About

Daniel A. Fletcher is the Principal Investigator and Department Chair holding the Purnendu Chatterjee Chair in Engineering Biological Systems in the Department of Bioengineering at UC Berkeley. He is also a Faculty Scientist at Lawrence Berkeley National Laboratory. The Fletcher Lab at UC Berkeley is a multi-disciplinary group of researchers who value creativity, diversity, and an adventurous approach to science. The lab embraces individuals with different scientific and personal experiences and aims to create an environment where everyone is supported to learn and explore, challenged to push the frontiers of knowledge, and launched into the next step of their career. The lab culture emphasizes teamwork and fun along the way.

Research topics

• Biology
• Biochemistry
• Chemistry
• Cell biology
• Biophysics
• Virology
• Molecular biology
• Medicine
• Computational biology
• Physics
• Chromatography
• Pathology
• Genetics

Selected publications

• BPS2026 – Messy eaters: Mechanisms of trogocytic membrane exchange in macrophages

  Biophysical Journal · 2026-02-01

  articleSenior author
  PublisherDOI

• Overcoming steric inhibition of antibody-dependent phagocytosis with tall adhesions

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-10

  articleOpen accessSenior authorCorresponding

  Macrophages recognize and phagocytose opsonized target cells, including those coated with IgG antibodies. This process relies on binding of IgG to Fcγ receptors (FcγR) expressed on the macrophage surface, resulting in formation of a phagocytic synapse. Since the surface of both macrophages and target cells are densely packed with macromolecules of diverse sizes, most of which are not directly involved in phagocytic signaling, it is possible for tall 'bystander' proteins to sterically interfere with FcγR engagement. Here, we use cell-like target particles to show that bystander proteins can inhibit phagocytosis by blocking synapse formation. We then demonstrate that adding a tall binding protein to the target particle can overcome inhibition by the crowded environment and substantially recover phagocytosis, a process we call kinetic enhancement. Using a cell-free system of giant unilamellar vesicles and synthetic binders, we demonstrate that kinetic enhancement is a tunable feature of interface formation that can determine whether short binders engage, and we present theory and computer simulations to explain the nonmonotonic dependence of phagocytosis on tall binding protein surface density. These findings point to a strategy for overcoming surface crowding on phagocytic targets by re-engineering transition states with tall adhesion proteins, one that could be used to promote short receptor binding at other cell-cell junctions. Significance Statement: Macrophages contribute to our immune defenses by phagocytosing pathogens and diseased cells. To accomplish this, they must first establish close contacts between receptors on their membranes and antibodies or other ligands decorating target cells. However, macrophage binding to the target can be disrupted by the presence of tall neighboring proteins and glycans-'bystander' molecules-that sterically prevent the two surfaces from coming into close contact. Counterintuitively, this inhibition can be overcome by the addition of even taller binding proteins between the macrophage and target cell, albeit at low concentrations. Using live cell and in vitro experiments, theory, and computer simulations, we show that tall binders can promote close contact that enables phagocytosis, even in the presence of bystander proteins that would normally block close contact.

  PublisherOA PDFDOI

• NTDscope: A multi-contrast portable microscope for disease diagnosis

  PLOS Global Public Health · 2026-02-12

  articleOpen accessSenior author

  Accurate diagnostics are essential for disease control and elimination efforts. However, access to diagnostics for neglected tropical diseases (NTDs) is hindered by limited healthcare infrastructure in many NTD-endemic regions, as well as by reliance on time- and labor-intensive diagnostic methods, such as smear microscopy. New diagnostic tools that are portable, rapid, low-cost, and meet World Health Organization (WHO) sensitivity and specificity targets are urgently needed to accelerate NTD control and elimination programs. Here, we introduce the NTDscope, a portable microscopy platform that enables point-of-care imaging and automated detection of parasites and other pathogens in patient samples. The NTDscope builds on and extends the capabilities of the LoaScope, a device that turned the camera of a mobile phone into a microscope and used on-board image processing to automatically quantify Loa loa microfilariae burden in whole blood samples. The NTDscope replaces the mobile phone of the LoaScope with a system-on-module (SOM) that enables the integration of multiple imaging modalities in a single package designed to improve robustness and expand applications. In this work, we demonstrate the use of the NTDscope as a portable brightfield, darkfield, and fluorescence microscope for samples including microfilariae and helminth eggs. We also show that the device can be used to quantify molecular assays, such as a lateral flow test and a CRISPR-Cas13a-based assay. The ability to combine the diagnostic capabilities of conventional microscopy with molecular assays and machine learning in a single device could expand access to diagnostics for populations in NTD-endemic areas and beyond.

