Recent Posts

5 July 2021 - by Trine Skuland, Dr Birgit Kvernflaten and Joona Räsänen
It is becoming clear that our gene functions are influenced by a variety of epigenetic factors throughout our lives and even before we are conceived. Environmental context may affect gene expression and which genes are 'activated' or not in children conceived via IVF may be influenced by the dietary and lifestyle habits of an embryo's parents or grandparents, as well as by the culture medium in which eggs and embryos are kept in vitro. These findings have implications for the way we think about fertility, assisted reproduction, and genetic identity.

Epigenetics and bioethics of human embryonic development is a multidisciplinary project that spans disciplinary boundaries in order to better understand how scientists, clinicians, patients, and society should respond to these challenges. The project is funded by the University of Oslo Life Sciences, as part of its convergence environments initiative which has seen interdisciplinary research groups formed to address major health and environmental challenges faced. The project started in 2017, and is now drawing towards its close. Here, three of our project members explain their work within the project.

Trine Skuland is a developmental biologist who works on epigenetic regulation of early embryo development.

When an egg and a sperm unite to form a zygote, numerous events need to be coordinated in order to achieve successful development. Out of the ~30,000 human genes, the right selection has to be switched on/off at the appropriate time point. No wonder these events are error-prone!

Upon fertilisation, extensive reprogramming happens in order to reset the epigenetic marks of the egg and the sperm DNA, and to set up a new pattern that is compatible with further embryo development. Epigenetic marks are chemical groups that are attached either to the DNA itself or to the proteins the DNA wraps around inside the cell nucleus. The pattern of these epigenetic marks will decide whether genes are activated or silenced.

When an embryo reaches the eight-cell stage, one of the most critical events takes place. This is when the first major set of genes is activated. My team is currently studying one specific epigenetic mark that we think is important for the embryonic genome activation and we hope our research will contribute in further characterisation of epigenetic factors involved in this crucial part of embryo development.

Our aim is to find another piece of the big genome activation puzzle in order to get a more complete picture of what is necessary for normal embryo development. This is as more than half of the embryos created during assisted reproduction develop abnormally and have to be discarded. Our ultimate goal is giving infertile people higher quality embryos to increase their chances of becoming parents.

Birgit Kvernflaten is a medical anthropologist who looks at prospective parents' experiences of assisted reproductive technologies. 

My role in the project is to explore prospective parents' experiences and perspectives of practices and treatments used in assisted reproduction. It starts from the idea that their experiences do not take place in a vacuum, but are shaped within a particular socio-cultural and political context. The project further aims to explore and understand prospective parents' experiences and perceptions of the status of the embryo, embryo donation, research, and selection, in light of increased epigenetic knowledge.

This project has highlighted how prospective parents' experiences of infertility treatment are related to and shaped by social and cultural discourses on Norwegian family life.

In Norway, biological or genetic ties are considered central to people's understanding of kinship and identity, shaping couples' negotiations about gamete donation, family, relationships, and responsibilities. Yet people's understanding of genes is also ambiguous. As for the concept of epigenetics; it seems it has not yet entered the public's imagination.

Although the role of environmental factors in shaping who we are is acknowledged in Norwegian society, couples tend to view genetics in a rather deterministic way, in that they believe it shapes both looks, personality, and risk of disease. While difficult to truly grasp, the role of genetics is central to people's ideas about reproduction and parenthood. New epigenetic knowledge raises questions about the interface between nature and nurture, as well as opening up discussion related to the role mothers and their bodies play in determining the health of future offspring.

Joona Räsänen is a bioethicist who works on the philosophical and ethical implications of epigenetics.

Epigenetics raises challenging ethical issues throughout the human life cycle. Epigenetic transmission from one generation to the next may raise questions of moral responsibility of parents and grandparents. Epigenetics plays an important role in a range of chronic diseases, such as diabetes. Our lifestyle habits during pregnancy and even before, may influence whether our future children will live healthy lives or suffer from lifelong illness.

It is commonly known that we should eat healthily for our own sake, but these developments in our understanding of epigenetic could imply that we should eat healthily for the sake of our future children as well. Does this demand too much of future parents?

Epigenetics seems to put prospective parents under pressure since they would be partly responsible for their future child's health even before the child is conceived. Pregnant women are often advised to abstain from alcohol and tobacco, but maybe it is worth reminding them to eat healthily as well – and this advice applies not only to future mothers, but to prospective fathers too, since epigenetic inheritance occurs through the male germline as well.

Conclusion

The interplay between science, anthropology, and philosophy in the context of epigenetics is complex. Skuland notes that a key aim for scientists working to unravel the epigenetic mechanisms involved in early embryo development, is to fulfil the needs of IVF patients to have their 'own' child. Dr Kvernflaten shows how genetics is central to patients' ideas about kinship and identity, yet epigenetics is still something unfamiliar to most prospective parents. Räsänen's example suggests that if parents did take on board some of the moral implications of epigenetics, they might find that the scope of their responsibility for future offspring is dramatically expanded.

