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The wood-eating termites evolved 140 million years ago in the Early Cretaceous. Symbiotic microbial communities developed in their hindguts that allowed them to survive on a diet of lignocelluloses, and coevolved into an obligate association that was vertically transmitted through the colony. A typical gut’s microbial community consists of several types of anaerobic protists and hundreds of prokaryotes, many of which are specialized to the gut, and include novel chemoautotrophic forms. Gut-inhabiting protists harbor ecto- and endosymbiotic prokaryotes that have been studied as analogs of early cellular evolution. Genomic studies have revealed a great deal more molecular genetic diversity in the community than was previously known, and are producing the first complete genomes of the bacterial endosymbionts. Experimental studies of the community have lagged because many of the organisms have proven difficult to culture.

Cancer cells rapidly evolve drug resistance through somatic evolution and, in order to continue growth in the metastatic phase, violate the organism-wide consensus of regulated growth and beneficial communal interactions. We suggest that there is a fundamental mechanistic connection between the rapid evolution of resistance to chemotherapy in cellular communities within malignant tissues and the rapid evolution of antibiotic resistance in bacterial communities. We propose that this evolution is the result of a programmed and collective stress response performed by interacting cells, and that, given this fundamental connection, studying bacterial communities can provide deeper insights into the dynamics of adaptation and the evolution of cells within tumours.

SUMMARYSingle-celled parasites like Entamoeba, Trypanosoma, Phytophthora and Plasmodium wreak untold havoc on human habitat and health. Understanding the position of the various protistan pathogens in the larger context of eukaryotic diversity informs our study of how these parasites operate on a cellular level, as well as how they have evolved. Here, we review the literature that has brought our understanding of eukaryotic relationships from an idea of parasites as primitive cells to a crystallized view of diversity that encompasses 6 major divisions, or supergroups, of eukaryotes. We provide an updated taxonomic scheme (for 2011), based on extensive genomic, ultrastructural and phylogenetic evidence, with three differing levels of taxonomic detail for ease of referencing and accessibility (see supplementary material at Cambridge Journals On-line). Two of the most pressing issues in cellular evolution, the root of the eukaryotic tree and the evolution of photosynthesis in complex algae, are also discussed along with ideas about what the new generation of genome sequencing technologies may contribute to the field of eukaryotic systematics. We hope that, armed with this user's guide, cell biologists and parasitologists will be encouraged about taking an increasingly evolutionary point of view in the battle against parasites representing real dangers to our livelihoods and lives.

The awareness that genes and genomes are extraordinarily rich historical documents from which a wealth of evolutionary information can be retrieved has widened the range of phylogenetic studies to previously unsuspected heights. The development of ef! cient sequencing techniques, which now allows the rapid sequencing of complete cellular genomes, combined with the simultaneous and independent blossoming of computer science, has led not only to an explosive growth of databases and new sophisticated tools for their exploitation, but also to the recognition that, in spite of many lateral gene-transfer events (LGT), different macromolecules are uniquely suited as molecular chronometers in the construction of nearly universal phylogenies. Cladistic analysis of rRNA sequences is acknowledged as a prime force in systematics and from its very inception had a major impact to our understanding of early cellular evolution. The comparison of small-subunit ribosomal-RNA (16/18S rRNA) sequences led to the construction of a trifurcated unrooted tree in which all known organisms can be grouped in one of three major monophyletic cell lineages, i.e. the domains bacteria (eubacteria), Archaea (Archaeabacteria) and eucarya (eukaryotes) (Woese et al ., 1990 ), which are all derived from an ancestral form, known as the last common ancestor (LCA). From a cladistic viewpoint, the LCA is merely an inferred inventory of features shared among extant organisms, all of which are located at the tip of the branches of molecular phylogenies. Some time ago it was surmized that the sketchy picture developed with the limited databases would be con! rmed by completely sequenced cell genomes from the three primary domains. This has not been the case: the availability of an increasingly large number of completely sequenced cellular genomes has sparked new debates, rekindling the discussion on the nature of the ancestral entity and its predecessors. As reviewed by Becerra et al . ( 2007 ), this is shown in the diversity of names that have been coined to describe it, which include, among others, progenote (Woese and Fox, 1977 ), cenancestor (Fitch and Upper, 1987 ), LUCA, last universal common ancestor (Kyrpides et al ., 1999 ) or, later on, last universal cellular ancestor (Philippe and Forterre, 1999 ), universal ancestor (Doolittle, 2000), LCC, last common community (Line, 2002 ), and MRCA, most recent common ancestor (Zhaxybayeva and Gogarten, 2004 ). Close analysis shows that these

Acquired drug resistance is a central problem in cancer medicine. The diverse molecular mechanisms of acquired drug resistance all arise through the same process of somatic (within-body) cellular evolution. Even targeted drugs are subject to this failure. Genetic instability causes high genetic diversity among the cells of most cancers, but because somatic evolution results from selection as well as mutation, some classes of therapies are less prone than others to failure through acquired resistance. Cytotoxins, whether targeted or not, are especially prone to acquired drug resistance. Among the most promising classes of therapies expected to be robust against acquired resistance are: those that target systemic cancer symptoms instead of cancer cells, those that target cell motility rather than survival and proliferation, and those that target secreted metabolites of cancer cells rather than the cells themselves.

Artesian groundwaters of high radionuclide concentration are ubiquitous and may have provided the large, sustained energy sources that were required to drive the multistage process of DNA and primordial cell evolution. The rapid, early development of the genetic code as well as its degeneracy can be attributed to exceptionally high radiation-induced mutation rates in this unique environment. The ability of double-strand DNA to direct enzymatic repair of radiation damage to single strands contributed importantly to its selective evolution. It is postulated that the polymerization of nucleotides took place at elevated temperatures within alpha-particle tracks of high ion and free-radical density, followed by rapid quenching to ambient conditions. It also is evident that radiation resistance and ploidy were important selection factors in cellular evolution.

Viruses are the most abundant life forms and the repertoire of viral genes is greater than that of cellular genes. It is also evident that viruses have played a major role in driving cellular evolution, and yet, viruses are not part of mainstream biology, nor are they included in the Tree of Life. A reason for this major paradox in biology is the misleading dogma of viruses as viral particles and their enigmatic evolutionary origin. This article presents an alternative view about the nature of viruses based on their properties during the intracellular stage of their life cycle, when viruses express features comparable to those of many parasitic cellular species. Supporting this view about the nature of viruses is a novel hypothetical evolutionary model for their origin from parasitic cellular species that fused with their host cells. By losing their membrane and cellular structure within the host cell, these new types of parasitic species gained full access to precursors for the synthesis of their specific molecules and to the host’s information processing machineries, such as translation, which created unique parasitic and evolutionary opportunities. To identify viruses during their intracellular stage of their life cycle, in which their specific molecules are free or dispersed within the host cell, this paper introduces the concept of “molecular structure” and labels viruses as “molecular organisms.” Among the extant viruses, the life cycle of poxviruses and other complex viruses that fuse with their host cells provides compelling evidence for the fusion model. One of the most remarkable implications of fusion model is that new viral lineages originated from parasitic cellular species throughout the history of life, and that this process might still be active. Surprisingly, it appears that several parasitic cellular species are currently evolving into molecular organisms. More remarkably though, according to this model, several parasites that are currently classified as cellular organisms are in fact genuine molecular organisms. The current evidence for the fusion hypothesis is strong and it is fully testable using both experimental and phylogenetic approaches. The academic and research implications of this model, which supports the inclusion of viruses in the Tree of Life, are highly significant. Some of these implications are discussed in more detail in two other articles of this series, which presents a unifying model for the origin and evolution of cellular and viral domains, including the origin of life.

