Wednesday, January 06, 2016

Magnetic body as genetic editor?

During my Facebook visit I found a highly interesting link to a recent finding that the tRNA in the sperm of rodents can alter the metabolism of the offspring (see the article). This is impossible according to the basic dogmas of genetics.

One of the first naive questions that popped up was following. Metabolism is associated with mitochondria: the article does not tell whether the silenced genes are ordinary or mitochondrial genes. The DNA associated with mitochondria is inherited from mother. Could tRNA represent father's contribution to the inheritance related to metabolism?

It however turned out that the attempts to understand the abstract of the article led to a series of questions, which allowed to develop a more detail the TGD vision about quantum biology although in this framework it is not possible to answer so specific questions as the one just posed. The abstract however serves as a good introduction to the relevant questions.

1. Two abstracts and some basic notions

Here is the abstract of the article.

Several recent studies link parental environments to phenotypes in subsequent generations. Here, we investigate the mechanism by which paternal diet affects offspring metabolism. Protein restriction in mice affects small RNA levels in mature sperm, with decreased let-7 levels and increased levels of 5′ fragments of glycine tRNAs. tRNA fragments are scarce in testicular sperm, but are gained as sperm mature in the epididymis. Epididymosomes—vesicles that fuse with sperm during epididymal transit—carry RNA payloads matching those of mature sperm, and deliver RNAs to immature sperm in vitro. Functionally, tRNA-Gly-GCC fragments repress genes associated with the endogenous retroelement MERVL, both in ES cells and embryos. Our results shed light on small RNA biogenesis and its dietary regulation during post-testicular sperm maturation and link tRNA fragments to regulation of endogenous retroelements active in the preimplantation embryo.

This does not say much to a layman. I would have of course forgotten the whole thing in five minutes unless I would have the passion to understand biology in TGD framework. Therefore I had not other way to procee than try to understand what above text might mean.

The first question concerns retroelement MERV. The following abstract gives some idea about the mechanism of the modification of genetic expression.

About half of the mammalian genome is occupied by DNA sequences that originate from transposable elements. Retrotransposons can modulate gene expression in different ways and, particularly retrotransposon-derived long terminal repeats, profoundly shape expression of both surrounding and distant genomic loci. This is especially important in pre-implantation development, during which extensive reprogramming of the genome takes place and cells pass through totipotent and pluripotent states. At this stage, the main mechanism responsible for retrotransposon silencing, i.e., DNA methylation, is inoperative. A particular retrotransposon called muERV-L/MERVL is expressed during pre-implantation stages and contributes to the plasticity of mouse embryonic stem cells. This review will focus on the role of MERVL-derived sequences as controlling elements of gene expression specific for pre-implantation development, two-cell stage-specific gene expression, and stem cell pluripotency, the epigenetic mechanisms that control their expression, and the contributions of the pluripotency marker REX1 and the related Yin Yang 1 family of transcription factors to this regulation process.

Some additional notions are needed in order to get some gist about what might be involved. Retrotransposons and transposons are transposable elements responsible for the editing of genome (the original genetic dogma assume that genome is given). This editing is quite extensive during the
first stages of cell differentiation. Genome is in the beginning totipotent in the sense that cells can differentiate to any cell type. In pluripotent phase cell can differentiate into all cell types of the adult organism. At the next step so called multipotent cells emerge and at the next steps more degrees of freedom are lost. This unavoidably brings in mind editing of computer programs and fixing the values of the parameters of the sub-program calls. The question is "Who is the editor?".

The mechanism affecting gene expression reduces to the repressing of certain retrotransposons responsible for the editing of DNA. The mechanism of silencing would in this particular case rely on larger than normal amount of tRNA-Gly-GCC fragments repressing the genes associated with MERVL. If I have understood correctly, this mechanism is different from DNA methylation. It is however clear that something much more general than I have realized earlier is involved.

2. Could TGD inspired biology provide insights?

The question was whether TGD inspired quantum biology could provide some insights about the situation? The attempt to say something about the findings just summarized in TGD framework led to the realization that one must replaced original perspective with a wider vision in which the finding discussed is just a special case. Second realization was how much biologists understand about the complex mechanisms involved and how rich the dynamics of the genome is. What TGD can possibly give is the vision about magnetic body as an intentional agent using biological body as a sensory receptor and motor instrument and about various mechanism used by magnetic body for control and communication purposes. Also the notion of bio-harmony suggests itself at the level of basic bio-molecules.

