What is Life? On the origin and mechanism of living systems
Chris Busby
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Abstract
In this small book, Busby presents the results of a lifetime search for the mechanism of life itself, ideas which began with his work on the mechanism of molecular drug interactions in the 1970s and upon which he has carried out fundamental research throughout the intervening 45 years, and contues to do so.
Related papers
The elusive life. Incisiveness and insufficiency of mechanistic biology
Euresis Journal, 2013
In the last few decades, mainly due to technological advances, the molecular objects and mechanisms being continuously at work in living beings, and supporting their unique performance, have become accessible to an unprecedented detail. In particular, the number of complete genome sequences being determined and annotated has been growing exponentially; exhaustive inventories of cellular RNAs (transcriptomes) are being established, revealing a multitude of non-protein-coding RNAs (ncRNAs) of unknown function; whole sets of different protein species populating cells and sub-cellular organelles (proteomes) are being massively identified, quantified and chemically characterized; genome-wide cartographies are being drawn for site-specific DNA methylation and chromatin protein signatures, revealing their interconnected influences on DNA accessibility and gene expression (epigenomes); protein-protein interactions, multiprotein complexes and gene-gene interactions occurring within living cells are being systematically put in light and integrated into networks of astonishing complexity (interactomes). Besides posing a serious challenge to our actual ability to manage and interpret such a high amount of analytical information, these “post-genomic” studies are opening new, surprising perspectives on the nature of genes, on the complexity of cellular regulatory networks, on the biogenesis, roles and interplay of biological macromolecules participating in these networks. We now realize, more clearly than ever before, that what we call life depends on a molecular scenario whose intricacy is destined to increase proportionally with the power of our analytical tools. Such a dependence of the living status on indefinitely ramified and dynamic chemical interaction networks appears to be in contrast with the unitary sense of being we experience, as living individuals, from the “inner side” of life, and the reasonable suspect may arise that even the ultimate analytical description of our material arrangement would not allow us to infer from it the living status we directly experience. Mainly based on Hans Jonas’ philosophical reflection on the living organism, I will discuss the thesis that life, even in its non-human forms, cannot be satisfactorily described in terms of the particular arrangements of chemical entities it depends on, and that a rational approach to the question of life should not exclude an inward, subjective dimension that is at the same time inaccessible to scientific investigation, yet essential to fully understand the objects revealed by it. Viewed in this light, modern biology offers a unique opportunity to appreciate the immeasurable character of reality, of which life itself is not simply a part, but the one and only point of access and manifestation.
The quest for the mechanisms of life
Biotechnology and Bioengineering, 2003
The genomic revolution, manifested by the sequencing of the complete genome of many organisms, along with technological advances, such as DNA microarrays and developments in high-throughput analysis of proteins, metabolites, and isotopic tracer distribution patterns, challenged the conventional ways in which questions are approached in the biological sciences: (a) rather than examining a small number of genes and/or reactions at any one time, we can now analyze gene expression and protein activity in the context of systems of interacting genes and gene products; (b) comprehensive analysis of biological systems requires the integration of all cellular fingerprints: genome sequence, maps of gene expression, protein expression, metabolic output, and in vivo enzymatic activity; and (c) collecting, managing, and analyzing comparable data from various cellular profiles requires expertise from several fields that transcend traditional discipline boundaries. While researchers in systems biology have still to address difficult challenges in both experimental and computational arenas, they possess, for the first time, the opportunity to unravel the mechanisms of life. The enormous impact of these discoveries in diverse areas, such as metabolic engineering, strain selection, drug screening and development, bioprocess development, disease prognosis and diagnosis, gene and other medical therapies, is an obvious motivation for pursuing integrated analyses of cellular systems. B
The Origin of Cellular Life and Biosemiotics
BIOSEMIOTICS, 2013