A new scenario of the origin of eukaryotic cell and multicellularity is presented. A concentric pH-gradient has been shown to exist in the cytosol of eukaryotic cells. The most probable source of such gradient is its self-formation in gradient of electric field between center and periphery of a cell. Theoretical analysis has shown that, for example, a cell of Saccharomyces cerevisiae has enough energy to continuously sustain such gradient of strength about 1.5 kV/cm, the value sufficient for effective isoelectric focusing of cytoplasmic proteins. Focusing of enzymes could highly increase the effectiveness of an otherwise diffusion-limited metabolism of large cells by concentrating enzymes into small and distinct parts of a cytoplasm. By taking away an important physical constraint to the volume of cytoplasm, the intracellular isoelectric focusing enabled evolution of cells 3-4 order of magnitude larger than typical prokaryotic cells. This opened the way for the origin of phagocytosis and lately for the development of different forms of endosymbiosis, some of them resulting in an endosymbiotic origin of mitochondria and plastids. The large volume of a cell-enabled separation of nuclear and cytoplasmic compartments which was a precondition for separation of transcription and translation processes and therefore also for the origin of various RNA-preprocessing mechanisms. The possibility to regulate gene expression by postprocessing RNA and to regulate metabolism by an electrophoretic translocation enzymes between different parts of cytoplasm by changing their isoelectric points opened the way for cell and tissue differentiation and therefore for the origin of complex multicellular organisms.

Chemoautorophs that fix carbon by the reductive tricarboxylic acid cycle represent one of the dominant bacterial life forms that make a major contribution to biomass production. From the viewpoint of biogenesis, construction of a canonical chart of intermediary metabolism for this class of organisms may help us to understand early cellular evolution and point us to the last universal common ancestor. Data-mining the KEGG Pathways database enabled us to integrate required biosynthetic pathways and derive a chart that represents the complete anabolic network of a reductive chemoautotroph. Compounds of this metabolic network together constitute a representative minimal metabolome that comprises 287 metabolites. These compounds have been classified into different groups including those compounds that form nodes in the network. It can be seen that a relatively sparse set of organic chemical reactions dominate the anabolic synthesis in the assembly of the minimal autotrophic metabolome. Empirical generalizations that result from analyzing this metabolic network may aid in elucidating selection rules that govern its emergence and further evolution and may also help in delineating attributes that impart the observed robustness to these metabolites.

STIV (Sulfolobus turreted icosahedral virus) has been the subject of detailed structural, genetic, transcriptomic, proteomic and biochemical studies. STIV arguably has been investigated in more detail than any other archaeal virus. As a result, we know more about STIV than other viruses infecting members of the Archaea domain. Like most viruses isolated from crenarchaeal hosts, STIV has little in common with viruses that infect eukaryotic and bacterial hosts and should be considered the founding member of a new virus family. However, despite this lack of obvious homology with other viruses, STIV has components of gene content, replication strategy and particle structure reminiscent of viruses of the Eukarya and Bacteria domains, suggesting an evolutionary relationship between viruses from all domains of life. The present mini-review describes the current knowledge of this virus and insights it has given us into viral and cellular evolution, as well as newly developed tools for the further study of STIV–host interactions.

Environmental and genetic mutations can transform the cells in a co-operating healthy tissue into an ecosystem of individualistic tumour cells that compete for space and resources. Various selection forces are responsible for driving the evolution of cells in a tumour towards more malignant and aggressive phenotypes that tend to have a fitness advantage over the older populations. Although the evolutionary nature of cancer has been recognised for more than three decades (ever since the seminal work of Nowell) it has been only recently that tools traditionally used by ecological and evolutionary researchers have been adopted to study the evolution of cancer phenotypes in populations of individuals capable of co-operation and competition. In this chapter we will describe game theory as an important tool to study the emergence of cell phenotypes in a tumour and will critically review some of its applications in cancer research. These applications demonstrate that game theory can be used to understand the dynamics of somatic cancer evolution and suggest new therapies in which this knowledge could be applied to gain some control over the evolution of the tumour.

Summary Blastocystis is a unicellular stramenopile of controversial pathogenicity in humans [1, 2]. Although it is a strict anaerobe, Blastocystis has mitochondrion-like organelles with cristae, a transmembrane potential and DNA [2–4]. An apparent lack of several typical mitochondrial pathways has led some to suggest that these organelles might be hydrogenosomes, anaerobic organelles related to mitochondria [5, 6]. We generated 12,767 expressed sequence tags (ESTs) from Blastocystis and identified 115 clusters that encode putative mitochondrial and hydrogenosomal proteins. Among these is the canonical hydrogenosomal protein iron-only [FeFe] hydrogenase that we show localizes to the organelles. The organelles also have mitochondrial characteristics, including pathways for amino acid metabolism, iron-sulfur cluster biogenesis, and an incomplete tricarboxylic acid cycle as well as a mitochondrial genome. Although complexes I and II of the electron transport chain (ETC) are present, we found no evidence for complexes III and IV or F1Fo ATPases. The Blastocystis organelles have metabolic properties of aerobic and anaerobic mitochondria and of hydrogenosomes [7, 8]. They are convergently similar to organelles recently described in the unrelated ciliate Nyctotherus ovalis[9]. These findings blur the boundaries between mitochondria, hydrogenosomes, and mitosomes, as currently defined, underscoring the disparate selective forces that shape these organelles in eukaryotes.

The emergence and evolution of metabolic pathways represented a crucial step in molecular and cellular evolution. In fact, the exhaustion of the prebiotic supply of amino acids and other compounds that were likely present in the ancestral environment, imposed an important selective pressure, favoring those primordial heterotrophic cells which became capable of synthesizing those molecules. Thus, the emergence of metabolic pathways allowed primitive organisms to become increasingly less-dependent on exogenous sources of organic compounds. Comparative analyses of genes and genomes from organisms belonging to Archaea, Bacteria and Eukarya revealed that, during evolution, different forces and molecular mechanisms might have driven the shaping of genomes and the arisal of new metabolic abilities. Among these gene elongations, gene and operon duplications undoubtedly played a major role since they can lead to the (immediate) appearance of new genetic material that, in turn, might undergo evolutionary divergence giving rise to new genes coding for new metabolic abilities. Gene duplication has been invoked in the different schemes proposed to explain why and how the extant metabolic pathways have arisen and shaped. Both the analysis of completely sequenced genomes and directed evolution experiments strongly support one of them, i.e. the patchwork hypothesis, according to which metabolic pathways have been assembled through the recruitment of primitive enzymes that could react with a wide range of chemically related substrates. However, the analysis of the structure and organization of genes belonging to ancient metabolic pathways, such as histidine biosynthesis and nitrogen fixation, suggested that other different hypothesis, i.e. the retrograde hypothesis or the semi-enzymatic theory, may account for the arisal of some metabolic routes.

