Human Health Sciences Group

Bioinformatics

The Human Health Sciences Group leverages advanced bioinformatics methodologies to support our mission of understanding and mitigating emerging biological and chemical threats to human health. Our specialized capabilities include comprehensive omics data analysis (miRNA-seq, ATAC-seq, Bulk RNA-seq, scRNA-seq, snRNA-seq, and spatial transcriptomics), functional and pathway enrichment analysis, integrated multi-omics data interpretation, cell differentiation trajectory and pseudotime analysis, cell–cell interaction modeling, and gene regulatory network inference. By combining these state-of-the-art analytical approaches, we elucidate biological mechanisms, identify biomarkers, and advance therapeutic discovery, contributing significantly to our group's interdisciplinary efforts in addressing chemical, pathogenic, and pharmacological challenges.

Illustration representing the bioinformatics research capabilities of the Human Health Sciences Group. The upper-left image shows a schematic overview of an experiment utilizing single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to analyze lung tissue from mice infected intranasally with a respiratory pathogen over a 14-day period. Single-cell RNA sequencing was performed using the 10x Genomics Chromium instrument, and spatial transcriptomics was conducted with the 10x Genomics Visium CytAssist platform. The upper-right image visualizes lung cell populations identified by scRNA-seq using a UMAP plot, with cells colored according to cell type. The lower images display spatial transcriptomic maps illustrating the spatial distribution and proportions of various lung cell types in non-infected (Day 0) and infected (Day 14) lung tissues. Warmer colors (red) indicate higher proportions, whereas cooler colors (blue) indicate lower proportions. This figure highlights our group's capability to integrate cutting-edge single-cell and spatial transcriptomics technologies to explore complex biological responses to infectious agents.

Biological accelerator mass spectrometry

Accelerator mass spectrometry (AMS) has been adopted as a powerful bioanalytical method for human studies in the areas of pharmacology and toxicology. The exquisite sensitivity (10^-18 mol) of AMS has facilitated studies of toxins and drugs at environmentally and physiologically relevant concentrations in humans. Such studies include risk assessment of environmental toxicants, drug candidate selection, absolute bioavailability determination, and more recently, assessment of drug target binding as a biomarker of response to chemotherapy, as well as countermeasure assessment.

Parallel Accelerator and Molecular Mass Spectrometry 

The Parallel Accelerator and Molecular Mass Spectrometry (PAMMS) system, developed by LLNL's BioAMS group, is a powerful platform that enables the separation and quantification of radiolabeled compounds. PAMMS integrates high-performance liquid chromatography with two parallel detection streams: AMS for ultra-sensitive quantification of radiocarbon-labeled analytes and molecular mass spectrometry for precise identification of parent compounds, metabolites, and degradation products. This dual-detection approach can be applied in both animal and human studies to characterize the metabolic fate of drugs, toxins, and other biologically relevant molecules, even at trace concentrations.

Lung microphysiological system

Our microphysiological system platform leverages human precision-cut lung slices (PCLS) to model clinically relevant responses to drugs, pathogens, and toxins. By preserving native tissue architecture, donor-specific traits, and cellular heterogeneity, PCLS provide a highly translatable ex vivo system. To further enhance biological relevance, we integrate circulating immune cells (PBMCs) to enable immune cell recruitment and dynamic cellular crosstalk. This advanced platform offers a powerful tool for accelerating therapeutic development, uncovering disease mechanisms, and bridging the gap between preclinical research and human outcomes.

Brain microphysiological systems

Microphysiological systems (MPS), particularly brain-on-chip (BOC) platforms, can replicate key structural and functional characteristics of the human brain. Some BOC platforms incorporate multi-electrode arrays (MEAs), which allow for non-invasive recordings of extracellular action potentials generated by neurons. Monitoring these action potentials provides valuable insights into neural and network activity, enabling the assessment of both short- and long-term compound effects, as well as the relationship between molecular or cellular changes and neural function in vitro. Our group has developed a suite of brain-relevant experimental tools for threat evaluation and medical countermeasure (MCM) assessment, including:

1. A moderate-throughput, multi-well 2D MEA system that supports tri-cultures of rat and human cell types (e.g., rat: neurons, astrocytes, oligodendrocytes, microglia; human: neurons, astrocytes, microglia).
2. A 3D BOC platform.
3. A novel human 3D neurovascular unit.

Each of these systems utilizes embedded MEAs for non-invasive functional readouts of neuronal activity and can be integrated with complementary analyses such as imaging, transcriptomics, and cytokine/chemokine profiling. Species-specific differences between rat and human models can also be explored in both the 2D and 3D platforms.

In collaboration with LLNL’s Engineering organization, our group utilizes advanced computational tools, statistical models, and machine learning techniques to analyze neural network structure and activity from functional data captured on brain-on-chip MPS. By combining electrophysiological recordings with our computational models and techniques, we can track network dynamics, assess synchronization, and evaluate pharmacological properties of human neural networks in vitro. This capability enables us to study how 2D and 3D neural networks respond to chemical and biological threat exposures, providing insights into network behavior and their functional connectivity.