Zev J. Gartner

University of California, San Francisco

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Christopher S. McGinnis

University of California, San Francisco

Adam R. Abate

Massachusetts Institute of Technology

Vasudha Srivastava

University of California, San Francisco

Eric D. Chow

University of California, San Francisco

David M. Patterson

University of California, San Francisco

David R. Liu

Harvard University

Lyndsay M. Murrow

University of California, San Francisco

Justin Farlow

University of California, San Francisco

Jonathan S. Weissman

Howard Hughes Medical Institute

Daeha Seo

Daegu Gyeongbuk Institute of Science and Technology

Cooperative Institutions

University of California, San Francisco

277

University of California, Berkeley

Howard Hughes Medical Institute

Harvard University

Stanford University

Massachusetts Institute of Technology

UCSF Helen Diller Family Comprehensive Cancer Center

Chan Zuckerberg Initiative (United States)

University of California System

Lawrence Berkeley National Laboratory

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Abseq: Ultrahigh-throughput single cell protein profiling with droplet microfluidic barcoding

Scientific Reports (2017)

Payam Shahi Samuel Kim John Haliburton Zev J. Gartner Adam R. Abate

Abstract Proteins are the primary effectors of cellular function, including cellular metabolism, structural dynamics, and information processing. However, quantitative characterization of proteins at the single-cell level is challenging due to the tiny amount of protein available. Here, we present Abseq, a method to detect and quantitate proteins in single cells at ultrahigh throughput. Like flow and mass cytometry, Abseq uses specific antibodies to detect epitopes of interest; however, unlike these methods, antibodies are labeled with sequence tags that can be read out with microfluidic barcoding and DNA sequencing. We demonstrate this novel approach by characterizing surface proteins of different cell types at the single-cell level and distinguishing between the cells by their protein expression profiles. DNA-tagged antibodies provide multiple advantages for profiling proteins in single cells, including the ability to amplify low-abundance tags to make them detectable with sequencing, to use molecular indices for quantitative results, and essentially limitless multiplexing.

Mass cytometry

10.1038/srep44447

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Citations (263)

Multistep Small-Molecule Synthesis Programmed by DNA Templates

Journal of the American Chemical Society (2002)

Zev J. Gartner Matthew W. Kanan David R. Liu

The translation of DNA sequences into synthetic products is a key requirement of our approach to evolving synthetic molecules through iterated cycles of translation, selection, and amplification. Here we report general linker and purification strategies for sequence-specific DNA-templated synthesis that collectively enable the product of a DNA-templated reaction to be isolated and to undergo subsequent DNA-templated reactions. Using these strategies, we have achieved the first multistep nucleic acid-templated small-molecule syntheses to generate two different molecules. In addition to representing a method for translating DNA templates sequence-specifically into corresponding multistep synthetic products, our findings also provide experimental support for previously proposed models invoking multistep nucleic acid-templated synthesis as mediating the prebiotic translation of replicable information into the earliest functional molecules.

Template

Linker

Sequence (biology)

10.1021/ja027307d

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Citations (156)

Multicolor Fluorescence Detection for Droplet Microfluidics Using Optical Fibers

Journal of Visualized Experiments (2016)

Russell H. Cole Zev J. Gartner Adam R. Abate

Fluorescence assays are the most common readouts used in droplet microfluidics due to their bright signals and fast time response. Applications such as multiplex assays, enzyme evolution, and molecular biology enhanced cell sorting require the detection of two or more colors of fluorescence. Standard multicolor detection systems that couple free space lasers to epifluorescence microscopes are bulky, expensive, and difficult to maintain. In this paper, we describe a scheme to perform multicolor detection by exciting discrete regions of a microfluidic channel with lasers coupled to optical fibers. Emitted light is collected by an optical fiber coupled to a single photodetector. Because the excitation occurs at different spatial locations, the identity of emitted light can be encoded as a temporal shift, eliminating the need for more complicated light filtering schemes. The system has been used to detect droplet populations containing four unique combinations of dyes and to detect sub-nanomolar concentrations of fluorescein.

