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What triggers programmed cell death in humans (from outside the cell)?


What triggers programmed cell death in humans? Is it decided by the brain (for the entire body)? Or is it a local decision of a cell by its environment? Something else?

I realize that there might be different cases. But I'd like to get a general idea of where (and why, actually) does this happen.

EDIT

As linked to by a comment below - one type of cell-death (Necrosis) just "happens" to a cell. And perhaps there are other types that are decided by the cell. What I'm asking about (and trying to understand more) is about the idea that cell-death might be initiated externally to the cell because it would be beneficial to the whole organism. Such as "the separation of fingers and toes" mentioned in Wikipedia . "Who" would initiate it? Are there examples of the CNS initiating it? Notifying the cell by nerves? By hormones? Are they initiated by neighboring cells? (And if so - what cells have the "clout" to send such signals?)

What I'm trying to understand is who decides when a cell dies in those cases where it's not the cell itself.


The answer is, in part, it depends. Let's think of the PI3K/AKT pathway. Akt actively phosphorylates BAD which abrogates the Bax/Bak apoptosis pathway. RTK's at the plasma membrane activate this pathway when bound with survival factors. In the absence of survival factors, Akt would become dephosphorylated and you'd have a net movement toward apoptosis. In a particular form of cell death called anoikis, this could be as simple as detaching from the extracellular matrix. So anything that halts the binding of survival factors could play a role.

In the case of immune response, activated Tc cells can induce apoptosis by secreting pore-forming enzymes as well as enzymes that directly activate caspases. The Tc cells also express Fas on their membrance which is involved in the extrinsic apoptosis pathway. TNF (tumor necrosis factor) may also bind cell surface receptors as sort of a death factor, and push towards apoptosis.

These are just examples, some generic searches about apoptosis, necroptosis, entosis, and a myriad of other programmed death mechanisms will yield a very comprehensive overview.


One event that comes to mind is the use of radiation on cancer patients. Radiation is an external event that can trigger apoptosis in humans 1. When cancer patients receive radiation, the treatment is localized. The brain isn't telling the cells to die it is the radiation effects on the cell.

Ionizing radiation can also induce apoptosis via the generation of free radical oxygen species 2.

Free radical oxygen species does this by searching for an electrons in the molecular make up of the cell 3.


Apoptosis: The Molecular Mechanism of Programmed Cell Death (Short Notes)

What is Apoptosis? Why apoptosis is known as the ‘Programmed Cell Death’?

The total number of cells in an organ or organism is fundamentally fixed to a specific range in all multicellular organisms. In every multi-cellular organism, the cell number is effectively controlled by two strategies- (a) by regulating cell Division and (b) by regulating cell Death. If cells are no longer needed, they commit suicide (self-destruction) by activating an intracellular death signaling programme. Thus, this death process is known as ‘Programmed Cell Death’. This programmed cell death pathway is called Apoptosis.

The term apoptosis in Greek literally mean ‘falling off’. Just like the old leaves ‘falloff’ from the trees without affecting the life of the plant, the apoptotic cell death will not interfere with the functioning of the organ and organism. The most striking feature of apoptosis is that if a cell undergoes the programmed cell death, the neighboring cells are not at all damaged. Apoptotic death of a cell and its subsequent phagocytosis by a neighboring cell or by a macrophage allow the organic components of the death cell to be effectively recycled.

The apoptosis is better known as the ‘Programmed Cell Death’. It is a natural well-orchestrated, well sequenced and timely executed chain of events leads to the death of a cell.

What are the characteristics of Apoptotic Cell Death?

An apoptotic cell death is characterized by:

Ø Shrinkage of the nucleus

Ø Loss of adhesion to the neighboring cells

Ø Formation of membrane blebs (externalization of inner leaflet of membrane)

Ø Condensation and fragmentation of the chromatin (DNA)

Ø Formation of small fragmented chromatin in membrane bounded structures called apoptotic bodies

Ø Rapid engulfment of the apoptotic cell debris by the process of phagocytosis

image source: cc wikipedia

What are ‘apoptotic bodies’?

During apoptotic cell death, the nucleus gets fragmented into many discrete chromatin bodies due to degradation of nuclear DNA. Each such nuclear fragment is surrounded by blebbed plasma membrane and these units were bud-off from the apoptotic cell. Thus, by the completion of apoptosis, the cell content is converted into many small vesicles called ‘apoptotic bodies’. Apoptotic bodies are immediately phagocytosed by the macrophages or surrounding healthy cell.

(image source: cc wikipedia)

Does apoptosis be Natural or Pathogenic?

