We are integrating study insights to decipher the unifying logic that governs health.

Phenotypic drug screening remains constrained by the vastness of chemical space and technical challenges scaling experimental workflows. To overcome these barriers, computational methods have been developed to prioritize compounds, but they rely on either single-task models lacking generalizability or heuristic-based genomic proxies that resist optimization. We designed an active deep-learning framework that leverages omics to enable scalable, optimizable identification of compounds that induce complex phenotypes. Our generalizable algorithm outperformed state-of-the-art models on classical recall, translating to a 13-17x increase in phenotypic hit-rate across two hematological discovery campaigns. Combining this algorithm […]

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 […]

Delineating cell populations is crucial for understanding immune function in health and disease. Spatial omics technologies offer insights by capturing three complementary domains: single-cell molecular biomarker expression, cellular spatial relationships and tissue architecture. However, current computational methods often fail to fully integrate these multidimensional data, particularly for immune cell populations and intrinsic functional states. We introduce Cell Local Environment and Neighborhood Scan (CellLENS), a self-supervised computational method that learns cellular representations by fusing information across three spatial omics domains (expression, neighborhood and image). CellLENS markedly enhances de novo discovery of […]

Th1 CD4+ T cells mediate protective antiMtb immunity across biological systemsand organisms. Bromley, Ganchua, et al.demonstrate that CD4+ T cells regulateimmune tone in TB granulomas and arenecessary for immune recall andprotection against reinfection. Followingreinfection, CD4+ T cells facilitate thedevelopment of a growth restrictive nichevia the induction of immuno-modulatorygenes and cellular interaction networks.

Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a key contributing factor to childhood malnutrition, growth stunting, and diminished oral vaccine responses. Although EE has been shown to be the by-product of a recurrent enteric infection, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE by performing high-throughput, single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE in Lusaka, Zambia (eight HIV-negative and three […]

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) which causes the disease COVID-19. SARS-CoV- 2 spike (S)-protein binds ACE2, and in concert with host proteases, principally TMPRSS2, promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues, and the factors that regulate ACE2 expression, remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 amongst tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing […]