Cancer: Evolution 2.0’s Blind Spot
…methylation of the carbon-5 position of cytosine, which results in differences in 5hmCs, may be the most commonly studied type of nutrient-dependent pheromone-controlled structural and functional eukaryotic modification that results from organizing base pair changes.
… 5hmC regulates changes in the compaction of the chromatin, cellular differentiation processes and the energy metabolism in embryonic stem cells.
My comment: Energy metabolism and changes in chromatin compaction are nutrient-dependent in all cell types of all individuals of all living genera. They just reported my claims with no claim about where the energy came from or how the energy was biophysically constrained in the context of RNA-mediated protein folding chemistry that must be linked from atoms to ecosystems via supercoiled DNA.
The journal article is free: Epigenomic Co-localization and Co-evolution Reveal a Key Role for 5hmC as a Communication Hub in the Chromatin Network of ESCs
Proteins editing and reading 5hmC signals co-evolve
We are still far from understanding the epigenomic “syntax” and how these and the other elements involved in epigenomic communication shape the functional landscape of mammalian genomes.
This conceptual framework constitutes the first explicit formulation to study chromatin as a biological communication system.
My comment: We established a model of chromatin structure as a biological communication system in 1996 in the context of sex differences in cell types “…in species as diverse as yeast, Drosophila, mice, and humans.”
Yet another kind of epigenetic imprinting occurs in species as diverse as yeast, Drosophila, mice, and humans and is based upon small DNA-binding proteins called “chromo domain” proteins, e.g., polycomb. These proteins affect chromatin structure, often in telomeric regions, and thereby affect transcription and silencing of various genes (Saunders, Chue, Goebl, Craig, Clark, Powers, Eissenberg, Elgin, Rothfield, and Earnshaw, 1993; Singh, Miller, Pearce, Kothary, Burton, Paro, James, and Gaunt, 1991; Trofatter, Long, Murrell, Stotler, Gusella, and Buckler, 1995). Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans (Adler and Hajduk, 1994; de Bono, Zarkower, and Hodgkin, 1995; Ge, Zuo, and Manley, 1991; Green, 1991; Parkhurst and Meneely, 1994; Wilkins, 1995; Wolfner, 1988). That similar proteins perform functions in humans suggests the possibility that some human sex differences may arise from alternative splicings of otherwise identical genes.
My comment: Our model, From Fertilization to Adult Sexual Behavior was extended across all living genera.
See: The Bull Sperm MicroRNAome and the Effect of Fescue Toxicosis on Sperm MicroRNA Expression.
Nutrient-dependent signals link the pheromone-controlled physiology of reproduction in soil bacteria to plant growth and transgenerational epigenetic inheritance in mammals. The signals do not evolve. Proteins don’t evolve. Bull sperm doesn’t evolve.
The neo-Darwinian “BS” evolved into a theory about chromatin as a biological communication system two decades after we reported that chromatin is the biological communication system of molecular epigenetics. There is still no defined boundary between epigenetics and genetics, which suggests our 1996 review answered Schrodinger’s question in the context of Darwin’s “conditions of life.” Life is nutrient-dependent and controlled by the physiology of reproduction.
See: What is Life?
Indeed, in the case of higher animals we know the kind of orderliness they feed upon well enough, viz. the extremely well-ordered state of matter in more or less complicated organic compounds, which serve them as foodstuffs. After utilizing it they return it in a very much degraded form -not entirely degraded, however, for plants can still make use of it. (These, of course, have their most power supply of ‘negative entropy’ the sunlight)
I reiterate: “After utilizing it they return it in a very much degraded form -not entirely degraded, however, for plants can still make use of it.” Plants can make use of the BS, but neo-Darwinian theorists cannot use it to support their ridiculous theories. Nothing ecologically adapts without light. Nothing co-evolves. Nutrient-dependent co-adaptation may occur to establish slight differences in the construction of ecological niches. But BS and other nutrients used to feed plants are required for niche construction.
Everything that neo-Darwinian theories based on their BS and other inferences was placed into the context of my atoms to ecosystems model. It was also reported in the context of the Structural diversity of supercoiled DNA.