In this paper, we present a modelling framework for cellular evolution that is based on the notion that a cell's behaviour is driven by interactions with other cells and its immediate environment. We equip each cell with a phenotype that determines its behaviour and implement a decision mechanism to allow evolution of this phenotype. This decision mechanism is modelled using feed-forward neural networks, which have been suggested as suitable models of cell signalling pathways. The environmental variables are presented as inputs to the network and result in a response that corresponds to the phenotype of the cell. The response of the network is determined by the network parameters, which are subject to mutations when the cells divide. This approach is versatile as there are no restrictions on what the input or output nodes represent, they can be chosen to represent any environmental variables and behaviours that are of importance to the cell population under consideration. This framework was implemented in an individual-based model of solid tumour growth in order to investigate the impact of the tissue oxygen concentration on the growth and evolutionary dynamics of the tumour. Our results show that the oxygen concentration affects the tumour at the morphological level, but more importantly has a direct impact on the evolutionary dynamics. When the supply of oxygen is limited we observe a faster divergence away from the initial genotype, a higher population diversity and faster evolution towards aggressive phenotypes. The implementation of this framework suggests that this approach is well suited for modelling systems where evolution plays an important role and where a changing environment exerts selection pressure on the evolving population.

Endosymbiotic relationships are common across the tree of life and have had profound impacts on cellular evolution and diversity. Recent molecular investigations of the amoeba Paulinella chromatophora have raised a timely and important question: should obligatory intracellular cyanobacteria in Paulinella be considered new organelles, or do plastids and mitochondria hold a unique stature in the history of endosymbiotic events? We argue that drawing a sharp distinction between these two organelles and all other endosymbionts is not supported by accumulating data, neither is it a productive framework for investigating organelle evolution.

In Search of Cell History: The Evolution of Life's Building Blocks . By Franklin M. Harold. 2014. University of Chicago Press. (ISBN 978-0-226-17428-0). 304 pp. Paperback. $36.00. This book provides a detailed account of what is known about how cells evolved and developed, and where the focus is directed within ongoing research. Throughout the book, Harold explores the various lines of evidence that make up aspects of cell history. However, he makes it clear that the origin of cells and the path of cellular evolution is not a straightforward story, and many aspects of this research lack a consensus among scientists. To that point, Harold says, “The realm of cell evolution is murky, and as yet thinly charted; if you go there, anticipate things never before seen, and pack a headlight that casts a wide beam” (p. 103). The book begins with an exploration of cells, genes, and evolution and sets up a continuing theme throughout the book that “the evolution of cells took place so long ago that all but the faintest traces of how it came about have been erased” (p. 16). Harold …

Within every living cell lurks a relic from the earliest stages of life on Earth, like a flint spear point in a modem military arsenal. Its discovery is overturning people's understanding of how they came to be--and could signal the end of the favored explanation of the origin of life, "RNA world". Life has a chicken-and-egg problem: enzymes are needed to make nucleic acids--the genetic material--but to build them they need the genetic information contained in nucleic acids. So most researchers assume that the earliest life, long before the evolution of cells, consisted of RNA molecules.

This synthesis has three main parts. The first discusses the overall tree of life and nature of the last common ancestor (cenancestor). I emphasize key steps in cellular evolution important for ordering and timing the major evolutionary innovations in the history of the biosphere, explaining especially the origins of the eukaryote cell and of bacterial flagella and cell envelope novelties. Second, I map the tree onto the fossil record and discuss dates of key events and their biogeochemical impact. Finally, I present a broad synthesis, discussing evidence for a three-phase history of life. The first phase began perhaps ca 3.5 Gyr ago, when the origin of cells and anoxic photosynthesis generated the arguably most primitive prokaryote phylum, Chlorobacteria (=Chloroflexi), the first negibacteria with cells bounded by two acyl ester phospholipid membranes. After this ‘chlorobacterial age’ of benthic anaerobic evolution protected from UV radiation by mineral grains, two momentous quantum evolutionary episodes of cellular innovation and microbial radiation dramatically transformed the Earth's surface: the glycobacterial revolution initiated an oxygenic ‘age of cyanobacteria’ and, as the ozone layer grew, the rise of plankton; immensely later, probably as recently as ca 0.9 Gyr ago, the neomuran revolution ushered in the ‘age of eukaryotes’, Archaebacteria (arguably the youngest bacterial phylum), and morphological complexity. Diversification of glycobacteria ca 2.8 Gyr ago, predominantly inhabiting stratified benthic mats, I suggest caused serial depletion of 13 C by ribulose 1,5-bis-phosphate caboxylase/oxygenase (Rubisco) to yield ultralight late Archaean organic carbon formerly attributed to methanogenesis plus methanotrophy. The late origin of archaebacterial methanogenesis ca 720 Myr ago perhaps triggered snowball Earth episodes by slight global warming increasing weathering and reducing CO 2 levels, to yield runaway cooling; the origin of anaerobic methane oxidation ca 570 Myr ago reduced methane flux at source, stabilizing Phanerozoic climates. I argue that the major cellular innovations exhibit a pattern of quantum evolution followed by very rapid radiation and then substantial stasis, as described by Simpson. They yielded organisms that are a mosaic of extremely conservative and radically novel features, as characterized by De Beer's phrase ‘mosaic evolution’. Evolution is not evenly paced and there are no real molecular clocks.

The First Cell arose in the previously pre-biotic world with the coming together of several entities that gave a single vesicle the unique chance to carry out three essential and quite different life processes. These were: (a) to copy informational macromolecules, (b) to carry out specific catalytic functions, and (c) to couple energy from the environment into usable chemical forms. These would foster subsequent cellular evolution and metabolism. Each of these three essential processes probably originated and was lost many times prior to The First Cell, but only when these three occurred together was life jump-started and Darwinian evolution of organisms began. The replication of informational molecules that made only occasional mistakes allowed evolution to form all the basic components of cellular life. Ribozymes, the first informational molecules, were also catalytic. Energy coupling required the formation of a closed lipid surface to generate and maintain an ion-motive gradient. The closed vesicle partitioned components and avoided dilution within the primordial sea. Closed membranes were essential for the first self-reproducing cell to arise and for its descendants to disperse. Subsequent cellular development after the origin of The First Cell led to the beginnings of intermediary metabolism and membrane transport processes. This long process, subject to strong evolutionary selection, developed the cellular biology that is now shared by all extant organisms.

Diatom algae arose by two-step endosymbiosis. The complete genome of the diatom Thalassiosira pseudonana has now been sequenced, allowing us to reconstruct the remarkable intracellular gene transfers that occurred during this convoluted cellular evolution.

