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Controversial New Guidelines Would Allow Experiments On More Mature Human Embryos

New guidance would ease restrictions on researching embryos in the lab. BSIP/Science Source hide caption

New guidance would ease restrictions on researching embryos in the lab.

For decades, scientists have been prohibited from keeping human embryos alive in their labs for more than 14 days. The prohibition was aimed at avoiding a thicket of ethical issues that would be raised by doing experiments on living human embryos as they continue to develop.

But on Wednesday, an influential scientific society recommended scrapping that blanket taboo, known as the "14-day rule." The International Society for Stem Cell Research released new guideline s that say it could be permissible to study living human embryos in the lab for longer than two weeks.

This guidance will now be considered by regulatory bodies in each country that conducts this type of research to decide what research will be permitted and how. Currently in the U.S., regulatory bodies at universities and other research institutions universally adhere to the 14-day rule. If the new guidance is adopted, it would be a major change.

"When you ask, 'Is this ethically bad?' Well, you also have to put the opposite: Are there ethical issues for not doing research in that period?" says Robin Lovell-Badge of the Crick Institute , who chaired the task force that wrote the guidelines. "In many ways, you could argue it would be unethical not to do it."

Studying embryos as they develop beyond 14 days could help scientists solve many medical problems, including infertility, miscarriages and birth defects, Lovell-Badge and others argue.

"There's very good reasons for doing this research. And people shouldn't be scared about it if there are robust mechanisms of review and oversight," Lovell-Badge says.

While many scientists and bioethicists are welcoming the new guidelines, others criticize them as being far too permissive.

"I think it's deeply troubling," says Dr. Daniel Sulmasy , a bioethicist at Georgetown University. "Now, any sign of respect for the human embryo is gone."

Others are especially concerned that the new guidelines include no clear stopping point for how long a developing embryo could be studied in a lab dish.

"If you don't have any endpoint, could you take embryos to 20 weeks? To 24 weeks? Is viability the only endpoint," asks Hank Greely, a Stanford University bioethicist who otherwise praises the new guidelines. "Is viability even an endpoint?"

Lovell-Badge defends the recommendations.

"I felt that it would be both difficult and a little pointless to propose any new limit, which would be arbitrary, much like 14 days," Lovell-Badge says.

The original cutoff was set at 14 days for a variety of reasons. For example, 14 days is around the time when an embryo starts to develop the first signs of a central nervous system. It's also when an embryo can no longer split into twins. At the time, scientists were far from being able to sustain living embryos in the lab anywhere close to 14 days.

But in recent years scientists have gradually extended how long they can sustain human embryos in lab dishes, increasing pressure from some researchers and bioethicists to revise the rule.

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Scientists create living entities in the lab that closely resemble human embryos.

At the same time, scientists developed the ability to create "embryoids," which are living entities made from human stem cells that have become increasingly complex and similar to human embryos. That added pressure to extend the rule so scientists could compare these new entities with naturally conceived embryos.

"That period of development between, say, 14 days, which is the current limit, and let's say 28 days, a huge amount is happening. It's a very critical period," Lovell-Badge says.

The guidelines stress such experiments should only be allowed after each country has a robust public debate and the public at large agrees that such research is acceptable. In addition, any experiments must be carefully monitored to make sure the research is absolutely necessary to learn something important, according to the guidelines.

"We're not saying it should now happen. We're saying it's possible for it to happen," Lovell-Badge says.

The guidelines could be especially influential in countries that do not have laws or regulations governing this kind of research.

In the U.S., the federal government is prohibited from funding for research involving human embryos. But that kind of research can be done with private money. And the National Institutes of Health has been waiting for the new guidelines to help decide whether to lift a moratorium on funding research involving chimera embryos.

"We are looking forward to reading the ISSCR guidelines," the NIH said in a statement to NPR. "ISSCR has long been a thoughtful voice for the international stem cell research community, and we will certainly think carefully about their report."

Martin Pera, a stem cell researcher at the Jackson Laboratory who was not involving in writing the guidelines, called them "responsible and well-considered" in an email to NPR. "Adoption of these guidelines by regulatory bodies will ensure that research that has wide-ranging potential to improve human health can proceed with appropriate ethical oversight."

The change in the 14-day rule is just one of a long list of sensitive lines of scientific research the new guidelines address, ranging from human cloning to gene-editing human embryos. Some research, such as human cloning and creating babies from gene-edited embryos, remains off-limits. But the guidelines generally take a more permissive stance, including opening the door to creating gene-edited babies someday if it would be safe and solve an important medical problem.

Scientists Create Early Embryos That Are Part Human, Part Monkey

The guidelines also detail rules that would allow researchers to create chimera embryos for research. These are embryos that are part human, part animal. They're made by injecting human stem cells into animal embryos. Scientists recently announced they had done this with monkey embryos .

The goal is to learn more about basic embryonic development and perhaps someday use these embryos to breed animals such as pigs and cows with human hearts, livers and kidneys for organ transplants. Those entities raise many difficult ethical questions. One concern is that the cells could end up in other parts of the animals' bodies, such as their brains.

"Surely there are some human-animal chimera experiments that are entirely permissible and good. But there are some that would be monstrous," wrote J. Benjamin Hurlbut, a Arizona State University bioethicist, in an email to NPR.

"Do we really need to hark back to Mary Shelley to remind ourselves that the production of monstrosity may well grow out of a misguided sense of the good — combined with the thrill of the power of control over life? What is at stake here if not that?" Hurlbut wrote.

To assuage such concerns, the guidelines recommend a variety of restrictions and steps that should be taken to prevent that from occurring.

"There is a way to genetically engineer both the embryo and the stem cells so that the stem cells will only make a particular organ," says Insoo Hyun, a bioethicist at Harvard and Case Western Reserve universities, who helped write the guidelines. "Nobody wants a chimeric embryo to grow into a part-human, part-animal thing that has human cells from head to toe mixed in."

But the guidelines could conceivably allow a human-monkey embryo to develop inside a monkey's womb. And so those requirements did little to satisfy critics.

"I think we have just not thought through the moral status of these novel beings," says Françoise Baylis, a bioethicist at Dalhousie University in Canada.

"I think a number of people would be, you know, rightfully concerned that, that there are very little constraints on what's happening with the human embryo."

Hurlbut, who called the new guidelines "breathtakingly expansive," agrees.

"What was ethically unthinkable just a few years ago is getting treated as not only permissible but even unproblematic now," Hurlbut says.

"Under these guidelines an oversight committee can deliberate behind closed doors and quietly give its blessing to scientists to impregnate a monkey with a partly human embryo, or to see how far into human development scientists can grow artificially constructed synthetic human embryos in bottles."

Others, however, praise the new guidelines.

"As this is a time of rapid advances in stem cell-based research, it is critical to have a set of guidelines that all researchers can refer to, regardless of the stage of their research," says Juan Carlos Izpisua Belmonte , a researcher at the Salk Institute, who created the part-human, part-monkey embryos.

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Scientists Debut Lab Models of Human Embryos

Four teams have coaxed human stem cells to organize themselves into embryo-like forms. The advance could shed light on fertility.

By Carl Zimmer

In its first week, a fertilized human egg develops into a hollow ball of 200 cells and then implants itself on the wall of the uterus. Over the next three weeks, it divides into the distinct tissues of a human body.

And those crucial few weeks remain, for the most part, a black box.

“We know the basics, but the very fine details we just don’t know,” said Jacob Hanna, a developmental biologist at the Weizmann Institute of Science in Israel.

Dr. Hanna and a number of other biologists are trying to uncover those details by creating models of human embryos in the lab. They are coaxing stem cells to organize themselves into clumps that take on some of the crucial hallmarks of real embryos.

This month, Dr. Hanna’s team in Israel , as well as groups in Britain , the United States and China , released reports on these experiments. The studies, while not yet published in scientific journals, have attracted keen interest from other scientists, who have been hoping for years that such advances could finally shed light on some of the mysteries of early human development.

Ethicists have long cautioned that the advent of embryo models would further complicate the already complicated regulation of this research. But the scientists behind the new work were quick to stress that they had not created real embryos and that their clusters of stem cells could never give rise to a human being.

“Our aims are never for the purpose of human reproduction,” said Tianqing Li, a developmental biologist at Kunming University of Science and Technology in China, who led one of the new studies.

Instead, Dr. Li and his fellow scientists hope that embryo models will lead to new treatments for infertility and even diseases such as cancer.

“We do it to save lives, not create it,” said Magdalena Zernicka-Goetz, a developmental biologist at the University of Cambridge and the California Institute of Technology, who led another effort.

For decades, the only human embryos that developmental biologists could study were specimens collected from miscarriages or abortions. As a result, scientists were left with profound questions about the start of human development. Thirty percent of pregnancies fail in the first week, and another 30 percent fail during implantation. Researchers have been at a loss to explain why a majority of embryos don’t survive.

After the development of in vitro fertilization in the 1970s, scientists began studying embryos donated from fertility clinics. Some countries banned the research, while others allowed it to proceed, typically with a 14-day limit . By then, the human embryo starts taking on some of its key features. A structure called the primitive streak , for example, organizes the head-to-foot arrangement that the body will take.

