Translational application of adaptive physiology in non-traditional animal models
Authors: Haptonstall Kacey , Keough Kathleen , McNamara Phil , Sajdak Ben , Goodman Linda , Grabek Katharine , Zehnder Ashley 
Published: May 2023

Many mammals have naturally evolved solutions to human biomedical problems. The genes and regulatory elements underlying their protective strategies are generally neither novel nor species-specific, but rather shared among all mammals, including humans. Adaptive physiology published in the literature provides a starting point to identify species with natural disease resistance in which to identify genomic targets that can be translated to therapeutics. When searching through available datasets for species of interest and evaluating the quality of existing transcriptomic, proteomic and genomic analyses, we prioritize species that would best integrate into our drug target discovery platform “Convergence.” Convergence consists of five unique applications to identify and validate the genomic loci underlying these phenomena synthesizing multi-omics data from mammals capable of resisting and reversing human pathologies and present a promising avenue towards development of new treatments. Here we present this target discovery platform, demonstrate examples from current bio-banked species, and explore the potential of using a phylogenetic approach for novel target discovery for the betterment of human health. Our foundational data included transcriptomic and epigenomic sequencing from bio-banked 13-lined ground squirrel (13-LGS) tissues collected at precise physiological time-points across hibernation. Convergence also incorporates multi-omic data sets curated from the literature for many disease-resistant species, as well as human data from hundreds of thousands of individuals. As an example application, the 13-LGS experiences multiple hypometabolic challenges during hibernation, including conditions of ischemic stress and reperfusion, yet these animals resist tissue pathology that would be expected in humans experiencing these conditions. Using bulk RNA-seq data, we applied Weighted Gene Correlation Network Analysis (WGCNA) and Corenet, two network-focused approaches, to identify coexpression networks and hub genes associated with physiological states of hibernation. Many of the identified gene coexpression modules were enriched for genes linked to hibernation physiology-relevant diseases including steatohepatitis and myocardial ischemia via DisGeNet. These enrichments suggest that genes driving hibernation states in the 13-LGS may also hold the key to human-relevant disease resistance and reversal. After our success with the 13-LGS model, we are focused on extending our methodology to other species. Naked mole rats have a resistance to cancer, the northern elephant seal is resistant to diabetes and obesity, and jellyfish exhibit regenerative potential that may be applied to neurons in humans. By applying Fauna’s Convergence platform to questions around disease resistance and reversal paradigms in multiple species, we are developing human therapeutics for a variety of clinical indications using solutions derived from evolutionary problem-solving.

The authors are employed by Fauna Bio Inc. and invested in their commercial success.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.