Coronavirus drug target, a Cas13 for RNA editing, immune hubs in tumors, and more.
By Broad Communications
Credit: Susanna M. Hamilton
Welcome to the September 3, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Immune cell hubs found in tumors
Researchers have found a level of spatial organization of cells in tumors not seen before. Postdoctoral fellows Karin Pelka, Matan Hofree, and Jonathan Chen, institute member Ana Anderson (Brigham and Women’s Hospital), core institute member Aviv Regev (on leave), Orit Rozenblatt-Rosen (now at Genentech), Nir Hacohen, co-director of the Cell Circuits Program, and colleagues discovered that immune cells in some human colorectal tumors gather together in clusters, by using a unique combination of single-cell profiling and imaging technologies, and newly developed data analysis approaches. The findings point to networks of interacting immune cells in certain types of colorectal tumors that tend to be more readily “seen” by the immune system, suggesting that cancers containing these hubs may be more likely to respond to immunotherapies. Read more in Cell and a Broad story.
Candidate target for coronavirus therapy
Antiviral therapy targets the virus itself, but another approach, called host-directed antiviral therapy, targets host responses that promote infection. InNature Communications, associate member Francisco Quintana and collaborators identified a possible therapeutic target for this approach: the aryl hydrocarbon receptor (AHR). The team found increased AHR signaling in human cells infected with multiple coronaviruses as well as in nasal swabs and lung cells from SARS-CoV-2-infected patients. Bioinformatic analyses of RNA expression identified AHR as a regulator of the cellular response to infection. Moreover, pharmacologic inhibition of AHR in human cells interfered with replication of SARS-CoV-2 and HCoV-229E, a coronavirus associated with the common cold.
Signal integration by inhibitory interneurons
At birth, our brains are prewired to receive sensory information from our surroundings. Stimuli become contextually meaningful through experience, a process thought to occur through a shift from receiving to evaluating sensory information in the cerebral cortex. In Neuron, postdoctoral researcher Leena Ibrahim, institute member Gord Fishell of the Stanley Center, and colleagues shed light on this shift. They find that certain inhibitory cortical interneurons (cINs) in the L1 layer of the visual cortex receive signals from the thalamus early in development, and that top-down feedback from higher order brain regions strengthens the same type of cINs later. Their findings show that establishing top-down feedback depends upon thalamic inputs early in postnatal development.
Introducing Cas13bt for RNA editing
RNA editing using CRISPR-Cas13 systems is a promising therapeutic strategy that allows for installation of temporary, non-heritable edits. However, therapeutic delivery of these systems remains challenging, due in part to the size of the proteins involved. A team led by Soumya Kannan, Han Altae-Tran, and core institute member Feng Zhang has now identified and characterized an “ultrasmall” family of Cas13b proteins, dubbed Cas13bt, that can be used to generate compact versions of RNA editors. These smaller editors can be packaged within a single adeno-associated virus for delivery, providing new opportunities for RNA editing. Read more in Nature Biotechnology.