Principles of human tissues 

Organs are made of cells that work together and communicate with each other in order to achieve joint functions. In order to make sense of their complexity requires principles that can guide our understanding of tissue biology. We ask questions about the general design principles of organs and tissues:

How do organs maintain a proper size despite the fact that their cells constantly divide and die?
How do organs maintain proper ratios of their different cell types?
How do organs adjust their function to match variation in distant tissues with which they communicate? How do tissues resist takeover by mutants the missense feedback signals?

Remarkably, there exist principles for tissue-level circuits that can address these challenges. These principles unify our understanding of very different tissues. The resulting feedback circuits are essential for organ function but have specific fragilities that lead to disease. Understanding the origins of diseases in this way can offer fresh perspectives on prevention and therapy.

Current topics in our group include principles of hormone circuits, origins of autoimmune diseases, origins and timescales of mood disorders, inflammation and fibrosis. Examples of our work, which uses mathematical models to explain a large number of diverse experimental findings:

A feedback loop in which glucose controls pancreatic beta cell proliferation and death allows organ size control and compensation for insulin resistance:
Dynamical compensation in physiological circuits

A biphasic mechanism in which glucose kills beta cells at high concentration is essential to resist mutant takeover but has a fragility that leads to type-2 diabetes.

Biphasic response as a mechanism against mutant takeover in tissue homeostasis circuits

Principles of cell circuits for tissue homeostasis:

Continuum of Gene-Expression Profiles Provides Spatial Division of Labor within a Differentiated Cell Type

Circuit Design Features of a Stable Two-Cell System

Senescent cells and the dynamics of aging