For years, the 14-day rule was a moot point because no one could keep embryos alive more than a few days after fertilization. Things became more complicated in 2016, when Dr. Zernicka-Goetz’s group and another team managed to keep embryos alive close to the 14-day mark . The embryos did not survive longer because the scientists destroyed them.

The accomplishment has led scientists to debate the possibility of allowing embryos to grow past 14 days. But even if those experiments were to become legal, they would still be hard to carry out because the supply of donated embryos is scarce.

In recent years, researchers have been looking for an easier way to study embryos: by making models of them in the lab. The scientists have taken advantage of the fact that stem cells, given the right environmental conditions, can turn into new kinds of tissues.

Adults have stem cells in only a few parts of the body. In the skin , for example, stem cells produce a range of new cells that heal wounds. In early embryos, on the other hand, all the cells have the potential to turn into a wide variety of tissues.

Last year, Dr. Zernicka-Goetz’s team and Dr. Hanna’s team used embryonic stem cells from mice to make models of embryos. Since then, they and other scientists have been trying to do the same with human embryonic stem cells.

Each team has used a different method, but they all take advantage of the same underlying biology. By the time a human embryo implants itself in the uterus, its cells have started to diverge into different types. One type of cell will go on to produce the cells of the body. The other types will produce tissues that surround the embryo during development, such as the placenta. These cell types send out molecular signals to each other that are essential for their development.

The researchers coaxed stem cells to mimic some of these cell types and then mixed them together. The cells swarmed together and spontaneously organized into clusters. The cells destined to become the embryo huddled in the middle, while the other types migrated to the outside.

As the cells communicated to each other, they divided and formed new structures that resembled parts of embryos. Dr. Mo Ebrahimkhani, a developmental biologist at the University of Pittsburgh, and his colleagues observed the formation of a yolk sac in their experiment, for example. Out of the yolk sac, they even observed the development of progenitors of blood cells.

Dr. Zernicka-Goetz and her colleagues likewise watched the development of cells that resembled the precursors of eggs and sperm.

“This was absolutely thrilling,” Dr. Zernicka-Goetz said. “It’s sometimes hard to believe that these stem cells are growing into these structures.”

If scientists can create close, reliable models of embryos, they will be able to run large-scale experiments to test potential causes of pregnancy failures, such as viral infections and genetic mutations.

The models could lead to other medical advances too, noted Insoo Hyun, a member of the Harvard Medical School Center for Bioethics who was not involved in the new studies.

“Once you get the embryo models in place and you can rely on them, that can be an interesting way to screen drugs that women take when they’re pregnant,” he said. “That would be an enormous benefit.”

Dr. Hanna and Dr. Ebrahimkhani also saw a possibility of using embryo models as a new form of stem-cell treatment for diseases such as cancer.

In conventional stem-cell transplants, doctors remove blood stem cells from the bone marrow before killing cancer cells with radiation or chemotherapy. They then return the healthy cells to the body.

Unfortunately, this method does not have a high success rate . Some researchers have suggested that earlier forms of stem cells would be more likely to cure patients.

Embryo models might make it possible for doctors to turn back time. Researchers would take skin cells from a patient and douse them with chemicals to put them into a stem-cell-like state. With other chemical baths, those stem cells could then be turned into an embryo model, which could in turn develop into the early blood cells the patient needs after a transplant.

Alysson Muotri, a developmental biologist at the University of California San Diego who was not involved in the new studies, cautioned that the new studies demonstrated only a preliminary step. For one thing, while the techniques sometimes resulted in embryolike clusters, they often failed.

“The work is in very early stages, and the current methods are far from reliable,” Dr. Muotri said.

Carl Zimmer writes the “Origins” column. He is the author of fourteen books, including “Life's Edge: The Search For What It Means To Be Alive.” More about Carl Zimmer

Limits for human embryo research have been changed: this calls for public debate

Researcher, Lecturer, Attorney, University of KwaZulu-Natal

Disclosure statement

Sheetal Soni does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

University of Kwa-Zulu Natal provides funding as a partner of The Conversation AFRICA.

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For 40 years, research into early human development has been guided by the principle that after 14 days, an embryo should not be used for research and must be destroyed. This rule has been part of the law of more than 12 countries. But new guidelines released by the International Society for Stem Cell Research have removed this rule. This makes it possible to conduct research on human embryos that are at more advanced stages of development.

Now, countries must revise their laws, policies and guidelines to reflect this change. But first, public debate is crucial to determine the limits of what sort of research should be allowed.

Over the decades human embryo research has allowed us to understand normal and abnormal human development, as well as early genetic diseases and disorders. Studying human embryos, as the earliest forms of human life, can give us insight into why miscarriages occur, and how our complex body systems develop. Human embryos are also important for stem cell research , where researchers try and create cell-based therapies to treat human diseases.

Often, extra embryos are created during in vitro fertilisation procedures. These extra embryos may be donated for research. They are cultured (or grown) in a laboratory and can be studied until they reach day 14 post-creation.

The 14-day rule has served as an international standard since 1990 when it was included in the Human Fertilisation and Embryology Act in the UK. At the time that it was introduced, it was not possible to keep human embryos alive in a laboratory for more than a few days. However, scientists have been recently been able to keep embryos alive for longer periods, between 12 and 13 days. The ethical, legal and social consequences of such research were also important considerations.

The 14-day rule and the new guidelines

Although the 14-day rule has been criticised as being arbitrarily decided, there are a number of reasons for the time frame.

After an egg cell is fertilised by a sperm cell, the resulting embryo consists of a few identical cells. Most embryos will implant in the uterus after the 14th day. After this point, the ‘primitive streak’ appears, which is the first sign of an embryo’s developing nervous system. The rule also identified the point at which the embryo shows signs of individuation, because it is no longer possible for the embryo to split into twins after 14 days. Some people reason that due to these events, it is at this stage that a moral being comes into existence, and it would not be ethical to perform research on embryos after this time.

There has been increasing pressure from some researchers to remove the 14-day rule , or at least extend it, as it prevents critical research from being undertaken. Extending the rule would allow important research into early human development to be done. The new guidelines make it possible to do research on embryos older than 14 days if the approval processes of the relevant ethics committees are followed.

A significant problem, however, is that there is no longer any limit on the time frame for research. Would it be permissible to do research on human embryos that are 20 days old or 40 days old? The guidelines specify no limit. The longer a human embryo is allowed to grow, the more recognisably human it becomes. At what point would we regard the research unethical, and at what point does the moral cost outweigh the benefits of research?

What the law says

Countries around the world take a variety of approaches to human embryo research. Some – like Italy and Germany – don’t allow it at all. Others, like the UK, allow research to continue until the embryo is 14 days old, after which it must be destroyed. There are also some which permit embryo research without identifying a limit. Some, like the US, do not have any law regulating it (but there are guidelines which contain reference to the 14-day rule).

In South Africa, reference to the rule is found in the National Health Act (2003) , which states that human embryo research may only be done with permission of the minister, and that the embryos must not be older than 14 days.

International guidelines are not legally binding. But the effect of the revised guidelines is that the international standard for best practice in scientific research has now changed. This means that countries which have implemented the rule in their laws will need to revise them so that they are in line with best practice in science.

The future of human embryo research

Human embryo research is a sensitive topic because people are divided on the moral status of the human embryo . Some people believe that the embryo, as the earliest form of human life, should be protected and not subjected to research at all. Others believe that while an embryo has some moral status, it cannot be protected in the same way as humans are, and may be used for some important research which could ultimately benefit people.

The decision to discard the 14-rule appears to have been made without public input. That does not encourage the public to trust in science, and public engagement should have come before such an an important rule was changed.

There are a number of approaches to working with the revised guidance. Bioethicist Françoise Baylis has suggested that project-specific time limits should be identified , based on the minimum amount of time required to address the stated research objectives. This would mean that some research would still be subject to the 14-day limit, while other studies would be permitted to exceed it. Another approach would be to keep the 14-day limit as the norm, and consider applications to exceed it case by case . Or the limit could be extended to 28 days .

The coming conversations surrounding embryo research will prove to be very important. The proverbial genie is out of the bottle, and public debate is crucial.

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Extend 14-day human embryo research limit to 28 days, urges ethicist

Key to discovering potential new treatments to reduce miscarriage and birth defects

It’s time to extend the legal limit on human embryo research from 14 to 28 days, because technology and knowledge have moved on during the 40 years since it was introduced, urges a leading ethicist in the  Journal of Medical Ethics .

This step is now key to discovering potential new treatments to ward off the risks of recurrent miscarriage and developmental abnormalities, contends Sophia McCully of King’s College, London.

The ‘14-day rule’ limits research on intact human embryos to this period, as it is only after 14 days that the central nervous system begins to develop. The law governing the rule applies in many jurisdictions and is upheld even in countries without relevant laws or guidelines.

“For the past 40 years, the 14-day rule has both governed and enabled embryo research and therapeutic innovation globally. It has been a piece of legislation and a rule of good practice, defining a clear boundary in which valuable research has been able to proceed against some considerable opposition,” writes the author.

