 All right. Thank you so much, everyone, especially to our speakers. Diana Blythe and Alison Murdoch for some really, really interesting things to think about. I do want to remind everyone that all of these talks will be archived on the Nobel website, especially for students and educators. If you want to review, there's been a lot of information that's been shared today. If you want to go back and remind yourselves of some of that information, please do so, and please feel free to use any of these materials in classes to share and kind of maybe pair some talks and discuss together. So thank you all. I think we're going to do the same kind of thing as we did yesterday and just kind of throw the discussion open to all of the panelists to share some thoughts, reactions, maybe tie it back to yesterday, and then after a bit, we'll start sharing some questions from the audience and online. Go ahead. I don't mind jumping in there. So first, I just wanted to comment and appreciate the clarity of the presentations, the accessibility, the fact that it drew us all in wherever our starting points were. So I just wanted to really thank my colleagues for presenting the way that they did, and I hope I'm sure that you agree. I think that's really a prerequisite for having good conversation and debate across a wide variety of people to be able to just have some basic sense of what we're talking about and presented in that way. So one comment and then one question that I just like to hear any of my colleagues' thoughts around. So the one point I would just say is that in terms of, it was a fleeting comment about the use of prisoners in research, and I would just say that we make bioethical strides, but we can also backslide as well bioethically. And so in fact, in the U.S., there has been recommendations to loosen the regulations around prisoner research, starting in 2006 with the Institute of Medicine's recommendations. And so I think we all need to stay very alert to the way in which things become, there's consensus built, but then the way that things evolve and can actually, we can actually start to, and I'm saying this in a critical light, I think, regarding prisoner research, where the human rights crisis around mass incarceration is such that we have to think about what it means to be included in research as not a straightforward good when the larger context in which you're being included in biomedical research is so oppressive and also so racially skewed. So the question, the question then just for anyone who has thoughts around it is, I'm going back to a really important set of points in Dr. Murdoch's talk around the composition of the regulatory committees. I appreciated the highlighting that patients were absent in that, and I thought that was really alarming. I also really appreciated the point around the kind of seeming lack of scientific understanding among those people who were there to represent the lay interests. And so the question I have is understanding the importance of including patient perspectives, understanding that those lay members and representatives should have some scientific understanding about what's going on in the clinic. My question then is, what forms of knowledge and experience do clinicians and researchers lack that should also be comprised in those committees? That is, there's an understanding, a common discourse about the need for scientific literacy among everyone. And so what I'm interested in is what forms of social literacy are necessary on regulatory committees? Who else do we think it should be part of the conversation? And I think that shifts the conversation not only to what researchers and clinicians know, which is vital, but also perhaps what they don't know. Is that the question? Well, let me give an instance of the, I think illustrates what you're talking about. We had a talk at our advisory council recently in which a parent whose child had Cushing's syndrome, which is a rare disease, but a very serious one. And the child went from being normal appearance to being fairly obese and nobody recognized that it was Cushing's. And they just kept telling the mother that she was a bad parent because she wasn't monitoring her child's food. And she went to several physicians and kept getting the same basically admonitions. And so they felt incredibly guilty. And yet they're watching their poor child, not growing and getting more obese. Finally, somebody recognized what was going on. They began treatment and the child is basically, you know, under diseases under control, normal weight and normal activities and all. But the torture that the poor parent went through in not only trying to advocate for the child, but being told by the medical community that it's all her fault is, it's mind boggling and so heart aching, I think. Patients' perspective and parents of children as patients' perspective are very hard for, I think, the medical community to recognize and especially in our country where physicians are becoming so, having to sort of treat so many so quickly and have little time to talk and especially around contraceptive advice, counseling, they don't get a proper amount of information. I wish, I really wish we could go to a national health service that would have more of the outcome-centered approach than the fee-for-service approach. That would be my thought. I'll further complicate your question about representation on boards and panels. I mentioned in passing that I'm sometimes asked to represent the disability community. That comes from an experience of people in marginalized constituencies being asked to join these panels and when we do, we work incredibly hard to speak up and speak out for our constituency as best we can and quickly realize how tokenized we are. A yucky example is speaking up and speaking out on federal ethics panels for the genome and then having scientists and others say, I never heard your perspective. It's really moving. Why don't you write about it? I realize that certain constituencies of professionals and researchers and so on don't have a way in the structure of their fields to learn other points of view. I don't mean to criticize science again, but I'm criticizing science. We need to have much more cross dialogue, which is the purpose of this event, so that we're minimizing the exploitation of this process of representing certain constituencies when the voices really are only tokenized. It's a really hard pathway. It's decades. I'm 66. I've been doing this for 30 years. The progress is incredibly slow, not only to be put on the panel's debate, but to have our voices heard. You know, I don't want to defend scientists too much, but there's a lot of information to take in all the time, and we tend to be in silos. Even the egg people don't speak to the sperm people. Try to get them to communicate across those disciplines amazingly hard. I think they would like to do that. I think they'd like to find the time to do that. We all can benefit from the opinions and exposure and experience of other people. I wish there were more hours in the day to be able to find the time to do those things. I think it's really interesting, coming from the perspective of the liberal arts and everything, and what a liberal arts institution is meant to do. A lot of that work has to happen, not when you're an expert and you're adding on these extra perspectives, but as a student in the classroom, the groundwork needs to be laid, and so sometimes students want to rush through their gen eds and say, okay, I got to check off this box in that box for sciences or history or whatever. The whole point of that process is to give students some kind of foundation, so that when they go off into the world, they engage in their own area of expertise, that they can come back and be like, oh, there was a class that I had to take, but really learned a lot from that now allows me to add in these, to take into account these other perspectives. So this is exactly the kind of conversation that we should all be having across disciplines. I don't think it's only scientists that have this issue. It's all of us, right, that have this. I have a similar experience to share, but the deficit of not being into liberal arts. At UC Berkeley, I got a grant a number of years ago to run a small seminar for advanced undergraduates called Regeneration, looking at reproduction and stem cell research and genomics, and I took, a colleague and I ran it and we interviewed, we had students applied and we took half students from the STEM fields and half from the social sciences and humanities and professional schools. It was, and half the students had visible and invisible disabilities and half didn't, and as far as we know, it was entirely self, it was entirely voluntary how you chose to identify, but that was how we structured the class, but several of the STEM students had almost no gaps in their schedule. So they literally often couldn't get there. So it was something as basic as the way that the undergraduate education was structured. There was no time in the day that they could come to the seminar, so we had to swap out some alternates for some of the people we'd originally chosen. And that's the kind of thing that more of the liberal arts ethos, I think, but it was a fabulous seminar, very, very interesting. Great. If we could bring the discussion back to the two specific talks we heard this morning. I would love to hear from all of the panel members up here if there were any additional kinds of things that you would like to talk about before we throw it open to the audience questions. I'm really curious, from Allison, I'm curious when papers first came out with Frankenbabies, things like that, and then after that there was the Nofield Council decision, things can go ahead. Did things come full circle again? How did the papers report on that decision and how were things communicated back after that decision? The reports that came back from the science journalists. So you've got two issues when it comes to the newspapers. You've got the actual report that you go and read, and for the news stories on the television, where they have a long session and you get five to ten minutes to talk about it, actually got quite reasonably well-informed reviews then, where they talk to different people, they looked at both the ethics, they talked to patients, they talked to clinicians, and you get a broad view. With exceptions, I think probably of the headline from the particular paper that I showed you, which was an extreme, and they always do that. But the science editors don't write the headlines, and the purpose of newspapers and television is to sell their medium. So they have, when I talked about what I call third-party interests, I put the media on that as well, because they do have an interest, but their motivation is different. Their motivation is to get people to buy their papers. So we need to be clear when we give them a voice to understand why they're giving that voice, why they're using that opinion, and read it that way. But we try to challenge about the three-parent headline, which is just horrible, and it is so demeaning to the whole meaning of parenthood. But eventually, the media centre, which is the UK organisation that sort of corrals us as scientists and clinicians when there are big issues like this, so we can present to face to face meetings with the science editors so we can be sure that our message is getting over clearly. Their message was that you're not going to win that one. They like that headline. It sells the papers. Just forget it. Go with it. So we have to go with that headline. So I'm still blown away by the video, which is just amazing. But I have a question. I thought that mitochondrial DNA was the place where you got back for generations to be able to determine whether or not that that was the most highly conserved. If you were trying to determine whether somebody, you know, parentage went back many, many generations, you used mitochondrial DNA. Does that contribute to anything or is that true or not true? No, that is true. And that's because, you know, as explained even in my family, you get intact mitochondrial DNA. But there are different types of DNA. So like blood groups, you get different types and different areas. And you can trace back human origins through centuries by saying this person must have come from Africa or they must have come from Indonesia. So you can trace back origins that way. So you're messing all that up now with the... You're messing all that up. Really greatly confused people in the future. Except that we're messing it up for people who in the process have acquired an abnormality. Spontaneous abnormalities occur in mitochondria all the time. So we're never going to cure it completely. There will be some people who will develop a problem. But once that problem is developed, it then gets passed down through the generations. So yeah, there's