Why programmed cell death occur

An extreme implication of this view is that bacterial antibiotic toxins such as those involved in membrane permeabilization, in DNA fragmentation, or in the modulation of enzyme activity involved in DNA topological changes such as DNA gyrases may also exert important vital functions other than killing cells.

But there is another level of heterogeneity. The chromosomal genome is made of a congregation of genes that propagate if, and when, the proteins they encode achieve the minimal degree of cooperation that allows the survival of the cells that harbor them.

In principle, the propagation of a given genome results from selective advantages that such a cooperation provides to the cells that harbor it. In summary, each cell can be viewed as a heterogeneous environment involving both competition and cooperation between different genetic modules in a given genome; and each colony of single-celled organisms as an environment involving both competition and cooperation between different cells harboring similar or mutant genomes.

By coupling cell survival to the nature of interactions between different gene products in a given cell, and to the nature of interactions between different cells in a given colony, the modules allowing both regulated self-organization and self-destruction that become selected in prokaryotes and in eukaryotes led to multiple variations on the theme of enforced cooperation. I believe that this is the main reason why the regulation of premature cell death may have represented, since the emergence of the first cell, one of the driving force in the evolution of life towards complexity.

Deciphering these ancient and intricate relationships between the regulation of cell survival, cell renewal and cell death, and understanding to what extent these processes may be selectively modulated by therapeutic intervention will probably represent one of the new frontiers of biology and medicine in this century.

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The spores disperse in search of a more hospitable environment. The stalk cells do not reproduce, so in a sense they sacrifice themselves. In most single-celled organisms particularly bacteria , it is not clear whether cell death follows the same pattern or biomolecular mechanisms as the apoptosis that occurs in higher organisms.

During replication, about 1 percent of the cells lose the parasitic plasmid in their DNA; the daughter cells still contain the toxin but can no longer manufacture the antidote, so they die. This is a rare instance of cellular murder rather than suicide. Newsletter Get smart. Sign up for our email newsletter.

Already a subscriber? Sign in. Thanks for reading Scientific American. Create your free account or Sign in to continue. See Subscription Options. Go Paperless with Digital. Robert Horvitz, an expert on apoptosis at the Massachusetts Institute of Technology, gives a brief response: "In short, the question of why programmed cell death occurs should be subdivided into two related questions: Why are cells that die by programmed cell death generated?

Get smart. Sign Up. Second, because in SICD it is the useful cells that die, cell regeneration, wound healing and probably also scar formation ensue, which again resembles necrosis but contrasts with apoptosis that eliminates archaic cells and therefore does not trigger regeneration. Because of the need for regeneration and wound healing, SICD involves complex communications between the dooming cells and the surrounding healthy cells on such important issues as how many cells need to be regenerated, when and where the minted cells should emerge, as well as whether fibroblasts need to step into help heal the wound.

Although necrosis is also followed by regeneration, its homicidal nature and the resulting swiftness of cell death may not allow for such complicated cell—cell communication. Since SICD is a programmed suicidal procedure, it resembles apoptosis by enticing scavenger cells to dispose of the cell corpse via complicated communications between the predator and the prey to coordinate the time and the location of the predation.

Both apoptosis and SICD may involve communications between the dying cells and their healthy siblings, but this aspect has gained little attention and few explorations. Third, if in SICD the death tally is exceedingly high and goes beyond the clearance capacity of scavengers, i.

Fourth, apoptosis can only occur in vivo but SICD and necrosis can occur in cell culture as well. Reiterated more clearly, SICD is well studied with much of the mechanism s well illustrated from cell lines in culture while unadulterated apoptosis is poorly studied with the mechanism s largely unknown.

Useful cells, either healthy or damaged ones, can age and eventually die of SD, but whether obsolete cells also undergo SD is an intriguing question that remains murky, because these cells may be removed much more efficiently via apoptosis. Moreover, SInLCD resembles necrosis that will cause regeneration and wound healing, probably in association with scar formation, but these activities do not follow SIalCD and apoptosis.

For those cell types that retain a regeneration ability, regeneration follows SD as it is the useful cells that die, making SD similar to SICD and necrosis but dissimilar to apoptosis.

Since, as aforementioned, apoptosis, as well as regeneration following SD, SICD and necrosis, require different spectra of cell—cell communication and interaction, SD has similarities and differences with apoptosis, SICD and necrosis in this aspect.

In our opinion, of the many cell death modes described in the literature, some are ad-hoc variants of apoptosis or SD in different physiological situations, while most others are ad-hoc variants of SICD in different pathological situations or in different cell lines because SICD resides between apoptosis and necrosis. For example, pyroptosis is SICD of macrophages in which pyrogens can be released to cause hyperthermia [ 28 ]. Although few studies have been conducted to explore the mechanisms of authentic apoptosis in vivo, there is some in vivo evidence supporting this conjecture: post-weaning involution of mouse mammary glands does not show aberrant activation of caspases and their downstream effector protein PARP-1 [ 71 ], and still occurs normally in caspase-3 knockout mice [ 72 ].

