 It is my pleasure to introduce Dr. Allison Murdoch. She is a professor of reproductive medicine at Newcastle University and the founder and the head of Newcastle Fertility Center at Life. Dr. Murdoch is a fellow of the Royal College of Obstetricians and Gynecologists and is the leading physician expert in this area of assisted reproductive technologies, such as in vitro fertilization, also known as IVF. She is also one of the first people in the world to have been granted approval to clone human embryos for the purposes of research. Dr. Murdoch has authored more than 90 publications in journals such as Nature, Human Reproduction, Stem Cells, and the British Medical Journal. She is the recipient of the Research Impact Award by The Guardian and the NHS Bright Ideas in Health Award. Recently, Dr. Murdoch has been part of the team of researchers developing mitochondrial transfer IVF technology that prevents transmission of mitochondrial diseases from mother to child. Dr. Murdoch has been involved both in the science of reproductive technologies and the regulation of reproductive technologies to permit their implementation in the United Kingdom. Please join me in welcoming Dr. Murdoch. Well, thank you for that very kind introduction and for the excellent hospitality that have been given since I've been here. I'm not sure about being introduced by Frankenstein, but then that's something you can take your way for. I'm going to talk to you about mitochondrial replacement procedures because I think that's what you wanted to hear. And I'll talk about the science, but the theme of what I'm going to talk about is mainly about the regulation of reproduction because that's really what this conference is about. How far do you go? If you want to stop it, you're going to regulate it. I'm going to talk about it from the perspective of the UK because that is where I have worked. My role in the programme in Newcastle, the mitochondrial work, has mainly been related to regulation and the ethical issues that are related to it. With some trepidation, though, I would like you perhaps to start about thinking not about what regulation we should put in place, but who makes the regulation and what's their motivation for that regulation? To illustrate what I mean, let's go back and look at the IVF clinic because I'm going to start with the regulation in the UK related to IVF. Okay, here is a couple who are trying to get pregnant. They made the decision to try and get pregnant privately. They might have told some of their close relatives and friends, but generally speaking, it was their private decision. If they have difficulty getting pregnant, they will go and see their doctor. What then happens is bound by the professional standards. It's confidential. There's lots of fertility treatments that could be offered to them very much within the realm of what is confidential to that group until they decide they need IVF. Then everybody wants to know. Everybody has a say in what they can and can't do. The motivations for these different people, for their need to have a say, are obviously very important and I respect them, but they are essentially having a third party interest in the discussion. They don't know the couple. They're not related to the healthcare providers. And yet, as you'll see as I go through my talk, it is these people that have had the main role in putting the regulation in place. An interesting discussion topic possibly. So I'm going to go back in regulation 40 years because that's nearly how old Louise Brown is, the first IVF baby. I remember when she was born, it seemed to me to be a big day. Interesting questions were raised at that time that might now seem rather odd. People said, well, because of her male mode of conception, is she illegitimate? Who legally has responsibility for embryos when they're outside the womb? So these are questions that weren't just related to the morality of doing IVF treatment. They were related to very practical issues that the government needed to sort out. So they asked Mary Walnut to write a report to consider these issues. And on the basis of that, that's when the first legislation, human fertilization embryology act came into place in the UK in 1990. And that was the basis, that foundation, that eventually led to the procedures, the legislation and the regulations that allowed us to carry out mitochondrial replacement. I'm going to talk in the middle about embryonic stem cells because that was a pretty another milestone in the regulatory processes. So let's go back to Warnock. The terms of reference were to consider recent and potential developments in medicine and science related to human fertilization embryology, to consider what policies and safeguards should be applied, including consideration of the social ethical and legal implications of these developments and to make recommendations. There were 14 members on the committee. They consisted of philosophers, ethicists, social workers, healthcare managers. There were six medically qualified people on the panel, but only one working in the field of fertility. And there was one scientist whose background was embryology. She was the only person on the committee who knew anything about the science of what was going on. It was perhaps not surprising, therefore, that there was a lot of different views amongst the panel and also some concern about the implications of the views that they had. The report states that members of the inquiry were reluctant to appear to dictate on matters of morals to the public at large. So clearly had some concerns about that, but of course the decisions that they came out with were entirely based on their moral views because they couldn't be based on any other views. There were no patient representatives on the committee. The oral