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University of Cambridge scientists 'extremely close' to creating artificial embryos

Synthetic embryo-like structure made of three stem cells types in yellow, pink and green
Synthetic embryo-like structure made of three stem cells types in yellow, pink and green

Work from international team could help us understand why many human pregnancies fail in their early stages

Dr Berna Sozen, University of Cambridge
Dr Berna Sozen, University of Cambridge

Cambridge scientists say they have come “extremely close” to creating artificial mouse embryos – and now plan to do the same for humans.

The astonishing work could help us understand why many human pregnancies fail in their early stages by enabling researchers to simulate this formative period of growth.

One of the research team described the “breathtaking moment” they saw the embryo-like structure produced by the mouse stem cells used in the study.

“Those moments are what we live for in science,” said Dr Berna Sozen, who co-authored a paper on the breakthrough, published in Nature Cell Biology.

The international team, led by Professor Magdalena Zernicka-Goetz at the University of Cambridge, used the mouse stem cells to produce structures capable of a key step in the life of any embryo, known as ‘gastrulation’.

It is the point at which it transforms from a single layer to three layers, determining which tissues or organs the cells will then develop into as the embryo grows.

“Our artificial embryos underwent the most important event in life in the culture dish,” said Prof Zernicka-Goetz. “They are now extremely close to real embryos. To develop further, they would have to implant into the body of the mother or an artificial placenta.”

In mammals, once an egg has been fertilised by a sperm, it divides multiple times to generate a small, free-floating ball featuring three types of stem cells – the body’s master cells – in what is known as the ‘blastocyst’ stage of development. These are:

Synthetic embryo like structure with embryonic part generated from the embryonic stem cells (pink) and and extra-embryonic tissues in blue
Synthetic embryo like structure with embryonic part generated from the embryonic stem cells (pink) and and extra-embryonic tissues in blue

• Embryonic stem cells (ESCs), which will make the future body and cluster together inside the embryo towards one end.

• Extra-embryonic trophoblast stem cells (TSCs), which will form the placenta.

• Primitive endoderm stem cells (PESCs), which will form the yolk sac, ensuring that the foetus’s organs develop properly and providing essential nutrients.

Prof Zernicka-Goetz and colleagues published a study in March 2017 describing how they had used a combination of genetically-modified mouse ESCs and TSCs, along with a 3D ‘jelly’ scaffold known as an extracellular matrix to grow a structure capable of assembling itself. Its development and architecture very closely resembled the natural embryo and the two types of stem cell demonstrated an extraordinary capacity to communicate, as if the cells were telling each other where to place themselves in the embryo.

But it was not capable of gastrulation, a step once described by eminent biologist Lewis Wolpert as “truly the most important time in your life”.

Prof Zernicka-Goetz explained: “Proper gastrulation in normal development is only possible if you have all three types of stem cell. In order to reconstruct this complex dance, we had to add the missing third stem cell.

“By replacing the jelly that we used in earlier experiments with this third type of stem cell, we were able to generate structures whose development was astonishingly successful.”

This meant the embryo-like structure was able to organise itself into the three body layers that all animals have – the inner (endoderm), middle (mesoderm) and outer (endoderm) layers. The researchers found the timing, architecture and patterns of gene activity also reflected that of natural development.

The breakthrough will enable the team to understand better the interaction of the stem cell types in the developing embryo.

Adjusting biological pathways in one cell type will enable them to see how it affects the behaviour of one or both of the other cell types.

“We can also now try to apply this to the equivalent human stem cell types and so study the very earliest events in human embryo development without actually having to use natural human embryos,” said Prof Zernicka-Goetz.

The studies will help researchers learn much more about the fundamental first stages of mammalian development, even enabling them to study what happens beyond day 14 in human pregnancies – the limit in UK law for using actual human embryos in the laboratory.

“The early stages of embryo development are when a large proportion of pregnancies are lost and yet it is a stage that we know very little about,” said Prof Zernicka-Goetz. “Now we have a way of simulating embryonic development in the culture dish, so it should be possible to understand exactly what is going on during this remarkable period in an embryo’s life, and why sometimes this process fails.”

Many human pregnancies fail around the time that the embryo implants into the wall of the mother’s uterus. The period after implantation has been largely inaccessible to scientists because events are occurring inside the uterus – and most women do not know at this stage that they are pregnant.

Dr Sozen, who came to Cambridge from her native Turkey to join Prof Zernicka-Goetz’s team, said: “Observing these self-developing embryo-like structures under the microscope is so exciting that I do not care even if there is a need to be in the lab in the middle of night.

“I still clearly remember the moment that I and my co-author saw these structures for the first time. It was a breathtaking moment.”

She said she is excited to contribute to Cambridge’s pivotal role in embryology and stem cell research: “I work in the same building where Nobel Laureate Bob Edwards succeeded in fertilising a human egg in vitro.

“Another Nobel Laureate Sir Martin Evans was the first to culture mouse embryonic stem cells and cultivate them in a laboratory at the University of Cambridge.

“These works revolutionised treatments for fertility and laid the foundations for human stem cell research. These great scientists paved the way for Magdalena’s pioneering research in embryology.

“I feel I couldn’t have been in any better place for my research than this.”

The research was funded by the European Research Council and Wellcome.

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