But it is now safe and timely to make a policy change and extend the rule without fear of any “moral and regulatory slippery slope,” she says. 

Many studies suggest that important changes in the embryo that occur before 14 days are likely to affect subsequent development. But without the ability to go further, their real significance will be hard to understand, she argues.

And as the embryo only starts to develop after 14 days, “how are we to learn about our beginnings if we cannot study them?” she asks.

Scientists now have the capacity to culture human embryos beyond 14 days, and there are compelling reasons for mandating the extension of this rule to 28 days, she contends.

These include greater understanding of the development of birth defects such as congenital heart disease, which affects around 8 in every 1000 babies; the potential to improve in vitro fertilisation (IVF) and reduce rates of miscarriage; and improved safety testing of new techniques, such as mitochondrial replacement therapy (MRT).

Many argue that animal embryos can be used instead of human ones, she says. And Macaque monkey embryos have been used for up to 20 days. But it’s not clear how closely these resemble human embryo biology and this question can’t be answered without doing the comparison, she highlights.

There are also ethical and philosophical reasons why the 14-day rule needs to be amended, she says.

It is legal to abort an embryo or fetus substantially ‘older’ than 14 days, and, with appropriate consent, to do research on its tissues, yet it is illegal to experiment on an embryo beyond 14 days that was never intended for implantation, she points out. 

With the introduction of tests in the UK to pick up three of the most severe chromosomal disorders, selective abortion has increased, she says. 

With the ability to uncover why an embryo might have abnormalities through experiments on intact embryos maintained beyond 14 days, and then use new technologies to avoid or correct the problem, the frequency of selective abortion and therefore embryo and fetal wastage might be reduced, she suggests.

“The 14-day rule has become limiting, and just because something has once worked does not mean it should stay the same or not strive to improve. As is clear to see, there are a multiplicity of reasons why embryo research beyond 14 days can help us realise the metamorphic potential of healthcare,” writes the author. 

“From this analysis, and that of others, there are no substantive ethical reasons for not altering the limit,” she argues. 

“Embryo research is a crucial undertaking and will help us to make many transformational discoveries, thus extending this very arbitrary limit is an endeavour that must be achieved,” she concludes. [Ends] 01/02/21

Notes for editors Research:  The time has come to extend the 14-day limit doi 10.1136/medethics-2020-106406 Journal:  Journal of Medical Ethics

Funding:  None declared

Link to Academy of Medical Sciences labelling system https://press.psprings.co.uk/ AMSlabels.pdf Externally peer reviewed? Yes Evidence type: Analysis; opinion Subjects: Researchers

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Q&A: Research with embryo models needs legal clarity

by Fabio Bergamin, ETH Zurich

Science often runs ahead of legislation—and this is now also true for research on embryo-like cell aggregates from human stem cells. Bioethicist Alessandro Blasimme of ETH Zurich explains why this controversial topic calls for legal clarity.

As publicly announced in June, three research teams from the U.K., the U.S. and Israel have independently succeeded in developing cell aggregates from human stem cells that very closely resemble the early human embryo.

These cell aggregates are considered the most faithful embryo models ever created. What's new about them is that human embryonic development can be initiated using cells other than gametes (ova and sperm); these embryo models are created from a single person's stem cells. Now the question is whether they should be used in research.

After all, research on real human embryos is ethically controversial and tightly restricted in many countries. Research on these new models, on the other hand, is not yet regulated by law in many countries. Ethicist Alessandro Blasimme of ETH Zurich has been studying ethical issues in biomedicine for years. In a recent study published in the journal Cell Stem Cell , he specifically addressed the new embryo models derived from human stem cells.

ETH News: Why are these embryo models significant to science?

Alessandro Blasimme: We still know very little about the first phases of human embryonic development. Since research in this field is highly regulated in many countries, embryo models offer scientists a close alternative for studying embryonic development and also relevant problems that may occur in early pregnancy.

For instance, how does an embryo implant in the uterus, and why are spontaneous miscarriages relatively common during this stage of pregnancy? Ultimately, such research could also lead to treatments for couples who are otherwise unable to have children. These extremely accurate models enable scientists to study embryonic life in a way that was simply not possible before.

In some countries, researchers are allowed to use real human embryos up to 14 days old. So far, the novel embryo models haven't been kept in culture for more than 14 days either. What's the benefit of these models when you can also do research on real embryos?

The researchers who developed human embryo models kept them in culture up to eight days probably due to current experimental limitations. Presumably, however, such embryo models will soon permit researchers to observe much later stages of embryogenesis.

Two of the research groups involved in these experiments, were recently able to generate mouse embryo models from stem cells up to the organogenesis, meaning that they were able to observe a beating heart develop and a brain emerge in these models. A further benefit is that while natural human embryos are created using ova harvested from women, embryo models don't require human egg cells.

Is it currently legal in Switzerland to work with human embryo models beyond the 14-day limit?

Research with embryos is not forbidden in Switzerland but it is strictly regulated. The limit here is seven rather than 14 days. However, the legal definition of what constitutes an embryo in Switzerland is very narrow. The new embryo models are not likely to be included. This means that at the moment working with such models is largely unregulated in Switzerland.

There are different methods for creating such embryo models. In some cases, human stem cells are genetically modified before being aggregated to form an embryo model. This would likely be prohibited in Switzerland. But there are also methods that don't require genetic engineering.

And in other European countries?

The legal situation—and in particular the definition of an embryo—varies from country to country. The legislation in Austria and Belgium, for example, defines embryos in a broad way that could also cover the new models. This means that the rules that apply to research with human embryo may be interpreted to apply also to embryo models derived from stem cells. In most countries, however, there are significant legal loopholes.

What does that mean for science?

Uncertain frameworks don't produce good science. It would harm publicly funded research if scientists were to exploit legal loopholes. That's all the more true in such a controversial field. Let's not forget that society has been debating the moral and legal status of embryos for decades. And while each country has achieved its own legal framework, the controversy is far from settled.

Legal clarity is important for research. Each country now has to ask itself whether it wants to allow embryo model research. National parliaments need to discuss the issue and then legislate accordingly.

What role can your field, bioethics, play here?

As a society, we need to answer practical questions: Should the law treat embryo models the same as embryos or not? And should research on these models be allowed and within what boundaries? One of the reasons why we published our study was to stimulate this discussion.

The task of us ethicists is to explore the reasons for and against using such embryo models for research and propose rules that are coherent and acceptable even if there is no definitive societal consensus on the topic. Legal loopholes hurt science. I personally think we should permit scientific research , but with rules that have been publicly discussed and can be accepted by society.

What is your opinion? Should the models be treated like real embryos?

The models are indeed very similar to natural human embryos. And both ethics and legal logic suggest treating like things alike. This doesn't necessarily mean extending existing rules and limitations also to embryo models. But the latest scientific developments are a good opportunity to also reflect on and to clarify existing rules.

Journal information: Cell Stem Cell

Provided by ETH Zurich

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A mouse embryo that has paused its development due to nutrient depletion

The embryos of many species can stop developing when starved of nutrients, only to restart the process once these are restored – and scientists may have figured out how they do it.

In the early stages of pregnancy , a fertilised egg turns into a blastocyst, a tiny cluster of dividing cells. This then implants into the uterine wall, eventually differentiating into the various organ tissues of a fetus.

When some animals face extreme circumstances, such as when food is scarce or when it is really cold, blastocysts pause their growth and enter a state of dormancy called embryonic diapause. This can last for several months in some species, with activity resuming once conditions improve. “It is a strategy to maximise the reproductive process and thus the number of young born and their survival,” says Bruce Murphy at the University of Montreal in Canada, who wasn’t involved in the research.

Human evolution: The astounding new story of the origin of our species

Now, Jiajia Ye at the Chinese Academy of Science and his colleagues have uncovered how an embryo can tell when to stall development.

They put 14 newly pregnant mice in a cage with food and 11 others in a cage without food. After 3.5 days, they found that the blastocysts of the well-fed mice developed as usual, but those of the starved mice hadn’t implanted in the uterus, indicating embryonic diapause.

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When these dormant blastocysts were then transplanted into the uteruses of well-fed mice, they started growing again.

In another part of the experiment, the researchers grew mouse embryos in petri dishes with different nutrients. They found that embryonic diapause seems to be caused by a lack of carbohydrates and proteins, while embryos exposed to normal levels of these nutrients grow as expected.

Closer inspection revealed that a sensor called Gator1 in the blastocysts can detect drops in carbohydrate and protein levels in the uterus. This then prevents a molecule that controls protein synthesis from being activated, which is necessary for blastocyst development.

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When the team injected the uteruses of pregnant mice that had been deprived of food with the necessary carbohydrates and proteins, embryonic growth resumed.

With a similar proces expected to occur in human embryos, Ye hope these findings could eventually be used to improve fertility treatments. Prior to in-vitro fertilisation (IVF), embryos are sometimes preserved by freezing, then transplanted into a uterus. This method of preservation is expensive and the embryos don’t always survive the thawing process. The team has shown it could be possible to preserve them through nutrient depletion, says Ye.

