Quasispecies productivity.

The quasispecies theory is a helpful concept in the explanation of RNA virus evolution and behaviour, with a relevant impact on methods used to fight viral diseases. It has undergone some adaptations to integrate new empirical data, especially the non-deterministic nature of mutagenesis, and the variety of behavioural motifs in cooperation, competition, communication, innovation, integration, and exaptation. Also, the consortial structure of quasispecies with complementary roles of memory genomes of minority populations better fits the empirical data than did the original concept of a master sequence and its mutant spectra. The high productivity of quasispecies variants generates unique sequences that never existed before and will never exist again. In the present essay, we underline that such sequences represent really new ontological entities, not just error copies of previous ones. Their primary unique property, the incredible variant production, is suggested here as quasispecies productivity, which replaces the error-replication narrative to better fit into a new relationship between mankind and living nature in the twenty-first century.

Self-empowerment of life through RNA networks, cells and viruses.

Our understanding of the key players in evolution and of the development of all organisms in all domains of life has been aided by current knowledge about RNA stem-loop groups, their proposed interaction motifs in an early RNA world and their regulative roles in all steps and substeps of nearly all cellular processes, such as replication, transcription, translation, repair, immunity and epigenetic marking. Cooperative evolution was enabled by promiscuous interactions between single-stranded regions in the loops of naturally forming stem-loop structures in RNAs. It was also shown that cooperative RNA stem-loops outcompete selfish ones and provide foundational self-constructive groups (ribosome, editosome, spliceosome, etc.). Self-empowerment from abiotic matter to biological behavior does not just occur at the beginning of biological evolution; it is also essential for all levels of socially interacting RNAs, cells and viruses.

Social Networking of Quasi-Species Consortia drive Virolution via Persistence.

The emergence of cooperative quasi-species consortia (QS-C) thinking from the more accepted quasispecies equations of Manfred Eigen, provides a conceptual foundation from which concerted action of RNA agents can now be understood. As group membership becomes a basic criteria for the emergence of living systems, we also start to understand why the history and context of social RNA networks become crucial for survival and function. History and context of social RNA networks also lead to the emergence of a natural genetic code. Indeed, this QS-C thinking can also provide us with a transition point between the chemical world of RNA replicators and the living world of RNA agents that actively differentiate self from non-self and generate group identity with membership roles. Importantly the social force of a consortia to solve complex, multilevel problems also depend on using opposing and minority functions. The consortial action of social networks of RNA stem-loops subsequently lead to the evolution of cellular organisms representing a tree of life.

Preliminary remarks to an integrative theory of evolution.

For nearly a century the main focus in biological disciplines such as molecular biology, biochemistry, genetics and evolutionary theory was cellular life as a machine like process in which mechanistic pathways regulate metabolism, genetic reading and translation into proteins and evolution by variations (random error replications) and selection. Modern biochemistry started with the cellular theory of life. Also the modern synthesis focused on cells at the starting event of life. The dominance of this paradigm lasted until ten years ago. Then the comeback of virology offered new empirical data and explanatory models of how viruses determine cellular life through an abundance of parasite host interactions that overrule cellular processes. The RNA world hypothesis demonstrated that prior to cellular life RNA group interactions were at the beginning of biological selection before cellular life emerged. Last but not least the central dogma of molecular biology collapsed when epigenetics demonstrated that history and developmental experiences of the past can be epigenetically imprinted and serve as identity markings that in every replication process of any cell in any organism on this planet the timely and locally coordinated replication is regulated and orchestrated by these programmings. In the light of this knowledge a better explanatory model than an extension of the modern synthesis will be more successful in the 21st century.

That is life: communicating RNA networks from viruses and cells in continuous interaction.

All the conserved detailed results of evolution stored in DNA must be read, transcribed, and translated via an RNA-mediated process. This is required for the development and growth of each individual cell. Thus, all known living organisms fundamentally depend on these RNA-mediated processes. In most cases, they are interconnected with other RNAs and their associated protein complexes and function in a strictly coordinated hierarchy of temporal and spatial steps (i.e., an RNA network). Clearly, all cellular life as we know it could not function without these key agents of DNA replication, namely rRNA, tRNA, and mRNA. Thus, any definition of life that lacks RNA functions and their networks misses an essential requirement for RNA agents that inherently regulate and coordinate (communicate to) cells, tissues, organs, and organisms. The precellular evolution of RNAs occurred at the core of the emergence of cellular life and the question remained of how both precellular and cellular levels are interconnected historically and functionally. RNA networks and RNA communication can interconnect these levels. With the reemergence of virology in evolution, it became clear that communicating viruses and subviral infectious genetic parasites are bridging these two levels by invading, integrating, coadapting, exapting, and recombining constituent parts in host genomes for cellular requirements in gene regulation and coordination aims. Therefore, a 21st century understanding of life is of an inherently social process based on communicating RNA networks, in which viruses and cells continuously interact.

