Drawing from the insights of biology, sustainable healthcare systems should prioritise robustness over optimisation.

The concept of performance has gradually become established in health policies. Presented as necessary and positive, it is often reduced to efficiency, which results in policies and management styles aimed at optimisation. While they are supposed to guarantee the sustainability of our healthcare systems, these practices have made them fragile. Insights from the life sciences help us understand why. Indeed, biologists observe that living beings do not prioritise optimisation but robustness. To cope with fluctuations, a robust organisation operates with redundancies, apparent waste, heterogeneity, organised fluctuations, slowness, and hesitation. It functions sub-optimally. This article offers a theoretical reflection and management directions for more robust healthcare systems.

Where physics and biology meet.

As part of this special issue on physics and biology, we invited several leading experts that bridge these disciplines to provide their views on the reciprocal contributions of each field and the benefits and challenges of working across physics and biology: introduction provided by Wallace Marshall.

A Practical Guide to 3D Printing for Chemistry and Biology Laboratories.

Three-dimensional (3D) printing promises a revolution in laboratory creativity by enabling rapid prototyping, broader availability of scientific apparatuses, and transformative scientific workflows. We believe all chemistry and biology laboratories should equip themselves with one or more 3D printers and a critical mass of scientists trained to operate them. This overview surveys the techniques, intricacies, and pitfalls associated with 3D printing of functional parts, including measurements, computer-aided design, slicing, limitations of 3D printing, troubleshooting, tips for tricky filaments, and 3D printer maintenance. A flow cells are essential tools in chemistry and biology laboratories, we discuss techniques relevant to the construction of watertight 3D-printed parts. Finally, we articulate a set of principles required for reporting 3D-printed innovations to improve the field's reproducibility and encourage iterative improvements by other scientists. Ideally, authors, peer reviewers, and editors will adopt these principles. We hope these protocols inspire a new generation of publications applying 3D printing in chemistry and biology-especially highly reproducible inventions with the requisite detail and associated documentation. Such reports will facilitate broad adoption and creative iteration of the most innovative designs, thus accelerating discovery in chemistry and biology. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC.

Synthesis at the Interface of Chemistry and Biology.

ConspectusChemical synthesis as a tool to control the structure and properties of matter is at the heart of chemistry─from the synthesis of fine chemicals and polymers to drugs and solid-state materials. But as the field evolves to tackle larger and larger molecules and molecular complexes, the traditional tools of synthetic chemistry become limiting. In contrast, Mother Nature has developed very different strategies to create the macromolecules and molecular systems that make up the living cell. Our focus has been to ask whether we can use the synthetic strategies and machinery of Mother Nature, together with modern chemical tools, to create new macromolecules, and even whole organisms with properties not existing in nature. One such example involves reprogramming the complex, multicomponent machinery of ribosomal protein synthesis to add new building blocks to the genetic code, overcoming a billion-year constraint on the chemical nature of proteins. This methodology exploits the concept of bioorthogonality to add unique codons, tRNAs and aminoacyl-tRNA synthetases to cells to encode amino acids with physical, chemical and biological properties not found in nature. As a result, we can make precise changes to the structures of proteins, much like those made by chemists to small molecules and beyond those possible by biological approaches alone. This technology has made it possible to probe protein structure and function in vitro and in vivo in ways heretofore not possible, and to make therapeutic proteins with enhanced pharmacology. A second example involves exploiting the molecular diversity of the humoral immune system together with synthetic transition state analogues to make catalytic antibodies, and then expanding this diversity-based strategy (new to chemists at the time) to drug discovery and materials science. This work ushered in a new nature-inspired synthetic strategy in which large libraries of natural or synthetic molecules are designed and then rationally selected or screened for new function, increasing the efficiency by which we can explore chemical space for new physical, chemical and biological properties. A final example is the use of large chemical libraries, robotics and high throughput phenotypic cellular screens to identify small synthetic molecules that can be used to probe and manipulate the complex biology of the cell, exemplified by druglike molecules that control cell fate. This approach provides new insights into complex biology that complements genomic approaches and can lead to new drugs that act by novel mechanisms of action, for example to selectively regenerate tissues. These and other advances have been made possible by using our knowledge of molecular structure and reactivity hand in hand with our understanding of and ability to manipulate the complex machinery of living cells, opening a new frontier in synthesis. This Account overviews the work in my lab and with our collaborators, from our early days to the present, that revolves around this central theme.

Organisms have gravity: taking an organism-centered approach in experimental biology.

When you take the time to observe another organism, there is a sort of gravity that can take hold, a mixture of curiosity and connection that expands and strengthens the more you interact with that organism. Yet, in research, a connection with one's study organism can, at times, feel countercultural. Study organisms are sometimes viewed more as tools to conveniently study biological questions. Here, we explicitly highlight the importance of organism-centered research not only in scientific discovery, but also in conservation and in the communication and perception of science.

A Concept of Complementarity Between Complexity and Redundancy can Account for Kant's Biological Teleology and Unify Mechanistic and Finalistic Biology.

Over 160 years after Darwin and 70 years after the discovery of DNA, two fundamental questions of biology remain unanswered: What differentiates the living from the nonliving? How can mechanistic and finalistic or holistic biology be unified? Niels Bohr introduced a concept of complementarity in quantum physics and based on the paradox of light as a simultaneous wave and particle, conjectured that a similar concept might exist in biology that would solve the paradox of life originating from the nonliving. Bohr proposed that two mutually exclusive-independent observations may be necessary to explain a phenomenon and provided support to Immanuel Kant's idea that the "purposive" behaviour of organisms could only be explained in teleological terms and that mechanical and teleological approaches were necessary and complementary to explain biology. We present a concept of complementarity whereby biochemical pathways or cellular channels for the flow of information are simultaneously complex and redundant and complexity and redundancy complement each other. The postulates of biological complementarity are that (1) it was an essential condition in the origin of life; (2) it provided physiological flexibility that allowed organisms to mount self-protection response and complexity to evolve in the face of deleterious mutations before the evolution of bi-parental sex; (3) it laid the foundation for the evolution of a choice of response when confronted with threat; and (4) it applies to all levels of biological organizations and, thus, can serve as a basis for the unification of mechanistic and holistic biology. It is proposed that teleology is simultaneously constitutive and heuristic: constitutive because organisms' "purposive" behaviours are adaptive and are grounded in mechanism (complexity and redundancy), and heuristic because with our finite cognition and our goal-oriented (humans alone are aware of "tomorrow") and anthropomorphic pre-disposition, teleology will remain useful as a guide to our making sense of the world, even how to ask a meaningful question.

Mega-scale experimental analysis of protein folding stability in biology and design.

Advances in DNA sequencing and machine learning are providing insights into protein sequences and structures on an enormous scale1. However, the energetics driving folding are invisible in these structures and remain largely unknown2. The hidden thermodynamics of folding can drive disease3,4, shape protein evolution5-7 and guide protein engineering8-10, and new approaches are needed to reveal these thermodynamics for every sequence and structure. Here we present cDNA display proteolysis, a method for measuring thermodynamic folding stability for up to 900,000 protein domains in a one-week experiment. From 1.8 million measurements in total, we curated a set of around 776,000 high-quality folding stabilities covering all single amino acid variants and selected double mutants of 331 natural and 148 de novo designed protein domains 40-72 amino acids in length. Using this extensive dataset, we quantified (1) environmental factors influencing amino acid fitness, (2) thermodynamic couplings (including unexpected interactions) between protein sites, and (3) the global divergence between evolutionary amino acid usage and protein folding stability. We also examined how our approach could identify stability determinants in designed proteins and evaluate design methods. The cDNA display proteolysis method is fast, accurate and uniquely scalable, and promises to reveal the quantitative rules for how amino acid sequences encode folding stability.

Transfer learning enables predictions in network biology.

