How to surpass cell death?

How to surpass cell death?

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Is it possible to surpass/decay cell death. For example to disable the process muscles cells death, by tweaking the transduction pathways:

If it's not possible in our age Medicine, what it would take to do such thing in theory. The idea is to tweak the cell dying mechanisms for example to preserve neural and muscle cells for longer time. I am also curious how to disable a pathway or part of it.

Yes; It is possible to inhibit cell death.

There are several possibilities, of which many - as correctly recognized by you - involve changes in the activity of the cell death pathway (or related ones);

For a long (but still incomplete) list of commercially available drugs that inhibit cell death, please see:

P.S.: Note that selectively inhibiting a pathway (note: not only cell-death) in only one cell type (or tissue - as you hinted at) usually requires a lot of tests and experimentation and isn't trivial.

How to surpass cell death? - Biology

Figure 1. The histological section of a foot of a 15-day-old mouse embryo, visualized using light microscopy, reveals areas of tissue between the toes, which apoptosis will eliminate before the mouse reaches its full gestational age at 27 days. (credit: modification of work by Michal Mañas)

When a cell is damaged, superfluous, or potentially dangerous to an organism, a cell can initiate a mechanism to trigger programmed cell death, or apoptosis. Apoptosis allows a cell to die in a controlled manner that prevents the release of potentially damaging molecules from inside the cell. There are many internal checkpoints that monitor a cell’s health if abnormalities are observed, a cell can spontaneously initiate the process of apoptosis. However, in some cases, such as a viral infection or uncontrolled cell division due to cancer, the cell’s normal checks and balances fail. External signaling can also initiate apoptosis. For example, most normal animal cells have receptors that interact with the extracellular matrix, a network of glycoproteins that provides structural support for cells in an organism. The binding of cellular receptors to the extracellular matrix initiates a signaling cascade within the cell. However, if the cell moves away from the extracellular matrix, the signaling ceases, and the cell undergoes apoptosis. This system keeps cells from traveling through the body and proliferating out of control, as happens with tumor cells that metastasize.

Another example of external signaling that leads to apoptosis occurs in T-cell development. T-cells are immune cells that bind to foreign macromolecules and particles, and target them for destruction by the immune system. Normally, T-cells do not target “self” proteins (those of their own organism), a process that can lead to autoimmune diseases. In order to develop the ability to discriminate between self and non-self, immature T-cells undergo screening to determine whether they bind to so-called self proteins. If the T-cell receptor binds to self proteins, the cell initiates apoptosis to remove the potentially dangerous cell.

Apoptosis is also essential for normal embryological development. In vertebrates, for example, early stages of development include the formation of web-like tissue between individual fingers and toes (Figure 1). During the course of normal development, these unneeded cells must be eliminated, enabling fully separated fingers and toes to form. A cell signaling mechanism triggers apoptosis, which destroys the cells between the developing digits.

Process of Apoptosis: With Diagram | Cell Death | Cell Signaling | Biology

After reading this article you will learn about the process of apoptosis which is characterised by chromatin condensation, with the help of suitable diagrams.

Apoptosis, the programmed cell death is characterized by chromatin condensation and cell shrinkage in the early stage and then the nucleus and cytoplasm fragment, forming membrane-bound apoptotic bodies which can be engulfed by phagocytes. In contrast, cells undergo another form of cell death, necrosis, swell and rupture. The released intracellular contents can damage surrounding cells and often cause inflammation. Apoptosis is an impor­tant process during normal development. It also involved in aging and various diseases such as cancer, AIDS, Alzheimer’s disease and Parkinson’s disease.

Programmed cell death, or apoptosis, is mediated by proteolytic enzymes called caspases, which are synthesized in the precursor forms as procaspases. When activated by vari­ous signals, caspases function to cause cell death in most organisms, ranging from C. elegans to human beings. Apoptosis provides a means deciding the shapes of body parts in the course of development and a means of eliminating cells producing anti-self antibodies or infected with pathogens as well as cells containing large amounts of damaged DNA. Cytotoxic T cells initiate apoptosis in cells to which they bind through T-cell receptor-class I MHC-peptide interactions aided by interactions with the coreceptor molecule CD8.

