Evolution of Evolution of Complex Complex SystemsSystems

Lecture 4: Cells and genomeLecture 4: Cells and genome

Peter Andras / Bruce CharltonPeter Andras / Bruce Charlton

peter.andras@ncl.ac.ukpeter.andras@ncl.ac.uk

bruce.charlton@ncl.ac.ukbruce.charlton@ncl.ac.uk

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ObjectivesObjectives

The cell systemThe cell system The language of the cellThe language of the cell Memories in the cell: RNA and DNAMemories in the cell: RNA and DNA Genome = information subsystem of the Genome = information subsystem of the

cellcell The genome systemThe genome system Identity of the cellIdentity of the cell Identity violation and adaptation in the cellIdentity violation and adaptation in the cell Cell and genome complexityCell and genome complexity

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CellsCells

Bacteria, plant and animal cells – Bacteria, plant and animal cells – constituents of tissuesconstituents of tissues

E.g., neuron, muscle cell etc.E.g., neuron, muscle cell etc.

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Cell structureCell structure

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Cell wall and membraneCell wall and membrane

Delimiting from the exteriorDelimiting from the exterior Defines outer formDefines outer form Semi-permeable structure composed Semi-permeable structure composed

of lipo – protein complexesof lipo – protein complexes

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Cytoplasm and cellular Cytoplasm and cellular organellesorganelles

Cytoplasm: solution of proteins and Cytoplasm: solution of proteins and metabolites organised in metabolites organised in membranes and intra-cellular membranes and intra-cellular matrixmatrix

Cellular organelles: perform Cellular organelles: perform various functions (cellular motion, various functions (cellular motion, secretion, digestion, etc.)secretion, digestion, etc.)

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The nucleusThe nucleus

DNA, chromatin, RNADNA, chromatin, RNA Contains the code describing cell Contains the code describing cell

componentscomponents Genes code proteinsGenes code proteins Adenin – A, Cytosin – C, Guanin – Adenin – A, Cytosin – C, Guanin –

G, Thymin – TG, Thymin – T DNA: organised in genes and non-DNA: organised in genes and non-

coding segmentscoding segments

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Cell behaviourCell behaviour

Selection of resources: channels, Selection of resources: channels, diffusion, fagocitosisdiffusion, fagocitosis

DigestionDigestion Generation of new proteins the main Generation of new proteins the main

building blocks of the cellbuilding blocks of the cell Multiplication: self-replicationMultiplication: self-replication Self-defence: secretion of self-Self-defence: secretion of self-

defensive proteins (e.g., anti-defensive proteins (e.g., anti-penicillin proteins)penicillin proteins)

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Cell behaviour – Revisited Cell behaviour – Revisited The cell produces proteins at the The cell produces proteins at the

ribosomes using RNA copies of the DNA ribosomes using RNA copies of the DNA genesgenes

The proteins participate in the The proteins participate in the transformation of other proteins and transformation of other proteins and metabolites (e.g., lipids, sugars, etc.)metabolites (e.g., lipids, sugars, etc.)

Some proteins select good resources (e.g., Some proteins select good resources (e.g., channel proteins), others trigger self-channel proteins), others trigger self-defence responses (e.g., receptor defence responses (e.g., receptor proteins), others act as enzymes proteins), others act as enzymes catalysing reactions between proteinscatalysing reactions between proteins

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Amino acidsAmino acids

20 amino acids, encoded by DNA / RNA20 amino acids, encoded by DNA / RNA

(www.chemie.fu-berlin.de/chemistry/bio/amino-acids_en.html)

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Amino acidsAmino acids

(www.chemie.fu-berlin.de/chemistry/bio/amino-acids_en.html)

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ProteinsProteins

primary structure: primary structure: amino acid sequenceamino acid sequence

secondary structure: secondary structure: -helix, -helix, -sheets-sheets

tertiary structure: tertiary structure: protein foldingprotein folding

quaternary structure: quaternary structure: active sitesactive sites

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Proteins in actionProteins in action