Mapping gene networks requires large amounts of transcriptomic data to learn the connections between genes, which impedes discoveries in settings with limited data, including rare diseases and diseases affecting clinically inaccessible tissues. Recently, transfer learning has revolutionized fields such as natural language understanding1,2 and computer vision3 by leveraging deep learning models pretrained on large-scale general datasets that can then be fine-tuned towards a vast array of downstream tasks with limited task-specific data. Here, we developed a context-aware, attention-based deep learning model, Geneformer, pretrained on a large-scale corpus of about 30 million single-cell transcriptomes to enable context-specific predictions in settings with limited data in network biology. During pretraining, Geneformer gained a fundamental understanding of network dynamics, encoding network hierarchy in the attention weights of the model in a completely self-supervised manner. Fine-tuning towards a diverse panel of downstream tasks relevant to chromatin and network dynamics using limited task-specific data demonstrated that Geneformer consistently boosted predictive accuracy. Applied to disease modelling with limited patient data, Geneformer identified candidate therapeutic targets for cardiomyopathy. Overall, Geneformer represents a pretrained deep learning model from which fine-tuning towards a broad range of downstream applications can be pursued to accelerate discovery of key network regulators and candidate therapeutic targets.

Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: A multivariate meta-analysis.

Mitochondria are maternally inherited organelles that play critical tissue-specific roles, including hormone synthesis and energy production, that influence human development, health, and aging. However, whether mitochondria from women and men exhibit consistent biological differences remains unclear, representing a major gap in knowledge. This meta-analysis systematically examined four domains and six subdomains of mitochondrial biology (total 39 measures), including mitochondrial content, respiratory capacity, reactive oxygen species (ROS) production, morphometry, and mitochondrial DNA copy number. Standardized effect sizes (Hedge's g) of sex differences were computed for each measure using data in 2258 participants (51.5% women) from 50 studies. Only two measures demonstrated aggregate binary sex differences: higher mitochondrial content in women's WAT and isolated leukocyte subpopulations (g = 0.20, χ2 p = .01), and higher ROS production in men's skeletal muscle (g = 0.49, χ2 p < .0001). Sex differences showed weak to no correlation with age or BMI. Studies with small sample sizes tended to overestimate effect sizes (r = -.17, p < .001), and sex differences varied by tissue examined. Our findings point to a wide variability of findings in the literature concerning possible binary sex differences in mitochondrial biology. Studies specifically designed to capture sex- and gender-related differences in mitochondrial biology are needed, including detailed considerations of physical activity and sex hormones.

Historicity at the heart of biology.

Most mathematical modeling in biology relies either implicitly or explicitly on the epistemology of physics. The underlying conception is that the historicity of biological objects would not matter to understand a situation here and now, or, at least, historicity would not impact the method of modeling. We analyze that it is not the case with concrete examples. Historicity forces a conceptual reconfiguration where equations no longer play a central role. We argue that all observations depend on objects defined by their historical origin instead of their relations as in physics. Therefore, we propose that biological variations and historicity come first, and regularities are constraints with limited validity in biology. Their proper theoretical and empirical use requires specific rationales.

Systematic analysis of noise reduction properties of coupled and isolated feed-forward loops.

Cells can maintain their homeostasis in a noisy environment since their signaling pathways can filter out noise somehow. Several network motifs have been proposed for biological noise filtering and, among these, feed-forward loops have received special attention. Specific feed-forward loops show noise reducing capabilities, but we notice that this feature comes together with a reduced signal transducing performance. In posttranslational signaling pathways feed-forward loops do not function in isolation, rather they are coupled with other motifs to serve a more complex function. Feed-forward loops are often coupled to other feed-forward loops, which could affect their noise-reducing capabilities. Here we systematically study all feed-forward loop motifs and all their pairwise coupled systems with activation-inactivation kinetics to identify which networks are capable of good noise reduction, while keeping their signal transducing performance. Our analysis shows that coupled feed-forward loops can provide better noise reduction and, at the same time, can increase the signal transduction of the system. The coupling of two coherent 1 or one coherent 1 and one incoherent 4 feed-forward loops can give the best performance in both of these measures.

Acute Coronary Syndromes (ACS)-Unravelling Biology to Identify New Therapies-The Microcirculation as a Frontier for New Therapies in ACS.

In acute coronary syndrome (ACS) patients, restoring epicardial culprit vessel patency and flow with percutaneous coronary intervention or coronary artery bypass grafting has been the mainstay of treatment for decades. However, there is an emerging understanding of the crucial role of coronary microcirculation in predicting infarct burden and subsequent left ventricular remodelling, and the prognostic significance of coronary microvascular obstruction (MVO) in mortality and morbidity. This review will elucidate the multifaceted and interconnected pathophysiological processes which underpin MVO in ACS, and the various diagnostic modalities as well as challenges, with a particular focus on the invasive but specific and reproducible index of microcirculatory resistance (IMR). Unfortunately, a multitude of purported therapeutic strategies to address this unmet need in cardiovascular care, outlined in this review, have so far been disappointing with conflicting results and a lack of hard clinical end-point benefit. There are however a number of exciting and novel future prospects in this field that will be evaluated over the coming years in large adequately powered clinical trials, and this review will briefly appraise these.

