About

Xiaowei Zhuang is the David B. Arnold, Jr. Professor of Science at Harvard University and an investigator at the Howard Hughes Medical Institute. She works in the areas of single-molecule biology and bioimaging, developing imaging techniques to study biological systems quantitatively. Her research focuses on creating imaging tools with molecular-scale resolution, single-molecule sensitivity, and dynamic imaging capabilities to visualize molecular interactions and processes inside living cells. Her lab applies expertise from chemistry, physics, biology, and engineering to address biological questions such as protein and nucleic acid interactions, virus infection mechanisms, and neuronal computation. Zhuang received her B.S. degree in Physics from the University of Science and Technology of China, her Ph.D. in Physics from the University of California at Berkeley, and completed postdoctoral training in biophysics at Stanford University. She began her faculty career at Harvard University in 2001, progressing from assistant to full professor by 2006. She joined the Howard Hughes Medical Institute as an investigator in 2005. Zhuang is a member of the National Academy of Sciences, a fellow of the American Association of the Advancement of Science, and a fellow of the American Physical Society. She serves on the editorial boards of several scientific journals, including Cell, eLife, the Annual Review of Biophysics, Chemical Physics Letters, and Optical Nanoscopy.

Research topics

• Biology
• Genetics
• Computational biology
• Neuroscience
• Cell biology
• Computer Science
• Evolutionary biology
• Chemistry
• Biochemistry
• Artificial Intelligence
• Remote sensing
• Bioinformatics
• Immunology
• Anatomy
• Medicine
• Cartography
• Endocrinology
• Environmental health
• Geography
• Cancer research

Selected publications

• Comprehensive Lineage Tracing Maps the Landscape of Cell Fate Decisions in Mouse Embryogenesis

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-09 · 1 citations

  articleOpen access

  . Here, we use PEtracer to continuously install heritable genetic marks as cells divide, reconstructing lineage trees that resolve ∼75% of cell divisions across >1.5 million cells from 16 mouse embryos collected at half-day intervals from E7.5-E10.0. We pair these trees with deep transcriptional profiling to chart the landscape of cell fate decisions during gastrulation and early organogenesis. Using these data, we quantify cell fate biases, restriction timing, progenitor pool sizes, and lineage relationships across the embryo, revealing strikingly reproducible lineage architecture across replicate embryos despite the regulative flexibility of mammalian development. We further show how lineage, spatial position, and signaling jointly determine fate outcomes and timing, with their relative influence varying by tissue. This dataset provides a quantitative framework for understanding cell fate specification and a lineage-resolved reference for generating and contextualizing developmental hypotheses at organismal scale.

  PublisherDOI

• Global cell-state and gene-program representations reveal conserved and context-specific perturbation responses of cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-18

  articleOpen accessSenior authorCorresponding

  Abstract Understanding how cell states change in response to genetic perturbations is critical for gene-function and therapeutics discovery. However, state-of-the-art deep-learning models trained on large single-cell omics datasets still struggle to accurately predict cellular responses to perturbations, highlighting the need for a better understanding of the cell-state space and how cells move through this space. Here, we present a contrastive learning model that integrates diverse scRNA-seq datasets into a global, interpretable cell-state manifold. We further develop a framework to integrate this global cell-state manifold with genome-scale perturbation data to identify gene-expression programs that define principal axes of cell-state transitions and functional embeddings of genes that define major perturbation classes. Applying this framework across Perturb-seq datasets on different cell types reveals conserved cellular responses to perturbations, as well as cell-type-specific rewiring of stress responses. Moreover, we perform a genome-scale Perturb-seq screen in human embryonic stem cells, validating and extending these findings and uncovering a class of mesenchymal transitions induced by diverse perturbations to cellular stress-response pathways.

  PublisherDOI

• Multiplexed optical barcoding and sequencing for spatial omics

  Scientific Reports · 2026-03-18

  articleOpen accessSenior authorCorresponding

  Spatial omics has brought a fundamental change in the way that we study cell and tissue biology in health and disease. Among various spatial omics methods, genome-scale imaging allows transcriptomic, 3D-genomic, and epigenomic profiling of individual cells with high spatial (subcellular) resolution but typically requires a preselection of targeted genes or genomic loci. On the other hand, spatially dependent barcoding of molecules followed by sequencing provides untargeted, genome-wide profiling but has a lower spatial resolution than imaging-based methods. Here, we report a spatial omics method that could potentially combine the power of the two approaches using optically controlled spatial barcoding followed by sequencing. Specifically, we utilize patterned light to encode the locations of molecules in tissues using oligonucleotide-based barcodes and then identify the barcoded molecular content, such as mRNAs, by sequencing. This optical barcoding method is designed with multiplexing and error-correction capability and achieved by a light-directed ligation chemistry that attaches distinct nucleic-acid sequences to the reverse transcribed cDNA products at different locations. As a proof of principle for this method, we demonstrated high-efficiency in situ light-directed ligation, spatially dependent barcoding with multiplexed light-controlled ligations at the single-cell level, and high-accuracy detection of spatially barcoded mRNAs in cells.

