Murburn Bioenergetics and "Origins-Sustenance-Termination-Evolution of Life": Emergence of Intelligence from a Network of Molecules, Unbound Ions, Radicals and Radiations
If DRS are produced in greater amounts, they could react among themselves, producing non-radical end-products and dissipating energy as heat (thermogenic uncoupling), an important inbuilt safety measure [20].
Fast DRS-detoxifying enzymes in “solution” and e-buffering molecules like cytochrome c in aqueous milieus or ubiquinone in membrane milieus are yet other agents in the evolutionary repertoire that enable DRS-based physiology [16].
Therefore, rather than seeing DRS as toxic and wasteful agents, it must be realized that DRS are the elixir of life. Yet, in spite of all the safeguarding measures (listed above) collateral reactions over prolonged periods can produce the deleterious effects of DRS, as chronically reflected in aging and acutely in pathophysiology.
Therefore, we arrive at the paradox: “What giveth life also taketh life”! Now, we stress yet another salient feature of cellular composition that originated very early: coacervation.
By definition, a coacervate is a complex colloidal system with discrete phases. From simple mixtures of amino acids, microscopically visible coacervates (without a membrane, akin to membrane-less organelles) can be obtained resembling “Fox microspheres” [21]. Considering only the initially most abundant amino acids [3,22] with Pro, Glu, Asp and Gly unfolded peptides can be formed, which are sticky and promote formation of coacervates (microspheres), a huge step of increase in order occurs, from molecular to “cell” size, and from “normal” to “polarized-oriented multi-layer” or POM-water with completely different properties [22,23]. Insertion of the hydrophobic residues Val and Ala allows formation of more folded regions suiting primitive catalytic activities. Val and Ala can form the short precursors of stable α-helices [5,22]. Such coacervates acquire several typical properties of cells (the “instant” PCHEMS) although lacking DNA, RNA and ribosomes (essential ingredients of central dogma). Some salient features [1,5,9,22]:
Produce POM-water exhibiting lower solvency for many solutes, including Na+, leading to exclusion without ion pumping, just a phase/phase equilibrium [6,22,23] together with DRS-related equilibriums [1].
Water molecules in POM-water together with water-polarizing oligopeptides coherently behave as a unit [6], all vibrating at a common frequency [24,25,26,27], one of the most essential properties of life (as evident/experienced in the conscious state).
Accumulate K+ (over Na+) even up to 1600 times [28] (without membrane pumps), just by selective adsorption on Asp and Glu carboxyl groups of the coacervate oligopeptide matrix [6,22,29], in conjunction with murburn equilibriums [1].
Can swell and shrink by colloid osmosis, without a membrane [6,7,22]. Volume changes effectuate all physicochemical parameters, an overlooked metabolic regulatory mechanism assuring dynamic coherence (cytotonus control) [30]. Accordingly, actin-like proteins became the (overlooked) activator of oxidative phosphorylation [5,30], also influencing (overlooked) metabolic control by cell perfusion [31].
An exclusion zone at their phase boundary characterized by charge separation and a boundary potential (without pumps), sensitive to environmental influences including IR/VIS/UV radiation [32] and internal-to-external DRS ratios [1], executes some sensory/effector functions. If prepared with added lecithin, the action potential trace obtained is almost indistinguishable from an axonal one [28]!
Exhibit long lifetime despite being low-entropic, excited and coherent. Without long-term (meta-)stability, evolution is impossible [33,34].
The properties listed above, along with Table 1, Table 2 and Table 3 illustrating murburn characteristics, mean that cells do not need to depend on an “intelligent membrane pumping ions” mechanism for deterministically governing their activities. Now, we can understand that cells take up energy to automatically organize in an equilibrium-driven fashion (although apparently far away from equilibriums in many distributions) to carry out their functions.
