 On behalf of the McLean Center of the Department of Obstetrics and Gynecology and the Bucksbaum Institute, I welcome you to this hour 13th lecture in the 2016-17 series on reproductive ethics. It is my pleasure now to introduce today's speaker, Professor Teresa Woodruff. Dr. Woodruff is the Thomas J. Watkins Memorial Professor and Vice Chair for Research in the Department of Obstetrics and Gynecology, the founder and director of the Women's Health Research Institute, and the director of the Center for Reproductive Science all at Northwestern University. Dr. Woodruff is an internationally recognized expert in ovarian biology. One of the major gaps in reproductive science had been the inability to mature follicles in vitro. As a graduate student at Northwestern, Dr. Woodruff became interested in addressing this gap. Through her research, she was able to clone two of the most powerful gonadal peptide hormones in hibbin and activin, and discovered the structure of these two master hormones. As a result of these findings, researchers have been able to produce live births in mice. Dr. Woodruff coined the term oncofertility to describe the application of this work toward the fertility of young women cancer patients. Between 1998 and 2008, Nature Medicine described this breakthrough, the one I just mentioned, as the most important achievement of that decade in reproductive science. Widely recognized for her work, Dr. Woodruff was awarded the Presidential Award for Excellence in Science, Mathematics and Engineering by Barack Obama in an Oval Office ceremony in 2011, and the Beacon Award from Frontiers in Reproduction in 2013, among many other awards. In 2013, she was named to Time Magazine's Most Influential Person list. Dr. Woodruff's talk today, as you can see behind me, is entitled Oncofertility, Ethics and Hope after Cancer. Please join me in giving a warm welcome to Teresa Woodruff. Well, thank you, Mark, for that introduction. It's such a pleasure to be here at University of Chicago with my neighbors and friends, and in particular, too. I think this is going to be toggled a bit to share with you some of the work that's happening in oncofertility, both here in Chicago as well as more globally. And the opportunity to frame some of the issues that have emerged in the arena of ethics is really an important opportunity. So I look forward to the discussion. Let me start by simply describing for you the problem. And that is that for many of us, we've not thought about the concerns of fertility after cancer, largely because for many years, people would have a cancer diagnosis and, as a consequence, would succumb to that disease relatively readily. But in the last three decades, primarily since we all, as a country, in fact, began to really tackle the problem of cancer directly, there have been an increase in the number of individuals who have survived their cancer diagnosis. And this is largely because of earlier diagnostics and better use of chemotherapeutics as well as the emerging biologic therapeutics that have been life-extending. Differential use of radiotherapy that have largely been responsible for the extension of life after that initial cancer diagnosis. And in addition, we've largely thought of cancer as a disease of aging. And in fact, that is correct. But there is a proportion of those individuals who have a cancer diagnosis each year who are in this younger age range where not only are they hoping to survive the disease, but they also are anticipating future family and certainly want to maintain reproductive function during their lifespan. So these same life-preserving treatments can, in fact, threaten fertility. And that's been one of the areas that we've been engaged in working on. So each year in the United States, about 1.4, I think this last year, 1.5 million newly diagnosed cancer patients, 90% of whom are in the older age range from 45 years and up. But that means that about 140,000 or 150,000 individuals each year are in the pediatric or this adolescent young adult category for whom reproductive function, gonadal function, is still very important. The disease is also recognized globally, about 10 million people around the globe have a cancer diagnosis and about 11% of these individuals are in the breast cancer category. Those individuals are many times diagnosed, even at younger ages of 40 and younger. And even as we began this work to really focus on young adults with cancer, we became increasingly aware of the needs of the pediatric, the pre-puberty cancer patient. And in the United States, there are 43 children that are diagnosed each year. Many of whom are treated here at Coomer and also at Lurie Children's. And the good news for these pediatric cancer diagnoses is even though it is an existential crisis that one can hardly imagine, it is yet the fact that about seven out of eight of those children will survive that initial cancer diagnosis. But these individuals are also significantly more at risk for infertility than their sibling cohort. And there is a direct correlation between radiotherapy and the infertility that is associated with that treatment. And in particular, with acute ovarian failure, that can be durable and long-lasting. Some of the statistics that I know in this group you're probably well aware of is the increase in survivorship that we've seen over the last three decades. Starting in the 70s and to the last half decade when data are available, we've seen an increase in survivorship in these pediatric pre-puberty cancer demographics. This was published just last year by Greg Armstrong and the childhood cancer survivor cohort from St. Jude's, such that 83 percent of children with a malignancy will achieve five-year survival. And the estimates from the National Cancer Institute are such that one in 750 people in the U.S. is a survivor of childhood cancer. And by 2020, the estimate is this number could be about 500,000. So those individuals have a variety of late effects that are associated with that cancer care, one of which has to do with their reproductive function. And even as we've focused on the cancer cohort, we've become aware of and begun to manage a variety of medical conditions where the treatment for that condition or the condition itself can render particularly a young female infertile. And so this can include patients with rheumatologic diseases that have durable drug, cytotoxic drug treatments, particularly for lupus or MS patients, undergoing bone marrow transplants or stem cell transplants, the beta-thalassemia patients, for example, individuals with Turner syndrome or fragile X carriers who are genetic mutations that predispose them to a premature ovarian failure. Those are individuals who often or their parents are looking for opportunities to manage or preserve that gonadal function prior to the time of sterility. And individuals who have mutations that are predisposing to a cancer risk. So we think of BRCA as one of that cohort of individuals. The young women often know their genetic risk factors at a very early age. So we're looking for medical interventions, medical management plans that can allow them to preserve fertility options for their family. And perhaps most recently it's our work on patients with disorders of sex development as well as individuals who are transitioning between genders and the interest of both the individual and in many cases the parent for maintaining the biological gamete of that individual. So for a male transition to female at eight years old, oftentimes the mother will be asking now for preservation, the crowd preservation of a testicular sample in the hope that that tissue can be used later for biological parenting. This is something I think will come up in the discussion later. This was featured on PBS NewsHour on their online version last weekend and has a great deal of discussion in the blogosphere about the validity of and the value of maintaining biological parentage for these individuals who are transitioning between sexes. Well, when we really began thinking of this was kind of in about 2005 and part of the issue is that fertility preservation at that time was in fact an option for males. And in fact I became aware of it because I was the basic science director for our cancer center at Northwestern and became aware of pediatric of boys of pubertal boys who were coming from our children's hospital down to our main hospital to bank sperm. And I thought that was really interesting and I asked what we were doing for the females. And the answer was of course well they need to be focusing on their survival not on their fertility but these young