Until the late 1970s cellular evolution was assumed to be a continuous, unbroken chain of progressive transformations that begun with the emergence of life itself and continued until the endosymbiotic origin of eukaryotes marked the major biological discontinu-ity. This scheme was challenged when the comparison of small subunit ribosomal RNA (16/ 18S rRNA) sequences led to the construction of a trifurcated, unrooted tree in which all known organisms can be grouped in one of three major monophyletic cell lineages, i.e., the domains Bacteria (eubacteria), Archaea (archaeabacteria), and Eucarya (eukaryotes). Information from one single molecular marker does not necessarily yield a precise reconstruction of evolutionary processes, but as shown by numerous phylogenies constructed from other genes such as those encoding polymerases, elongation factors, F-type ATPase subunits, heat-shock and ribosomal proteins, the identification of the three major lineages is not an artifact based solely upon the reductionist extrapolation of information derived from the rRNA tree, but a true reflection of an ancient trifurcation.

We introduce a three-dimensional model of the formation of proto-cell structures. Our model is based on an artificial chemistry extended from an earlier two-dimensional realization by Ono and Ikegami. This model describes the chemical reactions of a primitive metabolic system and the spatial interactions of simple amphiphilic molecules which organize into membrane-like structures. The results demonstrate the emergence of dynamic three-dimensional cellular structures from a “primordial soup”, and a variety of self-maintaining structures may be observed, depending on initial conditions.

A theory for the evolution of cellular organization is presented. The model is based on the (data supported) conjecture that the dynamic of horizontal gene transfer (HGT) is primarily determined by the organization of the recipient cell. Aboriginal cell designs are taken to be simple and loosely organized enough that all cellular componentry can be altered and/or displaced through HGT, making HGT the principal driving force in early cellular evolution. Primitive cells did not carry a stable organismal genealogical trace. Primitive cellular evolution is basically communal. The high level of novelty required to evolve cell designs is a product of communal invention, of the universal HGT field, not intralineage variation. It is the community as a whole, the ecosystem, which evolves. The individual cell designs that evolved in this way are nevertheless fundamentally distinct, because the initial conditions in each case are somewhat different. As a cell design becomes more complex and interconnected a critical point is reached where a more integrated cellular organization emerges, and vertically generated novelty can and does assume greater importance. This critical point is called the “Darwinian Threshold” for the reasons given.

Publisher Summary This chapter discusses the horizontal gene transfer (HGT) and the universal tree of life. The apparent occurrence of extensive HGT across the domains of life has prompted much speculation on its significance to early cellular evolution. Networks of genetic interactions at the base of the universal tree have been suggested to be so intense as to render useless the concept of a single cellular ancestor for contemporary lineages. A central issue surrounding the universal tree is the location of its root. Unlike the trees showing Archaea and eukaryotes as sister groups, protein trees clustering Archaea and Bacteria together (AB tree) always portray one or both domains as para/polyphyletic groups. Such tree topologies are evidence for HGT between Archaea and Bacteria, the patterns for which can often be complex. The alternative hypothesis, the rooting of the universal tree in eukaryotes, would require both the Archaea and Bacteria to undergo extreme genome simplification or “streamlining”.

Publisher Summary This chapter discusses the dynamics of bacterial genomes. It reveals that the availability of complete genome sequences for large numbers of microorganisms has catalyzed a paradigm shift on how evolutionary biologists view the bacterial chromosome. Two sets of processes that affect the character of microbial genomes, mutation and recombination, and their roles in microbial evolution are quite different. Mutational processes alter the sequences of existing genes. Ultimately, mutations produce all of the variation seen among extant organisms. Even when examining multiple species, only a small number of differences between any two forms of a gene may affect that gene's function or expression, if at all. Therefore, while mutational processes are ubiquitous, their impact in cellular evolution is necessarily smaller than their numbers suggest. Recombinational processes serve to reassort genes among genomes. Intraspecific recombination acts to distribute variant alleles—including, but not restricted to, those arising by mutational processes—among members of a bacterial species.

Due to the emergence of more diversified applications provided by smart devices such as smart phones, traditional telecommunications systems such as wireless cellular systems no longer meet the traffic demand. For example, ever popular short messages enabling online social network services or mobile healthcare services from smart phones and real-time phone services may require anywhere anytime coverage, while streaming videos or peer-to-peer multimedia sharing may demand somewhere sometime high-capacity support. These kinds of traffic may be supported to some degree with the current cellular technologies, but definitely not satisfactorily. There are tremendous research and implementation activities to improve service support via harmonized integration of heterogeneous telecommunications systems. In order to really support anywhere anytime support for diversified traffic with varying capacity support, new paradigms and technologies must be developed. The recently emerging multihop cellular systems, and integration of wireless cellular systems and ad hoc networking technologies may pave the way toward this goal.

The concept of Archaea (formerly Archaebacteria), introduced by Carl Woese at the end of the seventies, raised the hope that studying this third form of life on earth would help to reconstitute the Last Universal Common Ancestor (LUCA) to all living organisms. In the years that followed, a consensus emerged within the community of archaeobiologists about early cellular evolution and the nature of LUCA. In the new paradigm, Archaea are the sister group of Eukarya (formerly eukaryotes), and LUCA was a simple prokaryote with features between those of Archaea and Bacteria (1, 2). In this scenario, the complex and specific molecular traits of the Eukarya, such as nuclear pores, mRNA splicing, or an elaborated cytoskeleton, are late inventions in the eukaryal lineage. This paradigm is usually justified by the rooting of the universal tree of life in the bacterial branch and the finding of eukaryal features in Archaea at the molecular level. In our opinion however, it is also based on the prejudice that “pro”karyotes predated “eu”karyotes in the course of early cellular evolution. Prokaryotes of course predate “modern” eukaryotes in the history of life since all present-day eukaryotes have probably descended from an ancestor that had already engulfed the bacterial endosymbiont which gave birth to mitochondria, (e.g., 3). We think, however, that the relationships between present-day prokaryotes and the ancestral eukaryotic lineage (those which existed before the

The most remarkable period subsequent to the establishment of the genetic code, or more precisely to the establishment of the translation mechanism, concerns the period in which the chromosomes originated at the very beginning of the evolution of cells. It is widely believed that the intron-exon structure of genes was part of the first cell. It has been remarked that this view implies that the genes of the most advanced higher organisms may reflect the primitive genome structure more clearly than the genes of prokaryotes, as during their evolution bacteria and archaebacteria have eliminated their introns (Brenner, 1994). This idea is persuasive enough for looking at the contemporary eukaryotic cell as a potential source of information on the structure and function of the first cell. This viewpoint allows the possibility of facing some of the most difficult questions concerning the primordial cell. Perhaps amongst such difficult questions, the origin and evolution of chromosomes (Maynard-Smith and Szathmary, 1993) stands out. One general guiding line in this important aspect of the origin of the progenote is to explain the past in terms of processes that we may currently be present in cells. It seems likely that changes in a protocell that led to the eukaryotic cell were in some way related to the control of gene expression (Maynard-Smith, 1993). Unfortunately, there is yet no general understanding of this aspect of the eukaryotic cell. On the other hand, sufficient insights have been obtained, as shown in Secs. 2 and 3, to encourage discussions of the origin of the eukaryotic cell in the context of extraterrestrial life, as we shall see in Secs. 4 and subsequent work below.

