 Hello, and welcome to the Ethics in Research and Biotechnology Consortium series. I am your host, Insu Hyun, and today's topic is modifying humans as global governance of genome editing possible. If you are new to the series, welcome. If you are returning a participant, welcome back. I am a faculty member in the Center for Bioethics and the Director of Research Ethics. I'm also a professor of bioethics at Case Western Reserve University School of Medicine. It's my distinct pleasure today to introduce today's topic and speaker. But before I do that, I just wanted to take care of some housekeeping issues. Questions will be entertained at the end, toward the end of today's session for the last 30 minutes. So if you have questions that come up along the way, please use the Q&A feature at the bottom of your screen. Don't use a chat feature. Use the Q&A feature. That's the one to use. And we will curate those questions and try to get to as many of those as possible toward the end there. If you have any technical issues, then you might want to use the chat to message the panelists and staff members to help you out there. We have a Twitter handle, Harvard Bioethics, and a website, bioethics.hms.harvard.edu, subscribe. That's for a list of all upcoming events and talks. We'll have one a month of this series. And so we really look forward to seeing you in those. But without further ado, let me go ahead and introduce our speaker today, Robin Lovell Badge. He's a group leader and head of the division of stem cell biology and developmental genetics at the Francis Crick Institute in London. He discovered alongside Peter Goodfellow, the SRY gene on the Y chromosome that's the determinant of sex in mammals. Notoriously, back in 2018, during the Human Genome Editing Summit in Hong Kong, Robin was actually moderating the session when Zhen Kui He stood up and announced to the world that he had edited two Chinese babies that were brought to term, which created quite an uproar and a call increasingly for governance of this area of activity around the world. So that's the topic for today. I would like to turn it now over to Robin. All I saw, she also mentioned, so besides being notorious for being the moderator at that session, he also participated in two very key committees in the last few years. One was for the International Society for Stem Cell Research, the ISSCR. We updated our guidelines for research in stem cells and embryo research just this past May. And Robin was the chair of that entire task force and shepherd us through that event, that task. And then more recently, just finished up serving on the Committee for the World Health Organization on governance in Human Genome Editing. So he's going to speak to those issues today. But let me turn it over now to Robin. And Robin will actually start us off with some of the science of Human Genome Editing just so that we understand what's scientifically at stake here. And then we'll go into the governance issue. So go ahead, Robin, floor is yours. OK. Right. Am I on screen? Yeah. Yes. Fine. So I'll just share my screen and then we'll get going if I can find the right talk. Here we are. Well, thank you very much, Shinsu, for the introduction. Yeah, I've actually been involved in the topic of human genome editing since people really first started talking about it, which was 2015. Through various committees, international meetings, etc. And I was on the National Academy of Science study group that wrote a report about this, published in 2017. And, yeah, as Shinsu said, I was had the privilege to share the ICCR Task Force review when we covered the topic a little bit. That was it was like herding very well behaved cats. They weren't they weren't too bad, I have to say. There were lots of people on the on the task force. They were very good. And then more recently on this WTO Committee looking at governance. And so my second talk will deal with the WTO's output to do with governance of human genome editing. Well, let's let's do some introduction to human human to genome editing and where relevant human genome editing. So some of the slides may be a bit technical. Don't worry about the details. If you aren't interested, just try and get the message. So just very brief outline of the talk. So I'm going to go through methods of genome editing applications and and and technical issues. Now, human genome editing sort of burst on the scene or the idea of genome editing burst on the scene in in 2012. And it's through the work of Jennifer Dardner, Sharpentier and, of course, quite a few others. And the the methods have have developed so rapidly. It's really hard to keep track of the latest ones. And almost certainly I'm not going to be telling you about the latest methods, but they have expanded throughout pretty much all research centers probably around the world because genome editing is an amazing tool to study gene activity, gene function, screen for genes that may may play an important role in a variety of biological processes, etc, etc, etc. So amazingly powerful research tool. I'm not going to talk about applications in general lab research, except except for one area, which I will I will touch upon briefly. So and then the second talk will be on governance. So genome editing relies on mechanisms of DNA or generally relies on mechanisms of DNA repair to work. And so these are endogenous mechanisms that hijacks those to to make changes in DNA sequence. So it most often requires a nucleus enzyme to make either a double stranded or in some efforts a single stranded couple Nick in in DNA. There has to be a mechanism to recognize specific DNA sequences. And I'm going to move myself out of the way of this. OK, a mechanism to recognize specific DNA sequences, which can either be derived from DNA binding protein, such as transcription modified transcription factor at parts. So the zinc finger nucleases or tailings, and I'll mention those again very briefly in a minute, or complementary RNA. And that's the CRISPR based techniques, which I will mostly be talking about. If the aim is to make more than a simple mutation, then often you would include a DNA template with homologous arms, meaning the ends of that DNA template are identical to the target DNA. And that's to allow homology direct to repair, where you have recombination between the identical sequences. And that substitutes what's in your introduced DNA in place of what was there to begin with. So modified forms of the nucleus. So basically a dead version of the nucleus can also be used to alter the activity of genes. So you link it up with modifying enzymes, which modify epigenetic activity, chromatin structure, et cetera. And so you can modify activity of the genes without actually making any changes in DNA sequence. And these are techniques which have been developed over the last few years, but generally not thought about enough because they will pose a number of ethical issues and governance issues. And we could perhaps talk more about those later. So the methods, to say, rely on having a way of making a cutting DNA. And the first ones that were really, really developed and used and are still being used a little bit in gene therapy approaches are the zinc thing in nucleases. So these interact with, you can design these proteins to interact with specific DNA sequences. They interact with only one strand, so you have to have a pair of them. And each is linked then with a DNA cutting enzyme, which is usually FOK1 or FOC1. Tailings are very similar. Again, these are proteins that will bind DNA sequences and you can modify those. You can design those to recognize specific sequences. And again, you need two of them to interact operas at strands. The CRISPR-Cas9 system, or relations of that, are much simpler in a way because they rely on an RNA guide. And so you can make these RNA guides incredibly easily. You can actually just order them from a company. They are inexpensive, easy to make, much easier to design because it's just complementary RNA to the DNA sequence you want to modify. And then these have, as part of the guide RNA, as part of that sequence will interact with Cas9 protein. And Cas9 is a nuclease which cuts double-stranded DNA. So you can use these methods to alter coding regions of genes, create mutations, study gene protein function, gain a lot of function mutations, conditional mutations and discriminations, et cetera. You can use them to correct mutations in theory. You can alter splicing, so use them to promote exon skipping, alter regulatory reasons of genes, define enhancers, characterize chromatin domains, all sorts of things. You can use them to insert marker genes, which is very useful, for example, in developmental biology to follow the fate of cells. You will see where a particular gene is active. And you can insert bioactive genes from different species, things that are going to do something interesting to the cells, whether it's killing them or making them divide slower or faster, et cetera, et cetera. So incredibly versatile tools. Now, the first one I'm going to talk about is, sorry, let's go backwards, is simply using these techniques to make a double-stranded break-in