still a bit to sort of do. But that's how you follow it through. And you can follow the mail through by the Y chromosome in the same way. Do you make any kind of effort to match your donors to your recipient couples? There's been a lot of discussion about that because there is some relationship between you require some genes on the nucleus of a cell in order to activate the mitochondria. So there is some relationship. And there was some fear from mouse studies that if you if you didn't match the mitochondria, then you might get malfunction. That has largely now been thrown out because the mouse studies were done on inbred mice, very specific strains. Whereas human beings, we are what we call an ultimate wild type. We interbreed. All right. So from that basis, there's no evidence that you get incompatibility. You can meet people can breed with people from different ethnic groups, and you don't have mismatches. And as I showed in my slide, the my granddaughter's nuclear DNA is only 3% of her great, great, great grandmothers. So if there was an incompatibility, it would have shown up during that time. So now we are not specifically aiming to match. But it's one of those things that will be looked at and will be followed through. Do you also look to see whether the the continental origins, for example, whether some of the information that's given in the mitochondrial DNA is a match in the same way that you might match phenotypic things in picking an egg or sperm donor. Yeah, the function of the mitochondria is purely to produce energy. So you don't try to have them get the same results out of a genetic ancestry test. 23 in me. Yes, you don't try that at all. There are a couple of other questions about sort of some of the more technical aspects of mitochondria that we might throw in here, just in a clump, if I could. Why are this from a high school student? I think why are mitochondrial diseases only passed on by the mother? What traits and maybe you've talked about this, what traits are coded for by mitochondrial DNA? And then getting into the matter of mitochondrial transfer. Are there any circumstances where the donor mitochondria could be rejected by the patient? And how would that affect the embryo or the mother? Well, I think, as explained, it goes down the maternal line because it's the mitochondria in the egg that matter. mitochondria and sperm are lost at fertilization. So it's passed down intact through the maternal line. I'm beginning to lose track of what the other questions were now. What traits are coded for? The function of the mitochondria is simply to produce energy. All right. So there are lots of different things that can go wrong with the genes in the mitochondria. So you can get different forms of mitochondria disease. Some women could have all the mitochondria abnormal, but it'd be a relatively minor abnormality. So there's malfunction, but it's not, it's not doesn't mean that they don't function at all. And the way that mitochondria are distributed through the body will determine the disease that they get. So if, for instance, you have all your abnormal mitochondria in your muscles, that's when you start getting muscle and just to fit out problems. If it's in your pancreas, that's when you can start getting some forms of diabetes. And it's more than that in that sometimes they don't sometimes they present at birth. Sometimes they don't present till later in life because mitochondria are dividing and growing all the time. So there might be different weights, different rates at which the mitochondria divide. You might have a small number of mitochondria in a cell that are abnormal and they divide faster. I'm not a mitochondrial expert, I have to say. And I realize I'm very quickly getting into deep waters here. So people want to know the details of mitochondria disorders. You know, my colleague Dr. Amal is better placed than that. But the more now we understand about mitochondria disease and the problems that are associated with it, the more research is going into it. It doesn't get sexy stuff onto the advice. Would you feel comfortable sketching out the answer to that last question? Are there circumstances where the donor mitochondria could be rejected? Well, I think this is the issue that we were talking about is that there is a relationship between the gene, the function of the mitochondria and the function of the nucleus. So if there is an incompatibility problem, then theoretically, yes, it could be rejected. But all the evidence we would say at the moment, all the theoretical evidence, when you do these things, you don't just say, well, we'll have a go and see. You do a risk assessment first. You work out all the different steps, all the things that are happening and work out, well, what would happen if, and you look at the evidence, indirect evidence and direct evidence to see. And at some point you say, well, we've done the best we can. The next thing we can do, the only thing we can do is to do it in humans. There have been primates born from similar techniques without problem, not a lot, but enough to feel that we need now to move into humans. The problems with primates in terms of reproduction is that they are on the nearest representatives in the animal world, but they are still a long, long way for us in reproductive terms. Just to give you some figures, a baboon, the chance of conception, first one cycle of intercourse, about 80% chance of conception. In humans, you're probably down at about 15%. And that's our nearest relative. Great, thank you. We also had another question from a high school student who was wondering about that video that was so kind of exciting. And this person was asking, when transferring the nuclei, or what happens to the puncture in the egg, can that cause complication within the development of the embryo or the ability to fertilize the egg at all? Is it possible that there's more than one sperm that could get in? And so I think like, and so if we could maybe just clarify just that basic information of like what happens to the puncture, I guess. Well, the first thing that happens is that because we're doing pronuclear transfer, the sperm bit's already been done. Okay. We do a procedure called ixi to achieve fertilization, which is where you pick up a single sperm injected into the egg. If you do normal IVF, you put about 100,000 sperm with each egg. All right. So you would have that egg, as you saw it on the video, with lots of sperm spinning