Over a thousand of cytoplasmic, non organellar tRNA genes were extracted from the whole-genomes of more than 100 organisms spanning the Bacteria, Eukarya and Archaea (tRNomics). Also, whenever possible, the genes coding for modification enzymes acting on tRNA, particularly those involved in modification of nucleotides in the anticodon loop, were identified (Modomics). Combining these two data sets, we were able to reveal three main decoding strategies used by individual contemporary organisms to read the 62 (61+1 initiator) sense codons of mRNA. Based on the known phylogenetic relationships of the different organisms analyzed, this work allows to predict which RNA modification enzymes are essential for an accurate and efficient translation process, as well as to shed light on when these complex and diverse tRNA maturation processes probably emerged during cellular evolution.

A keystone of the molecular reductionist approach to cellular biology is a specific deductive strategy relating genotype to phenotype—two distinct categories. This relationship is based on the assumption that the intermediary cellular network of actively transcribed genes and their regulatory elements is deterministic (i.e., a link between expression of a gene and a phenotypic trait can always be identified, and evolution of the network in time is predetermined). However, experimental data suggest that the relationship between genotype and phenotype is nonbijective (i.e., a gene can contribute to the emergence of more than just one phenotypic trait or a phenotypic trait can be determined by expression of several genes). This implies nonlinearity (i.e., lack of the proportional relationship between input and the outcome), complexity (i.e. emergence of the hierarchical network of multiple cross-interacting elements that is sensitive to initial conditions, possesses multiple equilibria, organizes spontaneously into different morphological patterns, and is controled in dispersed rather than centralized manner), and quasi-determinism (i.e., coexistence of deterministic and nondeterministic events) of the network. Nonlinearity within the space of the cellular molecular events underlies the existence of a fractal structure within a number of metabolic processes, and patterns of tissue growth, which is measured experimentally as a fractal dimension. Because of its complexity, the same phenotype can be associated with a number of alternative sequences of cellular events. Moreover, the primary cause initiating phenotypic evolution of cells such as malignant transformation can be favored probabilistically, but not identified unequivocally. Thermodynamic fluctuations of energy rather than gene mutations, the material traits of the fluctuations alter both the molecular and informational structure of the network. Then, the interplay between deterministic chaos, complexity, self-organization, and natural selection drives formation of malignant phenotype. This concept offers a novel perspective for investigation of tumorigenesis without invalidating current molecular findings. The essay integrates the ideas of the sciences of complexity in a biological context. J. Surg. Oncol. 1998;68:70–78. © 1998 Wiley-Liss, Inc.

Background Nucleotide metabolism is central to all biological systems, due to their essential role in genetic information and energy transfer, which in turn suggests its possible presence in the last common ancestor (LCA) of Bacteria, Archaea and Eukarya. In this context, elucidation of the contribution of the origin and diversification of de novo and salvage pathways of nucleotide metabolism will allow us to understand the links between the enzymatic steps associated with the LCA and the emergence of the first metabolic pathways. Results In this work, the taxonomical distribution of the enzymes associated with nucleotide metabolism was evaluated in 1,606 complete genomes. 151 sequence profiles associated with 120 enzymatic reactions were used. The evaluation was based on profile comparisons, using RPS-Blast. Organisms were clustered based on their taxonomical classifications, in order to obtain a normalized measure of the taxonomical distribution of enzymes according to the average of presence/absence of enzymes per genus, which in turn was used for the second step, to calculate the average presence/absence of enzymes per Clade. Conclusion From these analyses, it was suggested that divergence at the enzymatic level correlates with environmental changes and related modifications of the cell wall and membranes that took place during cell evolution. Specifically, the divergence of the 5-(carboxyamino) imidazole ribonucleotide mutase to phosphoribosylaminoimidazole carboxylase could be related to the emergence of multicellularity in eukaryotic cells. In addition, segments of salvage and de novo pathways were probably complementary in the LCA to the synthesis of purines and pyrimidines. We also suggest that a large portion of the pathway to inosine 5’-monophosphate (IMP) in purines could have been involved in thiamine synthesis or its derivatives in early stages of cellular evolution, correlating with the fact that these molecules may have played an active role in the protein-RNA world. The analysis presented here provides general observations concerning the adaptation of the enzymatic steps in the early stages of the emergence of life and the LCA. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-800) contains supplementary material, which is available to authorized users.

Summary Most of the intermediary metabolism in cells occurs within the aqueous compartments. However, cells are not dilute bags of juice. They have evolved the capacity to exert exquisite organizational and structural control of their internal environments. It is probable that the design of present-day cells is retained from early cells' evolution of relationships among metabolism, cell architecture, and water. It is becoming increasingly apparent that much, if not most, of the water in cells is vicinal water and therefore altered in many of its properties, including viscosity and thermodynamic properties. The implications of altered water properties for cellular processes are profound. Water affects numerous functions of the cell, for example, cell volume, ion selectivity, membrane potentials, enzyme rate enhancement, and chromosome aberrations. The effects of temperature on biological systems have been discussed in this chapter. Because the properties of vicinal water change abruptly at T k , cells exhibit anomalous behavior at T k . For instance, survival and growth curves for a variety of living systems show remarkable changes at one or more of the transition temperatures. Since these changes are profound, one must speculate that vicinal water played a crucial role in cellular evolution. From cell metabolism to body temperature homeostasis, vicinal water continues to play a key role.

It has been currently estimated that the life generated about four billion years ago in the primitive sea as a result of the chemical evolution. There is no doubt that, at that time, the protoorganism was a prokaryotic monad, formed from a certain aggregate of primitive proteins, nucleic acids, and other macromolecules and wrapped with (phospho)lipid membrane. Some workers have proposed that the macromolecules involved in the formation of the life were adsorbed on surface of clay particles in the primeval soup (Cairns-Smith 1982). However, it seems very unlikely that such a simple aggregation of the macromolecules would lead to the formation of a vital cell. The reasons for such uncertainty which have been discussed (see Nakamura 1987c) are: (1) The extant cells, without exception, are wrapped by a single membrane consisting of phospholipid bilayer. (2) Life is expressed only in a closed, rather than open, system isolated from the environment by the plasma membrane.

Neoplasia appears to develop stochastically through a series of variable genetic events that drive multiple cycles of cellular adaptation and selection. This pathological cellular evolution produces variable cancer genomes that are characterized with structural complexity and clonal heterogeneity. Most importantly for drug discovery and development, common recurrent genetic events appear to be only the ‘tip of the iceberg’, and the next generation of genomic technologies are now revealing that most functionally relevant genetic aberrations are in fact not common or recurrent. Given this challenge of cellular and molecular heterogeneity, we have begun to explore new paradigms for translating genomic information into pharmacologically relevant insights to guide drug discovery and development. This presentation will introduce new technologies and integrated strategies to generate the necessary type of information from cancer genomes, and introduce a new ‘biointelligence’ based strategy for interpreting individual cancer genomes to gain insights into contextual dependencies and pharmacologically relevant vulnerabilities. In support of this new approach to genomics, emerging evidence is suggesting that the highly variable genetic events do converge on higher level concepts that represent shared pharmacologically tractable contexts of vulnerability. Finally, a scientific vision will be presented for practically applying these integrated pharmacogenomic strategies; a) in research to accelerate cancer drug discovery and development, and b) directly into clinical practice to support more precise medical genomics. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PL05-01.

