17.5: Reversible, irreversible, and cascade effects

A final consideration is whether, when a cell receives a signal, its response is transient - that is, does it return to its original state when the signal is removed or does it adapt to the presence of the signal, for example, through a negative feedback interaction that leads to decreased levels of receptor or critical response components, or does it move into a new cellular state, characterized by the expression of different genes and different cellular behaviors. As an example, if the signal up-regulates expression of a transcription factor that in turn regulates expression of other transcription factors that results in altered receptors and regulatory molecules, the cell can become physiologically and phenotypically different – becoming basically a new cell type. It may no longer respond to the original signal. In the first type of response, after a transient signal it "resets" back to its original state. The cell may even adapt (get used to) the presence of one level of signal, and require a higher level to continue to respond. The second type of response can be effectively irreversible, the cell has changed in terms of the genes it expresses, the proteins and molecules it contains. Chromatin organization may be altered, different genes become accessible or inaccessible. The same signaling molecule may produce no response or a different response. This second type of response is common in embryonic development, cells move from an originally totipotent state to an increasingly restricted one. An early embryonic cell may respond to signal(s) by forming into a range of cell types. At a later stage the same signals may not influence a differentiated cell. The differentiated state may be irreversible. A neuron, once formed, remains a neuron - a terminally differentiated cell type.

A technical breakthrough has been the development of protocols that can reverse terminal differentiation in some cell types. These enable us to reprogram a cell, producing what are known as induced pluripotent stem cells or iPS cells. These protocols do not work equally well with all differentiated cell types, which is one reason (among many) that the cells that go on to form gametes, the cells of the germ line, are maintained in a distinctive state compared to the cells that go on to form the body, the somatic cells, which are differentiated to various extents. The process of reprogramming a somatic cell is itself associated with stochastic effects, effects that can be best observed through single cell analyzes of gene expression. When a culture of supposedly identical cells are expose to the factors use to generate iPSCs, analysis of individual cells indicates that most cells fail to "reset", and that those that do can differ in significant ways from one another.^[579]

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