Journal reference:

Development DOI: 10.1242/dev.202091

• Embryology /

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Study finds embryos in hungry mouse moms postpone development

by The Company of Biologists

It's challenging to sustain a pregnancy when food is short, or conditions are otherwise tough. That's why many mammalian embryos can postpone their growth to get through periods of environmental stress and then re-enter development when conditions improve. This stalling of development is known as embryonic diapause, and understanding the mechanisms behind it might help improve infertility treatments, such as embryo freezing.

Now, researchers at the Center for Excellence in Brain Science and Intelligence Technology, the Chinese Academy of Sciences in Shanghai, China, have discovered how nutrient depletion is sensed by embryos growing in hungry mouse moms to induce diapause . They publish their study in the journal Development on 11 April 2024.

Lack of food is a known trigger of embryonic diapause, but it has not been clear how nutrient depletion in the mother's diet is sensed by the embryo.

"Seasonal starvation is one of the universal environmental stresses in nature," explained Professor Qiang Sun, who led the study. "However, the regulatory process of diapause in early-stage embryos is not fully understood. So, we decided to examine whether nutrient deprivation induces embryonic diapause."

By comparing hungry and well-fed pregnant mice, the team discovered that embryos in the hungry mice did not implant into the uterus and their growth paused at an early timepoint, when the embryo comprises a hollow ball of cells called the blastocyst. These embryos remained viable and could start developing again when transplanted into a well-fed mother.

To work out which nutrients were important to induce diapause, the researchers grew early-stage mouse embryos in dishes that contained different nutrients. They found that embryos grown in dishes lacking protein or carbohydrates paused their development, whereas the embryos exposed to normal nutrient levels did not stall and kept on developing.

The scientists then went on to reveal that nutrient sensors in the embryo can detect drops in protein or carbohydrate levels, which triggers the entry into diapause.

The finding that embryos grown without protein or carbohydrates can pause their development means that they can survive longer in the lab. In the future, this finding might lead to improvements in fertility treatments, which currently include approaches such as embryo freezing.

"We think our study can inspire the development of new methods for human embryo preservation," said Professor Sun. "Embryo cryopreservation is a widely used approach, but there is still no consensus on when cryopreserved embryos can be thawed and transferred into the uterus. Many clinical studies have shown that traditional frozen embryo transfer can increase the risk of problems during pregnancy. Therefore, it is necessary to develop alternative methods to preserve embryos."

Studies focusing on diapause may even have long-term implications for cancer treatments. "Dormant cancer cells which persist after chemotherapy resemble the diapaused embryos ," said Professor Sun.

"Consequently, we hypothesize that delving into the mechanism of diapause may have positive implications for cancer treatment and decreasing the chances of relapse."

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They were desperate to get pregnant. Then IVF gave them extra embryos.

One morning last spring, Ashley Harrolle put her 1-year-old daughter down for a nap and went to the kitchen. She pulled up her fertility clinic’s contact information. It was time to make the call.

In a freezer several hundred miles away sat a single embryo belonging to Harrolle and her husband. Once, it had represented a possible second child, but the couple had known for months that they wouldn’t be able to use it. After a rare and dangerous complication with her pregnancy, Harrolle couldn’t go through another.

It had been easy for the couple to decide to donate the embryo to science. They liked the idea that it would be used in training IVF providers.

But now, Harrolle was finding that actually giving it up was harder. She sat at the kitchen table in her Birmingham, Ala., home and stared at the number on her phone screen. Sudden grief hit her for the future that could have been — the future her family would never have.

“It all slapped me in one moment,” the 35-year-old therapist recalled in an interview. “I kind of realized, like, ‘Oh, s---. This is harder than I thought it was going to be.’”

She put down the phone.

What happens to spare embryos created during IVF is a question that was thrust into the national spotlight in February, after the Alabama Supreme Court ruled that frozen embryos were people and characterized discarding them as killing unborn children.

The ruling drew attention to a part of IVF considered standard practice in the United States — creating as many embryos as possible, which doctors say provides the best odds for success. Antiabortion advocates have long objected to it based on the argument that destroying unused embryos constitutes ending lives.

Those who have faced the dilemma of what to do with leftover embryos, however, say it is a highly personal and often emotional process. For many, it represents making a choice about whether to have more children.

They and reproductive-health experts described the decision as both medically routine and subjectively delicate, wrapped up in questions about family size, maternal health and personal finances. Many wait months or years to decide — or keep their embryos frozen indefinitely.

Watching the topic be turned into a campaign issue and dissected by strangers online has been difficult for some who have been through IVF, several women told The Washington Post. The discourse, they say, has obscured what families in fertility treatment experience.

“[To] find embryos that are potential success stories, we have to get a lot of eggs and a lot of embryos to select from,” said Michael Alper, a doctor and medical director at the multistate fertility provider Boston IVF. “That’s just the way human biology is.”

Some patients don’t end up with extras because they use all their embryos in attempts to conceive, said fertility doctor Serena Chen, director of advocacy at CCRM Fertility in New Jersey. For those who do, the amount of “blood, sweat, tears, money” that goes into creating the embryos can contribute to the difficulty of the decision.

Families who don’t want to use the embryos or keep them frozen can discard them, which doctors described as common; donate them for use in scientific research and training; or donate them to others seeking to have children. A fourth, relatively uncommon option discards embryos by transferring them into a woman’s body at a time when she’s unlikely to become pregnant.

“It’s a really personal conversation,” said Kimberly Mutcherson, a professor at Rutgers Law School and a reproductive-justice scholar. “It varies from person to person and couple to couple.”

The best chance

The July 2022 date was marked in Kaytee Schwartz-Davis’s Google calendar — the day the embryos she and her husband had created would no longer be theirs.

The couple had tried to conceive for 2½ years and had gone through two failed IVF embryo transfers before getting pregnant in 2020. When they ended up with six extra embryos after the birth of their son, Felix, they immediately thought of other families waiting and wanting to have children.

There was a long wait list for donated embryos, their clinic told them. Six would provide three families with two chances each at babies. Schwartz-Davis felt like they had to do it.

“It was more about helping other people” than feeling a strong attachment to the embryos, said Schwartz-Davis, 36, of Belmont, N.C. “Just hoping that maybe this will help someone not have to go through … the emotional devastation” of being unable to start a family.

Schwartz-Davis and her husband, Ryan Davis, didn’t struggle with the idea of having their genetic children born to other families, regarding them as the kids of whoever raises them. The difficult part was closing the door on having more children of their own.

“We were definitely sad,” she said. “It’s so final. Like, this is it. … There is just no chance that we’re going to have more kids.”

Embryo donation is a less commonly chosen option, said Chen, the doctor. It requires more effort and paperwork, and some parents balk at the idea of giving their embryos to strangers. It’s the path favored by antiabortion groups.

Schwartz-Davis and her husband had always wanted a big family, but after she navigated a pregnancy that included hyperemesis gravidarum — debilitating nausea — and intermittent bleeding, they decided not to try for a second child. Though that felt right, it wasn’t easy, especially as they watched friends have second babies.

Schwartz-Davis had been an egg donor after college, so she was familiar with donation. The couple decided to leave their information on the DNA-testing site 23andMe so they could be found. Otherwise, they were comfortable with never knowing whether children resulted from their donation.

The couple waited a year to fill out the paperwork after first contacting the clinic about donating, “just to be sure, 100 percent sure, we’re definitely not going to go through this again,” she said.

Finally, Schwartz-Davis decided it was now or never. The couple did bloodwork and urine testing. They provided childhood photos and answered questions about their favorite colors, movies and sports.

A three-month waiting period followed, giving them a window to change their minds. Schwartz-Davis watched the date on her calendar, but she was at peace. They had done the right thing for their family.

A biology major in college, Schwartz-Davis said she views embryos as cells, not people — and she knows from difficult personal experience that not all embryos result in pregnancies. Donating doesn’t necessarily mean their embryos will become people, but she looked at it as their best opportunity.

“At least this way, they have a chance of being a person and having a life — and maybe changing the world. Who knows, that sounds silly, but …” she said. “Otherwise they would just sit there frozen forever.”

Finding peace

On a cloudy morning in late January, Emily Ibison and her husband, Bryan, left their doctor’s office with good news — her second pregnancy, a surprise after an IVF-conceived baby, appeared healthy. They got in the car and, for the last time, drove to their fertility clinic in Indianapolis.

With them was the paperwork that would allow their embryos to be discarded through donation to science. They signed the papers at the front desk. It took only a few minutes.

Then they were driving home, not feeling much more than relief.

“It’s nice to have a sense of closure,” Ibison, 31, of Lafayette, Ind., said in an interview. “Being able to breathe that little sigh of relief that’s like, we’re getting off that roller coaster.”

After one successful IVF transfer in 2021, resulting in the birth of daughter Hazel the following July, Ibison waffled about what to do with their 15 leftover embryos. While she and her husband were fairly certain they would be happy as a family of three, they hadn’t made a final decision.

