#73. How Enhancers May Work [Biochemistry]

 CH

Red, theory; black, fact.

Picture of the author at the microscope circa 1999.
Terrible posture! This is where Egors come from. Kids, don't try this at home.

Background about 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 ("in trans"). 

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. 

My electrostatic theory of enhancer–promoter interaction

I propose a far different mechanism: when activated, the multiple enhancers 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 the RNA polymerase II cannot move down the DNA strand because unrelated chromatin loops are in the way, like trees fallen across the railway tracks. (Each "tree" eventually moves away because of Brownian motion.) This could also be the mechanism of chromatin decondensation generally, which is known to be a precondition for the expression of protein-coding genes.

05-28-2022: 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. 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.

#70. How Noncoding RNA May Work [chemistry]

 CH

Red, theory; black, fact.

Back, DNA; red, long noncoding RNA; green, transcription complex. I am assuming that transcription initiation involves a DNA-RNA triplex, but this is not essential to the theory. Imagine that a loop closes through an RNA running from bottom to top.

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.

What does long non-coding RNA do?

This 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. (lncRNA molecules also control chromatin remodeling, but this may be an aspect of stem-cell differentiation during development.) Despite the accumulation of much biochemical information, summaries of what lncRNA seems to do for the cell have been vague, unfocussed, and unsatisfactory (to me).

Control of gene expression: background

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.

Since I have a neuroscience degree, I naturally wonder if 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. But vertebrates also have something higher than spinal reflexes: operations by the brain. (Don't worry, I am not about to go off the deep end on you.)

My neuron-inspired theory of long non-coding RNA

I propose a coordinating role for the noncoding RNAs: rather than relying on a bunch of independently acting reflexes, eukaryotic cells can sense many promoter signals at once, as a gestalt, and respond with the expression of many proteins at once, as another gestalt. You do not need an entire brain 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, which causes further depolarization, so around we go. This potential positive feedback can be translated into terms of molecular biology by supposing 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 does occur. 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.

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

NE     EV     GE     

Red, theory; black, fact.

People get 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.

In other words, the mentally ill carry the unfavorable mutations that have to be selected out during this progress, and the mutation rate in certain categories of mutation affecting human brain development is elevated in modern humans by some sort of "adaptive" hot-spot system. "Adaptive" is in scare quotes here 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. I conjecture that there is no master program doing this coordination. Rather, I conceive of the human brain as comprising scores of tissue "parcels," each with its own gene to control the final size that parcel reaches in development. (This idea 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. This idea was outlined in post 10.

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. I have previously conjectured in these pages that the crossing-over phenomenon of egg and sperm maturation serves to create these linked pairs of mutations, where the two mutations are identified with the two ends of the DNA segment that translocates. (See "Can Irreducible Complexity Evolve?")

Most of the evolutionary expansion of the human brain appears to be focused on association cortex, which I conjecture implements 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.

Due to such tight coordination, I would expect that 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, you will have prefrontal cortex starved of sensory input. In the latter case, you will have sensory association cortex 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 can be seen as an attempt to compensate for weak nerve transmission with a tremendous 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 quite general.

In cases of genetically-determined frontal-parietal/temporal imbalance, I conjecture that the input-starved side develops something like denervation supersensitivity, making it prone to autonomous, noise-driven nervous activity.

If the growth excess is in sensory association cortex, this autonomous activity will manifest as hallucinations, resulting in a person with schizophrenia. If the growth excess is in the prefrontal cortex, however, the result of the autonomous activity will be mania or a phobia. Depression may originally have been an adaptation to the presence of a man-eating predator in the neighborhood, but in civilized contexts, it can get activated by the unpredictable (to the sufferer) punishments resulting from manic activity. If the mania is sufficiently mild to co-exist with depression, as in type II bipolar disorder, then the overall effect of the depressive component may be like a band-aid on the mania.

The non-overgrown association cortex might even 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.

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

EV     GE     

Red, theory; black, fact.

5-26-2018: 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.

However, I am seeing irreducible complexity all over the place these days. For example, your upper-jaw dentition must mesh pretty 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. But it did. (Let us gloss over the fact that that is an assumption, because the contrary seems to require non-local rules in development.)

Furthermore, how can any instinctive 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.