Two genetic codes: Repetitive syntax for active non-coding RNAs; non-repetitive syntax for the DNA archives.

Current knowledge of the RNA world indicates 2 different genetic codes being present throughout the living world. In contrast to non-coding RNAs that are built of repetitive nucleotide syntax, the sequences that serve as templates for proteins share-as main characteristics-a non-repetitive syntax. Whereas non-coding RNAs build groups that serve as regulatory tools in nearly all genetic processes, the coding sections represent the evolutionarily successful function of the genetic information storage medium. This indicates that the differences in their syntax structure are coherent with the differences of the functions they represent. Interestingly, these 2 genetic codes resemble the function of all natural languages, i.e., the repetitive non-coding sequences serve as appropriate tool for organization, coordination and regulation of group behavior, and the non-repetitive coding sequences are for conservation of instrumental constructions, plans, blueprints for complex protein-body architecture. This differentiation may help to better understand RNA group behavioral motifs.

The biocommunication method: On the road to an integrative biology.

Although molecular biology, genetics, and related special disciplines represent a large amount of empirical data, a practical method for the evaluation and overview of current knowledge is far from being realized. The main concepts and narratives in these fields have remained nearly the same for decades and the more recent empirical data concerning the role of noncoding RNAs and persistent viruses and their defectives do not fit into this scenario. A more innovative approach such as applied biocommunication theory could translate empirical data into a coherent perspective on the functions within and between biological organisms and arguably lead to a sustainable integrative biology.

Crucial steps to life: From chemical reactions to code using agents.

The concepts of the origin of the genetic code and the definitions of life changed dramatically after the RNA world hypothesis. Main narratives in molecular biology and genetics such as the "central dogma," "one gene one protein" and "non-coding DNA is junk" were falsified meanwhile. RNA moved from the transition intermediate molecule into centre stage. Additionally the abundance of empirical data concerning non-random genetic change operators such as the variety of mobile genetic elements, persistent viruses and defectives do not fit with the dominant narrative of error replication events (mutations) as being the main driving forces creating genetic novelty and diversity. The reductionistic and mechanistic views on physico-chemical properties of the genetic code are no longer convincing as appropriate descriptions of the abundance of non-random genetic content operators which are active in natural genetic engineering and natural genome editing.

Can subcellular organization be explained only by physical principles?

In a recent forum article, Dan Needleman and Jan Brugues argue that, despite the astonishing advances in cell biology, a fundamental understanding of even the most well-studied subcellular biological processes is lacking.(1) This lack of understanding is evidenced by our inability to make precise predictions of subcellular and cellular behaviors. They suggest that to achieve such an understanding, we need to apply a combination of quantitative experiments with new theoretical concepts and determine the physical principles of subcellular biological organization.(1) We discuss these issues and suggest that, besides biophysics, we need strong theoretical inputs from biocommunication theory in order to understand all the core agents of the cellular life and subcellular organization.

When Competing Viruses Unify: Evolution, Conservation, and Plasticity of Genetic Identities.

In the early 1970s, Manfred Eigen and colleagues developed the quasispecies model (qs) for the population-based origin of RNAs representing the early genetic code. The Eigen idea is basically that a halo of mutants is generated by error-prone replication around the master fittest type which will behave similarly as a biological population. But almost from the start, very interesting and unexpected observations were made regarding competition versus co-operation which suggested more complex interactions. It thus became increasingly clear that although viruses functioned similar to biological species, their behavior was much more complex than the original theory could explain, especially adaptation without changing the consensus involving minority populations. With respect to the origin of natural codes, meaning, and code-use in interactions (communication), it also became clear that individual fittest type-based mechanisms were likewise unable to explain the origin of natural codes such as the genetic code with their context- and consortia-dependence (pragmatic nature). This, instead, required the participation of groups of agents competent in the code and able to edit code because natural codes do not code themselves. Three lines of inquiry, experimental virology, quasispecies theory, and the study of natural codes converged to indicate that consortia of co-operative RNA agents such as viruses must be involved in the fitness of RNA and its involvement in communication, i.e., code-competent interactions. We called this co-operative form quasispecies consortia (qs-c). They are the essential agents that constitute the possibility of evolution of biological group identity. Finally, the basic interactional motifs for the emergence of group identity, communication, and co-operation-together with its opposing functions-are explained by the "Gangen" hypothesis.

Life is physics and chemistry and communication.

Manfred Eigen extended Erwin Schroedinger's concept of "life is physics and chemistry" through the introduction of information theory and cybernetic systems theory into "life is physics and chemistry and information." Based on this assumption, Eigen developed the concepts of quasispecies and hypercycles, which have been dominant in molecular biology and virology ever since. He insisted that the genetic code is not just used metaphorically: it represents a real natural language. However, the basics of scientific knowledge changed dramatically within the second half of the 20th century. Unfortunately, Eigen ignored the results of the philosophy of science discourse on essential features of natural languages and codes: a natural language or code emerges from populations of living agents that communicate. This contribution will look at some of the highlights of this historical development and the results relevant for biological theories about life.

