the brain and developing treatments for, you know, neurolog-, excuse me neurological conditions. But as it advances, as the technology advances, we need to make sure that our ethical frameworks and our regulatory frameworks can evolve with it. You know, I mentioned earlier things that we're faced with, like the organoid on the chip, we're also faced with things like, you know, so-called "organoid intelligence" the beginnings of, like, "biocomputing" by networking organoids and that's, on the slide is an image of a an early example of this. So a major challenge that arises from this will be moral status. As these organoids and as, kind of, assembloids and everything else, become more complex we're going to start to blur the lines between biological models and something more valuable, right. So we will need new ways to evaluate cognitive function, we will need new ways to evaluate moral status, consciousness, within these systems it, I just don't think it's a question we can afford to ignore and it's going to require serious scientific reflection and serious ethical reflection. Even though, you know, it is in some some way a speculative problem, on the regulatory front we have to ensure adaptability. So whether that means the creation of new oversight bodies, expanding existing regulations or the remit of existing bodies, which, you know, they are broadly resistant to, for good reason. It's crucial that we handle this responsib- responsibly. Again goal is to ensure that we don't stifle innovation, but that we have kind of clear robust boundaries to work within. It's also worth saying, just as a last thought, that most of the issues I've talked about here, however briefly, are pretty much applicable to other related technologies as well the really hot button one at, the moment that's just seeing the same sort of attention, possibly even more attention, in the same kinds of rooms, with the same themes coming up is the stem cell derived embryo model, most if not all of the issues there are similar to those here, though more particularly and more immediately around moral status, and possibly more contentious, anything involving the word 'embryo' tends to be. So, to end. I think that interdisciplinary collaboration is just essential here, right. This is not just a problem for neuroscientists or for bioethicists, it's a challenge that's across neuroscience, ethics, law, public policy soc-, you know, sociological studies as well. Policymakers, scientists, ethicists, we need to come together to think of frameworks that can encourage innovation and safeguard our principles. And as well as this, public engagement, I think is quite key, the societal implications of this kind of research are quite big, to understate it, and we need to make sure that the public is part of the conversation as we go forward. So to conclude, you know, this is an area with extraordinary potential but it's somewhere where we must tread very carefully and so, you know, how as we encounter new challenges do we, as a scientific community, and as an ethical community, how do we ensure that we're balancing those, with, kind of, innovation. So thank you for listening. Sorry that that was a very whistle stop tour, but um thank you for your time.

    [Kate Storey] Thank you very much David. I think it's a great start to having the discussion, which as you say really needs to be across disciplines and across peoples, from scientists doing experiments, and ethicists, and social-sociologists and everybody in the public. Will be affected by these issues. So thanks again. I should have said at the beginning though, that I didn't introduce you properly because I just wanted to say that you are an assistant professor in biolaw at the Durham law school so just to get that clear.

    [David Lawrence] Thank You.

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  • Maternal epigenetics and sins of ‘women of childbearing age’

    Dr Ilke Turkmendag, Reader in Biomedicine and Society, Newcastle Law School, Newcastle University

    In biomedicine, the accessibility of pregnant bodies for biomedical intervention raises important

    social, ethical and philosophical questions about exploitation and control (Turkmendag 2022).

    Maternal epigenetics has an interest in individuals’ reproductive capacity with the aim of developing

    therapeutical or environmental interventions to improve human health down the generations.

    Drawing on examples from social media and interview accounts of bioethicists and legal thinkers,

    this talk focuses on whether the increasing focus on “maternal effect” exerts power over women to

    take on new responsibilities.

    Kenney and Müller (2017: 27) suggest that “as evolutionarily adapted to being optimal gestational

    environments and caregivers, women’s bodies become de facto sites for research and intervention

    in relation to the health of her offspring.” In recent years, there has been an increase in the research

    into linking children’s early development to their mother’s lifestyle and behaviour during pregnancy,

    and even before conception. Poor prenatal diet, prenatal exposure to domestic violence, exposure

    to maternal distress, Caesarean delivery, alcohol intake before conception and during pregnancy are

    all linked to epigenetic changes that may cause health problems in the offspring. In this field, the

    uterus is seen as a micro-environment in which new generations take shape for better and worse.

    Hence scientists, especially those who work in the developmental origins of health and disease

    (DOHAD), seek to find out how to control the maternal environment and behaviour to advance the

    health of the offspring and next generations (Richardson et al 2014). Because epigenetics concerns

    how gene expression is influenced by the social realm, including a range of environmental conditions

    such as exposure to chemicals, pollution, and environmental hazards, the research findings in this

    area have direct policy relevance. For policy makers, rather than controlling the complex range of

    determinants of health, isolating and targeting the maternal body and “responsibilizing” mothers for

    the control of this micro-environment might seem more feasible (Turkmendag and Liaw 2022).

    While the findings from epigenetics research can generate useful insights to enhance people’s lives

    by tackling social inequality, they may also bring an undesirable effect of discriminating and

    stigmatising certain groups of people if they are used to make individuals accountable to

    circumstances that they may not have the capability to control (Richardson 2014, Turkmendag and

    Liaw 2022).

    Suggested reading material:

    Kenney, M. and Müller, R. (2017) “Of rats and women: narratives of motherhood in environmental

    epigenetics,” BioSocieties 12(1): 23–46, https://doi.org/10.1057/s41292-016-0002-7.

    Richardson, S., Daniels, C., Gillman, M. et al. Society: Don't blame the mothers. Nature 512, 131–132

    (2014). https://doi.org/10.1038/512131a

    Ethical Dimensions of Neural Organoids: Navigating Moral Status and Regulatory Challenges

    Dr David Lawrence, Assistant Professor in Biolaw, Durham Law School, Durham University

    Neural organoids, advanced three-dimensional models mimicking aspects of human brain

    development, are transforming our understanding of neurodevelopmental processes and diseases.

    Recent advancements—including the creation of assembloids, which integrate multiple organoid

    types, and other nervous system organoids like spinal cord models—further expand the scope of this

    research. By replicating more complex neural circuits and interactions, these innovations amplify

    ethical considerations surrounding their use.

    This talk explores the ontological, ethical, and regulatory challenges posed by neural organoids and

    related technologies. As these models increasingly emulate brain-like functions, they blur the lines

    between in vitro models and biological neural systems, raising pressing questions about sentience,

    consciousness, and moral status. Are neural organoids and assembloids merely research tools, or do

    they possess a form of moral status that warrants special ethical consideration?