My solution is to label the crossing-over events that occur during meiosis as "tetra-mutations." In crossing over, two homologous chromosomes pair up along their length and swap a long segment of DNA, a process requiring four double chain breaks and their corresponding repairs. Because of the presence of single-nucleotide polymorphisms, the homologous chromosomes are not exactly the same, so that each of the upstream sides of the four chain breaks ends up in a subtly different genetic environment. If the break point falls between a cis-acting regulatory element and the corresponding structural gene, for instance, the former may now control the expression of a slightly different protein. Thus, there could be as many as four distinct functional consequences of one crossing-over event. Why not call that a tetra-mutation?

In this way, a concerted change affecting four 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 tetra-mutation and the entire change increases fitness and is thus selected.

A single tetra-mutation could in principle produce viable altruism at one stroke because of the number of simultaneous changes involved. 

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 unfavorable statistics are at least partly offset by the existence of a dedicated system for producing tetra-mutations in large numbers, namely meiosis, part of the process of maturation of egg cells and sperm cells.

In the big picture, tetra-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 a ready explanation for the lack of transitional forms in the fossil record.

5-30-2018: Here is the search description again, in case you missed it or could not see all of it: Sexual reproduction may allow the evolution of irreducible complexity by increasing the intrinsic complexity of the basic building block of change, the mutation.

6-12-2018: Upon further reflection, it seems that the tetramutation construct described above lacks validity because during gamete maturation it falls apart into two bi-mutations, both of which cannot contribute to the same zygote. The bi-mutation is stable, however, because of the intervening translocated DNA segment. It is harder to see how a complex adaptation like altruism could evolve out of nothing but mono-mutations and bi-mutations, but that does not mean the theory put forward in this post is necessarily wrong. One must not argue from lack of imagination. It is an interesting question, actually, what is the minimum set of all mutation types necessary to account for all known adaptations.

8-27-2019: In my ignorance, I have undersold the bi-mutation idea. A very far-reaching change to the genetic information can occur during crossing-over that is not at all subtle and 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, with gene duplication. 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. Two questions come to mind. The first is, are anatomical features such as jaw length and axon targets somehow controlled by variations in gene dose? The second, which is a tangent, is, are broken genes really broken or just temporarily switched off by genetic drift at some mutational hot spot in the recognition site of some transcription factor? The analogy here is to a generator in a power plant that has been placed in stand-down mode because of a temporary decrease in the demand for electrical power.

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

EP    NE    GE

Red, theory; black, fact.

12-17-2017: In previous posts, I theorized that humans, along with all other sexually-reproducing species, have a long-range guidance system that I called proxy natural selection, or preferably, post-zygotic gamete selection (PGS), that is basically a fast form of evolution in which individual 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.

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.

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 are theorized to 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, I believe you have all the essential ingredients of classical natural selection, and all the potential, in a process that solves problems on an historical timescale.

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.

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. Check this out in the literature, and you will already find a strange diversity of cell-surface receptors on the spermatogonia. (I haven't looked at oogonia yet.&&) 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 behavioral traits, not their averages.

1-09-2018: 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. Exactly five second-messenger systems are known, these being based on: cyclic AMP, inositol triphosphate, cyclic GMP, arachidonic acid, and small GTPases (e.g., ras). However, many mammalian species have many more than the 32 chromosome pairs needed to saturate a 5-bit address space.

1-10-2018: 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.

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.

Each pair of homologous chromosomes may correspond to what in an earlier post was called a "PNS focus." 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.

A related concept is that a chromosome specifies an ancestral, generic cell type, like glial cells (4 subtypes known) or muscle cells (3 subtypes known). The great diversity of the neurons suggest that they must be reclassified into multiple basic types, perhaps along the lines suggested by the functional classification of the cranial nerves: general somatic, general visceral, and special somatic (i.e., specific senses).

1-09-2018: A third concept for function assignment to homologous pairs of chromosomes postulates a hypothetical maximally divided genome in which each cell type has its own chromosome pair, a state conjectured to seldom occur in nature. Co-evolution of clusters of cell types (e.g., neurons and glia; bone and cartilage) would create selection pressure for the underlying cell-type-specific chromosomes to become covalently linked into the larger chromosomes that we see in the actual karyotypes. Thus, each observed homologous pair would correspond to a few cell types that are currently co-evolving, which seems to return us to the system or organ concept. 