DNA. And this simply makes a cut in the DNA. And usually endogenous enzymes will nibble away a little bit or do something with the ends of the DNA. Oh, hang on, I must be missing some slides, sorry. OK, maybe I lost some slides here. Let's check again. So you can make simple break-in DNA, which, when repaired, relies on this mechanism called non-homology end joining, which tries to simply stick the broken ends together. And in that process, you often get an error. Most often, you'll get an error. And that can be a very simple way of making a mutation in a gene. If you want to use homology-directed repair, that's a lot more complicated. You have to have also introduce a DNA which can, you can have homologous combination to introduce your defined sequencing into the gene. Now, there's a problem here in that the homology-directed repair mechanisms are less efficient than this non-homology end joining mechanism. So the error-prone mechanisms are often more frequent in cells that, certainly, at particular stages of the cell cycle. So you're always running the risk when you're making a double-sounding cut-in DNA of having some sort of error. Now, that error could be on the on-target site where you could have a small mutation or sometimes even very large mutations. If you can get the homology-directed repair to work, that's beautiful at the target site, usually. But again, you always have to be careful that your screen sells properly for inappropriate events. Now, the other type of method that's really useful is so-called base editing. So this was developed by David Lu at MIT. And he developed this method, which is really quite precise because, and much more precise in a way, because it basically, you only nick one strand of the DNA in a particular place. And you can substitute one base pair for another through this process. So in this case, you use an inactivated or dead Cas9 linked to a relevant enzyme like cytosine deaminates. And in this case, a specific cytosine is chemically modified first from a uracil. Then, endogenous process is substituted at uracil with thymidine. And then DNA-mitra repair mechanisms, mismatch repair mechanisms, detect a problem and substitute the G with an A to now restore base pairing and you swap one base pair for another. This is a very, potentially very important technique. With a more recent work, he showed that you can make other base pair changes. And so single base pair substitutions can be used to correct or create a mutation in the coding region or regulatory region with actually quite high efficiency. And this is really important because about 50% of inherited diseases are in fact due to single base pair substitutions. So you can imagine that these methods could be really valuable for gene therapy in some way. However, these base pairing methods, these base editing methods can't be used for all mutations. And there are some very common ones like sickle cell disease, which you cannot use the base editing methods for because it's the wrong change, wrong basis being changed. But David Lu also developed a more recent method which he termed prime editing, which also uses a sort of modified Nikkeis. But it makes use of a modified reverse transcriptase linked to both the dead Cas9 and the Nikkeis and a modified guide RNA that both specifies the target site and encodes the desired edit. So don't worry about the details if you're not so interested in the details. But what this means is, so these guide RNAs essentially include an RNA primer sequence adjacent to the guide RNA recognition site that will prime this enzyme reverse transcriptase and the template sequence that, which will then get copied into the DNA substituted into the target sequence. And so this is a very nice way of making small precise changes to the genome. So from a single base pairs to maybe about 20 base pairs or so. And in a proof of principle experiments, David Lu's lab showed that it can be efficiently used to convert the sickle cell mutation, HPBVS to the wild type globin gene in that particular study up to about 50% with a very low rate of mistakes, you're like indels, small insertion or deletions. So these two methods of base editing and prime editing are very, very promising. They haven't been used enough yet in my view in gene therapy approaches, but I'm sure they will be. So genome, we'll talk first of all about somatic gene therapy. Gene editing is a new tool for this. Traditional gene therapy involved using, for example, a viral vector to integrate one or more copies of a functional version of the genome, random in the genome, hoping that it will be expressed in sufficiently, sufficient levels in the right tissue and at the right time to rescue the genetic defect. However, there are a number of issues with this. So the vector could integrate into and disable another gene or cause a topic activation of a nearby gene, which in rare cases of course could include oncogenes. Gene editing of course provides a way to make a desired change in the gene of choice, which could be to correct a disease-causing variant. The gene will of course then retain its normal expression pattern and other genes should not be affected. So, and this is really important for all sorts of mutations, including something like sickle cell disease. So there are two main approaches for doing somatic gene management or gene therapy. You can do this ex vivo outside the body by removing cells such as stem cells from bone marrow, editing these in in culture and then putting the say bone marrow stem cells back into the patient, probably having previously depleted the endogenous pool of stem cells in that patient using chemicals or in theory radiation but probably chemicals. So you reduce the endogenous stem cell pool. So the ones that you manipulate and put back will tend to take over. And be more dominant. So this method is very useful say for editing blood stem cells for treatments of cancer like CAR T cells or HIV, editing blood cells for sickle cell disease and thalassemia, et cetera. It has a problem in that because you are having to manipulate cells outside the body, you need very good facilities for doing this and it adds a lot to the cost of doing gene therapy in this way. The other approach is in vivo genome editing where you directly try and alter genes in the body. Now that you can imagine is technically much more challenging. It can involve a number of delivery methods including viruses, nanoparticles, lipid droplets, et cetera. And there's some evidence that this will work. Very recent evidence suggesting that you can edit liver cells for a metabolic disease. You can, some evidence using viral vectors that you can in animal models, target muscular dystrophy and I may talk about that in a second. And there are other approaches where you have particularly cells on the outside of the body if you like either the retina of the cornea, epithelial cells to, for example, reduce the risk of cancer due to papillomavirus, isn't it? So these methods are promising but they're technically challenging. And let's see whether we still have those slides. Just to say one of the first examples of using genome editing to treat patients was using, actually using fingers to mutate HIV receptor, HTCR5 in-age patients. And that looked sort of promising for a while. The CAR-T cell approach, I'm not gonna go into that in detail, but again, that's been used now quite a few times to treat effectively otherwise incurable cancers, basically modifying the patient's own immune cells to kill the cancer cells. And then there's some preclinical data from targeting beta-globin or actually often the regulator of, not beta-globin itself, but of gamma-globin to give you persistence of this fetal-globin. And that is looking quite good, both for sickle cell disease and beta-palatemia, at least in early trial results. So in all those, the genome editing is carrying an X fever. Muscadistrophy, just say muscadistrophy is of course quite a common and very devastating disease. This is much more challenging and of course you can't take out all the muscle cells of the body and put them back in. But, and there are many muscle cells in the body. So if you're getting, which can all be affected by this, the mutations that lead to muscadistrophy. So Eric Olson and colleagues and others have been taking a variety of approaches to try and deal with this, particularly using intravenous delivery of a viral vector, AV9, which preferentially targets muscle cells. And they were able to find, using either mice models or a dog model, that they could quite efficiently restore dystrophy and expression and muscle function in these animals. However, in the paper on using a dog model and more recent papers on muscle, on mice, Eric makes a very valid point that actually if you scale up the amount of virus that you have to introduce from mice to that you'd need for a human, you'll be introducing levels that were really very toxic. And so you, there needs to be much more efficient ways of introducing the gene emitting components. Now, when you take something like the liver, it turns out that this is much easier. So the liver will take up things from the bloodstream. And