P. Colm Malone

Diffusion Theory in Biology: A Relic of Mechanistic Materialism

Diffusion theory explains in physical terms how materials move through a medium, e.g. water or a biological fluid. There are strong and widely acknowledged grounds for doubting the applicability of this theory in biology, although it continues to be accepted almost uncritically and taught as a basis of both biology and medicine. Our principal aim is to explore how this situation arose and has been allowed to continue seemingly unchallenged for more than 150 years. The main shortcomings of diffusion theory will be briefly reviewed to show that the entrenchment of this theory in the corpus of biological knowledge needs to be explained, especially as there are equally valid historical grounds for presuming that bulk fluid movement powered by the energy of cell metabolism plays a prominent note in the transport of molecules in the living body. First, the theorys evolution, notably from its origins in connection with the mechanistic materialist philosophy of mid nineteenth century physiology, is discussed. Following this, the entrenchment of the theory in twentieth century biology is analyzed in relation to three situations: the mechanism of oxygen transport between air and mammalian tissues; the structure and function of cell membranes; and the nature of the intermediary metabolism, with its implicit presumptions about the intracellular organization and the movement of molecules within it. In our final section, we consider several historically based alternatives to diffusion theory, all of which have their precursors in nineteenth and twentieth century philosophy of science.

Heat conductance, diffusion theory and intracellular metabolic regulation

Summary— Diffusion theory played a major role in the development of biology as an exact science. The question is raised, however, as to its relevance and applicability in the molecular interactions which occur in metabolism in the living cell. This review looks at diffusion theory from its inception and subsequent introduction into biology, its shortcomings with regard not only to whole‐body physiology, but more pertinently at the intracellular level, with its failure to offer a rational basis for metabolic regulation in the internum of the cell. The conclusion is reached that although diffusion inevitably occurs within cells, its role is of little importance with regard to most metabolic activity. In comparison, perfusion of the internal surfaces of the cell by streaming of the fluid compartment of the cytoplasm seems to be the modus operandi which allows molecular interactions to occur at rates far beyond those that diffusion would permit, and at the same time offers a mechanism which permits sensitive control of metabolic activity.

Experimental Validation of Methods for Prophylaxis against Deep Venous Thrombosis: A Review and Proposal

The experimental procedure by which the valve cusp hypoxia (VCH) hypothesis of the etiology of deep venous thrombosis (DVT) was confirmed lends itself to testing of methods of prophylaxis. Similar animal experiments could end the present exclusive reliance on statistical analysis of data from large patient cohorts to evaluate prophylactic regimes. The reduction of need for such (usually retrospective) analyses could enable rationally-based clinical trials of prophylactic methods to be conducted more rapidly, and the success of such trials would lead to decreased incidences of DVT-related mortality and morbidity. This paper reviews the VCH hypothesis (“VCH thesis”, following its corroboration) and its implications for understanding DVT and its sequelae, and outlines the experimental protocol for testing prophylactic methods. The advantages and limitations of the protocol are briefly discussed.

Diffusion and Perfusion in the Living Cell: Implications for Metabolic Regulation and Organization

A tacit assumption throughout much of biology, based on the smallness of size of most metazoan cells, is that diffusion of molecules within the cytoplasm suffices for metabolic purposes. This long-standing premise is challenged. Because cells are rich in protein (20% or more on average), it follows that, irrespective of whether this macromolecular material exists mostly in true solution (which is most improbable) or out of solution in the form of an elaborate cytomatrix and cytoskeleton, the random movements of molecules (especially large and/or reactive ones) will be impeded. However, since molecules of all sizes can be distributed throughout the cytoplasm within a matter of a second or two, the presence of a system which facilitates dispersion is indicated.

Aetiology of Deep Venous Thrombosis - Implications for Prophylaxis

Clinical research on deep venous thrombosis (DVT) and thromboembolism (VTE) has focused in recent years on the contributions of potentiating factors, alone and in combination, to the risk of contracting these conditions. Many such ‘risk factors’ have been identified (Geerts et al., 2004) and are discussed elsewhere in this book. The National Institute for Clinical Excellence (NICE) in the United Kingdom has exploited this knowledge to make the prevention of DVT its main focus for 2011. In his keynote lecture introducing the policy and procedures adopted by NICE, Arya (2011) described the tools for evaluating risk in various patient groups and emphasised ‘anticoagulation’ in the design and implementation of evidence-based prophylactic measures. He claimed that the frequency of VTE in hospital patients should be reduced by 2/3 if the agreed protocols are followed. An achievement of that magnitude would be most welcome.

Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients

TO THE EDITOR: There seems to be a disconnect between the evidence-based guidelines from the American College of Physicians (ACP) (1) and its background review by Lederle and colleagues (2). It is pleasing to see that the background review on venous thromboembolism (VTE) prophylaxis had also been published, but it seems to have been ignored (at least in part) by the clinical guideline committee. Specifically, recommendation 2 states that pharmacologic prophylaxis with heparin is recommended for VTE prophylaxis in medical patients unless the assessed risk for bleeding outweighs the likely benefits and is graded as a strong recommendation with moderate-quality evidence. The discussion then states, “The clinical benefit of reduction of PEs outweighs the harm of increased risk for bleeding events” (1). Yet, Lederle and colleagues caution about the validity of pulmonary embolism (PE) data because “The funnel plot and Egger analyses suggested that the decrease in PE incidence may have been exaggerated by publication bias” (2). Given this caution, the lack of mortality benefit, and the increased risk for bleeding, why has the position been taken that VTE prophylaxis with heparin adds anything to the clinical management of the standard “higher-risk” medical patient, which is part of the population included in the background review by Lederle and colleagues? Where is the moderate-quality evidence to make such a strong recommendation? Is there any scenario that is readily identifiable when the risk for VTE is greater than the risk for bleeding? Surely, the normative approach based on the evidence is only to consider prophylaxis in specific circumstances (even though what they are has yet to be determined), rather than as the routine. Primum non nocere!