Click here to view SOURCES & REFERENCES and RELATED ARTICLES from the BIONEWS ARCHIVE or to leave a comment about this article.

5 July 2021 - by Trine Skuland, Dr Birgit Kvernflaten and Joona Räsänen
It is becoming clear that our gene functions are influenced by a variety of epigenetic factors throughout our lives and even before we are conceived. Environmental context may affect gene expression and which genes are 'activated' or not in children conceived via IVF may be influenced by the dietary and lifestyle habits of an embryo's parents or grandparents, as well as by the culture medium in which eggs and embryos are kept in vitro. These findings have implications for the way we think about fertility, assisted reproduction, and genetic identity.

Epigenetics and bioethics of human embryonic development is a multidisciplinary project that spans disciplinary boundaries in order to better understand how scientists, clinicians, patients, and society should respond to these challenges. The project is funded by the University of Oslo Life Sciences, as part of its convergence environments initiative which has seen interdisciplinary research groups formed to address major health and environmental challenges faced. The project started in 2017, and is now drawing towards its close. Here, three of our project members explain their work within the project.

Trine Skuland is a developmental biologist who works on epigenetic regulation of early embryo development.

When an egg and a sperm unite to form a zygote, numerous events need to be coordinated in order to achieve successful development. Out of the ~30,000 human genes, the right selection has to be switched on/off at the appropriate time point. No wonder these events are error-prone!

Upon fertilisation, extensive reprogramming happens in order to reset the epigenetic marks of the egg and the sperm DNA, and to set up a new pattern that is compatible with further embryo development. Epigenetic marks are chemical groups that are attached either to the DNA itself or to the proteins the DNA wraps around inside the cell nucleus. The pattern of these epigenetic marks will decide whether genes are activated or silenced.

When an embryo reaches the eight-cell stage, one of the most critical events takes place. This is when the first major set of genes is activated. My team is currently studying one specific epigenetic mark that we think is important for the embryonic genome activation and we hope our research will contribute in further characterisation of epigenetic factors involved in this crucial part of embryo development.

Our aim is to find another piece of the big genome activation puzzle in order to get a more complete picture of what is necessary for normal embryo development. This is as more than half of the embryos created during assisted reproduction develop abnormally and have to be discarded. Our ultimate goal is giving infertile people higher quality embryos to increase their chances of becoming parents.

Birgit Kvernflaten is a medical anthropologist who looks at prospective parents' experiences of assisted reproductive technologies. 

My role in the project is to explore prospective parents' experiences and perspectives of practices and treatments used in assisted reproduction. It starts from the idea that their experiences do not take place in a vacuum, but are shaped within a particular socio-cultural and political context. The project further aims to explore and understand prospective parents' experiences and perceptions of the status of the embryo, embryo donation, research, and selection, in light of increased epigenetic knowledge.

This project has highlighted how prospective parents' experiences of infertility treatment are related to and shaped by social and cultural discourses on Norwegian family life.

In Norway, biological or genetic ties are considered central to people's understanding of kinship and identity, shaping couples' negotiations about gamete donation, family, relationships, and responsibilities. Yet people's understanding of genes is also ambiguous. As for the concept of epigenetics; it seems it has not yet entered the public's imagination.

Although the role of environmental factors in shaping who we are is acknowledged in Norwegian society, couples tend to view genetics in a rather deterministic way, in that they believe it shapes both looks, personality, and risk of disease. While difficult to truly grasp, the role of genetics is central to people's ideas about reproduction and parenthood. New epigenetic knowledge raises questions about the interface between nature and nurture, as well as opening up discussion related to the role mothers and their bodies play in determining the health of future offspring.

Joona Räsänen is a bioethicist who works on the philosophical and ethical implications of epigenetics.

Epigenetics raises challenging ethical issues throughout the human life cycle. Epigenetic transmission from one generation to the next may raise questions of moral responsibility of parents and grandparents. Epigenetics plays an important role in a range of chronic diseases, such as diabetes. Our lifestyle habits during pregnancy and even before, may influence whether our future children will live healthy lives or suffer from lifelong illness.

It is commonly known that we should eat healthily for our own sake, but these developments in our understanding of epigenetic could imply that we should eat healthily for the sake of our future children as well. Does this demand too much of future parents?

Epigenetics seems to put prospective parents under pressure since they would be partly responsible for their future child's health even before the child is conceived. Pregnant women are often advised to abstain from alcohol and tobacco, but maybe it is worth reminding them to eat healthily as well – and this advice applies not only to future mothers, but to prospective fathers too, since epigenetic inheritance occurs through the male germline as well.

Conclusion

The interplay between science, anthropology, and philosophy in the context of epigenetics is complex. Skuland notes that a key aim for scientists working to unravel the epigenetic mechanisms involved in early embryo development, is to fulfil the needs of IVF patients to have their 'own' child. Dr Kvernflaten shows how genetics is central to patients' ideas about kinship and identity, yet epigenetics is still something unfamiliar to most prospective parents. Räsänen's example suggests that if parents did take on board some of the moral implications of epigenetics, they might find that the scope of their responsibility for future offspring is dramatically expanded.

