Human embryo models made from pluripotent stem cells are not synthetic; they aren’t embryos, either

Updated on 2023-10-23 21:44:37 90 0

· Hannah L. Landecker

· Amander T. Clark

· Embryo models are potentially highly impactful for human health research because their development recapitulates otherwise inaccessible events in a poorly understood area of biology, the first few weeks of human life. Casual reference to these models as “synthetic embryos” is misleading and should be approached with care and deliberation.

· Main text

· Introduction

· Human stem cell-based embryo models (embryo models) are organized 3D assemblies derived from diploid cells that recapitulate aspects of structured embryo development occurring in the pre-implantation and early post-implantation stages of human life. These cellular assemblies have captured the imagination of researchers as an appealingly tractable and controlled approach to understand infertility and early pregnancy loss, the earliest events in human embryo development, or the differentiation of cells in vitro. Traditionally, researchers studying the first weeks of human development have relied on disorganized stem cell differentiation in 2D or 3D or extrapolations from mammalian models, all the while knowing that enormous evolutionary differences have arisen in the tissue and in molecular strategies associated with early embryo development across species. The research community has long recognized a need to develop scientific models that more accurately reflect the beginnings of human life itself to arrive at sophisticated technologies and therapies for human health.

· Embryo models are made from human biological materials and they are explicitly intended to serve as models of early human life. They are surrogates

· whose use depends exactly on their status as not human embryos. They must be similar enough to human embryos to stand in for them in the study of otherwise inaccessible developmental stages relevant to questions of infertility, reproductive health, and stem cell biology; and yet dissimilar enough such that they are decidedly not the same as human embryos that develop in the reproductive tract. Unfortunately, early media coverage and some scientific discussion of these embryo models has landed on the descriptor “synthetic embryo,” a term that we believe is inaccurate, disrespectful, and potentially harmful when the intent is to generate surrogate models of human life without any intent for reproductive use. Here, we argue that the naming of such entities at the dawn of their more widespread use is critical for responsible and accurate science communication and for establishing rational regulatory frameworks that can enable the science to move forward with public trust.

· Human embryo models are not synthetic

· Embryo models are made from human pluripotent stem cells (PSCs). This process could involve starting with human embryonic stem cells (ESCs), derived from pre-implantation embryos, or human induced PSCs, derived from a sample of human tissue that has been reprogrammed or partially reprogrammed to a pluripotent state. Using these starting materials, embryo models can be generated in a variety of ways. Some involve differentiating the human PSCs on engineered devices or specialized tissue culture plates. In other examples, embryo models are generated by differentiating human PSCs or partially reprogrammed cells into trophoblast and primitive endoderm cells before combining these cell types with PSCs to promote cellular interactions and organized differentiation. Once made in the lab, embryo models are classified in two ways: non-integrated and integrated.

· The term “synthetic embryo” emerged with increasing frequency after a 2016 meeting in Paris called “Engineering the embryo.”

· Although “synthetic” has a range of connotations, many of them positive, the public is likely to understand it in terms of synthetic chemistry and products such as plastics, “forever” chemicals, and imitations of natural products, such as synthetic leather. Moreover, “engineering embryos” further amplifies an image of scientist-as-Creator, linked to the temporally concurrent, but rather unconnected, biotechnological field of endeavor called synthetic biology. Synthetic biology includes major initiatives aimed at redesigning and constructing new cells and organisms for useful purposes, usually through modifying and rearranging DNA.

· Major synthetic biology projects include the generation of bacteria or Saccharomyces cerevisiae. Importantly, the “engineering” inherent in these projects is almost exclusively directed at generating new-to-nature genes and chromosomes, with the assumption that the cellular components, and thus the cells and organisms that these engineered genetic constructs give rise to, will follow the instructions built into them by the scientist at the DNA level.

· Given how current embryo models are made, is it warranted to refer to them as “synthetic”? Certainly, broad connections arise between embryo models and synthetic biology from speaking in terms of “engineering” in both cases, with its emphasis on building and designing. It was an explicit “engineering ideal” for biology that gave rise to Jacques Loeb’s artificial parthenogenesis experiments of the 1890s, which caused a media stir around the “creation of life.” We might draw a direct line from Loeb’s “technologies of living substance” to today’s embryo models in both science and its public understanding.

· At the same time, just because one is led by association to “genetic engineering,” and thereby to “synthetic biology,” it is not inevitable—nor is it desirable—to accept this train of thought. Why recapitulate the story of hubris and unwarranted claims to total control of life visible in Loeb’s parthogenic sea urchins that fed into public suspicions about scientists playing God?