01-08-2019: The system specified by a chromosome may be called a cooperation system, and these may be organized in a hierarchy, following the general principles of spatial organization outlined in my post: "The Pictures in Your Head." Chromosomes activated earlier in development will specify system-like entities and those activated late in development will specify organ-like entities. Only the first-activated chromosome will apply to the entire organism.

Humans depend on complex social structures for their survival, and this comes out of our individual behavioral tendencies. Probably, most PGS adaptations to environmental fluctuations involve modifying these structures, which would come out of subtle modifications of individual behaviors. I think I am just repeating E.O. Wilson here. Our hard-wired species-fitness definitions would give rise to the primary emotions, perhaps in the hypothalamus or limbic system, by connecting specific stimuli to primary emotions in the manner of an if-then rule. 

Further out on the cortex, the specific stimuli being connected would get progressively more complex and learning-dependent, and progressively less concerned with the "what" of behavior (i.e., our species-specific taxes) and more with the "how" of behavior. In "how" mode, the complex stimuli become more like signposts to be consulted on a journey. PGS adaptations of our behavior would affect the hardwired aspects of this hypothetical transition zone. The primary emotions would then be like the highest hierarchical level of our motor program, or like the least-indented instructions of a conventional high-level computer program.

I conjecture that religion is important because it goes straight for this highest level. We all know that religion is kind of an emotional business, what with the organ music and the stained glass and all such as that, and this is why. I therefore conjecture that words spoken often from the pulpit, such as God, sin, forgiveness, devil, angel, soul, salvation, etc., all enclose a secret that writers such as Dawkins do not grasp: the emotions are the message. To illustrate this, let us attempt an emotional definition of the master symbol, "God."

God: feeling loved and secure to the point of invulnerability; feeling small in an agreeable way, as in the presence of mountains; feeling brotherly/sisterly towards one's fellow humans; blossoming in confidence into one's full potential; fearing nothing.

Perhaps that's enough to give the general idea. No doubt a whole dictionary could be compiled along these lines. When the priest strings these emotion-words together, he creates an experience for the congregation that could fairly be called a form letter from "God," assuming that the word "God" points to the PGS process itself. The job of the priest is to help the congregation relate on a deep level to the sacred texts and to see/feel how they apply to the challenges of the here and now.

7-05-2018: Another term for PGS would be "Yahwetion," from "Yahweh," the conventional modern spelling of the name of the god of ancient Israel, and the "tion" ending indicating a process, like evolution. This neologism advantageously steers people away from category errors like attempting to worship it, or appease it, or what have you.

The conventionally religious will complain that this would make prayer to God impossible, but not if prayer itself is re conceived as "auto socialization," following the educational theory of prayer. Then prayer becomes a fantasy conversation with anyone, living or dead, that you would like to have as a mentor, if it were possible.

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

EP    GE    

Red, theory; black, fact.

My first post on proxy natural selection (PNS) 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.

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. I also think that each activation of an emotion tends 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.

To relate this to the mechanism of PNS, the crossing-over events that went into making the sperm cell that made you would theoretically affect brain development more than anything else, specifically connecting some random stimulus to one of the unpleasant primary emotions. This creates your temperament, and thus your personality, which is the unique quality which you have to offer the world, and on which you are being tested by history. If the actions to which your own, special bete noir propel you are what the species objective function is looking for, you succeed, feel joy and serenity, and experience an altered methylation status of the DNA in your spermatogonia, if you are male, which (I conjecture) suppresses further crossing over in the manufacture of your own sperm, so that your personality type breeds true, which is what the population needs. 

PNS is quickie evolution to respond to challenges that come and go on less than a multi-thousand generation timescale, and I conjecture that it explains the complexities of sexual reproduction. You may object that trees, for example, 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.

Here is my own self-analysis in terms of PNS theory. My special emotional novelty that is potentially my gift to the world is a morbid fear of social rejection. This has motivated much more than the usual self-criticism of my own creative productions before they are communicated to others, for fear of rejection, leading to the kind of thing you are now reading. Social rejection/criticism hits me like a wall of flame that burns for days, or like some kind of rays coming out of the other person's head. The rejection that goes with the dating game has made it intolerable to me, leading to a lifelong celibacy that has freed all my resources for scientific pursuits. 

