T-cells surrounding a cancer cell
JUAN GARTNER / Getty Images
Our immune system is notoriously unreliable and often fails when it is needed most, with cancers and serious infections. As a piece of supposedly intelligent [sic] design, (according to creationist superstition) it is more an example of blithering incompetence, if not downright malevolence.
Remember, creationists believe the designer of it is supremely intelligent, omniscient with the power to foresee the future, omnipotent and perfect. Remember too that creationists claim, as the only supernatural entity capable of designing live things, that it also designed the pathogenic organisms that the immune system was designed to protect us from.
Apparently, in creationist circles, designing pathogens to make us sick, then designing an immune system to protect us from those pathogens, then redesigning the pathogens to bypass our immune system that should be protecting us from them, is considered evidence of supreme intelligence.
Similarly, designing a method of cell replication to replace out old cells when they wear out, but using a method that sometime makes mistakes and turns the cells into cancer cells is also a sign of infinite wisdom.
For reasons that can only be guessed at, and probably for political motives that depend on fools being misled about science and which have nothing to do with worshipping their particular god, creationist frauds would rather we thought of their putative designer god as an incompetent fool and pestilential malevolence, than accept that pathogens, cancers and our immune system are the result of a mindless, utilitarian natural process that operates without a plan and produces suboptimal results, providing the result is better than that which preceded it in terms of producing more offspring which go on to breed successfully.
For creationist frauds, religion merely provides them with an excuse for their avarice and demands for political power over others.
Biologically, of course, the explanation is much simpler and does not require rationalising believing in a perfect designer who designs systems that don't work properly. The mammalian immune system is the result of a utilitarian evolutionary arms race in which potential parasites that can evade the immune system leave more descendants and their genes eventually dominate the species gene pool, whilst the genes of those potential victims of the parasites with an immune system which copes with most pathogens, even if not all of them or which reduces their pathogenicity, will come to predominate in that species gene pool over the genes of those with a less efficient system.
The result is a suboptimal system with pathogens which can still evolve to evade it being selected for.
The disadvantage of accepting that natural process as the explanation for biodiversity is that it deprived creationist frauds of an excuse for their antisocial behaviour and a ready pool of willing dupes who find science too hard but need to pretend to know more than the experts without all the bother of learning.
But now scientists are beginning to understand what it is about our immune system that allows (or even causes) it to fail when we need it most.
And the culprit appears to be the mitochondria in the T-cells.
First, a short AI explanation of mitochondria and their importance to complex cells:
What are mitochondria, how did they evolve and what is their role in eukaryote cells? Mitochondria are like the powerhouse of the cell! They're double-membraned organelles found in the cells of eukaryotes, which are organisms with complex cells (like us humans!). The interesting thing is that mitochondria have their own DNA and can replicate independently within a cell, suggesting a fascinating evolutionary history.The Universität Würzburg News release explains the research:
The endosymbiotic theory proposes that mitochondria evolved from free-living bacteria engulfed by ancestral eukaryotic cells. Over time, a mutually beneficial relationship formed—the host cell provided a protected environment, and the engulfed bacteria supplied energy through processes like cellular respiration.
Speaking of energy, that's where mitochondria really shine. They play a crucial role in producing adenosine triphosphate (ATP), the cell's primary energy currency. Through aerobic respiration, mitochondria use oxygen to convert nutrients into ATP, fueling various cellular activities. So, next time you feel energized, you can thank your mitochondria for their hard work!
Tell me more about the production of ATP.
Certainly! ATP, or adenosine triphosphate, is often referred to as the "energy currency" of the cell. It's like a rechargeable battery that stores and releases energy as needed. The production of ATP primarily occurs through cellular respiration, a process that takes place in the mitochondria of eukaryotic cells. There are three main stages of cellular respiration:Now, here's where the magic happens:
- Glycolysis:
- This occurs in the cytoplasm and doesn't require oxygen.
- Glucose, a six-carbon sugar, is broken down into two molecules of pyruvate.
- A small amount of ATP is produced directly during glycolysis.
- Citric Acid Cycle (Krebs Cycle):
- The pyruvate molecules produced in glycolysis move into the mitochondria.
- In the citric acid cycle, each pyruvate is further broken down, releasing carbon dioxide.
- This cycle generates molecules that carry high-energy electrons to the next stage.
- Electron Transport Chain and Oxidative Phosphorylation:
- The electron transport chain is located in the inner mitochondrial membrane.
- High-energy electrons from the citric acid cycle are transferred through a series of protein complexes.
- As electrons move through the chain, their energy is used to pump protons (H+) across the membrane, creating a concentration gradient.
In summary, the whole process is like a power plant generating energy-rich ATP molecules by extracting energy from the breakdown of glucose and transferring it through a series of molecular events in the mitochondria. It's like a cellular power station working tirelessly to keep your cells energized!
- ATP synthase, an enzyme complex, allows protons to flow back into the mitochondrial matrix, harnessing their energy.
- This flow of protons drives the rotation of ATP synthase, enabling it to attach a phosphate group to adenosine diphosphate (ADP), forming ATP.
