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Continuous synthesis of E. coli genome sections and Mb-scale human DNA assembly
BAC stepwise insertion synthesis (BASIS) can be used to build synthetic genomes for diverse organisms, and continuous genome synthesis (CGS) enables the rapid synthesis of entire Escherichia coli genomes from functional designs.
- Jérôme F. Zürcher
- , Askar A. Kleefeldt
- & Jason W. Chin
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Article |
Genome editing of a rice CDP-DAG synthase confers multipathogen resistance
Editing of a rice gene that has a role in phospholipid synthesis has endowed rice plants with broad-spectrum resistance to disease, including protection from common bacterial and fungal pathogens, without decreasing the yield.
- Gan Sha
- , Peng Sun
- & Guotian Li
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Article
| Open Access
R-loop formation and conformational activation mechanisms of Cas9
Cryo-electron microscopy structures of Streptococcus pyogenes Cas9 in multiple DNA-bound states provide insights on the mechanism of Cas9 activation by target DNA.
- Martin Pacesa
- , Luuk Loeff
- & Martin Jinek
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Article
| Open Access
A time-resolved, multi-symbol molecular recorder via sequential genome editing
A DNA memory device, DNA Typewriter, uses sequential prime editing to record the order of multiple cellular events.
- Junhong Choi
- , Wei Chen
- & Jay Shendure
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Article
| Open Access
Structural basis for mismatch surveillance by CRISPR–Cas9
Cryo-electron microscopy structures of Cas9 during mismatch cleavage provide insight into the mechanisms that control off-target effects of Cas9, which will aid in the future design of high-fidelity Cas9 variants with reduced off-target cleavage.
- Jack P. K. Bravo
- , Mu-Sen Liu
- & David W. Taylor
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Article |
Base editing of haematopoietic stem cells rescues sickle cell disease in mice
A custom adenine base editor can edit the variant of the β-globin gene that causes sickle cell disease into a non-pathogenic variant in human and mouse cells, and transplantation of the edited cells rescues sickle cell disease in mice.
- Gregory A. Newby
- , Jonathan S. Yen
- & David R. Liu
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Article |
In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates
In a cynomolgus macaque model, CRISPR base editors delivered in lipid nanoparticles are shown to efficiently and stably knock down PCSK9 in the liver to reduce levels of PCSK9 and low-density lipoprotein cholesterol in the blood.
- Kiran Musunuru
- , Alexandra C. Chadwick
- & Sekar Kathiresan
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Article |
A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing
An interbacterial toxin that catalyses the deamination of cytidines within double-stranded DNA forms part of a CRISPR-free, RNA-free base editing system that enables manipulation of human mitochondrial DNA.
- Beverly Y. Mok
- , Marcos H. de Moraes
- & David R. Liu
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Article |
Search-and-replace genome editing without double-strand breaks or donor DNA
A new DNA-editing technique called prime editing offers improved versatility and efficiency with reduced byproducts compared with existing techniques, and shows potential for correcting disease-associated mutations.
- Andrew V. Anzalone
- , Peyton B. Randolph
- & David R. Liu
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Letter |
Off-target RNA mutation induced by DNA base editing and its elimination by mutagenesis
Cytosine and adenine base editors have undesired off-target effects on RNA, but this activity can be reduced in deaminase-engineered variants while preserving on-target DNA editing.
- Changyang Zhou
- , Yidi Sun
- & Hui Yang
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Article |
Total synthesis of Escherichia coli with a recoded genome
High-fidelity convergent total synthesis is used to produce
Escherichia coli with a 61-codon synthetic genome that uses 59 codons to encode all of the canonical amino acids.- Julius Fredens
- , Kaihang Wang
- & Jason W. Chin
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Letter |
Precise therapeutic gene correction by a simple nuclease-induced double-stranded break
Disease-causing microduplications can be corrected by harnessing an endogenous double-stranded break DNA repair pathway.
- Sukanya Iyer
- , Sneha Suresh
- & Scot A. Wolfe
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Article |
Transcriptional recording by CRISPR spacer acquisition from RNA
An RNA-adapting CRISPR–Cas system is coupled with amplification and sequencing steps to record, retrieve and analyse changes in the transcriptome of a bacterial cell over time.
- Florian Schmidt
- , Mariia Y. Cherepkova
- & Randall J. Platt
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Brief Communications Arising |
Large deletions induced by Cas9 cleavage
- Fatwa Adikusuma
- , Sandra Piltz
- & Paul Q. Thomas
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Letter |
CRISPR-guided DNA polymerases enable diversification of all nucleotides in a tunable window
A system that targets DNA polymerase activity with CRISPR-guided nickases to provide genetic diversification at user-defined loci enables forward genetic approaches.