The apoptosis is a natural process. About 10 10 to 10 11 cells in the human body dies every day by the process of apoptosis. Apoptosis is essential for the proper embryonic development in higher organisms. For example, the separation of fingers and toes in a developing human embryo occurs because cells between the digits undergo apoptosis during the embryonic development. Apoptosis also helps to prevent the perpetuation of lethal genetic damages in the body. The apoptotic cell death can occur in a cell when its genetic material is severely damaged and it cannot be rectified by the inbuilt DNA repair mechanism. Sometimes, the apoptosis can be pathogenic such as the death of healthy neurons which leads to the Alzheimer’s disease.

Webbed toes formation due to the lack of apoptotic cell death during embryonic development (cc wikipedia)

How was apoptosis discovered?

The term apoptosis was coined by John Kerr, Andrew Wyllie and A.R. Currie in 1972. The molecular basis of apoptosis was elucidated for the first time by the studies in a nematode Caenorhabditis elegans. The worm C. elegans constantly maintain their cell number in its embryonic and adult stages. During the embryonic development, the worm produces exactly 1090 cells. Among these 1090 cells, 131 cells are precisely destined to die by apoptosis during the development. Further studies in the worm identified a specific gene involved in controlling the apoptosis process and it is named as CED-3. A worm with inactive CED-3 gene by mutation fails to induce the apoptotic cell death in the embryonic development stage. This shows that CED-3 plays a crucial role in executing the process of programmed cell death. Later, scientists identified genes homologous to the CED-3 of C. elegans in other organisms including humans and subsequently named as Caspases.

Caenorhabditis elegans (image source: cc Wikipedia)

What are caspases? What is the importance of caspases in apoptosis?

Caspases are a family of proteins present in human and other animals which are homologous to the CED-3 gene product of C. elegans. Caspases are cysteine proteases involved in the execution of apoptotic cell death. Cysteine proteases are a category of protease enzymes with a cysteine residue at its active site. The caspases are produced as inactive zymogens called pro-caspases. Pro-caspases are activated to caspases during the early stages of apoptosis. Activation of pro-caspase to caspases is achieved by the catalytic removal of a part of the peptide chain. Activated caspases are responsible for most of the molecular events in the apoptosis signaling pathway.

How caspases execute apoptosis? What are the targets of caspases during apoptosis?

Caspases execute the apoptosis by selectively targeting and cleaving a large array of key molecules in the cells. Most important target molecules of caspases during apoptosis are given below:

(1). Protein Kinases: Protein kinases such as Focal Adhesion Kinase (FAK), Protein Kinase B (PKB), Protein Kinase C (PKC) and Raf1. Inactivation of the FAK cause detachment of the apoptotic cells from its neighboring cells due to the inhibition of cell adhesion.

(2). Lamin: Lamin form the inner lining of the nuclear membrane and thus the cleavage of lamins lead to the disintegration of nuclear lamina (nuclear membrane) and breakage of the nucleus.

(3). Cytoskeleton proteins: The cleavage of cytoskeleton proteins such as actin, tubulin and intermediate filaments lead to the shrinkage of the cells.

(4). CAD (Caspase Activated DNases): CAD is an endonuclease. In a normal cell, the CAD endonuclease exists in an inactive stage. The cleavage of CAD by caspase activates the CAD enzyme. Activated CAD then translocated into the nucleus and it cleaves and degrades the DNA.

What are apoptotic signals?

Any stimuli that can induce and initiate the programmed cell death pathway are called apoptotic signals. The source of apoptotic signals can be of two different types such as those from the external sources and those signals originated in the cell itself. Based on the source of signals, there are essentially two types of apoptotic signaling pathways. They are:

(1). Intrinsic Apoptotic Pathway: Here the apoptotic stimuli are originated internally in the target cell itself. The most important internal signal that induces intrinsic signaling is severe DNA damage that cannot be rectified by the DNA repair mechanism.
(2). Extrinsic Apoptotic Pathway: Here the stimuli are from the external source (not from the cell itself). The most important external apoptotic signals are cytokines such as Tumour Necrosis Factor (TNF). (The exact mechanism of intrinsic and extrinsic pathways of apoptosis will be discussed later).

Even though the signaling cascades of extrinsic and intrinsic pathways are separate, there is always cross-talk between these two pathways. The extrinsic pathway can induce the activation of the intrinsic pathway of apoptosis.

What are the significances of apoptosis?

Apoptosis is a beneficial event. Moreover, failure to regulate apoptosis can result in the damage of organs or organisms. The main significances of apoptosis are given below:

Ø Apoptosis help to maintain the homeostasis in multicellular organisms.

