Celebrating 25 years of cell biology

We celebrate the 25th anniversary of Nature Cell Biology with a series of commissioned content and an online collection of research articles across the journal’s broad scope. We look back at biological discoveries and discuss the roles of cell biologists in sustainability, our ongoing commitments to diversity, equity and inclusion, and goals for mentoring the next generation of cell scientists.

As cell biologists, we aim to better our communities, but basic research is costly: instruments require energy, experiments consume copious single-use materials. Though governments, international bodies and universities must work to reduce this carbon footprint, we find sustainable research can also be shaped by individual actions in the lab.

Climate change affects us all, and tackling it requires a concerted effort, but it isn’t always evident how cell biologists’ work can impact climate change. Here, I share my experience addressing climate change as a molecular cell biologist and educator.

Advances in technology dramatically accelerate biology research, with computation being a standout example. Typically, adapting a new technology follows stages from method creation, via proof-of-concept application to biology, to the development of usable tools. Creating user-friendly software to bridge computer science and biology is a crucial step, yielding high returns on investment and driving biological discoveries. However, we need dedicated resources and a shift in the academic reward system to harness the full potential of computer science in biology.

Intellectual freedom for scientists, unconstrained by commercial interests and direct application, fuels unexpected discoveries. Curiosity-driven, basic science has yielded a deeper understanding of how life forms develop and function in their environment and has had wide implications for health and our planet. Investing in this is vital for scientific progress and is worth protecting in a democracy.

Women and gender minorities make defining contributions to science. Despite increased representation of women across the scientific career ladder, institutions routinely fail to support their career advancement or value their input. For an equitable and intersectional future faculty, definitions of excellence must evolve to better value women’s contributions.

With biomedical sciences quickly outgrowing many other application areas in terms of data generation, there is a unique opportunity for life sciences to become one of the greatest beneficiaries of research in machine learning and AI, and also inspire foundational developments in it.

As Nature Cell Biology turns 25 years old, we asked cell biologists across the globe to share their thoughts on what a productive mentor–mentee relationship looks like and their views on training the next generation of cell biologists.

Totipotency is the absence of any developmental restriction, a feature naturally found in the early embryo right after fertilization. Generating an in vitro totipotent stem cell model is not a trivial task. For this reason, a set of stringent criteria for the identification of bona fide totipotent stem cells have been proposed.

Extracellular vesicles carry proteins and lipids between cells. In a giant step forward for the field, a 2007 study published in Nature Cell Biology showed that secreted vesicles contain genetic material that is active within acceptor cells, reviving interest in extracellular vesicle-based communication in plant and animal biology.

The interplay between DNA and its associated proteins has a crucial role in regulating gene expression and determining cellular identity. Here we revisit an earlier Nature Cell Biology study that established the chromatin signature associated with pluripotency.

Cell–cell adhesions are inevitably exposed to mechanical forces. A landmark paper by Yonemura et al. identified how tension alters molecular function of the cadherin adhesion apparatus. Its legacy lies in the many on-going efforts to understand how mechanical force is used in cell–cell communication.

Epithelial–mesenchymal transition (EMT) is crucial in embryogenesis and can be exploited by cancer cells to gain metastatic abilities. A hallmark of EMT is E-cadherin loss. In 2000, Snail was reported as the first E-cadherin repressor identified in the context of EMT, advancing our understanding of embryonic development and cancer progression.

Huck-Hui Ng is a senior group leader at the Genome Institute of Singapore of A*STAR. In this article, Ng revisits the 2009 Nature Cell Biology study in which he and his team described the role of Esrrb in somatic cell reprogramming.

Sarah Teichmann, head of cellular genetics at the Wellcome Sanger Institute, reflects on the dawn of the single-cell genomics era and a pivotal decision that changed the course of her career.

Pietro De Camilli is a professor of neuroscience and of cell biology at Yale University, CT, as well as an investigator in the Howard Hughes Medical Institute. Pietro discusses how his group’s 1999 Nature Cell Biology study linking amphiphysin with dynamin in clathrin-mediated endocytosis came to be.

Maria Antonietta (Antonella) De Matteis is a professor of biology at the University of Naples Federico II and leads the cell biology programme at the Telethon Institute of Genetics and Medicine in Pozzuoli, Italy. Antonella recalls the beginning of her research program on phosphatidylinositol 4-phosphate (PI4P) at the Golgi, published in our pages in 1999 and 2004.

Danfeng Cai, an assistant professor in the Department of Biochemistry and Molecular Biology at the Johns Hopkins Bloomberg School of Public Health, discusses her career path, including her work on the biomolecular condensation of YAP, and her excitement in her ongoing work on transcriptional condensates.

