**10. Degeneracy**

58 Biomedical Science, Engineering and Technology

This analogy can be taken further if the musicians themselves are thought of as receptors. What happens at the start of the practice session? The scores are handed out and each musician will look at the score and confirm that it is the right part, if only silently in their mind. A cello player will only wish to receive cello music: if they take violin music for example it will be in the wrong cleft and probably not able to be played. Violins not only have to get music for the violin but have the right one, being either in first or second violins. If a musician gets the wrong music they will not be able to use it and give the response that the conductor is hoping for. The musician will remain silent, even when they are supposed to be playing, like a cell receptor in the presence of the wrong ligand. It is not uncommon for musicians to return music and ask for the correct score like a receptor rejecting a ligand and leaving themselves free for the arrival of the correct ligand onto their music stand so cellular

Cell signalling is often presented as a neat array of components all in a line, as depicted in Figure 6A. In fact Krauss said: "The classical view of signalling pathways has been that of sequential transmission of signals in a linear signalling chain". This would be like listening to solo instruments, playing a linear line of notes on a page. Some representations of cell signalling show little else, making the systems look simple and easy to understand. But just as we don't often listen to single instruments, unless listening to a sonata perhaps, cell signalling is also a complex mix of many players, all adding to the harmony at the same time. As Krauss goes on to point out, signalling is far more complicated (Krauss, 2008).

Fig. 6. Signalling pathways are often depicted as a single series of components in a line, akin to a single line of music (A). However, they are usually much more complex, more like

several instruments all playing at the same time (B).

harmony can be obtained.

**9. Single instruments playing a simple string of notes** 

It is often a puzzle in molecular biology that proteins may be able to replace each other. Perhaps an inhibitor has been added which is supposed to remove the functioning of a cell signalling component, but the effect is far less than anticipated. In knock-out or knock-down studies, where the expression of a protein is completed ablated, or severely reduced, then the cell sometimes shows little effect (see Colucci-Guyon *et al*., 1994 as an example). In a cell signalling response, again often far less than anticipated is seen than from the theory (see Zhang *et al*., 1994 as an example). In such situations the most likely scenario is that proteins are replacing each other when needed, and protein function is said to be degenerate.

If proteins can replace each other in function can we again invoke a music analogy. The leader of the orchestra is a very important position, often helping and advising the conductor during practise sessions, but during the concert they are not redundant when it comes to control either. Like a signalling component in cells, the leader will be signalling to the rest of the violins when to start playing, so that the whole section plays together and sounds like one. However, what happens when the leader breaks a string. Violin strings are under a large amount of tension and break quite often. If the leader's violin breaks, does the orchestra have to stop. In reality, especially in a rehearsal, it probably would and a new string would be rapidly fitted. But if as in a cell, waiting for a response is not a pragmatic option and the orchestra has to continue then another violin player, probably the one in the second seat next to the leader, will take over and allow the orchestra to continue. One musician, just like the cell's protein, will take up the important role vacated by the other.

Other scenarios in music also can be envisaged. Often musicians can play more than one instrument, and especially in non-professional orchestras and groups it would not be uncommon for one player to take the place of an absence colleague. This would explain why the absence of what was thought to be an important player, or protein, can be seen to not have a devastating effect on the harmony of the music group, or cell.

## **11. Multiple functions of some proteins**

It has been recognised that proteins often have more than one role and are said to be "moonlighting" (Jeffrey, 2009). Here, as well as proteins being able to cover the roles of each other as in degeneracy, some proteins have other very disparate roles.

Some proteins had roles discerned many years ago only to have new additional roles assigned to them more recently. A good example here is cytochrome *c* which was for many years assigned to a redox role in the mitochondria, only later to be found to be instrumental in controlling apoptosis (Figure 7. Reviewed by Jiang & Wang, 2004). Glyceraldehyde 3 phosphate dehydrogenase is central to glycolysis, but it too has now been assigned cell signalling roles, in particular as a protein which translocates to the nucleus to control gene expression (Tristan *et al*., 2011).

Fig. 7. Cytochrome *c* has more than one function. Cytochrome *c* is normally found in the mitochondria. It resides associated with the inner mitochondrial membrane, where it acts to shuttle electrons from Complex III to Complex IV. However, there is a signalling pathway which leads to cell suicide, or apoptosis, in which cytochrome *c* leaves the mitochondria and moves into the cytoplasm. Here it interacts with the caspase system which leads to ultimately to cell death. Therefore cytochrome *c* has two very distinct and disparate functions.

Musicians and their instruments are like such moonlighting proteins. They may play a violin, but in fact such instruments can be used in multiple music genres. During the day the violinist may be in an orchestra, but some evenings may be playing jazz in the local bar. As with the proteins, their roles are not fixed, and translocation from one venue to another will allow them to partake in a new role. Furthermore, many if not most musicians are experts at more than one instruments. Therefore if an orchestra is short of a viola player, then perhaps a violinist can take their place. Or the change of instrument can be more dramatic, with a flutist can take over on the kettle drums. Just like many proteins, temporal and spatial location of the player, and the interactions in which they may partake, may dictate the exact role they play at any moment in time.
