Advancements in the Race to Develop Laboratory Models of Human Embryos: Prospects and Controversies

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The question remains an enigma in the scientific realm: How does an imperceptible human cell split and propagate, eventually culminating in the formation of a human body comprising over 30 trillion cells?

Human embryo development is still a largely mysterious and intricate process, beginning with the merging of sperm and egg. Although research on animals like mice, rabbits, chickens, and frogs has provided limited insights, the understanding of human embryo development, especially in the crucial initial month, remains largely unexplored due to strict regulations and controls.

Jacob Hanna, a professor of stem cell biology and embryology at the Weizmann Institute of Science in Israel, explains that while the remaining eight months of pregnancy primarily involve growth, the first month remains a mysterious and largely unknown stage of development. Gaining insight into this critical period would offer significant biomedical opportunities, enabling scientists to unravel the complexities of embryo development, ultimately leading to a deeper understanding of miscarriages, congenital birth defects, and the potential effects of medications taken during pregnancy. Remarkably, certain researchers propose a method to achieve this without relying on eggs or sperm.

Using the advancements in stem cell technology, laboratories worldwide are creating structures that resemble embryos - a collection of cells that function similarly to an embryo but are incapable of developing into a fetus.

The recent progress achieved in this field, resulting from years of meticulous scientific research, has generated both optimism and concern. This has triggered urgent discussions regarding the ethical implications of these models, including debates on how they should be treated in relation to human embryos and the potential for their misuse.

Scientists have successfully produced embryo-like structures in a laboratory setting. These cellular clusters, smaller than a grain of rice, signify the initial phases of human development, devoid of any organ formation. It is important to note that they lack both a functioning heart and a brain.

The most advanced models, which were unveiled in September by an Israeli team that Hanna was a part of, demonstrate all the vital cell types necessary for the development of embryos. These include the placenta, yolk sac, chorionic sac (outer membrane), and other tissues essential for embryo growth.

These structures were allowed to develop for eight days, reaching a developmental stage equivalent to the 14th day of a human embryo in the womb. This is a critical stage when natural embryos acquire the internal structures needed to progress to the next phase, which involves developing the precursor cells of body organs.

Hanna claimed that these models were the most precise ones developed thus far. Unlike models created by other teams, no genetic modification was performed to activate the genes required for producing various cell types. Only chemical nudges were utilized.

"It's not just about assembling the cells, and they're present," Hanna remarked. "But by observing the architecture, you also begin to notice intricate details." Hanna added.

Jacob Hanna, a professor of stem cell biology and embryology, pictured in his lab at the Weizmann Institute, Israel.

Courtesy Jacob Hanna/Weizmann Institute

How do you grow an embryo in a lab?

Hanna's team did not utilize fertilized eggs. Instead, they initiated their research with pluripotent stem cells, which are human cells with the capability to be transformed into various cell types and are extensively utilized in biomedical studies. A portion of these stem cells were obtained from adult human skin cells.

Subsequently, the team reprogrammed these cells into a state referred to as "naïve," which resembles the development of a natural human embryo on the seventh day when it implants itself in the uterus. The "naïve" cells were then categorized into three distinct groups.

One group, intended to form the embryo, remained untouched while the other two groups were stimulated using specific chemicals to activate genes responsible for the development of tissues necessary to support the embryo, including the placenta. Following two days, the three groups were then combined, according to Hanna.

"During the initial three days, there is not much visible progress, just a cluster of cells that are proliferating," he clarified. "However, by the fourth day, you can observe a definite structure taking shape, indicating where the embryo will form and where the yolk sac will be located."

In this image, taken on 22 May 2018 in Berlin, Germany, a researcher at the Max-Delbrueck-Centre for Molecular Medicine is seen handling a petri dish while observing a CRISPR/Cas9 process through a stereomicroscope. The photo, captured by Gregor Fischer/dpa and distributed by picture alliance via Getty Images, showcases the intricate work done in the field of molecular medicine.

Gregor Fischer/picture alliance/Getty Images

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By day seven, the synthetic human embryo models had formed aggregates consisting of approximately 120 cells, measuring about 0.01 millimeters in size. By day 14, the models had grown to contain around 2,500 cells and measured 0.5 millimeters in size.

According to Hanna and his team, these models accurately replicate the developmental process of an early embryo, acquiring all the necessary structures to initiate the transformation into a fetus. The internal organization of the models closely resembled the images found in embryology atlases from the 1960s. Furthermore, when the team applied secretions from the cells to a commercially available pregnancy test, the result was positive.

However, only 1% of the aggregated cells successfully underwent self-organization and formed an embryo-like structure. A significantly higher percentage would be required in order to enhance the usefulness of the embryo models for scientists. Hannah stated that achieving this goal is possible but would likely require several years of refining.

"I believe that these stem-cell based embryo models have immense potential for learning purposes. However, they currently have some limitations. The efficiency of their production is quite low, and it is crucial to significantly improve it to fully maximize the knowledge we can derive from these models," commented Peter Rugg-Gunn during a recent news briefing. Rugg-Gunn serves as the group leader and head of public engagement at the Babraham Institute, an institution dedicated to life science research.

What limitations exist for growing embryo models beyond 14 days, mainly due to the challenges and constraints of culturing these structures?

However, the significance of the 14-day mark lies in its designation as the cut-off point for permitted laboratory research on cultured human embryos. This restriction was put in place by the United Kingdom's Fertilisation and Embryology Act in 1990, as a response to public concerns regarding test tube babies and the ethical implications of disregarding the moral status of human embryos. Over time, the 14-day rule has been widely adopted by several other countries, gaining recognition as an internationally recognized ethical limit.