Our data provide relative comparisons of supercoiling-dependent twisted, writhed, curved, and kinked conformations and associated base exposure. Each of these structural features may be differentially recognized by the proteins, nucleic acids, and small molecules that modulate DNA metabolic processes.
My comment: The only way to understand any metaphorical epigenomic “syntax” is to start with the de novo creation of receptors that allow nutrients to enter cells. If theorists start with a metaphorical cell, they must continue to infer that cellular metabolism automagically emerged and led to the differentiation of cell types. Theorists will then be asked to explain the emergence of metabolism and the circular arguments that link the emergence of metabolism to other ignorant inferences about biologically-based cause and effect.
How did sex differences co-evolve? How do inferences link biophysically constrained cell type proliferation and differentiation from ecological variation via the atoms to ecosystems they placed into the context of 5hmC as a “communication hub?” How did 5hmC become the link to the chromatin network of embryonic stem cells? How did that happen outside the context of nutrient-dependent cell type differentiation at the dawn of the de novo creation of receptors and cells?
See also: Discovered: How to unlock inaccessible genes
The researchers first mapped the location of several “chromatin-remodeller enzymes” across the entire genome of the embryonic stem cells of the mouse.
My comment: Chromatin remodelling is nutrient dependent and it links what they call “chromatin-remodeller enzymes” to RNA-mediated cell type differentiation in species from yeasts to mammals via the conserved molecular mechanisms we detailed in the molecular epigenetic section of our 1996 review.
Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells [subscription required]
Two trends emerge: an activating [energy-dependent] remodeller in one class of genes is an inhibitor remodeller in the other class; and within the same class, an [energy-dependent] activating remodeller can be counteracted by an inhibitor remodeller. Taken together, [energy-dependent activating and inhibiting] remodellers work together at specific nucleosome positions adjacent to promoter region NFRs to elicit proper gene control.
The energy-dependent activating and inhibiting remodellers link hydrogen-atom transfer in DNA base pair in solution to the de novo creation of receptors in cell types. The failure to mention that everything above is based on the energy linked from ATP limits the explanatory power of their claims. If they included ATP it would become clear that nutient-dependent energy links everything currently known about hydrogen-atom transfer in DNA base pairs from ecological variation to ecological adaptation. The links have been established in the context of thermodynamic cycles of protein biosynthesis and degradation.
The cycles occur only when the DNA base pairs are in solutions with a properly controlled pH balance that protects supercoiled DNA from virus-driven entropy.
The de novo creation of receptors in the context of hydrogen-atom transfer in DNA base pairs is the starting point for the creation of different cell types. Creation of different cell types is nutrient energy-dependent RNA-mediated, and it links physics from chemistry to the conserved molecular mechanisms of life in all living genera
For example, see:
1) Non‐enzymatic glycolysis and pentose phosphate pathway‐like reactions in a plausible Archean ocean and
2) Conditional iron and pH-dependent activity of a non-enzymatic glycolysis and pentose phosphate pathway
We find reactions with the same pH optimum neighbor in an experimentally functional reaction network that shares topological similarity with modern cell’s glycolytic pathway and PPP. The coexistence of different pH optima in different parts of the network allows conditional activity, as it does in the modern cell. This implies that changing chemical conditions can, at least in a rudimentary sense, mimic an essential feature of the modern metabolic network, which is to regulate metabolism by the ability to turn metabolic pathways on and off.
My comment: An intelligent medical laboratory scientist can link reactions in a plausible Archean ocean from differences in temperature and differences in pH to spectophotometric assays of chemicals in human body fluids. For example, I can also link the pH of blood agar used to grow pathogenic bacteria from their nutrient-dependent energy transfer to healthy longevity or to virus-driven pathology.
Pathology arises when embryonic stem cells do not turn off their metabolic pathways. It’s called cancer. Virus-driven energy theft causes the pathology of cancer. The viruses cause changes in pH in different cell types in tissues such as circulating blood. The circulating blood links energy-dependent hydrogen-atom transfer in DNA base pairs to ecological adaptation in all invertebrates and vertebrates with circulating cell types, except when viruses steal the energy that is required for cell type differentiation.
Serious scientists know what happens when viruses steal energy and temporarily alter the picture of health.