My father was a general in the Canadian Armed Forces, and was most unlike this, but my older brother takes after him somewhat. What happened to sour my father's life so radically before my birth in 1953, so that his recombinotype (coined word) no longer bred true? I conjecture that it was the failure of the defeat of Nazi Germany to produce a true, lasting peace, only ushering in the nuclear cold war with the USSR. With this, "God" was telling us: "Don't study war no more."

Each of the four unpleasant "starting" emotions may sub serve one of the four pillars of the species objective function already listed in The intermind: Engine of History?. Thus: sadness, altruism; disgust, genetic diversity (due to point mutations; what is motivated here is the screening of such novelties, screening always being the expensive part); fear, memetic diversity (or motivating prescreening of memetic novelties); 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. 

#14. Three Stages of Abiogenesis [evolution, chemistry]

The iconic Miller experiment on the origin of life

Abiogenesis chemistry outside the box

EV    CH    

Red, theory; black, fact

Repair, growth, reproduction

"Abiogenesis" is the term for life originating from non-life.

Self-repair processes will be important in abiogenesis because life is made of metastable molecules that spontaneously break down and have to be continually repaired, which results in continuous energy dissipation. I will assume that self-repair in non-reproducing molecules is what eventually evolved into self-replication and life.

I also assume that the self repair process was fallible, so that it occasionally introduced a mutation. Favorable mutations would have increased the longevity of the self-repairing molecules. Nevertheless, a given cohort of these molecules would relentlessly decrease in numbers, but they would have been continuously replenished in the juvenile form by undirected chemistry on the early Earth. Eventually, at least one of them was able to morph self-repair into self-replication, and life began. I call this process of refinement of non-reproducing molecules "longitudinal evolution" by analogy to a longitudinal cohort study in medical science. The process bears an interesting resemblance to carcinogenesis, where an accumulation of mutations in long-lived cells also leads to an ability to self-replicate autonomously. Carcinogenesis is difficult to prevent, and so must be considered a facile process, suggesting that longitudinal evolution to the threshold of life was also facile.

A simple self-repairing molecule

The "enzyme ring" shown above is an example of a possible self-repairing molecule that I dreamt up. It is a ring of covalently-bonded monomers that are individually large enough to have good potential for catalyzing reactions, like globular proteins, but are small enough to be present in multiple copies like the standardized building blocks that one wants for templated synthesis.

If the covalent bond between a given pair of monomers breaks, the ring is held together by multiple, parallel secondary valence forces and hydrophobic interactions, until the break can be repaired by the ring's catalytic members. With continuing lack of repair, the ring eventually opens completely, and effectively "dies." To bring the necessary catalysts to the break site reliably, no matter where it is, I assume that multiple copies of the repair enzyme are present in the ring, and are randomly distributed. I also assume a temperature cycle like that of the polymerization chain reaction technology that repeatedly makes the ring single-stranded during the warm phase and allows it to collapse into a self-adhering, linear, double-stranded form during the cool phase. This could simply be driven by the day-night cycle. In the linear form, the catalytic sites are brought close to the covalent bond sites, and can repair any that are broken using small-molecule condensing agents such as cyanogen, which are arguably present on the early Earth under Miller-Urey assumptions. When the ring collapses, it does so at randomly selected fold diameters, so that only a few catalytic monomers are needed, since each will eventually land next to all covalent bonds in the ring except those nearby, which it cannot reach because of steric hindrance and/or bond angle restrictions. The other catalytic monomers in the ring will take care of these.

How it would grow

The mutation process of the enzyme ring could result from random ring-expansion and ring-contraction events, the net effect being to replace one kind of monomer with another. Expansion would most likely begin with intercalation of a free monomer between the bound ones at the high-curvature regions at the ends of the linear conformation. The new monomer would be held in place by the multiple, weak parallel bonds alluded to above. It could become incorporated into the ring if it intercalates at a site where the covalent bond is broken. Two bond-repair events would then suffice to sew it into the ring. The ring-contraction process would the the time-reversed version of this. 

In addition, an ability to undergo ring expansion allows the enzyme ring to start small and grow larger. This is important because, on entropy grounds, a long polymer is very unlikely to spontaneously cyclize. The energy-requiring repair process will bias the system to favor net ring expansion. Thus, we see how easily self-repair can become growth.

How it would reproduce

If large rings can split in two while in the linear conformation, the result is reproduction, without even a requirement for templated synthesis. Thus, we see how easily growth can become reproduction.

