Oligoribonucleotides are potentially capable of Darwinian evolution – they may replicate and can express an independent chemical phenotype, as embodied in modern enzymatic cofactors. Using quantitative chemical kinetics on a sporadically fed ribonucleotide pool, unreliable supplies of unstable activated ribonucleotides A and B at low concentrations recurrently yield a replicating AB polymer with a potential chemical phenotype. Self-complementary replication in the pool occurs during a minority (here ≈ 35 %) of synthetic episodes that exploit coincidental overlaps between 4, 5 or 6 spikes of arbitrarily arriving substrates. Such uniquely productive synthetic episodes, in which near-ideal reaction sequences recur at random, account for most AB oligonucleotide synthesis, and therefore underlie the emergence of net replication under realistic primordial conditions. Because overlapping substrate spikes are unexpectedly frequent, and in addition, complex spike sequences appear disproportionately, a sporadically fed pool can host unexpectedly complex syntheses. Thus, primordial substrate fluctuations are not necessarily a barrier to Darwinism, but instead can facilitate early evolution.
Cofactor; Origin of life; Replication; Selection; Initial Darwinian Ancestor
The development of a sequence-general nucleic acid copying system is an essential step in the assembly of a synthetic protocell, an autonomously replicating spatially localized chemical system capable of spontaneous Darwinian evolution. Previously described nonenzymatic template-copying experiments have validated the concept of nonenzymatic replication, but have not yet achieved robust, sequence-general polynucleotide replication. The 5′-phosphorimidazolides of the 2′-amino-2′,3′-dideoxyribonucleotides are attractive as potential monomers for such a system because they polymerize by forming 2′→5′ linkages, which are favored in nonenzymatic polymerization reactions using similarly activated ribonucleotides on RNA templates. Furthermore, the 5′-activated 2′-amino nucleotides do not cyclize. We recently described the rapid and efficient nonenzymatic copying of a DNA homopolymer template (dC15) encapsulated within fatty acid vesicles using 2′-amino-2′,3′-dideoxyguanosine−5′-phosphorimidazolide as the activated monomer. However, to realize a true Darwinian system, the template-copying chemistry must be able to copy most sequences and their complements to allow for the transmission of information from generation to generation. Here, we describe the copying of a series of nucleic acid templates using 2′-amino-2′,3′-dideoxynucleotide−5′-phosphorimidazolides. Polymerization reactions proceed rapidly to completion on short homopolymer RNA and LNA templates, which favor an A-type duplex geometry. We show that more efficiently copied sequences are generated by replacing the adenine nucleobase with diaminopurine, and uracil with C5-(1-propynyl)uracil. Finally, we explore the copying of longer, mixed-sequence RNA templates to assess the sequence-general copying ability of 2′-amino-2′,3′-dideoxynucleoside−5′-phosphorimidazolides. Our results are a significant step forward in the realization of a self-replicating genetic polymer compatible with protocell template copying and suggest that N2′→P5′-phosphoramidate DNA may have the potential to function as a self-replicating system.
The ribonucleoside triphosphate, deoxyribonucleoside triphosphate, 3' -diphosphate guanosine 5' -diphosphate (ppGpp), and 5-phosphoribosyl 1-pyrophosphate (PRPP) pools in Escherichia coli B were determined by thin-layer chromatography during changing conditions to ammonium starvation. The intracellular concentrations of all nucleotides were found to change in a well-defined order several minutes before andy observed change in the optical density of the culture. The levels of purine nucleoside triphosphates (adenosine 5' -triphosphate [CTP], dCTP) and uridine nucleotides (uridine 5' -triphosphate, deoxythymidine 5'-triphosphate). The deoxyribonucleotides thus behaved as the ribonucleotides. The levels of ppGpp increased 11-fold after the decrease in uridine nucleotides, when the accumulation of stable ribonucleic acid (RNA) stopped. The level of the nucleotide pool did not stabilize until 30 min after the change in optical density. The pool of dGTP dropped concomitantly with the pool of CTP. The nucleotide precursor PRPP exhibited a transient increase, wtih maximum value of four times the exponential levels at the onset of starvation. Apparently the cell adjusts early to starvation by reducing either the phosphorylating activity or the nucleotide biosynthetic activity. As in other downshift systems, the accumulation of stable RNA stopped before the break in optical density and before the stop in protein accumulation. Cell divisions were quite insensitive to the control mechanisms operating on RNA and protein accumulation under ammonium starvation, since the cells continued to divide for 21 min without any net accumulation of RNA.
A key event in the origin of life on this planet has been formation of self-replicating RNA-type molecules, which were complex enough to undergo a Darwinian-type evolution (origin of the "RNA world"). However, so far there has been no explanation of how the first RNA-like biopolymers could originate and survive on the primordial Earth.
As condensation of sugar phosphates and nitrogenous bases is thermodynamically unfavorable, these compounds, if ever formed, should have undergone rapid hydrolysis. Thus, formation of oligonucleotide-like structures could have happened only if and when these structures had some selective advantage over simpler compounds. It is well known that nitrogenous bases are powerful quenchers of UV quanta and effectively protect the pentose-phosphate backbones of RNA and DNA from UV cleavage. To check if such a protection could play a role in abiogenic evolution on the primordial Earth (in the absence of the UV-protecting ozone layer), we simulated, by using Monte Carlo approach, the formation of the first oligonucleotides under continuous UV illumination. The simulations confirmed that UV irradiation could have worked as a selective factor leading to a relative enrichment of the system in longer sugar-phosphate polymers carrying nitrogenous bases as UV-protectors. Partial funneling of the UV energy into the condensation reactions could provide a further boost for the oligomerization.
These results suggest that accumulation of the first polynucleotides could be explained by their abiogenic selection as the most UV-resistant biopolymers.
Organic chemistry on a planetary scale is likely to have transformed carbon dioxide and reduced carbon species delivered to an accreting Earth. According to various models for the origin of life on Earth, biological molecules that jump-started Darwinian evolution arose via this planetary chemistry. The grandest of these models assumes that ribonucleic acid (RNA) arose prebiotically, together with components for compartments that held it and a primitive metabolism that nourished it. Unfortunately, it has been challenging to identify possible prebiotic chemistry that might have created RNA. Organic molecules, given energy, have a well-known propensity to form multiple products, sometimes referred to collectively as “tar” or “tholin.” These mixtures appear to be unsuited to support Darwinian processes, and certainly have never been observed to spontaneously yield a homochiral genetic polymer. To date, proposed solutions to this challenge either involve too much direct human intervention to satisfy many in the community, or generate molecules that are unreactive “dead ends” under standard conditions of temperature and pressure. Carbohydrates, organic species having carbon, hydrogen, and oxygen atoms in a ratio of 1:2:1 and an aldehyde or ketone group, conspicuously embody this challenge. They are components of RNA and their reactivity can support both interesting spontaneous chemistry as part of a “carbohydrate world,” but they also easily form mixtures, polymers and tars. We describe here the latest thoughts on how on this challenge, focusing on how it might be resolved using minerals containing borate, silicate, and molybdate, inter alia.
Borates, silicates, and other minerals may have promoted prebiotic chemical reactions in which organic molecules produced RNA, rather than “dead end” polymers and tars.
DNA polymerases are defined as such because they use deoxynucleotides instead of ribonucleotides with high specificity. We show here that polymerase mu (pol μ), implicated in the nonhomologous end-joining pathway for repair of DNA double-strand breaks, incorporates both ribonucleotides and deoxynucleotides in a template-directed manner. pol μ has an approximately 1,000-fold-reduced ability to discriminate against ribonucleotides compared to that of the related pol β, although pol μ's substrate specificity is similar to that of pol β in most other respects. Moreover, pol μ more frequently incorporates ribonucleotides when presented with nucleotide concentrations that approximate cellular pools. We therefore addressed the impact of ribonucleotide incorporation on the activities of factors required for double-strand break repair by nonhomologous end joining. We determined that the ligase required for this pathway readily joined strand breaks with terminal ribonucleotides. Most significantly, pol μ frequently introduced ribonucleotides into the repair junctions of an in vitro nonhomologous end-joining reaction, an activity that would be expected to have important consequences in the context of cellular double-strand break repair.
