Stress links the Creation of Gravity, the Universe, and all Human Life

One of the most extraordinary and profound insights into the nature of the universe came in the 20th century when Albert Einstein first proposed his General Theory of Relativity. As opposed to gravity representing an “attractive force” as first described by Isaac Newton, Einstein’s General Theory of Relativity proposed that gravity is actually the result of the curving or warping of spacetime (space and time are considered inseparable) by matter and radiation that are present in spacetime (e.g. stars, planets, etc.). Essentially, spacetime is akin to a material or fabric that can be stretched or warped and it is this stretching or warping that creates gravity. An often-used analogy is the placement of a large massive object (represents a star) in the middle of a trampoline (represents spacetime) that distends or stretches the trampoline downward. A smaller object (represents a small planet) placed at the edge of the trampoline will flow down and follow the path of the downwardly-stretched trampoline, coming closer and seemingly being “attracted to” the larger more massive object.

Another equally astounding insight provided by Einstein’s General Theory of Relativity is what properties of matter and radiation lead to the warping of spacetime. Interestingly, as discussed below, the phenomenon of stress plays an indispensable role in Einstein’s field equations for general relativity and hence in the warping and curving of spacetime. Also, as I first hypothesized in several of my most recent publications, the induction of beneficial levels of cellular stress links restoration and/or maintenance of human consciousness, long-term memory formation, and the creation of all human life [40,93-95]. An eloquent restatement of the importance of beneficial levels of stress and cellular stress was intimated by the German philosopher Friedrich Nietzsche: “That which does not kill us, makes us stronger.” Indeed, it appears that the phenomenon of stress-induced creation, enhancement, maintenance, or restoration of both living and non-living things may be an overarching theme that is “imprinted” on the entire universe and everything in it, from a single-celled bacterium to gravity itself.

The indispensable role that stress plays in the warping of spacetime and the creation of gravity was recently explained in a straight-forward and succinct manner by Dr. Caleb A. Scharf, Director of Astrobiology at Columbia University [91]. An excerpt of Dr. Caleb’s explanation via Scientific American follows: 

“ The mathematical construct that guides us from mass to warped space-time is Einstein's field equation, a hairy monster that can nonetheless be tamed into a moderately non-threatening form:

On the right hand side of this equation the 'T' symbol contains information that we might insert about the distribution of matter and energy within a particular piece of space-time - like a planet, or a star, or a galaxy. This 'T' is also known as the stress-energy tensor. The left hand side 'G' symbol represents the resulting details of how space-time responds to this stuff, how it is warped or curved (also known as the Einstein tensor).

The phrase 'stress-energy tensor' is a clue to how this equation works. Mass and energy, and their behavior (rotating, moving, static), place stress on space-time, which responds according to its intrinsic properties.

So just how resilient is space-time? The bunch of physical constants on the right hand side of the field equation give us an answer. The ordinary G here is just Newton's gravitational constant, and c is the speed of light. If we plug in the measured values for these, the field equation suddenly looks rather different:

What does this mean? It means that from our perspective it takes a HUGE amount of stress on space-time to produce an appreciable amount of warp or curvature ('G'). In fact it takes objects like the Earth (all 6 trillion trillion kilograms of it) to warp space-time to a level that we're intimately familiar with.

To produce enough warp to create an object like a black hole - with an extreme, maximal amount of space-time curvature - the universe has to concentrate mass and energy to an extraordinary degree. In other words, an immense amount of stress has to be created. For example, producing an Earth-mass black hole would involve squishing all those kilograms into a region roughly the size of a US penny to generate enough local stress. It's analogous to how the fine point of a nail concentrates enough force to break wood fibers.

It turns out that space-time is very stiff, very resilient. But it can, and does, yield to stress. That's fortunate, because without a little bit of warping there'd be no stars or planets, and we'd not be here to celebrate Einstein's wonderful insights.”

Source: Just How Resilient Is Spacetime? By Caleb A. Scharf. https://blogs.scientificamerican.com/life-unbounded/just-how-resilient-is-spacetime/

As detailed by Dr. Scharf above, stress is absolutely indispensable for the warping of spacetime, the creation of gravity, and the creation of the universe as we know it. Strikingly, just the right amount of stress on a cellular level is also absolutely indispensable for the activation of human oocytes. As oocyte activation is an indispensable prerequisite for the creation of all human life, every human being alive today and any human being that has ever lived began their existence as an activated oocyte [2]. Hence, just the right amount of stress is responsible for the creation of all human life and gravity itself. 

Physiological oocyte activation is accomplished by the delivery of a sperm-borne oocyte activating factor called phospholipase C zeta (PLCζ). PLCζ activates human oocytes by inducing an intracellular signaling cascade that ultimately results in increased calcium (Ca2+) oscillations (a cellular stressor) in the oocyte, which drives oocyte activation to completion [1]. Artificial oocyte activation may also be achieved by the stress-inducing compounds ionomycin and A23187, both of which increase the levels of intracellular Ca2+ and are thus commonly known as Ca2+ ionophores [1]. Ionomycin and A23187 have been shown in several independent studies to effectively induce human oocyte activation, leading to the birth of normal, healthy children [3,4].

