Cellular senescence is a conserved stress-responsive program defined by durable proliferative arrest and extensive remodeling of chromatin, metabolism, intercellular signaling, and immune interactions. Initially described as a barrier to unlimited cell division, senescence is now recognized as a pleiotropic and heterogeneous biological process with roles in development, tissue repair, immune surveillance, tumor suppression, aging, fibrosis, and cancer progression. Despite its broad relevance, senescence remains challenging to define operationally, as its molecular features, functional outputs, and physiological consequences vary across cell types, tissues, and stimuli. This review summarizes core hallmarks of senescence while synthesizing how these features are differentially engaged, diversified, and repurposed across biological contexts. Focusing on cancer, we discuss how senescence influences tumor initiation, evolution, and therapeutic response through both cell-intrinsic and microenvironmental mechanisms. We further evaluate emerging strategies to therapeutically modulate senescence, highlighting both opportunities and unresolved challenges for precision intervention.

Traditional animal-based drug discovery has high failure rates, prompting the search for and adoption of human-centered new approach methodologies (NAMs). Rapid advances in stem cell-, organoid-, and in silico-based NAMs, supported by evolving frameworks from the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), now span the entire drug-discovery continuum, from disease modeling and drug design to efficacy testing. Our review highlights recent progress across these domains, including the identification of therapeutic candidates, the development of cutting-edge models and technologies, and the potential of NAMs themselves as treatments in preclinical and clinical contexts, while examining the key biological, technical, and regulatory bottlenecks that need to be addressed to enable robust translational adoption. We conclude by discussing the translational and societal considerations essential to the responsible adoption of NAMs and outlining future human-centric pipelines poised to redefine the landscape of drug discovery.

RNA is frequently chemically modified, with over 170 types of chemical modifications identified to date in cellular RNAs. These modifications, along with their effector proteins, constitute new layers of gene expression regulation by controlling either the fate of modified RNAs at nearly every stage of their life cycle or local transcription through modulating the nearby chromatin state and transcriptional complexes. This is especially evident in dynamic biological contexts such as cellular state transitions, signaling, immune responses, and stress adaptation. In this review, we discuss recent breakthroughs and promising avenues for future exploration. Particular attention is given to the functional significance of mRNA modifications, the emerging roles of modifications on chromatin-associated regulatory RNAs in chromatin and transcriptional regulation, and mechanistic insights that will guide future scientific interrogation of RNA modifications in gene expression regulation. We also highlight how these fundamental understandings are beginning to catalyze the development of novel therapeutic strategies.

Somatic mutations, or genetic changes occurring in cells after conception, are widespread in healthy tissues but are conventionally viewed as signs of pre-cancer or simply a consequence of aging. However, an emerging body of work has shown that somatic mutations can drive or protect against disease, which could inspire novel therapeutic strategies. The unexpected depth of genetic diversity within individuals also provides a massive substrate for discovering mutant genes selected for by disease. For instance, mutant hematopoietic cells can exacerbate inflammatory disease, and mutant hepatocytes can protect against liver disease. This suggests that somatic mutations, whether maladaptive or beneficial, could provide crucial insights into disease mechanisms, history, and reversal strategies. Somatic genetics offers a powerful, complementary approach to traditional germline genetics, which has had an enormous impact on biomedicine and drug development. This review explores the factors that shape the landscape of somatic mosaicism and discusses somatic mutations that cause or protect from disease. We highlight how somatic mutations are becoming a key discovery engine for disease genetics, moving rapidly toward drug target identification and clinical translation.

Rooted in place, plants must continuously respond and adapt to their ever-changing environment to survive, especially as climate change intensifies. Calcium ions (Ca²⁺) play a central role in plant responses to both biotic and abiotic challenges. Ca²⁺ signaling involves the coordinated action of channels and transporters that generate specific "Ca²⁺ codes," along with Ca²⁺-binding proteins that act as sensors to decode them. Studies over the past several decades have explored the molecular components that form the toolkit, pathways, and networks for the coding and decoding of Ca²⁺ signals in plants. This review focuses on the emerging mechanisms of calcium signaling in plants, beginning with an overview of the universal conceptual framework that governs the coding and decoding of Ca²⁺ signals, followed by examples of pathways in plant growth and reproduction, responses to abiotic stress and microbes, and systemic signaling in plants.

