We are interested in understanding the biological basis of cellular and organismic stress resilience. Many organisms in nature have evolved specialized traits to respond and adapt to severe environmental stresses, including hypothermia (cold) or hypoxia (low oxygen). For example, Arctic ground squirrels can tolerate extreme low levels of oxygen in the brain and heart during hibernation. Most nematodes, including those from the Antarctica and the common model organism C. elegans, can enter "suspended animation" states upon anoxia; they can also be frozen alive and suspend life that can be revived later virtually any long after freezing, unlike many other multicellular organisms. We use both cultured neural stem cells from hibernating Arctic ground squirrels and nematodes with extremophile-like phenotypes recapitulated in the laboratory as discovery tools to understand mechanisms of cellular and physiological resilience. Genes identified from such systems via large-scale experimental screens or computational mining often encode proteins of unusual properties that define novel mechanisms underlying cytoprotection, cellular organelle dynamics and organismic homeostasis in physiology and behaviors. Some were even acquired from extremophile microbes via horizontal gene transfers and functionally co-opted to confer stress resilience. We take advantage of findings from our research and aim to use synthetic physiology approaches to engineer biological systems that may foster new means of cytoprotection, organ transplantation, reversible cryo-preservation and therapeutics to treat ischemic, neurological and age-related disorders.