Click here to view SOURCES & REFERENCES and RELATED ARTICLES from the BIONEWS ARCHIVE or to leave a comment about this article.

21 June 2021 - by Dr Helen Robertson
Female infertility gets a great deal of airtime. From posters on the tube, to dramatic headlines with declarations of 'fertility falling off a cliff at 35 years of age', it's very clear that most of the public awareness around infertility focuses on women.

But this is only telling half the story. A historic lack of investment in targeted treatments means that male infertility hasn't received the attention necessary to raise awareness, open up the conversation, or provide therapeutic options that focus on the cause. More recent media have aimed to break the stigma associated with male infertility: a documentary hosted by comedian Rhod Gilbert (see BioNews 1083) and interviews with Love Island star Chris Hughes (see BioNews 1072) have begun to shed light on a previously neglected topic, but the lack of therapeutic options remains a challenge for individuals and couples facing fertility issues.

With this in mind, last week's online event 'What's in the Pipeline for Male Infertility' provided some much-needed insight into ongoing research into the causes and possible treatments for male fertility issues. The event was produced by the Progress Educational Trust (PET), the charity that publishes BioNews, and was supported by the Scottish Government. It was chaired by PET's director Sarah Norcross and featured speakers from the UK and USA, each working on different aspects of the male infertility story.

Norcross opened the event by providing some context on what current treatment looks like for male infertility. I was surprised to learn that the only regularly offered treatment option for male infertility is ICSI (intracytoplasmic sperm injection), which involves injecting sperm directly into an egg prior to normal IVF embryo transfer. However, ICSI is not a guaranteed route to pregnancy despite being offered as a 'catch-all' for many underlying causes of male infertility. So, what can we do to investigate and treat instances of male infertility, without requiring women to undergo a very invasive treatment that might not result in a successful pregnancy?

First to speak was Dr Sarah Martins Da Silva, senior lecturer in systems medicine at the University of Dundee. Dr Martins Da Silva, who was recently interviewed by Norcross for BioNews (see BioNews 1098), began her talk by explaining the underlying causes of male infertility, and how current therapeutic options (namely ICSI) fall short of providing a reliable solution. She then moved on to discuss the work she is currently involved with, investigating the importance of a protein called phospholipase C zeta (PLC zeta) in egg activation. Work by Dr Martins Da Silva and her team has found that sperm that are deficient in PLC zeta are linked to some instances of male infertility, likely due to a failure of egg activation at the point of fertilisation. By tackling this underlying issue, Dr Martins Da Silva has found that combining ICSI with an assisted egg activation technique – in instances where sperm is found to be low in PLC zeta – can result in improved fertilisation and successful pregnancy outcomes compared to ICSI alone. Focusing on PLC zeta might not be a universal solution, but the work presented by Dr Martins Da Silva shows it has a role as a therapeutic target when investigating male infertility in the future.

Next was Jamie Chorlton, head of clinical development for St George Street Capital, a charity that accelerates clinical trials for drugs with the potential to help patients with unmet needs. One of their current focuses is idiopathic male infertility (IMI) - cases of infertility in men which result from an unexplained reduction in sperm quality. As Chorlton explained, 80 percent of IMI cases have indicators of oxidative stress in semen. By reducing the activity of a pro-oxidant enzyme called myeloperoxidase (MPO), the levels of reactive oxygen species in sperm decreases, which in turn increases sperm quality and can lead to improved fertility. It is hoped that upcoming trials arranged over a three-year period by St George Street Capital will show if taking an MPO inhibitor can improve sperm quality and fertility. If successful, this preliminary work will see the drug licensed back to the original developer for further trials, with the potential for clinical application in instances of male infertility in the future.

The final two talks covered two areas of male infertility that have historically not been a priority: diagnosing male fertility from sperm samples, and pre-emptively treating male infertility as a result of cancer treatment in young men. Dr Tiffany Wood, founder and CEO of Dyneval, spoke about a tool she has developed based on complex fluid properties and how this can aid in sperm diagnosis. Methods for assessing semen have not improved for many years and rely on a slow, manual process. Previous forays into computer-aided semen analysis have been quite hit-or-miss, given their reliance on high concentrations of semen samples. As Dr Wood explained, Dyneval technology has already been successfully applied in agriculture settings and animal reproduction. By working with human fertility scientists (including Dr Martins Da Silva), it is hoped that Dyneval might also be used to assess sperm quality and health in a clinical setting too.

Lastly, Professor Robert Brannigan, from the Department of Urology at Northwestern University, Feinberg School of Medicine, Illinois, spoke about the importance of developing and applying methods that might aid male fertility after cancer treatment. This was something that I had previously read about for young female cancer patients, but it was the first time I had heard about such measures being used to preserve fertility in men. Professor Brannigan explained that although the cryopreservation of sperm is an existing approach, cryopreserving testicular tissue prior to cancer treatment is an emerging technology with the potential to aid fertility in pre-pubescent patients.

