{"id":1774,"date":"2005-11-04T16:03:00","date_gmt":"2005-11-04T16:03:00","guid":{"rendered":"https:\/\/bedfordresearch.org\/beta\/?p=1774"},"modified":"2026-05-27T00:53:13","modified_gmt":"2026-05-27T00:53:13","slug":"human-eggs-why-do-we-need-them-how-do-we-get-them","status":"publish","type":"post","link":"https:\/\/www.bedfordresearch.org\/symposium\/human-eggs-why-do-we-need-them-how-do-we-get-them\/","title":{"rendered":"\u201cHuman Eggs: Why Do We Need Them? How Do We Get Them?\u201d"},"content":{"rendered":"\n<figure class=\"wp-block-embed is-type-video is-provider-youtube wp-block-embed-youtube wp-embed-aspect-4-3 wp-has-aspect-ratio\"><div class=\"wp-block-embed__wrapper\">\n<iframe loading=\"lazy\" title=\"Dr. Anne McLaren&#039;s talk, &quot;Human Eggs: Why do we need them? How do we get them?&quot;\" width=\"500\" height=\"375\" src=\"https:\/\/www.youtube.com\/embed\/AfaypIOKIqM?feature=oembed\" frameborder=\"0\" allow=\"accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share\" referrerpolicy=\"strict-origin-when-cross-origin\" allowfullscreen><\/iframe>\n<\/div><figcaption class=\"wp-element-caption\">ANNE MCLAREN, PHD, \u201cHUMAN EGGS: WHY DO WE NEED THEM? HOW DO WE GET THEM?\u201d<\/figcaption><\/figure>\n\n\n\n<p class=\"wp-block-paragraph\">Dr. Anne McLaren of the Welcome Trust Cancer Research UK Gurdon Institute of the University of Cambridge. Professor Anne McLaren was arguably the most accomplished developmental biologist in the world at this time.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\">Auto-Generated Transcript: <\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">I\u2019m sure that many of you have known Dr\u202fMcLaren for your entire for your entire training career. I\u2019ve known Dr\u202fMcLaren for as long as I\u2019ve known what eggs were and have had the good fortune to meet her a couple of times through the years, so we\u2019re just delighted she\u2019s here.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">She\u2019s actually here visiting Dr\u202fBiggers and Betsy and spent a couple of days in New\u202fHampshire, so we\u2019re thrilled to have her and I\u2019ve asked John to introduce her because Dr\u202fBig knows her career and her goals and her future goals. One of the things I think everyone in this room is aware of is that a challenge that faces any kind of stem\u2011cell researcher\u2014especially if you want to do what the South\u202fKoreans just did\u2014is the ethical issues associated with asking women to donate eggs simply for research.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Although we\u2019ve sort of fussed with that for some time, I think we have that pretty well in hand as a foundation. The country at large is still struggling with that, and Great Britain has paved the way for years on establishing ethical standards for this kind of research, and Dr\u202fMcLaren has been a major player there.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">I\u2019m sure that John is going to tell us a little bit about her career. It\u2019s a pleasure for me to introduce her. She\u2019s been a long\u2011term friend and a former colleague of mine. I think we first started working together in 1956 and she\u2019s had a very distinguished career.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">I\u2019m not going to begin to cover all the things, but she is a Fellow of the Royal Society of London and had the distinction of becoming the first woman to hold office in that body. She was Foreign Secretary of the Royal Society for five years, former president of the British Society for the Study of Fertility, and president of Developmental\u202fBiology. She played a significant role as a member of the British\u202fWarnock Committee, developing the legislation\u2014the White\u202fReport\u2014that led to what some regard as model laws regulating experimentation on human embryos. She testified before the British\u202fParliament on this subject, represented Britain on ethics committees in\u202fEurope, and was awarded a distinguished Japan\u202fPrize two or three years ago. You can see she\u2019s had a remarkable career, and I\u2019d like now to introduce her to give her talk.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Well, thank you, John, for those kind words, and I\u2019m very grateful to\u202fAnne for inviting me to talk at this activated\u2011egg symposium. I was delighted and honored, but also somewhat reluctant because I don\u2019t work on eggs, have never worked on eggs, and don\u2019t actually know much about eggs.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">What I thought I\u2019d do is go through all the reasons we might want eggs and then how we can get hold of them. That\u2019s what this talk will be about. I don\u2019t know how long it\u2019ll be because I wasn\u2019t told until about five minutes ago what the program was. Let\u2019s see how it goes.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Human eggs\u2014first of all, why do we need them? Here is a human egg with its first polar body and its second metaphase plate and nice cumulus cells all around it. I think that\u2019s a human egg, and I reckon there are three main reasons we need eggs: traditional, clinical, and research.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The traditional use of eggs doesn\u2019t need much explanation. At the top, one of my favorite paintings, Cranach\u2019s&nbsp;<em>Adam\u202fand\u202fEve<\/em>, and at the bottom,&nbsp;<em>Mars\u202fand\u202fVenus.<\/em>&nbsp;That\u2019s all I shall say about the traditional purpose of eggs. It\u2019s obviously to make babies, and none of us would be here if it weren\u2019t for eggs.