It is important to note that this restriction does not apply to stem-cell based embryo models, which the International Society for Stem Cell Research deems not to fall under the definition of embryos. However, the organization does emphasize the need for ethical oversight in research involving these models.

In the future, it may be feasible to utilize these models for studying human development beyond the 14-day threshold. Hanna and other research teams have successfully advanced mouse embryo models to a later stage. Hanna envisions the possibility of extending human embryo models up to 40 days in the future.

Nevertheless, according to Hanna, concerns of a dystopian nature suggesting that scientists utilizing these models aim to establish an alternative method of generating human life are simply the fabric of science fiction.

"People often assume that we are attempting to replace pregnancy or gestation with this embryo model. However, this is not our objective. Moreover, I believe it is highly unlikely that it will ever be possible," he stated.

Based on current research, it is evident that embryo models are still in their early stages and exhibit significant scientific disparities when compared to a human embryo. Furthermore, they lack the capability to develop into a fetus.

"Emphasizing the fact that these models are not embryos, the International Society for Stem Cell Research has included a guideline that strictly prohibits the implantation of any stem cell-based embryo into a human or animal uterus. This regulation has been endorsed by various jurisdictions and societies, affirming the need to forbid such practices," stated Robin Lovell-Badge, a professor and head of the Laboratory of Stem Cell Biology and Developmental Genetics at the Francis Crick Institute in London. Professor Lovell-Badge, who was involved in drafting the guidelines, expressed these views during a briefing.

A stem-cell-based human embryo model, produced by Hanna and his colleagues, at the equivalent stage of development to day six in a natural human embryo.

Courtesy Jacob Hanna/Weizmann Institute

An ethical alternative?

Human embryo models, particularly if they can be generated in large quantities, are considered by many scientists as an ethical substitute for research conducted on scarce and valuable human embryos typically obtained as a by-product of IVF.

"Due to their stem cell foundation, we have the ability to expand everything. We can conduct experiments on these models that would otherwise be impossible on precious and rare human embryos. This fundamentally alters the range of experiments we can undertake and the inquiries we can address," explained Naomi Moris, head of the Developmental Models Laboratory at the Francis Crick Institute in London.

Prof. Hayashi, Osaka University

Scientists have successfully generated mice from two male parents by developing eggs from skin cells. This groundbreaking achievement opens up possibilities for various applications, such as drug screening and research. Currently, pregnant individuals are frequently omitted from drug trials due to apprehensions about jeopardizing the well-being of both the parent and the unborn child.

Moris carried out experiments in her laboratory using embryo models to observe the reactions of these models to medications such as thalidomide, a drug previously marketed as a morning sickness treatment but known to cause birth defects.

The objective was to determine whether the embryo models are vulnerable to these toxic drugs during the early stages of development, and subsequently assess their potential use in screening unknown drugs, as Moris stated.

Moris acknowledged that the models should not be categorized as embryos due to their stem-cell origins and the absence of certain characteristics. Nevertheless, she pointed out the impossibility of confirming this categorization definitively.

The "golden experiment," which would involve implanting the model into a uterus to observe its growth, cannot be conducted. Without the ability to perform this experiment, researchers are unable to determine whether they have surpassed the boundary and entered the realm of what can be considered an embryo. According to Moris, this is a complex and challenging question that lacks a simple answer.

In the field, there is speculation about a potential "tipping point" where human embryo models could be provided with similar protections as actual human embryos. As scientific advancements close the gaps between these models and real embryos, this protection becomes more feasible.

Furthermore, it is conceivable that future stem cell-based models could accurately replicate the developmental milestones observed in the emergence of primitive neural folds, arm buds, and early heart-like regions. These milestones have the potential to develop into functioning heart tissue, circulating blood, and neurons. This information comes from a paper on the necessity for national policy and governance regarding human embryos, which was published in the journal Genetics & Development in August.

"With continuous advancements, ensuring that the models do not possess the ability to experience pain, consciousness, or viability will become progressively challenging," stated the authors of the paper.

"As a result, it is only natural that the public will soon pose relevant questions regarding the appropriate regulation of embryo models. Are scientists employing them in an ethically responsible, socially acceptable, and sufficiently accountable manner?"

Hanna believes that it is feasible to design and genetically alter human embryo models in a way that restricts their development, preventing the production of brain cells or heart tissue. This approach aims to provide scientists with a means to address certain ethical concerns.

Researchers unanimously believe that as the research progresses, the developing field necessitates more effective regulation to determine what ought to be allowed and prohibited.

According to Moris, it is evident that the law is significantly falling behind advancements in science and technology.

"I believe researchers are highly motivated to be at the forefront of progress and establish necessary regulations," she commented. "As scientists, we prefer working within defined boundaries, and it would be reassuring if we could align with public perceptions of our field. It would greatly enhance our satisfaction if there were explicit guidelines and regulations that govern our work."

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The Governance of Stem-Cell Based Embryo Models project in the UK, in which Moris is participating, has brought together academic researchers, legal scholars, bioethicists, and research funders to develop a set of guidelines for utilizing this technology. Moris mentioned that the group anticipates releasing a draft governance framework early next year.

Bobbie Farsides, a professor of clinical and biomedical ethics at Brighton and Sussex Medical School, who is also a member of the group, expressed her admiration for the fact that scientists are actively involved in addressing the ethical concerns.

"When I initially worked in these types of environments, it strongly gave the impression that society or the public were concerned, while the lawyers and regulators were attempting to address the concerns of the scientists," Farsides remarked. "What we have at present is the scientists themselves acknowledging the need to address the public's worries. They are contemplating self-regulation, determining the boundaries they should not cross. This shift represents a significant transformation."