The three requirements for a Darwinian evolutionary process are replication, variation and selection. Dennett (2006) discusses various theories of how these three processes, especially selection, may have operated in the evolution of religion. He believes that the origins of religion, like the origins of language and music, may be approached scientifically. He hopes that such investigations will open a dialog between science and religion leading to moderation of current religious extremism. One problem with Dennett's program, illustrating the difficulty of breaking away from creationist thinking, is Dennett's own failure to consider how Darwinian methods may be used to study evolution of behavioral patterns over the lifetime of individual organisms.
religion; evolution; science; Darwinism; teleological behaviourism; intentional stance
Template-directed polymerization of chemically activated
monomers, such as nucleotide 5′-phosphorimidazolides, has been
studied as a model for nonenzymatic RNA replication during the origin
of life. Kinetic studies of the polymerization of various nucleotide
monomers on oligonucleotide templates have suggested that the A-form
(C3′-endo sugar pucker) conformation is optimal
for both monomers and templates for efficient copying. However, RNA
monomers are predominantly in the C2′-endo conformation when free in solution, except for cytidine, which is
approximately equally distributed between the C2′-endo and C3′-endo conformations. We hypothesized
that ribonucleotides undergo a switch in sugar pucker upon binding
to an A-type template and that this conformational switch allows or
enhances subsequent polymerization. We used transferred nuclear Overhauser
effect spectroscopy (TrNOESY), which can be used for specific detection
of the bound conformation of small-molecule ligands with relatively
weak affinity to receptors, to study the interactions between nucleotide
5′-phosphorimidazolides and single-stranded oligonucleotide
templates. We found that the sugar pucker of activated ribonucleotides
switches from C2′-endo in the free state to
C3′-endo upon binding to an RNA template.
This switch occurs only on RNA and not on DNA templates. Furthermore,
activated 2′-deoxyribonucleotides maintain a C2′-endo sugar pucker in both the free and template-bound states.
Our results provide a structural explanation for the observations
that activated ribonucleotides are superior to activated deoxyribonucleotides
and that RNA templates are superior to DNA templates in template-directed
nonenzymatic primer-extension reactions.
The Darwinian concept of biological evolution assumes that life on Earth shares a common ancestor. The diversification of this common ancestor through speciation events and vertical transmission of genetic material implies that the classification of life can be illustrated in a tree-like manner, commonly referred to as the Tree of Life. This article describes features of the Tree of Life, such as how the tree has been both pruned and become bushier throughout the past century as our knowledge of biology has expanded. We present current views that the classification of life may be best illustrated as a ring or even a coral with tree-like characteristics. This article also discusses how the organization of the Tree of Life offers clues about ancient life on Earth. In particular, we focus on the environmental conditions and temperature history of Precambrian life and show how chemical, biological, and geological data can converge to better understand this history.
“You know, a tree is a tree. How many more do you need to look at?”–Ronald Reagan (Governor of California), quoted in the Sacramento Bee, opposing expansion of Redwood National Park, March 3, 1966
Environmental temperature significantly influenced the evolution of early life forms. Reconstruction of ancestral DNA sequences is helping to reveal Earth’s temperature history.
The question of the primordial ancestor must be approached through the search for the origin of evolution, not through the search for the origin of life. There is a major issue with the concept of life because it is impossible to define, thus is not a scientific but a metaphysical concept. On the contrary, evolution may be defined by as few as three conditions. These do not necessarily involve biopolymers. However, such an approach must give clues to explain the emergence of distinct lineages to allow Darwinian natural selection. A plausible solution exists within an autotrophic lipidic vesicle-based model that is presented. The model requires the existence of hydrothermal sites such as the Lost City Hydrothermal Field leading to specific constraints. For this reason Mars and Europa may be questioned as possible cradles of evolution. If we replace the search for the origin of life by the one for the origin of evolution our priority first is to find a consensus on the minimal conditions that would allow evolution to emerge and persist anywhere in the universe.
origin of life; origin of evolution; open far-from-equilibrium systems; lipidic vesicles; heredity; hydrothermal vents
A little-noted result of the confirmation of multiple premises of the RNA-world hypothesis is that we now know something about the dawn organisms that followed the origin of life, perhaps over 4 billion years ago. We are therefore in an improved position to reason about the biota just before RNA times, during the era of the first replicators, the first Darwinian creatures on Earth. An RNA congener still prominent in modern biology is a plausible descendent of these first replicators.
Nucleotide cofactors such as NADP could represent relics of pre-RNA life on Earth. They may have been key elements of the first replicators, subsequently co-opted by RNA and then proteins.
