Phage Therapy Treats Resistant Lung Infection: Codon Index #49
Plus: Mitochondrial base editors cause many off-target mutations & sniffing cytomegalovirus extends mouse lifespan.
Hello. Thanks, as always, for reading.
TL;DR: A patient with cystic fibrosis and a treatment-resistant Mycobacterium abscessus infection was successfully treated with engineered bacteriophages in a major milestone for phage-based therapies. And mice that inhale cytomegalovirus vectors containing one of two genes, either telomerase reverse transcriptase or follistatin, live much longer than untreated mice.
Phage Cure
Felix d’Herelle, microbiology extraordinaire at the Institut Pasteur in Paris, first proposed in 1917 that bacteriophages — little viruses that infect bacteria — could eradicate bacterial infections. Phage therapies swelled in popularity and were a hot topic throughout the 1920s and 1930s. The approach was supplanted by penicillin and antibiotics in the 1940s, while phage therapy reverted to a ‘backwater’ sort of science; a fringe field of study.
Its return to science in the last decade, though, has been transcendent. For a new study in Cell, a 26-year-old patient with cystic fibrosis and a treatment-resistant infection of Mycobacterium abscessus was treated with two bacteriophages that completely eradicated his infection. This paper marks a major milestone; one that could prove pivotal for treating antibiotic-resistant infections in the future.
M. abscessus bacteria grow quickly and are multidrug-resistant. This patient had been battling an M. abscessus infection for about five years before he started on the phage treatment, and “was maintained on four to five drugs” for that time, according to the study.
Researchers on this paper — led by Jerry Nick, Graham Hatfull and Rebecca Davidson at National Jewish Health in Denver, Colorado and the University of Pittsburgh — first swabbed some of the bacteria from the patient and then screened for phages that were most effective at infecting and lysing those cells. They found two phages that, either alone or in combination, could destroy the bacteria — BPsΔ33HTH_HRM10 and D29_HRMGD40.
In September 2020, the patient was intravenously injected, twice a day, with a billion plaque-forming units of the first phage and 100 million of the second phage. He was thus injected, in this way, every day through at least March 2022, without any observable side effects.
About one year after phage treatment began, the patient received a lung transplant. A bit of tissue from that excised lung was tested for M. abscessus, and no bacteria were found. The patient was tested for anti-phage antibodies — and had lots of them — but this immune response didn’t dampen the phage therapy’s effects. This paper, then, will likely become the standard-bearer for many bacteriophage therapies yet to come.
Read more at Cell.
Sniffing Viruses
This is a strange study. I’m not sure what to think about it.
There are so-called “protective” factors that increase longevity. A protein called telomerase reverse transcriptase, or TERT, maintains telomere ends on chromosomes by adding a TTAGGG repeat. More TERT expression is typically correlated with a longer lifespan. Follistatin, a protein that binds to proteins in the TGF-β pathway, is another such protective factor.
For this study, researchers packaged a gene encoding the TERT or follistatin proteins inside of a cytomegalovirus vector, and shot those viruses into mice. Mice that inhaled or were injected with the TERT lived 41.4 percent (median value) longer than untreated animals. Mice that inhaled the follistatin lived 32.5 percent longer. Injected and inhaled modalities worked equally well.
TERT expression, the researchers found, peaked around 7 days post-injection or post-inhalation. Each virus was tested on nine female mice, and treatments started ebgan at 18 months of age (which is quite old for a mouse). Animals either received a mock injection (saline), inhaled empty cytomegalovirus, were injected with empty cytomegalovirus, or else were injected (or inhaled) cytomegalovirus packed with TERT or follistatin. Considering that the treatments began at 18 months of age in the mice, the survival curves seem extremely remarkable.
I’m excited to see how this study will be extended. Would other viral vectors work equally well, or is there some inherent property of cytomegalovirus that help them to prolong lifespan?
Read more at PNAS.