    Further complicating this landscape is the challenge of informed consent, particularly as the long-

    term and unforeseen applications of organoid research evolve. Traditional consent models may no

    longer suffice, prompting the exploration of dynamic consent approaches that can adapt to the

    shifting terrain of biotechnological innovation. Additionally, we will discuss the ethical dilemmas

    associated with creating human-animal chimeras through neural organoid transplantation, focusing

    on potential cognitive implications and animal welfare.

    We will also address the regulatory gaps in current oversight mechanisms, especially concerning the

    moral and sentience-related risks posed by advanced neural models. Existing legislation and

    guidance can struggle to keep pace with rapid technological advancements, leaving key questions

    unresolved. This underscores the need for flexible, interdisciplinary regulatory frameworks that can

    evolve alongside scientific progress, ensuring ethical governance without stifling innovation.

    Suggested reading material:

    Nuffield Council on Bioethics Neural Organoids in Research: Ethical Considerations (2024).

    https://www.nuffieldbioethics.org/assets/pdfs/Neural-Organoids-in-Research-Briefing-FINAL.pdf

    Pichl A, Ranisch R, Lawrence DR, Árnason G, et al. Ethical, legal and social aspects of human cerebral

    organoids and their governance in Germany, the United Kingdom and the United States, Frontiers in

    Cell and Developmental Biology 2023;11. https://doi.org/10.3389/fcell.2023.1194706

    Hartung T, Morales Pantoja IE, Smirnova L, Brain organoids and organoid intelligence from ethical,

    legal, and social points of view, Frontiers in Artificial Intelligence 2024;6.

    https://doi.org/10.3389/frai.2023.1307613

    Croxford J, Bayne T, The Case Against Organoid Consciousness, Neuroethics

    2024;17(1):13. https://doi.org/10.1007/s12152-024-09548-3

Human Embryo Models & in vitro Gametogenesis (February 2025)

Prof. Stephen Wilkinson (Lancaster University) discusses Stem Cell-Based Embryo Models (SCBEMs). These are systems made from stem cells to mimic various properties of embryos and are used to study developmental processes in the lab. These systems pose challenges for regulation as current rules to do not address many of the new scenarios that they present. Approaches to this were proposed in a recent report from the Nuffield Council on Bioethics.

Prof. Henry T. (Hank) Greely (Stanford University) discusses the implications of Human in vitro Gametogenesis, the process of creating eggs and sperm from adult human cells. The ability to produce offspring from gametes derived in this fashion has been demonstrated in other species, what will it mean for us when this technology is safe for human use? A question further explored in Hank’s book: The end of sex and the future of human reproduction

  • [Andy Copp] Right well I think we should make a start. So welcome to everybody who's joined us for this HDBI ethics seminar. So you'll remember this is the human developmental biology initiative a Wellcome funded multi-center program of research in human development, and this is ethics seminar number seven. So we've had a very informative and enjoyable series of ethics seminars and I'm sure today will be no exception to that.

    Just to say that those of you who've joined before we always say that some of the topics that are dealt with in these sessions can be contentious and some people hold very strong views. We hope that after the two speakers have given their talks and we have the Q&A that we'll be able to have an open inclusive discussion and we really encourage everybody to be to participate in that. Pilar has put details of the Slido login so you can put questions there if you want and she'll have a look at that account when we get to the Q&A, or you could write things in the chat, or of course when we get to the Q&A time you can put your hand up, and I'll go through people in order to ask their questions or make their points. We're recording this session, solely the speakers presentations, then we will turn off the recording and not record the actual discussion period.

    So I'm delighted to have two speakers here today Stephen Wilkinson and Hank Greely. They'll talk in sequence and then we'll have the Q&A after Hank's presentation. So our first speaker is Professor Stephen Wilkinson from Lancaster University. Stephen is a distinguished professor of bioethics and he's been involved in this kind of research for a number of years now. So he, together with Rossamund Scott at Kings, he led a Wellcome funded research program for eight years, 2013 to 2021, on the ethics and regulation of human reproductive donation. And he's now involved with another Wellcome project on the future of human reproduction. He works with colleagues in a variety of different fields, so: Design, English literature, Law, Linguistics, Philosophy, Psychology, and Sociology. So very multidisciplinary. Last year Stephen was appointed to the Nuffield Council on Bioethics, which many of us have interacted with and which does wonderful work in this area of ethical issues arising from ongoing research, and Stephen was a member of the council's working group on the stem cell-based embryo models which published a report in November last year. So thank you very much Stephen for agreeing to speak to us today. Title is: "Human stem cell-based embryo models: what are the ethical issues", over to you.

    [Stephen Wilkinson] Okay thank you very much. So let me just share my slides right you can see that? I've actually changed title to: "What are the issues?" because I realized that they're not all ethical issues. Thank you for that lovely introduction. Right so anyway thanks for the introduction.

    The first couple of things I'm going to say have possibly already been covered to some extent. So what I'm planning to do today is give you a few highlights from the Nuffield Council on Bioethics report from November last year called: "Human stem cell based embryo models: A review of ethical and governance questions". So that's just kind of me telling you what it says really. I will then also along the way weave in a few, sort of, broader points and some analysis of the conceptual and ethical issues raised by these entities. As Andrew has already mentioned I should put this on the table for disclosure I am a member of the Nuffield Council on Bioethics, I was a member of the working group behind the report, today is not an official view it's a personal view. I mean I'm happy to defend and what's in the report and so on but I'm trying to sort of pick up on the more general issues and themes raised in the report, not speaking in a sort of official capacity. And as Andrew also said, I should also say that, you know, I'm also part of a Wellcome funded project called: "The future of human reproduction" which looks at new reproductive biotechnologies from a, sort of, humanities and social science perspective and tries to think about new ways that we can think about those. So that's just putting all my disclosures on the table at the beginning.

