Domains for the occurrence of apoptosis
It is beyond the scope of this paper to elaborate on the various roles of apoptosis in detail, but the following examples (in healthy animals and humans) illustrate how ubiquitous apoptosis is in biology:
[1]Apoptosis is essential during vertebrate embryological development in order to correctly sculpt the multifarious tissues and organs that are forming. The classical example is that of the developing limbs. These initially form as ‘buds’, the digits (e.g. fingers) forming later on, by virtue of apoptosis of the cells in the interdigital areas.51,52
[2]Apoptosis plays a pivotal role during both T-and B-lymphocyte maturation.53 For instance, the elimination of mature T-cell clones in the peripheral blood seems to be a mechanism for establishing tolerance to self antigens.54 Also, apoptosis may be activated during normal B-cell ontogeny*.55,56
[3]The human eye is a classic example of so-called ‘immunologic privilege’ by virtue of the fact that the exposed eye surfaces express the Fas-L(CD95L) molecule. If the eye is attacked by virus, a massive inflammatory response ensues, but no long-term damage to the eye occurs because the Fas-L triggers apoptosis in the infiltrating cells (neutrophils* and T cells), which are all removed in a few hours.57 This is obviously essential to healthy vision!
[4]Apoptosis provides a safe, disposal mechanism for neutrophil granulocytes at inflamed sites. Human neutrophils ingest foreign microbes at sites of injury, but their prolonged survival (once the job is done) would cause chronic tissue damage. It is now thought that they actively generate ROIs (reactive oxygen intermediates) in order to mediate their own speedy demise.58
[5]Apoptosis serves a vital role in controlling the number of germ cells in the testis59 and selectively eliminates cells with high proliferative activity, that acquire irreparable genetic abnormalities; e.g. testicular temperature rise causes more mutations in prospective gametes but heating to higher temperatures results in aspermia*.60 That is, apoptosis is very important in limiting teratogenesis (the production of neonatal abnormalities)
[6]In the ovary, a vast amount of apoptosis occurs in the germ-line, throughout the later stages of pre-natal development and on into post-natal life. One example is that it sets the absolute number of oocytes (eggs) that are available for development and ovulation in adult life.61Figure 2. Schematic diagram of the morphological features of apoptosis and necrosis (adapted and redrawn from103).Click here for larger view.
[7]In non-pregnant women, the cyclic fluctuations of the menstrual cycle hormones determine the cellular fate (proliferation, differentiation, or apoptosis) of both mammary gland epithelium*62 and the uterine endometrium*.63 Menstruation itself is brought about by apoptosis of a specific endometrial cell population. In post-pregnancy women and mammals generally, regular suckling ensures that lactation continues. Conversely, at weaning, the gradual or abrupt cessation of milking of the mammary gland results in its gradual or rapid involution respectively. This involution (leading to milk stasis) is due to a net loss of glandular mammary tissue by apoptosis.64
[8]Human breast milk contains the common protein alpha-lactalbumin which, in its multimeric* form, has been reported to have potent apoptosis-inducing effects in tumour cell lines, but much less effect on a variety of normal cell types.65 I have personally confirmed these results in a series of experiments on fresh lymphocytes from healthy volunteers and from patients with chronic lymphocytic leukaemia.66 The original discovery was serendipitous67 and the precise function of this capability of breast milk is not fully understood. Perhaps the induction of apoptosis in transformed, but not mature, epithelial cells helps direct the normal growth of neonatal mucosal*epithelium and helps prevent neoplasia*.65
[9]In the nematode Caenorhabditis elegans, the morphological development is very precisely governed by which cells divide and which cells undergo apoptosis at specific stages.8,9
[10]Metamorphosis brings about pronounced morphogenetic changes in a short time as organisms change from the larval to adult stages. Apoptosis plays a central role in this process. Metamorphosis is well-known in numerous insect species, as well as certain vertebrate organisms. For instance, metamorphosis involves the complete remodelling of virtually every tissue/organ as tadpoles transform into frogs. Most organs, if they are not completely reabsorbed, at least undergo apoptotic deletion of certain cells.68[/list]
It is not really possible to do justice to the role of apoptosis in each of the above but the interested reader is referred to the references. A recommended recent book that covers some of this material in more detail is
When Cells Die. In the preface, the editors make the following, interesting comment:
‘Throughout the book, the clearestconsensus is thatan organism uses cell death in a very positive way—to sculpt its development, to arrange for rapid expansion and subsequent contraction of a cell population in the immune and reproductive systems, and to defend itself by destroying cells that have been infected or attacked’ [emphasis added].69
A biblical perspective on the purpose of apoptosis
It is clear from the foregoing, that apoptosis is an essential physiological mechanism and as such, would have been present in the pre-Fall world. However, as some of the above examples show, some apoptotic pathways are also triggered as a toxicological reaction. Thus, they are vital to an organism’s health (even survival) during exposure to pathogenic* microorganisms or environmental stress. Apoptosis can be viewed as the ultimate mechanism for maintaining phenotypic fidelity* in multicellular organisms.