Under some circumstances, such as when DNA damage is extensive, p53 also activates expression of genes that lead to apoptosis, the process of programmed cell death that nor­mally occurs in specific cells during the development of multicellular animals. In verte­brates, the p53 response evolved to induce apoptosis in the face of extensive DNA damage, presumably to prevent the accumulation of multiple mutations that might convert a normal cell into a cancer cell.

During apoptosis, the cell is digested by a class of proteases called caspases. More than 10 caspases have been identified. Some of them (e.g., caspase 8 and 10) are involved in the initiation of apoptosis, others (caspase 3, 6, and 7) execute the death order by destroying essential proteins in the cell (Fig. 5.13).

The apoptotic process can be summarized as fol­lows:

i. Activation of initiating caspases by specific signals.

ii. Activation of executing caspases by the initiating caspases which can cleave inactive caspases at specific sites.

iii. Degradation of essential cellular proteins by the executing caspases with their protease

iv. Death receptors- Fas/CD95, DR4/DR5, DR3, and TNFR (Tumor Necrosis Factor Re­ceptor).

v. Adaptors- FADD (Fas-associated death domain protein) and TRADD (TNFR-associated death domain protein).

vi. Activation- Binding of death ligands (FasL/CD95L, TRAIL/APO-2L, APO-3L and TNF) induces trimerization of their receptors, which then recruit adaptors and subse­quently activate the caspases (Fig. 5.14).

Cell Death

Sydney Brenner, Robert Horvitz and John Sulston’s discoveries concerning the genetic regulation of organ development and programmed cell death have truly opened new avenues for biological and medical research. We have all begun our lives in a seemingly modest way – as the fertilized egg cell, a tenth of a millimeter in size. From this small cell, the adult human being develops, with its hundred thousand billion cells, through cell division, cell differentiation and by formation of the various organs. To only make new cells is however not sufficient, certain cells must also die at specific time points as a natural part of the growth process. Think for example about how we for a short period during fetal life have web between our fingers and toes, and how this is removed by cell death.

The importance of cell differentiation and organ development was understood by many, but progress was slow. This was largely an effect of our complexity, with the large number of cells and many cell types – the forest could not be seen because of all the trees. Could the task to find the genetic principles be made simpler? Were there a species simpler than humans, but still sufficiently complex to allow for general principles to be deduced?

Sydney Brenner in Cambridge, UK, took on the challenge, and his choice was the nematode Caenorhabditis elegans. This may at first seem odd, a spool-shaped approximately 1 millimeter long worm with 959 cells that eats bacteria, but Brenner realized in the early 1960s that it was, what we today would call, “loaded with features”. It was genetically amenable and it was transparent, so that every cell division and differentiation could be directly followed in the worm under the microscope. Brenner demonstrated in 1974 that mutations could be introduced into many genes and visualized as distinct changes in organ formation. Through his visionary work, Brenner created an important research tool. The nematode had made into the inner circle of research.

John Sulston came to Brenner’s laboratory in 1969. He took advantage of that cell divisions could be followed under the microscope and assembled the cell lineage in the worm, showing which cells are siblings, first and second cousins. He found that cell divisions occurred with a very high degree of precision, the cell lineage was identical between different individuals. He also realized that certain cells in the lineage always died at a certain time point. This meant that programmed cell death was not a stochastic process, but rather occurred with a very high degree of precision. During the course of this work Sulston identified the first gene important for the cell death process: nuc-1.

Robert Horvitz came to work with Brenner and Sulston in 1974. Horvitz started a systematic search for genes controlling programmed cell death. He identified the key genes for the cell death process proper. The discovery of these central death genes, ced-3, ced-4 and ced-9, changed the view on programmed cell death from something rather obscure to a process with a strict genetic program. Horvitz also showed that there are human homologues to the death genes in the worm and that those have corresponding functions – the cell death machinery had deep evolutionary roots.

This year’s Nobel Prize celebrates the Joy of Worms. Brenner’s almost prophetic visions from the early 1960s of the advantages of this model organism have been fulfilled. It has given us new insights into the development of organs and tissues and why specific cells are destined to die. This knowledge has proven valuable, for instance, in understanding how certain viruses and bacteria attack our cells, and how cells die in heart attack and stroke.

Cell lineage – from egg to adult

All cells in our body are descendents from the fertilized egg cell. Their relationship can be referred to as a cellular pedigree or cell lineage. Cells differentiate and specialize to form various tissues and organs, for example muscle, blood, heart and the nervous system. The human body consists of several hundreds of cell types, and the cooperation between specialized cells makes the body function as an integrated unit. To maintain the appropriate number of cells in the tissues, a fine-tuned balance between cell division and cell death is required. Cells have to differentiate in a correct manner and at the right time during development in order to generate the correct cell type.

It is of considerable biological and medical importance to understand how these complicated processes are controlled. In unicellular model organisms, e.g. bacteria and yeast, organ development and the interplay between different cells cannot be studied. Mammals, on the other hand, are too complex for these basic studies, as they are composed of an enormous number of cells. The nematode C. elegans, being multi-cellular, yet relatively simple, was therefore chosen as the most appropriate model system, which has then led to characterization of these processes also in humans.

Programmed cell death

Normal life requires cell division to generate new cells but also the presence of cell death, so that a balance is maintained in our organs. In an adult human being, more than a thousand billion cells are created every day. At the same time, an equal number of cells die through a controlled “suicide process”, referred to as programmed cell death.

Developmental biologists first described programmed cell death. They noted that cell death was necessary for embryonic development, for example when tadpoles undergo metamorphosis to become adult frogs. In the human foetus, the interdigital mesoderm initially formed between fingers and toes is removed by programmed cell death. The vast excess of neuronal cells present during the early stages of brain development is also eliminated by the same mechanism.

The seminal breakthrough in our understanding of programmed cell death was made by this year’s Nobel Laureates. They discovered that specific genes control the cellular death program in the nematode C. elegans. Detailed studies in this simple model organism demonstrated that 131 of totally 1090 cells die reproducibly during development, and that this natural cell death is controlled by a unique set of genes.

The model organism C. elegans

Sydney Brenner realized, in the early 1960s, that fundamental questions regarding cell differentiation and organ development were hard to tackle in higher animals. Therefore, a genetically amenable and multicellular model organism simpler than mammals, was required. The ideal solution proved to be the nematode Caenorhabditis elegans. This worm, approximately 1 mm long, has a short generation time and is transparent, which made it possible to follow cell division directly under the microscope.

Brenner provided the basis in a publication from 1974, in which he broke new ground by demonstrating that specific gene mutations could be induced in the genome of C. elegans by the chemical compound EMS (ethyl methane sulphonate). Different mutations could be linked to specific genes and to specific effects on organ development. This combination of genetic analysis and visualization of cell divisions observed under the microscope initiated the discoveries that are awarded by this year’s Nobel Prize.

Mapping the cell lineage

John Sulston extended Brenner’s work with C. elegans and developed techniques to study all cell divisions in the nematode, from the fertilized egg to the 959 cells in the adult organism. In a publication from 1976, Sulston described the cell lineage for a part of the developing nervous system. He showed that the cell lineage is invariant, i.e. every nematode underwent exactly the same program of cell division and differentiation.

As a result of these findings Sulston made the seminal discovery that specific cells in the cell lineage always die through programmed cell death and that this could be monitored in the living organism. He described the visible steps in the cellular death process and demonstrated the first mutations of genes participating in programmed cell death, including the nuc-1 gene. Sulston also showed that the protein encoded by the nuc-1 gene is required for degradation of the DNA of the dead cell.

Identification of “death genes”

Robert Horvitz continued Brenner’s and Sulston’s work on the genetics and cell lineage of C. elegans. In a series of elegant experiments that started during the 1970s, Horvitz used C. elegans to investigate whether there was a genetic program controlling cell death. In a pioneering publication from 1986, he identified the first two bona fide “death genes”, ced-3 and ced-4. He showed that functional ced-3 and ced-4 genes were a prerequisite for cell death to be executed.