Ibison was most worried about later wishing for another child. After seeing her daughter born from one of the embryos, it was natural to wonder “who each one of those embryos could’ve become,” she said.

“That fear of regret was definitely part of it,” she said. “It’s hard to make a decision in one moment of life that’s going to affect the rest of your life.”

At the end of last year, the couple’s annual notice from the fertility clinic came in the mail: It was time to renew their embryo storage. Before Ibison could make a final decision, she discovered she was pregnant.

If the pregnancy appeared on track, the couple would be ready to discard the embryos, they decided. When they got to the clinic after their first OB/GYN appointment, the Ibisons checked the box to allow the embryos to be used in training.

A few weeks later, the Alabama ruling came down. When she saw it, Ibison was relieved she and her husband had already made their choice. Even though there was no threat to embryo disposal in Indiana, she could imagine state lawmakers someday restricting it.

“I definitely wouldn’t have wanted to end up in a decision where we couldn’t discard them and had to continue paying for that storage forever,” she said.

She said she wished people who haven’t gone through IVF, including politicians, understood the desperation couples feel when trying to start families, and how little is in their control.

“Nobody wants to be in this situation, and nobody wants to have to make the decision of whether or not to discard embryos,” Ibison said. “These are all the things we put ourselves through so we can just have a family.”

Closing a chapter

In Birmingham, Harrolle realized that giving up her single spare embryo felt like a shift in her life path. She would have to grieve it — the loss of a vision she’d once had for her life, the loss of her ability to choose how big her family would be, the loss of a potential future with two children.

Harrolle spent some time mentally preparing through therapy and journaling. Finally, she called the clinic. She and her husband, Jeff, filled out the paperwork and got it notarized.

They initialed the boxes: Donate all embryos that we have stored for research/training use.

Harrolle remembers relief, numbness and grief. With it came closure, knowing the decision was right.

After that, Harrolle didn’t think too often about the embryo — which she never viewed as a person — until the ruling in her state came down in February. Though Alabama legislators later passed a law shielding patients and providers from any liability for destroying embryos, Harrolle was shaken, worried for those in the thick of IVF.

“It felt as though it was being discussed in such a callous way. … Like, oh, if you throw away these embryos, you’re a murderer. Well, no! Not at all,” Harrolle said.

“I don’t think that people who are making the [policy] decisions understand the nuance. It’s not right or wrong; it’s not alive or not,” she said. “There’s nuance behind it.”

Harrolle — who was born through IVF in the late 1980s — described a sense of satisfaction in knowing their embryo would have a small purpose in research.

Without science, she wouldn’t have gotten the best thing in her life — little Alice, who was on the backyard swing on a recent weekday, chasing sunshine.

Talking about it, Harrolle began to cry.

“If we hadn’t gone through all this,” she said, “she wouldn’t be here.”

UCL Division of Biosciences

• Innovation and enterprise
• Biosciences Sharepoint

Research on tissue mechanics/metabolism (potentially relevant to cancer) awarded significant grants

9 April 2024

Alessandro Mongera, Lecturer in Developmental Mechanics in the UCL CDB, has been granted an AMS Springboard Award, together with an HFSP - a substantial and prestigious grant, for his research on the mechanical and metabolic control of embryo development

The goal of these projects is to connect PTs with metabolism, the chemical reactions in our bodies that produce energy and cell building blocks, and also with epigenetics in living embryos without affecting their normal development. 

The research will be conducted using, as a model, vertebral column formation in zebrafish.  Importantly, zebrafish allow the study of PTs, metabolism and epigenetics in living embryos (without affecting their normal development).  The research will focus on the formation of the vertebral column, a process that can occur only if the tissue switches from fluid to solid at proper locations.  

These studies have the potential to inform novel strategies for generating organs-in-a-dish as well as to block cancer inva sion, which is easier when the tissue behave like a fluid.

For further information on the Springboard award – see https://acmedsci.ac.uk/more/news/66m -springboard-emerging-research-leaders (Ale is listed 16th in the awardees list)

For further information on the HFSP Research Grant – see https://www.hfsp.org/sites/default/f ile s/2024-04/HFSPResearchGrant%20Award%20Booklet_2024.pdf (Ale is fourth in the UK list on p. 51 and the project is described on p. 21)

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• 28 March 2024

Scientists made a six-legged mouse embryo — here’s why

• Sara Reardon 0

Sara Reardon is a freelance journalist based in Bozeman, Montana.

You can also search for this author in PubMed   Google Scholar

A typical mouse embryo (left) has four limbs. An embryo in which a particular gene was switched off halfway through development has six limbs, and several of its internal organs protrude from its abdomen. Credit: Anastasiia Lozovska et al/Nat. Comms

You have full access to this article via your institution.

This six-legged animal isn’t an insect: it’s a mouse with two extra limbs where its genitals should be. Research on this genetically engineered rodent, which was published on 20 March in Nature Communications 1 , has revealed a way in which changes in DNA’s 3D structure can affect how embryos develop .

Developmental biologist Moisés Mallo, at the Gulbenkian Science Institute in Oeiras, Portugal, and his colleagues were studying one of the receptor proteins, Tgfbr1, in a signalling pathway that is involved in many aspects of embryonic development. The scientists inactivated the Tgfbr1 gene in mouse embryos about halfway through development to see how the change affected spinal-cord development.

Then, Mallo’s graduate student, Anastasiia Lozovska, came to his office to tell him she’d found that one of the bioengineered embryos had genitals that looked similar to two extra hind limbs. Her finding sent the research down an unexpected path. “I didn’t choose the project, the project chose me,” Mallo says.

A 3D reconstruction of the skeleton of the genetically altered embryo shows its extra and normal limbs (magenta and turquoise, respectively). Credit: Anastasiia Lozovska et al/Nat. Comms

Researchers have long known that, in most four-limbed animals, both the external genitalia (penis or clitoris) and hind limbs develop from the same primordial structures.

When Mallo’s team looked further into the six-legged mouse phenomenon, they found that Tgfbr1 directs these structures to become either genitalia or limbs by altering the way that DNA folds in the structure’s cells. Deactivating the protein changed the activity of other genes, resulting in extra limbs and no true external genitalia.

The researchers hope to determine whether Tgfbr1 and its relatives affect DNA structure in other systems such as metastatic cancer , and in immune function. They are also examining whether the same mechanism underlies the development of the reptilian hemipenis, a double penis that, in snakes, forms from primordial organs in lieu of legs.

Nature 628 , 247 (2024)

doi: https://doi.org/10.1038/d41586-024-00943-7

Lozovska, A. et al. Nature Commun . https://doi.org/10.1038/s41467-024-46870-z (2024).

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• v.36(12); 2019 Dec

Discarding IVF embryos: reporting on global practices

M. simopoulou.

1 Department of Physiology, Medical School, National and Kapodistrian University of Athens, Mikras Asias, 11527 Athens, Greece

2 Assisted Conception Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Vasilissis Sofias str, 11528 Athens, Greece

K. Sfakianoudis

3 Centre for Human Reproduction, Genesis Athens Clinic, Papanikoli, 15232 Athens, Greece

P. Giannelou

E. maziotis.

4 Democritus University of Thrace, Dragana, 68100 Alexandroupolis, Thrace Greece

P. Tsioulou

S. grigoriadis, e. simopoulos.

5 Conceive - The Gynecology Center, Dubai, United Arab Emirates

M. Lambropoulou

M. koutsilieris, j. c. harper.

6 Reproductive Science Group, Institute for Women’s Health, University College London, Gower Street, London, WC1E 6BT UK

Associated Data

To provide a global scale report on a representative sample of the clinical embryology community depicting the practice of discarding supernumerary IVF embryos.

A web-based questionnaire titled “Anonymous questionnaire on embryo disposal practices” was designed in order to ensure anonymous participation of practicing clinical embryologists around the world.

During a data collection period of 8 months, 703 filled-in questionnaires from 65 countries were acquired. According to the data acquired, the majority of practitioners, dispose of embryos by placing them directly in a trash can strictly dedicated for embryo disposal for both fresh and frozen cycles (39% and 36.7% respectively). Moreover, 66.4% of practitioners discard the embryos separately—case by case—at different time points during the day. Over half of embryologists (54%) wait until day 6 to discard the surplus embryos, while 65.5% do not implement a specially allocated incubator space as a designated waiting area prior to disposal. The majority of 63.1% reported that this is a witnessed procedure. The vast majority of embryologists (93%) do not employ different protocols for different groups of patients. Nonetheless, 17.8% reported the request to perform a ceremony for these embryos. Assessing the embryologists’ perspective, 59.5% of participants stated that the embryology practice would benefit from a universally accepted and practiced protocol.

Conclusion(s)

This study uniquely provides insight into global embryo disposal practices and trends. Results highlight the divergence between reported practices, while indicating the significance on standardization of practice, with embryologists acknowledging the need for a universally accepted protocol implementation.

Electronic supplementary material

The online version of this article (10.1007/s10815-019-01592-w) contains supplementary material, which is available to authorized users.

