Using single-cell techniques, the behaviors of individual stem cells are coming under ever-greater scrutiny. Such efforts are pushing the boundaries of technology development in cell biology and are getting to the heart of what defines cellular states, what drives cell-state changes, and what can we learn about biological systems from cell-to-cell variability. A prime example of this trend comes from recent work by Takahashi et al., 2019Takahashi S. Miura H. Shibata T. Nagao K. Okumura K. Ogata M. Obuse C. Takebayashi S.I. Hiratani I. Genome-wide stability of the DNA replication program in single mammalian cells.Nat Genet. 2019; 51: 529-540Crossref PubMed Scopus (40) Google Scholar, who have addressed whether replication timing across the genome is stereotyped between individual cells of the same cell type, and their results raise questions about the potential role of replication timing in the decision-making of differentiating stem cells. Previous studies with bulk sequencing of cell populations have revealed the basic principle that regions that replicate early tend to be euchromatic, actively transcribed, and in the nuclear interior, whereas late-replicating regions tend to be heterochromatic and at the nuclear periphery. Takahashi et al. have now designed and tested an approach to profile early- versus late-replicating regions at the single-cell level in mouse embryonic stem cells (mESCs), before and after differentiation and in an immortalized human retinal pigment epithelial cell line. Similar to another recent study by Dileep and Gilbert, 2018Dileep V. Gilbert D.M. Single-cell replication profiling to measure stochastic variation in mammalian replication timing.Nat. Commun. 2018; 9: 427Crossref PubMed Scopus (41) Google Scholar, the authors find that overall genome-wide replication timing is highly consistent between individual cells in a given state and that some regions exhibit more intrinsic variability than others. Going deeper, they reveal an interesting corollary: developmentally regulated genes exhibit higher-than-average variability in replication timing. Does this suggest a link between replication timing variability and developmental plasticity? The variability at these genes does in fact go away upon mESC differentiation. Future work may explore this facet of nuclear organization in stem cell “decision-making” or how this might be exploited to direct different differentiation endpoints. Getting to the molecular basis of the observations of studies such as Takahashi et al. will likely be aided by new approaches to study the behavior of proteins and protein complexes in single cells. In this vein, a recent study in our journal (Hainer et al., 2019Hainer S.J. Bošković A. McCannell K.N. Rando O.J. Fazzio T.G. Profiling of Pluripotency Factors in Single Cells and Early Embryos.Cell. 2019; 177: 1319-1329Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar) adapts a nuclease-based method for mapping the binding of transcription factors, known as CUT&RUN (Skene and Henikoff, 2017Skene P.J. Henikoff S. An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites.Elife. 2017; 6: e21856Crossref PubMed Scopus (584) Google Scholar), for use with very small cell numbers, even single cells. With this modified protocol, called ultra-low input CUT&RUN (uliCUT&RUN), Hainer and colleagues probe the distribution of transcription factors in mESCs and in vivo in pre-implantation embryos. In mESCs, they substantiate the long-standing conjecture that the fractional occupancy of transcription factors such as the pluripotency enabling NANOG and SOX2 in single cells is what underpins variable ChIP-seq (chromatin immunoprecipitation sequencing) peaks in bulk analyses. In early embryos, they further establish that NANOG binding in the inner cell mass requires the SWI/SNF chromatin remodeler, a feature not observed in similar analyses from cultured cells. This technological development will enable more accurate temporal reconstructions of transcription factor activity in individual cells and provides a new means of probing heterogeneity in vivo when tissue samples are limiting. One of the most powerful quantitative and high-throughput means of assessing levels of individual proteins in single stem cells comes from mass cytometry (cyTOF), in which antibodies to proteins of interest are conjugated to heavy metals to enable coupling of flow cytometry and time-of-flight mass spectrometry. A key advantage of cyTOF is the ability to monitor many proteins at once. Palii et al., 2019Palii C.G. Cheng Q. Gillespie M.A. Shannon P. Mazurczyk M. Napolitani G. Price N.D. Ranish J.A. Morrissey E. Higgs D.R. et al.Single-Cell Proteomics Reveal that Quantitative Changes in Co-expressed Lineage-SpecificTranscription Factors Determine Cell Fate.Cell Stem Cell. 2019; 24: 812-820Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar use this to impressive effect to assay the levels of 27 proteins across 13 time points (using temporal barcoding) during the differentiation of hematopoietic stem/progenitor cells (HSPCs). They specifically examine the trajectories of megakaryocyte-erythroid progenitors and find that both KLF1, which biases red blood cell fate, and FLI1, which biases megakaryocyte fate, are expressed in the same bipotential progenitors. They further show that the change in these lineage-specific transcription factors is gradual and not switch-like, as might be expected by a more rigid conceptualization of cell-fate decision-making. One anticipates that these gradual shifts in gene expression in developmental transitions (as observed by Palii et al.), the replication timing variability reported by Takahashi et al., and the conditional binding of transcription factors in early embryos (as seen by Hainer and colleagues) will all be reflected in changes in nuclear organization affecting the relevant loci. To confirm this and attain a more complete biophysical understanding of these transitions and their dynamics, will it one day be possible to track the compartmentalization and transcription factor occupancy of multiple developmentally important genetic loci in a single cell over time?