men with the so these men were being offered sperm banking but the young women with the same hope for survival of their disease as the males were not being offered any fertility management opportunities. And there were really three main gaps and to some extent we've addressed each of these gaps but certainly there are still additional work that needs to be done in each of these areas. So the first really was an information gap. Many oncologists just didn't really realize the profound effect that loss of gonadal function could have on the physiology of those cancer survivors. And so particularly for young women when there is an acute loss of gonadal function the individual goes through a profound menopause. And the symptomatology of menopause can be really very difficult to manage. But again my cancer colleagues would say well I've never heard a young cancer survivor tell me she's worried about hot flashes and it was said in somewhat of a derogatory way. But in fact of course the question wasn't being asked and the symptomatology associated with cancer survivorship can really get very mixed with the impression that maybe it's the chemotherapy or the radiation that's causing some of the symptoms rather than the loss of gonadal function. So we really needed to get information out to our oncology colleagues that this was really an important issue for young cancer patients. There was also a data gap that we really didn't know exactly what drugs would cause immediate sterilization and which ones might cause a short-term cessation and menstrual cyclicity for young women for example. But they may then go back to normal or regular cycles. And who would be affected later on where they might go into a menopause 10 or 15 years earlier than the normal population. And to some extent that is still an issue that we deal with today. Identifying what individual will be, will have a specific outcome is something that we're still trying to personalize as we develop a larger and larger databases. And then finally really was an option gap. And this is now on the reproductive endocrinologist side of the equation where we really did have options for young cancer patients which would include the assisted reproductive technologies that existed at the time which would include a hormone cycle to induce eggs and then either crowd preserve them or the embryos that could be fertilized with donor or partner sperm. But just as on the oncologist side in about 2005 they really weren't thinking about this as a prime issue, reproductive endocrinologist really weren't thinking about this patient cohort as their problem. And so we really had two medical practices that had opportunity to come together to build a new bridge for on behalf of the patient's medical management as well as fertility needs but we really didn't have the corridors of communication open between the two programs to enable this. And so we developed what we call now the Onco Fertility Consortium and that has been to largely bridge these main gaps in an ongoing way and to provide fertility options for young cancer patients. Let me just give you a little bit of an outline of how we've worked together and that includes bringing the basic science together with the medical practice and the patient needs and in order to really provide fertility options for young cancer patients especially at the early time when we weren't certain how easy it would be to hormonally stimulate cancer patients, we wanted to develop strategies that would take advantage of that ovary in the same way a male patient could sperm bank immediately and go back to cancer care to remove an ovary and then to be able to restore function with that tissue down the line was the logical arguments at the time. But to be able to do that we needed to know how to regulate follicle growth and oocyte maturation as well as to be able to cryopreserve this tissue for the long term. Sperm had been cryopreserved for many decades and we had a good sense of how to do that and what its quality would be. Ovarian tissue did not have that historical precedent so we needed to bring this fundamental science into the program. And that required the scientific community to come together in new ways to really bridge some of these disciplinary gaps. At the same time we were developing these basic science strategies. There were patients that every day needed fertility sparing options. And so at the same time the basic science was occurring we were developing strategies to meet this urgent unmet need for both males and females. And in addition to the cancer patient and survivor themselves we also had to deal with the transgenerational expectations of the parents. Something that we hadn't thought of at the outset which was that the parents would want would be interested in that biological heritage that was represented by fertility management at the time of cancer diagnosis. But again you're really faced with a very, a time of a lot of emotional upheaval for the family and so integrating in the decision around fertility management is something that's really quite profound but something that we've developed a series of strategies for that I think we'll get a chance to talk about later. So this required us to think in what I called a 360 way. If we develop the basic science breakthroughs that could represent maybe an important new breakthrough in a medical journal how could we take that medical breakthrough and actually put it into practice for cancer patients. And this required us not only to think about the options for IRB, approval and consent that had to do with taking out a functional healthy reproductive tissue before that first sterilizing treatment it also required us to think about issues of the legal concerns associated with removing that tissue, the issues associated with property of that tissue in a posthumous way thinking about the ethics of actually intervening in pre-puberty patients many of whom would not transition through puberty because of the sterilizing treatment but had not been offered fertility options and then insurance and reimbursement to be able to allow our providers to be reimbursed for services as well as for the patient to be able to make decisions in a way that wasn't about the economics of these various choices. Those became aspects of really thinking in a 360 way about the patient need. And we needed to span these different disciplines where oncologists really weren't used to thinking about the patient's eventualities. They could think about, they could advise about hair follicle loss but in many ways we're very uncomfortable talking about reproductive function, about sexuality and that's not unique to oncologists it really is very broadly within our medical disciplines that we're largely uncomfortable talking about reproductive health which is why I'm so delighted to be in this particular forum which is really focused on reproductive health and ethics. And on the same, by the same token the reproductive endocrinologists are very, had a very hard time dealing with urgently ill, critically ill patients because the individual that is typically seen within a reproductive endocrine practice is someone who has had over a year to understand and to come to grips with the infertility that they have. They've been on the web and are probably one of the most well self-taught patients that a physician will see. They know the lingo, they know the acronyms, they understand their own cycle. Almost no other individual knows all of that about their own reproductive health, particularly a 21-year-old, we just don't talk about reproductive health. And so add that complexity of the knowledge base of that individual with the critical illness and the series of decisions that have to be made and you come up with an issue where we really needed to build a whole new communication pattern between the provider and the cancer patients. So that required a different kind of multidisciplinary board and again we'll talk a little bit more in detail about each of these. So we actually coined the term oncofertility to really help to bridge these disciplinary gaps and ideas and in fact there is no hyphen between these terms because we didn't want there to be a pointing between disciplines that this is not my fault or my problem, this is yours. We really needed to unify everyone around this topic of oncofertility. And I guess when you coin a term you also get to build a ribbon which is what I guess I thought we got to do at the time. And so the oncofertility ribbon represents the interdisciplinarity of the field with the two different colors, the deep purple which is resonant