for example, it will take up these lipid nanoparticles which you can use to encapsulate messenger RNA for Cas9 protein and a single guide RNA targeting, in this case, TTR. So this is for hereditary, ATTR amygdalausis, which is a pretty bad disease. And if you reduce the TTR protein, that can, or the mutant TTR protein, that can rescue the patients. And there's some good evidence that this was working from early clinical trial results. There's some issues here. Of course, if you're doing a vivo gene emitting, you've got to know really where everything's going. So in this case, you hope it's targeting the liver. It probably doesn't matter if it targets other cell types in the body use, you hope it doesn't. Except you have to be very careful that it's not going to target germ cells because then you might inadvertently have a situation where you've got heritable gene emitting of a sort that you wouldn't want to have because probably embryos mutant in this gene wouldn't develop very well. So you have to be very careful where your gene emitting components are going. And we could talk about that if you want. So if we're gonna talk about heritable gene emitting, let's think of alternatives as well. So of course there are alternative ways of having children without a genetic disease. I'm not looking to go into all of these, but you've got obviously adoption, gamete donation, embryo donation. And then the one that if in a way is most similar to the way people think of heritable gene emitting being applied is pre-implantation genetic diagnosis or genetic testing for aneuploid. Not for aneuploid, not for aneuploid, genetic testing for monogenetic disease. So this would be you take a biopsy from your early embryo and then you test the biopsy cell whether or not the embryo is carrying a mutation and it's going to suffer from the disease. And then you discard those embryos and you only implant those that are not going to have a problem. So these methods are actually unacceptable for some individuals who don't like the idea of discarding any embryos. They would rather be able to rescue the embryos or the embryos. If often these are not efficient enough and women will have to in many cases undergo multiple rounds of PGD in order to have success and get a healthy child. And this puts a burden on women. The more rounds they have to go to the more burden that is. And of course there are cases where they cannot be used to retain a parental genetic connection but avoid having a child with a genetic disease. And that would be cases for example where you have an individual who is homozygous for a dominant genetic disease such as Huntington's disease or where both parents are homozygous for a recessive disease, mutation. And such as sickle cell disease for example. So you cannot use PGT in those cases because you'll never find embryos that are going to be free from the disease. And then just something to think about for the longer term. We also have to consider patients who have survived the breeding ages because of either conventional treatments or successful somatic genome editing where these patients are now surviving much longer. So you could take musclerodystrophy as an example. Generally, boys with musclerodystrophy don't survive long enough and are healthy enough to ever have contemplate having children but if you can correct the somatic cells with genome editing, then they might want to have children but their germline will not be corrected. So perhaps the demand for herosal genome editing will increase over the years as we become more successful with somatic gene therapies. So these are an example of those as I went through where you can have problems where PGT is not sufficient or not suitable. Another actually good example is for so-called savior siblings where you have to screen embryos for more than one allele. So you have to screen them in this case for a disease causing allele but also to provide an appropriate tissue match for a sibling that was born previously that you hoped to be able to use. For example, bone marrow cells to transplant to save that already worn sibling. In that case, it's really hard to find embryos that you can use and transfer and these women often have to undergo multiple rounds and it's often very unsuccessful. Simply being able to correct the harmful mutation would help the chances of success a lot. So if you're going to contemplate doing herosal genome editing, how would you do it? So the two main methods that people are thinking about. So one is to edit cells that give rise to sperm such as permatogonial stem cells or perhaps via induced peripotent stem cells which can be derived from patients or individuals and then use those IPS cells to derive gametes in vitro both either eggs or sperm in vitro. So the advantages of being able to grow stem cells which you can then do your editing in before you derive your sperm or egg is that you can screen the cells, make sure that they have the edit you wanted and no other problem in the genome. So no other off-target edits or incorrect on-target edits that they're perfect to use, gametes and then embryos. Now, as an example of this, permatogonial stem cells have been genetically altered in vitro for mice, rats and macaque, non-hemoprimates and used to obtain offspring after reintroduction of those permatogonial stem cells back into the testes of animals where again you deplete the endogenous stem cells before you do the transplant. And both ursites and sperm have been derived from mouse embryonic stem cells or induced peripatent stem cells entirely in vitro. So, and there's people working on trying to do this for humans for reasons other than making heritable genome editing to, for example, to as a way of correcting facility in children who've received cancer treatments who have inevitably been made sterile by those cancer treatments. The other approach, and this is the one that's received the most attention. And of course, it was the one that Dr. Heir Janku used inappropriately that Hintzu mentioned. I moderated that session when he talked about it. There were over 100 journalists in that session by the way. So this was one of the biggest challenges in my life to keep the journalists quiet and try and get JK to spill the beans as much as possible what he'd actually done. So this is, this other method is editing the early embryo or the fertilized egg or something. Now, there's some problems here because it's, the genome editing process can be a little slow sometimes. You inject the components into the fertilized egg, the zygote, but they may not act until the seconds, the seconds at the two-cell stage or even a little bit later. So you need to have a very, a way obviously to verify that you have correctly edited the embryo. So the, if the methods aren't 100% reliable. So you can of course use pre-implantation genetic diagnosis but if there is a risk of mosaicism then your pre-implantation genetic diagnosis becomes very unreliable because you don't know which cells you're taking for in your biopsy. You may have taken some edited ones or you may have taken unedited ones. You don't know what's happening in the rest of the embryo. So that becomes a big problem. Moreover, the methods we have available at the moment to obtain really accurate full genome sequences from single cells are not good enough. I mean, they're getting that, but they're not good enough. So this is a big problem. So you'd have to know that you really have methods that were about 100% reliable before you would attempt to take this route. The sort of three basic methods I described of genome editing have all been tried with human embryos. This is non-homology and joining where you make a mutation in a particular gene. And I should stress that my colleague, Kathy Nykan is doing this not to as proof of principle for doing herosal genome editing because she's interested in the biology of early human embryos. And so she was targeting particular gene to try and find out the role of that gene in early human embryos. And then both the homology direction repair route has been tried in quite a few papers with moderate success. Certainly not good enough, but it can work. And then the base editing methods have also been tried and they look good, but again, not sufficiently efficient. And there's a few little problems which I won't go into now, but sort of slightly off-target problems. So big problems can be unwanted events. And actually the incorrect on-target events including large deletions is a major problem because if this non-homology and joining method there's sort of where that particular process of just trying to, that cell tries to stick that broken ends together can often create big deletions in DNA. And that's a huge problem. And these can be hard to actually detect because if you're doing your DNA sequence, you've got to know whether you have now only one copy of that sequence because you've lost a whole region of chromosome or not. Loss of hemozagosity can also be a problem. So rather than deleting DNA or altering it the way you want, you've actually, you may have got recombination to introduce your right sequence, but actually the homology