evidence that they take did not include any patients. Mary Moore, though, was a very wise philosopher. And given the brief that she had, it's a statement that she made that moral conclusions cannot be separated from moral feelings, does not entail that there's no such thing as moral reasoning. And it was that moral reasoning that enabled the Warnock Report to come up with some very clear conclusions and recommendations that ultimately became part of the legislation in the UK. There were attempts between the report and between the legislation to try and stop IVF in the UK because one of the recommendations the Warnock Report was that IVF should be allowed to carry on. Several attempts made in Parliament and none of these were passed. So the Human Fertilization and Biology Act was passed in 1990 and the authority was established in 1991. What did the Act do? The first thing that it did was get over the issue of what the moral status of the embryo was. It sort of ducked that. It says, we're not going to look at the moral status of the embryo. We're going to put a legal definition on it. And it said, an embryo exists as soon as you mix sperm and an egg together. The advantage of that is it's a very precisely timed event. It meant that any clinic that was doing it, as soon as you did that, the resulting egg was titled legally an embryo and it came within the legislation. That gave it a very clear framework within clinics about what we couldn't and couldn't do and when we needed to be regulated and when we were not regulated. There were certain prohibitions connected with embryos and what we could do with them. For instance, we could only put the embryos back into a woman with the consent of the man that provided the sperm. We couldn't put the embryos back into an animal. Again, very clear rules about what we couldn't and couldn't do. And to break those rules was then and still is a criminal offence and we can end up in prison for two years, although the Act has never been successfully implemented in the UK. It defined parental orders and that made sure that it was clear who had responsibility for the child. If donor sperm were used, if the sperm donor signed all the appropriate forms and the couple signed all the forms, it was clear that the donor there was not the father of the child. It also established the authority and I think that's one of the ways that I think in the UK we perhaps have gone wrong. It established the authority that provides the licenses for treatment storage and research. That then took the regulatory processes of IVF away from the regulation of all other medical and scientific practice in the UK. And although it wasn't such a problem at the time because they were sticking to the rules at the time, there was then there has subsequently been a divergence and so we now have two different structures of regulation that do those core problems. The authority also writes the code of practice which tells us clinically and scientifically what we can and can't do. It's taken that away from the professional societies which in most other cases the medical practice would write that code and again it causes conflict. And one of the reasons why it has caused problems is that the regulations say that the HFEA must have at least half the members who are lay members. Currently nine out of 14 members on the authority are lay people. They are very eminent people in their own fields. There are theologians, there are healthcare managers, lawyers, philosophers, ethicists, social workers, actresses. They are, I respect their views but a lot of them don't have a lot of technical knowledge about the clinical service that they're regulating or the scientific work that they're doing. And I've certainly been on the situation of putting a license in to do work when it had to be passed to the next committee because there was no one on the committee that actually understood what the sounds was about. So that gets the question about whether the profession should be self-regulating or whether the profession should be regulated by lay people, interesting point for discussion. To go back to Warnock Row, one of the important things that was debated at the time was whether we should do embryo-based research. It always struck me as slightly bizarre that you could license a treatment but then at the same time potentially prohibit any research that might be carried out to try and improve that treatment or to make it better. Unfortunately, Warnock saw that and it said that legislation should provide that any research may be carried out on any embryo resulting from IVF up to the end of the 14th day after fertilization but subject to all other restrictions that may be imposed by the licensing body. 14 days is an interesting one that you might want to discuss. It also, though, is that little sentence that's important? Other restrictions that may be imposed by the licensing body. So although in the UK we have a very permissive legislation, we actually have a very strict regulator system that makes it not at all easy to get licenses to do embryo-based research. In Newcastle, we've had a research license continually since 1991 and that's given us a good track record of doing research on an ethically-based way but it is arduous, it's time-consuming and it is expensive to get licenses. Which is why there's perhaps certainly until stem cells, there was very little research that was done on human embryos and I think this is perhaps the main, the most important results of all the research that's been done. This is not just done in the UK, this has been done internationally. And this relates to an understanding of the genetic abnormality in human embryos. I don't think we were quite aware to we did IVF just how bad human reproduction is. And Uploidy, which means abnormal