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Taking the time for socially distant strolls through nature, amidst the furore created by a global pandemic, I am struck by the number of questions a biologist can ask about the workings of our world. Looking at a frog propel itself from stone to stone with its impressive hind legs, an evolutionary biologist may ask: ‘how did a frog come to be so suited for its environment?’ An ecologist would look at the same scene and wonder at the intricate balance between all elements of the ecosystem that are finely tuned to sustain life. My own thoughts, when looking at such a scene, stray to a question posed by developmental biologists: how can a complex being like an adult frog be built from its beginning as a single cell?

Almost all animals begin life as a fertilized egg cell, from which successive steps of growth and patterning mould the embryo into a fully-formed being. The initial single cell will undergo many rounds of division in order for the organism to reach its final size. But, as new cells emerge, they must go through a series of patterning steps to eventually reach the correct final identity. Without this, all creatures would just be a mass of unspecified cells of one type – a formless blob.

At the very core of the question of patterning in development is the idea of ‘symmetry breaking’. This term has come to mean many things over the years, but it is commonly defined as the moment in development where the first substantial difference in identity between cells - or parts of the embryo - arise [1]. In humans, for example, the initial embryo undergoes a few rounds of division before two different cell types can be distinguished by particular features and subsequent fate: (i.) trophectoderm cells, which sit on the outside of the embryo and eventually become the placenta, and (ii.) inner cell mass, which becomes the yolk sac and the organism itself. Once these cell types form, the embryo has broken symmetry.

The concept of symmetry breaking is so fascinating and important because it represents the origin of patterning in the embryo – once it occurs, the presence of different cell types allows variations and asymmetries in chemical signalling between cells across the embryo, allowing the embryo to mould itself into the right identity. Without proper symmetry breaking, the embryo will never be able to progress past its genesis as an unspecified mass.

The journey to understanding how symmetry breaking occurs has crossed continents - many scientists have each contributed a piece to the puzzle, but the biggest single contribution could be attributed to Professor John Gurdon, now a distinguished Nobel Laureate and eponymous co-founder of the Gurdon Institute in Cambridge. As a fresh-faced graduate student at The University of Oxford back in the 1970s, he conducted an experiment that would not only change the face of developmental biology, but would prove to be the advent of cloning[2].

Prior to Gurdon’s experiment, it was suggested that the solution to the symmetry breaking problem was rather simple: as each cell divides, the genetic material of the cell is partitioned, so each daughter cell receives a different cohort of genes. Since genes make the proteins that characterise the cell, the different genes acquired by each daughter cell upon division means that each new cell gains a different identity. Doubts about this simple solution were solidified when Gurdon transplanted the nucleus (containing the genetic material) of a skin cell of a frog into an egg cell without a nucleus. The resulting cell grew into a frog with the same characteristics of the skin cell donor. This showed that all the genes to make a whole frog lie within each cell of the organism, as the skin cell had all the information needed to make a frog, and could do so when put into the egg’s environment. This was the first indication for what became a central tenet in developmental biology: all cells of one organism have the same genes, and differences between cells in the organism are determined by which genes are ‘on’ or ‘off’.

In the case of the frog skin cell, only skin-making genes are ‘turned on’ until the other genes are re-activated following transplant of the nucleus into the egg. As a result of Gurdon’s experiment, the symmetry breaking question no longer became about partitioning genes across the embryo, but about turning on different genes in distinct cells for the first time.

It was in the quaint German city of Heidelberg, home to the European Molecular Biology Institute, that two future Nobel Laureates made another giant leap forward in our understanding of symmetry breaking and embryonic patterning in general[3]. Using the humble fruit fly as their easy-to-use model of choice, Christiane Nusslein-Volhard and Eric Wieschaus were able to identify many of the genes involved in patterning the head-tail axis of the fly. Their experiment, conducted in the late ‘70s, made use of chemical mutagens, which target and corrupt single genes at a time and produce fly larvae with defects. These mutant flies could be categorised by the segmented patterns on the fly’s body, and these categories were subsequently used to classify the specific genes and gene classes responsible for patterning. The two researchers identified an incredible 120 genes involved in the head-tail axis. Interestingly, some of the defective larvae were produced by mutant genes in the mother rather than just the offspring. This class of ‘maternal effect genes’ led to a key idea in symmetry breaking: that maternal proteins deposited unequally in the egg actually induce asymmetric activity of genes in different parts of the embryo; symmetry can be broken even before development has truly begun, and by proteins made by the mother rather than the offspring itself.