See: Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein
2007 A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission
2013 The major antigenic changes of the influenza virus are primarily caused by a single amino acid near the receptor binding site
2014 A single amino acid in the stalk region of the H1N1pdm influenza virus HA protein affects viral fusion, stability and infectivity
1973 Nothing in Biology Makes Any Sense Except in the Light of Evolution
….compared the amino acid sequences in cytochrome C in different branches of the living world. Most significant similarities as well as differences have been brought to light. The cytochrome C of different orders of mammals and birds differ in 2 to 17 amino acids, classes of vertebrates in 7 to 38, and vertebrates and insects in 23 to 41; and animals differ from yeasts and molds in 56 to 72 amino acids. Fitch and Margoliash prefer to express their findings in what are called “minimal mutational distances.” It has been mentioned above that different amino acids are coded by different triplets of nucleotides in DNA of the genes; this code is now known.
…the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla. ( p. 127)
See also: Receptor binding and pH stability – how influenza A virus hemagglutinin affects host-specific virus infection
My comment: The nutrient-dependent innate immune system typically controls host-specific virus infection. Ongoing virus onslaughts require the more permanent nutrient-dependent protection of supercoiled DNA. However, the viruses that become retroviruses due to gene losses and gains in the chromosomes of different species, can be reactivated by nutrient-stress or by social stress. Both forms of stress are linked via the same pathways to virus-driven genomic entropy during life history transitions, or to healthy longevity in the absence of stress.
See: Lineage-Specific Profiling Delineates the Emergence and Progression of Naive Pluripotency in Mammalian Embryogenesis
These results highlight metabolic differences, in particular with regard to amino acid biosynthesis, between the mouse and marmoset embryo.
This highly interdisciplinary study blends traditional embryology, genomics and bioinformatics.
My comment: Researchers who have not learned how energy theft by viruses is linked to pandemics in populations that have not ecologically adapted via RNA-mediated amino acid substitutions are pseudoscientists who also don’t know that the stability of supercoiled DNA protects organized genomes from virus driven entropy.
An accumulation of viruses causes a change in pH that alters thermodynamic cycles of protein biosynthesis and degradation. Stress-related reactivation of retroviruses links the change in pH from perturbed cycles of protein folding to all cancers via the return of somatic cell types to a pluripotent undifferentiated embryonic state.
See: Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells
My comment: Energy theft by viruses either kill or are biophysically constrained by the nutrient-dependent immune system. But biophysically constrained viruses may still be part of lineage specific cell types. I cannot explain this further except via the use of a metaphor. For example, I ride a smaller motorcycle than I once rode, with a smaller battery than any of the larger motorcycles I have ridden for the past 15 years. The battery was nearly dead, and I could not start my motorcycle yesterday. I put it on a “trickle” charger and started it today. The metaphor is that the charger provided a form of nutrient-like energy to the battery, which enabled me to use the fuel-injected gas energy that is required to run the engine that enables movement of what might in this case be considered a metaphorical life form.
We will next detail the current understanding of the transcriptional, epigenomic, and regulatory landscapes of the developing human neocortex and other regions of the CNS, noting the essential conserved features, as well as clade and species-specific differences, revealed by these studies.
See: Genomic Determinants of Vitamin D-Regulated Gene Expression
These studies highlight the role of chromatin in the expression of genes and the dynamic impact of the epigenetic landscape that contextualizes individual gene loci thus influencing the VDR’s transcriptional actions.
In my 2014 review of nutritional epigenetics I wrote:
Because vitamin C and other vitamins appear to epigenetically effect nutrient-dependent methylation at the level of single-base resolution in mammals, it has become more important to determine how base-pair changes alter intracellular interactions in embryonic stem cells or intercellular interactions in other cells that result in cascades of downstream intracellular and intercellular organizing interactions throughout life. Other vitamins, such as vitamin D, and metal ions such as calcium, iron, lead and manganese also appear to epigenetically alter these organizing interactions. Therefore, a biophysically constrained, nutrient-dependent, epigenetically-effected, receptor-mediated recognizable organized pattern of emergence can be viewed in the context of ecological variations and ecological adaptations.