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Then what about clinical? Unfortunately, there are a number of women and couples who aren\u2019t able to make babies that easily, and assisted reproduction or infertility treatment has become a big thing. One of the major causes of infertility is problems with ovulation, but this is one of the easiest problems to treat by hormone therapy.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The dose of hormone must be carefully controlled, and ultrasound screening is very important so that not too many eggs are shed, because there are awful stories of women becoming pregnant with seven, eight, or ten fetuses.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">If ovulation isn\u2019t the only problem, then the next step is IVF or ICSI. Egg recovery follows hormonal stimulation, producing more eggs than would normally be shed because not all fertilize or develop. ICSI\u2014injecting a single sperm into the egg\u2014proved amazingly effective. When first introduced, it surprised biologists, as only the \u201cbest\u201d sperm were thought to fertilize, but injecting any single sperm at random worked.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">One of my favorite paintings, Cranach\u2019s&nbsp;<em>Adam\u202fand\u202fEve<\/em>, and at the bottom we have the more pastoral&nbsp;<em>Mars\u202fand\u202fVenus.<\/em>&nbsp;That\u2019s all I shall say about the traditional purpose of eggs. It\u2019s obviously to make babies, and none of us would be here if it weren\u2019t for those eggs.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Then what about clinical? Unfortunately there are a number of women and couples who aren\u2019t able to make babies that easily, and so assisted reproduction and infertility treatment have become a big thing. I think I\u2019m right in saying that one of the major causes of infertility is problems with ovulation, and I\u2019m not a medical person, but I think I\u2019m also right in saying that this is one of the easiest of the infertility problems to treat by hormone treatment.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Of course, the dose of hormone needs to be carefully controlled, and ultrasound screening is very important so there aren\u2019t too many eggs shed, because there are these awful stories of unfortunate women who found themselves pregnant with seven, eight, or ten fetuses.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">But then if the ovulation problem is not everything, then obviously it\u2019s IVF or ICSI that comes next. Egg recovery after hormone stimulation yields more eggs than would normally be shed because not all fertilize, and not all the fertilized ones develop.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">ICSI, of course, is used if the sperm doesn\u2019t do its stuff with ordinary in vitro fertilization. A single sperm can be injected into the egg, and amazingly, that seems to be very effective. When it was first introduced, people\u2014particularly the sperm biologists\u2014were astonished, because there had been an idea that only the best sperm should reach and fertilize an egg. So taking one at random and injecting it seemed very curious indeed, but it worked remarkably well.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Egg donation is another important reason for wanting eggs. The developmental competence of eggs depends on their age, and age here means the age of the egg, not the age of the woman\u2019s body, because oocytes are formed before birth.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The older the woman, the older the eggs, and as the woman gets older, her eggs become less developmentally competent. Egg donation from younger women can restore a high level of fertility to older women. There are also women who don\u2019t ovulate eggs at all, one cause being Turner\u2019s syndrome, having only one X chromosome instead of two.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">These women can carry a pregnancy with the use of a donor egg, and that\u2019s why many people are on waiting lists for donor eggs.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">In the United Kingdom, the law is very strict about egg donation\u2014it prohibits payment for eggs but does allow expenses to be reimbursed. There\u2019s also something called egg-sharing, where a woman undergoing IVF donates some of her eggs to another couple in exchange for reduced treatment costs.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">That\u2019s the summary of the main clinical uses of eggs\u2014treating infertility and enabling preimplantation genetic diagnosis to avoid passing on genetic disease.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Then the final reason for wanting eggs is for women who need pre\u2011implantation genetic diagnosis.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">There are some couples who are at risk for a serious genetic disease because they are both heterozygous for a gene responsible for one of the many known severe disorders. Previously these couples either had to remain childless, or become pregnant not knowing whether the baby would be born with the genetic defect, and then perhaps undergo chorionic villus sampling or amniocentesis.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">If the result was bad, they would usually have a termination of pregnancy. Now pre\u2011implantation genetic diagnosis, as you know, avoids that. If you start with an eight\u2011cell embryo, you can take out one or two blastomeres and test those blastomeres\u2014usually by PCR, polymerase chain reaction\u2014to see whether they carry the genetic defect in homozygous form.