About

David V. Schaffer is the Hubbard Howe Jr. Distinguished Professor of Biochemical Engineering in the Department of Chemical and Biomolecular Engineering at the University of California, Berkeley. He holds a B.S. degree from Stanford University (1993) and a Ph.D. from the Massachusetts Institute of Technology (1998). His research program employs molecular and cellular engineering approaches to investigate biomedical problems, with particular interest in gene therapy and stem cell biology, focusing on applications to therapies for diseases of the nervous system. Dr. Schaffer has received numerous awards and honors, including the Lindsey Lectureship at Texas A&M, the Eagleson Award from the American Biological Safety Association, and the NSF CAREER Award, among others. He is recognized for advancing society through education and research in biomedical engineering.

Research topics

• Genetics
• Biology
• Computer Science
• Neuroscience
• Medicine
• Artificial Intelligence
• Bioinformatics
• Algorithm
• Cancer research
• Virology
• Computational biology
• Evolutionary biology

Selected publications

• TBK1-NQO1 negative feedback loop regulates antiviral innate immunity

  Cell Communication and Signaling · 2026-03-31

  articleOpen access

  TANK-binding kinase 1 (TBK1) is an essential kinase that phosphorylates transcriptional factors, which induce antiviral interferons and inflammatory cytokines against viral infection. Tight regulation of TBK1 is critical for innate immune responses and maintenance of homeostasis. Here, we report that NAD(P)H: quinone-oxidoreductase-1 (NQO1) forms a negative feedback loop with TBK1 to regulate innate antiviral immune responses. At the late time stages of virus infection, NQO1 specifically interacts with TBK1 and is phosphorylated at S82 of NQOI by TBK1. Interestingly, S82-phosphorylated NQO1 interferes with the self-association and phosphorylation of TBK1, resulting in reduced type I IFN signaling cascades. Depletion or reduced expression of NQO1 increases secretion of antiviral cytokines and resultes in less viral replication. In particular, NQO1−/− mice are more resistant to viral infection due to the enhanced secretion of antiviral cytokines. Taken together, these finding provide new insight into the molecular regulation of NQOI and TBK1 and suggest a critical role for NQOI in the homeostatic control of antiviral response and innate immune responses.

  PublisherDOI

• Optogenetic WNT signaling drives germ layer self-organization in a human gastruloid model

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-25

  articleOpen accessSenior authorCorresponding

  stem cell models of human gastrulation have been an advance for developmental biology, though elucidating mechanisms of germ layer formation remains challenging. While investigating whether spatially-patterned signaling is required for germ layer formation, we tested a "salt-and-pepper" signaling strategy in which WNT was optogenetically activated in a subset of human pluripotent stem cells (hPSC) uniformly mixed into an aggregate. Following mesendodermal specification, WNT-activated cells spatially segregated into a hemisphere, then underwent further differentiation and organization into mesoderm and endoderm. RNAseq-based lineage analysis revealed that WNT activation non-autonomously induced TGFβ/BMP signaling, leading to robust emergence of an anterior visceral endoderm-like population that patterned adjacent neural and mesendodermal fates. Transcriptional profiles and trajectories closely mirrored those observed during human gastrulation. Moreover, TGFβ or cadherin perturbation disrupted germ layer formation or spatial organization, respectively. This simple model thus enables mechanistic dissection of complex human lineage specifications and organization during gastrulation.

  PublisherOA PDFDOI

• Directed evolution of novel AAV capsids for enhanced delivery to mouse and human Schwann cells

  Molecular Therapy — Nucleic Acids · 2026-04-03

  articleOpen accessSenior author

  studies of mouse-tropic capsids confirmed higher selectivity, improved packaging titers, and decreased localization to the liver. These engineered AAVs are valuable tools for studying Schwann cells and offer new avenues for the treatment of peripheral nerve disorders.

