Research Roundup: March 6, 2020

How the immune system infiltrates tumors, genetic history of the Mediterranean islands, shaping physician-scientist training, and more.

Len Rubenstein
Credit: Len Rubenstein

Welcome to the March 6, 2020, installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

A bird's eye view on IBD

A complex variety of genetic and environmental factors come together to trigger and sustain inflammatory bowel disease (IBD). In a review in Nature, Daniel Graham and core institute member Ramnik Xavier of the Infectious Disease and Microbiome Program discuss how IBD stands as a model for leveraging human genetics to understand the molecular and cellular networks that regulate and maintain the gut immune system. They also discuss prospects for disease subtype classification based on core pathways revealed through genetics and look ahead to possible future directions in IBD care. 

Reconstructing migration movements to Mediterranean islands

Despite recent advances made in the study of ancient DNA, the genetic history of the Mediterranean islands has remained poorly understood. Reporting in Nature Ecology and Evolution, an international team co-led by senior associate member David Reich of the Program in Medical and Population Genetics (MPG) and collaborators is filling in the gaps with the largest study to date of the genetic history of ancient populations of Sicily, Sardinia, and the Balearic Islands, increasing the number of individuals with reported data from five to 66. The results reveal a complex pattern of immigration from Africa, Asia, and Europe that varied in direction and its timing for each of these islands. Read more in a press release from University of Vienna.

Interneurons linked to sensory hypersensitivity in autism spectrum disorder mouse model

Sensory hypersensitivity is a hallmark of autism spectrum disorders (ASD), and dysfunctional GABAergic interneurons in the neocortex have been implicated. Institute member Guoping Feng of the Stanley Center for Psychiatric Research and his colleagues have found a causal link between these cells and sensory abnormalities in a Shank3B knockout mouse model of ASD. The researchers found that these mice were more sensitive to a weak tactile stimulation than wildtype mice. In vivo calcium imaging of the knockout mice showed reduced activity in interneurons and increased activity in pyramidal neurons. When the team deleted Shank3 in vS1 inhibitory interneurons, they saw pyramidal neuron hyperactivity and increased stimulus sensitivity. Read more in Nature Neuroscience.

Testing a tumor’s territory

Immune cells in the tumor microenvironment (TME) can influence how some cancers respond to treatment, but it’s unclear if inherited genetic features influence how immune cells infiltrate the TME. A team led by associate member Eli Van Allen; Meng Xiao He, a graduate student in the Van Allen lab; Sohini Ramachandran of Brown University; and Sahar Shahamatdar in the Ramachandran lab analyzed seven million germline variants from The Cancer Genome Atlas and found nearly two dozen genes, one SNP, and several gene networks that are associated with immune infiltration around solid tumors. Described in Cell Reports, the work is an important step toward understanding predictors of response to immune checkpoint blockade therapies. 

Reading America's history in its genes

America's complicated history of immigration, migration, and admixture has greatly influenced genetic diversity across the United States. To understand how much, Alicia Martin in the Broad's MPG Program and colleagues at MIT used data from the National Geographic Society's Genographic Project to study the geographic patterns of genetic ancestry and admixture within the US over time, and learn how much Americans' genetics reflect historic demographic events. Writing in the American Journal of Human Genetics, they found distinct genetic traces within many populations that reflect the nation's migration history, and subtle but potentially important levels of diversity within certain groups. Read more in a Broad news story.

Re-examining physician-scientist training 

Growth of the physician-scientist pipeline in the US has expanded to nearly 120 schools, with over a third funded through the NIH. To characterize the success of physician-scientist training, it is important to use systematic, evidence-based investigation, as well as a deep understanding of scientific history, to inform actionable policy. In an F1000Research commentary, Models, Inference & Algorithms Initiative’s scientific advisor Gopal Sarma and collaborators used the “discovery-invention cycle” framework to analyze the structure and outcomes of integrated MD/PhD programs. The researchers emphasize the importance of deeply understanding individual career trajectories, as well as characterizing organizational details and cultural nuances, to drive new policy that shapes the future of the physician-scientist workforce.

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