Introduction

During in vitro fertilization (IVF) treatment, embryos of the highest implantation potential are included in the embryo transfer or cryopreservation process. Studies show that the optimal number of oocytes retrieved per cycle is 15 [ 1 ]; subsequently, supernumerary embryos are expected. The decision-making process regarding the fate of these embryos is considered to be the most challenging and crucial step during the entire IVF process [ 2 ]. From morphology grading to the emergence of prediction models [ 3 ], and the promise of artificial intelligence (AI) [ 4 , 5 ], the evolution of all these trends serves the era of personalized medicine by strengthening the practice of elective single embryo transfer (eSET) [ 6 ]. A byproduct of the eSET practice is surplus embryos [ 7 ].

Depending on their quality, the legal framework, the patients’ will, and the respective family planning status, surplus embryos may be subjected to certain options. Common practice dictates that good-quality embryos may be cryopreserved for future IVF cycles employing a frozen-thaw protocol [ 8 ].

With regard to cryopreserved stored embryos, in the case that it is decided that no further fertility treatments will be pursued, couples are faced with the challenging decision regarding disposition of their frozen embryos also known as “embryo disposal decision” (EDD) [ 9 ]. A successful attempt in childbearing most commonly signals the designation of cryopreserved embryos as surplus material. Surplus cryopreserved embryos that are stored during the process of assisted reproduction are not always reclaimed by the patients. In Sweden, 30% of couples during a 3-year period did not use their cryopreserved embryos in a subsequent cycle [ 10 ], and similar reports are documented in France [ 11 , 12 ] and Denmark [ 13 ]. Interestingly, there is the matter of “abandoned embryos” in storage; this term refers to cases where the couple/person cannot be reached and/or fails to provide the clinic with a decision pertaining to the embryos’ fate [ 14 ]. The safekeeping of abandoned embryos raises ethical and bureaucratic challenges for IVF clinics worldwide as published reports indicate that frozen embryos in storage have reached numbers in the range of 52,000 (UK, 1996), 71,000 (Australia, 2000), and 400,000 (USA, 2003) [ 15 , 16 ]. To address the prospect of unclaimed embryos, many clinics ask couples to make dispositional decisions prior to initiating IVF treatment.

Good-quality embryos may be donated to a research program especially in light of the most recent stem cell studies [ 17 ]. Additionally, the embryos may be donated to other couples facing infertility to known or anonymous persons [ 14 ]. Donating embryos to research or to a third-party experiencing infertility, or discarding consist of the three main options available in cases of fresh or cryopreserved embryos.

Poor-quality embryos that fail to qualify for embryo transfer or cryopreservation, as well as embryos subjected to preimplantation genetic testing (PGT) cycles diagnosed with a genetic or chromosome abnormality, are typically discarded. Interestingly, IVF professionals in countries such as USA where neither sex selection nor access to PGT is regulated also provide the option for “social sexing” leading to the subsequent disposal of healthy embryos [ 18 ].

The current literature provides an adequate number of studies describing patients’ views on the disposal procedure of their surplus embryos. Couples’ conceptualization of embryos is complex and may range from picturing these embryos as a little more than cohort of cells, or a tissue, to considering them as their unborn children [ 19 – 22 ]. In 2009, McMahon and Saunders reported that patients’ hesitancy to donate their embryos to other infertile couples was related to the belief that these surplus embryos were not only their potential children but were siblings to existing children. Patients’ indecisiveness and hesitation towards donation may be attributed to a feeling of responsibility for the well-being of the offspring [ 23 ]. Interestingly, more than one study reported that even though most couples view their surplus embryos as “potential life,” the majority of them chose an option resulting in the embryos’ disposal, or donation to research [ 8 , 24 – 26 ]. The disposition decision is known as being emotionally demanding for couples that are understandably focused on the first goal of achieving a clinical pregnancy [ 8 , 20 , 27 , 28 ]. Some couples, who chose to discard their embryos, described their decision as a “last-minute decision,” perhaps indicating their opposing views regarding embryo research and additionally the sentiment that they are unable to donate their embryos to another couple [ 8 ].

Hitherto, there is a lack of evidence and data regarding the different practices adopted in order to discard embryos in IVF laboratories as there is no universal protocol or a respective guideline or dedicated section in any code of practice. A guideline defines a statement that aims to rationalize particular practices according to a set routine. The rationale fueling design of the present study is to present the IVF community with a descriptive study on the various practices entailed in discarding surplus embryos providing an international report. The lack of published data, along with no documented thesis in literature, prompted our team of experts to approach this subject aiming to shed light to what is reported as the existing practice. This original study aims to serve as a platform voicing the current practices and understand what may be lacking. The scope of this survey, in combination with a comprehensive literature review on this topic, was to present the similarities and discrepancies reported on a global scale regarding embryo disposal practices on fresh and cryopreserved embryos. The practice of preimplantation embryo disposal pertains to the clinical embryologist disposing of the embryos, along with the respective couple/person subjected to ART who ultimately determine the embryos’ fate. The authors do not attempt to approach the issue of potential advantages entailed in a practice characterized by a common universal protocol on embryo disposal. This is a descriptive survey, and the questions included in the survey do not propose or evaluate potential benefits related to standardization of disposal practices. Nonetheless, such benefits may be entailed especially in light of the bioethical stance of the preimplantation embryo.

Materials and methods

A web-based questionnaire titled Anonymous questionnaire on embryo disposal practices was designed employing the “Google forms” format in order to ensure anonymous participation of IVF professionals around the world. The questionnaire can be found in supplementary material (Fig. 1 ). Demographic information regarding the name of the country and the state, where applicable, the IVF clinic was based was acquired. The questionnaire was divided into three sections. The first section focused on how IVF practitioners perform embryo disposal of surplus embryos. The second assessed the various approaches employed in order to satisfy the patient requests or requirements in regard to embryo disposal, while the third section aimed to assess the embryologists’ perspective and view in regard to implementation of a universal protocol. The IVF professionals’ practice, patterns, and opinions were assessed through “Yes,” “No,” multiple-choice questions, and short answers.

In an effort to reach a worldwide audience, various approaches were adopted to ensure participation. The authors contacted 68 organizations and associations on IVF practice and reproductive medicine. The inclusive list of all organizations contacted is available in supplementary material presented in Table 6 . The authors e-mailed the person responsible as indicated by the respective organizations. The e-mail aimed to introduce the academic affiliation involved in the study, describe the nature of the study, and present the recipient association/organization with the request to forward the questionnaire to embryologists, in order to promote the survey. In continuation, the authors employed the contact platforms available online in websites of IVF clinics to reach IVF professionals worldwide. Three thousand seven hundred and twenty-four (3724) IVF clinics worldwide were contacted. Table ​ Table1 1 of the “ Result s” section provides information on the number of IVF clinics contacted per continent, along with the respective responses from individual practitioners. Finally, in order to reach a wider audience and increase participation, the questionnaire link was posted online employing social media platforms such as special interest groups in LinkedIn and Facebook. It should be highlighted that providing a response rate could not be attempted herein. This is thoroughly explained in the dedicated limitation section that follows. The reason behind this limitation is that the responses correspond to individuals participating in the survey and are not representative of IVF units.

Number of IVF units contacted per continent along with respective responses contributed by individual practitioners

The answers were collected and analyzed in order to unfold trends and patterns on embryo disposal practices around the globe. Analysis of the responses was automatically conducted through the program employed by Google forms and was presented in the format of pie charts. Institutional Review Board approval was not required for this study as it did not involve human or animal subjects or collection of personal data.

Following contacting via e-mail the 68 Reproductive Medicine Organizations and Associations, the authors proceeded with e-mailing IVF clinics on a worldwide scale. Overall, 3724 e-mails were sent. A total of 391 IVF units were contacted in USA, 86 in Canada, 87 in Central America, and 297 in South America. A total of 1787 IVF units were contacted in Europe, 151 in Africa, 812 in Asia, and 113 in Australia (Table ​ (Table1). 1 ). Subsequently, the authors proceeded with posting the questionnaire online in social media platforms. Following an 8-month data collection period, the Google form platform was inactivated to collect and analyze data. A total of 703 filled-in questionnaires from 65 different countries that are listed alphabetically in supplementary material Table 1 were acquired. Overall, Europe followed by USA yielded the highest number of responses being 351 and 186, respectively. The number of responses is categorized by continent and county and is available in supplementary material presented in Tables 2 - 5 .

The results’ analysis is presented categorizing the responses with regard to the three aspects that the questionnaire aimed to investigate and report on namely: “How and when embryos are discarded,” “Approaches employed to accommodate patients’ requests,” and “Embryologists’ perspectives on implementation of a universal protocol for discarding embryos.”

With regard to the actual protocol, the preferred method regarding embryo disposal of surplus embryos of a fresh IVF cycle was reported to be “place them in a trash can strictly dedicated for embryo disposal” (39%) followed by “leave them on the bench prior to disposing in a trash can” (30.8%) and “use ethanol prior to disposing them in a trash can” (3.4%) (Fig. ​ (Fig.1). 1 ). The remaining 26.8% of respondents reported on a different practice for this procedure contributing to a list of different approaches documented herein (Table ​ (Table2). 2 ). Regarding cryopreserved embryos, the majority of embryologists opt to “place the carrier in a trash can strictly dedicated for embryo disposal while still frozen” (36.7%), followed by “leave the carrier on the bench prior to disposing the embryos in a trash can” (22%). A 17.7% of practitioners opt to “thaw embryos and leave them on the bench prior to disposing in a trash can.” The remaining 20.3% responded by describing a different practice for this procedure contributing to a list of different approaches (Table ​ (Table2 2 ).