Moreover, apoptotic death of mammary tumor cells in c-myc transgenic mice is actually associated with a decreased expression of Cyt-c [ 73 ]. However, a caveat needs to be given that these many ad-hoc variants of the four basic cell death modes are still meaningful and worth exploring as they reflect cell death, mainly SICD, at different particular circumstances, understanding of which is an important scientific footing for precision medicine or personalized medicine.

Stress can directly kill cells necrosis , can turn on intrinsic death program of cells SICD , and can goad aging-caused cell death SD , depending on the extent of stress and the cell type, as different cell types can withstand different extents of stress. For instance, as an adverse event, a given radiotherapy or chemotherapy can directly kill some normal cells necrosis but can only cause SICD or spur SD of some other normal cells while having no effect at all on a third set of normal cells, creating heterogeneity of cell death in a given tissue or organ.

Actually, heterogeneity of cell death is a common phenomenon when a tissue encounters a strong stressor [ 74 ]. It is also possible that a given stress causes death of the same cell via combined mechanisms, including SD, SICD and necrosis. In our cogitation, it is not that necrosis can also be a programmed event but it is because SICD is misconstrued as necrosis. Also, it is not that apoptosis may be immunogenic as well, as alleged in many studies [ 2 ], but it is because SICD is misconstrued as apoptosis.

All animals, including humans, have been programmed in their nuclear and probably also mitochondrial genomes to die eventually, and all cells in an animal will die along with the animal itself, if not earlier. There hitherto has not been any way to immortalize an animal, and not even an organ, but individual cells can be easily reprogrammed to be immortal, either spontaneously as bespoken by benign or malignant tumor cells appearing in humans, or intentionally as cancer researchers often do in labs.

Therefore, the program of cellular SD is not the program of aging of the organ or the animal. A related question that is still under debate is whether prokaryotic and unicellular eukaryotic cells undergo aging, since these unicellular organisms, typically bacteria, maintain their species by constant cell division [ 58 , 75 ]. Cancer cells are immortal and, even after the patient has died, can survive perpetually as cell lines, in which situation individual cancer cells resemble such unicellular organisms as bacteria that keep dividing to maintain themselves.

What still awaits clarification is whether cancer cells and even benign tumor cells also age, and thus also undergo SD, since in so many studies senescence is another nomenclature of cellular aging and since there are plentiful publications describing senescence of cancer cells [ 76 ].

In our logic, stress of any kind, such as an irradiation or a chemotherapy, is unable to induce or accelerate SD of immortal cells, such as cancer cells and various cell lines, either in vivo or in vitro, although it can kill these cells via necrosis or SICD. We are also contemplating over whether apoptosis, SD and SICD are really programmed events as stated in this and almost all other relevant articles.

A program is a pre-determined procedure, which in our opinion opposes the fact that most cells in animals are very plastic and can easily adapt to different changes in their microenvironment with a purpose for survival or for a better life, just like those of us who crave for a better life and increased longevity.

The fact that there have been so many ad-hoc modes of programmed cell death identified demonstrates the extreme flexibility of demise programs. If a program can be changed easily, i. Another question over which we have for long been pondering is whether apoptosis as a pure physiological event developed evolutionarily is encoded by a cellular structure, irreversible change of which is responsible for the irreversibility of the cell death procedure.

Or is apoptosis just like aging and type 2 diabetes that, unlike most other biological functions, lack a structural basis as some of us have wrangled before [ 58 ]? This is because no such cellular structure has been identified yet that is uniquely responsible for authentic apoptosis. What bedevils us the most is such a notion that necrotic cells putrefy to release immunogenic cellular materials to instigate inflammation.

Although this is true in lytic necrosis and probably at a late stage of some other types of necrosis, Fig. This trait seems dissonant with the above description that inflammation is one of the consequences and hallmarks of necrosis, but few articles discuss this incongruity.

We opine that there only two basic physiological cell death mechanisms, i. SICD and necrosis. SICD dwells between apoptosis and necrosis with similarities and differences between the two, which often makes it misconstrued as apoptosis or necrosis. More complicatedly, SICD can be easily adapted to different particular situations to become different variants that are named differently in the literature.

Authentic apoptosis does not occur in cell lines whose original death program has been reprogrammed to make the cells immortal, and does not occur in cell culture that is a stress to cells, uses cell lines, and lacks other cell types as other important players of apoptosis.

Many similarities and disparities among apoptosis, SD, necrosis and SICD delineated in this essay should help peers to distinguish these four basic cell death modes, and the variants derived from them, from one another. Particularly, apoptosis has evolutionarily developed to purge no-longer useful cells from the host tissue or organ, which is a yardstick to differentiate itself from SD, SICD and necrosis that cause death of useful cells and thus are followed by regeneration, wound healing and probably also scar formation.

Some notions, which have been ingrained in cell death research and firmly entrenched in the mind of many peers but may be preposterous, are also described in this essay as unanswered conundrums for future exploration and for peers to debate. How many ways to die? How many different models of cell death? Cell Death Differ.

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