· Moreover, important differences exist between the approaches central to synthetic chemistry and biology and the generation of embryo models through stem cell technologies. Researchers derive embryo models using donated human biological materials from in vitro fertilization (IVF) laboratories or patient biopsies. They apply what is known about derivation, reprogramming, and differentiation to coax and elicit certain biological trajectories, often dependent on the cells’ capacities for self-organization or inherent behaviors, to generate models that recapitulate developmental sequences. They are not built with artificial chromosomes. They do not arise de novo from new-to-nature DNA sequences put together entirely in a PCR machine. The term synthetic, denoting that which is made in the laboratory by combining chemical substances or referring to an artificial substitute for a natural product, might be appropriate when creating microbial cells with defined properties, but it is a poor fit for embryo models. Along with other stem cell technologies, such as organoids, embryo models are cellular assemblies, as much enabled as they are “built.”

· Embryo models are not embryos; they are models

· The second failure of the phrase synthetic embryo lies not only in the adjective, but in the noun. Given the current state of the technology, this term improperly suggests equivalency between the construct and the human embryo generated by fertilization. This suggestion leads observers to wrestle with the impossible yes-or-no question of whether these entities could one day be human embryos by scientific or legal definitions. By contrast, this second half of our commentary presents the positive case for the intentional and careful choice of language for embryo models. Here the noun—the thing being named—is a model, and the purpose of that model is front and center. From this starting point, we begin to address the questions we think researchers should be asking one another and communicating to the public: are these good models? What are they for? In whose service are they being made? Is their existence warranted by their current or potential role in knowledge production and the improvement of clinical care? Such close attention to grammar may seem pedantic, yet what is at stake is of enormous consequence both for science communication and the question of legal regulation in this new arena of scientific endeavor.

· The language of embryo models emerged in 2017 when “embryoid model” was coined to describe a non-integrated, amniotic sac model made from human PSCs.

· The term was carried forward by scientists and bioethicists to describe the emerging 3D models generated from mouse PSCs,

· and it was solidified by a 2020 National Academies of Science meeting, “Examining the State of the Science of Mammalian Embryo Model Systems.”

· Why is it better to think of these as models, and not straightforwardly as embryos, just made by a different route? The first answer is simple and points toward a certain humility concerning our current ability to recapitulate the early stages of human life. To date, these entities are likely very far from functional.

· In short, asking what these entities are models of, and whether they are good models in the sense of fidelity or utility, is essential for critical assessment of the work that remains to be done and realistic communication of the state of the field. The formation of human embryos in the body occurs in the fallopian tubes of the reproductive tract. Fertilization by sperm triggers the oocyte to complete meiosis II, releasing a second polar body and generating a zygote, a single cell encased in a thick extracellular matrix shell, called a zona pellucida. The zygote is diploid in that it contains chromosomes from both gametes enclosed in their own pro-nuclei. Once formed, the zygote undergoes a cleavage division forming a 2-cell embryo, which continues to cleave into smaller and smaller cells generating a morula-stage embryo, which undergoes compaction to generate the blastocyst encased in the zona pellucida. Currently, none of the embryo models have a zona pellucida; they do not develop from an oocyte, sperm, or zygote; they do not undergo embryonic genome activation or compaction; and they have missing cells, or in some cases extra cells with unknown identity.

· The second reason to lean into the status of these entities as models is to foreground their purpose. Why should we make an embryo model? The answer is the potential these models offer in developing knowledge or procedures to address human suffering. Some specific examples include infertility, a condition currently treated by IVF, yet success rates have not improved in decades. Other examples are developmental disorders, such as autism, which are complex diseases, often with unknown etiologies, speculated to arise in the first weeks of pregnancy. Early miscarriage is another common incident that would benefit from knowledge about non-genetic causes. In addition, pre-eclampsia and pregnancy complications can cause significant risk for mother and fetus, if untreated. Finally, stem cell research might benefit, as researchers may find that the differentiation of cells derived from embryo models has increased clinical utility compared to current differentiation approaches.

· The third reason to foreground the model is to face head-on the legitimate concern that one day the proxy will become indistinguishable from the original, and the line between human embryo model and human embryo will disappear. This discussion, exacerbated by the unfortunate nomenclature of the “synthetic embryo,” has focused primarily on the ontological status of these laboratory entities as embryos. Instead, the question “Is it a model?” should precede “Is it an embryo?” in the task of generating responsible oversight and regulation of embryo modeling. If it is not a model and has a purpose other than increasing knowledge about human reproduction, early development, and stem cell biology, or it is pushed toward biological features that are not essential to the activity and purpose of modeling, then it should not exist, regardless of current or future similarity or non-similarity to human embryos.