Quaternary structure, active sites, Quaternary structure, active sites, active site dynamicsactive site dynamics

Linking to other proteins, Linking to other proteins, metabolite molecules, ionsmetabolite molecules, ions

E.g., linking of sugar molecules E.g., linking of sugar molecules and enzymes to produce energy and enzymes to produce energy storage moleculesstorage molecules

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Protein interactionsProtein interactions

Proteins form protein complexes Proteins form protein complexes and intermediary productsand intermediary products

Enzyme proteins, functional cyclesEnzyme proteins, functional cycles

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Signalling pathwaysSignalling pathways

Receptors are activated by outside Receptors are activated by outside moleculesmolecules

Activated receptors trigger a series Activated receptors trigger a series of interactions between proteins and of interactions between proteins and proteins and metabolite moleculesproteins and metabolite molecules

E.g., neurotransmitter molecule E.g., neurotransmitter molecule links to receptor molecule, the links to receptor molecule, the linking triggers the opening of linking triggers the opening of channel moleculeschannel molecules

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Communications in the Communications in the cellcell

Spatio-temporal pattern of protein Spatio-temporal pattern of protein interactionsinteractions

Communication units: proteins and Communication units: proteins and other moleculesother molecules

Communications: molecular Communications: molecular interactions, primarily protein interactions, primarily protein interactionsinteractions

E.g., signaling pathways, cell wall E.g., signaling pathways, cell wall synthesissynthesis

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Referencing in the cellReferencing in the cell

Each interaction references other Each interaction references other interactions by taking their products interactions by taking their products as parts of new interactionsas parts of new interactions

E.g., functional cyclesE.g., functional cycles

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The system boundaryThe system boundary

Intense communications within the Intense communications within the cellcell

Rare communications with the Rare communications with the exterior of the cell (e.g., receptors exterior of the cell (e.g., receptors linking to transmitters)linking to transmitters)

Boundary: cell membraneBoundary: cell membrane

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Actions of the cellActions of the cell

Actions: sequence or pattern of Actions: sequence or pattern of communications:communications: that produce proteins incorporated in the that produce proteins incorporated in the

cell membrane as receptors or signallerscell membrane as receptors or signallers that lead to the production of proteins and that lead to the production of proteins and

other compounds of cell secretionsother compounds of cell secretions that lead to the production of body that lead to the production of body

movements of the cellmovements of the cell Actions are referred by other Actions are referred by other

communications within the cellcommunications within the cell

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Perceptions of the cellPerceptions of the cell

Receptors bind to messenger Receptors bind to messenger moleculesmolecules

Ions and molecules enter the cell Ions and molecules enter the cell and interact with proteins of the and interact with proteins of the cellcell

The results of perceptions are The results of perceptions are referenced by other cell referenced by other cell communicationscommunications

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The cell as a systemThe cell as a system

Protein interaction communications about Protein interaction communications about the cell – what is the cell and what is not the cell – what is the cell and what is not the cell – definition of the cell’s identitythe cell – definition of the cell’s identity

These interactions decide what can be These interactions decide what can be incorporated into further communications incorporated into further communications of the cell (i.e., into proteins and cell of the cell (i.e., into proteins and cell metabolites) and what cannot serve for metabolites) and what cannot serve for this purposethis purpose

The cell’s aim is the reproduction and The cell’s aim is the reproduction and expansion of itselfexpansion of itself

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Meaningful and Meaningful and meaninglessmeaningless

Meaningful: sequence / pattern of protein Meaningful: sequence / pattern of protein interactions that lead to the incorporation interactions that lead to the incorporation / elimination into / from the cell of / elimination into / from the cell of metabolites resulting new protein metabolites resulting new protein interactionsinteractions

Meaningless: sequence / pattern of Meaningless: sequence / pattern of protein interactions that lead nowhere, protein interactions that lead nowhere, i.e., the products of interactions cannot i.e., the products of interactions cannot be part of cell communications, but they be part of cell communications, but they are not eliminated from the cell – they are not eliminated from the cell – they constitute identity violations of the cellconstitute identity violations of the cell

