Can We Make an Embryo in a Dish?

Induced pluripotent stem cells and embryonic stem cells are functionally equivalent, but should we be concerned about making embryos in a dish?

Induced pluripotent stem cells (iPSCs) have been hailed as the discovery of the decade, providing an ethical alternative to embryonic stem cells (ESCs). Both types of stem cells are pluripotent, which means they can potentially make all of the cells in they body. This is contrasted to totipotent cells, which can give rise to an entire organism. The very early embryo consists of totipotent cells.

Induced pluripotent stem cells have technical advantages over ESCs because the patient’s cells can be used rather than donor cells, and they are easier to control compared to ESCs. However, one of the concerns with iPSCs was whether they are truly equivalent to ESCs because of the various transcription factors that need to be turned on or off to get the cells to regress back to their pluripotent state. This debate was laid to rest with a new research report in Science, demonstrating that while iPSCs are genetically distinct from ESCs, they are functionally equivalent.

Before deeming every iPSC procedure ethical and effective, consider the question several researchers from Australia, The Netherlands, and the U.K. ask in a Nature Methods commentary “What if stem cells turn into embryos in a dish?” Their reason for asking stems from research that shows how pluripotent stem cells (both iPSCs and ESs) can form organoids, small three-dimensional clumps of cells that are comprised of a particular organ’s cell type. The techniques to make pluripotent stem cells undergo the self-assembly and morphogenesis required to form an organoid also causes these cells to have many of the properties of embryos at the gastrulation stage of development.

Without delving too deeply into the complexities of embryonic development, the gastrulation stage is a key point when it comes to regulations for human embryo research. (See here for a simple summary of recent research about stem cells that have been dubbed “gastruloids”). The U.K. has a fourteen-day limit on human embryonic research. Human embryos are not allowed to remain intact in vitro beyond the fourteen-day point or after the formation of the primitive streak, whichever comes first. Australia has similar regulations. The pluripotent cells that appeared to reach the gastrulation stage seemed to form a primitive streak and showed signs of forming the beginnings of the Central Nervous System.

There are two things to consider. First, while these are hallmarks of a particular point in embryonic development, it is not the case that this clump of cells is an embryo. The stem cells are self-organizing, but they are without the same kind of holistic directionality that an embryo has. So while these stem cells proliferate in a more “organized” way than, say, a tumor, they lack key embryonic features. However, the authors pose an important question that needs to be addressed because the technology could eventually make embryos in a dish.

Consider two situations in which it is possible to make an embryo without two genetic contributors, a mother and a father. The first is cloning, or somatic cell nuclear transfer, and the second is making gametes using iPSCs.

Somatic cell nuclear transfer has been successfully done in both animals and humans, although only animal cloned embryos have been implanted and birthed. Cloned animals tend to be unhealthy and often die young. This continues to be an area of research, as evidenced by a recent article in Cell Stem Cell in which researchers from South Korea reported more efficient methods for cloning human embryos.*

Gametogenesis is another active area of research. If induced pluripotent stem cells could be induced to differentiate into gametes (egg and sperm), then this would theoretically allow the creation of an embryo. This embryo may only have one parent if the egg and sperm were made from the same donor. Or, it could be made from two parents who are the same gender. This is not yet possible because the oocyte is particularly tricky to form, but there is ongoing research attempting to produce both types of gametes from induced pluripotent stem cells.

Whether one uses somatic cell nuclear transfer or gametogenesis via iPSCs, the creation of a human embryo is ethically problematic for many reasons. The authors of the Nature Methods commentary raise important questions that hinge on when an embryo becomes an embryo in the laboratory setting. There are valid reasons to give the embryo a special status whether it is ever implanted in a uterus or not. As technology allows us to unravel the complex operations that go into meiosis and embryogenesis, we must carefully consider where moral lines are drawn.

Because making an embryo in a dish would be taking the technology too far, drawing ethical lines may require a nuanced approach to just what types of experiments are okay and where in the technical process the line must be drawn so that pluripotent stem cells remain at the pluripotent stage.

* Technically, “clones” like Dolly the sheep are really chimeras, meaning there is a small amount of DNA from the oocyte donor that is different from the nuclear DNA. The clone would produce an embryo from one genetic source if both the original cell and the oocyte came from the same animal.

11/07/15 – This post has been changed from the original to clarify some of the scientific terms.

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