Later, Horvitz showed that another gene, ced-9, protects against cell death by interacting with ced-4 and ced-3. He also identified a number of genes that direct how the dead cell is eliminated. Horvitz showed that the human genome contains a ced-3-like gene. We now know that most genes that are involved in controlling cell death in C. elegans, have counterparts in humans.

Of importance for many research disciplines

The development of C. elegans as a novel experimental model system, the characterization of its invariant cell lineage, and the possibility to link this to genetic analysis have proven valuable for many research disciplines. For example, this is true for developmental biology and for analysis of the functions of various signaling pathways in a multicellular organism. The characterization of genes controlling programmed cell death in C. elegans soon made it possible to identify related genes with similar functions in humans. It is now clear that one of the signaling pathways in humans leading to cell death is evolutionarily well conserved. In this pathway ced-3-, ced-4- and ced-9-like molecules participate. Understanding perturbations in this and other signaling pathways controlling cell death are of prime importance for medicine.

Disease and programmed cell death

Knowledge of programmed cell death has helped us to understand the mechanisms by which some viruses and bacteria invade our cells. We also know that in AIDS, neurodegenerative diseases, stroke and myocardial infarction, cells are lost as a result of excessive cell death. Other diseases, like autoimmune conditions and cancer, are characterized by a reduction in cell death, leading to the survival of cells normally destined to die.

Research on programmed cell death is intense, including in the field of cancer. Many treatment strategies are based on stimulation of the cellular “suicide program”. This is, for the future, a most interesting and challenging task to further explore in order to reach a more refined manner to induce cell death in cancer cells.

Learning More About How Cells Control a Death Pathway

Scientists have published complementary studies in Nature Communications that have greatly advanced our understanding of a protein called MLKL. They learned that variants of the gene that makes the protein can influence a person's risk of developing an inflammatory disease, and have identified steps in MLKL activation, which is critical to a cell death process called necroptosis.

Cells have to be able to recognize pathology and trigger cell death if necessary cells that are infected with bacteria or inflamed may kill themselves off to protect their neighbors. Necroptosis is one such cell death pathway, and it is tightly controlled MLKL is important for that regulation.

"While MLKL and necroptosis protect our bodies from infections, excessive necroptosis has been linked with inflammatory conditions such as inflammatory bowel diseases," said Associate Professor James Murphy. "Our research team has taken several complementary approaches to better understand how MLKL functions - which could improve the understanding and treatment of diseases involving excessive necroptosis."

In one study, the researchers applied imaging tools to visualize MLKL while cells became necroptotic, and two checkpoints in the process were identified.

"We could see how MLKL changed its location as necroptosis occurred, clumping and migrating to different parts of the cell as the cell progressed towards death," said the leader of that report, Dr. Andre Samson. "Intriguingly, we could see activated MLKL gather at the junctions between neighboring cells - potentially suggesting a way for one dying cell to trigger necroptosis in surrounding cells, which could be a form of protection against infections."

In work led by Dr. Joanne Hildebrand and Dr. Maria Kauppi, the investigators identified an MLKL variant. When they expressed the variant in lab models, a lethal inflammatory disease occurred.

"We discovered this form of MLKL contained a single mutation in a particular region of the protein that made MLKL hyperactive, triggering necroptosis and inflammation," said Hildebrand.

"By searching genome databases, we discovered similar variants in the human MLKL gene are surprisingly common - around ten percent of human genomes from around the world carry altered forms of the MLKL gene that result in a more-easily activated, more inflammatory version of the protein."

The searched to see whether the inflammation-linked MLKL variant was connected to disease. "We looked more closely at databases of genomes of people with inflammatory diseases to understand the prevalence of MLKL variants. Indeed, people with an autoinflammatory condition chronic recurrent multifocal osteomyelitis (CRMO) were much more likely to carry two copies of a pro-inflammatory variant of the MLKL gene than people without an inflammatory disease. This is the first time changes in MLKL have been associated with a human inflammatory disease," noted Hildebrand.