chromosomes, this is a single cell taken from embryo. You'll be aware that you should have two coppers of each gene in an embryo and clearly on this particular one, there are three coppers of the green ones and three coppers of the red ones. So this embryo is so genetically abnormal that it would never implant, it could never make a fetus. At least 50% of all human embryos, whether they're generated by IVF or they're generated by a spontaneous conception, have abnormalities in the embryos as bad as this. That enables us to give a much more realistic expectation to patients having IVF about what the chances of success will be. We're never going to achieve 100% success rate. It also raises questions for people who are concerned about the moral status of an embryo as how you would regard an embryo such as this, which has probably got less genetic relationship with a cabbage than with the genetics of a human being. Interesting point for discussion. So let me move on to embryonic stem cells. We're now moving 10 years on in time. I'm going to go through a little bit of the science first just so you understand what I'm talking about. The picture you say there for day one is a human embryo the day after the sperm has been put with it. And you can see the two little spots in the middle of those are the pronuclei showing the male and the female chromosomes. And it goes on and divides over subsequent days till you get to day five, which is when it is a blastocyst. You can see the cells around the outside that will become the afterbirth. There's a fluid chamber in the middle and you can see this little tiny dot of cells in the middle here, which we call the inner cell mass. And those are the cells that would eventually make the baby. We realized long time ago, and I'm going back now to 1960s. I remember seeing a lab book from Martin Evans, a noble laureate for some other work he did, where he had taken an embryo and put the inner cell mass out on a dish and found that these cells grow in a plate continuously. But it wasn't until Jamie Thompson in 1998 published it that a light suddenly dawned about what the clinical significance would be of growing embryonic stem cells in a dish like this. Each of these cells in the dish has all the information contained in it to make all the different cell types in the body. So each cell, if we could understand how to program it, could make a specific cell type. So if a patient was diabetic and needed a new pancreas, if we could teach these cells to say, make pancreatic cells, we could put them back in the patient and cure the diabetes. Or maybe it was heart cells they needed. Or maybe it was lungs they needed. And it's what this did was actually change the whole understanding of biology of cells and made us realize the plasticity in cells and that we could move them backwards and forwards from one cell type to the other. And that generated a whole new line of medicine called regenerative medicine. And again, an awful lot of hype related to that. There's still a lot of science needed along this line. It's not yet become widespread clinical use, but it is developing and it will get there. Going back to the early days though, in order to get embryonic stem cell lines, we needed to have embryos. So suddenly in the IVF lab, we realized that not only were we creating embryos that were going to be needed for clinical treatment, but potentially here was an option that we could do to do research and development to help a better understanding of early embryo development. But we needed to change the law in the UK in order to do this, because as it stood, the act that had been written in 1990, 10 years earlier, had no anticipation that we would need stem cells. The clauses under which we could do research were very specific. So we could do research to understand infertility, to understand discourages, but there was nothing that allowed us to create stem cell lines. So very quickly, time was found in parliament, went back to debate, and the license conditions were changed so that we could then use, do research on embryos to increase knowledge about the development of embryos, to increase knowledge about serious disease, and to enable such knowledge to be applied to develop treatments for serious disease. There was concern that we might be using embryos unnecessarily. So the UK stem cell bank was established, which meant that if we created a stem cell line, we had to put it in the bank so that others could then use that stem cell line for their own research without having to use too many embryos. At the same time, we suddenly found that there was a lot of funding available. Previously, to get funding for embryo research was extremely difficult, and some of the major research councils actually forbade using their funds to do any research. And here suddenly everybody wanted us to give money. So what was it in the regulatory terms that suddenly made parliamentary time easy to find, getting new legislation passed, funding made available? My experience from the time was that the people who were making the decisions realized that the clinical need might relate to them. They might be getting to the age where they were becoming diabetic. They might be the stages when they were needing heart transplant, the heart therapies. So suddenly the clinical need became more pressing than the moral concerns about the concerns of an embryo. And that balance changed over. On the back of the work that we did developing stem cells, we learned an awful lot about growing embryos in the laboratory in the early stage. We had a lot of goodwill related to the ethical processes that we've used. So when the whole question of mitochondria came up, we were well placed to try and do something. So, mitochondria, clinical story. Sharon was a patient in