Versatile system cores as a conceptual basis for generality in cell and developmental biology.

The discovery of general principles underlying the complexity and diversity of cellular and developmental systems is a central and long-standing aim of biology. While new technologies collect data at an ever-accelerating rate, there is growing concern that conceptual progress is not keeping pace. We contend that this is due to a paucity of conceptual frameworks that support meaningful generalizations. This led us to develop the core and periphery (C&P) hypothesis, which posits that many biological systems can be decomposed into a highly versatile core with a large behavioral repertoire and a specific periphery that configures said core to perform one particular function. Versatile cores tend to be widely reused across biology, which confers generality to theories describing them. Here, we introduce this concept and describe examples at multiple scales, including Turing patterning, actomyosin dynamics, multi-cellular morphogenesis, and vertebrate gastrulation. We also sketch its evolutionary basis and discuss key implications and open questions. We propose that the C&P hypothesis could unlock new avenues of conceptual progress in mesoscale biology.

Toward a foundation model of causal cell and tissue biology with a Perturbation Cell and Tissue Atlas.

Comprehensively charting the biologically causal circuits that govern the phenotypic space of human cells has often been viewed as an insurmountable challenge. However, in the last decade, a suite of interleaved experimental and computational technologies has arisen that is making this fundamental goal increasingly tractable. Pooled CRISPR-based perturbation screens with high-content molecular and/or image-based readouts are now enabling researchers to probe, map, and decipher genetically causal circuits at increasing scale. This scale is now eminently suitable for the deployment of artificial intelligence and machine learning (AI/ML) to both direct further experiments and to predict or generate information that was not-and sometimes cannot-be gathered experimentally. By combining and iterating those through experiments that are designed for inference, we now envision a Perturbation Cell Atlas as a generative causal foundation model to unify human cell biology.

A spatial expression atlas of the adult human proximal small intestine.

The mouse small intestine shows profound variability in gene expression along the crypt-villus axis1,2. Whether similar spatial heterogeneity exists in the adult human gut remains unclear. Here we use spatial transcriptomics, spatial proteomics and single-molecule fluorescence in situ hybridization to reconstruct a comprehensive spatial expression atlas of the adult human proximal small intestine. We describe zonated expression and cell type representation for epithelial, mesenchymal and immune cell types. We find that migrating enterocytes switch from lipid droplet assembly and iron uptake at the villus bottom to chylomicron biosynthesis and iron release at the tip. Villus tip cells are pro-immunogenic, recruiting γδ T cells and macrophages to the tip, in contrast to their immunosuppressive roles in mouse. We also show that the human small intestine contains abundant serrated and branched villi that are enriched at the tops of circular folds. Our study presents a detailed resource for understanding the biology of the adult human small intestine.

Constraint-based reasoning in cell biology: on the explanatory role of context.

Cell biologists, including those seeking molecular mechanistic explanations of cellular phenomena, frequently rely on experimental strategies focused on identifying the cellular context relevant to their investigations. We suggest that such practices can be understood as a guided decomposition strategy, where molecular explanations of phenomena are defined in relation to natural contextual (cell) boundaries. This "top-down" strategy contrasts with "bottom-up" reductionist approaches where well-defined molecular structures and activities are orphaned by their displacement from actual biological functions. We focus on the central role of microscopic imaging in cell biology to uncover possible constraints on the system. We show how identified constraints are used heuristically to limit possible mechanistic explanations to those that are biologically meaningful. Historical examples of this process described here include discovery of the mechanism of oxidative phosphorylation in mitochondria, molecular explanation of the first steps in protein secretion, and identification of molecular motors. We suggest that these instances are examples of a form of downward causation or, more specifically, constraining relations, where higher-level structures and variables delimit and enable lower-level system states. The guided decomposition strategy in our historical cases illustrates the irreducibility of experimentally identified constraints in explaining biological activities of cells. Rather than viewing decomposition and recomposition as separate epistemic activities, we contend that they need to be iteratively integrated to account for the ontological complexity of multi-level systems.

Cellular communities reveal trajectories of brain ageing and Alzheimer's disease.

Alzheimer's disease (AD) has recently been associated with diverse cell states1-11, yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-ß proteinopathy while the other mediates the effect of amyloid-ß on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing.

Comparative study of PGCs cultivation systems HiS and FAcs: a transcriptomic and cellular biology perspective.