Multiplex

10.3791/54010-v

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Citations (0)

Reducing batch effects in single cell chromatin accessibility measurements by pooled transposition with MULTI-ATAC

bioRxiv (Cold Spring Harbor Laboratory) (2025)

Daniel N. Conrad Kiet T. Phong Ekaterina Korotkevich Christopher S. McGinnis Qin Zhu

Large-scale scATAC-seq experiments are challenging because of their costs, lengthy protocols, and confounding batch effects. Several sample multiplexing technologies aim to address these challenges, but do not remove batch effects introduced when performing transposition reactions in parallel. We demonstrate that sample-to-sample variability in nuclei-to-Tn5 ratios is a major cause of batch effects and develop MULTI-ATAC, a multiplexing method that pools samples prior to transposition, as a solution. MULTI-ATAC provides high accuracy in sample classification and doublet detection while eliminating batch effects associated with variable nucleus-to-Tn5 ratio. We illustrate the power of MULTI-ATAC by performing a 96-plex multiomic drug assay targeting epigenetic remodelers in a model of primary immune cell activation, uncovering tens of thousands of drug-responsive chromatin regions, cell-type specific effects, and potent differences between matched inhibitors and degraders. MULTI-ATAC therefore enables batch-free and scalable scATAC-seq workflows, providing deeper insights into complex biological processes and potential therapeutic targets.

Transposition (logic)

10.1101/2025.02.14.638353

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Paracrine costimulation of IFN-γ signaling by integrins modulates CD8 T cell differentiation

Proceedings of the National Academy of Sciences (2018)

Matthew F. Krummel Jagdish N. Mahale Lion F. K. Uhl Emily A. Hardison Adriana M. Mujal

The cytokine IFN-γ is a critical regulator of immune system development and function. Almost all leukocytes express the receptor for IFN-γ, yet each cell type elicits a different response to this cytokine. Cell type-specific effects of IFN-γ make it difficult to predict the outcomes of the systemic IFN-γ blockade and limit its clinical application, despite many years of research. To better understand the cell-cell interactions and cofactors that specify IFN-γ functions, we focused on the function of IFN-γ on CD8 T cell differentiation. We demonstrated that during bacterial infection, IFN-γ is a dominant paracrine trigger that skews CD8 T cell differentiation toward memory. This skewing is preferentially driven by contact-dependent T cell-T cell (T-T) interactions and the localized IFN-γ secretion among activated CD8 T cells in a unique splenic microenvironment, and is less sensitive to concurrent IFN-γ production by other immune cell populations such as natural killer (NK) cells. Modulation of CD8 T cell differentiation by IFN-γ relies on a nonconventional IFN-γ outcome that occurs specifically within 24 hours following infection. This is driven by IFN-γ costimulation by integrins at T-T synapses, and leads to synergistic phosphorylation of the proximal STAT1 molecule and accelerated IL-2 receptor down-regulation. This study provides evidence of the importance of context-dependent cytokine signaling and gives another example of how cell clusters and the microenvironment drive unique biology.

10.1073/pnas.1804556115

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Citations (57)

Patterning and folding of intestinal villi by active mesenchymal dewetting

Cell (2024)

Tyler R. Huycke Teemu J. Häkkinen Hikaru Miyazaki Vasudha Srivastava Emilie Barruet

Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi, finger-like protrusions that enable nutrient absorption. However, the molecular and mechanical processes driving villus morphogenesis remain unclear. Here, we identify an active mechanical mechanism that simultaneously patterns and folds the intestinal epithelium to initiate villus formation. At the cellular level, we find that PDGFRA+ subepithelial mesenchymal cells generate myosin II-dependent forces sufficient to produce patterned curvature in neighboring tissue interfaces. This symmetry-breaking process requires altered cell and extracellular matrix interactions that are enabled by matrix metalloproteinase-mediated tissue fluidization. Computational models, together with in vitro and in vivo experiments, revealed that these cellular features manifest at the tissue level as differences in interfacial tensions that promote mesenchymal aggregation and interface bending through a process analogous to the active dewetting of a thin liquid film.

