#74. Protein Batteries and Protein Misfolding Diseases [biochemistry]

CH

Red, theory; black, fact

Disclaimer 

If you are a PD or AD patient or at risk and are seeking a cure outside the medical mainstream, this is not for you. This is written for researchers. 

Inside Alzheimer’s and Parkinson’s 

The commonest protein misfolding disease, Alzheimer disease, features an accumulation of insoluble proteins as amyloid plaques that damage neurons and lead to dementia and death. 

The amyloid precipitates from a solution of amyloid beta protein, which forms by a two-step proteolysis of amyloid precursor protein (APP), an integral membrane protein of neurons.

APP is thought to play a role in the initial stage of synaptic plasticity and contains a copper binding site. 

What is the Power Source Driving Precipitation?

Oxidation of the coordinated copper upon insertion of nascent APP in the plasma membrane could shift the coordination geometry of the copper ion from planar-triangular to pyramidal, with huge changes in the preferred bond angles. If the coordinating protein cannot accommodate these changes without input of activation energy, the result would be a “protein battery”: a protein carrying a metastable “charge” of conformational strain energy. A set mousetrap would be a familiar example of this. 

Role of the Power Source in the Healthy Brain

The local availability of this energy cache may be necessary to allow brief pre- and post-synaptic electrical coincidences to be rapidly captured as preliminary synaptic morphological changes. The calcium-binding site next to the copper binding site (growth factor-like domain) may be the electric field sensor. Coincidence detection would involve same-molecule binding of APP molecules on opposite sides of the synaptic cleft, triggered by propagation of unleashed conformational changes from the copper site into the main extracellular domain, called the heparan-binding domain. (Better known parts of the coincidence detecting system are the NMDA receptor and CAM kinase II).

How the Power Source Goes Wrong

Protein misfolding diseases of the brain may be powered by a short circuiting of the APP energy caches, or analogous caches in proteins subserving other functions. One of those other functions could be replenishing the supply of docked synaptic vesicles in response to a sudden increase in the average neuron firing rate. In that case, the relevant battery protein would be alpha synuclein, which is implicated in Parkinson disease. Local energy caches are also present in humanly engineered electronic circuits, where they are called decoupling capacitors.

Loss of Control of the Stored Energy

 The secretases implicated in Alzheimer disease etiology would serve to degrade the discharged APP molecules. Secretase alpha would act rapidly to clear action-potential-discharged APP that did not make a cross link, and secretase beta would act slowly to clear cross links. Secretase gamma completes the cleavage in both cases. Secretase alpha would have a recognition site for discharged APPs and secretase beta would have an allosteric recognition site for cross links. Secretase beta action releases amyloid beta, the battery part of APP. The stored energy in amyloid beta would drive the polymerization process that leads to amyloid formation. This energy release would involve a conformational change, consistent with the finding that amyloid protein is misfolded. The conformational change could expose hydrophobic residues on the surface of the protein, an energy-requiring step that could lead directly to precipitation due to hydrophobic bonding among the amyloid beta molecules.

This action is easier to imagine for the central hydrophobic domain of alpha synuclein, the immediate effect being not precipitation but pulling two arbitrary ligands on different alpha synuclein molecules into closer proximity for a faster reaction between them. The trigger appears to be phosphorylation of alpha synuclein, not electric field change.

Closing a Fatal Positive Feedback Loop

By mischance, the soluble amyloid beta oligomers that form as intermediates along the amyloid-generating pathway are able to spoof APP cross links, thereby driving ectopic secretase beta activity and closing a feedback loop. This feedback leads to an out-of-control production of amyloid beta that produces Alzheimer disease.

#73. The Self-exciting Small-world Network in Behavioral States and Disease [Neuroscience, Biochemistry]

NE   CH

Red, theory; black, fact

Seen at the Red Roots Trading Co. 

Disclaimer

If you are a cancer patient or at risk and are seeking a cure outside the medical mainstream, this is not for you; this post is written for researchers.

Conventional Thinking on the Nature of Cancer

The refractoriness of cancer (its treatment resistance) is thought by a few authors I read forty years ago to be due to a kind of in-body evolutionary process made possible by the high mutation rate characteristic of these cells. The anticancer drugs we apply to kill the cancer exert an evolutionary selection pressure on the individualistic cancer cells, killing most of them but leaving a residue of accidentally resistant cells that happen to have mutations conferring resistance. These resistant cells then grow back the cancer in a relapse, even harder to kill than before. And so it goes through treatment after treatment until the patient is dead.

But what if that’s wrong?

An Alternative Explanation of Cancer Refractoriness

This seems possible in terms of a “cancer state” that is sustained by re-entrant (circulating) metabolic signaling pathways that form a small-world network (SWN). Curing the cancer requires extinguishing the reentrant activity, but this is difficult because of the robustness of the SWN. If one node in the network is pharmacologically ablated, the signaling can always flow around it by alternative pathways through the network. Thus, robustness becomes refractoriness.