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Here, there are five embryos that have been sampled, and two of them did indeed carry the defect in homozygous form, so they obviously would not be returned to the woman\u2019s uterus, but the remaining three were normal.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Also the possibility of taking a few cells from the trophectoderm at the blastocyst stage, but although this is explored from a research point of view, it&#8217;s not used in clinical practice. This other slide shows that you could also do it after cryopreservation.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">So that\u2019s pre\u2011implantation genetic diagnosis.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Okay, so much for the clinical need for eggs. What about research? Well, I&#8217;ve listed a number of types of research here.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">First of all, we know a lot about the biochemistry and physiology of eggs, but still not enough. There are many unanswered questions, and if we knew the answers to all those questions it would be easier to design even better culture media for embryos than already exist. As most of you know, John Biggers has been extremely active and influential in this whole area, so if there are any questions about the biochemistry and physiology of eggs and the need for further research in that area, John\u2019s the person to ask.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Then, research about infertility treatment\u2014in vitro maturation.&nbsp;There are clinical conditions, and polycystic ovary syndrome (PCOS) is one of them, where too many follicles start developing and then they get ovulated prematurely at stage seven or stage eight. At that stage they&#8217;re not developmentally competent\u2014they would normally mature in the ovary in vivo before ovulation.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">If they are ovulated prematurely, they can still be matured in vitro. But again, the conditions, the culture medium, and the hormonal support have not been very well worked out. There have been a number of pregnancies from in\u2011vitro\u2011matured eggs that have then been fertilized or injected, but it&#8217;s by no means optimal. Recently, treatment with in\u2011vitro\u2011matured oocytes has been licensed in the U.K., and there have been some pregnancies, but as I say, this is an area where further research would be extremely useful.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Rejuvenation of aged eggs.&nbsp;This is another question people have tried to address. When I say aged eggs, I mean eggs from older women, which were laid down before birth and which are not as developmentally competent as they should be. It has been suggested that injecting a small amount of cytoplasm from younger eggs would rejuvenate them.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">There have been publications on this. There have been women who have had normal babies after such treatment, women who had been trying for years without success. On the other hand, whether or not the pregnancies were really due to the treatment is not established. Because of possible risks, this treatment is not encouraged in the U.S.A., and it is not licensed in the U.K. But again, it&#8217;s perhaps something that needs further research.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">There are two other clinical or medical problems that fall into the research area at present. One is mitochondrial defects and the other is stem\u2011cell therapy. I&#8217;d like to say a bit about both of those now.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Mitochondria.&nbsp;I&#8217;ve always found mitochondria fascinating. They\u2019re those little organelles in the cytoplasm of an egg. I think you have something like one hundred thousand of them, and each mitochondrial DNA strand is circular. There are one hundred thousand little circles, each with only sixteen kilobases of DNA and only thirty\u2011seven genes. Of those genes, most are RNA\u2011related, and only thirteen code for proteins.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The proteins they code for are almost all enzymes involved in oxidative phosphorylation\u2014I can never say that word properly\u2014and of course the mitochondria are responsible for providing energy for the cell.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">They\u2019re aliens, really\u2014invaders. It appears that back in the distant past, in the primeval soup, little bacteria hitched a ride on larger cells and provided them with more energy, while the larger cell provided nutrition and protection. For instance, the genetic code of mitochondrial DNA is not the same as that of nuclear DNA. They really are outsiders that have become insiders.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The important thing about mitochondria is that they are all inherited from your mother\u2014entirely maternal inheritance. Although the sperm has perhaps half a dozen or so little mitochondria compared with the hundred thousand in the egg, the sperm mitochondria all disappear and get degraded within a few hours of fertilization in normal cases.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Unfortunately, mitochondria sometimes have mutations, just like all DNA does, and they can become defective. At the top here we have a cell with normal, fully energy\u2011competent mitochondria, but sometimes a mutation develops, and the mitochondria replicate independently and distribute themselves randomly in daughter cells.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">You can get quite a variety of cell types: some fully energy\u2011competent, others hopeless, and every degree in between. These cause respiratory defects that are responsible for a number of very serious diseases, including some that can be lethal, and they are all maternally inherited.