    So to start what are stem cell based embryo models? Well the other thing I should say before getting going is what my background is. I'm a philosopher, really, by training and bioethics is my area. So obviously I'm not, I don't claim, any kind of scientific authority. I'm not a biological scientist, I'm not any sort of scientist. So there's lots of people in the audience who probably know more about the detail of this than I do, but in my understanding, and this is what it says in the report, is that: "Stem cell based human models is an umbrella term for a range of structures created from stem cells which resemble or replicate aspects of embryonic development. These stem cells are derived either from embryos embryonic stem cells or through the reprogramming of cells from other human tissue such as skin or blood cells (induced pluripotent stem cells).While a number of different terms are used to describe these structures we've adopted the term stem cell based embryo model recognizing the value of consistency with other formal guidelines and Frameworks". So one other thing to say at the start is I think I'm going to in this talk, it's a difficult thing to talk about, nobody can say 'SCBEMs' so there's two things I'm going to call them. I'll call them embryo models that's nice and easy using normal words, and I might also call them 'SKEMs' because in the working group we did have this discussion about whether you could pronounce 'SCBEMs' 'SKEMS'. So I say I'll say 'SKEMs' and I'll say 'embryo models' and they mean the same thing when they come out of my mouth in this talk. But yes the B is a bit problematic in terms of making that a catchy acronym. So that's what they are.

    Probably, again it's worth worth thinking about terminology because this often shapes the way people think about things. So some other things that they have been called are: "artificial embryos", "synthetic embryos", "embryoids", there's another acronym called "SHEEFs", which I've written out on the screen there: "synthetic embryos with embryo-like features". These are all terms that been, there's probably some other terms out there as well. The working group's view was very much that the key thing was to be understood and to interact with other existing work by other committees and other academic research and SCBEMs seems to be becoming, you know, the most commonly used expression. So that's what, that was what, was used, not necessarily because it's the best term in absolute terms, but it just fits in with existing uses in other places. And as I'll come on to say in a minute, I think the idea of "model" is, is, perhaps slightly tricky in this in this area. Or at least from a, from a, kind of "public understanding of science" point of view, might be a bit tricky.

    A key point about stem cell based embryo models is that some of them are a lot more like embryos than others. So as I understand it from hearing various talks and bits of evidence on this. Some of them are more like, sort of, stem cell lines trying to model particular tissue types, or or parts of the body and they're not whole things at all just modeling a particular type of embryonic tissue. And so those entities are a lot unlike embryos, they're not like embryos at all and there's just no way they could ever become, um have any reproductive potential. And that's so that, that, was one end of the spectrum. At the other end there are some entities, or at least could be some entities, which are a lot like embryos, morphologically, functionally and so on. And you know views vary on this, but I have, people have claimed, that, you know, ultimately there is a possibility that those things could have reproductive potential. Although that's as yet completely unconfirmed and would require, obviously that would be a long way down the track scientifically, and also would require a lot of ethical and legal debate before you got anywhere near that. But that's the, that's the, wide range you've got, sort of, individual tissue cell lines, tissue lines, ranging right the way through things that could in principle look a lot like an embryo. So that's, that's, one of the complexities of thinking about this as a unitary topic, ethically or from a government's perspective. You've just got really wide range of entities that you're thinking about and maybe in due course, our, the way we categorize things will become more nuanced and there'll be, this this term SCBEMs will disappear completely, and there'll be three other terms for three different types of things or 10 types, or 100 things, whatever it is maybe the maybe the categorization landscape could change quite quickly.

    On "model", I mean the reason why I'm always a bit nervous about, I think, I think I only heard of stem cell based models quite recently, maybe two to three years ago. Which was quite new to me. And I actually like a lot of people hear this expression for the first time, I think, was struggling to think "what is that?". So literally the first time I heard that expression I was thinking: "is the, is this some kind of simulation?, representation? is it a framework or something?". Because the word "model" can be used in lots of different ways, and I think when when you talk, when, you know, people ask you what you're doing and I say: "I'm on this working party on stem cell-based embryo models". People who are completely outside the field, more than half of those people, I think, we're quite surprise that a stem cell-based embryo model is physically quite a lot like an embryo. I think they thought it was going to be something else.

    So there are lots of senses of the term "model". I mean, I've put a few, I mean some of them are completely irrelevant, so you've got "fashion models", and you get "models" of phones and cars, and you know you can try to be a "model colleague" meaning you're exemplary. So those all, put those all to one side, but there's a few other senses of model which are in the same general ballpark. So you've got, you know, models can be representations, they can be frameworks, they can be simulations. So I think that's what throws people, when you say you're looking at embryo "models", they think, almost thinking, you might be looking at some kind of simulation or theoretical framework, or something. And that's, I mean you know I mean obviously you can explain what's going on, and then that's fine but I think from a public understanding point of view, I think there is a bit of a barrier set up by the term "model". And some of the events I've been in with members of the public they've struggled a bit with that, and they say: "well like why is it a model? why isn't it some embryo?". Anyway, so what we talk about here is a physical model, which is a perfectly reasonable kind of, perfectly reasonable sense of, the word "model". And some examp..., some other examples, of this use of the word model would be: "model aeroplane", "model car", "model village". They're physical things that are like the thing in some respect, but not so much like it that they are the thing. And in particular I think for physical models to be models rather than, rather than, the thing itself they have to, sort of, differ in a couple of ways. I mean normally, sometimes, they're a different size. So model aeroplanes are typically a lot smaller than real aeroplanes, and they also tend to lack important functional features. So in a model aeroplane, I mean if you could put eight passengers on a model airplane, flight across the Atlantic that would just be an aeroplane, it wouldn't be a model. So those are, I think those are, the key things that stop something from being the thing itself and make it a model and that's kind of what's going on here. I should say that maybe (a) on my slide is is parasitic on (b), so it might just be the function that's important, I mean perhaps size is just the thing that stops it from having a function. But anyway, I mean this might seem to be a bit round the houses, but I think it's worth thinking about, why is an embryo model an embryo model and not an embryo? And ultimately it boils down to this: that it lacks, it lacks, important functional properties. It isn't actually a different size, I mean size isn't really so relevant here, it's just about a function. So it could only really be a model I think if it if it can't do everything an embryo can do, and that's what happens with model airplanes, model cars and so on. So if an embryo model or "model", in inverted commas, became very similar to an embryo then I think there's at least a question about whether it would be an embryo. So it's worth bearing that in mind as we go. I don't think it's a hard distinction. The other thing to say, and again I'm probably getting overly pedantic about the meaning of "model" here, but in a lot of domains in the boundary between being a model of something and being the thing itself is actually a little bit vague. So I mentioned light-heartedly the aeroplane example but I mean those kind of transport examples probably are quite telling. So there are, there are I'm told, it's not my hobby or anything, but I'm told that there are large model railway things that can carry a passenger but they only go a short distance. So you know that's sort of moving into the borderline territory isn't it. It's got some of the functionality of a rail system, probably a lot of the functionality of the British rail system, and um it's yeah, but it's a. And you can imagine getting bigger and bigger train still saying well that's definitely a proper train now that's not a model. So and probably, it sounds a bit trite as an example, but probably embryo models are like that in the sense that you know it's a continuum of function and at some point it will tip into being an actual embryo. That's my view that's not sort of in the report.