Reconstructing early evolutionary events like the origins of informational and operational genes, membranes, and photophosphorylation is difficult because early evolutionary events can be masked by subsequent gene flows. Furthermore, as evolution progresses through both Darwinian survival of the fittest (tree-like evolution) and symbiotic/endosymbiotic cooperation (ring-like evolution), trees alone are not adequate to represent Earth’s evolutionary history. Here, we reconstruct and root the New Rings of Life and use it as a framework for interpreting early events in the evolution of life. Unlike the three-domain hypothesis, the rings do not fit all life into one of three immutable categories, but rather accommodate new gene flows as novel organisms are discovered. A draft of the Rooted Rings of Life is reconstructed by analyzing the phylogenetic distributions of indels (insertions/deletions) and genes coding for fundamental molecular processes. Their phylogenetic distributions are inconsistent with all trees. Hypergeometric distribution analyses of them strongly localize the root of the rings to a segment of the deepest ring (P < 10−21 and P < 10−194), and whole-genome analyses independently confirm the topology of the rooted rings (P < 7.1 × 10−6). The rings identify several large gene flows, including a flow of a thousand genes into the Halobacteria and the Eubacteria, the related photocyte flow, the flow of genes into the last common ancestor of the eocytes and the eukaryotes, and the informational and operational gene flows into the eukaryotes. The rooted rings also chronologically order steps in the evolution of extant taxa, that is, phototrophy evolved from Halobacteria (photophosphorylation) → Heliobacteria (photosynthesis) → Cyanobacteria (oxygenic photosynthesis).
photosynthesis; ether lipids; sporulation; indels; genomes; hypergeometric distributions
In this review, we describe the history of amniote sex determination as a classic example of Darwinian evolution. We suggest that evolutionary changes in sex determination provide a foundation for understanding important aspects of chromosome and genome organization that otherwise appear haphazard in their origins and contents. Species with genotypic sex determination often possess heteromorphic sex chromosomes, whereas species with environmental sex determination lack them. Through a series of mutations followed by selection at key genes, sex-determining mechanisms have turned over many times throughout the amniote lineage. As a consequence, amniote genomes have undergone gains or losses of sex chromosomes. We review the genomic and ecological contexts in which either temperature-dependent or genotypic sex determination has evolved. Once genotypic sex determination emerges in a lineage, viviparity and heteromorphic sex chromosomes become more likely to evolve. For example, in extinct marine reptiles, genotypic sex determination apparently led to viviparity, which in turn facilitated their pelagic radiation. Sex chromosomes comprise genome regions that differ from autosomes in recombination rate, mutation rate, levels of polymorphism, and the presence of sex-determining and sexually antagonistic genes. In short, many aspects of amniote genome complexity, life history, and adaptive radiation appear contingent on evolutionary changes in sex-determining mechanisms.
Amniotes; Archosauromorpha; Hemizygosity; Heterogamety; Pseudoautosomal region; Sexual antagonism; Viviparity
Ribo- and 2'-deoxyribonucleoside 5'-di- or triphosphates are commonly synthesized by reaction of inorganic phosphate or pyrophosphate with phosphorimidazolidates obtained by reaction of nucleoside 5'-phosphates with 1,1'-carbonyldiimidazole. The latter reaction, however, converted UMP, CMP, IMP, GMP, and AMP in high yield to the 2',3'-cyclic carbonate derivatives of their phosphorimidazolidates. Acidic treatment of the product from AMP gave AMP 2',3'-cyclic carbonate dihydrate; this was characterized by its uv, ir, and pmr spectra and by its conversion to adenosine 2',3'-cyclic carbonate by acid phosphatase and to AMP by basic hydrolysis. ADP or ATP synthesized by the phosphorimidazolidate method contained equal or greater amounts of their respective 2',3'-cyclic carbonates. The latter could be quantitatively converted to ADP and ATP, respectively, by 4-hr hydrolysis at pH 10.5, 22 degrees. ADP or ATP can be synthesized without concomitant 2',3'-cyclic carbonate formation by reaction of AMP with phosphorimidazolidates of inorganic phosphate or pyrophosphate.
