Recoding the Human Genome for Viral Resistance: Index #61
Recoding the Human Genome for Viral Resistance: Index #61
George Church's group takes a baby step.
I’m writing and editing weekly essays about science — history, problems with academia, alternative models — together with scientists, VCs, and entrepreneurs for New Science. I hope you’ll read them. You can subscribe here: newscience.substack.com.
Also, thanks to everyone who reached out at Future Forum. It was emotional to meet so many of you in person. The most common feedback: More hot takes! More opinions on the top papers each week! Ask and ye shall receive. Selected papers are now marked in bold, with little summaries written beneath them.
The Bio(tech) Index
(↑ = recommended article, * = open access, † = review, comment, etc. )
Basic Research
Utilization of diverse organophosphorus pollutants by marine bacteria. Despotović D…Tawfik DS. PNAS. Link
*Construction of a cross-species cell landscape at single-cell level. Wang R…Han X. Nucleic Acids Research. Link
↑The continuum of Drosophila embryonic development at single-cell resolution. Calderon D…Shendure J. Science. Link
This isn’t synthetic biology, really, but I don’t care. You should read this paper. Fly embryogenesis — an organism’s development from zygote to embryo — was studied in its entirety at the single-cell level. Chromatin accessibility was mapped in 1 million nuclei, and gene expression measured in half a million more nuclei, for all 20 hours of this process and “at the scale of minutes.” The result is a massive dataset — a foundational corpus — that explains enhancer usage and gene expression across the fly’s development.
↑*Architecture and self-assembly of the jumbo bacteriophage nuclear shell. Laughlin TG…Villa E. Nature. Link
Biomanufacturing & Metabolic Engineering
↑*Systematic strategies for developing phage resistant Escherichia coli strains. Zou X…Lee SY. Nature Communications. Link
Behold phage, reapers of death. Companies are terrified of them. If one phage sneaks its way into a bioreactor, the whole batch can be ruined. Genzyme shut down factories in 2008 and 2009 because of viral infections. Now, there’s a new way to make E. coli phage-resistant, and it’s really simple. First, mutate some of the ‘key’ components that phages hijack in the cell. Then, add in a ‘defense module’ (four genes; SspBCDE) that can recognize and cut non-self DNA, such as that introduced by phage. Adding in these genes does not reduce E. coli fitness; they grow like normal and become resistant to lots of different phage, including T5 and T7 and JMPW2.
*A versatile Cas12k-based genetic engineering toolkit (C12KGET) for metabolic engineering in genetic manipulation-deprived strains. Cui Y…Zhang D. Nucleic Acids Research. Link
*Novel genetic modules encoding high-level antibiotic-free protein expression in probiotic lactobacilli. Dey S…Sankaran S. bioRxiv (preprint). Link
†*What makes Yarrowia lipolytica well suited for industry? Park Y-K & Ledesma-Amaro R. Trends in Biotechnology. Link
*The influence of self-cycling fermentation long- and short-cycle schemes on Saccharomyces cerevisiae and Escherichia coli. Tan Y, Stein LY & Sauvageau D. Scientific Reports. Link
*Variability in Cell-Free Expression Reactions can Impact Qualitative Genetic Circuit Characterization. Rhea KA…Buckley PE. Synthetic Biology. Link
*Modulation of the cell wall protein Ecm33p in yeast Saccharomyces cerevisiae improves the production of small metabolites. Ramos-Viana V…Borodina I. FEMS Yeast Research. Link
Second-Generation Escherichia coli SuptoxR Strains for High-Level Recombinant Membrane Protein Production. Vasilopoulou E…Skretas G. ACS Synthetic Biology. Link
Spatiotemporal Regulation of Astaxanthin Synthesis in S. cerevisiae. Li M…Ye L. ACS Synthetic Biology. Link
*Bioreactor as the root cause of the “manganese effect” during Aspergillus niger citric acid fermentations. Fekete E…Karaffa L. Frontiers in Bioengineering and Biotechnology. Link
Biosensors & Biomaterials
†Engineered living bioassemblies for biomedical and functional material applications. Guimarães CF…Demirci U. Current Opinion in Biotechnology. Link