The finding that behavioral patterns of planaria can be remembered also by the piece of split planaria without brains is consistent with the idea that replication of magnetic body coding for behaviors is behind biochemical replication. That alleles of the same gene have different expression could be understood if the bio-harmony assignable to gene carries additional information besides the biochemical information.

These notions might also provide a fresh approach to epigenetics. Histone modification and DNA methylation are believed to induce kind of geometric locking preventing transcription. They could also affect the frequency assignable to DNA codon or some key unit so that the resonance condition making possible reconnection of U-shaped flux tubes allowing biomolecules to get in contact fails and transcription cannot proceed. Epigenetic inheritance could reduce to the inheritance of bio-harmony: the magnetic bodies of cells of offspring get in tune with those of parent. To how high degree magnetic body and bio-harmony are inherited? This becomes the key question.

2.1 Basic ideas related to magnetic body

Consider first some key ideas of TGD inspired quantum biology.

  1. In TGD framework magnetic body extends the pair formed by organism and environment to a kind of holy trinity. Magnetic flux tubes and the realization of genetic code in terms of dark proton sequences has been the key hypothesis. The model for cold fusion suggests that also more general dark nuclei must be allowed. Dark neutron sequences could correspond to genes separated by dark protons. Dark weak interactions with large value of heff effectively massless below neuron size scale would play central role and induce large parity breaking effects (chiral selection).

    The chemistry of DNA and tRNA would not be all that matters. DNA-nuclear/cell membrane as topological quantum computer with braided magnetic flux tubes would explain why organisms with virtually identical genomes are so different (we and our ancestors for instance). The hierarchy of magnetic bodies would be responsible for the development of intelligence and for cultural evolution. Flux tubes connecting DNA and mRNA as well as mRNA and tRNA molecules are present but it is difficult to say anything concrete.

  2. During the process of making sense of the abstract of the article, I learned that ontogeny can be seen as a kind of editing process for the text defined by the DNA. Control of control of... is involved so that situation is very complex. Who performs the editing? Does DNA edit itself and is the editing process defining evolution of genome coded by genome? Or is the editing performed by Darwinian selection at cell level? Or is the magnetic body the editor using genome also as its tool as TGD would suggest? What is important that in TGD framework self-organization in 4-D sense implied by Zero Energy Ontology replaces ordinary self-organization leading to asymptotic spatial patterns and select spatiotemporal patterns as asymptotic behavioral patterns defining various biological functions. The role of magnetic body is central in this process.

  3. Magnetic body contains cyclotron Bose-Einstein condensates and cyclotron frequencies determined by the strength of magnetic field would give for DNA and other biomolecules additional characteristics. In TGD based model for musical harmony DNA codons would correspond quite concretely to 3-chords but played using dark photons (also ordinary music represented as sounds could be transformed to dark photon music). If one accepts the icosahedral model of bio-harmonies predicting genetic code correctly, there would be 256 fundamental harmonies characterised by the allowed collection of 3-chords and they would add to the information carried by DNA molecules. I have constructed a program building random sequences of the allowed chords using the additional harmonic rule that two subsequent chords contain at least one common note and this music sounds rather harmonic (albeit boring in absence of any other elements!)

  4. Could one distinguish between different states/phases of DNAs, mRNAs, tRNAs, and amino acids in terms of harmony? Could their functioning depend on the harmony? With the inspiration coming from the connection of emotions and musical harmonies I have proposed that the harmony associated with a gene or organ could correlate with something analogous to an emotional state or mood - maybe micro-mood or microemotion could be the proper notion. Could amino-acids be happy, hilarious, melancholic, sad, depressed? Could one distinguish between different phases of DNA, RNA, tRNA, aminoacid collections characterized by the harmony in turn characterizing the of a cell, organelle, organ, or even organism? tRNA defines the map of the harmony associated with DNA codons to amino-acid harmony. Is the information about DNA codon and about corresponding 3-chord represented at the level of magnetic body of amino-acid- that is as the 3-chord, which it represents, and realized as the rules telling with which tRNAs amino-acid can reconnect?