70From a biblical perspective, the capacity for deployment of these abortive cell-processes (as a ‘stress-response’) was built into the genetic potential of all organisms by our Omniscient Creator. After the Fall (and the resulting curse on all Creation), the role for apoptosis must have diversified substantially. Conditions in the radically altered, post-Flood world would, no doubt, have added to the ‘work-load’ of the originally created apoptotic mechanisms. Obviously, with the passage of time, entropy was increasingly manifest by these originally perfect systems and we see the results today, when defective apoptotic responses sometimes lead to disease (see below).
It is of interest to creationists that failure of normal apoptosis has been proposed as a possible means to facilitate the aging process.
70Various experimental studies of the longevity of human lymphocytes have correlated apoptosis with aging.
71 Perhaps degeneration of apoptotic control increases with time so that it has a rate-limiting effect on the aging process. This has obvious implications for our thinking about the antediluvian long lifespans. Bergman has recently discussed this, with respect to the telomeres that protect the ends of normal cellular chromosomes.
72 These telomeres shorten with each cell division, eventually triggering senescence* and apoptosis. Bergman speculates that:
‘At some point in history human longevity could have changed as a result of some alteration of the telomerase system.’73
When apoptosis goes awry
Rather, apoptotic pathways have all the hallmarks of irreducible complexity and attempting to construct them in a step-wise fashion, whilst maintaining functionality at each step, would be futile in the extreme.The perfect functioning of an apoptotic mechanism depends on the genetic information being uncorrupted, as it was at Creation. Therefore, any loss of information, such as occurs when a gene that codes for a protein in an apoptotic cascade mutates, will almost certainly have drastic consequences. Indeed, the sensitivity of these mechanisms to the slightest change in the configuration of a single protein component, is a powerful argument
against neo-Darwinism. It is truly inconceivable that
randomchanges to gene-encoded information for these pathways could ever produce an improvement. Rather, apoptotic pathways have all the hallmarks of irreducible complexity
74 and attempting to construct them in a step-wise fashion, whilst maintaining functionality at each step, would be futile in the extreme.