Dewetting

10.1016/j.cell.2024.04.039

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Citations (20)

T cell circuits that sense antigen density with an ultrasensitive threshold

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Rogelio A. Hernández‐López Wei Yu Katie Cabral Olivia Creasey Maria del Pilar Lopez Pazmino

Abstract Overexpressed tumor associated antigens (e.g. HER2 and EGFR) are attractive targets for therapeutic T cells, but toxic cross-reaction with normal tissues expressing low antigen levels has been observed with Chimeric Antigen Receptor (CAR) T cells targeting such antigens. Inspired by natural ultrasensitive response circuits, we engineer a two-step positive feedback circuit that allows T cells to discriminate targets based on a sigmoidal antigen density threshold. In this circuit, a low affinity SynNotch receptor for HER2 controls the expression of a high affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells ╌ it both increases CAR expression and activation ╌ leading to a sigmoidal response. T Cells with this circuit show sharp discrimination between target cells expressing normal and disease levels of HER2, both in vitro and in vivo . One Sentence Summary A two-step positive feedback circuit generates engineered T cells capable of killing target cells with an ultrasensitive antigen density threshold.

10.1101/2021.01.21.427654

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Citations (5)

Non-autonomous cell proliferation in the mammary gland and cancer

Current Opinion in Cell Biology (2017)

Robert J. Weber Tejal A. Desai Zev J. Gartner

10.1016/j.ceb.2017.02.009

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Citations (11)

Dissecting the stem cell niche with organoid models: an engineering-based approach

Development (2017)

Lyndsay M. Murrow Robert J. Weber Zev J. Gartner

ABSTRACT For many tissues, single resident stem cells grown in vitro under appropriate three-dimensional conditions can produce outgrowths known as organoids. These tissues recapitulate much of the cell composition and architecture of the in vivo organ from which they derive, including the formation of a stem cell niche. This has facilitated the systematic experimental manipulation and single-cell, high-throughput imaging of stem cells within their respective niches. Furthermore, emerging technologies now make it possible to engineer organoids from purified cellular and extracellular components to directly model and test stem cell-niche interactions. In this Review, we discuss how organoids have been used to identify and characterize stem cell-niche interactions and uncover new niche components, focusing on three adult-derived organoid systems. We also describe new approaches to reconstitute organoids from purified cellular components, and discuss how this technology can help to address fundamental questions about the adult stem cell niche.

Organoid

Stem cell niche

10.1242/dev.140905

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Citations (73)

Human organoids: a new dimension in cell biology

Molecular Biology of the Cell (2019)

Ruth Lehmann Connie M. Lee Erika Shugart Marta Benedetti R. Alta Charo

Organoids derived from stem cells or tissues in culture can develop into structures that resemble the in vivo anatomy and physiology of intact organs. Human organoid cultures provide the potential to study human development and model disease processes with the same scrutiny and depth of analysis customary for research with nonhuman model organisms. Resembling the complexity of the actual tissue or organ, patient-derived human organoid studies may accelerate medical research, creating new opportunities for tissue engineering and regenerative medicine, generating knowledge and tools for preclinical studies, including drug development and testing. Biologists are drawn to this system as a new "model organism" to study complex disease phenotypes and genetic variability among individuals using patient-derived tissues. The American Society for Cell Biology convened a task force to report on the potential, challenges, and limitations for human organoid research. The task force suggests ways to ease the entry for new researchers into the field and how to facilitate broader use of this new model organism within the research community. This includes guidelines for reproducibility, culturing, sharing of patient materials, patient consent, training, and communication with the public.

Organoid

Model Organism

Scrutiny

Regenerative Medicine

Human disease

Human cell

10.1091/mbc.e19-03-0135

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Citations (111)