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Gastruloids: Embryo-like model gives University of Cambridge researchers a glimpse into black box of early human development

University of Cambridge researchers have given us a glimpse into the ‘black box’ of early human development by creating an embryo-like model from stem cells.

This new ‘gastruloid’ model provides insight into the human body plan, and resembles elements of an embryo at about 18 to 21 days old.

But it does not contain brain cells or any of the tissues needed for implantation in the womb, and is not capable of turning into a fully-formed embryo.

A gastuloid. Picture: University of Cambridge
A gastuloid. Picture: University of Cambridge

“Our model produces part of the blueprint of a human,” said Prof Alfonso Martinez-Arias, from the university’s Department of Genetics, who led the study. “It’s exciting to witness the developmental processes that until now have been hidden from view – and from study.”

It is hoped that understanding the processes at this early stage could help reveal the causes of human birth defects and diseases, and enable tests for them in pregnant women.

The body plan for an organism is formed by gastrulation, a process in which the three ‘germ layers’ of cells are formed in the embryo.

These later give rise to all the body’s major systems:

  • the ectoderm will make the nervous system
  • the mesoderm creates the muscles
  • the endoderm becomes the gut.

Legal restrictions prevent the culture of human embryos in the laboratory beyond day 14, when gastrulation begins. This international agreement, established by the 1978 Warnock Report in the wake of the development of IVF, reflects the time at which the embryo can no longer form a twin.

These restrictions mean gastrulation is often seen as the ‘black box’ period in human development.

But it is a critical time, when many birth defects can originate caused by, for example, alcohol, medications, chemicals or infections.

A comparison between a 20-day-old human embryo, left, and a human gastruloid, right. Image: University of Cambridge
A comparison between a 20-day-old human embryo, left, and a human gastruloid, right. Image: University of Cambridge

“Our knowledge of the process of gastrulation in human embryos is based on anatomical studies of embryos collected by various academic and medical institutions over the 20th century,” explained Prof Martinez-Arias and Dr Naomi Moris, also from the Department of Genetics.

“One example of such a collection is the Carnegie Collection of human embryos. However, there are very few specimens at early stages of development in these collections, which leads to a knowledge gap in our understanding of the process of gastrulation in humans.

“Human gastruloids provide a model to enable us to research this stage of development with a human cell-based model.”

By understanding human gastrulation better, scientists hope to learn more about infertility, miscarriage and genetic disorders.

Mice and zebrafish have been used as model organisms in the past to give us some insight into gastrulation.

But their use is limited, as such models may behave differently to human embryos when the cells start to differentiate into different types.

Alfonso Martinez Arias and Naomi Moris. Picture: University of Cambridge
Alfonso Martinez Arias and Naomi Moris. Picture: University of Cambridge

It is known that animal models can respond differently to some drugs – a problem that led to the anti-morning sickness drug thalidomide passing clinical trials after testing in mice, only to cause severe birth defects in humans.

Better models of human development are now sought as alternatives to animals – and the new gastruloid, developed in collaboration with the Hubrecht Institute in the Netherlands, offers great promise.

Dr Moris, the first author of the report, said: “This is a hugely exciting new model system, which will allow us to reveal and probe the processes of early human embryonic development in the lab for the first time.

“Our system is a first step towards modelling the emergence of the human body plan, and could prove useful for studying what happens when things go wrong, such as in birth defects.”

The researchers used defined numbers of human embryonic stem cells to generate the three-dimensional assembly of cells.

“Work with human embryonic stem cells (ESCs) usually involves growing them in flat, adherent colonies on plastic dishes and controlling their behaviour by the addition of specific factors,” they explained.

“This type of research has taught us a lot about the signals that are needed to convert cells towards different cell types, and their dynamics during this process.

A human gastruloid at 72 hours, imaged with a scanning electron microscope. Picture: Naomi Moris
A human gastruloid at 72 hours, imaged with a scanning electron microscope. Picture: Naomi Moris

“This new work to generate human gastruloids, which builds on our previous research with mouse gastruloids, allows cells to interact with each other in three-dimensional aggregates. In this arrangement, and under specific culture conditions, cells assume multiple identities in an ordered manner and co-ordinate this process to form an organised pattern.”