Hub Nodes

The robustness of SWNs depends on their hub nodes—nodes with an unusually large number of connections. The state theory of cancer articulated here therefore directs us to pharmacologically target the hub nodes for greatest therapeutic efficacy. However, a practical therapy also requires selectivity. If we make the leap to assuming that all cellular actions involve entering and leaving states, that all states are identifiable with particular re-entrant SWNs, and that due to the parsimony of evolution, there is much overlap among SWNs and sharing of nodes, it seems possible that the set of hub nodes of a particular SWN can be used as a biochemical address for that SWN, leading to the desired selectivity. The other overlapping SWNs in the treated cell can survive the loss of only one or two hub nodes due to treatment, but not the targeted SWN, which loses all of them.

Problems with the Facts

However, these ideas predict zero response to a single drug, not a large but temporary response. Progress in resolving this will involve consideration of state-trait relationships. For example, a predilection for entering a particular state could be a genetically determined trait, and some states could exist that suppress DNA repair, leading to increasing genetic diversity. Lack of selectivity of anticancer drugs could also be a factor, so that the same drug could delete multiple hub nodes but not all of them.

SWNs in the Brain

Behavioral states such as aggression and siege mentality (the foibles of, respectively, capitalism and communism) also show refractoriness that may have the same cause. In these cases, some likely hub nodes are the neuromodulatory cell groups of the brainstem. An example is the locus ceruleus (LC), which distributes noradrenalin widely in the brain. (Noradrenalin is also the postganglionic transmitter of most of the sympathetic nervous system.) The existence of disciplines such as meditation suggests that some of the SWNs incorporating the LC also incorporate hub nodes in cerebral regions accessible to consciousness, probably including the brain’s language areas. More visceral hub nodes such as blood sugar level are probably also included.

Ancient Foreshadowings of this Theory

The need to treat multiple hub nodes simultaneously to extinguish maladaptive reentrant signaling may have been stated before, but in proto-scientific terms:

“Put on the whole armour of God…”

Saint Paul

#72. The Restricted Weathering Theory of Abiogenesis [chemistry, evolution]

EV   CH

Red, theory; black, fact

Urban lichen in the original ecological niche

Starting at the Start

When the early Earth, which was initially molten, had cooled sufficiently to acquire a solid crust and allow liquid water to accumulate on the surface, the formation of the oceans presumably began.

The Original Energy Source: Weathering

Seawater forms from steam outgassing from volcanic vents, which simultaneously emit acid gasses such as hydrochloric acid. Therefore, the first rain would have been highly acidic. In the normal course of events, volcanic rain falls on surface rocks that contain sufficient alkalinity to completely neutralize the acid, contributing cations such as sodium in the process and producing salt water. 

Key Original Difference

However, shortly after the formation of the Earth’s crust, the surface rocks may have been mostly encapsulated in carbonaceous pyrolysis residues originating from carbon-bearing gasses in the atmosphere. How is the acid rain supposed to get to the rocks?

The Germ of an Idea

I postulate that sometimes it did, and sometimes it didn’t, leading to a scenario of nascent crust covered in interconnected puddles in which a broad range of pHs were simultaneously represented. At the connecting points, a pH gradient would have existed, which recalls the pH gradient across the mitochondrial membrane that powers ATP synthesis. So, that's basically my angle.

Second-iteration Theory

More simply, a lump of lava coated in a capsule of pyrolysis residue and immersed in acid rainwater will have a proton gradient across the capsule with the correct direction to model the inner mitochondrial membrane with its enclosed matrix.

The carbon-bearing gasses in the atmosphere would have been methane, carbon monoxide, and the result of their combination with water (formaldehyde),  nitrogen (cyanide and cyanogen), and sulfur (DMSO, only plausible), all triggered by solar ultraviolet. This suggests that the pyrolysis residues will contain sulfur, oxygen, and nitrogen heteroatoms, as does coal. An imaginary pore through the capsule will be lined with such heteroatoms, which are candidates for playing the role of the arginine, lysine, aspartate, and glutamate residues in the ATP synthase catalytic site. Protonation-deprotonation reactions would be available for powering the formation of polyphosphate (a plausible ATP precursor) from orthophosphate. The conformational changes so important in the modern ATP synthase do not appear to be available in this primordial system, so we need to demonstrate the presence of an equivalent. Conceivably, the phosphorus-rich chemicals diffuse up and down in the pore, producing proton transport as they do so that is linked to phosphate condensation reactions. Judging by the modern ATP synthase, coordination of phosphate to magnesium ions may also be part of the mechanism. Mafic rocks such as basalt, a likely early surface rock, are rich in magnesium.

Third-iteration Theory

The flux of acid through the pore will dissolve orthophosphate out of some minerals in the rock such as apatite. If we suppose that the pore is lined with carboxylic acid groups modelling glutamate and aspartate side chains, then at some depth in the pore the pH in the pH gradient will equal the pKa of the acid, and the acid groups will spend half their time protonated and half ionized, resulting in general acid-base catalysis in a narrow zone in the pore. Magnesium-complexed orthophosphate will be catalytically converted to an equilibrium mixture containing some pyrophosphate in this zone and then proceed to diffuse out the exterior opening of the pore before it can be converted back. As a result, the condensing agent pyrophosphate will be available in the early oceans for catalyzing the formation of organic macromolecules such as early proteins and nucleic acids, which are forerunners of important building blocks of modern life forms. 