During the long history of biological evolution, genome structures have undergone enormous changes. Nevertheless, some traits or vestiges of the primordial genome (defined as the most primitive nucleic acid genome for life on earth in this paper) may remain in modern genetic systems. It is of great importance to find these traits or vestiges for the study of the origin and evolution of genomes. As the shorter is a sequence, the less probable it would be modified during genome evolution. And if mutated, it would be easier to reappear at the same site or another site. Consequently, the genomic frequencies of very short nucleotide sequences, such as dinucleotides, would have considerable chances to be conserved during billions of years of evolution. Prokaryotic genomes are very diverse and with a wide range of GC content. Therefore, in order to find traits or vestiges of the primordial genome remained in modern genetic systems, we have studied the characteristics of dinucleotide frequencies across bacterial and archaeal genomes. We analyzed the dinucleotide frequency patterns of the whole-genome sequences from more than 1300 prokaryotic species (bacterial and archaeal genomes available as of December 2012). The results show that the frequencies of the dinucleotides AC, AG, CA, CT, GA, GT, TC, and TG are well-conserved across various genomes, while the frequencies of other dinucleotides vary considerably among species. The dinucleotide frequency conservation/variation pattern seems to correlate with the distributions of dinucleotides throughout a genome and across genomes. Further analysis indicates that the phenomenon would be determined by strand symmetry of genomic sequences (the second parity rule) and GC content variations among genomes. We discussed some possible origins of strand symmetry. And we propose that the phenomenon of frequency conservation of some dinucleotides may provide insights into the genomic composition of the primordial genetic system.
dinucleotide frequency; compositional analysis; whole-genome sequences; strand symmetry; GC content; primordial genome; origin and evolution of genomes
Changes in nucleotide pools and extracellular nucleotides during the developmental cycle of the myxobacterium Myxococcus xanthus were determined using a high-pressure liquid chromatography nucleotide analyzer. A general increase in all nucleotide pools occurred during the morphological phase of glycerol conversion of vegetative cells to myxospores. The levels of the nucleoside triphosphate pools remained high as the myxospore matured and throughout subsequent germination. Oxidized nicotinamide adenine dinucleotide levels were elevated in the dormant myxospore and then declined during germination. The adenylate energy charge value was 0.85 ± 0.02 for vegetative cells, germinating myxospores, and 6-h-old myxospores. It was interesting that the value for the so-called dormant myxospore was the same as that characteristic of physiologically active cells. The germinating myxospores excreted large quantities of uracil along with lesser quantities of purine nucleoside monophosphates. Although the source of the extracellular uracil cannot be determined from these experiments, it may have been derived from a shift in base ratios accompanying an assumed ribonucleic acid turnover during germination.
GTI-2040 is a potent antisense to the M2 subunit of the ribonucleotide reductase (RNR), an enzyme involved in the de novo synthesis of nucleoside triphosphates. We hypothesized that combination of GTI-2040 with the cytarabine (Ara-C) could result in an enhanced cytotoxic effect with perturbed intracellular deoxynucleotide/nucleotide (dNTP/NTP) pools including Ara-C triphosphate (Ara-CTP). This study aims to provide a direct experimental support of this hypothesis by monitoring the biochemical modulation effects, intracellular levels of Ara-CTP, dNTPs/NTPs following the combination treatment of Ara-C, and GTI-2040 in K562 human leukemia cells. GTI-2040 was introduced into cells via electroporation. A hybridization–ligation ELISA was used to quantify intracellular GTI-2040 concentrations. Real-time PCR and Western blot methods were used to measure the RNR M2 mRNA and protein levels, respectively. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay was used to measure the cytotoxicity following various drug treatments. A non-radioactive HPLC-UV method was used for measuring the intracellular Ara-CTP, while a LC-MS/MS method was used to quantify intracellular dNTP/NTP pools. GTI-2040 was found to downregulate M2 mRNA and protein levels in a dose-dependent manner and showed significant decrease in dNTP but not NTP pool. When combining GTI-2040 with Ara-C, a synergistic cytotoxicity was observed with no further change in dNTP/NTP pools. Importantly, pretreatment of K562 cells with GTI-2040 was found to increase Ara-CTP level for the first time, and this effect may be due to inhibition of RNR by GTI-2040. This finding provides a laboratory justification for the current phase I/II evaluation of GTI-2040 in combination with Ara-C in patients with acute myeloid leukemia.