The small intestinal epithelium represents the most rapidly self-renewing adult mammalian tissue, with a turnover time of 1-2 weeks. It contains ∼12 easily recognizable cell types with a wide diversity of functions, including nutrient absorption, mucus production, antimicrobial defense, and the regulation of metabolism by incretins like Glp1. The simple and repetitive crypt-villus architecture allows for easily interpretable experimentation in transgenic mice in vivo, while the human stem cell hierarchy is experimentally accessible in epithelial organoids in vitro. This review aims to comprehensively describe the design, the cellular constituents, and the molecular regulation of crypt-villus epithelial self-renewal. More generally, it highlights deviations from commonly held views on tissue stem cell biology: gut stem cells divide continually and symmetrically. They can be expanded indefinitely in vitro, while the plasticity of daughter cells can recreate stem cells during regeneration.

Cancer presents a remarkably instructive perturbation of mechanisms manifesting in our biology that have gone awry, eliciting a malady that is inexorably increasing in incidence and societal burden concomitant with healthier aging. The wealth of knowledge and data forthcoming from decades of cancer research can be organized into conceptually distinct but interconnected parametric dimensions that define the mechanistic foundation of the disease: aberrantly acquired functional capabilities (the hallmarks of cancer), enabling phenotypic characteristics, hallmark-conveying cells populating cancer microenvironments, and systemic interactions. Collectively, they provide a logical framework with which to illuminate the operating systems of these outlaw organs, from inception through multistage tumorigenesis to adaptive evolution. This review presents a concise synthesis of the hallmark conceptualization as it has been refined during the past 25 years, including a corollary hypothesis that mechanism-guided hallmark co-targeting could offer impactful new therapeutic strategies for treating human cancers.

The emergence and sustained spread of H5N1 in US dairy cattle since 2024 have demonstrated that highly pathogenic avian influenza (HPAI) is capable of establishing long-term transmission in livestock. Genomic surveillance has clarified national patterns of spatial diffusion, interspecies transmission, and viral evolution, but critical data gaps remain that impede efforts to track virus movements in real time, identify modes of transmission, and inform control efforts.

The ability to design and engineer mammalian genomes across arbitrary length scales would transform biology and medicine. Such capabilities would enable the systematic dissection of mechanisms governing gene regulation and the influence of complex haplotypes on human traits and disease. They would also facilitate the engineering of disease models that more faithfully recapitulate human physiology and of next-generation cell therapies harboring sophisticated genetic circuits. Over the past decade, advances in genome editing have made small, targeted modifications at single sites routine. However, achieving multiple coordinated alterations across long sequence windows (>10 kb) or installing large synthetic DNA segments in mammalian cells remains a major challenge. Recent advances in mammalian genome writing-the bottom-up design, assembly, and targeted integration of large custom DNA sequences, independent of any natural template-offer a potential solution. Here, we review key technological developments, highlight emerging applications, and discuss current bottlenecks and strategies for overcoming them.

Recent advances in regulatory T cell (Treg) biology and clinical application of Treg-based treatments show promise as a new generation of transforming therapeutics for immune-related disorders, positioning Tregs as a "living drug" to rebuild immune tolerance and repair damaged tissues simultaneously. This perspective summarizes the key knowledge on Treg biology and highlights the recent important discoveries in the development of clinical applications based on Treg biology, from low-dose interleukin-2 therapy showing promising results in trials for ALS and adoptive Treg transfer demonstrating efficacy in preventing GVHD to early pilot studies of CAR Tregs. Drawing on these advances, we provide perspectives on key research priorities and translational challenges and set forth a roadmap that integrates basic and clinical insights into developing next-generation therapies focusing on precision tolerance strategies.