Interestingly, as described further below, both ionomycin and A23187 are antibiotics that are naturally produced by certain species within the bacterial genus Streptomyces when those bacteria are subjected to stress [5,6]. Other structurally distinct compounds and methods that induce cellular stress have also been shown to active human oocytes, including ethanol, puromycin (an antibiotic and protein synthesis inhibitor produced by Streptomyces alboniger), as well as mechanical manipulation and electrical stimulation, both of with have been reported to result in the creation of normal children [7-11]. As mouse oocytes are considered models for human oocytes, ionomycin, A23187, anisomycin (an antibiotic and protein synthesis inhibitor produced by Streptomyces griseolus), mycophenolic acid (an immunosuppressant produced by the fungus Penicillium brevicompactum), cycloheximide (a protein synthesis inhibitor produced by Streptomyces griseus), carvacrol (a secondary plant metabolite produced by Origanum vulgare{oregano}), and phorbol 12-myristate 13-acetate (PMA, a secondary plant metabolite produced by Croton tiglium) each induce activation of mouse oocytes [12-22]. The oregano compound carvacrol has also recently been shown to active human oocytes [92]. Ionomycin, A23187, PMA, and reactive oxygen species (ROS) also induce the acrosome reaction in human sperm, a process characterized by the release of hydrolytic enzymes from the head of sperm which is necessary for oocyte penetration and thus indispensable for the creation of all human life outside of a clinical setting (ICSI bypasses the need for oocyte penetration) [23,24]. Additionally, although an over-production of ROS, similar to Ca2+, may lead to deleterious effects including cell death/apoptosis, low levels of ROS (induces cellular stress) have been shown to act as signaling molecules and ROS is significantly increased on or immediately following mouse oocyte activation [25,26].

Furthermore, the master metabolic regulator AMPK is critical for oocyte meiotic resumption and maturation (a process that precedes and is essential for oocyte activation), is found located across the entire acrosome in the head of human sperm, and is activated by increases in ROS and Ca2+ [27-29]. Ionomycin, A23187, ethanol, puromycin, mechanical force, electrical stimulation, anisomycin, mycophenolic acid, carvacrol, and PMA also induce AMPK activation, indicating that a common mechanism of action links chemically distinct compounds with the creation of human life [30-39]. This common mechanism of action likely centers on the induction of cellular stress, mediated by indirect increases in intracellular Ca2+, ROS, and/or the AMP(ADP)/ATP ratio, etc. as I originally proposed in 2016 [40]. Because the bacterial-derived antibiotics ionomycin and A23187 induce both the acrosome reaction in human sperm and human oocyte activation, producing normal, healthy children, it can be said that “non-human organisms have the power to create human life or the power to end life via inducing stress.” 

As explained below, the beneficial effects of cellular stress induction crosses species boundaries and may indeed play a role in facilitating natural selection, a process that underlies and drives evolution.

A number of bacterial species residing within the genus Streptomyces have proven to be extremely important and medicinally valuable as approximately 70% of clinically useful  antibiotics are derived from Streptomyces [41]. The antibiotics ionomycin and A23187 are naturally produced by Streptomyces conglobatus and Streptomyces chartreusensis, respectively [5,6]. Other important examples include the antibiotic tetracycline (produced by Streptomyces aureofaciens), the immunosuppressant rapamycin (produced by Streptomyces hygroscopicus), and the anti-helminthic avermectins (produced by Streptomyces avermitilis) [42]. Many soil and aquatic-dwelling species of Streptomyces can be found in harsh environments and are characterized by a unique life cycle, including spore germination followed by vegetative mycelium production, aerial hyphae formation, sporulation (i.e. spore formation), and antibiotic production [43,44]. Curiously, just as cellular stress induction leads to the creation of human life and other beneficial effects in human cells (see below), stress induction also promotes the induction of aerial hyphae formation, sporulation, and antibiotic production in many Streptomyces species (spp.). Indeed, a decrease in the levels of ATP and bacterial growth is associated with sporulation, aerial hyphae formation, and antibiotic production [42,45]. A reduction in glucose/nutritional deprivation, the preferred sugar/carbon source for many Streptomyces spp., also significantly increases antibiotic production [46]. An increase in intracellular ROS and Ca2+ is associated with spore germination, aerial hyphae formation, and antibiotic production [47-49]. Other cellular stressors, including heat shock and ethanol, also significantly increase antibiotic production, provocatively indicating that the effects of cellular stress crosses species boundaries, enhancing bacterial survival and facilitating the creation of human life [50,51].