    In contrast to DNA codons, which represent local information, harmony could represent holistic information and characterize entire genes or their intronic portions.

2.2 Problem

There is however a problem. DNA codons coding for the same amino-acid correspond to different 3-chords of harmony. One of these chords corresponds to amino-acid itself and the codons coding for amino-acid correspond to the orbit of this chord under subgroup of isometries of icosahedron moving the triangles of icosahedron along the orbit. This would apply also to mRNA and maybe also to tRNA. The chords at the orbit of amino-aicid are isomorphic (intervals are same) and obtained as transposes of each other.

The chords are isomorphic but not identical and this leads to the problem with resonance paradigm unless one gives up the idea that amino-acid corresponds to a unique DNA codon and assumes that there is analog of gauge invariance allowing to choose the preferred codon freely.

  1. The assumption about preferred DNA codon could be given up if one can choose the preferred DNA codon freely so that also the magnetic bodies of amino-acids are characterized by 3-chords and thus carry information about what DNA codon coded them. This is possible if one has the analog of fiber space structure with DNA codons coding for amino-acid defining the fiber and amino-acids defining the base. This fiber structure with discrete gauge invariance is strongly suggestive and I have proposed it for two decades ago but it seems that it poses strong conditions
    on the orbits of the subgroups of isometries of icosahedron.

    This condition is very restrictive. Simplifying somewhat: one considers 60 codons decomposing into 20+20+20 codings and each group of 20 codons codes for amino-acids belonging to different groups. There are twenty of them. The 20 triangles of icosahedron correspond to 3 DNA codons each and each of them corresponds to one and only one amino-acid. One has 3 subgroups of isometries corresponding to 20+20+20 decomposition.

    Can one perform a global gauge transformations realized as isometries and moving triangles along the orbits of one of the 3 subgroups involved - say isometry g1 of G1? These transformations would move the entire orbits of 2 subgroups involved - call them G2 and G3. What happens to the chords of G2 and G3: is their character changed completely so that these harmonies would be destroyed? It seems that this cannot work. Should one replace G2 and G3
    with their automorphs g1G2g1-1 and g1G3g1-1. Does this make sense? 3-chords defining give orbit should be invariant under automorphisms of Gi? This does not seem to be a realistic condition.

  2. Could different automorphs correspond to different collections of chords physically just as global gauge transformations generate different physical situations? Isometries of groups Gi would therefore define physically different realizations of bio-harmonies such that for each of them only one of the DNA codons coding for given amino-acid could actually perform the coding. Ordinary genetic code with many-to-one correspondence would make sense in statistical sense only. If this is true, the cyclotron frequency 3-chord assignable to amino-acid depends on the DNA coding it and implies physical distinctions.

  3. One can consider also a third alternative. DNA codon with same 3-chord as coding for amino-acid is in special role in that only it can resonate with the amino-acid! Could DNA codons correspond to same cyclotron frequency triplet (magnetic fields) but different value of heff so that one would have chord with respect to energy rather than frequency. Different values of heff for DNA codons coding for the same amino-acid would scale their cyclotron frequencies to the same amino-acid frequency while keeping cyclotron energies invariant? Cyclotron energy ratios for codons correspond to rational valued ratios Ei/Ej = heff(i)/heff(j)= n(i)/n(j). Amino-acid would correspond to fixed heff and this creates a problem: can DNA codon code for amino-acid with different value of heff. This option does not look attractive.

Second option looks most plausible. Of course, it is early to talk about a prediction: it might well be that I have mis-understood something.

2.3 Questions about bio-harmony

One can pose a lot of questions about bio-harmony.

  1. It is not necessary to assign any interpretation on the harmony. Just the harmony could be enough if it is forced to be same for DNA, corresponding mRNA, tRNA, and aminoacids. One can however make questions. Is the harmony inherited invariant and could it distinguish between different personality types about which we learned in old books of psychology? Or could the harmonies correlate with our own moods?

  2. Could differentiation selecting particular genes as expressed genes apply also to harmonies so that given gene would correspond only to a particular harmony and different copies of gene could correspond to different harmonies. Could this selection rely on the same mechanisms as ordinary differentiation realized in terms of epigenetic mechanisms and DNA editing? From the magnetic bodies of genes the harmony would be automatically transferred to the magnetic bodies of mRNA, tRNA and aminoacids since otherwise the transcription and translation do not work since magnetic bodies do not have common resonance frequencies and reconnection and resonant interaction is not possible.