2and advances of viral metagenomics that establish viruses as a quantitatively dominant component of the biosphere 3 , the evolution of viruses has become a topic of lively discussion 2,4–8 . Several scenarios were proposed according to which viruses antedated cells and contributed to their origin 4,5,7 . The Opinion article by Moreira and LopezGarcia extends this discussion 1 by making three fundamental points: viruses are not alive, contrary to claims that they are 2,5 ; viruses do not belong in the tree of life (TOL); and viruses are not ancient and are irrelevant for the reconstruction of cellular evolution.

The principles of the thermodynamics of irreversible processes which occur in biological cells considered as open systems, have been reviewed and applied in order to describe a possible evolution of cells during aging. The main featrue of such an approach is that cells operating in a steady state, optimize their free energy production by lowering their entropy production which is kept to a minimum. Instabilities can however occur which can lead the cell from one steady state to another characterized by a lower production of entropy. Concomitantly, the level of errors or entropy of the system will increase. The process will continue and the cell will go from one state to another until a critical level is attained where the cell can not cope any more with keeping its organization and will die. The effect of stresses and mitosis have been also considered in this model. Such an approach stresses that cells can only subsist as a whole in certain states which are the result of the genetic constitution but also of the optimalization of cellular functions given their requirement in energy and the fluctuations from the environmental changes. In this respect, it reconciles both programmed and stochastic theories of aging.

The origin of cells was crucial to the evolution of life: by creating the first discrete organisms it vastly strengthened organismic selection, at the expense of genie and population (group) selection which would have dominated early evolution. There are four major sorts of cell, two bacterial (kingdoms Eubacteria and Archaebacteria) and two eukaryotic (superkingdoms Archezoa and Meta- karyota): their origins are the most significant examples of quantum evolution in the history of life. Ultrastructural, molecular and fossil evidence suggest that the first cells were eubacteria, and that archaebacteria and the primitively amito- chondrial archezoa both evolved from a wall-less mutant eubacterium. Subsequently a tetraciliated archezoan metamonad phagocytosed purple non-sulphur and Gram-positive bacteria (both eubacteria), converting them into mitochondria and peroxisomes respectively, creating the first metakaryote. Metakaryota comprise five kingdoms: Protozoa, Chromista, Fungi, Animalia, Plantae. Chloroplasts evolved from symbiotic cyanobacteria, probably once only, either in the ancestral metakaryote or in the common ancestor of dinoflagellates, green and red algae. A separate symbiosis involving a proteromonad–like protozoan host and an aberrantly pigmented dinoflagellate symbiont created the kingdom Chromista, with chloroplasts located inside the rough endoplasmic reticulum. Euglenoids also may have obtained their chloroplasts secondarily from a eukaryotic symbiont, but a direct inheritance from the ancestral metakaryote cannot yet be ruled out. There is no evidence for a symbiotic origin of cilia or eukaryotes; the most primitive eukaryotes may be the monociliated archezoan Archamoebae. The first eubacteria were probably Gram-negative photoheterotrophs with an outer membrane outside their plasma membrane: this outer membrane probably evolved into the outer membrane of mitochondria and chloroplasts, but was lost in the ancestor (s) of Posibacteria and Thermotoga. The first cell perhaps evolved by “gastrulation” of an inside-out-cell bearing ribosomes and chromosomes on its outer surface. Archaebacteria and eukaryotes probably evolved from a Thermotoga-like eubacterium after it lost the murein cell wall: the archaebacterial ancestor evolved a new wall and isoprenoidal ether lipids, whilst the eukaryote ancestor instead evolved an actin/microtubulule endoskeleton allowing phagotrophy, endomembranes, nuclei, and sex (i.e., syngamy and meiosis) to evolve. The mechanisms and significance of these megaevolutionary events are discussed.

The easy distinction between higher animals and higher plants led earlier biologists to extend the animal and plant kingdoms down to the unicellular level and separate algae taxonomically from protozoa. There-after one group was studied by botanists and the other by zoologists, and the separation was perpetuated in spite of the difficulty of defining a boundary between algae and protozoa. Closer study raised many questions about the taxonomy of these ‘lower’ organisms. The current view of cellular evolution (e.g. Woese 1987; Sleigh 1989) is that among the first cells (progenotes) were prokaryotes of different types which evolved to give the diversity of bacteria; other progenotes gave rise to nucleated, and probably amoeboid, phagotrophic eukaryotes with cytoskeletal systems, and at an early stage flagella and golgi systems evolved. Most eukaryotes developed symbiotic associations with aerobic bacteria to form mitochondria, different groups having different forms of internal cristae.

Primitive atmosphere of the earth did not contain oxygen gas (O2) when the proto-cells were generated successfully as the result of chemical evolution and then evolved. Therefore, they first had acquired anaerobic energy metabolism, fermentation. The cellular metabolisms have often been formed by reorganizing to combine or recombinate between pre-existing metabolisms and newly born bioreactions. Photosynthetic metabolism in eukaryotic chloroplast consists of an electron-transfer photosystem and a fermentative reductive pentose phosphate cycle. On the other hand, O2-respiration of eukaryotic mitochondrion is made of Embden-Meyerhof (EM) pathway and tricarboxylic acid cycle, which originate from a connection of fermentative metabolisms, and an electron-transfer respiratory chain, which has been derived from the photosystem. These metabolisms already are completed in some evolved prokaryotes, for example the cyanobacterium Chlorogloea fritschii and aerobic photosynthetic bacteria Rhodospirillum rubrum and Erythrobacter sp. Therefore, it can be reasonably presumed that the eukaryotic chloroplast and mitochondrion have once been formed as the result of metabolic (and genetic) differentiations in most evolved cyanobacterium. Symbiotic theory has explained the origin of eukaryotic cell as that in which the mitochondrion and chloroplast have been derived from endosymbionts of aerobic bacterium and cyanobacterium, respectively, and has mentioned as one of the most potent supportive evidences that amino acid sequences of the photosynthetic and O2 -respiratory enzymes show similarities to corresponding prokaryotic enzymes. However, as will be shown in this discussion, many examples have shown currently that prokaryotic sequences of informative molecules are conserved well not only in those of the mitochondrial and chloroplast molecules but also in the nuclear molecules. In fact, the similarities in sequence of informative molecules are preserved well among the organisms not only in phylogenetically close relationships but also under highly selective pressure, that is under a physiological constraint for the species in their habitats. Therefore, the similarities in amino acid sequences of proteins between the prokaryotes and the organelles are not necessarily direct evidence for their phylogenetical closeness: it gives still less evidence for a symbiotic relationship between the prokaryotes and the organelles. The metabolic compartmentalization of the membranes is an important tendency in cellular evolution to guarantee high specificity and rate of the metabolisms. It is suggested from the data that the intracellular membranes are not static but undergo dynamic turnover. Furthermore, these facts strongly support the Membrane Evolution Theory which was proposed by one of the authors in 1975.