Dysregulation (too much or too little) of apoptosis can cause a wide spectrum of defects:
[1]Cancer. Defects of normal apoptotic processes have been discovered in many forms of cancer.75Normal cells maintain a balance between the rates of mitosis and apoptosis. However, apoptotic failure of a cell that has sustained one or more somatic mutations results in an immortalised ‘cellular anarchist’ (neoplastic* cell). Solid tumours (cancers) or an uncontrolled proliferation of haematopoietic cells (leukaemia and lymphoma) are the inevitable consequence. Since many genes regulate apoptosis, it is no surprise that defective genes have been noted in many cancers (so-called oncogenes), such as p5376 and bcl-2.77,78 Over-expression of Bcl-2 protein, as a result of bcl-2 oncogenesis, confers resistance to the neoplastic cells so that they are much less susceptible to chemotherapeutic drugs and radiotherapy.79[/list]
[2]AIDS. Apoptosis research has thrown light onto the causes of this immune deficiency syndrome. Among other things, it seems that expression of Fas(APO1/CD95), a ‘cell death’ receptor, is enhanced in individuals infected with HIV (human immunodeficiency virus), contributing to/causing an increase in the apoptotic rate of CD4+ T-lymphocytes.80 This is however, somewhat controversial among AIDS researchers.81,82[/list]
[3]Alzheimer’s disease (AD). Individuals with AD suffer premature or excessive neuronal cell loss in the brain during the aging process, together with other pathological effects (the formation of plaques, gliosis* and neurofibrillary tangles*). Compromised mitochondria may release a significant amount of calcium ions into the cytoplasm, so stimulating the caspases and DNases involved in apoptosis.83However, there is some ambiguity regarding the role of caspase-dependent neuronal apoptosis in AD due to contradictory experimental observations and a lack of convincingly apoptotic neurons in AD brains.84 Other AD research indicates that the apoptotic signal may not reach the terminal caspases.85 Thus, while apoptosis certainly seems to be implicated in AD, a causative role is questionable.[/list]
[4]Rheumatoid arthritis (RA). RA is an autoimmune disorder in which the body attacks its own cartilage in the synovial joint linings, leading to inflammation, painful swelling and eventually loss of joint function. It has been shown that chondrocytes (cartilage cells) of articulating bone surfaces are more prone to apoptosis in RA patients.86 This was recently found to be strongly associated with expression of pro-apoptotic proteins such as Fas(APO1/CD95) Fas-L and p53.87 The cause of RA is essentially due to multi-level aberrations that lead to defective apoptosis or hyperapoptosis.88[/list]
[5]Embryonic lethality. Mice are widely used as disease models in medical research. There are many reports in the scientific literature of murine embryos dying due to excessive apoptosis, either because a particular protein is overexpressed, or because it is deficient. For example, embryos die in utero around mid-gestation if they are deficient in cytochrome c89 or the nuclear factor kappaB.90 In both of the latter cases, the authors demonstrate that the protein deficiency renders the mice susceptible to apoptotic signals, mediated by TNF-α/TNFR1 signalling.[/list]
[6]Eye problems. Apoptosis has critical (and contrasting) roles in the various ocular tissues (cornea, lens and retina) and extraocular tissues (e.g. optic nerve) that contribute to vision. We saw earlier that it contributes to immunologic privilege in the healthy eye. It may also initiate healing of eye wounds but malfunctioning apoptotic pathways are also associated with opthalmological disease.91[/list]
In every case, small perturbations of apoptotic mechanisms (often resulting from a single somatic mutation) have debilitating, even lethal effects, belying ideas of genetic gradualism and corroborating Behe’s thesis of ‘irreducible complexity’.
74 It is clear that impairment of apoptosis compromises the body’s ability to effectively eliminate damaged or mutated cells, which would affect the organism’s survival if they lived on.
The therapeutic potential of manipulating apoptosis
Leading researchers in this field recently stated that:
‘Programmed cell death and apoptosis are very important aspects of a healthy life, and our access to manipulation of it will have vast consequences in many fields of medicine and agriculture.’92
Figure 3. Photomicrographs of cells (B-lymphocytes) from patients with Mantle cell lymphoma (MCL; A) and Chronic lymphocytic leukaemia (CLL; B). The cells were isolated from peripheral blood specimens (from patients with these neoplasms) using lymphocyte separation medium, cytocentrifuged onto glass microscope slides, air dried, fixed in methanol and stained with a Romanowsky (red/blue) stain.95 The photomicrographs are both to the same scale. The four smaller objects in A are erythrocytes (red blood cells). The immunophenotype (pattern of expression of cell proteins) of MCL cells is very similar to, but distinct from, that of CLL cells96 and the two malignancies have very different prognoses. However, both MCL and CLL cells only rarely express the ‘death receptor’ protein, Fas(APO1/CD95), in contrast to most other types of non-Hodgkin’s lymphoma.13
Click here for larger view.Restoration of the apoptotic response would be beneficial in many cases. This is a particularly fruitful avenue of research with respect to treating many cancers. Clearly, the very existence of cancer is testimony to the ongoing genetic degeneration that started with the Edenic curse.
93 In cancer and haematological* neoplasms, restoration of the apoptotic response to therapeutics would help to solve the longstanding problem of multi-drug resistance of malignant cells.
