Measurement in biological systems from the self-organisation point of view

Measurement in biological systems became a subject of concern as a consequence of numerous reports on limited reproducibility of experimental results. To reveal origins of this inconsistency, we have examined general features of biological systems as dynamical systems far from not only their chemical equilibrium, but, in most cases, also of their Lyapunov stable states. Thus, in biological experiments, we do not observe states, but distinct trajectories followed by the examined organism. If one of the possible sequences is selected, a minute sub-section of the whole problem is obtained, sometimes in a seemingly highly reproducible manner. But the state of the organism is known only if a complete set of possible trajectories is known. And this is often practically impossible. Therefore, we propose a different framework for reporting and analysis of biological experiments, respecting the view of non-linear mathematics. This view should be used to avoid overoptimistic results, which have to be consequently retracted or largely complemented. An increase of specification of experimental procedures is the way for better understanding of the scope of paths, which the biological system may be evolving. And it is hidden in the evolution of experimental protocols.Comment: 13 pages, 5 figure

Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia

Published first May 16, 2023Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance.Winnie L. Kan, Urmi Dhagat, Kerstin B. Kaufmann, Timothy R. Hercus, Tracy L. Nero, Andy G.X. Zeng, John Toubia, Emma F. Barry, Sophie E. Broughton, Guillermo A. Gomez, Brooks A. Benard, Mara Dottore, Karen S. Cheung Tung Shing, Héléna Boutzen, Saumya E. Samaraweera, Kaylene J. Simpson, Liqing Jin, Gregory J. Goodall, C. Glenn Begley, Daniel Thomas, Paul G. Ekert, Denis Tvorogov, Richard J. D, Andrea, John E. Dick, Michael W. Parker, and Angel F. Lope

Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis

The pathogenesis of acquired pulmonary alveolar proteinosis (PAP), a rare lung disease characterized by excessive surfactant accumulation within the alveolar space, remains obscure. Gene-targeted mice lacking the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) or the signal-transducing beta-common chain of the GM-CSF receptor have impaired surfactant clearance and pulmonary pathology resembling human PAP. We therefore investigated the hematopoietic effects of GM-CSF in patients with PAP. The hematologic response of 5 infants with congenital PAP to 5 mu g/kg/d was of normal magnitude. By contrast, despite normal expression of GM-CSF receptor alpha- and beta-common chains on peripheral blood myelomonocytic cells (n = 6) and normal binding affinity of bone marrow mononuclear cells for GM-CSF (n = 3), each of the 12 patients with acquired PAP treated displayed impaired responses to GM-CSF; 5 mu g/kg/d produced only minor eosinophilia, and doses of 7.5 to 20 mu g/kg were required to induce greater than or equal to 1.5-fold neutrophil increments in the 3 patients who underwent dose-escalation. However, neutrophilic responses to 5 mu g/kg granulocyte colony-stimulating factor (G-CSF) were normal (n = 4), In vitro, the proportion of hematopoietic progenitors responsive to GM-CSF (16.1% +/- 8.9%; P = .042) or interleukin-3 (IL-3: 19.3% +/- 7.7%; P = .063), both of which utilize the beta-common chain of the GM-CSF receptor complex, were reduced among patients with acquired PAP (n = 4) compared with normal bone marrow donor controls (47.2% +/- 25.9% and 40.9% +/- 18.6%, respectively). In the one individual who had complete resolution of lung disease during the period of study, this was temporally associated with correction of this defective in vitro response to GM-CSF and IL-3 on serial assessment. These data establish that patients with acquired PAP have an associated impaired responsiveness to GM-CSF that is potentially pathogenic in the development of their lung disease. Based on these observations, we propose a model of the pathogenesis of acquired PAP that suggests the disease arises as a consequence of an acquired clonal disorder within the hematopoietic progenitor cell compartment. (C) 1998 by The American Society of Hematology

Drug repurposing: misconceptions, challenges, and opportunities for academic researchers

Drug repurposing is promoted as a cost- and time-effective mechanism for providing new medicines. Often, however, there is insufficient consideration by academic researchers of the processes required to ensure that a repurposed drug can be used for a new indication. This may explain the inability of drug repurposing to fulfill its promise. Important aspects, often overlooked, include financial and intellectual property considerations, the clinical and regulatory path, and clinical equipoise, which provides ethical justification for randomized controlled trials. The goal of drug repurposing is to obtain a new regulator-approved label for an existing drug, and so, the trajectory for drug repurposing and traditional drug development is similar. Here, we discuss factors critical for a successful repurposed medicine to help academic investigators better identify drug repurposing opportunities.C. Glenn Begley, Mark Ashton, Jonathan Baell, Michael Bettess, Michael P. Brown, Brett Carter ... et al

Building on Weber to understand governance: exploring the links between identity, democracy and 'inner distance'

The paper builds up a conceptual picture of two types of governance - network and organic. In this process it highlights the legitimacies of co-ordination (interior authority and democracy) that lie outside Weber's typology of domination and are relatively neglected in governance literature. The exploration of interior authority, through discussion of identity and substantive liberty, reflects a perspective on human agency that acknowledges the interconnection of the social and non-social and links sociological understanding of agency with political philosophy. It is suggested that this theoretical work gives some necessary content to Weber's concept of inner distance. In turn, this also has implications for our understanding of what is involved in democratizing governance