In my 2014 review of nutritional epigenetics I wrote:
…calcitriol is the active form of vitamin D. Its effects on the microRNA(miRNA)/messenger RNA (mRNA) balance appear to protect against perturbed protein folding, which is associated with colorectal cancer. MiRNA-627 targets the mRNA that encodes an enzyme linked to histone demethylation and amino acid substitutions that increase stability of hydrogen bonds in DNA, which are important to protein folding (Padi, Zhang, Rustum, Morrison, & Guo, 2013).
My comment: Each day, others exemplify their ignorance of obvious links from atoms to ecosystems via what is currently known about hydrogen-atom transfer in DNA base pairs in solution that link RNA-mediated amino acid substitutions to cell type differentiation and the stability of organized genomes in all living genera.
For example, see this Nature Podcast on Ageing
My comment: Dr. Stroustrup isn’t sure whether the molecular mechanisms of RNA-mediated lifespan are the same in C. elegans and humans. I suspect that everything known to others about physics, chemistry, and the conserved molecular mechanisms of cell type differentiation, which links octopuses to primates, would convince Dr. Stroustrup and others to learn about what others already know. Simply put, the conserved molecular mechanisms that link C. elegans to humans are the same. That’s why they are called conserved molecular mechanisms. If the nutrient-dependent molecular mechanisms were not conserved, RNA-mediated differences in life span could be explained in the context of mutations and evolution.
See: The temporal scaling of Caenorhabditis elegans ageing
My comment: Stroustrup et al., (2016) used UV light and mutations to differentiation cause and effect in the context of the life-span of the model organism C. elegans. UV light was used to deactivate the bacteria fed to one population of organisms, which extended their lifespan, and disruption of feeding behavior by a mutation reduced the lifespan of another population of organisms.
In my model, cause and effect extends the anti-entropic virucidal effects of UV light from the death of viruses in the bacteria to the “inactivation” of the food. Inactivation in linked to increased lifespan in the context of thermodynamic cycles of protein biosynthesis and degradation that are not perturbed by the energy theft viruses use to support their replication, which changes the pH of cell types and limits nutrient-dependent RNA-mediated DNA repair of virus-driven damage. In that context, albeit apparently without knowing it, Stroustrup et al., (2016) link insulin/IGF receptor daf-2 to the activity of the heat shock factor hsf-1. They link disruption of hsf-1 to temporal rescaling and reduced longevity (i.e., lifespan). They do not link the population-wide changes in different organismal physiological states to nutrient-dependent genome organization, vitality, organ reserve, or resilience. They do not link resilience to nutrient-dependent pheromone-controlled ecological speciation, which was reported in System-wide Rewiring Underlies Behavioral Differences in Predatory and Bacterial-Feeding Nematodes.
That was reported as: The neurobiological consequence of predating or grazing
The patterns of synaptic connections perfectly mirror the fundamental differences in the feeding behaviours of P. pacificus and C. elegans”, Ralf Sommer concludes. A clear-cut result like that was not what he had necessarily expected. Previous studies in much simpler neural circuits – as in the marine snail Aplysia – had indicated that changes in behaviour do not have to coincide with changes in number and location of synapses. Differences in physiological properties of neurons or in their modulation by neurotransmitters can be sufficient to effect behavioural changes.
My comment: The consistency of what is being reported in the context of UV light altered diets compared to mutations the disrupt feeding behaviors becomes clear in the mouse model. Nutrient-dependent RNA-mediated amino acid substitutions are linked to morphological and behavioral phenotypes in Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity.
Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety- and depressive-like behaviors.
My comment: Nutrient-dependent RNA-mediated amino acid substitutions continue to be linked across species from microbes to humans via the conserved molecular mechanisms that link epigenetic to genetics with no defined boundary between epigenetics and genetics in the context of biophysically constrained cell type differentiation and the physiology of reproduction. It will not become clearer that the physiology of reproduction links RNA-mediated amino acid substitutions to supercoiled DNA and the chromosomal rearrangements linked from pheromones to biodiversity in species from microbes to man. However, the need for a model that links metabolic networks to genetic networks has become clear, as has the fact that the model will continue to be ignored.
For example, watch Perry Marshall ignore my model in my posts to his blogs.