On the Growth Rate of Non-Enzymatic Molecular Replicators

It is well known that non-enzymatic template directed molecular replicators X + nO ---> 2X exhibit parabolic growth d[X]/dt = k [X]^{1/2}. Here, we analyze the dependence of the effective replication rate constant k on hybridization energies, temperature, strand length, and sequence composition. First we derive analytical criteria for the replication rate k based on simple thermodynamic arguments. Second we present a Brownian dynamics model for oligonucleotides that allows us to simulate their diffusion and hybridization behavior. The simulation is used to generate and analyze the effect of strand length, temperature, and to some extent sequence composition, on the hybridization rates and the resulting optimal overall rate constant k. Combining the two approaches allows us to semi-analytically depict a fitness landscape for template directed replicators. The results indicate a clear replication advantage for longer strands at low temperatures.Comment: Submitted to: Entrop

Robust self-replication of combinatorial information via crystal growth and scission

Understanding how a simple chemical system can accurately replicate combinatorial information, such as a sequence, is an important question for both the study of life in the universe and for the development of evolutionary molecular design techniques. During biological sequence replication, a nucleic acid polymer serves as a template for the enzyme-catalyzed assembly of a complementary sequence. Enzymes then separate the template and complement before the next round of replication. Attempts to understand how replication could occur more simply, such as without enzymes, have largely focused on developing minimal versions of this replication process. Here we describe how a different mechanism, crystal growth and scission, can accurately replicate chemical sequences without enzymes. Crystal growth propagates a sequence of bits while mechanically-induced scission creates new growth fronts. Together, these processes exponentially increase the number of crystal sequences. In the system we describe, sequences are arrangements of DNA tile monomers within ribbon-shaped crystals. 99.98% of bits are copied correctly and 78% of 4-bit sequences are correct after two generations; roughly 40 sequence copies are made per growth front per generation. In principle, this process is accurate enough for 1,000-fold replication of 4-bit sequences with 50% yield, replication of longer sequences, and Darwinian evolution. We thus demonstrate that neither enzymes nor covalent bond formation are required for robust chemical sequence replication. The form of the replicated information is also compatible with the replication and evolution of a wide class of materials with precise nanoscale geometry such as plasmonic nanostructures or heterogeneous protein assemblies

Sociobiology, universal Darwinism and their transcendence: An investigation of the history, philosophy and critique of Darwinian paradigms, especially gene-Darwinism, process-Darwinism, and their types of reductionism towards a theory of the evolution of evolutionary processes, evolutionary freedom and ecological idealism

Based on a review of different Darwinian paradigms, particularly sociobiology, this work, both, historically and philosophically, develops a metaphysic of gene-Darwinism and process-Darwinism, and then criticises and transcends these Darwinian paradigms in order to achieve a truly evolutionary theory of evolution. Part I introduces essential aspects of current sociobiology as the original challenge to this investigation. The claim of some sociobiologists that ethics should become biologized in a gene-egoistic way, is shown to be tied to certain biological views, which ethically lead to problematic results. In part II a historical investigation into sociobiology and Darwinism in general provides us, as historical epistemology', with a deeper understanding of the structure and background of these approaches. Gene-Darwinism, which presently dominates sociobiology and is linked to Dawkins' selfish gene view of evolution, is compared to Darwin's Darwinism and the evolutionary' synthesis and becomes defined more strictly. An account of the external history of Darwinism and its subparadigms shows how cultural intellectual presuppositions, like Malthusianism or the Newtonian concept of the unchangeable laws of nature, also influenced biological theory' construction. In part III universal 'process-Darwinism' is elaborated based on the historical interaction of Darwinism with non-biological subject areas. Building blocks for this are found in psychology, the theory of science and economics. Additionally, a metaphysical argument for the universality of process- Darwinism, linked to Hume's and Popper's problem of induction, is proposed. In part IV gene-Darwinism and process-Darwinism are criticised. Gene-Darwinism—despite its merits—is challenged as being one-sided in advocating 'gene-atomism', 'germ-line reductionism' and 'process-monism'. My alternative proposals develop and try to unify different criticisms often found. In respect of gene-atomism I advocate a many-level approach, opposing the necessary radical selfishness of single genes. I develop the concept of higher-level genes, propose a concept of systemic selection, which may stabilise group properties, without relying on permanent group selection and extend the applicability of a certain group selectionist model generally to small open groups. Proposals of mine linked to the critique of germ-line reductionism are: 'exformation', phenotypes as evolutionary factors and a field theoretic understanding of causa formalis (resembling Aristotelian hylemorphism). Finally the process-monism of gene-Darwinism, process-Darwinism and, if defined strictly, Darwinism in general is criticised. 1 argue that our ontology and ethics would be improved by replacing the Newtoman-Paleyian deist metaphor of an eternal and unchangeable law of nature, which lies at tire very heart of Darwinism, by a truly evolutionary understanding of evolution where new processes may gain a certain autonomy. All this results in a view that I call 'ecological idealism', which, although still very much based on Darwinism, clearly transcends a Darwinian world view