World map presenting the allocation of the answers for questions 1,2,3 and 4

A representative list of responses reporting on the section of the questionnaire that inquired on “different practices”

With regard to the timing and the routine of the discard practice, the vast majority of practitioners opt to “discard embryos separately, case by case at different time points during the day” (66.4%) (Fig. ​ (Fig.1). 1 ). Nineteen-point seven percent (19.7%) “discard embryos cumulatively, at the end of the day (including all cases),” and 5.4% are performing a “single embryo disposal,” while 8.5% of the practitioners responded by describing a different practice (Table ​ (Table2). 2 ). The preferred time-point for embryo disposal was “wait until day 6 of the embryo development and then discard the embryos” (54%). A 19.2 % of the embryologists discard the surplus embryos “following cryopreservation-if employed” whereas a 7.9% discard the embryos “following embryo transfer.” Interestingly, 18.9% responded by describing a different approach (Table ​ (Table2). 2 ). The majority of IVF laboratories do not opt for a set-up employing a special incubator allocated as a waiting space (65.5%). Most importantly, embryo disposal in most laboratories is a witnessed procedure (63.1%), which is in compliance with a detailed Standard Operating Procedure (SOP) (54.3%).

Following on the report on Approaches employed to accommodate patients’ requests, the vast majority of laboratories does not operate different disposal protocols for different groups of patients (93%) and has not been asked to perform any special ceremony (82.2%) (Fig. ​ (Fig.2). 2 ). The ceremonies that have been requested are presented in Table ​ Table2 2 .

World map presenting the allocation of the answers for questions 5,6,7,8 and 10

Considering the final part of the survey reporting on the Embryologists’ perspectives on a universal protocol for discarding of embryos, it appears that most of the participants believe that the embryology practice would benefit from a universal protocol regarding embryo disposal (59.5%) (Fig. ​ (Fig.3 3 ).

World map presenting the allocation of the answers for question 11 evaluating the personal opinion of the participants on whether they believe that “the embryology practice would benefit from a universal protocol regarding embryo disposal”

Limitations of the study

It may be presumed that despite the anonymity ascertained through the format of the questionnaire, social reasons may have led some respondents not to disclose practices that are less than socially acceptable. Debating on an issue of bioethical nature, it is understandable that the opinions of non-respondents may have varied significantly from those of respondents.

In an effort to reach IVF professionals, the anonymous questionnaire was forwarded via e-mail on communication platforms addressing associations, organizations, and IVF clinics, and individual practitioners were invited to participate. Throughout this process, difficulties were encountered in conducting this research in the context of ascertaining responses or even ascertaining acknowledgment of the invitation to participate. This fact leads to the authors not being in a position to report on which organizations may have forwarded the questionnaire, introducing possible bias. Ultimately, it was not possible to reach a greater audience through Associations and Societies, which may have enabled collection of a larger dataset. Failing to receive the volume of feedback that was originally anticipated by the authors may have been attributed to such difficulties.

Maintaining the anonymity of the participants was imperative and was ensured through the employment of the Google forms platform. In turn, this approach enabled reflection of the individual practitioners’ opinion and current practice. This data corresponds only to the stated country of practice and not to an individual IVF clinic. Further to that, methodology could not warrant that a party did not respond twice. This equally presents as a limitation. The general rules that apply when forwarding a questionnaire and collecting electronically sourced data stand for this approach similarly. The value of the analysis is based on the principle that a participant will provide true data on an individual basis as requested.

As indicated previously, responses do not correspond to IVF units but rather to IVF professionals. This may be serving as a confounder in analyzing the results, and translating them in trends representing IVF units. It is the authors’ perspective presenting this study, that the individual practitioners’ opinion must be voiced and evaluated in order to improve the scientific and clinical practice. In the current study, the currency is not the IVF practice, but rather the IVF practitioner.

The authors cannot provide the reader with a true response rate. This could not be possible primarily due to the fact the questionnaire was distributed through organization, associations, IVF units, and social media platforms. One cannot extrapolate that the communication effort referring to a single e-mail sent on behalf of the authors corresponds to a single response.

An additional limitation in this survey is the language employed in the anonymous questionnaire. The English language is the lingua franca in the clinical and scientific field [ 29 ]. Nonetheless, the language barrier may be assumed to have served as an obstacle in sourcing data and reaching countries where English is not spoken, possibly resulting to lack of contribution from certain parts of the world.

This study highlights the existing diversity in human embryo disposal protocols employed in IVF laboratories worldwide. Following a comprehensive review of the literature, little has been published on embryo disposal practices on a worldwide scale. Gurmankin et al. in 2004 reported—for the first time—on the current embryo disposal practices in IVF clinics in the USA. This study highlighted the diversity regarding this laboratory procedure and the direct association to the existing controversial moral status of the human embryo particularly in the USA. During their survey, Gurmankin et al. mailed anonymous self-administered questionnaires to directors of 341 American IVF units yielding 217 responses [ 30 ]. In this report, the authors underline the variety documented regarding equally the laboratory practices for embryo disposal, along with the management of providing respective information to the couples, and their subsequent decision. Additionally, this study raises questions with respect to the rationale behind certain practices. “Could the moral sensitivity, ethical considerations and the controversial moral status of the human embryo in vitro influence and drive the practice?” The undefined moral status of the human embryo remains to be one of the most significant ethical dilemmas that has surfaced in the world of Assisted Reproduction Technology (ART) [ 31 ]. Although this immensely complicated issue is substantially discussed in the bioethical and philosophical literature, it remains unclear [ 31 ]. According to the current legislation dictating employment of human embryos in the USA, Australia, UK, and Europe, the human preimplantation embryo has very little or no independent moral status [ 32 ].

Both Thomas Douglas and Professor Julian Savulescu are renowned bioethicists and have contributed significant work which is recognized as world leading research in the field of medical and practical ethics. Addressing this complex subject of morality in human embryo research in 2009, they reported that all embryos are defined by a special moral value. This moral value is a pivotal component in the plan to form or extend a family and should be viewed as an essential factor when designing a study to fulfill a research purpose [ 33 ].

Clinical embryologists are being trained to culture, transfer, cryopreserve, or to discard human preimplantation embryos, while the moral status of human embryos in the very beginning of forming life remains undefined. Clinical embryologists may be viewed by some as acting to serve a higher purpose in an otherwise “grey” bioethical zone. In an effort to clarify this complex subject in 2017, John Janez Miklavcic and Paul Flaman exploring the personhood status of the human zygote, the embryo and the fetus, presenting as an undoubtable bioethical dilemma, argued that it is most reasonable to support the belief that the personhood status may be acquired at the point of human fertilization [ 34 ]. Based on the above, the bioethical status of the preimplantation embryo is undoubtable and deserves the respective courtesy and consideration. Even though aspects of practical nature may account as drivers of this diversity in shaping various practices of embryo disposal, considerations of moral and bioethical nature may be certainly implicated exerting a strong influence in defining practice. Perhaps the standing variety on disposal protocols, as evident by data sourced herein, may be potentially attributed to moral and bioethical perceptions surrounding the preimplantation embryo’s bioethical stance. Nonetheless, the present study does not allow for any direct associations to be drawn.

According to the “World Population Review,” there are 195 countries in the world hosting a population of 7,632,819,325 people that may inquire on infertility treatment in more than 3.564 IVF clinics worldwide. The standing legislation in the IVF World regarding embryo disposal protocols contributes significantly to a portraying a landscape of diversity. Legal frameworks vary between countries providing IVF services, a fact that serves as a restriction in clinical practice in certain cases, while at the same time fueling cross border reproductive care. Malta for instance is one of the countries that legislation does not permit embryo discarding. Instead, embryologists are allowed to inseminate up to three oocytes while all resulting embryos are required to be transferred [ 35 , 36 ]. It is this diversity indicated through data presented in this study that may strengthen the need for a common protocol on human embryo disposal.

The authors purposefully refrain from justifying or extrapolating on the responses collected; nonetheless, a critical analysis is attempted herein. This survey could be theoretically divided in three sections aiming to all-inclusively investigate the worldwide practice. The first section, including questions 1 to 6 and 8, focuses on how IVF practitioners perform embryo disposal of surplus embryos. In both fresh and frozen cycles, the majority of practitioners (39% regarding fresh and 36.7% regarding frozen cycles) dispose of the embryos by placing them directly in a trash can without thawing the embryos first in case of frozen embryos (Fig. ​ (Fig.1). 1 ). This may be viewed as the most straightforward and time-efficient option of performing the disposal. Such a practice maybe attributed to accommodating the hectic, time-demanding schedule commonly associated with IVF laboratories.