recombination has occurred over a large piece of DNA and you've lost hemozagosity over a large part of the chromosome. And that again can be very bad for all sorts of reasons. And then mosaicism is the big problem. Now there's constantly new methods being developed all the time. This was a very clever one developed by Janet Rosant and her lab where they essentially allowed the Cas9 enzyme, the RNA to interact with the DNA templates in a very efficient way. And so they got homologous recombination. So targeting to replace sequences with fluorescent reporter genes had about 95% efficiency, this was in maths. So these sorts of methods, and so there are many methods each of which seems to be able to improve efficiencies a bit, this one quite a lot. You could imagine that combining some of these together you might actually approach 100% success rate but no one has done that yet. Multiple ways of introducing your genetic components into cells that could be microinjection, transfection, viral vectors, different types of viral vectors, different nanoparticles. There's all sorts of issues you have to think about when you're introducing, I want to express Cas9 or guide RNAs. Generally you want the Cas9 enzyme around for a short time as possible. Otherwise it tends to, and the guide RNAs as well, otherwise you tend to get more and more off target events. So you want a quick burst and that can be a problem with some of the viral vectors, for example. So I think I'm probably going to just finish with a couple of provocative slides. So there've been a few experiments done in animal models where you can actually do genome editing on embryos in the oviduct or uterus using basically either electroporating or transfecting your components. You basically inject the components into the oviduct at the time when you know the embryos are going to be there. There's that number of electric shock and quite a few of the embryos will take up the components. So you can get genome editing to occur in an embryo where you haven't removed it from the mother at all. However, of course, these methods are very simply not safe enough or efficient enough. None of the methods are safe enough or efficient enough yet. I should stress to do hereditary genome editing, but these are particularly not. But you have statements made in the papers like this. I go naturally to female to retain reproductive function suggesting future use of the method for germline gene therapy. So those sorts of statements should be probably avoided at the moment. You can also use ad no associated viruses or other viruses. Again, introducing these in the oviduct or the uterus to modify myosemary in vivo. You clearly have no idea what you're doing, but there's a huge risk here that the risk for me is that the unscrupulous practitioners of IVF may say, oh, well, we could simply edit some embryos while we're doing IVF. Would you like to pay a little bit more money and we can try and get you a baby with whatever trait you want introduced? So that's a big ethical issue for me. So I'm gonna stop there and then I think Insu is gonna take over. Thank you so much, Robin. So I wanted to just briefly mention what the International Society for Stem Salar Research Science and Serial Guidelines say, but in the interest of time, I'm not gonna share our slides. I'll just say a few key talking points while Robin gets his WHO slide that ready. One is that we have to have a working definition of governance. And so I'm gonna put into the chat now the definition that I gleaned from the WHO report. Now you may not all agree with this working definition of governance, but this is the concept that the WHO is aspiring to work. I will say in looking at this particular definition, this is decidedly not exactly what the International Society did. What we try to do is just come up with general guidelines. This is again published in May, this past May. And just for review, general guidelines for what should be permitted and what should not be permitted at this time. So in this task force of Robin headed up that I've longed to, we basically landed on the following overall principles that meritorious science should go forward. It should be reviewed by independent process of scientific and ethical merit. And so on those grounds, all the in vitro work that Robin talked about. So everything short of transfer of the modified embryo or gametes into a human body could be done on a case-by-case basis after review. What should not be done at this time, mainly for safety reasons, is to transfer into the uterus human or non-human primate doesn't matter which one. Any modified human embryos using these technologies. So that's the basic overview of how we've approached it with the International Society. Again, not decidedly every element of governance, SWHS to find it. But with that, I wanna turn it back to Robin so he can show you what the WHO came up with using this basic framework. Okay, so sorry Robin, it wasn't much of a break, but I can have a quick gulp of my cold tea. Okay, sounds good. Back to you. All right, let's hope this is the one. Okay. All right, we're not quite getting the full screen. Here we are. Right, okay, is that okay? Yes, that's good. Yeah, okay. So I was on this, a member of this committee, it was a very interesting committee. We published our report in July, so not long ago. We are still actively working on aspects of it, and including trying to ensure that some of our recommendations actually happen. So let me go through a little bit about how we worked and who we were and then get into our major outputs of the committee. So it was a very international committee. We were chaired by co-chairs, Dr. Margaret Hamburg who was ex FDA commissioner. She's also done a lot of other roles in a high level in the US. And Justice Edwin Cameron, a very senior lawyer, if you like, a judge in South Africa. But we had members from many countries, each representing the various WHO regions around the world. And so apart from being geographically diverse, also in terms of expertise, wide range of expertise. So some people understand the science, some people who are very strong ethics to do with governance, et cetera, et cetera. So it was a very diverse group of individuals. Now, we had, it took about two years for us to do our work. We had a couple of in-person meetings initially before everything came to a grinding halt with the pandemic. But we still managed to meet something like six times by over Zoom as a whole, whole committees. We had working groups. We obviously, lots and lots of Zoom calls and lots and lots of emails. So this was a huge undertaking. And of course, I did this at the same time was trying the IS to see our guidelines update committee. So I have been frazzled, but I have to say both were very interesting and a lot of fun. So the charge from the director general of the WHO covered three topics. So that's somatic genome editing. So where you're editing typical body cells that are not part of the germline, as I've discussed already. What we're referring to as germline genome editing. So that's where you're doing lab-based research on experme nepricursors or early embryos, but you're not using these for reproduction. And then heritable genome editing where you are making genetic alterations that might be passed on to future generations. So this is germline for reproduction. We've been other way of saying this. I just point out at this point that so we were charged by the director general to do somatic genome gene therapies as well as heritable. Even though we had actually had a lot of criticism early on about doing the somatic genome editing because various organizations and companies said, oh, this is all well-regulated. We know how to do somatic gene therapies. We've been doing these for many years, but that was forgetting lots of things. Most of that effort has been in rich countries almost no effort, if any, in poorer countries. So the global south, for example. And just to give an example, we had as part of our process, we interviewed several company representatives, people doing somatic gene editing in North America, and not one of them had even thought about the possibility of using the methods in countries in Africa, for example. And of course, there's no mechanism of governance in those countries. And they hadn't thought about distributive justice and the cost of what they were doing and how that would bankrupt the health systems in those countries. But we'll get on to that later. So we felt it was very important. There's also, of course, the possibility of doing bad things with somatic gene editing. And that would include forms of enhancement that people might not like. And the whole idea of bogus clinics or unregulated clinics doing things which are bad for patients could occur. And so we felt it was really important to cover somatic gene editing as well as heritable. Another challenge from the director general was to address scientific, ethical, and societal issues of governance. I would stress that we, although we looked at the science, there was a parallel process going on, at least at the beginning, by the various national academies, particularly