The minimal unit of life is a cell. A cell is the minimum unit of replication encapsulating biochemical networks. It is also the minimum unit of selection for prokaryotes. The information of protein variation and the timing of their expression are encoded in the genome. The genome constrains the range of phenotypic variation but does not dictate it. The genome carries the primary information of phenotypic variation of an organism.
How was the first genome created? How did the first life emerge? By chance. Opportunistic. A soup of various peptides, nucleic acids, amino acids and other molecules called metabolites later. In this chaotic mixture, random biochemical reactions spontaneously occur. The lipid bilayer spontaneously wraps random molecules, which prevents diffusion. Peptides are the key molecules for biochemical reactions. The circular random long DNA sequence can carry tons of peptide sequences. Some peptides from the DNA sequence can accidentally form a cascade or cycle of biochemical reactions. Once cascades of biochemical reactions are formed, and if a part of these cascades is linked to a self-replicate system, life could begin.
If an auto-replication unit of networks is created by chance, it keeps replicating. Chaos can permit this to happen. Interestingly, however, as soon as the unit emerges as a connected network, Chaos acts destructively on it. This is the first state of SELF/non-SELF. Something that is part of the networks is SELF, contributing to forming the order of the networks. Others will be non-SELF, potentially destroying the order; thus, it is better to be removed from the system.
In analogy, a pool of tons of LEGO blocks with various colours and shapes. By simple self-assembly reactions, by chance, something looks like a castle emerges. If you want to imitate something that looks like a castle again, only LEGO pieces used in the original castle are the ones you want. Other extra pieces become the noise to distract the imitation and better to be removed from the pool. Preassembling a few pieces further constrains to build something else. In the original pool, you have a chance to make something like a tree, a car, a table, etc. But by removing the extra pieces and preassembling, you cannot make anything but a castle with high reproducibility. Have you wanted to make a castle? No. It does not matter. If a car is the one accidentally made and you want to imitate it, the same process would happen with a distinct set of LEGO pieces.
The circular random long DNA sequence that carries the chaos of peptides is opportunistically edited into different versions to trim the chaos to an order based on their requirement for replication in their environments. Importantly, DNA replication is an erroneous process. The default is errors. When an error happens in SELF, the system collapses. Errors in non-SELF are permitted. Deletions would be suitable for removing extra DNA sequences to eliminate the chaos from its genome. Only the auto-replication unit that keeps replicating continues as life.
I assume this is how prokaryotes emerged. No extra DNA sequence. All sequences are useful for survival (maintaining the network of biochemical reactions) and replication. Each prokaryote species could be a different editing version from a few original chaos or tons of varying chaos. Because the minimum unit of replication is a cell, they stay as monocellular organisms.
Survival and replication are the requirements to stay in this game. Each prokaryote is highly efficient by itself. All chaotic information was trimmed out – no detour. Highly stable. But the dead end. No extra sequence is available after editing. The chaos disappears after strengthening the order by trimming detours and focusing on efficiency. Without it, nothing fundamentally new emerges—no further innovation.
Then, how did eukaryotes evolve? Rebuilding a new chaos by fusions of multiple prokaryotes. Chloroplast and mitochondria are one of those prokaryotes but still maintain their DNA in their separate compartments. I speculate the nuclear membrane, ER, Golgi, plasma membrane, and cilium were originally distinct prokaryotes. They all come together and share their DNAs. Building a new big chaos. Individual biochemical networks are overlayed in one fused cell. They interact, merge, interfere, etc. A lot of detours. ATP is the standard rule based on oxygen consumption produced by chloroplast and mitochondria. If the replication system works in these fused cells, they keep going, similar to the conditions of prokaryotes. Once the system starts working, trimming the DNA sequence eliminates the chaos. In this state, they are eukaryotes but monocellular organisms.
This is the 2nd round of life history of ‘from chaos to order.’ Chromosome, mitosis, mating and meiosis are created. I speculate that all organelles are ruminants of fused prokaryotes. Diploid life cycle, mating and meiosis are critical to increase the robustness of an organism as a species. In haploid prokaryotes, the fidelity of DNA replication is a limiting factor for their genome size. When detrimental damage or an error mutation during replication is accidentally created, they cannot restore the original sequence—the end of continuity. On the other hand, in diploid organisms, there is the original copy in a cell, even if one copy is damaged. Two possibilities. First, use the original copy to repair the damaged one. Second, separate the damaged one through meiosis. At least one daughter inherits the original copy. Interestingly, the machinery used for repairing a damaged copy with the original one is also essential for successful meiosis. Probably, this robustness permits eukaryotes to carry a larger genome than prokaryotes.