Peptide-Based Supramolecular Systems Chemistry

Peptide-based supramolecular systems chemistry seeks to mimic the ability of life forms to use conserved sets of building blocks and chemical reactions to achieve a bewildering array of functions. Building on the design principles for short peptide-based nanomaterials with properties, such as self-assembly, recognition, catalysis, and actuation, are increasingly available. Peptide-based supramolecular systems chemistry is starting to address the far greater challenge of systems-level design to access complex functions that emerge when multiple reactions and interactions are coordinated and integrated. We discuss key features relevant to systems-level design, including regulating supramolecular order and disorder, development of active and adaptive systems by considering kinetic and thermodynamic design aspects and combinatorial dynamic covalent and noncovalent interactions. Finally, we discuss how structural and dynamic design concepts, including preorganization and induced fit, are critical to the ability to develop adaptive materials with adaptive and tunable photonic, electronic, and catalytic properties. Finally, we highlight examples where multiple features are combined, resulting in chemical systems and materials that display adaptive properties that cannot be achieved without this level of integration

The cellular impact of diminished DNA origin licensing capacity and its potential therapeutic exploitation

Genomic instability underlies various diseases including cancer. The maintenance of genomic stability requires accurate replication of the genome, proper segregation of duplicated DNA to progeny cells, and the capacity to respond effectively to DNA damage. Early sections of this thesis focus on the response to DNA double-strand breaks (DSBs) within compact regions of chromatin (heterochromatin). Here, methodology was optimised for monitoring the repair of site-specific DSBs within regions likely to be enriched for heterochromatin. This system was exploited to examine the function of the Artemis endonuclease in heterochromatic DSB repair. Later sections focus on factors involved in DNA replication and the response to replication stress. Among the various mechanisms involved in the DNA damage response (DDR) to replication stress, the licensing of excess origins of replication has been proposed to safeguard against replication failure. Here, the impact of diminished origin licensing capacity on the response to replication stress was compared in tumour and non-tumour cell lines. I present findings demonstrating that depletion of origin licensing factors causes hypersensitisation of tumour-derived but not non-tumour cell lines to replication stress-inducing agents. Further, combining diminished origin licensing capacity with depletion of the tumour suppressor, p53, or overexpression of the c-Myc oncogene impairs viability under conditions of replication stress in non-tumour fibroblasts. These findings suggest that tumour cells have a greater reliance on origin licensing capacity, raising the possibility that licensing factors might represent suitable targets for drugbased cancer therapy. Factors involved in replication origin licensing have also been implicated in the establishment of heterochromatin. Here, I examined higher-order chromatin structure and the ionizing radiation (IR)-induced DDR in cells from patients harbouring mutations in origin licensing factors. Findings from these studies provide evidence for the first time that origin licensing complex (ORC)-deficient Meier-Gorlin Syndrome (MGS) may be classified as a disordered chromatin syndrome