  PublisherDOI

• Spatial organization and detection of social odors in mouse primary olfactory system

  Cell · 2026-04-01

  articleOpen access

  The detection of olfactory cues is essential to signal food, predators, and social encounters. To determine how the sensory detection of physiologically relevant odors is systematically mapped into the mouse primary olfactory system, we used multiplexed error-robust fluorescent in situ hybridization (MERFISH) to construct a molecular atlas of olfactory receptor (OR) expression in the main olfactory epithelium (MOE) and olfactory bulb (OB). We comprehensively quantified the expression of the mouse OR repertoire and uncovered stereotypical gradients of sensory neuron distribution in the MOE along two axes, central-to-peripheral and apical-to-basal. Projections of sensory neurons mirror these two MOE gradients along the dorsal-ventral and anterior-posterior axes of the OB, respectively. Integration with sequencing data revealed candidate signaling molecules underlying this spatial organization. Co-imaging OR and activity marker expression identified distinct spatial domains of sensory responses in the MOE and OB, providing a topographical basis for olfactory responses to ethologically relevant odors.

  PublisherDOI

• Abstract 6605: Spatially-resolved single-cell transcriptome landscape of response and resistance to CDK4/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer

  Cancer Research · 2025-04-21

  article

  Abstract Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have significantly improved the treatment of hormone receptor (HR+) positive breast cancer. Clinical trials have demonstrated that addition of CDK4/6i to endocrine therapy (ET) improves both progression-free and overall survival in patients with HR+ metastatic breast cancer (MBC). Nevertheless, their impact remains limited by the eventual development of resistance. While a number of resistance mechanisms have been identified using both preclinical model systems and translational interrogation of patient specimens, these are not apparent in all cases. As part of the Human Tumor Atlas Network, we integrated genomic (whole-exome sequencing; n=47), single-nucleus transcriptomic (snRNA-seq; n=56), and spatial expression profiling (MERFISH and multiplex immunofluorescence; n=22 and n=17, respectively) from 58 clinically annotated MBC biopsy specimens collected before or after treatment with CDK4/6i plus ET to dissect the roles of tumor-intrinsic programs and the tumor microenvironment (TME) in CDK4/6i resistance. Transcriptomic analysis of the tumor cell compartment with snRNA-seq not only extended prior findings including an association between expression of cell-cycle programs and CDK4/6i resistance, but importantly identified additional programs associated with response and resistance including ciliogenesis, immune evasion, and inflammation. Additionally, tumor-intrinsic gene programs related to epithelial-to-mesenchymal transition had a decreased activity in ESR1 mutant biopsies, a mutational feature of CDK4/6i-resistant MBC associated with upregulated estrogen receptor pathway activity. In the TME, CD8+ T cells were depleted in the CDK4/6i-resistant biopsies, both before and after treatment. In contrast, the CDK4/6i-sensitive biopsies displayed pro-inflammatory features including an increased number of CXCL9+/CXCL10+ macrophages and clustering of CD8+ T cells in the vicinity of the malignant cells spatially. Notably, MERFISH also demonstrated an association between spatial architecture and CDK4/6i response, with the malignant cells in the CDK4/6i-resistant biopsies dispersed spatially compared to the sensitive biopsies. In summary, to the best of our knowledge, this study represents the largest spatially-resolved single-cell MBC cohort with curated CDK4/6i response status established to date. Our findings offer insights into potential biomarkers for CDK4/6i response based on tumor-intrinsic and tumor-microenvironment mechanisms, as well as therapeutic opportunities. Citation Format: Junko Tsuji, Jorge Gómez Tejeda Zañudo, Timothy R. Blosser, Ha T. Vu, Danielle Firer, Nick Maus, Kathleen L. Pfaff, Billie A. Porter, Jason L. Weirather, Anne Carlisle, Allison M. Frangieh, Elliot Boblitt, Aaron R. Thorner, Karla E. Helvie, Isabella E. Kallassy, Laura K. DelloStritto, Ragnhild Laursen, François Aguet, Mendy Miller, Melissa E. Hughes, Nancy U. Lin, Sara M. Tolaney, Eliezer M. Van Allen, Samouil L. Farhi, Xiaowei Zhuang, Barbara Engelhardt, Scott J. Rodig, Alex K. Shalek, Aviv Regev, Bruce E. Johnson, Nikhil Wagle, Gad Getz, Daniel L. Abravanel. Spatially-resolved single-cell transcriptome landscape of response and resistance to CDK4/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6605.

