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| Open AccessMouse genome rewriting and tailoring of three important disease loci
This study describes a method to insert large stretches of exogenous DNA into mammalian genomes, which is used to insert human ACE2 loci into mouse to produce a model of human SARS-CoV-2 infection.
- Weimin Zhang
- , Ilona Golynker
- & Jef D. Boeke
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Article
| Open AccessDesign and testing of a humanized porcine donor for xenotransplantation
Using kidneys from a genetically engineered porcine donor transplanted into a cynomolgus monkey model, the design, creation and long-term function of kidney grafts supporting life are explored.
- Ranjith P. Anand
- , Jacob V. Layer
- & Wenning Qin
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Article |
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 |
A swapped genetic code prevents viral infections and gene transfer
A study details the creation of an Escherichia coli genetically recoded organism that is resistant to viral infection, and describes a further modification that keeps the organism and its genetic information biocontained.
- Akos Nyerges
- , Svenja Vinke
- & George M. Church
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Article |
Co-opting signalling molecules enables logic-gated control of CAR T cells
Logic gating is used to develop a CAR T cell platform that is highly specific and allows the activity of T cells to be restricted to the encounter of two antigens, thus reducing on-target, off-tumour toxicity.
- Aidan M. Tousley
- , Maria Caterina Rotiroti
- & Robbie G. Majzner
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Article |
Recording gene expression order in DNA by CRISPR addition of retron barcodes
Retro-Cascorder, a system for time-ordered recording of transcriptional output, uses retrons as a tag to mediate DNA barcode acquisition in a CRISPR array.
- Santi Bhattarai-Kline
- , Sierra K. Lear
- & Seth L. Shipman
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Article
| Open AccessA 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 |
Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice
The bispecific IgG1-like CoV-X2 prevents SARS-CoV-2 spike binding to ACE2, neutralizes SARS-CoV-2 and its variants of concern, protects against disease in a mouse model, whereas the parental monoclonal antibodies generate viral escape.
- Raoul De Gasparo
- , Mattia Pedotti
- & Luca Varani
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Article |
De novo design of modular and tunable protein biosensors
A modular de novo designed biosensor platform consisting of a cage and key molecule is developed, and used to create sensors for seven distinct proteins including the spike protein from SARS-CoV-2 and anti-SARS antibodies.
- Alfredo Quijano-Rubio
- , Hsien-Wei Yeh
- & David Baker
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Article |
Computational design of transmembrane pores
An approach for the design of protein pores is demonstrated by the computational design and subsequent experimental expression of both an ion-selective and a large transmembrane pore.
- Chunfu Xu
- , Peilong Lu
- & David Baker
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Review Article |
Multispecific drugs herald a new era of biopharmaceutical innovation
The development and future prospects of prospectively designed multispecific drugs, which have the potential to transform the biopharmaceutical industry by enabling the targeting of currently inaccessible components of the proteome, are reviewed.
- Raymond J. Deshaies
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Article |
An engineered PET depolymerase to break down and recycle plastic bottles
Computer-aided engineering produces improvements to an enzyme that breaks down poly(ethylene terephthalate) (PET) into its constituent monomers, which are used to synthesize PET of near-petrochemical grade that can be further processed into bottles.
- V. Tournier
- , C. M. Topham
- & A. Marty
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Letter |
Population imaging of neural activity in awake behaving mice
A genetically encoded fluorescent voltage indicator, SomArchon, is used to image changes in membrane voltage from many neurons simultaneously in multiple brain regions of awake, behaving mice.
- Kiryl D. Piatkevich
- , Seth Bensussen
- & Xue Han
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Letter |
Modular and tunable biological feedback control using a de novo protein switch
DegronLOCKR designer-protein technology is used to implement synthetic positive- and negative-feedback systems in the yeast mating pathway as well as feedback control of a synthetic gene circuit.
