Cellular models for tissue function in development and ageing

Introduction

One of the most fundamental challenges in contemporary biology is, in fact, also one of the most classical ones: how to comprehend macroscopic tissue function from the activities of its microscopic cellular components. The remarkable advent of single cell genomics over the last decade is realizing this challenge at unprecedented scales.

Advances in Measurement

Measurements of the molecular states of thousands or even millions of cells can now be acquired efficiently, and tools for describing cellular states phenomenologically have become well established.

Challenges in Modeling

However, how to model ensembles of cells in tissues is paradoxically even more difficult than before, given this new unprecedented experimental resolution.

Development of a New Framework

To this end, we will develop a new computational and theoretical framework for understanding ensembles of single cells as they interact and dynamically differentiate, proliferate, or degrade.

Model Development

1. Parametric and mechanistic models for defining microscopic cell states over a mathematical manifold will be developed.
2. The dynamics of ensembles of cells over time and in space will be inferred from new experimental approaches capturing whole tissues over time or within spatially registered domains.

Description of Tissue Dynamics

Importantly, our models will describe tissue dynamics as changes in specific gene regulatory, epigenomic, and signaling programs.

Experimental Approaches

We will develop high-throughput experiments to combinatorially perturb embryonic and hematopoietic systems in order to test such models extensively.

Research Goals

Our research will thereby extend single cell-centric models toward describing dynamics in tissues, with experiments and data collection aiming at rapid translation of the models to actionable and testable strategies for manipulating systems of interest.

Applications

This will be applied to:

• Transparent and epigenetically precise cell type engineering
• Discoveries using a unique resource on human hematopoietic aging
• Deep tissue level analysis of combination immunotherapy