Alfonso Martinez Arias
Department of Genetics, University of Cambridge
Cambridge, CB2 3EH
We all start as a cell, a single cell within the womb of our mothers that grows to generate two cells and, repeating this pattern, multiplies into an amorphous mass that attaches itself to the uterine wall. Four weeks later, an embryo is discerned, a seedling of ourselves with an outline of a body organized with reference to an invisible compass. The head at one pole, sketches of a spinal cord, the muscles and the gut running along its length, with bumps that will form organs like the heart and the limbs in place. Over the next eight months this structure will grow to deliver a baby.
Understanding this process, how those cells acquire and execute the instructions to form specific organs and tissues, will provide important knowledge about a wondrous sequence of events and a reference to understand the origin of many diseases. The study of this process is under strict regulation because of the special nature of human embryos and difficulties associated with their observation since, like all mammals, we grow inside our mothers and depend on them for our nourishment.
Human embryos have been studied anatomically since the late 1800s but it was the development of in vitro fertilization in the 1970s that ushered in the opportunity of having and watching early human embryonic development in a dish. Eggs obtained from healthy females are fertilized in vitro and after allowing them to grow into a cellular mass, they are returned to the womb at the time that they would normally implant. Having the early embryo growing in a dish created an opportunity to study its development further, and this led to discussions about whether this experimental procedure is ethically acceptable, and if so, under what framework. These discussions led to a proposal called The Warnock Report, an internationally agreed set of rules and principles that regulate research with human embryos. The report established what is known as ‘the 14-day rule’, a line that defines a time-limit for the observation of human embryos in a dish; the date is not arbitrary. In a human embryo, 14 days following fertilization signals the start of gastrulation, a process that transforms the clump of cells into an outline of the organism through a carefully choreographed sequence of cell movements. This process proceeds until around day 21, a period when it is possible to distinguish the rudiments of the front and the back, the spine and the belly – features that define the emerging organism. This organization is called the body plan. In the case of humans, our knowledge of this transformation is based on anatomical studies of embryos collected at the beginning of the XX century in various academic institutions and gathered at the Carnegie Institution in Washington.
All animal embryos undergo gastrulation, and they share many features of this process. For example, frogs and mice use the same molecules and exercise similar cell movements during gastrulation, which suggests some generally conserved features across species. It is for this reason that mice are used as a close reference model for our understanding of human gastrulation, but while mice are an excellent reference system for general principles, there are details that are human-specific – and details matter. In the same way that the mouse genome is a good reference, but not a faithful compass for human biology, if we expect to learn about gastrulation in humans, we need to study this process in humans. Furthermore, there is evidence that a number of pathologies have their origin in the process of gastrulation, and it is for this reason that it would be useful to have some understanding of the normal cellular and molecular events that mediate the transformation of the clump of cells into the outline of the organism.
The description of a process will not necessarily expose the underlying mechanisms required to achieve it. To gain this knowledge, we also need to perform experiments with embryos. However, the difficulty of obtaining early human embryos for observation and experimentation, the current lack of appropriate techniques to maintain them developing in vitro for a long time, and the stipulations of the 14-day rule, create a significant challenge for the study of this crucial period in human development. The discovery of Embryonic Stem Cells has created opportunities to develop models of the events associated with early embryos and thus to gain insights into their mechanisms.
Embryonic Stem Cells are derived from early mammalian embryos and they have three important properties: they have the potential to develop into an organism, this potential is maintained in vitro for many generations and, under defined conditions, they can be instructed to become any cell of the organism. Over the last few years, human Embryonic Stem Cells have been used as a means to probe the instructions that guide the development of heart, muscle or gut cells and, in a series of experiments, they have been coaxed into disembodied structures, or organoids, that resemble specific organs like the kidney, the pancreas, the intestine or even the brain.
Building on work that we had done with mouse, we have created a human Embryonic Stem Cell based model of early human development that reproduces the emergence of the human body plan through the process of gastrulation (https://www.nature.com/articles/s41586-020-2383-9). It is for this reason that we call these self-organised structures: gastruloids. We believe that this model opens up avenues to study hitherto unknown aspects of human biology and disease.
Gastruloids cannot form a yolk sac or placenta since they lack all extra-embryonic tissues including the primitive endoderm, amnion and trophoblast. They also cannot form brain tissues since they lack any anterior neural derivatives. The human gastruloid model therefore does not have human organismal form or potential, and can be considered non-intact, non-viable and non-equivalent to in vivo human embryos. All research into the human gastruloid system has been reviewed and approved by the local Ethics committee of the University of Cambridge.
- Beccari, L., Moris, N., Girgin, M., Turner, D., Baillie-Johnson, P., Cossy, A.C., Lutolf, M., Duboule, D. and Martinez Arias, A. (2018) Multiaxial self organization properties of mouse embryonic stem cells gastruloids. Nature 562, 272-276.
- Moris, N., Anlas, K., van den Brink,S., Alemany,A., Schroeder, J., Gimire, S., Balayo, T., Oudenaarden, A. and Martinez Arias, A. (2020) An in vitro model of early anteroposterior organisation during human development. Nature.
- Morgan, L. (2009) Icons of life Univ. Calif. Press
- Turner, D., Baillie-Johnson, P. and Martinez Arias, A. (2016) Organoids and the genetically-encoded self-assembly of embryonic stem cells. Bioessays 38, 181-191.
- van den Brink, S., Baillie-Johnson, P., Balayo, T., Hadjantonakis, AK., Nowotschin, S., Turner, DA. And & Martinez Arias, A. (2014) Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse ES cells. Development 141, 4231-4242.
- van den Brink,S., Alemany,A., van Batenburg,V. Moris, N., Anlas, K., Blotenburg, M., Turner, D., Vivié, J., Martinez Arias, A. and Oudenaarden, A. (2020) Single cell and spatial transcriptomics reveals somitogenesis in gastruloids. Nature.
- Warnock, Mary. 1984. Report of the Committee of Inquiry into Human Fertilisation and Embryology. London: Her Majesty’s Stationery Office.