    So you might want to know why, why should we use SCBEMs? And there's sort of three big reasons and then on the slide, sorry it's so small, a list of examples are given in the report of ways it could be used. So one of the big advantages of stem cell-based embryo models is that it would provide you with a a sort of plentiful supply of research, could provide you, with a plentiful supply of research material compared to having to use actual embryos. So in terms of the scale and effectiveness, and cost effectiveness, of science it could give you a really useful research tool. The second, uh sorry, that's now, that's just about quantity really of, of material and how hard it is to get embryos for research.

    The second one's more about regulation, and perhaps possibly ethics. And the thought is that because of the 14-day rule, which I'll say a bit more about in a minute. We can't currently research on embryos 14 days after fertilization and there's a period which some people call the, sort of, "Black Box" period which is 14 to 28 days when a lot of really interesting things happen developmentally to human embryos but it's very very hard to study it because the 14-day rule prevents embryo research from going beyond that point. And it's hard to get material from other sources to study that. So there's this, sort of, so we don't know as much as we could and should about that period. And stem cell based embryo models would enable you to, or could enable you to, research on them instead during that during that period and enable you to find out things about embryonic development. I mean obviously there's a question about how closely they resemble embryos which you can't really answer definitively without doing the research on embryos. But, you know, the thought is you could get an indicative set of data about that, if you, if you got the models right. So again very scientifically advantageous and currently there's a block on that due to the 14 day rule.

    Urm. Finally this is the point at the bottom. So the Nuffield report does stress that SCBEMs research will complement rather than replace embryo research and it it goes out of its way to say there's not necessarily anything bad about embryo research and we shouldn't be trying to completely get rid of it. But some other people do say, and it's often said that SCBEMs research will, you know, reduce the amount of embryo research, or could ultimately reduce the amount of embryo research, that there is, and so if you're someone who does have concerns about embryo research then it's, that's, a positive for you. So that's an argument that's sometimes put out there. There's a long list of possible things we could do with SCBEMs research. So it might be, it might help with IVF success rates, developing new forms of of contraception, enable us to develop culture media for embryos, could potentially be used in training, or to improve techniques like freezing or thawing embryos. And further down the line, and perhaps more controversially, we've got things like, creating tissue for transplantation and eventually maybe even reproductive use, if it's deemed ethical and safe. But as I said earlier that's a long way down the tracks and would have to be after a considerable amount of ethical and public debate.

    All right. So I mentioned the 14 day rule, so this is a bit of a side point really, but probably worth you knowing. So the 14-day rule as I said prohibits embryo research after 14 days. 14 days after fertilization. It's a widely accepted, sort of, ethical convention and in some countries it's also part the law including the UK. But recently there's been some move away from that from a number of notable bodies. So the three examples, I won't read them out because I'm already becoming slightly conscious of time, is the ISSCR removed its support for the 14-day rule in its 2021 guidelines, suggesting that there should be, you know, public and societal debate about this. So they didn't sort of recommend getting rid of it but they stopped supporting it and, and, it's you know, said it would be worth looking at. The Health Council of the Netherlands in 2023 recommended that the 14 day rule be extended to 28 days, and most recently and most interestingly for us, the HFEA, very recently in November 2024, recommended that the law is changed to extend the time limit on embyo research. And they say we've seen significant advances since the law was introduced in 1990 and it's now increasingly possible for researchers to develop and sustain embryos before, sorry beyond 14 days, and this could provide valuable information in a strictly regulated environment, for the kind of reasons I just gave, with the black box period and and so on.

    Right, so now on to, I'll now give you a quick summary of some of the key recommendations in the report following that preamble. The first one is that, is support for existing proposals. So you may or may not know that in 2024 a UK code of practice was produced by Cambridge Reproduction and Progress Educational Trust that sets out standards for SCBEM research and recommends the establishment of an oversight committee and a register to review and record SCBEM research. So the Nuffield committee supports that proposal and thinks that it's a good proportionate first step. Obviously it's not, it won't do the job on a permanent basis, but it's a very good first step and gives us, would give us, a sort of, if you're like a dedicated committee, oversight committee, which is in some respects akin to an Ethics Committee or would oversee ethics committees that looked at this very specialist area of research. Now a committee doesn't yet exist but the Nuffield Council report supports it as a sort of good first step. And in particular thinking how long it can take to do things like proper legislative reform, for example is something that could be done you know relatively quickly, and so that's a good first step. So totally on board with that.

    Secondly what sort of legal status should embryo models have. So the report, the report makes clear, that its view is that stem cell-based embryo models and embryos should have quite distinct legal and regulatory statuses and that this should be reflected in the Human Fertilization and Embryology Act. So and "for governance purposes the, stem cell-based embryo model, should be considered to be distinct from the embryo even if a time may come when, for scientific purposes the two could become indistinguishable in terms of their capacity for onward development". So to just try and unpack that slightly, so there's different ways you could approach this. I mean one way of approaching it would be to look at SCBEMs on almost a case-by-case basis. Perhaps try and give some characterization of what features something has to have in order for it to count as an embryo, and perhaps that would be functional, perhaps it would be to do with reproductive potential, or there might be some sort of biological proxies for that. And then for each SCBEM you would have to do a sort of case-by-case assessment of whether it was an embryo or not. Now as you can imagine that's potentially really really complicated, and difficult, and requires judgment calls that even a very, even a very well-informed, well-meaning, conscientious person might find quite hard. Some of them could be easy, I mentioned earlier that some SCBEMs are nothing like embryos and perhaps that's easy. But in the middle and at the other end of the continuum there could easily be SCBEMs which, you know, we just don't know. And so the downside of that approach is it will put either scientists themselves or possibly, sort of, these ethics committees that are overseeing them in quite a difficult position of having to keep judging what the status of the entities is. So that's, so that's a possible approach but the committee thought it would be much better to have a distinct category.

