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electronic proof of concept paves the way DEVELOPMENT to the use of this technology to restore muscular activation, such as in foot drop (abnormal gait caused by nerve damage) or A new view of bladder dysfunction. Important challenges lie ahead to trans- late this result to a breakthrough in the development and prosthetic (and robotic) domain. So far, each application has focused on a single Transcriptome atlases of and dimension of the tactile stimulus, such regeneration enrich our understanding of development as slip detection, texture, or shape, or direction-of-motion classification. The next generation of tactile sensory systems By Richard M. Harland the embryo is dissociated into single cells, must integrate all of these to offer richer each of which merges with a drop contain- sensory information. The contribution of mong the major milestones in de- ing barcoded primers on a bead so that computational neuroscientists will be es- velopmental are those that mRNA can be amplified for high-through- sential to this field in order to understand authoritatively describe how cells put sequencing of cDNA. For embryos, the which feature of the neural code is related differentiate during development. dissociation and gentle handling of the large to each stimulus property and which neu- Conklin (1) described the mosaic de- and delicate cells were a crucial advance ral architecture can support the encoding velopment of in permitting the sequencing of enough and decoding of such information. A(sea squirt), in which specific and recog- cells to reconstruct expression in all Downloaded from In the proposed implementations, only nizable cells of the dividing embryo consis- cells, even in rare cells such as germ cells. one of the four types of mechanoreceptors tently produce specific tissues of the larva The barcodes identify transcripts from the of human glabrous skin has been emulated, and naturally pigmented myoplasm seg- single cells they were extracted from, and and a single type of transduction is avail- regates to the muscle lineage of the larva, similarities and differences in transcript able in each system. These single types of supporting the idea of localized cytoplasmic composition sort the cells into clusters, rep- transduction relate to both the physical determinants that influence fate. Later, resenting states of differentiation. http://science.sciencemag.org/ transduction properties (capacitive, resis- lineage tracer dyes were used to track the Technically, it is a challenge to capture all tive, piezoelectric, optical, etc.) and the fates of different regions in em- the different transcripts from a single cell, spiking behavior (e.g., fast with respect to bryos (2). More recently, careful observation slow-adapting receptors). The challenge produced the triumph of a complete cell will be to develop a hybrid system with lineage map of the nematode worm (Cae- transduction sites of different bandwidth, norhabditis elegans) embryo (3). On pages “These papers describe the dynamic range, resolution, sensitivity, and 980, 979, and 981 of this issue, Briggs et al. transcriptional information mechanical characteristics, with the help of (4), Farrell et al. (5), and Wagner et al. (6), materials science, and to implement neu- respectively, as well as Fincher et al. (7) and that forms the blueprints

