About

Karthik Shekhar is the John F. Heil, Jr. Professor in Chemical & Biomolecular Engineering at the University of California, Berkeley. He completed his B.S. and M.S. at the Indian Institute of Technology, Bombay in 2008, and earned his Ph.D. from the Massachusetts Institute of Technology in 2015. Following his doctoral studies, he was a Postdoctoral Fellow at the Broad Institute of MIT and Harvard from 2015 to 2019. His research focuses on cellular and systems biology, utilizing high-throughput single-cell genomic measurements to understand cellular diversity in complex tissues such as the mouse retina, and exploring their conservation across vertebrates including humans and non-human primates. He develops computational approaches rooted in machine learning to make precise biological inferences, aiming to reveal general mechanistic principles underlying cellular organization and molecular networks.

Research topics

• Pathology
• Biology
• Cancer research
• Psychology
• Medicine
• Immunology
• Neuroscience
• Genetics
• Cell biology

Selected publications

• Thickness effects in the electromechanical stability of charged biological membranes

  ArXiv.org · 2026-03-24

  articleOpen access

  Understanding how electric fields destabilize biological membranes is important for electroporation-based technologies and bioelectronic interfaces. However, theoretical descriptions of this phenomenon remain fragmented. Existing theories treat either electrostatics in membranes of finite thickness or electrohydrodynamic flows at idealized zero-thickness interfaces, leaving unresolved a unified description that simultaneously incorporates finite membrane thickness, surface charge, and bulk electrohydrodynamics. Here, we apply a recently-developed, dimension-reduction framework that captures the coupled electrohydrodynamic and mechanical effects governing height fluctuations of a charged lipid bilayer of thickness $δ$ in an electrolyte characterized by Debye screening length $λ$. We derive voltage- and charge-dependent renormalizations of the effective surface tension and bending rigidity, along with a dispersion relation governing undulatory instabilities. A wide range of prior theoretical results arise as limiting cases of our more general theory when finite-thickness effects are neglected or screening is asymptotically strong. The key new contribution arises from traction moments generated across the finite membrane thickness, which are absent in zero-thickness descriptions. Under physiological screening ($δ/λ\sim 4$), these contributions account for more than $>70\%$ of the total electrostatic correction to both surface tension and bending rigidity. The theory further reveals that surface charges can stabilize the membrane at physiological ionic strengths, increasing the effective tension and shifting electroporation thresholds in a manner that depends on charge asymmetry between the leaflets.

  PublisherOA PDF

• Sex-specific APOE4-dependent innate immunity regulates meningeal lymphatics, brain lipids, neuroinflammation, and cognition

  Neuron · 2026-03-01

  articleOpen access
  PublisherOA PDFDOI

• The Extreme Diversity Of Retinal Amacrine Cells Has Deep Evolutionary Roots

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-09 · 1 citations

  articleOpen accessSenior authorCorresponding

  Amacrine cells (ACs) comprise a heterogeneous class of inhibitory neurons in the vertebrate retina, exhibiting morphological and functional complexity rivaling that of cortical interneurons. Here, we integrate single-cell and single-nucleus transcriptomic atlases from 24 vertebrate species to reconstruct the evolutionary origins of this extreme diversity. We identify 42 orthologous AC types (oACs), most of which exhibit a one-to-one correspondence across amniotes and, in many cases, across vertebrates. While core molecular identities are conserved, AC types vary in abundance and gene expression across species, likely reflecting adaptations to distinct visual ecologies. AC diversity scales with that of retinal ganglion cells (RGCs), indicative of coevolution. Finally, we suggest that ACs arose from an AC-RGC hybrid precursor, with glycinergic ACs diverging early in vertebrate evolution, followed by a bifurcation between RGCs and GABAergic ACs. Together, these findings establish a unified evolutionary framework for understanding the diversity, development, and function of a class of inhibitory neurons across vertebrates.

  PublisherDOI

• Thickness effects in the electromechanical stability of charged biological membranes

  arXiv (Cornell University) · 2026-03-24

  preprintOpen access

  Understanding how electric fields destabilize biological membranes is important for electroporation-based technologies and bioelectronic interfaces. However, theoretical descriptions of this phenomenon remain fragmented. Existing theories treat either electrostatics in membranes of finite thickness or electrohydrodynamic flows at idealized zero-thickness interfaces, leaving unresolved a unified description that simultaneously incorporates finite membrane thickness, surface charge, and bulk electrohydrodynamics. Here, we apply a recently-developed, dimension-reduction framework that captures the coupled electrohydrodynamic and mechanical effects governing height fluctuations of a charged lipid bilayer of thickness $δ$ in an electrolyte characterized by Debye screening length $λ$. We derive voltage- and charge-dependent renormalizations of the effective surface tension and bending rigidity, along with a dispersion relation governing undulatory instabilities. A wide range of prior theoretical results arise as limiting cases of our more general theory when finite-thickness effects are neglected or screening is asymptotically strong. The key new contribution arises from traction moments generated across the finite membrane thickness, which are absent in zero-thickness descriptions. Under physiological screening ($δ/λ\sim 4$), these contributions account for more than $>70\%$ of the total electrostatic correction to both surface tension and bending rigidity. The theory further reveals that surface charges can stabilize the membrane at physiological ionic strengths, increasing the effective tension and shifting electroporation thresholds in a manner that depends on charge asymmetry between the leaflets.

  PublisherDOI

• Modeling neurodegeneration in the retina and strategies for developing pan-neurodegenerative therapies

  Molecular Neurodegeneration · 2025-10-14 · 3 citations

  reviewOpen access

  BACKGROUND: Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting "Solving Neurodegeneration," (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the creation of pan-neurodegenerative disease therapies. Since then, the fourth Catalyst for a Cure team (CFC4) was formed to explore commonalities between glaucoma and other neurodegenerative diseases. This review summarizes outcomes from the 2023 "Solving Neurodegeneration 2" meeting, a forum for CFC3 and CFC4 to share updates, problem solve, plan future research collaborations, and identify areas of unmet need or opportunity in glaucoma and the broader field of neurodegenerative disease research. MAIN BODY: We summarize the recent progress in the field of neurodegenerative disease research and present the newest challenges and opportunities moving forward. While translatability and disease complexity continue to pose major challenges, important progress has been made in identifying neuroprotective targets and understanding neuron-glia-vascular cell interactions. New challenges involve improving our understanding of the disease microenvironment and timeline, identifying the optimal approach(es) to neuronal replacement, and finding the best drug combinations and synergies for neuroprotection. We propose solutions to common research questions, provide prescriptive recommendations for future studies, and detail methodologies, strategies, and approaches for addressing major challenges at the forefront of neurodegenerative disease research. CONCLUSIONS: This review is intended to serve as a research framework, offering recommendations and approaches to validating neuroprotective targets, investigating rare cell types, performing cell-specific functional characterizations, leveraging novel adaptations of scRNAseq, and performing single-cell sorting and sequencing across neurodegenerative diseases and disease models. We focus on modeling neurodegeneration using glaucoma and other neurodegenerative pathologies to investigate the temporal and spatial dynamics of neurodegenerative disease pathogenesis, suggesting researchers aim to identify pan-neurodegenerative drug targets and drug combinations leverageable across neurodegenerative diseases.