Ø Apoptosis also helps to maintain the proper body size.

Ø Apoptosis maintains the constancy of cell number in an organ or organism.

Ø Apoptotic cell death is a pre-request for the proper embryonic development.

Ø By the process of apoptosis, the body can eliminate unwanted cells such as:

$ A cell with severely damaged DNA

$ A cell with fatal mutation

$ A pathogen (virus) infected cell

$ Unwanted cells formed during embryonic development

$ Cells that to be killed during proper neuronal architecture development

Ø Apoptosis also helps to kill T lymphocytes with receptors for the proteins present on the normal cell. These T cells are produced during the embryonic development. These dangerous T lymphocytes are eliminated by apoptotic cell death.

Ø Apoptotic cell death can be pathogenic in some cases.

Ø Apoptosis is involved in some neurodegenerative diseases such as Alzheimer’s, Parkinson’s disease, and Huntington’s disease by the elimination of essential neurons.

Ø Failure to induce apoptosis is the main reason for most of the cancers.

How the macrophages specifically recognize the apoptotic cells for phagocytosis?

Both the intrinsic and extrinsic pathway of apoptosis converges by activating the same executioner caspases, i.e., caspase-3. As the apoptotic signaling proceeds, the cell loses its contact with the neighboring cell and starts to shrink. The cell ultimately shrinks into one or more condensed membrane-enclosed structures called the apoptotic body. The apoptotic bodies are characterized by the presence of phosphatidyl serine on their outer surface. Phosphatidyl serine is a membrane lipid present only in the inner leaflet of plasma membrane. During apoptotic cell death, the plasma membrane flipping occurs which results in the externalization of phosphatidyl serine residues. These externalized phosphatidyl serine molecules are the ‘eat me signals’ for the macrophages. The macrophages recognize these ‘eat me’ signal and they completely phagocytosis the apoptotic bodies. Thus, the apoptotic cell death is completed without spilling the cellular content into the extracellular environment. This is very significant because the release of cell debris can trigger inflammatory responses which ultimately cause severe tissue damage.

What is the relationship between Apoptosis and Cancer?

Cancer is a pathological process of uncontrolled division of cells leading to tumor development. Some cancerous cells also have the potential to invade healthy tissues by a process called metastasis. The cancer is essentially the uncontrolled division of an abnormal cell with mutations of genetic damage. If the apoptotic signaling is properly working, these unwanted cells can be eliminated from the body by programmed cell death pathway. Thus the main reason for cancer is the failure to induce apoptosis in an unwanted cell and as a result of this, the unwanted cell perpetuates without any control.

Review Questions…

(1). Define Apoptosis.
(2). Why is apoptosis known as the ‘Programmed Cell Death’?
(3). What are the characteristics of Apoptotic Cell Death?
(4). What are apoptotic bodies?
(5). Does apoptosis be Natural or Pathogenic?
(6). What is meant by membrane blebbing?
(7). How was apoptosis discovered?
(8). What are caspases? What is the importance of caspases in apoptosis?
(9). How caspases execute apoptosis? What are the targets of caspases during apoptosis?
(10). What are apoptotic signals?
(11). What are the significances of apoptosis?
(12). What is the relationship between Apoptosis and Cancer?
(13). What is the difference between apoptosis and necrosis?
(14). What is the importance of apoptosis in embryonic development?
(15). What is the role of C. elegans in the discovery of apoptosis?
(16). Who discovered apoptosis?
(17). What is CED? What is its importance in apoptosis?
(18). What are the main targets of caspases in human during apoptosis?
(19). What is meant by intrinsic pathway of apoptosis?
(20). What is meant by extrinsic pathway of apoptosis?
(21). Give some examples of intrinsic apoptotic signals.
(22). Give some examples of extrinsic apoptotic signals.
(23). Differentiate pro-caspases and caspases.


Introduction

Cell death is an essential process in the generation of multicellular organisms, 1 involving two pathways with distinct morphological characteristics: apoptosis and necrosis. 2,3 Apoptosis, extensively investigated as programmed transcriptional activation of specific genes, 4 has hallmarks which include the activation of endonucleases, consequent DNA degradation into oligonucleosomal fragments, and activation of caspases. 5,6 The cytoplasm shrinks, but the organelles and plasma membrane retain their integrity for quite a long period. In vitro, apoptotic cells are ultimately fragmented into multiple membrane-enclosed spherical vesicles. In vivo, these apoptotic bodies are scavenged by phagocytes, inflammation is prevented, and cells die in ‘immunological anonymity’. 7