Background It is generally assumed that primordial cells had small genomes with simple genes coding for enzymes able to react with a wide range of chemically related substrates, interconnecting different metabolic routes. New genes coding for enzymes with a narrowed substrate specificity arose by paralogous duplication(s) of ancestral ones and evolutionary divergence. In this way new metabolic pathways were built up by primordial cells. Useful hints to disclose the origin and evolution of ancestral metabolic routes and their interconnections can be obtained by comparing sequences of enzymes involved in the same or different metabolic routes. From this viewpoint, the lysine, arginine, and leucine biosynthetic routes represent very interesting study-models. Some of the lys, arg and leu genes are paralogs; this led to the suggestion that their ancestor genes might interconnect the three pathways. The aim of this work was to trace the evolutionary pathway leading to the appearance of the extant biosynthetic routes and to try to disclose the interrelationships existing between them and other pathways in the early stages of cellular evolution. Results The comparative analysis of the genes involved in the biosynthesis of lysine, leucine, and arginine, their phylogenetic distribution and analysis revealed that the extant metabolic "grids" and their interrelationships might be the outcome of a cascade of duplication of ancestral genes that, according to the patchwork hypothesis, coded for unspecific enzymes able to react with a wide range of substrates. These genes belonged to a single common pathway in which the three biosynthetic routes were highly interconnected between them and also to methionine, threonine, and cell wall biosynthesis. A possible evolutionary model leading to the extant metabolic scenarios was also depicted. Conclusion The whole body of data obtained in this work suggests that primordial cells synthesized leucine, lysine, and arginine through a single common metabolic pathway, whose genes underwent a set of duplication events, most of which can have predated the appearance of the last common universal ancestor of the three cell domains (Archaea, Bacteria, and Eucaryotes). The model proposes a relative timing for the appearance of the three routes and also suggests a possible evolutionary pathway for the assembly of bacterial cell-wall.

The core enzymes of the DNA replication systems show striking diversity among cellular life forms and more so among viruses. In particular, and counter-intuitively, given the central role of DNA in all cells and the mechanistic uniformity of replication, the core enzymes of the replication systems of bacteria and archaea (as well as eukaryotes) are unrelated or extremely distantly related. Viruses and plasmids, in addition, possess at least two unique DNA replication systems, namely, the protein-primed and rolling circle modalities of replication. This unexpected diversity makes the origin and evolution of DNA replication systems a particularly challenging and intriguing problem in evolutionary biology. I propose a specific succession for the emergence of different DNA replication systems, drawing argument from the differences in their representation among viruses and other selfish replicating elements. In a striking pattern, the DNA replication systems of viruses infecting bacteria and eukaryotes are dominated by the archaeal-type B-family DNA polymerase (PolB) whereas the bacterial replicative DNA polymerase (PolC) is present only in a handful of bacteriophage genomes. There is no apparent mechanistic impediment to the involvement of the bacterial-type replication machinery in viral DNA replication. Therefore, I hypothesize that the observed, markedly unequal distribution of the replicative DNA polymerases among the known cellular and viral replication systems has a historical explanation. I propose that, among the two types of DNA replication machineries that are found in extant life forms, the archaeal-type, PolB-based system evolved first and had already given rise to a variety of diverse viruses and other selfish elements before the advent of the bacterial, PolC-based machinery. Conceivably, at that stage of evolution, the niches for DNA-viral reproduction have been already filled with viruses replicating with the help of the archaeal system, and viruses with the bacterial system never took off. I further suggest that the two other systems of DNA replication, the rolling circle mechanism and the protein-primed mechanism, which are represented in diverse selfish elements, also evolved prior to the emergence of the bacterial replication system. This hypothesis is compatible with the distinct structural affinities of PolB, which has the palm-domain fold shared with reverse transcriptases and RNA-dependent RNA polymerases, and PolC that has a distinct, unrelated nucleotidyltransferase fold. I propose that PolB is a descendant of polymerases that were involved in the replication of genetic elements in the RNA-protein world, prior to the emergence of DNA replication. By contrast, PolC might have evolved from an ancient non-templated polymerase, e.g., polyA polymerase. The proposed temporal succession of the evolving DNA replication systems does not depend on the specific scenario adopted for the evolution of cells and viruses, i.e., whether viruses are derived from cells or virus-like elements are thought to originate from a primordial gene pool. However, arguments are presented in favor of the latter scenario as the most parsimonious explanation of the evolution of DNA replication systems. Comparative analysis of the diversity of genomic strategies and organizations of viruses and cellular life forms has the potential to open windows into the deep past of life's evolution, especially, with the regard to the origin of genome replication systems. When complemented with information on the evolution of the relevant protein folds, this comparative approach can yield credible scenarios for very early steps of evolution that otherwise appear to be out of reach. Eric Bapteste, Patrick Forterre, and Mark Ragan.

Recent advances in genomics of viruses and cellular life forms have greatly stimulated interest in the origins and evolution of viruses and, for the first time, offer an opportunity for a data-driven exploration of the deepest roots of viruses. Here we briefly review the current views of virus evolution and propose a new, coherent scenario that appears to be best compatible with comparative-genomic data and is naturally linked to models of cellular evolution that, from independent considerations, seem to be the most parsimonious among the existing ones. Several genes coding for key proteins involved in viral replication and morphogenesis as well as the major capsid protein of icosahedral virions are shared by many groups of RNA and DNA viruses but are missing in cellular life forms. On the basis of this key observation and the data on extensive genetic exchange between diverse viruses, we propose the concept of the ancient virus world. The virus world is construed as a distinct contingent of viral genes that continuously retained its identity throughout the entire history of life. Under this concept, the principal lineages of viruses and related selfish agents emerged from the primordial pool of primitive genetic elements, the ancestors of both cellular and viral genes. Thus, notwithstanding the numerous gene exchanges and acquisitions attributed to later stages of evolution, most, if not all, modern viruses and other selfish agents are inferred to descend from elements that belonged to the primordial genetic pool. In this pool, RNA viruses would evolve first, followed by retroid elements, and DNA viruses. The Virus World concept is predicated on a model of early evolution whereby emergence of substantial genetic diversity antedates the advent of full-fledged cells, allowing for extensive gene mixing at this early stage of evolution. We outline a scenario of the origin of the main classes of viruses in conjunction with a specific model of precellular evolution under which the primordial gene pool dwelled in a network of inorganic compartments. Somewhat paradoxically, under this scenario, we surmise that selfish genetic elements ancestral to viruses evolved prior to typical cells, to become intracellular parasites once bacteria and archaea arrived at the scene. Selection against excessively aggressive parasites that would kill off the host ensembles of genetic elements would lead to early evolution of temperate virus-like agents and primitive defense mechanisms, possibly, based on the RNA interference principle. The emergence of the eukaryotic cell is construed as the second melting pot of virus evolution from which the major groups of eukaryotic viruses originated as a result of extensive recombination of genes from various bacteriophages, archaeal viruses, plasmids, and the evolving eukaryotic genomes. Again, this vision is predicated on a specific model of the emergence of eukaryotic cell under which archaeo-bacterial symbiosis was the starting point of eukaryogenesis, a scenario that appears to be best compatible with the data. The existence of several genes that are central to virus replication and structure, are shared by a broad variety of viruses but are missing from cellular genomes (virus hallmark genes) suggests the model of an ancient virus world, a flow of virus-specific genes that went uninterrupted from the precellular stage of life's evolution to this day. This concept is tightly linked to two key conjectures on evolution of cells: existence of a complex, precellular, compartmentalized but extensively mixing and recombining pool of genes, and origin of the eukaryotic cell by archaeo-bacterial fusion. The virus world concept and these models of major transitions in the evolution of cells provide complementary pieces of an emerging coherent picture of life's history. W. Ford Doolittle, J. Peter Gogarten, and Arcady Mushegian.