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• Establishing a continuum of cell types in the visual cortex

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-22 · 1 citations

  preprintOpen access

  The mammalian cerebral cortex is composed of neurons whose properties vary in a continuous fashion rather than falling into discrete cell types. In the mouse visual cortex, excitatory neurons in layer 2 and 3 (L2/3) form such a continuum along cortical depth, patterned by the graded expression of hundreds of genes. Here we sought to understand how this continuum develops and contributes to cortical wiring. Using single-nucleus multiomics (RNA- and ATAC-Seq) and spatial transcriptomics, we show that the L2/3 continuum is established in two phases. During the first postnatal week, a genetically hardwired program establishes a primitive continuum of cell identities spanning the depth of L2/3. The second program, promoted by visual experience, is later superimposed upon the preexisting continuum. This second phase is driven by activity-regulated transcription factors that drive the L2/3 depth-dependent expression of genes linked to synaptic function and plasticity. We show that neurons at different positions along the L2/3 continuum project preferentially to distinct higher visual areas and that visual deprivation disrupts targeting to some higher visual areas while sparing others. Thus, cortical continua emerge through a stepwise process in which genetic programs and sensory experience specify neuronal identity and sculpt intracortical wiring specificity.

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• A Standardized Nomenclature for the Rods and Cones of the Vertebrate Retina

  Preprints.org · 2025-02-05 · 1 citations

  preprintOpen access

  We propose a standardized naming system for vertebrate visual photoreceptors (i.e., rods and cones) that reflects our current understanding of their evolutionary history. Vertebrate photoreceptors have been studied for well over a century, but a fixed nomenclature for referring to orthologous cell types across diverse species has been lacking. Instead, photoreceptors have been variably - and often confusingly - named according to morphology, presence/absence of ‘rhodopsin,’ spectral sensitivity, chromophore usage, and/or the gene family of the opsin(s) they express. Here, we propose a unified nomenclature for vertebrate rods and cones that aligns with the naming systems of other retinal cell classes and that is based on the photoreceptor’s putative ancestral derivation. This classification is informed by the functional, anatomical, developmental and molecular identities of the neuron as a whole, including the expression of deeply conserved transcription factors required for development. The proposed names will be applicable across all vertebrates and indicative of the widest-possible range of properties, including their postsynaptic wiring, and hence will allude to their common and species-specific roles in vision. Furthermore, the naming system is open-ended to accommodate the future discovery of as-yet unknown photoreceptor types.

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• Spatial profiling of the interplay between cell type- and vision-dependent transcriptomic programs in the visual cortex

  Proceedings of the National Academy of Sciences · 2025-02-13 · 8 citations

  articleOpen accessCorresponding

  How early sensory experience during “critical periods” of postnatal life affects the organization of the mammalian neocortex at the resolution of neuronal cell types is poorly understood. We previously reported that the functional and molecular profiles of layer 2/3 (L2/3) cell types in the primary visual cortex (V1) are vision-dependent [S. Cheng et al. , Cell 185 , 311–327.e24 (2022)]. Here, we characterize the spatial organization of L2/3 cell types with and without visual experience. Spatial transcriptomic profiling based on 500 genes recapitulates the zonation of L2/3 cell types along the pial–ventricular axis in V1. By applying multitasking theory, we suggest that the spatial zonation of L2/3 cell types is linked to the continuous nature of their gene expression profiles, which can be represented as a 2D manifold bounded by three archetypal cell types. By comparing normally reared and dark reared L2/3 cells, we show that visual deprivation-induced transcriptomic changes comprise two independent gene programs. The first, induced specifically in the visual cortex, includes immediate-early genes and genes associated with metabolic processes. It manifests as a change in cell state that is orthogonal to cell-type-specific gene expression programs. By contrast, the second program impacts L2/3 cell-type identity, regulating a subset of cell-type-specific genes and shifting the distribution of cells within the L2/3 cell-type manifold. Through an integrated analysis of spatial transcriptomics with single-nucleus RNA-seq data, we describe how vision patterns cortical L2/3 cell types during the critical period.

