About

We conduct research in three major areas: DNA-Templated Synthesis, Protein Evolution & Delivery, and Genome Editing. These areas focus on creatively integrating chemistry and evolution to illuminate biology and enable new therapeutics.

Research topics

• Computer Science
• Medicine
• Pathology
• Computational biology
• Biology
• Genetics
• World Wide Web

Selected publications

• Cutting Edge Access: Needle Knife Fistulotomy for Difficult Biliary Cannulation

  Current Gastroenterology Reports · 2026-03-09

  articleOpen access

  PURPOSE OF REVIEW: Endoscopic retrograde cholangiopancreatography is an advanced endoscopic procedure used mainly for the purpose of biliary intervention. During an ERCP a duodenoscope is used to assess the ampulla of Vater to inject contrast medium into the common bile duct through biliary cannulation. Biliary cannulation can be challenging, with studies showing unsuccessful biliary cannulation with standard technique greater than 10%. Needle-knife fistulotomy is a unique precut sphincterotomy technique that can assist with difficult biliary cannulation. REVIEW OF FINDINGS: Needle-knife fistulotomy has transitioned from a "last-ditch" technique to sometimes a primary approach in select patient populations by endoscopists. The major impetus for this change is due to consistent results showing a lower risk of post-ERCP pancreatitis compared to other pre-cut methods. This review article will go in-depth on the technique of needle-knife fistulotomy, the benefits and suspected complications of needle-knife fistulotomy compared to traditional sphincterotomy techniques and the evolution of NKF as a first-choice option for biliary cannulation.

  PublisherOA PDFDOI

• [Dynamic distribution and clearance of ^99mTc-DTPA in brain extracellular space].

  PubMed · 2025-06-18

  article

  OBJECTIVE: Tc-DTPA) in different brain regions of adult rats after administration through brain extracellular space (ECS) pathway. METHODS: . They were put to death 4 h later. Their blood and urine were collected. The brain, cerebellum, heart, liver, spleen, lung, and kidney were taken and weighed by γ counter to measure its radioactivity. RESULTS: Tc-DTPA was administered through brain ECS, the radioactivity was concentrated in the brain, kidney and bladder. The tracer administered to the left caudate nucleus was preferentially drained to the right cerebellum, while the tracer administered to the right caudate nucleus was preferentially drained to the left cerebellum. There was a phenomenon of "contralateral cerebellar dominant drainage" in the caudate nucleus. The thalamic area preferentially drained to the ipsilateral cerebellum after administration. Four hours after administration via ECS, high radioactive uptake appeared in urine, cerebellum and brain, followed by blood and kidney. The radioactive uptake values of heart, liver, spleen and lung were low, which were mainly excreted through urinary system. CONCLUSION: Intracerebral ECS administration is a promising method of administration, but there are significant differences in distribution and clearance in different brain regions. This study further expands the content and significance of "ECS regions", and also provides an important theoretical foundation for the treatment of encephalopathy and the research of new drugs through brain ECS in the future.

  Publisher

• Ultrasmall Chemogenetic Tags with Group‐Transfer Ligands

  Angewandte Chemie · 2025-09-27

  article

  Abstract Chemogenetic tags facilitate exploration of activities of a protein‐of‐interest (POI) that lacks small‐molecule ligands; however, most tags are too large for several POIs. Here, we report two ultrasmall chemogenetic tags (mgTag and cTag) of 36 and 50 amino acids (aa) that, to the best of our knowledge, are the smallest. These tags exhibit transferase ‐type reactivity with their ligands, allowing the attachment of any moiety‐of‐interest to the tag. cTag utilizes an engineered C1 domain‐bearing cysteine that undergoes a group‐transfer reaction with its ligand. Likewise, mgTag utilizes an engineered zinc‐finger domain‐bearing cysteine that undergoes a group‐transfer reaction with its molecular glue ligand in the presence of cereblon (CRBN). While the fusion of HaloTag (297 aa) or SNAPTag (182 aa) to the KRAS G12D (188 aa) disrupted its growth‐signaling pathway, fusion of mgTag or cTag did not, pointing to the importance of tag size. Group‐transfer of BRD4 binder to tags appended to Abelson kinase (ABL) induced proximity between ABL and BRD4, resulting in the latter's phosphorylation. Deletion of the transferase ‐type reactivity reduced phosphorylation levels, suggesting that proximity‐inducing chimeras with group‐transfer design may be more efficacious. We envision these ultrasmall tags to have wide‐ranging applications, including in basic science, biotechnology, and medicine.