the National Council of Sciences in the US and the Royal Society in the UK, who were tasked with coming up with a so-called translational pathway. This was specifically for heritable gene editing. So they were tasked with looking to see whether the methods were good enough for uses and what type of use they might first be tried in. That's for heritable gene editing. So we didn't tread on their toes, but of course we kept their report in mind and the science in mind. Now the different time horizons, so of course there's already work on somatic gene editing now and that's going to expand rapidly in the future. There is some work on germline gene editing occurring now in several labs in the US, in Europe, China, and perhaps elsewhere. That's going to expand in the future. Heritable gene editing, the only attempt that we know of is Hei Jiangyu, which was a rather disastrous attempt for many reasons, but of course this may happen in the longer term. So the outputs we have are, and I'll touch on these in more detail, a global clinical trials registry on human gene editing. Then while we were, I think we were in our first meeting actually or maybe the second meeting, there was a report by the Russian scientist, Dennis Revrikov was saying that he wanted to do heritable gene editing. And we heard about this and we thought that this is way too premature and we asked the director general if he could do something about this. So he put out a very strong policy statement saying it would be irresponsible to you to naturally alter embryos reproduction now. And behind the scenes, clearly they, he or the WHO got in touch with the Russian authorities and very rapidly put a stop to Dennis Revrikov's activities. And so the very clear statement was made by the Russian government that heritable gene editing should not be attempted in Russia. A major output of ours was a governance framework for human gene editing. And then another one was recommendations for governance and oversight. And I'll touch upon both of those. So in terms of governance, we basically had to come up with a framework approach. So there's no, you cannot possibly have one simple rule that's going to lead to appropriate governance of this whole domain. It's just impossible. Different countries do things in different ways. So we came up with a framework approach which is clearly intended to identify the relevant issues and have a range of mechanisms that might address them and be developed in collaboration with the relevant stakeholders. It needs to be scalable. Well, a framework approach is scalable, it's sustainable and hopefully appropriate for use at institutional, national, regional and international levels. And rather than just being designed to work in countries which already have strong regulatory institutions and mechanisms to work in parts of the world where there is traditionally weaker regulation of scientific and clinical research and practice. And of course to provide those responsible for the other side to genome editing the tools and guidance they might need. Now, just a couple of maps for you. This one is just showing for germline. This is not for reproduction. This is the rules around the world for germline genome editing. And you'll see that there are a few countries that are in red, including Canada and Brazil and some parts of Europe. There are quite a few countries whereas green meaning is permitted. And then there are lots of countries around the world where there was no relevant information or whether they couldn't even be included in the survey. So this was work done by Frances Baylis and her colleagues. So Frances Baylis was a member of the committee as well. So this is in stark contrast to this map which is the current policies on heritable human genome editing. Now, there's a lot more red in this case. No green, still quite a few countries where there's no information or it's indeterminate even. So the Ukraine is indeterminate. Now, this is a slightly misleading map however, because for some countries, the depth if you like of the prohibition is very different from others. So in countries in Europe, there's quite a robust laws which say that this should not be allowed. In the US to take an example of a country which has a slightly tenuous ban on heritable genome editing there and it's correct me if I'm wrong, but this depends simply on a rider on an appropriations bill which is about one sentence long which prohibits the FDA who would have to regulate this area. It prohibits the FDA from even receiving an application to do a clinical trial on heritable genome editing. That rider has to be renewed each year. If it was forgotten about, it would mean that heritable genome editing would be legal and permissible in the US at least in several states. Right, to do this work, of course we had to base this on a number of ethical values and principles and these fall into two categories, those that inform how decisions are made, things like openness, transparency, et cetera, all these things, being responsible about science and resources. And then values and principles that inform what decisions are made. So inclusiveness, caution, fairness, social justice, non-discrimination, equal moral wealth, respect for person, solidarity and global health justice. The global health justice turned out to be a very important issue for us. Clearly our committee was made up of people from around the world including global south and it became very apparent that things were very, very unequal. So we consider a number of special challenges around human genome editing. So that's postnatal somatic human genome editing you've heard a lot about. Prenatal, so in utero, somatic human genome editing, so that's where you're modifying the fetus in utero where the fetus is a patient, but so is the mother a patient because you have to treat her as well in effect. So that adds another areas of interest if you like from ethical point of view and scientific point of view. Heralty for human genome editing, human epigenetic editing, so remember that's where you use the method but you don't actually modify any DNA sequence. These changes you make are unlikely to be heritable but they do mean you can alter gene activity and you could do that in a way that is to deal with a disease, genetic disease or other type of disease but you could also use it for enhancement and that was the last of our special challenges is generally about using any of these methods for enhancement. So the government framework come up with a whole range of different tools, institutions and processes and these range from sort of big international things like declarations, treaties, conventions, et cetera. Through judicial rulings, ministerial decrees, moratoria if you like, the role of national science, most in societies and institutions, patents, which is not a very interesting area and I'll touch upon that in a minute, professional self-regulation, public advocacy and activism, the role of journals, publishers, et cetera, et cetera. So these are all relevant tools and institutions and processes for governments. They may be more relevant in some jurisdictions than others but they are all relevant. Very importantly, as part of our government framework we came up with a number of scenarios. These are very important because they demonstrate how elements of the government framework come together and come together in practice, illustrate some of the practical challenges that may be encountered when implementing a framework, explore the different facets of the government's puzzle and test the utility of the framework approach. So those scenarios included somatic genome editing, particularly so doing a clinical trial for sickle cell disease in a country in Africa, clinical trials for hunting's disease, very different type of genetic disease, how you might deal with unscrupulous entrepreneurs and clinics, how you might deal with enhancement in this case for athletic ability. And then of course, how it would human genome editing where we consider the idea I mentioned that an IVF clinic could simply want to expand their services and include some heritable genome modification. And then we also have the prenatal and neutral somatic human genome editing. So those are very interesting scenarios and they're well worth reading through if you can. So we have a number of recommendations and I'm going to go through all of these one by one. So I'm not going to go and dwell on this slide at all except to say the one I'm not going to go through but it's a very important one is number nine. And that is one recommendation is that there should be a review of the recommendations in two or about three years time where the recommendations are reviewed. We see how much has been taken up what still needs to be done, whether our proposals are still relevant or other possibilities could happen. So our first recommendation was that the WHO and its director general should demonstrate both scientific and moral leadership. Clearly they've been trying to do this with the whole pandemic and that it was felt this was another area where they ought to be happening. So be open about the opportunities as well