Overall, it was interesting to see infertility being explored from a new perspective, and encouraging that many different approaches are being taken to understand the problem in a clinical setting.

Norcross then invited the audience to ask the put questions to the panellists. Many questions came from people looking for treatment options for male infertility, which emphasised how important the work being undertaken in this area is, and how it can impact upon lives on a personal level. As research progresses and the conversation about male infertility opens up, there are exciting prospects for improved treatments and earlier intervention.

21 June 2021 - by Dr Helen Robertson
Female infertility gets a great deal of airtime. From posters on the tube, to dramatic headlines with declarations of 'fertility falling off a cliff at 35 years of age', it's very clear that most of the public awareness around infertility focuses on women.

But this is only telling half the story. A historic lack of investment in targeted treatments means that male infertility hasn't received the attention necessary to raise awareness, open up the conversation, or provide therapeutic options that focus on the cause. More recent media have aimed to break the stigma associated with male infertility: a documentary hosted by comedian Rhod Gilbert (see BioNews 1083) and interviews with Love Island star Chris Hughes (see BioNews 1072) have begun to shed light on a previously neglected topic, but the lack of therapeutic options remains a challenge for individuals and couples facing fertility issues.

With this in mind, last week's online event 'What's in the Pipeline for Male Infertility' provided some much-needed insight into ongoing research into the causes and possible treatments for male fertility issues. The event was produced by the Progress Educational Trust (PET), the charity that publishes BioNews, and was supported by the Scottish Government. It was chaired by PET's director Sarah Norcross and featured speakers from the UK and USA, each working on different aspects of the male infertility story.

Norcross opened the event by providing some context on what current treatment looks like for male infertility. I was surprised to learn that the only regularly offered treatment option for male infertility is ICSI (intracytoplasmic sperm injection), which involves injecting sperm directly into an egg prior to normal IVF embryo transfer. However, ICSI is not a guaranteed route to pregnancy despite being offered as a 'catch-all' for many underlying causes of male infertility. So, what can we do to investigate and treat instances of male infertility, without requiring women to undergo a very invasive treatment that might not result in a successful pregnancy?

First to speak was Dr Sarah Martins Da Silva, senior lecturer in systems medicine at the University of Dundee. Dr Martins Da Silva, who was recently interviewed by Norcross for BioNews (see BioNews 1098), began her talk by explaining the underlying causes of male infertility, and how current therapeutic options (namely ICSI) fall short of providing a reliable solution. She then moved on to discuss the work she is currently involved with, investigating the importance of a protein called phospholipase C zeta (PLC zeta) in egg activation. Work by Dr Martins Da Silva and her team has found that sperm that are deficient in PLC zeta are linked to some instances of male infertility, likely due to a failure of egg activation at the point of fertilisation. By tackling this underlying issue, Dr Martins Da Silva has found that combining ICSI with an assisted egg activation technique – in instances where sperm is found to be low in PLC zeta – can result in improved fertilisation and successful pregnancy outcomes compared to ICSI alone. Focusing on PLC zeta might not be a universal solution, but the work presented by Dr Martins Da Silva shows it has a role as a therapeutic target when investigating male infertility in the future.

Next was Jamie Chorlton, head of clinical development for St George Street Capital, a charity that accelerates clinical trials for drugs with the potential to help patients with unmet needs. One of their current focuses is idiopathic male infertility (IMI) - cases of infertility in men which result from an unexplained reduction in sperm quality. As Chorlton explained, 80 percent of IMI cases have indicators of oxidative stress in semen. By reducing the activity of a pro-oxidant enzyme called myeloperoxidase (MPO), the levels of reactive oxygen species in sperm decreases, which in turn increases sperm quality and can lead to improved fertility. It is hoped that upcoming trials arranged over a three-year period by St George Street Capital will show if taking an MPO inhibitor can improve sperm quality and fertility. If successful, this preliminary work will see the drug licensed back to the original developer for further trials, with the potential for clinical application in instances of male infertility in the future.

The final two talks covered two areas of male infertility that have historically not been a priority: diagnosing male fertility from sperm samples, and pre-emptively treating male infertility as a result of cancer treatment in young men. Dr Tiffany Wood, founder and CEO of Dyneval, spoke about a tool she has developed based on complex fluid properties and how this can aid in sperm diagnosis. Methods for assessing semen have not improved for many years and rely on a slow, manual process. Previous forays into computer-aided semen analysis have been quite hit-or-miss, given their reliance on high concentrations of semen samples. As Dr Wood explained, Dyneval technology has already been successfully applied in agriculture settings and animal reproduction. By working with human fertility scientists (including Dr Martins Da Silva), it is hoped that Dyneval might also be used to assess sperm quality and health in a clinical setting too.