  PublisherDOI

• Virus-like particles enable targeted gene engineering and pooled CRISPR screening in primary human myeloid cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-14 · 4 citations

  preprintOpen access

  Primary human myeloid cells are promising candidates for immunotherapy, yet efficient and scalable technologies for genetic engineering and screening in these cells are limited. Here we present a virus-like particle (VLP)-based toolkit that delivers diverse CRISPR genome editing modalities to human monocytes, macrophages, and dendritic cells with high efficiency while preserving viability and innate immune responsiveness. VLP-mediated delivery of ribonucleoprotein payloads supports gene knockout, base editing and epigenetic silencing, and enables site-specific integration of large DNA sequences when combined with AAV donors for homology-directed repair. Leveraging sgRNA delivery via VPX-lentivirus combined with Cas9 protein delivery via engineered virus-like particle (eVLP) treatment ("SLICeVLP"), we performed the first pooled loss-of-function screens in human macrophages. We uncovered regulators of TNF production and CD80 expression in human macrophages, converging on TNFAIP3 as a central regulator of inflammatory polarization. TNFAIP3 ablation promoted a pro-inflammatory cell state that is resistant to suppressive polarization, and augmented cytotoxicity of engineered HER2 CAR-macrophages. Taken together, this technology platform enables unbiased discovery and characterization of functional gene targets in primary human myeloid cells.

  PublisherOA PDFDOI

• YAP1 drives aggressive and therapy resistant state in melanoma through reprogramming the chromatin and regulating immune evasive programs

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-15

  preprintOpen access

  Despite promising initial results in targeting the RAF-MEK-ERK cascade, resistance to BRAF/MEK inhibitors remains a critical challenge in nearly 50% of melanoma patients. Our study demonstrates that robust YAP1 activation in metastatic melanoma correlates with poor survival and drives transcriptional programs linked to therapeutic resistance. Mechanistically, YAP1 predominantly remodels the chromatin landscape in resistant tumors by partnering with BRD4 and TEAD, creating a permissive transcriptional state that sustains oncogenic signaling. Clinical validation in biopsies from resistant melanoma confirms elevated expression of YAP1 target genes. Furthermore, pharmacological inhibition of BRD4 or TEAD reduces YAP1-driven transcription and reactivates antitumor immunity programs. TEAD specific inhibitors (and not verteporfin which is a highly non-specific inhibitor) synergize with immune checkpoint blockade in in vivo model system by promoting increased CD8⁺ T cell infiltration and prolonged survival in the melanoma mouse model. Collectively, these findings reveal a chromatin-centric vulnerability in BRAF/MEK inhibitor-resistant melanoma and propose TEAD specific inhibitors as a promising dual strategy to overcome resistance and reinvigorate the immune response, offering a novel therapeutic avenue for patients.

  PublisherOA PDFDOI

• Ultrasmall Chemogenetic Tags with Group‐Transfer Ligands

  Angewandte Chemie International Edition · 2025-09-27 · 2 citations

  article

  Abstract Chemogenetic tags facilitate exploration of activities of a protein‐of‐interest (POI) that lacks small‐molecule ligands; however, most tags are too large for several POIs. Here, we report two ultrasmall chemogenetic tags (mgTag and cTag) of 36 and 50 amino acids (aa) that, to the best of our knowledge, are the smallest. These tags exhibit transferase ‐type reactivity with their ligands, allowing the attachment of any moiety‐of‐interest to the tag. cTag utilizes an engineered C1 domain‐bearing cysteine that undergoes a group‐transfer reaction with its ligand. Likewise, mgTag utilizes an engineered zinc‐finger domain‐bearing cysteine that undergoes a group‐transfer reaction with its molecular glue ligand in the presence of cereblon (CRBN). While the fusion of HaloTag (297 aa) or SNAPTag (182 aa) to the KRAS G12D (188 aa) disrupted its growth‐signaling pathway, fusion of mgTag or cTag did not, pointing to the importance of tag size. Group‐transfer of BRD4 binder to tags appended to Abelson kinase (ABL) induced proximity between ABL and BRD4, resulting in the latter's phosphorylation. Deletion of the transferase ‐type reactivity reduced phosphorylation levels, suggesting that proximity‐inducing chimeras with group‐transfer design may be more efficacious. We envision these ultrasmall tags to have wide‐ranging applications, including in basic science, biotechnology, and medicine.

  PublisherDOI

• Spatial determinants of tumor cell dedifferentiation and plasticity in primary cutaneous melanoma

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-24 · 3 citations

  preprintOpen access

  Early detection of melanoma through skin surveillance is critical for preventing metastatic progression. Primary cutaneous melanomas at early stage offer a unique opportunity to uncover fundamental mechanisms of tumor initiation, progression, and immune surveillance, but detailed spatial profiling of early disease remains limited. Here we integrate high-plex cyclic immunofluorescence (CyCIF) imaging, spatial transcriptomics, and conventional histology to identify factors associated with de-differentiation and dermal invasion in early-stage melanomas. We demonstrate a high level of variability from one primary cancer to the next, from one 100-300 cell microregion to the next within a single cancer, and from one cell to the next within a microregion. Intra-tumoral heterogeneity is influenced by local features of the microenvironment including proximity to T and myeloid cells and to perivascular environments. Thus, tumor plasticity and spatial heterogeneity arise early in melanoma development, potentially allowing for competition among multiple tumor states during the emergence of invasive disease.