  PublisherDOI

• The membrane skeleton is constitutively remodeled in neurons by calcium signaling

  Science · 2025-08-07 · 6 citations

  articleOpen accessSenior authorCorresponding

  The membrane skeleton in neurons adopts a periodic lattice structure in which actin filaments, capped by adducin and tropomodulin, form ring-shaped structures connected by spectrin tetramers along neurites. This membrane-associated periodic skeleton (MPS) is important for many neuronal functions. Using live-cell super-resolution imaging, we found that the MPS is surprisingly dynamic, undergoing local disassembly and reformation constitutively in axons. MPS remodeling is driven by calcium signaling, leading to actin-ring destabilization through protein kinase C-mediated adducin phosphorylation and to spectrin degradation by calpain. Formin, an actin-nucleating and -polymerizing enzyme, plays a dual role in MPS remodeling and maintenance. MPS remodeling is enhanced by neuronal activity and functionally facilitates endocytosis. Our results highlight the importance of a dynamic membrane skeletal structure in neuronal function.

  PublisherDOI

• Molecular and Spatial Organization of the Primary Olfactory System and its Responses to Social Odors

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-02 · 5 citations

  preprintOpen access

  Abstract The detection of olfactory cues is essential to signal food, predators, and social encounters. To determine how the sensory detection of physiologically relevant odors is systematically mapped into the mouse primary olfactory system, we used Multiplexed Error Robust Fluorescent In Situ Hybridization (MERFISH) to construct a molecular atlas of odorant receptor (OR) expression in the main olfactory epithelium (MOE) and olfactory bulb (OB). We comprehensively quantified the expression of the mouse OR repertoire and uncovered stereotypical gradients of sensory neuron distribution in the MOE along two, central-to-peripheral and basal-to-apical, axes. Projections of sensory neurons mirror MOE gradients along the dorsal-ventral and anterior-posterior axes of the OB, respectively. Integration with sequencing data revealed candidate signaling molecules underlying this spatial organization. Co-imaging OR and activity marker expression identified distinct spatial domains of sensory responses in the MOE and OB, providing a topographical basis for olfactory responses to ethologically relevant odors.

  PublisherOA PDFDOI

• Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

  Cancer Cell · 2025-05-27 · 1 citations

  erratum
  PublisherDOI

• Author Correction: A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features

  Nature Medicine · 2025-03-28

  erratumOpen access
  PublisherOA PDFDOI

• Whole-transcriptome-scale and isoform-resolved spatial imaging of single cells in complex tissues

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-30 · 6 citations

  preprintOpen accessSenior authorCorresponding

  Cell and tissue functions arise from complex interactions among numerous genes, and a systematic understanding of these functions requires isoform-resolved, whole-transcriptome-scale analysis of single cells with high spatial resolution. Here, we introduce a spatial transcriptomics method based on a novel in situ RNA amplification strategy, enabling short RNA sequence detection and hence spatially resolved expression profiling of individual cells at the whole-transcriptome scale with splice-isoform resolution. Using this approach, we imaged ~33,000 distinct RNAs, including ~23,000 genes and ~10,000 isoform-defining transcripts, in the mouse brain. Our data enabled systematic analyses of region- and cell-type-specific gene programs and ligand-receptor-based cell-cell communications. These data further revealed a rich spatial diversity and cell-type specificity in isoform usage across numerous genes and identified brain structures particularly enriched for specific isoform usage. We anticipate broad application of this method for molecular and cellular analysis of tissues, unlocking previously inaccessible discoveries in cell and organismal biology.

  PublisherOA PDFDOI

Recent grants

• In situ transcriptome imaging in single cells

  NIH · $5.1M · 2016–2022

• Developmental origins of mental illness: evolution and reversibility

  NIH · $38.3M · 2011–2024

• Illuminating molecular mechanisms of cellular functions by single-molecule and super-resolution imaging

  NIH · $2.1M · 2017–2022

• NIH Grant R01GM105637

  NIH · $1.3M · 2018

• NIH Grant R01GM068518

  NIH · $2.9M · 2014

Frequent coauthors

• Hazen P. Babcock

  Harvard University

  76 shared

• Jeffrey R. Moffitt

  Boston VA Research Institute

  75 shared

• Cheng Zhu

  The Wallace H. Coulter Department of Biomedical Engineering

  49 shared

• Claus Seidel

  49 shared

• Peter Hinterdorfer

  Johannes Kepler University of Linz

  49 shared

• Nynke H. Dekker

  Delft University of Technology

  49 shared

• Daniel J. Müller

  ETH Zurich

  49 shared

• Sunney Xie

  49 shared

Labs

• Zhuang GroupPI

Education

• Chodorow Postdoctoral Fellow, Physics

  Stanford University

  2001

• PhD, Department of Physics

  University of California at Berkeley

  1996

Awards & honors

• Member of the National Academy of Sciences
• Fellow of the American Association for the Advancement of Sc…
• Fellow of the American Physical Society
• Howard Hughes Medical Institute Investigator