  PublisherOA PDFDOI

• A Standardized Nomenclature for the Rods and Cones of the Vertebrate Retina

  Preprints.org · 2025-02-20 · 1 citations

  preprintOpen access

  We propose a standardized naming system for vertebrate visual photoreceptors (i.e., rods and cones) that reflects our current understanding of their evolutionary history. Vertebrate photoreceptors have been studied for well over a century, but a fixed nomenclature for referring to orthologous cell types across diverse species has been lacking. Instead, photoreceptors have been variably - and often confusingly - named according to morphology, presence/absence of ‘rhodopsin,’ spectral sensitivity, chromophore usage, and/or the gene family of the opsin(s) they express. Here, we propose a unified nomenclature for vertebrate rods and cones that aligns with the naming systems of other retinal cell classes and that is based on the photoreceptor’s putative ancestral derivation. This classification is informed by the functional, anatomical, developmental and molecular identities of the neuron as a whole, including the expression of deeply conserved transcription factors required for development. The proposed names will be applicable across all vertebrates and indicative of the widest-possible range of properties, including their postsynaptic wiring, and hence will allude to their common and species-specific roles in vision. Furthermore, the naming system is open-ended to accommodate the future discovery of as-yet unknown photoreceptor types.

  PublisherOA PDFDOI

• Spatiotemporal dynamics of ionic reorganization near biological membrane interfaces

  Physical Review Research · 2025-02-21 · 10 citations

  articleOpen accessSenior author

  Electrical signals in excitable cells involve spatially localized ionic fluxes through ion channels and pumps on cellular lipid membranes. Common approaches to understand how these fluxes spread assume that the membrane and the surrounding electrolyte comprise an equivalent circuit of capacitors and resistors, which ignores the localized nature of transmembrane ion transport, the resulting ionic gradients and electric fields, and their spatiotemporal relaxation. Here, we consider a model of localized ion pumping across a lipid membrane, and use theory and simulation to investigate how the electrochemical signal propagates spatiotemporally in and out of plane along the membrane. The localized pumping generates long-ranged electric fields with three distinct scaling regimes along the membrane: a constant potential near-field region, an intermediate monopolar region, and a far-field dipolar region. Upon sustained pumping, the monopolar region expands radially in plane with a steady speed that is enhanced by the dielectric mismatch and the finite thickness of the lipid membrane. For unmyelinated lipid membranes in physiological settings, we find remarkably fast propagation speeds of <a:math xmlns:a="http://www.w3.org/1998/Math/MathML"><a:mrow><a:mo>∼</a:mo><a:mn>40</a:mn><a:mspace width="0.16em"/><a:mi mathvariant="normal">m</a:mi><a:mo>/</a:mo><a:mi mathvariant="normal">s</a:mi></a:mrow></a:math>, allowing faster ionic reorganization compared to bare diffusion. Together, our paper shows that transmembrane ionic fluxes induce transient long-ranged electric fields in electrolyte solutions, which may play hitherto unappreciated roles in biological signaling.

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Recent grants

• Uncovering the molecular identity of retinal cell types, and their responses to nerve injury using single-cell transcriptomics

  NIH · $740k · 2018–2023

• NIH Grant K99EY028625

  NIH · $215k · 2020

Frequent coauthors

• Aviv Regev

  Broad Institute

  109 shared

• Joshua R. Sanes

  Harvard University Press

  88 shared

• Salwan Butrus

  University of California, Berkeley

  75 shared

• Yvonne Kölsch

  Max Planck Institute of Neurobiology

  43 shared

• Yi-Rong Peng

  University of California, Los Angeles

  43 shared

• Arup K. Chakraborty

  Massachusetts Institute of Technology

  39 shared

• Semir Beyaz

  Cold Spring Harbor Laboratory

  37 shared

• Irene E. Whitney

  Harvard University

  36 shared

Education

• Postdoctoral Fellow, Cell Circuits and Epigenomics

  Broad Institute

  2019

Awards & honors

• 2023 McKnight Foundation Scholar Award
• 2023 The Donald Sterling Noyce Prize for Excellence in Under…
• 2023 The Dr. Douglas H Johnson Award (National Glaucoma Rese…
• 2023 Scialog Fellow, Microbiome, Neurobiology and Disease
• 2022 Society of Hellmann Fellows