    And so what, and the argument for that is here. So it's really a pragmatic argument. The thought is as I've suggested it would be very very hard to to have a situation where some SCBEMs were treated as embryos and some weren't. So as it says in this quote: "differential treatment in law is based on the pragmatic ground that governance as a separate entity will be safer and more proportionate." So the problem with the alternative approach is it's messy, it's costly, it gives researchers a lack of certainty, and whereas this, we think, is going to be a much clearer sort of position. Provides clarity and certainty for researchers, it prevents, or at least reduces the risk of courts having to deal with a very difficult case and then potentially, perhaps, overreacting by bringing within the definition of embryo too many things. And so the thought was this would be a much clearer approach, and it will also provide the, could have the potential to provide, the public with reassurance particularly when combined with some of the 'red lines' which I'll talk about in a minute. Right I'll do that now.

    Red lines. Actually the more I say this the more I think red lines is a horrible cliche, so I apologize for that, I should call it something else, but anyway. The first one in the report is that the, well I'll read it out, it says: "Our proposed amendment to exclude SCBEMs from the definition of 'embryo' should be made in conjunction with a prohibition on transferring a human SCBEM to the in vivo reproductive tract of a human or non-human animal". So this is a very important sort of reassurance, and the thought would be that it would be illegal to implant a SCBEM into, well as I said, the reproductive tract of a human or non-human animal. So that's sort of completely blocking in a very sort of hard law way use of SCBEMs for reproductive purposes. I mean by as, by way of an aside, I should say, I can imagine a world where one of these instances wouldn't necessarily be unethical. So you can imagine a long way down the line if the technology, if the science, got to the point where we knew that SCBEMs were going to be reproductively safe and as effective as embryos, then in principle I'm not sure, personally, that I would support that forevermore as an ethical prescription, but as a sort of, as this recommendation, as a sort of, the here-and-now, real-world legal prohibition, that seems absolutely sensible to me.

    So that was the first one. The second one's about time or stage limits. And as I haven't said yet, but will now the 14-day rule doesn't really work very well for stem cell-based embryo models for a number of reasons. One of them is they have, there is, no point of fertilization So it's hard to know when the clock starts. A second one is that the pace of development can be very different from embryos, so I am told, so some, some SCBEMs develop much more quickly, or in different, or with different developmental stages from an embryo. And some of the entities, sort of can be created in a way which means they sort of come into existence at a much later developmental stage than conception. So a pure time limit doesn't make too much sense. So what the commit.., at the moment the proposal is the oversight committee sets a case-by-case time limit for each individual project. And you know the Nuffield report is supportive of that.

    But on top of that, the suggestion is, the key suggestion is, the one here: Which is that no embryo model should be developed with features consistent with Carnegie stage 23, which in a regular embryo is 56 to 60 days, or beyond if: It has the potential to develop capacities for pain or awareness; or if: The purpose of the research is to explore the feasibility of reproductive purposes; or if the model has been genetically altered to avoid capacities referred to in (i) or (ii) resulting in a model that would diminish public confidence in research if the model were to proceed beyond the threshold. So as you can see, and I won't have time to go into all of, unpack all of the detail of this, but it's there for you to look at. It's not a hard time limit, the thought is that you're taking these features and the kind, you're taking the features in Carnegie stage 23, which is as I say, it's a bundle of features that normal embryos have at this point in time. And you're saying that you mustn't go beyond that with stem cell based embryos. If, excuse me, if one of those three conditions is met. Pain or awareness, feasibility of reproductive purposes, or if there's been some attempt to sort of bypass that by genetic modification.

    Now the argument for this view is partly about, it's largely about arbitrariness, I think the thought was that this is a less arbitrary point than some other earlier ones, because in particular this represents the point at which embryos become fetuses. So where where they become classified as fetuses, and a lot of the developmental work that takes place in embryos has happened by that by that point. Now it's important to say that this isn't, first of all, this isn't an ethical boundary it's a practical boundary, and second of all it's an absolute top limit. So you'd have an oversight for, so for each project that comes along you'd have an oversight committee that sets, for that project, a time limit and that time limit would be based on the blend of ethical considerations and so what what the scientific justification was for carrying on for that long in time. So the oversight committee can set a much lower limit for any individual project, but the proposal is that this is the, sort of, absolute maximum which we have if those conditions are met. So it sort of overlayers that on it. So this is thought to be better than not having any limit at all and it's the least arbitrary version. And it may be that later on there has to be a lower limit or a different limit, but that's something that needs to be done, you know, in the context of a wider, sort of, public debate.

    I'm going to skip through the three-stage proposed regulation because it's I'm running out of time a little bit.

    So I will just summarize the main proposals, give you a couple of reflections, and then that's that. So, key proposals in the report: Embryo models shouldn't be regulated as embryos, there should be a distinct legal category. There should be a ban on reproductive implantation in humans or in other animals. There should be an upper limit, it's not a time limit, but it's based on Carnegie stage 23 which is a developmental stage that embryos, typical embryos, have around 56 to 60 days and, but that's in conjunction with potentially lower limits for individual projects set by an oversight committee. And as I skipped over there should be a three-stage evolution of a regulatory system which starts with the voluntary code, moves through primary legislation and regulatory sandboxes, and ends up with a statutory committee dealing with at least a subset of stem cell-based embryo models.

    So some final Reflections, which won't take too long. I mean first of all as I alluded to earlier the administrative legal categories in this area don't always necessarily need to reflect what I call their, sort of, ontological or scientific reality. I mean, by ontological I mean kind of what categories of things there really are in nature. So it may be that, sort of, ontologically, philosophically, scientifically, some SCBEMs are embryos but from a kind of administrative and legal point of view I still think it's defensible and sensible to keep that, keep them, apart. So, and there's lots of, I haven't got time to give you any examples, but we can think of lots of examples where the legal version of the concept isn't quite the same as the scientific or the philosophical version for reasons of efficiency and clarity and so on. Yeah, we could try to mess with the definition of embryo to, sort of, deal with this problem but I think most of the ways of doing that will probably be quite complicated or unmotivated. So you could for example say that something's only an embryo if it's the result of fertilization. You could say that embryos, proper embryos, have got some kind of dignity or symbolic value that SCBEMs don't have but that seems question begging, because I don't see why somebody couldn't, if they wanted to, attach symbolic value and dignity to SCBEMs if they're very embryo-like. And you could also talk about, you know, what's the intention of creating these entities? But again that seems that seems insufficient because, you know, embryos could be created for different purposes, or a SCBEM and an embryo could be created for the very same purpose. So those things I think are not going to work. So I think the approach proposed of keeping the administrative and legal categories distinct from the underlying ontological scientific reality is probably a good one and sensible sort of pragmatic solution.