knowledge of self and who I am and the green which is the spring green of eternal hopefulness for what's coming tomorrow. And we also have dots and smooth lines in our particular iconography. The dots representing eggs or sperm or embryos or tissue, that which is needed by you to provide that biological option and it moves into the ordinary ribbon structure but ours as you can see is slightly expectant. And that's been an important rubric around which we could kind of bring this field because again remember that at the time no one was thinking about this and even the males who were coming in were really somewhat one off. They happened to decide to sperm bank more often than not rather than being part of a program. And so that represented a way we could frame our dialogue. I also want to say at the outset that oftentimes we think about this fertility as the main endpoint but it is not the only endpoint. Fertility is something that many individuals will want to preserve but we also want to preserve the hormone function of the tissues so that women can maintain normal menstrual cycle, men the diurnal cycle from morning to evening in order to inform overall biological health of bone and heart and brain. And so that's just as important as we're going through these discussions as is the discussion of fertility and fecundity. So during the last 10 years or so there have been a number of strong practice guidelines that have been issued which have been really critical to the development of the field and they've come from all different societies not just here in the United States but around the globe but just to give you an example the American Society for Clinical Oncology, ASCO, ASRM and as well as our Allied Health Professionals all have had practice guidelines that say largely the same thing that there should be this prompt referral that we need to find specialists that can really take care of these young patients with these specialized needs and that we need to advance research and clinical trials to enable better treatment in the future. The American Academy of Pediatrics also went one step further to say that parents could act on behalf of their child in terms of fertility preservation. And this is important and I bring this slide today because of course this was one of the ethical concerns at the outset when we were putting this program together because you are taking out a functional tissue prior to that first sterilizing treatment. So the ethics of a surgical recovery and for pre-providal it's both testis as well as ovary so for both boys and girls there are differences in post-providal or pre-providal you can only take tissue out. That represented a major point of discussion for our ethics community and for the IRB community but of course the guidance from the American Academy of Pediatrics was important in some of these deliberations. So let me now take you just through very quickly some of the clinical issues and options so that we're kind of on the same stage, same page and then also a few of the emerging options then we'll talk a little bit about some of the ethical issues. So for the female it probably will surprise some of you but not all of you that we do take ovaries from pediatric patients as young as one month of age. And the reason for that is that females are born with all the follicles, all the gonadal reserve will ever have. And so that ovary has about a million follicles within the two tissues, the paired ovaries. And those follicles become activated as soon as birth and they become and as they activate most of them are lost through attrition about 400 of them of the million or so follicle pool are ovulated in a monthly cycle in women from about the age of 13 to about the age of 51 and a half. But the vast majority of those follicles activate and then are lost. And so you can see at birth on average the follicles are within the ovary and then are lost by 51 which is the time of menopause. Women can have a range of follicles higher and lower and so understanding for an individual where they are within their ovarian reserve represents one of the major biological challenges for our field. Because depending on how much ovarian reserve you have will suggest in many cases how long until you will have no more follicles available to you. And so one of the index cases from our program, well what I'm about to say which will be found is one of the index cases from our program I think she was a 17-year-old actually went and had radiation treatment and went into menopause at about 19 and a half years. She was treated at 12 or so and then went into menopause at 19 years. And so we suspect her ovarian reserve was about here. And in fact in her case we did have a piece of her tissue in the research lab and it was we confirmed that she had a low number of follicles. But in order to know where she is within that ovarian reserve we actually had to have a piece of the tissue. And so that simply represents one of the challenges of knowing where a patient is within their ovarian reserve. On the male side because sperm are produced from stem cells, if those stem cells are unaffected by the treatment they can in fact restore gonadal function and that represents the option for males. I'll also mention that for the patients the strategy we've used is to cryopreserve entire tissue ovary or testis and then 20% of the tissue then we ask the patient to consent to go to the research that we think is necessary to make the remaining 80% useful to them down the line. You saw the line where that patient she was 12 when treated with radiation and then went into menopause at 19. Well so what are the options and I think part of the reason this is getting hung up is this is a movie of sperm and it's in my female talk so it probably is having some kind of adverse event here within the slides. But what you're seeing are sperm that should be that are modal and so the option for males are really to bank sperm. So a semen sample is very easy to acquire from any male that's pubertal and above with the exception of our lymphoma patients who do come in largely as a spermic. And so there is an interaction between the cancer and reproduction which is something that we're very interesting and further study. We can also do tissue cryopreservation. We do talk about donor sperm because we want to have parity between the kinds of conversations we have between males and females and as well as adoption. So a male who doesn't bank sperm or who in the end may not have high quality sperm. We also want to talk about adoptive services for the females. This is also a movie. The options would be embryo or egg banking. Of course, egg banking became non-experimental about four years ago and that really changed the playing field for females with the cancer diagnosis. So they too could cryopreserve an autonomous germ cell rather than an embryo and that became a real game changer in our field. And the majority of adult cancer patients now actually do bank o-sites rather than tissue or embryos. We do talk about adoption even in that early timeframe when you're trying to think about medical management and the adoptive story was partly from a summer ethics and humanity summit that we ran for the first five years of the program and we had a group, one of our bioethicists from Canada asked why we were only offering biologic options. And as we began to look at this, we found that young female cancer patients were not allowed to actually adopt by adoptive services and so we set up a study to actually ask whether or not the adoptive services were discriminating against females specifically and overtly or were they just behind and didn't realize that many women were surviving their cancer diagnosis and in fact would be good mothers. And so we did that study and found the latter was the case setting the hypothesis up in that direction. And so after revealing that, then we did an interventional arm and we now have 15 adoptive services that are what we call cancer friendly and they will work with young females who have survived cancer in an adoptive setting. We also want to talk with young women who are cancer survivors about the fact that even though we may protect a biological gamete they may not be able to manage that pregnancy autonomously as well. They may need a surrogate or gestational carrier and this can be because the uterus and the cervix are also involved and damaged irreparably by the radiation or chemotherapy and of course the loss of hormones may also influence those tissues. And so for some cancer patients in particular sisters or aunts or often times willing to serve as