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">One in ten thousand women have serious mitochondrial genetic defects. That doesn\u2019t necessarily mean they show disease because there may only be a small proportion of defective mitochondria that don\u2019t show up phenotypically. But one in five thousand are at risk of developing the disease.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The diseases are quite varied, and nobody quite understands why. Respiratory failure obviously affects the heart\u2014cardiomyopathy\u2014and also the liver and sensory systems. A lot of deafness and optic problems\u2014retinitis pigmentosa, optic atrophy\u2014have a mitochondrial genetic component. Other affected systems include muscles, the urinary system, thyroid, and diabetes. Occasionally these defects can even lead to death.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">So it&#8217;s a serious problem, and it\u2019s very difficult to give women who have mild symptoms any sort of sensible genetic counseling.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The reason for that comes from work on mice\u2014this, mind you, is mice, not women\u2014but as often happens, we hope humans behave like mice. In mice, if one has a mitochondrial heteroplasmy, with a mutant mitochondrion around, and you look at primordial germ cells soon after the germ\u2011cell lineage has been established\u2014which happens during gastrulation\u2014you find that the proportion of mutant mitochondrial DNA is very uniform among different primordial germ cells.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">But there are about nine, ten, or eleven cell divisions between the establishment of the germ\u2011cell lineage and when you get primary oocytes entering meiosis. After that, no further cell division happens until ovulation. During those ten or so divisions, the mitochondrial mutations get segregated independently.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">As a result, primary oocytes are highly variable instead of uniform like the primordial germ cells. Some have a lot of mutant mitochondrial DNA, others very few. Since no further cell division occurs up to the time of mature oocytes, you never know whether any particular egg is going to be badly affected.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">A baby born after fertilization of such an egg might be very ill, might show no symptoms at all, or might be only mildly affected, like the mother.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">This makes genetic counseling very difficult.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Is there a way around this? Well, in principle, there is. If you had a donor egg from a normal woman, you could remove the nuclear genetic material from that egg and transfer into it the two pronuclei from the parent egg, and okay, you might have just a few defective mitochondria transferred along with the nuclei, but mostly you\u2019d have normal, clean, healthy mitochondria there, and the babies would be fine.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Now, this route has not been attempted, as far as I know, in any country. But Professor Doug Turnbull in Newcastle, in the U.K., has been interested for a long time in this possibility because he has many patients who are suffering in this way and want advice. He has just been licensed, after a great deal of argument and discussion, to start a research program on human material.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">He\u2019s shown in mice that it works\u2014proof of principle. He\u2019s taken mouse eggs and transferred pronuclei into an empty egg and got babies, and they\u2019re fine\u2014very few of the mutant mitochondria.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">What he\u2019s going to do is use eggs from IVF programs that are abnormal in that they have three pronuclei. As you know, these would never be used for clinical treatment in an IVF program. They can be donated for research rather than simply be discarded.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">He\u2019s going to remove the pronuclei from both and then put two pronuclei into the other cytoplasm\u2014a reciprocal exchange\u2014so that he has two reconstituted diploid zygotes. He will culture those for two days and do a number of tests. For instance, he\u2019ll remove a blastomere for analysis of the mitochondrial DNA to find out whether it looks normal or not.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">If, as often happens, there is some heteroplasmy in the donor eggs, he will be able to tell how much of this type of mitochondria has been transferred to the zygote and vice versa. He\u2019ll continue culturing up to the blastocyst stage to see what proportion of embryos develop that far and whether they look reasonable or not. Then he\u2019ll process those blastocysts for cytogenetic and epigenetic analysis\u2014looking at imprinted genes, methylation patterns, and mitochondrial DNA.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">This is a three\u2011year research program.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">He had quite a bit of argument with our licensing authority, the so\u2011called Human Fertilisation and Embryology Authority (HFEA), because our 1990 Act has a clause stating that changes to \u201cthe genetic structure\u201d of a cell or embryo are prohibited.