The larger genome allows the organisms to explore new opportunities. Basic 3D motifs and domains of peptides are already created in ancient prokaryotes. ‘Mix & match’ by fusing those motifs and domains further creates new biochemical reactions and cascades. Some proteins accidentally stick out to the extracellular environment. They may interact with any substrate or other proteins sticking out from other cells. Cells start aggregating to each other—the emergence of metazoans. Separation of somatic and germ cells should happen. Mitosis, Meiosis and Mating. The first division of the roles and functions for life continuity. I have no idea how this happens. Once somatic cells are generated, which cannot contribute to reproductive continuity, the unit of reproduction as an organism is shifted from individual cells to multicellular organisms. Somatic cells are the supporters of germ cells. A new nested network that constitutes a multicellular organism is established on top of individual cells. Although the minimum unit of replication is still a cell, the unit of reproduction (or selection) becomes the nested upper network, multicellularity.
For metazoans, ‘alive’ means the highest network that governs the multicellular organism is functional. Even if individual cells are ‘alive,’ the highest network can be dysfunctional. This is ‘death’. The conflicts between parts and a whole emerge. All of these were permitted because of the 2nd round of chaotic DNA sequences. However, the chaos is always disturbing the order. Once the order forms, the chaos should be suppressed or eliminated. In prokaryotes, all unnecessary DNA sequences were trimmed out. This could not be achieved in multicellular organisms because the necessity of individual replication units and the necessity of a whole organism are different. A part of the DNA sequence that does not need one cell type would be required for the other. Therefore, instead of trimming, other mechanisms to suppress the chaos are established in metazoans – such as rules for transcription and translation and epigenetic silencing like DNA and histone methylation.
‘Ontogeny recapitulates phylogeny’ is a very famous phrase by Ernst Haeckel. I see this recapitulation process in mammalian development. Soon after fertilization, the organism goes through the minimum state of DNA and histone methylation. Almost all methylation marks are erased at this transient stage. Chaos. Then, the chaos is progressively repressed towards the final destinations, somatic functional differentiated cells.
In animals, the biochemical chaos encoded in the genome is actively suppressed with various epigenetic mechanisms during development but not entirely eliminated from the genome. This means our cells still carry the hidden biochemical chaos in the genome in non-genic, introns, and non-coding frames. When the energy-dependent suppressive mechanisms are compromised, the inner hidden chaos reappears as cryptic transcription and translation. This happens when a cell gets highly stressed, like acute viral infection and cancer.
Epigenetic mechanisms and rules of transcription and translation work to suppress the chaos to create an order in a cell. Genetic, genomic and epigenetic alterations perturb this order in the cell. Whatever phenotypic changes that are not killing themselves will stay. The higher the stress cells get, the more access to the inner chaos for seeking detours because the stress compromises the energy-demanding suppressive mechanisms.
The conflict between parts and a whole is very interesting. Once the upper nested network is formed, each part cannot maximize its efficiency or benefits. In multicellular organisms, a part is a cell, the minimum replication unit. A whole is an organism, the minimum reproductive unit and the unit of selection. In analogy, this is similar to team sports like basketball and soccer. Players are the minimum unit. Teams are the unit of selection, win or lose. To win a game, the players must work together cooperatively to maximize the team's performance, not for the performance of individuals.
Cancer cells come out from this corporation as a whole of an organism. The minimum replication unit becomes independent from the whole because of epigenetic, genetic and genomic changes accumulated in the progeny of a single cell. There is no intention for cancer cells to dictate the whole. However, the robust detour networks consisting of an organism as a whole try to compensate for their selfish independent behaviours. Without this communication, the impact on the highest network will be minimal. The patients won’t die.
Some people explain this communication as manipulation, as if cancer cells have intentions. There is no intention and manipulation. As the nature of the robust networks, our body maintains a stable homeostatic state. However, the minimum replication unit becomes selfish to maximize its efficiency through errors during DNA replication and cell division. Maximizing the replication efficiency without consideration of overload, energy supply, and quality control. All alerts will be turned on. In addition, the energy-dependent suppressive mechanisms to the inner hidden chaos get compromised due to increased intrinsic and extrinsic stresses. The cells will have access to the chaos of biochemical reactions that are hidden in various forms of DNA sequences like cryptic transcription and translation. Cancer cells are highly opportunistic escapers from the constraint of a whole as an organism. Single-minded improvement in the efficiency of replication places all cellular alerting systems turn on-emergency. Nice neighbours, the surrounding local networks try to compensate for the emergency because those cells cannot be eliminated. In the end, the selfish network that keeps activating alerting systems terminates the highest network as a whole.
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