**6. Bidirectional translation from humans to pre-clinical models and back again**

The virtuous cycle of bidirectional translation works through the observation of disease phenotypes and processes in human patients, followed by replication and examination of the specific observation in normal and pathological pre-clinical models to discover novel modulators of complex disease mechanisms, and ultimately test those outcomes back in human patients. This process should be repeated until a safe and effective treatment paradigm is obtained or the disease process of better understood. This strategy clearly supports the hypothesis that breakthroughs

in human and experimental models fuel a sustainable model of human observation, pre-clinical model experimentation, and verification in humans. As direct support for this strategy, as discussed above, with the known observation that elevated IOP is the chief modifiable risk factor for POAG, Chintalapudi *et al.* used strains from the BXD family of mice and identified a novel gene modulator of IOP—calcium voltage-gated channel auxiliary subunit alpha2delta 1 (*Cacna2d1*)— that was confirmed in human GWAS investigations [74]. These findings were the platform that allowed for the discovery of pregabalin, an inhibitor of CACNA2D1, as a new IOP-lowering drug with a novel mechanism of action [74]. This, as well as the variety of molecular models discussed above, demonstrates the efficacy of bidirectional translation in driving the diagnosis, treatment, and prevention of complex diseases [95].

The collective generation of large datasets like GWAS have facilitated the identification of gene modulators of complex traits and disease mechanisms. Those tools alone, however, do not account for the complex interplay between inherited and environmental factors. Human limitations are clear; animal models are equipped with the biological resources to support the detailed analyses of disease progression. Pre-clinical models reveal instrumental pathophysiology, which when translated to humans, fuels the evolution of molecular, cellular, developmental, and physiological research [95]. However, glaucoma is a multifaceted disease, which one animal model alone cannot flawlessly emulate. Different animal models display unique features of the pathophysiology of the disease and each help further understanding of glaucoma progression as a whole.
