Amino acid-dependent cell type differentiation

By: James V. Kohl | Published on: April 16, 2015

mTORC1 is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
MCRS1 Binds and Couples Rheb to Amino Acid-Dependent mTORC1 Activation” reported as:

Oncogene regulated by nutrients identified

A protein that is a molecular link connects Rheb-GTP to mTORC1 activation, lysosomes, and amino acid responses. Depletion of the protein links a chain of interactions to mTORC1 inactivation. The authors address the complexity of the biophysically constrained chemistry of RNA-directed DNA methylation and RNA-mediated protein folding, which links ecological variation to ecological adaptation via amino acid sensing. Their findings can be placed into the context of my model of nutrient-dependent pheromone-controlled protein biosynthesis and ecological adaptations.
See this 5.5 minute-long video representation: Nutrient-dependent / Pheromone-controlled thermodynamics and thermoregulation. See also: Making sense of amino acid sensing.
Conclusion (with my emphasis): “The results presented by Rebsamen et al., Wang et al., Jewell et al., and Thomas et al. almost certainly foreshadow the complexity yet to be uncovered regarding amino acid sensing by mTORC1.”
The links from amino acid sensing to metabolic networks and genetic networks fit perfectly into my detailed model with its examples from different species.  The effects of amino acid substitutions on the stability of nutrient-dependent RNA-mediated protein folding can readily be differentiated from the effects of mutations, which cause physiopathology. Amino acid substitutions are linked to the increasing organismal complexity of nutrient-dependent biodiversity via thermodynamic cycles of protein biosynthesis and degradation that enable organism-level thermoregulation. The amino acid substitutions are fixed in the context of the nutrient-dependent physiology of reproduction. Mutations perturb protein folding, which is why they are not beneficial.
Theorists can now attempt to explain (and continue to fail to explain) how mutations are linked to biodiversity via the Evolution of High Mobility Group Nucleosome-Binding Proteins and Its Implications for Vertebrate Chromatin Specialization. This was reported as: Scientists unlock tangled mysteries of DNA
Excerpt: While today’s human body contains a variety of these proteins, Eirin-Lopez believes they evolved from a single ancestor millions of years ago. This finding, published recently in Molecular Biology and Evolution, is pivotal in unraveling the mysteries of DNA organization and regulation, and could someday lead to innovative biomonitoring strategies and therapies targeting a variety of diseases including cancer.
See my comments to the site. That belief has not been supported by any experimental evidence of biologically-based cause and effect.
Obviously, unsupported beliefs are not “…pivotal in unraveling the mysteries of DNA organization and regulation…” Experimental evidence that links top-down causation to biodiversity via RNA-mediated amino acid substitutions and cell type differentiation is pivotal.  See, for instance, this claim:  “We cannot conceive of a global external factor that could cause, during this time, parallel evolution of amino acid compositions of proteins in 15 diverse taxa that represent all three domains of life and span a wide range of lifestyles and environments. Thus, currently, the most plausible hypothesis is that we are observing a universal, intrinsic trend that emerged before the last universal common ancestor of all extant organisms.
My comment: Any approach to cell type differentiation that does not include what is currently known about nutrient-dependent amino acid substitutions is an approach that is based on pseudoscientific nonsense. Ridiculous theories about evolution will NOT  lead to “…innovative biomonitoring strategies and therapies targeting a variety of diseases including cancer.”

See, for comparison: MCRS1 Binds and Couples Rheb to Amino Acid-Dependent mTORC1 Activation