Necrosis has been referred to as accidental cell death caused by physical or chemical damage 3,7 and has generally been considered an unprogrammed process. It is characterized by a pyknotic nucleus, cytoplasmic swelling, and progressive disintegration of cytoplasmic membranes, all of which lead to cellular fragmentation and release of material into the extracellular compartment. In necrosis, decomposition is principally mediated by proteolytic activity, but the precise identities of proteases and their substrates are poorly known. 8 An elevation in cell-surface plasminogen binding and activation in damaged and dead cells has, however, been evident. 9

Within the foci of necrotizing cells, an acute inflammatory reaction ensues. 10 Cell damage leads to failure to exclude calcium from the cell interior, resulting in the activation of calcium-dependent phospholipases. 11 Arachidonic acid, liberated from membrane phospholipids by phospholipase A2, serves as the precursor for consequent biosynthesis of eicosanoids, which play important roles in various cellular phenomena including inflammation, proliferation, differentiation, immune functions, and carcinogenesis. 12,13 Cyclooxygenases (COXs) are rate-limiting enzymes in the conversion of arachidonic acid to prostanoids. COXs generate precursor prostaglandin (PG) endoperoxides, mainly PGH2, which are subsequently metabolized by specific isomerases to five primary bioactive prostanoids (PGE2, PGD2, PGF2α, PGI2, and thomboxane A2, TxA2). 14 The constitutive COX isoform, COX-1, is expressed in most mammalian cells, whereas in most healthy tissues expression of the inducible isoform, COX-2, is ordinarily low or undetectable. 14 COX-2 is encoded by an early-response gene 15 and can be rapidly and strongly induced by serum, growth factors, proinflammatory cytokines, hormones, tumour promoters, or bacterial endotoxins. 16 These findings suggest that COX-2 is responsible for synthesis of PGs at sites of inflammation, and these amplify pain and exacerbate fever and proinflammatory manifestations. 13

Cell death in cultured cells can be induced by a variety of stimuli including physiological activators, physical trauma, microbes, environmental toxins, or chemical compounds. 3,7,17 Outcome usually depends on cell type and severity of stimulus. 18 Effective inducers of necrosis in vitro include certain toxic compounds and heat shock. 19 The type of cell death in the centre of spheroids established from tumour cells has been designated ‘necrosis’, with its development being considered a multifactorial event in which hypoxia is the main effector. 20

Three-dimensional culture systems such as multicell spheroids mimic certain control mechanisms operating in vivo under various pathophysiological conditions. 21 Spheroids have been particularly useful in studies focused on mimicking tumour nodules. 21 Nodular growth is common in malignant, fast-growing tumours but can also appear in the skin as a result of the hyperproliferation of dermal fibroblasts characterized by distinctly greater cell density, as in dermal fibrosarcomas. 22 Most human cancer cell lines derived from solid tumours form growing spheroids. 23 In contrast to tumour cells, normal adherent cells cannot be stimulated to grow as multicellular aggregates. 23 It is evident that the growth of normal and tumour cells in three-dimensional arrangements is differently controlled.

Our aim was to characterize molecular mechanisms accompanying the death of normal cells in three-dimensional clusters. The rationale for choosing fibroblasts was that they are active participants in translating specific physiological signals 16 and are the key sentinel cells to first recruit specific cells to sites of inflammation. 24 We observed that clustering of these cells within spheroids is apparently a sufficient stimulus to trigger a series of spatio-temporal events leading to initiation and programmed progression of the process that culminates in upregulation of COX-2 and plasminogen activation, both evidently distinct consequences of necrotic cell death. It is important to note that this necrosis in fibroblast spheroids did not result from any extrinsic toxic compounds but was instead triggered by homotypic cell–cell interactions.


B) Apoptosis (main type of programmed cell death).

This is the type of cell death that occurs deliberately under physiological and genetic control, which involves a single cell or a small group of cells in a tissue. Unlike necrosis, in apoptosis, other cells in the tissue are not affected and functioning normally.  In fact, the word apoptosis is a Greek derivative which was originally used to describe the falling of individual leaves from a tree.

Main features of apoptosis:

1) Cell Shrinkage and condensation.

2) Cytoskeletal collapse.

3) Nuclear disassembly, and condensation and fragmentation of its chromatin.

4) Formation of apoptotic bodies following the disintegration of the cellular surface.

4) Phagocytosis of the apoptotic bodies by immune cells, such as macrophages, and epithelia adjacent to the cell.   

Apoptosis often is associated with:

A) Developmental cell loss.

