Making embryos: a new way?

Recently there have been some phenomenal reports describing the ability to generate human embryo-like entities directly from stem cells, circumventing the need for egg and sperm. In the same week, researchers from Israel reported the development of post-implantation mouse embryos outside of the uterus to the 'mid-point' of mouse pregnancy; an achievement previously firmly within the realm of science fiction. The work is clearly at the leading edge of cell and developmental biology and challenges the paradigms of what it takes to create an embryo. However, like many ground-breaking studies, it is essential to reflect on what lies beneath.

In 2018, Dr Nicolas Rivron and colleagues, then in the Netherlands, reported that embryonic stem cells could be combined with stem cells from the embryonic trophoblast and be used to reconstitute a blastocyst-like structure they termed a 'blastoid'. In itself, this was a remarkable achievement but the recent work by Dr Leqian Yu and colleagues at the University of Texas Southwestern Medical Centre, Dallas has taken this to a new level, by showing this could also be done using a single population of pluripotent stem cells. In the same issue of Nature, a second group working at the Australian Regenerative Medicine Institute, Monash, Australia, reported they had achieved similar result using induced pluripotent stem cells made from fibroblasts (ie, adult cells) as their starting material. Through molecular reprogramming, the cells were able to assemble three-dimensional embryo-like structures, which the authors from Monash referred to as iBlastoids. 

A critical point from these two studies is confirmation that both pluripotent embryonic stem cells and induced pluripotent stem cells are capable of generating blastocyst-like structures. Prior to this it was necessary to take a human blastocyst, divide it into its constituent parts of the inner cell mass and trophectoderm, culture those cells and then put the embryo back together. This new research has shown it is possible to create the two key cell types that constitute the blastocyst separately and build a new blastoid. 

Importantly, these approaches have already been independently replicated, for example, in the form of a preprint from the laboratory of Professor Magdalena Zernicka-Goetz.  

Arguably, what sets this research out as profound is its timing. The past year or so has seen the publication of first-rate pieces of research describing model systems of post-implantation development, where embryos can be supported to grow beyond the blastocyst stage within the laboratory outside of a uterus. The next step is to reveal the secrets of development after day 14 during human gastrulation. Research into this is restricted by international limits, however Dr Alejandro Aguilera Castrejon and colleagues described in detail how they had supported mouse embryos to stay alive in flasks from day 5.5 -11.5. Bearing in mind that the duration of pregnancy in mice is between 18 and 22 days, this represents a culture of embryos in a laboratory for more than 50 percent of pregnancy, a truly remarkable achievement. 

The confluence of timing of these three reports is remarkable, because it allows speculation on whether they might one day be combined with developments made in extra-uterine systems, such as that developed by Partridge and colleagues which described a method to maintain extremely premature lamb fetus for up to four weeks in an extra uterine device. The end result would be a theoretically complete in vitro system which allowed preimplantation embryos to progress through to advanced stages of fetal development outside of the uterus. Indeed, methods to extend culture of embryos in a laboratory will potentially offer a way to explore the opportunities presented by blastoids as model systems without the necessity to contemplate the terrifying notion of transferring these into living organisms.  

Scientifically, these developments could offer researchers an exciting opportunity to unravel more of the remaining mysteries of development without using embryos created using gametes. The uses of blastoids could be further observed using these recently discovered techniques that remove the need for a uterus, as could investigations into the impact of genome editing on embryos. Significant observational studies are also on the horizon, with the opportunity to watch in real time the transitions from blastocyst to fetus. There is much still to discover. 
    
These recent developments also raise the tantalising prospect of generating tissue for species nearing extinction. It is hard not to be moved by the fact that the northern white rhino is now functionally extinct. Considerable efforts are being made to reverse this by researchers at Leibniz University, in Hanover, Germany, who are attempting to use assisted conception methods to generate offspring from frozen gametes collected from the final white rhino. One can ask what might have been possible had stem cell lines been made available from this species? Is the generation of blastoids, combined with advanced ex utero approaches the cue to begin the discussion about what should be done? We are not yet in Jurassic Park territory (spoiler: DNA wouldn't be sufficiently well preserved from insects in amber anyway), but the pace of development should force circumspection and widespread discussion, because there are many issues to reach consensus over.

Perhaps central to all of this is the concept of parenthood. Where gametes are involved, this is reasonably straightforward to reconcile, however when a blastoid is generated, is there a need to consider its genetic origins, and if so, who is the parent? Is it the donor cells that were used to establish the blastoid or is it the donor of those cells? And what would the situation be in a theoretical 'composite blastoid', derived from stem cell populations from more than one donor?

Undoubtedly, the combined development of blastocyst-like structures, along with the development of techniques that may support their prolonged growth them outside of the womb are remarkable scientific achievements. However, the community of reproductive biologists, ethicists and other interested parties such as the Human Fertilisation and Embryology Association (HFEA), would be wise to seek a period of reflection to establish some priorities and agree some ground rules, to ensure that the work that is now possible is also publicly and professionally tolerable (see BioNews 1091).  

It is also worth considering that much remains to be done to optimise the way that we grow embryos for IVF, since questions remain about whether being conceived in vitro leaves a significant health imprint on the life of the offspring. It is also, I think, worth reflecting on how we describe such structures, particularly the terms 'blastoid' and 'iBlastoid', which, to a non-scientist may have little real meaning. Indeed, 'iBlastoid' sounds like the next device from Apple. Perhaps we should agree on a new language – and to begin, I'd propose the term Synthetic Human Embryo-Like Structures (SHELS) as a possible alternative that more accurately reflects the reality of the advances with a little more respect shown to the nature of the structures derived.