Eiji Hara is a professor at the Research Institute for Microbial Diseases, Osaka University, Japan. Eiji recalls the discovery of the basis for the irreversibility of cellular senescence, published in Nature Cell Biology in 2006.

Diehl et al. show that imbalance among nucleotide species is not sensed by canonical metabolic regulatory pathways, causing excessive cell growth despite a DNA replication block. ATR is needed to increase nucleotide availability in normal S phase.

Haque et al. report that the Hedgehog pathway kinesin KIF7 binds the transcription factor GLI via electrostatic coiled-coil interactions, and synergy between KIF7 and GLI underlies the recruitment of both proteins to microtubules and the cilium tip.

Andreu et al. show that force regulates nucleocytoplasmic transport by weakening the permeability barrier of nuclear pore complexes, affecting passive and facilitated diffusion in different ways.

By characterizing the composition of mitochondrial-derived vesicles (MDVs), König et al. define a MIRO1/2- and DRP1-dependent MDV biogenesis pathway and propose that MDVs maintain the mitochondrial proteome by shuttling assembled protein complexes to lysosomes.

Cai et al. show that YAP forms liquid-like condensates in the nucleus that compartmentalize YAP’s DNA binding cofactors and transcription co-activators to induce transcription of YAP-specific proliferation genes.

Harada et al. develop a chromatin integration labelling (ChIL) method to map distributions of histone modifications and DNA-binding factors at low-input or even single-cell levels.

Huang et al. identify IGF2BPs as an additional class of N⁶-methyladenosine (m⁶A) reader proteins. They find that IGF2BPs selectively bind to m⁶A-containing mRNAs and promote their stability.

The protein kinase ULK1 regulates autophagy induction but its mode of action is poorly understood. Guan and colleagues show that following nutrient starvation, ULK1-mediated phosphorylation of Beclin-1 is required for the activation of VPS34 lipid kinase within the autophagy complex ATG1–VPS34–Beclin-1. They also find that during starvation, the inhibitory effect of mTOR on ULK1 is relieved to increase the phosphorylation of Beclin-1.

Mitochondria are found to fuse at the onset of autophagy. This event, which is regulated by a cyclic AMP–PKA (protein kinase A) signalling pathway, increases ATP synthase activity to prevent starvation-induced cell death.

Lu et al. report that biomolecular condensation of cytoplasmic TDP-43 is regulated by HSPB1 to maintain its droplets in liquid and not gel/solid structures and that HSPB1 is decreased in spinal motor neurons with TDP-43 pathology in patients with amyotrophic lateral sclerosis.

Zhang et al. report that a non-canonical cGAS–STING pathway activates PERK–eIF2α to elaborate cap-dependent mRNA translation and contributes to senescence and fibrosis.

Wang et al. report that the nucleocapsid protein of SARS-CoV-2 forms phase-separated condensates to repress K63-linked ubiquitination and aggregation of mitochondrial antiviral-signalling protein, thus suppressing antiviral immunity.

Koester et al. show that, as hair follicle stem cells age, their ability to activate bivalent genes for self-renewal and differentiation is reduced due to increased niche stiffening and subsequent epigenetic effects.

Wang et al. analysed post-mortem samples of the lungs of patients with COVID-19 by bulk and single-nucleus RNA sequencing along with proteomics and discovered lung senescence as a feature of COVID-19 pathology.

Yang, Xue et al. demonstrate in intestinal organoids that region-specific cell fates drive actomyosin patterns and modulate luminal osmotic forces to coordinate morphogenesis.

Nakamura et al. find that the master transcriptional regulator of lysosomal biogenesis and autophagy TFEB is activated following LC3 lipidation during lysosomal damage and show the importance of this mechanism during kidney injury.

Artegiani, Hendriks et al. describe a CRISPR–Cas9-based method to efficiently generate human knock-in organoids using non-homologous end joining to study rare intestinal cell types and human hepatocyte division.

Turco et al. derive long-term genetically stable organoids from normal endometrium and the decidua that recapitulate characteristics of in vivo uterine glands, respond to hormones and differentiate into secretory and ciliated endometrial cells.

Ivaska and colleagues report that endocytosed integrins are able to signal from endosomes in an FAK-dependent manner. They further show that endosomal integrin signalling can promote anoikis resistance and lung colonization in cancer cells.

Imajo and colleagues report that the Hippo signalling pathway components YAP and TAZ act via TEAD to promote intestinal stem/progenitor cell proliferation and via Klf4 to trigger their differentiation.