Lastly, Professor Robert Brannigan, from the Department of Urology at Northwestern University, Feinberg School of Medicine, Illinois, spoke about the importance of developing and applying methods that might aid male fertility after cancer treatment. This was something that I had previously read about for young female cancer patients, but it was the first time I had heard about such measures being used to preserve fertility in men. Professor Brannigan explained that although the cryopreservation of sperm is an existing approach, cryopreserving testicular tissue prior to cancer treatment is an emerging technology with the potential to aid fertility in pre-pubescent patients.

Overall, it was interesting to see infertility being explored from a new perspective, and encouraging that many different approaches are being taken to understand the problem in a clinical setting.

Norcross then invited the audience to ask the put questions to the panellists. Many questions came from people looking for treatment options for male infertility, which emphasised how important the work being undertaken in this area is, and how it can impact upon lives on a personal level. As research progresses and the conversation about male infertility opens up, there are exciting prospects for improved treatments and earlier intervention.

14 June 2021 - by Dr Kamal Ahuja and Professor Nick Macklon
Among the highlights of the Human Fertilisation and Embryology Authority's (HFEA) latest report on trends in fertility treatment is a continuing upturn in the number of egg donation cycles performed in the UK. In the past 20 years the use of donor eggs with donor sperm has increased 50-fold –  from 27 cycles in 1991 to 1375 cycles in 2019 – while donor eggs with partner sperm increased 22-fold – to 3058 cycles in 2019. Altogether, in 2019, 4433 egg donation cycles were completed in the UK.

The HFEA attributes this increase to the wider use of egg donation in women of an older maternal age, noting a live birth rate of over 30 percent in all patients irrespective of age. Only 17 percent of patients aged 40 and over used donor eggs in 2019, but their use did nevertheless increase with age: eight percent among those aged 40-42, 21 percent for ages 43- 44 and 57 percent for ages 45-50. This trend is one we already see in the USA as reported by the United States Centres for Disease Control and Prevention, where over 12 percent (25,321 out of 196,454 cycles) of all treatment cycles are egg donation, usually in older patients.

The period covered by the report would also have found many UK women having egg donation in overseas clinics, in a pattern of cross-border care already analysed in studies from the European Society of Human Reproduction and Embryology. In addition, we had evidence as published in the journal Human Reproduction that during this period donor eggs and sperm were being sent across borders and between countries, as well as patients travelling to different countries for fertility treatment. However, in 2020 with the outbreak of the COVID-19 pandemic in March, many of these overseas clinics – in Spain, Ukraine, USA and Cyprus – would have been out of bounds to most egg donation patients from the UK, and still off limits in 2021. Based on these restrictions and observations of our own practice at the London Egg Bank, we think it can be stated with some confidence that the UK's primary source of donor eggs is no longer overseas clinics. Egg donation has come home.

Even factoring in the restrictions of the pandemic, this represents a seismic shift and one we forecasted in 2020 in the journal Reproductive Biomedicine Online. We wrote that using frozen eggs 'will quickly become the default standard practice in egg donation' in contrast to the previous use of 'fresh eggs' taken from women participating in IVF egg collections as egg sharers or donors related to patients. We further added that there will be no need for overseas travel, no need to wait for a suitable donor to become available at overseas clinics or for synchronised cycles. A greater choice of donors, and a more efficient programme at a lower cost will be available within the UK. The basis of this forecast was the development of vitrification technology and the ability it has conferred to frozen eggs to retain the same viability as fresh once warmed.

Our more recent publication in the journal Reproductive Biomedicine Online of an analysis of almost 500 egg freezing cycles and subsequent transfers in 705 recipients in a group of patients at the London Egg Bank demonstrates the extent to which vitrification is revolutionising egg donation in the UK and how domestic sourcing of donor eggs can now meet the demands and expectations of recipient patients.

The large group of altruistic donors in this study represents wholly UK sourced donor eggs recruited between January 2017 and December 2019 in a programme introduced to prospective donors and recipients via seminars, the London Egg Bank website and social media. The overall live birth rate per transfer among the 559 recipients matched to donors was 37.9 percent, which varied according to identified predictive factors in the donors (age and ovarian reserve). Estimates of cumulative live birth rates after three embryo transfers exceeded 60 percent. However, recipient age was not a significant predictor of outcome. Singletons were born in 95.5 percent of gestations.

This study not only demonstrates the excellent viability of frozen donor eggs in this series, but also reaffirms the potential to provide enough donor eggs to meet demand in the UK derived only from domestic altruistic donors and recipients turning to a local clinic for treatment. Concurring with the trend for older women to use donor eggs seen in the HFEA report, recipients in this study had a median age of 44 years, with age and low ovarian reserve the most common reasons for seeking treatment. Two-thirds of them had frozen embryos left in storage after treatment.

These results compare well with other studies, although one study from Spain in a large group of egg donation patients sought to compare outcomes from frozen and fresh donor eggs, while another from the USA involved predominantly the transfer of multiple embryos. Our study, over a period of three years, involved a consecutive group of treatments that involved only frozen-thawed eggs, and with a single embryo transfer rate of 87 percent.