  PublisherDOI

• X-Space MPI: Magnetic Nanoparticles for Safe Medical Imaging

  2026-01-19

  book-chapter

  One quarter of all iodinated contrast X-ray clinical imaging studies are now performed on Chronic Kidney Disease (CKD) patients. Unfortunately, the iodine contrast agent used in X-ray is often toxic to CKD patients’ weak kidneys, leading to significant morbidity and mortality. Hence, we are pioneering a new medical imaging method, called Magnetic Particle Imaging (MPI), to replace X-ray and CT iodinated angiography, especially for CKD patients. MPI uses magnetic nanoparticle contrast agents that are much safer than iodine for CKD patients. MPI already offers superb contrast and extraordinary sensitivity. The iron oxide nanoparticle tracers required for MPI are also used in MRI, and some are already approved for human use, but the contrast agents are far more effective at illuminating blood vessels when used in the MPI modality. We have recently developed a systems theoretic framework for MPI called x-space MPI, which has already dramatically improved the speed and robustness of MPI image reconstruction. X-space MPI has allowed us to optimize the hardware for five MPI scanners. Moreover, x-space MPI provides a powerful framework for optimizing the size and magnetic properties of the iron oxide nanoparticle tracers used in MPI. Currently MPI nanoparticles have diameters in the 10–20 nanometer range, enabling millimeter-scale resolution in small animals. X-space MPI theory predicts that larger nanoparticles could enable up to 250 micrometer resolution imaging, which would represent a major breakthrough in safe imaging for CKD patients.

  PublisherDOI

• Ocular Delivery of Viral Vectors for Retinal and Choroidal Vascular Diseases: A Review

  American Journal of Ophthalmology · 2025-07-28 · 3 citations

  reviewSenior author
  PublisherDOI

• Hydrogel fabrication techniques for advanced artificial sensory systems

  International Journal of Extreme Manufacturing · 2025-06-26 · 6 citations

  articleOpen access

  Abstract Artificial sensory systems, designed to emulate human senses like sight, touch, and hearing, have garnered significant attention for their potential to enhance human capabilities, improve human-machine interactions, and enable autonomous systems to better perceive their surroundings. Hydrogels, with their biocompatibility, flexibility, and water-rich polymer structure, are increasingly recognized as crucial materials in the development of these systems, especially in applications such as wearable sensors, artificial skin, and neural interfaces. This review explores various hydrogel fabrication techniques, including 3D bioprinting, electrospinning, and photopolymerization, which allow for the precise control of hydrogel properties like mechanical strength, flexibility, and conductivity. By tailoring these properties to mimic natural tissues, hydrogels offer transformative benefits in the creation of advanced, biocompatible, and durable sensory systems. We emphasize the importance of selecting appropriate fabrication methods to meet the specific functional requirements of artificial sensory applications, such as sensitivity to stimuli, durability, and ease of integration. This review further highlights the pivotal role of hydrogels in advancing future artificial sensory technologies and their broad potential in fields ranging from robotics to biomedical devices.

  PublisherDOI

• The Application of DNA Viruses to Biotechnology

  Viruses · 2025-03-14 · 1 citations

  reviewOpen accessSenior author

  The delivery of biomolecules to target cells has been a longstanding challenge in biotechnology. DNA viruses naturally evolved the ability to deliver genetic material to cells and modulate cellular processes. As such, they inherently possess requisite characteristics that have led to their extensive study, engineering, and development as biotechnological tools. Here, we overview the application of DNA viruses to biotechnology, with specific implications in basic research, health, biomanufacturing, and agriculture. For each application, we review how an increasing understanding of virology and technological methods to genetically manipulate DNA viruses has enabled advances in these fields. Additionally, we highlight the remaining challenges to unlocking the full biotechnological potential of DNA viral technologies. Finally, we discuss the importance of balancing continued technological progress with ethical and biosafety considerations.