The DRS–coacervate cooperation demonstrates that life emerges as a logical consequence of the principles of chemico-physics and their inherent non-linear mathematical structure, which leads to an increase in complexity and coherence. Within these laws there is place for random processes, among which meta-stable realms and coherent solutions are intrinsically present [1,3,5,33,34,35,36]. The latter, if occurring, will be selected almost a priori on behalf of their immense advantages. This framework allows subsequent advantageous, workable functionalities to be integrated into the existing dynamic structure with already great stability, so that success can be continued and expanded. These non-linear properties clearly lead to workable and purposeful mechanisms and functions, as illustrated irrefutably above: “purpose” again enters evolutionary thinking as an inherent outcome of chemico-physical laws [33,37], and not due to overt vital determinism. The logic outlines of pre-biotic evolution presented above illustrate the early origin and inherent stability of PCHEMS obtained by just random chemistry, thanks to their embedding in the primary deterministic aspect of physical and chemical laws.
Epicenters of murburn activity would be expected to differ from other regions in phase behavior. Taking an overall thermodynamic approach (which includes entropic aspects), it could be interpreted that many complex physiological processes are characterized by “order-to-disorder-to-order cycles” for physiological work output which go along with phase transitions of the locally involved coacervate system. A most striking example is that of muscle relaxation-to-contraction-to-relaxation cycles. The new understanding of the bioenergetics of cells and tissue systems presented in this review (as discernible from Figure 2) integrates this perspective. It was first elaborated by Bauer in 1935 [26,38] (and agrees with the view of Schrödinger [10]), who saw “work out of coherent order” as the only thinkable alternative for the unreal mechanistic proposal based on the physics of diluted solutions [5,6,7,27,39]. The idea was further elaborated by Ling [40] and recently corroborated kinetically and topologically in living yeast cells [41,42,43]. However, murburn concept remained the missing and primary part within this picture, until its recent revelation and impact. The cellular system components are redox-sensitive (with DRS as effectuators) and the redox dynamics within locales also determine CEM profiles (not just ionic fluxes!). Action potentials do not only depend on Na+, K+, ATP and known transporters but more primarily on O2 and one-electron transfers generating DROS. The same holds for muscle contraction and other motility mechanisms. Missing in the latter investigations is the insight from murburn concept that DR(O)S at normal (low) physiological concentrations also bring about energizing/altering impacts in water–ion interactions and fluid lattice organization.
It is already known that DROS can originate from oxidation of water with Fe3+ (Fe2+-UV/Fe3+ cycle: Box 1) and other suitable 1e-donors. Coherently polarized water can itself stock quasi-free electrons and execute “water respiration”, i.e., can act as a quite strong electron donor [26], and that DROS can directly effectuate solute–ion–water equilibriums [1], indicating a direct cooperation between coacervation and murburn physical chemistry (Figure 2 and Figure 3). As a next step, early DROS-dependent ATP-synthesis needs low water activity, which typically exists in coacervates, thereby connecting murburn and coacervation.
Stochastic murburn reactions effectuate the “primary” powering of chemical, electrical and mechanical processes. They also bring a kind of order and coherence (networking of components) by ensuring the most basic level of homeostasis through the logic of interconnectedness of all equilibriums inside (in contact with those outside) and maintenance of solvent/metabolite concentrations (owing to solvency, adsorption and osmotic/turgor forces), altogether making up an “analog/digital” sensory–integrator–effector system [1,14]. Besides the primary energizing through DRS-ECS in respiration [1,4], photosynthesis [1,44], photoreception [1,18], photodynamic therapy [44], etc., cells also possess a “secondary” cellular energizing system derived from the primary murburn dynamics (Figure 2 and Figure 3) via:
ATP adsorption/hydrolysis indirectly and intricately combined with direct DRS effects on “order disorder cycles”; and
electromagnetic (EM) emission followed by re-absorption (appreciated by physicists but neglected by most biologists [5,24,25,26,27,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]).