gestational carriers. At the same time we're talking about the likelihood of sterilization which really depends on the age and the treatment. We also want to talk about the fact that not everyone is sterilized by cancer treatment. And one of the misnomers is that cancer treatment is sterilizing and so when patients we have a study that shows that when oncologists don't talk with the cancer patient about fertility management they think that that doctor thinks they're not going to survive their disease and so that's one outcome. The other outcome is they think they're going to be sterilized and they're going to die but they're young, they're going out and they have sex and then we have an unintended pregnancy during a course of treatment. And so it's really critical that even in that earliest stage of cancer treatment protocol development for young males and females it is important to still talk about contraceptives a contraception during that time and many oncologists are uncomfortable talking about sexuality. So we have a great program here at U of C, Stacey Lindow runs on cancer, oncophotility and sexuality. We refer patients here. We have a program at Northwestern and that's really a critical conversation to have with the patients and that can avoid that likelihood that there might be another sequelae that's very, very difficult to manage for a provider and for that patient. And then the last option is for ovarian crowd preservation if the patient doesn't want to go through hormonal cycles or are unable to and want to maintain biological parenting as a potential option or for a pre-pubital patient so ovarian crowd preservation is the option. So taking out one ovary prior to that first sterilizing treatment this is a cross-section through a human ovary and what you're seeing here in the outer cortex of this human tissue are those immature follicles that make up that million follicle reserve and most of those follicles are dormant and one of the questions that we have at the basic science level is trying to understand why one follicle might begin activation and growth when a woman is 19 in its May and the follicle sitting right next to it won't begin that process for five or 10 or 20 years. So really understanding that fundamental biology is part of what we needed to do to be able to utilize this ovarian tissue for young cancer patients. But our hope is that particularly for our pediatric and young adult cancer patients that the basic science will keep up with their needs because for some of the patients who are crowd-preserving tissue at two or four or eight years of age we probably have 10 or 20 years to try and develop those strategies for follicle activation. So we also have had in the last 10 years now more than 100, this is actually out of date now, it's more than 100 human live births from this ovarian tissue that has come out prior to the cancer treatment and transplanted back into the patients. Now this can only go back into the cancer patient, cannot go back into a surrogate or gestational carrier but there have been now more than 100 live births and this is one of the babies born in St. Louis and our Uncle Fertility Colleagues group, Sherm Silver. But the issue we still have is we don't know the efficiency, there have been transplants around the globe and so knowing what the denominator is is something that we've been working very hard to develop but we do know that the tissue and the way we're crowd preserving it does maintain the function of those ovarian follicles. So that's really good news. We didn't know that when we started the programs and so for our cancer patients, both for the adults and for the parents of the children that means that tissue, that gonadal tissue is actually able to support full follicle development. Not all patients actually have natural pregnancy, about 50% go through an IVF cycle on that oocyte then is utilized by a gestational carrier. The other issue we have is cancer recurrence. So I told you that tissue comes out prior to the first sterilizing treatment. So what that means is those cancer cells may in fact be within that gonadal tissue and so the likelihood of transferring the disease back to an individual who's just survived cancer is not zero. And so that's why we're trying to develop additional strategies for utilizing that tissue without the transplant. And so that's actually shown here. So as we begin to think more and more about the pediatric cancer patients which is where a lot of our research is now focused right now it is to think about these gonadal tissues which have actually more ovarian follicles than the adults. So with an ovarian tissue from a two-year-old versus a 22-year-old versus a 32-year-old there are far more ovarian follicles in the younger tissue so more ovarian potential than in the older patients. And so this is actually a cross-section through one of our patients and I forget how old she is four years old in this particular image and so those are her ovarian follicles out in the cortex none of which have activated but this particular patient had ALL and so what you're seeing I hope you can see the green cells in this image those are the ALL cells that are now within that ovarian tissue. So we've crowd preserved an ovary for this patient but we know that she has that same disease within the tissue that we've crowd preserved so she would not be a good transplant candidate. And the treatment that she received is likely to render her infertile and probably have a difficulty going through puberty and so we're trying to develop strategies to take advantage of this tissue as I'll share with you in a moment that will allow us to restore not only again fertility in her adult years but potentially even the reproductive function as she leads up to puberty. So let me now take you through a couple of these emerging options then we're going to come back to some of the ethical issues that exist and I know you'll also recognize that there are many more than what I'll present and we can talk about those. So what we're trying to accomplish is the development of ovarian follicles a process that we know a little bit about but not everything about how activation occurs and we're trying to develop that outside the body in vitro and we want to have not only hormone production but coordinated high quality maturation of the oocyte that's enclosed within an individual follicle. We'd like to develop a strategy for managing endocrine hormone production because we're interested in that pubertal transition so that child who doesn't have the gonadal support has to be managed by exogenous hormones and being able to develop what I'll describe later as an ovarian bioprosthetic that really has these coordinated hormone cycles would provide her with that opportunity to go through a natural puberty and then ongoing durable menstrual cycles and that would allow for the support of systemic health. So that's our ultimate goal is to develop these various strategies. When we started this work I collaborated with a bio engineer Lonnie Shea who's now the chair of biomedical engineering at Michigan but I told him that we really wanted to develop an artificial structure that would house these ovarian follicles because we, like others, had been growing ovarian follicles for many years on flat plastic. And when we did that we could get hormone production but we could never get live healthy birth from the oocyte that was in that tissue. You can get very few numbers of follicles to mature from the mouse in the 2D plastic. In the human you can never get maturation of the oocyte and so we proposed that the three dimensional architecture of the follicle really mattered to oocyte maturation. And we know this in part because the oocyte doesn't undergo glycolysis. It actually requires the surrounding cells to provide it with the pyruvate to allow it to go through the later stages of metabolism. So when we were isolating these follicles on plastic it was as if we were making them diabetic for a little while. And so those oocytes have a very very rapid response to negative environment. And that's largely because the oocytes have to manage the genetic stability of this species. And so there are genetic pathways that are able to cause the loss or the apoptosis of those oocytes. So if we could maintain the oocyte with its surrounding cells we predicted that we would have better quality maturation status for the follicles. So Lonnie came up with this biomaterial called alginate. That could be utilized for a variety of reasons we don't have to go into today. But the important thing for me was to learn that it's actually the