Krausz, T. | bioRxiv Science

bioRxiv2026

A foundational in vivo platform for predicting human health outcomes

Rodents remain the workhorse of preclinical drug development, yet often fail to predict human clinical outcomes. Existing alternatives are similarly constrained. Cells in culture cannot recapitulate whole-organism physiology, and larger mammals cannot be studied at comparable throughput. Here we present a scalable, information-dense platform that can predict a drugs long-term human clinical outcomes from 24 hours of rodent behavior. A novel home-cage system continuously records behavior, generating thousands of features per hour. Models are trained on human clinical trial data to map these features onto outcomes including gastrointestinal adverse events, cardiac toxicity, neuropsychiatric side effects, and long-term weight loss. In addition to being an order of magnitude faster, the platform provides more accurate clinical predictions than standard long-term preclinical experiments. The approach readily extends to other outcomes, enabling rodents to serve as quantitative models for human clinical prediction.

pharmacology and toxicology↗

bioRxiv2025

Sex differences in GLP-1 signaling across species

Two billion humans are currently overweight or obese1. While glucagon-like peptide 1 receptor (GLP1R) agonists have emerged as the most promising treatment for this epidemic, side effects including nausea and vomiting constitute a significant obstacle to their use. Of the patients currently being treated, women represent nearly 70%. While early studies have noted sex differences in the response to these drugs, the nature of these differences remain poorly characterized. Using real world electronic medical record (EMR) data, we find that women experience more than double the rates of persistent nausea and vomiting when prescribed GLP1R agonists. To investigate this sex difference in greater detail, we developed novel, species-specific in vivo phenomic assays to quantify aversive behaviors. In both mice and rats, aversive responses to either semaglutide or tirzepatide were greater in females than males. To investigate the basis for this difference, we constructed a mouse single cell transcriptomic atlas of body and brain regions most relevant to the action of GLP-1. Using this atlas we find that multiple neuronal cell types involved in the processing of aversive stimuli and nausea had higher GLP1R expression in females than males. Heightened susceptibility of females to the aversive effects of GLP1R agonists could therefore involve increased activation of these brain circuits. Finally, we demonstrate that in mice, both the efficacy and tolerability of GLP1R agonists vary with the phase of the estrous cycle, being highest during proestrus (when estrogen levels peak) and lowest in diestrus (low estrogen levels). Similarly, we report that higher circulating estrogen levels in humans is associated with heightened risk of nausea and vomiting among women taking a GLP1R agonist. Based on these findings, we anticipate that women will continue to be disproportionately impacted by the adverse effects associated with all members of this drug class. Research to better understand and ultimately mitigate this heightened susceptibility is an important priority for new drug development in this area, and novel approaches to model the impact of endogenous hormone signaling will be critical to developing better treatments for more people.

systems biology↗