A Quick Guide to Embryo-Like Things: Products and Processes


Editor's Note: The following is a supplemental resource to Heather Zeiger, "Embryoids: Unique Entities or Protected Like Human Embryos?" Dignitas 24, no. 4 (2017): 9–12.




Product

Biological Artifact Cloned Embryo

Process

Alterred Nuclear Transfer (ANT) Somatic Cell Nuclear Transfer (SCNT)

Defining

Features

When first published, altered nuclear transfer (ANT) was theoretical. Today's embryoids may or may not satisfy the criteria for ANT. This process involves a reprogrammed somatic nucleus with unpredictable results sometimes resulting in nucleus + oocyte = hybrid cell; no global organization and will not re-establish whole organism

Somatic cell nuclear transfer involves a reprogrammed somatic nucleus with unpredictable results sometimes resulting in nucleus + oocyte = embryo; these go through developmental steps

Source

(Human

Unless Noted)

oocyte + genetically modified somatic cell nucleus

oocyte + somatic cell nucleus

Reference

William Hurlbut presentation to the President’s Council on Bioethics, “Altered Nuclear Transfer as a Morally Acceptable Means for the Procurement of Human Embryonic Stem Cells” December 2004; and Maureen Condic, “Alternative Sources of Pluripotent Stem Cells: Altered Nuclear Transfer” Cell Proliferation 41 (2007), doi: https://doi.org/10.1111/j.1365-2184.2008.00484.x.

Maureen Condic makes a distinction between ANT and SCNT in Maureen Condic, “Alternative Sources of Pluripotent Stem Cells: Altered Nuclear Transfer” Cell Proliferation 41 (2007), doi: https://doi.org/10.1111/j.1365-2184.2008.00484.x.

Ethical

Considerations

Some have questioned whether or not these would be severely disabled embryos?

These produce an embryo that, based on animal models, can grow into a fetus and eventually result in a live birth.

 




Product

Embryoid

Synthetic Embryo

Process

  Gametogenesis

Defining

Features

“We consider the term embryoid [as opposed to embryoid bodies] to represent a more organized embryoid body that arises as a consequence, for instance, of cell polarization induced by the [extracellular matrix] in the surrounding medium or due to the correct topology of multiple cell types representing an embryo at a certain time of development.”

This is still theoretical. Scientists have not been able to make synthetic human gametes from skin cells, though they have done this in mice. In 2014, scientists made primordial sperm cells from skin cells

Source

(Human

Unless Noted)

Embryonic Stem Cells (ESCs)

Induced Pluripotent Stem Cells (iPSCs) or iPSCs + Gamete

Reference

Quote from review article: Mijo Simunovic and Ali Brivanlou, “Embryoids, Organoids and Gastruloids: New Approaches to Understanding Embryogenesis,” Development 144 (2017): 977, doi: 10.1242/dev.143529.

Rob Stein, “‘Provocative’ Research Turns Skin Cells into Sperm,” All Things Considered, NPR May 1, 2014; Cyril Ramathal et al., “Fate of iPSCs Derived from Azoospermic and Fertile Men following Xenotransplantation to Murine Seminiferous Tubules,” Cell Reports 7, no. 4 (2014): 1284–1297, doi: https://doi.org/10.1016/j.celrep.2014.03.067; Antonio Regalado, “A New Way to Reproduce,” MIT Technology Review August 7, 2017.

Ethical

Considerations

Made from embryonic stem cells, which if derived from a human embryo is an unethical stem cell source. Also, it is not clear whether or not this is an embryo.

Several ethical issues outlined in referenced articles: 1) Any person can become a parent without a partner, regardless of gender; 2) The ability to produce a child from a single person; 3) The potential to “steal” genetic material from someone and copy their gametes; 4) Raises questions about what this might mean for familial lines; 5) Broad questions about potential eugenic uses and embryo selection.

 




Product

Gastruloid

Embryoid Body

Process

Micropatterned  

Defining

Features

Micropatterned into colonies of controlled size and shape. When they are spatially confined, form embryo-like features. When they are not spatially confined, they do not. Primitive streak forms before the 14-day mark and appears circular rather than linear. Three germ layers form after the activation of BMP4. Review article says that these are models of a gastrulating embryo either in 2D or 3D.

“Embryoid bodies have been widely used for some time as models of early development, and typically are disorganized 3D clusters of pluripotent or differentiated cells.”

Source

(Human

unless noted)

Embryonic Stem Cells (ESCs, specifically research by Warmflash et al.)

 

Reference

Aryeh Warmflash et al., “A Method to Recapitulate Early Embryonic Spatial Patterning in Human Embryonic Stem Cells,” Nature Methods 11, no. 8 (2014): 847– 854, doi: 10.1038/nmeth.3016; Reviewed in Mijo Simunovic and Ali Brivanlou, “Embryoids, Organoids and Gastruloids: New Approaches to Understanding Embryogenesis,” Development 144 (2017): 977, 982, doi: 10.1242/dev.143529.

Quote from review article: Mijo Simunovic and Ali Brivanlou, “Embryoids, Organoids and Gastruloids: New Approaches to Understanding Embryogenesis,” Development 144 (2017): 976–977, doi: 10.1242/dev.143529.

Ethical

Considerations

These are not embryos, but could lead to the production of synthetic embryos. Made from embryonic stem cells, which if derived from a human embryo is an unethical stem cell source.

