#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.

#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.

#66. How Enhancers May Work [biochemistry]

 CH

Red, theory; black, fact

Background on Enhancers

Enhancers are stretches of DNA that, when activated by second messengers like cyclic AMP, enhance the activity of specific promoters in causing the transcription of certain genes, leading to the translation of these genes into protein. Enhancers are known for causing the post-translational modification of the histones associated with them. Typically, lysine side chains on histones are methylated, doubly methylated, triply methylated, or acetylated. Serines are phosphorylated. In general, phosphorylation condenses chromatin and acetylation expands and activates it for transcription. Methylation increases positive electric charge on the histones, acetylation decreases positive charge, and phosphorylation increases negative charge. The enhancers of a promoter are usually located far away from it measuring along the DNA strand, and can even be on different chromosomes. 

The Mystery of Enhancer–promoter Interaction

How the distant enhancer communicates with its promoter is a big mystery. The leading theory is that the enhancer goes and sticks to the promoter, and the intervening length of DNA sticks out of the resulting complex as a loop. This is the "transcription hub" theory. 

An Alternative Theory of Interaction

When activated, the multiple enhancers may cause modification of their associated histones that place the same electric charge on all of them, which is also of the same sign as the charge on the promoter region. Mutual electrostatic repulsion of all these regions then expands the chromatin around the promoter. This effect reduces the fraction of the time that RNA polymerase II at the promoter cannot move down the DNA strand because unrelated chromatin loops are in the way, like trees fallen across the railway tracks. The result is gene activation.

It Gets Bigger

This could also be the mechanism of chromatin decondensation generally, which is known to be a precondition for the expression of protein-coding genes.

Possible Sophistications

The mutual electrostatic repulsion of enhancers does not necessarily accomplish decondensation directly, but may do so indirectly, by triggering a cascade of alternating chromatin expansions and histone modifications. Furthermore, this cascade is not necessarily deterministic. 

Future Directions

These ideas predict that raising the ionic strength in the nuclear compartment, which would tend to shield charges from each other, should inhibit gene activation. This manipulation will require genetic knockout of osmolarity regulating genes.

#63. How Noncoding RNA May Work [chemistry]

 CH

Red, theory; black, fact

Back, DNA; red, long noncoding RNA; green, transcription complex. A loop closes through an RNA running from bottom to top (not shown).

No junk DNA

The junk-DNA concept is quite dead, killed by the finding that the noncoding sections (sections that do not specify functional proteins) have base-pair sequences that are highly conserved in evolution and are therefore doing something useful.

Role of long non-coding RNA

So-called junk DNA is useful because the RNA transcripts made from it are useful, serving as controllers of the transcription process itself and thus, indirectly, of protein expression. Changes in protein expression may be considered the immediate precursor of a cell's response to its environment, analogous to muscle contractions in an intact human. Small noncoding RNAs seem to be repressors of transcription and long noncoding RNAs (lncRNA) may either repress or promote. Despite the accumulation of much biochemical information, summaries of what lncRNA does seem to me unfocussed and unsatisfactory.

Background on control of gene transcription 

The classical scheme of protein expression, due to Jacob and Monod, was discovered in bacteria, in which a signal molecule from the environment (lactose in the original discovery) acts by binding to a protein to change its conformation (folding pattern). The changed protein loses the ability to bind to DNA upstream from the sequence that specifies the lactase enzyme, where it normally acts to block transcription. The changed protein then desorbs from DNA, which triggers transcription of lactase messenger RNA, which is then translated into lactase enzyme, which confers on the bacterium the ability to digest lactose. Thus, the bacterium adapts to the availability of this food source.

All this can be modelled in neurobiological terms. Clearly, it's a reflex comparable to the spinal reflexes in vertebrates. An elementary sensorium goes in and an elementary response comes out. However, vertebrates also have something higher than spinal reflexes: operations by the brain.

A neuron-inspired theory of long non-coding RNA

Noncoding RNAs may have a coordinating role: rather than relying on a set of independently acting "reflexes," eukaryotic cells may be able to sense many promoter signals at once, as a gestalt, and respond with the expression of many proteins at once, as another gestalt. An entire brain is not needed to model this process, just one neuron. The synaptic inputs to the dendrites of the neuron can model the multiple promoter activations, and the eventual output of a nerve impulse (action potential) can represent the signal to co-express a certain set of proteins, which is hard-wired to that metaphorical neuron by axon collaterals. In real neurons, action potentials are generated by a positive feedback between membrane depolarization and activation of the voltage-gated sodium channel. This positive feedback can be translated into molecular biology as a cyclic, autocatalytic pattern of lncRNA transcription, in which each lncRNA transcript in the cycle activates the enhancer (which is like a promoter) of the DNA of the next lncRNA in the cycle. The neuron model suggests that the entire cycle has a low level of baseline activity (is "constitutively active" to some extent) but the inhibitory effect of the small noncoding RNAs (analogous to what is called the rheobase current in neurons) suppresses explosive activation. However, when substantially all the promoters in the cycle are activated simultaneously, such explosive transcription occurs. The messenger RNA of the proteins to be co-expressed as the coordinated response is generated as a co-product of lncRNA hyper-transcription, and the various DNA coding regions involved do not have to be on the same chromosome.

#44. The Denervation-supersensitivity Theory of Mental Illness [neuroscience, evolution, genetics]

NE  EV  GE    

Red, theory; black, fact

Midplane section of human brain annotated with the Brodmann areas, which are related to different functions

People contract mental illness but animals seemingly do not, or at least not outside of artificial laboratory models such as the unpredictable, mild-stress rodent model of depression. A simple theory to account for this cites the paleontological fact that the human brain has been expanding at breakneck speed over recent evolutionary time and postulates that this expansion is ongoing at the present time, and that mental illness is the price we are paying for all this brain progress.

The Evolution of the Human Brain

In other words, the mentally ill may carry the unfavorable mutations that have to be selected out during this progress. The mutation rate in certain categories of mutation affecting human brain development may be elevated in modern humans by some sort of "adaptive" hot-spot system. "Adaptive" is in scare quotes to indicate that the adaptation inheres in changes in the standard deviation of traits, not the average, and is therefore not Lamarkian.

In brain evolution, the growth changes in the various parts very probably have to be coordinated somehow. There may not be any master program doing this coordination. Rather, the human brain would comprise scores of tissue "parcels," each with its own gene to control the final size that parcel reaches in development. This is consistent with the finding of about 400 genes in humans that participate in establishing body size. All harmonious symmetry, even left-right symmetry, would have to be painstakingly created by brute-force selection, involving the early deaths of millions of asymmetrical individuals. 

Assuming that left and right sides must functionally cooperate to produce a fitness improvement, mutations affecting parcel growth must occur in linked, left-right pairs to avoid irreducible-complexity paradoxes. The crossing-over phenomenon in egg and sperm maturation may create these linked pairs of mutations, where the two mutations are identified with the two ends of the DNA segment that translocates. Since the two linked mutations are individually random, linkage per se does not eliminate asymmetry. That must be done by natural selection, as previously stated, so there is a subtlety here. Natural selection could equally well create adaptive asymmetry. The human heart and the claws of the fiddler crab are examples.

Functional Human Brain Anatomy 

Most of the evolutionary expansion of the human brain appears to be focused on association cortex, which would implement if-then rules like those making up the knowledge bases familiar from the field of artificial intelligence. The "if" part of the rule would be evaluated in post-Rolandic cortex, i.e., in temporal and parietal association cortices, and the "then" part of the rule would be created by the pre-Rolandic association cortex, i.e., the prefrontal cortex. The white matter tracts running forward in the brain would connect the "if" part with the "then" part, and the backward running white-matter tracts would carry priming signals to get other rules ready to "fire" if they are commonly used after the rule in question.

Possible Disorders of Brain Growth

Due to such tight coordination, the ideal brain will have a fixed ratio of prefrontal cortex to post-Rolandic association cortex. However, the random nature of the growth-gene bi-mutations, perhaps at mutational hot-spots, permitting human brain evolution will routinely violate this ideal ratio, leading to the creation of individuals having either too much prefrontal cortex or too much temporal/parietal cortex. In the former case, prefrontal cortex will be starved of sensory input. In the latter case, sensory association cortex will be starved of priming signals feeding back from motoric areas.

Denervation supersensitivity occurs when the normal nerve supply to a muscle is interrupted, resulting in a rapid overexpression of acetylcholine receptors on the muscle. This is an adaptation to compensate for weak nerve transmission with a re-amplification of the signal by the muscle. Analogous effects have been found in areas of the cerebral cortex deprived of their normal supply of sensory signals, so the effect seems to be general.

In cases of genetically-determined frontal-parietal/temporal imbalance, the input-starved side would develop denervation supersensitivity, making it prone to autonomous, noise-driven nervous activity.

Differential Growth-Related Brain Disorders 

If the growth excess is in sensory association cortex, this autonomous activity will manifest as hallucinations, resulting in schizophrenia. If the growth excess is in the prefrontal cortex, however, the result of the autonomous activity will be mania or a phobia.

The non-overgrown association cortex might secondarily develop the opposite of denervation supersensitivity as the result of continual bombardment with autonomous activity from the other side of the Rolandic fissure. This could account for the common observation of hypoprefrontality in cases of schizophrenia.

Picture credit: Wiki Commons

#38. Can Irreducible Complexity Evolve? [genetics, evolution]

EV   GE

Red, theory; black, fact

2 x 2

The Key Insight

Sexual reproduction may allow the evolution of irreducible complexity by increasing the intrinsic complexity of the basic building block of change, the mutation.

Irreducible Complexity 

Influential biologist Richard Dawkins wrote in "The God Delusion" that a genuine case of irreducible complexity will never be found in biology. A case of irreducible complexity would be some adaptation that would require an intelligent designer because it could never evolve one mutation at a time, and Dawkins believes there is no such intelligent designer in biology.

In classic natural selection, each mutation must be individually beneficial to its possessor in order for selection to increase its prevalence in the population to the point where the next incremental, one-mutation improvement becomes statistically possible. In this way, all manner of wondrous things are supposed to evolve bit by tiny bit. You have irreducible complexity if an advantageous evolutionary innovation requires two mutations,  but neither confers any advantage in isolation and so cannot be selected up to a sufficiently high frequency that the second mutation is likely to happen in the background of the first.

However, I am seeing irreducible complexity everywhere these days. 

Possible Cases of Irreducible Complexity

For example, your upper-jaw dentition must mesh accurately with that of your lower jaw or you can't eat. Thus, the process of evolutionary foreshortening of the muzzle of the great apes to the flat human face could never have happened, assuming that a single mutation affects only the upper or lower jaw. 

Furthermore, how can any biological signaling system evolve one mutation at a time? At a minimum, you always need both the transmitter adaptation and the receiver adaptation, not to mention further mutations to connect the receiver circuit to something useful.

The evolution of altruism presents a similar problem. The lonely first altruist in the population is always at a disadvantage in competition with the more selfish non-mutants unless it also has a signaling system that lets it recognize fellow altruists (initially, close relatives) and a further mutation that places the altruistic behavior under the control of the receiver part of this system. Thus, altruists would only be altruistic to their own kind, the requirement for altruism to be selected in the presence of selfishness. Finally, the various parts of this system must be indissolubly linked in a way that the non-altruists cannot fake.

A Solution   

Consider the crossing-over events that occur during meiosis as complex mutations: two changes to the genome from a single event, each corresponding to one end of the DNA segment that translocates. In crossing over, two homologous chromosomes pair up along their length and swap a long segment of DNA, a process requiring two double-chain breaks on each end, and their corresponding repairs. A very far-reaching change to the genetic information can occur during crossing-over that is termed unequal crossing-over. This form of the process arises because of inaccuracies, sometimes major, in the initial alignment of the homologous chromosomes prior to crossing-over. When the process is finished, one chromosome has been shortened and the other has been lengthened. This is the major source of gene duplication, which, in turn, is a major source of junk DNA, the part that is classified as broken genes.

A Mechanism for the Evolution of Complexity 

Anatomical features such as jaw length and axon targets may be controlled by variations in gene dose that originate in unequal crossing-over.

In this way, a concerted change affecting multiple distinct sites becomes possible. The two ends of the recombinant segment can in principle be functionally unrelated initially. They become related if both are affected by the same complex mutation and the entire change increases fitness and is thus selected.

A single complex mutation could in principle produce a communication channel at one stroke because of the number of simultaneous changes involved. 

Statistical Issues

The probability of a combination of simultaneous local changes being beneficial to the organism is much smaller on mathematical grounds than is the probability of a given single-nucleotide change being beneficial. However, these unfavourable statistics are at least partly offset by the existence of a dedicated system for producing complex mutations in large numbers, namely meiosis, part of the process of maturation of egg and sperm cells.

The Big Picture 

Complex mutations provide a way for a species to discontinuously jump into new niches as they open up, possibly explaining how a capacity for this kind of mutation could spread and become characteristic of surviving species over time. This idea also provides another explanation for the lack of transitional forms in the fossil record.

#33. Emotions [evolutionary psychology, genetics, neuroscience]

EP   NE   GE

Red, theory; black, fact

A Genetics Theory 

All sexually reproducing species may have a long-range guidance system that that could be called proxy natural selection, or preferably, post-zygotic gamete selection (PGS). This is basically a fast form of evolution in which particular body cells, the gametes, are the units of selection, not individuals. Selection is conjectured to happen post-zygotically (i.e., sometime after the beginning of development, or even in adulthood) but is retroactive to the egg and sperm that came together to create the individual. 

Each gamete is potentially unique because of the crossing-over genetic rearrangements that happen during its maturation. This theory explains the biological purpose of this further layer of uniqueness beyond that due to the sexual mixing of chromosomes, which would otherwise appear to be redundant.

Emotions Represent Fitness 

Our emotions are conjectured to be programmed by species-replacement group selection and to serve as proxies for increases and decreases in the fitness of our entire species.

The Corresponding Mechanistic Theory 

A further correlate of an emotion beyond the cognitive and autonomic-nervous-system components would be the neurohumoral component, expressed as chemical releasing and inhibiting factors that enter the general circulation via the portal vessels of the hypothalamus, blood vessels which are conventionally described as affecting only the anterior pituitary gland. These factors may reach the stem-like cells that mature into egg and sperm, where they set reversible epigenetic controls on the level of crossing-over that will occur during differentiation. 

Large amounts of crossing-over are viewed as retroactively penalizing the gametes leading to the individual by obfuscating or overwriting with noise specifically the genetic uniqueness of said original gametes. In contrast, low levels of further crossing-over reward the original gametes with high penetrance into the next generation. 

Here we have all the essential ingredients of classical natural selection, and all the potential, in a process that solves problems on an historical timescale.

The Limited Scope of Crossing-over

Crossing-over happens only between homologous chromosomes, which are the paternal and maternal copies of the same chromosome. Human cells have 46 chromosomes because they have 23 pairs of homologous chromosomes. 

The homologous-chromosome-specificity of crossing-over suggests that the grand optimization problem that is human evolution has been broken down into 23 smaller sub-problems for the needs of the PGS process, each of which can be solved independently, without interactions with any of the other 22, and which involves a 23-fold reduction in the number of variables that must be simultaneously optimized. 

In computing, this problem-fragmentation strategy greatly increases the speed of optimization. I conjecture that it is one of the features that makes PGS faster than classical natural selection.

Do Chromosome-specific Signaling Pathways Exist?

However, we now need 23 independent neurohumoral factors descending in the bloodstream from brain to testis or (fetal) ovary, each capable of setting the crossing-over propensity of one specific pair of homologous chromosomes. Each one will require its own specific receptor on the surface of the target oogonia or spermatogonia. In the literature, I already find a strange diversity of cell-surface receptors on the spermatogonia. I predict that the number of such receptors known to science will increase to at least 23. None of this is Lamarkism, because nervous-system control would be over the standard deviation of traits, not their averages.

Naively, this theory also appears to require 23 second messengers to transfer the signals from cell surface to nucleus, which sounds excessive. Perhaps the second messengers form a combinatorial code, which would reduce the number required by humans to log₂ (23) = 4.52, or 5 in round numbers. This is much better. Five second-messenger systems are known, these being based on: cyclic AMP, inositol triphosphate, cyclic GMP, arachidonic acid, and small GTPases (e.g., ras). The AND-element that would be required for decoding could be implemented straightforwardly as a linear sequence of transcription-factor binding sites along the DNA strand. However, many mammalian species have many more than the 32 chromosome pairs needed to saturate a 5-bit address space. If we expand the above list of second messengers with the addition of the calcium/calmodulin complex, the address space expands to 64 pairs of homologous chromosomes, for a total ploidy of 128. This seems sufficient to accommodate all the mammals. Thus, a combinatorial second-messenger code representable as a five- or six-bit binary integer in most organisms would control the deposition of the epigenetic marks controlling crossing-over propensity.