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Antibiotics, toxins, prionsAntibiotics, toxins, prions Antibiotics, toxins, prions generate Antibiotics, toxins, prions generate

interactions that lead to meaningless interactions that lead to meaningless communications communications faults and errors in faults and errors in the cellthe cell

I.e., they bind to proteins blocking their I.e., they bind to proteins blocking their activity and stopping normal activity and stopping normal communications by forming products communications by forming products that cannot participate in thesethat cannot participate in these

Many meaningless communications Many meaningless communications reduce the communications within the reduce the communications within the cell and lead to the disintegration of the cell and lead to the disintegration of the cell system cell system failure of the cell system failure of the cell system

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The language of the cellThe language of the cell The language units are sequences / patterns The language units are sequences / patterns

of protein and metabolite interactionsof protein and metabolite interactions The grammar: the rules and the conditional The grammar: the rules and the conditional

probabilities of such sequences and patterns probabilities of such sequences and patterns of interactionsof interactions

Referencing rules: what interactions are Referencing rules: what interactions are required to produce the necessary required to produce the necessary ingredients for the production of a new ingredients for the production of a new interactioninteraction

Continuation rules: given a set of Continuation rules: given a set of interactions what are the interactions that interactions what are the interactions that may be produced as continuation to themmay be produced as continuation to them

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Structures and subsystems of Structures and subsystems of the cellthe cell

Structures – constraints on communications Structures – constraints on communications constraints on referencing and continuation constraints on referencing and continuation rules of protein interactionsrules of protein interactions

Clusters of protein interactions satisfying Clusters of protein interactions satisfying additional constraints on protein interactionsadditional constraints on protein interactions

Constraints: e.g. being inside of a vesicle, being Constraints: e.g. being inside of a vesicle, being bound to some other moleculebound to some other molecule

Such clusters may constitute cellular organelles Such clusters may constitute cellular organelles or functional subsystems of protein interactionsor functional subsystems of protein interactions

E.g., respiration – mitochondria, movement – E.g., respiration – mitochondria, movement – centrosome, digestioncentrosome, digestion

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Memories of protein Memories of protein interactionsinteractions

mRNA molecules facilitate the reproduction of mRNA molecules facilitate the reproduction of interactions between chains of amino acids and interactions between chains of amino acids and single amino acids during protein synthesissingle amino acids during protein synthesis

mRNA molecules in one species may encode a mRNA molecules in one species may encode a combination of proteins that are encoded combination of proteins that are encoded separately in other speciesseparately in other species

RNA molecules generate the appropriate RNA molecules generate the appropriate combination of proteins within the cell to combination of proteins within the cell to produce the right behaviour of the cell through produce the right behaviour of the cell through protein interactionsprotein interactions

RNA molecules can be seen as memories of RNA molecules can be seen as memories of protein interactions, which facilitate the protein interactions, which facilitate the reproduction of these interactions within the reproduction of these interactions within the cellcell

See also recent result about gene correction in See also recent result about gene correction in Arabidopsis supposed to be mediated by RNAsArabidopsis supposed to be mediated by RNAs

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RNA interactionsRNA interactions

RNA molecules interact and regulate the RNA molecules interact and regulate the production of proteins within the cellproduction of proteins within the cell

siRNA, microRNA, other non-coding siRNA, microRNA, other non-coding RNAsRNAs

Premature mRNA includes the mRNA Premature mRNA includes the mRNA and also other small RNAs that and also other small RNAs that participate in RNA interactionsparticipate in RNA interactions

RNA interactions constitute a primary RNA interactions constitute a primary information subsystem of the cell information subsystem of the cell RNA worldRNA world

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Memories of RNA Memories of RNA interactionsinteractions

RNA molecules are produced by copying RNA molecules are produced by copying segments of the DNAsegments of the DNA

Premature mRNA – includes several RNAs, Premature mRNA – includes several RNAs, which may interactwhich may interact

