JCI's Conversations with Giants in Medicine: George Church

JCI Editor at Large Ushma S. Neill interviews the geneticist, innovator, and entrepreneur George Church, of Harvard and MIT. Dr. Church developed the methods for the first genome sequencing, and his subsequent work has brought down the price of sequencing over 10-million-fold. His was one of the two research groups that first got CRISPR/Cas9 to work for precise gene editing in human cells by a homologous recombination, and he has been behind countless other scientific innovations and disruptions, specifically in the world of precision genome sequencing.

Secondary insult reveals etiology of GATA2 enhancer mutation-associated blood disorder

The transcription factor GATA-2 is critical regulator of hematopoietic stem and progenitor cell (HSPC) development and function, and mutations in the enhancer region of GATA2 are linked to blood disorders. In this episode, Emery Bresnick and colleagues develop and characterize a mouse model that harbors a human disease-associated GATA2 enhancer mutation. In this model, hematopoietic development and function were normal unless the animals were exposed to a secondary stress that necessitated blood cell regeneration. The results of this study provide important insight into GATA-2-dependent pathogenesis.

Naturally occurring cone disorder in nonhuman primates

Achromatopsia is form of congenital retinal degeneration characterized by the loss of cone photoreceptor function, resulting in dramatic loss of visual acuity. Mouse models of cone disorders are available; however, clinical translation of these models is limited, as cone density in the murine retina is much less than that of humans. In this episode, Sara Thomasy and Ala Moshiri discuss the identification and characterization of a naturally occurring mutation in nonhuman primates that results in features that mirror human achromatopsia. This nonhuman primate model has high potential for therapeutic testing and optimization of gene editing and of cone cell replacement strategies.

Sphingolipid desaturase DEGS1 linked to rare leukodystrophy

Leukodystrophies are rare congenital disorders that affect the white matter of the brain, resulting in a range of neurological presentations. Several leukodystrophy-associated genes have been identified; however, the etiology of many cases remains unclear. In this episode, Aurora Pujol, Ali Fatemi, Marc Patterson, Javier Terriente, and Carlos Casasnovas discuss their collaboration, which led to the identification of a mutation in the endoplasmic reticulum lipid desaturase DEGS1 as the underlying cause of a leukodystrophy in 19 patients from 13 unrelated families. The mutation was linked to an imbalance of the DEGS1 substrate dihydroceramide and ceramide. In a DEGS1 knockdown zebrafish model, treatment with fingolimod reduced the imbalance between dihydroceramide and ceramide, decreased locomotor disability, and increased oligodendrocyte myelination, suggesting this strategy be explored for mutant DESG1-related disease.

Mast cell engagement of γδ T cells protects against viral infection

The skin is an important barrier to infections and contains resident immune cells poised to respond to pathogens. Tissue-resident mast cells are critical for pathogen surveillance and initial response. In this episode, Ashley St. John discusses her work, which reveals a previously unrecognized interaction between mast cells and γδ T cells in the skin that is critical for clearance of dengue virus (DENV). The results of this study indicate that mast cells serve as nonconventional antigen-presenting cells that are poised to activate γδ T cells early during viral infection and limit disease.