It Gets Bigger

If the above code works for transcription as well as epigenetic modification, then applying whatever stimuli it takes to produce a definite combinatorial second-messenger state inside the cell will activate one specific chromosome for transcription, so that the progeny of the affected cell will develop into whatever that chromosome specifies, be it an organ, a system, or something else. And there you may have the long-sought key to programming stem cells. You're welcome.

The requirement that the evolution of each chromosome contribute independently to the total increase in fitness suggests that a chromosome specifies a system, like the nervous system or the digestive system. We seem to have only 11 systems, not 23, but more may be defined in the future.

Illustration credit: By Edmund Beecher Wilson - Figure 2 of: Wilson, Edmund B. (1900) The cell in Development and Inheritance (2nd ed.), Category:New York: The Macmillan Company, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3155599

#24. Proxy Natural Selection from the Inside [evolutionary psychology, genetics]

EP   GE

Red, theory; black, fact

Morning hymn at Sebastian Bachs' By Toby Edward Rosenthal

What Does Darwinian Fitness Feel Like?

My first post on post-zygotic gamete selection (PGS) left open some questions, such as what it should feel like, if anything, when one is fulfilling the species objective function and being deemed "proxy-fit" by one's own hypothalamus.

How Our Emotions Program Us

I conclude that it's just what you would think: you feel joy and/or serenity. Joy is one of Ekman's six basic universal human emotions, the others being fear, anger, disgust, sadness, and surprise. I think that emotions collectively are the operations of the highest-level human behavioral program. (That is, the program in its broadest outlines.) The unpleasant emotions force you to get off the couch until they are taken care of, and joy lets you get back on. Thus, the unpleasant four are the starting emotions, and joy is the stopping emotion. 

Surprise may be a meta-emotion that tells you that your threshold for experiencing one of the other emotions is too high, and immediately lowers it. Each activation of an emotion may tend to lower the threshold for activating it next time, which implies a positive feedback loop capable of changing the personality to suit suddenly changed circumstances, especially if the emotion eventually begins issuing with no trigger at all.

Where Our Emotions Come From

To relate this to the mechanism of PGS, the crossing-over events that went into making the sperm cell that made a given person would theoretically affect brain development more than anything else, specifically connecting some random stimulus to one of the unpleasant primary emotions. This creates temperament, and thus  personality, which is the unique quality which they have to offer the world, and on which they are being tested by history. If the actions to which their own, special preferences propel them are what the species objective function is looking for, they succeed, feel joy and serenity, and experience an altered methylation status of the DNA in the spermatogonia if male, which suppresses further crossing over in the manufacture of sperm, so that their personality type breeds true, which is what the population needs. Famous musical families, for example, may originate in this way.

PGS is quick evolution to respond to challenges that come and go on less than a multi-thousand generation timescale, and it explains the complexities of sexual reproduction.

A Flaw in the Argument, Addressed

However, trees have no behavior, much less personalities, and yet they have sexual reproduction. However, trees probably adapt quickly not by behavioral change, but by changes in their chemistry. The chemistry in question would be the synthesis of pesticidal mixtures located in the central vacuole of each plant cell. In terms of such mixtures, each tree should be slightly unique, an easily testable prediction.

The Big Picture 

Each of the four unpleasant "starting" emotions may sub-serve one of the four pillars of the species objective function. Thus: sadness, altruism; disgust, genetic diversity (due to point mutations; what is motivated here is the screening of such novelties during mate selection, screening always being the expensive part); fear, memetic diversity (or motivating prescreening of memetic novelties through fear of public speaking); anger, dispersal.

Each of these emotions seems to have another use, in preserving the life of the individual, as opposed to the entire species. Thus: sadness, unfavorable energy balance; disgust, steering one away from concentrations of harmful bacteria; fear, avoidance of injury and death; anger, driving away competitors for food and mates.

Picture credits: https://commons.wikimedia.org/wiki/Commons:Copyright_tags/Country-specific_tags#United_States_of_America