The Center for Genomically Engineered Organs (CGEO) will combine cutting edge genomics, genome editing technology, and tissue engineering methods to develop improved models of complex tissues. These tissues will be producible in laboratories from reprogrammed or genetically modified stem or other cells, will contain multiple cell types and vasculatures, and will be designed and rigorously compared against natural (healthy or diseased) tissues so that they match closely at both a molecular level and in overall tissue architecture. These model tissues have potential to greatly expedite biomedical progress by providing researchers a way to conduct preliminary tests of theories about normal and disease biology quickly and inexpensively in their laboratories before they have to move on to costly and potentially invasive experiments on animals or humans. CGEOs research is divided into three Aims.
In Aim 1, CGEO will develop methods to comprehensively analyze tissues in situ at a molecular level, by acquiring high-throughput RNA expression, protein expression, and epigenomic data together in each of the tissue's individual cells, along with the locations of these molecules in these cells.
In Aim 2, CGEO will develop and apply innovative computational algorithms that compare the cells in the model tissues against their corresponding natural counterparts and assess systematically not only how closely their corresponding cell type molecular profiles match, but also compare their overall cell architectures and relationships. These algorithms will also specify how genome editing and engineering can be used to improve the matching between the engineered cells in the model tissue and the natural cells of the native tissue. CGEO will apply these technologies to build model tissues important to neurobiology and hematopoiesis, and, finally, in Aim 3, also apply them to in vitro cultured embryos and germ line tissues in mice, which has potential to reveal pathways that will enable models of all tissues to be generated in a laboratory. CGEO is a collaboration of six laboratories in the Boston area with combined expertise in advanced genomic and proteomic technology, genome engineering, developmental systems, stem cell technology, epigenetics, super-resolution microscopy, and tissue engineering. The CGEO team comprises Professors George Church (Principal Investigator), David Sinclair, and Chao-Ting Wu (all from Harvard Medical School), Ed Boyden (MIT), George Daley (Children's Hospital), and Jennifer Lewis (Wyss Institute at Harvard).
The Center for Genomically Engineered Organs will develop methods for making tissues in laboratories that closely match normal or diseased tissues in humans and animals. Such model tissues will accelerate biomedical research by providing easy ways to conduct preliminary tests of theories of normal tissue function, or that explore the effects of diseases and treatments, before moving to potentially invasive experiments or costly clinical trials. The Center will use cutting edge methods that allow vast number of individual molecules of DNA, RNA, and protein to be visualized in the individual cells of tissues, enable stem cells to be genetically edited and reprogrammed into other cell types, and that permit cells of different types to be assembled into complex vascularized tissues.
|Clarke, Ryan; Heler, Robert; MacDougall, Matthew S et al. (2018) Enhanced Bacterial Immunity and Mammalian Genome Editing via RNA-Polymerase-Mediated Dislodging of Cas9 from Double-Strand DNA Breaks. Mol Cell 71:42-55.e8|
|Shapiro, Rebecca S; Chavez, Alejandro; Porter, Caroline B M et al. (2018) A CRISPR-Cas9-based gene drive platform for genetic interaction analysis in Candida albicans. Nat Microbiol 3:73-82|
|Chan, Yingleong; Chan, Ying Kai; Goodman, Daniel B et al. (2018) Enabling multiplexed testing of pooled donor cells through whole-genome sequencing. Genome Med 10:31|
|Karagiannis, Emmanouil D; Boyden, Edward S (2018) Expansion microscopy: development and neuroscience applications. Curr Opin Neurobiol 50:56-63|
|Bester, Assaf C; Lee, Jonathan D; Chavez, Alejandro et al. (2018) An Integrated Genome-wide CRISPRa Approach to Functionalize lncRNAs in Drug Resistance. Cell 173:649-664.e20|
|Guo, Xiaoge; Chavez, Alejandro; Tung, Angela et al. (2018) High-throughput creation and functional profiling of DNA sequence variant libraries using CRISPR-Cas9 in yeast. Nat Biotechnol 36:540-546|
|Chavez, Alejandro; Pruitt, Benjamin W; Tuttle, Marcelle et al. (2018) Precise Cas9 targeting enables genomic mutation prevention. Proc Natl Acad Sci U S A 115:3669-3673|
|Oran, Daniel; Rodriques, Samuel G; Gao, Ruixuan et al. (2018) 3D nanofabrication by volumetric deposition and controlled shrinkage of patterned scaffolds. Science 362:1281-1285|
|Asano, Shoh M; Gao, Ruixuan; Wassie, Asmamaw T et al. (2018) Expansion Microscopy: Protocols for Imaging Proteins and RNA in Cells and Tissues. Curr Protoc Cell Biol 80:e56|
|Yeo, Nan Cher; Chavez, Alejandro; Lance-Byrne, Alissa et al. (2018) An enhanced CRISPR repressor for targeted mammalian gene regulation. Nat Methods 15:611-616|
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