A marked evolution in Alzheimer's disease (AD) therapy research is ongoing. In this perspective, we highlight emerging outcomes of tau-targeting approaches with disease-modifying potential evidenced by PET-based slowing of tau accumulation and early signs of cognitive benefit. We outline how decades of iterative amyloid β (Aβ)-trial refinement leading to the recent successes of approved anti-Aβ therapies have set the stage for accelerated optimization of next-generation trials. We summarize key learnings from first-generation tau immunotherapies and how these paved the way for early achievements in tau trials, while many challenges remain. Finally, we discuss the back-translation of clinical outcomes into fundamental insights on human tau pathobiology, and we outline challenges and future directions for AD therapy development including combination therapy and targets beyond Aβ/tau. Together, this provides a framework for next-generation AD and tau-therapy development toward increasingly efficient disease-halting interventions.

More than a century after their discovery, neutrophils continue to puzzle immunologists. Their remarkable migratory, cytotoxic, phagocytic, and degranulating capacities gave rise to the traditional perception that they are dedicated microbe hunters. Yet neutrophils possess an equally exceptional ability to acquire new traits across different environments, and when considered as a lineage collective, they are long-lived, reprogrammable, and retain memory of past insults. Here, we focus on the concept of the collective to make sense of both traditional properties and those that challenge existing dogmas. We model the structure of the collective as the combination of two biologically distinct compartments and discuss the unique properties that emerge beyond the sum of the individual cells. We hope that our review will stimulate discussion and spark new ideas about how neutrophils contribute to and can be exploited to promote health.

There is an urgent need for increased crop productivity to reduce food insecurity and improve sustainability. Photosynthesis converts sunlight energy into carbohydrates, providing the source of nearly all of humanity's food. Photosynthesis is a key target for improvement, owing to inherent inefficiencies in the biochemical process. Over the last decade of advancements in bioengineering, strategies to increase the efficiency of photosynthesis were tested with proven enhancements to crop yields in field trials. Simple strategies like increasing the content of photosynthetic proteins have reliably increased photosynthesis and productivity in crops, as have more complex strategies such as bypassing photorespiration. While insertion of carbon-concentrating mechanisms into C3 plants remains an engineering challenge, modeling suggests that achieving that would have the greatest gain for crop improvement. This review discusses the many successes in improving photosynthesis achieved over the past decade and quantifies the potential for future engineering targets to increase crop productivity.

Recent studies at molecular and genomic scales have enriched our understanding of life's most fundamental building block: the cell. However, bridging the gap between single-cell phenotypes and the emergent functions of tissues and organs remains a formidable challenge. Here, we suggest that the conceptual span from cells to tissues and organs is so large as to warrant intermediate stepping stones. Drawing inspiration from "network motifs"-discrete units of cell-level function that emerge from the interactions of a handful of genes or enzymes-we argue that similarly identifiable units of tissue-level function, which we term "mesoscale modules," emerge from coordinated "interactions" among relatively small numbers of cells and their extracellular milieu. We outline several such modules and propose that a concerted effort to study them will deepen our foundational understanding of tissue and organ functions. By developing these mesoscale insights, we anticipate a more tractable and mechanistic approach to complex human conditions rooted in tissue- and organ-scale dysregulation, including developmental defects, cancer, cardiovascular disease, immune-related disorders, infectious disease, and aging.

Epithelial-mesenchymal transition (EMT) is a fundamental mechanism involved in the morphogenesis of metazoans. Through this evolutionarily conserved multi-stage process, cells acquire quasi-epithelial to multiple intermediate morphologies with epithelial and mesenchymal attributes, rarely reaching a complete mesenchymal phenotype. Complex evolutionary-conserved morphogenetic movements in gastrulation are described extensively, as they exemplify the extent of epithelial cell plasticity in the animal kingdom. Nonetheless, a single-gene knockout can modify the mode of gastrulation while achieving the same body plan. Numerous interconnected mechanisms drive different degrees of EMT, including surface receptor signaling, metabolism, and epigenetics. EMT is reactivated in adult tissues during repair and disease, particularly in cancer initiation, progression to metastasis, and refractoriness to treatment. EMT also contributes to dormancy and drug tolerance, leading to minimal residual disease at the origin of recurrences. Multiple EMT states coexist in tumors, creating a dynamic ecosystem for generating an inflammatory microenvironment, stemness, invasion, and metastasis. This review provides an in-depth description of these aspects along with recent controversies and offers new opportunities to further explore the multiple functions of EMT. Examining the potential attributes of EMT in tissue repair, fibrosis, and cancer progression can provide new opportunities for therapeutic intervention.