thickener in ice cream. And so many of us eat it every day and when we have our high school programs it's great to have students eating their experiments just somehow reinforces the biology in a very very specific way. And maybe for adults it's easier to say that alginate is what looks like the pimento in the middle of a cocktail olive. It's not a pimento. It actually is alginate pressed into a little shape. And so that you can either go eat ice cream or you can have a cocktail. But you will now remember that alginate is the biomaterial that we use to grow ovarian follicles. And so with this material the follicles can be isolated and then begin to grow. And we don't want to go into the depths of the biology here. But the follicle has to not only maintain the oocyte it has to form the two compartments of the follicle the thica cell which makes androgen and the granulosa cell which makes estrogen. And this is just marking the thica cells that develop over time and internal are the granulosa cells. At the beginning these murine these are mouse in our early studies the mouse follicles don't make appreciable amounts of hormone. But over time they do begin to stimulate as these layers differentiate in culture the enzymes necessary for androgen progesterone and conversion to estrogen. Now this hadn't happened before in fact it was thought that it couldn't happen. And so that is why it happened to be the nature medicine breakthrough of the decade. More recently we've taken those follicles and we've asked if we could trigger one more step which is ovulation in vitro. Ovulation is one of the most remarkable of all biologies and I think of all the biology you can think of there's not one where there is an auto-catalytic self-destructive event of an internal organ. Why on earth would evolution develop this process by which an internal organ basically is instructed hormonally to break down the surface and allow the female gamete to move from the inside to the outside. And then that tissue reseals and that tissue transforms from the estrogen-producing follicle to the progesterone-producing luteal tissue. It's just one of the most remarkable biologies and it's very hard to study because that process occurs over a 30-minute timeframe. And it is a time of remarkable proteolytic breakdown so it's very difficult to study the genetic changes because you've got all the proteases, all the DNAs, all the RNAs that are breaking down these superficial cells. Well, so because of all those reasons we hadn't actually studied ovulation in our culture dishes but I had a student, an MD-PhD student, Robin Scorri and I begged her to try and look for ovulation events. So she actually did this and added LH in an ovulatory dose. In fact, what you're seeing is our follicle here and the movement of the breakdown of this outer surface in a rupture zone just like you would see in vivo and the oocyte that's now matured as a consequence of this hormone treatment moving from the inside to the outside. And I guess I didn't put it in, I modified the slide's deck so, but I really loved it so much. I have a series of 16 of these slides so that you could see this happening. But the other thing that's really remarkable about this is that we really only have one side of the tissue that's undergoing this breakdown. The remainder of the tissue is staying intact which is just what happens in vivo and for reasons that we really don't understand. So now we're going to be able to use the system to be able, we hope, to identify some of the factors that are involved in rupture and maybe develop a new contraceptive tool. We'll also be able to use it to show that some contemporary contraceptives really are only blocking ovulation and don't have any effect on embryogenesis which is one of the concerns some people have with some of the contraceptives. For the purpose of oncofertility, it tells us that in fact the way we're growing these follicles is in fact allowing for each of the stages of follicle maturation to occur including ovulation and luteolysis. And if this didn't occur, we would say well, perhaps some of the earlier stages of development aren't correct in vitro. But in fact, we've phenocopy all these stages. Well, then the question really becomes what's the quality of this oocyte? And in fact, the best way to show you high quality oocytes is to show you live births from those oocytes. And so these were our first live birth, newborn and new age. And we had a lot of other mice. It is in you. It would have been, you see something, I'm sure, if it had been born here. But we had new this, new that, and then my lab wouldn't let me name any more animals. And so these represent high quality gametes that actually can give rise to live, healthy offspring. But our next step really was to translate this into the human. And so one of the issues is, as many of you are aware through this series, is that we have federal jurisdiction, federal laws that have to do with this one time in biology which is called fertilization. And the Dickey-Wicker amendment says that we're unable to develop embryos from fertilization, which we didn't want to do, but we did want to take some of these human developed eggs, as I'll show you in a moment, and activate them pathogenically without any male paternal, without any paternal genome to see if in fact the maturational quality or potential of those in vitro grown oocytes was sufficient to at least support nuclear and cytoplasmic maturation. But of course, we're restricted from doing this, and so Lisa Kampel-Angelstein and Sarah Rodriguez and a graduate student of mine, Candace Tengen, together took this on in a series of three articles, the first of which we published in Science, which really talked about this restriction on reproductive science as a scientific misunderstanding, that in fact the parthenotes really should not come under this restriction because of the inability of those eggs to really support human offspring, and as a consequence of not stunning parthenotes, we were really leaving a 12-hour timeframe on the scientific off-ramp, and we weren't then able to understand better about gamete health, about fertilization, and we argued since all of our health ultimately comes from the earliest stages of embryo development, we couldn't understand anything about those early stages. So then in this, after that, we published a series of two other articles, if in fact there was scientific and medical rationale for parthenotes within biomedical research, was there a, what would be the policy implications of this, and in the third paper, how would we recommend, or was there an ethical issue? That was the second one. The ethics was the second paper. And then the third was, well, if there is a medical and scientific value and there's not an ethical issue with parthenotes, what would be a policy we could put into place to allow for this to occur in the United States? And so we took from other countries ways of studying parthenogenic activation and put into this paper a way forward for the United States. That has not come to fruition. Dickie Wicker has continued to be a writer on every amendment since we published this and for the last 20 years. But it still remains one of the issues that is most concerning. That being said, we were able to take this in vitro culture and mature human follicles. This is one of the human follicles from one of our patients, maturing egg and vitro. And then we could ovulate GV intact eggs. And this is after between 30 and 40 days in culture. And last year we published the first ever human M2 egg from a completely in vitro culture system. A really remarkable achievement that we didn't know whether or not we could accomplish. This came from a one and a half year series of patient tissues that came from our Uncle Fertility National Physicians Cooperative and there were 65 follicles from 45 patients and we achieved M2 in four of them. Not all of these follicles matured but the terminal number was four M2 eggs. So I've given you a little bit of background on some of the things we've done. We've looked at the biomaterial environment, the animal environment, the age from which the tissue comes. Is it pre-puberty or is it post-puberty? Does that make a difference? We've looked at the physical environment and some of the cells that surround the follicle to try and understand how they are influencing follicle maturation. And then we've looked at this long term durable environment as we translate to the human and then finally what I call the human environment. Which is what you're most interested in. Which has to do with policy, law and the religion. And