The efficiency of the pyrophosphate synthesis would be enhanced by a high phosphate concentration, which would be due to the restricted, under-film spaces in which the weathering processes were occurring.

Fourth-iteration Theory

The gradual expansion of the under-film weathered pockets eventually undermines the local pyrolysis film, causing a flake to detach. The remaining rock surface will be largely coated in the first organic polymers created by condensing agents at low temperature. The process then repeats, leading to successive generations of biofilm creation and detachment. At this point, an evolution-like biofilm selection process can be postulated. Polymer chain elongation from outer layer to inner layer would be likely. The outermost sub-layer will be at acidic pHs, which will cleave the outermost polymer into fragments. Some of these fragments will diffuse inward to the polymerization zone and influence events there, leading to a crude form of heredity. The programmed insertion of abscission points would have been an early development, and these may have prefigured the base pairing of modern polynucleotides. The sand produced as a byproduct of rock weathering will end up enmeshed in the polymer and will come off at abscission. 

Fifth-iteration Theory

Could all this happen inside narrow fissures in the rock? Not likely, because the pH gradient would be present only at the opening, a much smaller niche than the area under a surface film. However, the in-fissure microenvironment would be at alkaline pHs, where alkali-requiring reactions would be possible. An example would be the formose synthesis of C5 and C6 sugars from formaldehyde. A C5 sugar, ribose, is an essential ingredient in RNA synthesis. Fissures opening into the under-film spaces could supply sugars to the polymerization zone.

#71. A Cosmological Setting for a GR-QM Unification [physics]

PH

Red, theory; black, fact

To unify these points most simply, you have to go outside the region of points.

“The Sphere,” campus of the National Research Council, Ottawa 

Figure 1. The expanding 5-ball

Figure 2. A wave packet

The Big Picture

The spacetime of general relativity (GR) is here considered to be an expanding 4D hyperball (4-ball) on the surface of an expanding 5D hyperball (5-ball). The latter is surrounded by subatomic-sized 5-balls ("paramorfs") that can fuse with the big, nearby 5-ball, which is the mechanism by which the latter enlarges. (See Fig. 1). Technically, a “sphere” is just a surface, with a dimensionality one less than the embedding space. I use “ball” here to refer to the embedding space dimensionality.

The Little Picture

Each fusion event sends out a ripple on the surface of the big 5-ball that travels at the speed of light in vacuum. A sequence of fusions happening in the correct order causes the ripples to add up to a shock wave at some point. At the maximum of the shock wave, the surface of the 5-ball is thrown out especially far into the surrounding emulsion of paramorfs, where it makes contact with yet another paramorf, resulting in yet another fusion event and another ripple, which has the correct phase to add to the shock wave. The result is a self-sustaining cycle that leads to persistence and thus observable particle-like phenomena. (See Fig. 2). The shock-wave speed, or “group velocity” will be somewhat less than the speed of light, or “phase velocity” so that ripples will be bleeding out the front continuously. This feature of the theory was introduced to prevent the amplitude of the particle from growing without limit. If the particle is travelling exactly along the time dimension, this bleed will be into the future direction. Therefore, “the future” will have a limited physical reality.

This mechanism was inspired by the superradiant nitrogen laser, in which nitrogen is excited by a zone of corona discharge travelling at nearly the speed of light. This mechanism is also based on Born's rule of quantum mechanics (QM). If wave curvature rather than displacement amplitude determines paramorf fusion probability, then we get something even closer to Born’s rule, which states that the square of the wave function is proportional to the probability of observing a particle. The curvature of a sine wave is not its square, but the resemblance is striking. Perhaps an experimental verification of Born’s rule with unprecedented accuracy is warranted to distinguish the two theories. 

Making It Messier, Like Reality

The big 5-ball may be filled with an emulsion of yin paramorfs in a continuous yang phase, as well as being surrounded by an emulsion of yang paramorfs in a continuous yin phase. Droplets of yin space could get injected into the interior as a side effect after each yang paramorf fusion event. This would explain why curvature alone dictates fusion probability: a concavity reaching interior yin paramorfs is as effective as a convexity reaching exterior yang paramorfs, and no depletion zone will develop over time. Yin and yang space are terms coined in a previous post, “The Checkered Universe.”

The Inflationary Era

Particle formation is entropically disfavored (requires a precise configuration unlikely to arise by chance) and thus only happens when paramorf fusions are frequent due causes other than the presence of particles. Postulating that spontaneous fusions are more frequent when the curvature of the 5-ball is greater, spontaneous fusions will be abundant when the growing 5-ball is still tiny and thus intensely curved. This would be seen in our 4-ball as the inflationary era of the Big Bang. 