- Shakked O. Halperin
- , Connor J. Tou
- & John E. Dueber
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Letter |
Reprogramming human T cell function and specificity with non-viral genome targeting
A non-viral strategy to introduce large DNA sequences into T cells enables the correction of a pathogenic mutation that causes autoimmunity, and the replacement of an endogenous T-cell receptor with an engineered receptor that can recognize cancer antigens.
- Theodore L. Roth
- , Cristina Puig-Saus
- & Alexander Marson
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Article |
Evolved Cas9 variants with broad PAM compatibility and high DNA specificity
Phage-assisted continuous evolution of Cas9 variants with broad PAM compatibility and high DNA specificity that can be used for transcriptional activation, gene disruption and base editing.
- Johnny H. Hu
- , Shannon M. Miller
- & David R. Liu
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Letter |
Acoustic reporter genes for noninvasive imaging of microorganisms in mammalian hosts
Heterologous expression of engineered gas vesicles allows noninvasive, deep-tissue ultrasound visualization of engineered bacteria in vivo in mouse tumour models and in the gastrointestinal tract.
- Raymond W. Bourdeau
- , Audrey Lee-Gosselin
- & Mikhail G. Shapiro
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Letter |
Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents
CRISPR–Cas9 genome editing is used to correct a dominant-negative mutation in a mouse model of inherited deafness, resulting in improvements in cochlear function and hearing.
- Xue Gao
- , Yong Tao
- & David R. Liu
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Article |
Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage
A new DNA ‘base editor’ can change targeted A•T base pairs to G•C, allowing disease-associated mutations to be corrected and disease-suppressing mutations to be introduced into cells.
- Nicole M. Gaudelli
- , Alexis C. Komor
- & David R. Liu
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Review Article |
Expanding and reprogramming the genetic code
A review of the recent developments in reprogramming the genetic code of cells and organisms to include non-canonical amino acids in precisely engineered proteins.
- Jason W. Chin
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Letter |
RNA targeting with CRISPR–Cas13
The class 2 type VI RNA-guided RNA-targeting CRISPR–Cas effector Cas13 can be engineered for RNA knockdown and binding, expanding the CRISPR toolset with a flexible platform for studying RNA in mammalian cells and therapeutic development.
- Omar O. Abudayyeh
- , Jonathan S. Gootenberg
- & Feng Zhang
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Letter |
Enhanced proofreading governs CRISPR–Cas9 targeting accuracy
A new engineered version of SpCas9, called HypaCas9, displays enhanced accuracy of editing without significant loss of efficiency at the desired target.
- Janice S. Chen
- , Yavuz S. Dagdas
- & Jennifer A. Doudna
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Letter |
Synthetic recording and in situ readout of lineage information in single cells
A new system, termed MEMOIR, allows cells to record lineage and gene expression history within their own genome in a format that can be read out in single cells in situ.
- Kirsten L. Frieda
- , James M. Linton
- & Long Cai
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Letter |
Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9
A CRISPR/Cas9 genome editing framework has been developed that allows controlled introduction of mono- and bi-allelic sequence changes, and is used to generate induced human pluripotent stem cells with heterozygous and homozygous dominant mutations in amyloid precursor protein and presenilin 1 that have been associated with early onset Alzheimer’s disease.
- Dominik Paquet
- , Dylan Kwart
- & Marc Tessier-Lavigne
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Letter |
The crystal structure of Cpf1 in complex with CRISPR RNA
The crystal structure of monomeric Lachnospiraceae bacterium Cpf1 protein bound to CRISPR RNA is presented, establishing a framework for engineering LbCpf1 to improve its efficiency and specificity for genome editing.
- De Dong
- , Kuan Ren
- & Zhiwei Huang
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Letter |
Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage
CRISPR/Cas9 DNA editing creates a double-stranded break in the target DNA, which can frequently generate random insertion or deletion of bases (indels); a new genome editing approach combining Cas9 with a cytidine deaminase is described here, which corrects point mutations more efficiently than canonical Cas9, while avoiding double-stranded breaks and indel formation.
- Alexis C. Komor
- , Yongjoo B. Kim
- & David R. Liu
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Letter |
The CRISPR-associated DNA-cleaving enzyme Cpf1 also processes precursor CRISPR RNA
The CRISPR-associated protein Cpf1 from Francisella novicida is a novel enzyme with specific, dual-endoribonuclease–endonuclease activities in precursor crRNA processing and crRNA-programmable cleavage of target DNA.
- Ines Fonfara
- , Hagen Richter
- & Emmanuelle Charpentier
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Letter |
Structural basis for promiscuous PAM recognition in type I–E Cascade from E. coli
The structure of E. coli Cascade bound to foreign target DNA is presented, revealing the basis of the relaxed Cascade PAM recognition specificity, which results from its interaction with the minor groove, and demonstrating how a wedge in Cascade forces the directional pairing of the target strand with CRISPR RNA while stabilizing the non-target displaced strand.