The Origin and Early Evolution of Life

What is life? How, where, and when did life arise? These questions have remained most fascinating over the last hundred years. Systems chemistry is the way to go to better understand this problem and to try and answer the unsolved question regarding the origin of Life. Self-organization, thanks to the role of lipid boundaries, made possible the rise of protocells. The role of these boundaries is to separate and co-locate micro-environments, and make them spatially distinct; to protect and keep them at defined concentrations; and to enable a multitude of often competing and interfering biochemical reactions to occur simultaneously. The aim of this Special Issue is to summarize the latest discoveries in the field of the prebiotic chemistry of biomolecules, self-organization, protocells and the origin of life. In recent years, thousands of excellent reviews and articles have appeared in the literature and some breakthroughs have already been achieved. However, a great deal of work remains to be carried out. Beyond the borders of the traditional domains of scientific activity, the multidisciplinary character of the present Special Issue leaves space for anyone to creatively contribute to any aspect of these and related relevant topics. We hope that the presented works will be stimulating for a new generation of scientists that are taking their first steps in this fascinating field

Studies of a position effect and amine metabolism in Aspergillus

The purpose of these studies was mainly the investigation of a variegated position effect affecting the conidiation system of Aspergillus nidulans. Genetical and biochemical investigations were undertaken to explore the nature of the variegated process and therefore gain information about the mechanism(s) underlying the relationship of chromatin structure and gene expression. The main lines towards which these studies were finally orientated include (a) studies of the brlA12 by means of modifiers isolated as such or found in stock strains; such studies aim to trace other features of these mutants and to correlate them to their modifying action; (b) studies of the brlA12 by means of environmental effects on its variegation, caused by chemicals administered in the growth medium; such studies would produce evidence about the biochemical nature of the variegation; (c) search for biochemical defects either in brlAl2 itself or its modifiers in combination with the other approaches. The main points which emerged from the above studies can be summarised here as follows; (1) brlA12 grows normally on any nitrogen or carbon sources tested. Its variegation is shifted towards wild type appearance (increased conidiation) by salts, methylamine, and to a minor extent, by a number of other compounds, low pH and temperature. (2) A number of mutants isolated as such or found in the stock strains act as suppressors or enhancers of the variegation (increasing or reducing the conidiation further, respectively). (3) One class of the suppressors, represented by rev-2 is unable to utilize galactose as carbon source; no clear pattern correlating galactose utilization and brlA12 variegation has emerged however. A connection of galactose utilization and polyamine metabolism may exist (as in yeasts) since iproniazid, an amine oxidase inhibitor, repairs to some extent growth of these suppressors on galactose. (4) The suppressors which are defective on galactose are extra sensitive to molybdate, but this pattern is followed only by modifiers isolated as such; gam and some gal mutants which are all defective on galactose and enhance the brlA12 mutant are molybdate resistant. (5) Molybdate resistant strains (isolated as such or found to be modifiers of brlA12) act as enhancers with the exception of mo1A which has no effect on the variegation; this mutant however may have a different basis of resistance. (6) rev-2 has low viability rate and high spontaneous mutation frequency to selenate resistance. (7) rev-2 has subnormal growth on putrescine as nitrogen source and it is pigmented pink. The pigmentation is greatly enhanced if nitrate (or nitrite) is present at the same time (glucose as carbon source), in which case conidiation is extremely poor. (8) brlA12 and to a lesser extent all the brl mutants (non-variegated alleles) are also pigmented on putrescine plus nitrate but not on putrescine alone. (9) Preliminary investigations suggest that the pink pigment, which may be relevant to conidiation processes, may be a prodigiosin-like pigment with putrescine or a compound derived from putrescine as its biosynthetic precursor. (10) rev-2, rev-5, rev-7 do not alter the conidiation pattern of the non-variegated leaky br1A9; this may indicate that these suppressors affect chromatin structure in general rather than being conidiation specific. (11) Studies of polyamine metabolism did not reveal any differences in terms of polyamine uptake or putrescine oxidase and transaminase activities. An instance of possibly abnormally high internal putrescine pools for rev-2 after growth on this amine needs further investigation. Although studies of amine metabolism in this work were orientated to their connection with brlA12, a number of general aspects of polyamine metabolism and regulation in Aspergillus nidulans have been investigated; a number of mutants altered in polyamine metabolism were isolated, two catabolic enzymes for putrescine were characterised, and the uptakes and internal polyamine pools were studied. Also an activation of glutamate dehydrogenase by polyamines was examined. (Abstract shortened by ProQuest.)