An example of this is the development of mammalian limb with the five fingers. In fact, this process involves two steps. Firstly, the growth of the tissue occurs by cellular division. Secondly, it is important that interdigital cell death happens as well otherwise a webbed limb will develop rather than a five digit limb.

Another example is the death of tail cells at metamorphosis as tadpoles develop into adult frogs. This results in the disappearance of the tail as it is not required in the frog. In other cases, apoptosis occurs for the regulation of cell numbers. For instance, in the developing nervous system, it occurs to match the number of neurons to the number of target cells they innervate.  

B) Cell Senescence (cell replicative senescence), where cells slow proliferation and eventually ceases irreversibly. This phenomenon is known as Hayflick limit.  

C) Chronic cytotoxicity which is often a result of modulation or disruption of Ca2+ cellular homeostasis as well as the increase of reactive oxygen species in either mitochondria or any other compartment in the cell.

D) Removal of growth Factors as this normally, in many cells, leads to arrest of cell cycle followed by cell death.


Normally harmless cell molecule triggers neuron death

A vital intermediate in normal cell metabolism is also, in the right context, a trigger for cell death, according to a new study from Wanli Liu and Yonghui Zhang of Tsinghua University, and Yong Zhang of Peking University in Beijing, publishing 26th April 2021 in the open access journal PLOS biology. The discovery may contribute to a better understanding of the damage caused by stroke, and may offer a new drug target to reduce that damage.

Farnesyl pyrophosphate (FPP) is an intermediate in the mevalonate pathway, a series of biochemical reactions in every cell that contributes to protein synthesis, energy production, and construction of cell membranes. During a search for regulators of immune cell function, the authors unexpectedly discovered that FPP, when present at high concentrations outside of cells, caused rapid and extensive death of cells. FPP carries both a highly charged phosphate head and a long hydrophobic hydrocarbon tail, and by altering each in turn, the researchers showed that both were necessary for the effect, suggesting that FPP might interact specifically with some complementary receptors.

Depletion of extracellular calcium prevented the lethal effect of FPP, providing a further clue as to the mechanism. By knocking out a variety of cation channels, the team found that one, called TRPM2, contributed at a certain level to FPP-induced cell death, and that an inhibitor blocking FPP induced TRPM2 open can inhibit FPP induced cell death.

FPP is normally present in the microenvironment at too low a concentration to trigger cell death, but that may change during an ischemic stroke, as mevalonate pathway are known to be highly active in neurons and neurons could rapidly release their cellular contents in stress induced necrosis, leading to elevated levels of many otherwise-rare biomolecules in the microenvironment. The authors showed that in a mouse model of ischemic injury, the concentration of FPP rose, and that pre-administration of the calcium channel blocker could reduce the extent of injury. Moreover, inhibitors that prevent the metabolic production of FPP also reduced the extent of injury.

These results suggest that blockade of FPP's action could be a new avenue for reducing the damage from stroke, either by inhibiting TRPM2 to reduce calcium influx or targeting its metabolic synthesizing pathway. Much will need to be learned about this new cell death pathway first, including the duration of the window during which such interventions might be amenable to therapy.

Nonetheless, Liu and colleagues said, "These findings point to novel, potentially druggable targets to treat ischemic injury. In view of the complex nature of human ischemic injury, targeting this pathway might best be combined with current therapies to improve the therapeutic effects."

In your coverage please use these URLs to provide access to the freely available articles in PLOS Biology: http://journals. plos. org/ plosbiology/ article?id= 10. 1371/ journal. pbio. 3001134

Citation: Chen J, Zhang X, Li L, Ma X, Yang C, Liu Z, et al. (2021) Farnesyl pyrophosphate is a new danger signal inducing acute cell death. PLoS Biol 19(4): e3001134. https:/ / doi. org/ 10. 1371/ journal. pbio. 3001134

Funding: This work is supported by funds from Institute for Immunology and Center for Life Sciences, Tsinghua University. W.L. and B.K.R. were supported by UAEU-Tsinghua Asian Universities Alliance Joint-Grant (G00002992). YH. Z. was supported by National Natural Science Foundation (81991492), Beijing Natural Science Foundation (Z190015) and Beijing Advanced Innovation Center for Structural Biology. Y.Z. is supported by the National Key R & D Program of China (2017YFE0103400), National Natural Science Foundation of China (31771125, 31970911, 81521063), and Beijing Municipal Science & Technology Commission (Z181100001518001). W.H. is supported in part by grants from the National Institutes of Health in the United States (AI146226, AI137822, GM130555-6610, AI129422 and AI138497). X. Z. is supported in part by the Postdoctoral Fellowship of Peking-Tsinghua Center for Life Sciences and China Postdoctoral Science Foundation (2019M660361). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Cell Death

Like all living things, the various types of cells in plants, animals, and the many different cell types in humans must eventually die. Cell death occurs in one of two ways. Cells can be killed by the effects of physical, biological, or chemical injury. Additionally, cells are induced to kill themselves. Cell suicide is also referred to as apoptosis (from the Greek words apo, meaning from, and ptosis, meaning to fall or to drop).