Newcastle who started having children not long after the first IVF babies. She had six cesarean sections and had dead babies. They all died very soon after birth. In retrospect, her mother told her that she'd had three babies that had died soon after birth, and Sharon was the one that survived. One of Sharon's babies did survive. It was a healthy baby boy, but started to become ill at the age of four and died at the age of 18. In those early days, we didn't know much about mitochondria disease, but now it's clear that Sharon suffered from something called Lease disease, which is a mitochondrial defect that's passed down through the family. And it was stories like this that made us realize that we should be looking at something to try and help people with these conditions. First, let me say that the work I'm going to describe now in terms of mitochondrial place is not my work alone. It is a team effort. Doug Turbull is a neurologist in Newcastle. He is the expert in mitochondrial disease. Mary Herbert is the scientific director and embryologist, by the head of the IVF unit, and it's her scientific knowledge that has taken this to where it is now. And Louise Herbert is our senior embryologist. She has the green fingers that actually make it work. My role has been many other regulatory ethical issues over the years, and obviously as the head of the fertility center, I've been responsible for the women who've come along as egg donors to help us with this project. The other people on the side are the scientific team, the clinical team, some of them, and the lawyer who helped us through the regulatory processes. So a little bit of information first of all about what mitochondria are, so you'll understand what it is that we're doing. Every cell in the body will contain many mitochondria, 10, 100. There are small organelles that were probably in evolutionary term bacteria that got into the cell. Their only function is to make energy. So they are the things that allows the cells to get together to work as a multicellular organ. Because they were originally coming from a bacteria, they have a different set of genes from the genes that are in the nucleus of the cell, which are the things that give us our characteristics that make us male and female and tall and short. There are 37 genes within the DNA of the mitochondria as opposed to 36,000 in the nucleus, but they are genes and once you start using that term, suddenly it puts mitochondria into ethically a different situation. The diseases that are caused by abnormalities in the mitochondria are not the same as the diseases caused by single-style mutations that occur in the nucleus because it's much more complicated. Because you have lots of different numbers of mitochondria in different cells, you can have different proportions of abnormal mitochondria, because every cell needs energy if there is a deficiency in any cell, it will present with lots of different diseases. So now we know that liver failure, short-statute diabetes, muscle dystrophy, they are all different diseases, but the underlying problem in many cases we now know is due to a mitochondrial abnormality. It's estimated, but it's a crude estimate that maybe 1 in 6,000 babies born will develop a mitochondrial-based abnormalities. It's not an uncommon problem. One thing that's important about mitochondrial DNA is that it's inherited maternally. So the mitochondria that are in the egg, when the sperm gets to it, the sperm obviously has a few mitochondria, but we don't think that these mitochondria are lost after the sperm gets into the egg. So the mitochondria passed down the maternal line. These pictures, the old lady is my great-grandmother, and the youngest is my daughter and her daughter. So my granddaughter will have only about 3% because of sexual reproduction. She will only have about 3% of her great-grandmother's nuclear DNA, but she will have exactly the same mitochondrial DNA down the line. So if you want to do anything to break the chain of diseases of pastan, we have to break into that line and stop it happening. This concept is a little bit difficult. I take a little time to go through with it. Something we call the mitochondrial bottleneck and explains why in reproductive terms, it becomes so difficult to predict for someone who's carrying mitochondrial disease as Sharon was, what the likely outcome is going to be in pregnancy. Most women who have mitochondrial disease don't have all the mitochondria abnormality. They have what we call hetroplasm, which means they have some normal and some abnormal. Women's eggs are given to them. It put in their ovary when they're a foetus. So imagine eggs being made on a production line. And here's this little bottle full of different mitochondria being shaken in. So as each egg comes along, it gets a little bit of mitochondria added to it. If they're lucky, they'll get all blue ones and they'll be normal. If they're unlucky, they'll get all yellow ones and they'll be abnormal. And then as the egg goes on and divides and matures, the rate at which the individual mitochondria will divide and multiply will vary. So you might have a small proportion of abnormal, but then they divide more vigorously than the normal ones, so they become more. That means that basically because of this random allocation, it becomes totally unpredictable for the woman. And what are the reproductive consequences? Well, here is a real example. This mother had 38% of her mitochondria abnormal. She was actually, had no significant clinical symptoms. She was relatively well. But she had a daughter who had no abnormal mitochondria who was perfectly healthy, but a son who had 78% and died at the age of seven. So what advice are you going to give her if she wants to have another child? Well, here are her options. She