RNAi: From magic bullet to billion dollar baby

By: James V. Kohl | Published on: August 17, 2016

DNA operates through RNA, and when RNA interference was discovered in 1998, it seemed like a magic bullet that could fight disease by specifically shutting down problematic genes.

Before RNA interference was discovered pre-mRNAs were already linked to cell type differentiation in species from microbes to mammals.

From Fertilization to Adult Sexual Behavior (1996)

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.

RNA interference is antithetical to what we believed everyone knew. The alternative splicings were nutrient energy-dependent. That led us to explain how RNA-mediated cell type differentiation was biophysically constrained in the context of the physiology of pheromone-controlled reproduction in species from yeasts to humans.
See for comparison:

A Deubiquitinating Enzyme Interacts with SIR4 and Regulates Silencing in S. cerevisiae (1996)

As silencing in both yeast and Drosophila is similarly enhanced by mutations in particular ubiquitin processing enzymes, the regulation of silencing by these enzymes appears to be an evolutionarily conserved process.
Others have consistently failed to explain how energy-dependent changes in G protein-coupled receptors are biophysically constrained. They have portrayed all aspects of RNA-mediated cell type differentiation in the context of an evolutionarily conserved process.
Even the enzymatic regulation of silencing was placed into the context of the magic of neo-Darwinian evolutionary theory. Claims about energy-dependent alternative splicings were subsequently linked from codon usage to biophysically constrained RNA-mediated protein folding chemistry and the structure of functional DNA. But all claims that linked fertilization to adult sexual behavior in humans via food odors and pheromones were virtually ignored for two more decades.

In a classic case of what could have been “us versus them,” no comparisons were made. Explanations of energy-dependent RNA-mediated protein folding went missing and cell type differentiation continued to be linked to evolutionarily conserved processes via the “Just So” stories of neo-Darwinian theorists. The “magic bullet” of RNA interference (RNAi) was never fired. If it had been, it would have killed all neo-Darwinian theories.

Two decades later, the “magic bullet” is the “billion dollar baby” of George Church and others.

See: RNA-Guided Human Genome Engineering

Repetitive elements or endogenous viral elements can be targeted with engineered Cas+gRNA systems in microbes, plants, animals, or human cells to reduce deleterious transposition or to aid in sequencing or other analytic genomic/transcriptomic/proteomic/diagnostic tools (in which nearly identical copies can be problematic).

See also: Get Well in the RNAi Way-RNAi, A Billion Dollar Baby in Therapy

See also: HDAC inhibitor misprocesses bantam oncomiRNA, but stimulates hid induced apoptotic pathway

See also: Using RNA to Amplify RNA

Meantime, Joyce pointed to the evolutionary biology research application of studying the evolution of a self-replicating ribozyme. “If you had an RNA enzyme that was an RNA replicase that could copy RNAs exponentially, including copies of itself, then I would say it’s alive,” said Joyce . “Then it’s up to evolution. Whatever makes it better makes it better.”

There is no indication that any RNA enzyme emerged to link an RNA replicase to anything.  Joyce suggests an RNA replicase could copy itself and other RNAs exponentially. If so, that would make the enzyme a form of self-replicating ‘life’ that could ‘evolve.’ No serious scientist has ever made such a ridiculous suggestion or used it as a basis to get from emergence to the evolution of extant biodiversity.

See for comparison: Codon identity regulates mRNA stability and translation efficiency during the maternal-to-zygotic transition
The authors established the fact that ecological variation links energy-dependent selection for codon usage to biophysically constrained RNA-mediated protein folding biochemistry in the context of nutrient energy-dependent RNA-mediated amino acid substitutions.
The amino acid substitutions link metabolic networks and genetic networks via the innate immune system in the context of the physiology of reproduction. The amino acid substitutions also link the sun’s anti-entropic virucidal energy — as a source of quantised information — to supercoiled DNA, which prevents virus-driven genomic entropy in all living genera.

“The amino acid optimality code (Fig 6) provides an alternative perspective on sequence changes between paralogs in evolution and human disease.”

Theorists consistently fail to suggest how virus-driven energy theft and genomic entropy can be removed from their model without defeating the purpose of a model, which is to explain something that has not been explained by theories.
Models that cannot be validated are “Just So” stories. The stories are refuted by all who have linked energy-dependent changes from angstroms to ecosystems in all living genera.

See for example: Kondrashov and Kondrashov study shows the complexities of evolution at the mitochondrial tRNA level

The complexities of evolution at the level of mitochondrial tRNA link ecological variation to ecological adaptation. Mutations and natural selection have not been linked to evolution via experimental evidence of biologically-based cause and effect.

How can experimental evidence of biologically-based cause and effect be placed back into the context of the complexities of evolution?

There does not seem to be a definition of ‘evolution’ that fits within the context of Darwin’s ‘conditions of life.’ His conditions of life are nutrient energy-dependent and controlled by the physiology of energy-dependent reproduction.

Theorists removed energy-dependent ‘conditions of life’ and they substituted de Vries 1902 definition of ‘mutation’ for energy-dependent RNA-mediated amino acid substitutions. Theorists have continued to remove anything from consideration that is now known about virus-driven energy theft in the context of the physiology of reproduction. Virus-driven energy theft effects the energy-dependent physiology of reproduction in all living genera.

The question arose: How old are bacterial pathogens?

The answer must link viruses in bacteria to all pathology in the context of this claim:  “… viral latency is responsible for life-long pathogenesis and mortality risk…” and in the context of this accurate representation of biologically-based cause and effect: Structural diversity of supercoiled DNA.

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