Onward to the bacterium

To get from reproduction-competent enzyme rings to something like a bacterium, the sequence of steps might have been multiplication, coacervate droplet formation, cooperation within the confines of the droplet, and specialization. The first specialist subtypes may have been archivists, forerunners of the circular genome of bacteria; and gatekeepers, forerunners of the plasma membrane with its sensory and transporter sites. Under these assumptions, DNA would not have evolved from RNA; both would represent independently originated lines of evolution, but forced to develop many chemical similarities by the demands of templated information transfer.

Back to chemistry

During the classic experiment in abiogenesis, the Miller-Urey experiment, amino acids were formed in solution, but no-one has been able to show how these could subsequently have polymerized to functional protein catalysts. The origin of the monomers in my enzyme ring thus needs to be explained. However, the formation of relatively large amounts of insoluble, dark-colored "tars" is apparently facile under the Miller-Urey reaction conditions. The carbon in this tar is not necessarily lost to the system forever, like a coal deposit. In present-day anoxic environments relevant to the early Earth, at least three-quarters of modern biomass returns to the atmosphere as marsh gas. The driving force for these reactions seems to be not enthalpy reduction, but entropy increase.

Seen in the library of the University of Ottawa

Retrofractive synthesis

I therefore propose that if you wait long enough, and a diversity of trace-metal ions is present, then the abiogenesis tar will largely break down again, releasing large, prefab molecular chunks into solution. Reasoning from what is known of coal chemistry, these chunks may look something like asphaltenes, illustrated above, but relatively enriched in hydrophilic functional groups to make them water soluble. Hydrolysis reactions, for example, can simultaneously depolymerize a big network and introduce such groups (e.g., carboxylic acid groups). I propose that these asphaltene analogs are the optimally-sized monomers needed to form the enzyme ring.

#7. What is Intelligence? Part I. DNA as Knowledge Base [genetics, engineering]

EN     GE     

Red: theory; black, fact.

I have concluded that the world contains three intelligences: the genetic, the synaptic, and the artificial. The first includes (See Deprecated, Part 10) genetic phenomena and is the scientifically-accessible reality behind the concept of God. The synaptic is the intelligence in your head, and seems to be the hardest to study and the one most in need of elucidation. The artificial is the computer, and because we built it ourselves, we presumably understand it. Thus, it can provide a wealth of insights into the nature of the other two intelligences and a vocabulary for discussing them.

Artificial intelligence systems are classically large knowledge bases (KBs), each animated by a relatively small, general-purpose program, the "inference engine." The knowledge bases are lists of if-then rules. The “if” keyword introduces a logical expression (the condition) that must be true to prevent control from immediately passing to the next rule, and the “then” keyword introduces a block of actions the computer is to take if the condition is true. Classical AI suffers from the problem that as the number of if-then rules increases, operation speed decreases dramatically due to an effect called the combinatorial explosion.

A genome can be compared to a KB in that it contains structural genes and cis-acting control elements.(CCEs). The CCEs trigger the transcription of the structural genes into messenger RNAs in response to environmental factors and these are then translated into proteins that have some effect on cell behavior. The analogy to a list of if-then rules is obvious. A CCE evaluates the “if” condition and the conditionally translated protein enables the “action” taken by the cell if the condition is true.

Note that the structural gene of one rule precedes the CCE of the next rule along the DNA strand. Surely, would this circumstance not also represent information? However, what could it be used for? It could be used to order the rules along the DNA strand in the same sequence as the temporal sequence in which the rules are normally applied, given the current state of the organism’s world. This seems to be a possible solution to the combinatorial explosion problem, leading to much shorter delays on average for the transcriptase complex to arrive where it is needed. I suspect that someday, it will be to this specific arrangement that the word “intelligence” will refer.

The process of putting the rules into such a sequence may involve trial-and-error, with transposon jumping providing the random variation on which selection operates. A variant on this process would involve stabilization by methylation of recombination sites that have recently produced successful results. These results would initially be encoded in the organism's emotions, as a proxy to reproductive success. In this form, the signal can be rapidly amplified by inter individual positive feedback effects. It would then be converted into DNA methylation signals in the germ line. (See my post on mental illness for possible mechanisms.) DNA methylation is known to be able to cool recombination hot spots.

