‘Excuse me sir, we removed your stomach instead of your liver!’

Mostly, the outside of our body is almost symmetrical: on each side there is an arm and a leg and on top there is a head, which is also symmetrical. To put it simply, our right side could be a mirror image of our left side. Like we all know, this is completely different from the inside of our body where the liver is placed on the right, whereas the spleen is on the left as well as the pancreas. This asymmetric composition seems to be similar in every human. However, there are persons that, even though they look completely normal from the outside, have a mirrored intestinal positioning in comparison with other persons (Figure 1). This article will explain how this condition, situs inversus, is caused.

Figure 1: A. normal intestinal positioning; B. situs inversus intestinal positioning.
(http://posterng.netkey.at/esr/viewing/index.php?module=viewing_poster&doi=10.1594/ecr2013/C-0368)

In the growing human embryo, the positioning of the internal organs goes along with the determination of what is left and right. For a cell to know what tissue it has to form, it needs to know exactly where it is located in the embryo all the time: if it is left or right, dorsal or ventral (at the back or at the front) and posterior or anterior (on the top or at the bottom). Cell position knowledge is achieved by ‘cell-cell communication’, which is the exchange of signals containing specific information (Figure 2). Since we are made out of one single cell, it is important to know that the first determination of cell positioning is defined very early on. The dorsal side (its back) of the frog cell, for example, is defined by the site opposite from where the sperm fertilizes the egg. Because of cell-cell communication, each cell will know where it is positioned in relation to other cells after a division.

Figure 2: Cell-cell communication.
(http://www.lookfordiagnosis.com/mesh_info.php?term=Cell+Communication&lang=1)

After many divisions, cells will start to differ from each other, because of varying signals from varying neighbor cells. During this differentiation process, the ‘primitive node’ will originate at a specific position in the ‘primitive streak’ (Figure 3A), which is highly important to proper embryonic development. Cells of the node are provided with cilia, which are hair-like structures that extend from the cell-surface (Figure 3B). Cells around the node are ‘crown cells’, which are also provided with cilia and excrete an important signal called ‘Nodal’, which is key to the left/right determination. Cells that sense Nodal will produce even higher amounts of Nodal, which causes the activation of genes that will be used to become a tissue on the left side of the body. However, crown cells also produce ‘Cerberus’, which is a signal that stops all Nodal signals, ordering cells to become right-sided tissue (Figure 3A).

Figure 3: Left/right determination in human embryos (see text).

But how is Nodal then maintained in cells that should become left-sided tissue? This is due to the cilia of the node cells, since their clockwise rotating movement effectuates a flow from right to left (Figure 3B). On the contrary, crown cell cilia are immotile and will sense this flow on the left. This flow sense makes these cells left-sided tissue cells, because it makes them produce a Cerberus inhibiting signal, that stops Cerberus from stopping Nodal (making Nodal an active signal again) (Figure 3A). In conclusion, the flow effectuated by cilia will make the cells a signal to know whether they will become left- or right-sided tissues and eventually organs. When this mechanism is understood, you might follow that when the cilia do not work properly, there is a 50% chance that the left/right determination will be all messed up so that the left-sided organs end up on the right side. These persons have the situs inversus condition: a mirrored inside.

Overall, it is possible that your inside does not look at all like you think it does! People with situs inversus can be perfectly healthy without any medical symptoms. For example, only a quarter of these persons are associated with respiratory problems or infertility due to defect cilia, because these cilia are also present in the mucous membranes of the respiratory tract and are the engine behind the swimming movement of sperm cells. Furthermore, it can be very dangerous when a person with situs inversus is injured and the surgeons are just accustomed with the fact that the liver is on the right side of the body... Just imagine what an unpleasant surprise that would be!

By Annabel Dekker 05-10-2015