In chicken, primordial germ cells (PGC) are crucial for the preservation and manipulation of genetic resources in poultry production. The HiS and FAcs culture systems are two important methods for the in vitro cultivation of chicken PGCs. The purpose of this study was to compare and analyze the two cultivation systems for PGCs (His and FAcs culture systems) to assess their efficacy and applicability in supporting PGC growth, maintaining PGC characteristics, and lineage transmission ability. The study found that both HiS and FAcs culture systems could maintain the basic biological characteristics of chicken PGCs, including the simultaneous expression of pluripotency and reproductive marker genes, as well as the presence of abundant glycogen granules. Subsequently, we identified 2,145 differentially expressed genes (DEG) through RNA sequencing. GO and KEGG analysis revealed a large number of DEGs enriched in the cell adhesion and calcium ion binding pathways, and the analysis found that these genes maintained a higher level in HiS-PGCs. Further personalized analysis found that the regulatory genes for maintaining PGC pluripotency were highly expressed in HiS-PGCs, while germ cell-related genes showed similar expression in both systems. Additionally, through RNA sequencing data and cell proliferation ability, it was found that PGCs in the FAcs system had a higher proliferation rate and a faster cell cycle. Finally, it was discovered that the expression of cell migration-related genes was maintained at a higher level in HiS-PGCs, but the migration efficiency of HiS-PGCs did not show a significant difference compared to FAcs-PGCs. These results suggest that both HiS and FAcs culture systems can maintain the proliferation and basic characteristics of chicken PGCs, but differences exist in cell proliferation, pluripotency regulation, and cell adhesion. These findings provide new information for optimizing PGC cultivation systems and are important for the preservation and genetic improvement of chicken PGCs.

The Schema and Organization of the Cell: An Introduction to Ernst Brücke's Die Elementarorganismen (1861).

Ernst Brücke's 1861 essay Die Elementarorganismen has often been cited as a watershed in the history of physiology as well as in the history of cell theory. In its time it was widely read as a reform of animal cell theory, shifting the concept of the cell away from Schleiden and Schwann's original cell schema of a membranous vesicle with a nucleus, and towards the protoplasm theory that had developed in botany, centered on the cell's living contents. It was also notorious for its arguments against the necessity of both the nucleus and the cell membrane. An English translation of "The Elementary Organisms" is presented for the first time in this journal issue, with annotations and illustrations, https://doi.org/10.1007/s10739-024-09773-9 . Brücke's essay was not only an intervention into cell theory: historians can read it as a continuation of debates on the nature of the organism and theories of organization, and as an epistemological meditation on the microscope. In addition, although Brücke was known as a founder of the Berlin school of organic physics, "The Elementary Organisms" shows how he combined an avant-garde physicalist physiology with a much older tradition of comparative anatomy and physiology. The following introductory essay will provide a scientific biography of Ernst Brücke up to 1863, with background on debates on biological organization, cell theory, and muscle histology.

Riding the Wave of Ambivalence in Cell Biology.

Increasing evidence clearly shows that most functional molecules in the cell exert a dual role depending on the specific interactive context, biochemical pathway, or subcellular localization [...].

Maximizing Access to Cell Biology for PEERS: Retracting the term minority in favor of a more inclusive lexicon.

The word minority, when used incorrectly, is a condescending term that segregates, inaccurately represents groups as being smaller or less important, and fuels microaggressions. Scientific societies and other institutions have normalized using the word minority, or the "M word," to refer to members of underrepresented groups in Science, Technology, Engineering, and Mathematics (STEM). The message put forth using the term minority often directly conflicts with the inclusive agenda these societies seek to enact. More inclusive acronyms such as PEER (Persons Excluded because of their Ethnicity or Race) have been created to more accurately reflect the active process of exclusion by institutions. Here, we detail the rationale behind the decision to eradicate the word minority from the name of a prominent committee within the American Society for Cell Biology (ASCB). The ASCB Minority Affairs Committee changed its name to the Maximizing Access to Cell Biology for PEERS Committee. Herein, we emphasize the basis for the name change and highlight the contradictions intrinsic to the word minority in this context. We highlight why swift action is required for this rewording within the context of a committee dedicated to supporting the inclusion of PEERs in the scientific community.

The migrasome as a developmental learning paradigm in cell biology.

Migrasome is a newly discovered organelle composed of small vesicular structures enclosed in membrane structures. Since its discovery in 2014, migrasome has attracted increasing attention in cell biology due to its critical role in multiple disease processes. Its pivotal role in various disease processes, including cell migration, intercellular communication, removal of damaged mitochondria, embryogenesis localization, immune cell chemotaxis, and virus transmission, underscores its significance in biological systems. With research on migrasome steadily increasing, it becomes a unique resource for undergraduate cell biology education. For deeper understanding of migrasome, we applied a bibliometric approach. Here we conducted a comprehensive analysis of migrasome research by retrieving relevant literature from databases such as Web of Science, Scopus, and PubMed using the keywords "migrasome" or "migrasomes." Employing CiteSpace software and Prism, we analyzed annual publication trends, identified core authors and institutions, assessed national contributions, examined keywords, and scrutinized highly cited literature related to migrasome research. This study presents a comprehensive overview of migrasome research, elucidating its literature characteristics, key contributors, research hotspots, and emerging trends. By shedding light on the current status and future trajectories of migrasome research, we aim to provide valuable insights for teachers in cell biology education. We propose for the integration of migrasome research into undergraduate curricula to enhance the understanding of cell biology among premedical, medical, and biomedical students, thereby fostering a deeper appreciation for the intricate mechanisms governing cellular behavior and disease processes.