as the challenges inherent in human genome editing. Clearly state the ethical aspects of human genome editing. That requires statements on both somatic and household human genome editing as I discussed earlier on. Outlining the consequences of failing to address the ethical issues before us if we start using the technologies without careful reflection and intentional collaborative decision-making. And by collaborative I mean also across borders if possible. So of course we're all used to the whole idea of scientific research being very international and that's clinical applications as well and that's true in this whole area. WHO can't do everything but we felt that WHO should collaborate with relevant international bodies. And just as an example, that would include for example the International Biotics Committee of UNESCO to develop and implement a shared vision for an ongoing international process. The director general should also institute across institutional approach. So that's within WHO to task the teams involved in regulatory strengthening capacity building to begin working on integrating the topic human genome editing internal activities because they hadn't at all. Can be in a meeting of regulators from member states to address the feasibility of international agreements on regulatory approaches for human genome editing very critically for capacity building in various countries and the possibilities for harmonization of that might be difficult but at least they should be discussing this. And then there's a newly created science division within WHO and we felt that they should convene meetings on human genome editing in the different six different WHO regional offices with appropriate relevant people and organizations to talk about the issues. So one of our first outputs was actually to suggest that there should be a clinical trials registry established that allows anyone to simply find what is going on in terms of clinical trials in the space of human genome editing. So that should ultimately include both somatic genome editing clinical trials but also heritable ones. Although there are no, luckily there are no heritable gene editing trials at the moment. Methods are not safe enough remember. But we were informed when we were thinking about how these registry might work by some of the practices have gone on in the stem cell regenerative medicine field where you've had some very bad practices. So row clinics and practitioners offering unproven treatment sending these to patients for large amounts of money often it detriment to those patients. So we thought WHO should ensure that clinical trials using human genome editing are reviewed and approved by first of all the appropriate research ethics committee before inclusion in registry. Request that national and regional clinical trials registries make use of keywords to identify any clinical trials using human genome editing because it was apparent very early when we started to launch this that quite a few companies launching clinical trials were trying to escape scrutiny by avoiding any mention of genome editing or CRISPR or whatever. So they need to do this so that they can be captured. Develop an assessment mechanism to identify clinical trials that may be of concern. That's important because again that this experience from the stem cell field is that some companies doing stem cell treatments are posting things on clinical trials registry registries simply as a form of reverse treatment but not actually doing any clinical trial. So it has to be that has to be assessed that any such trial would have to be thrown out of the registry and therefore hopefully not be seen as an appropriate thing to follow by patients. Robin, I'd like to get a Q&A in about five minutes. Yeah, no, I'll get there very fast. So I was going to skip through the other slides quite fast but anyway, this was thought to be important and particularly for the members of the scientific community who are doing appropriate research on germline cells or embryos to support them to have an additional, if you like, registry on basic and pre-clinical research that might eventually lead to healthy genome editing. So I'm going to skip that in any way. I've already discussed some of this but there needs to be ways of having a responsible international research and medical travel. So we don't want ethics dumping. We don't want people, companies moving to less regulated areas to set up things they couldn't do in their own countries or patients going to places which are less regulated and therefore having dangerous treatments. There was a very important topic was so-called whistleblowing, although we felt that's an appropriate term and it's more like speaking up. So if people hear about things which are going on which are almost an inappropriate, illegal, unsafe then there ought to be a mechanism, simple mechanism for these to be reported. This is a really difficult topic. Can't be captured in one slide and we felt at least initially perhaps the WHO could do something about this and operate in a hotline if you like but that can't be the ultimate mechanism for this. There needs to be a lot more discussion about it. The other things like patents which is a huge area in itself of course inventors hold the patent. They can impose restrictions on the use of that patent. You don't necessarily want patent holders basically controlling what goes on in a whole research area because they simply because they happen to be the ones who hold the patent and particularly we don't want them restricting the use of valuable methods in resource constrained countries. And so there needs to be a lot of work done to make sure that there's appropriate ethical licensing is carried out. There needs to be a much better education, engagement, empowerment about the whole topic. And again, we called on the director general to start initiating this discussions with other organizations like the UN for example to really get to start having an inclusive dialogue on these things. And also for WHO to develop models of best practice for doing engagement, stakeholder dialogue, et cetera, et cetera that can be used for genome editing. And then finally, we thought that this is goes outside genome editing a little bit but we felt that there should be a set of officially endorsed clearly defined ethical values and principles for use by not just WHO but in fact other organizations that could be important generally for the WHO to progress towards its own goals but for other international organizations to also do that. And again, these were the ethical principles. So I'm gonna stop there, stop the shower and we can do the Q&A. Well, thank you so much, Robin. I mean, seeing all that work you guys did in the last few years, I'm amazed that you did that and you led the task force for ISCR. So I- I didn't get much sleep. I don't think so. Right. Well, I'm eager to move on to the questions. Several have come in but let me start things off with the question. Some people have already raised in the Q&A box. Why do you think WHO is the right organization to take this governance leave in this area? You know, I'm gonna channel Dan Wickler here. He raised a really good question. You know, he didn't see among the goals anything about relieving suffering, reducing the global burden of disease or producing risks to premature mortality, the types of things you'd normally expect WHO to be involved in. Surprisingly, those were not articulated among the goals and principles of values. And so the question sort of lingers. Well, why would WHO be the appropriate body for this? If you can start with that issue. Well, if you read the report, they actually are spelled out in the report itself. Perhaps it won't come across in the slides, particularly as I was rushing through them. But no, the whole idea of distributive justice, social justice is throughout the whole, well, both reports basically. No, it's very important. And I think we spend a lot of time worrying about issues of how you get all the different forms of in the framework approach, different forms of governance you might apply, including the patent issue, which I went through very fast. Patent holders can restrict the use of whatever they develop their product. And they can control, it's only used in particular jurisdictions in a way, they can control all sorts of things. And that we felt that was inappropriate. The scientific aspects, the typical gene therapy these days costs half a million dollars, or maybe even up to one and a half million dollars or more per patient. That is ridiculous. You cannot possibly have that cost for countries which are poorer, not well resourced. So we spent quite a lot of time in the report talking about both capacity building in the global side, for example, and also that stressing that you, when you are thinking about doing any sort of therapy based on genome editing or whatever, in fact, you should have primarily upfront the idea of how you're going to get these techniques applied to most people and including those in resourceful countries. So if the scientists are involved at an early point in discussing, well, how can we develop these