so actually I'm sorry. I thought I had taken this slide out. What makes a good egg is what we're continuing to work on and we're unable really to do these studies in the human. We can in the mouse trigger a series of regular maturation hallmarks from nuclear maturation. And now last year we showed that there's a cytoplasmic signal which is called the zinc spark that we can denote as one of those early signatures of the ability of that egg to persist. And in fact I didn't take this out. This is actually a parthenote from humans and so we could not do this under federal funding but we did get funding from faring pharmaceuticals. And what you're seeing is the zinc spark into human eggs at the time of parthenogenic activation compared to an egg that cannot go on to develop life healthy offspring. So that represents the utility of this kind of work to be able to from a cancer patient not transplant it back to that cancer patient until we're confident that in vitro follicle development supports fully mature gametes. So I thought I took this out. We got a lot of press last year on this. Everybody thought it was very cool that we had zinc sparks at the time of fertilization and there are literally fireworks and all this kind of stuff. We can talk about this later. This became one of the zinc spark became one of the major moments in assisted reproduction although we haven't put it in assisted reproduction yet but it is I think a way that in the future they'll be able to select eggs based on their zinc spark. So back to this which is the final science point and then I want to wrap up with some of the ethics and that is the emerging issue of developing an ovarian bioprosthetic and engineered tissue. So we can grow follicles but what we really want is a full tissue and so Monica Loranda, a student in my lab who's now took a position as a faculty member at Lurie Children's took these human ovaries where again there are cancer cells within this tissue. These come from our young pediatric cancer patients before chemotherapy or radiation desalularized that tissue and what you can see is the overall architecture of this organ and now she wants to resellularize that tissue with cells from native cells from mouse or from human as well as IPS derivatives from those individuals who may no longer have gonadal function. So the ultimate goal is IPS but here we show that in fact after 30 days so about 15 cycles or so we can get follicles to continue to develop and she transplanted these back into pre-puberty mice that could not go through puberty and all of the mice went through all the signatures of puberty. We also want to take that tissue and be able to develop a number of other materials for patients who don't have gonads if those gonads have been surgically resected we need a way to transplant back the tissue so we take the desalurized tissue and make what we call an ovary paper. This is a human follicle on the ovary paper it can then be sutured back. This happens to be to a cow ovary but it can be sutured many different places but we also use that tissue to now that material to now 3D print the architecture that we think will allow the follicles to mature. These are individual follicles within our 3D printed structure and we can take GFP positive mice transplant that back into a pre-puberty animal. We can get angiogenesis coming in with these follicles and that's what's one of the things that's really necessary for a durable transplant and in fact now we have life offspring the GFP is the positive pup. So that represents again a major breakthrough for this this again was a pre-puberty animal that was sterilized we transplanted it back through puberty and also then had live offspring. So that represents the potential opportunity of the future for developing we have knee transplants and this would be a soft organ transplant of a tissue that could restore a lost problem lost function. So all of these scientific goals have required us to ask very hard questions that we as basic scientists sometimes don't think about just like when we started we really weren't thinking about adoption we were thinking about biological parenting but then we did studies to try and do that. This is one of my favorite this came out in Time Magazine before I got the Time Magazine person of the year which I should mention I thank you for saying that but Beyonce and Jay-Z were way higher than I was on that list. I was above Nancy Pelosi and Rahm Emanuel but below Jay-Z and Beyonce. But we're really still at a financial crossroads. IVF really still is largely disproportion to people of wealth and the access grid is very much skewed in terms of our reproductive interventions and that's because of the way we've allowed the payer models for IVF to occur and we really need to come up with new strategies because we don't want oncologists looking at their patients and estimating whether or not they will be able to go through an assisted reproductive cycle. And that's something that happens today and that's something that we're working on. Religious constraints we've had ecumenical councils that really look at the different religious perspectives on these various interventions and for all the reproductive ethicists in the world in the room you'll be maybe not surprised but maybe surprised to know that the Catholic Church is one of the theologians that was on the program actually said that tissue transplant is within the doctrine of the Catholic Church. Kind of the first movement before the Zika came out from this Pope. The legal catch-22 goes like this. It is the issue of whether you take a tissue out or not from a pre-pure little child as a parent today and the impact when she or he becomes the age of majority or 18 or 20 and she or he asks why did this tissue come out of me I would not have wanted it or why did you not intervene and I am now sterile. That represents a legal catch-22 that we've deliberated on the issue of life and death. So we're all celebrating the good news of the cancer survivorship but in fact not everyone survives that disease. So we don't want to have kind of the discussion of interventions if there is no hope although some would argue that fertility interventions represent the hope that those patients need. Public priorities versus personal interests how do we get more traction in the public for providing the kind of insurance and reimbursement issues or thinking about insurance and reimbursement issues versus an individual's interest in this. The fidelity of the techniques I'm telling you a lot of research a lot of moving research that continues to develop and I told you there are 100 live births with the tissue transplant that's certainly good news and good news continues to develop but the fidelity of the techniques still is not known. We don't know the denominator now globally for example. This we talked about and then the privileged biology at the time of fertilization is really the Dickie Wicker amendment. So Lisa Kampel Engelstein who has spoken here and worked with some of you is now is at the Aldermarch Bioethics Institute was a student of mine under the original uncle fertility work who has published some of the issues and some of what comes to mind of course and these are her slides is the informed autonomous decision making how we think about that for adolescents are adolescents really being informed? Do you inform the adolescent? Do you form the patient? What's the right strategy? And are they being given false hope in a timeframe when they can't quite understand what it is that they're being asked to do by taking out a tissue? What is the fulcrum of I want to be a mother versus I want to have a surgical removal of a currently functioning tissue? She's also interested in the problems of parental pressure and support this transgenerational anticipation this transgenerational hope for the patient. Do they feel pressured to do this? And do they feel pressured then to use the frozen gamut if my mother went to this extraordinary extreme and this is the feminist critique of this does that then mean I have to gender identify as a female and does it mean that I need to have a baby when I'm 21 years of age? And that becomes one of the things that Lisa has been really thinking about and do they feel supported by their parents if they want this? So the discordant case where mom and dad have decided not to intervene but the child would want to what's the right strategy in that particular case? We looked at the cancer oh and then at Tsukoketo who is here is looking at the ethical consideration for pediatric patients in addition and we looked at adult