  PublisherDOI

• From biting to engulfment: curvature–actin coupling controls phagocytosis of soft, deformable targets

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-30

  articleOpen access

  Phagocytosis is a fundamental process of the innate immune system, yet the physical determinants that govern the engulfment of soft, deformable targets remain poorly understood. Existing theoretical models typically approximate targets as rigid particles, overlooking the fact that both immune cells and many biological targets undergo significant membrane deformation during contact. Here, we develop a Monte Carlo–based membrane simulation framework to model the interactions of multiple vesicles, enabling us to explore phagocytosis-like processes in systems where both the phagocyte and the target possess flexible, thermally fluctuating membranes. We first validate our approach against established observations for the engulfment of rigid objects. We then investigate how the mechanical properties of a soft target—specifically membrane bending rigidity govern the outcome of phagocytic interactions. Our simulations reveal three distinct mechanical regimes: (i) biting or trogocytosis, in which the phagocyte extracts a portion of the target vesicle; (ii) pushing, where the target is displaced rather than engulfed; and (iii) full engulfment, in which the target is completely internalized. Increasing membrane tension via internal pressure produces analogous transitions, demonstrating a unified mechanical origin for these behaviours. Qualitative comparison with experiments involving Giant Unilamellar Vesicles (GUVs, deformable microparticles) and lymphoma cells supports the relevance of these regimes to biological phagocytosis. Together, these results highlight how target deformability fundamentally shapes phagocytic success and suggest that immune cells may exploit mechanical cues to recognize among different classes of soft targets. Significance statement Phagocytosis is essential for immune defence, yet the physical principles governing the engulfment of soft, deformable targets remain poorly understood. Most theoretical models assume rigid particles, even though real cells undergo substantial shape changes during contact. Here, we develop a theoretical membrane model to simulate interactions between multiple vesicles, enabling a mechanistic exploration of phagocytosis of soft targets. We show that target membrane rigidity dictates whether it is fully engulfed, pushed away, or partially bitten. These mechanically driven regimes explain experimental observations of immune cells engaging with both artificial GUVs and lymphoma cells.

  PublisherDOI

• BPS2026 – Cell surface crowding: A tunable regulator of immune cell interactions

  Biophysical Journal · 2026-02-01

  article1st authorCorresponding
  PublisherDOI

• BPS2026 – Beyond diffusion: How influenza A navigates complex glycan landscapes

  Biophysical Journal · 2026-02-01

  articleSenior author
  PublisherDOI

• From biting to engulfment: curvature-actin coupling controls phagocytosis of soft, deformable targets.

  PubMed · 2026-01-28

  article

  Phagocytosis is a fundamental process of the innate immune system, yet the physical determinants that govern the engulfment of soft, deformable targets remain poorly understood. Existing theoretical models typically approximate targets as rigid particles, overlooking the fact that both immune cells and many biological targets undergo significant membrane deformation during contact. Here, we develop a Monte Carlo-based membrane simulation framework to model the interactions of multiple vesicles, enabling us to explore phagocytosis-like processes in systems where both the phagocyte and the target possess flexible, thermally fluctuating membranes. We first validate our approach against established observations for the engulfment of rigid objects. We then investigate how the mechanical properties of a soft target-specifically membrane bending rigidity govern the outcome of phagocytic interactions. Our simulations reveal three distinct mechanical regimes: (i) biting or trogocytosis, in which the phagocyte extracts a portion of the target vesicle; (ii) pushing, where the target is displaced rather than engulfed; and (iii) full engulfment, in which the target is completely internalized. Increasing membrane tension via internal pressure produces analogous transitions, demonstrating a unified mechanical origin for these behaviours. Qualitative comparison with experiments involving Giant Unilamellar Vesicles (GUVs, deformable microparticles) and lymphoma cells supports the relevance of these regimes to biological phagocytosis. Together, these results highlight how target deformability fundamentally shapes phagocytic success and suggest that immune cells may exploit mechanical cues to recognize among different classes of soft targets.

  Publisher

• From biting to engulfment: curvature-actin coupling controls phagocytosis of soft, deformable targets

  ArXiv.org · 2026-01-28

  articleOpen access

  Phagocytosis is a fundamental process of the innate immune system, yet the physical determinants that govern the engulfment of soft, deformable targets remain poorly understood. Existing theoretical models typically approximate targets as rigid particles, overlooking the fact that both immune cells and many biological targets undergo significant membrane deformation during contact. Here, we develop a Monte Carlo-based membrane simulation framework to model the interactions of multiple vesicles, enabling us to explore phagocytosis-like processes in systems where both the phagocyte and the target possess flexible, thermally fluctuating membranes. We first validate our approach against established observations for the engulfment of rigid objects. We then investigate how the mechanical properties of a soft target -- specifically membrane bending rigidity govern the outcome of phagocytic interactions. Our simulations reveal three distinct mechanical regimes: (i) biting or trogocytosis, in which the phagocyte extracts a portion of the target vesicle; (ii) pushing, where the target is displaced rather than engulfed; and (iii) full engulfment, in which the target is completely internalized. Increasing membrane tension via internal pressure produces analogous transitions, demonstrating a unified mechanical origin for these behaviours. Qualitative comparison with experiments involving Giant Unilamellar Vesicles (GUVs, deformable microparticles) and lymphoma cells supports the relevance of these regimes to biological phagocytosis. Together, these results highlight how target deformability fundamentally shapes phagocytic success and suggest that immune cells may exploit mechanical cues to recognize among different classes of soft targets.