methods so that they can be used to treat, for example, sickle cell disease patients in parts of Africa where most of them are, then they are more likely to come up with methods that are much less expensive than if you rely on companies in North America or Europe who are, their major goal is to make lots of money for them and their shareholders. So, and that's starting to happen. And I think the WHO is a good place to start a lot of this discussion because they are used to dealing with these. As for example, with COVID vaccines, efforts to try and get the vaccines distributed around the world, not just to the rich countries. Another question came in, is the Layla Richards case a success story at this point? Do you know, is she still doing well? As far as I know, I haven't heard for about a year, but absolutely fine. And there were also a couple of other children who are treated in the same place in London and they are doing fine. And I think the methods have been applied in other places around the world. And I personally haven't heard of bad effects and maybe I'm just not well informed, but I think the majority are doing well. Yeah, another question came in, what do you think is the best way to deal with the risk of Mosaicism? Well, as I said, I think, I personally think the best way is actually to do your genome editing in cells and culture where you can grow them up, expand them clonally and screen exactly what you have before you make an embryo, which then won't be Mosaic. Or you have to use efficient method, very efficient methods in the early embryo, like the one I mentioned from Donald Rossant's lab that's not been tried in human embryos or not be published to be used in human embryos yet. But that was a very efficient method, maybe slightly hard to apply in the human case. But if you combine that with all the other incremental improvements that have been made in the use of the components for genome editing, the way you introduce them, et cetera, you could actually approach maybe 100%, but maybe that's sort of wishful thinking, but that's the only way of dealing with Mosaicism because simply taking a biopsy is not gonna help. Now, in some types of genetic disease, maybe it doesn't matter if, say, only 50% of the cells are corrected from liver diseases, metabolic diseases, that would probably give a sufficient rescue to the child born, but it wouldn't be a problem. They would be fine. You just need to know that there's no bad thing and no incorrect on-target events or off-target events. Now, obviously any children from that individual that's born may or may not inherit the genome editing event, so you're pushing that down to the next generation, feeling. Thank you. Another question came in. Is there an obligation to allow parents to have a genetically related child? Because after all, this seems to be one of the main justifications for genome editing for heritable changes. What are your thoughts on that? My personal thought is that normally, one might try to seek out other alternatives to having children, but the question that remains, what if these alternatives are not acceptable to people for example, adoption or a gammy donation? It's not acceptable for people who insist that they and their partner have to have their genes in the child. Was this discussed at any level at the WHO, like this kind of very specific desire to have a genetically related child? We discussed it, of course. The Nuffields Council on Bioethics had thought about it and it's basically discussed quite a lot in their report on the topic of heritable genome editing. I've always thought, well, why does it really matter? If I wouldn't care particularly if I adopted a child or had embryos or sperm donation to have a child. But many individuals really do care. And you see that I've seen this firsthand in dealing with the whole topic of mitochondrial replacement techniques. So I've met quite a few of the mothers and the potential fathers. Some mothers at risk of having affected children. And you know, they will have an effect. Some of these individuals have had an affected child and they've known that the risk is very huge. If they try again, they'll have another affected child. And there was one woman in particular who I think had five children, all of whom died of mitochondrial disease. They are just so desperate to have genetically related children. Now, it seems a little illogical but it's really, it's something fundamental to people. They want to have their own genetic related children. Now, in terms of the other methods, so adoption in the UK, I don't know what it's like where you are, but in the UK, adoption is so hard. It's, you have to jump through so many hoops. You have to be at the right sort of age. I'm way too old to adopt. You have to have the right sort of, I mean, all sorts of things have to be vetted. So it's very, very hard. PGD, I discussed a bit. Quite a few individuals don't like the idea of PGD simply because you are destroying embryos that you're not implanting. And PGD is often not that efficient. There'd be various published studies on this. Mostly women have to undergo three rounds of IVF to be successful anyway. And having to have PGD on top of that can make it even more rounds of IVF. So it's a big burden on the women. And this is a question from the Center for Genetics and Society. I'm going to paraphrase it a little bit. Is there an outright prohibition on heritable genome editing in the WHO report as a starting point, or it's not kind of out of the gate that strong? No, it's just, it's stated very clearly that the methods are not safe enough now, or certainly not safe enough, so it shouldn't be attempted now. This was the commission's task if you like. We didn't feel it was our duty to say there should be a ban or anything now. Some countries might want to have a ban. It is banned in some countries. Others might not. We can't prescribe to all jurisdictions around the world. And I think it's, you know, that there were calls for a moratorium. But again, the moratorium would be very hard to get all countries to sign up to. You can't have a moratorium without knowing how that moratorium could end. So you have to have a process in place to decide when and where and how a moratorium could stop. Do you think there were any ethical or regulatory areas in your opinion that were not fully covered or addressed by the committee? Oh gosh, that's a hard one. We probably covered pretty much everything in our deliberations. Whether it's all made in the report, I don't know. We had a lot of, we had two consultations. We got lots of comments from all sorts of individuals and organizations. So I'd be surprised if we didn't think about everything. Whether everything quite made it into the final version, I don't know. But it's fairly comprehensive. Yeah, Robin, as you and I know, the ISIS or guidelines are frequently criticized. It's not having actually any bite. They're just recommendations. People can take them or leave it. There's no regulatory, you know, enforcement mechanism or anything like that for people who deviate from the guidelines. How do you think the WHO committee report sort of tries to handle that issue of, you know, Well, of course, you know, the WHO doesn't either have, they can't regulate anything. But what they can do is they can help empower jurisdictions, governments around the world to come up with ways of regulating in this whole domain. And so they can put pressure on for things to happen. And so, as I mentioned, that in his Rivercroft case, the Russian scientist case, the WHO leaned on the Russian government who immediately then enacted something to say, no, this is not going to be allowed in Russia. You know, you know what happened after JK in after his announcement in Hong Kong, China were very embarrassed about this. They imposed a legal ban on doing terrible genome editing in China. So it's, because it wasn't one before. So it doesn't take much sometimes to put the pressure on the jurisdiction to force and make a ban. I'm not sure that having outright bans is ultimately terribly useful because they're often very hard to overturn. So it's very easy to have a ban, very hard to undo a ban. And, you know, you might imagine that there will be circumstances where heralded genome editing becomes important to do. Now, you can get very speculative about this, but, you know, there may be traits that we want people to have to survive global warming, space travel, whatever. You can, your imagination can wonder, but you should never completely eliminate the possibility that sometimes this might be important for societies. And of course, for some individuals, it's going to be very important, you know. You cannot have a hunting dense patient having a genetic-related child. So if they're homozygous for disease, there is no other way of going to have it. There are hundreds of thousands of individuals in parts of Africa who are homozygous for sickle cell mutation. Inevitably, many of these individuals meet other, meet their partners who are also homozygous. They cannot have unaffected children. So how do you deal with these? Is it reasonable to say, oh, no, they can't have