Broad Institute of MIT and Harvard

Standard clinical trials for cancer drugs are expensive, lengthy, and often focused on advanced disease in which cures are unlikely. Arielle Medford, Ariel Carmeli, Alex Ritchie, Eric Lander, and Aparna Parikh propose a standing clinical trials platform to advance development of adjuvant therapies that prevent recurrence. Through this platform, patients after curative-intent therapy who show early molecular evidence of recurrence, based on circulating tumor DNA, would be invited to enroll in clinical trials that could be smaller and faster than conventional adjuvant trials. Read more in Nature Reviews Cancer. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

Cellular crosstalk is critical for tissues' function and regulation. To enable discovery of genes that regulate these interactions, Camilo Faust Akl, Francisco Javier Quintana, and colleagues developed a technique called SPEAC-seq, short for systematic perturbation of encapsulated associated cells followed by sequencing. The platform uses genome-wide CRISPR libraries, droplet-based cell culture, and microfluidic sorting to enable unbiased characterization of cell-cell interactions. As proof of concept, they investigated interactions between microglia and astrocytes, discovering thousands of microglial regulators of NF-κB protein activation in astrocytes, which helps control central nervous system inflammation. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

Blocking the protein PD-1 with antibodies reduces CD8+ T cell exhaustion and can improve control of tumors and viral infections. However, scientists do not fully understand how exhausted T cells regulate PD-1. In Nature Immunology, Sarah Weiss, Arlene Sharpe, Debattama (Deb) Sen, and colleagues studied epigenetic regulation of PD-1 in a mouse model. Using CRISPR-Cas9 genome editing, they deleted the OCR enhancer and found that its loss reduces PD-1 expression in chronic but not acute infection, creating a sweet spot of optimal expression compared to cells with the enhancer or with a complete genetic knockout of PD-1. The edited T cells controlled viral infection better without the excess immunopathology seen in knockout cells. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

Congratulations to Broad associate member Gary Ruvkun and Victor Ambros of UMass Chan Medical School for receiving the 2024 Nobel Prize in Physiology or Medicine for the discovery of microRNA! #NobelPrize

The Center for ELSI Resources and Analysis (CERA) and the Broad Institute of MIT and Harvard have announced a new partnership aimed at enhancing the integration of ethics and health equity into genetics and genomics research. This initiative will foster collaboration between ELSI researchers and genomic scientists, with the goal of improving the timeliness and impact of ethical recommendations and promoting exploration of health equity issues in the research process. You can learn more about these efforts in an article where I had the privilege of being featured. https://lnkd.in/exx9TddA Broad Institute of MIT and Harvard and ELSIhub | CERA

Different mutations in the von Hippel-Lindau (VHL) tumor suppressor gene cause increased risk of kidney cancer as well as hemangioblastomas (tumors of the central nervous system) and paragangliomas (neuroendocrine tumors), but scientists do not fully understand how. In PNAS, Muhannad Abu-Remaileh (PhD), William Kaelin, and colleagues found that neuroblastoma cell lines lose their fitness when the protein encoded by VHL does not function. This occurs when transcription factors that respond to low-oxygen cellular environments called Hypoxia-Inducible Factors (HIFs) — known to drive some cancers — increase. Collectively, this suggests a “Goldilocks model” wherein increased levels of HIFs cause the growth of some tumors, but above a certain level prevent their formation. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

A new study reveals how the fusion of the PRKACA and DNAJB1 genes drives fibrolamellar carcinoma, a rare liver cancer affecting children and young adults. Using a patient-derived cell line, other models, and tumor samples,Ilaria G. Gritti, Jinkai Wan, Taranjit Gujral, Nabeel Bardeesy, Ph.D., and colleagues showed that the gene fusion’s protein product inactivates salt-inducible kinases, which stimulates two transcriptional coactivators, CRTC2 and p300. Described in Cancer Discovery, the results define a core signaling axis by which the fusion protein reprograms gene expression and promotes cell transformation, in addition to defining downstream therapeutic vulnerabilities. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

A genome-wide association study by Broad researchers Siwei Chen and Benjamin Neale in Nature Neuroscience reveals new genetic links to different types of epilepsy. Epilepsy is one of the most common neurological disorders, but while scientists have long known that genetics play a major role in epilepsy risk, identifying all of the specific genetic contributions has been challenging. The findings point to genes involved in how neurons communicate and fire, suggesting potential targets for new therapies and more tailored treatment methods. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

In 2019, a team led by Anna Greka, MD, PhD discovered that a rare genetic kidney disorder, Mucin 1 kidney disease, develops because a cargo transporting protein called TMED9 latches onto a misfolded mutant protein called MUC1-fs, entraps it, and prevents its disposal. Using cryo-electron microscopy, Anna; Boston Children's Hospital's Le Xiao, Xiong Pi, and Hao Wu; and colleagues including members of the Proteomics Platform and Kidney Disease Initiative have now identified the structural principles that allow TMED9 to bind to molecular cargoes like MUC1-fs. Their findings, published in Science Advances, explain how TMED9 traps misfolded proteins in the cell and promotes kidney disease and other rare toxic proteinopathies. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch #KidneyDisease

With the ability to encode any protein, messenger RNA (mRNA) has the potential to treat a wide range of conditions, but it only gets translated into protein briefly before degrading. In Nature Biotechnology, Hongyu Chen, Dangliang Liu, Abhishek Aditham, Xiao Wang, and colleagues describe LEGO, a systematic way of modifying mRNA to achieve specific therapeutic effects, such as mRNAs that last longer or produce more protein. The researchers used the framework to develop multi-capped mRNA for protein replacement and vaccine treatments that, in mice, produced significantly more protein than standard mRNA. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch