Introduction
Stefan GrimmGiven the gravity of the decision between life and death, it is surprising that scientists
have only recently begun to unravel the mysteries of apoptosis, the cellular suicide
program. Two aspects contributed to the continued neglect of apoptosis as a
fundamental decision of cells.
It is a fast process. While many cells undergo apoptosis (estimates range up to 10^9
a day), they are rapidly swallowed by neighboring phagocytotic cells and are therefore
hard to detect. The other reason was a psychological hurdle. Many scientists wondered
why Nature would want cells to be able to kill themselves. Cell death might just be
a direct consequence of an insult and therefore an inevitable fate of the cell.
Now, however, scientists have realized that all cells are able to receive distinct
signals, interpret these signals as suicide stimuli, and induce a discrete genetic program
that leads to cell death. Rather than a passive fate, apoptosis is therefore an active
process that is initiated by the cell and is governed by gene activities that induce or
inhibit apoptosis. It must therefore be distinguished from necrosis, which is
unregulated, passive cell death. From this fundamental insight it follows that Nature
must ‘want’ cells to perish upon a given stimulus; it must be a biologically meaningful
response. But this also requires that the signal is known and deemed grave enough
to warrant the demise of a cell.
Proapoptotic stimuli come in a bewildering array of different forms; they can either
be generated by other cells or originate within the doomed cells. They can constitute
positive signals, such as the activation of membrane receptors (Chapter 1), but might
also arise from neglect, as in the case of an absent survival factor. In any event, the
original signal activates a cellular ‘sensor’ that transmits the signal to downstream
proteins that are part of signal transduction pathways. This is accomplished by genes
that form a highly interconnected lattice of checks and balances of (mostly) protein-
protein interactions (Chapters 3 , 4 ) that evaluate the stimulus in relation to other
signals that the cell is receiving and compute the appropriate output. If a decision for
cell death is reached, the endpoint of such a cascade is the activation of a certain class
of ubiquitous proteases: caspases (Chapter 2). These are cysteine proteases that reside
in every cell in an inactive form and are activated for cell death. They can then cleave
specific substrates in the cell and generate the typical morphology of an apoptotic
cell. The fact that apoptotic cells demonstrate a steroetyped appearance was one of
the first hallmarks of apoptosis to be discovered (Kerr et al., 1972). The cells shrink