94 For example, in healthy people, Fas(APO-1/CD95)-mediated apoptosis is thought to be responsible for the removal of anergic*, autoreactive B-lymphocytes from the peripheral blood circulation; i.e. part of a normally functioning immune system. Once activated, mature B-cells acquire surface Fas-expression and concomitant sensitivity to apoptosis, induced by Fas-ligand on Th1 (T-helper) cells. However, malignant cells from patients with B-cell chronic lymphocytic leukaemia or mantle cell lymphoma (see Figure 3) usually lack surface Fas expression, rendering them resistant to Fas-mediated apoptosis. I recently co-authored the report of a study, in which we attempted to re-sensitize such neoplastic lymphocytes to apoptosis using the cytokine, interleukin‑2.
97Inhibition of inappropriate apoptosis could be beneficial in other cases. This is particularly the case, where cellular degeneration results from a disease process that causes too much apoptosis. Approaches aimed at reducing apoptosis are an active research area for scientists studying viral pathogenesis (e.g. HIV infection),
80 neuronal degeneration (e.g. Alzheimer’s disease)
83 and rheumatoid arthritis,
87,88 for example.
Conclusions: apoptosis from a creation/evolution perspective
Faced with the growing realisation that apoptosis is one of
the fundamentally important biological processes, some evolutionists are beginning to grapple with such crucial questions as how it originated and how it was selected for, according to Darwinian, selectionist dogma. Comments such as the following are predictable:
‘Many of the genes that control apoptosis are conserved throughout evolution from mammals to nematodes, flies, and viruses.’98
Similarly,
‘The preservation of a process throughout evolution indicates that the process is fundamental and too important to be modified.’99
Clearly however, this type of remark merely begs the question of how apoptosis is supposed to have evolved in the first place.
100 Another paper by this author reviews the few evolutionists’ attempts to explain apoptotic origins and argues that the very existence of apoptosis actually falsifies evolution.
101 Contrary to the impression given, the great
diversity exhibited by apoptotic pathways, notwithstanding fundamental similarities, is a hallmark of Creative Design.
102 Apoptosis is widely distributed among disparate species and tissues. Also, whereas a single mechanism of action would be predicted by reductionists, we observe multiple effectors.
So, just how far back did apoptosis originate in an evolutionary world? According to the evolutionary paradigm, injurious agents (e.g. irradiation, cosmic radiation, free radicals, hypoxia/hyperoxia*, environmental chemicals) and hyperthermic conditions have characterised the early Earth’s history at one time or another. Thus, a sophisticated apoptotic response would have been especially necessary at the very stage in Earth’s history when multicellular, eukaryotic cells are supposed to have evolved (during the late Precambrian)! Even today, apoptosis serves an essential role in terms of ‘cellular altruism’. It helps to ensure that an organism’s genetic integrity is not compromised, by removing some somatic cells that have sustained irreparable, genetic mutations. Crucially, apoptosis also helps to maintain a
species’genetic integrity, by eliminating aberrant germ cells that would otherwise carry intact but faulty genes into the next generation. Thus, on the hypothetical early Earth of the evolutionist, fully-functional apoptosis would have been
much more important than it is today!
In summary, a creationist perspective is cognizant that apoptosis:
[1]is as vital and ubiquitous to life as mitosis;
[2]is programmed and tightly regulated—speaking of a Programmer who put the information into cells originally;
[3]is irreducibly complex—it only takes one part of the mechanism to malfunction and the whole process is badly affected, especially illustrated by cancer;
[4]shouts Design (Romans 1:20);
[5]is a Created mechanism—part of the ‘very good’ declaration of God (Genesis 1:31).
Acknowledgements
I am sincerely grateful to the Lord for planting the idea for this article in the first place, to Carl Wieland for his encouragement, and to the two reviewers, whose comments have helped me to enhance the paper.
