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Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1 . Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed.AAV2, HAdV and HHV-6 phylogeny excluded emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T-cells and B-lineage cells.Proteomic comparison of liver tissue from cases and healthy controls, identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins.HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and in severe cases HHV-6B, may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Recent advances in stem cell engineering have led to an explosion in the use of organoids as model systems for studies in multiple biological disciplines. Together with breakthroughs in genome engineering and the various omics, organoid technology is making possible studies of human biology that were not previously feasible. For vision science, retinal organoids derived from human stem cells allow differentiating and mature human retinal cells to be studied in unprecedented detail. In this review, we examine the technologies employed to generate retinal organoids and how organoids are revolutionizing the fields of developmental and cellular biology as they pertain to the retina. Furthermore, we explore retinal organoids from a clinical standpoint, offering a new platform with which to study retinal diseases and degeneration, test prospective drugs and therapeutic strategies, and promote personalized medicine. Finally, we discuss the range of possibilities that organoids may bring to future retinal research and consider their ethical implications.

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