Difficult to reproduce exactly. Because these seem to be “disorganized” they are probably similar to the products of ANT.

 




Process

Parthenotes 

Organoid

Product

Parthenogenesis Self-Organization (General)

Defining

Features

When an oocyte is artificially activated, it forms an embryo that cannot make a placenta because it is lacking male gamete genetic components (based on mouse studies). “The establishment of parthenogenetic clinical grade human embryonic stem cell lines for use in cell or tissue therapies will only be possible, if research laboratories obtain enough biological material from ART centers to evaluate activation strategies, derivation, and culture media adequate for future therapeutic use of phESC lines.”  (Bos-Mikich et al.) Parthenotes are indistinguishable from naturally fertilized embryos, but cannot develop to term.

Three-dimensional cluster of a particular cell type; “a structure in which pluripotent or progenitor stem cells are differentiated into multiple cell populations that self-organize/assemble into a tissue that resembles an organ in vivo.”

Source

(Human

unless noted)

Oocytes

iPSCs or ESCs

Reference

Quote from Adrian Bos-Mikich et al., “Parthenogenesis and Human Assisted Reproduction,” Stem Cells International (2016), doi: http://dx.doi.org/10.1155/2016/1970843; see also Jason Hipp and Anthony Atala, “Tissue Engineering, Stem Cells, Cloning, and Parthenogenesis: New Paradigms for Therapy,” Journal of Experimental & Clinical Assisted Reproduction 1, no. 3 (2004), doi: https://doi.org/10.1186/1743-1050-1-3.

Quote from Mijo Simunovic and Ali Brivanlou, “Embryoids, Organoids and Gastruloids: New Approaches to Understanding Embryogenesis,” Development 144 (2017): 976 –985.

Ethical

Considerations

Seems to produce a damaged and nonviable embryo. Additional ethical issues surrounding how oocytes are obtained.

Difficult to reproduce two similar organoids. Do these actually mimic in vivo tissues? Sometimes these are made from embryonic stem cells and the related ethical concerns with such sources.

 




Process

PASE  (Post-Implantation Amniotic Sac Embryoid) also referred to as “Asymmetric Cysts”

Artificial Embryo

Product

Biomimetic 3D Culture 3D Scaffolding and Genetic Modification

Defining

Features

Epithelial cyst similar to amniotic sac; human amniotic ectoderm-like tissue (the ectoderm is the germ layer that ultimately forms the nervous system and skin layer).

“the PASE continues to develop through an active symmetry-breaking process that establishes the bipolar amniotic ectoderm-epiblast pattern, with the cyst wall continuously thinning only at the prospective amniotic pole. . . . Altogether, PASE development in vitro recapitulates the progressive, asymmetric morphogenesis, and cell fate patterning observed during peri- and post-implantation human amniotic sac development.”

PASE seems to form a primitive streak (change in cell type to mesenchymal cells). This presents the “first embryoid model for studying post-implantation human amniotic sac development, which is drastically different from that in mice.”

This has been done in mouse studies. “Here, we combine mouse embryonic stem cells (ESCs) and extra-embryonic trophoblast stem cells (TSCs) in a 3D-scaffold to generate structures whose morphogenesis is remarkably similar to natural embryos. By using genetically-modified stem cells and specific inhibitors, we show embryogenesis of ESC- and TSC-derived embryos, ETS-embryos [embryonic trophoblast stem embryos], depends on crosstalk involving Nodal signaling. When ETS-embryos develop, they spontaneously initiate expression of mesoderm and primordial germ cell markers asymmetrically on the embryonic and extra-embryonic border . . . . Our study demonstrates the ability of distinct stem cell types to self-assemble in vitro to generate embryos whose morphogenesis, architecture, and constituent cell-types resemble natural embryos.”

Source

(Human

unless noted)

hESCs (3 different lines) and an iPSC line

Mouse ESCs and Mouse Trophoblast Stem Cells

Reference

Quotes from Yue Shao et al., “A Pluripotent Stem Cell-Based Model for Post-Implantation Human Amniotic Sac Development,” Nature Communications 8, no. 208 (2017), doi: https://doi.org/10.1038/s41467-017-00236-w.

Quote from Sarah Ellys Harrison et al., “Assembly of Embryonic and Extra-Embryonic Stem Cells to Mimic Embryogenesis In Vitro,” Science March 2, 2017, doi: 10.1126/science.aal1810.

Ethical

Considerations

In their ethics statement: “The PASE model generated in this study lacks primitive endoderm and trophoblast, and thus cannot form yolk sac and placenta. In addition, there is no evidence of the presence of anterior [primitive streak] cells, endoderm cells, or [primordial germ cells] in this embryoid system. Instead, only posterior [primitive streak]/mesoderm cells are found (in addition to amniotic ectoderm-like cells and pluripotent epiblast-like cells). Therefore, the PASE model does not have human organismal form or potential. Furthermore, given that amniotic sac development starts on [day past fertilization] 7 in vivo, and that all experiments were terminated by no later than day 5 in vitro, the culture of PASE in this study terminates before effectively reaching 14 developmental days.”

Concern for genetic modifications that would be passed down. If this were ever done in humans, these would be made from embryonic stem cells. Also, similar ethical issues for gametogenesis, as this sounds like parthenogenesis + genetic modification.