Circuits
Standardized excitable elements for scalable engineering of far-from-equilibrium chemical networks. Schaffter SW…Schulman R. Nature Chemistry. Link
↑*Pattern formation and bistability in a synthetic intercellular genetic toggle. Magalhães B-dF…Bennett MR. bioRxiv (preprint). Link
*Exploiting the Nonlinear Structure of the Antithetic Integral Controller to Enhance Dynamic Performance. Filo M…Khammash M. bioRxiv (preprint). Link
Computational Tools & Models
↑*Generating experimentally unrelated target molecule-binding highly functionalized nucleic-acid polymers using machine learning. Chen JC…Liu DR. Nature Communications. Link
↑*A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation. Khatri BS & Burt A. PNAS. Link
*Precision engineering of biological function with large-scale measurements and machine learning. Tack DS…Ross D. bioRxiv (preprint). Link
*Artificial selection methods from evolutionary computing show promise for directed evolution of microbes. Lalejini A…Zaman L. eLife. Link
↑I-TASSER-MTD: a deep-learning-based platform for multi-domain protein structure and function prediction. Zhou X…Zhang Y. Nature Protocols. Link
Sprod for de-noising spatially resolved transcriptomics data based on position and image information. Wang Y…Wang T. Nature Methods. Link
CRISPR & Gene Editing
↑*Multiplex base editing to convert TAG into TAA codons in the human genome. Chen Y…Church G. Nature Communications. Link
I first met George Church back in 2018. He talked about the merits of recoding the human genome for viral resistance even then. His team’s efforts started small, in bacteria, but proved wildly successful. In 2013, Lajoie et al. replaced all the UAG codons in E. coli with UAA. Freeing up a codon makes it possible to add nonstandard amino acids into proteins; it also makes cells resistant to bacteriophage, which have trouble deciphering the ‘recoded’ genome.
The latest Church lab paper reports a multiplexed base editor that can convert TAG —> TAA for 33 essential genes via a single transfection in human cells. It’s the first step towards, perhaps, a fully recoded human genome. But is this project lunacy? I think mostly. Will the news cover it as if scientists are gonna recode human embryos before IVF or something? Yes.
↑Hypercompact adenine base editors based on transposase B guided by engineered RNA. Kim DY…Kim Y-S. Nature Chemical Biology. Link
*Transcription-coupled donor DNA expression increases homologous recombination for efficient genome editing. Gao K…Gao G. Nucleic Acids Research. Link
*Robust counterselection and advanced λRed recombineering enable markerless chromosomal integration of large heterologous constructs. Bubnov DM…Sineoky SP. Nucleic Acids Research. Link
DNA Assembly
↑*Rapid and accurate assembly of large DNA assisted by in vitro packaging of bacteriophage. Nozaki S. bioRxiv (preprint). Link
*New* Longevity
*Systemic induction of senescence in young mice after single heterochronic blood exchange. Jeon OH…Conboy IM. Nature Metabolism. Link
Medicine & Diagnostics
*Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes. Russell BJ…Zarrinpar A. Cell. Link
†*Phage engineering and phage-assisted CRISPR-Cas delivery to combat multidrug-resistant pathogens. Khambhati K…Singh V. Bioengineering & Translational Medicine. Link
↑Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria. Wu RL…VRC 614 Study Team. The New England Journal of Medicine. Link
A phase I trial for an antibody-based malaria ‘protector’ (not a vaccine). It was tested in healthy adults who had never had malaria or a malaria vaccine, at three doses: 1, 5, or 20 mg per kilogram of body weight. A total of 23 participants — 17 who received the antibody, and 6 controls — were deliberately exposed to mosquitoes carrying Plasmodium falciparum at a U.S. Army facility in Maryland. The antibody has a half-life in blood serum of 56 days, and was protective: None of the participants who received an intravenous dose of 5 mg per kg of body weight, or higher, developed parasitemia. One participant had an adverse event.