could decide not to have another child or she could adopt a child or she could have an egg donated by someone else, but then it wouldn't have the nuclear DNA that she has. She could have prenatal diagnosis to do an amniocentesis when she is pregnant. But of course, if then there's enough normality, she's then got to make the decision about whether to have the pregnancy aborted. We can do PGD, which is where you do IVF, take an embryo, take a biopsy, look at the mitochondria and decide which ones to put back. We do that and that is an option that's available for some people. But technically it can be difficult to do because you've got to balance the viability of the embryo that you get with the proportion of abnormal mitochondria that you see in it. And you're lucky if you get an embryo out of the batch that's gonna have no abnormality at all. But it's a risk reduction. So this is where we decided to think about something new, pronuclear transfer. The concept itself is really very simple. You take a donor egg from someone who's got normal mitochondria and you take an egg from the woman who wants to get pregnant and you fertilize both of them. And then you take out the genetic material in the nucleus from both the donor egg and the woman who wants to become pregnant and you put her, the genetic material in the nucleus from her egg into the donated egg. So the result that you have is an embryo that contains the genetic material from mom and dad but will contain normal mitochondria. It seems such a very simple context to do but in practical terms, obviously it's not quite as easy. In order to do this in UCAS, we went through several steps over a period of now 15 odd years. The first thing to do was to do research in mice, proof of concept to show that the mice could actually successfully survive the process. We then moved on to using abnormally fertilized eggs in humans. These were embryos that were created as part of the IVF program but were genetically abnormal then and could not be used for treatment. That work was published in Nature and then we moved on to using normally fertilized eggs from volunteer donors and we published that last year. I'm going to show you a very quick video of the process that is actually being done. At the moment there now is taking very carefully one of the pronuclei out from the center of the egg, embryo, this is an egg, a fertilized egg. To give you some idea of size here, that egg you can't see with a naked eye, you could probably easily fit three, four of them on the point of a pin. The needle that is doing the biopsy work is about the size of a human hair. So what's happened now is she's made a little hole in the zone, that's the shell on the outside of the egg and she's taking out now the second pronuclei. At this stage, the male and the female genetic misheal has not mixed together, so it's not got any unique genetic identity. The advantage of doing it at this stage is that all the chromosomes are within that little round package, they're not separate. So we're taking not only the chromosomes but we're taking the structures, the proteins that are required for normal division of those proteins. We have to be careful as well that we don't take out any of the mitochondria at the same time that are coming from the abnormal embryo. We add a protein then to the mixture to try and help the pronuclei fuse back in and this shows both the two normal pronuclei being put back into the recipient, into the donor's egg with the normal mitochondria. Very carefully. You have to have a steady hand to do this sort of work. And patience. And finally, she'll just give it a good poke for good luck. Okay, for those of you that are interested in the science, you can go and look at the publication in nature and it really is inappropriate that I try to put the whole of that paper into one slide. But here is the very brief summary. 92% of the embryos survived the process. 35% of them developed into blastocystis. This is slightly less than we would normally get in a normal IVF program, but it was consistent with potentially a viable clinical program. As I said before, we expect half the chromosomes, half embryos to have abnormal chromosomes and that's what we saw. We found 15 out of 30 of the pronuclei transfer with abnormal compared with 5 out of 11 of the controls. We looked at gene expression and found that they were pretty similar to the IVF embryos that we created. Importantly, we also looked at how much mitochondria was carried over between the woman who was affected and the resulting embryo. It was less than 2% in 78% to 79% of the embryos. The importance of 2% is that if the amount of abnormal mitochondria is as small as that, it is almost impossible that that abnormality will not only present, not present in the individual itself, but also will not be passed on to the next generation of children. So on the basis of that, we present our information, but at the same time, there was another debate going on. So finished with the science now. When we started doing this work, it would be illegal to do it in the UK in clinical practice. So in order to think ahead to the point at which it might be necessary, we had to change legislation. To change legislation, you've got to convince people in Parliament that it is necessary, and then there becomes a public debate, and then we get Frankensteins. And I'm afraid this is the sort of difficulty we have in raising some of these issues in a public arena. I think there were two things that helped us to get the legislation through in the UK. And the first was the level of the ethical moral debate that took place. The Nuffield Council on Bioethics is an independent ethical body. It's nothing to do with Parliament, with the government, but its status is such that its views are accepted