· Whereas regulating the activity of embryo modeling and the ontological status of the model are of course related, emphasizing who and what the model is for, in terms of knowledge or clinical care, better equips us to include and engage tissue donors, scientists, and potential beneficiaries as stakeholders. There are precedents for the consensus-driven regulation of embryo modeling. Cloned embryos are generated in an embryology lab by the transfer of a diploid somatic nucleus into an enucleated oocyte. The purpose of creating cloned embryos was to demonstrate the possibility of human nuclear reprogramming, a key step to the later widespread technology of induced reprogramming to generate human induced PSCs, which transformed stem cell research. Due to an international consensus, and in some jurisdictions laws that prohibited the transfer of cloned human embryos to a uterus, a regulatory framework allowing some research with cloned embryos as a model was established. Action around the prohibition of the transfer of embryo models into a uterus seems a sensible precautionary step, regardless of the state of the science. Moreover, it would underline the point that the purpose of these models is to address human suffering, not to create human beings.

· By spotlighting the status of embryo models and the purposes toward which they are being developed, researchers will be better positioned to navigate the definitional swamp that faces human embryo research. Many embryo definitions are already strategic in that they include the scientific or medical purpose in the definition. A position statement led by the International Committee for Monitoring Assisted Reproductive Technologies that includes professional societies that perform reproductive care in Europe, Asia, Africa, Middle East, USA, and Latin America defines the embryo as a biological organism resulting from the division of a zygote and ending 8 completed weeks after fertilization or 10 weeks of gestation.

· The decision to refer to the beginning of an embryo at the 2-cell stage (and not the zygote) enabled reproductive care in countries where embryo cryopreservation was not allowed.

· Paradoxically, the challenge that engenders the need for such models—working on natural human embryos in these early stages or in vivo—also makes it difficult to know just how similar or different they are to a natural embryo. As with other biotechnologically generated reproductive materials, using legal definitions to determine whether embryo models are embryos simply leaves one with the answer that it depends on the definition and jurisdiction. Such misfit between scientific and legal definitions stalls research and publications, leaving embryo models to linger in regulatory uncertainty. This limitation indicates the need for publicly engaged, scientifically honest discussions about where embryo models stand in existing regulations and the steps to develop guidelines where none exist.

· The conversation we should be having

· In light of these arguments, we suggest that the research community would be best served by the existing plain-spoken and direct terminology of the embryo model. There are reasons beyond accuracy for this choice. First, the use of synthetic is disrespectful to the human origins of the materials and to the donors’ intentions, whose predominant motivation, documented in qualitative studies, is to provide embryos or tissues for research with the belief that their cells will help others.

· Regardless of whether these donors ever know that the donated cells end up as embryo models, we should not be emphasizing the scientist as Creator in this narrative. Open and respectful characterization of these entities as models, given shape by science, that play a crucial role in knowledge production is preferable to pretensions that they originate purely from the hand of the inventor. We need to discuss and amplify all the different senses in which embryo models are composed of human materials and imbued with human intention. This debate is a launching point for a more concerted public participation in and discussion of this science, not the point at which to shut it down by obscuring the material origins of research tools.

· Second, we must not lose sight of the fact that these are models, used as proxies to investigate questions of human health. We have argued that it is inaccurate to call embryo models synthetic. It is doubly misleading to use the term embryo as a noun unmodified by any term other than synthetic. By contrast, continued insistence on the model keeps the question of intention front and center: models of what? For whom? The value of highlighting and exploring the differences between human embryo models and human embryos proper is an important step for scientific humility about the power and limits of these tools. It also emphasizes the questions that these proxies could answer: understanding and alleviating infertility and recurrent miscarriage, fostering developmental health, or improving stem cell differentiation. Calling these entities “synthetic embryos” or muddying the waters with Frankenstein narratives might make for good headlines in a news cycle, but it inaccurately portrays the science as being bent on the making of replicant human beings. The purpose of embryo models is not to make human beings from in vitro entities. The purpose is to use them to explore human biology in ways that are not harmful to nascent or actual human persons.

· Concerns have been voiced that these embryo models could potentially cross the line between human embryo models and human embryos.

· This is reason enough to continue to insist in both word and deed that the aim is to make a good model, not to make persons. Models must allow the accurate study of early development and implantation biology with living human materials yet be constrained by accepted measures that limit threats to social and ethical boundaries around personhood. These boundaries will always be contested. However, their open and inclusive debate is best served by honoring the human origins and intent of the donated materials with which embryo models are made, highlighting the need to which these models answer, and dispensing with hubris as a starting principle.

· Acknowledgments

· We would like to gratefully acknowledge the support of the NIH-NHGRI National Human Genome Research Institute R21HG012248-02 (H.L.L. and A.T.C.) and the NIH-NICHD Eunice Kennedy Shriver National Institute of Child Health and Human Development R01HD079546 (A.T.C.).