In silico labeling in cell biology: Potential and limitations.

In silico labeling is the computational cross-modality image translation where the output modality is a subcellular marker that is not specifically encoded in the input image, for example, in silico localization of organelles from transmitted light images. In principle, in silico labeling has the potential to facilitate rapid live imaging of multiple organelles with reduced photobleaching and phototoxicity, a technology enabling a major leap toward understanding the cell as an integrated complex system. However, five years have passed since feasibility was attained, without any demonstration of using in silico labeling to uncover new biological insight. In here, we discuss the current state of in silico labeling, the limitations preventing it from becoming a practical tool, and how we can overcome these limitations to reach its full potential.

The French Society for Cell Biology celebrates its 40th anniversary this year!

The French Society for Cell Biology (SBCF) is actively involved in communicating the latest advances and organizing scientific events, as well as supporting young researchers, in this field. The SBCF also supports and organizes outreaching activities designed to raise public awareness of science in general and cell biology in particular. The Society, in its present form, was founded in 1984. To mark this milestone, we are organizing a memorable symposium hosted by the Académie des Sciences (https://sbcf.fr/en/event/symposium-des-40-ans-de-la-sbcf/) on September 10, 2024.

Bringing cell biology into classroom: tips to culture and observe skeletal muscle cells in high school and college.

Watching living cells through a microscope is much more exciting than seeing pictures of cells in high school and college textbooks. However, bringing cell cultures into the classroom is challenging for biology teachers since culturing cells requires sophisticated and expensive instruments such as a CO2 incubator and an inverted phase-contrast microscope. Here, we describe easy and affordable methods to culture and observe skeletal muscle cells using the L-15 culture medium, tissue culture flask, standard dry incubator, standard upright microscope, and modified Smartphone microscope. Watching natural living cells in a "Do-It-Yourself (DIY)" way may inspire more students' interest in cell biology.

Bridging structural and cell biology with cryo-electron microscopy.

Most life scientists would agree that understanding how cellular processes work requires structural knowledge about the macromolecules involved. For example, deciphering the double-helical nature of DNA revealed essential aspects of how genetic information is stored, copied and repaired. Yet, being reductionist in nature, structural biology requires the purification of large amounts of macromolecules, often trimmed off larger functional units. The advent of cryogenic electron microscopy (cryo-EM) greatly facilitated the study of large, functional complexes and generally of samples that are hard to express, purify and/or crystallize. Nevertheless, cryo-EM still requires purification and thus visualization outside of the natural context in which macromolecules operate and coexist. Conversely, cell biologists have been imaging cells using a number of fast-evolving techniques that keep expanding their spatial and temporal reach, but always far from the resolution at which chemistry can be understood. Thus, structural and cell biology provide complementary, yet unconnected visions of the inner workings of cells. Here we discuss how the interplay between cryo-EM and cryo-electron tomography, as a connecting bridge to visualize macromolecules in situ, holds great promise to create comprehensive structural depictions of macromolecules as they interact in complex mixtures or, ultimately, inside the cell itself.

From Blur to Brilliance: The Ascendance of Advanced Microscopy in Neuronal Cell Biology.

The intricate network of the brain's neurons and synapses poses unparalleled challenges for research, distinct from other biological studies. This is particularly true when dissecting how neurons and their functional units work at a cell biological level. While traditional microscopy has been foundational, it was unable to reveal the deeper complexities of neural interactions. However, an imaging renaissance has transformed our capabilities. Advancements in light and electron microscopy, combined with correlative imaging, now achieve unprecedented resolutions, uncovering the most nuanced neural structures. Maximizing these tools requires more than just technical proficiency. It is crucial to align research aims, allocate resources wisely, and analyze data effectively. At the heart of this evolution is interdisciplinary collaboration, where various experts come together to translate detailed imagery into significant biological insights. This review navigates the latest developments in microscopy, underscoring both the promise of and prerequisites for bending this powerful tool set to understanding neuronal cell biology.

Editor Profile: Andrey Abramov.

In this special interview series, we profile members of The FEBS Journal editorial board to highlight their research focus, perspectives on the journal and future directions in their field. Professor Andrey Abramov is a cell biologist and biophysicist at University College London's Queen Square Institute of Neurology. He has served as an Editorial Board Member of The FEBS Journal since 2015.

Proteomics Impact on Cell Biology to Resolve Cell Structure and Function.

The acceleration of advances in proteomics has enabled integration with imaging at the EM and light microscopy levels, cryo-EM of protein structures, and artificial intelligence with proteins comprehensively and accurately resolved for cell structures at nanometer to subnanometer resolution. Proteomics continues to outpace experimentally based structural imaging, but their ultimate integration is a path toward the goal of a compendium of all proteins to understand mechanistically cell structure and function.