Stem Cells Open Developmental ‘Blackbox’
14 Days. This is the maximum number of days researchers are allowed to sustain an embryo. In 1979, when this policy was first proposed by the Ethics Advisory Board of the US Department of Health, Education and Wealthfare, culturing an embryo ex vivo (removed from the body) was an extremely difficult and expensive task, and so 14 days was a generous limit. With recent advances in developmental biology and laboratory techniques, culturing embryos beyond this juridical limit is now well within reach. In fact, just recently, research groups have reported that they have sustained human embryos in vitro (outside the body) for up to 13 days, coming very close to the limit.
The 14 days limit was established by the bioethical discussions that emerged as in vitro fertilisation started to gain traction. The rationale behind setting the limit to 14 days has four components. Firstly, until the end of the second week, twinning can still occur. Furthermore, the primitive streak does not start to develop until 14 days after fertilisation and so there is no differentiation of tissue into nervous cells. Thirdly, in natural circumstances there is considerable embryo loss up until this point. Lastly, implantation is not complete until this point, and if this doesn’t occur, the embryo can not further develop.
As embryology research continues to gather momentum, members of the scientific community warn of a possible collision with international policies that take into account the ethical implications of culturing embryos ex vivo, such as the 14-days rule, and consider the 14 day limit indispensable for the integrity of medical ethics. They therefore strongly advise against a revision of these policies.
On the other hand, the 14-day limit legally prohibits scientists from sustaining embryos through gastrulation (the formation of the three germ layers required for subsequent organogenesis). This jurisdiction thus prevents them from gaining valuable insight into key processes in embryological development — and hence many developmental diseases — as many of them occur just after the first 14 days.
Just last week, however, researchers from the University of Cambridge and the Dutch Hubrecht Institute found a way to study gastrulation by using stem cells to create an artificial model of a third-week embryo, pictured below. This will allow the study of early human development beyond the 14-day limit for embryos, and hence could provide key insights into the mechanisms behind various developmental disease processes.
Image analysis of a human gastruloid marked for anteroposterior patterning. Green shows the posterior (tail) end of the embryo and pink marks the posterior (head) end where heart cells would develop. Image credit: Naomi Moris, University of Cambridge. To create this embryonic ‘blueprint’, the researchers treated embryonic stem cells with various chemical signals, inducing the formation of human gastruloids. Following a rigorous protocol, the researchers observed the differentiation of these embryonic stem cells into the three germ layers (endoderm, mesoderm and ectoderm) that later give rise to the neural, musculoskeletal and digestive systems.
Regarding ethical implications, the researchers emphasized that no formation of extra-embryonic tissue was observed, which would be required for implantation into the uterus. Furthermore, there was no sign of further differentiation into brain tissue, indicating that the gastruloids cannot generate human life, and are therefore not equivalent to natural human embryos. For this reason, they could investigate the dynamics of third-week embryo development without colliding with ethical regulations.
This recent development has huge potential in the medical context. Not only could it give valuable insight into the onset of genetic disorders and birth defects, as well as miscarriages, but it could also allow scientists to artificially grow tissues for transplants and treatments for a wide range of diseases.
Remarkably, these gastruloids are able to form the node. This structure is a key signalling centre during embryonic development and necessary for establishing the axes of the embryo, from which the body patterns emerge. Disrupted right-left patterning has shown to cause birth defects that often lead to chronic heart diseases. While studying the disruption of right-left patterning traditionally required animal models, this new advance delivers an attractive alternative.
Finally, it is important to note the potential problems that may arise from this new development, as with all new technologies. It remains possible for embryonic germ layers cultured in vitro to form their respective structures, such as neural tissue undergoing neurulation which would cross the line from a 3D cell aggregate to a sentient structure. As the 14-day rule does not apply here, it is important for legislation to follow up and fill the gap to continually ensure ethical practices in developmental biology.
Nevertheless, this breakthrough represents a promising advance and it will be interesting to see how newly acquired knowledge can be applied to alleviate suffering in the context of regenerative medicine and push epistemological boundaries.
While I, as a student of science, am fascinated by the vigour and enthusiasm of scientists to discover and explore, I am equally aware of the importance of debating the ethical implications of scientific advances and would certainly hope that scientists do not try to outpace ethical legislation in this regard. For this reason, I was excited to hear that the scientists from the University of Cambridge and the Hubrecht Institute managed to open the ‘black box’ of post-third-week embryo development without crossing the line that others had come dangerously close to numerous times over the last decade. It is an elegant example demonstrating that it is possible to make paradigm-shifting discoveries without sending ethics into a tailspin.