    So I've given you quite a lot to think about there. Thanks for the invite. I'm happy to take questions later at the end, but otherwise thank you very much.

    [Andy Copp] Thank you Stephen that was great and as you say you've given everybody a lot to think about. So we will come back to you with questions after Hank's talk.

    So now we'll move on to Hank Greely our second speaker. Hank is the Deane F. and Kate Edelman Johnson professor of law and also professor by courtesy, I love that title, professor by courtesy of genetics at Stanford University. I hasten to add that Hank is not sitting up in the middle of the night in California he's actually visiting Spain at the moment so he's on a more reasonable time frame for this, this presentation. He has specialized for many years in ethical legal and social issues arising from advances in the biosciences. He's been particularly interested in genetics, neuroscience, human stem cell research, and he chairs the steering committee of Stanford University Center for biomedical ethics and also Stanford Center for Law and biosciences. So we're really looking forward to your presentation Hank. The title is: "Human in vitro Gametogenesis and its Possible Implications". So thank you for joining us and over to you.

    [Hank Greely] My pleasure thank you for inviting me. So first I have no slides I know that's practically unheard of in the scientific field. It's never been clear to me whether it's against my religion to use slides or whether I'm allergic and it would cause an anaphylactic shock, but either way whether it's damnation or whether it's instant death I've just never been willing to take the risk. So I am a talking head.

    I do want to talk about in vitro gametogenesis and specifically I want to talk about four things: First how we would go about making gametes; Second why we would go about making gametes; Third the issues ethical, legal, practical, political, and otherwise that in vitro gametogenesis would raise; And then fourth some thoughts on what I think should be done.

    I will say that this topic first came into my mind in October 2010 so 15 years, almost 15 years ago. I was at a stem cell conference in Munster, Germany and one of my colleagues, a religious studies professor from University of Chicago, then at Northwestern named Laurie Zoloth, was talking about these new exciting induced pluripotent stem cells and all the things they could do. And she said, it's one sentence: "And what if you could use them to make Gametes?", and I thought: "Huh? What if you could use them to make gametes what would that mean?", and I thought you know I need to think about this some more and then I concluded well maybe I need to write something about this. It took me about six months to write a book about it, although it took me six years to find the six months in which I wrote the book, but in 2016 I published a book called: "The End of Sex and the Future of Human Reproduction". It's now closing in on 9 years old but I still think it's a pretty good reflection of my current thinking about where things are going to go. So I'm not giving you any slides but, "the end of sex in the future human reproduction" available at bookstores everywhere, as long as they're called Amazon.

    So let's go. First how to make how to make gametes? Well one thing is, what are gametes? I think this audience knows them, knows that. One thing I hadn't realized until recently was that the word gamete actually comes from the proto-indoeuropean verb "to marry" it was turned into a term for eggs and sperm in 1878 by a German scientist named Eduard Strasburger and it's been used that way ever since. Almost all of us, have made, are making, or will make gametes. I suspect that there are no prepubescent males in this audience so probably there's nobody who's going to make gametes, who hasn't been making gametes yet, but there are a lot of them in the population. One of the things that hurt me most about writing the end of sex was the chapter I had to slice up most bitterly, most strenuously, because it was too long and too complicated was the chapter on how human reproduction works naturally. Which is weirder than I had ever imagined. How gametes are made, when gametes are made, where gametes are made, is truly amazing. Extra-embryonic tissue, yolk sack, migrations, partial meiosis before birth for eggs, all sorts of weird stuff. All I'm going to say about it is, for most of us it works, we make gametes.

    So we know gametes can be made, the question is how could you make them in vitro? Now presumably you could use embryonic stem cells. Most of the attention, for reasons that I think will become clear, has been focused on induced pluripotent stem cells. Because that way we could take cells from Andrew and we could, from his skin, we could take fibroblasts from Andrew and we could make sperm from Andrew that would have half of Andrew's DNA. Or we could make eggs from Pilar that would have half of Pilar's DNA. Because induced pluripotent stem cells, if we're using the person who intends to be the parent as the source of the donor cells that become the induced pluripotent stem cell they've got that genome. Whereas if you're using human embryonic stem cells you've got embryonic cells that are from a variety of different parents. So you could use ESCs, most of the attention is on iPSCs so far it has clearly worked, in mice. Now of course we all know that the way scientists will eventually cure all humans of all diseases is figure out a way to turn us all into mice, because we can cure everything in mice. And one of the things that I've learned by studying reproduction, is reproduction is often very oddly species specific. I mean mice and rats are pretty close. Mice were cloned very quickly, rats it took forever. Dogs and cats, pretty close, cats were cloned quickly, dogs very very very slowly. So the fact that it's been done in mice is evidence that it can be done. It is not very strong evidence that it can be done in humans but it seems to show that there's no there's no general block.

    In theory what you do is take these induced pluripotent stem cells, turn them into, in a first step, primordial germ cells. This is something that happens when we're embryos, when we were embryos. Not, probably shouldn't be allowed to happen if we were embryo models but that's Stephen's talk not mine. So when we were embryos early on we form these primordial germ cells. The primordial germ cells are not yet differentiated as to whether they're going to become eggs or sperm. It is only after the primordial germ cells then migrate into the tissues that will become either testes or ovaries, that the second stage takes place, where they differentiate into either eggs, or proto-eggs pre-eggs, or sperm, pre-sperm in these embryonic and then fetal gonads. In theory what people are trying to do, and what's worked with mice, is basically take iPSCs and expose them to cells, and sort of quasi organs that replicate the environment in which, in nature, these pluripotent stem cells become, first primordial germ cells, and then either eggs or sperm. The best results have come from two labs in Japan that of Mitinori Saitou and that of Katsuhiko Hayashi, Hayashi was originally Saitou's student but they now both have labs at different universities. Back as long as 12 years ago they were able to make living healthy mice from stem cells that had been turned into eggs and stem cells that had been turned into sperm. They weren't able to do it at a high level of efficacy, it wasn't very efficient. It was about one twentieth as efficient as using actual eggs and sperm from mice, but they were able to do it. And they weren't able to do it with complete success, there were, even the ones that were born alive often had various disabling conditions. Over the years they've worked on it and I think things are getting better but it's still, even in mice, not very efficient and not particularly safe, but it has been done. In 2023 they took another step and were able to take cells from a male mouse, and in a nice tricky way involving waiting for Y chromosomes to drop out as cell lines propagated, turn them into eggs and have live born mice that had quote: "two fathers" close quote. One provided the sperm one provided the induced pluripotent stem cells that became eggs and the result was actually some mice. So with mice good progress is being made. Problem is we don't care that much about mice.

