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 that 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.
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:
Circuit Design Features of a Stable Two-Cell System
Hormone circuits
Hormone circuits in textbooks and math models are expected to work on the timescale of minutes to hours - the lifetime of the hormones, and on the timescale of a day due to circadian rhythm. We added to this picture interactions that provide a timescale of weeks-months. These are well characterized changes in the functional mass of the hormone glands (eg growth of the thyroid or adrenal gland). This growth is due to the growth-factor effects of the hormones in each pathway. Although characterized, these effects have not been considered on the system level.
Our gland-mass models of the human stress pathway (HPA - accompanied by longitudinal measurements of hair cortisol), thyroid axis, beta cells and ovaries explain phenomena on the timescale of weeks-months. These phenomena include addiction, depression, bipolar disorder mood episodes, prediabetes, subclinical thyroid diseases, ovarian dynamics and PCOS, and hormone seasonality. The growth and shrinkage of glands also provides systems level functions such as dynamic compensation (strict homeostasis of key variables and strict robustness of their dynamic response curves to a given stimulus) in the face of variation in physiological parameters such as insulin resistance, blood volume and metabolic state of the cells.
A New Model For the Hpa Axis Explains Dysregulation of Stress Hormones on the Timescale of Weeks
Hormone seasonality in medical records suggests circannual endocrine circuits
An opponent process for alcohol addiction based on changes in endocrine gland mass