In an effort to gain a better understanding of human embryogenesis, we have recently begun to use human gastruloids as an experimental model to investigate the organisation and dynamics of the formation of the bodyplan.
Find out more about this model system by reading our latest publication or by looking at our FAQs below.
Helpful Information about Human Gastruloids
WHAT IS A GASTRULOID?
A gastruloid is a three-dimensional structure made up of Embryonic Stem Cells (ESCs), that models certain features of early embryo development. In particular, gastruloids transition from an initial rounded to an elongated shape (a transformation similar to the early shape changes of the developing embryo), and generate cells associated with the three primary cell layers of early embryos (the germ layers) that are necessary for development of the different tissues and organs. Over time, these cells become organized with reference to a coordinate system, much as they do in the embryo. Gastruloids do not contain any brain cells or the cells necessary for the embryo to interact with the maternal environment.
WHAT IS GASTRULATION?
Gastrulation is the process that generates cells of the three germ layers (mesoderm, endoderm and ectoderm) of the embryo and organises them relative to one another. These germ layers are the precursors of the different cell types that will organize tissues and organs. An important feature of gastrulation involves the emergence of a system of coordinates that orients the cells into two main axes: head/tail (anterior-posterior) and back/belly (dorsal-ventral).
WHY CAN’T WE STUDY HUMAN EMBRYOS AT THIS STAGE?
Since the development of IVF in the 1970s, discussions have arisen around the use of human embryos for research. This led to a proposal called the Warnock report, a 1978 internationally agreed set of rules that regulate research with human embryos. The report established what is known as ‘the day 14 rule’, a line that defines a time-limit for the observation of human embryos in a dish.
A human embryo at 14 days old will start the process of gastrulation. This is a process that transforms a group of cells into an individual organism: the embryo organises its cells into germ layers that will eventually give rise to the different tissues and organs. Before this time, the embryo can be split into two and will give rise to two individuals, or twins.
Our knowledge of the process of gastrulation is therefore based on anatomical studies of embryos collected by various academic and medical institutions over the 20th century. 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.
HOW IS THIS WORK NEW?
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. 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.
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 coordinate this process to form an organised pattern.
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. 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.
WHAT IS THE POINT OF THIS RESEARCH?
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. At the moment, these studies would require human embryos at early stages of development, which presents ethical and moral challenges.
One solution to this, is to look for models which mirror the events of a human embryo. Over the years, animal models have provided a large amount of information due to their similarity to humans in terms of the course of development and the genes associated with these processes. In particular the mouse has been an extremely useful tool to provide insight into mammalian development. However, there are differences between mouse and human embryos which suggest that if we want to fully understand human development, we need to use human models.
Gastruloids derived from human Embryonic Stem Cells (ESCs) are a reproducible and experimentally tractable model system that we believe provide an opportunity to explore the early stages of human development without having to use human embryos.
IS A GASTRULOID AN EMBRYO?
No, gastruloids are not embryos, nor do they have the potential to become embryos. 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.
As models, gastruloids are simplified systems that mimic some aspects of embryo development, in a manner that facilitates further study. Models are simplified representations of reality that allow for the exploration of the properties and behaviour of otherwise complicated systems. For example, a flight simulator is a very sophisticated model of an aeroplane but it is not an aeroplane; it will not fly and will not carry people or cargo. Still, it allows us to learn a great deal about how to fly a plane and how to solve many of the problems that can arise in a real flight by simulating them. In the same manner gastruloids have many features of an embryo but, because they lack other features and potential, they allow us to study the mechanisms underlying the emergence of tissues and organs without using embryos.
ARE HUMAN GASTRULOIDS ETHICAL?
We believe so. Human gastruloids do not show any evidence of cell types associated with the brain, nor do they form the cells required for implantation. 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.
Our research was subject to review and approval from the Human Biology Research Ethics Committee of the University of Cambridge, in compliance with the ISSCR 2016 guidelines.
WHAT IS THE FUTURE OF GASTRULOIDS?
The research published so far provides a protocol for generating human gastruloids, and a characterisation of their properties. The details of this technique can, and will, be improved to increase the utility of the system, and further details characterising their properties will improve our understanding of the early steps in human development. It is probable that in the future human gastruloids could be made from induced Pluripotent Stem Cells (iPSCs) rather than Embryonic Stem Cells.
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.