A longer-timescale process involving meiotic crossing-over may create novel rules of conduct by breaking DNA between promoter and structural gene of the same rule, a process analogous to the random-move generation discussed in my post on dreaming. Presumably, the longest-timescale process would be creating individual promoters and structural genes with new capabilities of recognition and effects produced, respectively. This would happen by point mutation and classical selection.

How would the genetic intelligence handle conditional firing probabilities in the medium to low range? This could be done by cross linking nucleosomes via the histone side chains in such a way as to cluster the CCEs of likely-to-fire-next rules near the end of the relevant structural gene, by drawing together points on different loops of DNA. The analogy here would be to a science-fictional “wormhole” from one part of space to another via a higher-dimensional embedding space. In this case, “space” is the one-dimensional DNA sequence with distances measured in kilobases, and the higher-dimensional embedding space is the three-dimensional physical space of the cell nucleus.

The cross linking is presumably created and/or stabilized by the diverse epigenetic marks known to be deposited in chromatin. Most of these marks will certainly change the electric charge and/or the hydrophobicity of amino acid residues on the histone side chains. Charge and hydrophobicity are crucial factors in ionic bonding between proteins. The variety of such changes that are possible.

Mechanistically, there seems to be a great divide between the handling of high and of medium-to-low conditional probabilities. This may correspond with the usual block structure of algorithms, with transfer of control linear and sequential within a block, and by jump instruction between blocks.

Another way of accounting for the diversity of epigenetic marks, mostly due to the diversity of histone marks, is to suppose that they can be paired up into negative-positive, lock-key partnerships, each serving to stabilize by ionic bonding all the wormholes in a subset of the chromatin that deals with a particular function of life. The number of such pairs would equal the number of functions.

Their lock-key specificity would prevent wormholes, or jumps, from forming between different functions, which would cause chaos. If the eukaryotic cell is descended from a glob-like array of prokaryotes, with internal division of labor and specialization, then by one simple scheme, the specialist subtypes would be defined and organized by something like mathematical array indexes. For parsimony, assume that these array indexes are the different kinds of histone marks, and that they simultaneously are used to stabilize specialist-specific wormholes. A given lock-key pair would wormhole specifically across regions of the shared genome not needed by that particular specialist.

 A secondary function of the array indexes would be to implement wormholes that execute between-blocks jumps within the specialist's own program-like KB. With consolidation of most genetic material in a nucleus, the histone marks would serve only to produce these secondary kind of jumps while keeping functions separate and maintaining an informational link to the ancestral cytoplasmic compartment. The latter could be the basis of sorting processes within the modern eukaryotic cell.

#6. Mental Illness as Communication [neuroscience, genetics]

NE     GE     

Red, theory; black, fact.

The effects of most deleterious mutations are compensated by negative feedback processes occurring during development in utero. However, if the population is undergoing intense Darwinian selection, many of these mutations become unmasked and therefore contribute variation for selection. (Jablonka and Lamb, 2005, The MIT Press, "Evolution in Four Dimensions")

However, since most mutations are harmful, a purely random process for producing them, with no pre-screening, is wasteful. Raw selection alone is capable of scrubbing out a mistake that gets as far as being born, at great cost in suffering, only to have, potentially, the very same random mutation happen all over again the very next day, with nothing learnt. Repeat ad infinitum. This is Absurd, and quarrels with the engineer in me, and I like to say that evolution is an engineer. Nowadays, evolution itself is thought to evolve. A simple example of this would be the evolution of DNA repair enzymes, which were game-changers, allowing much longer genes to be transmitted to the next generation, resulting in the emergence of more-complex lifeforms.

An obvious, further improvement would be a screening, or vetting process for genetic variation. Once a bad mutation happens, you mark the offending stretch of DNA epigenetically in all the close relatives of the sufferer, to suppress further mutations there for a few thousand years, until the environment has had time to change significantly.

Obviously, you also want to oppositely mark the sites of beneficial mutations, and even turn them into recombinant hot spots for a few millennia, to keep the party going. Hot spots may even arise randomly and spontaneously, as true, selectable epi-mutations. The downside of all this is that even in a hot spot, most mutations will still be harmful, leading to the possibility of "hitchhiker" genetic diseases that cannot be efficiently selected against because they are sheltered in a hot spot. Cystic fibrosis may be such a disease, and as the hitchhiker mechanism would predict, it is caused by many different mutations, not just one. It would be a syndrome defined by the overlap of a vital structural gene and a hot spot, not by a single DNA mutation. I imagine epigenetic hot spots to be much more extended along the DNA than a classic point mutation.

