New Tools for Systems Biology

 

Single Cell Genomics and Transcriptomics:

Cells respond heterogeneously to chemical and genetic perturbations.  The origin of this heterogeneity ranges from differences in cell morphology, microenvironment, and cell cycle stage to diversity in gene expression, epigenetic state, and genomic stability.  Hence, single cell approaches are crucial to unbiased, system-wide analyses of biological samples.  We are developing microfluidic devices, fluorescent probes, and sequencing tools to study transcription in individual cells.  For more information, please see our recent papers here, here, here, and here.

Cancer Systems Biology:

Our cancer biology research takes advantage of the technologies described above and has historically focused on malignant brain tumors. Our earlier work involved molecular profiling of gliomas, resulting in multiple studies describing the cellular composition and molecular states that co-occur within individual tumors and appear across patients. More recently, we have combined acute slice culture of surgical specimens with single-cell genomics to analyze cell type-specific drug responses in gliomas. This approach preserves the native cellular composition and spatial features of solid tumors, allowing us to simultaneously assay the sensitivies of multiple transformed and microenvironmental cell types, including those that are poorly represented in conventional patient-derived models. Our cancer systems biology research benefits from active collaborations with many colleagues including Jeff Bruce, Peter Canoll, Andrea Califano, and Cory Abate-Shen, and we are gradually expanding to applications in other cancer types.

Systems Immunology:

The immune system plays key roles in almost all aspects of human biology including development, tissue homeostasis, cancer, and response pathogens and disease. Our lab has developed experimental and computational tools for characterizing the diversity and function of tissue resident immune populations in human organs. Major biological questions include: How are tissue-associated T cells functionally distinct from circulating T cells? What factors regulate the maturation of T cells in human tissues? How do tissue resident immune populations age? Why do different pathogens and vaccines induce dramatically different durations of protective immunity (memory)? We work on all of these questions in an exciting collaboration with the Farber lab at Columbia. For more information, please see our recent papers here and here.

Translatomics - Systems Biology of Protein Synthesis:

We recently reported cell type-specific measurements of protein synthesis in the brain and in brain tumors, combining the RiboTag system with ribosome profiling and computational deconvolution. 

Current translatomics projects in the lab are addressing several broad questions about translational regulation:

  • What is the subcellular distribution of translation in cells with complex morphologies, like neurons?
  • While bulk proteomics has become robust and sensitive, what about methods for cell type-specific or subcellular proteomics? 
In previous studies, we have developed tools for genome-wide measurements of protein synthesis including:
  • High-sensitivity approaches to ribosome footprinting (recently published here)
  • Highly-multiplexed translation measurements for genome-wide screens