Ara-CTP; GTI-2040; HPLC-UV
It has normally been assumed that ribonucleotides arose on the early Earth through a process in which ribose, the nucleobases, and phosphate became conjoined. However, under plausible prebiotic conditions, condensation of nucleobases with ribose to give β-ribonucleosides is fraught with difficulties. The reaction with purine nucleobases is low-yielding and the reaction with the canonical pyrimidine nucleobases does not work at all. The reasons for these difficulties are considered and an alternative high-yielding synthesis of pyrimidine nucleotides is discussed. Fitting the new synthesis to a plausible geochemical scenario is a remaining challenge but the prospects appear good. Discovery of an improved method of purine synthesis, and an efficient means of stringing activated nucleotides together, will provide underpinning support to those theories that posit a central role for RNA in the origins of life.
Ribonucleotides required for RNA must have formed de novo on the early Earth. Condensation of nucleobases with ribose is problematic, however, and an alternative pyrimidine ribonucleotide synthesis reaction may have occurred.
A large body of evidence suggests that neural plasticity contributes to learning and to disease. Recent studies suggest that cortical map plasticity is typically a transient phase that improves learning by increasing the pool of task relevant responses. Here, I discuss a new perspective on neural plasticity and suggest how plasticity might be targeted to reset dysfunctional circuits. Specifically, a new model is proposed in which map expansion provides a form of replication with variation that supports a Darwinian mechanism to select the most behaviorally useful circuits. Precisely targeted neural plasticity provides a new avenue for the treatment of neurological and psychiatric disorders and a powerful tool to test the neural mechanisms of learning and memory.
vagus nerve stimulation; rehabilitation; neuropathology; sparse coding; neuromodulation; tinnitus
Four recombinant plasmid clones (pPS305, pPS308, pPS317, and pPS319) coding for Escherichia coli ribonucleotide reductase have been characterized in vivo and in vitro. Each clone carried a different missense mutation affecting the B1 subunit. Measurements were made of deoxyribonucleoside triphosphate pools. Cells carrying the wild-type plasmid, pPS2, overproduced ribonucleotide reductase 10 to 20 times. As a consequence of this elevated enzyme level, the deoxyribonucleotide pools were approximately three times higher. All four mutant clones showed disturbed deoxyribonucleotide pools. The in vitro studies involved chromatography on affinity media, measurements of enzyme activity and allosteric regulation with a variety of substrates and effector molecules, and direct photoaffinity labeling in the presence of dTTP. Clones pPS305 and pPS308 were shown to code for catalytically defective enzymes, whereas clones pPS317 and pPS319 were shown to code for allosterically altered enzymes. The characterized missense mutations can thus be localized to areas involved in regulation of the substrate specificity or to the active site of protein B1. The alteration of the deoxyribonucleotide pools found in cells containing the allosterically defective clones pPS317 and pPS319 clearly demonstrated in vivo significance for the allosteric control of protein B1 in E. coli cells.
Evolution is assumed to begin in a very particular compartmentalized location with periodic conditions. A highly diversified world is the driving force for the continuous increase in complexity by colonizing increasingly less favourable regions. Modeling the “origin-of-life” a Darwinian cyclic process is simulated (multiplication with sporadic errors followed by a construction and selection).
Starting from a RNA-world (R-strands of R1 and R2 monomers building Hairpin-Assembler devices) and introducing another kind of monomers (A1 and A2 which interlink to the Hairpin-Assembler devices such that they become bound and form an A-oligomer) it is shown that a simple translation apparatus evolves producing enzymes (specific sequences of A1 and A2 monomers given by the sequences of R1 and R2 monomers on the assembler-strands). Later on D-strands are introduced, which are not capable of participating in the synthesis of A-oligomers. These D-strands become carriers of the genetic information and induce the formation of increasingly complex entities of functionally interplaying components.
