**15. Setting up for the future**

62 Biomedical Science, Engineering and Technology

nitric oxide (to be S-nitrosylated) or hydrogen peroxide (to be oxidised). Disruption of the redox state of the cell towards the oxidised state is referred to as oxidative stress, a condition of cells with is extremely important not only to control cell function but also to regulate processes such as apoptosis. Oxidative stress has been implicated in numerous diseases, including degenerative disease (Kadenbach *et al.*, 2009). Therefore it is extremely important for this basal redox state to be maintained, much like a basal note of the bagpipe. It needs to be there, allowing continuity of the harmony of the cell. However, there does need to be the involvement of signals such as hydrogen peroxide and nitric oxide. It may be that the basal redox state in some cases maintains the thiol groups in a state to enable compounds such as nitric oxide to react and have its effect. This would be like the pitched notes on the bagpipe being strident above the background tonal level. On the other hand, if the background is disturbed, perhaps during oxidative stress, such thiols would have already reacted with for example hydrogen peroxide and be no longer available for a reaction it would normally partake in. A disruption of the basal background harmony has altered the effect of the other signals, and the overall effect is quite different. For normal signalling to resume, the

One of the intriguing aspects of cell signalling is the timing of the signals and how they fit together temporally. To get a full understanding of signalling needs a full appreciation of both the spatial and temporal aspects of any signal, but particularly how they might be working together in time and space. Early work in this area concentrated on calcium ion signalling, and it was reported that calcium ions were not only altered transiently in some systems but this transient change in ion concentrations actually followed an oscillating pattern. A superb example of this is shown by Alberts *et al.* (1994). Here, the oscillations are dependant on the concentration of the initial signal added. It is not the amplitude of the change which seems to be important in this signalling, but rather the frequency of the oscillations. However, temporal fluctuations on the concentrations of signals are not unique to calcium ions. The biphasic nature of other signalling systems has also been reported, for example with reactive oxygen species (Bleeke *et al.,* 2004) and also with insulin signalling (Rorsman *et al*., 2000). If hydrogen peroxide levels are followed for example, they increase quickly but transiently, but after a period of relatively low activity the levels once again rise, often to be sustained for the second period. This may be reflected in levels of other signals too, such as nitric oxide. Therefore, at any moment in time the levels of signals may be rising and falling, and it is probably the combined nature of such changes which brings about the desired response in the cell. It is pattern of change which should be considered, rather than

Music is often written in a pattern. As discussed above, Lane likens biological variations and patterns to musical variations (Lane, 2010). But musical patterns are often phased too. A prime example here is the fugue. Oxford Dictionaries describe a fugue as being written in such as way that "…a short melody or phrase (the subject) is introduced by one part and successively taken up by others and developed by interweaving the parts." A superlative example of such a work is the fugue in the *Toccata and Fugue in D minor*, BWV 565, by

Cell signalling in some cases needs to be thought of in this manner. Hydrogen peroxide and nitric oxide can be considered as two lines of music, one being interwoven with the other. One

background "tonal" redox state would need to be restored.

**14. Timing and phasing: Oscillations and waves** 

the individual changes which might be being recorded.

Johann Sebastian Bach.

In music there are often times when the phrasing and harmony just does not sound quite right. This is usually very transient and the harmonies resolve very quickly. Perhaps a composer has asked for a F and a G to be played together. If they were the adjacent notes the resulting discord would be very obvious, but often such notes are played with two or three octaves between them – in those cases the discord is not so blatant. However, often that harsh nature of the discord will mean that when the music does harmonise the end result is more pleasing than it would have been without the disharmony. The composer has set the scene for the final resolution. Again using Beethoven as an example, he does this to great effect in the "*Moonlight Sonata*", where the listener is treated to slight disharmony and one is waiting in anticipation for the resolution, which when it comes is delightful. It brings depth and feeling to the work. Therefore the composer is setting up for the future, ensuring that what subsequently arrives results in a success.

Cells need constantly to be setting the scene and making sure that they are ready for the future. And of course cell signalling is the key to doing this. Signalling often leads to adaptation, where the cell sets itself up for future possible events (Neill *et al*., 2002). Music often sets the scene in a strident and discordant, or stressful, way to allow for future harmony. In cells exposure to one stress can lead to cells being able to cope better with subsequent stress in the future, and not only to the same stress. Temperature stress in plants for example can lead to adaption to future stress by other abiotic and biotic stress factors. Instead of viewing sub-lethal stress as a negative thing in cell signalling perhaps we should be more like the composer who is prepared to chose a discord to ensure the future has a better outcome. The composer is adapting our ear, just as cell signalling is adapting the functioning of the cell for future events.

In cell signalling adaptation and preparing for the future may require long term activity, and will no doubt involve the control of gene expression with an alteration of the complement of proteins in the cell. Perhaps the cell will alter its levels of certain receptors or signalling proteins, and this will enable the cell to have a faster or more tailored response in the future. This would be like a disc jockey in the night club being asked for a certain genre of music, but realising that he didn't have it. There would be a period of short term stress. Instead of being caught out in the future, a trip to the music shop would ensure that he would be "adapted" for future requests, so lessening the chance of stress, and also allowing alternatives to be played which may relieve an otherwise stressful situation. Our cell signalling would "take a trip to our genome" and so ensure that they are ready for future "requests" from their environment.