Excerpt (with my emphasis): “MCRS1 was initially described as a nucleolar protein p120 interactor (Ren et al., 1998), associated with transcription regulation (Andersen et al., 2010; Ivanova et al., 2005; Lin and Shih, 2002; Wu et al., 2009). However, it participates in other processes, including cellular senescence (Hsu et al., 2012), cell division, and survival by interacting with the centrosomal protein Nde1 (Hirohashi et al., 2006) and is reportedly an essential RanGTP-regulated factor for bipolar spindle assembly protecting them from depolymerization (Meunier and Vernos, 2011) MCRS1 regulates mTORC1 independently of microtubule networks and its nuclear function argues that cells may contain several MCRS1 pools with different functions, without excluding a general role of MCRS1 in scaffolding small GTPase proteins.”
My comment: What aspect of evolution argues for the role of mutations in cell type differentiation? How are mutations linked to increasing organismal complexity via the physiology of nutrient-dependent reproduction? See for example: Was ribosome the first self-replicator? 
Excerpt: “…does it make sense to talk about dark variants of cell and cell membrane? Can one tell whether it was pro-cell or bio-molecules that emerged first? It seems that all these structures could have emerged simultaneously. What emerged was dark matter and its emergence involved the emergence of all the others. Hens and eggs emerged simultaneously.”
My comment: Who pays for research that reports the simultaneous emergence of hens and eggs? Who pays for research that links mutations to the evolution of biodiversity and also links mutations to cancer? Who pays the price that must be paid for touting pseudoscientific nonsense since the time that neo-Darwinism was invented? Why isn’t every serious biologist Combating Evolution to Fight Disease?
See, for comparison: Clinically Actionable Genotypes Among 10,000 Patients With Preemptive Pharmacogenomic Testing and Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults. See also, this 2.5 minute-long video: Pharmacogenomics at Mayo Clinic.
It is already past time to move forward from “Oncogene regulated by nutrients identified
Excerpt (with my emphasis) : “Although in our study we published the results obtained from these colorectal samples, we are also studying the relationship between this protein and diseases of the liver, the primary metabolic organ,” explains Djouder.
See also: Nutrient-dependent/pheromone-controlled adaptive evolution: a model.

Excerpt (with my emphasis): The recently detailed mouse model (Li et al., 2013) builds on what is known about olfactory/pheromonal communication in species from microbes to man and incorporates works from mammals that elucidate the molecular mechanisms that are clearly involved. Sex-dependent production of a mouse ‘chemosignal’ with incentive salience appears to have arisen de novo via coincident adaptive evolution that involves an obvious two-step synergy between commensal bacteria and a sex-dependent liver enzyme that metabolizes the nutrient chemical choline.

The result of this synergy is (1) a liver enzyme that oxidizes trimethylamine to (2) an odor that causes (3) species-specific behaviors. Thus, the complex systems that biology required to get from nutrient acquisition and nutrient metabolism to species-specific odor-controlled behavior is exemplified by adaptive evolution of an attractive odor to mice that repels rats (see for review Li et al., 2013).

Excerpt 2) “… the epigenetic ‘tweaking’ of the immense gene networks that occurs via exposure to nutrient chemicals and pheromones can now be modeled in the context of the microRNA/messenger RNA balance, receptor-mediated intracellular signaling, and the stochastic gene expression required for nutrient-dependent pheromone-controlled adaptive evolution. The role of the microRNA/messenger RNA balance (Breen, Kemena, Vlasov, Notredame, & Kondrashov, 2012; Duvarci, Nader, & LeDoux, 2008; Griggs et al., 2013; Monahan & Lomvardas, 2012) in adaptive evolution will certainly be discussed in published works that will follow.”
My comment: If the link from nutrient-dependent microRNAs to amino acid substitutions and cell type differentiation and behavior in mammals is not yet clear, see:
Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression
Alternative splicing of the androgen receptor in polycystic ovary syndrome
Search the presentation abstracts from SFN 2013 for  MicroRNA and GnRH and 2014 MicroRNA and GnRH
For example, see: Tuning fertility: miRNA regulation of GnRH genetic network
See also: Alternative RNA Splicing in Evolution (2012)
Excerpt:  “…alternative splicing is, perhaps, the most critical evolutionary factor determining the differences between human beings and other creatures.”

