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

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 the individual changes which might be being recorded.

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 Johann Sebastian Bach.

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 rising and falling in unison with the changes in the other. But of course it would be naïve to think in these terms for just two signals such as these. Both nitric oxide and hydrogen peroxide can impinge on calcium signalling, so phasing of changes in calcium ion concentrations will need to be considered too. But a myriad of other signals will be employed at any moment in time in a cell so the overall response, or set of responses needs to be orchestrated by the phasing and overall shifting pattern of signals being employed by the cell.