ral models that can take into account the Plass et al. (8), mark another innovation: a of development…” on August 6, 2019 different characteristics of skin description of in all of the receptors. The ultimate system will include cells of fish and frog embryos (4–6) and in temperature sensors and proprioception. j the adult regenerating (flatworm) so inevitably, some important transcripts (7, 8). These papers describe the transcrip- can be missed. This technical limitation REFERENCES tional information that forms the blue- is further complicated by biological varia- 1. Y. Kim et al., Science 360, 998 (2018). 2. C. Bartolozzi, L. Natale, F. Nori, G. Metta, Nat. Mater. 15, prints of development and regeneration in tion in gene expression between similar 921 (2016). these . cells. Although the recovered population of 3. C. Mead, Proc. IEEE 78, 1629 (1990). Although we now understand many transcripts is not comprehensive, it is good 4. H. P. Saal, X. Wang, S. J. Bensmaia, Curr. Opin. Neurobiol. 40, 142 (2016). mechanisms underlying developmental enough to recognize cells that are similar, 5. S. Panzeri, C. D. Harvey, E. Piasini, P. E. Latham, T. Fellin, decisions, such as the inheritance of local- or different, and cluster them accordingly. Neuron 93, 491 (2017). ized RNAs or stereotypical arrangement By analyzing cells from different embry- 6. K. E. Friedl, A. R. Voelker, A. Peer, C. Eliasmith, IEEE Robot. of signaling and responding cells, there is onic stages, trajectories of differentiation Autom. Lett. 1, 516 (2016). 7. T.-S. Chou, L. D. Bucci, J. L. Krichmar, Front. Neurorobot. 9, still a great deal that we do not know; for can be reconstructed over time, because 6 (2015). example, experiments have sampled many cells follow a progressive pathway of tran- 8. Z. Yi, Y. Zhang, J. Peters, Sens. Actuators A Phys. 255, 46 important regulators of cell fate, but the scriptional changes as they differentiate. As (2017). 9. C. Bartolozzi et al., in IEEE/RSJ International Conference complete set of transcripts that regulate cell cells become different, these paths branch on Intelligent Robots and Systems (IROS), Vancouver, fate decisions has been unattainable. to provide a molecular picture of emerging 2017, pp. 166–173. These studies demonstrate the power of differentiation, and the transcripts that de- 10. M. Regoli, N. Jamali, G. Metta, L. Natale, in 2017 18th International Conference on Advanced Robotics (ICAR), single-cell RNA sequencing (scRNA-seq) fine the differences can be identified. Sat- Hong Kong, 2017, pp. 47–54. in producing detailed and comprehensive isfyingly, the differences include ones that 11. D. W. Tan et al., Sci. Transl. Med. 6, 257ra138 (2014). plots of gene expression correlations with have been identified and characterized by 12. C. M. Oddo et al., eLife 5, e09148 (2016). 13. L. Osborn, R. R. Kaliki, A. B. Soares, N. V. Thakor, IEEE Trans. emerging cell fates. This technology has previous methods. Reassuringly, the vari- Haptics 9, 196 (2016). adapted previous single-cell microfluidics; ous computational approaches to cluster- 14. D. M. Rager et al., in 35th Annual International Conference ing cell types provide consistent outcomes. of the IEEE Engineering in Medicine and Biology Society Adding human annotation of the branches (EMBS), 2013, pp. 5922–5925. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3200, USA. of differentiation, on the basis of known 10.1126/science.aat3125 Email: [email protected] markers, superimposes them onto devel-

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opmental anatomy, providing a reconstruc- for multiple lineages in individual cells has the trajectories of differentiation from stem tion of transcription in early embryos at the been documented for a few cell types (10) cells to be reconstructed in “pseudotime.” In cellular level. This manual annotation can but is now documented for dozens of cell these cases, they describe trajectories from account for the loss of spatial information fate decisions. Examination of the tran- (stem cells) that describe the de- when the was dissociated and scription factors that are coexpressed at de- velopment of the entire organism. is complemented by a semiautomated ap- cision points will suggest new experiments Where is this scRNA-seq technique proach (5). on the cooperation between transcriptional leading? The studies of embryo- The studies have developed impressive regulators. Cells that appear to be superfi- genesis by Farrell et al. and Wagner et visualization tools that allow us to see how cially similar, coming from the same region al. show that, in principle, scRNA-seq is cells start to differentiate, and, after em- of the embryo, may express nonoverlapping a rapid assay to understand the pheno- barking on specific lineages, how cell fate is transcripts, indicating a fundamental het- types of mutants, with loss of Chordin, a reinforced and specialized over time. Over- erogeneity in cell identity, something that bone morphogenetic protein antagonist, all, the developing show an initial has been difficult to establish by whole- or loss of Nodal signaling. Previous work trunk of unresolved cell types, from which tissue analysis. is confirmed, and the additional observa- large branches and eventually “fine twigs” The fish and frog have been extensively tion that the alteration of signaling does of specialization emerge. As the branches studied, so a lot of the information in these not cause formation of any new cell types, spread, the expression of known mRNAs studies provides fine detail, but in an ani- but instead alters the proportions of cell confirms that cells are be- types that would develop coming restricted to specific in the wild-type , is fates. From these datasets, provided. This technique we can infer the progress is currently prohibitively Downloaded from of individual cells over time expensive for routine use, and some of the variation in but, just as genotyping routes that cells take toward by DNA sequencing has the differentiated state. Al- largely replaced laborious though most branches be- genetic mapping, so too come progressively divided, might scRNA-seq provide http://science.sciencemag.org/ an exception occurs where a more cost-effective ap- two divergent branches proach to understanding from neural crest and pha- complex phenotypes than ryngeal arches coalesce multiple rounds of hypoth- again, consistent with the eses and experiments. The idea that neural crest cells comparison of transcrip- adopt a fate appropriate to tomes also highlights simi- their local environment (9). larities and differences in Importantly, the scRNA- distantly related