around. And we wouldn't want to do that because you wouldn't want any more sperm to get in. So we only put one sperm in. The shell around the outside of the egg, which is called a zona, it is an egg shell. When we do the ixi procedure to put the sperm in, we make a hole because we have to make a hole with a needle to go through. But you can do that with just the needle going through. For these procedures, because it's a slightly bigger pipette that you're using, you need to make a little hole in the techniques that you can use. There's different things you can use. You can use a laser to actually make a tiny hole in that. These techniques of actually making holes in the zona have been used in fertility practice for many, many years. They call it assisted hatching because as the egg then goes on and divides and grows, there are initially, when it gets to the blaster stage, it's still the same size as it was at two cells. But eventually it gets bigger and bigger. The shell expands, expands and it hatches. It literally hatches. It just sets the embryo comes out. There is evidence from IVF treatment that hatching maybe not be the best thing because there's an increased risk that a bit of the embryo come about too early. And then you can get identical twins. And that's not good news because more things can go wrong. So in the IVF field now, we probably don't really recommend assisted hatching to be done. But those techniques are fairly standard. They're standard if you're doing PGD, if you want to take a single cell out to do a genetic diagnosis, you're making a hole in the zone to do that. So again, when you're doing your risk analysis, you're saying, well, in order to do the transfer, we're going to have to make a hole. Is making a hole going to be a problem? Where's the previous evidence? The previous evidence is we've done this lots of times than IVF before. We know the risks. We know the benefits. We think therefore that that particular the process is not going to be a problem. Great. Thank you. And if we could switch gears a little bit, we have some questions regarding contraception. And one person would like to know what you think that male contraception will do to the rate of STIs. So will this have effect on STI transmission? Will condom you like, you know, where will condom use fit in that? Is this something that, you know, people who work on the area of contraception, do you think about the public health, you know, kind of consequences of maybe people saying, well, pregnancy is our main concern. Let's let's just go with that. And we don't have to bother with condoms anymore. Well, I think it's it's not an easy question to answer. It's probably true that there will be less condom usage if men are using a method of contraception. But it would be stupid for them to have a new relationship with somebody where they're not using a condom. So I think it again would go with counseling. And you would say to the individual who's using the contraceptive method, by the way, this does not protect you from transmission of disease. And therefore, you need to protect yourself. But once people are in a long term trusting relationship, there tends to be not as much condom usage or, you know, other options prevail. So I think it's something people worry about. It's not a good reason to not develop a male contraceptive, but it is something that people should be aware of. And it'd be nice if we could find a way of controlling for those diseases in other ways. Right. It reminds me of Alison, I think you said yesterday that, you know, these things are not mutually exclusive, that we need to work on the medical side of things, the scientific side of things, but also pay attention to the social aspects. Right. And actually, Gustavus did a survey, which I think you mentioned, kind of trying to access what public attitudes are towards male contraception. And we found that, you know, 80% of women would be in long term relationships, would be, you know, happy to have male contraceptives be used in conjunction with their own usage. But in short term relationships, 30% of women were like, I would still like condoms. So I think those conversations need to be happening, you know, just kind of across the board. And, you know, they can be an additive effect as well. So, you know, the condom gives extra assurance if one is trying to be. And as I've said before, I don't think the women will necessarily, particularly women who are in new relationships will not stop using their method. Right. The guy does not wear a big C on his forehead. You know, so you're not really 100% sure. Right. They are, by the way, there is a device on that slide that came out of some early research looking for sperm specific antigens in which you can actually do, if the man will ejaculate into the cup, you can determine how many sperm he has. And you can determine if he has sufficiently low number that he's acceptable. There's that to go with, but maybe a little extreme. I want to say that. That would be a little tricky. I'd like you to fill out. I think the theater of public policy had some great ideas last night about how to do that. There's actually maybe a related question here that also brings up something that Yuri might be able to speak to from the survey. You touched on it briefly, Dr. Blythe, that contraception has been traditionally the responsibility of women and women have a particular investment in it, obviously. Can you comment more on what you're finding in your research or are you finding in your research? Anything you'd like to talk about with respect to men's interest in these procedures? I'm sorry, in these contraceptions? Well, there are many stories. There are couples for whom women cannot use a method of contraception for whatever reason. And they are limited to condoms of vasectomy, which may not be optimal. So in some of my slides, when I'm talking about the methods for female and I talk about trying to develop safer methods, one of the slides is the safest method for some women may be a male contraceptive. So there is that possibility. I think that men may independently want to have protection from fathering a child that didn't intend to father, didn't want to father. And so there are many stories. There are many reasons. It is hard and interesting to discuss when we're talking about this effectiveness trial in couples, how do we assess the risk benefit relationship? Because in the female, she's willing to assume a certain