  PublisherOA PDF

• LUCas: Light-Uncaged Cas13a using photocleavable interfering guide RNAs

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-04 · 1 citations

  articleOpen accessSenior authorCorresponding

  Abstract CRISPR diagnostics have emerged as powerful tools for detecting infectious diseases, with the RNA endonuclease Cas13a enabling sensitive and specific, amplification-free RNA detection through collateral trans -cleavage of fluorescent reporters. However, background cleavage from unbound enzyme, contaminating nucleases, and unsynchronized initiation of reactions limits assay sensitivity and interpretability. A strategy to precisely control the onset of Cas13a catalytic activity, essentially a molecular “starting gun”, would address these challenges and expand assay design space. Here, we introduce Light-Uncaged Cas13a (LUCas), a light controllable system that directly gates Cas13a using a photocleavable interfering guide RNA (pc-igRNA) that suppresses trans -cleavage activity even in the presence of target RNA. Brief UV illumination releases this suppression, restoring full activity. Quantitative kinetic analysis reveals an approximately 100-fold suppression of trans -cleavage activity prior to photo-activation. Importantly, LUCas also suppresses target-independent background activity, enabling a predictive, background-limited determination of assay sensitivity. Using measured kinetic parameters, we predict and experimentally validate the limit-of-detection of the LUCas system. Finally, we demonstrate a multiplexed detection strategy termed “temporal barcoding,” which enables quantitative detection of viral co-infections in a single bulk reaction. Together, these results establish LUCas as a general framework for mechanistically informed, light-based control of Cas13a activity.

  PublisherOA PDFDOI

• From biting to engulfment: curvature-actin coupling controls phagocytosis of soft, deformable targets

  arXiv (Cornell University) · 2026-01-28

  preprintOpen access

  Phagocytosis is a fundamental process of the innate immune system, yet the physical determinants that govern the engulfment of soft, deformable targets remain poorly understood. Existing theoretical models typically approximate targets as rigid particles, overlooking the fact that both immune cells and many biological targets undergo significant membrane deformation during contact. Here, we develop a Monte Carlo-based membrane simulation framework to model the interactions of multiple vesicles, enabling us to explore phagocytosis-like processes in systems where both the phagocyte and the target possess flexible, thermally fluctuating membranes. We first validate our approach against established observations for the engulfment of rigid objects. We then investigate how the mechanical properties of a soft target -- specifically membrane bending rigidity govern the outcome of phagocytic interactions. Our simulations reveal three distinct mechanical regimes: (i) biting or trogocytosis, in which the phagocyte extracts a portion of the target vesicle; (ii) pushing, where the target is displaced rather than engulfed; and (iii) full engulfment, in which the target is completely internalized. Increasing membrane tension via internal pressure produces analogous transitions, demonstrating a unified mechanical origin for these behaviours. Qualitative comparison with experiments involving Giant Unilamellar Vesicles (GUVs, deformable microparticles) and lymphoma cells supports the relevance of these regimes to biological phagocytosis. Together, these results highlight how target deformability fundamentally shapes phagocytic success and suggest that immune cells may exploit mechanical cues to recognize among different classes of soft targets.

  PublisherDOI

Recent grants

• NIH Grant R01GM074751

  NIH · $2.4M · 2016

• Mechanical regulation of actin binding proteins

  NIH · $1.5M · 2019–2024

• NIH Grant R01GM072736

  NIH · $1.2M · 2011

• CAREER: Biomechanics of Polymerization Motors and Cell Motility

  NSF · $400k · 2004–2009

• NIH Grant R01GM114671

  NIH · $1.4M · 2020

Frequent coauthors

• Jennifer A. Doudna

  University of California, Berkeley

  118 shared

• Sungmin Son

  University of California, Berkeley

  110 shared

• Gavin J. Knott

  Monash University

  77 shared

• Ka Man Carmen Chan

  City University of Hong Kong

  69 shared

• Eva M. Schmid

  University of California, Berkeley

  65 shared

• Tai‐De Li

  65 shared

• Andrew R. Harris

  Carleton University

  62 shared

• Peter Bieling

  Max Planck Institute of Molecular Physiology

  54 shared

Labs

• Fletcher LabPI

  The Fletcher Lab is made up of a talented, interactive, and multi-disciplinary group of researchers who value creativity, diversity, and an adventurous approach to science.

Education

• Postdoctoral Fellow, Biochemistry

  Stanford University Medical Center

• PhD, Mechanical Engineering

  Stanford University

• B.S., Mechanical & Aerospace Engineering

  Princeton University

• D.Phil., Engineering Science

  University of Oxford