#9. The Two–test-tube Experiment: Part I [neuroscience]

Your Brain is Like This.

NE

Red, theory; black, fact.

The the motivating challenge of this post is to explain the hemispheric organization of the human brain. That is, why we seem to have two very similar brains in our heads, the left side and the right side.

Systems that rely on the principle of trial-and-error must experiment. The genetic intelligence mentioned in previous posts would have to experiment by mutation/natural selection. The synaptic intelligence would have to experiment by operant conditioning. I propose that both these experimentation processes long ago evolved into something slick and simplified that can be compared to the two–test-tube experiment beloved of lab devils everywhere.

Remember that an experiment must have a control, because "everything is relative." Therefore, the simplest and fastest experiment in chemistry that has any generality is the two-test-tube experiment; one tube for the "intervention," and one tube for the control. Put mixture c in both tubes, and add chemical x to only the intervention tube. Run the reaction, then hold the two test tubes up to the light and compare the contents visually (Remember that ultimately, the visual system only detects contrasts.) Draw your conclusions.

My theory is basically this: the two hemispheres of the brain are like the two test tubes. Moreover, the two copies of a given chromosome in a diploid cell are also like the two test tubes. In both systems, which is which varies randomly from experiment to experiment, to prevent phenomena analogous to screen burn. The hemisphere that is dominant for a particular action is the last one that produced an improved result when control passed to it from the other. The allele that is dominant is the last one that produced an improved result when it got control from the other. Chromosomes and hemispheres will mutually inhibit to produce winner-take-all dynamics in which at any given time only one is exposed to selection, but it is fully exposed. 

These flip-flops do not necessarily involve the whole system, but may be happening independently in each sub-region of a hemisphere or chromosome (e.g., Brodmann areas, alleles). Some objective function, expressing the goodness of the organism's overall adaptation, must be recalculated after each flip-flop, and additional flip flopping suppressed if an improvement is found when the new value is compared to a copy of the old value held in memory. In case of a worsening of the objective function, you quickly flip back to the allele or hemisphere that formerly had control, then suppress further flip flopping for awhile, as before. 

The foregoing implies multiple sub-functions, and these ideas will not be compelling unless I specify a brain structure that could plausibly carry out each sub-function. For example, the process of comparing values of the objective function achieved by left and right hemispheres in the same context would be mediated by the nigrostriatal projection, which has a crossed component as well as an uncrossed component. More on this next post.

#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.