Biologically grounded scientific methods: The challenges ahead for combating epidemics.

The protracted COVID 19 pandemic may indicate failures of scientific methodologies. Hoping to facilitate the evaluation and/or update of methods relevant in Biomedicine, several aspects of scientific processes are here explored. First, the background is reviewed. In particular, eight topics are analyzed: (i) the history of Higher Education models in reference to the pursuit of science and the type of student cognition pursued, (ii) whether explanatory or actionable knowledge is emphasized depending on the well- or ill-defined nature of problems, (iii) the role of complexity and dynamics, (iv) how differences between Biology and other fields influence methodologies, (v) whether theory, hypotheses or data drive scientific research, (vi) whether Biology is reducible to one or a few factors, (vii) the fact that data, to become actionable knowledge, require structuring, and (viii) the need of inter-/trans-disciplinary knowledge integration. To illustrate how these topics interact, a second section describes four temporal stages of scientific methods: conceptualization, operationalization, validation and evaluation. They refer to the transition from abstract (non-measurable) concepts (such as 'health') to the selection of concrete (measurable) operations (such as 'quantification of ́anti-virus specific antibody titers'). Conceptualization is the process that selects concepts worth investigating, which continues as operationalization when data-producing variables viewed to reflect critical features of the concepts are chosen. Because the operations selected are not necessarily valid, informative, and may fail to solve problems, validations and evaluations are critical stages, which require inter/trans-disciplinary knowledge integration. It is suggested that data structuring can substantially improve scientific methodologies applicable in Biology, provided that other aspects here mentioned are also considered. The creation of independent bodies meant to evaluate biologically oriented scientific methods is recommended.

Causal and non-causal explanations in code biology.

In the philosophy of science, we can consider debates about the nature of non-causal explanations in general (e.g. Reutlinger, Saatsi 2018; Lange 2017) and then especially those in the life sciences (e.g. Huneman, 2018; Kostic 2020). These debates are accompanied by the development of a new mechanism that is becoming the major response to the nature of scientific explanation in the life sciences (e.g. Craver, Darden 2013; Craver 2006); and also by the development of a design explanation (e.g. Eck, Mennes 2016) that represents a modern variant of a functional explanation. In this paper, we will methodically: 1. evaluate the plurality of explanatory strategies in contemporary science (chapter 2). 2. describe the mechanical philosophy and mechanistic explanation (Glennan 2016; Craver, Darden 2013, etc.) (chapter 3). 3. explicate the role of mechanisms in code biology (Barbieri 2015, 2002, etc.) and its relation to the new mechanism (chapter 4). 4. fulfill the main goal of the paper - to apply mechanistic explanations in code biology (Barbieri 2019, etc.) and to apply their suitability for this scientific domain (chapter 5).

Defining life and evolution: Essay on the origin, expansion, and evolution of living matter.

This essay aims to define the origin, expansion, and evolution of living matter. The first formations, identified as remains, fossils, traces etc. of life are almost as old as the Earth itself. During four billion years, life on the Earth has continuously existed and been implemented in the range of conditions, ensuring the liquid state of water. During the entire period of life existence, its evolution was proceeding with the tendency of multidirectionality, after each catastrophe tending to the diversity and vastness of distribution, and all the currently living species, regardless of their complexity, have the same evolutionary age. The property of reproductive surplus (multiplication) is inherent in all the living matter. The reproduction of all the living matter is implemented via the "development" - a process of continuous occurrence of something new that did not exist in the previous moment in the reproduced individual at each specific moment of time with the tendency towards the reproduction of a "copy". In its fundamental basis, Life is based on a programme, its material support is implemented and exists not in the field of causative-consecutive events, but in the field of programmed-causative-consecutive events. This predetermines the "biology laws", the behaviour of the material constituent of Life at each time period, and the future of the material constituent of life.