The researchers placed the embryonic stem cells in small wells, where they formed tight aggregates.

After they were treated with chemical signals, the gastruloids could be observed lengthening along a head to tail axis, known as the anteroposterior axis.

Genes were turned on in specific patterns along this axis that reflected elements of a mammalian body plan.

By examining which genes were expressed in these human gastruloids after 72 hours, the researchers found a clear signature of the event that gives rise to body structures such as thoracic muscles, bone and cartilage.

“This is the first time that a three-dimensional structure made of human ESCs has been shown to so-closely model the developing human embryo,” said the researchers.

“The finding is particularly important because we have very little information about the early stages of development in human embryos and therefore, human gastruloids may provide a new model that we can use to find out more about normal human development and what happens when the process goes wrong.”

But they stressed that the gastruloids would never be able to progress past the very early stages of development, meaning they conform to ethical standards.

The work was reviewed and approved by the ethics committee of the University of Cambridge.

“Gastruloids lack the potential to make a brain and therefore they are incomplete structures. They also lack the cells that are necessary to allow the embryo to implant into the uterus, meaning they could not be implanted, and would not proceed much further in development,” said the researchers.

They added: “Significantly, they lack the morphology (shape) of an early human embryo, and therefore do not manifest human organismal form. As such, they are non-intact, non-autonomous, and non-equivalent to human embryos, and do not have human organismal potential.

“As models, gastruloids are simplified systems that mimic some aspects of embryo development, in a manner that facilitates further study.”

A growing human gastruloid, imaged at, from left, 24 hours, 48 hours and 72h after embryonic stem cell aggregation. Picture: Naomi Moris
A growing human gastruloid, imaged at, from left, 24 hours, 48 hours and 72h after embryonic stem cell aggregation. Picture: Naomi Moris

To assess how these models compared to human embryos, the scientists compared them to the Carnegie Collection of Embryology, which contains a continuum of human embryos, including day-by-day growth over the first eight weeks.

The comparison suggested that gastruloids partially resemble human embryos aged 18 to 21 days.

“When we look at the organisation of gene expression in human gastruloids, we notice that the order of certain genes along the top-tail axis (anterior-posterior) is reminiscent of a process called ‘somitogenesis’ in mammalian embryos,” explained Prof Martinez-Arias and Dr Moris.

“Somitogenesis generates the length of our body axis through the sequential production of blocks of cells, called ‘somites’, that will produce the ribs, vertebrae and thoracic muscles. The number of somites along the body axis is related to the age of the embryo. The Carnegie embryo collection shows that the first somites appear in the human embryo around day 16-17 and that the process is ongoing by day 19-20.

“Therefore, the gene expression within human gastruloids suggests that somitogenesis is ongoing, which is why we suggest that they display some of the features of a human embryo at around day 19-20.”

It only takes gastruloids three to five days to reach this point because they start at a more advanced stage than a fertilised egg cell.

The work could have multiple applications.

A false colour scanning electron microscope image of human gastruloid. Picture: Naomi Moris
A false colour scanning electron microscope image of human gastruloid. Picture: Naomi Moris

“Understanding human development is an important endeavour that will provide knowledge about ourselves, a platform to understand disease and, in the future, a basis for regenerative medicine, the ability to produce tissues and organs for transplant,” said the researchers.

“We believe that in the future, it will be possible to use human gastruloids to improve our understanding of normal human development, and to examine what happens when things go wrong – including modelling diseases caused by genetic mutations and exposure to environmental perturbations. Because they can be grown in large numbers, it is possible that they could be used for drug screening purposes and to develop additional assays for a variety of uses.”

In future, it may also be possible to move away from using embryonic stem cells, which are a type of cell derived from mammalian embryos before they implant. In humans, they typically come from IVF-derived embryos, and this is regulated by the HFEA and UK Stem Cell Bank.

But it may be possible to switch to using induced pluripotent stem cells (iPSCs). These are a type of cell obtained by reprogramming adult differentiated cells. They have the same properties as embryonic stem cells, and reduce the need to use embryos. Critically, they can also be derived from individuals with specific pathologies.

The research was funded by the Medical Research Council, the Leverhulme Trust and the Isaac Newton Trust.

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