RNA-binding proteins (RBPs) are best known as effectors along the entire gene expression pathway and as constituents of RNA-protein machines such as the ribosome and the spliceosome. Around 1,000 RBPs account for these functions in mammalian cells. The total number of RBPs has recently more than tripled to include many "well-known" proteins such as metabolic enzymes or membrane proteins, sparking debate about the biological relevance of their RNA binding. We examine the experimental basis underlying the dramatic expansion of the RBPome, consider arguments that challenge its relevance, and discuss recent data that describe new RBP and RNA functions. We suggest that the scope of interplay between RNA and proteins is underexplored and that riboregulation of proteins represents an emerging theme in cell biology and translational medicine.

Interferons (IFNs) are signaling proteins that play fundamental roles during health and disease. Although types I, II, and III IFNs are structurally and functionally different, all IFNs signal via an intricate network of Janus kinases, named after the Roman god of time and duality. IFNs are characterized by activities that vary over time and can lead to opposing outcomes. IFNs have protective roles during bacterial, viral, and fungal infections but can also drive numerous inflammatory and autoimmune diseases. In this review, we provide an overview of the cellular and molecular mechanisms governing IFN induction and responses, emphasizing their roles in infections, tumorigenesis, and inflammatory, autoimmune, and genetic diseases, with particular attention to mucosal tissues. Overall, we spotlight how the balanced production of distinct members of the IFN families over time is necessary to exert their protective functions and the detrimental consequences for the host when this balance is lost.

Despite the evolution of hardwired homeostatic mechanisms to balance food intake with energy needs, the obesity epidemic continues to escalate globally. However, recent breakthroughs in delineating the molecular signaling pathways by which neural circuits regulate consummatory behaviors, along with transformative advances in peptide-based pharmacotherapy, are fueling the development of a new generation of safe and effective treatments for obesity. Here, we outline our current understanding of how the central nervous system controls energy homeostasis and examine how emerging insights, including those related to neuroplasticity, offer new perspectives for restoring energy balance and achieving durable weight loss. Together, these advances provide promising avenues for treating obesity and managing cardiometabolic disease.

Rapid advancements in artificial intelligence (AI), particularly large language models (LLMs) and multimodal AI, are transforming medicine through enhancements in diagnostics, patient interaction, and medical forecasting. LLMs enable conversational interfaces, simplify medical reports, and assist clinicians with decision making. Multimodal AI integrates diverse data like images and genetic data for superior performance in pathology and medical screening. AI-driven tools promise proactive, personalized healthcare through continuous monitoring and multiscale forecasting. However, challenges like bias, privacy, regulatory hurdles, and integration into healthcare systems must be addressed for widespread clinical adoption.

In a matter of years, single-cell omics has matured from a pioneering technique employed by just a handful of specialized laboratories to become a ubiquitous feature of biological research and a key driver of scientific discovery. The widespread adoption and development of single-cell omic assays has sparked mounting enthusiasm that these technologies are poised to also enhance the precision of diagnosis, the monitoring of disease progression, and the personalization of therapeutic strategies. Despite initial forays into clinical settings, however, single-cell technologies are not yet routinely used to inform medical or surgical decision-making. Here, we identify and categorize key experimental, computational, and conceptual barriers that currently hinder the clinical deployment of single-cell omics. We focus on the potential for single-cell transcriptomics to guide clinical decision-making through the development of combinatorial biomarkers that simultaneously quantify multiple cell-type-specific pathophysiological processes. We articulate a framework to identify patient subpopulations that stand to benefit from such biomarkers, and we outline the experimental and computational requirements to derive reproducible and actionable clinical readouts from single-cell omics.