As we have seen, the delayed response of gene expression to internal state can result in oscillations around median values. This is the situation when the cell needs to maintain a "constant" internal state. But the same underlying phenomenon, the delayed responses of genes, can also lead to progressive changes in internal state and gene expression pattern. Transcription factors are proteins; they too are products of particular genes. A single transcription factor can influence the expression of several genes, including those encoding other transcription factors. This is the principle underlying progressive changes of internal state.
Suppose a transcription factor (let us call it F1) is present when the internal state is S1. Suppose F1 causes genes A, B and C to be expressed, and that gene C encodes a second transcription factor, F2. When the proteins encoded in genes A, B and C have been made, the internal state is S2 -different from S1. In particular, F2 is now present. Now suppose that F2 causes genes D, E and H to be expressed, changing the internal state to S3. If H (say) encodes yet another transcription factor, F3, then a progressive change is underway. Thus, when the pattern of gene expression involves genes for transcription factors, changes in gene expression change the internal state progressively. S3 succeeds S2 as G2 succeeds G1. Such progressive change goes in a predetermined direction in predetermined stages: it is programmed.
Programmed changes in cells can take several different forms. They can be cyclic, so that after a succession of internal states S1, S2, S3 ... the cell returns to S1. (There are corresponding changes in the gene expression pattern: G1, G2, G3 ... and back to G1.) Eukaryotic cell division involves a complicated process known as the cell cycle, which exemplifies this kind of progression. At one internal state during the cell cycle, the cell's entire
15 In some cases this pulsatile behaviour depends indirectly on the overcorrection phenomenon described in the text; in other cases it might have a different though analogous cause (reciprocal influences of one cell type on another). This is a topic for the next chapter, where we discuss the responses of cells to stimuli from outside, including signals from other cells.
DNA is copied (duplicated). In a subsequent internal state, the daughter chromosomes condense and separate. This is followed by division of the cell into two daughter cells, both of which return to the initial state (S1) of the parent cell. The cell cycle then commences again. One turn of the cycle doubles the number of the cells, so this process is fundamental to both reproduction and growth in eukaryotes. Thus, another two of the seven traditional properties of living organisms emerge from the interplay between gene expression and internal state.
Another form of programmed change is cell differentiation. In chapter 3 we mentioned the two hundred different types of cells making up a human body. This variety is the result of differentiation. Differentiation involves a linear sequence of internal states and patterns of gene expression, not a cyclic one. The progression is finite; there is a final state known as terminal differentiation. In a differentiating cell, a progressively smaller and smaller set of genes is expressed at a progressively higher and higher rate. A terminally differentiated cell might have very high rates of transcription of half a dozen genes, perhaps even just one or two. Genes that are required for basic metabolism and structural maintenance are also expressed, but usually at low tick-over rates. More or less all other genes are switched off. Energy and manufacturing resources are focused almost exclusively on developing the activities necessary for the cell's specialist role in the body. Amongst the genes that are switched off during differentiation are those encoding the cell cycle proteins; terminally differentiated cells usually cannot divide.
A third form of programmed change is programmed cell death or apoptosis. In multicellular organisms, almost any cell type seems capable of embarking on a sequence of gene-expression and internal state changes that is ultimately fatal. This is a highly organised form of suicide. No cell contents or debris leak into the rest of the body. Instead, the remains of the dead cell are packaged into small membrane-bound bundles. These are easily engulfed as endocytic vesicles by other cells and digested by their lysosomes (see chapter 3).
At first sight apoptosis might seem a peculiar, negative process, but it is essential for multicellular organisms. In a developing human embryo, for example, the little buds of tissue that will ultimately become arms have flat, blunt ends. To make these flat blunt ends into fingers and thumbs, the cells between the incipient fingers and thumbs must be eliminated. This is done
by apoptosis. Were it not for apoptosis during development, none of us would be born with separate digits. Programmed cell death is also used for removing abnormal or virally infected cells.
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