David R. Liu
Broad Institute
Molecular biologyChemistryDNABiochemistryBiology
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Publications 360
#1Ruth E Hanna (Broad Institute)H-Index: 4
#2Mudra Hegde (Broad Institute)H-Index: 6
Last. Yossef Baidi (Broad Institute)
view all 14 authors...
Understanding the functional consequences of single-nucleotide variants is critical to uncovering the genetic underpinnings of diseases, but technologies to characterize variants are limiting. Here we leverage CRISPR-Cas9 cytosine base editors in pooled screens to scalably assay variants at endogenous loci in mammalian cells. We benchmark the performance of base editors in positive and negative selection screens and identify known loss-of-function mutations in BRCA1 and BRCA2 with high precision...
#1Julie Rolla (OSU: Ohio State University)
#2Amy ConnollyH-Index: 13
view all 19 authors...
Evolutionary algorithms borrow from biology the concepts of mutation and selection in order to evolve optimized solutions to known problems. The GENETIS collaboration is developing genetic algorithms for designing antennas that are more sensitive to ultra-high energy neutrino induced radio pulses than current designs. There are three aspects of this investigation. The first is to evolve simple wire antennas to test the concept and different algorithms. Second, optimized antenna response patterns...
#1Jeffrey C. Davis (Harvard University)H-Index: 1
#2Tiago C. Alves (Yale University)H-Index: 13
Last. Doug Melton (Harvard University)H-Index: 114
view all 9 authors...
Summary Stem cell-derived β (SC-β) cells could provide unlimited human β cells toward a curative diabetes treatment. Differentiation of SC-β cells yields transplantable islets that secrete insulin in response to glucose challenges. Following transplantation into mice, SC-β cell function is comparable to human islets, but the magnitude and consistency of response in vitro are less robust than observed in cadaveric islets. Here, we profile metabolism of SC-β cells and islets to quantify their capa...
#1Cecile Gstalder (Harvard University)
#2David R. Liu (Harvard University)H-Index: 73
Last. Scott L. Carter (Harvard University)H-Index: 67
view all 24 authors...
The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a melanoma patient who displayed heterogeneous responses to anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, while a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to ...
#1Jonathan Y. Hsu (MIT: Massachusetts Institute of Technology)H-Index: 6
#2Andrew V. Anzalone (Broad Institute)
Last. Luca Pinello (Harvard University)H-Index: 22
view all 8 authors...
Prime editing (PE) is a versatile genome editing technology, but design of the required guide RNAs is more complex than for standard CRISPR-based nucleases or base editors. Here we describe PrimeDesign, a user-friendly, end-to-end web application and command-line tool for the design of PE experiments. PrimeDesign can be used for single and combination editing applications, as well as genome-wide and saturation mutagenesis screens. Using PrimeDesign, we also constructed PrimeVar, the first compre...
#1Tingting Jiang (UMMS: University of Massachusetts Medical School)H-Index: 2
Last. Gregory A. Newby (Broad Institute)H-Index: 7
view all 17 authors...
CRISPR-Cas9-associated base editing is a promising tool to correct pathogenic single nucleotide mutations in research or therapeutic settings. Efficient base editing requires cellular exposure to levels of base editors that can be difficult to attain in hard-to-transfect cells or in vivo. Here we engineer a chemically modified mRNA-encoded adenine base editor that mediates robust editing at various cellular genomic sites together with moderately modified guide RNA, and show its therapeutic poten...
#1Diana D. Shi (Brigham and Women's Hospital)H-Index: 5
#1Diana D. Shi (Brigham and Women's Hospital)
Last. Ayal A. Aizer (Brigham and Women's Hospital)H-Index: 27
view all 9 authors...
Abstract Background The use of targeted therapies and immune checkpoint inhibitors has drastically changed the management of patients with melanoma and brain metastases. Specifically, combination therapy with ipilimumab, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, has become a preferred systemic therapy option for patients with melanoma and asymptomatic brain metastases. However, the efficacy and toxicity profile of th...
#1Meng Xiao He (Harvard University)H-Index: 3
#2Michael S. Cuoco (Broad Institute)H-Index: 3
Last. Laura Dellostritto (Harvard University)
view all 26 authors...
Metastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients. Both ...
#1Michelle Richter (Broad Institute)H-Index: 1
#2Kevin T. Zhao (Broad Institute)H-Index: 5
Last. Daniel E. Bauer (Harvard University)H-Index: 34
view all 12 authors...
Applications of adenine base editors (ABEs) have been constrained by the limited compatibility of the deoxyadenosine deaminase component with Cas homologs other than SpCas9. We evolved the deaminase component of ABE7.10 using phage-assisted non-continuous and continuous evolution (PANCE and PACE), which resulted in ABE8e. ABE8e contains eight additional mutations that increase activity (kapp) 590-fold compared with that of ABE7.10. ABE8e offers substantially improved editing efficiencies when pa...
1 CitationsSource
#1Qiupeng Lin (CAS: Chinese Academy of Sciences)H-Index: 1
#2Yuan Zong (CAS: Chinese Academy of Sciences)H-Index: 7
Last. Jordan L. Doman (Broad Institute)H-Index: 3
view all 12 authors...
Prime editors, which are CRISPR–Cas9 nickase (H840A)–reverse transcriptase fusions programmed with prime editing guide RNAs (pegRNAs), can edit bases in mammalian cells without donor DNA or double-strand breaks. We adapted prime editors for use in plants through codon, promoter, and editing-condition optimization. The resulting suite of plant prime editors enable point mutations, insertions and deletions in rice and wheat protoplasts. Regenerated prime-edited rice plants were obtained at frequen...
4 CitationsSource