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">My argument would be that such a procedure doesn\u2019t change the genetic structure. It changes the genetic content, in the sense of the mitochondrial DNA content. What the 1990 Act was actually concerned about when it referred to genetic structure was transgenesis, because, at that time, transgenic technology was just starting up, and people were very worried that someone might start creating transgenic human embryos.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">In this procedure, there\u2019s no change to any gene\u2014it\u2019s simply replacing defective mitochondria with normal mitochondria.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">If his research program shows no evidence of abnormalities in those developing human embryos, I think he will then apply for a very limited program of clinical treatment for women who otherwise would not have dared to become pregnant, with careful monitoring and follow\u2011up.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Okay, then finally, on the research side, stem\u2011cell therapy, and I\u2019m not going to say much about this because you all know too much about stem\u2011cell therapy.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">You all know that there are all those awful diseases and that there are a whole number of cell types that, if one had a lot of them, could treat those diseases. You know exactly what a stem cell is\u2014that it can make more of itself or it can differentiate into every other cell type you can think of.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">You also know that you can get stem cells from an adult\u2014and \u201cadult\u201d always means anything postnatal really\u2014from the brain, bone marrow, or satellite cells of muscle. They\u2019re all very useful for particular purposes and will be even more useful when there\u2019s been more research. Cord blood has stem cells in it\u2014very useful.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Then early embryos\u2014pre\u2011implantation embryos\u2014can give rise to embryonic stem cells from the blastocyst stage. Unfertilized eggs, if they\u2019re activated parthenogenetically, as Ann Kiang has usefully pointed out, can also be used to make human embryonic stem cells, which would then be immunologically identical with the woman who had provided the unfertilized egg.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Back in the early days of 1998, when Jamie Thompson published the first derivation of human embryonic stem cells, this is what he showed. The upper panel is what he actually did\u2014taking the isolated inner cell mass and culturing it. The bottom panel shows what he hoped might one day happen\u2014that it would make kidney cells, heart cells, bone marrow cells, and so forth, which could be used for therapy. Things are moving on. We\u2019ve probably got this far, but not, I think, really that far though some people would disagree\u2014maybe that will come up later today.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Now, as far as human embryonic stem cells go, and as John\u202fBiggers mentioned, one of the major problems is an ethical problem, because of course these come from fertilized eggs. If you believe that the moral value of an embryo from the one\u2011cell stage onward is equal to that of a newborn baby or an adult human being, as some people do, then any research that causes that embryo to stop developing\u2014even if it was going to die anyway\u2014is akin to murder.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">I respect that view, but I don&#8217;t agree with it. Most of the people in my country think that the moral value of an embryo increases as it develops, first into a fetus and then into a baby. This point of view was reflected in the U.K.\u202fParliament back in\u202f1990 when that Act was passed. In both our Houses of Parliament there was a strong vote in favor of allowing human embryo research under very strictly regulated and controlled conditions.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">They also felt that if a research project required the creation of embryos for research, that also should be allowed, and that has proved to be very useful\u2014though it&#8217;s been used in only very few circumstances.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">This is a list of the countries that agree with the U.K. in allowing derivation of human embryonic stem cells from spare embryos from IVF. I should, of course, have said that Jamie\u202fThomson got these human embryos from IVF\u202fclinics with informed consent of the couple, the woman who was donating the embryos for research.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">In most cases, whether they are fresh or have been frozen for some years, if they&#8217;re not going to be used for that woman&#8217;s treatment nor donated to another woman for treatment, they would simply be allowed to die. It&#8217;s these spare embryos that are now often donated for research, and that research can include the derivation of human embryonic stem cells.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">However, what\u2019s this got to do with eggs? Nothing much\u2014these are embryos. But if they\u2019re going to be used for therapy, then there\u2019s the problem of graft rejection. If they\u2019ve been derived from an embryo donated by an IVF\u202fclinic, they will not be immunologically compatible with the patient who\u2019s being treated with the stem\u202fcells.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">One possibility being put forward is to use somatic\u2011cell nuclear transfer\u2014that is, the cloning procedure, the same process of transferring a nucleus from a somatic diploid cell into an empty egg, exactly the procedure used for Dolly\u202fthe sheep and other cloned animals.