Researching human embryo development is difficult for several reasons, technical and ethical. There is the question of where to source the embryos, and ethical questions around how long to let them develop. Most countries follow the standard that human embryos can only be allowed to develop until day 14.
This line of research is also extremely useful, as much of the early anatomical organization is happening during this period. Researchers want to understand what can and does go wrong in this early stage of development to help develop methods of preventing problems. This research is particularly relevant to in-vitro fertilization (IVF) – success rate is 55% for women under 35 and decreases from there.
Researchers, however, have been working on an alternative to harvested human embryos – developing embryo models from stem cells. An embryo model functions substantially like a normal embryo, but lacks the ability to develop to a live birth. Laws limiting embryo research may therefore not applies to such models, yet they can teach us a great deal about normal embryo development.
Creating embryo models from stem cells has already been achieved in mice, and a recently published study now extends this to humans – Complete human day 14 post-implantation embryo models from naïve ES cells. “ES” cells refers to embryonic stem cells. To review some stem cell nomenclature, a stem cell is a kind of immature cell that can develop into other types of mature cells. A multipotent stem cell can develop into multiple cell types. A pluripotent stem cell can develop into any mature cell type in an organism. A totipotent stem cells can develop into any cell type in the organism or outside the organism, such as the placenta and yolk sac. Embryonic stem cells are totipotent stem cells harvested from embryos.
What does it mean that these ES cells are “naïve”? Apparently a specific operational definition is difficult, but it essentially means that the genetics of the ES cells have not yet differentiated in any way. Rudolf Jaenisch, a stem cell researchers, states:
The naive ESC state that we have defined is, based on gene expression, DNA methylation and X chromosome inactivation, very close to that of the human cleavage stage embryo.
There are also induced stem cells, including induced pluripotent stem cells (iPSC) and to some extent induced totipotent stem cells. The current study did not use induced stem cells, but natural embryonic stem cells. Research into how equivalent induced and harvested stem cells are is ongoing. At this point it look like they are pretty close, but perhaps not yet fully equivalent. This study bypasses that question by using embryonic stem cells.
What the researchers did was take those naïve ES cells and then treat them chemically in order to coax them into developing into the four basic stem cell types that make up a developing embryo – epiblasts, which become the embryo itself; trophoblasts, which become the placenta; hypoblasts, which become the yolk sac; and extraembryonic mesoderm cells. The trick was mixing these four cell types together in the proper ratio.
Starting with 120 cells, the cells spontaneously organized themselves into the basic configuration of an embryo. That is one of the features necessary to be a proper embryo model. The other is that the structure then needs to develop through normal developmental milestones. It can’t just sit there, it has to grow like an embryo. Their model demonstrated both these features, and so can be considered an embryo model. They allowed it to develop for 14 days, complying with the standards of human embryo research even though it may not have been strictly legally necessary.
However, only 1% of their cell mixtures formed an embryo model. This is an important proof of concept, but the researchers still have a long way to go to perfect this technique. But already they have demonstrated some key features of such models. For example, the placental trophoblasts should form a complete layer surrounding the other cell types. If this layer does not fully develop, then an embryo will not form. Meanwhile, the epiblasts formed a typical bilayer, beginning the organism necessary to form a human.
This model can potentially provide a critical window into early human development. Right now we rely heavily on other animals, such as mice or chickens, but there are important differences with humans which limit what we can conclude from this research. A human embryo model can potentially answer a lot of questions. But researchers agree the methods need to be improved with a much higher success rate.
It is important to note that this embryo model cannot develop into a fetus. It is already passed the stage of implantation, and so would not serve as a method of IVF. But still researchers seem to be entering a murky ethical area. How long can such embryo models be allowed to develop before they look too much like a fetus? It’s one thing to experiment on a clump of cells, and another to experiment on something that looks like a developing human. Even if the difference is mainly emotional, such research is likely to generate a lot of attention and controversy. That is why it was probably wise for the researchers to stop at day 14, to minimize potential controversy for now. But it is likely to come.
It will also be interesting to see if such embryo models can be successfully created from induced stem cells, rather than embryonic stem cells. For now, probably not, but this could serve as an important marker for when induced stem cells achieve equivalence to embryonic stem cells. This research has been advancing incrementally but steadily for the last two decades, and will likely continue to do so.
This milestone is one more reminder that we are increasingly gaining control over the fundamental aspects of life – cellular machinery and genetics. The implications are likely to be profound.