Single-cell analyses are propelling us ever closer to answering questions that have long-motivated research in cell and developmental biology. What is the range of cellular diversity? What defines a cell type? How do cell types evolve and differ between species? And how do individual cells of a given cell type differ from each other and for what purposes? Recent achievements offer glimpses of the vast panorama emerging from this rapidly moving field. Cell atlases are one foundational pillar of these efforts with new studies providing an in-depth look at cell type diversity in mice. The recently reported Tabula Muris used two approaches to analyze tens of thousands of cells: one approach is based on microfluidics and the other is based on fluorescence-activated cell sorting (FACS) (Tabula Muris Consortium et al., 2018Tabula Muris ConsortiumOverall coordinationLogistical coordinationOrgan collection and processingLibrary preparation and sequencingComputational data analysisCell type annotationWriting groupSupplemental text writing groupPrincipal investigatorsSingle-cell transcriptomics of 20 mouse organs creates a Tabula Muris.Nature. 2018; 562: 367-372Crossref PubMed Scopus (1013) Google Scholar). Both approaches enabled creation of a map of cell types across 20 organs, with the FACS approach capable of detecting a greater number of genes per cell. A value of the characterizations of cellular identity based on gene expression is that it allows for gene regulatory networks that underpin them to be uncovered. These vast and valuable data join those reported earlier this year by Han et al., 2018Han X. Wang R. Zhou Y. Fei L. Sun H. Lai S. Saadatpour A. Zhou Z. Chen H. Ye F. et al.Mapping the Mouse Cell Atlas by Microwell-Seq.Cell. 2018; 172: 1091-1107Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar, who used microwell-seq to analyze 400,000 cells from across the major organs of the mouse, including fetal and neonatal tissue. These atlases provide a foundation for the discovery of new cellular and systemic insights into disease once the many mouse models of illness are examined in similar depth. Future work will also likely examine the fascinating changes that occur in aging, particularly with respect to tissue-specific alterations in cellular heterogeneity. Heterogeneity also typifies cellular responses to pathogen infection. Hagai et al., 2018Hagai T. Chen X. Miragaia R.J. Rostom R. Gomes T. Kunowska N. Henriksson J. Park J.-E. Proserpio V. Donati G. et al.Gene expression variability across cells and species shapes innate immunity.Nature. 2018; (Published online October 24, 2018)https://doi.org/10.1038/s41586-018-0657-2Crossref PubMed Scopus (93) Google Scholar now delve deep into the inter-species and cellular basis for this by examining single-cell response of two cell types—dermal fibroblasts and mononuclear phagocytes from a variety of species—to challenge by a synthetic double-stranded RNA to mimic viral infection and lipopolysaccharide to simulate bacterial infection. With this information, they identify genes involved in the innate immune response whose expression levels diverge between species and show these are enriched for cytokines. Interestingly, these same genes are also shown to be more variable between cells within a species. The molecular basis for this heterogeneity is shown to be linked to the presence of TATA box in promoters of more highly variable genes, while the presence of CpG-islands in promoters is associated with less variable expression. This suggests that TATA box containing promoters have been selected in vertebrate evolution to tune tissue-wide responses such that only some cells will encode cytokines to elicit a controlled tissue-wide defense. It would be reasonable to presume that expression variability between single cells could be related to differences in promoter accessibility and nucleosome positioning at those genes. Lai et al., 2018Lai B. Gao W. Cui K. Xie W. Tang Q. Jin W. Hu G. Ni B. Zhao K. Principles of nucleosome organization revealed by single-cell micrococcal nuclease sequencing.Nature. 