Appropriate combinations of RNA molecules Appropriate combinations of RNA molecules are produced from active parts of the DNA are produced from active parts of the DNA leading to appropriate regulation of protein leading to appropriate regulation of protein production – segments of the DNA facilitate production – segments of the DNA facilitate the reproduction of RNA interactionsthe reproduction of RNA interactions

DNA can be seen as memory of RNA DNA can be seen as memory of RNA interactions, and implicitly also as a memory interactions, and implicitly also as a memory of protein interactionsof protein interactions

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The information The information subsystemsubsystem

DNA segments, RNAs and proteins interact to DNA segments, RNAs and proteins interact to regulate the dynamics of active parts of the regulate the dynamics of active parts of the DNADNA

These interactions between DNA segments These interactions between DNA segments and other molecules constitute the information and other molecules constitute the information subsystem of the cellsubsystem of the cell

Genome: description of all proteins produced Genome: description of all proteins produced and used in the cell, regulating the appropriate and used in the cell, regulating the appropriate production of them mediated by RNAs and production of them mediated by RNAs and RNA interactionsRNA interactions

The genome is the information subsystem of The genome is the information subsystem of the cell system the cell system

The genome defines the identity of the cellThe genome defines the identity of the cell

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Prokaryotes Prokaryotes

Bacteria: no nucleus, diffuse genomeBacteria: no nucleus, diffuse genome The information subsystem is there but The information subsystem is there but

is not yet organised as an integrated is not yet organised as an integrated and well separated subsystem (i.e., it is and well separated subsystem (i.e., it is organised in functional plasmids)organised in functional plasmids)

Large part (>75%) direct coding Large part (>75%) direct coding genome, relatively high level of genome, relatively high level of interaction between the whole genome interaction between the whole genome and the proteins of the celland the proteins of the cell

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Eukaryotes Eukaryotes

Cells with proper nucleusCells with proper nucleus Genome in the nucleus, Genome in the nucleus,

surrounded by nuclear membranesurrounded by nuclear membrane Separated information subsystemSeparated information subsystem Low proportion (even <5%) direct Low proportion (even <5%) direct

coding genomecoding genome

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GenomeGenome

A – adenin, C – cytosin, G – guanin, A – adenin, C – cytosin, G – guanin, T – thyminT – thymin

Coding / non-coding regulatory / Coding / non-coding regulatory / junk segmentsjunk segments

Organized into base pairs (AT, CG) Organized into base pairs (AT, CG) and codons (triplets of base pairs) and codons (triplets of base pairs) coding amino acidscoding amino acids

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Gene regulationGene regulation

Regulatory networks of genes and Regulatory networks of genes and regulatory genome segmentsregulatory genome segments

Up and down regulation of the Up and down regulation of the amount of proteins produced amount of proteins produced within the cellwithin the cell

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Communications in the Communications in the genomegenome

Sequences and patterns of Sequences and patterns of interacting / inter-regulating genes interacting / inter-regulating genes and regulatory segmentsand regulatory segments

E.g., gene regulatory networksE.g., gene regulatory networks

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Referencing in the Referencing in the genomegenome

New communications reference New communications reference earlier / other regulatory actionsearlier / other regulatory actions

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The system boundaryThe system boundary

Intense regulatory interactions Intense regulatory interactions within the genomewithin the genome

Few interactions with the outside Few interactions with the outside of the nucleusof the nucleus

Signalling proteins trigger Signalling proteins trigger cascades of regulatory interactions cascades of regulatory interactions turning on and off the production turning on and off the production of series of proteinsof series of proteins

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Genome actionsGenome actions

Actions: production of mRNA, tRNA Actions: production of mRNA, tRNA and other RNA molecules that are and other RNA molecules that are sent out into the cell to interact sent out into the cell to interact with proteins therewith proteins there

These processes are also These processes are also referenced by further genome referenced by further genome interactionsinteractions

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Genome perceptionsGenome perceptions

Perceptions: triggering the activity of Perceptions: triggering the activity of genes and regulatory genome genes and regulatory genome segments by proteins produced in the segments by proteins produced in the cellcell