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">If one used that same procedure on a human egg, the blastocyst and resulting embryonic stem cells would be immunologically compatible with the donor of the somatic nucleus. You all know about this\u2014it&#8217;s often called \u201ctherapeutic cloning,\u201d which is a dreadful term, because there\u2019s nothing therapeutic about the cloning itself. The stem\u202fcells may, perhaps, later be used for therapy, but that\u2019s a separate matter.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Cloning for stem\u202fcells would work like this: the patient has the disease; the doctor collects somatic cells, recovers their nuclei, and transfers a nucleus into an empty donor egg whose own genetic material has been removed. The embryo is cultured, the stem\u202fcells are recovered and then differentiated into whatever cell type the patient requires for treatment.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Now, I\u2019m very skeptical myself as to whether this labor\u2011intensive and costly procedure will ever be realistic in any healthcare\u202fsystem. But, as you all know, the recent papers from South\u202fKorea have at least provided proof of principle.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">As I mentioned, Ann\u202fKiang has suggested that it\u2019s possible to obtain from a woman her own egg, which could develop parthenogenetically, and then you wouldn\u2019t need any donor egg. You could culture those stem\u202fcells into whatever tissue type that woman required for treatment\u2014and that would be fine. Tough on you chaps, but there we are; Ann\u202fhas a point.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">This procedure is much more attractive, I think, in the U.K. than in the U.S., because in the U.K. there\u2019s a great shortage of donor eggs. In the\u202fU.S., one can at least buy donor eggs. But if a woman could provide her own, the parthenogenetic approach would be far more appealing in the U.K., where obtaining donor eggs is difficult.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Even if one didn\u2019t use the cloning approach, there are other\u2014and perhaps more realistic\u2014ways to get over the graft\u2011compatibility problem. You can sometimes use stem\u202fcells from the patient themselves; you can use genetic manipulation to remove incompatibility antigens; you can create a large stem\u2011cell bank to provide close genetic matches; you can induce specific immunological tolerance in the patient; and, of course, immunosuppressive drugs continue to improve.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">On the other hand, the cloning procedure could still be of enormous importance\u2014not for therapy, in my opinion, but for research. There are patients with very rare genetic diseases, maybe only forty, fifty, or sixty patients in the entire world. We know very little about those genetic disorders. If we could make stem\u2011cell lines from skin cells of those patients, the research value would be tremendous.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Similarly, for common but genetically complex diseases, such stem\u2011cell lines would make it easier to identify both genetic and non\u2011genetic bases of the condition.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">As a result of this possibility, two licenses have now been issued in the\u202fU.K. for cloning for research\u2014one to Alison\u202fMurdoch in Newcastle, who will be looking at diabetes, making stem\u2011cell lines from diabetic patients, and one to Ian\u202fWilmut in\u202fEdinburgh, who\u2019s concerned with motor\u202fneuron\u202fdisease, a very mysterious disorder about which we know almost nothing genetically.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Okay, so that\u2019s the first part\u2014that\u2019s <em>why<\/em> we need eggs. How can we <em>get<\/em> them?<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Possible sources of oocytes include eggs donated by women, which, for clinical use, is the only practical method at the moment.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Now, the problems here are commercialization\u2014what philosophers call commodification\u2014and the potential exploitation of women. If you pay women large amounts of money, they may donate eggs, but there are health risks. The procedure is time\u2011consuming and uncomfortable, involving many hormone injections. There are also risks of hyperstimulation unless the ovary is properly monitored by ultrasound, and, of course, hyperstimulation can sometimes lead to death.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">There have also been suggestions of a possible link to ovarian cancer, though there\u2019s no solid evidence supporting that.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">In Europe\u2014not only in the\u202fU.K. but in Europe generally\u2014it isn\u2019t permitted to pay money for egg donation. In the\u202fU.S., it is permitted, and I believe quite large sums are sometimes paid. I\u2019ve even heard that some young women can pay their way through college by donating eggs.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">So that\u2019s a different ethical stance. In the\u202fU.K., we don\u2019t allow payment, but we <em>do<\/em> allow what\u2019s called egg sharing.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Now, most\u202fIVF treatment in the U.K. is private and expensive. Some is covered by the\u202fNHS, but not enough, so many couples can\u2019t afford\u202fIVF or can only afford one cycle. If the woman produces a reasonable number of eggs that fertilize well, she is permitted to donate some to another couple in need, and in return she gets a second cycle free or at a reduced rate.