A problem is that the paramorfs themselves are the most intensely curved elements in this system. Possibly, a binary paramorf fusion event releases so much energy in such a confined space that the fusion product immediately splits apart, resulting in no net effect overall. Analogously, in gas-phase chemistry, some two-molecule reactions will not go without a third “collision partner” to carry off some of the energy released. 

Time

The surface of our 4-ball would be formed by the stable particles radiating out of our local inflationary zone on the 5-ball into newly-created, blank 4-surface (see Figure 1). This radiation would define the post-inflationary era. Our time dimension would be one of the radii. These particles propagate in time the given, as opposed to time the clock reading. The position of the particle along its track is the clock reading.

Mechanistic Variations

The illustrated mechanism of particle creation (see Figure 2) is periodic-deterministic and may account for photons and leptons. The corresponding chaotic mechanism may account for baryons, and the corresponding probabilistic mechanism may account for dark matter. The close relationship we see today between protons and electrons could have been due to their relationship during the inflationary era; the vicinity of one could have served as an incubator for the other.

Consistency with Relativity

The multitude of expanding spacetime ripples predicted to be around any massive object would comprise the spacetime curvature referred to by the Einstein tensor of the relativistic field equations. The asymmetry of the wave packet that leads to the shock wave accounts for momentum. According to special Relativity, mass-equivalent energy is just the spacetime component of the momentum along the time axis.

A Geometric Underpinning for this Theory

Fixing radius = 1, the 5-ball has the greatest volume of any ball dimensionality. (See the Wiki on “n-sphere”) Thus, this dimensionality could have been forced by some principle of minimizing the radius-to-volume ratio, call it a compaction principle (in a physical, not topological sense), the existence of which is already implied by the assumed ball shape. We cannot invoke gravity here to produce compaction because gravity emerges at a higher level of description than this. A surface tension-like effect related to the permittivity of free space may serve, which is already implied by invoking ripples on the surface. However, mention of ripples implies that the governing differential equation has oscillatory solutions, which seems to also require a medium with inertia, which may be related to the permeability of free space.

Beyond Geometry

If an overarching process of yin-yang separation existed, which would explain why all observations are ultimately observations of contrasts, this process would arguably have a smoothing effect on any resulting interfaces. Such smoothing would suggest surface tension when considered spatially and inertia when considered temporally. I suspect that electromagnetism and matter waves emerge from these simple ingredients. Conservation of paramorf volume would enter the mathematical proof as a constraint.

A limitation of this theory is that it does not explain the assumed presence of discrete, ancient inflationary zones on the surface of the 5-ball.

A Sixth Dimension Is Necessary

Close inspection of the volume versus dimensionality curve for n-balls of radius 1 suggests that maximum volume occurs at a fractional dimensionality somewhat above 5, which looks to be about five and a quarter. Under the compaction principle, this circumstance would lead to a squashed (oblate) 6-ball about one-quarter as thick as it is wide, with greatest curvature at the equator. (Here I am making an analogy with the Earth’s surface, which is an oblate spheroid.) This uneven distribution of curvature would result in the equatorial region losing its inflationary status later than at the poles, suggesting that the universal equatorial region spawned all the particles we can now see during the late inflationary era and that our familiar 3-space corresponds to a line of latitude on the oblate 6-ball travelling steadily toward a pole. 

This scenario allows the existence of ancient, dilute matter of non-equatorial origin coexisting with our 3-space. This ancient, dilute matter could account for cosmic rays and some of the diffuse cosmic gamma glow. Some of these ancient particles would by chance approach us in our future light cones and would therefore interact with our 3-space as antimatter. The resulting annihilation events would produce gamma rays and neutrinos. Those particles that escape annihilation could potentially re-emerge from our spacetime in our past light cones and at a different point, becoming matter cosmic rays. Cosmic particles following spacelike trajectories may not interact strongly with us, like two waves crossing at right angles, but Born's rule predicts some interaction.

A Second Limitation of this Theory

Relativity theory denies the existence of an absolute frame of reference, which I have just re-introduced in the form of the surface of a large ball. Perhaps this limitation can be addressed by showing that the concept of no absolute frame of reference can be replaced with the concept of space-tilted matter, in which the lengths of meter sticks change due to a tilt of the structure of Figure 2 so that propagation is no longer purely in time, but now has a component in space, and the length change must be to a degree necessary to guarantee the null result of the Michelson--Morley experiment.

High Dimensionality

The surface of a 6-ball is a 5-dimensional space. Particle propagation on this surface uses up one of these dimensions, turning it into time. However, the resulting spacetime has four dimensions of space and we see only three. What happened to the other one? Most likely it was largely suppressed by black hole formation shortly after the inflationary era. Black hole formation should be very facile in four spatial dimensions because gravitational orbits are unstable and radiative cooling is relatively efficient. This places us on the event horizon of one of these 4-D black holes and suggests that the event horizon actually is the membrane it seems to be in some theoretical studies. Considered geometrically, the event horizon is a surface and will therefore have a dimensionality one less than that of the bulk. Life on this surface will therefore be three dimensional.

