From farm to lab: gene-edited sheep transforming bone research.

For more than half a century, mice have been the workhorse of biomedical research. Their small size, rapid reproduction, and well-characterized genetics make them ideal disease models, and genome editing has enabled transgenic, knock-out, and knock-in lines that mimic numerous human conditions. These advances transformed modern biology, yielding fundamental insights into cancer, metabolism, immunity, and more. Their strengths notwithstanding, mouse models have important limitations, as biology does not scale neatly across species. Differences in physiology, size, and metabolism can obscure-or even distort-experimental outcomes. Nowhere is this clearer than in musculoskeletal research. Human bones are dynamic tissues that undergo Haversian remodeling, whereas mice exhibit limited Haversian remodeling and display distinct temporal growth trajectories. Moreover, mice have monophyodont dentition and craniofacial development diverges in ways that impact maxillofacial studies, and aging timelines differ. These differences limit our ability to understand human bone disorders from murine models alone. Biotechnology offers a new path forward: advances in genome sequencing, assembly and molecular engineering enable precise DNA editing in larger domesticated species-sheep, goats, and pigs-whose skeletal size, biomechanics, growth patterns, and remodeling dynamics more closely mirror humans. By introducing targeted, patient-relevant mutations, large-animal models can replicate mechanisms difficult to capture in mice and support longitudinal, clinically-relevant phenotyping-imaging, histomorphometry, serum biomarkers, and functional testing-in a translatable human-like context. The implications are profound. Large-animal models can validate disease pathways, refine biomarkers, and evaluate drugs, biologics, and implants, potentially improving treatment strategies and reducing clinical failures and costs. This shift does not diminish the value of mice, whose genetic tractability and cost-effectiveness ensure a central and continued important role in discovery. Rather, it adds a complementary strategy: expand to gene-edited large-animal models when human skeletal-like biology matters and where mice fall short, thereby bridging the gap between fundamental research and clinical reality.