- Robert P. Hayes
- , Yibei Xiao
- & Ailong Ke
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Article |
BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis
A CRISPR-Cas9 approach is used to perform saturating mutagenesis of the human and mouse BCL11A enhancers, producing a map that reveals critical regions and specific vulnerabilities; BCL11A enhancer disruption is validated by CRISPR-Cas9 as a therapeutic strategy for inducing fetal haemoglobin by applying it in both mice and primary human erythroblast cells.
- Matthew C. Canver
- , Elenoe C. Smith
- & Daniel E. Bauer
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Article |
In vivo genome editing using Staphylococcus aureus Cas9
The physical size of the commonly used Cas9 from Streptococcus pyogenes poses challenges for CRISPR-Cas genome editing systems that use the adeno-associated virus as a delivery vehicle; here, smaller Cas9 orthologues are characterized, and Cas9 from Staphylococcus aureus allowed targeting of the cholesterol regulatory gene Pcsk9 in the mouse liver.
- F. Ann Ran
- , Le Cong
- & Feng Zhang
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Letter |
In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system
The CRISPR/Cas system has been used to induce the Eml4–Alk chromosomal inversion in mice, a characteristic chromosomal rearrangement seen in human non-small cell lung cancers; the mice developed lung cancer and responded to the ALK inhibitor crizotinib, which is used to treat lung cancer patients with the EML4–ALK rearrangement; this general strategy can be used to engineer other disease-associated chromosomal rearrangements in mice and potentially in other organisms.
- Danilo Maddalo
- , Eusebio Manchado
- & Andrea Ventura
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Letter |
Structural basis of PAM-dependent target DNA recognition by the Cas9 endonuclease
Crystal structure of the RNA-guided endonuclease Cas9 bound to a guide RNA and a target DNA duplex reveals how base-specific recognition of a short motif known as PAM in the DNA target results in localized strand separation in the DNA immediately upstream of the PAM, allowing the target DNA strand to hybridize to the guide RNA.
- Carolin Anders
- , Ole Niewoehner
- & Martin Jinek
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News |
Transgenic fish swims up regulatory stream
A fast-growing salmon moves closer to US approval after a fishy delay.
- Amy Maxmen
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News |
Pig geneticists go the whole hog
Genome will benefit farmers and medical researchers.
- Alison Abbott
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News |
Politics holds back animal engineers
Funds and approvals lag for transgenic livestock in US.
- Amy Maxmen
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News |
Animals engineered with pinpoint accuracy
More accurate genetic modification has created allergen-free cow's milk and pigs that could serve as a model for atherosclerosis.
- Amy Maxmen
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Letter |
Androgenetic haploid embryonic stem cells produce live transgenic mice
Mouse androgenetic haploid embryonic stem cell lines can be established by transferring sperm into an enucleated oocyte; the cells maintain haploidy and stable growth over 30 passages, express pluripotent markers, are able to differentiate into all three germ layers, contribute to germlines of chimaeras when injected into blastocysts and can produce fertile progeny that carry genetic modifications to the next generation.
- Wei Li
- , Ling Shuai
- & Qi Zhou
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News |
Maize cells produce enzyme-replacement drug
A genetic tweak keeps problematic plant sugars off therapeutic proteins.
- Monya Baker
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Review Article |
Exploiting diversity and synthetic biology for the production of algal biofuels
- D. Ryan Georgianna
- & Stephen P. Mayfield
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News |
Artificial jellyfish built from rat cells
Reverse-engineered life form could be used to test drugs.
- Ed Yong
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News |
Florida abuzz over mosquito plan
Biotech firm’s bid to control dengue fever using genetically modified insects faces growing public opposition.
- Amy Maxmen
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Outlook |
Vaccines: The take-home lesson
The nearly century-long search for a malaria vaccine might end in the bottom of a cup.
- Sarah DeWeerdt
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Books & Arts |
Q&A: Transgene curator
Next month in Pittsburgh, Pennsylvania, artist Richard Pell opens the Center for PostNatural History — a museum of bioengineered organisms. He talks about the joys and pitfalls involved in collecting genetically modified maize, mosquitoes and zebrafish.
- Jascha Hoffman
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Research Highlights |
Silkworms spin spider-like silk
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Letter |
Biomimetic self-templating supramolecular structures
- Woo-Jae Chung
- , Jin-Woo Oh
- & Seung-Wuk Lee
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Brief Communications Arising |
Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes
- Mohan Viswanathan
- & Leonard Guarente
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Letter |
Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans
- Caroline J. Breitbach
- , James Burke
- & David H. Kirn
Transgenic ferret models define pulmonary ionocyte diversity and function