Embryos Grown Without a Womb

When we hear the words “test tube” or “designer” baby we may be quick to imagine sci-fi dystopias like Gattaca and Brave New World, seemingly absurd or far from reality. Little did we expect the rapid technological advancements that could bring these fictitious works to the forefront of modern life...

The successful birth of the first in vitro fertilisation (IVF) baby, Louise Brown, in 1978 provoked concerns about the potential of this new-fangled technology. In response, the Human Embryo and Fertilisation Authority (HFEA) was established, led by Mary Warnock, a prominent philosopher. Since its establishment, the HFEA has regulated human embryo use in the lab, regulating that human embryos can only be kept for 14 days post-fertilisation. However, in 2021, a game-changing study was published. Mouse embryos, complete with organs, were entirely cultivated in glass bottles in the lab, way beyond the stage of growth which has historically been possible. These embryos were grown entirely without a uterus, begging the question, could this be done in humans? And morally, how do we decide what constitutes a human embryo if the embryo never came from a human? Where do we draw the ethical line?

Under normal circumstances, a developing mammalian embryo, whether it be human, mouse, rabbit or monkey, begins to earmark cells for their future purposes within a few days of fertilisation. You can think of it as a bit like a confetti balloon: cells making up the outer part of the embryo - the balloon itself - are called the trophectoderm. These will form the placenta and the membranes that surround a developing foetus, and they are essential for the embryo to implant into the uterine lining and begin to grow. Meanwhile, the cells in the centre of the growing embryo, the "confetti", will become the foetus proper.

Until now, mouse embryos that were grown in dishes in the lab were unable to continue their development beyond the third or fourth day post-fertilisation, i.e. the confetti balloon stage, because they had no uterus environment. But Jacob Hanna’s group, at the Weizmann Institute of Science, have found a way around this roadblock¹. They grew the embryos in rotating glass bottles in a cocktail of nutrients, with specialised oxygen and atmospheric pressure monitors. As well as developing organs, the embryos showed signs of limb development and beating hearts. The development of these embryos well beyond halfway through the normal mouse gestation period opens up avenues for previously unexplored experimental questions about embryology, especially when combined with genome editing approaches.

Three years ago, He Jiankui, previously a researcher at Southern University of Science and Technology, publicly proclaimed to have created the world’s first genome-edited human babies. Using the gene editing tool called CRISPR-Cas9, Jiankui claimed to have altered a gene called CCR5 in human embryos produced by in vitro fertilisation. Altering the CCR5 gene is known to confer resistance to HIV infection, but Jiankui’s work on human embryos without evidence of risk of HIV infection provoked public and scientific outrage.

Hanna and colleagues’ experiments were not performed using human embryos. However, this research, amidst the still-reeling scientific furore of Jiankui’s work, has catapulted back into the public discourse the role of embryo research in biomedical laboratories. Technical limitations currently prevent the growing of human embryos in non-uterine conditions. One obvious impediment is the significantly longer gestation period of human babies compared to mice. However, given the modern-day relative ease of CRISPR-Cas9 genome editing and its functionality in human embryos, it is not unreasonable to believe that it could one day be possible to grow selected and edited embryos entirely outside the body.

Genome editing, including in humans, occurs in one of two ways. The first outcome is “somatic”, these are the normal cells of the body that make up the vast majority of your body, including your organs, soft tissue and bones. The second is “germ line”. The germ line refers to a specific population of cells required for reproduction. In women, these are the eggs, and in men, sperm. These two unique cell types have the exclusive ability to give rise to the next generation. Altering genes in these cells means the changes are passed from the parents to their offspring.

Therefore, a genome edit performed in a somatic tissue stays in that one person. This can, and has been done in some specific medical examples. Conversely, and importantly, a genome change performed in the germ cells, can be passed to the next generation and is therefore inheritable. Inherently, this creates a moral dilemma. Unlike editing adult somatic cells, performing genome editing in the early embryo, before the stage at which cells form organs, will almost undoubtedly result in germline editing. Therefore, is it okay to genome edit the somatic cells, knowing that this can never be passed on? Is it okay to edit the germline, knowing that this could be passed on, unknowingly and non-consensually, to the next generation?

One other rapidly progressing development in reproductive biology is the potential to produce these germ cells, the egg and sperm, entirely outside of the body. With this technology, the entire reproductive process could in theory be completed outside of the human body. Unlike the other somatic cells of the body, which have two copies of every gene and are referred to as ‘diploid’, the sperm and egg have just one copy of each chromosome and are dubbed ‘haploid’. These differences in DNA content cause technological complications for creating germ cells in the lab. But if scientists can work out how to reliably reproduce germ cells in a dish by persuding somatic cells to lose one copy of each chromosome and develop happily in an environment outside of the ovary or testis then they would be well on the way to surmounting these problems.

A group led by Mitinori Saitou at Kyoto University developed the first protocol for producing a germ cell precursor outside of the body in 2011². Using a complex cocktail of nutrients, sex hormones and proteins for growth, they were able to force mouse stem cells to transform their identity into germ cell-like cells. When the germ cell-like cells were then transplanted into a mouse testis or ovary, they developed into sperm and eggs. Groups have since expanded the culture conditions to extend how far sperm are able to grow in the dish. These sperm-like cells could be manually injected into eggs and transferred into a mouse uterus, and healthy pups were born. Experiments forcing skin cells to revert into a stem cell, before inducing a germ cell-like state was also performed using human skin³. These human germ cell-like cells were never transplanted back into a human.

In 2017, At the Francis Crick Institute, a team led by James Turner, took skin cells from mice that had an unusual three copies of some parts of the DNA genome. This is a state called trisomy⁴. Being trisomic can cause disorders such as Down Syndrome, or infertility in Klinefelter’s syndrome. The trisomic skin cells were cultivated in fluid-filled dishes, before adding a blend of different nutrients which forced the cells to change their identity, becoming stem cells. Surprisingly, during this process, the cells lost the additional DNA. This revealed to the researchers one possible way to induce diploid cells to become haploid sperm-like cells, using the technique developed by Saitou and colleagues. The sperm-like cells successfully fertilised eggs, and produced healthy mouse pups. These studies have paved the way for using reprogrammed skin cells to potentially help infertile people to have children.

Given the developments in lab-grown sperm and eggs, it would be lacking of me not to consider self-identity in the argument for what is right in reproductive science. If a person grew entirely in a dish, created from lab grown eggs and sperm, throughout embryonic development, until ready for “birth”, might they feel bereft of identity? Of familial links and cultural identifiers? Who would they believe are their true ‘biological parents’, if these parents were skin cells scientifically reprogrammed into a new identity? Combining this knowledge with the potential for embryo genome editing, we must find a way to balance these scientific progressions with the need for sense of self.

There is a great deal of potential and power in these technological applications of reproductive science. How we decide what is ethically right or wrong is ultimately up to the decisions of the public, the scientists and the regulatory authorities. How close are we really to the fictitious realm of Gattaca and Brave New World? How do we decide what makes us truly human?