Cell death is important in disease and the aging process. Cellular suicide is also necessary in the fetal development of some organs and tissues.

Cell death that results from injury can be caused by mechanical damage such as tearing, or can be due to physical stresses such as heat. A third-degree sunburn, for example, results in the death of many skin cells. Exposure to toxic chemicals such as acids, corrosive bases, metabolic poisons, and other chemicals is also lethal to many types of cells. Excessive drinking of alcohol (ethanol) causes death of liver cells in humans.

Substances that dehydrate cells can also cause cell death. If the environment outside of a cell contains more salt than the interior of the cell, water flows out of the cell in an attempt to dilute the outside environment. The loss of water can disrupt the functioning of the cell to the point of death. This is called plasmolysis. Conversely, if the interior of a cell is saltier than the exterior environment, water flows into the cell. The cell can swell and burst. This phenomenon is called plasmoptisis.

Some diseases and infections cause chemical cell death. For example, infection of the upper respiratory cells with viruses that causes the common cold kills cells during the viral life cycle.

Causes of chemical or mechanical cell death are varied. Some agents act on the membrane that surrounds cells. The membrane can be dissolved or damaged. Other agents disrupt enzymes that the cell requires to sustain life. Still other agents can disrupt the genetic material inside the cell.

The process of programmed cell death, apoptosis, or suicide, is a necessary part of the functioning of an individual cell and, in multi-celled organisms such as humans, of the whole organism. For example, reabsorption of a tadpole's tail during the change from tadpole to frog involves apoptosis. Sloughing of uterine cells in women at the start of menstruation is due to apoptosis of the cells lining the uterine wall. Additionally, apoptosis of extraneous cells during development of a human fetus produces the distinct fingers and toes.

Apoptosis is also important as a means of dealing with threats to an organism. For example, the human immune system contains cells that can stimulate apoptosis of other cells that have been infected with a virus. Similarly, cells with damaged genetic material undergo cell death. Thus, apoptosis helps the entire organism function efficiently by eliminating cells that threaten the whole organism.

Programmed cell death occurs either by the withdrawal of a chemical signal that is required to continue living, or by exposure to a chemical signal that begins the death process. Once stimulated to die, apoptotic cells shrink, develop irregular cell surfaces, and show disintegration of genetic material within their nuclei. Eventually, these cells break into small membrane wrapped fragments that are engulfed by nearby cells. The apoptosis process is complex, and involves interactions between numbers of different biochemical compounds. This helps ensure that apoptosis does not initiate by accident, and that the process is limited only to specifically targeted cells.

Molecular biologists Sydney Brenner, Robert Horvitz, and John Sulston were awarded the 2002 Nobel Prize in Physiology or Medicine for their pioneering studies on the genetic regulation of programmed cell death. Their studies, which were carried out in the 1980s using a nematode worm as the model system, has since been shown to have relevance to the process of cell death in humans.


Cell Apoptosis

Apoptosis is programmed cell death (PCD). Cells in the body basically kill themselves based on preprogrammed sequences in their genetic code. The process of death utilizes chemical events that change the structure of the cell, and ultimately break it down, either to be used by other cells or expelled from the body as waste. This differs from cell necrosis, in which the cell dies and simply begins to decay, usually releasing harmful substances into the body.

Cells go through apoptosis for a variety of reasons. Cell death can occur in cells that no longer perform a function (for example: the tail of a tadpole as it turns into a frog). Apoptosis can also occur in cells that become a threat to the body, such as cells that have been infected by a virus, cells with damaged DNA, cancer cells, and active auto-immune cells which have served their function and are no longer needed.

Often apoptosis is induced by the production in the cell of p53, a protein that senses DNA damage usually caused by oxidants. (Antioxidants can prevent the damage from occurring in the first place.) P53 is expressed by the p53 gene on the DNA itself. Apoptosis can also be induced by a buildup of proteins that have not been properly processed. Another induction method involves death activator molecules sent from other parts of the body that can bind to receptors on the cell to cause apoptosis.


Scientists Calculate the Speed of Death in Cells, and It's Surprisingly Slow

Cells in our bodies die all the time, and now we know just how fast.