According to Maxwell’s laws, moving charges produce an EM field, i.e., displacements of electrons (localized excitations, e-transfers, Lewis effects, etc.) and mineral, organic, macromolecular ions and larger charged structures (often pulsed group processes at longer wavelengths). In cells, it spans the range from a few Hz to the photonic range (IR/VIS/UV). It is amply demonstrated that many frequencies are internally re-absorbed by means of resonance and are used to coordinate cellular activities [46,47,48,49,50,51,52,53,54,55,56,57,58,59]. Herein, the exergonic murburn processes/reactions are the primary emitters and may produce “high-quality energy” [17] radiation (even UV! Box 3) which other cellular systems capitalize on through re-absorption. Therefore, cellular murburn equilibriums give not just interactions among molecules and ions and are not just be affected by radiations [18,44], they also result in the creation of localized electrode effects and complex macroscopic electromagnetic fields forming a CEM [45], whose effects can be affected/compounded by coacervation.
In coacervates (but not in dilute solutions) compounds are ordered so that the produced EM field can reach a certain degree of coherence, particularly since most water molecules are also ordered [5,6,7,24,25,26,27]. Though murburn reactions are stochastic, they take place in an overall milieu which is highly ordered (particularly water). The DRS-dependent in-fluid ATP synthesis occurs with ordered water of low activity [4]. Though the direct EM emissions by murburn reactions may have limited order, surrounding coherent water or other ordered arrangements of molecules can take up the radiation and re-emit it in coherent form, in turn resonantly reaching other ordered systems (microtubules, centrosomes, centrioles [48,49,50,51,52,53,54], DNA [55,56]) with a broad absorption range. This would allow conversion into coherent EM waves, re-emitted at (different) typical frequencies, which may be instructive to diverse cellular activities [5,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. In present-day cells, the degree of coherence is high; for microtubules even quantum coherence and photonic resonant “phase-correlated” signal transduction are directly observed [51,52,53]. For instance, cytoskeleton-associated EM-field dynamics deep in cytoplasm precede and orchestrate ionic effects at the neuron membrane [53]! There is much evidence that the cellular EM matrix could serve as a cue and can even directly integrate chemical [46,47,48,54,59], electrical [51,52,53] and mechanical [54] activities, morphogenesis, tissue repair [57,58], brain functioning and development [51,52,53,54], tissue-wide DNA intertalk [55,56] and information transfer between separated individual systems [60,61].
The remarkable “mitogenic” UV information transfer from a germinating onion to a non-germinating onion, discovered by Gurwitsch in 1912 [5,17,46,57,60], made him suggest that high-energy DRS reactions are responsible—they feature since the origin (Box 3) and may be the only reactions able to reach UV emission. The overall bioenergetics scheme of interactive/holistic cellular networking and energy flow is captured in Figure 3.
It is now established that ECS-DRS-based murburn mechanisms are involved in all types of cells at ubiquitous loci [1], thereby serving as a metabolic/physiological pillar of life. It is thus reasonable to posit that “healthy” murburn-DRS levels/dynamics are associated with coordinated electromagnetic patterns throughout the various protein/organellar/cellular/tissue loci (Figure 2), which could also depend upon local functions and topologies. Sonnenschein and Soto [62] regard “proliferation with variation and motility” as the “normal state” of all cells and the state of cells in a healthy well-organized, differentiated and well-controlled tissue as the “special state”, obtained as the result of contact inhibition with a whole set of regulatory mechanisms connected to it. Interactional problems among neighboring cell types may induce development of cancer, whereby cancer cells regain the “normal” state of “proliferation with variation and motility”. An important test validating this hypothesis stems from the observations that: (a) cancerous and degenerated cells show distinct morphologies, water structure, coacervation properties and EM field as compared to healthy cells and (b) cancer cells can reverse their malignant state when experimentally placed in a sufficiently extensive healthy tissue environment [63,64,65].