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The argument in favor of this is that it gives two women a chance at the babies they want; without it, neither would have as good a chance. The argument against is that it amounts to buying eggs. Ethicists debate whether monetary payment is ethically different from exchange\u202fin\u202fkind, and I\u2019m not going to go into that here.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Failed\u2011to\u2011fertilize oocytes\u2014these come from\u202fIVF clinics where the egg is placed with sperm\u202f24\u202fhours later\u2014no pronuclei, no fertilization. Now, these eggs have been used\u2014for instance, Roger\u202fPedersen used them in San\u202fFrancisco\u2014and successfully made human embryonic stem\u2011cell lines from eggs of this sort. It\u2019s what Alison\u202fMurdoch in Newcastle will be using for research, but I don\u2019t think it\u2019s practical, at least for clinical use.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Then\u202fin\u2011vitro\u202fmaturation of immature or primordial oocytes. Now, we\u2019re not talking about the same sort of in\u2011vitro maturation that I mentioned earlier\u2014before, we were talking about the stage\u2011seven or stage\u2011eight in\u2011vitro maturation. What I\u2019m talking about now are these little tiny primordial follicles with primary oocytes in them, of which there are, before birth, maybe hundreds of thousands in every ovary, and even after birth tens of thousands. Every adult woman of reproductive age has large numbers of these primordial follicles in the ovary.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">If these could be recovered\u2014a small slice of ovary removed and matured in\u202fvitro\u2014they could be a source of almost unlimited eggs for donation. John\u202fEppig in Bar\u202fHarbor has done a lot of work on this in mice. He managed to mature these to a stage where they could be fertilized, but in the early experiments that he did, out of hundreds and hundreds that he tried, only one turned into a mouse. That mouse was, for obvious reasons, called\u202fEggbert, and it was a miserable mouse\u2014it had all sorts of defects and medical problems. For a while, he abandoned that form of research, but he started again recently. I\u2019m not quite sure what he\u2019s doing differently\u2014I don\u2019t know whether anybody quite knows what he\u2019s doing differently\u2014but anyway, he now has, I believe, dozens of very healthy, fertile, happy\u202fEggberts running around in the lab.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">That\u2019s interesting.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Then there\u2019s the possibility\u2014again, for research only\u2014of using animal oocytes. Hui\u202fZhen in\u202fChina used rabbit oocytes, removing the rabbit genetic material, putting in human skin\u202fcells, and getting good blastocysts which were indubitably human in the sense of the nuclear\u202fDNA, making stem\u2011cell lines. But the stem\u2011cell lines didn\u2019t do all that well, and I haven\u2019t heard much from her recently. There\u2019ve also been attempts, I think, to use cow oocytes in the same way, and this might be useful for research.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Then oocytes derived from embryonic stem\u202fcells\u2014this is a fascinating development in my view. A paper, for example, from Hans\u202fSch\u00f6ler\u2019s\u202fgroup, which reports H\u00fcbner\u202fet\u202fal, used embryonic stem\u202fcells, which, as we\u2019ve already talked about, are pluripotent and can make all cell\u202ftypes. Because they can make all cell\u202ftypes, it\u2019s reasonable that they should also be able to make germ\u202fcells.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Sure enough, when he cultured embryonic stem\u202fcells\u2014this is all in mice\u2014he found patches of cells which showed Oct\u20114, an oocyte\u2011specific germ\u2011cell transgene, lighting up; those are these green patches here. He also found that they sometimes looked as if they were migrating\u2014which is the time at which they show this specific Oct\u20114 transgene.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">He also found cells that showed this red\u202fVasa\u202fprotein, which is expressed in post\u2011migratory germ\u202fcells\u2014germ\u202fcells after they\u2019ve reached the genital\u202fridge. He got these clumps of cells, rather like those you get\u202fin\u202fvivo, expressing both the Oct\u20114\u202fprotein and the Vasa\u202fprotein. He followed them for another couple of weeks and then found that some of the cells detached and started staining for a marker which is specific for meiosis in germ\u202fcells.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">These are derived from the ES\u202fcells; these are derived\u202fin\u202fvivo. He showed that the\u202fScp3\u202fmarker was expressed in the nucleus, and the nucleus started looking rather diffused in type. The pictures in his paper, of course, are much better than these. Finally, he got cells that looked like mature\u202foocytes\u2014they got extruded from something that looked like a follicle. They had something that looked like a polar\u202fbody; they were in a zona of sorts but a rather fragile zona.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">If these went on for another few weeks\u2014and we\u2019re now up to about six or seven\u202fweeks\u2014he found within these groups of somatic (follicle) cells what looked like a two\u2011cell embryo and eventually three\u202fcells. Again, you can see the zona pellucida around sixteen\u202fcells sharing the specific Oct\u20114\u202fprotein, developing into blast\u2011like objects. Some of the\u202fblastocysts looked very like proper blastocysts, and again Oct\u20114 in the inner cell\u202fmass, and PCR\u202fanalysis showed that they indeed expressed all the right genetic markers.