Scientists found that death travels in unremitting waves through a cell, moving at a rate of 30 micrometers (one-thousandth of an inch) every minute, they report in a new study published Aug. 10 in the journal Science. That means, for instance, that a nerve cell, whose body can reach a size of 100 micrometers, could take as long as 3 minutes and 20 seconds to die.

That may sound morbid, but it's precisely this lethal tide that keeps us alive and healthy. Apoptosis &mdash or programmed cell death &mdash is necessary for clearing our bodies of unnecessary or harmful cells, such as those that are infected by viruses. It also helps shape organs and other features in a developing fetus. (There is a second way cells can die, called necrosis, which is a different process that occurs as an unplanned response to a stressful event).

If this process doesn't work properly, the consequences can be dire. For example, cancerous cells, happily living on, having slipped the grasp of the Grim Reaper, begin to spread instead of dying off. [5 Ways Your Cells Deal With Stress]

"Sometimes our cells die when we really don't want them to &mdash say, in neurodegenerative diseases. And sometimes our cells don't die when we really do want them to &mdash say, in cancer," senior author Dr. James Ferrell, a professor of chemical and systems biology and biochemistry at Stanford University, said in a statement. "And if we want to intervene, we need to understand how apoptosis is regulated."

Apoptosis is also sometimes called "cellular suicide," because it is a process of self-destruction. It begins with a signal either from the inside or the outside that informs enzymes within the cells called caspases to start cleaving the cell. But it had been unclear how apoptosis, after being triggered, actually spread through the cell.

To figure this out, Ferrell and his team observed the process in one of the larger cells present in nature: egg cells of Xenopus laevis, or African clawed frogs. They filled test tubes with fluid from the eggs and triggered apoptosis, which they watched unfold by tagging involved proteins with fluorescent light. If they saw fluorescent light, it meant apoptosis was taking place.

They found that the fluorescent light traveled through the test tubes at a constant speed. If apoptosis had carried on due to simple diffusion (the spreading of substances from an area of high concentration to one of low concentration), the process would have slowed down toward the end, according to the study.

Since it didn't, the researchers concluded that the process they observed must be "trigger waves," which they likened to "the spread of a fire through a field." The caspases that are first activated, activate other molecules of caspases, which activate yet others, until the entire cell is destroyed.

"It spreads in this fashion and never slows down, never peters out," Ferrell said in the statement. "It doesn't get any lower in amplitude because every step of the way it's generating its own impetus by converting more inactive molecules to active molecules, until apoptosis has spread to every nook and cranny of the cell."

The team then wanted to watch this process occur inside the egg itself, as it would in nature. They noticed that when frog eggs died, they darkened in color. So, they initiated conditions that would naturally lead to the death of a frog egg and imaged what happened. Similarly, the cell darkened at the average rate of 30 micrometers per minute.

Such trigger waves are actually pervasive in nature, Ferrell said. Trigger waves also help cells reproduce, neurons propagate signals through the brain and viruses spread from cell to cell. Ferrell and his team hope to find out where else in biology trigger waves occur.


Scientists Hack a Human Cell and Reprogram It Like a Computer

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Cells are basically tiny computers: They send and receive inputs and output accordingly. If you chug a Frappuccino, your blood sugar spikes, and your pancreatic cells get the message. Output: more insulin.

But cellular computing is more than just a convenient metaphor. In the last couple of decades, biologists have been working to hack the cells’ algorithm in an effort to control their processes. They've upended nature's role as life's software engineer, incrementally editing a cell’s algorithm---its DNA---over generations. In a paper published today in Nature Biotechnology, researchers programmed human cells to obey 109 different sets of logical instructions. With further development, this could lead to cells capable of responding to specific directions or environmental cues in order to fight disease or manufacture important chemicals.

Their cells execute these instructions by using proteins called DNA recombinases, which cut, reshuffle, or fuse segments of DNA. These proteins recognize and target specific positions on a DNA strand---and the researchers figured out how to trigger their activity. Depending on whether the recombinase gets triggered, the cell may or may not produce the protein encoded in the DNA segment.

A cell could be programmed, for example, with a so-called NOT logic gate. This is one of the simplest logic instructions: Do NOT do something whenever you receive the trigger. This study's authors used this function to create cells that light up on command. Biologist Wilson Wong of Boston University, who led the research, refers to these engineered cells as “genetic circuits.”

Here's how it worked: Whenever the cell did contain a specific DNA recombinase protein, it would NOT produce a blue fluorescent protein that made it light up. But when the cell did not contain the enzyme, its instruction was DO light up. The cell could also follow much more complicated instructions, like lighting up under longer sets of conditions.