The beneficial effects of low-level cellular stress induction also extends to plants, as many plants produce secondary metabolites in response to stress partly for the purpose of self-defense, analogous to antibiotics. Similar to the harsh, stressful environments often inhabited by Streptomyces spp., the Great Basin Bristlecone Pine (Pinus Longaeva), considered the oldest living non-clonal organism on the planet ( >5000 years old), thrives in an exceptionally harsh environment, characterized by increased elevations and exposure to UV radiation, nutritionally-deprived soils, harsh temperatures, and mechanical stress due to wind variances, leading early researchers to conclude that it’s longevity is intimately associated with adversity [52-54]. Conversely, Pinus Longaeva species that are located in less stressful environments (i.e. lower elevations) are strongly associated with younger age classes (<875 years) [55].  Similarly, the Creosote bush (Larrea tridentate), considered one of the oldest living clonal organisms on the planet (>11,000 years old), also thrives in harsh environments including the Mohave Desert [56]. AMPK, which increases lifespan and healthspan in several model organisms, is the primary sensor of cellular stress in eukaryotic organisms (e.g. plants and humans) and the plant AMPK orthologue SnRK1 as well as Ca2+ and ROS are critical for seed germination, fertilization, root gravitropism, and secondary metabolite production [57-64]. The secondary plant metabolites PMA (which activates mouse oocytes and promotes the acrosome reaction in human sperm) and artemisinin (an anti-malarial drug) both activate AMPK and the antibiotic A23187 also increases production of the secondary metabolite resveratrol in grape cell cultures, again indicating that exposure to low-level stressors may promote extension of lifespan and initiate the creation of human life [17,23,39,65,66].     

Organismal exposure to beneficial levels of stress may also play a critical role in evolution. As first noted by Charles Darwin, evolution is driven by natural selection, a process characterized by environmentally-induced phenotypic changes that may lead to inheritable survival and reproductive advantages [67]. From “On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life”, Darwin explained that “if there be, owing to the high geometrical powers of increase of each species, at some age, season, or year, a severe struggle for life, and this certainly cannot be disputed;……But if variations useful to any organic being do occur, assuredly individuals thus characterised will have the best chance of being preserved in the struggle for life;” [67].  This “struggle for life” Darwin spoke of is embodied by selective pressures which may be abiotic (i.e. light, wind, temperature, etc.) or biotic (predation, disease, competition, etc.) [68,69]. As alluded to above, such selective pressures are indeed sources of cellular stress, sensed by both prokaryotes and eukaryotes, that induce beneficial responses (at appropriate levels), leading to the acquisition of phenotypes conducive for continued survival. Both biotic (e.g. infection) and abiotic (e.g. heat) stressors/selective pressures activate AMPK (which is evolutionarily conserved among eukaryotes) in human cells [70,71]. A phenomenon often cited as an example of natural selection on a readily observable timescale is the development of bacterial resistance to antibiotics, resulting in problematic mutant strains that may be life-threatening for some individuals (i.e. the elderly and immunocompromised) [72]. Intriguingly, lethal levels of bactericidal antibiotics have been shown to kill microorganisms via the induction of ROS, sub-lethal levels of bactericidal antibiotics however increase mutagenesis and bacterial resistance via induction of lower levels of ROS, and heat as well as nutritional stress increase bacterial resistance to antibiotics, providing compelling evidence that continuous exposure to low levels of stress likely plays a significant role in natural selection and evolution [73-75].

Moreover, in addition to being created by stress, gravity likely also functions as a cellular stressor/selective pressure that has influenced the development of organisms on Earth since the emergence of the very first lifeform. Gravity exerts its effects on living organisms via the application of force, which is experienced by human cells in the form of mechanical loading or stress [76]. The application of force or a mechanical load has recently been shown to activate AMPK and simulated microgravity (i.e. hind limb unloading in mice) significantly decreases AMPK activation [77,78]. Spaceflight also inhibits the activation of T cells (immune cells essential for adaptive immunity), whereas the application of force and AMPK activation promote T cell activation [79-81]. Interestingly, spaceflight has recently been shown to decrease the levels of the master antioxidant transcription factor Nrf2 and the heat shock-inducible protein HSP90a but increase the levels of the growth-promoting kinase mTOR in mice [82]. AMPK however inhibits mTOR but increases the phosphorylation, nuclear retention, and transcriptional activity of Nrf2 [57,83,84]. Also, HSP90 interacts with and maintains AMPK activity and HSP90 is necessary for progesterone-induced human sperm acrosome reaction [85,86]. Interestingly, rapamycin, an immunosuppressant produced by Streptomyces hygroscopicus, extends lifespan in genetically heterogeneous mice, activates AMPK in vivo in normal aged mice, and increases human sperm motility [42,87,88]. Simulated microgravity via the use of NASA-designed rotating wall vessels (RWVs) however drastically reduces rapamycin production (~90%) whereas the antibiotic gentamycin increases rapamycin production by Streptomyces hygroscopicus, providing further evidence that cellular stress, in the form of mechanical loading induced by gravity, is essential for development, function, and survival of Earth-bound organisms [89,90].

In conclusion, the link between Einstein’s General Theory of Relativity, antibiotic production by bacteria, plant-derived compounds with therapeutic value (e.g. metformin, etc.), and the creation of all human life is stress, or, in the words of Nietzsche: “That which does not kill us, makes us stronger.”

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