children? You know, Robin, in looking at the values and principles outlined, they're very cosmopolitan, right? They're very liberal, that transparency, accountability to the public. I mean, aside from the director sort of putting some pressure on authoritarian regimes to be stricter, you know, I mean, so much of this activity. We're also putting pressure on them to be open. So that's why we put in transparency and openness and all these other things in there, because we want countries like Russia and China and Ukraine and others to be far more open about what they're doing. Right, right. Yeah, I just, that was kind of curious, because one might think that so much of this activity in China, Russia, maybe even like the Middle East and Qatar, these are authoritarian regimes and I'm not sure how well, I mean, aside from exhorting them to be more open and transparent, I mean, I'm not really sure how well that would translate into actual governance in some of these locales. Just kind of curious about that tension. Well, again, that's why, you know, this whole idea of speaking up with foreblowing becomes important as well, because, you know, even in those authoritarian countries, you know, someone there will know what's going on in the lab next door and if they can speak up, if they have a way of speaking up, that's not gonna get them in trouble. So they can do this via the dog radio or via another organization that could receive information about what's going on. You can then use that information to then stop what's going on indirectly. So you can get pressure put on by whether it's by the WHO, by other organizations, peer pressure, any one of these other mechanisms of governance that can say, this should not be happening. You know, most scientists want to stay within the safe boundaries of what's permissible, same with most clinicians. Rather, it's if you want to go outside that box. Now, you could argue, well, in some countries, they're so authoritarian, they've decided that they really want this sort of thing to happen. They want to have herosal genome editing to make, you know, super armies, for example, apart from being a stupid idea in the first place. If that was to become known in the international community, then a huge amount of pressure could be put to bear on that to stop. It's the same, you know, in the same way a nuclear preparation, et cetera, et cetera. But, you know, it's difficult, but what else can you do? We had a very provocative question coming from Ben Hurlbad. Hi, Ben. Hi, Ben. Would you give your own personal thoughts on the question posed by this event? Is global governance of genome editing possible? The WHO recommendations rely heavily on status quo practices and the international science. For example, the whistleblowing hotline presumes that existing consensus exists about whether or not something should be reported. So, you know, just some thoughts on, you know, whether it's even possible to do this. It depends what you mean by global governance. I don't think you can ever have one mechanism. There cannot be one globally agreed to law that's going to say this should be done, this shouldn't be done. I think the chances of having a, you know, perfect international treaty are zero on this topic. But I think by adopting from the framework relevant methods that could apply in particular jurisdictions that you can and then have hopefully lots of communication between relevant individuals and institutions. You can have some sort of global governance. I think that is possible. I think many jurisdictions do talk to each other. They will start to agree mechanisms that they are happy with. Now, it may be that some countries will never permit household genome editing whereas others will. So you just have to, they have to allow for that to happen. So you're never going to have a simple law governing this everywhere. It's just not going to work however you do it. But to have all these different pressures put on to make sure that people behave properly and only do things when they are safe, when they are justified, when they're justified for the individuals who are seeking to have a genetic-related child, for example. Do you think there are ethical differences, different issues regarding using CRISPR to modify the activity of genes versus using them to actually edit the genes? Well, as far as we know, these sort of AP genetic changes are not inherited. So these, most of them won't be. So that, if you like, that makes it a little simpler. You don't have to worry so much about that. But of course, you can use them for enhancement. You could easily modify someone to have greater oxygen update for if they're an athlete, for example, in a way that you couldn't detect with DNA. So you would have to have some other way of knowing that an edit's happened than you might not, because it could indeed, it could actually be fairly transient. So it's, I think there are ethical issues that are unique to that, which I suppose, which is the detectability, if you like. So you don't necessarily know what's happened. Now, that doesn't mean you shouldn't do them, but I just think that it requires a different way of assessing what's happened and precisely what's been done. So I see in the chat that Marcy Donofsky says, I misrepresented a question from the center for genesis, I apologize for that Marcy. I was on the fly trying to paraphrase, and I think I just got it wrong. So let me just read the question to you, Robin. Okay. And see if you can answer Marcy's question. As one of the authors of the Global Survey on Existing Policies on Heritable and Genome Editing, what jumped out at us was this, the extent and degree of current agreement that outright prohibit heritable genome editing. Shouldn't this be the starting point of discussion about governance of reproductive germline editing? So she thinks like, already people are in agreement about this. Well, actually I don't think they are. And I think so that's one of the other areas where I think the maps give a misleading impression. So some countries have sort of defaulted, if you like, to prohibit heritable genome editing by signing up to the Oviedo Convention, which appears to say that this is not legal. But it doesn't mean that those countries, if they thought about it, would actually want to ban heritable genome editing. And there are several countries, which as you will know, Marcy, that didn't sign up to that convention, some because they felt it was too tough, some that it wasn't tough enough. So there was a lot of, it wasn't an equal agreement to the convention to begin with. And even by those who signed up to it, it's almost certainly not equal. So, and as I mentioned, the U.S. is one situation where it's a very tenuous ban on it and it hasn't really been debated properly in the U.S. So how can you have a form of governance that hasn't been debated at all in a country? It seems to me inappropriate. So that has never been a vote in anywhere sensible to say that this shouldn't happen. And that's true of many jurisdictions. So, yeah. So let me just take like one or two more questions. This is a question that came up from Peter Acain. Do you think that the WHO can get leaders of four countries who often are not concerned about the health sector of their countries to commit to acquiring such technologies when they become safe and available? Well, I think the WHO sort of as an organization may be best place to try and do that. But of course, you know, people will be aware that one of the reasons why some countries don't spend enough time thinking about particular things like genome editing is because they've got other more urgent things to worry about. So they've got a neighbor who wants to invade them. They've got, you know, the wars going on. There are other demands on their time and resources. So why on earth would they think start thinking about genome editing when they've got all these other things to worry about? But when the time is right, yes, they should be asked to be involved in thinking about these things. Well, thank you so much. I think we're pretty much out of time. We had so many great questions come out. I'm sorry that we couldn't get to all them. But I think this just clues you in on the interest that people have on this topic and on the work that the WHO committee did and your very hard work over the past two years. So thank you so much for sharing your expertise and the best in your time. Well, you know, if people want to email me that questions, as he says very foolishly, I'm quite happy to have a go at trying to answer them. Great. I don't expect an immediate response. Well, thank you. So with that, I'm going to conclude today's session. I want to remind everybody to be back on October 15th, same time on Friday. This topic will be on CAR T cell therapies and our presenter will be Karen Jacobsen from Harvard Medical School and Dana Farber Cancer Institute. So we'll look forward to that. That's actually a nice follow up to today. So with that, I want to thank everybody for joining us. I want to thank Ashley Troutman for her help in helping to organize this. And we will see you next month. Thank you, everyone. Ready?