Ferroptosis is a form of non-apoptotic cell death with unclear physiological relevance. Conrad and colleagues now report that unrestrained ferroptosis can lead to renal failure. They also identify a small molecule that limits ferroptosis in vivo.

Liu and colleagues find that MLKL translocates to the plasma membrane to induce TNF-induced necroptosis, possibly through an effect on calcium influx and the action of the cation channel TRPM7.

Human high-density lipoprotein (HDL) is found to transport endogenous miRNAs in plasma and to deliver them to recipient cells where they can silence mRNA reporter targets. HDL miRNAs isolated from atherogenic mice models or human atherosclerotic subjects induce changes in gene expression different from the ones seen with control HDL–miRNA populations.

Cancer cells preferentially use aerobic glycolysis to generate ATP, consuming glucose in the process. The tumour suppressor p53 is now shown to suppress glucose consumption by inhibiting the pentose phosphate pathway (PPP). Tumour-associated p53 mutations lack this inhibitory effect.

α-Catenin can respond to myosinII-mediated forces in cell–cell junctions through a force-dependent interaction with vinculin that regulates adherens junction development.

Using an optimized Ribo-seq protocol that is applicable for low-input samples, Xie, Li and colleagues revealed the translation landscape during oocyte-to-embryo transition and in pre-implantation embryos.

Chen et al. perform single-cell analysis and identify transcriptomic remodelling in epithelial cells, macrophages, T cells, fibroblasts and endothelial cells, which together regulate prostate cancer progression.

Posfai, Schell, Janiszewski et al. assess candidate totipotent stem cells with in vitro and in vivo assays of increasing stringency to evaluate their developmental potential and lineage contributions.

Boretto et al. demonstrate that organoids derived from patients with various types of endometrial pathologies can model disease traits and diversity, and can be used as a drug-screening tool.

Xia and colleagues provided a map for transcriptome-wide distribution of m⁶A RNA methylation in eight human fetal tissue types.

Romani et al. identify a response to reduced actomyosin contractility involving inhibition of Lipin-1, accumulation of SREBP transcription factors at the Golgi apparatus and activation of SREBP transcription driving increased lipid synthesis.

Gao and colleagues characterize genome-wide H3K9me3 distributions in pre- and post-implantation mouse embryos, providing a resource to further our understanding of epigenomic dynamics during mammalian embryogenesis.

Liu et al. show that reduced m⁶A mRNA methylation in endometrial cancer is oncogenic. Mechanistically, the AKT pathway is activated in these tumours due to altered expression of AKT regulators carrying m⁶A on their transcripts.

Gao et al. provide a comprehensive single-cell transcriptomic resource of four organs from the human fetal gastrointestinal tract and adult large intestine.

Tzahor and colleagues show that ErbB2 signalling is required for cardiomyocyte proliferation in fetal and postnatal mouse hearts, and that its activation in adult hearts promotes cardiomyocyte proliferation and regeneration following myocardial ischaemic injury.

Bao and colleagues report that glioblastoma cancer stem cells produce periostin, which in turn recruits tumour-associated macrophages to the tumour site to foster growth.

Wang and colleagues report that cancer-cell-derived extracellular vesicles that contain miR-122 reprogram glucose metabolism of premetastatic niche cells to alter nutrient availability and promote metastasis.

N⁶-methyladenosine (m6A) is an abundant internal modification of messenger RNA (mRNA) that has been reported recently in thousands of mammalian mRNAs and long non-coding RNAs (lncRNAs). Zhao and colleagues identify two methyltransferases responsible for this modification in mammalian cells, and demonstrate that they are required for embryonic stem cell self-renewal maintenance through an effect of the modification on the degradation of developmental regulator transcripts.

Adult differentiated cells can be reprogrammed to lineage-restricted proliferating neural precursors in vitro. Zhang and colleagues show that the transcription factor SOX2 is sufficient to reprogram resident astrocytes in the mouse brain to neuroblasts that can proliferate and differentiate following treatment with histone deacetylase inhibitors and differentiating factors BDNF and noggin.

Adipocytes have been suggested to arise from prospective progenitors of endothelial or haematopoietic origin. Rödeheffer and colleagues use lineage tracing to rule out that this is the case for white adipocytes, and show that they instead arise from CD24⁺ cells that are characterized by the expression of PdgfR (platelet-derived growth factor receptor).

The orphan nuclear receptor Esrrb induces reprogramming of mouse embryonic fibroblasts to pluripotent stem cells in cooperation with Oct4 and Sox2.