Professor Dave again, let’s kill some cells. As we discussed when learning about the nature of cancer, sometimes things can go terribly wrong within a cell. If mutations arise such that the activity of a cell threatens the survival of the entire organism, that cell must be neutralized, and that’s why a process called apoptosis has evolved. This is the method by which faulty cells that pose a threat to an organisms will undergo self-destruction, essentially programmed cell death, and this is precisely why mutations in genes that code for enzymes that regulate apoptosis are an extremely common cause of cancer. If enzymes can’t carry out self-destruction, a cell will proliferate until a tumor forms. Given the importance of apoptosis to any complex biological system, let’s take a closer look and see how this works on the molecular level. In the most basic sense, apoptosis involves cellular agents chopping up everything within the cell. All the DNA, all the organelles, everything becomes fragmented, and the cell itself shrinks to form lobes, which pinch off and are then digested by specialized cells called scavenger cells. This is important, because if a dying cell simply leaked its components totally intact, such as its enzymes, these could potentially be incorporated into other cells and initiate the same faulty mechanisms in those. So everything must be destroyed. In order to understand exactly how this all happens, let’s examine the two ways in which apoptosis can be initiated. Signals can come either from outside of the cell, or inside of the cell. If outside, nearby cells release signaling molecules that initiate signal transduction that results in the expression of genes whose protein products carry out apoptosis. Alternately, if the DNA within a cell becomes damaged beyond repair, a series of protein-protein interactions can act as a signal that triggers apoptosis. Let’s get a closer look at these signaling pathways. This is a nematode named C. elegans. It’s basically a small worm, so small in fact that it’s made of only about one thousand cells. Because there are so few cells, researchers can more easily trace the ancestry of any given cell, from embryonic development onwards, and it is the case that apoptosis occurs at specific times during the natural development of the organism. In this particular organism, there are two important genes which encode proteins that are essential for apoptosis. These genes are called ced-3 and ced-4, which stand for “cell death”. The proteins they code for have corresponding names, Ced-3 and Ced-4, with a capital C. These proteins are present in all the cells, but in an inactive form. In addition, the gene ced-9 produces the protein Ced-9, which sits in the outer mitochondrial membrane, and acts as a brake that regulates apoptosis. If the signal to undergo apoptosis is received by the cell, signal transduction results in a conformational change in Ced-9 that renders it unable to halt apoptosis, in turn resulting in the production of proteases and nucleases, which are enzymes that chop proteins and DNA. These proteases are called capsases, and the main one in C. elegans is the Ced-3 protein we mentioned earlier. In humans, things are a bit more complicated, with many more different capsases involved, utilizing different pathways depending on the cell type and the signal received. Often times, an external signal results in mitochondrial proteins forming small pores in the outer membrane, such that other proteins within the mitochondrion are released, which in turn promote apoptosis. Some of these components have totally different functions within the cell, such as cytochrome c, which is part of the electron transport chain, but outside of the mitochondrial matrix, it acts as an apoptotic factor. Other times, an internal signal from the nucleus is received, if DNA damage is considerable, or from the endoplasmic reticulum, if protein misfolding occurs. But as we said, while apoptosis is sometimes a last resort for a misbehaving cell, it is often an essential aspect of organismal development. This occurs to varying degrees with different vertebrates to produce hands, feet, paws, and other such limbs. It is required for normal development of the nervous system. And the fact that this process occurs in most eukaryotic life, even single-celled yeasts, demonstrates that this basic mechanism evolved very early in eukaryotic development. Problems with this mechanism lead to a variety of degenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Protein aggregation can activate an enzyme that triggers apoptosis, resulting in the death of neurons and loss of brain function. And once again, as we said, when apoptosis is supposed to occur but is unable, due to mutation in genes that code for these apoptotic enzymes, cancer is a probable outcome. So that’s a basic introduction to apoptosis.