Recent successes of systems biology clarified that biological functionality is multilevel. We point out that this fact makes it necessary to revise popular views about macromolecular functions and distinguish between local, physico-chemical and global, biological functions. Our analysis shows that physico-chemical functions are merely tools of biological functionality. This result sheds new light on the origin of cellular life, indicating that in evolutionary history, assignment of biological functions to cellular ingredients plays a crucial role. In this wider picture, even if aggregation of chance mutations of replicator molecules and spontaneously self-assembled proteins led to the formation of a system identical with a living cell in all physical respects but devoid of biological functions, it would remain an inanimate physical system, a pseudo-cell or a zombie-cell but not a viable cell. In the origin of life scenarios, a fundamental circularity arises, since if cells are the minimal units of life, it is apparent that assignments of cellular functions require the presence of cells and vice versa. Resolution of this dilemma requires distinguishing between physico-chemical and biological symbols as well as between physico-chemical and biological information. Our analysis of the concepts of symbol, rule and code suggests that they all rely implicitly on biological laws or principles. We show that the problem is how to establish physico-chemically arbitrary rules assigning biological functions without the presence of living organisms. We propose a solution to that problem with the help of a generalized action principle and biological harnessing of quantum uncertainties. By our proposal, biology is an autonomous science having its own fundamental principle. The biological principle ought not to be regarded as an emergent phenomenon. It can guide chemical evolution towards the biological one, progressively assigning greater complexity and functionality to macromolecules and systems of macromolecules at all levels of organization. This solution explains some perplexing facts and posits a new context for thinking about the problems of the origin of life and mind.
How can a chemical system act purposefully? Bridging between life and non-life
Journal of Physical Organic Chemistry, 2008
One of life's most striking characteristics is its purposeful (teleonomic) character, a character already evident at the simplest level of life-a bacterial cell. But how can a bacterial cell, effectively an aqueous solution of an assembly of biomolecules and molecular aggregates within a membrane (that is itself a macromolecular aggregate), act purposefully? In this review, we discuss this fundamental question by showing that the somewhat vague concept of purpose can be given precise physicochemical characterization, and can be shown to derive directly from the powerful kinetic character of the replication reaction. At the heart of our kinetic model is the idea that the stability that governs replicating systems is a dynamic kinetic stability, one that is distinctly different to the thermodynamic stability that dominates the inanimate world. Accordingly, living systems constitute a kinetic state of matter as opposed to the thermodynamic states that dominate the inanimate world. Thus, the model is able to unite animate and inanimate within a single conceptual framework, yet is able to account for life's unique characteristics, amongst them its purposeful character. As part of that unification, it is demonstrated that key Darwinian concepts are special examples of more general chemical concepts. Implications of the model with regard to the possible synthesis of living systems are discussed.
HOW BIOLOGICAL INTERACTION EXPLAINS THE ORIGIN OF
By definition, a cell is the smallest unit of biological life. This means that every living thing can be fundamentally narrowed down to a composition of cells working together for the furtherance of that being in existence. With the dawn dawn of the evolutionary theory that bespeaks of life commencing some 〜3.8 billion years ago with RNA strands that underwent evolution to become DNA, which led to what we have now as life in the world, or with the Panspermia hypothesis, assuming that life on Earth was seeded from space, what is being considered in this work pertains to the origin of life. In addition to the plethora of intuitive stances that concern the origin story of life, this work will only add to the these. The major hypothesis in this work is that the continuity of life, as pertaining to its procession from parent to offspring provides fundamental links to the origin of life and this is the major consideration that will be given. It is thus apparent that the cells that would be considered are germ cells and not somatic cells. A cursory look at the continuity of life, should give us clues as regards how life originated. We nonetheless, take into consideration the fact that some features due to its non-use have gone extinct, thus taking with them the needed knowledge to breaking even as regards our inquiry. Even at that, we propose that conjectures, hypothetically, can be made based on the physical evidence that is available to us today.
Seeking the Chemical Roots of Darwinism: Bridging between Chemistry and Biology
Chemistry – A European Journal, 2009
Molecules, Information and the Origin of Life: What Is Next?
Molecules
How life did originate and what is life, in its deepest foundation? The texture of life is known to be held by molecules and their chemical-physical laws, yet a thorough elucidation of the aforementioned questions still stands as a puzzling challenge for science. Focusing solely on molecules and their laws has indirectly consolidated, in the scientific knowledge, a mechanistic (reductionist) perspective of biology and medicine. This occurred throughout the long historical path of experimental science, affecting subsequently the onset of the many theses and speculations about the origin of life and its maintenance. Actually, defining what is life, asks for a novel epistemology, a ground on which living systems’ organization, whose origin is still questioned via chemistry, physics and even philosophy, may provide a new key to focus onto the complex nature of the human being. In this scenario, many issues, such as the role of information and water structure, have been long time neglect...
Molecular “Vitalism”
Cell, 2000
pore, and ribosome all have substructures, moving parts, and integrated assemblies like conventional ma-Harvard Medical School Boston, Massachusetts 02114 chines (Cell, 1998). Yet other biological systems, which might seem machine-like, on closer examination oper-† Department of Molecular and Cell Biology University of California at Berkeley ate on very different principles. Even the simple signalresponse of an allosteric enzyme is not machine-like Berkeley, California 94720 when examined in detail. Allosteric proteins have intrinsically active and inactive conformations, which exist in some ratio in the absence of an external signal (Monod In the early nineteenth century, views on the nature of et al., 1965; Henry et al., 1997). Interconversion between living organisms were broadly divided into two categothe states is spontaneous, driven by thermal energy. ries, chemical and vitalist. The former held that life was Allosteric effectors bind preferentially to one of the a consequence of complex, but ultimately knowable states, perturbing the equilibrium, and leading to inhibiphysicochemical processes, while the latter posited tion or activation. However, the allosteric effector does some nonnatural, perhaps unknowable, properties of not directly change the chemistry or conformation of living systems. Vitalism was progressively undermined the protein appreciably, but merely stabilizes one of the by Wohler's synthesis of urea (1828) and by Pasteur's two preexisting states-a case of state selection. Like inability to demonstrate spontaneous generation (1862), macroscopic machines there is an input and an output, as well as by Darwin's Origin of Species (1859) and but unlike machines the intervening linkages are statisti-Virchow's cell theory (1855). By the turn of the twentieth cal and not mechanical. More complex "protein macentury the remarkable properties of living systems were chines" like the ribosome can bias the statistics toward more evident than ever, but vitalism was no longer indetermined outcomes by hydrolyzing NTP, but the esvoked to explain them. The modern scientific quest for sential role of statistical thermodynamics in their levers the chemical basis of life had begun in earnest. Although and springs should not be forgotten. heredity was known as an important property of living Bacterial chemotaxis also appears superficially to be organisms, investigations of the chemical basis of life a simple signal-response machine, where an attractant concentrated as much on other attributes, such as meor repellent is perceived by receptors on the bacterial tabolism and movement. At the close of the twentieth century, genetics reigns surface to generate a signal that is converted to directed triumphant as the central theme in biological thought. movement. We could imagine all sorts of linkages that The sequence of the human genome is widely seen as would control a motor or a steering mechanism to guide the starting point for biological investigation in the next the bacterium by chemical signals. In fact, bacterial checentury, and the debate on the origin of life largely demotaxis is based on the modulation of random movefines "alive" as equivalent to "accurately transmitting a ment by ligand binding, resulting in a biased random genetic blueprint." We do not question the importance walk. The specific path any bacterium takes is not diof genetics, nor dispute the role of DNA as the blueprint rectly informed by the binding of the ligand, nor does for all the components of living systems, but we think the individual bacterium at any moment sense a spatial it worth asking to what extent the "postgenomic" view gradient (Berg, 1988). This is quite different from any of modern biology would convince a nineteenth century machine of human design! vitalist that the nature of life was now understood. How Biological systems look even less like machines when close are we to understanding how a single cell funcone considers spatial organization. They can generate tions or how an embryo develops? If the answer is not order from disorder and can arrive at functional states so close, will true understanding of living systems come and responses