The gene bicoid, identified by Nusslein-Volhard and Wieschaus, is a good example of how a maternal effect gene acts to facilitate symmetry breaking in the fruit fly[5]. Bicoid RNA, which produces the Bicoid protein, is deposited into the developing fruit fly egg by the mother before fertilization, and reaches highest concentration at one end of the embryo. At this end, it activates genes ultimately associated with head formation, whereas at the other end these genes are not activated. Thus, bicoid mutants do not have a proper head. Similarly, in the nematode worm egg – another conventional model organism - the asymmetric distribution of proteins known as PAR proteins in the egg is responsible for symmetry breaking.

The theme of symmetry breaking seen in these two simple organisms is clear: if there is a factor which is present in different concentrations across the embryo, and this factor activates different genes depending on its presence and concentration, then each part of the embryo will have different active genes and a different identity. All that is required is a method to distribute this factor asymmetrically across the embryo, like an external stimulus (e.g. gravity or light) or the factor’s interaction with some internal cell machinery.

After understanding basic principles of symmetry breaking in these ‘simpler’ systems, an obvious question - and the ultimate goal of most research programmes - is to ask whether these ideas apply similarly to the human embryo. The answer? Yes and no.

The mouse embryo, which also undergoes symmetry breaking to produce inner cell mass and trophectoderm populations, is the best model for mammalian development and is thought to be quite representative of human development. The conventional theory of symmetry breaking in the mouse is the ‘polarity’ model. At the 8-cell stage, as an accumulation of internal processes beginning at fertilization, each cell of the embryo becomes polar: it has two different ends, in the same way that a polar magnet has a negative and positive end. The outer, ‘positive’ end is characterised by a specific cocktail of proteins, while the other end is facing inward at the embryo. After the emergence of this polarity, the cells divide in such a way that some daughter cells retain the ‘positive’ end, and others retain the ‘negative’ end. Ultimately, the embryo has different types of cells - ‘negative’ cells that become the aforementioned inner cell mass, and ‘positive’ cells that become the trophectoderm - so symmetry is broken[5].

Similarly to the fly and worm situation, there are proteins asymmetrically distributed in the embryo which activate different genes at different places. In fact, some of the proteins which make up the ‘positive’ end of a polar cell are PAR proteins, also seen in worms and fruit flies, and hinting at the conservation of many features in development across the animal kingdom. However, unlike those models, the mouse does not have an egg patterned by maternally deposited proteins and only breaks symmetry much later, and the ‘positive’ and ‘negative’ cell types retain a flexibility in their fate not seen in the other systems. Recent evidence emerging from developmental biology labs, such as that of Magdalena-Zernicka Goetz here in Cambridge, has begun to suggest that mechanisms other than polarity might be at play in the earlier embryo, bearing some resemblance to the fly and worm systems [1]. As is always the case in science, our understanding is constantly being updated.

Watching a frog splash its way across a pond always reminds me of the many coordinated mechanisms that have succeeded in order for it to be there. We only understand a small fraction of these, however, and much is still left to be learnt.

Adiyant Lamba is a PhD student at Trinity Hall College studying early mammalian development, and is a news editor at BlueSci




References
  1. [BACK] Chen, Q., Shi, J., Tao, Y. and Zernicka-Goetz, M., 2018. Tracing the origin of heterogeneity and symmetry breaking in the early mammalian embryo. Nature Communications, 9(1).
  2. [BACK] Gurdon, J., 2013. The cloning of a frog. Development, 140(12), pp.2446-2448.
  3. [BACK] Wieschaus, E. and Nüsslein-Volhard, C., 2016. The Heidelberg Screen for Pattern Mutants of Drosophila: A Personal Account. Annual Review of Cell and Developmental Biology, 32(1), pp.1-46.
  4. [BACK] Driever, W. and Nüsslein-Volhard, C., 1988. The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner. Cell, 54(1), pp.95-104.
  5. [BACK] Mihajlović, A. and Bruce, A., 2017. The first cell-fate decision of mouse preimplantation embryo development: integrating cell position and polarity. Open Biology, 7(11), p.170210.