|
anergic | in a state of being unable to react to antigenic (immunogenic, allergenic) substances. |
apoptosis | an active process (requiring energy) involving the programmed deletion of scattered cells by fragmentation into membrane-bound bodies which are phagocytosed by other cells. No inflammatory response occurs. |
aspermia | a total absence of spermatozoa (sperm cells) in an ejaculate. |
caspases | a group of enzymes which are particularly involved in the transduction of signals for apoptosis. |
chromatin | the genetic material of the nucleus, made up of DNA and protein. During mitosis, the chromatin condenses into chromosomes. |
clonalselection | the specific recognition of foreign protein (antigen) by a small proportion of the body’s circulating lymphocytes, followed by the rapid expansion of this lymphocyte clone for specific antibody production and immunologic memory. |
differentiation (cells/tissues) | the development of morphology and/or functions that were not part of the original cells/tissues; occurs to bring about greater specialisation. |
dysregulation | dys is a prefix meaning mis- or un-, so this refers to abnormal regulation. |
embryogenesis | the formation of the characteristic configuration of an embryo’s body. |
endometrium | the mucous membrane that forms the uterus lining, consisting of columnar epithelium and glands; its structure and thickness vary in accordance with the menstrual cycle. |
epithelium | the cellular layer that covers all free body surfaces, e.g. cutaneous (skin) and mucous layers. |
erythrocyte | a red blood cell; lacking a nucleus and specialised for oxygen transport. |
eukaryotic/eukaryote | literally means those organisms with ‘good nuclei’ in their cells (i.e. all animals, plants and fungi); the nucleus is membrane-bound and its DNA is associated with proteins to form chromosomes. The cytoplasm also contains many organelles (e.g. mitochondria) that are absent from prokaryotes (e.g. bacteria and ‘blue-green algae’). |
gliosis | an overgrowth of the astrocytes (star-shaped neural cells) in an area of brain or spinal cord damage. |
haematological | pertaining to the blood and blood-forming tissues. |
homologous regions | similar/equivalent amino-acid sequence; an evolutionist would interpret this as evidence of their common molecular origin in a putative ancestor. |
hypoxia/hyperoxia | respectively, too little oxygen or too much oxygen; i.e. oxygen tension (a key physical property for living organisms) changes with pressures that differ from 1 atmosphere. |
inflammation | essentially, a pathological process that results from some sort of injury, usually involving redness, heat, swelling and pain. |
macrophages | large, long-lived, phagocytic cells that are a major part of the body’s immune defences; their morphology varies a great deal, but all are derived from monocytic stem cells of the bone marrow. |
membrane asymmetry | the phospholipid (‘fatty’) membranes of living cells have many associated protein molecules, some spanning the entire membrane, some located towards the outside of the cell and some inside; basically a non-symmetrical arrangement. |
mitochondria | subcellular organelles; the power houses found in all eukaryotic cells that provide the energy (in the form of ATP) to drive all cellular reactions. |
mucosal | pertaining to a mucous membrane (tissue layer); various types of mucosa line the body’s tubular cavities, such as the stomach, intestines, trachea, uterus etc. They are composed of epithelium and mucous glands. |
multimeric | a grouped arrangement of several identical molecules, e.g. a trimer consists of three molecules. |
necrosis | cell death that results from injury or a pathological condition; it is a passive, chaotic process. |
neoplasia/neoplastic | a pathological process that results in neoplastic tissue; i.e. abnormal cells that proliferate uncontrollably and generally more rapidly. |
neurofibrillarytangles | the accumulations of disorganized filamentous tissue between nerve cells; patients with Alzheimer’s disease exhibit these in the hippocampus and cerebral cortex (brain regions). |
neutrophils | a class of granulocytes, mature white blood cells with a lobed nucleus and a granular cytoplasm; so-called because their nuclear material does not show a particular affinity for either the acidic or basic stains that are commonly used in haematological laboratories. |
ontogeny | the history of an organism’s development. |
pathogenic | having the capacity to cause disease. |
phagocytosis | literally means ‘cell-eating’; phagocytes are cells which ingest (then digest) foreign particles, bacteria, necrotic tissue, etc. |
phenotypic fidelity | describes how faithfully the observable characteristics (manifestation of the genetic makeup) of an organism are conserved. |
pluripotentstem cells | non-specialised, primordial cells that can differentiate into a wide variety of cell types. |
RNA | abbreviation for ribonucleic acid, a class of single-stranded molecules involved in protein synthesis. |
senescence | a state of being old, in which normal function is declining as death approaches. |
trimerisation | the process of forming a substance that is composed of three molecules of a monomer. |
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