It is tempting to suppose that the methylation islands found on DNA are these hot spots, but the scanty evidence available so far is that methylation suppresses recombinant hot spots, which are generally defined non-epigenetically, by the base-pair sequence.

The human brain has undergone rapid, recent evolutionary expansion, presumably due to intense selection, presumably unmasking many deleterious mutations affecting brain development that were formerly silent. Since the brain is the organ of behavior, we expect almost all these mutations to indirectly affect behavior for the worse. That explains mental illness, right?

I'm not so sure; mental illnesses are not random, but cluster into definable syndromes. My reading suggests the existence of three such syndromes: schizoid, depressive, and anxious. My theory is that each is defined by a different recombinant hot spot, as in the case of CF, and may even correspond to the three recently-evolved association cortices of the brain, namely parietal, prefrontal, and temporal, respectively. The drama of mental illness would derive from its communication role in warning nearby relatives that they may be harbouring a bad hot spot, causing them to find it and cool it by wholly unconscious processes. Mental illness would then be the push back against the hot spots driving human brain evolution, keeping them in check and deleting them as soon as they are no longer pulling their weight fitness-wise. The variations in the symptoms of mental illness would encode the information necessary to find the particular hot spot afflicting a particular family.

Now all we need is a communication link from brain to gonads. The sperm are produced by two rounds of meiosis and one of mitosis from the stem-like, perpetually self-renewing spermatogonia, that sit just outside the blood-testes barrier and are therefore exposed to blood-borne hormones. These cells are known to have receptors for the hypothalamic hormone orexin A*, as well as many other receptors for signaling molecules that do or could plausibly originate in the brain as does orexin. Some of these receptors are:

• retinoic acid receptor α
• glial cell-derived neurotrophic factor (GDNF) receptor
• CB2 (cannabinoid type 2) receptor
• p75 (For nerve growth factor, NGF)
• kisspeptin receptor.

*Gen Comp Endocrinol. 2016 May 9. pii: S0016-6480(16)30127-7. doi: 10.1016/j.ygcen.2016.05.006. [Epub ahead of print] Localization and expression of Orexin A and its receptor in mouse testis during different stages of postnatal development. Joshi D1, Singh SK2.

PS: for brevity, I left out mention of three sub-functions necessary to the pathway: an intracellular gonadal process transducing receptor activation into germ line-heritable epigenetic changes, a process for exaggerating the effects of bad mutations into the development of monsters or behavioral monsters for purposes of communication, and a process of decoding the communication located in the brains of the recipients.

#1. Intro [evolutionary psychology, evolution]

This is the sort of thing I write:

EP       EV      

Red, theory; black, fact.

EP

Religion is the last proto-science (e.g., alchemy, astrology). 
(Parts cut to Deprecated page, Part 2.)

***

EV

The eukaryotic cell arose from a clonal array of prokaryotes that selectively lost some of its internal partition walls while following the colony path to complexity. The remaining partitions gave rise to the internal membrane systems of present-day eukaryotes. Those prokaryote colonists specializing in chemiosmotic processes such as oxidative phosphorylation and photosynthesis could not lose any of their delimiting walls because of the need to maintain concentration gradients, so they remain bacterium-like in morphology to this day. This is an alternative to the phagocytotic theory of the origin of mitochondria and chloroplasts. Modern blue-green algae genetically resemble the DNA in chloroplasts, and modern aerobic bacteria have genetic resemblances to the DNA in mitochondria, but this is not necessarily differential support for the phagocytosis theory. The resemblances can be accounted for by convergent evolution or by the existence of an ancestor common to the modern organisms and the ancient colony formers I suppose here.

11-15-2017

These prokaryote colonies would have originally reproduced by sporulation, not mitosis, which would have come later. The "spores" would be actively-metabolizing prokaryotes and before growing into further colonies, would be subject to natural selection. In the spore phase, the rapid evolvability of typical prokaryotes would have been recovered, allowing the formation of large, slow-growing colonies without sacrifice of the high evolvability of the original solitary prokaryotes. Modern-day eukaryotes often secrete tiny bodies called exosomes containing all the macromolecules of life. Exosomes may be the evolutionary vestige of the sporulation phase of the original eukaryotes.