Information regarding the timing each laboratory chooses to discard the embryos as part of the disposal protocol was documented. Furthermore, 66.4% of practitioners discard the embryos separately, case by case , at different time points during the day, which similarly strengthens the scenario of favoring a straightforward practice instead of dedicating a special time during the day to perform this as a separate procedure (Fig. ​ (Fig.1). 1 ). In Table ​ Table2 2 among other practices, a longer than day 6 incubation time, prior to discarding the embryos, has been reported. Fifty-four percent (54%) of embryologists wait until day 6 to discard the surplus embryos (Fig. ​ (Fig.1). 1 ). Such an approach may ensure practicing the act of disposal in a safe fashion, as D6 signals the end of the embryo culture. The longest time reported in this study was the 14-day suspension of surplus embryos in the incubator environment, always in accordance to the 14-day limit with regard to maintaining human embryos in culture [ 37 ]. It has been years since the paper published by “Nature” on being able to study embryos in the laboratory for 14 days. Understandably, the possible requirement to amend the 14-day rule or change it to a 28-day rule [ 38 ] has already been reported [ 39 ].

As reported in Table ​ Table2, 2 , there are various protocols employed worldwide for discarding human embryos in fresh and in cryopreserved cycles during infertility treatment. Ethanol or water may be implemented in order to proceed with degeneration of embryos on the bench. Implementation of the “grave yard” incubator was described in our results. Nonetheless, 65.5% of practitioners do not use a special allocated incubator as a “waiting space” prior to the disposal procedure (Fig. ​ (Fig.2). 2 ). A specially allocated waiting space could perhaps not be a feasible option for an IVF laboratory where allocating incubator space may be difficult.

Through this survey, 63.1% of embryologists reported that embryo disposal is a witnessed procedure, while 54.3% reported that a detailed SOP for this procedure is in place (Fig. ​ (Fig.2). 2 ). Although the majority of the clinics (54.3%) refer to the procedure employing an SOP, this result may signal an alert and classify this as non-optimal practice. Ideally, percentages referring to both witnessing of the procedure and employing a detailed SOP for the disposal procedure should be closer to 100% ensuing a safe and effective practice minimizing room for error.

In the second part of the survey, questions 7, 9, and 10 assess the various approaches employed in order to satisfy patient requests or requirements in regard to embryo disposal (Fig. ​ (Fig.2). 2 ). As mentioned above, in order to mitigate the abandoned embryos scenario, IVF clinics request that couples proceed with an embryo disposition decision (EDD). Embarking on such a decision may be highly challenging for couples as they may encounter difficulties in committing to any of the provided options. They may often get emotional experiencing feelings of regret about making the wrong decision. Occasionally, further options may be required to be presented if the standard protocol of embryo discarding fails to meet the couples’ needs [ 31 ]. The couples’ psychology during infertility treatment is of utmost importance and respective attention must be provided. It has been reported that couples may consider their embryos as their unborn children or even existing children [ 24 , 40 – 42 ]; hence, the process of grief for the loss when their embryos have to be discarded is a reality. Taking into consideration this psychological perceptive, it may come as no surprise that this survey verifies—as anticipated—that it is not rare for IVF practitioners worldwide to be asked for burial services, prayers prior to discarding the surplus embryos, or even the option for the embryos to be released to the couple presenting them with a “take-home” option. The general population is familiar with the options that death may be followed by burial or cremation according to the person’s beliefs and will [ 43 ]. Interestingly, optional burial services can nowadays be provided by specific funeral homes that offer a service described as a corporal and spiritual care for the so-called embryonic human beings. In recent years, the option of swirling ashes into glass art creations available from companies has even become available and communicated through social media. Should the preimplantation embryo be allowed the same burial options? Should human life be considered equal from the first hours of the zygote formation to the point that death by natural causes takes place? May such questions claim answers or at least a thesis from the scientific community of clinical embryologists who are being called to discard the supernumerary preimplantation embryos? These questions merit an analysis on the bioethical perspectives raised in this context. Nonetheless, such an approach is not attempted herein, as this study focuses on presenting the various practices, trends, and opinations rather than analyzing the respective issues stemming from this practice in light of the bioethical stance of the preimplantation embryo.

Notably, the majority of practitioners (93%) responded that they do not employ different protocols for different groups of patients, while 17.8% reported that they have been asked to perform some kind of a ceremony for disposal of these embryos (Fig. ​ (Fig.2). 2 ). In particular, some practitioners have reported performing a religious or quasi-religious disposal ceremony. Some clinics require the couple’s participation in disposal, some allow it but do not require it, while other clinics discourage or forbid it. All these documented requests from patients with different religious concerns raise questions on whether and how could religious ceremonies be adopted in IVF clinical routine practice. If so, should these ceremonies be practiced as an individual exception treatment following a special request, or should all couples irrespectively be presented with the option in a horizontal fashion?

This survey additionally raises questions regarding the rationale, the driver, and the need fueling certain clinical practices. Why do certain protocols require cryopreserved embryos to thaw prior to their disposal? Do they regard this practice as one following a more natural course regarding the physiology of the embryo? How does the scientific community respond to certain protocols allowing and encouraging couples to proceed with discarding their own surplus embryos, while other protocols consider this practice as deviating from standard procedure? Such major discrepancies may significantly differentiate the clinics, and what may merit further investigation is whether disclosure of the embryo disposal protocol by the clinics could serve as an incentive for couples in reaching an informed decision when contemplating which IVF unit to pursue treatment in. As literature fails to provide evidence, while nothing systematic has been reported, the couples’ role in this remains ambiguous.

The third and last section of the survey, including question 11, aims to assess the embryologists’ perspective. As a result, more than half of the practitioners (59.5%) contributing to this survey reported that the embryology practice would benefit from a universal protocol (Fig. ​ (Fig.3 3 ).

Our results, along with the practices presented in Table ​ Table2, 2 , highlight the divergence between the reported practices. This is heightened in light of the fact that all the reported percentages are close to 50% indicating that there is clearly “room” for variety in practice. Notably, no option achieved a true majority status by percentages over 50%. Albeit practicing clinical embryology may entail that diversity is acceptable and in fact a coveted quality trait in an embryologist, on the subject of embryo disposal practices, the clinical embryology field would certainly benefit from more consistency rather than diversity. The majority of IVF clinics worldwide identify as a principal priority cryopreservation of surplus embryos. Our results present that practitioners diverse in protocols regarding management of supernumerary embryos, responsibility for disposal, and use of ceremonies employed during the disposal procedure. Variation was also noted in allowing the couples’ involvement in the disposal procedure itself or alternatively in keeping it strictly a laboratory routine procedure. Despite its limitations, this study uniquely provides insight into global embryo disposal practices and trends and raises questions bearing on the standardization and perhaps the possibility of regulation of clinical practices, while strengthening the need for defining and concurring on a commonly accepted universal protocol. From another perspective, the practice of embryo disposal may unquestionably harbor religious concerns which may influence and define practice accordingly [ 44 ]. Nonetheless, concerns of bioethical nature related to the practice may be argued in light of the fact that the process employed to discard an embryo may not be viewed as being associated or affecting the final status of the embryo. This perspective may render the presently documented divergence on the disposal practices as of limited consequence. A key parameter in attempting to define optimal practices in discarding IVF embryos is concurring on the status of the preimplantation embryo. As this remains unclear, the need for adopting a universally accepted practice may be in return strengthened.

In regard to the standing diversity on disposal protocols, this data may serve as the trigger for design and conduction of innovative multi-sectional studies. Future studies may attempt a multifactorial approach in depicting the current status on embryo disposal practices. This would enable an all-inclusive portrait encompassing various levels of the practice and their respective associations. Surveys could focus on evaluating practical issues regarding embryology practice, along with quality and safety issues, and further entailing psychological perspectives, ethical reflections, along with religious concerns surrounding the practice of disposal in light of the bioethical stance of the preimplantation embryo. Most importantly, it would be interesting to analyze viewpoints focusing on the perceptions concerning equally both sides, the practicing embryologists and the patients. Overall, this article contributes significantly to the literature addressing disposition of surplus embryos. The authors attempt to highlight the notable variability among IVF practice on a global scale. This study may serve as an incentive to consider the value of a commonly accepted protocol, especially as results articulate the importance of implementing standardization regarding embryo discard practices.

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Acknowledgments

We are very appreciative to all embryologists, clinicians, and scientists at the Department of Physiology of the National and Kapodistrian University of Athens Medical School, at the Centre for Human Reproduction at Genesis Hospital, and at the Assisted Conception Unit of the 2nd Department of Obstetrics and Gynecology at Aretaieion Hospital. The authors also thank Dr. Gerry Celia Laboratory Director and Assistant Professor at Jones Institute at Eastern Virginia Medical School in Norfolk for sharing the survey in order to reach embryologists on a global scale. Finally, we acknowledge the input of all practitioners taking the time to contribute to our survey by sharing their protocols and practices.

Compliance with ethical standards

The authors declare that they have no conflict of interest.

M. Simopoulou and K. Sfakianoudis joint first authorship.

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