survivors of childhood cancer to try and understand their attitudes about the fertility concerns as an early way of trying to index whether or not we should have an IRB associated with fertility interventions and found that the cancer patients themselves said they didn't have much recall about the cancer particularly for the very young ones but they are living every day with the inability to go out on a date because they have in the case of the ones that we recruited menstrual cycle problems or in fact we're sterile. So at Tsukko is looking at a child's right for fertility preservation she's looking at this from the global perspective trying to understand how we as a global community look at this not just as an American community and that the children in other conditions are thought to be appropriate for decision-making about cancer so how do we think about their decisioning as it relates to not just fertility but their knowledge of what the late effects might be and that's a very very difficult fulcrum that is still being discussed and studied. And then finally how do we educate better about reproductive health? I think many of the issues we have in reproductive sciences because we're frankly uncomfortable talking about reproductive health and many people in the public don't understand the first thing about a male's daily cycle testosterone high in the morning low in the evening and really have a hard time understanding the biology or the function of the menstrual cycle. That then leads to an inability sometimes to make decisions about their reproductive health and particularly in a timely way and it also flows into our public policy domain with discussions that sometimes are really not informed about the biology but about opinion. And so we created Reprotopia that is a K to Gray that hope many of you visit. We'd like to put some ethical discussion on this website as well but it's largely meant to be for public way to find information about reproductive health and information. We also have a series of books and where's the one about ethics? This one is actually the best seller. So this is on ethical, legal, social and medical perspectives of oncofertility and I would urge any of you who are interested in going deeper in this topic to get it from the library. And so these are when, again, you create a word and a term and whatever you get to write the books on it. So these represent I think the up-to-date information. This one just came out last week and this one will be out in about two months and I'm done with writing books by the way. So Julie, good luck. I'm all done. But they represent great ways when topics are not in the medical textbooks to provide access to contemporary problems and thinking in a one-stop shopping area. So with that, what I hope is we look forward 20 years from now instead of back 10 years from now that we'll have continual better cancer control and treatment and higher selectivity of patients. So about 20% of the patients are going to be sterilized the other 80% or not. So how do we identify those individuals who are on that lower spectrum of the ovarian reserve for females and who are going to be most susceptible as males? We don't right now have an index to do that and that's something we hope to do over the next 10 years. We're also working very hard to develop neo-adjuvant fertile protective. So instead of having to have a mother imagine taking a tissue out of her pre-puberty child to be able to have something that would block that follicle loss would be a much better medical management of this particular issue. I told you about the in vitro follicle maturation for those patients who do have the tissues that have been taken out and have the cancer within that tissue. So that's continuing as well as the development of potentially ovarian bioprosthetics which would provide restoration of endocrine support for the patients as well as the potential for fertility. And then eventually of course we'd like to eliminate the field if in fact the cancer biologists in the room can in fact find a better way to treat cancer and not hair follicles oral ovarian follicles I think will be in a much better position to say sayonara to the word and I think that would be a great thing that we could do. Well I really want to thank you for this opportunity to come and talk in this forum. It's really a powerful one and an important one today. So I really applaud you for what's happening here. My students have come and joined you for other of these symposium I suspect will be back. We do have a great number of colleagues that I worked with on this and I think I mentioned them as well as funding for the work and certainly if you have any questions all of the protocols and IRBs and letters of medical consent all of that is open on the website and excuse me so if there's any questions you have certainly join us there in that community. So again Mark thank you very much for the invitation. Sure. A question to that is you know in the event that the pediatric or adolescent patient does not survive. Right. What is the discussion? So the discussion is up front. We decided the ankle fertility consortium for tissue and for gametes of both sexes that there would be no posthumous reproduction. Of course that can be challenged eventually if someone chooses to challenge it but for right now that's the way we have all of the consents established. And have there been any attempts to challenge that legally? No. Nothing. You know it's a young field in many ways. Many of the patients have not come back to utilize the tissues. Only a few. So to date we haven't had any of those questions emerge. We did write a law review in the Santa Clara law journal on some of these issues. So we tried to take an a priori look at what might come down the path and so we provide justification for each of these decisions there. But I suspect some of it will come up eventually. Yes. I ordered for them to also have autonomy over their own bodies even though they're young and how was that conversation had to make sure parents aren't pressuring? Right. I think it's a very delicate line and so in some ways it also depends on state and country. So in different states there are different age of reproductive majority that's different from the age of medical autonomy. And that has to do with when you can make autonomous decisions about contraception or autonomous decisions about abortion. And that changes state by state. And so is aqua fertility under that kind of age of majority or is it really the medical the traditional age of majority? So we've made it the traditional medical age of majority saying that cancer is a medical issue and but I think that's also something that's really an important decision. We particularly in the case of trans of children or young adults who are transitioning between sexes that's where the parents interest in the biological gamete has sometimes come into conflict with that child's or that young adults. Many of the individuals who are transitioning are in conflict with their with their gender that they were with the sex that they were identified with. And so that biological gamete is also something that they're in conflict with. But the parent has an interest in that gamete. And so the psychologists who are part of the discussions are trying to identify in whose interest is this gamete or tissue being preserved. And to try and sort that out so that there would be value to the individual without later coercion to use that tissue or gamete against that individual's will. So this is definitely an area of emerging concern and something that we're continuing to work on. It's a great question. This isn't an ethics question but you know you go to medical school nobody teaches you how to build a practice. Right. And I imagine you go to graduate school and you learn the science but nobody teaches you how to get publicity. Right. But you seem to have a knack for that. Well, yeah I think that's an interesting point and I think in some ways reproductive science is also kind of trying to stay a little bit under the radar in part because we're all uncomfortable talking about sexuality and reproductive science. I think in our particular field that is to our detriment. So I think some of the science that we've done and some of the recognition is because it's really extraordinary. I mean the zinc spark is one of the most we didn't set out to discover that in fact it's a true discovery. We had no idea there would be a release of a metal at the time of fertilization and that captured the imagination of I mean on the same day last year that Slate was talking about