  3. Does given harmony characterize given gene or the entire cell? All basic biomolecules associated with a gene would naturally correspond to the same harmony. If the rRNAs associated with ribosomes are in harmony mutually cellular harmony seems to be the only option. If ribosomes have their own harmonies, only certain ribosomes can translate given gene. This would bring in additional control tool. The most plausible picture is that the situation depends on what happens in the self-organization process. Some organs/organisms are more harmonious, others not so harmonious. Harmony need not be given fixed to remain the same: magnetic body can have motor actions changing the cyclotron frequencies. Moods could reflect the character of harmony at gene level.

  4. Does magnetic body control the differentiation by posing restrictions on gene expression or vice versa? The idea about magnetic body as intentional agent suggests that the first option is correct. There would be hierarchy of magnetic bodies with magnetic bodies at the higher level controlling bodies at the lower level. The value of Planck constant would label the hierarchy levels and also DNA codons would be characterized by "intelligence quotient" defined by heff/h. This would be nothing but the analog for the hierarchy of program modules and I have earlier considered the realization of this hierarchy.

  5. The selection of harmony could take place and be analogous to cell differentiation. This would be a self-organization process in which magnetic bodies of genes, cells, etc.. tune themselves to resonance with each other by modifying their magnetic fields by controlling their thickness (for monopoles flux the flux is invariant). Something analogous to the development of social skills. This could pose resonance as a constraint on processes like replication, transcription, reverse transcription, silencing, enhancing, editing, etc.... It might induce the differentiation at gene level.

    Editing processes for genome could be seen as being induced by the motor actions of the magnetic body involving reconnection and change of the value of heff changing the length of the flux tube and bringing biomolecules near to each other or separating them. This selection would also apply to the intronic part of DNA proposed to be responsible for topological quantum computation like processes. The copies of same fragment appearing in intronic portion and copies of genes could correspond to different harmonies.

It would be nice to identify some biological phenomenon difficult to understand in standard framework but having an elegant explanation in terms of magnetic body.
  1. The notion of harmony could manifest itself at the level of genes as different expressions for the copies of same gene if they correspond to different notions of harmony. The copies of gene are known as alleles. The alleles can indeed give rise to different phenotypic traits such as different pigmentation.

  2. Morphogenesis provides examples of this kind of phenomena (see this). The first key idea is that DNA and cell replication is induced by the replication of magnetic bodies serving as information carriers. The second key idea is that inzero energy ontology (ZEO) magnetic body is 4-dimensional and represents behavioral patterns rather than only 3-dimensional patterns. For instance, memory as behavioral patterns can be inherited by the piece of planaria worm not containing the brain. The explanation could be that the magnetic body carries behavioral patterns replicated in the splitting of the worm.

  3. Epigenetics studies changes of gene expression not caused by the change of DNA itself. Epigenome is the highly dynamic part of DNA controlling expression of the rather stable part of genome. One might regard stable part of genome as hardware and epigenome as topological quantum computer programs assignable to magnetic body and modifying gene expression epigenetically. Comment sign in computer code serves as a computer scientific metaphor for epigenetic control by repression.

The modelling of epigenesis in terms of magnetic body and bio-harmonies deserves a separate discussion.
  1. The modification of transcription rate is the basic tool of epigenetic regulation. There are two basic mechanisms involved. Histone modification affects the histones of chromatin so that the transcription is repressed or activated. Histone modification takes place by several mechanisms. DNA methylation occurs for CpG pair and if it occurs for a promoter region it represses the transcription and serves as a kind of gene lock. The degree of methylation serves as a measure for the effectiveness of repression. I do not know whether the locking is absolute at the level of single gene or whether only the transcription rate is reduced. Two mechanisms are mentioned in the Wikipedia article. Methylation can impede geometrically some step in the transcription. Methylated site can be also accompanied by proteins affecting histones in chromatin and in this manner impede transcription.

  2. The notions of magnetic body and bio-harmony suggest an alternative - one might even hope fundamental - mechanism of repression. Methylation (histone modification) could affect some cyclotron frequency associated with DNA codon (histone). In the optimal situation for transcription the DNA and protein catalyzing the transcription or mRNA are in resonance. When cyclotron resonance condition is not exactly satisfied, the reconnection rate for the U-shaped flux tubes associated with the molecules involved in the process is reduced and also transcription is repressed.