↑*¬Post-Gastrulation Synthetic Embryos Generated Ex Utero from Mouse Naïve ESCs. Tarazi S…Hanna JH. Cell. Link
↑*Engineering micro oxygen factories to slow tumour progression via hyperoxic microenvironments. Wang W…Li R. Nature Communications. Link
*Spatiotemporal control of engineered bacteria to express interferon-γ by focused ultrasound for tumor immunotherapy. Chen Y…Yan F. Nature Communications. Link
†Prototype mouse models for researching SEND-based mRNA delivery and gene therapy. Gurumurthy CB, Quadros RM & Ohtsuka M. Nature Protocols. Link
*A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development. Benedetti V…Broccoli V. Science Advances. Link
Intracavity generation of glioma stem cell–specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy. Chen C…Jiang X. Science Translational Medicine. Link
Plants
*Pathway elucidation of bioactive rhamnosylated ginsenosides in Panax ginseng and their de novo high-level production by engineered Saccharomyces cerevisiae. Li C…Wang P. Communications Biology. Link
*Spatial resolution of an integrated C4+CAM photosynthetic metabolism. Moreno-Villena JJ…Edwards EJ. Science Advances. Link
*†CRISPR/Cas-based tools for the targeted control of plant viruses. Robertson G, Burger J & Campa M. Molecular Plant Pathology. Link
†Horizontal gene transfer from genetically modified plants - Regulatory considerations. Philips JG, Martin-Avila E & Robold AV. Frontiers in Bioengineering and Biotechnology. Link
*CRISPR/Cas9-mediated generation of non-motile mutants to improve the harvesting efficiency of mass-cultivated Euglena gracilis. Ishikawa M…Mochida K. Plant Biotechnology Journal. Link
Protein & Molecular Engineering
↑*From peptides to proteins: coiled-coil tetramers to single-chain 4-helix bundles. Naudin EA…Woolfson DN. bioRxiv (preprint). Link
↑*Multifunctional synthetic nano-chaperone for peptide folding and intracellular delivery. Pak I-S…Min D-H. Nature Communications. Link
*An efficient opal-suppressor tryptophanyl pair creates new routes for simultaneously incorporating up to three distinct noncanonical amino acids into proteins in mammalian cells. Osgood AO…Chatterjee A. bioRxiv (preprint). Link
*DNA Origami Presenting the Receptor Binding Domain of SARS-CoV-2 Elicit Robust Protective Immune Response. Oktay E…Veneziano R. bioRxiv (preprint). Link
*Precise epigenomic editing with a SunTag-based modular epigenetic toolkit. Guhathakurta S…Kim Y-S. Epigenetics. Link
*Generation of a recombinant antibody for sensitive detection of Pseudomonas aeruginosa. Lim G-M…Jeong H-J. BMC Biotechnology. Link
Tools & Technology
↑PROBER identifies proteins associated with programmable sequence-specific DNA in living cells. Mondal S…Khavari PA. Nature Methods. Link
Autoinducer-fluorophore conjugates enable FRET in LuxR proteins in vitro and in cells. Styles MJ…Blackwell HE. Nature Chemical Biology. Link
A yeast-based in vivo assay system for analyzing efflux of sugars mediated by glucose and xylose transporters. Rojas SAT, Boles E & Oreb M. FEMS Yeast Research. Link
*Combi-seq for multiplexed transcriptome-based profiling of drug combinations using deterministic barcoding in single-cell droplets. Mathur L…Merten CA. Nature Communications. Link
*Quantitative assaying of SpCas9-NG with fluorescent reporters. Baccouche A…Genot A. bioRxiv (preprint). Link
*Implementation of a Novel Optogenetic Tool in Mammalian Cells Based on a Split T7 RNA Polymerase. Dionisi S…Khammash M. ACS Synthetic Biology. Link
*Efficient detection and assembly of non-reference DNA sequences with synthetic long reads. Meleshko D…Hajirasouliha I. Nucleic Acids Research. Link
Other…
↑Potential of non-Saccharomyces yeast to produce non-alcoholic beer. Vaštík P…Šmogrovičová D. FEMS Yeast Research. Link
*Single mutation makes Escherichia coli an insect mutualist. Koga R…Fukatsu T. Nature Microbiology. Link
*In vivo study of the immune response to bioengineered spider silk spheres. Deptuch T…Dams-Kozlowska H. Scientific Reports. Link
More soon,
— Niko McCarty
Twitter: @NikoMcCarty // Email: niko@newscience.org