2018; 562: 281-285Crossref PubMed Scopus (79) Google Scholar now introduce a technique that combines FACS, micrococcal nuclease digestion to cleave DNA between nucleosomes, and DNA fragment sequencing. This makes it possible to simultaneously reveal nucleosome positioning and chromatin accessibility in single cells. This assessment, which included hundreds of individual cells from three different mouse cell types, reveals insights that were previously masked by bulk analyses. The first is that nucleosomes around transcriptional start sites in silent parts of the genome are regularly spaced, but their position between individual cells varies considerably. In contrast, nucleosomes at start sites in actively transcribed regions have more heterogeneity in spacing but are positioned more precisely. These would appear to represent differences in chromatin stability and the activity of chromatin remodeling factors in the active regions. The authors show that spacing between nucleosomes is bimodal, with peaks at 190bp and 300 bp, which correlate with differential accessibility. Moreover, variation in gene expression is shown to be correlated to variation in nucleosome positioning. The authors expand this assessment to tackle questions related to differentiation and intriguingly imply that the heterogeneity observed in cultured naive CD4 T cells and embryonic stem cells in the presence or absence of nucleosomes at key enhancers marks cells primed for differentiation. Another factor that could impact variability between cells is the more mysterious role that 3D organization plays, particularly at the level of topologically associated domains (TADs). TADs are neighboring regions (or domains) of chromosomes within which chromatin shows higher contact probabilities than those of inter-domain contacts. Although these have been examined in bulk and in a pairwise fashion, until now, there has not been a way of assessing them in a widespread manner in individual cells. In this context, the effort by Bintu et al., 2018Bintu B. Mateo L.J. Su J.-H. Sinnott-Armstrong N.A. Parker M. Kinrot S. Yamaya K. Botettiger A.N. Zhuang X. Single-resolution chromatin tracing reveals domains and cooperative interactions in single cells.Science. 2018; 362https://doi.org/10.1126/science.aau1783Crossref PubMed Scopus (445) Google Scholar employs sequential hybridization with 30 kb readout probes (a multiplex adaptation of fluorescence in situ hybridization), which enables tracing of large regions of chromatin and their comparison between cells. They find that TAD-like chromatin domain structures are present in single cells. Although the boundaries of these TAD-like structures differ between cells and could be present at all locations in the genome, they do appear to be preferentially placed near CTCF and cohesin binding sites. However, TAD-like structures are still present in single cells even when cohesin is depleted, an observation that is not evident from existing studies of chromatin at the population-average level. In having this more expansive and intricate view of chromatin organization, the authors reveal that three-way interactions between chromatin segments are commonplace. In future work, it will be interesting to determine whether stereotypy or variability in these associations can be linked to specific impacts on gene expression or cellular responses. There is an increasingly impressive array of new tools with which to explore individual cells. Beyond the richness of data that comes from each of these efforts, cross-comparison and merging of insights from multiple platforms becomes an increasingly urgent task. In addition, many of these approaches are also in principle compatible with widescale CRISPR editing and screening tools, and it may become commonplace to characterize specific single cell phenotypes while simultaneously identifying modulators of their frequency.

With the complexities of organelle communication and their dynamics under intense investigation, what are the new principles that are emerging, and where is the field headed? Cell's Robert Kruger recently discussed these questions with Erika Holzbaur, Jennifer Lippincott-Schwartz, and Ivan Dikic. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.