by Parliament. If you're interested in the full debate, I would advise you to go and read this report. It covers really in depth all the issues that were discussed. I've just picked out two that I think were important for us in managing it. The first was something that we discussed briefly yesterday, which was germline therapy. That at that time, that discussion was before the question about CRISPR, so it was preempting the issues, and it was a red line. Germline therapy was not allowed. That means we could not, we were not encouraged to do anything to an embryo that would then be passed on, not only to that child, but that child's children. But actually, that was exactly what we wanted to do with mitochondrial DNA replacement. A lot of debate by the Norfolk Council, but eventually they did agree, yes, that they said, yes, this is germline therapy, but actually it's okay. We think that it's the right thing to do. The other important issue that they discussed was what was the status of the mitochondrial donor, because there were two issues. In one case, you could think this donor is the same as an egg donor, remembering that in the UK, if you donate your eggs to someone else for fertility purposes, you have to agree that that child can contact you when the child's 18, so you are not anonymous to the recipient. We felt that mitochondrial donation was more like giving a blood donation, giving a kidney, and therefore the donor should be regarded the same way and should be anonymous. That ended up being the conclusion that the Norfolk Council came to and that was what was eventually adopted into the legislation. So that very in-depth ethical view, taking it away from the headline tabloid ethical debate, we think was very important in getting the messages through. And this, I think, was perhaps even more crucial, which was that we listened to the voice of the patient and we listened to the need of the patients for these particular treatment. The Lilly Foundation was very important and this Lilly was a little girl who died of mitochondrial disease at the age of eight months and her parents set up the foundation in order to help and support research and development and treatment. So it was parents who were part of the foundation who took their babies onto the television studios and said, my baby's dying, this is why we're doing it. And it was that humanitarian viewpoints about what we were trying to do that I think eventually won the day and got us the regulatory changes that were necessary. So an overview now, just to close, final timeline then for regulatory approval. There was the Act of Parliament in 1990 and it was reviewed and revised in 2008. At that point, we knew that the mitochondrial place was going to come, was going to come. And so legislation was put through then that meant that the government could actually go back to Parliament to have a debate on that issue only without going back to the primary legislation, which technically would have been a really much more difficult thing for them to do. So those regulations to try and make the change, we persuaded the Department of Health that that should be taken more seriously. It was put before Parliament in 2014. It was eventually approved by Parliament in February 2015. It then was in October that year before it became law in the UK. The HFAA looked at the scientific data, not just our data that we've published but international data that have been done righted to this sort of work in the beginning of middle of last year. On the basis of their review, they decided to accept applications in November last year. We accepted our licence then and we were approved our licence in March this year. So these things do not happen quickly. People tend to think we talked about CRISPR happening really, really fast. This particular thing has not happened fast. It's gestation period has been very long. Now you're going to ask me, well, what have we been doing since March? I'm not going to tell you, I'm sorry. We are accountable to the patients we treat, to those who fund us and to our regulators. We are an NHS clinic. We're not a business. We're not a TV reality show. And I think if we start presenting this sort of work in that way, there are significant ethical consequences that we need to avoid. To illustrate this, let me just go back to a picture that you might recognise. Bob Edwards, noble laureate, with his team, Jean Purdy, Patrick Steptoe, provided the treatment that resulted in the first successful IVF baby for Leslie Brown, that resulted in Louise Brown, who's shown here with her son, naturally conceived. I don't think Louise Brown ever gave permission to be identified as the first IVF baby. And don't forget, the first IVF babies were actually considered a bit like freaks. I don't actually think she's unhappy about it. The language is perhaps not right to say that she's exhibited around the world still, but she does go around and do that. And nowadays, I don't think that is ethically acceptable. And certainly, I would not want the first babies to be conceived from mitochondrial replacement to be subject to the same concerns. So, my final slide. What's regulation for? This is a typical party that lots of IVF units done. This is a party we held in our unit for a bunch of five-year-olds and their parents. The purpose of this seminar is talking about reproductive technologies. How far have we gone? How far should we go? If 40 years ago, you'd said, IVF is a step too far, we should stop it, which many people did, then a lot of these parents would have remained infertile, and none of these children would have been born. So, I'll leave you with that food for thought for further discussion. Thank you very much. Thanks so much, Dr. Murdock, for that splendid talk. We will reconvene the panel.