  PublisherOA PDFDOI

• Nickase fidelity drives EvolvR-mediated diversification in mammalian cells

  Nature Communications · 2025-04-19 · 5 citations

  articleOpen access

  In vivo genetic diversifiers have previously enabled efficient searches of genetic variant fitness landscapes for continuous directed evolution. However, existing genomic diversification modalities for mammalian genomic loci exclusively rely on deaminases to generate transition mutations within target loci, forfeiting access to most missense mutations. Here, we engineer CRISPR-guided error-prone DNA polymerases (EvolvR) to diversify all four nucleotides within genomic loci in mammalian cells. We demonstrate that EvolvR generates both transition and transversion mutations throughout a mutation window of at least 40 bp and implement EvolvR to evolve previously unreported drug-resistant MAP2K1 variants via substitutions not achievable with deaminases. Moreover, we discover that the nickase's mismatch tolerance limits EvolvR's mutation window and substitution biases in a gRNA-specific fashion. To compensate for gRNA-to-gRNA variability in mutagenesis, we maximize the number of gRNA target sequences by incorporating a PAM-flexible nickase into EvolvR. Finally, we find a strong correlation between predicted free energy changes underlying R-loop formation and EvolvR's performance using a given gRNA. The EvolvR system diversifies all four nucleotides to enable the evolution of mammalian cells, while nuclease and gRNA-specific properties underlying nickase fidelity can be engineered to further enhance EvolvR's mutation rates.

  PublisherOA PDFDOI

• Advances in AAV capsid engineering: Integrating rational design, directed evolution and machine learning

  Molecular Therapy · 2025-04-02 · 45 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

• Design and Characterization of 4D-710, an Aerosolized Gene Therapy for Cystic Fibrosis Lung Disease

  American Journal of Respiratory Cell and Molecular Biology · 2025-10-22 · 3 citations

  article

  Abstract Cystic fibrosis (CF) is an autosomal recessive disease caused by variants in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Delivery of a functional CFTR transgene to airway epithelial cells (AEC) offers the potential to provide durable restoration of normal CFTR function. Adeno-associated virus (AAV) vectors are the leading platform for the delivery of in vivo gene therapy; however, wild-type AAV vectors exhibit a limited capacity to transduce airway cells and evade pre-existing human neutralizing antibodies (NAb). We therefore employed a directed evolution platform to invent a novel AAV capsid (A101) with the capacity to efficiently transduce AECs, including in the presence of NAbs, following aerosolized administration to nonhuman primates (NHP). We then engineered 4D-710, a gene therapy comprising the A101 vector and a CFTR transgene with a partial deletion in the regulatory domain (CFTRΔR) to facilitate vector packaging. 4D-710 exhibited efficient transduction of human bronchial epithelial (HBE) cell air–liquid interface (ALI) cultures in vitro and robust functional activity in CF HBE ALI cultures. Aerosolized administration of 4D-710 to NHPs was well tolerated and resulted in dose-dependent transgene expression and increased CFTR protein in diverse AEC types compared to vehicle controls. No significant differences in CFTRΔR mRNA levels were observed in lung samples from NHPs with pre-existing serum anti-capsid NAbs compared to NAb-negative NHPs. These findings demonstrate the tolerability and feasibility of A101-mediated transgene delivery and expression in primate airways. A clinical trial evaluating aerosol delivery of 4D-710 in adults with CF (NCT05248230) is underway.

  PublisherDOI

Recent grants

• NIH Grant R21DE018044

  NIH · $382k · 2011

• NIH Grant R21EY016994

  NIH · $396k · 2009

• Mechanisms of Neural Stem Cell Mechanoregulation

  NIH · $5.3M · 2012–2027

• NIH Grant R01ES020903

  NIH · $2.0M · 2017

• NIH Grant R21EB003007

  NIH · $344k · 2006

Frequent coauthors

• Sanjay Kumar

  University of California, Berkeley

  71 shared

• Adam P. Arkin

  University of California, Berkeley

  65 shared

• John G. Flannery

  53 shared

• Ravi S. Kane

  Georgia Institute of Technology

  46 shared

• Deniz Dalkara

  Inserm

  37 shared

• Kevin E. Healy

  32 shared

• Tomasz J. Nowakowski

  University of California, San Francisco

  27 shared

• Hyun‐Cheol Lee

  26 shared

Education

• PhD, Chemical Engineering

  Massachusetts Institute of Technology

  1998

• BS, Chemical Engineering

  Stanford University

  1993

Awards & honors

• Distinguished Lindsey Lectureship, Texas A&M (2012)
• Eagleson Award, American Biological Safety Association (2012…
• Fellow, American Institute for Medical and Biological Engine…
• Robert W. Vaughan Lectureship, California Institute of Techn…
• American Chemical Society BIOT Division Young Investigator A…