The ability to forecast which cancers will likely come back after treatment could help improve patient outcomes and might also point to new vulnerabilities to exploit in future therapies. For clinical oncologists the obstinate cancer cells that withstand treatment and are most often undetectable by microscope, are known as “minimal residual disease.” For instance, individuals with acute myeloid leukemia (AML) typically have a massive burden of cancerous cells at the start of treatment, but after high-dose induction chemotherapy this is drastically reduced and many patients go into remission. Yet, for many of these the disease will eventually come back. How can relapse be predicted during remission? In a recent study, Jongen-Lavrencic et al., 2018Jongen-Lavrencic M. Grob T. Hanekamp D. Kavelaars F.G. Al Hinai A. Zeilemaker A. Erpelinck-Verschueren C.A.J. Gradowska P.L. Meijer R. Cloos J. et al.Molecular Minimal Residual Disease in Acute Myeloid Leukemia.N. Engl. J. Med. 2018; 378: 1189-1199Crossref PubMed Scopus (432) Google Scholar use next-generation sequencing of blood or bone marrow samples from individuals treated and in remission for acute myeloid leukemia (AML) to understand the mutation patterns of minimal residual disease and show which profiles have a higher association with disease recurrence. The authors conduct targeted sequencing to assess “molecular minimal residual disease” in 430 AML patients. When comparing the resulting molecular profiles with frequency of relapse and relapse-free survival, they show that individuals with persisting mutations in one or more of a trio of genes DNMT3A, TET2, and ASXL1 (so-called DTA mutations) do not have a high risk of recurrence, whereas those with persisting non-DTA mutations were at heightened risk over the 4-year period of follow up. What ties these three genes together is that they are frequently impacted with mutations that accrue during normal aging and so are not only associated with malignant disease. The authors also show that combining this type of molecular profiling with the standard-of-care flow cytometry methods to detect minimal residual disease improves the ability to predict outcomes over flow cytometry alone. This supports the idea that molecular characterization of minimal residual disease for other cancer could be an important prognostic tool for patient outcomes in many post-treatments settings. Future work will be needed to explore what these profiles suggest about additional potential therapy options or therapeutic development for AML. The concept of minimal residual disease has been long established in acute lymphoblastic leukemia. Although minimal residual disease can be detected in up to half of adult patients in remission, there has been no standard therapy to treat it and avoid relapse. It is for this reason that the recent FDA approval of Blinatumomab for ALL patients with minimal residual disease is a critical step forward. Blinatumomab is an existing treatment for ALL and it works by simultaneously binding CD3 on T cells and CD19 antigen on malignant B cells to promote their cytotoxic killing. The results of the phase II trial supporting the accelerated FDA approval are reported by Gökbuget et al., 2018Gökbuget N. Dombret H. Bonifacio M. Reichle A. Graux C. Faul C. Diedrich H. Topp M.S. Brüggemann M. Horst H.A. et al.Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia.Blood. 2018; 131: 1522-1531Crossref PubMed Scopus (414) Google Scholar and are unique in that they use minimal residual disease as both the criteria for inclusion and the absence of detectable minimal residual disease as the trial’s primary end point. The possibilities for this kind of preventative treatment based on molecular defined and detected residual disease appears a completely open terrain with untold routes yet to explore.

Design, build, test, repeat—the essence of design thinking and a guiding principle of synthetic biology. Given the complexities of biological systems, there are bottlenecks that slow this virtuous design cycle for many of its potential applications. Yet, in the realm of small protein design and testing, the floodgates have just been thrust open.