amount of risk of the product and side effects of the product because the pregnancy that might result from not using the product has more risk of the same possible bad thing happening like blood clots or pulmonary embolism. But so she wants to avoid the risks of pregnancy and is willing to accept the risk of the drug. Now the man is taking the drug. He has no risk, physical risk of all that. His partner may. So his risk is, you know, what he's willing to tolerate in terms of side effects or health risk for the benefit of his partner. So it's an interesting question. It's not an easy one to answer. We struggle with it. And the FDA will struggle with it in terms of approving products that have a certain side effect profile in the in the people that you have treated. Do you do you do surveys to find out what side effects they are willing to accept? Well, we don't do so much on the what are you willing to tolerate from a hypothetical method, but when methods we're actually using, we're trying to get as much information from them about side effects and acceptability as possible. How do you find that the side effects men are willing to accept differ from those that women accept from side effects of hormonal contraception? Well, I'm not again, it's very individual. And and some people have more tolerance for side effects than others. The study, there's a very well known study that was stopped in Europe. It was an injectable method. And by the way, there was an article in the paper that said it was a US study. It was not in the US only in Europe and in other places. We were not involved in it. It was stopped because of a concern of a couple of individuals who had severe depression. There were the men who were on the study when the study was stopped, did not want to stop taking the drug. 85% of them said they would be willing to take it. If you know, that's higher than any of the numbers I showed you of acceptability on methods. They really liked it. So whatever side effects they were having, they were certainly willing to tolerate because they were not happy at having to discontinue in the study. I have a contraception question for you in the light of work in freezing and fertility preservation in a number of contexts. Why don't we now now that we have egg vitrification procedures routinely just freeze eggs, freeze sperm have a one off vasectomy, a one off tubal litigation with minor side effects associated with those once. And I know that there's a generator problem. We need to keep our liquid nitrogen cold. But assuming we have appropriate backup generators, why presumably that would be cheaper to the health care systems and it would be have far fewer side effects. It would be far less capricious, far less acceptable. Really be cheaper to the health care system to have to have all of these samples. Everyone in the world basically, I mean that's you're, you're scaling up to vast numbers. I'm not sure that that we really could possibly do that wouldn't you worry, you got to mix up in the samples, you know, bad enough you have to worry about whether or not you're getting the right baby to take home in the hospital, but getting it, you know, you're trusting some technician to go and get your sample out of some freezer that didn't break down somewhere along the way and freezers break down. I'm more thinking you keep your own. Granny's Ash and you're all wiped down. I think I think you have to, this is that would be very futuristic. And I don't know, but I do wish on a more serious note, I wish the fertility preservation field talked a lot more, talk about silos to the contraceptive field, because they're really in the same business. And they're just not talking to one another. And the idea of turning the egg into suspended animation until you want it to work, instead of having those eggs just dying away every month from, you know, in utero to adulthood, it will be nice to be able to just control that whole process, which is what fertility preservation people are trying to do. And if you were freezing your gametes young, you would also have less of a problem of delayed child bear. How young are you going to get these things out of these poor girls? We would ask the mother, what's the optimal age? Well, that's the problem. Some of these children undergoing chemotherapy and they have to make that decision very young and they, you know, it's not an easy procedure to get those eggs out of them. Yeah, so I think I think the bottom line you have to remember that having babies, the natural way is actually much more fun. And it is actually what most people do and want to do and we really need to be careful that we just don't get it too technical. I have concerns about the egg freezing issue. It was developed as a technology because young women were having cancer treatment and the cancer treatment was making them infertile. And whereas for men in that situation we could freeze their sperm, we couldn't do anything for women. And so we said, okay, now we've developed the ways we can freeze eggs. We can freeze their eggs and we can give them a chance when they survive their cancer treatment to have a normal life and a normal family. And that then has become probably for commercial reasons into the social sector. And we end up with social freezing. I don't like that at all. It's not common in the UK. It's certainly not part of the NHS system. Just technically for a start, it's a very bad insurance policy. Remember what I said to you about abnormalities? How likely it is that eggs are going to be genetically abnormal? So if you have a batch of eggs frozen, say you do one cycle and you have an average maybe eight eggs frozen, your chance of a baby is probably not that high. Would you take out an insurance policy that will only pay out 25% of the times if your house burns down? You probably wouldn't. You'd want 100% guarantee on that. So realistically if you want to do it, you're going to have a lot to freeze a lot more eggs. You're going to have to freeze 10, 20 eggs to give you a reasonable chance, which means going through more than one pickup procedure. The whole question you say about storing eggs, keeping them, I think we really had to be careful not to get the whole thing too technical and reserve IVF and the technology for people who really need it. And can I question you, can I come back to your question about contraception? Because in the UK, it's an issue I've raised in the UK as well. The clinics that do with