Uri Alon Lab

Physiological and pathological processes such as inflammation and cancer emerge from interactions between cells over time¹. However, methods to follow cell populations over time within the native context of a human tissue are lacking because a biopsy offers only a single snapshot. Here we present one-shot tissue dynamics reconstruction (OSDR), an approach to estimate a dynamical model of cell populations based on a single tissue sample. OSDR uses spatial proteomics to learn how the composition of cellular neighbourhoods influences division rate, providing a dynamical model of cell population change over time. We apply OSDR to human breast cancer data^{2, 34}, and reconstruct two fixed points of fibroblasts and macrophage interactions^5,6. These fixed points correspond to hot and cold fibrosis⁷, in agreement with co-culture experiments that measured these dynamics directly⁸. We then use OSDR to discover a pulse-generating excitable circuit of T and B cells in the tumour microenvironment, suggesting temporal flares of anticancer immune responses. Finally, we study longitudinal biopsies from a triple-negative breast cancer clinical trial³, in which OSDR predicts the collapse of the tumour cell population in responders but not in non-responders, based on early-treatment biopsies. OSDR can be applied to a wide range of spatial proteomics assays to enable analysis of tissue dynamics based on patient biopsies.

How heritable is human life span? If genetic heritability is high, longevity genes can reveal aging mechanisms and inform medicine and public health. However, current estimates of heritability are lowtwin studies show heritability of only 20 to 25%, and recent large pedigree studies suggest it is as low as 6%. Here we show that these estimates are confounded by extrinsic mortalitydeaths caused by extrinsic factors such as accidents or infections. We use mathematical modeling and analyses of twin cohorts raised together and apart to correct for this factor, revealing that heritability of human life span due to intrinsic mortality is above 50%. Such high heritability is similar to that of most other complex human traits and to life-span heritability in other species.

Elevated cortisol in chronic stress and mood disorders causes morbidity including metabolic and cardiovascular diseases. There is therefore interest in developing drugs that lower cortisol by targeting its endocrine pathway, the hypothalamicpituitaryadrenal (HPA) axis. However, several promising HPA-modulating drugs have failed to reduce long-term cortisol in mood disorders, despite effectiveness in other hypercortisolism conditions such as Cushings syndrome. The reasons for these failures remain unclear. Here, we use a mathematical model of the HPA axis to demonstrate that the pituitary and adrenal glands compensate for drug effects by adjusting their functional mass, a feedback mechanism absent in Cushing tumors. Our systematic in silico analysis identifies two interventions targeting corticotropin-releasing hormone (CRH) as effective for lowering long-term cortisol. Other targets either fail due to gland mass compensation or harm other aspects of the HPA axis. We propose CRH-neutralizing antibodies and CRH-synthesis inhibitors as potential targets for reducing long-term cortisol in mood disorders and chronic stress. More generally, this study indicates that understanding the slow compensatory mechanisms in endocrine axes can be crucial to prioritize drug targets.