With the ongoing liberalization of cannabis laws in many parts of the United States that are decriminalizing its recreational and/or medical use, there is much discussion about the benefits of cannabinoids and how to mitigate potential negative societal repercussions of increased access to them. At risk of being overshadowed amidst this debate is the fascinating biology coming to light about how cannabinoids mediate their effects, including the crystal structures of human CB1 cannabinoid receptors (Hua et al., 2016Hua T. Vemuri K. Pu M. Qu L. Han G.W. Wu Y. Zhao S. Shui W. Li S. Korde A. et al.Cell. 2016; 167: 750-762.e14Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, Shao et al., 2016Shao Z. Yin J. Chapman K. Grzemska M. Clark L. Wang J. Rosenblum D.M. Nature. 2016; (Published online November 16, 2016)https://doi.org/10.1038/nature20613Crossref Scopus (263) Google Scholar), and surprising insights about where in the cell they act (Herbert-Chatelain et al., 2016Herbert-Chatelain E. Desprez T. Serrat R. Bellocchio L. Soria-Gomez E. Busquets-Garcia A. Zottola A.C.P. Delamarre A. Cannich A. Vincent P. et al.Nature. 2016; (Published online November 9, 2016)https://doi.org/10.1038/nature20127Crossref Scopus (249) Google Scholar, Younts et al., 2016Younts T.J. Monday H.R. Dudok B. Klein M.E. Jordan B.A. Katona I. Castillo P.E. Neuron. 2016; 92: 479-492Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Both plant-based and synthetic cannabinoids piggyback their pharmacology on a collection of endogenous molecules and their receptors together known as the endocannabinoid system. In broad strokes, endocannabinoids are neuromodulatory and have central roles in memory, mood, pain, inflammation, and appetite. Because of these attributes, this system has been an attractive target for therapeutic development. In this context, the recent failed phase I safety trial of a small-molecule inhibitor of fatty acid amide hydrolase, aimed at boosting endocannabinoid levels, highlights the need for a better understanding of both the basic biology of the endocannabinoid system and specific therapeutic targets (Kerbrat et al., 2016Kerbrat A. Ferré J.C. Fillatre P. Ronzière T. Vannier S. Carsin-Nicol B. Lavoué S. Vérin M. Gauvrit J.Y. Le Tulzo Y. Edan G. N. Engl. J. Med. 2016; 375: 1717-1725Crossref PubMed Scopus (126) Google Scholar). Although in this case it is surmised that the severe neurologic symptoms, and in one case fatality, that occurred with high dosing of the experimental compound were due to off-target effects, the tragic outcome and open questions underscore the desirability of pursuing highly specific compounds. The recent crystal structures of the human CB1 receptor should accelerate this effort. CB1 is the main target for both psychoactive ligands (such as trans-Δ9-tetrahydrocannabinol [THC] from cannabis) and endogenous ones (such as anandamide and 2-arachidonyl glycerol [2-AG]). It is a class A G-protein-coupled receptor (GPCR), and consistent with its many roles, it is thought to be the most common GPCR in the central nervous system. The structures from the two groups, respectively, capture the receptor in an inactive state bound to taranabant (Shao et al., 2016Shao Z. Yin J. Chapman K. Grzemska M. Clark L. Wang J. Rosenblum D.M. Nature. 2016; (Published online November 16, 2016)https://doi.org/10.1038/nature20613Crossref Scopus (263) Google Scholar) and a derivative of rimonabant called AM6538 (Hua et al., 2016Hua T. Vemuri K. Pu M. Qu L. Han G.W. Wu Y. Zhao S. Shui W. Li S. Korde A. et al.Cell. 2016; 167: 750-762.e14Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar). Both taranabant and rimonabant are inverse agonists developed for the treatment of obesity that failed to attain regulatory approval due to side effects, including depression. Although pharmacologically distinct from receptor activators, the structures nevertheless permit modeling of the binding pocket for THC and endogenous ligands. The insights into the unique features of the CB1 pocket will aid in the computational design of new inhibitors and activators. And given that THC is known to have wide safety margins, it can be hoped that the new structures will provide insights into the reasons for this, which might assist in developing new compounds with better safety and fewer side effects. A frequent undesirable effect of cannabinoid intoxication is memory impairment, and understanding the specific mechanisms underlying this may inform new ways of mitigating this problem while maintaining other potential benefits. A study by Herbert-Chatelain et al., 2016Herbert-Chatelain E. Desprez T. Serrat R. Bellocchio L. Soria-Gomez E. Busquets-Garcia A. Zottola A.C.P. Delamarre A. Cannich A. Vincent P. et al.Nature. 