contraception are actually called family planning clinics. Now family planning is not about not having babies. It's about having babies when you decide not to use contraception. So there is a very clear mix between the two. And it comes back to something as saying yesterday about date about times. And there should be some instruction when you take your contraception about discussion about, well, when are you going to have your family? It's all part of the same process. And I would tend to agree with you as well that, you know, a good communication, that level is really quite important. Just to add another, I read an article the other day about hyperovarian stimulation syndrome, or ovarian hyper stimulation syndrome. And as another kind of wrinkle to the whole, like, oh, just freeze your eggs. It's not actually that simple process. And then also kind of medically as well. You're getting into a slightly technical, there was a condition called ovarian hyper stimulation syndrome, which is a complication. To do IVF, you need more than one egg that just increases your chances statistically. So you give women medication. And on average, you're going to produce about 10 follicles, and you're going to get about eight eggs from that. There are some women who have ovaries that are just stuffed full of eggs. We call them polycystic ovaries. They're really, really super ovaries. They're being medicalized as being problems, but actually these are, these are wonder women. When you superovulate them, they can have 20, 30, 40, 50 eggs. And if you collect all those eggs and you do the procedure, their ovaries can become very swollen. I think they can get metabolic problems that can be quite serious. And to some people's practice is then to make embryos and freeze the eggs, freeze the embryos or make, keep the freeze the eggs at that stage, stop all the treatment, let everything settle down and bring them back and put the embryos back at a later stage. It is, it is a side effect of IVF, but the risk of it for someone who doesn't have super ovaries is extremely low. That's the 1% for women that does have super ovaries. It's one of those risks you tell them about. You say this is the risk you're going to take. Do you want to go through treatment? For instance, we would not take someone as a, as a volunteer egg donor who had that risk because the risk is too high for them. But if someone wants to get pregnant, then they want to get pregnant, you know. We had a question come in with someone who would like to know if there was any religious pushback to similar legislation that you were talking about in the UK. Because I think, you know, that's something that would certainly be an issue in the US. Okay. We are very fortunate in the UK that not only is it, there's not, there are religious views, but it's not a party political view. So when there's been debates in parliament, they have not had, you know, a three-line whip from the parties. So people can vote on their conscience, not a longer party line, which means that the legislation hasn't bounced backwards, depending on who's in power at any particular time, and that's really good. Yes, there are religious groups who campaign against sister perception techniques and a lot of the reproductive techniques and mitochondria transfer that we discuss. They, they lobby loudly. They heckle at meetings. They have a voice. I don't have a problem with them having a voice. They have a say, but they are a minority. And in the debates that have gone to parliaments and to regulation and legislation, they don't, their voice has not taken priority. There has been debate about whether there should be someone with these views on the regulatory authority. And that's been an interesting debate. The chair of the authority has always had the view that there isn't much point in having such a person sitting on the authority because they would always vote against everything in principle. So the views of these people are tend to be taken into account in, in light of consultations that they do. So if they're going to, for instance, they, when we did the mitochondrial stuff before they decided to allow us to put into application, they held a public consultation and they took written evidence. So that was the time of which people who had those views could put their views forward to them, but they don't actually formally sit on the authority. Right. And there was another question as well. Actually, someone from the audience here was wondering about, you know, so how does it work for people who are doing work and in other fields? You know, can you could you, for example, move to the US and do work here? Or like, you know, is there like a researchers without borders kind of situation? Or how does that work in terms of different countries policies? There is there are some groups. There's the Hickston Group, which is an international group and Cambridge, which has looked at some of these issues, these cross-border issues. I think they are difficult because ethics is not absolute. Moral issues are not absolute. So what might be ethical in one country might not be ethical in another country. And when you can, you do clinical trials that obviously is something that you need to take into account. Scientists move between different countries to do different research and patients move to between different countries to access treatment that might not be available in one country or another. So those rules and regulations, if you're making the rules and regulations, you have to think about the consequences. If the consequences is you're going to drive your top scientists to work in a different country who's benefiting. There are more difficult questions about your top scientists goes from here. Does work say in the UK gets lots of prizes, comes back to US where what they were doing might be illegal. How is their community going to regard them? Are they going to accept the fact that they have done work that's illegal in this country? Lots of big issues there. But the reality is that scientists move around. You know, it's not too difficult to get an aeroplane. It's more difficult to get work visa. But if you're going with a research grant, it's not usually that difficult. Right. So another thing to think about in terms of the structures that we put in place, right, how does that impact the opportunities for researchers and what you're allowing to happen or not allow can impact that? Well, as I mentioned, our male