this Rush Limbaugh was saying how great it was. So when does that happen? So I think the public is ready for this work if it's in a way that they can understand and access it. And my sense is that particularly for reproductive health in part some of the reason I'm very interested in this is every time there is a political cycle except for this last one where there was no talk of science but before that where there was talk of science in many cases when it came to reproductive science it would be wrong. And I would get mad until I decided well it's really my fault I have not educated enough. And I think unless we're ready to present the work that we're doing within a common language in a way that everyone can access we are our own worst enemies because why is it that most people don't understand the menstrual cycle? That's really remarkable that shouldn't happen. So if getting people to think about the zinc spark gets them to think about menstrual cyclicity I think that's something that we should engage in. And so you know I think that's part of it. I did a reproductive science MOOC for college students because I figure even if you did get high school education or grade school education on sex ed by the time you get to college when you really need it nobody's talking to you, right? And so we know the education is low and that may contribute to the rape statistics the sexuality the sexually transmitted disease issues. Why does America have one of the highest sexually transmitted disease rates in the developed world? It's remarkable. And I think it's because we're uncomfortable talking about reproductive science reproductive health the terminology of our bodies. And so you know the MOOC that we did I called it Reproduction 101 because I wanted to be about reproduction. And then when it came out of the Coursera it was called Sex 101. I said no, no, no it's Reproduction 101. And they said no if you call it Reproduction 101 nobody will take it if you say Sex 101 they'll all take it. And so you know I don't think it's intention we don't use a publicist we don't go out and seek it. What we do is we create good science in a way that a consumer can understand it and our consumer is our public our consumer our high school students in a way that they can use it. And in fact I guess if I am on a soap box a little bit I think too often we think of science in a vicious cycle from grant to paper to grant again. And we figure out how these papers are going to inform my next grant and how this grant is going to allow me to fund my lab so I can have students to get the next paper. And to me that vicious cycle is illegitimate. That's not what we're doing in science. We have to break that gravitational force and move outward to develop new ways to allow either that fundamental knowledge. And this is for both medical applications I've told you here but also fundamental knowledge. Fundamental knowledge needs to break out and be able to be delivered to the public in a way that consumers can use it. And I think that also translates to medical practice. We had to develop the medical practice plans to allow two practices two services that didn't had never seen each other before didn't understand each other's management plans. We had to develop the practicing practice management plans but those two practice managements were laid to each other. Oncologists were laid a reproduction reproductions laid to oncology. How do we get them together? And so breaking that grant paper and back again idea is what we all have to be doing. Part of that is public part of that is that we're all laid to each other. How do I communicate what I'm doing in a way that we can all take advantage of it? It's hard to do because we think we don't have time because of the way the finances are set up to fund people like me by grants and I don't get a grant unless I get a so those are things that I think are really important. My question relates to that and I think that some of us who do research in reproductive health perhaps also shy away from media attention correct. Correct. Because of a concern that if there's additional attention to what we're doing that may adversely affect our ability to get grants. That's right. The spotlight we yeah. We have a particularly difficult problem in our field. I don't know how many people are broad or how many people are within reproductive science. But if you look at the NIH the funding to reproductive health is infinitesimal relative to everything else. And you know I think that the fact is we all are here because of reproduction. And so NICHD I think the fact that we haven't been able to really advocate for let's even make it in the easier terms women and children I think it's about all of us but women and children is what we say is reproductive health at NICHD. The fact that we can't get more funding for women and children just makes no sense to me. So we have to we have to take back some of the language. We have to not worry so much about what might be said about what we're doing. Otherwise we really get the problem is we have bigger political problems because then people misuse the terminology of our field and let's all be really completely frank here the terminology of reproductive health and sexuality are the curse terms of humanity. So anything that has to do with reproductive science becomes the least common denominator terminology for epithets for expression that mothers try to get you not to say. Dirty is largely about our field. So if we don't take back the terms if we don't take back our field we will continue to be I think marginalized and will continue to propagate to the next generation of students an inability to speak about sexuality about sex about Parthenotes. And I think that's to our ultimate detriment. We can't have the ethics conversation if nobody's in the room or if people have already been predisposed to an opinion that is now intractable because that's what they think is true. And so when we did our MOOC and then Reprotopia you know the MOOC originally part of the reason for doing it is that we teach high school students and if you're legitimately trying to find out something about your health or sexuality or anatomy you often end up in a very unsavory part of the web. And so a mother looking at a 16 year old who's just trying to find out what the word vulva is might look at that history for that boy and say oh my god you know what's happening to my son you know or to a to a young woman who's trying to find out something about contraception maybe even just out of curiosity or maybe because she was looking at menstrual cycle and there's the contraceptive stuff. And so the mother thing oh she's going to have sex you know and so the problem is we conflate all these different things. And so what I decided with reproductive stuff is well I wanted a place where people could get the information they need at any age and if you Google us you'll find us but sometimes we are and in fact first time we Googled I was like there are five other porn sites in the top 10 with me and I'm like well at least at least if you're Googling for porn you get me you know that's that's not bad so we have to be present I think that's the key we can't have the conversation in isolation and we can't be authoritative resources for our field unless we actually are willing to have conversations and say words and use terms in a way that people can access and I would say that's the charge to our field that's also why I think IVF has been allowed to float in its charges I mean it's it's a willingness to pay model what other part of medicine is a willingness to pay model it's just those are the kind of things those are the consequences of not being willing to talk about reproductive science and medicine but part of it is this grant issue you know we don't have the funding to be able to do what we want to do so then we clench up and try and go down to our base how can I keep my job versus you know how can I create new intellectual content how can I be on the front lines of discussions like these but they're all intertwined and I think we're going to have to think differently about how how we engage the public in the discipline that's so important to their health but uncle fertility has been really interesting because before this people talk about IVF and really think it's shame on that woman for getting education you know this is one of the little foils of the field uncle fertility you know people think this is something we really should deal with so we may be able to get some movement in IVF in part because people are now thinking about it in a much broader way