seq data capture cells at such as bony fish (zebraf- on August 6, 2019 branch points, a previously ish) and frogs that will lead inaccessible cell state in to analysis of how different which fate choices are made. cell types may have evolved Resolution of the decision from common ancestors. shows which transcription The gene expression landscape of a developing zebrafish embryo is visualized. Dots Just as the emergence of factors are enriched and represent snapshots of individual cell states measured by scRNA-seq during the first day genomic information forced may determine cell fate. In of development. Cells of the early embryo are at the center, with differentiating cells radiating communities to join together most cases, it appears that along branches to form neural (red), epidermal (blue), and mesendodermal (green) tissues. to annotate , there decisions are binary, al- is tremendous benefit to an- though there are examples where there is mal like the regenerating planarian, which notating developmental processes and search a choice between multiple fates. Specific has only recently become a standard model for new insights and discoveries as a commu- cases document a mixed cell state, for ex- of regeneration and development, there nity. Now that these data are available, the ample, in the choice between prechordal are new cell types and developmental tra- door to imagining new uses is wide open. j plate and notochord where a substantial jectories to be discovered. The analyses of fraction of cells appear bipotential, even the regenerating planarian highlights how REFERENCES 1. E. G. Conklin, The Organization and Cell-Lineage of after territories have been defined. Such scRNA-seq provides a fast start to establish- the Ascidian Egg (Academy of Natural Sciences of cells must resolve their expression quickly ing the molecular anatomy of the organism, Philadelphia, 1905). to adopt the fate of their local community, including rare cell types, which will acceler- 2. W. Vogt, Wilhelm Roux Arch. Entwickl. Mech. Org. 120, 384 (1929). or presumably be eliminated. ate research in this and other new models. 3. J. E. Sulston et al., Dev. Biol. 56, 110 (1977). Apart from the amount of information The studies of Fincher et al. and Plass et 4. J. A. Briggs et al., Science 360, eaar5780 (2018). to be digested from these transcriptome al. on the regenerating planarian also il- 5. J. A. Farrell et al., Science 360, eaar3131 (2018). atlases, what other nuggets have emerged? lustrate, for a whole organism, what had 6. D. E. Wagner et al., Science 360, 981 (2018). 7. C. T. Fincher et al., Science 360, eaaq1736 (2018). The information enriches what we already been achieved in previous work on tissue 8. M. Plass et al., Science 360, eaaq1723 (2018). know and additionally identifies transcripts renewal during homeostasis, where cells 9. P. A. Trainor et al., Nat. Rev. Neurosci. 1, 116 (2000). that had not previously been associated asynchronously differentiate from a vari- 10. R. A. Nimmo et al., Trends Cell Biol. 25, 459 (2015). with pathways of differentiation. The si- ety of precursors. The clustering

multaneous expression of determinants of progressive changes in transcripts allows 10.1126/science.aat8413 SCHOOL MEDICAL WAGNER/HARVARD DANIEL PHOTO:

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