External measurements of the EM field show only the small amount of EM radiation produced in cells, tissues and entire bodies, which has not been internally re-absorbed [46]. Yet it is an indication of what happens inside. Of particular importance is that normal cells decrease their emissions with higher cell density, which means a higher degree of energy recuperation. In contrast, tumor cells have increased emission with higher cell density, and this becomes more pronounced the more malignant the cells are! Also, photonic emissions (“biophotons”) of tumor cells lose their coherence [46]. This is correlated [5] with observations of Damadian [66] that cell water ordering typical of healthy tissue is diminished or lost in tumors, as directly shown by proton-NMR (and MRI development thereof). Fröhlich [24] derived the coherent aspect characterized by its common frequency for the excited polarized protein–water system. Thereafter, he developed the idea of the existence of a global coherent oscillation with a characteristic long wavelength compared to the size of cells, whereby “phase correlation” over the entire tissue synchronizes its mechanical–electrical dynamics [67]. Destabilization of this unifying system occurs when a critical number of cells lose the common frequency, below and above which the destabilized cells respectively recover the right frequency or become disordered, with altered mitotic and adhesive properties. Webb [68] experimentally corroborated it by showing that healthy tissue emits only two series of coherent millimeter waves, one associated with proteins, the other with DNA, whereas tumors emit greater quantities of lower-frequency, less coherent radiation. This implicitly suggests the possibility of reversing the cancerous state (as observed [63,64,65]), if the interactions/signatures could be fixed with chosen frequency inputs methods [69].
We envisage a time when, just like MRI is used for assessing the structural states of tissues, functional DRS-EM dynamics could be addressed with such investigative, but also therapeutic, approaches.
Warburg [70] argued that an increased glycolytic–respiratory ratio is “the” cause of cancer, which was statistically confirmed by Acebo [71]. Why do well-oxygenated tumors convert glucose to lactate in cytoplasm instead of subjecting it to mitochondrial respiration? Is respiration suppressed (as many believe), or is there excess DROS production through mitochondrial overload, another possibility to explain the Warburg effect [72]? The latter agrees with decreased water ordering [56] and with murburn concept, whereby overload induces radical activity/quenching, which may produce excessive “mitogenic effects” [60]. These imply that factors messing with mitochondrial function can be causative, including radiation of diverse wavelengths (from X-rays to even ELF waves), toxic metal ions, pesticides, components of some cosmetic and household products, hydrogenated fats and additives in processed food, soot particles, air pollutants including DRS, etc. In a meta-study covering over 2000 articles, Geesink and Schmieke [73] distilled the mathematical “frequency law” determining which frequencies are dissonant with the body (harmful, destabilizing) and which are harmonic (beneficial). Such approaches/data could aid biomedical and other device developers in the future! Plankar et al. [74] collected the arguments which demonstrate that loss of coherence precedes mutagenesis, supporting Fröhlich’s hypothesis. Our works suggest that healthy mitochondrial function is a crucial cellular ECS-DRS-EM-coherence contributor, which, if impaired, is perhaps responsible for pathogenic states. Such murburn-based insights also allowed us to propose new perspectives to address cancer therapy [75].
Murburn concept (ECS-DRS) forms the primary drive and bioenergetics pillar of cellular life. From this perspective, it can be easily discerned that TMP is a consequential effect of the ECS-DRS murburn process and not the driving force of life. The useful work performed by an automobile is not directly from exhaust or noise (which is analogous to the TMP), but it is because of the “burning of fuel which produces an expansive gas” that the vehicle runs! Murburn is the core logic of how cells automate and integrate to function as “simple chemical engines” (SCEs), a thermodynamically viable system that does useful work, and how “electronic intelligence emerges” (and is not resident in the ion-pumping membrane, as misperceived earlier!) from a discretized distribution and network of molecules and ions.