In another study examining MLKL is vertebrate species, researchers found significant differences between the versions carried by different animals. Often, proteins that are really important to biology are very similar, or highly conserved, from one species to another, which was not the case here.

"To our surprise, the structures of MLKL were quite different between different vertebrate species - even between closely related species such as rats and mice. In fact, rat MLKL is so different from mouse MLKL that the rat protein cannot function in mouse cells - which is surprising as many proteins are interchangeable between these two species," said the study leader, Dr. Katherine Davies.

"We think that evolutionary pressures such as infections may have driven substantial changes in MLKL as vertebrates evolved. Animals with variant forms of MLKL may have been able to survive some pressures better than other animals, driving changes in MLKL to accumulate, much faster than for many other proteins," added Davies. "Together with the data for human variations in MLKL, this suggests MLKL is critical for cells to balance beneficial inflammation, which protects against infections, with harmful inflammation that causes inflammatory diseases."

Effects of apoptosis recovery

One possible function of anastasis is as a cellular survival mechanism, posits Tang, limiting the permanent damage that would occur in response to a temporary situation. For instance, tissues in a developing organism might randomly experience transient shortages of growth factors, an event that could trigger apoptosis at a time when cells are proliferating at a rapid rate. Montell and her colleagues found that anastasis can happen during development in Drosophila, with cells surviving caspase activation in the larval brain and in the imaginal discs that, during metamorphosis, develop into adult limbs and organs. 10

Anastasis may also promote evolutionary change, Tang says. “Our recent studies demonstrated the occurrence of anastasis in germ cells of Drosophila after transient exposure to physiological and environmental stresses such as starvation or cold shock,” he notes. 9 This raises the possibility that these cells might acquire new mutations generated during apoptosis that could be passed on to progeny.

Anastasis might serve more purposes than simple protection. In 2012, the Tangs and Montell found that while cells rescued from apoptosis could repair genetic damage, sometimes there were errors in the way they knit their genomes back together. As a result, a percentage of the surviving cells had chromosomal abnormalities and other genetic defects that led to malignant growth. This suggests that repeatedly bringing cells to the brink of death might explain the higher risk of cancer in tissues exposed to repeated assaults, such as liver cancer due to alcoholism and oral, esophageal, or stomach cancer that can result from the regular consumption of very hot beverages. 7 Even with failed apoptosis, where damage is much less severe before recovery, cells’ genomes sometimes become unstable, and some of the cells even turn malignant, according to research conducted by Tait, Ichim, and their colleagues. 3 “We’re following cells to see if there are long-term consequences for cancer progression, and we’re finding they can experience genomic instability,” says Ichim. “They can be more aggressive, and form bigger tumors in mice.”

The revelation might change how scientists define life and death on the cellular level.

Cells’ ability to recover from programmed cell death might also play a role in some cancers’ ability to evade therapeutic approaches. Radiation and many commonly used chemotherapy drugs induce apoptosis, and while this may kill most tumor cells, any that survive might result in relapse and metastasis. 9 Moreover, cancer cells that survive such therapies might conceivably develop new mutations that help them resist drugs, says Dedhar, who is currently searching for molecular pathways that are activated in cancer cells that “recovered from the brink of death.”

Tang and his colleagues have also found that anastasis can activate genes in Drosophila linked with angiogenesis and cell migration, 7 processes that could enhance nutrient absorption and remove waste to help cells recover from apoptosis, he says. At the same time, these changes could enhance the spread of cancer cells.

Given the potential links between cancer and anastasis, interventions that target this process could help prevent the development of cancer, or treat it once it appears, Tang says. “Suppressing anastasis in dying cancer cells during and after cancer treatment could be a novel therapeutic strategy to cure cancers by inhibiting cancer relapse.”

Conversely, he notes, targeting anastasis could one day treat diseases that stem from the loss of unrenewable cells, such as cardiomyocytes or neurons. “Currently, one of the major efforts in my lab focuses on identifying key anastasis regulators and small molecules that promote or suppress anastasis,” Tang says. “Our findings will provide us a list of essential tools to control anastasis, thereby launching new fields of research for exploring the potential functions and therapeutic applications of anastasis.”