 

In addition, this theory clearly provides a multiverse, because there can be many such hyper black holes, thereby answering the fine-tuning-for-life problem that inspired the anthropic principle.

String theory posits that a particle is a one-dimensional vibrating string embedded in three dimensions. However, my theory posits that a particle is a three dimensional system embedded in six dimensions. We are situated in a privileged location in 6-space in which three of these dimensions have an inward and outward direction. An analogous point in 3-space would be the corner of a cube. The wave component of particles would oscillate along a vector that can rotate in a wholly extradimensional plane, and with an axis of rotation perpendicular to all three dimensions of space, possibly coinciding with time. This would be the spin of the particle. In the cube analogy, one of the edges parallel to the time dimension is spiraling. If the vector rotates in a plane contained within 3-space, this would be the circular polarization of light. A baryon might consist of a trio of fermions, one on each of the three edges meeting at the cube corner and each offset a short distance back from the corner. This arrangement might create a tiny, semi-closed chamber where ripples are concentrated and thus intensified. This, in turn, would enhance paramorf capture, which would dynamically stabilize the structure.

See Figure 3. In this figure, the instantaneous structure resembles one edge of a cube merging with a surface. The line between points A may function as a closed chamber for fusion ripples because of the right-angle relationships at each end, leading to intensified shock waves inside and intensified paramorf fusion. This, in turn, dynamically maintains the geometry shown.

Etymology: "warped spacetime," Greek: paramorfoménos chorochrónos, thus: "paramorf."

Figure 3. A hyper-black hole progressing across the surface of the big 6-ball. The three spatial dimensions of relativity theory have been suppressed for clarity and are represented by points A; t is time.

Tilting at a Conceptual Unification

In general, spacetime structures would tend to evolve to greater efficiency in paramorf capture, and deviations from these structures will appear to be opposed by forces. This can be cited as a general principle in exploring the present theory.

For example, two fermions could capture paramorfs cooperatively: capture by one triggers an expanding ripple that reaches the other and triggers its own capture. This second capture then sends a ripple back to the first fermion, where it triggers a third capture, and so on. This duetting action is formally like light bouncing back and forth between parallel mirrors, as in the light-clock thought experiment of special Relativity, and recalling the Michelson—Morley interferometer. If duetting efficiency maintains the length of meter sticks, we have the beginnings of the long-sought explanation of the null result of the Michelson—Morley experiment in terms that allow the existence of a medium for the wave aspect of particles.

Velocity in space relative to the medium upsets the spatial relationships necessary for efficient duetting, triggering a compensatory reorganization of the spacetime structure to re-optimize paramorf capture efficiency, by the general principle enunciated above. This leads to the Fitzgerald contraction, one of the two basic effects previously explained in terms of special Relativity. The Fitzgerald contraction was recently proven to be directly unobservable; rather, a rotation of the front of the object away from the line of travel is observed, as predicted by Penrose and Tyrell. https://doi.org/10.1038/s42005-025-02003-6. If this rotation looks the same from all observation angles (elevations), it would have to be a rotation into extradimensional space, which the present theory allows, and it is easy to visualize how that would maintain the efficiency of duetting at high velocity. Therefore, close study of the relativistic rotation effect may provide a window on extradimensional space.

The other basic relativistic effect is time dilation; if fermions are always literally travelling along a time dimension as postulated here in connection with the space-tilted matter concept, a greater velocity along any spatial direction must come at the expense of a lesser velocity along the time dimension, leading to time dilation.

Synchronization and anti-synchronization of fusion events between adjacent particles could account for the narrowness of the time slice we seem to be living in.

Duetting could account for attractive forces between fermions and duetting with destructive interference could account for repulsive forces. A difficulty is that the simple ripple model is one-sided whereas destructive interference assumes sinusoidal disturbances, which are two-sided. This could be remedied by assuming that the ripples have profiles like wavelets or the Laplacian of the Gaussian.

At the Limit of this Vision

Paramorf-ripple dynamics looks remarkably biological, featuring elementary processes that recall feeding and natural selection. Their cosmological setting cannot be the end of the story, however, because one naturally wonders where the entire ensemble of yin and yang space came from and why it has a bipartite nature. To answer these questions, it may be necessary to conceive an elemental version of the ultimate power of living things: reproduction. The ineffably great multiplicity of things demands an explanation.

Questions Arising 

• Do we need a new representation system to tackle the question of ultimate origins? 
• Do we merely need to shift from visual to verbal? 
• Is the concept of differentiation valuable here? For example, primordial undifferentiated space and time, primordial undifferentiated time and causation, or primordial undifferentiated somethingness and nothingness. 
• Is entropy increase the ultimate source of all differentiation? 
• Is the concept of primordial fluctuations valuable here? For example, should I proceed as I did in the abiogenesis post, from vacuum fluctuation to persistence by self-repair to growth to reproduction? 
• What is the effect of a vacuum fluctuation in the background of a previous fluctuation?
• Is circularity a key concept here? 
• Is positing an ultra-simplified version of something well known in other disciplines, a kind of consilience, a useful operation? 
• Is the concept of a primordial less-structured space valuable? For example, a topological space is less structured than a Euclidean space. 
• Is the strategy of bringing the observer into the system under study valuable here?
• The further back I go, the fewer the raw materials, but the fewer the constraints. How do I keep from losing my way?

