Research summary

Single-cell genomic, transcriptomic, and proteomic approaches provide an exciting new avenue for the dissection of the complex set of cell types and states that comprise tissues from essentially organism. However, tissues are not amorphous collections of cells, and the spatial and functional organization of cells within tissues is absolutely critical to the function of all tissues. Thus, to understand tissue function and dysfunction we must know not just the types of cells present within any given tissue but their spatial and functional organization.

Broadly speaking, the mission of our laboratory is to

1) develop novel image-based methods to single-cell 'omics--methods that quantify genome-wide properties of single cells via direct high-resolution fluorescence imaging within intact tissue samples

2) leverage these new technologies to understand how tissue function and dysfunction arise from the behaviors of the individual cells that comprise that system

Below we provide a summary of our basic research directions.

Research directions

New technology for highly multiplexed, high-throughput in situ single-cell 'omics

New innovations for the in situ single-cell 'omics toolbox

The ability to directly image genome-wide properties of individual cells within intact tissues promises exciting new avenues for the dissection of a wide range of biological problems.

Our laboratory will substantially optimize and improve MERFISH for the purpose of in situ single-cell transcriptomics with the goal of whole transcriptome imaging within millions of cells in large contiguous tissue blocks.

In parallel, we will develop novel approaches for massively multiplexed protein imaging within intact samples and combine these approaches with MERFISH to allow the simultaneous imaging of the transcriptome and proteome within individual cells.

Finally, we will continue to develop the computational resources and tools necessary to both efficiently process the massive imaging data that we will collect as well as extract new biological insights from these data. These efforts will include improved decoding and processing algorithms for MERFISH and methods for exploiting spatial context in both the identification of cell types as well as the inference of functional interactions between neighboring cells.

The mammalian microbiome is an important modulatory of host physiology

Understanding microbiome-host interactions

The mammalian gut microbiome has emerged as an important modulator of a surprisingly wide range of host physiological states from the more obvious--the ability of the host to utilize nutrients--to the far more surprising--the progression of neurodegenerative diseases!

Our laboratory is broadly interested in revealing the molecular mechanisms behind the complex interactions between the gut microbiome and the host with the long-term goal of driving the development of better clinical tools and interventions.

We will make inroads on this complex problem by creating comprehensive cellular atlases of the mouse gut microbiome and the mouse gut.

Understanding the spatial structure of the gut microbiome

Spatial structure within the gut microbiome

We know quite a lot about the composition, activity, and response to perturbations of the mammalian gut microbiome. However, we know very little about the spatial structure of this complex community on functionally relevant lengths scales of a few microns up to hundreds of microns.

Are there defined ecological niches created by host gut structures that provide priviledged environments for subsets of the gut microbiome?

Does the metabolic activity and the metabolic byproducts produced by commensal bacteria depend critically on their location within the gut or their proximity to other members of the microbiome?

Are the bacterial-bacterial interactions that are critical to the dynamics within this community sensitive to its organization?

We will address these and more questions by leveraging spatially resolved gene expression measurements to map out the spatial structure within synthetic and native microbial communities within the mouse gut. This work will provide new insights into the interactions, both between bacteria and between bacteria and the host, that are critical mediators of the activity and stability of the microbiome.

Understanding the composition and organization of the gut epithelial layer

Organization of the gut epithelial layer and its interaction with the microbiome

Single-cell transcriptomic approaches have revealed that we still do not have a comprehensive description of the cell types that exist within the mammalian gut. Yet an understanding of these cell types and their spatial and functional organization is critical for an understanding of the ways in which the gut senses and shapes the microbiome and the methods by which the composition and activity of the microbiome reshapes the activity and abundance of cell types within the epithelial layer of the gut.

We will utilize spatially resolved gene expression measurements to identify the epithelial, immune, and stromal cell types distributed throughout the gut, map their spatial organization, and investigate their functional interactions both within the host gut as well as with the gut microbiome.