- Andrew H. Ng
- , Taylor H. Nguyen
- & Hana El-Samad
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Article |
De novo design of bioactive protein switches
A technique for the de novo design of switchable protein systems controlled by induced conformational change is demonstrated for three functional motifs, in vitro and in yeast and mammalian cells.
- Robert A. Langan
- , Scott E. Boyken
- & David Baker
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Letter |
An ultra-stable gold-coordinated protein cage displaying reversible assembly
An artificial protein cage is readily assembled by metal ion coordination and disassembled by reducing agents, and displays excellent chemical and thermal stability.
- Ali D. Malay
- , Naoyuki Miyazaki
- & Jonathan G. Heddle
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Letter |
Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors
CRISPR DNA base editors induce transcriptome-wide off-target RNA editing, which can be reduced by using engineered variants that retain on-target DNA editing activities.
- Julian Grünewald
- , Ronghao Zhou
- & J. Keith Joung
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Letter |
Controlling orthogonal ribosome subunit interactions enables evolution of new function
Orthogonal ribosomes are engineered in which the two subunits are stapled together in a way that limits association with endogenous subunits in cells, enabling the evolution of new functionality in the orthogonal ribosome.
- Wolfgang H. Schmied
- , Zakir Tnimov
- & Jason W. Chin
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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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Article |
De novo design of a fluorescence-activating β-barrel
The elucidation of general principles for designing β-barrels enables the de novo creation of fluorescent proteins.
- Jiayi Dou
- , Anastassia A. Vorobieva
- & David Baker
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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 |
Evolution of a designed protein assembly encapsulating its own RNA genome
Computationally designed icosahedral protein-based assemblies can protect their genetic material and evolve in biochemical environments, suggesting a route to the custom design of synthetic nanomaterials for non-viral drug delivery.
- Gabriel L. Butterfield
- , Marc J. Lajoie
- & David Baker
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Letter |
Gigadalton-scale shape-programmable DNA assemblies
By using DNA sequence information to encode the shapes of DNA origami building blocks, shape-programmable assemblies can be created, with sizes and complexities similar to those of viruses.
- Klaus F. Wagenbauer
- , Christian Sigl
- & Hendrik Dietz
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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 |
CRISPR–Cas encoding of a digital movie into the genomes of a population of living bacteria
The authors encode pixel values of a short motion picture into the DNA of a population of Escherichia coli.
- Seth L. Shipman
- , Jeff Nivala
- & George M. Church
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Letter |
Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling
The authors describe water-soluble surrogate Wnt agonists, with specificity towards some frizzled (FZD) receptors, which can maintain human intestinal organoid cultures and have effects on the mouse liver in vivo.
- Claudia Y. Janda
- , Luke T. Dang
- & K. Christopher Garcia
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Article |
High-fidelity CRISPR–Cas9 nucleases with no detectable genome-wide off-target effects
A high-fidelity variant of Streptococcus pyogenes CRISPR–Cas9 is reported that lacks detectable off-target events as assessed by genome-wide break capture and targeted sequencing methods.
- Benjamin P. Kleinstiver
- , Vikram Pattanayak
- & J. Keith Joung
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Letter |
Engineered CRISPR-Cas9 nucleases with altered PAM specificities
CRISPR-Cas9 nucleases are widely used for genome editing, but the range of sequences that Cas9 can recognize is constrained by the need for a specific protospacer adjacent motif (PAM); here the commonly used Streptococcus pyogenes Cas9 (SpCas9) is modified to recognize alternative PAM sequences, enabling robust editing of endogenous gene sites in zebrafish and human cells not currently targetable by wild-type SpCas9.
- Benjamin P. Kleinstiver
- , Michelle S. Prew
- & J. Keith Joung
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Letter |
Synthesis and applications of RNAs with position-selective labelling and mosaic composition
A hybrid solid–liquid phase transcription method and automated robotic platform synthesizes position-specific, fluorescence- or isotope-labelled RNA.