Snail universe beside the Rideau canal. There may be perspectives in which what we consider our own universe looks no grander than this.

Zen weeds in the Rideau Canal. No explanation.

#70. How the Cerebellum May Adjust the Gains of Reflexes [neuroscience]

NE

Red, theory; black, fact

The cerebellum is a part of the brain involved in ensuring accuracy in the rate, range, and force of movements and is well known for its regular matrix-like structure and the many theories it has spawned. I myself spent years working on one such theory in a basement, without much to show for it. The present theory occurred to me decades later on the way home from a conference on brain-mind relationships at which many stimulating posters were presented.

Background on the cerebellum

The sensory inputs to the cerebellum are the mossy fibers, which drive the granule cells of the cerebellar cortex, whose axons are the parallel fibers. The spatial arrangement of the parallel fibers suggests a bundle of raw spaghetti or the bristles of a paint brush. These synapse on Purkinje cells at synapses that are probably plastic and thus capable of storing information. The Purkinje (pur-kin-gee) cells are the output cells of the cerebellar cortex. Thus, the synaptic inputs to these cells are a kind of watershed at which stimulus data becomes response data. The granule-cell axons are T-shaped: one arm of the T goes medial (toward the midplane of the body) and the other arm goes lateral (the opposite). Both arms are called parallel fibers. Parallel fibers are noteworthy for not being myelinated; the progress of nerve impulses through them is therefore steady and not by jumps. The parallel fibers thus resemble a tapped delay line, and Desmond and Moore proposed this in 1988.

The space-time graph of one granule-cell impulse entering the parallel-fiber array is thus V-shaped, and the omnibus graph is a lattice, or trellis, of intersecting Vs.

The cerebellar cortex is also innervated by climbing fibers, which are the axons of neurons in the inferior olive of the brainstem. These carry motion error signals and play a teacher role, teaching the Purkinje cells to avoid the error in future. Many error signals over time install specifications for physical performances in the cerebellar cortex. The inferior olivary neurons are all electrically connected by gap junctions, which allows rhythmic waves of excitation to roll through the entire structure. The climbing fibers only fire on the crests of these waves. Thus, the spacetime view of the cortical activity features climbing fiber impulses that cluster into diagonal bands. I am not sure what all this adds up to, but what would be cute?

A space-time theory

Cute would be to have the climbing fiber diagonals parallel to half of the parallel-fiber diagonals and partly coinciding with the half with the same slope. Two distinct motor programs could therefore be stored in the same cortex depending on the direction of travel of the olivary waves. This makes sense, because each action you make has to be undone later, but not necessarily at the same speed or force. The same region of cortex might therefore store an action and it’s recovery.

The delay-line theory revisited

As the parallel-fiber impulses roll along, they pass various Purkinje cells in order. If the response of a given Purkinje cell to the parallel-fiber action potential is either to fire or not fire one action potential, then the timing of delivery of inhibition to the deep cerebellar neurons could be controlled very precisely by the delay-line effect. (The Purkinje cells are inhibitory.) The output of the cerebellum comes from relatively small structures called the deep cerebellar nuclei, and there is a great convergence of Purkinje-cell axons on them, which are individually connected by powerful multiple synapses. If the inhibition serves to curtail a burst of action potentials in the deep-nucleus neuron triggered by a mossy-fiber collateral, then the number of action potentials in the burst could be accurately controlled. Therefore, the gain of a single-impulse reflex loop passing through the deep cerebellar nucleus could be accurately controlled. Accuracy in gains would plausibly be observed as accuracy in the rate, range, and force of movements, thus explaining how the cerebellum contributes to the control of movement. (Accuracy in the ranges of ballistic motions may depend on the accuracy of a ratio of gains in the reflexes ending in agonist vs. antagonist muscles.)

Control of the learning process

If a Purkinje cell fires too soon, the burst in the deep-nucleus neuron will be curtailed too soon, and the gain of the reflex loop will therefore be too low. The firing of the Purkinje cell will also disinhibit a spot in the inferior olive due to inhibitory feedback from the deep nucleus to the olive. I conjecture that if a movement error is subsequently detected somewhere in the brain, this results in a burst of synaptic release of some monoamine neuromodulator into the inferior olive, which potentiates the firing of any recently-disinhibited olivary cell. On the next repetition of the faulty reflex, that olivary cell reliably fires, causing long-term depression of concurrently active parallel fiber synapses. Thus, the erroneous Purkinje cell firing is not repeated. However, if the firing of some other Purkinje cell hits the sweet spot, this success is detected somewhere in the brain and relayed via monoamine inputs to the cerebellar cortex where the signal potentiates the recently-active parallel-fiber synapse responsible, making the postsynaptic Purkinje cell more likely to fire in the same context in future. Purkinje cell firings that are too late are of lesser concern, because their effect on the deep nucleus neuron is censored by prior inhibition. Such post-optimum firings occurring early in learning will be mistaken for the optimum and thus consolidated, but these consolidations can be allowed to accumulate randomly until the optimum is hit.