Wong says that you could use these lit up cells to diagnose diseases, by triggering them with proteins associated with a particular disease. If the cells light up after you mix them with a patient’s blood sample, that means the patient has the disease. This would be much cheaper than current methods that require expensive machinery to analyze the blood sample.

Now, don't get distracted by the shiny lights quite yet. The real point here is that the cells understand and execute directions correctly. “It’s like prototyping electronics,” says biologist Kate Adamala of the University of Minnesota, who wasn’t involved in the research. As every Maker knows, the first step to building complex Arduino circuits is teaching an LED to blink on command.

Pharmaceutical companies are teaching immune cells to be better cancer scouts using similar technology. Cancer cells have biological fingerprints, such as a specific type of protein. Juno Therapeutics, a Seattle-based company, engineers immune cells that can detect these proteins and target cancer cells specifically. If you put logic gates in those immune cells, you could program the immune cells to destroy the cancer cells in a more sophisticated and controlled way.

Programmable cells have other potential applications. Many companies use genetically modified yeast cells to produce useful chemicals. Ginkgo Bioworks, a Boston-based company, uses these yeast cells to produce fragrances, which they have sold to perfume companies. This yeast eats sugar just like brewer’s yeast, but instead of producing alcohol, it burps aromatic molecules. The yeast isn’t perfect yet: Cells tend to mutate as they divide, and after many divisions, they stop working well. Narendra Maheshri, a scientist at Ginkgo, says that you could program the yeast to self-destruct when it stops functioning properly, before they spoil a batch of high-grade cologne.

Wong’s group wasn't the first to make biological logic gates, but they’re the first to build so many with consistent success. Of the 113 circuits they built, 109 worked. “In my personal experience building genetic circuits, you’d be lucky if they worked 25 percent of the time,” Wong says. Now that they’ve gotten these basic genetic circuits to work, the next step is to make the logic gates work in different types of cells.

But it won't be easy. Cells are incredibly complicated---and DNA doesn’t have straightforward “on” and “off” switches like an electronic circuit. In Wong’s engineered cells, you "turn off" the production of a certain protein by altering the segment of DNA that encodes its instructions. It doesn't always work, because nature might have encoded some instructions in duplicate. In other words: It’s hard to debug 3 billion years of evolution.


Programmed Cell Death Protects Against Infections

They are the largest group of white blood cells: neutrophil granulocytes kill microorganisms. Neutrophils catch microbes with extracellular structures nicknamed Neutrophil Extracellular Traps (NETs) that are composed of nucleic acid and aggressive enzymes.

A group of scientists lead by Arturo Zychlinsky at the Max-Planck-Institute for Infectious Biology in Berlin, Germany discovered, how the neutrophils form this snaring network (Journal of Cell Biology, online, January 8, 2007). Once triggered, the cells undergo a novel program leading to their death. While they perish, the cells release the content of their nuclei. The nucleic acid, mingled with bactericidal enzymes, forms a lethal network outside the cell. Invading bacteria and pathogenic fungi get caught and killed in the NETs.

Every minute, several million neutrophils leave the bone marrow and are ready to defend the body of invading germs. They are the immune system&rsquos first line of defence against harmful bacteria and migrate into the tissue at the site of infection to combat pathogens. For more than hundred years it was known that neutrophil granulocytes kill bacteria very efficiently by devouring them. After eating the germs neutrophils kill tehm with antimicrobial proteins.

The group of scientists lead by Arturo Zychlinsky at the Max-Planck-Institute for Infectious Biology discovered a second killing mechanism: neutrophil granulocytes can form web-like structures outside the cells composed of nucleic acid and enzymes which catch bacteria and kill them. The scientists were able to generate impressive micrographs of these nets. But it remained a mystery how the granulocytes could mobilise the contents of their nuclei and catapult it out of the cells.Only after lengthy live cell imaging and biochemical studies it became clear how neutrophils make NETs. The cells get activated by bacteria and modify the structure of their nuclei and granules, small enzyme deposits in the cytoplasm.

"The nuclear membrane disintegrates, the granules dissolve, and thus the NET components can mingle inside the cells", explains Volker Brinkmann, head of the microscopy group. At the end of this process, the cell contracts until the cell membrane bursts open and quickly releases the highly active melange. Once outside the cell, it unfolds and forms the NETs which then can trap bacteria.

Surprisingly, this process is as effective as devouring bacteria: "NETs formed by dying granulocytes kill as many bacteria as are eaten up by living blood cells", says Arturo Zychlinsky. Thus, neutrophils fulfil their role in the defence battle even after their deaths.

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