Comparison of model organisms used in phenotypic screens.

Commonly accepted numbers for generation time and brood size are listed, along with media for animal maintenance, evolutionary divergence, gene number and genome size [29]. Also listed, the evolutionary divergence from man and the amino acid sequence identity to the human BMP receptor ALK2 (hALK2). Unit cost: approximate cost of animals needed to screen a 96-well plate of compound libraries, in triplicate. *For mice, this is the approximate cost to purchase 288 mice from Jackson Labs. **Cost of iPSC varies significantly depending on differentiated cell type, culture methods and screening conditions. Relative throughput/ease of scalability: ++++, very high (close to in vitro HTS); +++, high (up to tens of thousands compounds/week); +, low (up to hundreds of compounds/week).

Proposed zebrafish phenotypic screens incorporating human genome–phenome information to accelerate therapeutic discovery.

Human genome–phenome information provided by electronic health record (EHR)-coupled DNA database and by human genetic diseases studies drive formulation of therapeutic hypotheses (“human biology-based therapeutic hypotheses”). To test these hypotheses, zebrafish models of human genetic diseases are generated by genomic editing and employed in phenotypic screen for novel or known compounds which ameliorate the disease phenotypes. These compounds are then advanced for further development, including compound optimization and testing in appropriate preclinical disease models. Alternatively, a target-agnostic morphology-based screen is carried out. Subsequently, targets of hit compounds identified, and each target evaluated in silico against human genome–phenome database to determine whether a viable therapeutic hypothesis can be formulated. If so, these hits are advanced for further development, including compound optimization and testing in appropriate preclinical disease models.