contraceptive trials being done on four continents, right, quite a few different countries. And that's an exciting opportunity because we hope to get different perspectives as in terms of acceptability and usage from the different cultures. All right. So potential global impact, right, for male contraception and availability. One of the things we spoke about in our student session yesterday with respect to transnational research is, again, thinking about the structures and how the knowledge moves, how the products move and how if we look at, you know, the outsourcing of research and clinical trial research around the world, we see a pattern in which researchers need often populations that are not already stuffed with drugs, like in the US. So what we call naive populations that so often the work of Edrian and Petrina has shown that what happens is we use different populations as clinical trial subjects, but often the power dynamics and the economic dynamics are such that these very same people don't have access to whatever the results are of the research. So they're test subjects, but not then able to consume or take part in the medical advances that happen. And so part of what we have to think about is that power dynamic that, yes, we want to think about sort of lowering the borders of research, but that might mean being able for us in the West to be able to go and move and do things, but then the economic imperatives mean that then there are very high walls for people to access what is developed. And so we need to think about that dynamic. That's actually true for any clinical trial of an investigational product that, whether it's in the US or any other country that I know of, the people who participate in the clinical trial when the trial ends do not get to continue to use the drug. And we've had times when people said, please, can we continue to use the drug? We really like it. There is compassionate use, but that's a rare phenomenon. And so no, I think that's a good point that it's not even the only a factor of doing things across borders, but for people here. And we know that even for the human subjects research here, there are class dynamics involved in terms of people being professional clinical trial subjects that is going from trial to trial because you get stipends. And so there's class dynamics that then are you able to benefit from the things that you're participating in? Yeah, we've had two sites in New York in which an individual will enroll in both sites trying to, you know, that takes a bit of doing to discover. But it is, it's a problem, but we are so grateful to the volunteers. I mean, you put up with a little bit of that because if we don't have volunteers, we never develop anything, no. So then the question is beyond being grateful, what other benefits should trial participants be, you know, privy to, right? We can't get very much money in our studies because we don't want it to be coercive. Right. And so it's, it really is a volunteer act of, you know, wanting to help and benefit and contribute. If anyone's interested in it, the Norfield Council did a report a couple of years ago on human bodies, which is about donating. It was in the clinical scenario donating kidneys and things, but also donating for clinical research and looking at in detail all the ethical issues that were involved. So if people are interested in that area, I would suggest it might be a report that would be worth reading. Yeah. And so then this actually leads us to another question that an audience member had with regard to access and health insurance. I mean, you know, would male contraceptives, you know, of the kinds that are in the pipeline, would they be covered under health insurance about how much do you think it would cost? Is this something that actually, you know, people around the world or that would be accessible? Because, I mean, even the contraceptive options available today for women, access is an issue. So mine is even new things. And so. Well, so if I rule the world, insurance will be available to everybody that, and in fact, the drugs would be available to everybody at no charge. Right. However, it will be a new product I'm sure in the beginning, there will be more restrictions on it than methods that have been out in the field for forever and ever. But hopefully, it will be something that will be available. Because we're testing it around the world, we hope to have the ability to have approval in multiple regulatory areas someday. I hope it would be covered by insurance. You know, in our current environment, we're not sure what's going to be covered by insurance in the near future, but we would expect it to be. And if it were to be covered by insurance, would it start out like, you know, really expensive in the beginning, but maybe a number of years down the road, it starts to get cheaper? Or would it kind of debut at a reasonable? I think, well, I don't I don't understand all those marketing calculations, but it seems to me that if it's too expensive, it won't get used. And therefore, the belief is it has to be affordable. Right. Any other thoughts or questions? I had to go. I've got one thing that came up in both of the talks this morning, which I thought might be interesting to discuss, which is sort of expectation management around science. Both of you sort of discussed how long it takes to do this sort of thing. And, you know, I think especially these days, we're used to a new iPhone coming out every single year. And we can see technological progress happening from year to year to year. Biology is not nearly that fast. And so I just sort of wanted to maybe open up for discussion. You know, these programs are the result of decades of hard, frankly, boring kind of slogs through science and a lot of failure and a lot of trial. And then suddenly something big happens. And certainly, you know, with with CRISPR, it's it's this big hype machine, but it's nowhere near as advanced as anything that we heard about this morning. So, you know, it's something that I sort of wanted to open up for discussion on the panel. How can we as scientists maybe communicate with people what how science actually works and how it eventually gets translated to commute to changing people's lives. So when I get asked for interviews, I start out with the reporters and they're all very enthusiastic. And I get them really depressed by the end. It's going to take me four years to get this trial finished on a product