RNA sociology: group behavioral motifs of RNA consortia.

RNA sociology investigates the behavioral motifs of RNA consortia from the social science perspective. Besides the self-folding of RNAs into single stem loop structures, group building of such stem loops results in a variety of essential agents that are highly active in regulatory processes in cellular and non-cellular life. RNA stem loop self-folding and group building do not depend solely on sequence syntax; more important are their contextual (functional) needs. Also, evolutionary processes seem to occur through RNA stem loop consortia that may act as a complement. This means the whole entity functions only if all participating parts are coordinated, although the complementary building parts originally evolved for different functions. If complementary groups, such as rRNAs and tRNAs, are placed together in selective pressure contexts, new evolutionary features may emerge. Evolution initiated by competent agents in natural genome editing clearly contrasts with statistical error replication narratives.

Life is more than a computer running DNA software.

In his recent interview for the Guardian Craig Venter is elaborating about a household appliance for the future, Digital Biological Converter (DBC). Current prototype, which can produce DNA, is a box attached to the computer which receives DNA sequences over the internet to synthesize DNA; later in future also viruses, proteins, and living cells. This would help the household members to produce, e.g., insulin, virus vaccines or phages that fight antibiotic resistant bacteria. In more distant future, Craig Venter's hope is that the DBC will generate living cells via so-called "Universal Recipient Cell". This platform will allow digitally transformed genomes, downloaded from the internet, to form new cells fitted for the particular needs such as therapeutics, food, fuel or cleaning water. In contrast to this, the authors propose that DNA sequences of genomes do not represent 1:1 depictions of unequivocal coding structures such as genes. In light of the variety of epigenetic markings, DNA can store a multitude of further meanings hidden under the superficial grammar of nucleic acid sequences.

Pragmatic turn in biology: From biological molecules to genetic content operators.

Erwin Schrödinger's question "What is life?" received the answer for decades of "physics + chemistry". The concepts of Alain Turing and John von Neumann introduced a third term: "information". This led to the understanding of nucleic acid sequences as a natural code. Manfred Eigen adapted the concept of Hammings "sequence space". Similar to Hilbert space, in which every ontological entity could be defined by an unequivocal point in a mathematical axiomatic system, in the abstract "sequence space" concept each point represents a unique syntactic structure and the value of their separation represents their dissimilarity. In this concept molecular features of the genetic code evolve by means of self-organisation of matter. Biological selection determines the fittest types among varieties of replication errors of quasi-species. The quasi-species concept dominated evolution theory for many decades. In contrast to this, recent empirical data on the evolution of DNA and its forerunners, the RNA-world and viruses indicate cooperative agent-based interactions. Group behaviour of quasi-species consortia constitute de novo and arrange available genetic content for adaptational purposes within real-life contexts that determine epigenetic markings. This review focuses on some fundamental changes in biology, discarding its traditional status as a subdiscipline of physics and chemistry.

Rethinking quasispecies theory: From fittest type to cooperative consortia.

Recent investigations surprisingly indicate that single RNA "stem-loops" operate solely by chemical laws that act without selective forces, and in contrast, self-ligated consortia of RNA stem-loops operate by biological selection. To understand consortial RNA selection, the concept of single quasi-species and its mutant spectra as drivers of RNA variation and evolution is rethought here. Instead, we evaluate the current RNA world scenario in which consortia of cooperating RNA stem-loops (not individuals) are the basic players. We thus redefine quasispecies as RNA quasispecies consortia (qs-c) and argue that it has essential behavioral motifs that are relevant to the inherent variation, evolution and diversity in biology. We propose that qs-c is an especially innovative force. We apply qs-c thinking to RNA stem-loops and evaluate how it yields altered bulges and loops in the stem-loop regions, not as errors, but as a natural capability to generate diversity. This basic competence-not error-opens a variety of combinatorial possibilities which may alter and create new biological interactions, identities and newly emerged self identity (immunity) functions. Thus RNA stem-loops typically operate as cooperative modules, like members of social groups. From such qs-c of stem-loop groups we can trace a variety of RNA secondary structures such as ribozymes, viroids, viruses, mobile genetic elements as abundant infection derived agents that provide the stem-loop societies of small and long non-coding RNAs.

At the dawn of a new revolution in life sciences.

In a recently published article Sydney Brenner argued that the most relevant scientific revolution in biology at his time was the breakthrough of the role of "information" in biology. The fundamental concept that integrates this new biological "information" with matter and energy is the universal Turing machine and von Neumann's self-reproducing machines. In this article we demonstrate that in contrast to Turing/von Neumann machines living cells can really reproduce themselves. Additionally current knowledge on the roles of non-coding RNAs indicates a radical violation of the central dogma of molecular biology and opens the way to a new revolution in life sciences.