  PublisherOA PDFDOI

• 380 Cutaneous eruptions associated with lifileucel, a first-in-class tumor-infiltrating lymphocyte therapy, and interleukin-2 in individuals with metastatic melanoma: a retrospective prognostic analysis

  Regular and Young Investigator Award Abstracts · 2025-11-01

  articleOpen access
  PublisherOA PDFDOI

• Mechanisms of tumor persistence in metastatic melanoma following successful immunotherapy

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-15

  articleOpen access

  ABSTRACT Persistent stable lesions represent a common but ambiguous outcome in melanoma patients receiving immune checkpoint inhibitors (ICIs). However, these lesions are infrequently removed and poorly characterized. Here, we perform in-depth multi-omics spatial profiling on persistent stable lesions from six ICI-treated patients. In one, the proportion of viable and proliferating tumor cells was similar to that of site-matched tumors from patients progressing during ICI. Extensive infiltration with cytotoxic T cells and a high level of programmed cell death were also observed. Some quiescent cancer cells were present, but this was not the dominant tumor state. A second stable lesion, while pathologically negative, also contained proliferative tumor nests with proximate immune cells. These findings provide evidence in patients for extended tumor mass dormancy in which cell death balances ongoing proliferation and further demonstrate that persistent stable lesions can be reservoirs of viable tumor cells with implications for clinical monitoring and management. SIGNIFICANCE This study demonstrates that, following immunotherapy, persistent stable melanomas can arise through tumor mass dormancy rather than quiescence. Mass dormancy is characterized by active tumor cell proliferation and compensatory programmed cell death. Thus, viable tumor cells in some stable lesions have the potential to reactivate disease should ongoing immunosurveillance fail.

  PublisherDOI

• Comparative analysis of CRISPR-Cas9, lentiviral transduction, and base editing for sickle cell disease in a murine model

  Blood Advances · 2025-10-28

  articleOpen access

  ABSTRACT: Sickle cell disease (SCD) is a red blood cell disorder caused by a mutation in the β-globin gene, leading to sickle hemoglobin polymerization under low oxygen conditions. Both CRISPR-Cas9 editing and lentiviral transduction have shown promising clinical outcomes, but it remains unclear which approach is superior. Alternatively, new editing tools such as base editing may also be promising and reduce risks of genotoxicity. To compare these approaches, we studied them in an immunocompromised mouse model. We optimized ex vivo conditions in CD34+ hematopoietic stem and progenitor cells (HSPC) and infused edited SCD HSPC into busulfan-conditioned nonirradiated NOD,B6.SCID Il2rγ-/-KitW41/W41 (NBSGW) mice. Ex vivo analysis confirmed successful editing and transduction. At 16 weeks, bone marrow analysis showed similar human CD45+ cell engraftment across all groups (75%-90%). In the competitive transplantation group, there was a lower amount of B-cell lymphoma/leukemia 11A enhancer editing than base editing and lentiviral transduction. A secondary transplantation model yielded similar results. An antisickling assay showed significantly higher red blood cell sickling reduction in the base editing, transduction, and competitive transplantation groups compared to CRISPR-Cas9. In conclusion, although all methods showed therapeutic potential, base editing and lentiviral transduction provided superior outcomes over CRISPR-Cas9-mediated editing in a competitive murine transplantation model.

  PublisherOA PDFDOI

Recent grants

• Dissecting Therapeutic Resistance and Progression in Metastatic Melanoma Through Clinical Computational Oncology

  NIH · $1.2M · 2018–2023

• NIH Grant R01GM065400

  NIH · $2.5M · 2012

• NIH Grant R01GM065865

  NIH · $5.1M · 2016

Frequent coauthors

• Eliezer M. Van Allen

  Broad Institute

  335 shared

• Genevieve M. Boland

  124 shared

• Giuseppe Tarantino

  115 shared

• Elizabeth I. Buchbinder

  Harvard University

  113 shared

• Jihye Park

  Yonsei University

  111 shared

• Brendan Reardon

  Harvard University

  101 shared

• Felix Dietlein

  Broad Institute

  100 shared

• Ryan J. Sullivan

  89 shared

Labs

• David R. Liu GroupPI

Education

• MD, Medicine

  Johns Hopkins Medicine

  2011

• MPH, School of Public Health

  Johns Hopkins University

  2010

• MS, Computer Science

  Stanford University

  2001

• BA, Economics

  Stanford University

  1999

Awards & honors

• Richard Merkin Professor and Director of the Merkin Institut…
• Broad Institute Core Institute Member
• Director of the Chemical Biology and Therapeutic Sciences Pr…
• Howard Hughes Medical Institute Investigator
• Thomas Dudley Cabot Professor of the Natural Sciences and Pr…