Role of other motor structures

The Laplace transform was previously considered in this blog to be a neural code, and its output is a complex number giving both gain and phase information. To convert a Laplace transform stored as poles (points where gain goes to infinity) in the cerebral cortex into actionable time-domain motor instructions, the eigenfunctions corresponding to the poles, which may be implemented by damped spinal rhythm generators, must be combined with gains and phases. If the gains are stored in the cerebellum as postulated above, where do the phases come from? The most likely source appears to be the basal ganglia. These structures are here postulated to comprise a vast array of delay elements along the lines of 555 timer chips. However, a delay is not a phase unless it is scaled to the period of an oscillation. This implies that each oscillation frequency maps in the basal ganglia to an array of time delays, of which none are longer than the period. These time delays would be applied individually to each cycle of an oscillation. Such an operation would be simplified if each cycle of the oscillation were represented schematically by one action potential.

Photo by Robina Weermeijer on Unsplash

#69. Role of Personalities in the Human Swarm Intelligence [population]

PO

Red, theory; black, fact

Each of the Big Five personality traits may be a dimension along which people differ in some socially important behavioral threshold. These are, respectively: openness > uptake of innovations; conscientiousness > uptake of taboos; extraversion >  committing to collectivism*; agreeableness (-) > becoming militant; neuroticism > engaging in/submitting to persecution. The personality trait is written on the left of the ">" and the putatively impacted social threshold is on the right.

These threshold spectra may enable social shifts that are noise-resistant, sensitive to triggers, and rapid. Noise resistance and sensitivity together are called good “receiver operating characteristics,” a concept often used in the scientific literature.

A metaphor that suggests itself is lighting a camp fire. The spark is first applied to the tinder. Ignition of the tinder ignites the kindling. Ignition of the kindling ignites the small sticks. Ignition of the small sticks ignites the big sticks, and everything is consumed.

Orderly fire-starting appears to require a spectrum of thresholds for ignition in the fuel, as may orderly social shifts. To further extend the metaphor, note that the fuel must be dry (i.e., situational factors must be permissive).

Social novelties may spread upward to higher-threshold social strata by meme propagation reinforced by emotional contagion. The emotional energy necessary for emotional contagion would come from the individual’s interaction with the novelty, which would feature a positive feedback.

The governing neuromodulators of personality may be as follows:

• Acetylcholine-Openness
• Noradrenalin-Neuroticism 
• Serotonin-Agreeableness 
• Histamine-Conscienciousness
• Dopamine-Extraversion 

Our capacities for all of the enumerated social shifts were selected in evolution and most can be assumed to be still adaptive when correctly triggered. In today’s world, shifts to persecution are probably the least likely to still be adaptive, and could be a holdover from our Homo erectus stage. Persecution leads to refugee production, and refugee production could have been the reason that guy was such a great disperser.

As the geologists say, “The present is the key to the past.”

* A possible anti-invasion adaptation and predictable from geography. The sociological term for the corresponding failure mode may be siege mentality.

#68. A Tripartite Genetic Code [genetics]

GE

Red, theory; black, fact

The filamentous alga Cladophora.

There are three genetic codes, not one. Conventional thinking holds that there is just one code, which encodes the amino acid sequence of proteins into DNA. Here are the two new ones:

A morphology code for the multicellular level

In the context of a growing embryo, control of the orientation of mitosis is arguably at the origin of organ and body morphology. For example, all cell division planes parallel will result in a filamentous organism like Cladophora. Planes free to vary in only one angle (azimuth or elevation) will produce a sheet of cells, a common element in vertebrate embryology. Programmed variation in both angles can produce a complex 3D morphology like the vertebrate skeleton. Thus we begin to see a genetic code for morphology, distinct from the classical genetic code that specifies amino acid sequences. 

The nucleus is tethered by cytoskeletal elements such as lamin, nesprin, actin, and tubulin to focal adhesions on the cell membrane, non-rotatably, so that all angle information can be referred to the previous mitotic orientation.

Observational Support 

The nucleus is usually spherical or ovoid and is about ten times more rigid than the surrounding cytoplasm, features which may be related to the demands of the morphology read-out process. Consistent with this, blood is a tissue without a morphology, and the nucleated cells of the blood have nuclei that are mostly irregular and lobate. The lymphocytes found in the blood have round nuclei, however, but these cells commonly form aggregates that can be considered to possess a simple morphology.

