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

New Horizons in Studying the Cellular Mechanisms of Alzheimer's Disease

Following an analysis of the state of investigations and clinical outcomes in the Alzheimer’s research field, I argue that the widely accepted ‘amyloid cascade’ mechanistic explanation of Alzheimer’s disease appears to be fundamentally incomplete. In this context, I propose that a framework termed ‘principled mechanism’ (PM) can help remedy this problem. First, using a series of five ‘tests’, PM systematically compares different components of a given mechanistic explanation against a paradigmatic set of criteria and hints at various ways of making the mechanistic explanation more ‘complete’. I will demonstrate these steps using the amyloid explanation, highlighting its missing or problematic mechanistic elements. Second, PM makes an appeal for the discovery and application of ‘biological principles’ that approximate ceteris paribus generalisations or laws and are operative at the level of a biological cell. Although thermodynamic, evolutionary, ecological and other laws or principles from chemistry and the broader life sciences could inform them, biological principles should be considered ontologically unique. These principles could augment different facets of the mechanistic explanation but also allow further independent nomological explanation of the phenomenon. Whilst this overall strategy can be complementary to certain ‘new mechanist’ approaches, an important distinction of the PM framework is its equal attention to the explanatory utility of biological principles. Lastly, I detail two hypothetical biological principles and show how they could each inform and improve the potentially incomplete mechanistic aspects of the amyloid explanation and how they could provide independent explanations for the cellular features associated with Alzheimer’s disease

Relativism as a means to alleviate biology from genomic reductionism: But is the remedy effective?

For the past several decades, biomedical research has principally been centered on molecular biology and genomic science. Although many molecular pathways and players in different disease and normal biological processes have been elucidated over this period, the much hoped-for “true” understanding of cellular and organismic functions has arguably not been achieved. Furthermore, current mainstream research paradigms from neurodegenerative disease to oncology to evo-devo research do not signal a clear path forward as to how that desired “true” understanding could be achieved. Here three questions can be raised: Why are we where we are in biology? What is the level and type of understanding that should and can be reached? And how do we get there? Denis Noble’s recent book makes illuminating contributions to answering these questions, providing a thoughtful analysis of the historical and contextual basis of the current state of biological research

A framework for philosophical biology

Advances in biology, at least over the past two centuries, have mostly relied on theories that were subsequently revised, expanded or eventually refuted using experimental and other means. The field of theoretical biology used to primarily provide a basis, similar to theoretical physics in the physical sciences, to rationally examine the frameworks within which biological experiments were carried out and to shed light on overlooked gaps in understanding. Today, however, theoretical biology has generally become synonymous with computational and mathematical biology. This could in part be explained by a relatively recent tendency in which a "data first", rather than a "theory first", approach is preferred. Moreover, generating hypotheses has at times become procedural rather than theoretical, therefore perhaps inadvertently leading some hypotheses to become perfunctory in nature. This situation leaves our understanding enmeshed in data, which should be disentangled from much noise. Given the many unresolved questions in biology and medicine, big and small, ranging from the problem of protein folding to unifying causative frameworks of complex non-Mendelian human diseases, it seems apt to revive the role of pure theory in the biological sciences. This paper, using the current biomedical literature and historical precedents, makes the case for a "philosophical biology" (philbiology), distinct from but quite complementary to philosophy of biology (philobiology), which would entail biological investigation through philosophical approaches. Philbiology would thus be a reincarnation of theoretical biology, adopting the true sense of the word "theory" and making use of a rich tradition of serious philosophical approaches in the natural sciences. A philbiological investigation, after clearly defining a given biological problem, would aim to propose a set of empirical questions, along with a class of possible solutions, about that problem. Importantly, whether or not the questions can be tested using current experimental paradigms would be secondary to whether the questions are inherently empirical or not. These issues will be illustrated using a range of specific examples. The final goal of a philbiological investigation would be to develop a theoretical framework that can lead observational and/or interventional experimental studies of the defined problem, a framework that is structured, generative and expandable, and, crucially, one that simplifies some aspect(s) of the said problem