We are deciphering the factors that inform health across scales to help maintain & restore it.

Systems biology aims to achieve holistic insights into the molecularworkings of cellular systems through iterative loops of measurement,analysis and perturbation. This framework has had remarkablesuccess in unicellular model organisms, and recent experimental andcomputational advances — from single-cell and spatial profiling toCRISPR genome editing and machine learning — have raised the excitingpossibility of leveraging such strategies to prevent, diagnose and treathuman diseases. However, adapting systems-inspired approachesto dissect human disease complexity is challenging, given thatdiscrepancies between the biological features of human tissues andthe experimental models typically used to probe function (which weterm […]

Pediatric Inflammatory Bowel Disease (IBD) remains challenging to treat and difficult to prognosticate. Although multiple immune cell types coordinate pathology in both Crohn’s disease (CD) and ulcerative colitis (UC), specifying which cell types and cell states portend better or worse response to major IBD treatment strategies, including anti-TNF therapies (the only FDA-approved therapy for pediatric IBD), remains challenging. Here, we present the results of the PREDICT study, which enrolled 79 treatment-naïve pediatric patients at the time of diagnostic endoscopy, enabling a comprehensive transcriptomic, histologic, and serologic analysis of 40 CD […]

Viral variant and host vaccination status impact infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), yet how these factors shift cellular responses in the human nasal mucosa remains uncharacterized. We performed single-cell RNA sequencing (scRNA-seq) on nasopharyngeal swabs from vaccinated and unvaccinated adults with acute Delta and Omicron SARS-CoV-2 infections and integrated with data from acute infections with ancestral SARS-CoV-2. Patients with Delta and Omicron exhibited greater similarity in nasal cell composition driven by myeloid, T cell and SARS-CoV-2hi cell subsets, which was distinct from that of ancestral cases. Delta-infected […]

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and […]

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding […]

SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper respiratory symptoms, suggesting potential to constrain viral pathology to the nasopharynx. Which cells SARS-CoV-2 primarily targets and how infection influences the respiratory epithelium remains incompletely understood. We performed scRNA-seq on nasopharyngeal swabs from 58 healthy and COVID-19 participants. During COVID-19, we observe expansion of secretory, loss of ciliated, and epithelial cell repopulation via deuterosomal expansion. In mild/moderate COVID-19, epithelial cells express anti-viral/interferon-responsive genes, while cells in severe COVID-19 have muted anti-viral responses despite equivalent viral loads. […]