And see: From Fertilization to Adult Sexual Behavior
Excerpt: “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: Evolutionary theorists have delayed scientific progress that might otherwise have led to rapid advances in disease prevention and treatment. Theorists still seem to know nothing about cell type differentiation. Yet, Eva Jablonka, who co-authored Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life claims that “…we have learned that cells are very clever. They have a genetic-engineering kit within each cell, which it can use in all kinds of circumstances. Evolution has led to very clever and sophisticated systems, including systems that can direct their own evolution. There’s nothing wrong with it, and we shouldn’t be surprised at it. In fact, we would be surprised if it didn’t happen, in the long term. I don’t see why it is not evolution.” — See: Beyond Genetic Evolution. A Conversation With Eva Jablonka 
David Sloan Wilson then decides to move forward with “…the second dimension of evolution, epigenetics. Now we do have mechanisms, and we can begin to understand how epigenetics counts as an inheritance system.”
Theorists have ignored the mechanisms. In the molecular epigenetics section of our 1996 Hormones and Behavior review, we detailed the mechanisms of RNA-mediated cell type differentiation. Clearly, the conserved molecular mechanisms have been known to serious scientists for almost two decades. The conserved molecular mechanisms have not been addressed by most evolutionary theorists. Alternatively, the mechanisms have been placed into the context of ridiculous theories.  See page 327  of  Evolution in Four Dimensions.
Excerpt (with my emphasis): “…where there were networks of RNA-mediated interactions, natural selection could have led to some RNA molecules responding to changes in conditions in a way that inhibited the activities of other molecules with a similar sequence. They might have modified the structure of these molecules by base-pairing with them, for example. Later in evolutionary history, as the division of labor between nucleic acids (eventually DNA) as information carriers and proteins as the main enzymes and regulatory molecules increased, vestiges of earlier RNA control systems may
have remained. These could have become modified to fit the new information system and defend it against foreign RNA and DNA sequences.

What we have just said is very vague and speculative, and based on no evidence whatsoever.”

My comment: Our evidence-based approach to RNA-mediated cell type differentiation linked the nutrient-dependent pheromone-controlled physiology of reproduction in species from microbes to primates. It led to accurate representations of how cell type differentiation occurs in the context of the biophysically constrained chemistry of protein folding in all genera. For example, Sabatini’s group appears to have linked “Nutrient-sensing mechanisms and pathways” from the light-induced de novo creation of amino acids to the RNA-mediated stability of all organized vertebrate genomes via insertion of glycine in the GnRH decapetide.
See: Evolution of Constrained Gonadotropin-releasing Hormone Ligand Conformation and Receptor Selectivity
Abstract excerpt: “…substitution of glycine for a chiral amino acid in GnRH during evolution allows a more constrained conformation for receptor binding and that this subtle single amino acid substitution in a site remote from the ligand functional domains has marked effects on its structure and activity.
Kochman (2012) wrote: “The discovery of the fact that one decapeptide molecule, among the GnRHs, was constructed perfectly at the beginning of 400 million years evolution and that it is not possible to improve its physiological potency using the any natural amino acid is, in my opinion, important, fascinating and beautiful” (p. 19).
See also: “SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance.
I can only speculate on what these findings mean in the context of everything currently known to serious scientists about links from physics to chemistry and the conserved molecular mechanisms the enable all extant and extinct biodiversity on this planet. I think it is likely that the balance of viral microRNAs and nutrient-dependent microRNAs is nutrient-dependent and epigenetically inherited as a system of control that enables fixation of other nutrient-dependent amino acid substitutions via the physiology of reproduction, which is controlled by the metabolism of nutrients to species-specific pheromones in species from microbes to humans.
I cannot prove that mutations do not link evolution to biodiversity. I was not taught to believe in ridiculous theories, so the thought never occurred to me that I would need to prove that the idea of mutation-driven evolution is pseudoscientific nonsense. I became a medical laboratory scientist who performed diagnostic testing on people. For example of the latest information on diagnostic testing see:
New blood test can predict future breast cancer
The link from nutritional epigenetics and pharmacogenomic profiles is apparent. Both predict outcomes via metabolic networks and genetic networks during life history transitions.
The networks link nutrient-dependent amino acid substitutions from RNA-directed DNA methylation to the stability of organized genomes in all genera.
Now that nutrient excess has been linked to colorectal cancer, it will be interesting to see how long it takes to link mTORC1 signaling from nutrient sensing to epigenetically-effected sex differences in hormone-organized and hormone-activated physiopathology.
Again, see: Scientists identify an oncogene regulated by nutrients See also: Brain development suffers from lack of fish oil fatty acids, study finds
The amount of experimental evidence that supports my model of RNA-mediated cell type differentiation is overwhelming. I can barely finish one new blog post before at least one more journal article is published as a refutation of evolutionary theory.  What’s worst is that the evolutionary theorists have continued to tout their pseudoscientific nonsense, and they don’t comment on the fact that their theories continue to be ridiculed by serious scientists.

Notify of
Inline Feedbacks
View all comments

Want more on the same topic?

Swipe/Drag Left and Right To Browse Related Posts: