The challenges of purely mechanistic models in biology and the minimum need for a 'mechanism-plus-X' framework

Ever since the advent of molecular biology in the 1970s, mechanical models have become the dogma in the field, where a "true" understanding of any subject is equated to a mechanistic description. This has been to the detriment of the biomedical sciences, where, barring some exceptions, notable new feats of understanding have arguably not been achieved in normal and disease biology, including neurodegenerative disease and cancer pathobiology. I argue for a "mechanism-plus-X" paradigm, where mainstay elements of mechanistic models such as hierarchy and correlation are combined with nomological principles such as general operative rules and generative principles. Depending on the question at hand and the nature of the inquiry, X could range from proven physical laws to speculative biological generalizations, such as the notional principle of cellular synchrony. I argue that the "mechanism-plus-X" approach should ultimately aim to move biological inquiries out of the deadlock of oft-encountered mechanistic pitfalls and reposition biology to its former capacity of illuminating fundamental truths about the world

Biophysics and systems biology

Biophysics at the systems level, as distinct from molecular biophysics, acquired its most famous paradigm in the work of Hodgkin and Huxley, who integrated their equations for the nerve impulse in 1952. Their approach has since been extended to other organs of the body, notably including the heart. The modern field of computational biology has expanded rapidly during the first decade of the twenty-first century and, through its contribution to what is now called systems biology, it is set to revise many of the fundamental principles of biology, including the relations between genotypes and phenotypes. Evolutionary theory, in particular, will require re-assessment. To succeed in this, computational and systems biology will need to develop the theoretical framework required to deal with multilevel interactions. While computational power is necessary, and is forthcoming, it is not sufficient. We will also require mathematical insight, perhaps of a nature we have not yet identified. This article is therefore also a challenge to mathematicians to develop such insights

The Biocentric Design Model: How Features of Living Things Go Beyond Irreducible Complexity and Specified Complexity, and How Creation Science Could Foment New Discoveries in Biology

This paper highlights features of living organisms that go beyond that of machines on the one hand and computational devices on the other. These features exceed those of human crafted artifacts, as well as demonstrate insight and creativity in their creation. It will be demonstrated that they cannot arise from natural processes but are the result of mind and intelligence. It is hoped that the biocentric design attributes described here would augment irreducible complexity and specified complexity as evidence of design in living organisms. The issues addressed are of particular relevance in the light of recent discoveries in epigenomics and metagenomics, as well as developments in the new disciplines of systems biology and synthetic biology. Just as these disciplines focuses on designing biological systems, so too biology is no less than the science of how living organisms are designed. This paradigm shift could lead to the discovery of universal laws and scientific explanations of how living organisms are designed, superseding historical narratives in evolutionary biology

Without magic bullets: the biological basis for public health interventions against protein folding disorders

Protein folding disorders of aging like Alzheimer's and Parkinson's diseases currently present intractable medical challenges. 'Small molecule' interventions - drug treatments - often have, at best, palliative impact, failing to alter disease course. The design of individual or population level interventions will likely require a deeper understanding of protein folding and its regulation than currently provided by contemporary 'physics' or culture-bound medical magic bullet models. Here, a topological rate distortion analysis is applied to the problem of protein folding and regulation that is similar in spirit to Tlusty's (2010a) elegant exploration of the genetic code. The formalism produces large-scale, quasi-equilibrium 'resilience' states representing normal and pathological protein folding regulation under a cellular-level cognitive paradigm similar to that proposed by Atlan and Cohen (1998) for the immune system. Generalization to long times produces diffusion models of protein folding disorders in which epigenetic or life history factors determine the rate of onset of regulatory failure, in essence, a premature aging driven by familiar synergisms between disjunctions of resource allocation and need in the context of socially or physiologically toxic exposures and chronic powerlessness at individual and group scales. Application of an HPA axis model is made to recent observed differences in Alzheimer's onset rates in White and African American subpopulations as a function of an index of distress-proneness

Twenty years of "Lipid World": a fertile partnership with David Deamer

"The Lipid World" was published in 2001, stemming from a highly effective collaboration with David Deamer during a sabbatical year 20 years ago at the Weizmann Institute of Science in Israel. The present review paper highlights the benefits of this scientific interaction and assesses the impact of the lipid world paper on the present understanding of the possible roles of amphiphiles and their assemblies in the origin of life. The lipid world is defined as a putative stage in the progression towards life's origin, during which diverse amphiphiles or other spontaneously aggregating small molecules could have concurrently played multiple key roles, including compartment formation, the appearance of mutually catalytic networks, molecular information processing, and the rise of collective self-reproduction and compositional inheritance. This review brings back into a broader perspective some key points originally made in the lipid world paper, stressing the distinction between the widely accepted role of lipids in forming compartments and their expanded capacities as delineated above. In the light of recent advancements, we discussed the topical relevance of the lipid worldview as an alternative to broadly accepted scenarios, and the need for further experimental and computer-based validation of the feasibility and implications of the individual attributes of this point of view. Finally, we point to possible avenues for exploring transition paths from small molecule-based noncovalent structures to more complex biopolymer-containing proto-cellular systems.711473 - Minerva Foundation; 80NSSC17K0295, 80NSSC17K0296, 1724150 - National Science FoundationPublished versio

DNA as information

This article reviews contributions to this theme issue covering the topic 'DNA as information' in relation to the structure of DNA, the measure of its information content, the role and meaning of information in biology and the origin of genetic coding as a transition from uninformed to meaningful computational processes in physical systems