A morphology code for the single-cell level in cells with nuclei

A third genetic code would be a code for single-cell morphology, and cell morphology can be very elaborate, especially in neurons. This will probably involve storing information about cytoskeleton morphology in DNA. Neurons express especially many long noncoding RNAs (lncRNA), so I suggest that these transcripts can carry morphological information about cytoskeletal elements. This information could be read out by using the lncRNA as a template on which to assemble the cytoskeletal element, then removing the template by enzymic hydrolysis or by some enzyme analogous to a helicase. Greater efficiencies could be achieved by introducing some analog of transfer RNAs. LncRNAs are already implicated in transcriptional regulation, and this might be done indirectly by an action on the protein scaffolding of the chromatin. Moreover, as predicted, lncRNAs are abundant in cytoplasm as well as in the nucleus, and the cytoplasm contains the most conspicuous cytoskeletal structures. The template idea is similar to but goes beyond the already-established idea that lncRNAs act as scaffolds for ribonucleoprotein complexes. Since cytoskeletal elements are made from monomers of few kinds, we would expect the template to be highly repetitious, and lncRNAs are decidedly repetitious. Indeed, transposons and tandem repeats are thought to drive lncRNA evolution. See https://doi.org/10.1038/s41598-018-23334-1, in Results, subsection: "Repetitive sequences in lncRNAs," p. 4 in the PDF.

Why Three Codes?

The issue driving the evolution of the two additional genetic codes may be parsimony in coding (advantageously fewer and shorter protein-coding genes).

Disclaimer 

This next paragraph was written for researchers, not for patients or those at risk for cancer who may be seeking a cure outside the medical mainstream. 

Cancer Research May Be Held Back by the One-Code View

Mutations in the proposed cytoskeletal genome could be at the origin of cancer. Cancer cells will proliferate in a culture dish past the point of confluence, unlike healthy cells. If the cytoskeleton is required to sense confluence, as seems likely, a defective cytoskeleton incapable of performing this function could lead directly to uncontrolled growth and thus cancer. It is not clear how the immune system could detect a mutation like this, since no amino acid sequence is affected. Possibly, a special evolved system or reflex exists that telegraphs such mutations to the cell surface where the immune system has a chance of detecting them. The clustering of antigens on the cell surface is already known to enhance immunogenicity, so this hypothetical system may output a clustering signal on the cell surface that talks to the cytoskeletons of circulating immune-system cells. Alternatively, the immune-system cells may directly interrogate the body cells’ ability to detect confluence. For these ideas to apply to blood-borne cells such as leukocytes, the failure event would have to happen during maturation in the bone marrow while the cell is still part of a solid tissue.

YAP1 protein, which promotes cell proliferation when localized to the nucleus, may be gated through the nuclear pores by some kind of operculum attached to the lamin component of the nuclear envelope. The operculum would move down from the pore, thus unblocking it, when a region of nuclear membrane flattens in response to a localized loss of tensile forces in the cytoskeleton. The flattening causes a local excess of lamin area, which leads to buckling and delamination, which is coupled to operculum movement. A mutation that makes the operculum leaky to YAP1 when closed could lead to cancer. This mutation could be in an lncRNA that scaffolds key components of the nuclear membrane’s supporting proteins. A more subtle mechanism would be for the buckling and delamination to happen on a molecular scale and lead to a uniform regional increase in the porosity of the lamin layer, which would gate YAP1 permeation.

Loss of tissue adjacent to the cell would cause a loss of cytoskeletal tension on the nucleus not only on that side of the nucleus, but also on the side opposite. If these two slack regions directly dictate centriole placement on the next round of mitosis, then the new cell will automatically be placed to fill in the tissue hole. (This may constitute an important mechanism of wound healing and suggests a link between morphology and carcinogenesis.)

Evolutionary Considerations 

The multicellular morphology code was postulated to arise from precise control of the orientation of the plane of mitotic division. It now seems likely that this control will be implemented via bespoke cytoskeletal elements, since complex single-cell morphology and its genetic code probably preceded complex multicellular morphology in evolution. 

Mechanism of Multicellular Morphology Readout

These bespoke elements might be inserted into a cytoskeletal apparatus surrounding the nucleus that has commonalities with devices such as gimbals and armillary spheres. The centrioles are likely to be key components of this apparatus. Each centriole may create a hoop of microtubules encircling the nucleus, and the two hoops would be at right angles, like the centrioles themselves when parked outside the nucleus between cell divisions. During mitosis, in-plane revolution of one of the hoops through 180 degrees would be responsible for separating the centrioles. After this, both centrioles must be on this same hoop. Alternatively, the centrioles may move by synthesis at the new locations followed by disassembly of the old centrioles. Each hoop then forms a circular track for adjusting azimuth and elevation, respectively, relative to anchor points left over from the previous round of mitosis. The bespoke elements would lie along these tracks and function as variable-length shims. The remainder of the apparatus would translate these lengths into angles. The inner hoop would pass through two protein eyelets connected to the outer hoop and the outer hoop would pass through an eyelet connected to the anchor. The shims would fix the along-track distances between an inner eyelet and the outer eyelet and between an inner eyelet and a centriole (Fig. 1).

Figure 1. A hypothetical cytoskeletal apparatus for orienting mitosis; C, centrioles; zigzag, shims; dotted, a nuclear diameter; double line, anchor to cell membrane; EL, elevation; AZ, azimuth 

Top picture credit: Cladophora flavescens, Phycologia Britannica, William Henry Harvey, 1851.