Early in the 20th century, three hypotheses were advanced for the origin of viruses: (1) viruses are degenerate intracellular parasites; (2) viruses are relics of precellular life; and (3) viruses are cellular genes that escaped. Research in the latter half of the 20th century revolutionized our knowledge of the physical nature of viruses, but comparable progress in understanding viral origins is conspicuously lacking. It has long been appreciated that viruses need not be a monophyletic group. Beyond that, the three classical hypotheses can be restated today, with only minor refinements.1.The degenerate parasite hypothesis currently has few supporters, ostensibly because the absence of intermediate forms and the extent of the implied degeneration render such speculation non-productive; ironically, the decline in favor of this hypothesis coincided with general acceptance of an endosymbiont origin for organelles, which presents some of the same problems.2.From the outset, the precellular life hypothesis faced the dilemma that viruses require cellular hosts and therefore could not have preceded them; a currently viable, related hypothesis is that some RNA viruses originated in the RNA world.3.Most virologists today probably view at least the larger DNA viruses as escaped cellular genes. Molecular genetics has gradually replaced the primitive concept of individual genes going out on their own with scenarios where blocks of genes (possibly from diverse cellular sources) comprise functional modules that merged with one another, giving the typical virus a chimeric ancestry 1.xSee all References, 2.xEvolution of the lambdoid phages. Campbell, A and Botstein, D. : 365–380See all References. Simplistic searches for primordial cellular modules have generally been confounded by the presence of degraded relics of viral DNA (defective proviruses) in most chromosomes 3xDefective bacteriophages and incomplete prophages. Campbell, A. : 259–328See all References3.At the dawn of the 21st century, it is gratifying that this subject is receiving renewed attention 4.xThe origins and ongoing evolution of viruses. Hendrix, R.W et al. Trends Microbiol. 2000; 8: 504–508Abstract | Full Text | Full Text PDF | PubMed | Scopus (229)See all References, 5.xEvolution on life's fringes. Balter, M. Science. 2000; 289: 1866–1867Crossref | PubMed | Scopus (27)See all References. Hendrix et al.4xThe origins and ongoing evolution of viruses. Hendrix, R.W et al. Trends Microbiol. 2000; 8: 504–508Abstract | Full Text | Full Text PDF | PubMed | Scopus (229)See all References4 postulate that the initiating event was the occurrence of the icosahedral capsid, and cite examples of cellular proteins assembling into icosahedra. There is much to recommend this idea: capsids (icosahedral or helical) are the most characteristically viral structures known and are essential for the viral lifestyle. Hendrix et al. focus on tailed double-stranded (ds) DNA bacteriophages, in which icosahedral capsids are the rule. In making capsid formation the primary event, they imply a separate origin for helical viruses.Most viral capsids are not complete delivery systems, but for some simpler viruses, such as picornaviruses, they are. Hendrix et al.4xThe origins and ongoing evolution of viruses. Hendrix, R.W et al. Trends Microbiol. 2000; 8: 504–508Abstract | Full Text | Full Text PDF | PubMed | Scopus (229)See all References4 discuss a possible role for primitive viral capsids as vehicles for the lateral transfer of host genes. The importance of this is debatable. Pre-cells might have transferred DNA rather easily, through cell fusion or transformation, with subsequent selection acting more to create barriers than to circumvent them 6xLateral gene transfer in prokaryotes. Campbell, A.M. Theoret. Pop. Biol. 2000; 57: 71–77Crossref | PubMed | Scopus (39)See all References6. At any rate, such a role is not a cornerstone of their hypothesis. They correctly state that encapsidation of DNA provides a selfish advantage to the encapsidation genes, which would at least sometimes be transferred.Another major feature of their scheme is the ongoing acquisition of small DNA segments (‘morons’) that can add to viral genomes, as extensively documented in their previous work. Extrapolating this process into the past, viral evolution probably included many such additions, as well as fusions of larger modules. Such serial acquisitions could well also be crucial to cellular evolution 7xGene transfer, speciation and the evolution of bacterial genomes. Lawrence, J.G. Curr. Opin. Microbiol. 1999; 2: 519–523Crossref | PubMed | Scopus (161)See all References7. The databases for the extent of gene transfer into viral and host genomes are not totally independent: more than one-third of the genes in Escherichia coli that were classified as alien by codon usage patterns 8xCodon usages in different gene classes of the Escherichia coli genome. Karlin, S et al. Mol. Microbiol. 1998; 29: 1341–1355Crossref | PubMed | Scopus (155)See all References8 lie within defective prophages 9xSee all References9.We can hope for a lively round of discussion by students of a wider range of viruses, some of which has already commenced 5xEvolution on life's fringes. Balter, M. Science. 2000; 289: 1866–1867Crossref | PubMed | Scopus (27)See all References5.

It's been well established that the energy-producing mitochondria and photosynthesizing chloroplasts of today's cells originated from bacteria that took up residence in some ancestral cell. But new studies indicate that such organelles can also be acquired when a complex cell engulfs another complex cell. On page 1485 , researchers report that single-cell parasites, including Toxoplasma , which causes infections in AIDS patients, and malaria-causing Plasmodium , apparently got their chloroplast-like organelles when an ancestor engulfed an algal cell. Not only do the new findings shed light on cellular evolution, but the plastids found in the parasites may be new targets for drug therapies.

A computer branching model is used to analyze cellular evolution. Attention is given to certain key amino acids and nucleotide residues (ferredoxin, 5s ribosomal RNA, and c-type cytochromes) because of their commonality over a wide variety of cell types. Each amino acid or nucleotide residue is a sequence in an inherited biological trait; and the branching method is employed to align sequences so that changes reflect substitution of one residue for another. Based on the computer analysis, the symbiotic theory of cellular evolution is considered the most probable. This theory holds that organelles, e.g., mitochondria and chloroplasts invaded larger bodies, e.g., bacteria, and combined functions to form eucaryotic cells.