Center for Genomic Editing and Recording: Development and Application of Next-Generation Genome and Epigenome Editing Methods to Advance the Study and Treatment of Human Disease

CENTER FOR GENOME EDITING AND RECORDING: PROJECT SUMMARY Recent advances in DNA sequencing and bioinformatics have generated vast numbers of sequence variants associated with disease that, in principle, hold the keys to breakthroughs in preventive medicine and therapeutic intervention. However, realizing the promise of personalized medicine will require accurate manipulation of DNA sequences and gene expression as well as interrogation of the functional consequences of sequence variants at a scale and level of accuracy not currently possible. The Center for Genome Editing and Recording (CGER) will address these challenges by creating technologies to detect, alter and record the sequence and output of the genome in individual cells and tissues. The CGER will exploit the programmable DNA binding and nickase activity of CRISPR-Cas proteins as well as engineered zinc finger and TALE proteins to create a new generation of tools to precisely engineer the genome and epigenome. These platforms will enable high-precision engineering of both the nuclear and mitochondrial genomes as well as heritable silencing or activation of messenger RNAs, long noncoding RNA and a host of other regulatory elements such as enhancers and insulator regions. Critically, these alterations can be made without introducing double stranded breaks to DNA, thereby avoiding DNA toxicity and minimizing reliance on complex and difficult-to-control endogenous DNA repair pathways. Collectively, these technologies will usher in a new era of safer, high precision and multiplexed genome and epigenome editing. In addition, we will exploit these platforms to develop higher-level multichannel molecular recorders that will allow us to track and reconstruct the life history of cells in an in vivo setting. We will add the ability to follow cells in space and time as well as record the history of their past cellular states to the existing phylogenetic lineage tracing systems pioneered in the previous embodiment of this Center. The center will be led by a team that collectively has a remarkable track record of developing bold, impactful new tools to expand their precision, efficacy, safety and scope, and finally exploiting these new capabilities to develop novel strategies to explore fundamental biological and biomedical problems. Our multidisciplinary team has a rich history of working together, which has been greatly accelerated by the CEGS structure in a manner that would simply not be possible if each co-PI had been working on similar problems in isolation. Leveraging the capabilities of the Whitehead Institute, MIT, The Broad Institute, Harvard University, Harvard Medical School, The Lewis Sigler Institute for Integrative Genomics at Princeton and the Massachusetts General Hospital, we aim to create transformative capabilities and have access to state-of-the- art research facilities as well as resources for training, education and outreach that will attract diverse talent to the field of genomics research.