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.

If the immune system is an interconnected network, then the evolution of an archetype that is ideal for fighting one pathogen should result in trade-offs decreasing its ability to fight others. How many archetypes are there in an immune system? We infected diverse mice with Plasmodium chabaudi and identified five distinct archetypes of responses on the basis of the hosts position in microbial load, immune activity, and host damage space. To better understand the nature of these archetypes, we developed a mathematical model of a generalized host-pathogen system. This model explains the number and distribution of archetypes across a population of diverse hosts. Mice resilient to P. chabaudi exhibited poor outcomes when challenged with influenza, SARS-CoV-1, or Mycobacterium tuberculosis, and vice versa, supporting our trade-off hypothesis.