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">These actually look extremely like the sort of pictures one gets from parthenogenetic development of the\u202fLT\u202fstrain of mice. So maybe they have something in common with that. We don\u2019t know whether they\u2019re developmentally competent\u2014these blastocysts were not put back in a uterus, as far as we know.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">That\u2019s that, but there are other labs that have also pursued this line. This is a diagram from Asim\u202fSands\u2019\u202f<em>News<\/em><em>\u202f<\/em><em>and<\/em><em>\u202f<\/em><em>Views.<\/em> For example, in the lab of\u202fGeijsen\u202fet\u202fal, they made embryoid bodies from the ES\u202fcells and treated them with retinoic\u202facid, which makes primordial germ\u202fcells multiply. They found that some of the somatic cells were expressing the\u202fSry\u202fgene, the testis\u2011specific gene, and within those patches of\u202fSry\u202fthey got germ\u202fcells becoming apparently haploid and turning into what looked very like sperm\u2014which were then injected into eggs to fertilize those eggs.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">But again, the blastocysts that resulted from that fertilization, as far as we know, have not got any further in development.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Toyooka\u202fet\u202fal in\u202fJapan\u2014that\u2019s in\u202fNo\u2019s\u202fgroup\u2014they also got male germ\u2011cell development from ES\u202fcells and put them with testis somatic tissue and got sperm.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">In\u202fAustralia, they\u2019ve done the same sort of thing with human embryonic stem\u202fcells and got apparently primordial germ\u202fcells and embryoid bodies.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">So the final possibility, before I get onto that, oocytes from bone\u202fmarrow or peripheral blood. This possibility was raised first of all in a paper from Jonathan\u202fTilly\u2019s\u202flab (Johnson\u202fet\u202fal, last\u202fyear), where they showed pictures of what they thought were oogenic stem\u202fcells in an adult ovary.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The pictures in that paper were not terribly convincing to\u202fme\u2014they looked rather like what you get in cultured\u202fovaries when oocytes are actually exiting from the edge of the ovary. I wasn\u2019t convinced they were really undergoing mitosis and dividing, and it wasn\u2019t clear whether any were undergoing meiosis to develop into oocytes.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">This year, he has another paper, from the same group, now in\u202f<em>Cell<\/em>, showing that in infertile female mice\u2014whether they were genetically sterile or chemically\u202fsterilized\u2014you could apparently get new\u202foocytes appearing if you treated them with a bone\u2011marrow transplantation or even peripheral\u2011blood transplantation. He claimed that these adult mouse ovaries could produce hundreds of new\u202foocytes within\u202f24\u202fhours.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">That, in itself, is a surprising claim, because normally to get from oogonia to meiotic oocytes takes at least a week, and one couldn\u2019t help wondering whether there were pre\u2011existing follicles that perhaps, after their chemical treatment, started maturing again.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">He used donor\u2011derived GFP\u2011labeled oocytes, and they seemed to turn up in the ovaries after the peripheral\u2011blood transplantation, and the pictures from the bone\u2011marrow transplants looked particularly convincing\u2014more convincing than the peripheral\u2011blood transplants.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">If this is really true, I think it\u2019s fascinating.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">[Applause]<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Dr. Anne McLaren of the Welcome Trust Cancer Research UK Gurdon Institute of the University of Cambridge. Professor Anne McLaren was arguably the most accomplished developmental biologist in the world at this time. Auto-Generated Transcript: I\u2019m sure that many of you have known Dr\u202fMcLaren for your entire for your entire training career. I\u2019ve known Dr\u202fMcLaren [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":293,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[39,52,19],"tags":[],"class_list":["post-1774","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-39","category-home","category-keynote"],"acf":[],"_links":{"self":[{"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/posts\/1774","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/comments?post=1774"}],"version-history":[{"count":4,"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/posts\/1774\/revisions"}],"predecessor-version":[{"id":2468,"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/posts\/1774\/revisions\/2468"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/media\/293"}],"wp:attachment":[{"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/media?parent=1774"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/categories?post=1774"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bedfordresearch.org\/symposium\/wp-json\/wp\/v2\/tags?post=1774"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}