2016; (Published online November 9, 2016)https://doi.org/10.1038/nature20127Crossref Scopus (249) Google Scholar suggests surprisingly that an important cellular locus of cannabinoid action in memory is mitochondria. It has been known that cannabinoids can activate CB1 at the plasma membrane and also at mitochondrial membranes, although the specific function of the latter has been unclear. Through the deletion of its first 22 amino acids, the authors disrupt trafficking of CB1 to mitochondria in mouse hippocampal neurons. This intervention makes the mice unresponsive to the amnesia-inducing effects of CB1 receptor agonist. The signaling pathway triggered by cannabinoids in mitochondria leads to the phosphorylation of proteins that conduct oxidative phosphorylation—in particular NDUFS2, a respiratory complex I subunit—and blocking this signaling pathway curbs the amnesic effects of cannabinoids. In sum, the findings suggest that one route to memory gated by cannabinoids goes through mitochondria via the modulation of energy metabolism. The connection, however, is undoubtedly complex, as it has been reported that CB1 agonists increase mitochondrial respiration at low doses and decrease it at high ones (Koch et al., 2015Koch M. Varela L. Kim J.G. Kim J.D. Hernández-Nuño F. Simonds S.E. Castorena C.M. Vianna C.R. Elmquist J.K. Morozov Y.M. et al.Nature. 2015; 519: 45-50Crossref PubMed Scopus (276) Google Scholar). Teasing apart these phenomena in individual biological contexts might be aided by discoveries from Younts et al., 2016Younts T.J. Monday H.R. Dudok B. Klein M.E. Jordan B.A. Katona I. Castillo P.E. Neuron. 2016; 92: 479-492Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, who show that a functionally important consequence of CB1 activation by endocannabinoids is pre-synaptic protein synthesis. The findings add support to the notion that axons in the mammalian central nervous system are a site of translation, a subject of long scientific disagreement, unlike post-synaptic compartments, where translation regulation is long appreciated to have a critical role in synaptic plasticity. Endocannabinoids are generated post-synaptically and travel across the synapse to modulate the pre-synaptic neurons. Here, the authors show that presynaptic protein synthesis stimulated by endocannabinoids is essential to the long-term depression of GABA release from hippocampal interneurons. They further establish that this effect is mediated by the mTOR pathway, which has previously been implicated in the amnesic effects of cannabinoids. In light of the report by Herbert-Chatelain et al. discussed above, a mTOR-mitochondria axis of regulation could be central to what is happening in axon terminals in response to endocannabinoids in memory processes. A composite view from these studies promises increased opportunities for developing therapies with greater molecular and cellular specificity and reveals a nexus between cannabinoids and cellular metabolism that might be critical to understanding the context dependence and diversity of cannabinoid functions.

The conference day has officially gone into overtime—after all the talks, posters, dinner, and drinks, we’re now headed back to our hotels in the city, a half-hour’s drive down the mountainside. I’m a few rows back from the front of the bus, and it’s crowded-bar-on-a-Friday-night loud and just as energized. Over the noise, I catch only enough of my seatmate’s question to strike up a conversation about the best talks of the day. As we chat, the bits and pieces of the other conversations around us mix and mingle with our own thoughts. Across the way, two post-docs are swapping stories about dealing with the two-body problem in their job searches. It’s nice to see they’ve dropped their initial wariness from having learned earlier in the day that they share similar unpublished results. A row ahead, an emeritus professor recounts setting up his first lab in the early 70s. From the glimpses I get of the junior faculty sitting next him, the story is a funny one and I wonder what parts remind her of her own recent experience. A sharp turn in the road knocks off-balance a third-year grad student standing in the aisle. She is saved from falling by her labmate and the surprisingly quick reflexes of a National Academy member standing beside her. Without missing a beat, she continues to describe a malfunctioning microfluidic device that is slowing the revision of her first paper. Behind me, a PI is attempting to maintain a strictly scientific discussion: “There’s so much redundancy with these receptors.” A brief pause, followed by the clicking sound of a laptop opening, “It’s easier to just show you.” Still others are discussing grant success rates or a recent fishing trip or have slipped into their native tongues, making me wish I knew Chinese or Turkish or what I’m guessing is Croatian, as they share personal stories and scientific inspirations that I hope I’ll have the chance to hear more about during the next days of the meeting. After a few more minutes chatting with my fellow passenger—having now moved on to the topic of co-authorship issues—the conversation comes to a natural pause. I glance out the window, seeing the last of the trees and fields before we arrive at the streets of the city. The noise of the bus and the thoughts in my head converge and go quiet, and in their place arises a feeling—gratitude. I take a moment to savor it. A day at a great conference, with the special alchemy that comes from bringing diverse perspectives, ideas, and aspirations to a single place and time—this is what we strive to create in each issue of Cell. New discoveries lay the