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Scientists at Mount Sinai Hospital have developed a new technology to simultaneously analyze the functions of hundreds of genes with a resolution reaching the single cell level. The method is based on a bar coding approach using a new protein.
Since sequencing the first human genome in the early 2000s revealed a set of more than 20,000 genes encoding proteins, scientists have not yet been able to characterize the many functions of a individual gene. Without this information, our understanding of how the human genome works – and how to use it to predict, prevent, treat and even cure a disease – is limited.
In 2012 and 2013, scientists have come up with a powerful new approach to gene editing, called CRISPR, that can be used to determine gene functions. CRISPR has taken the scientific world by storm, but researchers are still struggling to use CRISPR to study the thousands of genes and their multiple possible roles.
Pro-codes
The new technology developed by scientists at Mount Sinai's Icahn School of Medicine addresses the genomics challenge of analyzing the genome on an unprecedented scale. The research, led by Dr. Aleksandra Wroblewska, Postdoctoral Fellow and Maxime Dhainaut, Ph.D., is a new tool for bar code coding and tracking CRISPR using synthetic proteins called epitopes.
Protein barcodes, called Pro codes, make it possible to use hundreds of CRISPRs to destroy a multitude of genes.
Although there are existing technologies for grouping CRISPRs, these approaches rely heavily on DNA as a barcode and only allow a low-resolution analysis of gene function. Using the Pro-Code technique, Mount Sinai researchers have been able to demonstrate to scientists a way to more fully characterize the biological effects of a gene.
Target of immunotherapy against cancer
In this study, researchers used Pro-Code technology to look for genes needed by the immune system to protect against cancer. They generated CRISPRs aimed at suppressing genes suspected of regulating the immune system and coupled them with Pro-Codes.
Pro-Code / CRISPR libraries were then introduced into breast cancer cells and tumors were stimulated by killer T cells designed to recognize cancer cells. Most cancer cells were rapidly cleared by T cells, but some cells survived death.
Pro-Code technology identified which genes were lost in resistant cells, some with unrecognized roles in cancer cell sensitization in the immune system. Studies have also identified a negative regulator of immune control point PD-L1, a major clinical target for cancer immunotherapy.
"Much remains to be done to fully understand the human genome. We still do not know what most genes do and how they are connected. "" Pro-Code technology could dramatically accelerate one of the major goals of the post-genomic era: the annotation of the human genome. This discovery will be the key to discover genes responsible for diseases that may lead to new therapeutic targets. This has already brought us new insights into cancer immunology. "
said senior author Brian Brown, Ph.D., associate professor of genetics and genomic sciences and associate director of the Institute of Immunology at the Icahn Institute.
Aleksandra Wroblewska, Maxime Dhainaut, Benjamin Ben-Zvi, Samuel A. Rose, Eun Sook Park, El-Ad David Amir, Anela Bektesevic, Alessia Baccarini, Miriam Merad, Adeeb H. Rahman, Brian D. Brown
Protein barcodes enable high-dimensional single-cell CRISPR displays
Cell (2018). DOI: 10.1016 / j.cell.2018.09.022
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