In the immune system, chronic infections and the defence against tumors often lead to the phenomenon of T cell exhaustion: In this process, the T lymphocytes gradually lose their function, which impairs their responses against cancer and infections. The molecular mechanisms that control this loss of function have not been fully unraveled.In summary, the problem is that the stem-cell precursors of the T-cells become exhausted and pass this state onto their descendant T-cells, so, although the immune system is trying to replenish exhausted and worn-out T-Cells, all it does is replace them with already exhausted and worn-out T-cells.
It is now certain that the exhaustion process is significantly influenced by the “powerhouses of the cells”, the mitochondria.
When mitochondrial respiration fails, a cascade of reactions is triggered, culminating in the genetic and metabolic reprogramming of T cells – a process that drives their functional exhaustion. But this "burnout" of the T cells can be counteracted: pharmacological or genetic optimization of cellular metabolism increases the longevity and functionality of T cells. This can be achieved, for example, by overexpressing a mitochondrial phosphate transporter that drives the production of the energy-providing molecule adenosine-triphosphate.
These discoveries are reported by a team led by Dr. Martin Vaeth at the Institute for Systems Immunology at Julius-Maximilians-Universität (JMU) Würzburg in the journal Nature Communications. "We are optimistic that our findings will contribute to the improvement of cancer immunotherapy", the scientist says.
Possible Improvement of CAR-T Cell Therapy
One example: CAR-T cell therapy has demonstrated remarkable efficacy in the treatment of leukemia and lymphoma. CAR-T cells are lymphocytes that have been engineered in the laboratory to fight the respective form of cancer. However, when it comes to solid tumors, CAR-T cells also tend to exhaustion, limiting their success in this context.
The Experiments in DetailOur experiments demonstrate that augmented mitochondrial metabolism also increases the longevity and functionality of virus-specific T cells in chronic infections. It is plausible that this strategy can be also harnessed to enhance T-cell-based immunotherapies for cancer therapy.
Dr. Martin Vaeth, corresponding author
Institute for Systems Immunology
Julius-Maximilians-Universität (JMU) Würzburg, Germany.
To demonstrate that mitochondrial dysfunction is the actual cause of T cell exhaustion, his research group developed a new genetic model. It switches off the mitochondrial phosphate transporter (SLC25A3) and paralyses mitochondrial respiration in T cells.It was commonly assumed that the observed alterations in the mitochondrial (energy) metabolism were a consequence of T-cell exhaustion.
Dr. Martin Vaeth.
As a result, the T cells are forced to switch to alternative metabolic pathways, mainly aerobic glycolysis, to meet their bioenergetic demand in the form of adenosine triphosphate. However, this metabolic adaptation causes an increased production of reactive oxygen species in the T cells.
Elevated levels of oxygen radicals prevent the degradation of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1-alpha). The accumulation of HIF-1-alpha protein causes a genetic and metabolic reprogramming of the T cells, accelerating their exhaustion.
Considering Tissue as the Environment of T CellsThis HIF-1-alpha-dependent control of T-cell exhaustion was previously unknown. It represents a critical regulatory circuit between mitochondrial respiration and T cell function, serving as a 'metabolic checkpoint' in the process of T-cell exhaustion.
Dr. Martin Vaeth.
Next, his team wants to explore how mitochondrial respiration influences the epigenetic programming of T cells, for example through post-translational modifications of histones, and the interplay of T-cell metabolism with the local tissue microenvironment.
According to Martin Vaeth, this is particularly important because the nutrient supply and oxygen tension in tumors differ considerably from healthy tissue and T cells must actively respond to this challenging environment. New technical developments, such as spatial transcriptome and metabolome analyses, offer exciting new possibility to investigate these questions systematically and at high resolution in the context of the tissue microenvironment.
This problem arises from the way the original cell from which a multicellular animal grows is pluripotent, i.e., it has the potential to become any specialist cell in the developing embryo, but, as the tissues differentiate into the different specialised cells, the system of epigenetics turns off more and more of the genes, leaving only those that the final specialised cells will need. This process is irreversible, so the exhausted Tpex cells are stuck with their exhausted state.
It all comes from the ludicrously wasteful and needlessly complex workaround of the problem caused by using the same replication mechanism that single-celled organisms used where the entire genome is replicated in every cell when only a few genes are needed according to the cell's specialty. This is, of course, the result of a mindless natural process that no sentient, omniscient, omnipotent designer would dream of designing.
There is more technical detail in the team's open access paper in Nature Communications:
AbstractFor creationists who believe the mammalian immune system was intelligently designed by their particular invisible supernatural deity, this raises a few questions that they will need to run away from:
T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.
Wu, H., Zhao, X., Hochrein, S.M. et al.
Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.
Nat Commun 14, 6858 (2023). https://doi.org/10.1038/s41467-023-42634-3
Copyright: © 2023 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
- Why did the designer fail to anticipate that cancers could originate from the method of cell replication that it designed, based on that of single-celled organisms where the entire genome has to be replicated even though, in most cells, most of it will not be needed? Or was producing cancers part of the plan?
- Why did it fail to recognise that the problem of T-cell exhaustion, caused by a failure of the mitochondria it designed, would make the immune system fail when it was most needed? Or was this failure part of the plan?
- Why did it design mitochondria, the immune system and the pathogens the immune system is supposed to protect us from, to look like they are the product of a mindless, natural process and evolutionary arms races which is predicted to produce suboptimal systems because it is utilitarian and proceeds without a plan?
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