4.3: Active (altruistic) cell death

One type of behavior you might think would be impossible for evolutionary processes to produce would be the active, intentional or programmed death of a cell or an organism. Yet, such behaviors are surprisingly common in a wide range of systems¹²⁰. The death and release of leaves from deciduous trees in the autumn is an example of a programmed cell death process known generically as apoptosis. The programmed cell death process amounts to cellular suicide. It plays important roles in the formation of various structures within multicellular organisms, such as the fingers of your hands, which would develop as paddles without it, as well as playing a critical role in development of the immune and nervous systems, topics well beyond the scope of this book (but extremely important)¹²¹. The process of programmed cell death is distinct from accidental cell death, such as occurs when a splinter impales a cell or you burn your skin. Such accidental death leads to what is known as necrosis, in which cellular contents are spilled out of the dying cell. It often provokes various organismic defense systems to migrate into the damaged area, primarily to fight off bacterial infections. The swelling and inflammation associated with injury is an indirect result of necrotic cell death. In contrast, apoptotic cell death occurs by a well-defined pathway and requires energy to carry out. Cell contents are retained during the process, and no inflammatory, immune system response is provoked. In general it appears to play specific and important roles within the context of the organism. Commitment to active cell death is generally very tightly controlled. A detailed discussion of the molecular mechanisms involved in apoptosis is beyond the scope of this course.

Here we will consider active/programmed cell death in the context of simpler systems, specifically those formed by unicellular organisms. In unicellular organisms, active cell death is a process triggered by environmental stresses together with quorum sensing. In this situation, a subset of the cells will “decide” to undergo active cell death by activating a pathway that leads to the death of the cell. Now when one cell in a densely populated environment dies, its contents are released and can be used by the living cells that remain. These living cells gain a benefit, and we would predict that the increase in nutrients will increase their chances of their survival and successful reproduction. This strategy works because as the environment becomes hostile, not all cells die at the same time. As we will see later on, this type of individualistic behavior can occur even in a group of genetically identical cells through the action of stochastic processes.

So how do cells kill themselves (on purpose)? Many use a similar strategy. They contain a gene that directs the expression of a toxin molecule, which by itself will kill the cell. This gene is expressed in a continuous manner. Many distinct toxin molecules have been identified, so they appear to be analogous rather than homologous. Now you may well wonder how such a gene could exist, how does the cell survive in the presence of a gene that encodes a toxin. The answer is that the cell also has a gene that encodes an anti-toxin molecule, which typically binds to the toxin and renders it inactive. Within the cell, the toxin-anti-toxin complex forms but does no harm, since it is inactive–the toxin’s activity is inhibited by the binding to the anti-toxin molecule. The toxin and anti-toxin molecules differ however in one particularly important way. The toxin molecule is relatively stabile - once made it exists for a substantial period of time before it is degraded by other molecular systems within the cell. In contrast, the anti-toxin molecule is unstable. It is rapidly degraded. The anti-toxin molecule can be maintained at a high enough level to inhibit the toxin only if new anti-toxin molecules are continually synthesized. In a sense the cell has become addicted to the toxin-anti-toxin module.

What happens if the cell is stressed, either by changes in its environment or perhaps infection by a virus? Often cellular activity, including the synthesis of cellular components (such as the anti-toxin) slows or stops. Now can you predict what happens? The level of the stable toxin molecule within the cell remains high, decreasing only slowly, while the level of the unstable anti-toxin drops rapidly. As the level of the anti-toxin drops below the threshold level required to keep the toxin inactive, the now active toxin initiates the process of active cell death.

In addition to the dying cell sharing its resources with its neighbors, active cell death can be used as a population-wide defense mechanism against viral infection. One of the key characteristics of viruses is that they must replicate within a living cell. Once a virus enters a cell, it typically disassembles itself and sets out to reprogram the cell’s biosynthetic machinery to generate new copies of the virus. During the period between viral disassembly and the appearance of newly synthesized viruses, the infectious virus disappears - it is said to be latent. If the cell kills itself before new viruses are synthesized, it also kills the infecting virus. By killing the virus (and itself) the infected cell acts to protect its neighbors from viral infection - this can be seen as the kind of altruistic, self-sacrificing behavior we have been considering¹²².

Contributors and Attributions

• Michael W. Klymkowsky (University of Colorado Boulder) and Melanie M. Cooper (Michigan State University) with significant contributions by Emina Begovic & some editorial assistance of Rebecca Klymkowsky.

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