    I have considered also the radical possibility that the dynamics at the level of magnetic body is fundamental for biology
    and that magnetic body defines templates for the bio-molecular self-organization making dark matter dynamics visible. This is probably too extremist view and it would seem that biochemistry affects the cyclotron frequencies assignable to the magnetic body by affecting the strengths of magnetic fields also at dark magnetic flux tubes.

  3. The notions of epigenetic code and histone code have been proposed. Epigenetic code would consist of histone modifications and additional modifications such as DNA methylation. The codeword of the epigenetic code could code for some larger unit than protein: say gene or entire cell. The hypothesis is that the chromatin-DNA interactions are induced by histone tail modifications (such as methylation, acetylation, ADP-ribosylation, ubiquitination, citrullination, and phosphorylation). There are 4 histones and the position of modification varies as well as the modifier (the above modifications are not the only ones) so so that the number of modifications is very large.

    The addition of bioharmonies to the genetic information could simplify the situation dramatically since the modifications could be seen as defining of of the 256 bio-harmonies with 64 chords each (this for fixed scale which varies if the value of magnetic field strength is varied: biophoton spectrum in visible is proposed to represent the range of values of magnetic field). The most plausible starting hypothesis is that given harmony characterizes the gene. Much simpler option would be that the harmony characterizes entire cell or even group of cells.

    If the modification by kicking cyclotron frequency out of harmony is enough to repress transcription, almost endless number of bio-chemical manners to achieve would exist but the epigenetic code could be very simple at the basic level as TGD would predict. Each bio-harmony would provide a representation of genetic code in terms of 3-chords predicting correctly the DNA-amino-acid correspondence (there are actually two slightly differing codes explaining the presence of 21st and 22nd amino-acid and deviations from the standard code). The states of dark protons (or neutrons) are also proposed to realize genetic code: it is an open question whether these codes imply each other as they should.

  4. The understanding of transgenerational epigenetic inheritance raises difficult challenges. One should understand how histone modification and DNA methylation could be transferred in cellular division or inherited by the offspring. Transgenerational interaction of the genomes seems necessary. In TGD framework the interaction of magnetic bodies of via resonance mechanism could transfer the epigenetic programs to the offspring. Offspring could "learn" the epigenetic programs of the mother by tuning.

  5. Gregory Carey gives nice real life examples about the complexities of epigenesis identified quite generally as gene regulation (see this). He compares the gene regulation involved with the handling of a stressful situation to "nightmarish Rube Goldberg mousetrap" and sees the process as extremely ineffective from engineering point of view. For instance, the hormones secreted to blood circulation are distributed to the entire body. The whole thing could be carried out in brain! He also wonders why evolution is so inefficient. All cells have same genome although most of the genes are silenced. Second strand of DNA is totally un-used and most of DNA consists of introns. His explanation is that evolution does not make long term plans but finds just a solution to a particular without thinking it from a wider perspective: "If it ain't broke, don't fix it".

    I tend to see this differently. If entire body is coherent quantum entity, engineering based thinking does not make sense. Entire body and also magnetic body must be informed from the stress situation since the reaction is holistic. The genes which are not used for gene expression might be used for other purposes. Topological quantum computation could be this purpose in TGD framework and repressed genes could be thus used for quantum information processing. Information processing could be actually the dominating function of the DNA of higher vertebrates.

To sum up, magnetic body could be seen as the "boss" controlling the gene expression and also the evolution of genome in longer scales. Magnetic body would use biomolecular mechanisms for its purposes. This would bring in a new kind of inheritance. For instance, magnetic body could use the tRNA-Gly-GCC repressing the repression of MERVL to modify gene expression in such a manner that DNA codons corresponding to 3-chords of particular bio-harmony become preferred and the expressed genes correspond to a particular harmony. The most spectacular almost-prediction would be that genetic code is many-to-one only in statistical sense.

For more detailed view see the article Magnetic body, bio-harmonies, morphogenesis, and epigenetics or the chapter Quantum model for hearing of "TGD and EEG".

For a summary of earlier postings see Links to the latest progress in TGD.

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