Synthetic embryo with brain and beating heart created by University of Cambridge scientists

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In an extraordinary breakthrough that is the culmination of 10 years of work, Cambridge scientists have created a synthetic mouse embryo with a brain, beating heart and the foundation of all the body’s other organs, using stem cells.

The researchers, who described it as “a dream come true”, say it could unlock the mystery of why some pregnancies fail in the early stages, enable the healing of organs and accelerate the creation of synthetic human organs for transplantation.

The University of Cambridge team, led by Professor Magdalena Zernicka-Goetz, developed the embryo model without eggs or sperm.

Magda Zernicka-Goetz. Picture: Simon Zernicki-Glover

Instead, they used stem cells - the body’s master cells, which can develop into almost any cell type - and then mimicked natural processes in the lab.

Using the right proportions and environment, cultured stem cells representing each of the three types of tissue found in early mammalian development were guided to promote their growth and interaction with each other, until they eventually self-assembled into an embryo.

“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 Prof Zernicka-Goetz, professor in mammalian development and stem cell biology in the 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.”

The researchers are now developing an analogous model of the human embryo as they peer into the ‘developmental black box’ - the period of embryonic development that takes place at the time of implantation.

Prof Zernicka-Goetz revealed that her mentors had discouraged her from pursuing this work during her PhD, fearing it would be difficult to shine a light on it.

But as she began her own research group at Cambridge, she persisted.

“I was so taken by the question of how the embryo self-organises that I didn’t give up and, inch by inch, we have worked our way forward,” she said.

Natural (top) and synthetic (bottom) embryos to show comparable brain and heart formation. Image: Amadei and Handford

The team induced the expression of a particular set of genes and established a unique environment for their interactions to get the stem cells to communicate with each other.

They self-organised into structures that progressed through successive developmental stages until they had beating hearts, the foundations of the brain and the yolk sac where the embryo develops and derives its nutrients in its first weeks.

Other synthetic embryos have been created before, but the new Cambridge models reached a stage where the entire brain, including the anterior portion, began to develop.

The team had suspected this was taking place during their earlier studies from 2018 and 2021, which used the same component cells to develop into embryos at a slightly earlier stage.

By progressing development just one day further, they have proved that their model is the first in the world to signal development of the anterior portion and the whole brain.

“This opens new possibilities to study the mechanisms of neurodevelopment in an experimental model,” said Prof 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.”

Successful development of a human embryo requires a dialogue between the tissues that will form it and the tissues that will connect it to the mother.

In the week after fertilisation, three types of stem cells develop - one that will eventually form the body’s tissues and two that support embryonic development. One of these ‘extraembryonic’ stem cell types will become the placenta connecting the foetus to the mother to provide oxygen and nutrients. The other is the yolk sac where the embryo grows.

But many pregnancies are known to fail at the point where the three types of stem cells start sending their mechanical and chemical signals to one another.

“So many pregnancies fail around this time, before most women realise they are pregnant,” said Prof Zernicka-Goetz, who is also professor of biology and biological engineering at Caltech. “This period is the foundation for everything else that follows in pregnancy. If it goes wrong, the pregnancy will fail.”

Natural (top) and synthetic (bottom) embryos to show comparable brain and heart formation. Image: Amadei and Handford

For a decade, her group in Cambridge has explored these early stages to understand why some pregnancies fail and some succeed.

Prof Zernicka-Goetz explained: “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.

“This accessibility allows us to manipulate genes to understand their developmental roles in a model experimental system.”

The researchers discovered that extraembryonic cells signal to embryonic cells not only by chemical signals but also mechanistically, or through touch, guiding 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.

“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,” said Prof Zernicka-Goetz.

“The majority of embryo model studies focus on embryonic stem cells, but don’t consider the significant role of extraembryonic cells. We mixed the right proportions of both embryonic and extraembryonic stem cells.

“We learnt how the extraembryonic tissues direct the embryonic stem cells along the right pathways to signal formation of the correct structures; how cells move between compartments as the multi-layered body plan arises; and how this correctly sets the scene for neurulation - the process where tissue folds to form the neural tube and, in turn, the brain and spinal cord.”

Prof Zernicka-Goetz said her own experiences have fostered her determination to uncover the secrets of foetal development.

“During my own pregnancy, I was shocked when an early screening showed abnormalities. The sampling was of extraembryonic cells so I waited for the amniocentesis, which samples foetal cells that have fallen into the amniotic fluid. These were normal, which put my mind at ease,” she recalled.

“The experience led me to study mosaic aneuploidy - a condition in which the embryo has cells with the wrong number of chromosomes alongside chromosomally normal cells. Incredibly, we found that these abnormal cells can be eliminated, and the normal, healthy cells compensate for their absence. For some reason this mechanism doesn’t operate in the tissues that build the placenta, and we’re still trying to understand why and how.”

[Read more: Development of head-to-tail axis in early human embryos explored by University of Cambridge and Wellcome Sanger Institute]

The research team is now building on its work with mouse models to develop similar human models.

These could potentially be directed towards the generation of specific organ types to understand mechanisms behind crucial processes that would be impossible to study in real embryos.

UK law permits human embryos to be studied in the laboratory only up to the fourteenth day of development.

If the team’s work is successful with human stem cells, it could lead to the development of synthetic organs for patients awaiting transplants.

“There are so many people around the world who wait for years for organ transplants,” said Prof Zernicka-Goetz, a fellow of Sidney Sussex College, Cambridge. “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.

“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.”

She attributed her determination to succeed against the odds partly to her upbringing.

“It’s certainly true that carrying out this type of work requires passion and resilience. I grew up in Poland under a Communist regime, which meant that travelling wasn’t allowed and thinking differently was not encouraged. There was immense social pressure to conform, and a lot of us rebelled against that.

“A silver lining of this was a desire to think independently and to persevere despite discouragement. That shaped me as a scientist too,” she said.

The research, published in Nature, was supported in part by the European Research Council and Wellcome and NIH Pioneer Awards to Prof Zernicka-Goetz, who added: “It is an incredible feeling and a privilege to have this direct insight into the origins of a new life. It’s like discovering a new planet that we didn't know existed.”

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