- Yu Liu
- , Erik Holmstrom
- & Yun-Xing Wang
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Letter |
A semi-synthetic organism with an expanded genetic alphabet
Triphosphates of hydrophobic nucleotides d5SICS and dNaM are imported into Escherichia coli by an exogenous algal nucleotide triphosphate transporter and then used by an endogenous polymerase to replicate, and faithfully maintain over many generations of growth, a plasmid containing the d5SICS–dNaM unnatural base pair.
- Denis A. Malyshev
- , Kirandeep Dhami
- & Floyd E. Romesberg
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Outlook |
Antibiotic resistance: An infectious arms race
Winning the fight against infectious bacteria requires staying ahead of the organisms' uncanny ability to flank our frontal assaults. By Karyn Hede.
- Karyn Hede
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Outlook |
Perspective: The age of the phage
It's time to use viruses that kill bacteria again, say Shigenobu Matsuzaki, Jumpei Uchiyama, Iyo Takemura-Uchiyama and Masanori Daibata.
- Shigenobu Matsuzaki
- , Jumpei Uchiyama
- & Masanori Daibata
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Outlook |
Perspective: Synthetic biology revives antibiotics
Re-engineering natural products provides a new route to drug discovery, says Gerard Wright.
- Gerard Wright
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Outlook |
Diagnostics: Detection drives defence
Devices that quickly identify bacterial infections would benefit health and slow the spread of resistance.
- Rebecca Kanthor
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Outlook |
Drug development: Time for teamwork
In the face of more drug-resistant bugs and fewer new drugs, partnerships promise a resurgence of antibiotics.
- Mike May
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Outlook |
Public health: The politics of antibiotics
Policy-makers and medical experts need to think globally if we are to prevent an antibiotic 'tragedy of the commons'.
- Megan Cully
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Outlook |
Microbiology: Resistance fighters
Science goes back to nature to decipher and disrupt the mechanisms by which germs evade antibiotics.
- Bill Cannon
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Outlook |
Drug discovery: Leaving no stone unturned
New antibiotic treatments could be found by combining novel and existing drugs, in drug-free nanoparticles, or at the bottom of the sea.
- Katharine Gammon
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Spotlight |
Spotlight on Immunology
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Letter |
Synthetic analog computation in living cells
Synthetic analog gene circuits can be engineered to execute logarithmically linear sensing, addition, ratiometric and power-law computations in living cells using just three transcription factors.
- Ramiz Daniel
- , Jacob R. Rubens
- & Timothy K. Lu
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News |
Proteins made to order
Researchers design proteins from scratch with predictable structures.
- Jessica Marshall
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Article |
Principles for designing ideal protein structures
Rules that allow the design of strongly funnelled protein folding energy landscapes by relating secondary structure patterns to protein tertiary motifs are used to produce ideal protein structures stabilized by completely consistent local and non-local interactions.
- Nobuyasu Koga
- , Rie Tatsumi-Koga
- & David Baker
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Review Article |
Microbial engineering for the production of advanced biofuels
- Pamela P. Peralta-Yahya
- , Fuzhong Zhang
- & Jay D. Keasling
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Letter |
Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung
In a porcine cystic fibrosis model, lack of cystic fibrosis transmembrane conductance regulator (CFTR) is shown to result in acidification of airway surface liquid (ASL), and this decrease in pH reduces the ability of ASL to kill bacteria; the findings directly link loss of the CFTR anion channel to impaired defence against bacterial infection.
- Alejandro A. Pezzulo
- , Xiao Xiao Tang
- & Joseph Zabner
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Research Highlights |
Proteins designed to self-assemble
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Letter |
Programmable single-cell mammalian biocomputers
In synthetic biology, the use of regulatory proteins that bind either DNA or RNA to reprogram mammalian cellular functions allows a variety of computational ‘logic circuits’ to be built in a plug-and-play manner, which may pave the way for precise and robust control of future gene-based and cell-based therapies.
- Simon Ausländer
- , David Ausländer
- & Martin Fussenegger
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News |
Enzymes grow artificial DNA
Synthetic strands with different backbones replicate and evolve just like the real thing.
- Helen Shen
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