over a range of starting points, sizes of from further annotating the database of genes, or must components, and sizes of final product. As an example, we explore the physicochemical nature of living sysconsider the relationship between cell size and the size tems? In this essay we discuss a few personal favorite of the organism. In the 1940s Gerhard Fankhauser exexamples, starting from macromolecular assembly and perimented with the effects of ploidy on newt developincreasing in complexity and scale to patterning in vertement (Fankhauser, 1945). Polyploid embryos, generated brate embryology. Our discussion illustrates the nature by suppressing early cleavages, had fewer but larger of biological organization and explores the potential cells. Cells in all tissues were affected, but the tissues chemical principles behind them. Although the units we of the organism and the adult itself remained the normal consider, proteins, cells, and embryos are manifestly size. The consequence of ploidy was seen most clearly the products of genes, the mechanisms that promote in well-defined structures, such the pronephric duct (the their function are often far removed from sequence inforearliest kidney rudiment). Fankhauser found that the mation. In a light-hearted, millennial vein we might call average number of epithelial cells forming the duct deresearch into this kind of integrated cell and organismal creased with increased ploidy, while the duct size and physiology "molecular vitalism." wall thickness remained the same diameter! As shown in Figure 1, in pentaploid embryos there were just one to three cells straining to maintain a circular duct of The Limitations of Machine Analogies in Biology Analogies to machines are widely used in molecular dimensions that required three to five cells in diploid embryos and five to eight cells in haploid embryos. In biology to understand the nature of cellular processes.
Physical theories, automata, and the origin of life
Natural automata and useful simulations. Washington: …, 1996
Protein interaction world–an alternative hypothesis about the origins of life
The protein interaction world hypothesis about the origins of life is introduced in this paper. According to this hypothesis, life emerged as a self reproducing and expanding system of protein interactions, which is conceptualized as an abstract communication system. We describe key components of abstract communication systems and how such systems work, including the role of memories of communications. Protein interaction systems are made of communications that are the interactions between proteins. In the context of the protein interaction world hypothesis RNA molecules
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2018.03.20-ESSENCE AND EMERGENCE OF BIOLOGICAL LIFE (2002)
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The chemical space of prebiotic chemistry is extremely large, while extant biochemistry uses only a few thousand interconnected molecules. Here we discuss how the connection between these two regimes can be investigated, and explore major outstanding questions in the origin of life. As we search for habitable and inhabited planets beyond Earth, defining life and understanding how it originates is critical to designing life detection missions 1. Though scientists from many fields have tried to understand the origins of life, and many hypotheses exist, a precise definition of life remains elusive 2 , and we do not presently know how life began. From interstellar observations and carbonaceous meteorites, it is known that complex organic chemistry occurs widely in primitive solar system environments (e.g., ref. 3). Conversely, we have the single data point of the chemistry produced by our biosphere. The space between these data points is sparsely filled by experiment, model, and hypothesis. Experimentally addressing the chemical origins of life is complicated by the size of organic chemical space 4 , and the tandem sparsity and complexity of reactions which could give rise to autocatalytic, replicative and ultimately living chemistry. A large amount of chemistry remains to be explored, and it is likely the field will benefit from a combination of experimental, observational and computational studies. For example, computational chemists can algorithmically explore chemical space using graph "grammars" 5 much more rapidly than "wet" chemists can experimentally, though such computations are still hampered by accuracy and computational capacity 6. Origins of life models, regardless of biases along heterotrophic/autotrophic axes 7 , all depend on the origin of chemical reaction networks. But life is more than a collection of reactions and compounds, it is a systemic phenomenon characterized by feedbacks that modulate kinetics. Within reaction networks, slight differences in reactivity can cause large systemic effects. Network closure, in which the edges (in this case reactions) and nodes (here, chemical compounds) of a network form a single connected component 8 , is a unifying concept defining hierarchically functional and selectable biological units (e.g., metabolic pathways, genes, organelles, cells,
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