Haha, I wrote the rant but accidentally deleted it. Time to check my s100b plasma levels. Hopefully I can recreate the gist.
This is sparked by Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration
One of the most frustrating things for me exploring this field is how many conceits are deployed by the field which don’t actually have anything resembling concrete definitions. An example of this is the term “neurodegeneration”, it seems like a consistent idea until you dive into and discover a completely heterogeneous number of concepts which are attached to it.
Worse, we don’t really study these constructs under conceit at all, it’s always attached through that underlying hodgepodge of conditions, ranging from things like ALS and SMA to Alzheimer’s and Parkinson’s. This significantly harms our understanding and handicaps possible solutions because it creates overly specific data which can’t/doesn’t get generalized to support the term they are assumed to be a class of.
So this is an attempt to give a single definition of the term under the model, and provide an example of mechanics.
All cells physically store information received from their environment as part of the mechanic which allows adaptive response, part of our current criteria (for better/worse) of biological life. This information physically modifies the cell and it’s metabolic/catalytic processes. The “response” component of life is this metabolic/catalytic change to external “information”.
Complex organisms are able to generate specialized responses to information from the same base “genetic plan”/DNA. Epithelial cells for example provide a computation buffer between the internal and external world, allowing more complex internal specializations of processing to occur. Imagining how cell walls provide a buffer for ribosomal activity occur is pretty close to the specialized response of epithelial cells.
This allows interdependent systems to be formed which can evaluate external information in a more flexible way, including and especially comparisons against prior data. These systems also allow for a higher degree of metabolic efficiency, as it can evaluate much more narrow chunks of larger information sets.
This information and the processing necessary has a metabolic cost, and organisms develop along this boundary between entropy and information.
To maintain this balance, organisms (and cells) must have a mechanic which keeps information size commensurate to the metabolic potential of the cell. Cells which have high metabolic potential, e.g. human astrocytes can store and process large amounts of information, while cells with low metabolic potential, e.g. simpler archaea can store very little information. When a cell experiences higher metabolic demand than can be sustained, it collapses the metabolic/catalytic chain and the energy required by the processes holding the cell together collapse, resulting in degradation.
All cells, as they acquire information, become more metabolically expensive to sustain over time, ultimately resulting in the collapse of the energy processing necessary to support the processes physically maintaining the properties of the cell, and they die.
An interesting counter point to this which is often invoked is that some cnidaria appear to avoid death altogether and live almost indefinite lifespans. But it is how they do it which is supports the model, they have programming which literally dumps all the cellular information they’ve acquired to revert to a more naive version of their cellular plan. Just as interesting are the instances in which they cant revert, such as when they experience too great of an environmental (particularly chemical) insult or after mating, which crosses them past their physiological reversion point. In other words, once their distinct information has been transferred, they eventually die just like everything else.
Back from that digression, information management is a critical function of all organisms. Besides the information that cells collect themselves, there’s also the wildcard of external information injection which can modify the metabolic load required which creates a significant randomizer to all this. On a cellular level, viral payloads can range from benign to symbiotic to completely metabolically overwhelming. And on an organism level we see this interaction constantly with the birds in the trees or the parasite that makes mice freeze.
Cells don’t really have a way to “know” what information is native unless it matches their DNA plan, and organisms don’t know either. So one of the systems more complex organisms have developed is a way to detect and process information which may be foreign, and execute an appropriate response to that information. Yep, this is the “immune system”.
Degenerative conditions occur when the metabolic requirement of stored information becomes too high to sustain. Our immune system is responsible for keeping that requirements within certain bounds, and it’s job is to detect and remove duplicate information and/or potentially hostile foreign information. Immune involvement in degeneration comes when the metabolic output is tagged as “over metabolic/foreign”.
Cancers are the result of an information change in a cell which causes it to metabolize outside of the genetic plan safeguards, and the immune system doesn’t recognize it as “over metabolic”. They do this because immune systems have to maintain a significant degree of “slop” to accommodate necessary adaptive information being written to cells.
Anyway, related to the work itself, many types of degeneration are the product of the immune system not recognizing cells which have crossed a metabolic break point as “safe” cells, and begin phagocytosing them. The offending cells often reach this breakpoint because they produce metabolic products inefficiently, produce metabolic products which interfere with the metabolic process itself, or write information which is inappropriate for it’s cellular specialization (sort of like “jumping off it’s DNA track”).
Degeneration is ultimately the result of an organism balancing between entropy and information, and in the end entropy always wins.
Edit: What about conditions like multiple sclerosis under the model?
It’s not discussed a lot, but oligodendrocytes are very heavily involved in the intercellular/metabolic exchange of information, and are heavily written to as part of the process. One of the primary functions of oligos appears to be metabolic sustainment of chemical signals in other cells, especially neurons.
In order to keep the timing of the chemical reaction that pushes the chemical messengers out of the other end of a cell in a consistently timed fashion, it becomes necessary to have a way to keep the metabolic reaction taking place along the cell at a consistent level of energy. Too much energy it goes too fast, too little it goes to slow or doesn’t transfer. Oligos modify the energy environment of neurons via myelin, which allows stable timing and strength between the end points.
This isn’t something more complex organisms know how to do right away, there is a baseline genetic plan, but all that goes out of the window once exposed to the complexity of an environment. An organism must learn how to maintain stable timing between points in order to produce a behavioral response more complex than “instinct” or the genetic plan.
Astrocytes coordinate this timing and then write that to the oligos, which in turn modify the metabolic programming that myelin executes. It is this extra information writing to oligos that can “confuse” immune system function. The general idea is very similar to microglial overpruning of synaptic targets in astrocytes/neurons in that they are specifically attacking cells exhibiting change in information that they don’t recognize as “native” (or think have crossed their metabolic breakpoint).
Edit 2: Does this mean the immune system has a similar type of memory as the <information system> which can degrade?
Yes, and I’d argue that one of the key things we understand about the immune system, that “memory” cells are stored antibody programs rather than information about the pathogen itself is almost exactly the same as how “cognitive” engrams work. Under the model we don’t directly store the stimuli itself, we only store a reaction to stimuli, and it is these reactions which are combined into our top level maps. It may not be too inappropriate to imagine certain B and T cell classes as storing “floating” engrammatic information.
“Better” metabolics gives these cells more access to energy which allows them to more efficient/faster information processing capabilities, but they still work largely the same way as any other cell does despite their specialization.
I hope that answers the question, but I think it’s also sort of asking if other systems process reactions like the information system and immune system do, and right now I’m tempted to say no as they would represent an “internal/native” information processing system and and an “external” information processing system.
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