While some predictive factors (mainly relating to the donor) do have an influence on outcome, the results of this study should be reassuring to patients that a UK-based domestic egg donation programme can achieve excellent results comparable with those of other cryobanks across the world. The restrictions of the COVID-19 pandemic may well have frustrated most cross-border initiatives in the past year or so, but frozen egg banking can flourish here in the UK, and is now in a prime position to meet the patient demands implicit in the HFEA's latest review.

14 June 2021 - by Dr Kamal Ahuja and Professor Nick Macklon
Among the highlights of the Human Fertilisation and Embryology Authority's (HFEA) latest report on trends in fertility treatment is a continuing upturn in the number of egg donation cycles performed in the UK. In the past 20 years the use of donor eggs with donor sperm has increased 50-fold –  from 27 cycles in 1991 to 1375 cycles in 2019 – while donor eggs with partner sperm increased 22-fold – to 3058 cycles in 2019. Altogether, in 2019, 4433 egg donation cycles were completed in the UK.

The HFEA attributes this increase to the wider use of egg donation in women of an older maternal age, noting a live birth rate of over 30 percent in all patients irrespective of age. Only 17 percent of patients aged 40 and over used donor eggs in 2019, but their use did nevertheless increase with age: eight percent among those aged 40-42, 21 percent for ages 43- 44 and 57 percent for ages 45-50. This trend is one we already see in the USA as reported by the United States Centres for Disease Control and Prevention, where over 12 percent (25,321 out of 196,454 cycles) of all treatment cycles are egg donation, usually in older patients.

The period covered by the report would also have found many UK women having egg donation in overseas clinics, in a pattern of cross-border care already analysed in studies from the European Society of Human Reproduction and Embryology. In addition, we had evidence as published in the journal Human Reproduction that during this period donor eggs and sperm were being sent across borders and between countries, as well as patients travelling to different countries for fertility treatment. However, in 2020 with the outbreak of the COVID-19 pandemic in March, many of these overseas clinics – in Spain, Ukraine, USA and Cyprus – would have been out of bounds to most egg donation patients from the UK, and still off limits in 2021. Based on these restrictions and observations of our own practice at the London Egg Bank, we think it can be stated with some confidence that the UK's primary source of donor eggs is no longer overseas clinics. Egg donation has come home.

Even factoring in the restrictions of the pandemic, this represents a seismic shift and one we forecasted in 2020 in the journal Reproductive Biomedicine Online. We wrote that using frozen eggs 'will quickly become the default standard practice in egg donation' in contrast to the previous use of 'fresh eggs' taken from women participating in IVF egg collections as egg sharers or donors related to patients. We further added that there will be no need for overseas travel, no need to wait for a suitable donor to become available at overseas clinics or for synchronised cycles. A greater choice of donors, and a more efficient programme at a lower cost will be available within the UK. The basis of this forecast was the development of vitrification technology and the ability it has conferred to frozen eggs to retain the same viability as fresh once warmed.

Our more recent publication in the journal Reproductive Biomedicine Online of an analysis of almost 500 egg freezing cycles and subsequent transfers in 705 recipients in a group of patients at the London Egg Bank demonstrates the extent to which vitrification is revolutionising egg donation in the UK and how domestic sourcing of donor eggs can now meet the demands and expectations of recipient patients.

The large group of altruistic donors in this study represents wholly UK sourced donor eggs recruited between January 2017 and December 2019 in a programme introduced to prospective donors and recipients via seminars, the London Egg Bank website and social media. The overall live birth rate per transfer among the 559 recipients matched to donors was 37.9 percent, which varied according to identified predictive factors in the donors (age and ovarian reserve). Estimates of cumulative live birth rates after three embryo transfers exceeded 60 percent. However, recipient age was not a significant predictor of outcome. Singletons were born in 95.5 percent of gestations.

This study not only demonstrates the excellent viability of frozen donor eggs in this series, but also reaffirms the potential to provide enough donor eggs to meet demand in the UK derived only from domestic altruistic donors and recipients turning to a local clinic for treatment. Concurring with the trend for older women to use donor eggs seen in the HFEA report, recipients in this study had a median age of 44 years, with age and low ovarian reserve the most common reasons for seeking treatment. Two-thirds of them had frozen embryos left in storage after treatment.

These results compare well with other studies, although one study from Spain in a large group of egg donation patients sought to compare outcomes from frozen and fresh donor eggs, while another from the USA involved predominantly the transfer of multiple embryos. Our study, over a period of three years, involved a consecutive group of treatments that involved only frozen-thawed eggs, and with a single embryo transfer rate of 87 percent.

While some predictive factors (mainly relating to the donor) do have an influence on outcome, the results of this study should be reassuring to patients that a UK-based domestic egg donation programme can achieve excellent results comparable with those of other cryobanks across the world. The restrictions of the COVID-19 pandemic may well have frustrated most cross-border initiatives in the past year or so, but frozen egg banking can flourish here in the UK, and is now in a prime position to meet the patient demands implicit in the HFEA's latest review.

24 May 2021 - by Dr Emma Green
A new model able to predict cognitive decline in Alzheimer's disease could help to develop personalised treatments.

With an aim to identify therapeutic targets, researchers at McGill University, Canada, combined results from brain scans with gene activity data. This allowed them to explore the relationship between changes in gene expression and physical changes in the brain across normal brain ageing and cognitive decline associated with Alzheimer's disease.

'We wanted to combine whole-brain gene activity measurements with clinical scan data in a comprehensive and personalised model, which we then validated in healthy ageing and Alzheimer's disease' said lead author Quadri Adewale.

The study included brain scans from 460 people across a minimum of three time points with participants classed as a healthy control with no symptoms, with early mild cognitive impairment, late mild cognitive impairment, or probable Alzheimer's disease. These scans were then combined with gene expression data from over 3700 tissue samples through the Allen Human Brain Atlas data portal. From this data, the team was able to create a model that was able to predict the extent of cognitive decline from changes observed in the brain scans.

From these results, the team also identified eight genes that corresponded with cognitive changes in healthy controls, and 111 genes linked to cognitive changes in Alzheimer's disease. Sixty-five different biological pathways controlled by these genes were identified, and most were related to neurological and cognitive decline.

However, newly identified genes could assist in the development of new therapeutic targets to prevent Alzheimer's disease progression.

Senior author Dr Yasser Iturria-Medina, assistant professor in the department of neurology and neurosurgery, said 'Our study provides unprecedented insight into the multiscale interactions among ageing and Alzheimer's disease-associated biological factors and the possible mechanistic roles of the identified genes. This personalised model offers novel insights into the multiscale alterations in the elderly brain, with important implications for identifying targets for future treatments for Alzheimer's disease progression'.

The team will focus their future work on using personalised gene expression data from blood samples which could strengthen their model. They also plan to test this formula on other neurodegenerative disorders including Parkinson's disease and frontotemporal dementia.

This research was published in the journal eLife.

The HFEA legislations - recommendations was originally created in 1990 and has been revued on a regular basis to date.                       
However the question that was evident:
Is it fit for purpose in todays changing family structures ??

At Mensfe we found the (attached) overview of the seminar (organised by PETS) on this questions and related issues informative.

Professor Jackson discussed how one of the main challenges faced by the Warnock committee was coming up with realistic proposals when faced with morally challenging questions. The report identified the need for lay representation in regulation, the need for tough sanctions, and highlighted the benefits of using a code of practice within regulation that would allow flexibility and updates in regulation. Most challenging was the importance of drawing some lines and moral boundaries that could not and should not be crossed. The regulatory model created from the recommendations of the report has been very resilient and has worked for other non-departmental government bodies such as the Human Tissue Authority.

Professor Jackson noted that the Warnock Report was relatively progressive compared to the political background of the time where 'Victorian values' were being promoted. The Report does not suggest any statutory restrictions on treatments for single-sex households or homosexual couples, but instead suggests flexible and respectful legislation. The legacy of Baroness Warnock, concluded Professor Jackson, was in her placing value on expertise and demonstrating the benefits of a deliberative approach to law reform.

The next speaker was Professor Sarah Franklin, director of the University of Cambridge's Reproductive Sociology Research Group. Professor Franklin began by emphasising how the birth of Louise Brown was the 'birth of a "legal vacuum"' in which there was no legal precedent for the regulation of IVF, hence the importance of the Warnock Report.

Professor Franklin's talk focused on the 14-day rule suggested by the report, in which embryos can only be kept alive in laboratory conditions for up to 14 days. Professor Franklin argued that not only was this decision a scientific contract, but also a social one, drawing a clear line that would demonstrate that although 'controversial' research would be allowed to proceed, a strict limit would be enforced. The difficulty in drawing this line was that it would never be right for everyone, but even though the HFE Act has been amended the 14-day rule has – so far – endured. Moreover, it has been taken up as a 'default global standard' and has been used as a 'textbook case for developing successful regulatory policy', a testament to the Warnock Report.

The next speaker was Peter Thompson, chief executive of the HFEA, speaking of the impact of the Warnock Report on the HFEA. He explained that the HFEA's powers and work are a product of the Warnock Report, and of the consensus Baroness Warnock managed to forge. He praised the report's approach to scientific, regulatory, and social issues, while noting that its framework enables certain regulatory lines to be revisited, to take into account more recent developments.

Thompson spoke of how the regulatory regime initiated by the Warnock Report has stood the test of time remarkably well, and said that much of it continues to fulfil its purpose. Nonetheless, he added, it would be surprising if an exercise from the 1980s was not showing its age in 2021.

Finally, Professor Alison Murdoch, professor of reproductive medicine at Newcastle University, spoke from a clinical point of view of the impact of the Warnock Report. She said that Baroness Warnock and her colleagues took on a daunting task, and that their report was pragmatic and wise, having benefited patients, practitioners and researchers alike.

Professor Murdoch noted that at the moment, particularly in England, the provision of IVF is dominated by the private sector, and that many couples are childless because of their inability to access healthcare. To resolve this, she suggested that IVF should be considered more of a core service of the National Health Service (NHS).