that's in phase two B, not even phase two A, but phase two B studies of clinical stuff. And then if that all works really well, I get to start all over again on a phase three, which the FDA usually wants to phase three large studies. I told you about the 20,000 cycles for women. Well, that's about 2000 women using the product for a year. So that's a really large trial for men. And it's going to be at least 10 years for a product that's already so far advanced in clinical trials. So when I say something exciting happens in a mouse and they talk about five years, I just laugh at them because they're not even gonna see a patient for at least 10 to 15 years, most likely, if it's a drug, if it's a systemic drug. If it's a device, possibly it might be faster, but for a systemic drug, you need to have a huge body of safety in animals before you can expose men or women to the product. Could you talk a little bit about, cause people have been asking, women have had the birth control options for 50 years and so like, why don't men have it? And so we hear you saying that it takes a really long time. When did people start asking the question, like, hey, we should develop this for men? Back in 1961 in prisons, you know, it was going on. They were obviously considering it at that point. So it was about the same time the pill came out for women. They were recognizing that there might be ways of controlling sperm production in men and people were interested in it. But it is a very hard thing to have a drug that doesn't have side effects. And again, sometimes you don't find out those side effects until you get into humans and then something serendipitous happens. And how long did it take from kind of, you know, beginning-ish to the endpoint for the female pill? What was that timeline like? Like, how long were they working on that before they were able to? It was about 20 years, I think. About 20 years. So then for male contraceptive pill, because the process is so much more complicated, it's taken a lot longer and will continue to take a while. Well, I think there has been the challenge of the oral contraceptive for testosterone. And we haven't been able to get away from that using the methods that we know exist. You know, the progestins that we know we can give orally, but we still have to replace the testosterone somehow. The popularity of the gel has actually been very surprising. I don't think anybody realized how popular the various testosterone gels were going to be in the US, but they are a multi-billion-dollar enterprise now. So, and men like them, they find them acceptable to use. In some ways, the contraceptive regimen could have some health benefits in that because you're supplying testosterone exogenously at a very constant level that it will make for more energy and more alertness and more better muscle maintenance and so forth. I mean, there are some potential advantages to making sure that the testosterone is in the normal range, even at the same time that you're suppressing the sperm production in the testes, right, so. So that perhaps answers another viewer's question, which was could there be therapeutic secondary uses for male contraception in the way that there are for. We always would love to have health benefits, the potential for some of the molecules that I was talking about where we're talking the DMAU. They do not get converted into the five-alpha reductives product that causes male pattern baldness, so there's the potential for that, but not that that's not a good thing. That may not be a good thing. Don't want to get into any kind of criticism here. And I mentioned the Nestero makes you smarter because one of the things that Nestero seems to be doing is it is working to stimulate myelin regeneration and possibly in some diseases where myelin regeneration would be a good thing to protect, but in the process of doing that, they put rats in a maze and the rats that were treated with the Nestero did better than the rats on the placebo, so my story is it makes you smarter than I'm there for. At least if you're a maze follower. Yeah, getting to the cheese, it's going great. And there's also a really interesting question that relates to something that we know that you're interested in just from your webpage, but that we haven't talked about in this conference, is concerned about the environmental impacts of more hormones in the water supply. So I know that you are involved in kind of green contraception initiatives and it kind of links back to previous Nobel conferences and future ones about kind of the environment and things like that. And I wonder if you could just take a couple of minutes to tell us about that because until I read that on your website, I was like, oh right, so. So ethanol estradiol is the synthetic estrogen that is in most combined female hormonal contraceptives. And it is a very, very powerful hormone. It's between 150 to 700 times more potent than natural estradiol. And it's not broken down, so it's excreted mostly intact and it can get into the water supply. And sometimes if you're monitoring the rivers, the levels can get up high enough that it would be detrimental to the fish that are in those waters and can cause the fish to feminize and then you don't get the next generation of fish. That's a bad thing. And the only source of it is from hormonal contraceptives. Ethanol estradiol works really well for the purpose of some of the reasons that was put there in the first place in terms of controlling bleeding while taking the progestin that's controlling ovulation. But it's not necessarily the best molecule we're looking at ways to replace it with natural estradiol which is broken down and would not be as toxic to the water. So I think that in the future, the world will hopefully move toward a greener contraceptive method. What we're talking about here are not molecules that have those same kind of toxic expectations. So we think it will be better. I'm not a big fan of ethanol estradiol but it's what's in all the products and it's hard to get it out. Right. Works well. Thank you for thinking of all these other things. Thank you. Any final questions or comments before we break for lunch? Do you have any? I would just remind you that I'm looking at the schedule and we officially begin at 1.30, however the musical prelude is at 1.15, an invitation to visit some of the many exhibits and yes, there will be free cookies. Thank you everyone for a great time. Thank you very much.