    In humans there has been a great deal of interest. There has been a little bit of work in non-humans, particularly some interesting work in cattle. But most of the attention has focused on humans, and there the work is not nearly as, has progressed, not nearly as far. People are not mice. Primordial germ cells have been produced, or things that look a lot like primordial germ cells, some of them have been taken some of the way, some of the steps, from primordial germ cell to mature oocyte or to mature sperm. But no one, as far as I know, no one has announced that they've been able to produce a mature human egg or mature human sperm using iPCSs. Yet. That could change tomorrow. There are currently at least five different labs around the world, and when I say at least five different labs I say that with some sorrow, I wish there were more. But I know of five in particular the two labs in Japan; Azim Surani at Cambridge has been doing this kind of work last year he published a paper on making human primordial germ cell like cells from pluripotent cells; Amander Clark at UCLA has been doing this, and there's a Chinese group that has been publishing on these issues. I've not been quite clear on what exactly they're doing but they had a recent paper on how they were able to make, I believe it was eggs, by changing the epigenetics making 20 different CRISPR edits in a cell line that may turn out to be interesting. There's also something going on in another forum. Back in about 2023 IVG had its moment in the venture capital sunlight and at least four different companies were formed in or around 2023 with the goal of making in vitro gametogenesis in humans. "Conception biosciences" got the most publicity, they had a very publicity eager founder, who is a gay male who wants eventually to be able to have genetic children who are half his genes and half his his male partner's genes. "Ivy Natal" is another company, "Vitra Labs" is a third and there is one of the 4,619 spin-off companies from George Church at Harvard is called "Gameto" which was also aimed at this goal, although recently they've been moving more into ex vivo oocyte maturation and they had an interesting paper on that published within the last couple of months. So nobody has gotten to the proof of principle stage with humans. Yet. People are trying there's not a lot of public research funding support for this kind of work. Not that there's likely to be any public research funding support for any kind of bio work in my country anytime soon. We'll see, we live in hope and fear but,

    reproductive stuff does not get a lot of funding for various political reasons. But there is some venture capital funding coming in and there are some labs that have been able to get some funding and do some work. So it has gotten to the point where recently the HFEA held a workshop on this and concluded that this is something that is plausible enough that could well happen within the next 10 years, that they think more attention needs to be paid to it. A conclusion on which I heartily agree. But it's nice to have my view joined by the HFEA.

    So second why do it? The biggest reason to do this is infertility that's caused by people not having gametes, or having so few, or so such disabled gametes, that they can't have children. Now there are many ways for people to be infertile, many of them have nothing to do with gamete production. I mean traditionally things like blocked Fallopian tubes or difficulties in ejaculation led to infertility those are things that IVF can deal with, in vitro fertilization can deal with.

    IVF can't deal, directly with the lack of gametes. I mean it can do it indirectly by using donor gametes, something Stephen's written quite a lot about but it can't make new gametes for you. So if you are a male who say had mumps when you were 12 years old there's a good chance that you don't make sperm. If you were somebody who had cancer treatment in your adolescence or early adulthood there's a good chance that you don't have any functional gametes. If you are somebody who was born with a particular condition that rendered you agametus you can't have biological genetically related children, unless IVG works. There are no good numbers on how many such people there are. I know some of them. I believe that there are hundreds of thousands of couples in the United States perhaps as many as several million who fall into this category. Multiply that 20 fold by the proportion of the US population compared to the proportion of the world's population, you get a lot of people who want to have, who cannot have genetic children. Some of them don't care, some of them are happy not to have children. Some of them aren't happy but you know if it's God's will, or Darwin's will, or whoever's will, you know they'll live with it. Some people get desperately unhappy. This is a source of great suffering, it's not physical suffering, but I don't think suffering has to be physical, in fact I think the worst suffering is not physical. There are people who go through five and ten rounds of IVF at great expense and great physical and emotional trauma, in a desperate effort to do something that they can't do. So I think the best reason for IVG is to let people who desperately want to have genetic children quote "of their own" close quote. And I put that in scare quotes because you know frankly I think providing the sperm is the least important thing about being a father, that adoptive parents are true parents. But there are people who really want for various reasons to have a genetically related child and they suffer. There are other issues. Egg harvest is the hardest, most expensive, and most, only really dangerous and risky part, of IVF. It's one of those areas where life is unfair, sperm harvest is rarely unpleasant, difficult, or risky. Egg harvest is always unpleasant, difficult, risky, and expensive. You could get more eggs for research purposes and then you could use them for expanding pre-implantation genetic testing, something I will come back to.

    Third point. The consequences, the issues raised by IVG. First, and this is most important, we tend not to think of this as an ethical issue but it is for me always the most important ethical issue, safety. It is fundamentally unethical to do things unreasonably unsafe to people, and that's particularly true, I think when the people you are you are doing something unsafe to are people who've never been able to consent. The parents were able to consent, but babies born who might have serious serious problems because of being born through IVG they never had a chance to consent. I don't think that's a stop, I mean I didn't I don't remember the consent form I signed saying yeah I'm willing to be born, in particular to these people, and we do things that affect early development embryos and fetuses all the time because we have to. But I do think it makes safety even more important. So the biggest ethical issue is: "Is it safe?" and I think that will take at least 10 years of preclinical and clinical work before you can even, mainly 10 years of probably pre-clinical work with non-human primates as well as other species before you can even get to a phase one human clinical trial. But if things went well I think you could get to a phase one trial within 10 years and then you know work your way up and see how safe it is and isn't.