Professor Murdoch argued that it was time for a thoroughgoing review of the HFE Act, because it needs more incremental adjustments, and there are problems that need 'putting right'. She acknowledged that challenging discussions would need to take place for any changes to be made, and acknowledged some apprehension about reopening the HFE Act in Parliament, but said there had been a shift in the public perception of assisted reproductive technologies and this needed to be taken into account.

Sarah Norcross then invited the audience to ask the panellists questions. Questions focused on changes in the fertility sector, and whether the HFEA's remit needs to be amended.Norcross posted a virtual poll, asking whether attendees thought there should be a new inquiry into the regulation of assisted reproduction and embryo research in the UK, similar to the Warnock committee. 81 percent of attendees stated that they thought there should be a new enquiry, and Norcross asked the panellists whether they agreed.

Thompson pointed out that if people wanted speedy change, that an expert committee was not the way to do this. The Warnock Report took two years to complete, and several more years before its recommendations were translated into legislation.

Baroness Ruth Deech, a former chair of the HFEA and a member of the House of Lords, was in attendance and said 'Parliament would be very reluctant to find time for another HFE Act after a Commission'. She argued that it was 'far better to keep extending whatever discretion there is in the Act and use regulations'. There would be significant challenges in establishing a new inquiry.

Ectogenesis:
12 April 2021 - by Professor John D Loike
Three new reports in Nature illuminate the potential to transform artificial wombs from a laboratory tool into a procedure to grow and maintain a human embryo from fertilisation until birth.

Two papers reported the generation of human blastocysts by culturing non-embryonic cells under specific conditions to transform them into blastocyst-like structures, called blastoids. In one study scientists treated stem cells derived from an established stem cell line with specific growth factors to generate the blastoids. In the second study, scientists used adult skin cells to reprogram them into blastoids. 

In the same issue, Nature reported that scientists have developed an artificial womb that allows the development of early mouse embryos into a fetus that contained fully formed organs. In this study, scientists at Weizmann Institute of Science implanted mouse blastocysts into their artificial placenta that contained special media and gases to study organ development, unconstrained by the need to image these structures inside a uterus. These mouse embryos were healthy until day 11 before dying, maintaining viable gestation for about halfway through the animals' normal 20-day gestation. I believe, it's only a matter of time when this technology will be further developed to generate healthy newborn pups.

Society needs to consider the potential health benefits emerging from these studies to decide whether the benefits trump ethical principles and guidelines. We need to consider the definition of humanhood, and the idea of generating a human being in the absence of a woman's body.

Generating and developing a human from fertilisation to 'birth' (especially in the absence of the sperm and egg) challenges our definition of what it means to be a human being. We believe a human being gestated in an artificial womb is still human and deserves human dignity. Humanhood, should not be restricted only to an organism born from a human but should include the generation of an organism that looks human and is composed of the essential genetic code of homo sapiens.

However, the cultural ethical challenges arising from this technology can be daunting. How will people feel if women don't need to become pregnant in order to produce children?  Many women feel biologically and psychologically connected to the fetus they are gestating. Moreover, the absence of human pregnancy may impact epigenetic processes and change the mother-child bonding. One could argue, however, that pregnancy may not be a critical process for human development and bonding, since normal human development occurs post-gestationally, in many families that have adopted children. In addition, the burden of medical responsibility for maintaining these embryos in an artificial placenta would fall on our overloaded hospital system. Should health insurance fund this technology?

In addition, it is important that regulators, politicians, physicians, scientists, religious scholars, and concerned citizens reflect on the nature of the internationally accepted '14-day rule,' which limits the growth of artificially generated human embryos for more than 14 days, when normally the primitive streak appears in the embryo, which is a band of cells that forms and is regarded as a precursor of the neural tube and nervous system. Both Nature reports were mindful of this 14-day rule and did not maintain these artificially generated embryos past 14 days.

The use of stem cell lines or adult cells, rather than sperm and eggs, avoids one important ethical issue associated with early human embryological research – the destruction of a traditional human embryo. Normally, premature embryos that gestate in utero less than 25 weeks face serious, if not fatal, consequences. The Nature ectogenesis article coupled with a previous report on how to better maintain premature sheep fetuses in an artificial womb may help us learn how to maintain the health and development of premature human fetuses. However, a profound ethical issue arises if scientists combine the two technologies (ie, generating human blastocyts from skin cells or stem cell lines and the artificial placenta). Attempting to gestate an embryo in vitro, from start to finish, sets the stage for a revolution in human gestation. 

Because of the complex nature of ethical ectogenesis, it would be appropriate for the US National Academy of Science to organise a committee to examine these ethical issues, decide whether there should be limits on scientific ectogenesis research, and propose policies to guide decision-making. Perhaps, at this time research should focus only on the use of ectogenesis in treating premature fetuses and restrict the development of creating a completely viable artificial placenta. In an era of rapidly advancing science, our experts at the National Academy of Science should be proactive in providing research guidelines regarding ectogenesis.