Researchers from the University of Cambridge have created synthetic model embryos with brains, beating hearts, with the potential to grow other organs from mouse stem cells. The research is touted as a new way to recreate the first stages of life.
A team of researchers led by Professor Magdalena Zernicka-Goetz used stem cells to develop the embryo model, rather than eggs or sperm. Stem cells are master cells which can develop into almost any other cell type in the body.
Model embryos, such as those grown by the researchers, could help further understandings of why some embryos go on to develop into a healthy pregnancy, while others do not. The results could also be used to guide repair and development of synthetic human organs to be used in transplants.
To create the embryos, researchers mimicked natural processes to guide three types of stem cells found in early development of mammals until they started interacting. The researchers could get the stem cells to ‘talk’ to each other by manipulating genes and establishing the right environment for the cells.
From there, the stem cells organised themselves into structures that developed beating hearts and the foundations of the brain. They also grew the yolk sac where embryos get nutrients from during their first few weeks of life.
n a research first, these embryos reached a point where the entire brain, including the front portion, began to develop. No other stem-cell derived model has ever reached this stage.
Professor Zernicka-Goetz’s group in Cambridge has been studying these earliest stages of pregnancy for a decade. They want to understand why some pregnancies fail and some succeed.
“The stem cell embryo model is important because it gives us accessibility to the developing structure at a stage that is normally hidden from us due to the implantation of the tiny embryo into the mother’s womb,” said Zernicka-Goetz. “This accessibility allows us to manipulate genes to understand their developmental roles in a model experimental system.”
“Our mouse embryo model not only develops a brain, but also a beating heart, all the components that go on to make up the body,” said Professor Zernicka-Goetz, who is Professor in Mammalian Development and Stem Cell Biology in Cambridge’s Department of Physiology, Development and Neuroscience. “It’s just unbelievable that we’ve got this far. This has been the dream of our community for years, and major focus of our work for a decade and finally we’ve done it.”
For a human embryo to develop successfully, the tissues that will become the embryo and the tissues that will connect the embryo to the mother need to have a ‘dialogue’. In the first week after fertilisation, three types of stem cells develop: one that will become the tissues of the body, and two that support the embryo’s development.
One of the tissues that support the embryo’s development is the placenta, which connects the foetus to the mother and provides oxygen and nutrients. The other is the yolk sac, where the embryo grows and gets nutrients from from during early development.
Many pregnancies fail at the point when the three types of stem cells begin to send chemical and mechanical signals to each other. Professor Zernicka-Goetz, also Professor of Biology and Biological Engineering at Caltech, explained: “So many pregnancies fail around this time, before most women realise they are pregnant. This period is the foundation for everything else that follows in pregnancy. If it goes wrong, the pregnancy will fail.”
The researchers found that the extraembryonic cells signal to embryonic cells by chemical signals. They also communicate mechanistically, or through touch, to guide the embryo’s development.
“This period of human life is so mysterious, so to be able to see how it happens in a dish – to have access to these individual stem cells, to understand why so many pregnancies fail and how we might be able to prevent that from happening – is quite special,” said Zernicka-Goetz. “We looked at the dialogue that has to happen between the different types of stem cell at that time – we’ve shown how it occurs and how it can go wrong.”
The model is also the first to signal development of the front portion of the brain, and indeed the whole brain. “This opens new possibilities to study the mechanisms of neurodevelopment in an experimental model,” said Zernicka-Goetz.
“In fact, we demonstrate the proof of this principle in the paper by knocking out a gene already known to be essential for formation of the neural tube, precursor of the nervous system, and for brain and eye development. In the absence of this gene, the synthetic embryos show exactly the known defects in brain development as in an animal carrying this mutation. This means we can begin to apply this kind of approach to the many genes with unknown function in brain development.”
Current research was carried out in mouse models, but the researchers are developing similar human models. These may be used to generate of specific organ types to understand processes that would be otherwise impossible to study in real embryos.
At present, UK law permits human embryos to be studied in the laboratory only up to the 14th day of development. If the methods developed by Zernicka-Goetz’s team are shown to be successful with human stem cells in future, they could also be used to guide development of synthetic organs for patients awaiting transplants.
Zernicka-Goetz said: “There are so many people around the world who wait for years for organ transplants. What makes our work so exciting is that the knowledge coming out of it could be used to grow correct synthetic human organs to save lives that are currently lost. It should also be possible to affect and heal adult organs by using the knowledge we have on how they are made.”
She added: “This is an incredible step forward and took 10 years of hard work of many of my team members – I never thought we’d get to this place. You never think your dreams will come true, but they have.”