Other Papers
(↑ = recommended article, * = open access, † = review article, )
Basic Research
↑*A prebiotically plausible scenario of an RNA–peptide world. Müller F…Carell T. Nature. Link
Revival of light signalling in the postmortem mouse and human retina. Abbas F…Vinberg F. Nature. Link
*A synthetic communication system uncovers self-jamming of bacteriophage transmission. Pathania A…Kushwaha M. bioRxiv (preprint). Link
A splitCas9 phenotypic screen in Toxoplasma gondii identifies proteins involved in host cell egress and invasion. Li W…Jimenez-Ruiz E. Nature Microbiology. Link
*Genome-wide CRISPR screens using isogenic cells reveal vulnerabilities conferred by loss of tumor suppressors. Feng X…Chen J. Science Advances. Link
Biomanufacturing
↑*Metabolite trafficking enables membrane-impermeable-terpene secretion by yeast. Son S…Lee JY. Nature Communications. Link
*†Advances and challenges in photosynthetic hydrogen production. Redding KE…Gutekunst K. Trends in Biotechnology. Link
*Expanding the use of ethanol as a feedstock for cell-free synthetic biochemistry by implementing acetyl-CoA and ATP generating pathways. Liu H, Arbing MA & Bowie JU. Scientific Reports. Link
*Pathway Engineering, Re-targeting, and Synthetic Scaffolding Improve the Production of Squalene in Plants. Bibik JD…Hamberger BR. ACS Synthetic Biology. Link
*Codon-Reduced Protein Synthesis With Manipulating tRNA Components in Cell-Free System. Li J, Tang M & Qi H. Frontiers in Bioengineering and Biotechnology. Link
Biomaterials
*A sustainable single-component “Silk nacre”. Xu Z…Bai H. Science Advances. Link
Computational Tools & Models
*DLEB: a web application for building deep learning models in biological research. Wy S…Kim J. Nucleic Acids Research. Link
*BioTransformer 3.0—a web server for accurately predicting metabolic transformation products. Wishart DS…Metz TO. Nucleic Acids Research. Link
CRISPR & Genetic Control
*Genome editing in animals with minimal PAM CRISPR-Cas9 enzymes. Vicencio J…Moreno-Mateos MA. Nature Communications. Link
*PERSIST platform provides programmable RNA regulation using CRISPR endoRNases. DiAndreth B…Weiss R. Nature Communications. Link
↑*Modulating gene regulation function by chemically controlled transcription factor clustering. Wu J…Lin Y. Nature Communications. Link
Genome Editing
↑Mitochondrial base editor induces substantial nuclear off-target mutations. Lei Z…Yi C. Nature. Link
*Double-tap gene drive uses iterative genome targeting to help overcome resistance alleles. Bishop AL…Gantz VM. Nature Communications. Link
*Targeting double-strand break indel byproducts with secondary guide RNAs improves Cas9 HDR-mediated genome editing efficiencies. Bodai Z…Komor AC. Nature Communications. Link
*Introduction of loxP sites by electroporation in the mouse genome; a simple approach for conditional allele generation in complex targeting loci. Bernas G…Schmouth J. BMC Biotechnology. Link
Medicine & Diagnostics
↑↑↑Noninvasive assessment of gut function using transcriptional recording sentinel cells. Schmidt F...Platt RJ. Science. Link (Read more at ETH Zurich and Science news).
*†The clinical progress of mRNA vaccines and immunotherapies. Barbier AJ…Anderson DG. Nature Biotechnology. Link
*Three SARS-CoV-2 antibodies provide broad and synergistic neutralization against variants of concern, including Omicron. Wang S…Xia N. Cell Reports. Link
Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker. Mansurov A…Hubbell JA. Nature Biomedical Engineering. Link
*In vivo hitchhiking of immune cells by intracellular self-assembly of bacteria-mimetic nanomedicine for targeted therapy of melanoma. Gao C…Wang R. Science Advances. Link
*Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Qi C…Shen L. Nature Medicine. Link
*Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age. Creech CB…KidCOVE Study Group. The New England Journal of Medicine. Link
*Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial. Julg B…Barouch DH. Nature Medicine. Link
↑CRISPR/Cas9-based genome editing for the modification of multiple duplications that cause Duchenne muscular dystrophy. Wang D…Wang N. Gene Therapy. Link
*Adenovirus type 5 SARS-CoV-2 vaccines delivered orally or intranasally reduced disease severity and transmission in a hamster model. Langel SN…Tucker SN. Science Translational Medicine. Link
Plants
Targeted base editing in the mitochondrial genome of Arabidopsis thaliana. Nakazato I…Arimura S. PNAS. Link
*Efficient C-to-G editing in rice using an optimized base editor. Tian Y…Lu Y. Plant Biotechnology Journal. Link
†Molecular farming using transgenic rice endosperm. Zhu Q, Tan J & Liu Y. Trends in Biotechnology. Link
*A catalogue of resistance gene homologs and a chromosome-scale reference sequence support resistance gene mapping in winter wheat. Kale SM…Mascher M. Plant Biotechnology Journal. Link
Protein & Molecular Engineering
*Systematic optimization of Cas12a base editors in wheat and maize using the ITER platform. Gaillochet C…Jacobs TB. bioRxiv (preprint). Link
Hyperaccurate Ribosomes for Improved Genetic Code Reprogramming. Shakya B, Joyner OG & Hartman MCT. ACS Synthetic Biology. Link
*A programmable pAgo nuclease with RNA target preference from the psychrotolerant bacterium Mucilaginibacter paludis. Li W…Ma L. Nucleic Acids Research. Link
*AGBE: a dual deaminase-mediated base editor by fusing CGBE with ABE for creating a saturated mutant population with multiple editing patterns. Liang Y…Lai L. Nucleic Acids Research. Link
Tools & Technology
*Expanding luciferase reporter systems for cell-free protein expression. Sato W…Adamala KP. bioRxiv (preprint). Link
Automated Leak Analysis of Nucleic Acid Circuits. Zarubiieva I…Phillips A. ACS Synthetic Biology. Link
High-Throughput Regulatory Part Prototyping and Analysis by Cell-Free Protein Synthesis and Droplet Microfluidics. Gan R…Nicol R. ACS Synthetic Biology. Link
*Technical pipeline for screening microbial communities as a function of substrate specificity through fluorescent labelling. Leivers S…Westereng B. Communications Biology. Link
Miscellaneous
↑*Plants grown in Apollo lunar regolith present stress-associated transcriptomes that inform prospects for lunar exploration. Paul A, Elardo SM & Ferl R. Communications Biology. Link
†The tremendous biomedical potential of bacterial extracellular vesicles. Xie J…Vandenbroucke RE. Trends in Biotechnology. Link
More soon,
— Niko // @NikoMcCarty // niko@codonmag.com