    Then you get to a variety of really sometimes interesting, sometimes bizarre, IVG specific items like: If we could make eggs or sperm from skin cells well 90 year olds have skin cells why not make eggs from 90 year olds? Sperm are being made by 90 year olds at least 90 year olds, some 90 year olds. But eggs aren't being made by 90 year olds, eggs aren't being made usually by 50 year olds, in fact almost all eggs seem to have been made before a female child is even born. They were made in utero. If you could make more eggs, there are a lot of people who would be older, who can't make eggs anymore, or don't have any useful eggs anymore, who might want to do this. But do we have concerns about 90-year-old genetic mothers? Do we have concerns about 9-year-old genetic mothers? Do we have concerns about making people genetic parents who have been dead? You may remember that Dolly the famous sheep, the world's most famous sheep, was cloned from a cell line made from a ewe that had died three years before Dolly was born. Freeze cells well, turn them into iPSCs, thaw them turn them into iPSCs, turn them into gametes, you can have dead parents. Now of course we've had dead fathers, who died after conception but before birth, but this could look very different. What about this one it's hard to steal eggs, it's really hard, it's hard to steal sperm, it's really hard to steal eggs. It's not that hard to steal somebody's cells if Andrew has a paper coffee cup and he throws it away, I'm sure he doesn't I'm sure he's more environmentally responsible than to use paper coffee cups, but if he throws it away there are probably some living cells from Andrew on that coffee cup, and maybe if I picked it up I could make him a dad without him ever knowing it. Now of course there would be a big commercial market for Andrew's sperm I'm sure but if we made him a famous soccer player, football player, there'd be an even bigger market, I suspect. Mbappé, you know people should follow, who just had a a hat trick against Manchester City last night, here in, here in Madrid where I am. The Bernabéu stadium is two blocks from where I'm living. I heard the crowd his sperm would I'm sure command a big premium, especially if he didn't know anything about it. What about this one: If we can make eggs from men or sperm from women, and why would we want to do that? Well one of those classes of people who don't have the egg and sperm are same-sex partners, they may both make gametes but they both make the same gamete, and you need opposite gametes, if we could make eggs from men or sperm from women that in, that fixes the fertility problems of gay couples. But what if we took Pilar's fibroblasts and made eggs and Pilar's fibroblasts and made sperm and made Pilar embryos and transferred them into Pilar's uterus and nine months later Pilar gave birth to, what exactly? I called it a "unababy", note it is not a clone, for every genetic locus where Pilar is homozygous it's going to be the same but where she's heterozygous. let's say, Pilar, let's say Pilar's blood type is type A and she's a heterozygote of A and O, you get to the classic Mendelian distribution. There's a one quarter chance that the "unababy" would be AA, a one quarter chance it would be OO, and a 50/50 chance it would be AO. So it's not a clone it's closer than a sib, what is that? Or let's take a couple, we'll go back to couples. We make an embryo we kill it, use the hESCs to make another embryo meanwhile we've taken some other couples we've taken 16 couples and we make embryos from each of them and from the embryos we make from each of them we make eggs and sperm and we keep crossing and crossing and crossing until you've got one embryo that has 32, that has 32 parents. Multiplex parenting. Now you know in a way all of us have 32 parents, you just have to go back to great great grandparents and we've got 32 genetic ancestors, probably although one of them may have dropped out at that point thanks to recombination. But that's kind of weird. And then of course a very different IVG, but important ethical issue, at least in my country, is access. Is everybody going to get this? Almost certainly not at least not at first, it'll be rich people only, people who can afford it, and I think even in countries that have a more civilized approach to healthcare, probably IVG is not going to be high on the list of things that the National Health Service is going to be eager to pay for. My guess, I don't know your system very well, but it's a guess.

    So last set of issues and this is what the book went into in great detail. If IVG works let's say you're a couple who wants to have babies and you don't want to have unababies or multiplex babies, you just want to have normal everyday babies. You don't need to use IVF but if you use PGT, if you use IVG to get the eggs you avoid egg harvest which cuts out a lot of the cost, and a lot of the unpleasantness and the risk. IVF becomes easy. If you do IVF by the way how many embryos can you make? How many eggs do you get? Well with regular egg harvest with a healthy young woman you get you know 0 to 25, usually around 10 to 15. If you're making them from a cell line, from an induced pluripotent stem cell line, how many eggs do you get? How many do you want? Hundreds, thousands, millions? So in the book I use as a hypothetical, you make a 100 embryos, you do a whole genome sequencing on each of those 100 embryos and you ask the prospective parents which one or two do you want us to try to transfer? It takes embryo selection to a much higher level and I think that actually could happen. In the book I predicted will happen and will be relatively common not for enhancement purposes. We don't know enough about genes for enhancement to do any real significant enhancement, but for health purposes. About 1 to 2% of every birth is the birth of a baby who has a serious or will have a serious disease that could have been predicted through prenatal genetic testing. If you could avoid that you're avoiding human suffering for the baby and the family, you're also avoiding a lot of health care costs. I think health, health insurers and health plans, health programs might be quite interested in paying for IVG if it meant they didn't have to pay as much in taking care of children who had serious genetic diseases. So I think that may be where we eventually end up. IVG as you can see is something I find deeply interesting and think has lots of consequences.

    Last Point: What should we do? First we should watch it carefully. Second I think we should fund the research, I mean frankly I see no good argument against IVG, apart from safety, always important. But carefully proven IVG, carefully proven safe IVG for people who are agametously infertile, and for me that would include gay and lesbian couples. I think there's no good argument against it, there will be arguments against it, but I don't think there are good arguments against it. I would fund research toward that. I would engage with the public. I would focus very heavily on what kind of proof of safety you would require and then start deciding what your country wants to allow, and wants not to allow. Different countries will make different decisions. Everybody should ban involuntary reproduction. Everybody should ban stealing Andrew's cells to make him a dad without his knowledge. That shouldn't be legal. Although there may be some exceptions, if Andrew gets hit by a lorry and he and somebody had been planning to have babies, he's dead he can't give consent maybe there's a postumus exception there. That's I think one of the easy ones, different countries will differ. They need to start thinking about it. So I hope in 30 minutes I have given you an introduction. Go buy, you know "the end of sex" it's not a scary as its title, it's on Kindle it's like probably seven pounds, of which I would get at least 30 pence. So thanks for your time and attention and I'm looking forward to those royalties just rolling in because I've yet to make the minimum wage on that book. Thank you.

    [Andy Copp] Thank you very much Hank that's...

    [Hank Greely] You're still obviously flustered by thought of being an involuntary Dad.

    [Andy Copp] I'm not buying any more coffee and paper cups ha ha

    [Hank Greely] Gobsmacked.

    [Andy Copp] Well thank you very much. That was tremendous.

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