These processes lead to the These processes lead to the generation of new genome generation of new genome communications (e.g., cascades of communications (e.g., cascades of turning on or off of genes and turning on or off of genes and regulatory genome segments) regulatory genome segments)

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The genome as a systemThe genome as a system

Genome segment interaction Genome segment interaction communications about the identity of the communications about the identity of the cellcell

These interactions decide what is accepted These interactions decide what is accepted as fitting to the identity of the cell and what as fitting to the identity of the cell and what is not (i.e., which coding segments of the is not (i.e., which coding segments of the genome should be active and produce genome should be active and produce mRNAs, tRNAs, and which should not)mRNAs, tRNAs, and which should not)

The genome’s aim is its own maintenance The genome’s aim is its own maintenance and expansionand expansion

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Genome expansionGenome expansion

Genome expansion: replication of Genome expansion: replication of the genomethe genome

Genome replication induces cell Genome replication induces cell division division expansion of the cell expansion of the cell

Multi-nuclear cells ?Multi-nuclear cells ?

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System language in the System language in the genomegenome

Language units: regulatory Language units: regulatory interactions of genome segmentsinteractions of genome segments

Grammar: the rules of conditional Grammar: the rules of conditional continuation probabilities of such continuation probabilities of such interactions interactions

Referencing rules and continuation Referencing rules and continuation rulesrules

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Meaningful and Meaningful and meaninglessmeaningless

Meaningful: regulatory interactions that Meaningful: regulatory interactions that lead to continuation and to the production lead to continuation and to the production of RNAs and proteins that fit the identity of of RNAs and proteins that fit the identity of the cell and produce appropriate the cell and produce appropriate communications within the cellcommunications within the cell

Meaningless: interactions that don’t fit the Meaningless: interactions that don’t fit the identity of the cell and lead to meaningless identity of the cell and lead to meaningless communications within the cell (e.g., viral communications within the cell (e.g., viral DNA, some mutated DNA) – faults and DNA, some mutated DNA) – faults and errorserrors

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VirusesViruses

Pure DNA in lipo-peptide envelopePure DNA in lipo-peptide envelope Possibly: a cell memory alone in an Possibly: a cell memory alone in an

optimised / simplified form which optimised / simplified form which waits for the cell to incorporate it, waits for the cell to incorporate it, so that it can multiplyso that it can multiply

They are usually meaningless in They are usually meaningless in the host cell and may cause cell the host cell and may cause cell deathdeath

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Faults, errors and failureFaults, errors and failure Fault: communication that doesn’t fit the Fault: communication that doesn’t fit the

language – e.g. interactions of wrong proteins language – e.g. interactions of wrong proteins produced after antibiotic treatment of a produced after antibiotic treatment of a bacterium, viral genome interactionsbacterium, viral genome interactions

Error: lack of continuation communications – Error: lack of continuation communications – e.g. lack of expected protein interactions in an e.g. lack of expected protein interactions in an environment lacking critical nutrientsenvironment lacking critical nutrients

Failure: large scale contraction of the cell Failure: large scale contraction of the cell system due to faults and errors – e.g. effect of system due to faults and errors – e.g. effect of antibiotic on bacteria, radioactive damage to antibiotic on bacteria, radioactive damage to the genomethe genome

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Adaptation – Cell Adaptation – Cell E.g. the nutrient environment of a E.g. the nutrient environment of a

bacterium changes; a neuron receives a bacterium changes; a neuron receives a certain pattern of spike inputcertain pattern of spike input

Cell perception – difference between Cell perception – difference between expectation and actual protein interactions expectation and actual protein interactions – an error in the context of expectations– an error in the context of expectations

A new set of protein interactions is A new set of protein interactions is triggered aimed to remove the root of triggered aimed to remove the root of experienced identity violation – i.e. experienced identity violation – i.e. prevent the formation of unsatisfied prevent the formation of unsatisfied expectationexpectation