Ultimately, a better understanding of anastasis might not only help save cells from disease and injury, but also teach scientists more about cell death in general. “The Holy Grail question is whether we can predict the fates of cells at the single-cell level,” Gong says. “For instance, if we irradiate a tumor, we might know that maybe 90 percent of the tumor will shrink, but we can’t tell which 90 percent. Predicting which cells will die and in which way will ultimately help us minimize side effects and maximize beneficial effects. It’s cell death 2.0.”


There is an oft-quoted phrase from George EP Box, a British statistician, stating that 𠆊ll models are wrong, but some are useful'. As models are by necessity an approximation of reality, all models are ‘wrong'. However, when carefully developed and solidly anchored in high-quality data, models can be predictive, leading to testable and falsifiable hypotheses and thereby allowing us to learn about the system under study. Here we have discussed the frequently observed phenotypic heterogeneity in the response of human cells to various death-inducing stimuli as well as the sources of this variability and implications for measuring and modeling cell death. We are entering an era of 𠆋iology in the second moment' where the focus is not the average, or dominant, behavior exhibited by a population of cells, but rather the focus is on the variance, and we anticipate that this new focus will continue to contribute to our understanding of the regulation of cell death in health and disease.

Cell-to-cell heterogeneity can be inferred from population-based data. (a) Schematic of drug dose-response curves with differing hill slope coefficients (HS). The curves have an increasingly shallow slope as HS becomes smaller. Hypothetical data points are plotted for the scenario where HS=1 (dark blue curve) and the parameters of the logistic sigmoid function describing this curve are depicted (E0, E50, Emax, Einf and EC50). (b) Hypothetical distributions for a homogenously distributed quantitative trait (blue) and for a heterogeneous trait with a bimodal distribution (red) are show at the top. At the bottom, a reference, or 𠆎xpected', distribution of population-based measurements for the homogeneously distributed trait (gray line) is compared with a hypothetical distribution of measurements from small numbers of cells. As the proportion of ‘high' versus ‘low' cells fluctuates from sample to sample, the variability in measurement values is broader than the reference distribution if the trait has a bimodal distribution (red histogram), indicating the presence of cell-to-cell heterogeneity.

Characterizing Different Kinds of Cell Death

The most well-studied form of cell death is called apoptosis. Apoptosis is a type of programmed cell death sometimes likened to cellular suicide, in which a cell breaks down in a regulated, systematic fashion. Apoptosis can occur in response to cell damage, but it&rsquos also a normal part of development in embryos. For example, apoptosis in the hands and feet allows individual fingers and toes to form, by killing cells in the spaces in between them.

In the March 2019 study, the researchers focused on the development of the gastrointestinal and reproductive tracts of the C. elegans worm, a popular lab model for studying development. Research from a team at Rockefeller University had suggested that forms of cell death other than apoptosis were important in the formation of parts of the worm&rsquos body. Dr. Overholtzer&rsquos team decided to continue this line of inquiry.

In particular, the researchers looked at the role of cell death in the formation of the cloaca, the dual-purpose orifice at the hind end of worms, as well as many other organisms, from which excrement is discharged. In males, it is also where sperm are released. It turns out that entosis is vital to ensuring that the genital tract connects to the cloaca. Without it, male worms are sterile.

Assessing Cell Death

Careful microscopic examination of culture vessels may reveal obvious cell death characterized by cell crenation, blebbing, and debris consisting in part of cell ‘ghosts’, or membranous remains. For more subtle cases, there are a variety of assays available for assessing cell death in cultures. Perhaps the most accessible of these is the trypan blue exclusion assay that is based on the principle that healthy cells with intact membranes will exclude the dye, and is quickly performed on detached or suspension cells by hemacytometer. Viability assays can be used to distinguish and quantify live cells. These assays assess cell viability by measuring cellular functions such as enzyme activity, ATP production, plasma membrane function, and cell adherence.


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