origin of life; evolution; genetic apparatus; genetic code; emergence and storage of information; self organisation; fundamental conditions; assembler; hairpin; RNA world; assembler-hairpin-enzyme device; RNA-protein world; DNA-RNA-protein world; computer simulation
Fermentation of glucose to lactate in the presence of sufficient oxygen, known as aerobic glycolysis or Warburg effect, is a universal phenotype of cancer cells. Understanding its origin and role in cellular immortalization and transformation has attracted considerable attention in the recent past. Intriguingly, while we now know that Warburg effect is essential for tumor growth and development, it is thought to arise because of genetic and/or epigenetic changes. In contrast to the above, we propose that Warburg effect can also arise due to normal biochemical fluctuations, independent of genetic and epigenetic changes. Cells that have acquired Warburg effect proliferate rapidly to give rise to a population of heterogeneous progenitors of cancer cells. Such cells also generate more lactate and alter the fitness landscape. This dynamic fitness landscape facilitates evolution of cancer cells from its progenitors, in a fashion analogous to Darwinian evolution. Thus, sporadic cancer can also occur first by the acquisition of Warburg effect, then followed by mutation and selection. The idea proposed here circumvents the inherent difficulties associated with the current understanding of tumorigenesis, and is also consistent with many experimental and epidemiological observations. We discuss this model in the context of epigenetics as originally enunciated by Waddington.
Electronic supplementary material
The online version of this article (doi:10.1007/s13148-011-0030-x) contains supplementary material, which is available to authorized users.
Cancer epigenetics; Warburg effect; Crabtree effect; Cellular heterogeneity; Biological noise; Aerobic glycolysis; Bistability
Both quantitative and methodological techniques exist that foster the development and maintenance of a cumulative knowledge base within the psychological sciences. Most noteworthy of these techniques is meta-analysis which allows for the synthesis of summary statistics drawn from multiple studies when the original data are not available. However, when the original data can be obtained from multiple studies, many advantages stem from the statistical analysis of the pooled data. The authors define integrative data analysis (IDA) as the analysis of multiple data sets that have been pooled into one. Although variants of IDA have been incorporated into other scientific disciplines, the use of these techniques are much less evident in psychology. In this paper the authors present an overview of IDA as it may be applied within the psychological sciences; a discussion of the relative advantages and disadvantages of IDA; a description of analytic strategies for analyzing pooled individual data; and offer recommendations for the use of IDA in practice.
Accumulating experimental evidence suggests that the gene regulatory networks of living organisms operate in the critical phase, namely, at the transition between ordered and chaotic dynamics. Such critical dynamics of the network permits the coexistence of robustness and flexibility which are necessary to ensure homeostatic stability (of a given phenotype) while allowing for switching between multiple phenotypes (network states) as occurs in development and in response to environmental change. However, the mechanisms through which genetic networks evolve such critical behavior have remained elusive. Here we present an evolutionary model in which criticality naturally emerges from the need to balance between the two essential components of evolvability: phenotype conservation and phenotype innovation under mutations. We simulated the Darwinian evolution of random Boolean networks that mutate gene regulatory interactions and grow by gene duplication. The mutating networks were subjected to selection for networks that both (i) preserve all the already acquired phenotypes (dynamical attractor states) and (ii) generate new ones. Our results show that this interplay between extending the phenotypic landscape (innovation) while conserving the existing phenotypes (conservation) suffices to cause the evolution of all the networks in a population towards criticality. Furthermore, the networks produced by this evolutionary process exhibit structures with hubs (global regulators) similar to the observed topology of real gene regulatory networks. Thus, dynamical criticality and certain elementary topological properties of gene regulatory networks can emerge as a byproduct of the evolvability of the phenotypic landscape.
Dynamically critical systems are those which operate at the border of a phase transition between two behavioral regimes often present in complex systems: order and disorder. Critical systems exhibit remarkable properties such as fast information processing, collective response to perturbations or the ability to integrate a wide range of external stimuli without saturation. Recent evidence indicates that the genetic networks of living cells are dynamically critical. This has far reaching consequences, for it is at criticality that living organisms can tolerate a wide range of external fluctuations without changing the functionality of their phenotypes. Therefore, it is necessary to know how genetic criticality emerged through evolution. Here we show that dynamical criticality naturally emerges from the delicate balance between two fundamental forces of natural selection that make organisms evolve: (i) the existing phenotypes must be resilient to random mutations, and (ii) new phenotypes must emerge for the organisms to adapt to new environmental challenges. The joint effect of these two forces, which are essential for evolvability, is sufficient in our computational models to generate populations of genetic networks operating at criticality. Thus, natural selection acting as a tinkerer of evolvable systems naturally generates critical dynamics.
Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.
bile acids; genomic instability; colon cancer