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Adaptation – GenomeAdaptation – Genome Identity violations experienced by the cell system Identity violations experienced by the cell system

translate into identity violations experienced in translate into identity violations experienced in the information subsystem of the cellthe information subsystem of the cell

The information subsystem acts by identity The information subsystem acts by identity revision communications in the form of revision communications in the form of generating RNAs that were not present in the generating RNAs that were not present in the previous moment in the cell leading to the previous moment in the cell leading to the production of new proteins and the adaptation of production of new proteins and the adaptation of the cell’s protein interaction systemthe cell’s protein interaction system

E.g. changing receptor and ion channel E.g. changing receptor and ion channel expression pattern in neurons in response to expression pattern in neurons in response to received stimulireceived stimuli

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Adaptation of the genomeAdaptation of the genome

RNA mediated corrective RNA mediated corrective adaptation of the genome in adaptation of the genome in mutant Arabidopsismutant Arabidopsis

Emergence of antibiotic resistant Emergence of antibiotic resistant bacteria – identity revision by bacteria – identity revision by mutation and selectionmutation and selection

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Complexity of cellsComplexity of cells

Prokaryotes (bacteria) are simpler Prokaryotes (bacteria) are simpler and produce low amount of and produce low amount of biomassbiomass

Eukaryotes are more complex, Eukaryotes are more complex, having a differentiated and having a differentiated and integrated cell information integrated cell information subsystem, and produce high subsystem, and produce high amount of biomassamount of biomass

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Complexity of the genomeComplexity of the genome

Genomes with more regulatory Genomes with more regulatory and less coding parts are more and less coding parts are more complex as they model a larger complex as they model a larger part of their environment, part of their environment, producing better actions / producing better actions / perceptionsperceptions

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Summary - 1Summary - 1

Cell:Cell: Communications: protein interactionsCommunications: protein interactions Cell systemCell system Cell languageCell language Action and perceptionAction and perception Meaning and meaninglessMeaning and meaningless Structure and subsystemsStructure and subsystems MemoryMemory Information subsystemInformation subsystem

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Summary – 2 Summary – 2

Genome:Genome: CommunicationsCommunications LanguageLanguage Genome systemGenome system Action and perceptionAction and perception Meaning and meaninglessMeaning and meaningless Complexity Complexity

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Q&A – 1 Q&A – 1

1.1. Is it true that nucleic acids are part of Is it true that nucleic acids are part of proteins ?proteins ?

2.2. Is it true that neurotransmitter Is it true that neurotransmitter molecules may become part of the cell molecules may become part of the cell system communications in neurons ?system communications in neurons ?

3.3. Is it true that the secretion products of Is it true that the secretion products of a cell are part of the cell system ?a cell are part of the cell system ?

4.4. Is it true that a prion may cause Is it true that a prion may cause meaningless communications within a meaningless communications within a cell ?cell ?

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Q&A – 2 Q&A – 2

5. Is it true that the change of active sites 5. Is it true that the change of active sites of a protein represents the effect of a of a protein represents the effect of a communication reference in the cell communication reference in the cell system ?system ?

6. Is it true that the penicillin may become 6. Is it true that the penicillin may become part of a cell system if it contains part of a cell system if it contains penicillinase enzymes ?penicillinase enzymes ?

7. Can we see the ion combination rules 7. Can we see the ion combination rules as part of the cell language grammar ?as part of the cell language grammar ?

8. Is it true that the genome is the 8. Is it true that the genome is the information subsystem of the cell ?information subsystem of the cell ?

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Q&A – 3 Q&A – 3

9. Is it true that the generation of an mRNA 9. Is it true that the generation of an mRNA is a result of referencing to other genome is a result of referencing to other genome communications ?communications ?

10. Is it true that mRNAs represent the 10. Is it true that mRNAs represent the perceptions of the genome system ?perceptions of the genome system ?

11. Is it true that the language of the 11. Is it true that the language of the genome system is defined by grammatical genome system is defined by grammatical rules representing the conditional rules representing the conditional probabilities of genome communications ?probabilities of genome communications ?