The pre-biotic “burning” activity of iron producing DR(O)S initiated the direction towards life: synthesis of hydroxy-, keto-, carboxylic and amino acids and later ATP by random murburn chemistry. Early coacervations increased complexity from the molecule to the “cell-size” level and from “normal” water to highly ordered water, affording several typical life properties (except those of the central dogma). A significant amount of the emitted electromagnetic energy is re-absorbed by coherent cellular systems (microtubules, centrosomes, centrioles, DNA, etc.) and re-emitted coherently at different wavelengths, which is “healthy dynamics” for the normal functioning of cells. External radiations and select chemicals could perturb DRS metabolism, leading to a disturbed (less coherent) CEM affecting cellular coordination, including chromosome/DNA integrity, explaining why cancer/mutagenesis is preceded by decreased coherence [74]. The non-genetic/hormonal/neuronal modalities of regulations/control via analog–digital logics [14,76] should be investigated in this context. While much remains to be explored, we have conclusively demonstrated that ideas like ETC-CRAS and ion pumping do not abide by the laws of physics, whereas the murburn–coacervate view (and associated CEM view) affords us a tangible/holistic perspective to understand the underlying chemical–physical logic of health and diseases. This was elaborated upon in the two-part review of how murburn concept enables spontaneous and automated operation of multiple systems, starting from a molecular level and seamlessly integrated all the way to the macroscopic levels [77,78]. Many recent investigations demonstrate that DROS play an important, though not understood, adaptive, regulatory role in cell motility [79,80,81,82,83].
DRS (murburn) can also bring about inheritable and epigenetic changes in DNA (and also cross-react with diverse cellular components) and its cumulative effects lead to death. Thus, murburn can drive evolution, generate diversities in species and also explain differences among identical twins.
Chemico-physical mechanisms in (biological) living systems are affected and explored/ratified by probing with inhibitory agents. Murburn concept is the only thermodynamic/kinetic explanation available explaining the globally debilitating effect of cyanide on physiology, ascertaining the significance of DRS to life, with full context to the structures of proteins and membrane physiology [84,85,86,87]. While the primary oxygen activation reaction is: O2 + e− → *O2− (−250 kJ/mol) (which explains how the mitochondrial/chloroplast quinones can effectively enhance catalysis via this equilibrium, as its one-electron reduction is comparable with −247 kJ/mol), the cyanide-catalyzed DRS cycling to water is: *OH + *O2− → OH− + O2 (−275 kJ/mol) [87,88]. Thereby, when cyanide is present, DRS are unavailable for essential life-sustaining activities owing to electrons sinking into the life solvent of water, as espoused by the murburn “thermodynamic pull” theory. The stoichiometric heme binding at cytochrome oxidase fails as an explanation in this regard [86]. Further, it is improbable that cells/neurons also evolved highly specific high-throughput ion channels as some currently believe.
If so, how could cyanide perturb the cellular functions? Since (i) DRS like NO (and CO too!) are recognized as a molecular messenger [89] and DRS-based signaling is described more and more in the literature [90], (ii) DRS production is also known to be directly correlated to ATP synthesis (and trans-membrane potential) in mitochondria in routine physiology [91] and photodynamic (low-level laser) therapy [92], (iii) DRS production activities are associated with good health measures like exercise [93] and longevity [94], (iv) the perception of DRS is changing [95], and redox activities of small molecules like vitamin C and proteins like cytochrome c have been recharted, our attribution to murburn concept as a founding bioenergetics–coherence principle and seamless integrator of chemico-physical functions of life [1,14,76,77] is validated. Affording such recognition also enables us to specifically explain diverse conundrums like: non-specific post-translational modifications, the unusual hormetic enhancement of heme-enzyme activity by azide (erstwhile presumed to serve as a potent inhibitor!) and idiosyncratic effects of diverse drugs, lack of stereoselectivity in biological halogenation reactions [1,77,78], etc. Recently, researchers found that mitochondria isolated from cancer or non-cancer cells could impact the respiratory activity of each other when they were physically separated from one another [96]. Such non-chemical signaling between disconnected mitochondria can only be explained via electromagnetic radiations, which can be produced by the high-energy-yielding DRS/ROS reactions (some of which are listed in Box 3). Thus, such potent and bewildering findings can also be efficiently reasoned with murburn concept! Quite simply, with murburn concept, we can understand the Janus, i.e., both the Dr. Jekyll and Mr.