Cell death in health and disease

Abstract

Cell death is clearly an important factor in development, homeostasis, pathology, and in aging, but medical efforts based on controlling cell death have not become major aspects of medicine. There are several reasons why hopes have been slow to be fulfilled, and they present indications for new directions in research. Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely-associated and interacting proteins. But cells have many options other than apoptosis. These include autophagy, necrosis, atrophy, and stepwise or other alternate means of self-disassembly. The response of a cell to a noxious or otherwise intimidating signal will depend heavily on the history, lineage, and current status of the cell. Many metabolic and other processes adjust the sensitivity of cells to signals, and viruses aggressively attempt to regulate the death of their host cells. Another complicating factor is that many death-associated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them. In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion.

1

The very late appearance of characteristics of apoptosis in metamorphosing insect cells. Upper row: appearance of lysosomes during the involution of the salivary gland of Drosophila, which in our hands has completely collapsed by 13 hrs after the beginning of puparium formation. Monodansylcadaverine detects no resolvable organelles prior to onset of metamorphosis, but by 6 hrs there are numerous perinuclear autophagic vacuoles (arrows) and by 9 hrs the vacuoles fill the cytoplasm (three figures on left). Lysotracker red ® detects modest activity by 9 hrs and large autophagic vacuoles by 12 hrs. Middle row: By 3 hrs into metamorphosis, the fine filamentous actin network, detected by rhodamine phalloidin, has given way to fine granular clumps of actin, which become more pronounced by 9 hrs. By 10 hrs the actin is in vacuoles that appear to be lysosomes, or clustered near the cell membranes. Lower row: Evidence for apoptosis occurs only very late. Both exteriorization of phosphatidylserine as detected by annexin V (left two panels) and appearance of TUNEL-positive nuclei (right two panels) occur after the 11^th hr.We also confirmed the presence of caspase-positive granules at 12 hrs but, failing an interpretation of the significance of the granules, we withhold an interpretation. From doctoral research of Farhan S. Khan.

2

Phenotype resulting from application of the pan-caspase inhibitor, zVAD.fmk, to zebrafish embryos. The notochord (No) is longer than normal and consequently buckles, leading to severe deformity of the embryo.We have not been able to establish that the increased size results from failure of cells to die or directly from the inhibition of caspases. Ey: eye; Yk: yolk. From doctoral research of Nathaniel Abraham.