groundwork, to be sure, but it is the surrounding discussion, debate, and synthesis that provide the glue that connects the scientific building blocks together. Leading Edge, our front section, marks its ten-year anniversary this month and continues to be that glue for Cell. The founding principles of Leading Edge are to foster communication between scientific disciplines about what is most exciting in biology and to offer a window on the larger policy, ethical, and economic contexts that impact the research community. In moving into a second decade, we will carry these principles forward but will be further guided by two touchstones that capture what we think Leading Edge should do: synthesize and relate. The scientific literature is complex and ever-expanding. For us, synthesize means making complicated topics easy to digest so that we can direct readers to the most important trends, connect scientific communities, and foster the cross-pollination of ideas. Fulfilling this goal will mean a continued emphasis on our anchor formats: Reviews, Minireviews, and Previews, as well as more recent additions, such as Snapshots, Perspectives, and Primers, to give readers ready access to both maturing and emerging fields and technologies. Responding to the growing worldwide call to accelerate the pipeline from basic biological insights into improved human health, we recently introduced Bench to Bedside, which connects readers to the latest developments in the pipeline of new drugs and biologics and conveys at a glance the basic biology and timeline of discoveries that made new medical advances possible. But behind all the experiments, analysis, and models are the people. In aspiring to our second goal—relate—we pursue content that speaks to the day-to-day experience of being a scientist and that offers inspiration for readers by conveying the human side of discovery. In short, we want Leading Edge to be infused with the boisterous energy, unique personalities, and differing perspectives that you’d find on the conference bus described above. Our new Stories format, for instance, presents personal experiences of discoveries, recounts events that have shaped careers, or tells how particular challenges have been faced. This year’s Lasker Award winners wrote our first collection of Stories, which appeared in the September 10th issue. In future issues, Stories will come from individuals from all walks of science and career stages. In providing a more personal perspective, Stories stands aside Commentary and Voices, existing formats that offer viewpoints (in long and short form, respectively) on trends, policies, careers, or approaches to doing science. In the coming year, you can expect new experiments from Leading Edge, including venues for early career researchers to share their opinions and lively discussions between individuals with differing points of view as they exchange ideas on timely topics. We also want an even closer connection with our readers, and a key part of promoting openness and clarity of communication is sharing our thoughts directly. There are many ways in which Cell editors express what they are thinking, and you should look in the coming year for a steady stream of topical editorials, Select features (discussions of studies in other journals that have caught our eye), and posts on our website in the Cell Press CrossTalk blog. The other half of the equation is to hear what’s on your mind. To open an additional channel of communication, the Cell editors are hosting a monthly Skype session called “Let’s Chat!” Whether it’s a discovery you want to tell us about or an interesting experience you’d like to share, we’re ready to listen. As always, you should feel uninhibited in reaching out to any member of the editorial team to set up a time to talk or catch us in person when we are out and about in the community. At any given time, one or more of us are at meetings, visiting labs, or giving talks on editorial practice or scientific editing as a career. Given the depth of our focus on communication and how to strengthen it, it is not by coincidence that “Communication” will also be the overarching theme of our upcoming 2016 special review issue. As I type this, the Cell Press office is filled with half-packed crates and the squeaking sound of moving carts. We’re in the midst of relocating to a new space nearby. A virtue of our new environs is that it is open plan with no walls to separate colleagues—part of our drive to facilitate collaboration and accelerate innovation. As we break down our own walls and create a more dynamic working environment, we hope you find the pages of Cell abuzz with new energy and that you too, in this season of transition and renewal, will be inspired to share with us your thoughts, feelings, and perspectives.

beta-amyloid accumulation is a hallmark of Alzheimer's disease pathology, but how does it cause cognitive impairment? New findings described in this issue's Select examine how beta-amyloid impacts signaling events at the synapse at early stages of disease progression. And at later stages, one study suggests that Alzheimer's patients exhibit a pronounced deficiency in their capacity to metabolize beta-amyloid.